Archives

Management Of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents

ABSTRACT

 

In the early 1990’s, clinicians’ choices for pharmacological management of type 2 diabetes were limited to insulin, sulfonylureas, and metformin. Since then, multiple classes of agents have been discovered, approved, and put into clinical use. Through a series of cardiovascular outcome trials and other clinical trials, some classes of agents have been found to have benefits on atherosclerotic cardiovascular disease, congestive heart failure, and chronic kidney disease, sometimes independent of glycemic control. As a result, diabetes management has shifted away from a “one size fits all” care to an individualized approach for each patient. Important factors to consider include efficacy, cost, side effects, adherence and treatment burden, comorbidities, mechanisms of action, and non-glycemic effects on atherosclerotic cardiovascular disease, congestive heart failure, and chronic kidney disease. The goal of this chapter is to discuss an approach to pharmacological management that reviews current guidelines, discusses choosing appropriate glycemic targets, and presents the rationale for choosing certain medications in different situations.

 

INTRODUCTION

 

Foundational to the treatment of type 2 diabetes is glucose control. Diabetes increases the risk of microvascular and macrovascular complications, as well as mortality, morbidity, and healthcare costs. While lifestyle interventions are the basis for glucose control, most people will eventually need one or more pharmacologic treatments. This is because type 2 diabetes is a disease characterized by progressive beta-cell loss and dysfunction, leading to deterioration of metabolic control over time. Because of the growth in the number of antihyperglycemic agents in recent years, there are now more choices than ever in terms of how to achieve glucose control. Agents should be chosen with a goal of achieving glucose control, reducing risk of microvascular and macrovascular disease, and minimizing treatment burden (1-8)

 

SELECTION OF GLYCEMIC TARGETS

 

The first step in the approach to glycemic control in type 2 diabetes is the selection of an appropriate glycemic target. Glycemic control can be measured in a variety of ways, including hemoglobin A1c, self-monitoring of blood glucose (SMBG), and continuous glucose monitoring. Continuous glucose monitoring (CGM) makes available a range of metrics, including time in target, percent of time with hypoglycemia, percent of time with hyperglycemia, and glucose variability (as determined by standard deviation or coefficient of variation). Hemoglobin A1c has traditionally been the metric used in clinical trials. However, there is increasing interest in the use of time in range from CGM, as it is not subject to the same measurement limitations as hemoglobin A1c, responds more quickly to changes in glucose, and better reflects glucose variability (4, 6, 9, 10). Note that the hemoglobin A1c may not be accurate in conditions in which there is altered red blood cell turnover or in the presence of some hemoglobin variants. Further details can be found in the Endotext chapter (Monitoring Techniques-Continuous Glucose Monitoring, Mobile Technology, Biomarkers of Glycemic Control (11)).

 

Professional societies such as the American Diabetes Association (ADA) and the American Association of Clinical Endocrinology (AACE) differ somewhat on their recommendations for glycemic targets. However, the tenant of individualization of glycemic targets is central to both of their recommended approaches. The ADA recommendations are shown in Table 1, and were modified to include time in range targets from CGMs in 2021 (4, 12). In contrast, the AACE clinical guidelines state that “An A1c of < 6.5% (48 mmol/mol) is considered optimal if it can be achieved in a safe and affordable manner, but higher targets may be appropriate for certain individuals and may change for a given individual over time.” (1)

 

Table 1. Glycemic Target Recommendations from the American Diabetes Association 2021 Standards of Medical Care in Diabetes

An A1c goal for many nonpregnant adults of <7% without significant hypoglycemia is appropriate.

If using ambulatory glucose profile/glucose management indicator to assess glycemia, a parallel goal for many non-pregnant adults is time in range of >70% with time below range <4% and time <54 mg/dL <1%.

On the basis of provider judgement and patient preference, achievement of lower A1c levels than the goal of 7% may be acceptable and even beneficial if it can be achieved safely without significant hypoglycemia or other adverse effects of treatment.

Less stringent A1c goals (such as <8% [64 mmol/mol]) may be appropriate for patients with limited life expectancy or where the harms of treatment are greater than the benefits.

Adapted from American Diabetes Association (4).

 

The differing recommendations of the ADA and AACE are based, in part, on considerations and interpretations of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (Veterans Affairs Diabetes Trial) trials. A discussion of these trials is outside the scope of this chapter, but excellent summaries can be found elsewhere (1, 4, 13-17).

 

The primary risk of lower glycemic targets is hypoglycemia. In general, rates of hypoglycemia are unappreciated (18). A meta-analysis has found that among individuals with type 2 diabetes on insulin, the average incidence of hypoglycemia is 23 mild or moderate events and 1 severe episode annually (19). In 2015, there were 235,000 emergency room visits in the U.S. for hypoglycemia among adults with type 2 diabetes. This corresponds to a rate of 10.2 per 1,000 adults with diabetes (20). Hypoglycemia is associated with significant morbidity, mortality, and decreased quality of life. For example, among Medicare beneficiaries in 2010, hospitalizations for hypoglycemia were associated with an adjusted 30-day readmission rate of 18.1% and 30-day mortality rate of 5% (21). The use of glucose lowering drugs with a low potential for hypoglycemia allows one to safely achieve lower glycemic targets.

 

Other risks of lower glycemic targets include increased burden of treatment, polypharmacy, cost, and side effects from particular medications (weight gain, pancreatitis, etc.). Lower glucose targets early in the course of the disease can have a favorable legacy effect which can last for years later. Conversely, individuals with multiple comorbidities and complications from diabetes show less benefit from lower glucose targets. Factors to consider in the individualization of glycemic targets are shown in Table 2 (4).

 

Table 2. Factors Guiding Individualization of Glycemic Targets

 

Favoring lower glucose targets

Favoring higher glucose targets

Low risks associated with hypoglycemia and other drug adverse effects

High risks associated with hypoglycemia and other drug adverse effects

Newly diagnosed

Long standing diabetes

Long life expectancy

Short life expectancy

No important comorbidities

Many comorbidities

No vascular complications

Severe vascular complications

Highly motivated patient with excellent self-care capabilities

Patient preference for less burdensome therapy

Available resources and support system

Limited resources and support system

Adapted from American Diabetes Association (4).

 

For most patients, an A1c goal of <7% will be appropriate. However, for older patients with multiple comorbidities, an A1c goal of 8-8.5% is more appropriate, and will minimize risks of hypoglycemia, increased treatment burden, and potential side effects. Major exceptions to this goal would be patients with a short life expectancy for any reason (severe comorbidities, very old age, etc.) in which the risks of tight control outweigh the long-term benefits inreduction of complications that may never be realized. In these populations, the goal is to avoid hypoglycemia and symptomatic hyperglycemia (4, 6).

 

GENERAL PRINCIPLES

 

Table 3 outlines basic principles of type 2 diabetes management, as formulated by the AACE and the American College of Endocrinology.

 

Table 3. Principles of Type 2 Diabetes Management

Lifestyle modification underlies all therapy (e.g., weight control, physical activity, sleep, etc.)

Avoid hypoglycemia

Avoid weight gain

Individualize all glycemic targets

Optimal A1c is <6.5% or as close to normal as is safe and achievable

Therapy choices are patient centric based on A1c at presentation and shared decision-making

Choice of therapy reflects presence of atherosclerotic cardiovascular disease, congestive heart failure, and renal status

Comorbidities must be managed for comprehensive care

Get to goal as soon as possible – adjust at < 3 months until at goal

Choice of therapy includes ease of use and affordability

Continuous glucose monitoring is highly recommended, as available, to assist patients in reaching goals safely

Adapted from the American Association of Clinical Endocrinology and the American College of Endocrinology (1).

 

Specific medication choices should be tailored to the needs of the individual patient. Important factors to consider include initial A1c, duration of diabetes, comorbidities, cardiac, cerebrovascular and renal status, cost, risk of hypoglycemia, available social supports, and patient preference.

 

Classes of Antihyperglycemic Medications

 

The number of classes of diabetes medications available have increased greatly since the 1990’s, as shown in Figure 1. In 2022 a new type of incretin was added to the antihyperglycemic armamentarium – a combined GIP/GLP-1 receptor agonist (22-26). A thorough discussion of the available medication types can be found in other Endotext chapters, including Oral and Injectable (Non-Insulin) Pharmacologic Agents for Treatment of Type 2 Diabetes and Insulin – Pharmacotherapy, Therapeutic Regimens and Principles of Intensive Insulin Therapy (27, 28).

Figure 1. The History of Antihyperglycemic Agents. Figure adapted from White (29).

It is recognized that diabetes effects many organ systems throughout the body. Because of the multiple abnormal pathways, different medications can target different defects, and therefore work in a complementary fashion (see Table 4). Understanding has grown from the original “terrible triumvirate” with abnormalities of the beta cell (reduced insulin secretion), the liver (increased endogenous glucose production) and the peripheral insulin resistance. Overtime there was recognition of the “ominous octet”, and now there is understanding of even more pathways/defects (30-32). Characteristics of the most commonly used medications are shown in Tables 5 and 6.

 

Table 4. Pathways in the Treatment of Type 2 Diabetes

Pathway

Defect

Medication classes

Beta cell dysfunction

Decreased beta cell function and mass

Incretins, sulfonylureas, meglitinides

Incretin effect

Decrease in the incretin effect

Incretins

 

Alpha cells

Increase in glucagon

Incretins, pramlintide

Adipose tissue

Insulin resistance, increased lipolysis

Metformin, thiazolidinediones

Muscle

Insulin resistance, decreased peripheral glucose uptake

Metformin, thiazolidinediones

Liver

Insulin resistance, increased glucose production

Metformin, thiazolidinediones

Brain

Increased appetite, decreased morning dopamine surge, increased sympathetic tone

Incretins, dopamine agonists, appetite suppressants

Colon/biome

Abnormal microbiome, possible decreased GLP-1 secretion

Probiotics, incretins, metformin

Immune dysregulation/inflammation

 

Incretins, anti-inflammatories, immune modulators

Stomach/small intestine

Increased rise of glucose absorption

Incretins, pramlintide, alpha glucosidase inhibitors

Kidney

Increased glucose reabsorption

SGLT-

2 inhibitors

GLP-1 = glucagon-like peptide 1; SGLT-2 = sodium-glucose co-transporter 2.  Adapted from Schwartz (32).

 

Table 5. Antihyperglycemic Agents and Mechanisms of Action

 

Class

Primary Mechanism of Action

a-Glucosidase inhibitors

·       Delay carbohydrate absorption from intestine

Amylin analogue

·       Decrease glucagon secretion

·       Slow gastric emptying

·       Increase satiety

Biguanide

·       Decrease hepatic glucose production

·       Increase glucose uptake in muscle

Bile acid sequestrant

·       Decrease hepatic glucose production?

·       Increase incretin levels?

DPP-4 inhibitors

·       Increase glucose-dependent insulin secretion

·       Decrease glucagon secretion

Dopamine-2 agonist

·       Activates dopaminergic receptors

Meglitinides

·       Increase insulin secretion

GLP-1 receptor agonists / combined GIP and GLP-1 receptor agonists

·       Increase glucose-dependent insulin secretion

·       Decrease glucose secretion

·       Slow gastric emptying

·       Increase satiety

SGLT-2 inhibitors

·       Increase urinary excretion of glucose

Sulfonylureas

·       Increase insulin secretion

Thiazolidinediones

·       Increase glucose uptake in muscle and fat

·       Decrease hepatic glucose production

DDP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; SGLT-2 = sodium-glucose co-transporter 2.  Adapted from AACE 2015 and slideshow (2, 33)

 

Table 6. Characteristics of Commonly Used Antihyperglycemic Medication Classes

Drugs

Ability to Lower Glucose

Risk of Hypoglycemia

Weight Change

Effect on ASCVD

Effect on CHF

Effect on Renal Disease

2ndgeneration SU

High

Yes

Increase

Neutral

Neutral

Neutral

Metformin

High

No

Neutral-modest weight loss

Potential benefit

Neutral

Neutral

TZDs

High

No

Increase

Potential benefit (pioglitazone)

Increased

Neutral

DPP-4 inhibitors

Intermediate

No

Neutral

Neutral

Potential increase (saxagliptin, alogliptin)

Neutral

SGLT-2 inhibitors

Intermediate

No

Decrease

Potential benefit

Benefit

Benefit – reduced progression of renal failure

GLP-1 receptor agonists

High

No

Decrease

Benefit

Neutral-Potential Benefit

Benefit-decreased proteinuria

DDP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; SGLT-2 = sodium-glucose co-transporter 2; SU = sulfonylurea; TZD = thiazolidinediones. Adapted from American Diabetes Association and Endotext Chapter Pharmacological Agents for the Treatment of Type 2 Diabetes (5, 27)

 

Therapeutic Inertia

 

Reassessment of patient’s achievement of their glycemic goals as well as the appropriateness of these goals at regular intervals is necessary. In diabetes, therapeutic inertia can include both the failure to advance or to de-intensify treatment when appropriate to do so. Failure to escalate therapy when appropriate is associated with worse microvascular and macrovascular outcomes and higher health costs (34, 35). Furthermore, several studies have shown that achieving A1c targets early in the course of the disease is associated with maintaining lower A1c levels for longer (35-37). Delays in appropriate deintensification of therapy is also a widespread problem (35, 38, 39). A number of factors contribute to therapeutic inertia, many of which can be classified as patient-related factors, physician-related factors, and health care system factors (see Table 7) (40). In addition, societal level factors, such as health care payment models, society inequity, and social determinants of health care contribute to therapeutic inertia.

 

Table 7. Factors Contributing to Therapeutic Inertia in Diabetes Care

 

Patient-related

Physician-related

Healthcare system-related

Denial of disease

Time constraints

No clinical guidelines

Lack of awareness of progressive nature of disease leading to feeling of “failure”

Lack of support

No disease registry

Lack of awareness of implications of poor glycemic control

Concerns over costs of treatment and testing

No visit planning

Fear of side effects (hypoglycemia, weight gain)

Reactive rather than proactive care

No active outreach to patients

Concerns over ability to manage more complicated treatment regimens

Underestimation of patient’s needs

No decision support

Too many medications

Lack of information/understanding of new treatment options

No team approach to care

Treatment costs

Lack of information on side effects/fear of causing harm

Poor communication between physician and staff

Poor communication with physician

Lack of clear guidance on individualizing treatment

 

Lack of support

Concern over patient’s ability to manage for complicated treatment regimens

 

Lack of trust in physician

Concerns over patient adherence

 

Adapted from Okemah (40).

 

ALGORITHM FOR ANTIHYPERGLYCEMIC MEDICATIONS

 

There are a number of algorithms available to guide the choice of antihyperglycemic medications for type 2 diabetes. These include algorithms from the American Diabetes Association, the American Association of Clinical Endocrinology and American College of Endocrinology, and the European Society of Cardiology and the European Association for the Study of Diabetes, among others. While these differ in the details, they share a similar approach (1-3, 5, 28, 41, 42). The cornerstone of treatment of type 2 diabetes is comprehensive lifestyle education. This includes diabetes self-management education and support (DSMES), medical nutrition therapy, routine physical activity, smoking cessation counseling, and psychosocial care. DSMES has been shown to result in improved quality of life, reduced all-cause mortality risk, and health care costs (43-49). Specific lifestyle goals, if possible, include at least 150 minutes of moderate exercise per week and a reduction in body weight by 5-10% (1, 49). Weight loss in type 2 diabetes can improve glycemic control, result in diabetes remission, and cause improvements in blood pressure, lipids, hepatic steatosis, obstructive sleep apnea, osteoarthritis, and renal function (1, 2, 50-53).

 

Initiating Treatment

 

For individuals requiring pharmacologic treatment, monotherapy is a reasonable approach for patients whose A1c is close to goal. Historically, metformin has been recommended as the first line agent, unless there are contraindications. However, in light of the growing evidence supporting use of GLP-1 receptor agonists and/or SGLT-2 inhibitors to decrease atherosclerotic cardiovascular disease (ASCVD), heart failure, and/or chronic kidney disease, there has been movement to consider use of these agents before metformin (1, 5, 42). In 2022, the ADA modified its previous recommendations that metformin be used as a first line agent in the absence of contraindications (54). The ADA now recommends that “First-line therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification…. Other medications (glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors), with or without metformin based on glycemic needs, are appropriate initial therapy for individuals with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease” (5). AACE recommends that “The choice of diabetes therapies must be individualized based on attributes specific to both patients and the medications themselves…. The choice of therapy depends on the patients cardiac, cerebrovascular, and renal status” (1). Thus, the ADA and AACE are now in agreement that GLP-1 receptor agonists and SGLT-2 inhibitors should be considered as first line agents in certain patients (1, 5). Of note, use of these agents as first line treatment can often still be limited by cost and insurance coverage considerations.

 

Combination Therapy

 

Many patients will require combination treatment. Initial combination treatment should be considered in individuals with an elevated A1c. AACE recommends initial combination treatment for A1c > 7.5%, while the ADA recommends initial combination treatment for patients with A1c 1.5-2% above their glycemic target (1, 5). For individuals with A1c > 9-10% with symptoms of hyperglycemia or catabolism, insulin therapy should be the initial treatment. For individuals with A1c > 9-10% without symptoms, initial treatment with dual or triple therapy without insulin can be considered, although insulin is often needed. Generally, medications are added, instead of substituting medications. This is because of the progressive nature of diabetes, and because medications can be chosen that act in complementary manners. Important exceptions to this is that incretin agents should not be combined (i.e. DDP-4 inhibitors and GLP-1 receptor agonists), and that sulfonylureas and meglitinide are typically stopped when prandial insulin is initiated.

 

Durability

 

The natural history of type 2 diabetes is one of progressive beta cell failure that leads to the need to intensify a medical regimen over time. This generally means starting with one medication and adding others as needed tomeet glycemic goals. Some medications are able to maintain glycemic control for longer than others, and thus have a more favorable effect on the natural history of diabetes, likely by successfully modifying and improving the underlying abnormal physiology.

 

In general, sulfonylureas have been found to be less durable than other diabetes medications. For example, in the A Diabetes Outcome Progression Trial (ADOPT), among patients with newly diagnosed diabetes, the 5-year failure rate for sulfonylureas was 15% for rosiglitazone, 21% for metformin, and 34% for glyburide (55). While sulfonylureas are able to affect an increase in insulin production, they are unable to correct the underlying beta cell dysfunction.

 

Metformin

 

Metformin is traditionally considered the first line agent due to low risk of hypoglycemia, good antihyperglycemic efficacy, ability to promote weight loss, and cost. Compared to sulfonylureas, its effects tend to be more durable, and there is stronger data supporting its cardiovascular safety (56). Metformin commonly causes gastrointestinal side effects, which can often be minimized by starting at a low dose and gradually titrating and using extended release formulations (57). While the maximum dose is 850 mg three times a day, most people do not titrate past 1000 mg twice a day. Metformin is associated with an increased risk of lactic acidosis, and should not be used in individuals at increased risk of lactic acidosis, such as in chronic kidney disease or hepatic disease. While metformin used to have contraindications based on creatinine levels, in 2016 the FDA changed these recommendations (58). Current renal dosing guidance is shown in Table 8 (1, 5, 59-62). Metformin can also lead to vitamin B12 malabsorption and/or deficiency, which can lead to anemia and peripheral neuropathy, and so B12 levels should be monitored periodically (63).

 

Table 8. Metformin Dosing Recommendations

eGFR (mL/min/1.73 m2)

Recommendation

> 60

No adjustments

Monitor annually

45-60

No adjustments

Monitor every 3-6 months

30-45

Initiation generally not recommended, but can be considered

Continuation of therapy:  maximum dose of 500 mg twice a day

< 30

Contraindicated

eGFR = estimated glomerular filtration rate. Adapted from multiple sources (1, 5, 59-62).

 

Patients with ASCVD, Congestive Heart Failure, or Chronic Kidney Disease

 

For patients with high-risk or established ASCVD, heart failure, or chronic kidney disease, GLP-1 receptor agonists and SGLT-2 inhibitors should be considered independent of baseline A1c, individualized A1c target, or metformin use. As described in Endotext chapter Pharmacological Agents for the Treatment of Type 2 Diabetes, the GLP-1 receptor agonists dulaglutide, liraglutide, and semaglutide have been shown to reduce cardiovascular events in individuals at high-risk or with established ASCVD (1, 5, 27, 64-66). In secondary analysis, improvement in renal outcomes were also seen in prespecified secondary outcomes in these trials (LEADER, SUSTAIN-6, and REWIND) (64-66). Markers of high-risk of ASCVD can include patients 55 years or older with coronary, carotid, or lower-extremity artery stenosis of >50% or left ventricular hypertrophy (5). Contraindications to the use of GLP-1 receptor agonists include history of pancreatitis and a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 2A or 2B. Some agents (exenatide, lixisenatide) are not approved in the setting of chronic kidney disease. Increase in the progression of retinopathy was seen in the pivotal trial of semaglutide, but it is unclear whether that was an effect specific to the medication or a consequence of the rapid glucose lowering (65). Tirzepatide is a novel combined GIP and GLP-1 receptor agonist which has showed substantial A1c lowering and weight loss (22-26). The tirzepatide cardiovascular disease outcome trials are still ongoing.

 

SGLT-2 inhibitors have been shown to reduce diabetic kidney disease progression, hospitalizations for heart failure, and ASCVD (5, 7, 8, 67-82). See in Endotext chapter Pharmacological Agents for the Treatment of Type 2 Diabetes for additional details (27). SGLT-2 inhibitors with benefits on progression of diabetic kidney disease include canagliflozin, empagliflozin, and dapagliflozin. SGLT-2 inhibitors with proven effects on ASCVD include empagliflozin and canagliflozin. SGLT-2 inhibitors with proven effects on heart failure include empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. SGLT-2 inhibitors are contraindicated in patients with a history of or increased risk of diabetic ketoacidosis, due to increased risk of euglycemic diabetic ketoacidosis with these agents. In addition, they should be used caution in individuals with frequent bacterial urinary tract infections or genitourinary yeast infections, high risk for fractures and falls, foot ulceration, or other factors predisposing to diabetic ketoacidosis.

 

An area of ongoing discussion is the use of SGLT-2 inhibitors in individuals who already have advanced chronic kidney disease. At estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2, SGLT-2 inhibitors are unlikely to result in substantial glucose lowering. However, they have been shown to have beneficial effects on delaying the progression of chronic kidney disease in patients with eGFRs down to 25 mL/min/1.73 m2 (7). Patients with advanced chronic kidney disease on SGLT-2 inhibitors must be monitored closely, and counselled to maintain adequate fluid intake and avoid hypoglycemia.

 

Thus, for individuals with established ASCVD or at high risk for ASCVD, either a GLP-1 receptor agonist with proven cardiovascular disease benefits (dulaglutide, liraglutide, semaglutide) or an SGLT-2 inhibitor with proven cardiovascular disease benefit (empagliflozin, canagliflozin) should be strongly considered, potentially as a first line agent. For patients with heart failure, a SGLT-2 inhibitor with a proven benefit for heart failure hospitalizations should be considered, potentially as a first line agent. For patients with chronic kidney disease and albuminuria, a SGLT-2 inhibitor should be strongly considered regardless of glycemic control. If SGLT-2 inhibitors are not tolerated or are contraindicated, a GLP-1 receptor agonist can be considered. For patients with chronic kidney disease without albuminuria, either a GLP-1 receptor agonist with proven cardiovascular disease benefit or a SGLT-2 inhibitor with proven cardiovascular disease benefit can be considered. In addition, combination therapy with GLP-1 receptor agonist and SGLT-2 inhibitor likely has synergistic effects on glucose lowering and CVD prevention, and thus should be considered (8, 83).

 

Note that some SGLT-2 inhibitors and GLP-1 receptor agonists have indications for individuals without diabetes (see Table 9).

 

Table 9. Antihyperglycemic Medications with Indications in Individuals Without Diabetes

Medication

Indication

Liraglutide (Saxenda)

As an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater or BMI of 27 kg/m2and at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus, dyslipidemia) (84)

Semaglutide (Wegovy)

As an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater or BMI of 27 kg/m2and at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus, dyslipidemia) (85)

Dapagliflozin (Farxiga)

Reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV) (86)

Dapagliflozin (Farxiga)

Reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease at risk for progression (86)

Empagliflozin (Jardiance)

Reduce the risk of cardiovascular death plus hospitalization for heart failure in adults with heart failure and reduced ejection fraction (87)

BMI = body mass index; eGFR = estimated glomerular filtration rate; NYHA = New York Heart Association.

 

Patients at Risk for Hypoglycemia

 

While hypoglycemia should be avoided for all patients, it is especially important in patients with hypoglycemia unawareness, in older patients, and in patients with multiple comorbidities or diabetes complications. Medications with a higher risk of hypoglycemia should be avoided in these patients, and include sulfonylureas, meglitinides, and insulin. Medications to consider with a low risk of hypoglycemia include metformin, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors, or thiazolidinediones.

 

If a sulfonylurea must be added, a later generation agent should be chosen. Meglitinides also can be considered in some patients, and generally have a lower risk of hypoglycemia (and also less A1c lowering potential) than sulfonylureas. Basal insulins with lower risk of hypoglycemia can also be chosen. The risk of hypoglycemia is lowest for degludec and glargine U-300, followed by glargine U-100 and detemir, with the highest risk of hypoglycemia with Neutral Protamine Hagedorn (NPH) insulin (5).

 

Patients with Compelling Need for Weight Loss

 

Most patients with diabetes have obesity or overweight, and thus benefit from medications that promote weight loss. Two of the pillars of the AACE’s treatment approach to individuals with diabetes are lifestyle modifications including weight control, and avoiding weight gain. Both GLP-1 receptor agonists and SGLT-2 inhibitors can result in weight loss, although effects are generally greater for GLP-1 receptor agonists (5, 52). Liraglutide and semaglutide also have separate indications for weight loss regardless of diabetes status. In general, the degree of weight loss for semaglutide and liraglutide is greater than that of dulaglitude, which is greater than that of exenatide (5, 52). The combined GIP and GLP-1 agonist tirzepatide has shown even greater weight loss than that for GLP-1 receptor agonists (23, 25). In contrast, medications such as sulfonylureas, thiazolidinediones, and insulin tend to lead to weight gain (1, 5).

 

Patients Where Cost is an Issue

 

For many patients, cost can be a substantial barrier to care. Many patients are uninsured or underinsured. One in four patients on insulin report rationing their insulin doses due to cost (88). Patients should be asked about barriers to care. Often medication assistance programs and rebate programs can be used to decrease or eliminate the cost burden for patients. If these approaches are not successful, medications should be chosen keeping in mind the out-of-pocket cost for the patient. The cheapest medications are metformin, sulfonylureas, and thiazolidinediones. The typical approach, unless there are contraindications, is to start with metformin, then if additional agents are necessary to add sulfonylureas and then thiazolidinediones. If additional agents are needed, insulin can be added. Human insulins (regular, NPH) are cheaper than analogue insulins, and are discussed in the Insulin Therapy section.

 

Insulin Therapy

 

For individuals with A1c > 9-10% with symptoms of hyperglycemia or catabolism, insulin therapy should be the initial treatment. Once the initial glucotoxicity has resolved, some individuals will be able to stop insulin, especially if they are able to make lifestyle modifications and achieve weight loss.

 

Individuals who are on maximal non-insulin therapy and still not at their goal A1c should have insulin initiated. Insulin should not be presented as a “threat” to patients. The natural history of type 2 diabetes should be discussed with patients, so that they understand that escalation of therapy and/or initiation of insulin are common, and do not represent a “failure” on the patient’s part.

 

If individuals are not already taking a GLP-1 receptor agonist, it should be considered prior to starting insulin. There are a number of insulin titration regimens that can be followed (1, 5). If cost is an issue, NPH and Regular insulin can be used. In patients with type 2 diabetes, insulin analogues do not always have a major advantage over human insulin products. Most studies comparing analogue insulins to human insulin products have not shown an improvement in glycemic control or reduced risk of severe hypoglycemia, although they do show reduced risk of overall and nocturnal hypoglycemia (89, 90).

 

A number of algorithms are available for insulin initiation and titration (1, 5). The key is to continue to adjust the insulin doses until the patient achieves their glycemic target. Typically, the patient is first started on basal insulin, and then the dose is gradually increased. The appropriateness of their preexisting diabetes medications should be evaluated when basal insulin is started. Most medications can be continued, but consideration can be given to stopping medications without cardiovascular, congestive heart failure, or renal benefit. Patients should be regularly assessed for “overbasalization.” Signs of overbasalization are shown in Table 10.

 

Table 10. Signs of Overbasalization

Basal dose > 0.5 IU/kg

Elevated bedtime-morning differential (> 50 mg/dL)

Elevated post-preprandial differential

Hypoglycemia

High glucose variability

Adapted from American Diabetes Association (5)

 

At that point, prandial insulin should be initiated. If patients have a meal that is substantially larger than others (typically supper), prandial insulin can be started at the largest meal, and then additional doses added as needed. Most individuals with type 2 diabetes use a fixed prandial dose for meals, or a fixed dose with a correctional scale. However, individuals with highly variable meals or minimal insulin reserve (as assessed with a c-peptide measurement), using a carbohydrate to insulin ratio (as is done in type 1 diabetes) can be helpful. As with the initiation of basal insulin, when prandial insulin is initiated the patient’s preexisting diabetes regimen should be evaluated. In particular, sulfonylureas and meglitinides should be stopped when prandial insulin is added.

 

For patients where cost is an issue, human insulins can be more affordable than analogue insulins. In general, insulin doses should be decreased by 20% when switching from analogue insulin to human insulin in order to minimize the risk of hypoglycemia (89, 90).

 

The volume of insulin that can absorbed at a given time and given site can be a factor limiting insulin titration, especially as patients get to higher doses. For patients on over 200 units of insulin a day, switching to concentrated insulin formulations should be considered. In the past, U-500 regular insulin was the only option available. It has dose dependent pharmacokinetics, typically intermediate between regular and NPH insulin. In more recent years, U-200 degludec, U-300 glargine, and U-200 lispro have become available, and are often easier to use than U-500 regular insulin. While U-500 is available in vials and pens, if at all possible pens should be used, in order to reduce the chance of dosing errors.

 

Some individuals with type 2 diabetes on basal-bolus insulin regimens can benefit from an insulin pump (91, 92). Insurance coverage for insulin pumps for people with type 2 diabetes varies. When coupled with a CGM, some pumps allow for hybrid closed loop dosing, in which insulin doses are adjusted automatically based on current glucose values from the CGM.

 

CONCLUSION

 

Pharmacologic management of type 2 diabetes requires an individualized approach that weighs important factors such as efficacy, cost, side effects, adherence and treatment burden, comorbidities, mechanisms of action, and non-glycemic effects. Appropriate selection of medication can not only result in improved glucose control, but also have favorable effects on obesity, atherosclerotic cardiovascular disease, congestive heart failure, and chronic kidney disease.

 

ACKNOWLEDGMENT

 

Thank you to Tricia Santos Cavaiola MD and Jeremy H. Pettus MD, the previous authors of this chapter

 

DISCLOSURES

 

  1. Schroeder has no conflicts of interest to disclose.

 

REFERENCES

 

  1. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2020 Executive Summary. Endocr Pract. 2020;26(1):107-39.
  2. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. 2015;21 Suppl 1:1-87.
  3. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9.
  4. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S83-S96.
  5. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S43.
  6. American Diabetes Association. 13. Older Adults: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S195-S207.
  7. American Diabetes Association. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S175-S84.
  8. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S144-S74.
  9. Smith EM. Using continuous glucose monitoring in clinical practice. Clinical Diabetes. 2020;30(5):429-38.
  10. Wright EE, Jr, Morgan K, Fu DK, Wilkins N, Guffey WJ. Time in range: how to measure it, how to report it, and its practical application in clinical decision-making. Clinical Diabetes. 2020;30(5):439-48.
  11. Reddy N, Verma N, Dungan K. Monitoring Technologies - Continuous Glucose Monitoring, Mobile Technology, Biomarkers of Glycemic Control. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2020.
  12. American Diabetes Association. Summary of Revisions: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S4-S6.
  13. Duckworth WC, Abraira C, Moritz TE, Davis SN, Emanuele N, Goldman S, et al. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications. 2011;25(6):355-61.
  14. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-59.
  15. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376(9739):419-30.
  16. Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-72.
  17. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187-92.
  18. Lash RW, Lucas DO, Illes J. Preventing Hypoglycemia in Type 2 Diabetes. J Clin Endocrinol Metab. 2018;103(4):1265-8.
  19. Edridge CL, Dunkley AJ, Bodicoat DH, Rose TC, Gray LJ, Davies MJ, et al. Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies. PLoS One. 2015;10(6):e0126427.
  20. Centers for Disease Control and Prevention. National Diabetes Statistics Report 2020: Estimates of Diabetes and Its Burden in the United States 2020 [Available from: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
  21. Lipska KJ, Ross JS, Wang Y, Inzucchi SE, Minges K, Karter AJ, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med. 2014;174(7):1116-24.
  22. Rosenstock J, Wysham C, Frias JP, Kaneko S, Lee CJ, Fernandez Lando L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-55.
  23. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-15.
  24. Ludvik B, Giorgino F, Jodar E, Frias JP, Fernandez Lando L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-98.
  25. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-24.
  26. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022;327(6):534-45.
  27. Feingold KR. Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2021.
  28. Donner T, Sarkar S. Insulin - Pharmacology, Therapeutic Regimens and Principles of Intensive Insulin Therapy. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2019.
  29. White JR, Jr. A Brief History of the Development of Diabetes Medications. Diabetes Spectr. 2014;27(2):82-6.
  30. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.
  31. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288-96.
  32. Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, 3rd, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the beta-Cell-Centric Classification Schema. Diabetes Care. 2016;39(2):179-86.
  33. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan Slideshow 2015 [Available from: https://pro.aace.com/disease-state-resources/diabetes/clinical-practice-guidelines/aaceace-clinical-practice-guidelines.
  34. Khunti K, Seidu S. Therapeutic Inertia and the Legacy of Dysglycemia on the Microvascular and Macrovascular Complications of Diabetes. Diabetes Care. 2019;42(3):349-51.
  35. Gabbay RA, Kendall D, Beebe C, Cuddeback J, Hobbs T, Khan ND, et al. Addressing Therapeutic Inertia in 2020 and Beyond: A 3-Year Initiative of the American Diabetes Association. Clin Diabetes. 2020;38(4):371-81.
  36. Mauricio D, Meneghini L, Seufert J, Liao L, Wang H, Tong L, et al. Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA. Diabetes Obes Metab. 2017;19(8):1155-64.
  37. Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268-75.
  38. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med. 2015;175(3):356-62.
  39. Hambling CE, Seidu SI, Davies MJ, Khunti K. Older people with Type 2 diabetes, including those with chronic kidney disease or dementia, are commonly overtreated with sulfonylurea or insulin therapies. Diabet Med. 2017;34(9):1219-27.
  40. Okemah J, Peng J, Quinones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Adv Ther. 2018;35(11):1735-45.
  41. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-701.
  42. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255-323.
  43. Cooke D, Bond R, Lawton J, Rankin D, Heller S, Clark M, et al. Structured type 1 diabetes education delivered within routine care: impact on glycemic control and diabetes-specific quality of life. Diabetes Care. 2013;36(2):270-2.
  44. Cochran J, Conn VS. Meta-analysis of quality of life outcomes following diabetes self-management training. Diabetes Educ. 2008;34(5):815-23.
  45. He X, Li J, Wang B, Yao Q, Li L, Song R, et al. Diabetes self-management education reduces risk of all-cause mortality in type 2 diabetes patients: a systematic review and meta-analysis. Endocrine. 2017;55(3):712-31.
  46. Robbins JM, Thatcher GE, Webb DA, Valdmanis VG. Nutritionist visits, diabetes classes, and hospitalization rates and charges: the Urban Diabetes Study. Diabetes Care. 2008;31(4):655-60.
  47. Duncan I, Ahmed T, Li QE, Stetson B, Ruggiero L, Burton K, et al. Assessing the value of the diabetes educator. Diabetes Educ. 2011;37(5):638-57.
  48. Strawbridge LM, Lloyd JT, Meadow A, Riley GF, Howell BL. One-Year Outcomes of Diabetes Self-Management Training Among Medicare Beneficiaries Newly Diagnosed With Diabetes. Med Care. 2017;55(4):391-7.
  49. American Diabetes A. 5. Facilitating Behavior Change and Well-being to Improve Health Outcomes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S60-S82.
  50. Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344-55.
  51. Garvey WT, Garber AJ, Mechanick JI, Bray GA, Dagogo-Jack S, Einhorn D, et al. American association of clinical endocrinologists and american college of endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20(9):977-89.
  52. American Diabetes Association. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S113-S24.
  53. American Diabetes Association. 5. Facilitating Behavior Change and Well-being to Improve Health Outcomes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S53-S72.
  54. American Diabetes Association. Summary of Revisions: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S8-S16.
  55. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-43.
  56. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med. 2016;164(11):740-51.
  57. Flory JH, Mushlin AI. Effect of Cost and Formulation on Persistence and Adherence to Initial Metformin Therapy for Type 2 Diabetes. Diabetes Care. 2020;43(6):e66-e7.
  58. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function 2016 [Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain.
  59. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34(6):1431-7.
  60. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-75.
  61. Lalau JD, Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Belpaire F, De Broe ME. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care. 2018;41(3):547-53.
  62. Kidney Disease: Improving Global Outcomes Diabetes Work G. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115.
  63. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-61.
  64. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22.
  65. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-44.
  66. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-30.
  67. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.
  68. Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(21):2099.
  69. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-306.
  70. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-57.
  71. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-46.
  72. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.
  73. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020;383(15):1425-35.
  74. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-24.
  75. Wheeler DC, Stefansson BV, Batiushin M, Bilchenko O, Cherney DZI, Chertow GM, et al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics. Nephrol Dial Transplant. 2020;35(10):1700-11.
  76. Cannon CP, McGuire DK, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, et al. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J. 2018;206:11-23.
  77. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function. Circulation. 2018;138(15):1537-50.
  78. Bakris GL. Major Advancements in Slowing Diabetic Kidney Disease Progression: Focus on SGLT2 Inhibitors. Am J Kidney Dis. 2019;74(5):573-5.
  79. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-34.
  80. Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, et al. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019;140(9):739-50.
  81. Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017;46(6):462-72.
  82. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. J Am Soc Nephrol. 2017;28(1):368-75.
  83. Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med. 2021;385(10):896-907.
  84. Novo Nordisk. Saxenda Prescribing Information 2020 [Available from: https://www.novo-pi.com/saxenda.pdf.
  85. Novo Nordisk. Wegovy Prescribing Information 2021 [Available from: https://www.novo-pi.com/wegovy.pdf.
  86. AstraZeneca Pharmaceuticals. Farxiga Prescribing Information 2021 [Available from: https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0be9cb1b-3b33-41c7-bfc2-04c9f718e442/0be9cb1b-3b33-41c7-bfc2-04c9f718e442_viewable_rendition__v.pdf.
  87. Boehringer Ingelheim Pharmaceuticals. Jardiance Prescribing Information 2021 [Available from: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf.
  88. Herkert D, Vijayakumar P, Luo J, Schwartz JI, Rabin TL, DeFilippo E, et al. Cost-Related Insulin Underuse Among Patients With Diabetes. JAMA Intern Med. 2019;179(1):112-4.
  89. Lipska KJ, Hirsch IB, Riddle MC. Human Insulin for Type 2 Diabetes: An Effective, Less-Expensive Option. JAMA. 2017;318(1):23-4.
  90. Lipska KJ. Insulin Analogues for Type 2 Diabetes. JAMA. 2019;321(4):350-1.
  91. Grunberger G, Sherr J, Allende M, Blevins T, Bode B, Handelsman Y, et al. American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus. Endocr Pract. 2021;27(6):505-37.
  92. American Diabetes Association. 7. Diabetes Technology: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.

 

Acute and Subacute, and Riedel’s Thyroiditis

ABSTRACT


The thyroid, like any other structure, may be the seat of an acute or chronic suppurative or non-suppurative inflammation. Various systemic infiltrative disorders may leave their mark on the thyroid gland as well as elsewhere. Infectious thyroiditis is a rare condition, usually the result of bacterial invasion of the gland. Its signs are the classic ones of inflammation: heat, pain, redness, and swelling, and special ones conditioned by local relationships, such as dysphagia and a desire to keep the head flexed on the chest in order to relax the paratracheal muscles. The treatment is that for any febrile disease, including specific antibiotic drugs if the invading organism has been identified and its sensitivity to the drug established. Otherwise, a broad-spectrum antibiotic may be used. Surgical drainage may be necessary and a search for a pyriform sinus fistula should be made, particularly in children with thyroiditis involving the left lobe. Important to differentiate from the acute bacterial infection of acute suppurative thyroiditis (AST), is subacute (granulomatous) thyroiditis (SAT) which is far more common than AST and is characterized by a more protracted course, usually involving the thyroid symmetrically. The gland is also swollen and tender, and the systemic reaction may be severe, with fever and an elevated erythrocyte sedimentation rate. During the acute phase of the disorder, tests of thyroid function often disclose a suppression of TSH, increased serum concentrations of T4, T3, and thyroglobulin while a diminished thyroidal RAIU is observed. The cause of SAT has been established in only a few instances in which a viral infection has been the initiating factor. There may be repeated recurrences of diminishing severity. Usually, but not always, the function of the thyroid is normal after the disease has subsided. Subacute thyroiditis may be treated with rest, non-steroidal anti-inflammatory drugs or aspirin, and thyroid hormone. If the disease is severe and protracted, it is usually necessary to resort to administration of glucocorticoids, but recurrence may follow their withdrawal. It is precisely the observational nature of SAT therapy combined with the use of glucocorticoids that make it so critical to rule out the bacterial etiology of AST in the patient presenting with a painful thyroid. Riedel's thyroiditis is a chronic sclerosing replacement of the gland that is exceedingly rare. The process extends to adjacent structures, making any surgical intervention very difficult and potentially harmful. The exact cause of Riedel’s thyroiditis remains unknown, and no specific treatment is available beyond limited resection of the thyroid gland to relieve the symptoms of tracheal or esophageal compression. The use of anti-inflammatory medical treatments has been demonstrated to have significant benefits to outcome. Sarcoidosis may involve the thyroid, and amyloid may be deposited in the gland in quantities sufficient to cause goiter. In all of these diseases, it may be necessary to give the patient levothyroxine replacement therapy if the function of the gland has been impaired.

 

CLASSIFICATION

 

The diagnostic term thyroiditis includes a group of inflammatory or inflammatory-like conditions. The terminology that has been employed is confusing, and no classification is ideal. We prefer the following nomenclature, which takes into account the cause when known.

 

1, Infectious thyroiditis, also referred to as either acute or chronic, and which in fact may be either, along with the qualifying term suppurative (AST), nonsuppurative, or septic thyroiditis. It includes all forms of infection, other than viral, and is caused by invasion of the thyroid by bacteria, mycobacteria, fungi, protozoa, or flatworms. The disorder is rare.

 

  1. De Quervain's thyroiditis, commonly known as (painful) subacute thyroiditis (SAT) but also termed subacute nonsuppurative thyroiditis, granulomatous, pseudotuberculous, pseudo-giant cell or giant cell thyroiditis, migratory or creeping thyroiditis, and struma granulomatosa. This condition, most likely of post viral origin, lasts for a week to a few months, with a tendency to recur.

 

  1. Autoimmune thyroiditis, commonly referred to as chronic, Hashimoto's, or lymphocytic thyroiditis and also known as lymphadenoid goiter and struma lymphomatosa. This indolent disease usually persists for years and in the Western world is the principal cause of non-iatrogenic primary hypothyroidism. Nonspecific focal thyroiditis, characterized by local lymphoid cell infiltration without parenchymal changes, may be a variant of the autoimmune disease. The condition is covered in detail in the Endotext chapter on Hashimoto’s Thyroiditis.

Another form of thyroiditis, also believed to be of autoimmune cause, has been described. It has been variably referred to as painless, silent, occult, subacute, subacute nonsuppurative, and atypical (silent) subacute thyroiditis, as well as “hyperthyroiditis”, transient thyrotoxicosis with low thyroidal RAIU and lymphocytic thyroiditis with spontaneously resolving hyperthyroidism. There is no agreement on an inclusive name. The features of this disease entity overlap with de Quervain's thyroiditis and Hashimoto's thyroiditis. The clinical course, with the exception of a very high erythrocyte sedimentation rate and pain in the thyroid are indistinguishable from de Quervain's thyroiditis. Yet, histologically, the condition cannot be differentiated from a milder form of Hashimoto's disease. This condition often occurs in the postpartum period and is also termed postpartum thyroiditis. All forms of autoimmune thyroiditis are considered in other Endotext chapters.

 

  1. Riedel's thyroiditis, another disorder of unknown etiology. Synonyms include Riedel's struma, ligneous thyroiditis and invasive fibrous or chronic sclerosing thyroiditis. This condition is characterized by overgrowth of connective tissue that often extends into neighboring structures.

 

  1. Miscellaneous varieties of thyroid inflammation or infiltration including local manifestations of a generalized disease processes. Among these are sarcoid and amyloid involvement of the thyroid. Radiation and direct trauma to the thyroid gland may also cause thyroiditis. Rarely, acute thyroiditis has been reported after parathyroid surgery (1).

 

INFECTIOUS THYROIDITIS

 

The thyroid gland is remarkably resistant to infection. This has been attributed to its high vascularity, lymphatic drainage, the presence of large amounts of iodine in the tissue, the fact that hydrogen peroxide is generated within the gland as a requirement for the synthesis of thyroid hormone, and its normal encapsulated position away from external structures. Acute suppurative thyroiditis (AST) is a rare condition, reported to account for 0.1-0.7% of thyroid disease (2,3) which may result in up to 12% or higher mortality if left untreated (2,4,5). In the pre-antimicrobial era, the case fatality rate of AST was as high as 22% (6) which makes early recognition of AST crucial in order to prevent life-threatening complications.

 

Predisposing Factors

 

Acute thyroiditis may involve a normal gland, arise in a multinodular goiter (7) or even Hashimoto’s thyroiditis. Presence of certain predisposing factors (Table 1) makes the gland susceptible to infections. A persistent fistula from the pyriform sinus may make the left lobe of the thyroid particularly susceptible to abscess formation, particularly in children (8-18). In one study, 7 out of 48 (15%) of children undergoing piriform sinus fistula surgery presented with a thyroid abscess (19). The possibility of a persistent thyroglossal duct should be considered for patients with midline infections (20). The infection of the thyroid gland is a result of direct extension from an internal fistula from the pyriform sinus (11,13,14,21-24). This tract is thought to represent the course of migration of the ultimobranchial body from the site of its embryonic origin in the fifth pharyngeal pouch (15). Careful histopathological studies of these fistulae have demonstrated that they are lined by squamous columnar or ciliated epithelium and occasionally form branches in the thyroid lobe (11,14). In addition, occasional cells positive for calcitonin have been found in the fistulae and increased numbers of C-cells were noted in the thyroid lobe at the point of termination of the tract. The predominance of acute thyroiditis in the left lobe of the thyroid gland, particularly in infants and children, is explained by the fact that the right ultimobranchial body is often atrophic and does not develop in the human (as well as in other species such as reptiles). Ninety-two percent of cases involve the left thyroid lobe, 6% the right lobe, and 2% are bilateral (25). The left-sided predominance may be due to embryological asymmetry of the transformation of the fourth branchial arch to form the aortic and innominate arteries (26) or to poor development of the ultimobrachial body on the right side of the embryo (27).

 

Recurrent left-sided thyroid abscess has also been reported due to a fourth branchial arch sinus fistula (28). A review of 526 cases of congenital fourth branchial arch anomalies (29) noted that they presented with acute suppurative thyroiditis in 45% of cases. Acute thyroiditis from a periapical abscess of an inferior molar has been reported (30). Acute suppurative thyroiditis associated with thyroid metastasis from esophageal cancer has also been reported (31).Acute thyroiditis can occur in an immuno-compromised state, predisposing them to unusual bacteria such as nocardia (32,33), salmonella(34) and fungi like candida (35-38), coccidioides immitis (39) and aspergillus (40). Among patients > 20 years old in the study by Yu et al. 32/66 (49%) were immunocompromised (5). Occasionally, acute bacterial suppurative thyroiditis occurs in children receiving cancer chemotherapy (41). Rarely, infection will occur in a cystic or degenerated nodule (42,43) or presumed hematogenous spread in the setting of endocarditis (44). Acute thyroiditis has arisen as the initial presentation of juvenile systemic lupus erythematosus (45) and has also occurred due to septic emboli derived from infective endocarditis (44,46,47). As will be discussed, the principal differential diagnosis is generally between acute (AST), infectious, and subacute (SAT), meaning post-viral (non-infectious) inflammation of the gland.

 

Table 1. Predisposing Factors for Acute Thyroiditis

Pyriform sinus fistula

Third and fourth arch abnormalities

Immunocompromised states

Rarely: endocarditis, tooth abscess, fine needle aspiration

 

Etiology

 

Virtually any bacterium can infect the thyroid (Table 2), but at times no causative organism can be demonstrated. Streptococcus, staphylococcus, pneumococcus, salmonella (34,48-51), Klebsiella (52), Bacteroides, Treponema pallidum, Pasteurella spp (53,54),  porphyromonas (55), Eikenella (51,56-58), and Mycobacterium tuberculosis (59-63) have all been described. Rare cases of disseminated nocardia infections with thyroiditis along with subcutaneous nodules have been reported (32,64-66). This subject has been extensively reviewed (21,36,67). In addition, certain fungi, including Coccidioides immitis (39), Aspergillus (40,68), Actinomyces (69-71), Blastomyces (72,73), Candida albicans (35-38), Actinobacter baumanii (5), Cryptococcus (74), and Pneumocystis (75) have also been associated with thyroiditis. In a recent meta-analysis, 94% of the patients with fungal AST were immunocompromised (76). Most of these patients who were immunocompromised either had malignancy or AIDS  (33,34,77,78). Rarely acute suppurative thyroiditis is due to thyroid abscess with deep neck infection (79) and fistulous connection (80). Coccidioides immitis from infected donor tissue in an immunocompromised host has also been reported (39). Thyroid abscess due to clostridium perfringens has been reported (81) and clostridium septicum is almost always associated with carcinoma of the colon (82). Metastatic breast cancer has been described as presenting clinically with acute thyroiditis (83). Hashimoto’s disease (84,85), large goiters (86), or thyroid cancer could predispose individuals (87), but AST could also arise by hematogenous or lymphatic spread or by iatrogenic infections after fine needle aspiration biopsy (FNA). Recently, the role of diagnostic fine needle thyroid aspiration has been emphasized as a factor in the cause of acute suppurative thyroiditis (81,88-92). Care should be taken when performing FNA in patients who may be susceptible to tracking of infection into the thyroid.

 

Table 2. Microbiology of Acute Suppurative Thyroiditis

Usual Organisms
Aerobic: Staphylococcus aureus, Streptococcus pyogenes, Streptococcus epidermidis, Streptococcus pneumoniae, Escherichia coli (111)

Anaerobic: Clostridium septicum (82), gram-negative bacilli, Peptostreptococcus spp.

Rare Organisms

Bacterial: Atypical mycobacteria, Clostridium perfringens (81), Eikenella corrodens, Enterobacteriaceae, Haemophilus influenza, Klebsiella spp., Mycobacterium tuberculosis, Porphyromonas (55), Salmonella spp., Streptococcus viridans, Treponema pallidum, Brucella. (112), Lactococcus (113), Citrobacter freundii (114), Nocardia

Fungal: Aspergillus spp., Blastomyces, Candida spp., Coccidioides immitis, Pneumocystis jiroveci

Parasitic: Trypanosoma (21), Echinococcus spp.,

 

Pathology

 

Pathological examination reveals characteristic changes of acute inflammation. With bacterial infections, heavy polymorphonuclear and lymphocytic cellular infiltrate is found in the initial phase, often with necrosis and abscess formation. Fibrosis is prominent as healing occurs. In material obtained by fine needle aspiration, the infectious agent may be seen on a gram, acid fast or appropriate fungal stain (13), and grown out in culture for antibiotic sensitivity assessment.

 

Clinical Manifestations

 

Although acute thyroiditis is quite rare (about two patients per year in a large tertiary care hospital), cases of suppurative thyroiditis are increasing due to the higher incidence of immune-compromised patients. A recent meta-analysis of about 200 cases of AST published in 148 articles between 2000-2020 noted that the median duration of symptoms prior to presentation was 6 days [IQR 3-12 days] in bacterial AST and longer symptom duration in fungal (21 days [IQR 12-26]) and tuberculous AST (30 days [18-60]) (76).

 

Recently, another case series of six otherwise healthy adult patients without anatomic anomalies with AST was published (93). Of the 6 patients, 5 were female and the median age at presentation was 51 years (28-73 years). None had third or fourth left branchial cleft anomalies or an immunosuppressed state. All patients were successfully treated with antibiotics for an average of 13.5 days (10–41 days), drainage occurred in three, and surgery was performed twice in the acute phase in one and at a later state in another. The length of hospital stay was 7.5 days (4–79 days). AST has been estimated to be much more common in the pediatric age group because of its relationship with pyriform sinus fistulae, where 90% of lesions develop in the left lobe of the thyroid (44) although it is still quite unusual. It has been estimated that about 8% of cases occur in adulthood (25,44,94-99). The dominant clinical symptom is pain in the region of the thyroid gland that may subsequently enlarge and become palpably hot and tender. The patient is unable to extend the neck and often sits with the neck flexed in order to avoid pressure on the thyroid gland. Swallowing is painful. There are usually signs of infection in structures adjacent to the thyroid, local lymphadenopathy as well as temperature elevation and, if bacteremia occurs, chills. Gas formation with suppurative thyroiditis has been noted (100-103). Symptoms are generally more obvious in children than in adults. Adults may present with a vague slightly painful mass in the thyroid region without fever, which may raise the possibility of a malignancy. Suppurative thyroiditis may even spread to the chest producing necrotizing mediastinitis and pericarditis in the absence of a pyriform sinus fistula (79,104-106). It may occur more commonly in the fall and winter following upper respiratory tract infections.

White cell counts are elevated in 80% of bacterial AST but in only 40% and 26% of fungal and tuberculous AST respectively.

 

Previous reviews have found that thyrotoxicosis was not common in AST (5). The recent meta-analysis by Lafontaine et al. found that 42% of bacterial and 40% of fungal AST cases were thyrotoxic at presentation and at least 36% of bacterial AST cases had significant thyrotoxicosis with fT4 more than twice the upper limit of normal (76). Tuberculous AST was least likely to be associated with hyperthyroidism (12%). Thyrotoxicosis due to AST is plausible, given the pathogenesis of AST and the release of pre-formed thyroid hormone secondary to the destruction of thyroid follicles. It is therefore important to consider AST in patients with apparent hyperthyroidism and a painful neck, making the differentiation with SAT difficult (76).

 

In general, there are no signs or symptoms of hyper- or hypothyroidism. However, exceptions to both have been reported particularly if the thyroiditis is generalized, such as occurs with fungal processes (74) or mycobacterial infections. At times, even in patients with bacterial thyroiditis, destruction of the thyroid gland is extensive enough to release thyroid hormone in amounts sufficient to cause symptomatic thyrotoxicosis (54,59). Associated thyrotoxicosis has also been reported in children and adults (17,54,88,107); in one series, 12% presented with thyrotoxicosis, and 17% were said to be hypothyroid (5). This variety of thyroid function findings clearly increases the difficulty of differentiating AST from SAT as both present with thyroidal pain. Unique presentations of AST have been reported where initial thyrotoxicosis has been followed by hypothyroidism and spontaneous normalization of thyroid function after treatment of the AST (55,108). Complications described in various cases included internal jugular vein thrombophlebitis, mediastinitis and pericarditis, esophageal perforation, fistula and obstruction, laryngeal edema requiring tracheostomy, obstructive symptoms, Horner’s syndrome and multisystem organ failure (76).

 

Diagnosis

 

Pain in the anterior neck will usually lead to a consideration of thyroiditis. The meta-analysis by Lafontaine et al. showed that the most common symptoms in bacterial AST were neck pain (89%) and fever (82%), followed by dysphagia (46%). Neck pain and fever were the most common symptoms in all cases, occurring in 78% and 63% of fungal AST, and 40% and 48% of tuberculous AST cases respectively (76). Since the differential diagnosis will lie between acute suppurative thyroiditis and subacute thyroiditis, it is critical to compare the history, physical, and particularly laboratory data in these two conditions (see Table 4). In general, the patient with acute thyroiditis appears septic, has greater and more localized pain in the thyroid gland, may have an associated upper respiratory infection, has lymphadenopathy and may be immuno-compromised. Localization of tenderness to the left lobe should suggest the possibility of an infection as should any erythema or apparent abscess formation. The presence of an elevated white blood count with a shift to the left would argue for infection, however, elevations in sedimentation rate are common in both acute and subacute thyroiditis. As mentioned above, patients with bacterial thyroiditis are usually euthyroid but a thyrotoxic presentation has been noted in 8-12% (5,109) and hypothyroidism was noted in 17% of one series (109). Thyrotoxicosis is clearly more common with longer duration, 52% at 7 days and 65% by 30 days of neck pain in patients with subacute thyroiditis (110). The thyrotoxic presentation therefore poses a difficult differential diagnostic problem to separate AST from SAT, which may have significant impact in the selection of initial therapy.

Depending on the patient’s age and clinical circumstances, one may wish to proceed with invasive or non-invasive studies. Discriminating tests differentiating AST from SAT have been considered a radio-nuclide uptake (RAIU) and/or scanning usually showing a very low uptake value in subacute thyroiditis with a normal value found in the patient with localized mild bacterial thyroiditis (21). More frequently however both conditions are associated with a low 123-I uptake at initial presentation (33,108,115,116) limiting the power of iodine based nuclear studies to effectively differentiated these two conditions.

 

In the early inflammatory phase of AST, when obvious abscess formation is not evident, an ultrasound may show a localized hypoechoic process with an obscure border and effacement between the thyroid and surrounding perithyroidal tissues(117). During the acute inflammatory stage of AST, clear cut abscess formation is noted in the affected thyroidal tissue (117). Perithyroidal unifocal hypoechoic space and effacement of the plane between the thyroid and perithyroidal tissues have been noted to be specific signs of AST (117). Alternatively, the application of sonoelastography may reveal very stiff lesions corresponding to the areas of the thyroid which are especially painful (118) during acute phases of the AST episode which soften significantly as the patient responds to treatment (118). As AST resolves with appropriate treatment, ultrasound images may demonstrate deformity of the gland characterized by atrophy of the affected lobe, air/fluid levels in the thyroidal tissue and scarring of the perithyroidal tissues (117).

 

A CT scan may be useful in identifying the location of the abscess, but is required only in unusual situations (119). The CT findings also vary with the stage of AST. In the early inflammatory stage, nonspecific low density areas in the swollen thyroid along with potential tracheal displacement may be seen (117). In the acute inflammatory stage, a CT can also demonstrate edema of the ipsilateral hypopharynx, and abscess formation.  In the late inflammatory stage, deformity of the thyroid, atrophy of the affected lobe and scarring of the perithyroidal tissues may be observed (117). Recent reviews indicate a significant role for CT in the initial evaluation of those with AST (2,117). As outlined above, during the earliest stages of AST both CT and ultrasound findings may fail to effectively differentiate between AST and SAT. In this circumstance, the use of a fine needle aspiration (FNA) has been demonstrated to be very useful as outlined below. Localization of gallium to the thyroid gland in the course of an evaluation for a fever of unknown origin is very useful finding confirming thyroid inflammation as the source of the problem but the differential of gallium positive thyroid tissue will also include the presence of Riedel’s thyroiditis (120).

 

If an infectious process is identified, particularly of the left lobe of a younger individual, then a barium swallow should be performed with attention to the possibility of a fistulous tract located on the left side between the pyriform sinus and the thyroid gland. The barium swallow has very good sensitivity in detecting the presence of the fistula tracts as 89-97% of those examined in early and acute stages of AST have been confirmed with this technique (117). Other methods of documenting the presence of a fistula are also utilized. On follow up ultrasound an ‘emerging echogenic tract sign’ suggests an associated pyriform sinus thyroid fistula (121). During a CT scan procedure the patient can be asked to blow into a syringe, the so called “trumpet maneuver”, which may help to identify a piriform sinus fistula (122), a reported series suggests that timing may influence the ability of this maneuver to demonstrate the presence of a fistula as only 20% of those examined in the acute inflammatory phase revealed a fistula while 54% of those evaluated in the late inflammatory phase had a fistula documented (117) with the “trumpet maneuver”. A ‘light guided procedure’ to visualize the tract may also help (123). Transnasal flexible fiberoptic laryngoscopy has become increasingly utilized to identify the presence of fistular tracts (2). This approach has been estimated to have similar sensitivity of documenting the tracts as barium swallow and CT methods (124-126) and can also be utilized for the instillation of chemo-cauterizing agents at an appropriate time after the resolution of the acute infection (109,124,126,127).

 

Occasionally, pain from an infectious process elsewhere in the neck will present as anterior neck tenderness. For example, a retropharyngeal abscess may present with typical symptoms of acute thyroiditis. The thyroid gland, however, will have a normal ultrasound appearance, be normal on scanning, and only on CT scan will the retropharyngeal abscess be recognized. The tendency for the pain of thyroid inflammation to be referred to the throat or ears should be kept in mind, although recognition of the anatomic source of the problem is usually not difficult in patients with acute thyroiditis due to their localized symptoms. While patients with tuberculosis or parasitic infections tend to have a more indolent course, these infections can present with acute symptoms and this possibility should be considered if the epidemiology is consistent. For example, thyroidal echinococcosis occurs in countries in which this parasite is endemic (128). Trypanosomiasis of the thyroid has also been reported (21).

 

A fine needle aspiration (FNA) performed in the acute phase of AST is important as an aspirate has a superior ability to differentiate the patient with AST from those with subacute thyroiditis not only by cytological criteria and also provides appropriate bacteriologic specificity allowing smears and cultures providing a more accurate antibiotic selection (2) for the patient documented to have AST. In addition, transcutaneous drainage of the infectious material can be performed to relieve pressure on a displaced trachea in patients with a compromised airway (2). Finally FNA may be seen as the most accurate means of differential diagnosis (129) when a thyrotoxic presentation is encountered. Establishing a firm diagnosis of AST allows timely antibiotic therapy to be prescribed when a trial of glucocorticoids for empirically assumed SAT might result in both delay in diagnosis as well as initiation of a potentially wrong therapy (55).

 

Prompt treatment is necessary as the infection may cause destruction of the thyroid and the parathyroid glands, spread to other organs, or cause abscess rupture, vocal cord palsy and fistulae to the trachea or esophagus (130,131).

 

Treatment

 

There has been a trend toward less invasive management during active inflammation and infection (2). A recent study observed that 32% of the cases with bacterial AST were managed with antibiotics and a single needle aspiration, 3% required multiple needle aspirations, and 13% had a needle aspiration and antibiotics but subsequently required surgery. In both the immediate surgery group and those with needle aspiration and antibiotics, incision and drainage was the most common procedure (57% and 53% respectively), followed by partial thyroidectomy (30% and 40%) with or without excision of a fistula tract, and total thyroidectomy (13% and 7%). The median duration of antibiotics was 17 days (IQR 14- 30) (76).

In contrast, only 22% of cases of fungal AST went directly to surgery (11% for incision and drainage, 11% underwent a partial thyroidectomy), 56% had a single needle aspiration and antifungals, and 22% failed needle aspiration and antifungals and subsequently required surgery. The mean duration of antifungal therapy was 42 days. Of the patients with tuberculous AST, 41% had needle aspiration and antibiotics; only 3% failed needle aspiration and antibiotics and subsequently required partial thyroidectomy (76).

 

Despite a lack of randomized controlled trials, algorithms for acute and long-term management have been suggested by several authors. Miyauchi (115), who has extensive experience with the condition, has cautioned that consideration of the basic anomaly predisposing the patient to thyroid gland infection must be duly considered. Microscopic examination and appropriate staining of a fine needle aspirate often aid the diagnosis and choice of antibiotic therapy. The procedure is best done under ultrasound guidance so that the source of the specimen is identified. It may also serve as a mechanism for decompression of an abscess and can be repeated to facilitate healing. Some abscesses will require surgical exploration and drainage. The choice of therapy will also depend on the immune status of the patient. Systemic antibiotics are required for severe infections. Candida albicans thyroiditis may be treated with appropriate doses of amphotericin B and fluconazole. Successful antifungal combination therapy and a surgical approach for Aspergillus spp associated AST has been reported (132). The proper treatment of an acute thyroiditis in children generally requires the surgical removal of the fistula (11,13,14), although surgical treatment should be delayed until the inflammatory process is resolved (133,134). Combining this with partial thyroidectomy may further decrease the recurrence rate (12,29). In addition, a lobectomy may be the safer option as it provides an adequate identification of the recurrent laryngeal nerve in the re-operative field (135). Alternatively, fistula tract ablation can be achieved either by surgical resection which has been associated with recurrence free survival (117), or less invasively obliterated with the instillation of a chemo-cauterizing agent which has also been demonstrated to result is satisfactory outcomes (117,124,126,127). Newer, minimally invasive transoral video-laryngoscopic surgery (TOVS) (136) and endoscopy assisted surgery (137) have been reported to be safe and reliable methods of pyriform sinus fistula treatment. Ultrasound-guided aspiration with or without lavage had a good treatment effect and without adverse events for the management of AST secondary to pyriform sinus fistula (138).

 

Prognosis

 

The disease may occasionally prove fatal (106). In some patients with thyroiditis, the destruction may be sufficiently severe that permanent hypothyroidism results (7). Thus, patients with a particularly diffuse thyroiditis should have follow-up thyroid function studies performed to determine the need for thyroid hormone replacement. Surgical removal of a fistula or branchial pouch sinus (133,134) is required to prevent recurrence.

 

SUBACUTE THYROIDITIS

 

Case Illustration

 

J.G., a 56-year-old woman, presented to her primary care physician in January, with 4 weeks of low anterior neck pain and 2 days of fatigue, chills and shivers. She was prescribed a course of antibiotics with no relief. A non-contrast CT scan of the neck was done which showed mild diffuse thyroid enlargement, multiple nodules and area of hypo-attenuation in the right lobe with no evidence of abscess formation. She was referred to Endocrinology for further evaluation. Upon further questioning, she reported having intermittent fever, nervousness, and slight difficulty during swallowing, nearly 5-pound weight loss but no changes in her appetite or bowel habits. A family history of thyroid disease was not elicited. She has been taking Naproxen 200 mg four times a day and a full dose aspirin with minimal relief.

 

On physical examination she appeared to be in pain, BP was 144/88, and pulse 108/min and regular. Clinically, she appeared euthyroid. The thyroid gland was estimated to be 40 grams in weight and was tender, firm, and slightly irregular. The remainder of the examination was non-contributory.

 

Laboratory data included an erythrocyte sedimentation rate of 58 mm/min, FT4 of 2.7 ng/dl (reference range 0.76 to 1.46 ng/dl), FT3 5.8 pg/ml (2.3 to 4.2 pg/mL) and a negative thyroid stimulating immunoglobulin. CRP was 31.3 mg/L (reference range 0.0-8.0 mg/L). RAI uptake was 1%.

 

Subacute thyroiditis (SAT) sometimes referred to as granulomatous or De Quervain's thyroiditis is a spontaneously remitting inflammatory condition of the thyroid gland that may last for weeks to several months (21,139,140). It has a tendency to recur. The gland is typically involved as a whole, and thyroidal RAIU is much depressed. Transient hyperthyroxinemia, elevation of the serum thyroglobulin concentration and the erythrocyte sedimentation rate, and sometimes the WBC, during the early acute phase are characteristic if not pathognomonic.

 

Etiology

 

An infections cause can rarely be established. A tendency for the disease to follow upper respiratory tract infections or sore throats has suggested initiation by a viral infection. Earlier suggestions that the disease may represent a bacterial infection have been disproven. An autoimmune reaction is also unlikely. The development during the illness of cell-mediated immunity against various thyroid cell particulate fractions or crude antigens appears to be related to the release of these materials during tissue destruction (141,142).

 

Although the search for a viral cause has usually been unrewarding, a few cases have been associated with the virus that causes mumps (139,143). The disease has occurred in epidemic form. High titers of mumps antibodies have been found in some patients with subacute thyroiditis, and occasionally parotitis or orchitis are associated with the thyroiditis. The mumps virus has been cultured directly from thyroid tissue involved by subacute thyroiditis. Although the mumps virus may be one discrete etiologic factor, the disease has also been reported in association with other viral conditions including measles, influenza, H1N1 influenza (144) adenovirus infection, infectious mononucleosis (145), myocarditis, HIV (146), cat scratch fever, and coxsackie virus (147). SAT has been reported following hand-foot-mouth disease due to coxsackie B4 (148), cytomegalovirus (149), hepatitis E virus (150,151) and scrub typhus infection (116).  Case reports suggesting SAT as a rare facet of Dengue expanded syndrome have been published (152-154).

 

Most recently, SAT has been associated with SARS-COV-2/COVID 19 infection (155). Two comprehensive studies (156,157) failed to find evidence of enteroviruses in 27 patients and Epstein-Barr (EB) virus or cytomegalovirus in 10 patients, respectively, but a single case report has implicated EB virus in a case of subacute thyroiditis with typical clinical features (158) and cytomegalovirus has been reported in an infant (159).

 

Numerous attempts to culture viruses from cases not associated with mumps have failed. Virus-like particles have been demonstrated in the follicular epithelium of a single patient suffering from subacute thyroiditis (147). However, viral antibody titers to common respiratory tract viruses are often elevated in these patients. Since the titers fall promptly, and multiple viral antibodies may appear in the same patient, the titer elevation may represent an anamnestic response to the inflammatory condition. It is likely that the thyroid gland could respond with thyroiditis after invasion by a variety of different viruses but no single agent is likely to be causative (160).

 

Histocompatibility studies show that 72% of patients with subacute thyroiditis manifest HLA-BW35 (161). Familial occurrence of subacute thyroiditis associated with HLA-B35 has been reported (162-165). The correlation between the SAT occurrence and the presence of HLA-B*18:01 and DRB1*01, as well as HLA-C*04:01 has been demonstrated, with the latter one being in linkage disequilibrium with a well-known SAT risk haplotype HLA-B*35 (166). These new three antigens, together with the known HLA-B*35, allow confirmation of a genetic predisposition in almost all patients with SAT. The haplotypes HLA-B*18:01, -DRB1*01 and HLA-B*35 are all independent SAT risk factors. Recent studies demonstrated for the first time that the risk of SAT recurrence is indeed HLA-dependent, and the high-risk group includes patients with co-occurrence of HLA-B*18:01 and -B*35 (166). It seems that the presence of HLA B18:01 significantly changes the course of SAT.  The risk of recurrence was significantly influenced by the presence of HLA-B*18:01, but only with the concurrent presence of HLA-B*35. Although demonstration that the co-occurrence of HLA-B*18:01 and -B*35 carries the risk of SAT recurrence should be confirmed in further studies.

 

Thus, a susceptibility to subacute thyroiditis seems genetically influenced and it has been suggested that subacute thyroiditis might occur by transmission of viral infection in genetically predisposed individuals (159). A reported association between subacute thyroiditis and acute febrile neutrophilic dermatosis (Sweet's syndrome) (167,168), may imply a common role for cytokines in both these conditions.

 

New treatments, particularly those in which there is manipulation of the immune system, have led to the development of a subacute thyroiditis like clinical course (169). Infusion of interleukin 2 caused hyperthyroxinemia with a low radioiodine uptake in six patients who received this in combination with tumor necrosis factor (TNF) α or γ interferon (170). The patients proceeded through the pattern of hyperthyroidism followed by transient hypothyroidism, with a re-establishment of normal thyroid function typical of patients with autoimmune painless thyroiditis. However, none of the patients had detectable antithyroid antibodies. This condition is thus intermediate between subacute lymphocytic (painless) thyroiditis and subacute thyroiditis, which is typically painful.

 

The advent of immunotherapy has revolutionized cancer therapy. Immune checkpoint inhibitors (ICI) are a group of monoclonal antibodies that target the receptors cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its associated ligand (PD-L-1). The thyroid gland is the endocrine gland most frequently affected in association with immune checkpoint inhibitors (ICIs).  With the increase in use of immunotherapy for various malignancies, thyroid immune related adverse events (irAE) are on the rise (171). Thyroid dysfunction has been more frequently associated with PD-1 inhibitors rather than CTLA-4 inhibitors (172). About 20% of the patients receiving PD-1 inhibitors present with thyroid dysfunction, occurring early in the course of treatment (median onset 6 weeks after first infusion) (173,174) The exact underlying pathophysiologic mechanisms for thyroid irAEs are still unclear. It has been thought to be secondary to destructive, immune mediated thyroiditis and may include T cell, NK cell, and/or monocyte-mediated pathways (175). However, the onset and clinical manifestations are highly variable and not all patients develop the classic thyroiditis like presentation(176). Based on the limited data available, the PD-1 inhibitor induced thyroiditis may histologically present as a granulomatous inflammation with active destruction of thyroid follicles(177).  

 

In one of the studies, in which thyroid function was prospectively monitored in patients with melanoma receiving PD-1 inhibitor therapy, most patients presenting with thyrotoxicosis developed hypothyroidism within 1-3 months (173). A recent study that looked at thyroid dysfunction in patients with melanoma undergoing CTLA-4 or PD-1 based treatment reported many distinct phenotypes (178). Of the 1246 patients studied, 42% developed thyroid irAEs. The most common presentation was subclinical hyperthyroidism followed by overt hyperthyroidism, subclinical hypothyroidism, and overt hypothyroidism.

 

The most common thyroid dysfunction is thyrotoxicosis followed by hypothyroidism. Incidences of hypothyroidism were lower with the anti-CTLA-4 antibody (2.5%-5.2%) than with anti-PD-1/anti-PD-L1 (3.9%-8.5%), while combination therapy was associated with the highest estimated incidence (10.2%-16.4%). Similarly, for thyrotoxicosis differences according to the class of ICIs had been reported, with ipilimumab having low frequencies (0.2%–1.7%), anti-PD-1/anti-PD-L1 drugs having higher frequencies (0.6%–3.7%), and combination therapy having the highest frequency (8.0%–11.1%) (179). Moreover the risk of thyrotoxicosis was significantly greater with anti-PD-1 antibodies than with anti-PD-L1 antibodies and differences among anti-PD-1 drugs were also observed, with nivolumab having lower risk for hyperthyroidism than pembrolizumab (179).

 

In the majority of the patients who develop thyroid dysfunction, ICI therapy can be continued, unless they experience symptoms of severe thyrotoxicosis or there is concern for thyroid storm (180). Current guidelines recommend initiation of beta-blockers for symptomatic relief and if there is persistence of hypothyroidism, levothyroxine should be initiated after ruling out adrenal insufficiency, which can also occur with ICI therapy.

 

Patients have developed subacute thyroiditis after influenza vaccination (181-183) suggesting immune alteration as a contributory factor. In patients with chronic hepatitis C, studies following interferon therapy (IFN) have shown that a minority (15%) developed a destructive thyroiditis while others had a mild elevation of TSH (170,184). IFN can exacerbate previous thyroid autoimmunity and cause destructive thyroidal changes de novo. Subacute thyroiditis has also been noted in patients treated with combination therapy of IFN plus ribavirin for this disease (185,186) as well as during treatment of hepatitis B with interferon-a (187). Peginterferon alpha-2a has been reported to cause subacute thyroiditis (188) and the condition has been seen in Takayasu's arteritis suggesting an immune abnormality (189). On the other hand, SAT has also been reported in patients receiving long-term immunosuppressive therapy suggesting a minimal role for activating autoimmunity in the condition (190,191). A phase 2 trial conducted with alemtuzumab, a monoclonal anti-CD52 antibody for relapsing and remitting type of multiple sclerosis found that 34% of the subjects developed thyroid dysfunction and 4% had subacute thyroiditis (192). Use of TNF inhibitor therapy has been associated with thyroid dysfunction that closely resembles subacute thyroditis (193,194). A recent report of SAT associated with the use of the kinase inihibitor, dasatinib has been published (195). Other reports of the occurrence of a SAT-like picture with renal cell carcinoma (196), following the administration of cardiac catheterization dye (197),after gastric bypass(198), or after ginger ingestion (199) do not clearly contribute to an enhanced understanding of its etiology.

 

SARS-COV-2 Infection and Subacute Thyroiditis

 

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has infected more than 190 million people worldwide and the pandemic is still spreading. The first case of SAT after a SARS-CoV-2 infection was published from Italy in 2020 (155). Although additional cases were soon reported, this entity is likely underrecognized (200-202).

 

A case series of 4 patients with SAT after SARS-COV2 infection was published (155). In this case series, all 4 patients were female (age, 29-46 years). SAT developed 16 to 36 days after the resolution of coronavirus disease 2019 (COVID-19). Neck pain radiated to the jaw and palpitations were the main presenting symptoms and were associated with fever and asthenia. One patient was hospitalized because of atrial fibrillation. Laboratory exams during the acute phase of SAT, available for 3 patients, were typical of destructive thyroiditis: thyroid hormones, and particularly free thyroxine, were increased, TSH was low to undetectable, serum thyroglobulin was high, and TSH receptor antibodies were undetectable.

 

At neck ultrasound (performed in all patients) the thyroid was enlarged, with diffuse and bilateral hypoechoic areas. At color Doppler ultrasonography (performed in 3 patients) thyroid vascularization was absent. One patient had a thyroid scintiscan with 99mtechnetium, which showed absent uptake, as typical of the destructive phase of SAT. Symptoms subsided in all patients a few days after they commenced treatment (prednisone 25 mg/day in 3 patients and nonsteroidal anti-inflammatory drug in 1 patient). Six weeks after the onset of SAT symptoms, inflammatory markers had returned to normal range in all patients. Two patients were euthyroid and 2 were diagnosed with subclinical hypothyroidism. No patient experienced a relapse of COVID-19.

 

Expression of the mRNA encoding for the ACE-2 receptor has been documented in thyroid follicular cells, making them a potential target for SARS-COV-2 entry (203). The expression of ACE-2 mRNA in follicular cells was confirmed by analyzing primary cultures of thyroid cells, which expressed the ACE-2 mRNA at levels similar to thyroid tissues. It is important to note that, as recently demonstrated, SARS-CoV-2 infection requires the ACE-2 receptor to coexist with type II serine protease trans-membranes (TMPRSS2) (204).

 

More recently, three cases of SAT were reported from Turkey after inactivated SARS-CoV-2 vaccination (CoronaVac®) was administered. Three female healthcare workers presented with anterior neck pain and fatigue 4 to 7 days after SARS-CoV-2 vaccination and were diagnosed to have SAT, as a part of an autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). This can be seen as a postvaccination phenomenon that occurs after exposure to adjuvants in vaccines that increase the immune responses. However, two of these patients were in the postpartum period, which may have facilitated the development of ASIA syndrome after the SARS-CoV-2 vaccination (205).

 

Pathology

 

The thyroid gland may be adherent to its capsule or to the strap muscles, but it can usually be dissected free, a feature distinguishing subacute thyroiditis from Riedel's thyroiditis. The involved tissue appears yellowish or white and is firmer than normal. The gland is enlarged, usually bilaterally and uniform, but may be asymmetrical, with predominant involvement of one lobe. Although the lesion may extend to the capsular surface, it can also be confined to the thyroid parenchyma or merely be palpable as a suspiciously hard area.

 

Macroscopically, yellow-white, solidified foci of different sizes are visible, which occur focally, asymmetrically or less often, bilaterally. Clinically and macroscopically, malignancy can be suspected due to the ill-defined delimitation of these foci. There is a characteristic picture of a granulomatous inflammatory reaction with focal destruction of the follicular epithelial cells histologically. Due to the destruction of the follicles in the early stages of the disease, colloid emerges; neutrophils dominate, which can form granulomas with central micro-abscesses (206).

 

In the florid phase, lymphocytes, histiocytes and plasma cells predominate in the inflammatory infiltrate. The typical granulomas of this phase consist of cell necrosis, macrophages, multinucleated colloid phagocytic giant cells and lymphocytes (207).

 

The regeneration phase is characterized by focal fibrosis of the affected thyroid area with regenerative cell and nuclear changes in the immediately adjacent unaffected thyroid tissue. The characteristic juxtaposition of the different histological stages of inflammation indicates that the disease is evolving in parallel zones (206).

 

The macroscopic pathologic picture of subacute thyroiditis frequently bears a striking resemblance to a thyroid malignancy. The lesion is firm to dense in consistency, pale white in color, and has poorly defined margins that encroach irregularly on the adjacent normal thyroid. Microscopically, one sees a mixture of subacute, chronic, and granulomatous inflammatory changes associated with zones of parenchymal destruction and scar tissue. Early infiltration with polymorphonuclear leukocytes is replaced by lymphocytes and macrophages. The normal follicles may be largely replaced by an inflammatory reaction, but a few small follicles containing colloid remain (Fig. 1, below). Three dimensional cytomorphological analysis of fine needle aspiration biopsy samples from patients with subacute thyroiditis examined with scanning and transmission electron microscopy has shown a loss of a uniform, honeycomb cellular arrangement; variation in size and a decrease or shortening of microvilli in follicular cells together with the appearance of round or ovoid giant cells (208). The most distinctive feature is the granuloma, consisting of giant cells clustered about foci of degenerating thyroid follicles (Fig. 1). Mast cells play an important part in the repair process of thyroid tissue affected by the disease via production of growth factors and biomolecules which modulate thyroid folliculogenesis and angiogenesis (209).The early literature contains accounts of tuberculous thyroiditis, a diagnosis largely based on the granulomatous tissue reaction, from which the descriptive but unfortunate term pseudotuberculous thyroiditis arose (210). Data on the mechanism of inflammation and the pathogenesis of subacute thyroiditis at the cellular level are sparse. However, a study of apoptosis and expression of Bcl 1-2 family proteins in 11 patients with SAT suggests that apoptotic mechanisms may be involved in the development of SAT (211). Growth factor rich monocytes/macrophages (containing VEGF, beta FGF, PDGF and TGF beta 1) are involved in the granulomatous stage (212). EGF is important in the regenerative stage as it has mitogenic effects on the thyrocyte. VEGF and beta FGF contribute to the angiogenesis at both these stages of the disease. Factors influencing the severity of the acute phase response during the course of SAT include serum interleukin -1 receptor antagonist, which may have a significant anti-inflammatory role (213); also, a decrease in TNF alpha results in earlier resolution of experimentally induced granulomatous thyroiditis (214). TNF- related apoptosis-inducing ligand (TRAIL) has been shown to promote resolution of granulomatous autoimmune thyroiditis in animal models (215).

Figure 1. Subacute thyroiditis. Note the discrete granulomas, with giant cells, and the diffuse fibrosis (85 X).

Incidence and Prevalence

 

Subacute thyroiditis is encountered in up to 5% of patients with thyroid illness (216). Woolner et al. (210) collected 162 cases diagnosed on clinical grounds at the Mayo Clinic over a 5-year period; during the same time, 1,250 patients with Graves' disease were seen. Thus, the disease had approximately one-eighth the incidence of Graves' disease in this clinical population. Between 1970 and 1997, in the Epidemiology Project in Olmsted county, Minnesota 94 patients with subacute thyroiditis were identified (217). They report an incidence of 12.1 cases per 100,000/year with a higher incidence in females than in males (19.1 and 4.1 per 100,000/year, respectively). It is most common in young adulthood (24 per 100,000/year) and middle age (35 per 100,000/year), and it decreases in frequency with increasing age.

 

During an evaluation of subtypes of hypothyroidism over a 4-year period in Denmark, an incidence of subacute thyroiditis of 1.8% was found in a cohort of 685 patients with hypothyroidism (218). Although the disease has been described at all ages, it is rare in children (24,140). Female patients have outnumbered male patients in a ratio of 1.9-6:1, with a preponderance of cases in the third to fifth decades (67,139,210,219,220) and it has been noted as a rare cause of hyperthyroidism in pregnancy (221,222).

 

Clinical Manifestations

 

Characteristically, the patient has severe pain and extreme tenderness in the thyroid region. A small number of patients have been noted to present with painless or minimally painful subacute thyroiditis following viral symptomatology (223). These may be regarded as atypical subacute thyroiditis patients but the natural history of their disease is not known. Subacute thyroiditis has been reported to occur during the first trimester of pregnancy (221).When the symptom is difficulty in swallowing, the disorder may be initially mistaken for pharyngitis. Transient vocal cord paresis may occur (224). At times, the pain begins in one pole and then spreads rapidly to involve the rest of the gland ("creeping thyroiditis"). Pain may radiate to the jaw or the ears. Malaise, fatigue, myalgia and arthralgia are common. A mild to moderate fever is expected, and at times is high, swinging fever with temperatures above 104°F (40.0°C). The disease may reach its peak within 3 to 4 days, subside, and disappear within a week, but more typically, a gradual onset extends over 1 to 2 weeks and continues with fluctuating intensity for 3 to 6 weeks. Several recurrences of diminishing intensity extending over many months have also been reported.

 

The thyroid gland is typically enlarged two or three times the normal size or larger and is tender to palpation, sometimes exquisitely so. It is smooth and firm. Occasionally the condition may be confined to one lobe (225,226). Approximately one-half of the patients present during the first weeks of the illness, with symptoms of thyrotoxicosis, including nervousness, heat intolerance, palpitations - including ventricular tachycardia (227), tremulousness, and increased sweating. These symptoms are caused by excessive release of preformed thyroid hormone from the thyroid gland during the acute phase of the inflammatory process. At least 3 cases of thyroid storm due to subacute thyroiditis have been described (228,229) and adverse cardiac outcomes have been reported even in individuals without preexisting cardiac history or lesions (230). As the disease process subsides, transient hypothyroidism occurs in about one-quarter of the patients. Ultimately thyroid function returns to normal and permanent hypothyroidism occurs in less than 10 percent of the cases (21,67,139). Occasionally the condition may be painless and present as fever of unknown origin (231-233) or associated with other findings and mimicking conditions such as temporal arteritis (234). Some clinical and laboratory features recorded in 2 series of SAT are shown in Table 3 (110,235). Liver function test abnormalities are found in half the patients and return to normal in a few months (236).

 

Table 3. Clinical Features of Subacute Thyroiditis

 

Japan

Israel

Number

852

56

Females (%)

87

70

Season

summer-autumn

no effect

Recurrence

1.6%

9%

Temp >380

28%

--

Thyrotoxic symptoms

60%

--

Hypothyroid phase

--

55%

Laboratory - peak levels

1 week

--

Antithyroid antibodies

--

25%

Ultra Sound

Bilateral hypoechogenicity

50%

70%

Nodules

--

70%

Disease duration (days)

--

77

--: no data. Data derived from refs (110,235).

 

Diagnosis

 

Table 4 provides a comparison between the clinical and laboratory findings of patients with subacute and acute thyroiditis (21,237-242). Laboratory examination may disclose a moderate leukocytosis. A striking elevation of the erythrocyte sedimentation rate, at times above 100 mm/hr, or an elevated level of serum C-reactive protein (243) are useful diagnostic clues. The identification of CRP in salivary samples can also provide a convenient source for documenting the presence of abnormal levels in patients with SAT (244). Short of a tissue diagnosis, the characteristic combination of elevated erythrocyte sedimentation rate, high serum T4, T3, (T3:T4 <20) and hyroglobulin concentrations in the presence of low thyroidal RAIU, TSH, and an absent or low titer of circulating TPO and TG antibodies are the most helpful parameters. While the estimation of thyrotropin receptor antibodies (TRAb) in a thyrotoxic patient may be clinically useful in identifying Graves' disease, there have been reports of positive TRAb in patients with subacute thyroiditis although the frequency of this finding is low (245-249). Mild anemia and hyperglobulinemia may be present.

 

The value of a 99m-Tc-pertechnetate scintigraphy as a marker of disease activity and severity has been described (250). Pertechnetate scanning, which is inexpensive and convenient, typically reveals little to no uptake, and thus no thyroid tissue visualization during the SAT process (250,251), a finding consistently reported in the literature (144,148,230,252-254). Further imaging studies have shown diffuse increased uptake of Tc-99m sestamibi (251) and Tc-99m tetrofosmin (250)  in the thyroid region of patients in the acute phase (thyrotoxic) of subacute thyroiditis suggesting an ability of both agents to detect the inflammatory process associated with the disease (250,251). In the same patients Doppler flow assessment ultrasonography has shown an absence of vascular flow in the acute phase and the utility of this finding in the differential diagnosis of unclear cases has been emphasized (255,256). Standard ultrasonographic images are characterized by a hypoechoic appearance of the affected tissue, the volume of which correlates with the severity of clinical discomfort (257,258). Cervical adenopathy may be observed (259). The application of newer technologies such as sonoelastography has the capacity to demonstrate markedly decreased elasticity (enhanced stiffness) in SAT lesions (118). Subacute thyroiditis may obscure the coexistence of papillary carcinoma in cases presenting with ultrasonographically diffuse hypoechoic areas (260). Subacute thyroiditis with thyrotoxicosis may also be distinguished from Graves' hyperthyroidism by using T1- and T2- diffusion weighted magnetic resonance imaging (261) and as an intense area of uptake on (18) F-FDG PET/CT (254,262), although these investigation may not be necessary. Altered F-18 FDG uptake in skeletal muscle and reduced hepatic uptake has been observed during the hyperthyroid phase (263,264). Rarely, a sensor-navigated (124) iodine PET/ultrasound (I-124-PET/US) fusion has been implemented to establish this diagnosis (265). Fine needle aspiration biopsy is often diagnostic although patients are often alarmed at the prospect of this test due to the pain in the thyroid. However FNA may be helpful in ruling out malignancy (266) and the infection associated with localized, painful lesions of AST (see above).

 

Table 4. Features Useful in Differentiating Acute Suppurative Thyroiditis and Subacute Thyroiditis

 

Characteristic

Acute Thyroiditis

Subacute Thyroiditis

History

Preceding upper respiratory infection

88%

17%

 

Fever

100%

54%

 

Symptoms of thyrotoxicosis

Uncommon

47%

 

Sore throat

90%

36%

Physical examination of the thyroid

Painful thyroid swelling

100%

77%

 

Left side affected

85+%

Not specific

 

Migrating thyroid tenderness

Possible

27%

 

Erythema of overlying skin

83%

Not usually

Laboratory

Elevated white blood cell count

57%

25-50%

 

Erythrocyte sedimentation rate (>30 mm/hr)

100%

85%

 

Abnormal thyroid hormone levels (elevated or depressed)

5-10%

60%

 

Alkaline phosphatase, transaminases increased

Rare

Common

Needle Aspiration

Purulent, bacteria or fungi present

~100%

0

 

Lymphocytes, macrophages, some polys, giant cells

0

~100%

Radiological

123I uptake low

Common

~100%

 

Abnormal thyroid scan

92%

Non-visualized

 

Thyroid scan or ultrasound helpful in diagnosis

75%

Non-specific

 

Gallium scan positive

~100%

~100%

 

18F-FDG-PET

Positive

Positive

 

Barium swallow showing fistula

Common

0

 

CT scan useful

Varies

Not indicated

Clinical Course

Clinical response to glucocorticoid treatment

Transient

100%

 

Incision and drainage required

85%

No

 

Recurrence following operative drainage

16%

No

 

Pyriform sinus fistula discovered

96%

No

Modified from Szabo and Allen (21); see also Shabb & Solti (266)

 

If subacute thyroiditis affects only one part of the thyroid gland, the serum T4 concentration and overall thyroidal RAIU may be entirely normal. A thyroid scan done with either radioactive iodine or 99m-Tc-pertchnetate will demonstrate failure of the involved areas of the gland to concentrate the tracer. When the thyroid is diffusely involved, which is more typical, a dramatic disturbance in iodine metabolism is observed.

 

During the initial phase of the disease, the RAIU is depressed or entirely absent and the concentrations of serum T4 and T3 are often elevated but the ratio of T3 to T4 is typically less than 20 (compared to > 20 in typical Graves’ disease). Due to the concomitant release of non-hydrolyzed iodoproteins from the inflamed tissue, the serum thyroglobulin level is also high. During this phase, the serum TSH level is low. Analysis of the TSH suppression reported over 20 years ago with a sensitive assay, measured in thyrotoxic patients, indicated that patients with SAT may demonstrate suppressed but detectable levels of TSH while those with Graves’ disease or silent thyroiditis typically have undetectable TSH values (267). It has been postulated that those with SAT are evaluated sooner in the course of thyrotoxicosis due to the pain of the condition, and thus the duration of the thyrotoxicosis is less, leading to proportionally less TSH suppression. This finding has been proposed to be useful in the differential diagnosis of these thyrotoxic states (267). The TSH response to TRH stimulation is also typically suppressed (238) due to the high levels of circulating thyroid hormone. Iodide that is collected and metabolized by the gland is rapidly secreted because of the decreased ability to store colloid (240). At this time, the involved tissue shows decreased but not necessarily depleted stores of iodine, as determined by x-ray fluorescence (237,240), a study which is not readily available in most clinical settings in the USA. Administration of TSH will fail to produce a normal increase in RAIU. Evidently, thyroid cell damage reduces the ability of the gland to respond to TSH. As the process subsides, the serum T4, T3, and TG levels decline, but the serum TSH level remains suppressed. The normal concentrations of SHBG sometimes observed in the thyrotoxic phase probably reflects the short duration of exposure to increased thyroid hormone (268). Later, during the recovery phase, the RAIU becomes elevated with the resumption of the ability of the thyroid gland to take up and concentrate iodide in response to TSH. The serum T4 concentration may fall below normal; the TSH level may become elevated. Usually after several weeks or months, all the parameters of thyroid function return to normal (Fig. 2). Restoration of iodine stores appears to be much slower and may take more than a year after the complete clinical remission (237,240). In about 2% of patients subacute thyroiditis may trigger auto-reactive B cells to produce TSH receptor antibodies, resulting in TSH antibody associated thyroid dysfunction in some patients (246).This finding may be a potential explanation of the apparent occurrence of Graves’ disease following an episode of SAT (249,269,270).

Figure 2. Thyroid function in a patient during the course of de Quervain’s (subacute) thyroiditis. During the thyrotoxic phase (days 10 to 20), the serum TG concentration was greatly elevated, the FTI was high, TSH was suppressed; the erythrocyte sedimentation rate was 86 mm/hr, and the thyroidal RAIU was 2 percent. The thyroglobulin level and FTI declined in parallel. During the phase of hypothyroidism (days 30 to 63), when the FTI was below normal, a modest transient increase in the serum thyroglobulin level occurred in parallel with the increase in serum TSH. All parameters of thyroid function were normal by day 150, 5 months after the onset of symptoms.

Differential Diagnosis

 

The patient presenting with painful neck symptoms is frequently empirically treated with antibiotics with minimal evaluation in general practice only later to be found to have thyroid related disease (253). With an acutely enlarged, tender thyroid, an RAIU near zero, and elevated serum T4, T3, (T3:T4 <20), thyroglobulin concentrations, and ESR, the diagnosis is almost certain. Circulating thyroid autoantibodies are absent or the titer is low. Among the diagnostic alternatives, the uncommon presentation of thyrotoxicosis in infectious thyroiditis must be considered (55) and the possibility of invading bacteria excluded (see Table 2 and 4). Rarely a fever of unknown origin may suggest temporal arteritis but is actually due to subacute thyroiditis (234). Additionally, because of the radiation of painful thyroid into the jaw area the presence of dental pain may be confused with SAT (271). The thyroid in Hashimoto's thyroiditis may be slightly tender and painful, but this event is rare, and the typical disturbances in iodine metabolism and erythrocyte sedimentation rate are rarely found. Markers of inflammation such as CRP as measured in the saliva are normal in Hashimoto’s thyroiditis when compared to controls but are grossly elevated in the patient with SAT (244).

 

Standard thyroid ultrasonography may appear similar with hypoechoic tissue in both Hashimoto’s thyroiditis and SAT. Doppler measured blood flow is usually robust in Hashimoto’s thyroiditis and Graves’ disease but minimal in SAT while assessment by sono-elastography reveals that the SAT gland is profoundly stiffer than Hashimoto’s thyroiditis tissue which is itself somewhat stiffer than normal controls (118). The radio nuclide thyroid uptake and scanning in Hashimoto’s thyroiditis is variable with elevated, depressed or normal results reported. 18F-FDG-PET in Hashimoto’s on the other hand is similar to that seen in SAT with usually very positive uptake reported (254,272,273). Magnetic resonance imaging does not differentiate between Hashimoto’s thyroiditis and SAT (261) and is therefore, like 131/123-I and PET scanning, of little value in separating the patient with painful Hashimoto’s from the SAT patient.

 

Hemorrhage into a cyst in a nodular thyroid gland may be acutely painful and therefore confused with subacute thyroiditis although the condition may be associated with an initially autonomously functioning nodule (274). The clinical presentation of a nodule hemorrhage is usually sudden and transient, a fluctuant mass may be found in the involved region, which may be confirmed as fluid filled and avascular ultrasonographically, and further differentiated as the erythrocyte sedimentation rate is normal. Occasionally, subacute thyroiditis mimics endogenous hyperthyroidism (Graves’ or toxic nodular goiter) in a patient whose RAIU is suppressed by the administration of exogenous iodine. This event occurs particularly in thyrotoxicosis induced by iodine (Jod-Basedow phenomenon) (241). The sudden onset of subacute thyroiditis, the presence of toxic symptoms without the typical signs of long-term hyperthyroidism, the tender gland, the constitutional symptoms, and the high erythrocyte sedimentation rate are helpful in making the differentiation. In some instances, measurement of antibodies and thyroid-stimulating immunoglobulins, and observation of the course of the illness may be required to confirm the diagnosis.

 

The single disease entity that is probably most difficult to differentiate from SAT is a variant of lymphocytic thyroiditis (242). This condition is unrelated to iodine ingestion and most likely is a variant of autoimmune thyroiditis. The patient presents with goiter, thyrotoxicosis, and a low RAIU. The biochemical course of the disease is indistinguishable from that of subacute thyroiditis and proceeds from a thyrotoxic phase through a hypothyroid phase to spontaneous remission with normalization of thyroid function. The goiter is however, typically painless and there are no associated systemic symptoms. This condition has been formerly confused with subacute (de Quervain's) thyroiditis, which likely has led to the descriptive terms of silent, painless, or atypical subacute thyroiditis to refer to this entity. The most helpful distinguishing features, short of histologic examination of biopsy material, are the absence of pain, the positivity of anti-thyroid antibodies and a normal erythrocyte sedimentation rate.

 

Localized subacute thyroiditis, with induration, mild tenderness, and depressed iodine uptake visualized on scan, can clearly be very suggestive of acute suppurative thyroiditis or even thyroid cancer. One series indicated a surprisingly high frequency of focal involvement observed among those with SAT (256). Indeed, this differential is quite difficult when incidentally discovered lesions are evaluated. Focal thyroid lesions incidentally identified by 18F-FDG-PET/CT are said to have malignant potential in up to 14-63% of cases (275,276). Among the other diagnostic findings reported to account for such FDG-PET incidentalomas is focal SAT (262). Usually, the degree of pain and tenderness, elevated erythrocyte sedimentation rate, leukocytosis, and remission or spread to other parts of the gland make clinical differentiation possible. Traditional ultrasonography may reveal localized hypoechoic area in the thyroid and gray-scale and Doppler sonography may be helpful in this situation (255,277). Sonoelastography of these nodular lesions yields abnormally inelastic results in both SAT as well as thyroid cancer (278). Occasionally, magnetic resonance imaging (261), where the image of SAT is characterized by low intensity, may assist the clinician in differential of these nodular lesions. The hypoechoic area on ultrasound can reflect the degree of inflammation and thyroid hormone levels (257). However, a fine needle aspiration may be necessary for a definitive differentiation between these two processes (274), as well as the other entities noted above (129).

 

Therapy

 

In some patients with SAT, no treatment is required. However, for many, some form of analgesic therapy is warranted to treat the symptoms of the disease until it resolves. At times, this relief of symptoms can be achieved with non-steroidal anti-inflammatory agents or aspirin. However, if this fails, as it often does when the symptoms are severe, and after acute suppurative thyroiditis had been definitively ruled out as outlined above, prednisone administration should be employed (67,139).Compared to the use of NSAIDs, use of steroids has been shown to reduce time to resolution of symptoms (279). Large doses promptly relieve the symptoms through non-specific anti-inflammatory effects. Treatment is generally begun with a single daily dose of 40 mg prednisone. After one week of this treatment, the dosage is tapered over a period of 6 weeks or so. The relief of the tenderness in the neck is so dramatic as to be virtually diagnostic of subacute thyroiditis. As the dose is tapered, most patients have no recrudescence of symptoms, but occasionally this does occur, and the dose must be increased again. A dose as low as 15 mg of prednisolone has been shown to be as effective (280) and further studies should be conducted to determine the lowest effective doses.  A newer therapeutic approach with local injection of lidocaine and dexamethasone through an insulin syringe has been reported to alleviate symptoms earlier than standard treatment with systemically administered prednisone and needs further evaluation in larger studies (281). The recurrence rate of subacute thyroiditis after cessation of prednisolone therapy is about 20% but no predictive factors have been found in routine laboratory data between recurrent and non-recurrent groups of patients (282). A recent study that evaluated the results of the steroid and NSAID treatments in SAT in relation to persistent hypothyroidism and recurrence, concluded that NSAIDs fail to provide clinical remission in more than half of SAT patients, and symptomatic response to NSAIDs is lower in patients with higher ESR and CRP levels. Despite the high recurrence rate observed in steroid-treated SAT patients, steroid treatment appears to be protective against permanent hypothyroidism. Steroid therapy should therefore be considered, especially in anti-TPO positive SAT patients and patients with high-level ESR and CRP (283). In this study, initial laboratory data, treatment response, and long-term results of 295 SAT patients treated with ibuprofen or methylprednisolone were evaluated. After the exclusion of 78 patients, evaluation was made of 126 patients treated with 1800 mg ibuprofen and 91 patients treated with 48 mg methylprednisolone. In 59.5% of 126 patients treated with ibuprofen, there was no adequate clinical response at the first control visit. In 54% of patients, the treatment was changed to steroids after a mean of 9.5 days. Symptomatic remission was achieved within two weeks in all patients treated with methylprednisolone. The total recurrence rate was 19.8%, and recurrences were observed more frequently in patients receiving only steroid therapy than in patients treated with NSAID only (23% vs. 10.5% p:0.04). Persistent hypothyroidism developed in 22.8% of patients treated only with ibuprofen and in 6.6% of patients treated with methylprednisolone only. Treatment with only ibuprofen (p:0.039) and positive thyroid peroxidase antibody (anti-TPO) (p:0.029) were determined as the main risk factors for permanent hypothyroidism.

 

During the recovery process, there may be a marked but transient increase in the 24-hour radioactive iodine uptake which can reach levels typically seen in Graves' disease but of course thyrotoxicosis is not simultaneously present. This elevation of iodine uptake occurs prior to re-establishment of normal thyroid function and should not be confused (taken out of context) with hyperthyroidism due to Graves ‘disease. Surgical intervention is not the primary treatment for subacute thyroiditis but rarely this has been performed due to presence of indeterminate cytology on FNA (284-286) or pain (287). Experience from the Mayo clinic (284) has shown, however, that if surgery is performed for a clinically indeterminate thyroid nodule, resection is safe and with low morbidity. Because of the possibility of associated papillary cancer further cytological examination should be performed in patients presenting with a persistent hypoechoic area larger than 1 cm by ultrasonography (260).

 

Prognosis

 

In most patients, there is a complete and spontaneous recovery and a return to normal thyroid function. However, the thyroid glands of patients with SAT may exhibit irregular scarring between islands of residual functioning parenchyma, although the patient has no symptoms. A recent study that followed 61 patients for 2 years following diagnosis of SAT explored the early indicators of hypothyroidism and the final changes in thyroid volume in SAT patients (288). They noted that the thyroid gland volumes of SAT patients, especially those with hypothyroidism, were smaller than those of healthy controls after the acute stage of the disease. They also suggested that the higher early maximum TSH value within 3 months after SAT onset may be the risk factor for the incidence of hypothyroidism 2 years later.

 

SAT may recur in up to 2.8 to 4 % of patients (219,289). Up to 10% of the patients may become hypothyroid and require permanent replacement with levothyroxine. The choice of treatment, use of steroid, NSAID or both may not predict the development of permanent hypothyroidism.(290) In a retrospective study of 252 patients with SAT, permanent hypothyroidism occurred in 5.9%. All of these had bilateral hypoechoic areas on thyroid ultrasound at initial presentation suggesting that this may be a useful prognostic marker for the potential development of thyroid dysfunction after SAT (291). However, permanent hypothyroidism was significantly less common in SAT compared to the outcome noted in amiodarone induced thyrotoxicosis type 2 (destructive thyroiditis) (292). It is of interest that elevated levels of serum thyroglobulin may persist well over a year after the initial diagnosis, indicating that disordered follicular architecture and/or low grade inflammation can persist for a relatively long period (293).

 

A minority (< 1%) of those presenting with clinical SAT in Japan have been reported to return (n= 7) a mean 4.7 months later with findings consistent with Graves’ disease (GD) (269). Review of the other 26 cases summarized in the report of Nakano et al. indicates a similar interval between the diagnosis of SAT and subsequent GD presentation, a clearly elevated RAIU in the GD phase of all the reports where an uptake is reported (14/26 [54%]) and a change in thyroid antibody positivity in 50% of those evaluated in both (6/26 [23%]) the SAT and GD presentation(269). Combining the case series by Nakano et al. with their review of the literature, 21/31 [68%] of cases labeled as SAT were diagnosed clinically without a radioactive iodine uptake assessment, and a further 4/12 [33%] of those diagnosed as SAT with a RAIU available had an uptakes greater than 10% at the time of diagnosis(269). This brings into question the true incidence of this reported transition from presumably non-autoimmune SAT to clearly immune mediated GD.

 

RIEDEL'S THYROIDITIS

 

Riedel’s thyroiditis is a chronic sclerosing thyroiditis, occurring especially in women, that tends to progress inexorably to complete destruction of the thyroid gland and frequently causes pressure symptoms in the neck (294-296). Initially described by Semple in 1864 and Bolby in 1888 (297), it was later reported in 1896 by Riedel as an “eisenharte Struma” (iron hard goiter) fixed and usually painless enlargement of the thyroid (294,298,299). It is exceedingly rare with estimated incidence of 1.06 cases per 100,000 population and 37/57,000 (0.06%) of thyroid surgical outcomes over a 64 year period (300). In the Mayo Clinic series (300), it occurred approximately one-fiftieth as frequently as Hashimoto's thyroiditis. It is more frequent in women (F:M 3.1:1) (67,163,294,301,302) who were recently reported to represent 81% of those with confirmed Riedel’s in a Mayo clinic series and further confirmed in a meta-analysis (302,303). Riedel’s thyroiditis is principally reported to occur in the 30- to 50 year age group and has a reported median age of 47 years (67,301-303).

 

Pathology

 

The thyroid gland is normal in size or enlarged, focally or symmetrically involved, and extremely (woody) hard. The gland is replaced by the inflammatory process which may extend into adjacent structures including parathyroid, skeletal muscle, nerves, blood vessels as well as the trachea (304). Gross observation of the mass reveals a pale gray appearance similar to a malignant lesion (305). There are no tissues planes visible and the cut surface of the mass is stark white due to the hypovascularity of the tissue (306). Histologically, normal tissue is replaced by inflammatory cells, predominantly lymphocytes, plasma cells, eosinophils (301,307), and small amounts of colloid (308-310) in a dense matrix of hyalinized connective tissue. Characteristically, an inflammatory reaction of the venous vascular structures has been described (305).  An oft-stated criterion useful in assuring the pathologic diagnosis is to note the absence of granulomatous tissue and malignancy (301,305,306). A potentially difficult differential diagnostic decision may be encountered with diffuse sclerosing variant of papillary thyroid cancer and the nodular sclerosing variant of Hodgkin’s disease (302), rare sarcomas of the thyroid region (311), or with the pauci-cellular variant of anaplastic thyroid cancer, both of which, although similar in gross appearance, will have distinctive histopathologic immunohistochemical findings (312).

 

Etiology

 

Although the etiology remains unclear, Riedel’s thyroiditis has been characterized in various ways including as the cervical manifestation of a systemic fibrosing disorder with identical histopathological appearance (313). Further, Riedel’s thyroiditis has been called a variant of Hashimoto’s, a primary infiltrative disease of the thyroid and even a manifestation of end stage de Quervain’s thyroiditis (295,308,314,315). Riedel’s thyroiditis has been reported following subacute thyroiditis (315) and a case of concurrent Riedel’s, Hashimoto’s and acute thyroiditis has also been reported (316). The report of a case of Graves’ disease following Riedel’s thyroiditis (317) and the observation that the B cell proliferation observed in the course of these diseases has been shown to be polyclonal (318) supports the notion of autoimmune mechanisms in the etiology of the Riedel’s condition. The occurrence of marked tissue eosinophilia and the extracellular deposition of eosinophil granule major basic protein suggests a role for eosinophils and their products in the development of fibrosis in Riedel's thyroiditis (307). Fibrosis may also be related to the action of TGF beta 1, as seen in murine thyroiditis (319). Most recently links between Hashimoto’s, IgG4-related systemic disease (IgG4-RSD) and Riedel’s thyroiditis have been reported (320-322). Supporting evidence showing the presence of IgG4-bearing plasma cells in thyroidectomy specimens and other affected organs (302,322,323). A comprehensive review of potential etiology has been published (304).

 

IgG4-related disease (IgG4-RD) was first described in 1961 as a distinctive presentation of pancreatitis which was observed to be associated with hypergammaglobulinemia (324). A specific association with IgG4 was published in 2001 (325) and eventually an international consensus was established to define the criteria for recognizing IgG4-RD (326,327). Through this understanding of pathophysiology, the term IgG4-RD has been adopted to describe a common underlying pathology found in a variety of fibrosing disorders that over the years have been designated in various ways primarily based on the organ of involvement and the names of the initial authors of reports describing their occurrence.  Under the umbrella of IgG4-RD, newer nomenclature captures entities such as Mikulicz syndrome as  IgG4 related dacryoadentis and sialadenitis, and Riedel’s thyroiditis as IgG4 related thyroid disease (IgG4RTD) (328,329). More recently, IgG4 related thyroid disease has included Riedel’s thyroiditis, fibrosing variant of Hashimoto’s thyroiditis and few patients of Graves’ orbitopathy to represent IgG4-related thyroid disease (330). One or several organs may be involved at the time of diagnosis or subsequent to the identification of IgG4-RD in a particular organ. The most frequently involved organs include the pancreas, bile ducts, salivary glands, lachrymal glands and kidneys (328). The majority of cases are identified by the presence of characteristic fibrosing pathology and it is expected that serum IgG4 levels be elevated in most cases. The diagnosis if IgG4-RD is based on the identification of a (1) mass in one or more organs associated with an (2) elevated serum IgG4 level (greater than 1.35 g/L) and (3) histopathology demonstrating marked lymphocytic and plasma cell infiltration, more than 10 IgG4 positive plasma cells per high powered field (greater than a 40% IgG4/IgG ratio) and storiform fibrosis(326,331). Definitive diagnosis is assured when all 3 criteria are present, the diagnosis is probable when the first and 3rd criteria are met and possible when only the 1st and second criteria are present (328).

 

Based on these criteria, the position of Riedel’s thyroiditis among the IgG4-RDs would be considered probable as the vast majority of cases reported thus far are not associated with elevated serum IgG4 levels although the typical histopathologic criteria are met when applied. A recent review of 10 cases studied in Japan confirmed the IgG4-RD connection in histopathological data and note a paucity of serum IgG4 levels in their summary of the published literature (332). Most recent cases specifically noting this association and including the association with IgG4-RD in their titles document the first and third diagnostic criteria (322,332-335), while only a few have documented an elevated serum IgG4 level (336,337). A recent series of cases from Sweden, where serum IgG4 levels were measured in 66% of the subjects, indicated that none of the 4 evaluated had elevated serum IgG4 levels (338). The most recent meta-analysis does not detail any serum IgG4 data among the 212 subjects reviewed in published reports from 1925-2019 (302).

 

Clinical Features

 

Riedel’s thyroiditis usually presents as a hard thyroid mass, frequently associated with compressive symptoms including dyspnea, stridor, hoarse voice, dysphagia for months before diagnosis (6,67,294,295,300-303) and historically has been diagnosed by a surgeon faced with an inflammatory mass of fibrosclerosing tissue (339,340)when expecting a thyroid tumor (309). Intraoperative diagnostic confusion with anaplastic thyroid cancer (312), sarcoma of the thyroid (311), thyroid lymphoma (341), or fibrosing Hashimoto’s thyroiditis (342) have been reported. A case of asymptomatic Riedel’s associated with a benign follicular adenoma has also been reported (343). Riedel’s thyroiditis may occur in a multinodular goiter or as a rapidly growing hard neck mass in a previously normal gland mimicking thyroid cancer (340,344,345). As the extent of the fibrosis increases, or concomitant Hashimoto’s is present, involvement of a critical mass of the thyroid tissue results in primary hypothyroidism in 25-80% of cases (295,303,309,310,346). Antithyroid antibodies may be present in 36-90% of reported cases (296,302,303). A detailed breakdown of antibodies encountered has recently been reported in the context of systemic review of documented Riedel’s thyroiditis reports where TPO was positive in 43% of those tested, thyroglobulin antibodies were detected in 27% of those evaluated and thyrotropin receptor antibodies were considered present in 20% when they were drawn (302). Extension of the inflammatory process into underlying parathyroid glands may result in non-surgical hypoparathyroidism (346-351) in up to 14% cases encountered (303).  The fibrosis may remain relatively stable or progress resulting in local complications by compressing the trachea or esophagus and resulting in symptoms of local pressure, dyspnea, dysphagia as well as stridor out of proportion of the size of the mass (352,353), with subsequent hoarseness, and aphonia, with involvement of the recurrent laryngeal nerves (342,349). Further extension of the inflammatory process involving other neck structures can result in Tolosa-Hunt syndrome (354), Horner’s syndrome (349), or occlusive phlebitis of cervical vessels (355-357). The occurrence of cerebral sinus thrombosis suggests that Riedel's thyroiditis may cause venous stasis, vascular damage, and possibly hypercoagulability (358).  Estimates as high as 38% associate Riedel's thyroiditis with similar fibro-sclerotic processes in other areas (303). Subcutaneous fibrosclerosis has also been noted but it is very rare (359).  The lesions appear in the lacrimal glands, orbits (360), parotid glands (361), mediastinum (300,303,305,309), coronary arteries (303), retroperitoneal tissues (295,300,346,362,363), bile ducts (301,364) and pancreas (364) in varying combinations in the syndrome of multifocal fibro-sclerositis (365,366).

 

Clinical Evaluation

 

Initially the patient with a thyroid mass will need an assessment of thyroid function, and may benefit from screening thyroid antibodies (367). A complete blood count reveals normal to elevated white blood cell counts. The erythrocyte sedimentation rate is usually moderately elevated (308,309). Due to the potential of hypoparathyroidism an assessment of calcium status is prudent (304). Ultrasonography of the thyroid typically reveals a diffuse, hypoechoic, hypovascular appearance due to the extensive fibrosing process (317,340,346,368,369). Unique to the findings in Riedel’s thyroiditis is an encasement of the carotid arteries, not typically seen in other forms of multinodular or Hashimoto’s goiter (303,370). Sonographic elastography demonstrates significant stiffness of the tissue compared to normal thyroid (370). At this point in the evaluation, a fine needle aspiration (FNA) of the thyroid mass is usually obtained. FNA results are typically non-diagnostic due the lack of thyroid follicular cells (67,301,303,306) but may contain evidence of the inflammatory process (303), fibrous tissue and myofibroblasts (371), or even cytopathology findings consistent with follicular neoplasm (348). A novel case illustrates a potential use of FNA to obtain protein used in proteomic analysis which was successful in differentiating the tissue of a patient with Riedel’s thyroiditis from the tissue profile of anaplastic thyroid cancer (372).

 

In patients with significant obstructive symptomatology, a neck computed tomography (CT) study may be ordered to assess tracheal integrity. CT images characteristically demonstrate hypodense tissue which does not enhance with iodinated contrast in the affected area (368). CT images readily reveal extrathyroidal extension of the inflammatory process (368,373), and have been reported to document arterial encasement in about half of subjects and jugular involvement in about one third of cases (303). Magnetic resonance imaging (MRI) can be expected to show hypointense images on both T1 and T2 weighted images (368) and variable enhancement patterns after gadolinium enhancement (368,369,373-375). Unlike the hypointense images produced by CT and MRI, 18FDG-PET images have shown metabolic activity not only in extrathyroidal masses associated with the systemic inflammatory process but also increased glucose metabolism in the Riedel’s thyroid, likely as a result of active inflammation involving lymphocytes, plasma cells and fibroblast proliferation (370,376,377). FDG metabolic activity can also be used to assess a patient's response to therapy (376,377), but not all reports of this phenomenon have documented the usefulness of this effect (370).

Although not typically indicated in the evaluation of a eu- or hypothyroid individual with a thyroid mass, 99mTc-pertechnetate or 123/131-I scanning in Riedel’s thyroiditis is typically compromised due to low uptake and patchy images typical of other forms of chronic thyroiditis (301,308,309). An exception to the utility of radionuclide scanning is found in the thyrotoxic patient presenting with a thyroid mass. In those with Graves’ disease or a toxic thyroid nodule, the hyperfunctioning portion of the thyroid is indeed well visualized while the portion involved with Riedel’s thyroiditis typically demonstrates no uptake (317). Finally, it has been documented that gallium scanning may, as expected, also demonstrate significant uptake in the Riedel’s lesion (120).

 

Establishing the diagnosis of Riedel’s thyroiditis requires histopathologic confirmation at the present time. Biopsy material may be obtained by Tru-cut needle biopsy (378), open biopsy (67), or at the time of decompressive thyroidectomy. Histopathologic findings required to establish this diagnosis include: 1) the presence of an inflammatory process in the thyroid with extension into surrounding tissue; 2) the inflammatory infiltrate should contain no giant cells, lymphoid follicles, oncocytes or granulomas; 3) there should be evidence of occlusive phlebitis; and 4) there should be no evidence of thyroid malignancy (379). More recent work has suggested that the IgG4+ plasma cells per high powered field (HPF) and an IgG4+/IgG+ > 40% criteria for IgG4-Related Disease is seldom met in the thyroid and more modest finding of 10 IgG4+ plasma cells/HPF and a IgG4+/IgG ratio of 20% would be a more appropriate diagnostic threshold (380). In light of recent work defining Riedel’s thyroiditis as a potential manifestation of the IgG4-related systemic sclerosing disease, the role of incorporating immunohistochemical assessment of tissue lymphocytes and the measurement of serum IgG4 levels into working diagnostic criteria is very supportive but remains to be defined.

 

Management of Riedel's Thyroiditis

 

Although there is no specific therapy for Riedel's thyroiditis, several management strategies are available dependent on the clinical features of the disease in the individual patient. Patients commonly undergo surgery for relief of obstructive symptoms. Histopathology then allows for the definitive establishment of the diagnosis. Most are then treated medically for associated hormone deficiencies with levothyroxine and /or calcium along with calcitriol, but with exception of one case where reduction of the size of the inflammatory mass was observed (345), this supplementation is not thought to influence the course of the disease. Finally, anti-inflammatory treatment aimed at diminishing the inflammatory tissue mass is applied and may even result in resolution of limited biochemical findings such as primary hypoparathyroidism (351).

 

Surgical therapy for debulking and symptom relief should usually be limited to isthmusectomy (6,67,301,348) when total thyroidectomy is not possible. Due to the obliteration of tissue planes there is an enhanced danger of hypoparathyroidism and recurrent laryngeal nerve injury even when limited surgery is performed by experienced surgical specialists as documented in a series from the Mayo clinic where 39% of patients with Riedel’s thyroiditis suffered surgical complications (303). Previous and contemporary experience therefore recommends that extensive surgical procedures be considered inappropriate (67,303,306,348). Microscopic surgery has been attempted to minimize complications (381).

 

Medical therapy to arrest progression of symptomatic disease should be pursued after establishment of a firm diagnosis. Corticosteroid therapy has been found to be effective in some cases (296,302,347,351,358,365,374,378,382-387), probably most in those with active inflammation (322,386). Initial doses of up to 100 mg per day of prednisone have been used (301) but sustained improvement has been reported with lower doses of 15-60 mg per day for about 3 months (302,341,349,365,382,385,387). There are no controlled trials of steroid therapy in Riedel's and a variety of medications have been used including most frequently prednisone, prednisolone, dexamethasone methylprednisolone, and betamethasone (302). Although some patients obtain long-term benefit after steroid withdrawal (313,365,386) others may relapse, usually leading to reintroduction of glucocorticoids or the addition of alternative anti-inflammatory therapy (349,388,389). The reasons for this variation are unclear but inflammatory activity and duration of disease may be relevant factors. More recently, the observation that smoking history may play a role in the responsiveness of Riedel’s pathology to glucocorticoid therapy has been published (303).

 

In those who fail to respond to glucocorticoid therapy, or relapse after withdrawal, tamoxifen therapy is the next most common therapy reported to have been tried. Twenty eight reports have described an encouraging response with this agent when administered in doses of 20 mg daily  for an average of 8 months, admittedly in only a small number of patients (302,349,351,388,390-395). It is possible that tamoxifen acts in Riedel's by inhibition of fibroblast proliferation through the stimulation of TGF beta (396-398). Tamoxifen in combination with prednisone or tamoxifen as monotherapy have both been reported to be effective (349,388,393,395). There appears to be a persistent benefit of tamoxifen therapy during continued application in most but not all cases (303,389). Limited data on effective therapy with other immunosuppressive agents indicates that responses to azathioprine in doses ranging from 40 to 150 mg daily have been reported in 4 patients (302). Also a combination of mycophenolate mofetil and prednisone has been observed to have successfully treated an individual who failed a prednisone and tamoxifen combination (389) and 3 cases of rituximab use have also been reported to be useful (334,399,400). The potential usefulness and relative effectiveness of these interventions awaits confirmation.

Summary of Riedel’s Thyroiditis

 

Riedel’s thyroiditis should be suspected in patients presenting with a thyroid mass and unique clinical features. Findings increasing the likelihood of Riedel’s thyroiditis include local restrictive or infiltrative symptoms out of proportion to the size or extent of the mass or simultaneous hypocalcemia. Surgical intervention should be limited to rule out the presence of malignancy and obtain the histopathologic confirmation. Once the diagnosis of Riedel’s thyroiditis is established, a search for related fibrotic conditions and medical treatment should be pursued. Replacement with levothyroxine and, when appropriate, calcium and active vitamin D metabolites should be begun when indicated along with anti-inflammatory medications.

 

RARE INFLAMMATORY OR INFILTRATIVE DISEASES

 

In addition to the varieties of thyroiditis already mentioned, which are diseases specifically of the thyroid gland, generalized or systemic diseases may also involve the thyroid gland (67). The lesions of sarcoid may appear in the thyroid gland of 1-4% of patients with systemic sarcoidosis (401). Thyroid dysfunction has been reported very infrequently (1-3%)(402) in systemic sarcoidosis but a recent series of patients with cutaneous sarcoidosis noted abnormal TSH values in 26% compared to the US population expectation of about 10% (402). Most thyroid dysfunction was mild, a male to female ratio of abnormal thyroid function of 1:1 was noted, Caucasians were more frequently affected than African Americans and 20% of those with abnormal TSH were eventually classified as hypothyroid (402). Infiltration of the thyroid with sarcoidosis is reported to occur in about 5% of patients with sarcoidosis (403). Multinodular goiter has been described as an initial presenting manifestation in a woman eventually diagnosed with systemic sarcoidosis (401). This case illustrates the difficulty in diagnosing the cause of supine dyspnea in patients with sarcoidosis, illustrating the potential of a thyroid contribution to the overall clinical picture (401).

 

Deposits of amyloid are quite common in systemic amyloidosis (404) but this uncommonly causes goiter (404-407). Although transthyretin amyloidosis is primarily associated with amyloid deposits in the heart and the nervous tissue, familial forms of amyloidosis due to transthyretin gene mutations are associated with deposits of amyloid in multiple tissues (408). AL amyloidosis (primary), linked to plasma cell dyscrasias can be local or systemic. Localized primary amyloidosis presenting with isolated amyloid goiter are rare (405,409,410). Secondary amyloidosis is associated with chronic inflammatory conditions such as Familial Mediterranean Fever (FMF) (411), inflammatory bowel disease (412), rheumatoid arthritis (407,413), end-stage renal disease (414), tuberculosis (415) and bronchiectasis (416).   Clinically, an amyloid goiter may be progressive, diffuse and rapidly lead to compressive symptoms (404,405,411). Thyroid function in association with an amyloid goiter is normal in 2/3 of cases, 1/7 present with hypothyroidism and fewer demonstrate other abnormalities of thyroid function (404). In addition to the focal deposition of amyloid in thyroid tissues associated with most cases of medullary thyroid cancer (417,418), several cases of papillary thyroid cancer have been reported in association of amyloid goiter (404,419-421). Amyloid goiter may be readily diagnosed by fine needle aspiration biopsy (422) and has been reported in conjunction with infiltration of other endocrine organs such as the pituitary (406). It has been suggested that the thyroid FNA is relatively safe and sensitive to confirm the presence of systemic amyloidosis(404,423). Some may require surgery to relieve the compressive symptoms or for a confirmatory diagnosis. Using a calcitonin immunostaining technique may help delineate between amyloidosis and medullary thyroid cancer (424). Once the diagnosis of amyloid goiter is established, the patient should be screened for predisposing causes and the extent of the disease.

 

Painless thyroiditis has been noted in a woman with rheumatoid arthritis and secondary amyloidosis infiltrating the thyroid gland (425). Radiotherapy for tonsillar carcinoma has been reported to result in thyroiditis (426). Irradiation to the thyroid during therapy for breast cancer or lymphoma can also induce hypothyroidism.  Following 131-I therapy for Graves’ disease or toxic multinodular goiter, thyroiditis, which is occasionally symptomatic, may develop. This situation is discussed in other Endotext chapters. Therapy should be directed toward the primary disease rather than the thyroid, but administration of thyroid hormone may be necessary if destruction of thyroid tissue is sufficient to produce hypothyroidism. Finally, surgery to the neck, associated with mechanical manipulation of the thyroid during laryngectomy or parathyroid surgery can result in a painless subacute thyroiditis like picture (427-429).

 

ACKNOWLEDGEMENT  

 

The authors are grateful to the extensive groundwork performed by Dr. John Lazarus, the founding author of this chapter. Additionally, we are privileged to update this summary with the most recent developments in the field while maintaining the historical perspective of those who have preceded us.

 

REFERENCES

 

  1. Chan GC, Lee PC, Kwan LP, Yip TP, Tang SC. Acute thyroiditis: An under-recognized complication of parathyroidectomy in end-stage renal failure patients with secondary hyperparathyroidism. Nephrology (Carlton).2017;22(7):572.
  2. Paes JE, Burman KD, Cohen J, Franklyn J, McHenry CR, Shoham S, Kloos RT. Acute bacterial suppurative thyroiditis: a clinical review and expert opinion. Thyroid. 2010;20(3):247-255.
  3. Al-Dajani N, Wootton SH. Cervical lymphadenitis, suppurative parotitis, thyroiditis, and infected cysts. Infect Dis Clin North Am. 2007;21(2):523-541, viii.
  4. Hendrick JW. Diagnosis and management of thyroiditis. J Am Med Assoc. 1957;164(2):127-133.
  5. Yu EH, Ko WC, Chuang YC, Wu TJ. Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review. Clin Infect Dis. 1998;27(5):1286-1290.
  6. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003;348(26):2646-2655.
  7. Dugar M, da Graca Bandeira A, Bruns J, Jr., Som PM. Unilateral hypopharyngitis, cellulitis, and a multinodular goiter: a triad of findings suggestive of acute suppurative thyroiditis. AJNR Am J Neuroradiol. 2009;30(10):1944-1946.
  8. Chi H, Lee YJ, Chiu NC, Huang FY, Huang CY, Lee KS, Shih SL, Shih BF. Acute suppurative thyroiditis in children. Pediatr Infect Dis J. 2002;21(5):384-387.
  9. Chang P, Tsai WY, Lee PI, Hsiao PH, Huang LM, Lee JS, Peng SF, Li YW. Clinical characteristics and management of acute suppurative thyroiditis in children. J Formos Med Assoc. 2002;101(7):468-471.
  10. Brook I. Microbiology and management of acute suppurative thyroiditis in children. Int J Pediatr Otorhinolaryngol. 2003;67(5):447-451.
  11. Hatabu H, Kasagi K, Yamamoto K, Iida Y, Misaki T, Hidaka A, Endo K, Konishi J. Acute suppurative thyroiditis associated with piriform sinus fistula: sonographic findings. AJR Am J Roentgenol. 1990;155(4):845-847.
  12. Parida PK, Gopalakrishnan S, Saxena SK. Pediatric recurrent acute suppurative thyroiditis of third branchial arch origin--our experience in 17 cases. Int J Pediatr Otorhinolaryngol. 2014;78(11):1953-1957.
  13. Lucaya J, Berdon WE, Enriquez G, Regas J, Carreno JC. Congenital pyriform sinus fistula: a cause of acute left-sided suppurative thyroiditis and neck abscess in children. Pediatr Radiol. 1990;21(1):27-29.
  14. Miyauchi A, Yokozawa T, Matsuzuka F, Kuma K. Acute suppurative thyroiditis; infection in thyroid nodules or infection through a piriform sinus fistula. Thyroidol Clin Exp 1998;10:75-79.
  15. Miyauchi A, Matsuzuka F, Kuma K, Katayama S. Piriform sinus fistula and the ultimobranchial body. Histopathology. 1992;20(3):221-227.
  16. Shah SS, Baum SG. Diagnosis and Management of Infectious Thyroiditis. Curr Infect Dis Rep. 2000;2(2):147-153.
  17. Fukata S, Miyauchi A, Kuma K, Sugawara M. Acute suppurative thyroiditis caused by an infected piriform sinus fistula with thyrotoxicosis. Thyroid. 2002;12(2):175-178.
  18. Gan YU, Lam SL. Imaging findings in acute neck infection due to pyriform sinus fistula. Ann Acad Med Singapore. 2004;33(5):636-640.
  19. Sheng Q, Lv Z, Xiao X, Zheng S, Huang Y, Huang X, Li H, Wu Y, Dong K, Liu J. Diagnosis and management of pyriform sinus fistula: experience in 48 cases. J Pediatr Surg. 2014;49(3):455-459.
  20. Mohan PS, Chokshi RA, Moser RL, Razvi SA. Thyroglossal duct cysts: a consideration in adults. Am Surg.2005;71(6):508-511.
  21. Szabo SM, Allen DB. Thyroiditis. Differentiation of acute suppurative and subacute. Case report and review of the literature. Clin Pediatr (Phila). 1989;28(4):171-174.
  22. Hopwood NJ, Kelch RP. Thyroid masses: approach to diagnosis and management in childhood and adolescence. Pediatr Rev. 1993;14(12):481-487.
  23. Sai Prasad TR, Chong CL, Mani A, Chui CH, Tan CE, Tee WS, Jacobsen AS. Acute suppurative thyroiditis in children secondary to pyriform sinus fistula. Pediatr Surg Int. 2007;23(8):779-783.
  24. Wasniewska M, Vigone MC, Cappa M, Cassio A, Scognamillo R, Aversa T, Rubino M, De Luca F. Acute suppurative thyroiditis in childhood: spontaneous closure of sinus pyriform fistula may occur even very early. J Pediatr Endocrinol Metab. 2007;20(1):75-77.
  25. Cases JA, Wenig BM, Silver CE, Surks MI. Recurrent acute suppurative thyroiditis in an adult due to a fourth branchial pouch fistula. J Clin Endocrinol Metab. 2000;85(3):953-956.
  26. Miyauchi A, Matsuzuka F, Kuma K, Takai S. Piriform sinus fistula: an underlying abnormality common in patients with acute suppurative thyroiditis. World J Surg. 1990;14(3):400-405.
  27. Kingsbury BF. On the fate of the ultimobrachial body within the hyman thyroid gland. Anat Rec. 1935;61:155-167.
  28. Minhas SS, Watkinson JC, Franklyn J. Fourth branchial arch fistula and suppurative thyroiditis: a life-threatening infection. J Laryngol Otol. 2001;115(12):1029-1031.
  29. Nicoucar K, Giger R, Pope HG, Jr., Jaecklin T, Dulguerov P. Management of congenital fourth branchial arch anomalies: a review and analysis of published cases. J Pediatr Surg. 2009;44(7):1432-1439.
  30. Acocelia A, Nardi P, Sacco, Agostini T. Acute thyroiditis of odontogenic origin. Minerva Stomatol. 2007;56:461-467.
  31. Dai L, Lin S, Liu D, Wang Q. Acute suppurative thyroiditis with thyroid metastasis from oesophageal cancer. Endokrynol Pol. 2020;71(1):106-107.
  32. Vandjme A, Pageaux GP, Bismuth M, Fabre JM, Domergue J, Perez C, Makeieff M, Mourad G, Larrey D. Nocardiosis revealed by thyroid abscess in a liver--kidney transplant recipient. Transpl Int. 2001;14(3):202-204.
  33. Teckie G, Bhana SA, Tsitsi JM, Shires R. Thyrotoxicosis followed by Hypothyroidism due to Suppurative Thyroiditis Caused by in a Patient with Advanced Acquired Immunodeficiency Syndrome. Eur Thyroid J.2014;3(1):65-68.
  34. Kazi S, Liu H, Jiang N, Glick J, Teng M, LaBombardi V, Szporn AH, Chen H. Salmonella thyroid abscess in human immunodeficiency virus-positive man: a diagnostic pitfall in fine-needle aspiration biopsy of thyroid lesions. Diagn Cytopathol. 2015;43(1):36-39.
  35. Massolt ET, Rijneveld AW, Vernooij MW, Kevenaar ME, van Kemenade FJ, Peeters RP. Acute Candida thyroiditis complicated by abscess formation in a severely immunocompromised patient. J Clin Endocrinol Metab. 2014;99(11):3952-3953.
  36. Berger SA, Zonszein J, Villamena P, Mittman N. Infectious diseases of the thyroid gland. Rev Infect Dis.1983;5(1):108-122.
  37. Fernandez JF, Anaissie EJ, Vassilopoulou-Sellin R, Samaan NA. Acute fungal thyroiditis in a patient with acute myelogenous leukaemia. J Intern Med. 1991;230(6):539-541.
  38. Gandhi RT, Tollin SR, Seely EW. Diagnosis of Candida thyroiditis by fine needle aspiration. J Infect.1994;28(1):77-81.
  39. McAninch EA, Xu C, Lagari VS, Kim BW. Coccidiomycosis thyroiditis in an immunocompromised host post-transplant: case report and literature review. J Clin Endocrinol Metab. 2014;99(5):1537-1542.
  40. Alvi MM, Meyer DS, Hardin NJ, Dekay JG, Marney AM, Gilbert MP. Aspergillus thyroiditis: a complication of respiratory tract infection in an immunocompromised patient. Case Rep Endocrinol. 2013;2013:741041.
  41. Imai C, Kakihara T, Watanabe A, Ikarashi Y, Hotta H, Tanaka A, Uchiyama M. Acute suppurative thyroiditis as a rare complication of aggressive chemotherapy in children with acute myelogeneous leukemia. Pediatr Hematol Oncol. 2002;19(4):247-253.
  42. Yildar M, Demirpolat G, Aydin M. Acute suppurative thyroiditis accompanied by thyrotoxicosis after fine-needle aspiration: treatment with catheter drainage. J Clin Diagn Res. 2014;8(11):ND12-14.
  43. Unluturk U, Ceyhan K, Corapcioglu D. Acute suppurative thyroiditis following fine-needle aspiration biopsy in an immunocompetent patient. J Clin Ultrasound. 2014;42(4):215-218.
  44. Inoue K, Kozawa J, Funahashi T, Nakata Y, Mitsui E, Kitamura T, Maeda N, Kishida K, Otsuki M, Okita K, Iwahashi H, Imagawa A, Shimomura I. Right-sided acute suppurative thyroiditis caused by infectious endocarditis. Intern Med. 2011;50(23):2893-2897.
  45. Robazzi TC, Alves C, Mendonca M. Acute suppurative thyroiditis as the initial presentation of juvenile systemic lupus erythematosus. J Pediatr Endocrinol Metab. 2009;22(4):379-383.
  46. Cabizuca CA, Bulzico DA, de Almeida MH, Conceicao FL, Vaisman M. Acute thyroiditis due to septic emboli derived from infective endocarditis. Postgrad Med J. 2008;84(994):445-446.
  47. Yegya-Raman N, Copeland T, Parikh P. Acute Suppurative Thyroiditis in an Intravenous Drug User with a Preexisting Goiter. Case Reports in Medicine. 2018.
  48. Chiovato L, Canale G, Maccherini D, Falcone V, Pacini F, Pinchera A. Salmonella brandenburg: a novel cause of acute suppurative thyroiditis. Acta Endocrinol (Copenh). 1993;128(5):439-442.
  49. Dai MS, Chang H, Peng MY, Ho CL, Chao TY. Suppurative salmonella thyroiditis in a patient with chronic lymphocytic leukemia. Ann Hematol. 2003;82(10):646-648.
  50. Su DH, Huang TS. Acute suppurative thyroiditis caused by Salmonella typhimurium: a case report and review of the literature. Thyroid. 2002;12(11):1023-1027.
  51. Akhanli P, Bayir O, Bayram SM, Hepsen S, Badirshaev M, Cakal E, Saylam G, Korkmaz MH. Acute spontaneous suppurative thyroiditis caused by Eikenella corrodens presented with thyrotoxicosis. Einstein (Sao Paulo). 2020;18:eRC5273.
  52. Bukvic B, Diklic A, Zivaljevic V. Acute suppurative klebsiella thyroiditis: a case report. Acta Chir Belg.2009;109(2):253-255.
  53. Fernandez Pena C, Morales Gorria MJ, Morano Amado LE, Lopez Miragalla MI, Pena Gonzalez E. Pasteurella spp: a newmicroorganism to the cause of acute suppurative thyroiditis. An Med Interna. 1999;16:637-638.
  54. McLaughlin SA, Smith SL, Meek SE. Acute suppurative thyroiditis caused by Pasteurella multocida and associated with thyrotoxicosis. Thyroid. 2006;16(3):307-310.
  55. Spitzer M, Alexanian S, Farwell AP. Thyrotoxicosis with Post-Treatment Hypothyroidism in a Patient with Acute Suppurative Thyroiditis Due to Porphyromonas. Thyroid. 2011.
  56. Iniguez JL, Duyckaerts V, Badoual J. [Acute thyroiditis caused by Eikenella corrodens and abnormality of the left pyriform sinus]. Arch Fr Pediatr. 1989;46(10):745-747.
  57. Queen JS, Clegg HW, Council JC, Morton D. Acute suppurative thyroiditis caused by Eikenella corrodens. J Pediatr Surg. 1988;23(4):359-361.
  58. Yoshino Y, Inamo Y, Fuchigami T, Hashimoto K, Ishikawa T, Abe O, Tahara D, Hayashi K. A pediatric patient with acute suppurative thyroiditis caused by Eikenella corrodens. J Infect Chemother. 2010;16(5):353-355.
  59. Nieuwland Y, Tan KY, Elte JW. Miliary tuberculosis presenting with thyrotoxicosis. Postgrad Med J.1992;68(802):677-679.
  60. Das DK, Pant CS, Chachra KL, Gupta AK. Fine needle aspiration cytology diagnosis of tuberculous thyroiditis. A report of eight cases. Acta Cytol. 1992;36(4):517-522.
  61. Orlandi F, Fiorini S, Gonzatto I, Saggiorato E, Pivano G, Angeli A, Pasquali R. Tubercular involvement of the thyroid gland: a report of two cases. Horm Res. 1999;52(6):291-294.
  62. Terzidis K, Tourli P, Kiapekou E, Alevizaki M. Thyroid tuberculosis. Hormones (Athens). 2007;6(1):75-79.
  63. Kataria SP, Tanwar P, Singh S, Kumar S. Primary tuberculosis of the thyroid gland: a case report. Asian Pac J Trop Biomed. 2012;2(10):839-840.
  64. Karabinis A, Douzinas E, Clouva P, Papanicolaou M, Kakaviatos N, Bilalis D. [Acute necrotic thyroiditis caused by Candida albicans immediately after acute hemorrhagic rectocolitis]. Presse Med. 1993;22(1):34.
  65. Carriere C, Marchandin H, Andrieu JM, Vandome A, Perez C. Nocardia thyroiditis: unusual location of infection. J Clin Microbiol. 1999;37(7):2323-2325.
  66. Lewin SR, Street AC, Snider J. Suppurative thyroiditis due to Nocardia asteroides. J Infect. 1993;26(3):339-340.
  67. Singer PA. Thyroiditis. Acute, subacute, and chronic. Med Clin North Am. 1991;75(1):61-77.
  68. Tan J, Shen J, Fang Y, Zhu L, Liu Y, Gong Y, Zhu H, Hu Z, Wu G. A suppurative thyroiditis and perineal subcutaneous abscess related with aspergillus fumigatus: a case report and literature review. BMC Infect Dis.2018;18(1):702.
  69. Karatoprak N, Atay Z, Erol N, Goksugur SB, Ceran O. Actinomycotic suppurative thyroiditis in a child. J Trop Pediatr. 2005;51(6):383-385.
  70. Park YH, Baik JH, Yoo J. Acute thyroiditis of actinomycosis. Thyroid. 2005;15(12):1395-1396.
  71. Trites J, Evans M. Actinomycotic thyroiditis in a child. J Pediatr Surg. 1998;33(5):781-782.
  72. Moinuddin S, Barazi H, Moinuddin M. Acute blastomycosis thyroiditis. Thyroid. 2008;18(6):659-661.
  73. Rao N, Mann SJ. Fine needle aspiration cytology of acute blastomycosis thyroiditis. Diagnostic Cytopathology.2017;45(12):1119-1121.
  74. Avram AM, Sturm CA, Michael CW, Sisson JC, Jaffe CA. Cryptococcal thyroiditis and hyperthyroidism. Thyroid.2004;14(6):471-474.
  75. Zavascki AP, Maia AL, Goldani LZ. Pneumocystis jiroveci thyroiditis: report of 15 cases in the literature. Mycoses. 2007;50(6):443-446.
  76. Lafontaine N, Learoyd D, Farrel S, Wong R. Suppurative thyroiditis: Systematic review and clinical guidance. Clin Endocrinol (Oxf). 2021;95(2):253-264.
  77. Orkar KS, Dakum NK, Kidmas AT, Awani KU. Pyogenic thyroiditis and HIV infection. West Afr J Med.2001;20(2):173-175.
  78. Tien KJ, Chen TC, Hsieh MC, Hsu SC, Hsiao JY, Shin SJ, Hsin SC. Acute suppurative thyroiditis with deep neck infection: a case report. Thyroid. 2007;17(5):467-469.
  79. Iwama S, Kato Y, Nakayama S. Acute suppurative thyroiditis extending to descending necrotizing mediastinitis and pericarditis. Thyroid. 2007;17(3):281-282.
  80. Premawardhana LD, Vora JP, Scanlon MF. Suppurative thyroiditis with oesophageal carcinoma. Postgrad Med J. 1992;68(801):592-593.
  81. Valina S, Lotter O, Schaller HE, Rahmanian-Schwarz A. [Abscess Formation after Puncture of a Thyroid Cyst - A Case Report.]. Zentralbl Chir. 2011.
  82. Kale SU, Kumar A, David VC. Thyroid abscess--an acute emergency. Eur Arch Otorhinolaryngol.2004;261(8):456-458.
  83. Jimenez-Heffernan JA, Perez F, Hornedo J, Perna C, Lapuente F. Massive thyroid tumoral embolism from a breast carcinoma presenting as acute thyroiditis. Arch Pathol Lab Med. 2004;128(7):804-806.
  84. Robillon JF, Sadoul JL, Guerin P, Iafrate-Lacoste C, Talbodec A, Santini J, Canivet B, Freychet P. Mycobacterium avium intracellulare suppurative thyroiditis in a patient with Hashimoto's thyroiditis. J Endocrinol Invest. 1994;17(2):133-134.
  85. Visser R, de Mast Q, Netea-Maier RT, van der Ven AJ. Hashimoto's thyroiditis presenting as acute painful thyroiditis and as a manifestation of an immune reconstitution inflammatory syndrome in a human immunodeficiency virus-seropositive patient. Thyroid. 2012;22(8):853-855.
  86. Kale SU, Kumar A, David VC. Thyroid abscess: an acute emergency. Eur Arch Otorhinolarngol.2004;261(8):456-481.
  87. Kalladi Puthanpurayil S, Francis GL, Kraft AO, Prasad U, Petersson RS. Papillary thyroid carcinoma presenting as acute suppurative thyroiditis: A case report and review of the literature. Int J Pediatr Otorhinolaryngol.2018;105:12-15.
  88. Nishihara E, Miyauchi A, Matsuzuka F, Sasaki I, Ohye H, Kubota S, Fukata S, Amino N, Kuma K. Acute suppurative thyroiditis after fine-needle aspiration causing thyrotoxicosis. Thyroid. 2005;15(10):1183-1187.
  89. Chen HW, Tseng FY, Su DH, Chang YL, Chang TC. Secondary infection and ischemic necrosis after fine needle aspiration for a painful papillary thyroid carcinoma: a case report. Acta Cytol. 2006;50(2):217-220.
  90. Puthanpurayil SK, Francis GL, Kraft AO, Prasad U, Petersson RS. Papillary thyroid carcinoma presenting as acute suppurative thyroiditis: A case report and review of the literature. International Journal of Pediatric Otorhinolaryngology. 2018;105:12-15.
  91. George MM, Goswamy J, Penney SE. Embolic suppurative thyroiditis with concurrent carcinoma in pregnancy: lessons in management through a case report. Thyroid Research. 2015;8.
  92. Sicilia V, Mezitis S. A case of acute suppurative thyroiditis complicated by thyrotoxicosis. J Endocrinol Invest.2006;29(11):997-1000.
  93. Falhammar H, Wallin G, Calissendorff J. Acute suppurative thyroiditis with thyroid abscess in adults: clinical presentation, treatment and outcomes. BMC Endocr Disord. 2019;19(1):130.
  94. Takai SI, Miyauchi A, Matsuzuka F, Kuma K, Kosaki G. Internal fistula as a route of infection in acute suppurative thyroiditis. Lancet. 1979;1(8119):751-752.
  95. Yamashita J, Ogawa M, Yamashita S, Saishoji T, Nomura K, Tsuruta J. Acute suppurative thyroiditis in an asymptomatic woman: an atypical presentation simulating thyroid carcinoma. Clin Endocrinol (Oxf).1994;40(1):145-149; discussion 149-150.
  96. Miyauchi A, Matsuzuka F, Takai S, Kuma K, Kosaki G. Piriform sinus fistula. A route of infection in acute suppurative thyroiditis. Arch Surg. 1981;116(1):66-69.
  97. Nonomura N, Ikarashi F, Fujisaki T, Nakano Y. Surgical approach to pyriform sinus fistula. Am J Otolaryngol.1993;14(2):111-115.
  98. Himi T, Kataura A. Distribution of C cells in the thyroid gland with pyriform sinus fistula. Otolaryngol Head Neck Surg. 1995;112(2):268-273.
  99. Bar-Ziv J, Slasky BS, Sichel JY, Lieberman A, Katz R. Branchial pouch sinus tract from the piriform fossa causing acute suppurative thyroiditis, neck abscess, or both: CT appearance and the use of air as a contrast agent. AJR Am J Roentgenol. 1996;167(6):1569-1572.
  100. Gaafar H, El-Garem F. Acute thyroiditis with gas formation. J Laryngol Otol. 1975;89(3):323-327.
  101. Bussman YC, Wong ML, Bell MJ, Santiago JV. Suppurative thyroiditis with gas formation due to mixed anaerobic infection. J Pediatr. 1977;90(2):321-322.
  102. Reksoprawiro S. Suppurative thyroiditis with gas formation. Asian J Surg. 2003;26(3):180-182.
  103. Al-Kordi RS, Alenizi E, Elgazzar AH. Acute suppurative thyroiditis with abscess, gas formation, and thyrotoxic crisis. Nuklearmedizin. 2008;47(4):N44-46.
  104. Lemariey, Hamelin, Muler. [Acute thyroiditis complicating mediastinitis]. Ann Otolaryngol. 1955;72(7):571-573.
  105. Dordain ML, Coutant G, Algayres JP, Jancovici R, Pats B, Daly JP. [Suppurative mediastinitis secondary to acute thyroiditis in a patient under corticotherapy]. Presse Med. 1997;26(7):319-320.
  106. Pereira O, Prasad DS, Bal AM, McAteer D, Abraham P. Fatal descending necrotizing mediastinitis secondary to acute suppurative thyroiditis developing in an apparently healthy woman. Thyroid. 2010;20(5):571-572.
  107. Yung BC, Loke TK, Fan WC, Chan JC. Acute suppurative thyroiditis due to foreign body-induced retropharyngeal abscess presented as thyrotoxicosis. Clin Nucl Med. 2000;25(4):249-252.
  108. Wu C, Zhang Y, Gong Y, Hou Y, Li S, Zou Y, Ge J. Two cases of bacterial suppurative thyroiditis caused by Streptococcus anginosus. Endocr Pathol. 2013;24(1):49-53.
  109. Miyauchi A, Inoue H, Tomoda C, Amino N. Evaluation of chemocauterization treatment for obliteration of pyriform sinus fistula as a route of infection causing acute suppurative thyroiditis. Thyroid. 2009;19(7):789-793.
  110. Nishihara E, Ohye H, Amino N, Takata K, Arishima T, Kudo T, Ito M, Kubota S, Fukata S, Miyauchi A. Clinical characteristics of 852 patients with subacute thyroiditis before treatment. Intern Med. 2008;47(8):725-729.
  111. Hong JT, Lee JH, Kim SH, Hong SB, Nam M, Kim YS, Chu YC. Case of concurrent Riedel's thyroiditis, acute suppurative thyroiditis, and micropapillary carcinoma. Korean J Intern Med. 2013;28(2):236-241.
  112. Akdemir Z, Karaman E, Akdeniz H, Alptekin C, Arslan H. Giant Thyroid Abscess Related to Postpartum Brucella Infection. Case Reports in Infectious Diseases. 2015.
  113. Campos R, Perez B, Armengod L, Munez E, Ramos A. Lactococcus lactis thyroid abscess in an immunocompetent patient. Endocrinologia y Nutricion. 2015;62(4):204-206.
  114. Mohi GK, Datta P, Chander J, Das A. Citrobacter freundii as a cause of acute suppurative thyroiditis in an immunocompetent adult female. Indian Journal of Pathology and Microbiology. 2017;60(2):282-284.
  115. Miyauchi A. Thyroid gland: A new management algorithm for acute suppurative thyroiditis? Nat Rev Endocrinol.2010;6(8):424-426.
  116. Kim S, Park TS, Baek HS, Jin HY. Subacute painful thyroiditis accompanied by scrub typhus infection. Endocrine. 2013;44(2):546-548.
  117. Masuoka H, Miyauchi A, Tomoda C, Inoue H, Takamura Y, Ito Y, Kobayashi K, Miya A. Imaging studies in sixty patients with acute suppurative thyroiditis. Thyroid. 2011;21(10):1075-1080.
  118. Ruchala M, Szczepanek-Parulska E, Zybek A, Moczko J, Czarnywojtek A, Kaminski G, Sowinski J. The role of sonoelastography in acute, subacute and chronic thyroiditis - a novel application of the method. Eur J Endocrinol. 2011.
  119. Bernard PJ, Som PM, Urken ML, Lawson W, Biller HF. The CT findings of acute thyroiditis and acute suppurative thyroiditis. Otolaryngol Head Neck Surg. 1988;99(5):489-493.
  120. Yung G, Kannangara K, Bui C, Mansberg R, Champion B. Riedel thyroiditis demonstrated on gallium scintigraphy. Clin Nucl Med. 2010;35(8):614-617.
  121. Park NH, Park HJ, Park CS, Kim MS, Park SI. The emerging echogenic tract sign of pyriform sinus fistula: an early indicator in the recovery stage of acute suppurative thyroiditis. AJNR Am J Neuroradiol. 2011;32(3):E44-46.
  122. Miyauchi A, Tomoda C, Uruno T, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Fukata S, Amino N, Kuma K. Computed tomography scan under a trumpet maneuver to demonstrate piriform sinus fistulae in patients with acute suppurative thyroiditis. Thyroid. 2005;15(12):1409-1413.
  123. Ukiyama E, Endo M, Yoshida F, Watanabe T. Light guided procedure for congenital pyriform sinus fistula; new and simple procedure for impalpable fistula. Pediatr Surg Int. 2007;23(12):1241-1243.
  124. Kim KH, Sung MW, Koh TY, Oh SH, Kim IS. Pyriform sinus fistula: management with chemocauterization of the internal opening. Ann Otol Rhinol Laryngol. 2000;109(5):452-456.
  125. Smith SL, Pereira KD. Suppurative thyroiditis in children: a management algorithm. Pediatr Emerg Care.2008;24(11):764-767.
  126. Pereira KD, Smith SL. Endoscopic chemical cautery of piriform sinus tracts: a safe new technique. Int J Pediatr Otorhinolaryngol. 2008;72(2):185-188.
  127. Jordan JA, Graves JE, Manning SC, McClay JE, Biavati MJ. Endoscopic cauterization for treatment of fourth branchial cleft sinuses. Arch Otolaryngol Head Neck Surg. 1998;124(9):1021-1024.
  128. Rauhofer U, Prager G, Hormann M, Auer H, Kaserer K, Niederle B. Cystic echinococcosis of the thyroid gland in children and adults. Thyroid. 2003;13(5):497-502.
  129. Mordes DA, Brachtel EF. Cytopathology of subacute thyroiditis. Diagn Cytopathol. 2011.
  130. Adler ME, Jordan G, Walter RM, Jr. Acute suppurative thyroiditis: diagnostic, metabolic and therapeutic observations. West J Med. 1978;128(2):165-168.
  131. Schweitzer VG, Olson NR. Thyroid abscess. Otolaryngol Head Neck Surg. 1981;89(2):226-229.
  132. Nicole S, Lanzafame M, Cazzadori A, Vincenzi M, Mangani F, Colato C, El Dalati G, Brazzarola P, Concia E. Successful Antifungal Combination Therapy and Surgical Approach for Aspergillus fumigatus Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports. Mycopathologia. 2017;182(9-10):839-845.
  133. Pereira KD, Losh GG, Oliver D, Poole MD. Management of anomalies of the third and fourth branchial pouches. Int J Pediatr Otorhinolaryngol. 2004;68(1):43-50.
  134. Nicoucar K, Giger R, Jaecklin T, Pope HG, Jr., Dulguerov P. Management of congenital third branchial arch anomalies: a systematic review. Otolaryngol Head Neck Surg. 2010;142(1):21-28 e22.
  135. Kruijff S, Sywak MS, Sidhu SB, Shun A, Novakovic D, Lee JC, Delbridge LW. Thyroidal abscesses in third and fourth branchial anomalies: not only a paediatric diagnosis. ANZ J Surg. 2014.
  136. Kamide D, Tomifuji M, Maeda M, Utsunomiya K, Yamashita T, Araki K, Shiotani A. Minimally invasive surgery for pyriform sinus fistula by transoral videolaryngoscopic surgery. Am J Otolaryngol. 2015;36(4):601-605.
  137. Xiao X, Zheng S, Zheng J, Zhu L, Dong K, Shen C, Li K. Endoscopic-assisted surgery for pyriform sinus fistula in children: experience of 165 cases from a single institution. J Pediatr Surg. 2014;49(4):618-621.
  138. Yang H, Li, Ye X, Cheng J, Jia Z, Huang X, Wang X, Xu Y. Aspiration with or without lavage in the treatment of acute suppurative thyroiditis secondary to pyriform sinus fistula. Arch Endocrinol Metab. 2020;64(2):128-137.
  139. Volpe R. The management of subacute (DeQuervain's) thyroiditis. Thyroid. 1993;3(3):253-255.
  140. Ogawa E, Katsushima Y, Fujiwara I, Iinuma K. Subacute thyroiditis in children: patient report and review of the literature. J Pediatr Endocrinol Metab. 2003;16(6):897-900.
  141. Tamai H, Nozaki T, Mukuta T, Morita T, Matsubayashi S, Kuma K, Kumagai LF, Nagataki S. The incidence of thyroid stimulating blocking antibodies during the hypothyroid phase in patients with subacute thyroiditis. J Clin Endocrinol Metab. 1991;73(2):245-250.
  142. Galluzzo A, Giordano C, Andronico F, Filardo C, Andronico G, Bompiani G. Leukocyte migration test in subacute thyroiditis: hypothetical role of cell-mediated immunity. J Clin Endocrinol Metab. 1980;50(6):1038-1041.
  143. Parmar RC, Bavdekar SB, Sahu DR, Warke S, Kamat JR. Thyroiditis as a presenting feature of mumps. Pediatr Infect Dis J. 2001;20(6):637-638.
  144. Dimos G, Pappas G, Akritidis N. Subacute thyroiditis in the course of novel H1N1 influenza infection. Endocrine.2010;37(3):440-441.
  145. Volta C, Carano N, Street ME, Bernasconi S. Atypical subacute thyroiditis caused by Epstein-Barr virus infection in a three-year-old girl. Thyroid. 2005;15(10):1189-1191.
  146. Bouillet B, Petit JM, Piroth L, Duong M, Bourg JB. A case of subacute thyroiditis associated with primary HIV infection. Am J Med. 2009;122(4):e5-6.
  147. Satoh M. Virus-like particles in the follicular epithelium of the thyroid from a patient with subacute thyroiditis (deQuervain's). Acta Pathol Jpn. 1975;25:499-501.
  148. Engkakul P, Mahachoklertwattana P, Poomthavorn P. de Quervain thyroiditis in a young boy following hand-foot-mouth disease. Eur J Pediatr. 2011;170(4):527-529.
  149. Andre R, Opris A, Costantino F, Hayem G, Breban M. Cytomegalovirus subacute thyroiditis in a patient treated by infliximab for psoriatic arthritis. Joint Bone Spine. 2016;83(1):109-110.
  150. Martinez-Artola Y, Poncino D, Garcia ML, Munne MS, Gonzalez J, Garcia DS. Acute hepatitis E virus infection and association with a subacute thyroiditis. Annals of Hepatology. 2015;14(1):141-142.
  151. Mo ZM, Dong YX, Chen XL, Yao HY, Zhang B. Acute transverse myelitis and subacute thyroiditis associated with dengue viral infection: A case report and literature review. Experimental and Therapeutic Medicine.2016;12(4):2331-2335.
  152. Mangaraj S. Subacute thyroiditis complicating dengue fever - Case report and brief review of literature. Trop Doct. 2021;51(2):254-256.
  153. Sheraz F, Tahir H, Saqi J, Daruwalla V. Dengue Fever Presenting Atypically with Viral Conjunctivitis and Subacute Thyroiditis. J Coll Physicians Surg Pak. 2016;26(6 Suppl):S33-34.
  154. Assir MZ, Jawa A, Ahmed HI. Expanded dengue syndrome: subacute thyroiditis and intracerebral hemorrhage. BMC Infect Dis. 2012;12:240.
  155. Brancatella A, Ricci D, Viola N, Sgro D, Santini F, Latrofa F. Subacute Thyroiditis After Sars-COV-2 Infection. J Clin Endocrinol Metab. 2020;105(7).
  156. Luotola K, Hyoty H, Salmi J, Miettinen A, Helin H, Pasternack A. Evaluation of infectious etiology in subacute thyroiditis--lack of association with coxsackievirus infection. APMIS. 1998;106(4):500-504.
  157. Mori K, Yoshida K, Funato T, Ishii T, Nomura T, Fukuzawa H, Sayama N, Hori H, Ito S, Sasaki T. Failure in detection of Epstein-Barr virus and cytomegalovirus in specimen obtained by fine needle aspiration biopsy of thyroid in patients with subacute thyroiditis. Tohoku J Exp Med. 1998;186(1):13-17.
  158. Espino Montoro A, Medina Perez M, Gonzalez Martin MC, Asencio Marchante R, Lopez Chozas JM. [Subacute thyroiditis associated with positive antibodies to the Epstein-Barr virus]. An Med Interna. 2000;17(10):546-548.
  159. Al Maawali A, Al Yaarubi S, Al Futaisi A. An infant with cytomegalovirus-induced subacute thyroiditis. J Pediatr Endocrinol Metab. 2008;21(2):191-193.
  160. Desailloud R, Hober D. Viruses and thyroiditis: an update. Virol J. 2009;6:5.
  161. Buc M, Nyulassy S, Hnilica P, Stefanovic J. HLA-BW35 and subacute de Quervain's thyroiditis [proceedings]. Diabete Metab. 1976;2(3):163.
  162. Hamaguchi E, Nishimura Y, Kaneko S, Takamura T. Subacute thyroiditis developed in identical twins two years apart. Endocr J. 2005;52(5):559-562.
  163. Kabalak T, Ozgen AG. Familial occurrence of subacute thyroiditis. Endocr J. 2002;49(2):207-209.
  164. Zein EF, Karaa SE, Megarbane A. Familial occurrence of painful subacute thyroiditis associated with human leukocyte antigen-B35. Presse Med. 2007;36(5 Pt 1):808-809.
  165. Kramer AB, Roozendaal C, Dullaart RP. Familial occurrence of subacute thyroiditis associated with human leukocyte antigen-B35. Thyroid. 2004;14(7):544-547.
  166. Stasiak M, Tymoniuk B, Stasiak B, Lewinski A. The Risk of Recurrence of Subacute Thyroiditis Is HLA-Dependent. Int J Mol Sci. 2019;20(5).
  167. Kalmus Y, Kovatz S, Shilo L, Ganem G, Shenkman L. Sweet's syndrome and subacute thyroiditis. Postgrad Med J. 2000;76(894):229-230.
  168. Richard J, Lazarte S, Calame A, Lingvay I. Sweet's syndrome and subacute thyroiditis: an unrecognized association? Thyroid. 2010;20(12):1425-1426.
  169. Vassilopoulou-Sellin R, Sella A, Dexeus FH, Theriault RL, Pololoff DA. Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. Horm Metab Res. 1992;24(9):434-438.
  170. Amenomori M, Mori T, Fukuda Y, Sugawa H, Nishida N, Furukawa M, Kita R, Sando T, Komeda T, Nakao K. Incidence and characteristics of thyroid dysfunction following interferon therapy in patients with chronic hepatitis C. Intern Med. 1998;37(3):246-252.
  171. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-580.
  172. Gonzalez-Rodriguez E, Rodriguez-Abreu D, Spanish Group for Cancer I-B. Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events. Oncologist. 2016;21(7):804-816.
  173. de Filette J, Jansen Y, Schreuer M, Everaert H, Velkeniers B, Neyns B, Bravenboer B. Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab. J Clin Endocrinol Metab.2016;101(11):4431-4439.
  174. Lee H, Hodi FS, Giobbie-Hurder A, Ott PA, Buchbinder EI, Haq R, Tolaney S, Barroso-Sousa R, Zhang K, Donahue H, Davis M, Gargano ME, Kelley KM, Carroll RS, Kaiser UB, Min L. Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy. Cancer Immunol Res. 2017;5(12):1133-1140.
  175. Delivanis DA, Gustafson MP, Bornschlegl S, Merten MM, Kottschade L, Withers S, Dietz AB, Ryder M. Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms. J Clin Endocrinol Metab. 2017;102(8):2770-2780.
  176. Muir CA, Menzies AM, Clifton-Bligh R, Tsang VHM. Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer. Thyroid. 2020;30(10):1458-1469.
  177. Neppl C, Kaderli RM, Trepp R, Schmitt AM, Berger MD, Wehrli M, Seiler CA, Langer R. Histology of Nivolumab-Induced Thyroiditis. Thyroid. 2018;28(12):1727-1728.
  178. Muir CA, Clifton-Bligh RJ, Long GV, Scolyer RA, Lo SN, Carlino MS, Tsang VHM, Menzies AM. Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment. J Clin Endocrinol Metab.2021;106(9):e3704-e3713.
  179. Stelmachowska-Banas M, Czajka I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr Connect. 2020;9(10):R207-R228.
  180. Deligiorgi MV, Panayiotidis MI, Trafalis DT. Endocrine adverse events related with immune checkpoint inhibitors: an update for clinicians. Immunotherapy. 2020;12(7):481-510.
  181. Hernan Martinez J, Corder E, Uzcategui M, Garcia M, Sostre S, Garcia A. Subacute thyroiditis and dyserythropoesis after influenza vaccination suggesting immune dysregulation. Bol Asoc Med P R.2011;103(2):48-52.
  182. Hsiao JY, Hsin SC, Hsieh MC, Hsia PJ, Shin SJ. Subacute thyroiditis following influenza vaccine (Vaxigrip) in a young female. Kaohsiung J Med Sci. 2006;22(6):297-300.
  183. Momani MS, Zayed AA, Bakri FG. Subacute thyroiditis following influenza vaccine: a case report and literature review. Italian Journal of Medicine. 2015;9(4):384-386.
  184. Shen L, Bui C, Mansberg R, Nguyen D, Alam-Fotias S. Thyroid dysfunction during interferon alpha therapy for chronic hepatitis C. Clin Nucl Med. 2005;30(8):546-547.
  185. Kryczka W, Brojer E, Kowalska A, Zarebska-Michaluk D. Thyroid gland dysfunctions during antiviral therapy of chronic hepatitis C. Med Sci Monit. 2001;7 Suppl 1:221-225.
  186. Parana R, Cruz M, Lyra L, Cruz T. Subacute thyroiditis during treatment with combination therapy (interferon plus ribavirin) for hepatitis C virus. J Viral Hepat. 2000;7(5):393-395.
  187. Omur O, Daglyoz G, Akarca U, Ozcan Z. Subacute thyroiditis during interferon therapy for chronic hepatitis B infection. Clin Nucl Med. 2003;28(10):864-865.
  188. Moser C, Furrer J, Ruggieri F. [Neck pain and fever after peginterferon alpha-2a]. Praxis (Bern 1994).2007;96(6):205-207.
  189. Ohta Y, Ohya Y, Fujii K, Tsuchihashi T, Sato K, Abe I, Iida M. Inflammatory diseases associated with Takayasu's arteritis. Angiology. 2003;54(3):339-344.
  190. Obuobie K, Al-Sabah A, Lazarus JH. Subacute thyroiditis in an immunosuppressed patient. J Endocrinol Invest.2002;25(2):169-171.
  191. Ozdogu H, Boga C, Bolat F, Ertorer ME. Wegener's granulomatosis with a possible thyroidal involvement. J Natl Med Assoc. 2006;98(6):956-958.
  192. Daniels GH, Vladic A, Brinar V, Zavalishin I, Valente W, Oyuela P, Palmer J, Margolin DH, Hollenstein J. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab. 2014;99(1):80-89.
  193. Kawashima J, Naoe H, Sasaki Y, Araki E. A rare case showing subacute thyroiditis-like symptoms with amyloid goiter after anti-tumor necrosis factor therapy. Endocrinology Diabetes and Metabolism Case Reports. 2015.
  194. Senlis M, Ottaviani S, Gardette A, Palazzo E, Coustet B, Dieude P. Subacute thyroiditis in psoriatic arthritis treated by adalimumab. Joint Bone Spine. 2017;84(6):745-746.
  195. Vazquez Friol MDC, Bravo Blazquez I, Tejera Perez C. Subacute thyroiditis by dasatinib. Med Clin (Barc).2020;155(6):270-271.
  196. Algun E, Alici S, Topal C, Ugras S, Erkoc R, Sakarya ME, Ozbey N. Coexistence of subacute thyroiditis and renal cell carcinoma: a paraneoplastic syndrome. CMAJ. 2003;168(8):985-986.
  197. Calvi L, Daniels GH. Acute thyrotoxicosis secondary to destructive thyroiditis associated with cardiac catheterization contrast dye. Thyroid. 2011;21(4):443-449.
  198. Carneiro JR, Macedo RG, Da Silveira VG. Thyrotoxicosis after gastric bypass. Obes Surg. 2004;14(5):699-701.
  199. Sanavi S, Afshar R. Subacute thyroiditis following ginger (Zingiber officinale) consumption. Int J Ayurveda Res.2010;1(1):47-48.
  200. Ippolito S, Dentali F, Tanda ML. SARS-CoV-2: a potential trigger for subacute thyroiditis? Insights from a case report. J Endocrinol Invest. 2020;43(8):1171-1172.
  201. Asfuroglu Kalkan E, Ates I. A case of subacute thyroiditis associated with Covid-19 infection. J Endocrinol Invest. 2020;43(8):1173-1174.
  202. Ruggeri RM, Campenni A, Siracusa M, Frazzetto G, Gullo D. Subacute thyroiditis in a patient infected with SARS-COV-2: an endocrine complication linked to the COVID-19 pandemic. Hormones (Athens).2021;20(1):219-221.
  203. Rotondi M, Coperchini F, Ricci G, Denegri M, Croce L, Ngnitejeu ST, Villani L, Magri F, Latrofa F, Chiovato L. Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis. J Endocrinol Invest. 2021;44(5):1085-1090.
  204. Ma D, Chen CB, Jhanji V, Xu C, Yuan XL, Liang JJ, Huang Y, Cen LP, Ng TK. Expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in human primary conjunctival and pterygium cell lines and in mouse cornea. Eye (Lond). 2020;34(7):1212-1219.
  205. Iremli BG, Sendur SN, Unluturk U. Three Cases of Subacute Thyroiditis Following SARS-CoV-2 Vaccine: Postvaccination ASIA Syndrome. J Clin Endocrinol Metab. 2021;106(9):2600-2605.
  206. Synoracki S, Ting S, Schmid KW. [Inflammatory diseases of the thyroid gland]. Pathologe. 2016;37(3):215-223.
  207. Harach HR, Williams ED. The pathology of granulomatous diseases of the thyroid gland. Sarcoidosis.1990;7(1):19-27.
  208. Chang TC, Lai SM, Wen CY, Hsiao YL. Three-dimensional cytomorphology in fine needle aspiration biopsy of subacute thyroiditis. Acta Cytol. 2004;48(2):155-160.
  209. Toda S, Tokuda Y, Koike N, Yonemitsu N, Watanabe K, Koike K, Fujitani N, Hiromatsu Y, Sugihara H. Growth factor-expressing mast cells accumulate at the thyroid tissue-regenerative site of subacute thyroiditis. Thyroid.2000;10(5):381-386.
  210. Woolner LB, Mc CW, Beahrs OH. Granulomatous thyroiditis (De Quervain's thyroiditis). J Clin Endocrinol Metab. 1957;17(10):1202-1221.
  211. Koga M, Hiromatsu Y, Jimi A, Toda S, Koike N, Nonaka K. Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis. J Clin Endocrinol Metab.1999;84(6):2221-2225.
  212. Toda S, Nishimura T, Yamada S, Koike N, Yonemitsu N, Watanabe K, Matsumura S, Gartner R, Sugihara H. Immunohistochemical expression of growth factors in subacute thyroiditis and their effects on thyroid folliculogenesis and angiogenesis in collagen gel matrix culture. J Pathol. 1999;188(4):415-422.
  213. Luotola K, Mantula P, Salmi J, Haapala AM, Laippala P, Hurme M. Allele 2 of interleukin-1 receptor antagonist gene increases the risk of thyroid peroxidase antibodies in subacute thyroiditis. APMIS. 2001;109(6):454-460.
  214. Chen K, Wei Y, Sharp GC, Braley-Mullen H. Decreasing TNF-alpha results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis. J Leukoc Biol. 2007;81(1):306-314.
  215. Fang Y, Sharp GC, Yagita H, Braley-Mullen H. A critical role for TRAIL in resolution of granulomatous experimental autoimmune thyroiditis. J Pathol. 2008;216(4):505-513.
  216. Greene JN. Subacute thyroiditis. Am J Med. 1971;51(1):97-108.
  217. Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab.2009;94(6):1853-1878.
  218. Carle A, Laurberg P, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Jorgensen T. Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol. 2006;154(1):21-28.
  219. Fatourechi V, Aniszewski JP, Fatourechi GZ, Atkinson EJ, Jacobsen SJ. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab.2003;88(5):2100-2105.
  220. Qari FA, Maimani AA. Subacute thyroiditis in Western Saudi Arabia. Saudi Med J. 2005;26(4):630-633.
  221. Anastasilakis AD, Karanicola V, Kourtis A, Makras P, Kampas L, Gerou S, Giomisi A. A case report of subacute thyroiditis during pregnancy: difficulties in differential diagnosis and changes in cytokine levels. Gynecol Endocrinol. 2011;27(6):384-390.
  222. Hiraiwa T, Kubota S, Imagawa A, Sasaki I, Ito M, Miyauchi A, Hanafusa T. Two cases of subacute thyroiditis presenting in pregnancy. J Endocrinol Invest. 2006;29(10):924-927.
  223. Daniels GH. Atypical subacute thyroiditis: preliminary observations. Thyroid. 2001;11(7):691-695.
  224. Dedivitis RA, Coelho LS. Vocal fold paralysis in subacute thyroiditis. Braz J Otorhinolaryngol. 2007;73(1):138.
  225. Nakamura S, Saio Y, Ishimori M. Recurrent hemithyroiditis: a case report. Endocr J. 1998;45(4):595-600.
  226. Sari O, Erbas B, Erbas T. Subacute thyroiditis in a single lobe. Clin Nucl Med. 2001;26(5):400-401.
  227. Alper AT, Hasdemir H, Akyol A, Cakmak N. Incessant ventricular tachycardia due to subacute thyroiditis. Int J Cardiol. 2007;116(1):e22-24.
  228. Sherman SI, Simonson L, Ladenson PW. Clinical and socioeconomic predispositions to complicated thyrotoxicosis: a predictable and preventable syndrome? Am J Med. 1996;101(2):192-198.
  229. Swinburne JL, Kreisman SH. A rare case of subacute thyroiditis causing thyroid storm. Thyroid. 2007;17(1):73-76.
  230. Kim HJ, Jung TS, Hahm JR, Hwang SJ, Lee SM, Jung JH, Kim SK, Chung SI. Thyrotoxicosis-induced acute myocardial infarction due to painless thyroiditis. Thyroid. 2011;21(10):1149-1151.
  231. Mizokami T, Okamura K, Sato K, Hirata T, Yamasaki K, Fujishima M. Localized painful giant-cell thyroiditis without inflammatory signs in a euthyroid patient followed by serial sonography. J Clin Ultrasound.1998;26(6):329-332.
  232. Muqtadir F, Ahmed A, Gufran K, Bin Hamza MO. CASE OF SUBACUTE THYROIDITIS PRESENTING AS THE CAUSE OF PYREXIA OF UNKNOWN ORIGIN. Journal of Evolution of Medical and Dental Sciences-Jemds.2015;4(88):15373-15375.
  233. Popovska-Jovicic B, Canovic P, Gajovic O, Rakovic I, Mijailovic Z. Fever of unknown origin: Most frequent causes in adults patients. Vojnosanitetski Pregled. 2016;73(1):21-25.
  234. Cunha BA, Chak A, Strollo S. Fever of unknown origin (FUO): de Quervain's subacute thyroiditis with highly elevated ferritin levels mimicking temporal arteritis (TA). Heart Lung. 2010;39(1):73-77.
  235. Benbassat CA, Olchovsky D, Tsvetov G, Shimon I. Subacute thyroiditis: clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005. J Endocrinol Invest.2007;30(8):631-635.
  236. Matsumoto Y, Amino N, Kubota S, Ikeda N, Morita S, Nishihara E, Ohye H, Kudo T, Ito M, Fukata S, Miyauchi A. Serial changes in liver function tests in patients with subacute thyroiditis. Thyroid. 2008;18(7):815-816.
  237. Fragu P, Rougier P, Schlumberger M, Tubiana M. Evolution of thyroid 127I stores measured by X-ray fluorescence in subacute thyroiditis. J Clin Endocrinol Metab. 1982;54(1):162-166.
  238. Gordin A, Lamberg BA. Serum thyrotrophin response to thyrotrophin releasing hormone and the concentration of free thyroxine in subacute thyroiditis. Acta Endocrinol (Copenh). 1973;74(1):111-121.
  239. Intenzo CM, Park CH, Kim SM, Capuzzi DM, Cohen SN, Green P. Clinical, laboratory, and scintigraphic manifestations of subacute and chronic thyroiditis. Clin Nucl Med. 1993;18(4):302-306.
  240. Rapoport B, Block MB, Hoffer PB, DeGroot LJ. Depletion of thyroid iodine during subacute thyroiditis. J Clin Endocrinol Metab. 1973;36(3):610-611.
  241. Savoie JC, Massin JP, Thomopoulos P, Leger F. Iodine-induced thyrotoxicosis in apparently normal thyroid glands. J Clin Endocrinol Metab. 1975;41(4):685-691.
  242. Woolf PD. Transient painless thyroiditis with hyperthyroidism: a variant of lymphocytic thyroiditis? Endocr Rev.1980;1(4):411-420.
  243. Pearce EN, Bogazzi F, Martino E, Brogioni S, Pardini E, Pellegrini G, Parkes AB, Lazarus JH, Pinchera A, Braverman LE. The prevalence of elevated serum C-reactive protein levels in inflammatory and noninflammatory thyroid disease. Thyroid. 2003;13(7):643-648.
  244. Rao NL, Shetty S, Upadhyaya K, R MP, Lobo EC, Kedilaya HP, Prasad G. Salivary C-Reactive Protein in Hashimoto's Thyroiditis and Subacute Thyroiditis. Int J Inflam. 2010;2010:514659.
  245. Fujii S, Miwa U, Seta T, Ohoka T, Mizukami Y. Subacute thyroiditis with highly positive thyrotropin receptor antibodies and high thyroidal radioactive iodine uptake. Intern Med. 2003;42(8):704-709.
  246. Iitaka M, Momotani N, Hisaoka T, Noh JY, Ishikawa N, Ishii J, Katayama S, Ito K. TSH receptor antibody-associated thyroid dysfunction following subacute thyroiditis. Clin Endocrinol (Oxf). 1998;48(4):445-453.
  247. Kamijo K. TSH-receptor antibody measurement in patients with various thyrotoxicosis and Hashimoto's thyroiditis: a comparison of two two-step assays, coated plate ELISA using porcine TSH-receptor and coated tube radioassay using human recombinant TSH-receptor. Endocr J. 2003;50(1):113-116.
  248. Takasu N, Kamijo K, Sato Y, Yoshimura H, Nagata A, Ochi Y. Sensitive thyroid-stimulating antibody assay with high concentrations of polyethylene glycol for the diagnosis of Graves' disease. Clin Exp Pharmacol Physiol.2004;31(5-6):314-319.
  249. Fang F, Yan S, Zhao L, Jin YB, Wang YF. Concurrent Onset of Subacute Thyroiditis and Graves' Disease. American Journal of the Medical Sciences. 2016;352(2):224-226.
  250. Hiromatsu Y, Ishibashi M, Miyake I, Nonaka K. Technetium-99m tetrofosmin imaging in patients with subacute thyroiditis. Eur J Nucl Med. 1998;25(10):1448-1452.
  251. Hiromatsu Y, Ishibashi M, Nishida H, Kawamura S, Kaku H, Baba K, Kaida H, Miyake I. Technetium-99 m sestamibi imaging in patients with subacute thyroiditis. Endocr J. 2003;50(3):239-244.
  252. Alonso O, Mut F, Lago G, Aznarez A, Nunez M, Canepa J, Touya E. 99Tc(m)-MIBI scanning of the thyroid gland in patients with markedly decreased pertechnetate uptake. Nucl Med Commun. 1998;19(3):257-261.
  253. Janssen OE. [Atypical presentation of subacute thyroiditis]. Dtsch Med Wochenschr. 2011;136(11):519-522.
  254. Song YS, Jang SJ, Chung JK, Lee DS. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and Tc-99m pertechnate scan findings of a patient with unilateral subacute thyroiditis. Clin Nucl Med.2009;34(7):456-458.
  255. Kunz A, Blank W, Braun B. De Quervain's subacute thyroiditis -- colour Doppler sonography findings. Ultraschall Med. 2005;26(2):102-106.
  256. Park SY, Kim EK, Kim MJ, Kim BM, Oh KK, Hong SW, Park CS. Ultrasonographic characteristics of subacute granulomatous thyroiditis. Korean J Radiol. 2006;7(4):229-234.
  257. Omori N, Omori K, Takano K. Association of the ultrasonographic findings of subacute thyroiditis with thyroid pain and laboratory findings. Endocr J. 2008;55(3):583-588.
  258. Cappelli C, Pirola I, Gandossi E, Formenti AM, Agosti B, Castellano M. Ultrasound findings of subacute thyroiditis: a single institution retrospective review. Acta Radiol. 2014;55(4):429-433.
  259. Ohta T, Nishioka M, Nakata N, Fukuda K, Shirakawa T. Significance of perithyroidal lymph nodes in benign thyroid diseases. Journal of Medical Ultrasonics. 2018;45(1):81-87.
  260. Nishihara E, Hirokawa M, Ohye H, Ito M, Kubota S, Fukata S, Amino N, Miyauchi A. Papillary carcinoma obscured by complication with subacute thyroiditis: sequential ultrasonographic and histopathological findings in five cases. Thyroid. 2008;18(11):1221-1225.
  261. Tezuka M, Murata Y, Ishida R, Ohashi I, Hirata Y, Shibuya H. MR imaging of the thyroid: correlation between apparent diffusion coefficient and thyroid gland scintigraphy. J Magn Reson Imaging. 2003;17(2):163-169.
  262. Yeo SH, Lee SK, Hwang I, Ahn EJ. Subacute thyroiditis presenting as a focal lesion on [18F] fluorodeoxyglucose whole-body positron-emission tomography/CT. AJNR Am J Neuroradiol. 2011;32(4):E58-60.
  263. Kim MH, Kim DW, Park SA, Kim CG. Transiently Altered Distribution of F-18 FDG in a Patient with Subacute Thyroiditis. Nuclear Medicine and Molecular Imaging. 2018;52(1):82-84.
  264. Yoshida K, Yokoh H, Toriihara A, Fujii H, Harata N, Isogai J, Tateishi U. F-18-FDG PET/CT imaging of atypical subacute thyroiditis in thyrotoxicosis A case report. Medicine. 2017;96(30).
  265. Freesmeyer M, Opfermann T. Diagnosis of de quervain's subacute thyroiditis via sensor-navigated (124)Iodine PET/ultrasound (I-124-PET/US) fusion. Endocrine. 2015;49(1):293-295.
  266. Shabb NS, Salti I. Subacute thyroiditis: fine-needle aspiration cytology of 14 cases presenting with thyroid nodules. Diagn Cytopathol. 2006;34(1):18-23.
  267. Ito M, Takamatsu J, Yoshida S, Murakami Y, Sakane S, Kuma K, Ohsawa N. Incomplete thyrotroph suppression determined by third generation thyrotropin assay in subacute thyroiditis compared to silent thyroiditis or hyperthyroid Graves' disease. J Clin Endocrinol Metab. 1997;82(2):616-619.
  268. Vierhapper H, Bieglmayer C, Nowotny P, Waldhausl W. Normal serum concentrations of sex hormone binding-globulin in patients with hyperthyroidism due to subacute thyroiditis. Thyroid. 1998;8(12):1107-1111.
  269. Nakano Y, Kurihara H, Sasaki J. Graves' disease following subacute thyroiditis. Tohoku J Exp Med.2011;225(4):301-309.
  270. Hallengren B, Planck T, Asman P, Lantz M. Presence of Thyroid-Stimulating Hormone Receptor Antibodies in a Patient with Subacute Thyroiditis followed by Hypothyroidism and Later Graves' Disease with Ophthalmopathy: A Case Report. European Thyroid Journal. 2015;4(3):197-200.
  271. Tesfaye H, Cimermanova R, Cholt M, Sykorova P, Pechova M, Prusa R. Subacute thyroiditis confused with dental problem. Cas Lek Cesk. 2009;148(9):438-441.
  272. Meller J, Sahlmann CO, Scheel AK. 18F-FDG PET and PET/CT in fever of unknown origin. J Nucl Med.2007;48(1):35-45.
  273. Yasuda S, Shohtsu A, Ide M, Takagi S, Takahashi W, Suzuki Y, Horiuchi M. Chronic thyroiditis: diffuse uptake of FDG at PET. Radiology. 1998;207(3):775-778.
  274. Liel Y. The survivor: association of an autonomously functioning thyroid nodule and subacute thyroiditis. Thyroid. 2007;17(2):183-184.
  275. King DL, Stack BC, Jr., Spring PM, Walker R, Bodenner DL. Incidence of thyroid carcinoma in fluorodeoxyglucose positron emission tomography-positive thyroid incidentalomas. Otolaryngol Head Neck Surg. 2007;137(3):400-404.
  276. Van den Bruel A, Maes A, De Potter T, Mortelmans L, Drijkoningen M, Van Damme B, Delaere P, Bouillon R. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab. 2002;87(4):1517-1520.
  277. Zacharia TT, Perumpallichira JJ, Sindhwani V, Chavhan G. Gray-scale and color Doppler sonographic findings in a case of subacute granulomatous thyroiditis mimicking thyroid carcinoma. J Clin Ultrasound. 2002;30(7):442-444.
  278. Xie P, Xiao Y, Liu F. Real-time ultrasound elastography in the diagnosis and differential diagnosis of subacute thyroiditis. J Clin Ultrasound. 2011;39(8):435-440.
  279. Sato J, Uchida T, Komiya K, Goto H, Takeno K, Suzuki R, Honda A, Himuro M, Watada H. Comparison of the therapeutic effects of prednisolone and nonsteroidal anti-inflammatory drugs in patients with subacute thyroiditis. Endocrine. 2017;55(1):218-223.
  280. Kubota S, Nishihara E, Kudo T, Ito M, Amino N, Miyauchi A. Initial treatment with 15 mg of prednisolone daily is sufficient for most patients with subacute thyroiditis in Japan. Thyroid. 2013;23(3):269-272.
  281. Ma SG, Bai F, Cheng L. A novel treatment for subacute thyroiditis: administration of a mixture of lidocaine and dexamethasone using an insulin pen. Mayo Clin Proc. 2014;89(6):861-862.
  282. Mizukoshi T, Noguchi S, Murakami T, Futata T, Yamashita H. Evaluation of recurrence in 36 subacute thyroiditis patients managed with prednisolone. Intern Med. 2001;40(4):292-295.
  283. Sencar ME, Calapkulu M, Sakiz D, Hepsen S, Kus A, Akhanli P, Unsal IO, Kizilgul M, Ucan B, Ozbek M, Cakal E. An Evaluation of the Results of the Steroid and Non-steroidal Anti-inflammatory Drug Treatments in Subacute Thyroiditis in relation to Persistent Hypothyroidism and Recurrence. Sci Rep. 2019;9(1):16899.
  284. Duininck TM, van Heerden JA, Fatourechi V, Curlee KJ, Farley DR, Thompson GB, Grant CS, Lloyd RV. de Quervain's thyroiditis: surgical experience. Endocr Pract. 2002;8(4):255-258.
  285. Ranganath R, Shaha MA, Xu B, Migliacci J, Ghossein R, Shaha AR. de Quervain's thyroiditis: A review of experience with surgery. American Journal of Otolaryngology. 2016;37(6):534-537.
  286. Park HK, Kim DW, Lee YJ, Ha TK, Kim DH, Bae SK, Jung SJ. Suspicious Sonographic and Cytological Findings in Patients With Subacute Thyroiditis Two Case Reports. Diagnostic Cytopathology. 2015;43(5):399-402.
  287. Mazza E, Quaglino F, Suriani A, Palestini N, Gottero C, Leli R, Taraglio S. Thyroidectomy for Painful Thyroiditis Resistant to Steroid Treatment: Three New Cases with Review of the Literature. Case Reports in Endocrinology.2015.
  288. Zhao N, Wang S, Cui XJ, Huang MS, Wang SW, Li YG, Zhao L, Wan WN, Li YS, Shan ZY, Teng WP. Two-Years Prospective Follow-Up Study of Subacute Thyroiditis. Front Endocrinol (Lausanne). 2020;11:47.
  289. Iitaka M, Momotani N, Ishii J, Ito K. Incidence of subacute thyroiditis recurrences after a prolonged latency: 24-year survey. J Clin Endocrinol Metab. 1996;81(2):466-469.
  290. Saklamaz A. IS THERE A DRUG EFFECT ON THE DEVELOPMENT OF PERMANENT HYPOTHYROIDISM IN SUBACUTE THYROIDITIS? Acta Endocrinologica-Bucharest. 2017;13(1):119-123.
  291. Nishihara E, Amino N, Ohye H, Ota H, Ito M, Kubota S, Fukata S, Miyauchi A. Extent of hypoechogenic area in the thyroid is related with thyroid dysfunction after subacute thyroiditis. J Endocrinol Invest. 2009;32(1):33-36.
  292. Bogazzi F, Dell'Unto E, Tanda ML, Tomisti L, Cosci C, Aghini-Lombardi F, Sardella C, Pinchera A, Bartalena L, Martino E. Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis. J Endocrinol Invest. 2006;29(8):694-699.
  293. Izumi M, Larsen PR. Correlation of sequential changes in serum thyroglobulin, triiodothyronine, and thyroxine in patients with Graves' disease and subacute thyroiditis. Metabolism. 1978;27(4):449-460.
  294. Riedel BM. Die chronische zur Bildung eisenharter Tumoren fuehrende Entzuendung der Shilddruese. Verh Ges Chir. 1896;25:101-105.
  295. de Lange WE, Freling NJ, Molenaar WM, Doorenbos H. Invasive fibrous thyroiditis (Riedel's struma): a manifestation of multifocal fibrosclerosis? A case report with review of the literature. Q J Med. 1989;72(268):709-717.
  296. Zimmermann-Belsing T, Feldt-Rasmussen U. Riedel's thyroiditis: an autoimmune or primary fibrotic disease? J Intern Med. 1994;235(3):271-274.
  297. Goodman HI. Riedel's Thyroiditis: a review and report of two cases. American Journal of Surgery.1941;54(2):472-478.
  298. Riedel BM. Vorstellung eines Kranken mit chronischer Strumitis. Verh Ges Chir. 1896;26:127-129.
  299. Riedel BM. Ueber Verlauf und Ausgang der chronischer Strumitis. Munch Med Wochenschr. 1910;57:1946-1947.
  300. Hay ID. Thyroiditis: a clinical update. Mayo Clin Proc. 1985;60(12):836-843.
  301. Guimaraes VC. Subacute and Reidel's Thyroiditis. In: Jameson JL, De Groot LJ, eds. Endocrinology: Adult and Pediatric. Vol 2. 6th ed. Philadelphia: Elsevier; 2010:1600-1603.
  302. Zala A, Berhane T, Juhlin CC, Calissendorff J, Falhammar H. Riedel Thyroiditis. J Clin Endocrinol Metab.2020;105(9).
  303. Fatourechi MM, Hay ID, McIver B, Sebo TJ, Fatourechi V. Invasive fibrous thyroiditis (riedel thyroiditis): the mayo clinic experience, 1976-2008. Thyroid. 2011;21(7):765-772.
  304. Hennessey JV. Clinical review: Riedel's thyroiditis: a clinical review. J Clin Endocrinol Metab. 2011;96(10):3031-3041.
  305. Balach ZW, LiVolsi VA. Pathology. In: Braverman LE, Utiger RE, eds. Werner & Ingbar's The Thyroid; A Fundamental and Clinical Text. Ninth ed. Philadelphia: Lippincott Williams & Wilkins; 2005:427.
  306. Lee SL, Ananthakrishnan S. Infiltartive thyroid disease. In: Rose BD, Mulder JE, eds. UpToDate. Wellesley, MA: BDR, Inc.; 2011:1-21.
  307. Heufelder AE, Goellner JR, Bahn RS, Gleich GJ, Hay ID. Tissue eosinophilia and eosinophil degranulation in Riedel's invasive fibrous thyroiditis. J Clin Endocrinol Metab. 1996;81(3):977-984.
  308. Volpe R. Subacute and Sclerosing Thyroiditis. In: De Groot LJ, ed. Endocrinology. 3rd ed. Philadelphia: WB Saunders; 1995:742-751.
  309. Schwaegerle SM, Bauer TW, Esselstyn CB, Jr. Riedel's thyroiditis. Am J Clin Pathol. 1988;90(6):715-722.
  310. Beahrs OH, McConahey WM, Woolner LB. Invasive fibrous thyroiditis (Riedel's struma). J Clin Endocrinol Metab. 1957;17(2):201-220.
  311. Torres-Montaner A, Beltran M, Romero de la Osa A, Oliva H. Sarcoma of the thyroid region mimicking Riedel's thyroiditis. J Clin Pathol. 2001;54(7):570-572.
  312. Wan SK, Chan JK, Tang SK. Paucicellular variant of anaplastic thyroid carcinoma. A mimic of Reidel's thyroiditis. Am J Clin Pathol. 1996;105(4):388-393.
  313. Katsikas D, Shorthouse AJ, Taylor S. Riedel's thyroiditis. Br J Surg. 1976;63(12):929-931.
  314. LiVolsi VA, LoGerfo P, eds. Thyroiditis. Boca Raton: CRC Press; 1981.
  315. Cho MH, Kim CS, Park JS, Kang ES, Ahn CW, Cha BS, Lim SK, Kim KR, Lee HC. Riedel's thyroiditis in a patient with recurrent subacute thyroiditis: a case report and review of the literature. Endocr J. 2007;54(4):559-562.
  316. Pirola I, Morassi ML, Braga M, De Martino E, Gandossi E, Cappelli C. A Case of Concurrent Riedel's, Hashimoto's and Acute Suppurative Thyroiditis. Case Report Med. 2009;2009:535974.
  317. McIver B, Fatourechi MM, Hay ID, Fatourechi V. Graves' disease after unilateral Riedel's thyroiditis. J Clin Endocrinol Metab. 2010;95(6):2525-2526.
  318. Kojima M, Nakamura S, Yamane Y, Shimizu K, Sugiharal S, Masawa N. Riedel's thyroiditis containing cytologically atypically appearing B-cells: a case report. Pathol Res Pract. 2003;199(7):497-501.
  319. Chen K, Wei Y, Sharp GC, Braley-Mullen H. Characterization of thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis. J Leukoc Biol. 2000;68(6):828-835.
  320. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K. Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int. 2009;59(9):636-641.
  321. Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med. 2006;4:23.
  322. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken).2010;62(9):1312-1318.
  323. Yamamoto M, Takahashi H, Shinomura Y. [IgG4-related systemic disease/systemic IgG4-related disease]. Rinsho Byori. 2010;58(5):454-465.
  324. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas--an autonomous pancreatic disease? Am J Dig Dis. 1961;6:688-698.
  325. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med.2001;344(10):732-738.
  326. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21-30.
  327. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Sumida T, Mimori T, Tanaka Y, Tsubota K, Yoshino T, Kawa S, Suzuki R, Takegami T, Tomosugi N, Kurose N, Ishigaki Y, Azumi A, Kojima M, Nakamura S, Inoue D. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1-14.
  328. Palazzo E, Palazzo C, Palazzo M. IgG4-related disease. Joint Bone Spine. 2014;81(1):27-31.
  329. Dutta D, Ahuja A, Selvan C. Immunoglobulin G4 related thyroid disorders: Diagnostic challenges and clinical outcomes. Endokrynologia Polska. 2016;67(5):520-524.
  330. Stan MN, Sonawane V, Sebo TJ, Thapa P, Bahn RS. Riedel's thyroiditis association with IgG4-related disease. Clinical endocrinology. 2017;86(3):425-430.
  331. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Kloppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181-1192.
  332. Takeshima K, Inaba H, Ariyasu H, Furukawa Y, Doi A, Nishi M, Hirokawa M, Yoshida A, Imai R, Akamizu T. Clinicopathological features of Riedel's thyroiditis associated with IgG4-related disease in Japan. Endocr J.2015.
  333. Pusztaszeri M, Triponez F, Pache JC, Bongiovanni M. Riedel's thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4-related sclerosing disease? Thyroid. 2012;22(9):964-968.
  334. Soh SB, Pham A, O'Hehir RE, Cherk M, Topliss DJ. Novel use of rituximab in a case of Riedel's thyroiditis refractory to glucocorticoids and tamoxifen. J Clin Endocrinol Metab. 2013;98(9):3543-3549.
  335. Sakai Y, Imamura Y. Case report: IgG4-related mass-forming thyroiditis accompanied by regional lymphadenopathy. Diagnostic pathology. 2018;13(1):3.
  336. Oriot P, Amraoui A, Rousseau E, Malvaux P, Dechambre S, Delcourt A. Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up. Acta Clin Belg. 2014;69(6):446-450.
  337. Ghys C, Depierreux M, Ozalp E, Velkeniers B. Cervical lymph nodes, thyroiditis and ophthalmopathy: the pleomorphic face of an immunoglobulin g4-related disease. Eur Thyroid J. 2014;3(4):252-257.
  338. Falhammar H, Juhlin CC, Barner C, Catrina SB, Karefylakis C, Calissendorff J. Riedel's thyroiditis: clinical presentation, treatment and outcomes. Endocrine. 2018;60(1):185-192.
  339. Lu L, Gu F, Dai WX, Li WY, Chen J, Xiao Y, Zeng ZP. Clinical and pathological features of Riedel's thyroiditis. Chin Med Sci J. 2010;25(3):129-134.
  340. Annaert M, Thijs M, Sciot R, Decallonne B. Riedel's thyroiditis occurring in a multinodular goiter, mimicking thyroid cancer. J Clin Endocrinol Metab. 2007;92(6):2005-2006.
  341. Vigouroux C, Escourolle H, Mosnier-Pudar H, Thomopoulos P, Louvel A, Chapuis Y, Varet B, Luton JP. [Riedel's thyroiditis and lymphoma. Diagnostic difficulties]. Presse Med. 1996;25(1):28-30.
  342. Sheu SY, Schmid KW. [Inflammatory diseases of the thyroid gland. Epidemiology, symptoms and morphology]. Pathologe. 2003;24(5):339-347.
  343. Ozgur T, Gokce H, Ustun I, Yaldiz M, Akin MM, Gokce C. A case of asymptomatic riedel thyroiditis with follicular adenoma in a patient with a multinodular goiter: an unusual association. Eur Thyroid J. 2012;1(3):204-207.
  344. Shahi N, Abdelhamid MF, Jindall M, Awad RW. Riedel's thyroiditis masquerading as anaplastic thyroid carcinoma: a case report. J Med Case Reports. 2010;4:15.
  345. Kumar SS, Fraser S, Scarsbrook A, Maclennan K, Lansdown M, Murray RD. Atypical Presentation of Riedel's Thyroiditis: Multifocal Nodular Fibrosis and Resolution with Levothyroxine. Eur Thyroid J. 2012;1(4):259-263.
  346. Best TB, Munro RE, Burwell S, Volpe R. Riedel's thyroiditis associated with Hashimoto's thyroiditis, hypoparathyroidism, and retroperitoneal fibrosis. J Endocrinol Invest. 1991;14(9):767-772.
  347. Chopra D, Wool MS, Crosson A, Sawin CT. Riedel's struma associated with subacute thyroiditis, hypothyroidism, and hypoparathyroidism. J Clin Endocrinol Metab. 1978;46(6):869-871.
  348. Marin F, Araujo R, Paramo C, Lucas T, Salto L. Riedel's thyroiditis associated with hypothyroidism and hypoparathyroidism. Postgrad Med J. 1989;65(764):381-383.
  349. Yasmeen T, Khan S, Patel SG, Reeves WA, Gonsch FA, de Bustros A, Kaplan EL. Clinical case seminar: Riedel's thyroiditis: report of a case complicated by spontaneous hypoparathyroidism, recurrent laryngeal nerve injury, and Horner's syndrome. J Clin Endocrinol Metab. 2002;87(8):3543-3547.
  350. Nazal EM, Belmatoug N, de Roquancourt A, Lefort A, Fantin B. Hypoparathyroidism preceding Riedel's thyroiditis. Eur J Intern Med. 2003;14(3):202-204.
  351. Stan MN, Haglind EG, Drake MT. Early Hypoparathyroidism Reversibility with Treatment of Riedel's Thyroiditis. Thyroid. 2015;25(9):1055-1059.
  352. Heufelder AE, Hay ID. Further evidence for autoimmune mechanisms in the pathogenesis of Riedel's invasive fibrous thyroiditis. J Intern Med. 1995;238(1):85-86.
  353. Heufelder AE, Bahn RS. Modulation of Graves' orbital fibroblast proliferation by cytokines and glucocorticoid receptor agonists. Invest Ophthalmol Vis Sci. 1994;35(1):120-127.
  354. Khan MA, Hashmi SM, Prinsley PR, Premachandra DJ. Reidel's thyroiditis and Tolosa-Hunt syndrome, a rare association. J Laryngol Otol. 2004;118(2):159-161.
  355. Meijer S, Hoitsma HF, Scholtmeijer R. Idiopathic retroperitoneal fibrosis in multifocal fibrosclerosis. Eur Urol.1976;2(5):258-260.
  356. Meyer S, Hausman R. Occlusive phlebitis in multifocal fibrosclerosis. Am J Clin Pathol. 1976;65(3):274-283.
  357. Geissler B, Wagner T, Dorn R, Lindemann F. Extensive sterile abscess in an invasive fibrous thyroiditis (Riedel's thyroiditis) caused by an occlusive vasculitis. J Endocrinol Invest. 2001;24(2):111-115.
  358. Vaidya B, Coulthard A, Goonetilleke A, Burn DJ, James RA, Kendall-Taylor P. Cerebral venous sinus thrombosis: a late sequel of invasive fibrous thyroiditis. Thyroid. 1998;8(9):787-790.
  359. Natt N, Heufelder AE, Hay ID, Grant CS, Goellner JR. Extracervical fibrosclerosis causing obstruction of a ventriculo-peritoneal shunt in a patient with hydrocephalus and invasive fibrous thyroiditis (Riedel's struma). Clin Endocrinol (Oxf). 1997;47(1):107-111.
  360. Egsgaard Nielsen V, Hecht P, Krogdahl AS, Andersen PB, Hegedus L. A rare case of orbital involvement in Riedel's thyroiditis. J Endocrinol Invest. 2003;26(10):1032-1036.
  361. Hines RC, Scheuermann HA, Royster HP, Rose E. Invasive fibrous (Riedel's) thyroiditis with bilateral fibrous parotitis. JAMA. 1970;213(5):869-871.
  362. Rao CR, Ferguson GC, Kyle VN. Retroperitoneal fibrosis associated with Riedel's struma. Can Med Assoc J.1973;108(8):1019-1021.
  363. Julie C, Vieillefond A, Desligneres S, Schaison G, Grunfeld JP, Franc B. Hashimoto's thyroiditis associated with Riedel's thyroiditis and retroperitoneal fibrosis. Pathol Res Pract. 1997;193(8):573-577; discussion 578.
  364. Brihaye B, Lidove O, Sacre K, Laissy JP, Escoubet B, Valla D, Papo T. Diffuse periarterial involvement in systemic fibrosclerosis with Riedel's thyroiditis, sclerosing cholangitis, and retroperitoneal fibrosis. Scand J Rheumatol. 2008;37(6):490-492.
  365. Owen K, Lane H, Jones MK. Multifocal fibrosclerosis: a case of thyroiditis and bilateral lacrimal gland involvement. Thyroid. 2001;11(12):1187-1190.
  366. Hamed G, Tsushima K, Yasuo M, Kubo K, Yamazaki S, Kawa S, Hamano H, Yamamoto H. Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis. Respirology. 2007;12(3):455-457.
  367. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167-1214.
  368. Ozgen A, Cila A. Riedel's thyroiditis in multifocal fibrosclerosis: CT and MR imaging findings. AJNR Am J Neuroradiol. 2000;21(2):320-321.
  369. Papi G, Corrado S, Cesinaro AM, Novelli L, Smerieri A, Carapezzi C. Riedel's thyroiditis: clinical, pathological and imaging features. Int J Clin Pract. 2002;56(1):65-67.
  370. Slman R, Monpeyssen H, Desarnaud S, Haroche J, Fediaevsky LD, Fabrice M, Seret-Begue D, Amoura Z, Aurengo A, Leenhardt L. Ultrasound, Elastography, and Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging in Riedel's Thyroiditis: Report of Two Cases. Thyroid. 2011.
  371. Harigopal M, Sahoo S, Recant WM, DeMay RM. Fine-needle aspiration of Riedel's disease: report of a case and review of the literature. Diagn Cytopathol. 2004;30(3):193-197.
  372. Iacconi P, Giusti L, Da Valle Y, Ciregia F, Giannaccini G, Torregrossa L, Proietti A, Donatini G, Mazzeo S, Basolo F, Lucacchini A. Proteomic approach used in the diagnosis of Riedel's thyroiditis: a case report. J Med Case Rep. 2012;6:103.
  373. Perez Fontan PJ, Cordido Carbillido F, Pompo Felipe F, Mosquera Oses J, Villalba Martin C. Riedel thyroiditis: US, CT, and MR evaluation. J Comput Assist Tomogr. 1993;17(2):324-325.
  374. Lo JC, Loh KC, Rubin AL, Cha I, Greenspan FS. Riedel's thyroiditis presenting with hypothyroidism and hypoparathyroidism: dramatic response to glucocorticoid and thyroxine therapy. Clin Endocrinol (Oxf).1998;48(6):815-818.
  375. Takahashi N, Okamoto K, Sakai K, Kawana M, Shimada-Hiratsuka M. MR findings with dynamic evaluation in Riedel's thyroiditis. Clin Imaging. 2002;26(2):89-91.
  376. Drieskens O, Blockmans D, Van den Bruel A, Mortelmans L. Riedel's thyroiditis and retroperitoneal fibrosis in multifocal fibrosclerosis: positron emission tomographic findings. Clin Nucl Med. 2002;27(6):413-415.
  377. Kotilainen P, Airas L, Kojo T, Kurki T, Kataja K, Minn H, Nuutila P. Positron emission tomography as an aid in the diagnosis and follow-up of Riedel's thyroiditis. Eur J Intern Med. 2004;15(3):186-189.
  378. Moulik PK, Al-Jafari MS, Khaleeli AA. Steroid responsiveness in a case of Riedel's thyroiditis and retroperitoneal fibrosis. Int J Clin Pract. 2004;58(3):312-315.
  379. Papi G, LiVolsi VA. Current concepts on Riedel thyroiditis. Am J Clin Pathol. 2004;121 Suppl:S50-63.
  380. Yu Y, Liu J, Yu N, Zhang Y, Zhang S, Li T, Gao Y, Lu G, Zhang J, Guo X. IgG4 immunohistochemistry in Riedel's thyroiditis and the recommended criteria for diagnosis: A case series and literature review. Clin Endocrinol (Oxf).2021;94(5):851-857.
  381. Jung K-Y. Surgical Treatment for Riedel’s Thyroiditis: a Case Report. International Journal of Thyroidology.2017;10(1):66-69.
  382. Vaidya B, Harris PE, Barrett P, Kendall-Taylor P. Corticosteroid therapy in Riedel's thyroiditis. Postgrad Med J.1997;73(866):817-819.
  383. Tutuncu NB, Erbas T, Bayraktar M, Gedik O. Multifocal idiopathic fibrosclerosis manifesting with Riedel's thyroiditis. Endocr Pract. 2000;6(6):447-449.
  384. Hostalet F, Hellin D, Ruiz JA. Tumefactive fibroinflammatory lesion of the head and neck treated with steroids: a case report. Eur Arch Otorhinolaryngol. 2003;260(4):229-231.
  385. Bagnasco M, Passalacqua G, Pronzato C, Albano M, Torre G, Scordamaglia A. Fibrous invasive (Riedel's) thyroiditis with critical response to steroid treatment. J Endocrinol Invest. 1995;18(4):305-307.
  386. Thomson JA, Jackson IM, Duguid WP. The effect of steroid therapy on Riedel's thyroiditis. Scott Med J.1968;13(1):13-16.
  387. Rodriguez I, Ayala E, Caballero C, De Miguel C, Matias-Guiu X, Cubilla AL, Rosai J. Solitary fibrous tumor of the thyroid gland: report of seven cases. Am J Surg Pathol. 2001;25(11):1424-1428.
  388. Few J, Thompson NW, Angelos P, Simeone D, Giordano T, Reeve T. Riedel's thyroiditis: treatment with tamoxifen. Surgery. 1996;120(6):993-998; discussion 998-999.
  389. Levy JM, Hasney CP, Friedlander PL, Kandil E, Occhipinti EA, Kahn MJ. Combined mycophenolate mofetil and prednisone therapy in tamoxifen- and prednisone-resistant Reidel's thyroiditis. Thyroid. 2010;20(1):105-107.
  390. De M, Jaap A, Dempster J. Tamoxifen therapy in steroid-resistant Riedels disease. Scott Med J. 2002;47(1):12-13.
  391. Dabelic N, Jukic T, Labar Z, Novosel SA, Matesa N, Kusic Z. Riedel's thyroiditis treated with tamoxifen. Croat Med J. 2003;44(2):239-241.
  392. Erdogan MF, Anil C, Turkcapar N, Ozkaramanli D, Sak SD, Erdogan G. A case of Riedel's thyroiditis with pleural and pericardial effusions. Endocrine. 2009;35(3):297-301.
  393. Jung YJ, Schaub CR, Rhodes R, Rich FA, Muehlenbein SJ. A case of Riedel's thyroiditis treated with tamoxifen: another successful outcome. Endocr Pract. 2004;10(6):483-486.
  394. Clark CP, Vanderpool D, Preskitt JT. The response of retroperitoneal fibrosis to tamoxifen. Surgery.1991;109(4):502-506.
  395. Pritchyk K, Newkirk K, Garlich P, Deeb Z. Tamoxifen therapy for Riedel's thyroiditis. Laryngoscope.2004;114(10):1758-1760.
  396. Butta A, MacLennan K, Flanders KC, Sacks NP, Smith I, McKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M, et al. Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res. 1992;52(15):4261-4264.
  397. Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR, Sporn MB, Baum M. Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer. 1990;62(3):405-409.
  398. Arteaga CL, Tandon AK, Von Hoff DD, Osborne CK. Transforming growth factor beta: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells. Cancer Res. 1988;48(14):3898-3904.
  399. Falhammar H, Juhlin C, Barner C, Catrina S, Karefylakis C, Calissendorff J. Riedel's thyroiditis: clinical presentation, treatment and outcomes. Endocrine. 2018;60(1):185-192.
  400. Hunt L, Harrison B, Bull M, Stephenson T, Allahabadia A. Rituximab: a novel treatment for refractory Riedel's thyroiditis. Endocrinology, diabetes & metabolism case reports. 2018;2018.
  401. Hoang TD, Mai VQ, Clyde PW, Glister BC, Shakir MK. Multinodular goiter as the initial presentation of systemic sarcoidosis: limitation of fine-needle biopsy. Respir Care. 2011;56(7):1029-1032.
  402. Anolik RB, Schaffer A, Kim EJ, Rosenbach M. Thyroid dysfunction and cutaneous sarcoidosis. J Am Acad Dermatol. 2012;66(1):167-168.
  403. Vailati A, Marena C, Aristia L, Sozze E, Barosi G, Inglese V, Luisetti M, Bossolo PA. Sarcoidosis of the thyroid: report of a case and a review of the literature. Sarcoidosis. 1993;10(1):66-68.
  404. Ozdemir D, Dagdelen S, Erbas T. Endocrine involvement in systemic amyloidosis. Endocr Pract.2010;16(6):1056-1063.
  405. Sethi Y, Gulati A, Singh I, Rao S, Singh N. Amyloid goiter: a case of primary thyroid amyloid disease. Laryngoscope. 2011;121(5):961-964.
  406. Ozdemir D, Dagdelen S, Erbas T, Sokmensuer C, Erbas B, Cila A. Amyloid goiter and hypopituitarism in a patient with systemic amyloidosis. Amyloid. 2011;18(1):32-34.
  407. Kazdaghli Lagha E, M'Sakni I, Bougrine F, Laabidi B, Ben Ghachem D, Bouziani A. Amyloid goiter: first manifestation of systemic amyloidosis. Eur Ann Otorhinolaryngol Head Neck Dis. 2010;127(3):108-110.
  408. Vanguri VK, Nose V. Transthyretin amyloid goiter in a renal allograft recipient. Endocr Pathol. 2008;19(1):66-73.
  409. Lari E, Burhamah W, Lari A, Alsafran S, Ismail A. Amyloid goiter - A rare case report and literature review. Ann Med Surg (Lond). 2020;57:295-298.
  410. Joung KH, Park JY, Kim KS, Koo BS. Primary amyloid goiter mimicking rapid growing thyroid malignancy. Eur Arch Otorhinolaryngol. 2014;271(2):417-420.
  411. Vergneault H, Terre A, Buob D, Buffet C, Dumont A, Ardois S, Savey L, Pardon A, Michel PA, Boffa JJ, Grateau G, Georgin-Lavialle S. Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review. J Clin Med. 2021;10(9).
  412. Aydin B, Koca YS, Koca T, Yildiz I, Gerek Celikden S, Ciris M. Amyloid Goiter Secondary to Ulcerative Colitis. Case Rep Endocrinol. 2016;2016:3240585.
  413. Seker A, Erkinuresin T, Demirci H. Amyloid Goiter in a Patient with Rheumatoid Arthritis and End-Stage Renal Disease. Indian J Nephrol. 2020;30(2):125-128.
  414. Jakubovic-Cickusic A, Hasukic B, Sulejmanovic M, Cickusic A, Hasukic S. Amyloid Goiter: A Case Report and Review of the Literature. Saudi J Med Med Sci. 2020;8(2):151-155.
  415. Villa F, Dionigi G, Tanda ML, Rovera F, Boni L. Amyloid goiter. Int J Surg. 2008;6 Suppl 1:S16-18.
  416. Goldsmith JD, Lai ML, Daniele GM, Tomaszewski JE, LiVolsi VA. Amyloid goiter: report of two cases and review of the literature. Endocr Pract. 2000;6(4):318-323.
  417. Hamed G, Heffess CS, Shmookler BM, Wenig BM. Amyloid goiter. A clinicopathologic study of 14 cases and review of the literature. Am J Clin Pathol. 1995;104(3):306-312.
  418. Pinto A, Nose V. Localized amyloid in thyroid: are we missing it? Adv Anat Pathol. 2013;20(1):61-67.
  419. Coca-Pelaz A, Vivanco-Allende B, Alvarez-Marcos C, Suarez-Nieto C. Multifocal papillary thyroid carcinoma associated with primary amyloid goiter. Auris Nasus Larynx. 2011.
  420. Nessim S, Tamilia M. Papillary thyroid carcinoma associated with amyloid goiter. Thyroid. 2005;15(4):382-385.
  421. Coli A, Bigotti G, Zucchetti F, Negro F, Massi G. Papillary carcinoma in amyloid goitre. J Exp Clin Cancer Res.2000;19(3):391-394.
  422. Ozdemir BH, Akman B, Ozdemir FN. Amyloid goiter in Familial Mediterranean Fever (FMF): a clinicopathologic study of 10 cases. Ren Fail. 2001;23(5):659-667.
  423. Ozdemir BH, Uyar P, Ozdemir FN. Diagnosing amyloid goitre with thyroid aspiration biopsy. Cytopathology.2006;17(5):262-266.
  424. Hill K, Diaz J, Hagemann IS, Chernock RD. Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section. Head Neck Pathol. 2018;12(2):269-273.
  425. Bando Y, Ushiogi Y, Toya D, Tanaka N, Fujisawa M. Painless thyroiditis associated with severe inflammatory reactions in amyloid goiter: a case report. Endocr J. 2001;48(3):323-329.
  426. Bryer-Ash M, Lodhi W, Robbins K, Morrison R. Early thyrotoxic thyroiditis after radiotherapy for tonsillar carcinoma. Arch Otolaryngol Head Neck Surg. 2001;127(2):209-211.
  427. Espiritu RP, Dean DS. Parathyroidectomy-induced thyroiditis. Endocr Pract. 2010;16(4):656-659.
  428. McDermott A, Onyeaka CV, Macnamara M. Surgery-induced thyroiditis: fact or fiction? Ear Nose Throat J.2002;81(6):408-410.
  429. Blenke EJ, Vernham GA, Ellis G. Surgery-induced thyroiditis following laryngectomy. J Laryngol Otol.2004;118(4):313-314.

Medical and Surgical Therapy of Erectile Dysfunction

ABSTRACT

 

Erectile dysfunction (ED) is the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse. Approximately 23% of men aged 40-80 years worldwide have symptoms of ED. The prevalence of ED is higher in older men but this condition can occur in men of any age. The prevalence of ED ranges between 30-90% in men with diabetes and may be the presenting symptom for the disease in almost a third of cases. In this chapter, we review the physiology of penile erection and pathophysiology of ED. We review contemporary medical treatments for ED, surgical options for patients that fail medical management, and novel therapies in development. We also briefly review priapism, the condition of prolonged penile erection not associated with sexual desire.

 

INTRODUCTION

 

Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (1). ED may result from psychological, neurologic, hormonal, vascular, or medication-induced causes.  Approximately 23% of men aged 40-80 years worldwide have symptoms of ED (2). ED occurs in men of all ages; the prevalence increases with age (3, 4).  Diabetes is a common and important case of ED due to the diseases impact on both neurological and vascular factors germane to penile erection (5).

 

PHYSIOLOGY OF PENILE ERECTIONS

 

Penile erection is a neurovascular event modulated by psychological and hormonal status. The penis is innervated by autonomic and somatic nerves. The autonomic nervous innervation of the penis consists of sympathetic fibers (derived from the T11-L2 spinal cord level) and parasympathetic fibers (derived from the S2-4 spinal cord level) which merge to form the cavernous nerves in the pelvis. The autonomic nervous innervation of the penis regulates corporal smooth muscle and arterial contraction and relaxation, which are the primary drivers of penile tumescence. The somatic portion of the pudendal nerve is responsible for penile sensation and the contraction and relaxation of the bulbocavernosus and ischiocavernosus striated muscles. These muscles are important for maximal penile erection and for expulsion of semen during ejaculation (6, 7).

 

The penis is flaccid in the resting state.  Suppression of penile erection and maintenance of the flaccid state is mediated by the sympathetic nervous system and adrenergic nerve terminals.  Vascular factors such as endothelin may also contribute to resting smooth muscle tone in the penis. Smooth muscle tone is ultimately mediated by activation of the myosin light chain, which tends to increase contraction. The RhoA/Rho kinase pathway also plays a critical role in smooth muscle contraction by suppressing myosin light chain phosphatase. A depiction of contractile molecules which mediate penile flaccidity is presented in Figure 1.

Figure 1. Pathways that Promote Contraction and Oppose Erection

Penile erection is induced in part by suppression of sympathetic tone. A number of brain centers integrate erotic stimuli and contribute to erection by suppressing the sympathetic nervous system. The neurotransmitter dopamine appears to play a critical role in central nervous system-based stimulation of erection whereas serotonin plays a mostly (but not universally) inhibitory role (8, 9).

 

Erection also requires activation of the parasympathetic nervous system; this is mediated in large part by release of nitric oxide (NO) from nonadrenergic-noncholinergic cavernous nerve terminals in the genital vascular system. NO is produced in nerve tissue by neuronal nitric oxide synthase (nNOS). NO activates soluble guanylyl cyclase, which cleaves guanosine triphosphate (GTP) to produce cyclic guanosine monophosphate (cGMP). cGMP in turn activates cGMP-specific protein kinases, which phosphorylates certain proteins and ion channels, resulting in: opening of the potassium channels and hyperpolarization; sequestration of intracellular calcium by the endoplasmic reticulum; and inhibition of calcium channels, blocking calcium influx. The consequence is a drop in cytosolic calcium content(10). Decline in calcium content results in smooth muscle relaxation via relaxation of the actin myosin cross-bridges. There is resultant vasodilation in the arteries and arterioles supplying the erectile tissue. A several-fold increase in blood flow occurs, with a concomitant increase in compliance of the corporeal sinusoids from relaxed cavernous smooth muscle. The increase in blood flow triggers activation of endothelial nitric oxide synthase (eNOS) that further increases NO production and maintenance/enhancement of vasodilation (11). A graphical depiction of the NO/cGMP relaxant pathway is depicted in Figure 2.  Additional vasodilation may be accomplished through the cyclic adenosine monophosphate pathway, depicted in Figure 3.

Figure 2. The NO cGMP Pathway in Erection

Figure 3. The cAMP Pathway in Erection

With enhancement of corporal blood flow there is rapid filling and expansion of the corporal sinusoidal system against the tunica albuginea. The subtunical venular plexuses are compressed between the corporeal sinusoids and the tunica albuginea, resulting in almost total occlusion of venous outflow (12, 13). With trapping of blood within the corpora cavernosa the flaccid penis becomes erect; during the full erection phase intracavernous pressures increases to approximately 100 mm Hg. With increasing sexual arousal, the bulbocavernosus reflex is triggered, causing the ischiocavernosus muscles to forcefully compress the base of the blood-filled corpora cavernosa and the penis. During this rigid erection phase the penis (including the corpus spongiosum and glans) becomes very hard, with intracavernous pressure reaching several hundred mm Hg in some cases.  During this phase, arterial inflow may cease or even reverse (i.e., arterial blood flows retrograde towards the heart) (14)

 

With sexual climax or cessation of arousal, the penis returns to the flaccid state. Flaccidity is initiated in large part by hydrolysis of cGMP to guanosine monophosphate by phosphodiesterase type 5 (PDE5). Other phosphodiesterases are found in the corpus cavernosum, but they do not appear to play a major role in detumescence. Detumescence is also mediated by sympathetic discharge during ejaculation, leading to vasoconstriction and cessation of NO release from the cavernous nerves and corporal endothelium. The sub-tunical venous channels open with contraction of the trabecular smooth muscle, permitting egress of trapped blood and restoring flaccidity (10).

 

CLASSIFICATION OF ERECTILE DYSFUNCTION

 

ED may be mediated by defects in the neuronal, hormonal, arterial, or cavernosal systems. ED is commonly associated with specific medications. ED is also strongly associated with psychological distress. ED is in most cases multifactorial, with at least some element of a psychogenic component as a primary cause or as secondary development in reaction to the ED state. Some disease states (e.g., diabetes) may cause ED via multiple mechanisms (Table 1).

 

Table 1. Classification and Common Causes of Erectile Dysfunction

Category of Erectile dysfunction

Common disorders

Pathophysiology

Neurogenic

-Stroke

-Alzheimer’s disease 
-Spinal cord injury 
-Radical pelvic surgeries 
-Diabetic neuropathy

-Pelvic injury

-Interrupted neuronal innervation 
-Failure to initiate NO release

Psychogenic

-Depression
-Psychological stress
-Performance anxiety 
-Relationship problems

-Impaired nitric oxide (NO) release 
-Loss of libido

-Sympathetic nervous system activation

Hormonal

-Androgen deficiency
-Hyperprolactinemia

-Diabetes

-Chronic opioid use

-Loss of libido

-Inadequate NO release

-Morphological changes in penis (atrophy)

Vasculogenic (arterial and cavernosal)

-Hypertension

-Atherosclerosis 
-Hyperlipidemia

-Diabetes mellitus

-Obesity 
-Trauma/pelvic fracture

-Tobacco use
-Peyronie’s disease

-Impaired penile veno-occlusion

-Inadequate arterial inflow

Drug-induced

-Antihypertensives
-Antiandrogens 
-Antidepressants 
-Alcohol abuse 

-Central nervous system suppression
-Decreased libido 
-Alcoholic neuropathy 
-Vascular insufficiency

Systemic diseases

-Aging
-Diabetes mellitus
-Chronic renal failure 
-Generalized atherosclerotic disease

-Multifactorial 
-Neuronal and vascular dysfunction

 

Sexual function progressively declines as men age, although this decline need not be considered any more “natural” than the development of diabetes, hypercholesterolemia, hypertension, or any other disease state more common in the aged. With age, the latency period between sexual stimulation and erection increases, erections are less turgid, ejaculation is less forceful, ejaculatory volume decreases, and the refractory period between erections lengthens (15). In most cases aging is also associated with a decrease in penile sensitivity to tactile stimulation, a decrease in serum testosterone concentration, and an increase in cavernous muscle tone (16).

 

Erectile dysfunction is more common in patients with neurologic disorders such as Parkinson's and Alzheimer's diseases, stroke and cerebral trauma (17). This may be due to both a decrease in libido and/or inability to initiate the erectile process. Spinal cord injury patients have varying degrees of erectile dysfunction largely dependent on the location and extent of the lesion. Men with lesions of the sacral spine may have disruption of the sacral reflex arc and may not respond to genital stimulation. Men with spinal cord injury that preserves the sacral segments may retain reflexogenic erections but may struggle to obtain erection related to mental arousal, which is generated by cortical suppression of sympathetic tone (6). Although erections of some form are often possible in men with spinal cord injury, they are typically less rigid and of shorter duration compared to erections in men without spinal cord injury. Even in men without spinal cord injury, sensory input from the genitalia remains essential to achieving and maintaining reflexogenic erection. This input may be compromised due to peripheral neuropathy in men with diabetes (18).

 

About 50 percent of men with chronic diabetes mellitus are reported to have ED, although this number dramatically increases with age. In addition to the disease's effect on small vessels, it may also affect the cavernous nerve terminals and endothelial cells, resulting in deficiency of neurotransmitters (10). Additionally, corporal smooth muscle relaxation in response to neuronal- and endothelial-derived nitric oxide (NO) is impaired in men with diabetes, possibly due to the accumulation of glycosylation products (19-21).

 

Chronic renal insufficiency (CRI) has frequently been associated with diminished erectile function, impaired libido, and infertility (22, 23).The mechanism of ED in CRI is likely multifactorial and includes low serum testosterone, vascular insufficiency, medication-related, depressed libido, and autonomic and somatic neuropathy (24-26).  Diabetes is a major risk factor for CRI and hence CRI is a relevant consideration in men with diabetes.

 

Psychogenic ED may relate to performance anxiety, strained relationship, lack of sexual arousal, and overt psychiatric disorders such as depression and schizophrenia (27). The strong relationship between psychogenic stress and sexual dysfunction is well established (28).

 

Androgen deficiency is associated with diminished libido and less frequent nocturnal erections (29). However, erection response is preserved in many men with low serum testosterone, suggesting that androgens are beneficial but not essential for erection (30). Men with diabetes are at increased risk of androgen deficiency; serum testosterone testing is often warranted in diabetic men with or without ED (29, 31). Prolactin is another pituitary hormone that has inhibitory activity on central dopaminergic activity and gonadotropin-releasing hormone secretion. Hyperprolactinemia has been linked to reproductive and sexual dysfunction.

 

Vascular disease is a common and important cause of ED (32). Common vascular risk factors associated with generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, trauma, and pelvic irradiation (33). Focal stenosis of the common penile artery is not common but can be a cause of ED in men who have sustained repetitive and/or severe pelvic or perineal trauma (e.g. biking accidents, pelvic fractures) (34).

 

Veno-occlusive dysfunction (VOD) results from disruption of the blood trapping capacity of the tunica albuginea of the corpora. In this situation there may be inadequate compression of the subtunical venules during the full erection phase (35). Venous leak ED may also be the result of degenerative changes that affect the penis including Peyronie's disease, penile scarring, and diabetes mellitus. A patient may develop VOD from traumatic injury to the tunica albuginea such as a penile fracture. Venous leak can also be seen in anxious men with excessive adrenergic tone causing structural alterations of the cavernous smooth muscle and endothelium and insufficient trabecular smooth muscle relaxation (36).

 

Virtually all drugs have been associated with ED although some classes are more prone to sexual side effects than others. Central neurotransmitter pathways, including serotonergic, noradrenergic, and dopaminergic pathways involved in sexual function, may be disturbed by antipsychotics and antidepressants (27).  Although any antihypertensive agent could theoretically cause ED by decreasing the availability of blood to the corporal arteries (i.e., a pressure-head phenomenon), differences are noted between various classes of medications (37).  Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are relatively less likely to cause ED. Beta-adrenergic blocking drugs may lead to erectile dysfunction by potentiating a-1 adrenergic activity in the penis, although more modern beta blockers with eNOS activity (such as nebivolol) may help minimize this effect (38) . Thiazide diuretics have been reported to cause erectile dysfunction by an unknown mechanism (39)Anti-androgens are another common drug type that may contribute to ED(40).  

 

Recreational drugs including cigarettes and alcohol affect erectile function. Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle. More importantly, chronic use may accelerate atherosclerotic changes in penile microvasculature (41). Alcohol in small amounts may improve erections and increase libido because of its vasodilatory effect and the suppression of performance anxiety. However, large amounts of alcohol can cause central sedation, decreased libido and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy; this may in turn affect penile nerve function (42).

 

EVALUATION OF ERECTILE DYSFUNCTION

 

Erectile dysfunction may be the first manifestation of many disease states, including diabetes mellitus, coronary artery disease, hyperlipidemia, hypertension, spinal-cord compression, pituitary tumors, and pelvic malignancies. ED is a sentinel event for major adverse cardiac events and is therefore an indication for formal cardiovascular evaluation (32). The evaluation of a patient with ED requires a thorough history (medical, sexual, and psycho-social), physical examination and appropriate laboratory tests (creatinine, fasting glucose, lipid profile, total testosterone, and bioavailable or free testosterone) aimed at detecting underlying metabolic disease states (1). If the man's testosterone concentration (free, total, or bioavailable) is low, serum prolactin and luteinizing hormone should be assayed to detect abnormalities of the hypothalamic-pituitary axis (29, 31).

 

After assessing the therapeutic needs and goals of the patient, further diagnostic and treatment options can be offered. The patient’s partner(s) should be involved in treatment planning and decision making (1). In men who do not have a sexual partner, there should be discussion about goals in terms of future sexual relationships.  Decisions on treatment should be based on patient goals and risk tolerance. If the patient has a regular partner, it is beneficial to involve them in conversations about goals and treatment options. The most recent AUA guideline on ED recommends that all treatments be considered first line. Most men are best served by a progression from minimally to maximally invasive options; however, a properly counseled man may elect to bypass less invasive options if he so desires and if deemed medically appropriate (1).  

 

The patient's performance status and cardiovascular health should be evaluated, in consultation with a cardiologist, if necessary, in order to assess the patient's ability to tolerate sexual activity (43). Patients who have poor exercise tolerance should consider physical conditioning prior to resuming sexual activity (43). Exercise, healthy diet, and weight loss may be sufficient to partially restore erection response in some men (44)

 

Men with complex ED may benefit from a referral for further testing and treatment by a sexual medicine specialist, sex therapist, or medical provider with expertise in a specific health condition germane to sexual responses (Table 2). The indications for specialty referral include complex gonadal or other endocrine disorders, neurologic deficit suggestive of brain or spinal cord disease, deep-seated psychologic or psychiatric problems, post-traumatic or lifelong erectile dysfunction and unstable cardiovascular disease (1).  

 

Table 2. Medical Workup of Erectile Dysfunction

Test

Indications

Combined injection and stimulation (CIS), Intracavernous injection of vasodilator followed by penile self-stimulation)

Assessment of penile vascular function and presence of penile deformities with erection.

Therapeutic test in men who choose intracavernous therapy for ED

CIS with color Duplex ultrasonography (CDU)

Assessment of arterial inflow and veno-occlusive potential of the penis

Assess for fibrosis/plaque formation/calcification of the corpora

Cavernosography

Assessment for congenital or traumatic venous leakage in men with veno-occlusive ED by CDU (rarely utilized in contemporary practice)

Pelvic arteriography

Assess for arterial lesions in men with arterial ED by CDU (rarely utilized in contemporary practice)

Ambulatory nocturnal penile tumescence and rigidity (Rigiscan®)

Assess nocturnal erection responses (Historically used to differentiate psychogenic from organic erectile dysfunction but prone to unreliability and seldom utilized in contemporary practice)

 

Peyronie’s disease (PD) is an acquired fibrotic disorder of the penis that merits specific mention in the context of managing ED (45). The condition remains poorly understood but is thought to involve a genetic predisposition to collagen deposition and inflammation in connective tissues after minor traumas as may be experienced during sexual activity. Men with PD are at increased risk of other fibrotic conditions including Dupuytren’s contractures and tympanosclerosis (45).  

 

PD was once thought to be quite rare; with the introduction of highly effective therapy for ED many cases of PD that might have once gone unrecognized are now diagnosed. Prevalence estimates vary but signs of PD may be detected by experienced examiners in approximately 9% of men presenting for evaluation by an experienced urologist (46).

 

The classical manifestation of PD is penile curvature, but the disorder may also be associated with pain, narrowing, corporal fibrosis, and hinging (45). The single US-FDA approved medical therapy for PD is injections of Clostridial collagenase into the tunica albuginea of the corporal bodies followed by a course of penile modeling. This therapy has been associated with modest but significant improvements in penile curvature compared to placebo injections (47). In cases of severe deformity and/or failure of medical therapy, surgical intervention may be required. Surgery for PD can take the form of 1) plication of the convex side of the penis with sutures to induce straightening, 2) incision with grafting of the concave or narrowed portion of the corpora, or 3) placement of a penile prosthetic device in cases where there is concomitant severe ED (45, 48).

 

MEDICAL MANAGEMENT OF ERECTILE DYSFUNCTION

 

Medical management options with demonstrated efficacy in management of ED are presented in table 3.

 

Table 3. Treatment Options for Erectile Dysfunction

Treatment 

Cost 

Advantage 

Disadvantage 

Recommendation

Psychosexual Therapy 

Variable

-Non-invasive

-Partner involved

-Potentially curative for psychogenic ED 

-Time consuming

-Costly

-Knowledgeable experts may not be available in all geographic areas

Useful as primary or adjunct therapy in almost all cases

Oral: PDE 5 inhibitor (sildenafil, tadalafil, vardenafil, avanafil) 

$1-50 /dose Oral

-Effective in 1-2 hours

-Up to 24-hour action (tadalafil)

-May be taken on demand or as daily supplement (tadalafil only)

-Strict contraindication in men on nitrates and relative contraindication with some other drugs

-Potential for side effects

First-line treatment for the majority of patients

Vacuum Constriction Device 

$150- 450 /device 

No systemic side effects 

-May compromise ejaculation

-May cause discomfort and/or numbness

-Marginal penile rigidity

Low risk but marginal efficacy in producing erections sufficient for sexual activity

Transurethral: MUSE®1 

$25 /dose 

-Local therapy

-Few systemic side effects 

-Moderately effective

-Requires training

-May cause penile pain 

Marginal clinical response in many cases and pain with administration limit efficacy

Penile injection (Caverject®, Edex®, or compounded drugs)2

$5-30 /dose 

-Highly effective

-Few systemic side effects 

-Requires injection

-May cause penile pain

-High dropout rate.

-Risk of priapism or fibrosis 

Highly effective in men who fail or are not candidates for PDE5I

Penile Prosthesis (all types) 

$8,000- 15,000 

-Produces a reliably rigid penile shaft 

-Risk of device infection

-Requires surgery

-Requires replacement after mechanical failure

For men dissatisfied with medical management who are willing to have surgery

Vascular Surgery 

$10,000- 15,000 

-Potentially curative 

-Requires surgery

-Poor results in older men with generalized vascular disease 

Restrict to arterial bypass surgery in specialized centers for select healthy young men with traumatic arterial disruption as cause of ED. Surgery for venous leak is no longer recommended as a standard of care in any patient.

1.MUSE® signifies Medicated Urethral System for Erection. It contains alprostadil pellet. 2.Caverject® and Edex® both contain injectable alprostadil. Drug mixtures contain two or three of the following drugs: papaverine, phentolamine and prostaglandin, atropine.

 

Androgens

 

Historically, androgens were thought to enhance male sexual function. However, androgen therapy has only been shown to be of clinical benefit in men with low serum testosterone and symptoms potentially referable to hypogonadism (29). There is controversy over what constitutes a “low” level of testosterone with cut points for normal ranging between 264-350 ng/dL depending on definitions based on population norms and/or increased odds of symptoms potentially referable to low serum testosterone. (29, 31, 49, 50). Assessment of serum free testosterone (ideally with equilibrium dialysis or other highly precise methodology) is controversial and recommended in select cases by some experts (51) but not by others (31, 52). The sexual benefits of supplementation in men with low serum testosterone primarily pertains to libido but mild improvements in erectile function in patients may occur with testosterone supplementation alone (53). The United States Testosterone Trial demonstrated moderate improvement of erectile function with testosterone gel therapy compared to placebo in men ≥ 65 years and serum total testosterone concentrations ≤ 275 ng/dl; these men were not a priori screened for erectile dysfunction.(54)

 

Testosterone cypionate, enanthate, and undecanoate may be used for intramuscular replacement therapy.  A standard dosing regimen is 200 mg intramuscularly every two weeks although different dosing regimens have been described. Lower doses at shorter intervals may produce less pronounced variation in serum testosterone levels between doses.

 

Several daily transdermal testosterone preparations (testosterone patches or gels) are available. Daily application of these preparations raises serum testosterone concentrations to within the normal range in over 90 percent of men. The most common adverse effects of testosterone patches are skin irritation and contact dermatitis. Gel formulations are less prone to skin irritation but care must be taken to avoid skin-to-skin contact and transfer of testosterone to others (e.g., spouse, children) for at least 2 hours post dosing (29).  

 

Recent refinements in testosterone supplementation include novel testosterone pellets, which are implanted in a minor office procedure and provide 2-4 months of therapeutic testosterone levels (55).  A ten week depot testosterone preparation was recently approved for use in the United States; this long acting formulation may obviate the need for frequent injections (56). These long-acting formulations may be considered for patients who have tolerated shorter acting formulations and reported significant benefit.  Additional recent innovations that have achieved FDA approval include subcutaneous injectable testosterone and nasal testosterone (31).

 

Testosterone treatment may contribute to polycythemia, acne, edema, and decreased HDL cholesterol. Testosterone may also lead to estrogen by aromatization in adipose tissue; this may lead to gynecomastia and theoretically to higher risk of deep venous thrombosis. Men receiving androgen replacement therapy require routine follow up appointments with measurement of hematocrit, serum testosterone, and PSA. It is prudent to have more frequent checks in the early phase after initiation of therapy (29).

 

Due to the well-established benefits of surgical or medical castration for the management of advanced prostate cancer there has been a long-standing concern that testosterone supplementation may increase the risk of prostate cancer (31, 57). This relationship is based primarily on conjecture; there is an emerging body of literature which suggests that testosterone supplementation does not materially alter the risk of prostate cancer development (58). There is limited evidence that men with low serum testosterone may be at greater risk of aggressive prostate cancer (59), although there is currently no evidence that supplementation moderates this risk. Numerous reports have been published of men with successfully treated prostate cancer using testosterone supplements with no increase in risk for PSA recurrence (60). Some clinicians have also reported continued testosterone supplementation in men with untreated prostate cancer; until more data are available providers in general practice should exercise caution with respect to testosterone supplementation in men with untreated prostate cancer (57, 61).

 

The issue of cardiac safety and testosterone received a great deal of media attention in the mid 2010s. High profile publications in prestigious journals reported increased rates of cardiovascular events and mortality in men using testosterone supplements (62, 63). Testosterone is known to exert several effects that may increase cardiac risk. At the same time, the known benefits of testosterone include increased lean body mass, decreased adiposity, and improved insulin sensitivity (64). Men with low serum testosterone are known to be at greater risk of all-cause mortality (65). Higher rates of cardiac events in men taking testosterone supplement may be due to baseline risk rather than additional risk from supplementation.  

 

Type 5 Phosphodiesterase Inhibitors (PDE5I)

 

Oral therapy with a type 5 phosphodiesterase inhibitor (PDE5I, e.g., sildenafil, vardenafil, tadalafil, and avanafil) is in the most frequently utilized first-line therapy men with ED (1).  PDE5I block the inactivation of cGMP and result in increased smooth muscle relaxation and penile arterial blood flow. In the absence of sexual stimulation these medications have minimal effect on penile blood flow; this relationship may explain frequent PDE5I “failure” in men not properly counseled on proper use of this class of drugs.

 

Numerous placebo-controlled studies have been conducted on the safety and efficacy of sildenafil since it was approved for clinical use in 1998 (66). Sildenafil has been consistently shown to increase the number of erections, penile rigidity, orgasmic function, and overall sexual satisfaction compared to placebo in men with ED of every etiology, including diabetes and radical prostatectomy. Similar data exist for the other drugs in this class.

 (67-69)

 

Most clinical trials of PDE-5 inhibitors show only mild to moderate, self-limited adverse events associated with all of the PDE-5 inhibitors (70). The most common complaints in men using PDE-5 inhibitors are headache (16 percent), flushing (10 percent), dyspepsia (7 percent), nasal congestion (4 percent), and visual disturbances/ color sensitivity (3 percent). Tadalafil distinguishes itself from vardenafil and sildenafil by the relative lack of visual side effects. It does however have the possible adverse effect of back pain and/or myalgia (71).

 

PDE5I have an excellent track record of cardiac safety (72). To date, tens of millions of men in over 100 countries have used sildenafil. Since the release of the drug, over 200 deaths temporally associated with sildenafil therapy were reported to the Food and Drug Administration in the United States of America. Sexual activity is a likely contributor to myocardial infarction in men with heart disease, with sildenafil acting to enable men not previously active to engage in sexual activity (73, 74).  PDE5I therapy is safe for most men, although men with cardiovascular disease should consult with their cardiologist prior to engaging in sexual activity. The Princeton III guidelines provide recommendations for management of ED in men with cardiovascular disease. Princeton III recommends risk stratification before initiation of therapy; men at low-risk may be treated whereas men with high-risk (e.g., recent MI, unstable angina, NYHA Class III or IV heart failure, unstable arrythmia) should not be treated until their situation stabilizes.  Men who do not fall neatly into low- or high-risk categories should undergo cardiac evaluation (43).

 

A lower starting dose (25 mg of sildenafil, 5 mg of vardenafil or tadalafil, 50 mg of avanafil) is recommended in patients who may attain and maintain higher plasma levels of PDE5I. These include patients who are older than 65, have severe renal impairment, or take potent CYP450 3A4 inhibitors. Patients who take ritonavir should not take more than 25 mg of Sildenafil in a 48-hour period.

 

Patients using PDE5I and requiring alpha-blocker therapy for hypertension or benign prostate hyperplasia should start at low doses of PDE5 inhibitor, which can be titrated to affect. To avoid symptomatic hypotension, PDE5 inhibitors should not be taken within 4 hours of an alpha-blocker. One study found a significant rate of hypotension (28% versus 6% with placebo) in patients taking concomitant doxazosin and tadalafil (75).  The rate of hypotension matched that seen in placebo-treated patients in patients taking tamsulosin and tadalafil, and some studies suggest that the interaction has less clinical relevance in patients who have undergone long-term alpha-blocker therapy. It is likely that all four PDE5I commercially available in the US interact to some degree with alpha-blockers and that concurrent use of alpha-blockers and PDE5I may cause patients to develop orthostatic hypotension. Other antihypertensive agents appear to be well tolerated by men concurrently taking PDE5I.

 

PDE5I have been associated with spontaneous non-arteritic ischemic optic neuropathy (NAION), the most common acute optic neuropathy. Estimated annual incidence is 2.3 to 10.3 per 100,000 and is more common in Caucasians than African Americans, Asians, or Latinx persons. Most NAION patients do not become legally blind, but the degree of visual acuity and visual field loss is typically significant.

 

Risk factors common to NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, age over 50 years, coronary artery disease, and smoking (76).  A large review of ophthalmology records in the United States and Europe reported a very slight but statistically significant relationship between NAION and PDE5I use within the last 30 days. The authors concluded that use of PDE5I may be associated with an increase of approximately three NAION cases per 100,000 men over the age of 50 (77, 78). Men using PDE5I should be counseled to stop treatment and contact their physician immediately should visual changes or loss occur. Men with a history of NAION should not use PDE5 inhibitors (79).

 

PDE5I have also been implicated in several cases of hearing loss. Several dozen cases of PDE5 inhibitor associated hearing loss have been reported and some research has indicated mechanisms by which hearing loss may be attributable to action of these drugs (80, 81). Men who experience hearing impairment while using PDE5 inhibitors should halt treatment until they are able to speak with their doctors regarding long-term risk of hearing loss.

 

 SILDENAFIL

 

Sildenafil (Viagra®, Pfizer) works best when taken on an empty stomach (especially avoiding high lipid foods) and reaches maximum plasma concentrations within 30 to 120 minutes (mean 60 minutes). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about 4 hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. The efficacy of sildenafil has been extensively studied in patients with other coexisting diseases (82). No significant difference in response rate was noted comparing a normal cohort of patients with patients with hypertension (83), spinal cord injury (84), depression (85), and the elderly (86). Patients with a neurogenic etiology for ED (e.g., radical prostatectomy, diabetes) have a lower response rate to sildenafil compared to patients without a neurogenic cause; the drug is still effective for many of these men, however (87, 88) (Table 4).

 

 Table 4. Success of Sildenafil* in Men with Erectile Dysfunction

Response

Cause of Erectile Dysfunction

 

Diabetes Mellitus

Spinal Cord Injury

Radical Prostatectomy

Psychogenic

Depression

 

(N = 268)

(N = 178)

(N = 107)

(N = 179)

(N = 151)

Improved erection

Placebo

10%

12%

15%

26%

18%

Sildenafil

57%

83%

43%

84%

76%

Successful intercourse

Placebo

12%

13%

N/A

29%

NA

Sildenafil

48%

59%

43%

70%

N/A

*Sildenafil dosage 50 to 100 mg (source: Sildenafil package insert (Pfizer Inc. New York, NY., 1998))

 

VARDENAFIL

 

Vardenafil (Levitra® and Staxyn®, Bayer/GSK) is a potent and highly selective PDE5I. Its chemical structure is quite similar to sildenafil however in in vitro studies the selectivity and potency of vardenafil are superior. The medication can be given in either 10 or 20 mg oral dosage (Levitra®) or a 10 mg sublingual dissolving lozenge (Staxyn®). The time to peak plasma concentration is 40-55 minutes. Vardenafil has been shown to be highly efficacious in a wide range of clinical indications (89, 90). In one multicenter phase III trial patients with diabetes (type I and II) were found to respond to 20 mg dosage of vardenafil significantly better than a similar control group. The effect also seemed to improve after 12 weeks of treatment (91). Although similar in chemical structure, the in vitro potency and selectivity of vardenafil are superior to that of sildenafil.  Evidence that these in vitro effects translate to superior results in vivo are lacking.

 

Several newer studies have demonstrated vardenafil to have a faster onset of action than seen with other medications of the same class. In particular, one study (ONTIME) found that 21% of men with moderate to severe erectile dysfunction obtained erections of sufficient firmness for sexual intercourse at 11 minutes after using 20 mg of Vardenafil. At 25 minutes, 53% of patients obtained erections sufficient enough for penetration as compared to placebo (26%). The statistically superior response to vardenafil versus placebo was observed in all times from 11-25 minutes (92). Like sildenafil, absorption of vardenafil is impaired when the medication is taken after a high fat meal (93). The side effects most frequently seen with vardenafil include flushing, dyspepsia, headache, and visual disturbances (94) Adverse events reported in men taking vardenafil closely resemble those in men taking sildenafil and tadalafil. Headache (21%), flushing (13%), and dyspepsia (6%) are seen at various frequencies depending on dosages used. 

 

TADALAFIL

 

Tadalafil (Cialis®, Eli Lilly, USA) is a PDE5I which has a distinctly different chemical structure from vardenafil and sildenafil (71). Because tadalafil has lower affinity for PDE-6 (localized to the eye) it is associated with a low incidence of visual side effects. Tadalafil is dosed at 5, 10 and 20 mg on demand and is also available as a daily dose medication at 2.5 and 5 mg. Tadalafil’s erection potentiating effect may onset within 30-45 minutes of dosing but may last as long as 24-48 hours (95). Similar to other PDE5I, the risk of serious adverse events with tadalafil is low. In addition to the lack of visual side effects, tadalafil also tends to have a reduced incidence of facial flushing compared to the other PDE5I. The incidence of back/muscle pain is generally higher with tadalafil as compared to other PDE5I.

 

Absorption of tadalafil is minimally impacted upon by food intake.  An integrated analysis from five randomized control double blind placebo trials revealed that men with varying severities of ED significantly improved with Tadalafil therapy at 10 and 20 mg dosages. The mean IIEF score (International Index of Erectile Dysfunction score) increased by 6.5 and 7.9 at the 10 and 20 mg dosage of tadalafil. This increase was statistically significant compared to placebo (96).

 

In pharmacological studies tadalafil appears to be rapidly absorbed and reaches a peak serum concentration by 2 hours. The most salient unique property of tadalafil is its half-life of approximately 17.5 hours. The absorption and excretion of tadalafil does not appear to be affected by food or alcohol. In a study of the delayed efficacy of tadalafil, at 36 hours post dose 62% of men taking the 20 mg treatment dose reported successful sexual intercourse compared to 33% of men who had taken placebo (97).

 

Like sildanafil and vardenafil, tadalafil potentiates the hypotensive effects of nitric oxide and it is therefore contraindicated in patients taking nitrate medications. Tadalafil appears to be very well tolerated in most studies. The most frequently reported adverse events are headache and dyspepsia. Back pain, nasal congestion, myalgia, and nasal congestion have also been reported but tend to be mild. The rate of treatment discontinuation from adverse events is low at 2.2% compared with the placebo discontinuation rate of 1.3% (96).

 

AVANAFIL

 

A fourth PDE5 inhibitor called avanafil (Stendra®, Vivus) was approved for use in the United States in May of 2012 and became commercially available in 2014 (98). The chemical structure of avanafil differs from that of the three other drugs from the PDE5 inhibitor class. Avanafil is available in 50, 100, and 200 mg dosing and is efficacious in men with diabetes related ED (98). Avanafil is distinguished by having a rapid onset of action and a half-life of approximately 5-10 hours (99). The side effect profile is relatively similar to other drugs from the PDE5 inhibitor class (100).

 

STRATEGIES FOR MEN WHO FAIL TO RESPOND TO PDE5 INHHBITORS

 

Several strategies may salvage men who report failure with PDE5 inhibitors. An important first step is re-education on the correct use of the medications. Many patients need to be reminded that these medications are reliant on central mechanisms and that they will not work well without erotic stimulation. Up to 55% of sildenafil initial non-responders will respond after education (101). Dose titration or selection of an alternative PDE5I may be of benefit. Sildenafil, vardenafil, and avanafil tend to absorb more slowly (and hence have lower efficacy) after a high fat meal; tadalafil absorption is less dependent on timing of meals.

 

Assay of serum testosterone should also be considered in PDE5I failures. Testosterone supplementation has also been associated with improvements in response to PDE5I (102).  A randomized controlled trial of testosterone plus PDE5I therapy vs. testosterone alone  in men with ED did not show additive benefit from supplementation (103). However, this study was limited in that, during the pre-testosterone treatment run-in phase of the trial with administration of a PDE5I drug, mean serum testosterone levels improved to above the enrollment criterion of 330 mg/dL in both the placebo and testosterone treatment arms (103). The mechanism of the testosterone increase during the run-in in these cohorts is unclear but complicates interpretation of these data.

 

PDE-5 INHIBITORS AND CARDIOVASCULAR SAFETY

 

There has been concern about the cardiovascular safety, but controlled and post-marketing studies of the four FDA-approved PDE5I have demonstrated no increase in myocardial infarction or death rates in either double-blind, placebo-controlled trials or open-label studies when compared with expected rates in the study populations. Patients with known coronary artery disease or heart failure receiving PDE5I did not exhibit worsening ischemia, coronary vasoconstriction, or worsening hemodynamics on exercise testing or cardiac catheterization (43). Sexual activity, regardless of PDE5I use, has been associated with incremental increase in risk of cardiac events, an effect that is attenuated in patients who regularly engage in physical exertion.(104) An ability to perform exertion equivalent to 3-4 metabolic equivalents (METS) is consistent with cardiac reserve sufficient for most sexual activity; demands of up to 6 METs may be required for more exertional sex (105).

 

The vasodilator effects of PDE5 inhibitors may be more marked in patients with hypertension or coronary artery disease.  As with all vasodilators, caution is advised in certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension, and hypovolemia (43).  Caution is advised when an alpha-blocker and a PDE-5 inhibitor are taken within a close time frame, as a drug interaction can lead to excessive vasodilation and hypotension (106).

 

Nitrates are absolutely contraindicated in patients taking PDE5I (table 5) (1). These include organic nitrates, including sublingual nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate (so-called “poppers,” a recreational drug). Past use of nitrates, e.g., more than two weeks before the use of PDE5I, is not considered a contraindication. Patients who develop angina during sexual activity with a PDE5I or any ED medical therapy should be instructed to discontinue sexual activity and consider seeking emergency medical care. The patient should inform emergency medical personnel that a PDE5I was taken. Sublingual nitroglycerin should not be taken in this context as this may lead to serious hypotension.

 

Table 5. Recommendations for PDE5I in Men With Cardiac Disease*

1. Men using nitrate drugs should not use PDE5I.  If a man develops angina and has taken a PDE5I he should present to the ER rather than taking a short acting nitrate drug (e.g., nitroglycerin).

2. Men with stable coronary disease not needing nitrates on a consistent basis may take PDE5I if the risks of the medication have been carefully discussed with the patients by their physician. If the patient routinely requires nitrates for mild or moderate exercise induced angina, PDE5I should not be prescribed.

3. All men taking an organic nitrate (including recreational amyl nitrate) should be informed about the nitrate/PDE5I hypotensive interaction.

4. Men must be warned of the danger of taking PDE5I in the 24-hour period before or after taking a nitrate preparation.

5. Pre-PDE5I stress testing may be indicated in some men with cardiac disease to assess the risk of cardiac ischemia during sexual intercourse.

6. Initial monitoring of blood pressure after taking PDE5I may be indicated in: men with congestive heart failure who have borderline low blood pressure and low volume status; and men being treated with a complicated, multidrug antihypertensive regimen.

*Adapted from materials provided by the Princeton III Consensus Conference (43)

 

Other Treatments of Erectile Dysfunction

 

In patients for whom PDE5I or are contraindicated, alternative management options include the vacuum constriction device (VCD), trans-urethral suppositories (MUSE®), and intra-cavernous injection (ICI) therapy (1).

 

VACUUM CONSTRICTION DEVICES (VCD)

 

VCD produces erection via vacuum suctioning of venous blood into the corporal spaces.  Blood is subsequently trapped with a constriction device placed at the base of the phallus. Its potential side effects include discomfort, petechiae, numbness, and interference with ejaculation (1). The erection induced by the VCD is based on trapping of venous blood and therefore the erection may be colder and less firm than natural erections. Some men also experience pain and/or difficulty with operating the device. No constrictive device should be left on the penis for more than 60 minutes and the device should be promptly removed if there are signs of numbness or ischemia.

 

MUSE®

 

The Medicated Urethral Suppository for Erections (MUSE®) is a transurethral prostaglandin suppository that has several advantages including local application, minimal systemic effects, and the rarity of drug interaction. However, this type of secondary treatment has failed to gain popularity due to its major drawbacks including moderate to severe penile pain, low response rate, and inconsistent efficacy (107) It has been extensively studied in Europe and the United States and was found to be effective in 43 percent of men with erectile dysfunction of various organic causes. The most common side effects were penile pain (32 percent) and urethral pain or burning (12 percent) (108). Using an adjustable constriction device placed at the base of the penis after MUSE® administration resulted in an increase in successful sexual intercourse in 69 percent of men (109). The standard starting dose for MUSE® is 500-μg dosed in the office. Depending on the patient's response, this dose can be titrated from 250-1000 μg. It is important to administer the test dose in the office due to the risks of urethral bleeding, vasovagal reflex, hypotension, and priapism that can occur with this medication. There is a theoretical risk of prostaglandin transfer during vaginal intercourse after use of MUSE®; for this reason, MUSE® should not be used to facilitate vaginal intercourse in a partner who is pregnant.

 

INTRACAVERNOUS MEDICATIONS

 

There are several intracavernous medications available for the treatment of ED including papaverine, prostaglandin E1 (PgE1), and phentolamine (1, 110). These medications are commonly utilized in combinations which yield superior results and lower risk profiles due to synergistic properties between drugs. Of these, prostaglandin E1 is the only drug that is FDA approved as a single agent monotherapy injection for ED. The most common intracavernosal therapies used in the U.S. are two or three-drug mixtures containing papaverine, phentolamine and/or alprostadil (typically known as Bimix if contains the first two or Trimix if it contains all three) in varying concentrations. Some experts utilize atropine for injection-based ED therapy, which is compounded with trimix to form so called quadmix.  The usual dose of mixed solution ranges from 0.1 to 0.5 ml. These solutions have demonstrated efficacy and have been in clinical use for almost four decades. 

 

Due to risk of priapism or needle injury, men must receive appropriate training and education by medical personnel before beginning injection therapy for ED. The goal is to achieve an erection that is adequate for sexual intercourse but does not last for more than four hours. The two major side effects of intracavernous injection are priapism and fibrosis (penile deviation, nodules or plaque). Priapism is typically preventable through careful dose titration. Post-injection compression is recommended to reduce the likelihood of bleeding or bruising.  

 

In the U.S., the only FDA approved intracavernosal drug for ED is PgE1 (i.e., trade names Edex® and Caverject®). PgE1 results in erections usable for intercourse in more than 70 percent of treated men after appropriate dose titration (110). The usual dose ranges from 5 to 40 μg as a monotherapy. The most frequent side effect is painful erections that occur in 17 to 34 percent of men (110, 111). This hyperalgesic effect is most prominent in men with partial nerve injury, such as those with diabetic neuropathy and those who have undergone radical pelvic surgery. PgE1 has been associated with risk for priapism and corporal fibrosis as well (112, 113).

 

Papaverine is a non-specific phosphodiesterase inhibitor that increases cAMP and cGMP concentrations in penile erectile tissue (114). It is usually dosed at 15 to 60 mg. Specific side effects from papaverine include priapism and corporal fibrosis.

 

Phentolamine is a competitive alpha-adrenergic receptor antagonist. It is used in combination with papaverine (115, 116). Standard doses of phentolamine range from 0.5 to 3mg. The potential side effects of phentolamine include hypotension and reflex tachycardia.

 

Although the response rate to injection therapy is high, in long-term studies 38 to 80 percent of men cease to use the treatment over time (117). To avoid the cumbersome nature of injection therapy, some men alternate injection therapy with sildenafil or MUSE®, preferring injection in circumstances when an erection of longer duration is desired. Alternatively, in men whom injection therapy alone fails or is insufficient, combination of injections with PDE5I has been utilized in some settings (118). The risk of priapism is magnified in these cases so this option should be considered only in men with severe ED who require intensive stimulation to induce erection response.

 

OTHER DRUGS

 

Yohimbine (alpha 2-adrenetric receptor antagonist) (119), apomorphine (dopaminergic agonist) (120), and bremelanotide (a melanocortin analog) (121) have been investigated for ED but are not currently accepted standard treatments for ED (1).

 

SURGICAL MANAGEMENT OF ERECTILE DYSFUNCTION

 

Surgery is indicated for the management of ED refractory to medical management. One of the earliest contemporary surgical approaches to ED was described by Wooten in 1902, who recommended ligation of the dorsal vein of the penis as a means for restoring erections (122). The superficially placed rigid prosthesis made from synthetic material soon followed (123). These early prostheses tended to shift under the penile skin and were generally unsatisfactory.  

 

Truly modern penile prostheses originated in the early 1970s; these devices were revolutionary in that they were designed to be placed within the corpora cavernosa.  Although early models had substantial limitations, these devices were the first penile prosthetics to provide acceptable functional and cosmetic results (124, 125).

 

Penile arterial bypass surgery was also first reported as a treatment for ED in the 1970s (126).  Venous surgery for ED was re-introduced with modifications in the early 1980s to treat corporal veno-occlusive dysfunction (127).

 

While penile prosthetic devices are generally effective for a wide range of patients, vascular surgery (both arterial and venous) for ED has been effective only in very select patients, typically healthy young men with either congenital or traumatic ED. The 2018 AUA Guidelines on Erectile Dysfunction recommend against venous surgery for ED and recommend arterial revascularization only in highly select patients in centers of excellence (1). Penile prosthesis placement is the standard surgical treatment for ED.

 

Arterial Revascularization

 

Arterial revascularization offers patients the possibility of restoration of normal erectile function without the necessity of medications, injections or devices. Penile arterial bypass surgery was first described in the early 1970s (126) and has undergone many modifications since its early description (128). Penile arterial insufficiency is most frequently the result of general arteriosclerosis associated with medical conditions such as hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. In patients with arterial insufficiency from these entities, penile revascularization is unlikely to be of benefit as penile small vessel disease is likely to be present. Healthy young men with traumatic disruption of a discrete segment of the penile vasculature are the population who has the greatest chance of benefit from penile arterial revascularization (1, 128).

 

Penile arterial insufficiency is diagnosed by performing an intracavernous injection test followed by self-stimulation (audiovisual or manual). Duplex ultrasonography of the penis performed during injection and stimulation test can help delineate echogenicity of corporal tissues, peak flow velocity of cavernosal arteries, thickness of tunica albuginea and cavernosal arteries, diameter and wave form of arteries. If arterial insufficiency is confirmed, selective penile/pudendal arteriogram is necessary to identify penile vascular anatomy, demonstrate communication between cavernosal and dorsal arteries and confirm location of obstructive/traumatized arterial lesion (129).

 

Several techniques of revascularization have been described (128). Anastomosis of the epigastric artery to the dorsal penile artery (revascularization) or the deep dorsal vein (arterialization) is a common approach. Long term results in these patients are highly variable. Careful selection and refinements in technique can improve success rates.  Young men with arterial insufficiency secondary to pelvic trauma are the ideal patients for this procedure (128). The most frequent side effect with penile arterialization is glans hyperemia. This can occur in up to 13% of patients who have undergone epigastric artery-deep dorsal vein anastomosis. Other potential complications include infection, hematoma and thrombosis of anastomosis.

 

Venous Surgery

 

Venogenic dysfunction is often suspected during evaluation by the finding of a sub-optimal erectile response to intracavernosal injection despite a normal arterial response on duplex Doppler sonography (129). The presence of persistent end-diastolic flow of greater than 5 cm/sec on duplex sonography may signify venous leak ED. Appropriate conduct of duplex sonography requires repeat dosing of erectogenic agents; this is omitted by some practitioners and may contribute to a false positive finding of venous leak in a patient who would have a normal response to repeat dosing (129).

 

The gold standard confirmatory test for the diagnosis of venous leak ED is dynamic infusion cavernosometry and cavernosography (DICC). Cavernosometry and cavernosography can be used to document the severity of venous leakage as well as visualize the sites of leakage (130). Like duplex Doppler ultrasound of the penis, these procedures require administration of an erectogenic agent.  An abnormal cavernosometry result is 1) an intracavernosal infusion rate of greater than 10cc/minute of saline to maintain the erection or 2) a drop of intracavernosal pressure of greater than 50 mmHg within 30 seconds of terminating the saline infusion (131, 132).  An abnormal cavernosogram (performed immediately after cavernosometry) shows visualization of penile veins or venous leakage from the crura on films taken immediately after intracavernous injection of diluted contrast.

 

As venous surgery for ED is no longer a recommended standard of care, these tests are primarily of historical interest outside of a clinical trial setting.

 

Prosthetic Surgery

 

When there is lack of efficacy or dissatisfaction with medical management of ED, penile prosthesis placement is the procedure of choice for restoration of penile rigidity (48).  Penile prosthesis surgery is irreversible in that corporal tissue is permanently altered such that physiologic erections are no longer possible. Contemporary prostheses include two or three- piece hydraulic pumps and semi-rigid/malleable rods.

 

Most malleable prostheses are made of silicone rubber with a central intertwined metallic core.  The advantages of malleable devices are that they are easy to implant, easy to operate, and have few mechanical parts with minimal risk for mechanical failure.  The major disadvantage of the semi-rigid devices is that the penis is never fully rigid nor fully flaccid. These devices may interfere with urination, are difficult to conceal, and have a higher likelihood of device erosion. Malleable prosthesis is most commonly utilized in resource poor settings or for patients who want a device of minimal complexity (48, 133).  Examples of malleable prostheses are presented in Figures 4 and 5

Figure 4. Genesis® from Coloplast

Figure 5. Spectra™ from Boston Scientific

Two-piece inflatable prostheses consist of a pair of cylinders attached to a scrotal pump.  The reservoir is in the proximal portion of the cylinders. The prosthesis can be deflated by bending the penis at mid-shaft.  While these devices permit some appearance of flaccidity, the lack of a separate reservoir does limit the amount of detumescence that can be attained.  These devices represent a compromise between ease of use/placement and potential for expansion (48).  A two-piece penile prosthesis is shown in Figure 6.

Figure 6. Ambicor™ Two-piece Prosthesis from Boston Scientific

Three-piece inflatable prostheses are the gold standard for treatment of medically refractory ED.  These devices consist of paired penile cylinders, a scrotal pump, and a reservoir for saline that is placed in the suprapubic space or posterior to the rectus fascia. Three-piece prostheses provide excellent rigidity when erect and a more natural appearance when flaccid. When fully erect, they are as rigid as the two-piece device. In the flaccid state, they surpass flaccidity of two-piece prostheses (48).  Hydraulic three-piece penile implants account for about 85% of the US market. Examples of three-piece penile prosthesis are presented in Figures 7 and 8.

Figure 7. AMS 700™ Three-piece Prosthesis from Boston Scientific

Figure 8. Titan® Three-piece Prosthesis from Coloplast

Prostheses have very high satisfaction rates (>90%) in management of ED and modern prosthetics are very durable with mean lifespans of 10-15 years (134, 135).  This high satisfaction rate is likely due to the capacity of prostheses to allow for spontaneous and repeated reliable erections without external medications or devices. However, men willing to undergo implantation of a penile prosthetic are a self-selecting group and may not be representative of the general male population with ED.  

 

Infection remains the most devastating and feared complication of penile implant surgery. Modern prostheses allow for antibiotic impregnation and elution (136). In the setting of high volume surgeons, infection rates are less than 2% for first-time prosthesis (137).  Although some studies suggest that elevated HbA1c levels may predict a higher rate of infections in diabetics having penile prosthesis surgery, more recent studies refute this. Elevated HbA1c may not be a risk factor for infection but poor short-term blood sugar control (defined by morning fasting glucose levels >200 ng/ml) was associated with higher infection risk (138).

 

Patients must be counseled that it may take a significant amount of time to become comfortable operating penile implants.  Many men express dissatisfaction with penile length after prosthesis placement; careful counseling and setting reasonable expectations may help mitigate post-operative concerns.

 

PRIAPISM

 

Priapism is a prolonged penile erection in the absence of sexual stimulation. Two subtypes of priapism have been described; current nomenclature differentiates these as non-ischemic and ischemic (139).

 

Non-Ischemic Priapism

 

Non-ischemic (formerly known as high-flow) priapism, is relatively rare. In this scenario, injury to a cavernosal artery, usually after perineal or direct penile trauma, results in uncontrolled high arterial inflow within the corpora cavernosa. Non-ischemic priapism is typically painless and the penis only semi-erect.  Patients with arterial priapism typically seek medical attention later than those with ischemic priapism, due to the fact that non-ischemic priapism causes less pain and discomfort (139).

 

Non-ischemic priapism is not considered a medical emergency. In some series men have lived for many years with the condition (140).  In such cases men obtain additional tumescence with sexual arousal. In the setting where treatment is desired, conservative management (e.g., observation, ice packs, etc.) may allow the injured cavernous artery to seal off and restore normal blood flow to the corporal bodies. Androgen blockade with ketoconazole or gonadotropin-releasing hormone agonists have been reported as successful in management of non-ischemic priapism, possibly by reducing spontaneous erections and enabling healing of the fistula tract (141). In refractory cases, super selective arteriography allows for the exact determination of the site of injury and treatment through embolization (142). Surgical exploration and ligation of the fistula tract may also be considered by experienced surgeons. There is a risk of ED associated with aggressive treatment of high flow priapism, especially with the use of permanent embolic agents (143).

 

Ischemic Priapism

 

Ischemic (formerly known as low-flow) priapism is much more common and is characterized by inadequate venous outflow from the penis; this restricts arterial inflow and creates an acidotic hypoxic environment leading to a painful prolonged erection(139). Ischemic priapism is accurately conceptualized as compartment syndrome of the penis. This more common type of priapism has become a well-recognized clinical entity because of the widespread use of intracavernous agents for erections. Ischemic priapism is also commonly associated with blood dyscrasias (e.g., sickle cell disease, thalassemia, leukemia), advanced pelvic malignancies, and medications such as trazodone (139).

 

Ischemic priapism is a serious medical condition and can lead to permanent penile fibrosis and ED. When effectively treated early (within 6-12 hours of onset) little risk of permanent injury exists. Tissue injury is visible after 12 hours of ischemia, characterized as interstitial edema. Within 24 hours, there is destruction of the sinusoidal endothelium and adherence. Men with priapism of over 36 hours duration rarely if ever recover normal erectile function (139, 144).  Men using vasoactive drugs for penile self-injection should be instructed to seek medical attention if they experience an erection persisting longer than 3-4 hours.

 

Aspiration of corporal blood via a large bore needle is the procedure of choice to facilitate detumescence in ischemic priapism that is not mediate by intracavernous injection therapy. (139). In most cases, aspiration is followed by installation of a sympathomimetic agent; the agent of choice for the treatment of ischemic priapism is phenylephrine at a dosage of 100-250 ug per mL. The sympathomimetic agent is injected into the cavernous body via the same needle in 2-5 minute intervals until the penis is no longer rigid. At this concentration, little impact on the systemic BP is seen in most men although blood pressure and heart rate should be monitored.  

 

The recent AUA Guideline on Priapism suggests that aspiration may be omitted and the clinician may proceed immediately to phenylephrine injection in the setting of priapism induced by erectogenic injections (139). The AUA priapism guideline does not recommend the use of over-the-counter remedies for priapism such as pseudoephedrine, terbutaline, exercise, or ice packs because these have marginal efficacy and may delay initiation of effective therapy.  These remedies may be tried by patients, but patients should come promptly to a clinic or ER for definitive treatment(139).

 

Detumescence often occurs with initial injection and will first be noted with return of the arterial pulsations of the penis. Cases refractory to aspiration and sympathomimetic agents (typically those of longer duration) may require surgical shunting procedures to return the penis to a flaccid state (145, 146).

 

Although exchange transfusion and oxygenation is recommended by some for management of sickle cell related ischemic priapism (147), definitive management by phenylephrine irrigation with or without aspiration should not be delayed (148).

 

The long-term sequelae of ischemic priapism may include penile scarring and fibrosis, penile deformity, and ED. Strategies to avoid these complications include education in men using erectogenic agents and rapid treatment of priapism as it occurs. Some highly reliable patients with recurrent priapism related to sickle cell disease or other blood dyscrasia can be instructed on self-administration of phenylephrine (149).

 

CONCLUSIONS

 

As our understanding of the basic mechanisms of erectile function continues to grow, new and improved therapies for the management of ED will continue to emerge. We have witnessed a dramatic change in the treatment of men with erectile dysfunction over the past 30 years. Treatment options have progressed from psychosexual therapy and penile prostheses in the 1970s, through arterial revascularization, vacuum constriction devices, and intracavernous injection therapy in the 1980s, to transurethral and oral drug therapy in the 1990s.  Restoration of erectile capacity and facilitation of satisfying sexuality will remain an important goal for men and their sexual partners in the future.

 

ACKNOWLEDGEMENT

 

This manuscript was adapted from a prior version which included contributions from the following authors; William O. Brant, MD, Derek Bochinski, MD, Anthony J. Bella, MD.

 

REFERENCES

 

  1. Burnett, A.L., et al., Erectile Dysfunction: AUA Guideline. J Urol, 2018. 200(3): p. 633-641.
  2. Laumann, E.O., et al., A population-based survey of sexual activity, sexual problems and associated help-seeking behavior patterns in mature adults in the United States of America. Int J Impot Res, 2009. 21(3): p. 171-8.
  3. Laumann, E.O., et al., Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res, 2005. 17(1): p. 39-57.
  4. Nguyen, H.M.T., A.T. Gabrielson, and W.J.G. Hellstrom, Erectile Dysfunction in Young Men-A Review of the Prevalence and Risk Factors. Sex Med Rev, 2017. 5(4): p. 508-520.
  5. Kamenov, Z.A., A comprehensive review of erectile dysfunction in men with diabetes. Exp Clin Endocrinol Diabetes, 2015. 123(3): p. 141-58.
  6. Giuliano, F., Neurophysiology of erection and ejaculation. J Sex Med, 2011. 8 Suppl 4: p. 310-5.
  7. Steers, W.D., Neural pathways and central sites involved in penile erection: neuroanatomy and clinical implications. Neurosci Biobehav Rev, 2000. 24(5): p. 507-16.
  8. Giuliano, F. and O. Rampin, Neural control of erection. Physiology &amp; Behavior, 2004. 83(2): p. 189-201.
  9. Peeters, M. and F. Giuliano, Central neurophysiology and dopaminergic control of ejaculation. Neurosci Biobehav Rev, 2008. 32(3): p. 438-53.
  10. Dean, R.C. and T.F. Lue, Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am, 2005. 32(4): p. 379-95, v.
  11. Musicki, B. and A.L. Burnett, eNOS Function and Dysfunction in the Penis. Experimental Biology and Medicine, 2006. 231(2): p. 154-165.
  12. Banya, Y., et al., Two Circulatory Routes Within the Human Corpus Cavernosum Penis: A Scanning Electron Microscopic Study of Corrosion Casts. Journal of Urology, 1989. 142(3): p. 879-883.
  13. Fournier, G.R., et al., Mechanisms of Venous Occlusion During Canine Penile Erection: An Anatomic Demonstration. Journal of Urology, 1987. 137(1): p. 163-167.
  14. Aboseif, S.R. and T.F. Lue, Hemodynamics of penile erection. Urol Clin North Am, 1988. 15(1): p. 1-7.
  15. Araujo, A.B., B.A. Mohr, and J.B. McKinlay, Changes in sexual function in middle-aged and older men: longitudinal data from the Massachusetts Male Aging Study. J Am Geriatr Soc, 2004. 52(9): p. 1502-9.
  16. Echeverri Tirado, L.C., J.E. Ferrer, and A.M. Herrera, Aging and Erectile Dysfunction. Sex Med Rev, 2016. 4(1): p. 63-73.
  17. Thomas, C. and C. Konstantinidis, Neurogenic Erectile Dysfunction. Where Do We Stand? Medicines (Basel), 2021. 8(1).
  18. Fukui, M., et al., Andropausal symptoms in men with Type 2 diabetes. Diabetic Medicine, 2012. 29(8): p. 1036-1042.
  19. Defeudis, G., et al., Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev, 2022. 38(2): p. e3494.
  20. Angulo, J., et al., Enhancement of both EDHF and NO/cGMP pathways is necessary to reverse erectile dysfunction in diabetic rats. J Sex Med, 2005. 2(3): p. 341-6.
  21. Ryu, J.-K., et al., Erectile Dysfunction Precedes Other Systemic Vascular Diseases Due to Incompetent Cavernous Endothelial Cell-Cell Junctions. Journal of Urology, 2013. 190(2): p. 779-789.
  22. Lai, C.-F., et al., Sexual Dysfunction in Peritoneal Dialysis Patients. American Journal of Nephrology, 2007. 27(6): p. 615-621.
  23. Lew-Starowicz, M. and R. Gellert, The Sexuality and Quality of Life of Hemodialyzed Patients—ASED Multicenter Study. The Journal of Sexual Medicine, 2009. 6(4): p. 1062-1071.
  24. Bagcivan, I., et al., The evaluation of the effects of renal failure on erectile dysfunction in a rabbit model of chronic renal failure. BJU International, 2003. 91(7): p. 697-701.
  25. Kielstein, J.T. and C. Zoccali, Asymmetric Dimethylarginine: A Cardiovascular Risk Factor and a Uremic Toxin Coming of Age? American Journal of Kidney Diseases, 2005. 46(2): p. 186-202.
  26. Maio, M.T., et al., Calcification of the Internal Pudendal Artery and Development of Erectile Dysfunction in Adenine‐Induced Chronic Kidney Disease: A Sentinel of Systemic Vascular Changes. The Journal of Sexual Medicine, 2014. 11(10): p. 2449-2465.
  27. Waldinger, M.D., Psychiatric disorders and sexual dysfunction, in Neurology of Sexual and Bladder Disorders. 2015, Elsevier. p. 469-489.
  28. Makhlouf, A., A. Kparker, and C.S. Niederberger, Depression and erectile dysfunction. Urol Clin North Am, 2007. 34(4): p. 565-74, vii.
  29. Bhasin, S., et al., Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2018. 103(5): p. 1715-1744.
  30. Boloña, E.R., et al., Testosterone Use in Men With Sexual Dysfunction: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials. Mayo Clinic Proceedings, 2007. 82(1): p. 20-28.
  31. Mulhall, J.P., et al., Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol, 2018. 200(2): p. 423-432.
  32. Gandaglia, G., et al., A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol, 2014. 65(5): p. 968-78.
  33. Andersson, K.-E., Erectile Physiological and Pathophysiological Pathways Involved in Erectile Dysfunction. Journal of Urology, 2003. 170(2S).
  34. Levine, F.J., A.J. Greenfield, and I. Goldstein, Arteriographically determined occlusive disease within the hypogastric-cavernous bed in impotent patients following blunt perineal and pelvic trauma. J Urol, 1990. 144(5): p. 1147-53.
  35. Rajfer, J., A. Rosciszewski, and M. Mehringer, Prevalence of corporeal venous leakage in impotent men. J Urol, 1988. 140(1): p. 69-71.
  36. Christ, G.J., et al., Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in alpha-adrenoceptor responsiveness with age and disease in isolated tissues. Br J Pharmacol, 1990. 101(2): p. 375-81.
  37. La Torre, A., et al., Sexual Dysfunction Related to Drugs: A Critical Review. Part IV: Cardiovascular Drugs. Pharmacopsychiatry, 2014. 48(01): p. 1-6.
  38. Shindel, A., S. Kishore, and T. Lue, Drugs Designed to Improve Endothelial Function: Effects on Erectile Dysfunction. Current Pharmaceutical Design, 2008. 14(35): p. 3758-3767.
  39. Chang, S.W., et al., The impact of diuretic therapy on reported sexual function. Arch Intern Med, 1991. 151(12): p. 2402-8.
  40. Nguyen, P.L., et al., Adverse Effects of Androgen Deprivation Therapy and Strategies to Mitigate Them. European Urology, 2015. 67(5): p. 825-836.
  41. Biebel, M.G., A.L. Burnett, and H. Sadeghi-Nejad, Male Sexual Function and Smoking. Sexual Medicine Reviews, 2016. 4(4): p. 366-375.
  42. Grover, S., et al., Sexual dysfunction in patients with alcohol and opioid dependence. Indian journal of psychological medicine, 2014. 36(4): p. 355-365.
  43. Nehra, A., et al., The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc, 2012. 87(8): p. 766-78.
  44. Glina, S., I.D. Sharlip, and W.J.G. Hellstrom, Modifying Risk Factors to Prevent and Treat Erectile Dysfunction. The Journal of Sexual Medicine, 2013. 10(1): p. 115-119.
  45. Nehra, A., et al., Peyronie's Disease: AUA Guideline. The Journal of urology, 2015. 194(3): p. 745-753.
  46. Mulhall, J.P., et al., SUBJECTIVE AND OBJECTIVE ANALYSIS OF THE PREVALENCE OF PEYRONIE’S DISEASE IN A POPULATION OF MEN PRESENTING FOR PROSTATE CANCER SCREENING. Journal of Urology, 2004. 171(6 Part 1): p. 2350-2353.
  47. Gelbard, M.K., L. Chagan, and J.P. Tursi, Collagenase Clostridium histolyticum for the Treatment of Peyronie's Disease: The Development of This Novel Pharmacologic Approach. The Journal of Sexual Medicine, 2015. 12(6): p. 1481-1489.
  48. Levine, L.A., et al., Penile Prosthesis Surgery: Current Recommendations From the International Consultation on Sexual Medicine. The Journal of Sexual Medicine, 2016. 13(4): p. 489-518.
  49. Travison, T.G., et al., Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab, 2017. 102(4): p. 1161-1173.
  50. Wu, F.C., et al., Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med, 2010. 363(2): p. 123-35.
  51. Bhasin, S. and N. Ozimek, Optimizing Diagnostic Accuracy and Treatment Decisions in Men With Testosterone Deficiency. Endocr Pract, 2021. 27(12): p. 1252-1259.
  52. Yeap, B.B., et al., Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust, 2016. 205(4): p. 173-8.
  53. Corona, G., et al., Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. European Urology, 2017. 72(6): p. 1000-1011.
  54. Snyder, P.J., et al., Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374(7): p. 611-24.
  55. McCullough, A.R., et al., A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel((R))) insertion. J Sex Med, 2012. 9(2): p. 594-601.
  56. Corona, G., E. Maseroli, and M. Maggi, Injectable testosterone undecanoate for the treatment of hypogonadism. Expert Opin Pharmacother, 2014. 15(13): p. 1903-26.
  57. Khera, M., et al., A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol, 2014. 65(1): p. 115-23.
  58. Golla, V. and A.L. Kaplan, Testosterone Therapy on Active Surveillance and Following Definitive Treatment for Prostate Cancer. Current urology reports, 2017. 18(7): p. 49-49.
  59. Léon, P., et al., Low circulating free and bioavailable testosterone levels as predictors of high-grade tumors in patients undergoing radical prostatectomy for localized prostate cancer. Urologic Oncology: Seminars and Original Investigations, 2015. 33(9): p. 384.e21-384.e27.
  60. Natale, C., et al., Testosterone Therapy After Prostate Cancer Treatment: A Review of Literature. Sex Med Rev, 2021. 9(3): p. 393-405.
  61. Dupree, J.M., et al., The safety of testosterone supplementation therapy in prostate cancer. Nat Rev Urol, 2014. 11(9): p. 526-530.
  62. Basaria, S., et al., Adverse events associated with testosterone administration. The New England journal of medicine, 2010. 363(2): p. 109-122.
  63. Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013. 310(17): p. 1829-36.
  64. Cittadini, A., A.M. Isidori, and A. Salzano, Testosterone therapy and cardiovascular diseases. Cardiovasc Res, 2021.
  65. Muraleedharan, V. and T. Hugh Jones, Testosterone and mortality. Clinical Endocrinology, 2014. 81(4): p. 477-487.
  66. Goldstein, I., et al., Oral Sildenafil in the Treatment of Erectile Dysfunction. New England Journal of Medicine, 1998. 338(20): p. 1397-1404.
  67. Hatzimouratidis, K. and D. Hatzichristou, How to treat erectile dysfunction in men with diabetes: from pathophysiology to treatment. Curr Diab Rep, 2014. 14(11): p. 545.
  68. Madeira, C.R., et al., Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis. World J Urol, 2021. 39(3): p. 953-962.
  69. Phe, V. and M. Roupret, Erectile dysfunction and diabetes: a review of the current evidence-based medicine and a synthesis of the main available therapies. Diabetes Metab, 2012. 38(1): p. 1-13.
  70. Wright, P.J., Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract, 2006. 60(8): p. 967-75.
  71. Padma-Nathan, H., Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. The American Journal of Cardiology, 2003. 92(9): p. 19-25.
  72. Chrysant, S.G., Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension. Curr Hypertens Rep, 2013. 15(5): p. 475-83.
  73. Herrmann, H.C., et al., Hemodynamic Effects of Sildenafil in Men with Severe Coronary Artery Disease. New England Journal of Medicine, 2000. 342(22): p. 1622-1626.
  74. Muller, J.E., Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators. JAMA: The Journal of the American Medical Association, 1996. 275(18): p. 1405-1409.
  75. Kloner, R.A., et al., Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group. Am J Hypertens, 2001. 14(1): p. 70-3.
  76. Hattenhauer, M.G., et al., Incidence of Nonarteritic Anteripr Ischemic Optic Neuropathy. American Journal of Ophthalmology, 1997. 123(1): p. 103-107.
  77. Campbell, U.B., et al., Acute Nonarteritic Anterior Ischemic Optic Neuropathy and Exposure to Phosphodiesterase Type 5 Inhibitors. The Journal of Sexual Medicine, 2015. 12(1): p. 139-151.
  78. Flahavan, E.M., et al., Prospective Case-crossover Study Investigating the Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy and Phosphodiesterase Type 5 Inhibitor Exposure. Urology, 2017. 105: p. 76-84.
  79. Pomeranz, H.D., The Relationship Between Phosphodiesterase-5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy. Journal of Neuro-Ophthalmology, 2016. 36(2): p. 193-196.
  80. Hong, B.N., et al., High dosage sildenafil induces hearing impairment in mice. Biol Pharm Bull, 2008. 31(10): p. 1981-4.
  81. Thakur, J.S., et al., Hearing loss with phosphodiesterase-5 inhibitors: a prospective and objective analysis with tadalafil. Laryngoscope, 2013. 123(6): p. 1527-30.
  82. Carson, C.C., et al., The efficacy of sildenafil citrate (Viagra) in clinical populations: an update. Urology, 2002. 60(2 Suppl 2): p. 12-27.
  83. Kloner, R.A., Pharmacology and Drug Interaction Effects of the Phosphodiesterase 5 Inhibitors: Focus on α-Blocker Interactions. The American Journal of Cardiology, 2005. 96(12): p. 42-46.
  84. Lombardi, G., et al., Ten-year follow-up of sildenafil use in spinal cord-injured patients with erectile dysfunction. J Sex Med, 2009. 6(12): p. 3449-57.
  85. Seidman, S.N., et al., Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry, 2001. 158(10): p. 1623-30.
  86. Wagner, G., et al., Sildenafil Citrate (VIAGRA(R)) Improves Erectile Function in Elderly Patients With Erectile Dysfunction: A Subgroup Analysis. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2001. 56(2): p. M113-M119.
  87. Blander, D.S., et al., Efficacy of sildenafil in erectile dysfunction after radical prostatectomy. Int J Impot Res, 2000. 12(3): p. 165-8.
  88. Jarow, J.P., A.L. Burnett, and A.M. Geringer, Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol, 1999. 162(3 Pt 1): p. 722-5.
  89. van Ahlen, H., et al., The Real-life Safety and Efficacy of Vardenafil: An International Post-marketing Surveillance Study - Results from 29 358 German Patients. Journal of International Medical Research, 2005. 33(3): p. 337-348.
  90. Young, J.M., Vardenafil. Expert Opinion on Investigational Drugs, 2002. 11(10): p. 1487-1496.
  91. Goldstein, I., et al., Vardenafil, a New Phosphodiesterase Type 5 Inhibitor, in the Treatment of Erectile Dysfunction in Men With Diabetes. Diabetes Care, 2003. 26(3): p. 777-783.
  92. Montorsi, F., et al., Earliest Time to Onset of Action Leading to Successful Intercourse with Vardenafil Determined in an At‐Home Setting: A Randomized, Double‐Blind, Placebo‐Controlled Trial. The Journal of Sexual Medicine, 2004. 1(2): p. 168-178.
  93. Rajagopalan, P., et al., Effect of High-Fat Breakfast and Moderate-Fat Evening Meal on the Pharmacokinetics of Vardenafil, an Oral Phosphodiesterase-5 Inhibitor for the Treatment of Erectile Dysfunction. The Journal of Clinical Pharmacology, 2003. 43(3): p. 260-267.
  94. Hellstrom, W.J., et al., Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl, 2002. 23(6): p. 763-71.
  95. Forgue, S.T., et al., Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol, 2006. 61(3): p. 280-8.
  96. Brock, G.B., et al., Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol, 2002. 168(4 Pt 1): p. 1332-6.
  97. Young, J.M., Tadalafil Improved Erectile Function at Twenty-Four and Thirty-Six Hours After Dosing in Men With Erectile Dysfunction: US Trial. Journal of Andrology, 2005. 26(3): p. 310-318.
  98. Goldstein, I., et al., Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc, 2012. 87(9): p. 843-52.
  99. Jung, J., et al., Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers. Clin Ther, 2010. 32(6): p. 1178-87.
  100. Kyle, J.A., D.A. Brown, and J.K. Hill, Avanafil for erectile dysfunction. Ann Pharmacother, 2013. 47(10): p. 1312-20.
  101. Hatzichristou, D., et al., Sildenafil failures may be due to inadequate patient instructions and follow-up: a study on 100 non-responders. Eur Urol, 2005. 47(4): p. 518-22; discussion 522-3.
  102. Buvat, J., et al., Hypogonadal Men Nonresponders to the PDE5 Inhibitor Tadalafil Benefit from Normalization of Testosterone Levels with a 1% Hydroalcoholic Testosterone Gel in the Treatment of Erectile Dysfunction (TADTEST Study). Journal of Sexual Medicine, 2011. 8(1): p. 284-293.
  103. Spitzer, M., et al., Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction. Annals of Internal Medicine, 2012. 157(10): p. 681.
  104. Dahabreh, I.J. and J.K. Paulus, Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis. JAMA, 2011. 305(12): p. 1225-33.
  105. Oliva-Lozano, J.M., et al., What Are the Physical Demands of Sexual Intercourse? A Systematic Review of the Literature. Arch Sex Behav, 2022. 51(3): p. 1397-1417.
  106. Kloner, R.A., Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions. Am J Cardiol, 2005. 96(12B): p. 42M-46M.
  107. Werthman, P. and J. Rajfer, Muse therapy: preliminary clinical observations. Urology, 1997. 50(5): p. 809-811.
  108. Padma-Nathan, H., et al., Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med, 1997. 336(1): p. 1-7.
  109. Lewis, R.W., Transurethral Alprostadil with MUSE TM (medicated urethral system for erection) vs intracavernous Alprostadil - a comparative study in 103 patients with erectile dysfunction. International Journal of Impotence Research, 1998. 10(1): p. 61-61.
  110. Linet, O.I. and L.L. Neff, Intracavernous prostaglandin E1 in erectile dysfunction. Clin Investig, 1994. 72(2): p. 139-49.
  111. Porst, H., The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol, 1996. 155(3): p. 802-15.
  112. Canale, D., et al., Long-term intracavernous self-injection with prostaglandin E1 for the treatment of erectile dysfunction. Int J Androl, 1996. 19(1): p. 28-32.
  113. Chew, K.K., et al., Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impot Res, 1997. 9(4): p. 225-9; discussion 229-30.
  114. Stief, C.G. and U. Wetterauer, Erectile Responses to Intracavernous Papaverine and Phentolamine: Comparison of Single and Combined Delivery. Journal of Urology, 1988. 140(6): p. 1415-1416.
  115. Jeremy, J.Y., et al., Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br J Urol, 1997. 79(6): p. 958-63.
  116. Stief, C.G. and U. Wetterauer, Erectile responses to intracavernous papaverine and phentolamine: comparison of single and combined delivery. J Urol, 1988. 140(6): p. 1415-6.
  117. Purvis, K., I. Egdetveit, and E. Christiansen, Intracavernosal therapy for erectile failure—Impact of treatment and reasons for drop-out and dissatisfaction. International Journal of Impotence Research, 1999. 11(5): p. 287-299.
  118. Moncada, I., et al., Combination therapy for erectile dysfunction involving a PDE5 inhibitor and alprostadil. Int J Impot Res, 2018. 30(5): p. 203-208.
  119. Ernst, E. and M.H. Pittler, Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials. J Urol, 1998. 159(2): p. 433-6.
  120. Heaton, J.P., et al., Recovery of erectile function by the oral administration of apomorphine. Urology, 1995. 45(2): p. 200-6.
  121. Rosen, R.C., et al., Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res, 2004. 16(2): p. 135-42.
  122. Wooten, J.S., Ligation of the dorsal vein of the penis as a cure for atonic impotence. Texas Medical Journal, 1902. 18: p. 325-327.
  123. Simmons, M. and D.K. Montague, Penile prosthesis implantation: past, present and future. International Journal of Impotence Research, 2008. 20(5): p. 437-444.
  124. Scott, F.B., W.E. Bradley, and G.W. Timm, Management of erectile impotence. Use of implantable inflatable prosthesis. Urology, 1973. 2(1): p. 80-2.
  125. Small, M.P., Small-Carrion penile prosthesis: a report on 160 cases and review of the literature. J Urol, 1978. 119(3): p. 365-8.
  126. Michal, V., R. Kramar, and J. Pospichal, Femoro-pudendal by-pass, internal iliac thromboendarterectomy and direct arterial anastomosis to the cavernous body in the treatment of erectile impotence. Bull Soc Int Chir, 1974. 33(4): p. 343-50.
  127. Kim, E.D. and K.T. McVary, Long-Term Results With Penile Vein Ligation for Venogenic Impotence. Journal of Urology, 1995. 153(3): p. 655-658.
  128. Munarriz, R., N. Thirumavalavan, and M.S. Gross, Is There a Role for Vascular Surgery in the Contemporary Management of Erectile Dysfunction? Urol Clin North Am, 2021. 48(4): p. 543-555.
  129. Sikka, S.C., et al., Standardization of Vascular Assessment of Erectile Dysfunction. The Journal of Sexual Medicine, 2013. 10(1): p. 120-129.
  130. Delcour, C., et al., Impotence: evaluation with cavernosography. Radiology, 1986. 161(3): p. 803-806.
  131. Hatzichristou, D.G., et al., In Vivo Assessment of Trabecular Smooth Muscle Tone, its Application in Pharmaco-Cavernosometry and Analysis of Intracavernous Pressure Determinants. Journal of Urology, 1995. 153(4): p. 1126-1135.
  132. Nehra, A., et al., Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol, 1996. 156(4): p. 1320-9.
  133. Shah, R., Twenty-five years of the low-cost, noninflatable, Shah Indian penile prosthesis: The history of its evolution. Indian J Urol, 2021. 37(2): p. 113-115.
  134. Kim, D.S., et al., AMS 700CX/CXM Inflatable Penile Prosthesis Has High Mechanical Reliability at Long-Term Follow-Up. The Journal of Sexual Medicine, 2010. 7(7): p. 2602-2607.
  135. Ohl, D.A., et al., Prospective evaluation of patient satisfaction, and surgeon and patient trainer assessment of the Coloplast titan one touch release three-piece inflatable penile prosthesis. J Sex Med, 2012. 9(9): p. 2467-74.
  136. Al Mohajer, M. and R.O. Darouiche, Infections Associated with Inflatable Penile Prostheses. Sexual Medicine Reviews, 2014. 2(3-4): p. 134-140.
  137. Serefoglu, E.C., et al., Long‐Term Revision Rate due to Infection in Hydrophilic‐Coated Inflatable Penile Prostheses: 11‐Year Follow‐up. The Journal of Sexual Medicine, 2012. 9(8): p. 2182-2186.
  138. Cakan, M., et al., Risk factors for penile prosthetic infection. Int Urol Nephrol, 2003. 35(2): p. 209-13.
  139. Bivalacqua, T.J., et al., Acute Ischemic Priapism: An AUA/SMSNA Guideline. J Urol, 2021. 206(5): p. 1114-1121.
  140. Hakim, L.S., et al., Evolving concepts in the diagnosis and treatment of arterial high flow priapism. J Urol, 1996. 155(2): p. 541-8.
  141. Mwamukonda, K.B., et al., Androgen Blockade for the Treatment of High-Flow Priapism. The Journal of Sexual Medicine, 2010. 7(7): p. 2532-2537.
  142. Kim, K.R., et al., Treatment of High-flow Priapism with Superselective Transcatheter Embolization in 27 Patients: A Multicenter Study. Journal of Vascular and Interventional Radiology, 2007. 18(10): p. 1222-1226.
  143. Savoca, G., et al., Sexual function after highly selective embolization of cavernous artery in patients with high flow priapism: long-term followup. J Urol, 2004. 172(2): p. 644-7.
  144. Bennett, N. and J. Mulhall, Sickle cell disease status and outcomes of African-American men presenting with priapism. J Sex Med, 2008. 5(5): p. 1244-1250.
  145. Brant, W.O., et al., T-Shaped Shunt and Intracavernous Tunneling for Prolonged Ischemic Priapism. Journal of Urology, 2009. 181(4): p. 1699-1705.
  146. Burnett, A.L. and P.M. Pierorazio, Corporal “Snake” Maneuver: Corporoglanular Shunt Surgical Modification for Ischemic Priapism. The Journal of Sexual Medicine, 2009. 6(4): p. 1171-1176.
  147. Marouf, R., Blood transfusion in sickle cell disease. Hemoglobin, 2011. 35(5-6): p. 495-502.
  148. Merritt, A.L., C. Haiman, and S.O. Henderson, Myth: blood transfusion is effective for sickle cell anemia-associated priapism. CJEM, 2006. 8(2): p. 119-22.
  149. Teloken, C., et al., Intracavernosal etilefrine self-injection therapy for recurrent priapism: one decade of follow-up. Urology, 2005. 65(5): p. 1002.

 

An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs

ABSTRACT

 

The epidemic of obesity cries out for strategies to prevent it, and for treatment when prevention fails. Yet despite the obvious need, the path to developing anti-obesity medications is strewn with failures. This review examines some historical developments in the management of obesity prior to the 20th century followed by more recent efforts to find a “cure.” Since obesity has been a human disease since paleolithic times, discussion of treatment prior to the scientific revolution in about 1500 CE will include comments on treatment of obesity in Grecian Medicine and the Treatment of Sancho “The Fat” King of Leon in 10th century northern Spain. We will then trace treatment trends through time, ending in the early 21st century. In the first half of the 20th century there were 3 main themes associated with drug treatment of obesity: use of thyroid hormones, the interlude with dinitrophenol as drug regulation was beginning to expand, and the introduction of amphetamines and Rainbow Pills. In the second half of the 20th century many new treatment approaches were explored as the scientific basis for understanding regulation of food intake expanded, particularly after the discovery of leptin in 1994. The fact that amphetamine could be addictive led to the search for compounds that acted in the central nervous system with retained the anorectic properties but were not addictive. Both anti-depressant and anticonvulsive drugs were evaluated with disappointing results. The idea of enhancing energy expenditure with thermogenic drugs was pursued but led to a dead end. Peptides, metabolic drugs and drugs that act on the gastrointestinal track are currently under exploration. This chapter makes an effort to answer the question of why it has been so difficult to develop effective medications for the management of obesity.

 

INTRODUCTION

 

 “When we say that science is essentially progressive this does not mean that in his quest for truth man follows always the shortest path.  Far from it, he beats about the bush, does not find what he is looking for but finds something else, retraces his steps, loses himself in various detours, and finally after many wanderings touches the goal”. Georges Sarton (1)

 

This brief historical review will examine some of the ‘wanderings’ that have occurred in the search for medications to use in the management of obesity (anti-obesity medications, or AOM’s). It is set against the broader long-time changes in our knowledge of how obesity develops and the result of attempts to treat it effectively. Over human history since the Cognitive Revolution some 75,000 years ago (2), knowledge has expanded logarithmically (Figure 1). There is every indication that it is continuing to expand as evidenced by the explosion of knowledge around the SARS-Covid-19 Pandemic of 2020 and its detrimental impact of people with obesity.

Figure 1. Expansion of Knowledge since the Cognitive Revolution

Beginning in the upper Paleolithic era between 25,000 and 35,000 years ago we find the first representations of obesity in human figurines, including the Venus of Hohle Fels (3), and mere 10,000 years later the Venus of Willendorf (4). The agricultural revolution and domestication of animals occurred about 10,000 years ago and during this period there were many other representations of the human with obesity from many parts of the world. Compared to the long 15,000 year interval between carving of the Venus of Willendorf and the Agricultural Revolution we are living in a very small slice of time. This slice might appropriately begin with the Scientific Revolution dated to 1543 CE, when Copernicus published his theory of the heliocentric nature of the planetary system, Vesalius published his anatomy on the fabric of the human body and the subsequent Industrial Revolution that began about 1750 CE (5). During the next 500 years, the oxygen theory of metabolism was articulated by Laennec (1793), the first law of thermodynamics was published by von Helmholtz (1848), the concept of cells as the basic of life was presented by Schwann and Schleiden (1839), and the first clear differentiation of types of obesity were made by Babinski (1900), Frohlich (1901), and Cushing (1912). The 20th century has brought enormous changes to health care and offers great promise for people with obesity, but the road to discovery of medications for treatment of obesity has been a tortuous one but one that finally offers promise of success.

 

In the past 100 years, earnest efforts to deploy anti-obesity treatments were repeatedly tried and failed. The first three are the story of thyroid hormones, the story of dintrophenol, and the story of amphetamines. These 3 medications were tested in people with obesity against a background of growing governmental regulation of medicines and rapidly expanding knowledge about the causes of obesity. Although the timing for different treatments often overlap, Figure 2illustrates the gradual evolution to the present day. We begin with the colorful history of the Rainbow Pills, followed by the anorectic drugs. The year 1994 marks a major milestone – it was the year that leptin was discovered – a discovery that gave obesity a strong biological base from which further discoveries have continued (6).

Figure 2. Historical events and the development of anti-obesity medications in the past 100 years

There are three underlying principals in developing any treatment for managing obesity:  First, do no harm. This is a principal that dates back at least to the time of Hippocrates 2500 years ago. The second concept is that treatments don’t work unless used. If you don’t take the medicine designed to treat obesity you can’t expect the obesity to disappear as if by magic.  Third, if an individual being treated for their obesity doesn’t lose weight for one reason or another it is unreasonable to anticipate that they will get any benefits that might be associated with weight loss.

 

THE FAILURE OF MEDICATIONS USED TO TREAT OBESITY

 

Management of obesity is strewn with misadventures (Table 1) (7). Below is a selected list of failures in the search for treatments for obesity. Some of these problems occurred before marketing, but others only after the drug had been approved for marketing.

 

Table 1.  Some of the Unintended Consequences that have Led to the Withdrawal of Medications Used for Management of Obesity

Year

Drug

Alleged Mechanism

Reason for Discontinuation

1892

Thyroid

Thermogenesis

Hyperthyroidism

1932

Dintrophenol

Thermogenesis

Disapproved due to Cataracts/Neuropathy

1937

Amphetamine

Sympathomimetic

Disapproved due to Addiction

1961-90

Human chorionic gonadotropin

Reduce food intake

Disapproved - Ineffective compared to placebo

1971

Aminorex

Sympathomimetic

Withdrawn after marketing due to Pulmonary hypertension

1985

Gelatin-based very low-calorie diet

Reduce food intake

Cardiovascular Deaths (Torsade de Points)

1991-95

Fluoxetine

Serotonin reuptake inhibitor

Weight regain after loss

1985-98

β-3 Agonists

Increased thermogenesis

Limited Effect; Increased HR

1997

Fenfluramine

Serotonergic receptor activation (? 5HT2c)

Withdrawn after marketing due to cardiac valvulopathy and pulmonary hypertension

1998

Phenylpropanolamine

Sympathomimetic

Withdrawn after marketing for Strokes

1999

Leptin

Leptin receptor agonist-reduced food intake

Limited Weight Loss

2003

Ephedrine/Caffeine & Herbal Ma Huang

Sympathomimetic and adrenergic blocker

Withdrawn after marketing for Heart attacks/stroke

2003

Ciliary Neurotrophic Factor

Acts on leptin receptor

Produced neutralizing antibodies

2007

MK-0557

Neuropeptide Y5 (NPY) receptor antagonist-reduced food intake.

Limited effectiveness

2007

Ecopipam

D2/D5 agonist-Reduce food intake

Suicidality

2008

Tesofensine

Triple Monoamine Reuptake Inhibitor

Raised blood pressure

2009

Melanocortin-4 Receptor Agonist

Reduce Food Intake

Limited effectiveness, priapism

2010

Capsinoids

Thermogenesis

Limited effectiveness

2010

Rimonabant

Endocannabinoid agonist

Suicidality

2011

Sibutramine

Triple Reuptake Inhibitor

Withdrawn after marketing for cardiovascular toxicity

2020

Lorcaserin

Serotonergic Reduce Food Intake

Cancer

 

TREATMENT OF OBESITY BEFORE THE SCIENTIFIC REVOLUTION, c. 1543 CE

 

Diet (meaning limiting total calories) and exercise have been the cornerstones of treatment for the patient with obesity since at least the time of Hippocrates 2500 years ago. Following are a few examples of where medications have been used as adjuncts, and sometimes as the main line of treatment throughout these many centuries.

 

Greco-Roman Medicine

 

The problem of obesity was well known to physicians in the Greco-Roman period from 500 BCE to 500 CE. “An Egyptian pharaoh was said to have a middle wider than the span of his slave’s outstretched arms.” Nichomachus of Smyrna “…was so huge that he couldn’t even get up from his bed” ((8); p 20). Dionysius of Heraclea was so obese that his attendants needed to stick pins into him to keep him from falling asleep on his throne. In retrospect some observers think he may have had a sleep disturbance like sleep apnea (9). The enormous size of a Roman Senator was such that he could only walk when two of his slaves carried his belly for him.

 

Among the earliest attempts at producing weight loss by adding compounds to the treatment regimen have been ascribed to Soranus of Ephesus, a 2nd century CE Greek physician.  Much of what we know about Soranus’ work in the 2nd century CE comes from translations by Caelius Aurelianus in the 5th Century. Both describe obesity as a disease where the body keeps acquiring additional flesh beyond what is needed. They believe it is an “unsightly affliction” because there are no apparent symptoms other than the increase of flesh. The Greek model of disease involved four humors (blood, phlegm, yellow bile, and black bile) being out of balance.  Treatment was needed to rebalance what was out of balance – for obesity this meant less intake and more output through purgatives and diuresis (10). Soranus’ regimen consisted of laxatives and purgatives along with exercise, heat, and massage. Indeed, laxatives have been a recurrent theme in the historic management of obesity. Induction of vomiting was also used for treating both the obese and to remove excess alcohol during Roman orgies. “Fat individuals should vomit in the middle of the day, after a running or marching exercise and before taking any food”. The emetic for this purpose was half a cup of the hyssop plant (0.15 L) ground with three liters of water to which vinegar and salt are added.  Vinegar was another favorite for use in the context of humoral medicine ((8); p 18). Since obesity was considered as a “moist and cool” condition in the humoral view of health, vinegar which is dry and warm would be an appropriate balancing agent. We will see vinegar resurface in later periods.

 

Obesity in the Hindu Tradition

 

Ayurvedic Medicine originated in India more than 3,000 years ago and is derived from the Sanskrit words ayur (life) and veda (science or knowledge). In India, Ayurvedic Medicine is considered a form of medical care equal to conventional Western medicine, traditional Chinese medicine, naturopathic medicine, or homeopathic medicine. Practitioners of Ayurveda in India undergo state-recognized, institutionalized training. Two names are primarily associated with the early writings on Ayurvedic medicine, Sushruta and Charaka. Although the exact dates are unclear, they probably lived between 600 BCE and 100 CE. Sushruta, often referred to as the “Father of Indian Medicine” or the “Father of Plastic Surgery,” developed the Sushruta Samhita, one of the foundational texts of Ayurvedic Medicine. The second text, the Charaka-Samhita or “compendium of Charaka,” was composed by Charaka. Both texts remained foundational for 2 millennia and were translated into many foreign languages. They both discussed general principles of medicine, pathology, diagnoses, anatomy, therapeutics, pharmaceutics, and toxicology. The Sushruta Samhita provides more exposure to surgery. These texts are credited with very early recognition of the sugary taste of diabetic urine and that this disease often affected indolent, overweight people who ate excessively, especially sweet and fatty foods. “[O]vereating... causes illness and shortens life span. It is a contraindication to the use of compresses or mild enemas. For treatment of obesity two suggestions are made…The vigorous massage of the body with pea flour counteracts phlegm diseases and obesity...The gullet hair compress and flesh of a wolf remedy [to treat] goiters, dropsy and obesity.” (11).

 

Obesity in the Islamic Tradition:  10th and 11th Century

 

In the 7th century following the revelations from God, the prophet Muhammad began preaching his religious beliefs that gradually unified Arabia into a single entity. The Islamic religion spread rapidly across the Middle East, North Africa and into the Iberian Peninsula. Centers of cultural excellence in Baghdad in the east, and in Cordoba, on the Iberian Peninsula soon appeared. We will focus on two physician-scholars and their impact on management of obesity in the 10th and 11th century. Ibn Sinha (980-1037 CE), anglicized as Avicenna was from the Middle Eastern part of the Islamic Caliphate, and the Jewish physician Hasdai ibn Shaprut (917-970 CE) from the Western Islamic area of Cordoba on the Iberian Peninsula.

 

Abu Ali Ibn Sina (Avicenna) was a prolific and influential author who published the most influential medical textbook of the Middle Ages called the Canon (12, 13). The Canon contains no personal experiences and no new ideas but was rather a summary of existing knowledge and was widely used in medical schools for hundreds of years. Avicenna surpassed both Aristotle and Galen in his dialectical subtlety (14, 15), and by some estimates published more than 100 medical books, as well as books in other areas. Avicenna describes how to manage the patient with obesity in four stages:  1) Produce a rapid descent of the food from the stomach and intestines, in order to prevent completion of absorption by the mesentery (16); 2) Take food which is bulky but feebly nutritious (17); 3) Take the bath before food, often (18); and 4) Hard exercise (19).

 

Hasdai ibn Shaprut enters this story because he treated King Sancho I (aka Sancho the Fat). Sancho I (935-966) became king of Leon (Pamplona, Spain) in 958 A.D when the elder King Ordono III died. Sancho’s reign was short-lived because of his fatness. “The nobility of Leon thought of him as weak-willed because of his obesity” and he was deposed (20). Sancho’s grandmother, Toda Arnez, who had once ruled the kingdom, was determined to help Sancho regain his throne. First, she took him to the local physicians who were unsuccessful in helping him lose weight. Although she loathed the Muslims, who occupied the southern part of the Iberian Peninsula in the 10th century, Toda and Sancho sought the help of Hasdai ibn Shaprut (917-970 CE), a brilliant and learned Jewish physician living in Cordoba. Shaprut was physician to the Muslim Caliph, Abd al Rahman in Cordoba, a major cultural center in the 10th century. Cordoba in the 10th century occupied a place similar to Rome in the 1st century or New York City in the 20th century. It was also renowned as one of the great medical centers of the late Middle Ages. In a day when house calls were still in fashion, Shaprut went to Pamplona to evaluate Sancho, and agreed to take him as a patient, but advised that it would be a long treatment requiring Sancho to relocate to Cordoba. Because of the seriousness of the problem, both medically and politically, Sancho and his grandmother Toda moved from Pamplona to the Muslim southern Iberian city of Cordoba. The medicine that Sancho received was “Theriaca.” This mixture of ingredients is said to have originated with Mitridates VI in Grecian times. He developed it as an antidote for snake bites. It can be compounded with up to 64 or more ingredients, with principal ingredients being opium, ginger, cinnamon, myrrh, saffron, and castor oil, a well-known laxative. Over time, Sancho gradually lost weight. When he returned to Leon as a leaner man who could mount his horse, and he was able to retake his throne. From this story, it is clear that not even kings and rulers are immune to obesity or the bias against obesity that led to his overthrow. Apparently, a king may be cruel, but not fat. Another lesson is that medical treatment of obesity can be effective if properly done. For Sancho, theriac had a dramatic success and allowed him to regain his throne and his kingdom (21).

 

DRUGS FOR TREATMENT OF OBESITY:  1500-1900 CE

 

The year 1543 CE is an appropriate one for demarcating a big divide in our view of progress in the management of obesity. It was the year that the Polish monk, Copernicus, published his book showing that the planets revolved around the sun, thus destroying the long-held view that the sun rotates around the earth. Less than 50 years earlier, movable type was invented by Gutenberg in Mainz, Germany a discovery that revolutionized the transmission of knowledge. In 1492 Columbus discovered the New World, opening up new wealth, cultures and lands and products such as tobacco that affect body weight. At about the same time, the dramatic events of the Protestant Reformation begun by Martin Luther challenged the primacy of the Roman Catholic Church. In the same year as Copernicus published his book, the first scientifically accurate book on human anatomy was published by Vesalius. Heady times these!

 

The five centuries since the scientific revolution have seen the industrial revolution (ca 1750), the second agricultural revolution (1750-1900) and the internet revolution of the present day. This expanding base of knowledge (Figure 1) provides the intellectual basis for understanding obesity as we know it today.

 

Sixteenth Century

 

The 16th century is often labeled the “century of discovery.” It is also the century where the corpulent King Henry VIII showed what happens when excess food is abundant, and exercise too little. Christopher Columbus had just discovered the New World in 1492 and brought tobacco, tomatoes, and many other products back to Europe with him. Tobacco became a treatment for obesity. We now know that nicotine is addictive, and that smoking can both reduce food intake and stimulate energy expenditure (22). Cessation of smoking is associated with weight gain (22), making this one of the challenges of stopping smoking. In the 16th century, the use of vinegar originally described many centuries earlier was again used as a treatment for obesity. However, obesity was less common in the 16th century, and maintaining good health through diet and exercise remained the goals for healthy living.

 

Seventeenth Century

 

Obesity gradually increased in prevalence such that strategies for its management appeared in textbooks for physicians in the 17th century. There were several formulas for treating “obesitas or corpulency,” listed in the textbook by Theophile Bonet (Bonetus), a leading physician of the time.  They give a flavor of the strategies beyond diet and exercise that were used by physicians to treat obesity in the 17th century. To quote from Bonet ((23); p 390):

 

  1. “Chiapinius Vitellius, Camp Master-General, a middle-aged man, grew so fat, that he was forced to sustain his belly by a swathe, which came about his neck: And observing that he was every day more unfit for the Wars than others, he voluntarily abstained from Wine, and continued to drink vinegar as long as he lived; upon which his Belly fell, and his Skin hung loose, with which he could wrap himself as with a Doublet. It was observed that he lost 87 pounds of weight. [Note: Vinegar and cleansing, or cathartic agents have a long history for treating obesity-See Grecian Medicine above] (Underlining mine).
  2. “Lest any great mischief should follow, we must try to subtract by medicine, what a spare diet will not; because it has been observed, that a looseness either natural, or procured by Art, does not a little good. But this must be done by degrees and slowly, since it is not safe to disturb so much matter violently, lest it should come all at once. Therefore, the best way of Purging is by Pills, of Rheubarb, Aloes each 2 drachms [1drachm = 1/8 ounce or 60 grains], Agarick 1 drachm, Cinnamon, yellow Sanders, each half a drachm.  Make them up with Syrup of Chichory. They must be taken in this manner; First, 1 Scruple* must be given an hour and a half before Meal; then two or three days afterwards, take half a drachm or two scruples before Meal. Thus, purging must be often repeated at short intervals, till you think all the cacochymie is removed.  *[scruple – a unit of apothecary weight equal to about 1.3 grams, or 20 grains] [Note: Purgatives also go back to Grecian Medicine]
  3. “A certain Goldsmith, who was extreme fat, so that he was ready to be choaked, took the following Powder in his Meat, and so he was cured; Take of Tartar two ounces, Cinnamon three ounces, Ginger one ounce, Sugar four ounces. Make a Powder.
  4. Horstius found the things following to take down fat Men; especially onions, Garlick, Cresses, Leeks, Seed of Rue, and especially Vinegar of Squills: Let them purge well: Let them Sweat, and purge by Urine: Let them use violent exercise before they eat: Let them induce hunger, want of Sleep and Thirst. Let them Sweat in a Stove and continue in the Sun. Let them abstain from Drink between Dinner and Supper: for to drink between Meals makes Men fat.
  5. “I knew a Nobleman so fat, that he could scarce sit on Horse-back, but he was asleep; and he could scarce stir a foot. But now he is able to walk, and his body is come to itself, only by chewing of Tobacco Leaves, as he affirmed to me. For it is good for Phlegmatick and cold Bodies.
  6. “Let Lingua Avis, or Ash-Keyes be taken constantly about one drachm in Wine. According to Pliny it cures Hydropical persons, and makes fat people lean” (23). 

 

Eighteenth Century

 

The 18th century witnessed publication of the first two English monographs dealing exclusively with obesity. In each book, the author proposed a new way of treating obesity based on his own theory of how obesity developed. The first book by Dr. Thomas Short was published in 1727 (24). From Short’s perspective, treatment of obesity required restoring the natural balance and removal of the secondary causes. If possible, one should pick a place to live where the air is not too moist or too soggy and one should not reside in flat, wet countries or in the city or the woodlands. He thought that exercise was important and that the diet should be “moderate spare and of the more detergent kind” (24).

 

The second book was by Dr. Malcolm Flemyng, a graduate of the medical school in Edinburgh (25). His approach to treatment of obesity was based on the results of a patient that he presented to the Royal Society in London in 1757 and subsequently published in 1760. Flemyng’s theory was that sweat, urine, and feces all contained “oil” and that effective treatment for obesity required increased loss of “oil” by one or more of these 3 routes. Thus, laxatives, diuretics and sweating were his principal approach to the treatment of obesity. To quote Flemyng:

“Now we are so happy as to be in possession of a diuretic medicine, which has that quality [increases the quantity of urine and “renders the animal oil more mixable with the watery vehicle of the blood, that otherwise it would be” (a diuretic which) in a singular degree; and is withal so safe, as that it may be taken in large quantities every day for years together, without remarkably impairing the general health: that medicine is soap” ((25); p. 19).

 

Flemyng believed that obesity, or corpulency as it was often called, could be prevented as well as cured by the medical use of soap. In his book he presents a physician weighing 291 pounds (20 stone 11 lbs.) who lost more than 28 lbs. (2 stone) with this treatment.

 

DRUG TREATMENT OF OBESITY IN MODERN TIMES:  1900-2020 CE

 

The progress of science from 1543 onward has had an impact on obesity that is nicely illustrated in the effects on measurement of body composition. From the time of Hippocrates 2500 years ago it has been possible to assess obesity at the whole-body level, referred to as Level I in the model of Wang et al (26). With the accurate description of human anatomy beginning with Vesalius in 1543, obesity could be viewed from the tissue and organ level (level II). In 1839 the concept of the “cell” was introduced leading to a cellular analysis of obesity or Level III in this model. As chemistry advanced in the 19th century, obesity could be viewed at the molecular level or Level IV in this model. Finally in the 20thcentury techniques for measuring body composition at the atomic level were introduced adding Level V to the model. Advancing basic science thus clearly provided a base for improving measurements of body composition and for understanding how and why obesity develops.

 

Thyroid Hormone:  1893-1994

 

THE BEGINNING

 

The introduction of thyroid hormone as a treatment for obesity can be dated to 1893 and represents the first drug used on a rational basis for treatment of this problem. In 1888 the Myxedema Commission published a report on a disease called myxedema, a form of severe hypothyroidism (27). They found that it resulted from failure of the thyroid gland. Patients with myxedema have a puffy type of weight gain, slowing of their thought processes and speech, and, if severe, a drop in body temperature and coma. When these patients are treated with thyroid extract, all these symptoms, including the weight gain are reversed. Proof of a cause-and-effect relationship of the thyroid gland to myxedema came when the thyroid was removed and the symptoms were corrected by treatment with thyroid hormone extract.

 

In 1893, less than 5 years after the Myxedema Commission Report, the use of thyroid preparations for treatment of obesity had appeared in medical literature. Thyroid extract was the major form of thyroid hormone available until thyroxine was isolated by Kendall in 1915 (28) and synthesized in 1926 by Harrington (29).

 

THE GENIE IS OUT OF THE B0TTLE: 1893 to 1953

 

Once it was clear that thyroid could increase metabolic rate, the genie was out of the bottle.  In 1893 in his report on “Cases of Myxedema and Acromegalia Treated with Benefit of Sheep’s Thyroid” Dr. J.J. Putnam from the Massachusetts General Hospital included a footnote ((30); p. 130) saying:

“Dr. Barron has very kindly written to me that he has used the treatment [with thyroid] in 5 cases of ordinary corpulence. One lost twenty-eight pounds in 6 weeks, three a moderate amount, and all lost more or less. I [Putnam] am trying it in two cases but have no results to report as yet” (30).

 

Following in the footsteps of this this report were two others: one by Yorke-Davies in 1894 (31) and another independently by Wendelstadt (32) describing the use of thyroid substance to treat patients with obesity. Their communications, and that of Leichtenstern (33), brought a short wave of popularity for the treatment of corpulency [obesity] by thyroid preparations that, along with iodine, soon became the mainstays of patent medicines and various nostrums used for weight loss. As Foxcroft notes:

“It [iodine] was one of the secret ingredients in some of the most popular and widely advertised patent medicines against fat including: Allan’s Anti-Fat; Frank J Kellogg’s Safe Fat Reducer; Dr. Bertha C. Day’s Fort Wayne prescriptions, Marmola, Newman’s Obesity Cure, Chichester’s Corpus Lean, Rengo, Dr. Gordon’s Elegant Pill, Corpulin, Elimiton, Phy-th-rin, San-Gri-Na Trilene tablets – all these contained either fucus (bladderwrack) or thyroid extract, or Ipecac (a plant-based emetic), camphor (an appetite suppressant), potassium acetate (a diuretic) and digitalis ( a stimulant)” ((8); p. 103).

 

Many of these ingredients were subsequently found in “Rainbow Pills” that were popular later in the 20th century (See below).

 

From the beginning, use of thyroid hormone to treat obesity raised concerns (8). For example, Woods Hutchinson, a medical professor in the United States who frequently wrote for women's magazines such as Cosmopolitan, said in1894 that physicians didn't have any idea how thyroid, often prescribed with potassium (and sometimes arsenic), worked:

"Both [thyroid and arsenic] cause, in some curious manner which we do not as yet understand, such an interference with the normal metabolism of the body as to cause the burning up and elimination of considerable amounts of body fat."

 

Hutchinson further noted that if patients lost more than ten percent of their body weight—the "movable ten percent," he called it—the results could be injurious. "The appetite becomes impaired, the sleep broken, and the heart's action irregular." If prolonged, the drug would set up a "serious and obstinate disturbance of the nervous system, and particularly of the nerves controlling the heart, accompanied by palpitation, sweating, weakness, and intense nervousness." (8)

 

Also expressing concern was Professor Sajous, first President of the Endocrine Society who said:

“The fact that thyroid preparations in sufficient doses promote the rapid combustion of fats has caused them to be used extensively in this disorder…In large doses (thyroid gland) imposes hyperoxidation upon all cells…we behold gradual emaciation beginning with the adipose tissues, which are the first to succumb. Hence the use of thyroid preparations in obesity. Briefly, in all cases of obesity in which thyroid gland is rationally indicated, the feature to determine is whether directly or indirectly hypothyroidea underlies the adiposis.” (34)

 

Administration of thyroid hormone to obese subjects whose basal metabolism is normal seemed illogical and was contraindicated according to some physicians (35, 36). However, Evans and Strang, two highly respected physicians, did use thyroid therapy in two percent of their cases, selecting those in which the initial level of the twenty-four-hour resting metabolic rate was not greatly above “ideal” (37). Two other physicians, Lyon and Dunlop, reported on the effects of diet and thyroid treatment in 24 hospitalized patients with obesity who were prescribed a 1000 kcal/d diet. The average daily weight loss was 162 g/d. When non-toxic doses of thyroid were added, the average daily weight loss increased to 273 g/d and then fell back to 153g/d when thyroid was withdrawn (38).

 

Some physicians used thyroid hormone as an adjunct to a hypocaloric or sub-maintenance diet in all forms of obesity, provided that that there were no contraindications. In an outpatient study of 106 unselected patients with obesity, Bayer and Gray treated 100 with diet alone, 51 with added thyroid and 23 with added dinitrophenol (see below) (39). Diet alone produced a weight loss of 15 lbs. (6.8 kg) in 3 1/2 months, after which weight stabilized following a loss of 10 to 20 pound (4.5 to 9.1 kg). Next, 41 of these patients were given thyroid extract averaging 1½ grains (96 mg/d) per day and lost a further 11 pounds (5.0 kg). Eleven other patients were given dinitrophenol at an average dose of 165 mg/d and lost a further 12 pounds (5.4 kg). This study demonstrated the value of adding either thyroid or dinitrophenol after weight loss ceased on a sub-maintenance calorie diet. Both drugs seemed to be more effective when the metabolic rate was low. When one drug followed the other there was a small additional weight loss, which was similar at about 4 pounds (1.8 kg) with either order of transfer.

 

One downside to using supraphysiologic doses of thyroid hormone in the management of obesity is that it increases the catabolism of protein, and thus the loss of lean body mass, which is a proportionally larger amount of the weight loss than is the loss of fat (40).

 

At the time of World War II, the status of thyroid hormone was summarized in two monographs. In the first famous monograph, Obesity and Leanness by Rony, 1940 (41), the author wrote:

“When thyroid is administered to obese subjects with a normal level of basal metabolism, living on unrestricted diet, a few of the subjects lose considerable weight when the basal metabolism is increased by 10 to 20 per cent. However, administration of non-toxic doses of thyroid is not followed by appreciable loss of weight in most subjects as long as the food intake remains unrestricted. In other words, for most obese patients a sub-maintenance [hypocaloric] diet must accompany thyroid administration if consistent loss of weight is to be effected.” ((41), p 257).

 

Further, Rony concluded

“Therefore, in the absence of contraindications a trial with thyroid in the later stages of the sub-maintenance regime seems to be justified in most cases of obesity.” ((41), p 259).

 

His contraindications to use of thyroid were:

  1. Advanced Age. Rarely used in individuals > 50 years old and never > 60 years old.
  2. Hypertension
  3. Valvular or myocardial heart disease, arrhythmia, tachycardia, regardless of origin
  4. High basal metabolic rate.
  5. Marked vasomotor disturbances during the menopause
  6. Marked nervous irritability or emotional instability
  7. Intolerance to small doses of thyroid, manifested by rapid pulse, palpitations of the heart, tremor, insomnia or suppression of menstruation.”

 

In 1949, ten years after Rony’s report on thyroid hormone usage in obesity, Rynearson and Gastineau from the Mayo Clinic provided another summary (42). They noted, as documented earlier, that thyroid hormone was introduced into clinical practice in 1894 and rapidly grew in popularity because of the belief that many patients with obesity had low metabolic rates that were consistent with hypothyroidism. In addition to “replacement doses” some clinicians began using higher doses of thyroid hormone that were “calorigenic”; that is they raised metabolic rate by as much as 15-20% (43). Another rationale for the use of thyroid hormone was to restore to “normal” the metabolic rate that declined with weight loss (38, 44-47). As Rynearson and Gastineau noted, Wilder had shown that if adequate amounts of protein were provided in the diet, metabolic rate did not fall (48), removing this argument for the use of thyroid hormone. Although thyroid hormone was widely used to treat obesity in 1949, there were several, mainly academic physicians, who opposed its use including Professor Means from the Massachusetts General Hospital at Harvard Medical School (47), Professor Severinghaus from the University of Michigan (49, 50), and others (51).

 

Opposition to use of thyroid hormone also came from two reports that failed to find weight loss from treatment with thyroid hormone (52, 53). As Rynearson and Gastineau noted, thyroid hormone also increased heart rate, putting a load on the cardiovascular system as well as increasing protein breakdown (54, 55). Rynearson and Gastineau concluded by adding their caution about the use of thyroid hormone to treat obesity. However, caution at the academic level did not necessarily translate into caution by practitioners in the office.

 

TRIIODOTHYRONINE IS DISCOVERED AFTER WORLD WAR II AND THE WATER GETS MUDDIER      

 

The identification of triiodothyronine by Gross and Pitt-Rivers in 1952 opened the door on a new chapter in the use of thyroid hormones for treatment of obesity (56). Triiodothyronine is derived from thyroxine by deiodination and works more rapidly with a shorter half-life than thyroxine. Studies of triiodothyronine were aided by the development of a radioimmunoassay that was specific for this molecule (57). During weight loss, circulating levels of T3 decline, as does energy expenditure. This raised the obvious question of whether increasing the level of this hormone back to pre-weight loss levels would reverse the lower metabolism and thus enhance weight loss and weight loss maintenance. This hypothesis was tested by Byerley & Heber (58) who showed that during a 10 day fast where serum T3 and metabolic rate both declined, restoring T3 to normal levels during the last 3 days of the fast did not raise the metabolic rate.

 

According to Garrow in 1974, the results of weight studies with triiodothyronine vary from modest enthusiasm to outright condemnation (59). In one study (60), T3 was given in more or less physiological levels of 105 mcg/d to 29 patients with obesity. Weight loss averaged 8.6 kg (19 lbs) over 17 weeks. However, after one-year weight loss was only 3.6 kg, leading the authors to conclude that T3 in these doses was not a valuable tool for treating obesity. In a second study, Hollingsworth et al (61) treated 17 patients who weighed between 110 and 179 kg with an 800 kcal/d diet along with a placebo or triiodothyronine 225 mcg/d, about triple the maintenance dose. Weight loss over 6 months in the patients treated with T3 was 21.9 kg compared to 13.3 kg in the placebo-treated patients. In still another early study, Drenick and Fisler used triiodothyronine or thyroxine to help patients who had lost weight in the hospital maintain their weight loss (62). These 21 men had lost 42.3 kg in the hospital and were able to maintain most of it, although with troublesome side effects of T3. After reviewing these three studies using triiodothyronine, Garrow concludes:

 

“Thyroid preparations are not a satisfactory substitute for a low energy diet, but in a severely obese person who has become adapted to a low energy diet after several months, and hence has ceased to lose weight, thyroid hormones may provide the only practical line of treatment. It should be emphasized that this line of treatment should only be used if it is certain that the patient is in fact on a low energy diet, and usually this means supervision in hospital for a period of at least 2-3 weeks with appropriate measurements of metabolic rate.” ((59); p 171)

 

Against this pessimistic view of triiodothyronine, Garrow relates his personal experience with individuals who are “resistant” to weight loss even under observation. He studied two patients living on the United Kingdom’s Medical Research Council’s metabolic ward at the Northwick Park Hospital who claimed to have “refractory” obesity. The first was a 54-year-old woman who had a low metabolic rate, but normal thyroid function tests and who lost only 1 kg/week while eating an 800 kcal/d diet while under observation. Dr. Garrow treated her with 100 mcg/d of triiodothyronine along with a selective beta-blocker to prevent tachycardia. On this treatment she lost 21 kg in 6 weeks with remission of her angina pectoris. A similar patient with significant osteoarthritis also benefited from triiodothyronine. Garrow summarizes these studies by saying:

 

“…there are patients who do not lose much weight on an 800 kcal diet under close supervision, and this is due to a low metabolic rate, although there is no clinical or biochemical evidence of hypothyroidism. In such cases it seems justifiable, if the obesity is disabling, to increase the metabolic rate with thyroid preparations, providing that this process is properly controlled” ((59); p 279-281).

 

It was about this time, in 1981, that 3 cases of death were reported in individuals who were taking high doses of thyroxine (T4) (63), an observation that raised a red flag. However, the debate about use of thyroid hormones to treat obesity has continued into the 21st Century. In a review in 2002, Krotkiewski concluded the following on the use of triiodothyronine, thyroxine, or thyroid extract to ameliorate the metabolic effects of a very low calorie diet on serum T3 or metabolic rate (64):

“Thus, it seems reasonable to recommend small doses of T3 as an adjunct to dietary treatment of obesity in the following groups of patients:

  1. In patients receiving beta-adrenergic receptor blockers, showing verified resistance to dietary therapy.
  2. In overweight patients on T4 replacement therapy after successful treatment of hyperthyroidism.
  3. In overweight patients on habitual food intake receiving T4 replacement therapy (previously hypothyroid).
  4. In patients showing `dietary treatment-resistant' weight increase while stopping cigarette smoking.
  5. In patients eating a very-low calorie diet (VLCD) and/or a low-calorie diet (LCD) showing low T3, parallel to slowed rate of body weight loss despite continued calorie restriction.
  6. In patients with abdominal obesity and metabolic syndrome, resistant to dietary treatment or showing inadequate improvement in associated metabolic aberrations.
  7. In patients showing, before or during dietary treatment, signs and symptoms of sub-clinical hypothyroidism.

 

Triiodothyronine acts through one of 2 receptors, the T3 receptor alpha (TRα) and T3 receptor beta (TRβ). The TRα receptor appears to mediate the effects on heart rate, whereas the TRβ receptor mediates the effect on cholesterol and on metabolic rate (65). Activation of the TRβ receptor may provide a strategy for lowering lipoprotein cholesterol and for increasing metabolic rate in animals and human beings.

 

Thus, the status of thyroid hormone in management of the patient with obesity is still open for further investigations with the last word yet to be written.

 

Dinitrophenol:  1918-1938

 

Dinitrophenol has had more than one life. First, as an explosive during World War I. Then, as a weight loss agent. Finally, as a drug for potential use in neurological diseases (66). I will focus on its use as a weight loss drug.

 

DINITROPHENOL: INITIAL BENEFITS AND TOXICITIES

 

During the rapid growth of the chemical industry in Germany in the late 19th and early 20th centuries, many compounds were made for dyeing cloth. A major offshoot of this development was the introduction of dyes to stain histological samples for study of tissue structure under the microscope. Another outgrowth was a supply of chemicals to synthetic organic chemists and pharmacologists. Paul Ehrlich (1854-1915) was a pioneer with these dyes and can be called “The Father of Pharmacology.” Among his many contributions to biomedical science is his concept of the “magic bullet” – the idea that a chemical molecule could act like a key in a lock to provide a way to target chemicals to treat disease-causing processes within cells. One of the fruits of his labor was arsphenamine, or salvarsan; also called “606,” for the number of different molecules that were tried before he found his “magic bullet” for the treatment of syphilis (5).

 

Another product of the chemical industry that had a direct impact on obesity was the synthesis of 2,4-dinitrophenol. French factory workers preparing this chemical in munitions factories during World War I were noted to lose weight. As Perkins put it in his lengthy report on Munitions Intoxications in France: “Workers claim that they have grown thin to a notable extent after several months of work with DNP” ((67); p 2341).

 

This observation was picked up by Tainter and his colleagues at Stanford University in 1931.  They initially conducted animal experiments with DNP before using it in patients (68, 69).   During studies for drug safety, they noted that the therapeutic index of dinitrophenol, that is the relation of therapeutic to toxic effects, was razor thin, so they proceeded carefully with their clinical studies. They treated 20 men and 150 women with obesity using doses of dinitrophenol up to 0.3 g daily along with a moderately restricted diet. Of these individuals, 71 had been treated previously with dietary measures, thyroid hormone, or both. The average total dose of drug was 26 kg per patient and an average treatment duration of 88 days. Weight loss averaged 17.1 lb. (7.8 kg) or 1.4 lb. (0.64 kg) per week and only 5 patients failed to lose weight. The largest weight loss was 82 lb. (37.3 kg) which occurred over 198 days. Mild toxicity occurred in 28 individuals, and consisted of skin rashes, pruritus, and peripheral neuritis. There was no evidence of changes in red or white blood cells and no change in blood pressure. In his review in 2007, Colman noted that, by 1934, Tainter estimated that as many as 100,000 Americans had used dinitrophenol emphasizing the “desire” of Americans to become slimmer (70).

 

In 1934 Tainter and his colleagues wrote: “It can now be said that dinitrophenol is of definite value as a drug for treating obesity” (71). He also reported three deaths, skin rashes and the yellow skin color associated with DNP as well as rashes and peripheral neuritis in some patients – a finding indicating the drug should be discontinued (72). However, it wasn’t long until other problems surfaced including cataracts (73) as well as neuropathy. By one estimate, 2,500 people lost their sight using dinitrophenol. Reports of deaths also continued to be reported.

 

Other clinicians did not have the same enthusiasm as Tainter. In 1935, McGavack from San Francisco reviewed the use of dinitrophenol by some 290 individuals and reached several conclusions (74). First, the loss of weight using diet and dinitrophenol was not strikingly greater than with diet alone. Second, many people had distressing symptoms from its use. Third, there were significant toxic effects of the DNP on body function and tissues. Finally, the reported deaths from dinitrophenol when used in accepted therapeutic dosages made it hard to justify for widespread use in treating overweight, which he called the relatively benign condition. This was supported by two other studies that compared the effects of DNP to other ways of managing the patient with obesity. Bayer and Gray (39) reported on 100 individuals who were treated diet alone (920 kcals/d), or with diet and the addition of either thyroid extract (up to 3 grains/d) or dinitrophenol up to 300 mg/d. On diet alone, weight stabilized in 72 of these patients after 4 months and an average 15 lb. (6.8kg) weight loss. Thyroid extract induced an extra weight loss averaging 11 lb. (5.0 kg) in 41 patients during 90 days of treatment with thyroid extract, compared to dinitrophenol, which produced an average loss of 12 lbs. (5.5 kg) in 13 patients over 50 days. Dinitrophenol seemed to be most effective when the BMR was normal. In a second report Strang and Evans observed greater weight losses in the cases receiving dinitrophenol than in those treated by diet alone but felt that the difference was hardly striking enough to offset the discomfort and possible damage of treatment with DNP (75).

 

With this information as a background in 1935, the Council on Pharmacy and Chemistry of the American Medical Association concluded that the dinitrophenol was too hazardous to include in the AMA publication of New and Non-official Remedies (76). At the time that dinitrophenol was being touted for obesity in 1935, the US FDA was limited in its power to regulate drugs based on The Food and Drugs Act, which was passed in 1906 and brought the FDA into existence. It wasn’t until this law was updated as the Food, Drug, and Cosmetic Act of 1938 that the FDA had the authority needed to act against drugs like dinitrophenol. In 1938, they turned their attention on the Isabella Laboratories which was selling capsules containing 1.5 g of dinitrophenol as Formula 281. When the hazards became clear, the FDA moved to ban DNP as too dangerous for use in humans (70).

 

THE DINITROPHENOL RENAISSANCE:  1980 –

 

Although it had been banned in 1938, dinitrophenol made a come-back in 1981 (77). In this year, a Texas physician named Dr. Bachynsky began to process industrial DNP and put it into tablets which he dispensed and marketed under the trade name ‘Mitcal’. He advertised that ‘Mitcal’ produced weight loss by a mechanism he called intracellular hyperthermia i.e., uncoupling of oxidative phosphorylation. In subsequent court proceedings it was alleged that over 14,000 people were treated with Mitcal by Dr. Bachynsky. Individuals using Mitcal started reporting adverse effects, such as fever, shortness of breath and sweating, to the US Food and Drugs Administration in late 1982. Additionally in 1984, there was a fatality associated with an intentional overdose of ‘Mitcal’. Dr. Bachynsky was convicted in 1986 of drug law violations, fined and prohibited from dispensing DNP to any patients. However, Dr. Bachynsky continued to use DNP for a variety of different ‘medicinal claims.’ He was eventually jailed for fraud in 2008 in the USA for developing DNP for use in Europe as a cancer treatment again called intracellular hyperthermia therapy.

 

Outside of the medical community, DNP is still marketed on the Internet without regulation, primarily to body builders who are attempting to lose weight. To address this growing use, the Food Standards Agency in 2011 issued a warning that this product is “not fit for human consumption” given its short- and long-term effects. Nonetheless, gym enthusiasts continue to obtain and use DNP, even though there were sporadic reports of deaths (78). To obtain insight into the reasons for this continued use of DNP, Ainsworth et al interviewed 14 users who reported that the internet was the main source of their information about DNP (79). The authors found that these individuals valued “self-control” and their own judgment in minimizing potential risks. This is, of course, against the background of continuing deaths associated with use of DNP. In their review, Grundlingh et al plotted the deaths associated with DNP by decade (77). In the 1930s there were 8 deaths, which declined to only one per decade in the 1940s and 1950s during the time of stringent regulation. Subsequently, after 4 decades with no deaths, thirteen deaths were recorded in the first decade of the 21st century.

 

In addition, DNP at doses that do not affect weight is being explored for its potential use in neurodegenerative disease where mitochondrial dysfunction is often observed. DNP has been shown to induce neurotrophic growth factors involved in neuronal health, cognition, and learning. It is now being investigated through approved FDA channels with an Investigational New Drug Application for a group of neurodegenerative diseases such as Huntington’s disease, multiple sclerosis, and Duchenne’s muscular dystrophy (80).

 

In summary, DNP has had many lives. As an explosive during World War I, as a treatment for obesity during the 1930’s (first discredited and then resurfacing in the 1980s), as a weight control agent for body-builders using the internet to obtain supplies, and most recently as a potential agent for treatment of neurodegenerative diseases.

 

Amphetamine:  1932-1968

 

SYNTHESIS AND INITIAL TESTING

 

The rise, fall, and return to restricted medical use of amphetamine is the story of the first psychoactive mood-altering prescription drug (81). Amphetamine might be described as a Janus drug – that is it has two faces – one the pharmacological side to constrict blood vessels, suppress food intake, and either stimulate the central nervous system or calm it in individuals with attention deficit disorder. The other face is the potential for abuse, first recognized in the late 1930s and brought into stark focus by “street-use” of methamphetamine.

 

Amphetamine is a sympathomimetic drug originally labeled in 1910 (82). The name amphetamine comes from its chemical structure – α-methyl-β-phenethylamine. It was first synthesized in 1887 by the Romanian chemist Edeleanu, who was working in Germany. The stimulant properties of his compound, phenylisopropylamine as he called it, were unknown until it was independently resynthesized and tested clinically by Gordon Alles. Alles, a chemist in California, was searching for an alternative decongestant to compete with ephedrine in the treatment of allergy and asthma. In 1929 Alles synthesized what he called beta-phenyl-isopropylamine (amphetamine). To test the clinical effects of his discovery, Alles became a “human guinea” when he was injected with 50 mg, a relatively large dose of his product. Within seven minutes he noted that his nose was dry and clear when he sniffed. His blood pressure climbed dramatically and by 17 minutes he noted heart palpitations. He also had a “feeling of well-being.” That evening at a dinner party he grew chatty, considering himself unusually witty. He recorded that he had a “Rather sleepless night. Mind seemed to run from one subject to another” (83). In 1932 Alles patented his compound and its medical uses (81).

 

In 1933 Smith, Kline and French (SKF), an American pharmaceutical company began selling Benzedrine, a decongestant that they had patented that was identical to the one Alles had patented (81).

 

1935 was another key year in the history of amphetamine. Alles thought that the stimulant properties of amphetamine might help people suffering with narcolepsy, a disorder of sleep. He supplied amphetamine to Myron Prinzmetal, who had worked with Alles as a medical student at the University of California, San Francisco (UCSF), to test in patients with narcolepsy. Prinzmetal et al published their affirmation of this effect in 1935 (84) and their findings were soon replicated by Ullrich et al in 1936 (85). Both groups showed that the drug did reduce sleep time in people with narcolepsy, and this became an indication for amphetamine use. Of interest to this paper, these authors also noted that the patients who were treated for narcolepsy also lost weight.

 

To explore amphetamine as an agent that might improve mood, SKF teamed up with Dr. Abraham Myerson, a highly respected professor of psychiatry working at both Tufts and Harvard who operated a well-funded laboratory. His books for the public had given him public visibility. In addition to his work on amphetamine for psychiatric problems, Myerson picked up on the reported weight loss during treatment for narcolepsy. Together with Mark Falcon-Lesses, Myerson designed a clinical trial to assess the effects of amphetamine for weight loss (86). A group of 16 women and 1 man were treated for 6 to 23 weeks with Benzedrine sulfate in doses of 10 to 30 mg/d. Patients weighed between 145 and 316 lbs. (66 to 144 kg) when the trial began and lost an average of 1.46 lbs/week (0.66 kg/week) during treatment. There were no untoward side effects, and the results were published in the prestigious New England Journal of Medicine in 1938 (86). As Rasmussen summarized the situation in 1938: ”Despite the study by Lesses and Myerson, SKF did not market Benzedrine Sulfate to treat obesity, although the firm did follow-up earlier observations by Nathanson and others that Benzedrine resulted in weight loss. For instance, SKF sponsored testing of the drug’s impact on metabolic rate and trials evaluating its effects on appetite. Initially, SKF thought that marketing of Benzedrine for weight loss might interfere with its development as a respectable psychiatric drug. On the other hand, SKF might have realized that amphetamine was “selling itself” for weight loss since many smaller companies were profiting from the weight loss market, even though they were violating the patents owned by SKF. However, by the end of World War II amphetamine and methamphetamine were extensively used by both the Allied and Axis forces because they seemed to enhance performance and SKF would move to capture the weight-loss market” (87).

 

In a review of 1946, Bett described the setting for amphetamine (Benzedrine) and obesity this way: “The value of Benzedrine sulphate as an ‘adjunct' to diet and other measures in the treatment of obesity may thus be summarized: it decreases appetite and helps the patient to follow a diet, possibly also by producing a sense of well-being. Increasing activity, it promotes proper balance between energy output and caloric intake. It educates the patient to new eating habits, so that weight loss is maintained after stopping the drug.  It has no appreciable effect on basal metabolic rate.” (88).

 

AMPHETAMINE AND ADDICTION  

 

A warning about the risk of addiction with the use of amphetamine was sounded in an editorial in the Journal of the American Medical Association (JAMA) in 1938 (89). The observation that the use of Benzedrine over long periods is "certainly not without danger, particularly to the circulatory system," prompted this comment from Lesses : (90)"…the drugs to which human beings become addicted are the narcotics. There is no evidence in the entire literature of medicine that stimulants become habit forming." This, in retrospect, was clearly inaccurate. Even though in Myerson’s clinical experience with Benzedrine for more than two years in a very large number of cases he had not seen "a single case of addiction in the sense that a person, otherwise, now feels it necessary to take the drug habitually and in ascending doses to produce the desired effect."  In 1937 abuse of the drug was reported among Midwestern college students, particularly at the University of Minnesota. Moreover Benzedrine Sulfate tablets were taking on the identity as “pep pills” or “pepper-uppers” in the popular imagination as Myerson recognized two years later (91). Based on the growing evidence of abuse, amphetamine became a strictly regulated prescription drug, but its illegal use in the popular culture has been difficult to control and addiction to methamphetamine has become a major modern problem.

 

AMPHETAMINE REVIVAL FOR TREATING ATTENTION DEFICIT/HYPERACTIVITY DISORDER 

 

Racemic amphetamine can be used to treat Attention Deficit Hyperactivity Disorder (ADHD) and binge-eating disorder. Lisdexamfetamine, a combination of lysine and d-amphetamine, which is hydrolyzed once inside the red blood cell has become a drug of choice for this diagnosis (92). Although recreational use of amphetamine produces serious risk of addiction, this is unlikely to occur when amphetamine-derivatives are used at therapeutic doses for long-term treatment of attention deficit disorder. In fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance abuse as an adult.

 

Rainbow Pills:  1940-1968

 

Rainbow Pills are a continuation of the amphetamine story (93). The Miriam Webster Dictionary defines Rainbow Pills as “any of a combination of pills (as of amphetamines, laxatives, and thyroid hormones) typically of different colors that were formerly taken to curb appetite and promote weight loss” (“Rainbow pill.” The Merriam-Webster.com Medical Dictionary, Merriam-Webster Inc., https://www.merriam-webster.com/medical/rainbow%20pill. Accessed 5 January 2020).

 

I have picked the start date of 1940 for the beginning of the Rainbow Pill period since it was the date for the first of 27 meetings sponsored by Western Research Laboratories held to introduce weight loss specialists to the use of their Rainbow Pills. Their 27th Annual Symposium on Obesity was held in Denver on April 13-15, 1967, and I was in attendance. Amphetamine was one of the many-colored pills included in what came to be called the "rainbow diet pill" regimen. In addition to amphetamine, Rainbow Pills included thyroid hormone, laxatives, diuretics, and digitalis (Table 2).

 

Table 2.  Ingredients in One or More of The Rainbow Pills

Ingredients for Weight Loss

Ingredients to Mask Side Effects

d-Amphetamine

Cardiac glycosides (digitalis)

Diuretics

Barbiturates

Thyroid hormones

Corticosteroids

Laxatives

Potassium

Phenolphthalein

Belladonna

Herbal ingredients

Glandular extracts

Adapted from (93).

 

Digitalis was included since it can cause “nausea,” with weight loss as a consequence. The downside of digitalis is that it has a narrow window of tolerance between its therapeutic effect and toxicity. Diuretics were included to increase fluid (and weight) loss even though this is not fat loss. As we noted earlier, “diuresis” was one strategy used for weight loss dating from Greco-Roman times. Rainbow Pills often contained a barbiturate to suppress some of the side effects of amphetamine stimulation. To reduce middleman costs, the distribution of these pills to patients was directly from the physicians’ own offices rather than through a pharmacy.

 

The route to regulate Rainbow Pills was a prolonged one. Following the Pure Food and Drug Act of 1906 and the formation of the U.S. Food and Drug Administration (FDA), enforcement powers of the FDA were significantly enhanced with passage of the Food, Drug and Cosmetic Act of 1938. In 1962, the Kefauver-Harris amendmentrequired drug manufacturers to provide proof of both the safety and effectiveness of their drugs prior to approval for sale to the public.   It also required drug advertising to disclose accurate information about side effects, and stopped cheap generic drugs being marketed as expensive drugs under new trade names and calling them new "breakthrough" medications.

 

In 1967-1968, a number of deaths attributed to use of Rainbow Pills triggered a Senate investigation and the gradual implementation of greater restrictions on drug marketing for obesity management. At the beginning of my research career into the causes and treatment of obesity, the U.S. Senate Select Committee held their first hearings on the misuse of anti-obesity medications (94). As a young Assistant Professor, I was invited to give a talk at the 28th Annual Western Research Laboratories Symposium on Obesity being held in the elegant Brown Palace hotel in downtown Denver, Colorado. The title of my talk was “Some New Thoughts on the Treatment of Obesity: Growth Hormone; Thyroid Hormone and Appetite Control.” Other topics on the program included “Abnormal Thyroid Transport Mechanisms in Obesity” by Dr. Irving B. Perlstein; “Exercise and Fitness Programs for the Overweight” by Captain McHargue from the US Air Force Academy; “Is the sound medical management of obesity successful? (A preliminary study of 6,000 cases histories) by Wilmer Asher; “Digitalis and The ‘Normal’ Heart, Some Controversial Aspects” by Richard Bloomfield; and finally “Obesity and its effects on Man-Hours of Work Loss” by Dr. Raymond E. Dietz. The invitees included physicians and their staff involved in delivering weight loss programs around the country. At the Saturday morning breakfast, a prominent member of the group sat down next to me. He had been summoned to testify before Senator Hart at the Rainbow Pill Hearings in the U.S. Senate (94). He said, slamming his fist on the table, that “Senator Hart had accused him of making more than $1 million dollars a year.” He went on to say, “I hardly ever made more than $750,000 per year”!  This was 1968, and I was a young faculty member making a mere $12,000 per year. I listened in astonishment!  I was undeterred from my academic career by the possibilities of making large amounts of money from treating patients with obesity, and my table mate continued to operate his financially rewarding clinics for many more years.

 

RAINBOW PILLS RESURFACE

 

After the rainbow diet pills were banned in the US in the late 1960s, they largely disappeared from the market during the 1970s and 1980s. They reappeared in Brazil in South America and in Spain in the 1980s. The re-entry of Rainbow Pills into the United States market was facilitated by passage of the Dietary Supplement Health and Education Act and Supplement Act (DSHEA Act) of 1994 which states that dietary supplements do not require premarket review by the FDA. More about the DSHEA Act later. Thus, federal regulators are powerless to stop the pills from hitting store shelves, and thanks to the Internet, the distribution network of rainbow pills is larger than ever and they can purchased in many forms (93).

 

Benzocaine

 

Benzocaine is a topical anesthetic that in lozenge form can numb the nerve endings in the mouth, which might, in turn, reduce the pleasure of eating. To test this, 40 women with obesity received one of four treatments: 1) a chewing gum containing 96 mg/day of benzocaine alone, 2) phenylpropanolamine alone at a dose of 75 mg/day, 3) the combination of these two agents; and 4) a placebo gum and pill. At the end of 8 weeks, those treated with phenylpropanolamine lost twice as much weight as the placebo-treated group, whereas those receiving benzocaine lost essentially no weight (95, 96). Interestingly, weight loss in the group receiving the combination of phenylpropanolamine and benzocaine was equal to that of the placebo group.  Clearly local anesthesia in the mouth using benzocaine is of no value in the treatment of obesity.

 

Anorectic Sympathomimetic Drugs: 1950-1997

 

Amphetamine is the grandfather of this class of drugs. Amphetamine reduces food intake, and through activation of the sympathetic nervous system, raises blood pressure and has neurophysiological effects. Efforts by chemists to separate these physiological effects occupied much of the period between the end of World War II with approval of the final sympathomimetic anorectic drugs, fenfluramine and chlorpentermine, in 1973.

 

The anorectic sympathomimetic drugs can be divided into three groups. The first is a non-prescription sympathomimetic appetite suppressant, phenylpropanolamine that is no longer approved in the US for management of obesity. The second group is comprised of sympathomimetic drugs approved before 1973. The third group is comprised of drugs approved after 1973, until the removal of fenfluramine and dexfenfluramine from the market in 1997.

 

PHENYLPROPANOLAMINE FOR WEIGHT LOSS: 1938-2000

 

Phenylpropanolamine was synthesized as early as 1910 (82). Like other sympathomimetic drugs, it can raise blood pressure and constrict small blood vessels, thus leading to its use as a nasal decongestant. Phenylpropanolamine was first used commercially during the 1930s as an intravenous treatment for postoperative hypotension (97). The drug was patented in 1938, and in 1939 it was noted to suppress appetite. From the 1960s until it was removed from the US market in 2000, it was sold without prescription as a decongestant since the US Food and Drug Administration (FDA) recognized it as safe under the standard of Generally Recognized As Safe (GRAS). Phenylpropanolamine was given GRAS status as an appetite suppressant based on an analysis of weight loss in published studies (98-100). The weight loss was modest – only an additional 0.5 kg per week. This was similar to the results reported by Scoville for other anorectic drugs (101). Other studies performed after 1985 reported slower weight loss, averaging only 0.21 kg/week more than in the placebo-treated subjects. In addition, weight loss began slowing after the first 4 weeks, and at the end of these studies, phenylpropanolamine subjects had lost only 0.14 kg/week more than those receiving placebo. There is only one controlled trial of phenylpropanolamine that lasted up to 20 weeks (100). After 6 weeks, the phenylpropanolamine-treated group had lost 2.4 kg (0.43 kg/week) compared with 1.1 kg (0.18 kg/week) in the placebo group. Twenty-four subjects continued in an optional extension to 20 weeks and lost 5.1 kg (6.5%) compared with 12 placebo-treated subjects who only lost 0.4 kg (0.5%) of their initial body weight (P < 0.05).

 

For many years phenylpropanolamine was sold over-the-counter under the trade name Dexatrim, which was owned by Thompson Medical Company. When the patent protection for phenylpropanolamine ended in the 1980s, Ciba-Geigy began a marketing campaign for Acutrim (Oros TM), an over-the-counter product containing phenylpropanolamine. In a randomized 14-week randomized, clinical trial, participants who took Acutrim lost 8.0% of their body weight compared to 5.4% in those receiving the placebo (102).

 

Concerns about detrimental effects of phenylpropanolamine on blood pressure and the cardiovascular system had been a recurring issue. To examine this possibility critically, a double-blind, multicenter clinical trial funded in part by Thompson Medical, examined the effects of phenylpropanolamine on the changes in blood pressure in 881 individuals (103). In this parallel arm study, one group received a placebo three times a day, a second group received 75 mg of a sustained-release form of phenylpropanolamine once daily followed by two placebo capsules, and a third group received 25 mg of immediate-release phenylpropanolamine three times a day. Thirty percent of the 811 participants were above their ideal body weight. Blood pressure increased significantly in the first 6 hours following the 25 mg dose, and even more in those receiving the sustained-release preparation. However, the authors did not consider this to be clinically important (103). Baseline body weight and diastolic blood pressure were significant and independent determinants of the pressor effect of phenylpropanolamine.

 

This study, however, did not allay concerns about effects of phenylpropanolamine on blood pressure and the risk of stroke. To provide more perspective, an epidemiological study was designed to compare individuals using phenylpropanolamine who had had a hemorrhagic stroke with a control group without a history of stroke. This study found a significant association between hemorrhagic stroke and the use of phenylpropanolamine (104). As a result of this study and two years after Thomson Medical sold its interest in Dexatrim to Chattem Pharmaceuticals, the FDA took steps on Nov 6, 2000 to remove phenylpropanolamine from all drug products in the United States and requested that all drug companies discontinue marketing products containing phenylpropanolamine. This was one of the first examples of off-target effects derailing the clinical use of a drug in the management of obesity.

 

ANORECTICS: 1959-1973

 

Anorectic drugs refer to medications derived from the chemical backbone of amphetamine, which act as sympathomimetics, specifically mimicking the effects of the neurotransmitter norepinephrine. After attention was drawn to the risk of dependence and addiction from amphetamine, organic chemists began the search for drugs that retained the appetite suppressant properties but that did not have the abuse potential of amphetamine (105). The structural features needed to retain anorectic activity were defined. They included a chain between the amino group and the phenyl ring restricted to two carbon atoms; the binding of the amino group to a secondary carbon atom; and substitutions at other positions, which may lead to reduction in anorectic activity.

 

A large number of molecules were synthesized and tested for their effects on food intake and risk of habituation (106)and some of the marketed one are shown in Table 3.

 

Table 3.  Drugs Evaluated by the Food and Drug Administration in 1973

Generic Name

Proprietary Names

Year Approved

DEA Schedule

Current Status

d,l-amphetamine

Benzedrine & Many others

1936

II

Not approved for obesity

d-amphetamine

Dexedrine & Many others

Before 1952

II

Not approved for obesity

Methamphetamine

Desoxyn & Many others

1947

II

Not approved for obesity

Phenmetrazine

Preludin

1959

II

Not Marketed

Benzphetamine

Didrex

1962

III

Available by prescription

Phendimetrazine

Plegine

1960

III

Available by prescription

Chlorphentermine

Pre-Sate

1962

III

Not Marketed

Phentermine

Ionamin, Wilpo

1959

IV

Most widely used drug for obesity

Mazindol

Sanorex; Mazanor

1980

III

Not Marketed

Diethylpropion

Tenuate; Tepanil

1959

IV

Available by prescription

Data from (100, 107)

 

At the request of the Bureau of Drugs at the FDA, a group of “Consultants on Anorectic Drugs” was empaneled. They issued their report in 1973, the same year that the NIH sponsored a major conference on obesity (107). In his letter to the Director of the Bureau of Drugs at the FDA, Dr. Thaddeus Prout, Chairman of this review group summarized the view of the consultants on current anorectic drugs (108). Their conclusions are summarized in abbreviated form as follows:

  1. “Adult obese subjects instructed in dietary management and treated with anorectic drugs on the average tend to lose more weight than those treated with placebo in relatively short-term trials.”
  2. “The amount of weight loss associated with the use of an “anorectic” drug varies from trial to trial.” [Note: In an aside this germane comment was made: “Dr. Scoville noted in answer to a question that there were no statistically significant overall differences comparing two anorectic drugs.” (p 498).]
  3. “The magnitude of increased weight loss of drug treated patients over placebo treated patients was only a fraction of a pound a week.”
  4. “…the total impact of drug-induced weight loss over that of diet alone must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors inherent in their use.”.
  5. “The amphetamines, including methamphetamine have been widely abused in numerous populations. It is thus in the best interest of the public health to limit the use of amphetamines as far as is compatible with adequate therapy.”
  6. “Evidence presented for newer “anorectic” congeners of the amphetamine family and non-amphetamine drugs do not set them apart as having higher benefit or lower risks than older available drugs. The risk potential of fenfluramine may be an exception to this general statement.”
  7. “There is no evidence in the data reviewed which showed that combination of an ‘anorectic’ agent with other drugs increase the benefits or reduce the risks of the ‘anorectic’ agent.”
  8. “There is no clinical data which support the parenteral use of these drugs in the treatment of obesity.”

 

Based on these findings, The FDA Consultant Panel also made several recommendations summarized below:

  1. “That all “anorectics” reviewed (dl-amphetamine, d-amphetamine, methamphetamine, benzphetamine, phentermine, chlorphentermine, chlortermine, phenmetrazine, phendimetrazine, fenfluramine, mazindol, diethylpropion), with the exception of fenfluramine, be placed on Schedule II on the basis of abuse potential.”
  2. That combinations of “anorectics” with other drugs be evaluated in accordance with the policy of the FDA on combination drugs”.
  3. That amphetamines prepared for, or in a form suitable for, parenteral use not be approved for use in the treatment of obesity.
  4. “The single-entity oral “anorectic” preparations including the amphetamine be permitted to be labeled for restricted use in obesity provide that they are used in association with a specific weight reduction program and that the clinically trivial contribution of these drugs to the overall weight reduction is properly emphasized. To carry out the latter recommendation, a statement such as that made in the conclusions drawn from this review must be included in all labeling and promotional products. This statement should include the following points: Studies of the effect of “anorectic” drugs in the treatment of obesity when compared with the effects of patients treated in a similar manner without the use of the drugs demonstrated that the magnitude of weight loss of drug treated patients over no-drug treated patients was only a fraction of a pound a week. The rate of weight loss was greatest in the first weeks of study for both the drug and the non-drug treated subjects and tended to decrease in succeeding weeks. The natural history of obesity is measured in years whereas the studies offered for review are restricted to a few weeks duration. Thus, the total impact of ‘drug induced” weight loss over that of diet alone must be considered clinically trivial. The limited usefulness of these agents must be measured against any possible risk factors such as nervousness, insomnia, and drug habituation that might be inherent in their use. Moreover, these agents can only be recommended for short term use in the treatment of obesity in a carefully monitored and specified weight reduction program under the care of a physician” (108).
  5. That future approval of all ‘anorectic’ drugs prepared for future use be based on demonstration of efficacy as measured by statistical superiority of the drug over placebo in trials using FDA recommended protocols. These protocols should include provisions, among others, for the testing of a specific target populations, specification of a minimum duration trial to assure clinical relevance of the study, and give consideration to the handling of patient dropout.
  6. Further, that appropriate summary data derived from efficacy studies be presented in labeling and in all promotional material to indicate the degree of weight loss that was found.For this purpose guidelines note in (4) above should be supplemented by the addition of the specific facts found for the specific drug under consideration.

 

Shortly after this letter, the US FDA issued new Guidelines on Labeling for Single-Entity Amphetamine Products. The FDA also approved d,l-fenfluramine, chlortermine, and mazindol.  These were the last drugs in this class to be approved. Chlortermine is no longer marketed and d,l-fenfluramine and d-fenfluramine have been removed from the market as described below. All the derivatives of amphetamine have been tarred with the same brush – that of risk for addiction. Since then, for better or for worse and whether deserved or not, as amphetamine fell from grace, a similar pall fell over the entire class of derived compounds. As we will see, one of these derivatives, fenfluramine, had no demonstrated abuse potential at all and yet was still regulated by the U.S. Government as though it did.

 

AMINOREX- ANORECTIC WITHDRAWN FOR TOXICITY

 

Aminorex demonstrates the law of unintended consequences as applied to drug development for obesity management. This drug is an “amphetamine-like” drug that was developed by McNeil pharmaceuticals in the United States and licensed in 1965 for sale in Germany, Austria, and Switzerland under the trade names of Menocil or Apiquel (109). Soon after its launch, Berne, Switzerland noted an increase in the diagnosis of pulmonary hypertension. This was eventually linked to the use of aminorex, which appears to have been responsible for a 5 to 20-fold increase in incidence of primary pulmonary hypertension (PPH) in Switzerland. In Berne, up to 20% of those taking aminorex who were admitted to the hospital died, with up to 50% more dying over the next 10 years. A retrospective analysis in deaths in Austria, Switzerland, and Germany during the late 1960s showed that this drug was responsible for most of the cases of PPH between 1968 and 1972. Experimental studies subsequently confirmed that aminorex can produce pulmonary hypertension in animals (110-112).

 

This outbreak of PPH was the canary in the coal mine signaling a potential relationship between some β-phenethylamines and PPH, a form of plexogenic arteriopathy (113). Primary pulmonary hypertension (PPH) is a rare disease that occurs with a frequency of about 1–2 per million persons per year. Pulmonary artery systolic pressure is directly related to body mass index.   The risk of PPH appears to have a genetic basis which was brought to the fore by 3 anorectic drugs, aminorex, fenfluramine, and chlorphentermine which modulate serotonin activity (113).  A retrospective case-control study including 95 cases from several European centers and 355 matched controls estimated that the use of appetite suppressant medications may have increased the odds ratio by 10 to 23-fold for an incidence to 28–43 cases per million per year (114). Kramer and Lane reexamined the data from the aminorex cases to provide a comparison with fenfluramine (113). They estimated the odds ratio for developing primary pulmonary hypertension after exposure to aminorex was 97.8 (95% CI 78.9 –121.3) and that nearly 80% of the cases of this disease in the affected countries could be attributed to aminorex. Using the French and Belgian cases in the dexfenfluramine study (114), the authors estimated the odds ratio for developing primary pulmonary hypertension after exposure to dexfenfluramine to be 3.7 (95% CI 5 1.9 –7.2) for 3 months or more exposure and 7.0 (95% CI 5 2.8 –17.6) for exposures lasting more than 12 months (111). Dexfenfluramine, in contrast to aminorex, was estimated to increase the background rate by 20% or less. Such unanticipated “off-target” toxicity and the capacity for widespread involvement on a population basis given the high prevalence of obesity as a chronic disease has influenced the US FDA’s cautionary approach to initial approval and recommendation for swift removal in after-market surveillance for all drugs in this category.

 

PHENTERAMINE- A SURVIVOR

 

Phentermine is one of the derivatives of α-methyl-β-phenethylamine backbone of amphetamine that was approved for marketing by the U.S. FDA in 1959. Unlike other members of this group, which have had problems with toxicity or lack of use, phentermine accounts for over 75% of the anti-obesity medications used in 2019 (115). Phentermine, like many other sympathomimetic amines, acts on the trace amine-associated receptor 1 (TAAR1) where it facilitates the efflux of norepinephrine, and to a lesser extent the efflux of dopamine and serotonin (116, 117)

 

At the time of phentermine’s approval in 1959, most clinical trials for weight loss drugs lasted 12 weeks or less. However, several studies have evaluated the longer-term use of phentermine (118-120). In one older study (118), a group of patients received a placebo, the second group received phentermine resin 30 mg/day, while the third group was treated with phentermine resin alternating with placebo at 1-month intervals. The two groups given phentermine in either intermittent or continuous form lost similar amount of weight which averaged 20.5% of their initial body weight compared to only 6% in the placebo group. The group treated intermittently showed the effect of stopping and starting an active drug to placebo relative to continuous treatment. These authors concluded that intermittent phentermine was preferable because it was cheaper, gave equivalent weight loss, and reduced exposure to medication; although this runs counter to current concepts of chronic disease management in which continuous use is recommended. In another older study (120), patients with osteoarthritis were treated with phentermine-resin, 30mg/day for 6 months or with placebo. The group treated with phentermine lost 12.6% of their body weight, compared to 9.2% in the placebo group. In a third older study (119), 59 subjects were treated for 14 weeks with either a placebo or phentermine 30 mg/day.  The group receiving phentermine lost 8.7% of their body weight compared with only 2.0% in the placebo-treated group.  Two more recent studies have evaluated the effects of phentermine in children (121) and in adults (122). In a retrospective study of children treated with lifestyle or lifestyle plus phentermine, the group receiving phentermine lost significantly more weight at 1, 3 and 6 months with no significant changes in blood pressure (121). A study in adults compared phentermine alone, canagliflozin alone, or phentermine plus canagliflozin against placebo in a double-blind RCT. Over 6 months, the placebo-treated group lost 1.1% vs 4.6% in the group receiving phentermine alone and 8.1% in the combined treatment group (122). Despite the significant weight loss, blood pressure was not different from placebo and heart rate was significantly increased in the group treated with phentermine supporting the concerns about the effect of phentermine on the cardiovascular system.

 

As with other sympathomimetic drugs, concerns have been raised about an increase in blood pressure and abuse in those taking phentermine. Subsequent studies have demonstrated that when used appropriately (e.g., those without contraindications such as uncontrolled hypertension or hyperthyroidism, active vascular disease, arrhythmias, or glaucoma), phentermine does not result in behaviors associated with substance abuse or withdrawal symptoms (123, 124), or raise blood pressure on average. In fact, observational studies and a small number of prospective randomized, controlled studies have demonstrated either neutral effects or reductions in blood pressure during long-term phentermine use and no increased risk for adverse cardiac events (125-128). A recent summary of reported after market adverse events of the FDA approved combination tablet Qsymia, containing both phentermine and topiramate, has failed to link use of this drug with cardiac valvulopathy, myopathy, or pulmonary hypertension (129). Phentermine is the most widely prescribed anti-obesity drug used for management of obesity today because it is a generic drug and thus low in cost and appears to have a track record of safety (115). While it is a “survivor” in terms of continued use as an anti-obesity medication, its reputation often suffers amongst providers and the public from “guilt by association” with fenfluramine use as described below.

 

Fenfluramine/Dexfenfluramine: 1973-1997 – Doomed by its Toxicity  

 

Fenfluramine has structural similarities to amphetamine. However, to the surprise of most workers in the field it had a very different mechanism of action. Fenfluramine was developed in France in the 1960s and marketed there in 1964 (130). Instead of being a sympathomimetic drug and mimicking the effects of norepinephrine, as other anorectic drugs do, fenfluramine acted to block the re-update of serotonin at its nerve endings. In addition, one of the metabolites of fenfluramine, norfenfluramine, acted as a serotonin agonist (131, 132). Treatment of animals with most sympathomimetic drugs reduces brain norepinephrine; treatment with fenfluramine does not. Rather, fenfluramine reduces brain serotonin. The discovery that fenfluramine acted on the serotonergic system to reduce food intake led to a whole new area of research into drugs for the management of obesity.

 

Following clinical trials, fenfluramine was approved by the US FDA in 1973 for management of obesity (130). It was given a Schedule IV designation by the Drug Enforcement Agency because of its chemical similarity to other sympathomimetic anorectic drugs with abuse potential. However, fenfluramine behaves differently and many who took the drug complained of a dysphoria, and it was not used to replace amphetamine-drug abuse in substitution trials.

 

The anorectic effects of fenfluramine reside almost entirely in the dextro-isomer of this compound, named dexfenfluramine. When this was recognized, The International Dexfenfluramine (or INDEX) trial was designed to establish the safety and efficacy of dexfenfluramine (133). With this data in hand, dexfenfluramine was approved by the US FDA for management of obesity in the United Stated in 1994.

 

The first set-back for fenfluramine occurred in 1981 when the first 2 cases of pulmonary hypertension were reported (134), similar to the earlier reports of pulmonary hypertension in patients treated with aminorex. Between 1980 and 1993 there had been a total of 12 cases of pulmonary hypertension associated with fenfluramine (135). This data was emerging as a series of publications showed dramatic weight loss efficacy by combining fenfluramine with phentermine (commonly referred to a “Fen-Phen”), two anti-obesity medications with differing mechanisms of actions (136). The weight loss of 8.4 kg with the combination was similar to the individual agents, but there were fewer side effects when they were used together. This was followed by a single center NIH-funded trial of fenfluramine and phentermine lasting 4 years (137). By the end of the first 32 weeks, those receiving the combination of fenfluramine and phentermine, had lost 15.9% of their weight compared to 4.9% in the placebo group. The results supported and amplified the pilot data from this group. Patients with obesity treated with the combination of phentermine and fenfluramine lost more weight and, in many cases, were able to maintain the lower weight for more than two years during this study.

 

When the dramatic weight loss with Fen-Phen began to circulate widely in the 1990’s, fenfluramine and phentermine use exploded in popularity across the country. Patients and doctors alike were thrilled with the results and for the first time it appeared that Americans with obesity were winning the battle of expanding waistlines. Medical offices dispensing Fen-Phen opened up all over the country. In 1994 prescriptions for fenfluramine were mentioned less than 100,000 times among drug prescriptions. However, in 1995 when Fen-Phen hit the market, mentions of fenfluramine rose by 5-fold to over 500,000 prescriptions before peaking at nearly 4 million prescriptions (138).

 

The second set-back for fenfluramine and, by association, for phentermine occurred in July 1997 when the first case-series of valvular heart disease in patients taking Fen-Phen appeared in the prestigious New England Journal of Medicine (139). Despite the fact that the total participants in that study numbered only 24, the report included only women, pre-existing valvular heart disease could not be ruled out, and no control group was included to account for the known associations between obesity and both valvopathy and pulmonary hypertension, urgent meetings by the U.S. Food and Drug Administration with academic groups around the country assembled enough information to convince the FDA that up to 30% of the patients treated with fenfluramine (alone and in combination with phentermine) might develop valvular heart disease (140). On September 15, 1997, fenfluramine and dexfenfluramine were removed from the market worldwide. The Fen-Phen success had been shattered by the off-target consequences foretold by aminorex decades earlier and added another sad ending to a therapy that offered such promise in the management of the patient with obesity.

 

Sibutramine: 1988-2010

 

Sibutramine is a triple amine reuptake inhibitor affecting norepinephrine, serotonin, and dopamine. Its use as a weight loss medication was an outgrowth of a clinical program searching for effective drugs to treat depression conducted by Boots Pharmaceuticals in the United Kingdom (141). The effects of sibutramine on weight loss caught the attention of the company in 1988, which then commissioned a short clinical trial. During this eight-week study with two doses of sibutramine, Weintraub and his colleagues demonstrated a doubling of weight loss over that achieved with placebo with the low dose and a nearly four-fold increase with the high dose over the weight loss compared to the placebo group (142). With this promising background a full-scale clinical program was designed. There was a clear dose-response to the drug in a six-month clinical trial (143). In a two-year trial, sibutramine reduced body weight by nearly 12% at 6 months. In contrast, the weight loss in the placebo-group gradually faded and at two years they were only 3% lighter than at baseline. These strong clinical results were marred by an increase in blood pressure. Following the phase 3 clinical trials, approval for marketing was requested from the US FDA and the Committee for Proprietary Medicinal Products (CPMP) in Europe. Because of the increased blood pressure observed in some patients, the CPMP would only approve the drug if the company would conduct a long-term study to evaluate potential cardiovascular outcomes. This trial was begun, and the drug was approved for marketing by Knoll Pharmaceuticals, a Division of BASF in Germany who had purchased it from Boots Pharmaceutical and who subsequently sold it Abbott Laboratories in the US.

 

The Sibutramine Outcomes (SCOUT) trial was the result of this requirement (144). It began enrolling participants in January 2003 with a completion date of November 2005. By this time a total of 10,742 individuals with obesity and either a high risk of cardiovascular disease or diabetes had been randomized to treatment for up to six years with either sibutramine or placebo to determine whether use of sibutramine along with a weight management program would impact the risk for cardiovascular complications in this selected population. Despite reductions in blood pressure from baseline in both the sibutramine and placebo groups, to the dismay of the investigators sibutramine produced a significantly greater increase in CVD events (HR: 1.16, 95% CI 1.03-1.31, P = 0.02) as estimated from a composite end-point of nonfatal myocardial infarction (MI), nonfatal cerebrovascular accidents (CVA), cardiac arrest, and CV death (144). In absolute terms, cardiovascular events occurred in 11.4% of those assigned to treatment with sibutramine versus 10.0% for those treated with placebo.

 

Following this report, the U.S. FDA convened their Endocrine Advisory Panel to ask the question of whether this drug should continue to be marketed. The Panel recommended that sibutramine should be removed, although not everyone agreed with this conclusion. In a dissenting article, "Sibutramine: gone, but not forgotten", Dr. David Haslam (chairman of the National Obesity Forum) wrote that the SCOUT study was flawed as it only covered high-risk patients and did not consider patients with obesity who do not have cardiovascular complications or similar contraindications(145). The trial also had two other issues. First, patients with CVD who did not lose weight when taking the drug nonetheless continued treatment for up to 6 years, something that no responsible physician would do. Second, the intent-to-treat analysis of the results included patients who lost weight as well as those who did not lose weight. If your hypothesis is that the benefits in reducing the risk of cardiovascular disease and diabetes result from weight loss, then including patients who do not lose weight unduly biases the conclusions. It is, so to speak, like shooting yourself in the foot. A re-analysis of the data using only those who lost weight while taking sibutramine showed a lower rate of CVD events in those treated with sibutramine (146). Despite this re-analysis, the European Medicines Agency recommended suspension of marketing authorization for sibutramine, and on January 21, 2010, based on the results of the SCOUT trial, it was removed from the market in Europe. Abbott Laboratories in the US followed suit and announced on October 8, 2010 that it was terminating marketing of sibutramine in the US market under pressure from the FDA.

 

Lessons Learned:

  1. The first lesson from the SCOUT trial is that using intent-to-treat statistical methods, which retains individuals who do not lose weight, the drug produced harm.
  2. The second lesson is that when individuals who successfully lose weight while taking the drug are analyzed, instead of all comers, there is an overall statistical benefit – that is those who lose weight benefit from the weight loss
  3. The third lesson is that since individuals with obesity are generally at increased risk for detrimental cardiovascular outcomes, requiring documentation that new anti-obesity drugs do not have detrimental CVD effects became the rule.
  4. Despite its withdrawal from the market in 2010, sibutramine can still be found in products for sale on-line. The U.S. FDA found it in 69 of 72 products that were tested. These products appear to come from overseas, mainly China, and may pose health hazards (https://www.fda.gov/drugs/questions-answers/questions-and-answers-about-fdas-initiative-against-contaminated-weight-loss-products. Content Current as of 02/28/2018.  Accessed March 9, 2021)

 

Tesofensine  

 

Tesofensine, like sibutramine, is a triple monoamine reuptake inhibitor, which means it blocks the reuptake of serotonin, norepinephrine, and dopamine. The initial clinical data on the potential effectiveness of this drug for weight loss came from studies in neurological diseases including Parkinson’s disease and Alzheimer’s disease where treatment with tesofensine produced significant weight loss (147). This was followed by a randomized double-blind clinical trial in 203 patients who were randomly assigned to placebo or doses of 0.25, 0.5 or 1 mg/d of tesofensine (148). After 24 weeks the placebo-treated group lost 2.0% of their body weight compared with 6.5% in those given 0.25 mg/d of tesofensine, 11.2% in the 0.5 mg/d dose and 12.6% in the 1.0 mg/d dose. Although the clinical profile was relatively free of untoward side effects, there was, as with sibutramine, a small increase in heart rate and blood pressure. The cardiovascular risks identified in the SCOUT trial of sibutramine may also apply to tesofensine and provide a potential hurdle for approval of this drug.

 

Although no further data has appeared regarding tesofensine as a single anti-obesity agent since 2013, the combination of tesofensine (up to 0.5 mg/d) and metoprolol (50 mg/d) (Tesomet) was granted FDA approval in 2021 as an orphan drug in the treatment of both Prader-Willi syndrome and hypothalamic obesity based on results of a recent phase 2A trial (149). The combined use with a beta-blocker mitigated changes to pulse rate and BP and may be standard in development of other anti-obesity medications from this class of drugs.

 

Lorcaserin- Potential Cancer Risk      

 

Lorcaserin is the most recent casualty among drugs used in the management of patients with obesity. It is a selective serotonin (5-HT2C) receptor agonist (thereby avoiding potential for adverse effects on cardiac valves and pulmonary artery pressures induced by other serotonin receptors—see fenfluramine above), which reduced food intake in experimental animals and humans. Following completion of Phase 3 studies (150), an application for approval of Lorcaserin for marketing was submitted to the US FDA. An FDA Advisory Panel met on September 16, 2010, but rather than approving the drug, they voted 9-5 against approval based on two concerns, one about efficacy of the drug and the other about its safety. They were particularly concerned about the findings of tumors in experimental animals treated with lorcaserin. Following this Advisory Committee, the FDA decided, on 23 October 2010, not to approve lorcaserin for marketing. Arena, the manufacturer of lorcaserin conducted a new round of studies and on May 10, 2012, another FDA Advisory Panel was convened. This time they voted to recommend lorcaserin for marketing. A trial combining lorcaserin, a serotonergic drug, with phentermine, enhanced weight loss somewhat but did not mimic the dramatic results with Fen-Phen (151).

 

Even though lorcaserin had been engineered to be selective for the 5-HT2C receptor rather than the 5-HT2B receptor, which is located on heart values and mediates the valvulopathy associated with fenfluramine and other serotonin medications, a post-marketing cardiovascular outcomes trial was commissioned. This trial, called CAMELLIA-TIMI, enrolled 12,000 patients who were at high risk for cardiovascular events. After a median of 3.3 years of treatment with Lorcaserin or placebo, the authors concluded that: “In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that in the placebo”, termed non-inferiority (152). In the original publication of this trial, the overall incidence of cancer was slightly greater but not statistically different between the lorcaserin (7.7%) and placebo (7.1%) groups over the 3.3 years of follow-up. However, during post marketing monitoring, the FDA found that the point estimates for cancer rate ratios were consistently greater than 1.0 in the lorcaserin group compared to placebo, and finally became significant 2.5 years after study completion (153). The main cancers were skin, prostate, GI, and respiratory. Based on this significant increase in cancer risk, the FDA requested Eisai, the manufacturer of Lorcaserin (Belviq), to withdraw the drug on Feb 13, 2020 and the company complied.

 

Although there were signals in the initial submission that might have been a warning for this risk, it was not until well after completion of the trial and several years into general use that a potentially latent severe adverse event became apparent.

 

Histamine and Histamine Antagonists  

 

Histamine is a naturally occurring monoamine produced by decarboxylation of the amino acid, histidine. Histamine is located in neurons in the brain, in mast cells scattered around the body, and in the gastrointestinal track. There are four histamine receptors that mediate its effects, mainly located in the brain, the gut, and the immune system. The H-1 receptors in the brain are involved in wakefulness, appetite regulation, and endocrine function. In the periphery, H-1 receptors are in smooth muscles and endothelium where they are involved in bronchoconstriction, vasodilatation, and the sensation of itching. The H-2 receptors are in the stomach where they mediate gastric acid secretion, as well as in the brain, although their function in the brain is less clear. Injection of histamine into the brains of animals reduced food intake (154). Conversely, blocking histamine receptors with alpha-fluormethylhistidine, which irreversibly inhibits histidine decarboxylase, increases food intake. Similarly blocking histamine breakdown with metoprine, an inhibitor of histamine N-methyltransferase, also suppresses food intake in animals (155). Another piece of evidence suggesting a role for histamine receptors in food intake comes from data showing antipsychotic drugs that produce weight gain bind to histamine H-1 receptors with higher affinity than with any other monoamine receptor (156). Finally, the use of H-1 containing products to relive allergy is associated with weight gain (157).

 

The H-3 histamine receptor differs from the other two by being an autoreceptor which inhibits the action of other histamine receptors. There have been several studies examining histamine-related drugs as potential candidates for management of obesity. Betahistine is a weak, orally active agonist of the histamine H-1 but a potent antagonist of the histamine H-3 auto-receptor, which raises the ambient levels of histamine and has been approved to treat vertigo. In a randomized, placebo-controlled 12-week clinical trial, 281 people with obesity were given 8, 16 or 24 mg/d of betahistine or placebo twice daily. The overall weight loss was not significantly different between treatment groups, but the subgroup of white women under age 50 lost -4.24±3.87 kg compared to -1.65±2.96 kg (P<0.005) (158).

 

The histamine H-2 receptor antagonist, cimetidine was reported to reduce body weight in experimental animals (159)and in patients with type 2 diabetes (160), prompting one of the authors to conduct a trial in patients with obesity (161). In this small randomized clinical trial by a single author, a general practitioner from Norway, 60 participants (five females) received 200 mg of cimetidine or a matching placebo 3 times a day before meals along with a high fiber diet.  The treatment group lost 9.5 kg, which was significantly more weight than the 2.2 kg lost by placebo-treated controls. The editors of the British Medical Journal who were reviewing this paper received another manuscript from Rasmussen and colleagues in Denmark attempting to replicate the Norwegian Study (162). These investigators also included 60 patients (nine female) in the same age range as in the Norwegian study. In the first eight weeks participants were randomized to either cimetidine or placebo. In this trial weight loss was almost identical with the cimetidine-treated group losing 5.7 kg compared to 5.9 kg in the placebo-group. When this second paper was received by the British Medical Journal, the editor was concerned by the contradictory results of the two group and possibility of scientific misconduct. Dr. Richard Smith, editor of BMJ, sent both papers to Dr. John Garrow, MD, PhD, one of the leading British scientists in obesity research (163). In his published response Garrow noted that a weight loss of 9.5 kg in 8 weeks is a remarkably good result in this period, so good in fact that it might not be a measured outcome, but rather a manufactured one. There was also no attrition in either group, which is again remarkable. The similarity of weight loss from week to week and the fact that both the heavier and lighter patients lost the same amount of weight was also surprising and unexpected. Garrow was “baffled” at why there should be such a large difference in weight loss between these two studies (7.4 kg in the Norwegian Study and 0.2 kg in the Danish Study) both having been conducted in nearby Nordic nations. The editor of BMJ, Dr. Richard Smith was also concerned as he noted in a paper about scientific misconduct that he published after he left his role as editor of the British Medical Journal (164). The case was referred to the University of Oslo, and to the faculty in Tromsö where Dr. Stoa-Birketvedt was a general practitioner.  No evidence of misconduct was identified after reviewing the records and she was exonerated. As Dr. Florholmen, one of Stoa-Birketvedt’s collaborators on several studies and Dr. Leeds note in a comment on the Scientific Misconduct, “…scientific journals have an equally strong moral obligation to make a clear statement when a suspect investigator has been found not guilty” (165). This was not done in this case, but Stoa-Berketvedt and her colleagues went on to report a 42-month follow-up of her initial study. Twenty-two of the original patients continued in a cimetidine intervention group and received cimetidine for eight weeks, twice a year along with behavioral strategies and a diet. The 33 subjects in the non-intervention group received neither the cimetidine nor the behavior/diet treatment. After 42 months, body weight was stable in those in the cimetidine group compared to a gain of 7.5 kg in the other group (166).

 

Ranitidine, another histamine H-2 antagonist was tested for its potential to slow weight gain in patients receiving anti-psychotic drugs. In a meta-analysis, patients receiving ranitidine along with their anti-psychotic medication, gained less weight than their controls (167), suggesting a role for the H2 receptor in modulating energy balance under selected circumstances.

 

Fluoxetine for Weight Loss  

 

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) approved by the U.S. FDA to treat depression and several other conditions including obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. Fluoxetine was discovered by Eli Lilly & Company in 1972 and it began widespread use in 1986 (168). The World Health Organization's List of Essential Medicines includes fluoxetine, and in 2016 there were more than 23 million prescriptions for this drug, making it the 29th most prescribed medication in the United States. Fluoxetine at a dose of 60 mg per day (3 times the usual dose for treatment of depression) produced dose-related weight loss in overweight patients, which initiated studies into whether this drug, at this higher dose, could be developed as an anti-obesity medication. Initial studies up to 6 months in duration were promising, but with longer duration of treatment two unexpected outcomes occurred. First, there were substantial differences in weight loss between studies. In a meta-analysis of 6 studies, one study reported a loss of –14.5 kg and another reported a weight gain of + 0.40 kg (169). Another meta-analysis showed no significant weight loss difference between fluoxetine and placebo (170). The mean difference in weight loss at 12 months of -0.33 kg (95%CI –1.49 to 0.82 kg) favoring fluoxetine.

 

The second problem for fluoxetine was that after 16 to 24 weeks of treatment, patients began to regain weight, even while continuing the drug. Darga et al. were the first to note the rebound in weight with continued treatment (171). After a weight loss of 11.7% during 29 weeks of treatment, weight began to rebound and was only 7.8% at 12 months which was not significantly different from placebo. In a review of 6 studies with 719 patients randomized to fluoxetine and 722 randomized to placebo, weight loss at 6 months in the placebo group was 2.2 kg versus 4.8 kg in the fluoxetine-treated group (172). At one year, however the weight losses were no longer statistically different at 1.8 kg in the placebo group and 2.4 kg in the fluoxetine-treated group. Regaining 50% of the lost weight during the second six months of treatment on fluoxetine terminated clinical trials by Eli Lilly of fluoxetine as a weight loss agent. Similar results were true for another SSRI, sertraline (172, 173).

 

This weight “rebound” after six months of treatment with these SSRI’s was part of the reason that the US Food and Drug Administration moved to require trials lasting up to a year for new weight loss medications (172, 174).

 

Bupropion as a Single Agent for Weight Loss

 

Bupropion (WellbutrinR; Others) was first synthesized in 1969 by Nariman Mehta and patented by Burroughs-Wellcome Company in 1974. It is a norepinephrine- and dopamine-reuptake inhibitor approved by the US Food and Drug Administration for the treatment of depression and as an aid in smoking cessation. It was the 28th most prescribed medication in 2016 and the fourth most prescribed antidepressant in the U.S. with more than 23 million prescriptions. Two multi-center clinical trials have examined the effect of bupropion, as a single agent, on weight loss in patients with obesity, in patients with depressive symptoms, and in patients with uncomplicated obesity. In one study, 421 overweight patients with depressive symptom were randomized with 213 receiving the 400 mg/d dose of bupropion and 209 receiving the placebo for 24 weeks. The 121 subjects in the bupropion group who completed the trial lost 6.0 ± 0.5 % of initial body weight compared to 2.8 ± 0.5 % in the 108 subjects in the placebo group (p<0.001) (175). Another study in patients with uncomplicated overweight randomized 327 subjects in equal proportions to bupropion 300 mg/d, bupropion 400 mg/d, or placebo (176). Of the 69% who remained in the study after 24 weeks, weight losses were 5 ± 1% in the placebo group, 7.2 ± 1% in the 300 mg/d dose, and 10.1 ± 1% in the group receiving 400 mg/d (p<0.001). At 24 weeks, the placebo group was further randomized to either the 300mg or 400mg group and the trial was extended to week 48. In this trial, non-depressed subjects responded better to bupropion than those with depressive symptoms.

 

Even though the combination of bupropion and naltrexone is currently approved for management of complicated overweight and obesity, bupropion alone is a reasonable choice for people with depression and problems with weight control.

 

Topiramate as a Single Agent for Weight Loss

 

Topiramate is a substituted fructose molecule that was discovered by Bruce E. Maryanoff and Joseph F. Gardocki working at the McNeil Pharmaceuticals Laboratories in 1979. It was approved by the US FDA in 1996 to treat epilepsy with generalized or focal seizures and subsequently to prevent migraine headaches. It has also been used to treat alcohol dependence. The drug acts on several systems. It is a carbonic anhydrase inhibitor that can produce a mild metabolic acidosis and altered taste for carbonated beverages. It acts as a voltage-gated modular of sodium and calcium channels. It also activates both the GABA-A receptors and AMPA/kainite receptors.

 

In the 1990s, Johnson & Johnson, the parent company of McNeil Pharmaceuticals, noted that topiramate use was associated with significant weight loss and initiated trials to evaluate its effectiveness as a stand-alone medication for overweight and obesity. The magnitude of the weight loss at the higher doses of 192 and 256 mg/d rivals that of the Fen/Phen combination discussed earlier (177-179). Reaching a weight-loss plateau at the two highest doses did not occur until nearly one year of treatment. After the initial studies, further clinical development was abandoned because of the negative effects of this drug on mental function, including memory loss and difficulties with concentration and attention. For patients with these side effects, the clinical efficacy for weight loss did not counterbalance the side effects and its development as a single agent was suspended.

 

Zonisamide as a Single Agent for Weight Loss

 

Zonisamide is chemically a sulfonamide that is approved by the US FDA for use in Parkinson’s Disease and as an antiepileptic drug. It has serotonergic and dopaminergic activity, as well as being an inhibitor of carbonic anhydrase (like topiramate) and is an inhibitor of sodium and calcium channels. Weight loss was noted in the clinical trials for the treatment of epilepsy. To evaluate its potential use in management of obesity, Gadde et al conducted in a 16-week randomized controlled trial in 60 obese subjects (180) who were prescribed a calorie-restricted diet and a placebo or doses of zonisamide 100 mg/d and increasing to 400 mg/d. The zonisamide group lost 6.6% of initial body weight at 16 weeks compared to 1% in the placebo group. In a second randomized placebo-controlled trial, 225 patients with obesity received either placebo or zonisamide 200 mg/d or 400 mg/d. Neurological, psychiatric, and gastrointestinal adverse events occurred in the zonisamide-treated groups, but weight loss in the placebo-treated group was 4.0 kg after 1 year, 4.4 kg in the group receiving zonisamide 200 mg/d and 7.3 kg in the group receiving zonisamide 400 mg/d (181). Similar to topiramate, for patients with these side effects, the clinical efficacy does not outrank them enough to use as an anti-obesity medication.

 

Naltrexone as a Single Agent for Weight Loss

 

Both exogenous and endogenous opioids can stimulate food intake (182), effects that can be blocked by antagonists to opioid receptors. Naloxone, a short-term antagonist to opioid receptors, reduces fat intake in experimental animals (183). This suggested that naloxone might be a potential treatment for obesity. To test this idea Atkinson et al, in1982, gave single doses of naloxone to both lean individuals and individuals with obesity  and found a reduction of food intake only in those with obesity (184). The problem for naloxone as a treatment for obesity is its short duration of action.

 

Naltrexone in contrast, is a longer-lasting derivative that has been tested in several clinical trials (185-190). These trials were disappointing, and naltrexone has not been tried at the higher doses that might be required to produce a reduction in weight because of its potential for hepatic toxicity. In 1992 de Zwaan and Mitchell concluded in a review of naloxone and naltrexone (191) that “studies do not justify the routine use of naloxone and naltrexone in patients with Prader-Willi syndrome, obesity, bulimia nervosa, or anorexia nervosa because of their unprofitable risk/benefit ratios, although further work, particularly focused on some of the newer antagonists, should be undertaken.” Limited duration of action, limited efficacy, and toxicity at higher doses (192) were the downfall of opioid receptor antagonists as single anti-obesity agents.

 

Ecopipam and Dopamine D1/D5 Receptor Modulators for Weight Loss

 

Dopamine in the dorsal striatum of the brain is involved with the behavioral restraint of eating and the emotional components regulating eating behavior in human beings (193). This suggests that blockade of dopamine receptors might be a strategy for management patients with obesity. At least five dopamine receptors have been identified (194). The D1 and D5 receptors are very similar to each other, as are D2, D3, and D4 receptors. Agonists to the D1/D5 receptors reduce the duration of feeding primarily by decreasing the frequency of eating. On the other hand, D2 agonists reduce the rate of eating. A role for D1-like receptors in modulation of food intake has been established in animal models (195), suggesting that such a drug might have clinical use.

 

Ecopipam is a selective dopamine D1/D5 antagonist that was evaluated in four randomized, double-blind, multicenter trials that compared ecopipam (n=1667) to placebo (n=1118) in individuals with obesity, with or without type 2 diabetes (196). In dose-ranging Phase 2 studies, subjects received 10, 30, or 100 mg daily for 12 weeks. In a 52-week Phase 3 study, individuals received a single 50 mg or 100 mg daily dose of ecopipam combined with a weight loss program. Primary efficacy variables were the proportion of subjects losing more than 5% of their weight from baseline at 12 weeks (Phase 2) or the distribution of percentage weight loss from baseline at 52 weeks (Phase 3). After 12 weeks in the Phase 2 study, 26% of subjects administered 100 mg/d of ecopipam lost more than 5% of their weight vs. 6% of placebo-treated subjects (P<0.01). In the Phase 3 studies, ecopipam 100 mg produced a 3.1% to 4.3% greater weight loss than placebo at 52 weeks. More subjects administered ecopipam vs. placebo achieved a 5% to 10% or >10% weight loss in two phase 3 studies in the patients without diabetes.

 

These clinical trials were stopped prematurely because of unexpected psychiatric adverse events which occurred in 31% of those receiving ecopipam compared to 15% in those receiving placebo. These events included depression, anxiety, and suicidal ideation. Although ecopipam was effective for achieving and maintaining modest weight loss in subjects with obesity, the adverse effects on mood terminated its development as a drug for the management of weight loss (196). As is apparent in several non-selective centrally-acting medications, off target effects in the brain (in this case depression and suicidal ideation) can derail development or proceeding to approval.

 

Dopamine D2 Agonists as Single Weight Loss Agents

 

Prolactinomas are tumors of the pituitary gland that produce prolactin, and they are associated with weight gain. These tumors can be treated medically with dopamine D2 agonists such as cabergoline or bromocriptine. Bromocriptine, a specific D2 agonist, has been reported to decrease body weight in patients with obesity (197), but in a systematic analysis of this drug and cabergoline in the treatment of prolactinomas, there was no significant effect on body weight, although there was a significant reduction in hemoglobin A1c in patients with diabetes (198).  A form of this drug (bromocriptine) is available for the treatment of diabetes (199), but it does not affect body weight.

 

Cannabinoid Receptor Antagonists

 

The rimonabant story is one of a “near-miss” with promising beginnings but a sad, and possibly inappropriate, ending. Tetrahydrocannabinol is the active ingredient of Marihuana-Cannabis and was shown to stimulate food intake in 1984. There are two endogenous cannabinoid receptors CB-1 (470 amino acids in length) and CB-2 (360 amino acids in length) that were identified six years later. The CB-1 receptor has almost all the amino acids that comprise the CB-2 receptor with additional amino acids at both ends. CB-1 receptors are distributed throughout the brain in the areas related to feeding. They are also found on fat cells and in the gastrointestinal track. The CB-2 receptors are primarily on immune cells. There are two well-characterized endogenous endocannabinoids called anandamide and 2-arachidonyl glycerol. When injected into the brain, these endocannabinoids increase food intake. The rewarding properties of cannabinoid agonists are mediated through the mesolimbic dopaminergic system (200-203).

 

Rimonabant was the first specific antagonist of the CB-1 receptor. It inhibits intake of sweet foods by marmosets and reduces intake of high-fat foods in rats. Whereas intake of standard rat chow is not affected by rimonabant. In addition to inhibiting the intake of highly palatable foods, pair-feeding experiments in diet-induced obese rats showed that the rimonabant-treated animals lost 21% of their body weight compared with 14% in the pair-fed controls (202-205).

 

With this background and the safety of the drug, a clinical program testing rimonabant as a potential weight loss drug was initiated and four phase 3 trials of rimonabant for the treatment of patients with obesity have been published. The first trial, called Rimonabant in Obesity (RIO)-Europe (206), was intended to be conducted only in Europe, but slow recruitment led to inclusion of 276 subjects from the United States. In this 2-year trial, a total of 1507 patients with a BMI > 30 kg/m2 without comorbidities or a BMI >27 kg/m2 with hypertension or dyslipidemia were stratified on whether they lost more or less than 2 kg during a run-in period. They were then randomized in a ratio of 1:2:2 to receive placebo, 5 mg/day or 20 mg/day of rimonabant. A diet with 600 kcal/day below energy requirements was prescribed. There was a 4-week run-in period followed by 52 weeks of drug treatment. Of those who started, 61% (920) completed the 1st year. From baseline at the end of the run-in period, those in the placebo group who completed the trial lost 2.3 kg, those on the low-dose of rimonabant lost 3.6 kg, and those receiving the high-dose group lost 8.6 kg. After this and other extensive trials, Rimonabant was approved in Europe, but was not approved by the FDA because of concerns about suicidality. As this concern grew, marketing of rimonabant was suspended in Europe on Oct 23, 2008 just over 2 years after its approval because of these psychiatric problems.

 

Against the problem of depression and suicidal ideation, were benefits on blood pressure, lipid profile, and the cardiovascular risk profile. At the time of its removal from the market, several trials were on-going. In the SERENADE Trial (207), rimonabant significantly improved control and body weight in patients with diabetes. In the ARPEGGIO trial, also in patients with diabetes, rimonabant proved to be beneficial for control of diabetes and for the loss of weight (208).   Progression of arterial thickening over 30 months was not slowed by rimonabant, compared to placebo (209). This and several other studies suggest that a 5% loss of body weight over a 30-month period with rimonabant is not sufficient to modify the progression of atherosclerosis in the carotid artery in obese patients with metabolic syndrome. In another cardiovascular outcome trial 18 months of treatment failed to show an effect for rimonabant on disease progression with the primary end point of percent atheroma volume (PAV) but, tantalizingly, there was a favorable effect on the secondary end point of total atheroma volume (TAV) (210). Ultimately, the CRESCENDO trial to examine cardiovascular outcomes in a total 18,695 patients randomized to rimonabant or placebo was stopped prematurely due to concerns about increased suicide rates in individuals receiving rimonabant (211). This led to termination of all the rimonabant studies along with studies of other cannabinoid antagonists. Whether the benefits would have outweighed the risks is something we will never know.

 

In a recurring theme for centrally acting agents, specificity for both receptor type and brain location are important in avoiding off-target behavioral effects that can doom an anti-obesity medication.

 

The two cannabinoid receptors are also widely distributed and include the liver and fat cells, which raises the possibility that drugs acting only on the peripheral CB-1 receptors might be effective treatments for obesity.  Experimental data in animals shows that this is indeed possible, and we will have to await further developments in this area (212).

 

Yohimbine

 

Yohimbine is an alpa-2 adrenergic antagonist that modulates lipolytic response to epinephrine.  It is an indole alkaloid derived from the bark of the Pausinystalia johimbe tree in Africa as well as from an unrelated tree in South America (Aspidosperma quebracho-blanco). Yohimbine is a plant extract sold as a dietary supplement that has had a number of claims for beneficial responses, including as an aphrodisiac, weight control, and erectile dysfunction, but data supporting any of these claims is scant or absent (213).

 

Drugs That Increase Energy Expenditure

 

As unwanted weight gain leading to overweight and obesity results from a prolonged positive imbalance between energy intake and energy expenditure, it would be ideal for an anti-obesity medicine (or combination of medicines) to impact both. Energy expenditure can be partitioned into several components (214). The first is basal or resting energy expenditure, which is the energy needed to maintain body temperature, brain activity, cellular gradients for sodium and potassium, cardiac function, respiration, and other “basal” functions. This so-called “basal” or “resting” energy expenditure accounts for about 2/3 of total daily energy expenditure in most people and can be modified with exposure to cold or heat. The second component is the energy needed to move the body (activity), which is also the most variable component since it depends on the amount and intensity of the activity performed. Some very active people can increase total energy expenditure by 50% or more above basal levels, whereas in others with low levels of physical activity, this will account for less than 25% of daily energy use. The final component of energy expenditure is that involved with the ingestion, digestion, and absorption of food. This is the so-called “thermic effect of food,” or in earlier times, “specific dynamic action.”

 

The regulatory model of body weight would point to development of anti-obesity drugs that increase energy expenditure through promotion of negative energy balance. Thyroid hormone is the prototypical thermogenic agent and has already been discussed in detail. Other drugs in several categories are considered below based on their mechanisms of action (215). The first are agents that are sympathomimetic amines with ephedrine at the top of the list. Next are the drugs acting on the adrenergic receptors that affect thermogenesis. The third group are the catechins, which occur naturally in tea. Finally, we discuss capsaicin that produces the feelings of “heat” on the tongue when eating hot peppers.

 

EPHEDRA AND EPHEDRINE

 

The story of ephedra and ephedrine, one of its active components, is mixed with good science, commercial exploitation, and governmental inadequacies. There were several key players in this story. The first is Arne Astrup, MD a professor of Medicine in Copenhagen who was a key figure in demonstrating the efficacy of using the combination of ephedrine and caffeine in the management of obesity. The second are two US Senators, Senator Orin Hatch representing the State of Utah and Senator Tom Harkin representing the State of Iowa. Finally, there is Michael Ellis, CEO of Metabolife, the largest purveyor of ephedra compounds and who is also representative of the entrepreneurs who marked their products directly to the consumer.

 

Ephedrine with and without caffeine

 

Ephedrine has been used to treat asthma for more than 75 years. As a sympathomimetic amine, it also stimulates thermogenesis in animals and human beings (216). In 1971 Dr. Eriksen, a Danish general practitioner in the town of Elsinore, Denmark noted that his asthmatic patients receiving ephedrine, caffeine, and phenobarbital often lost weight. Word of his “discovery” spread and by 1977 over 70,000 people were taking this compound called, appropriately, the ‘Elsinore Pill’ (217). One side effect of the Elsinore Pill was skin rashes, which were thought to be related to the phenobarbital. To understand the Elsinore pill better, Malchow-Moller et al. conducted a trial comparing ephedrine and caffeine without phenobarbital against diethylpropion, a known anorectic drug (217). Over the 12 weeks of treatment both active medications produced a similar weight loss of just over 8 kg, which was much more than placebo.

 

Following-up on this lead, Astrup and his colleagues explored ephedrine alone and in combination with caffeine as a potential treatment for obesity (218). The duration of the thermogenic effect of ephedrine is amplified by theophylline or caffeine, which slows the degradation of cyclic-AMP. Caffeine and other xanthines appear to prevent the body from becoming resistant to the effects of ephedrine by inhibiting phosphodiesterase and the adenosine receptor (219). The response to ephedrine was dose-related and persisted during chronic treatment. The mechanism by which ephedrine affects body weight is, in part, due to its effect upon thermogenesis, but it also clearly reduces food intake.

 

Several clinical trials with ephedrine and ephedrine plus caffeine have been reported (220). In a 6-month trial, Astrup et al. compared placebo, caffeine 600 mg/day, ephedrine 60 mg/day, and the combination of caffeine 600 mg/day with ephedrine 60 mg/day in 180 subjects with obesity (221). Withdrawals were equal in all groups with 141 subjects completing the trial. Weight loss was significantly greater in the group receiving the combination of caffeine and ephedrine (16.6 kg vs. 13.2 kg, P = 0.0015). Weight loss in the caffeine-only group and the ephedrine-only group was not different from that in the placebo group. Side effects of tremor, insomnia, and dizziness were transient and by eight weeks were no different than the placebo group. Blood pressure fell equally in all four groups. After six months the medication was stopped for two weeks to assess withdrawal symptoms. One hundred twenty-seven subjects then entered a 6-month open-label study of caffeine 600 mg/day with ephedrine 60 mg/day (221). The 99 subjects who completed the study lost an additional 1.1 kg, and no clinically significant withdrawal symptoms were observed.

 

The combination of caffeine and ephedrine, like the combination of phentermine and fenfluramine produced 16% weight loss during the initial six months that was maintained over the ensuing six months. In a 15-wk trial, patients with obesity lost significantly more weight when receiving ephedrine 20 mg and caffeine 200 mg daily compared to patients receiving dexfenfluramine 30 mg a day (222). Based on these and other data, the Danish Health Authority approved the use of ephedrine and caffeine as a combination drug for the management of obesity. After problems with ephedra, the plant-based source of ephedrine surfaced in this United States in the 1990s, marketing authority was withdrawn in Denmark.

 

Ephedra: An Herbal Medication

 

Ephedra has its historical roots going back several thousand years in Chinese medicine.  Ephedrine is one of the principal alkaloids in the ephedra plant and was originally isolated by Nagai in 1885 and then rediscovered by Chen and Schmidt in the 1920s (223, 224). During the middle of the 20th century, ephedrine was a major drug used to treat asthma, only falling out of favor when newer and better drugs, such as amphetamine, were developed.

 

Ephedra sinica, also known by its Chinese name Ma huang, has been used medicinally to treat asthma, hay fever, and common colds. It is a source of six principal components, including ephedrine and pseudoephedrine, which are sympathomimetic amines that provide the stimulant and decongestant properties of this plant. Dietary supplements containing ephedra alkaloids were widely marketed over the counter for treatment of obesity in the 1990s. This direct marketing to the public without having to go through the Food and Drug Administration to prove their safety and efficacy was made possible when the US Congress passed the Dietary Supplements and Health Education Act in 1994 (DSHEA) (225). This law effectively put dietary supplements out of the reach of regulation by the US Food and Drug Administration. The work described above on ephedrine by Astrup and his colleagues in the 1980s and 1990s provided the rationale for the mass marketing of ephedra to the public in the United States since there were no regulatory barriers in the way. Under the DSHEA act, products could be marketed if a health claim was not raised in the marketing materials. However, weight loss was an obvious market for these products. Metabolife became one of the leading distributors of ephedra products and amassed sales that surpassed a billion dollars a year. Although they were not regulated by the FDA, they needed to protect themselves from US Federal Trade Commission, which could go after them for false advertising. Based on the work of Astrup et al (221), Metabolife commissioned a study of their product compared to placebo, hopeful that the outcome would support their claims. Indeed, a scientific paper by Boozer C, et. al. did just that (226).

 

However, complaints that ephedra alkaloids, such as those marketed by Metabolife, were unsafe began to reach the US Food and Drug Administration, including serious side effects and deaths. Unknown to the FDA at the time, Metabolife had received over 14,000 complaints of adverse events associated with its product that were not initially made public. In response to accumulating evidence of adverse effects and deaths related to ephedra, in 1997 the US Food and Drug Administration (FDA) reviewed the data and then finally banned the sale of supplements containing ephedra in 2004. This ban was challenged in court by the manufacturers of ephedra products, but it was ultimately upheld by the US Court of Appeals of the Tenth Circuit in 2006. Documentation of adverse events that could be attributed to unregulated ephedra supplements published in a report in JAMA (227). These effects include severe skin reactions, irritability, nervousness, dizziness, trembling, insomnia, headache, dehydration, profuse perspiration, itchy scalp and skin, vomiting, and hyperthermia. Cardiovascular effects including irregular heartbeat, heart attack, stroke and death were the most serious.

 

Michael Ellis, co-founder of Metabolife, was sentenced to six months in federal prison in 2008 for his failure to report adverse effects from his company's products to the US FDA. In the midst of this, the Dietary Supplement Industry created a public relations group called the Ephedra Education Council, to oppose the changes to the marketing of products containing ephedra, and commissioned a scientific review by a private consulting firm, which, as might be expected, reported that ephedra was safe. The Ephedra Education Council also attempted to block publication of a study confirming wide discrepancies between the labeled potency of supplements and the actual amount of ephedra in the product. Both Senators Orrin Hatch (R. Utah) and Tom Harkin (D. Iowa), authors of the Dietary Supplements Health and Education Act, questioned the scientific basis for the US FDA's proposed labeling changes and suggested that the number of problems reported were insufficient to warrant regulatory action. At the time, Senator Hatch's son was working for a firm hired to lobby Congress and the US FDA on behalf of ephedra manufacturers—a potential conflict of interest.

 

BETA-AGONISTS

 

Broadly, adipose tissue is divided into “white” fat, “beige” fat and “brown” fat. Beige and brown adipocytes are progressively enriched with iron-containing mitochondria, resulting in progressively darker brownish hues. Animal studies reported that heat production by brown fat in mammals could be increased by diet. The thermogenic response to a meal was mediated, in part, by release of norepinephrine from the rich supply of sympathetic nerves that supply brown adipose tissue and could thus be blocked by severing the sympathetic nerves to this tissue. The adrenergic receptor mediating this response was different from the previously defined beta-1 and beta-2 adrenergic receptors and was subsequently named the beta-3 receptor (228). Activation of the beta-3 receptor increased the activity of a mitochondrial uncoupling protein, allowing for free passage of proteins across the inner membrane, thereby short-circuiting the production of high energy phosphate bonds in ATP during metabolism and “wasting” the energy instead as heat. Stock and Rothwell (229) showed that brown adipose tissue plays a key role in dissipating additional calories rather than storing them as fat. In the animal that has overeaten a highly palatable diet, there is a thermogenic response to norepinephrine that is blocked by propranolol, a β-adrenergic blocking drug, confirming the importance of β-adrenergic receptors in this response.

 

Cloning of the beta-3 adrenergic receptor by Strosberg (230) opened up the way to develop drugs that could increase energy expenditure (231, 232). The first generation of beta-3 agonists were developed against the rodent receptor and highlight the problems associated with cross-species differences. A few of these compounds were tested in human beings, and the data are summarized in Table 4. Four drugs demonstrated an increase in energy expenditure and an increase in heart rate (BRL 26830A; BRL35135; Ro16–8714; Ro40–2148). The only first generation atypical β-adrenergic agonist to have a long-term clinical trial is BRL 26830A (R*,R*)-(6)-methyl-4-[2-[(2-hydroxy-2-phenylethyl)amino]propyl]-benzoate, (E)-2-butenedioate (2:1) (220, 233). This compound stimulates oxygen consumption even in the leptin deficient genetically obese (ob/ob) mouse and causes weight loss and a decrease in body fat, while at the same time conserving or increasing lean body mass (231). In human studies, it increases oxygen consumption for up to six weeks (234).

 

In an 18-wk double-blind randomized trial in 40 patients with obesity prescribed

an 800-kcal, low-fat, high-fiber diet, Connacher et al (235) reported that the treated group lost a mean ± SD of 15.4 ± 6.6 kg over 18 weeks compared with 10.0 ± 5.9 kg in the placebo group (P=0.02). The metabolic rate decreased less in the experimental group (5.35 to 5.11 kJ/min) than in the placebo-treated group (5.22 to 4.98 kJ/min) (P = 0.08). An increase in tremor, probably due to activation of β-2-adrenergic receptors, was the principal drawback (236). There were no effects on hunger or satiety (237).

 

A second drug from Beecham Research Laboratories (BRL-35135) was structurally similar to the previous drug (BRL 26830A) and also produced an increase in RMR and an improvement in glucose tolerance. The mild tremor noted with the previous drug was also seen with this compound (238). Another compound from the Imperial Chemical Industries (ICI-D7114) developed against the rodent receptor was nearly devoid of thermogenic activity (239). A pair of compounds developed by Hoffmann LaRoche (Nutley, NJ) (Ro 16–8714 and Ro 40–2148) were thermogenic in lean and obese subjects (240) but caused significant increases in heart rate. The final compound from the rodent receptor assays (CL-316, -243, or BTA-243) was not thermogenic but in a short-term clinical trial improved glucose disposal (241).

 

The question then became would the thermogenic responses be sufficient to produce weight loss without untoward side effects. Several compounds have reached clinical evaluation, but the therapeutic response with the most specific drugs developed against the human beta-3 receptor have been disappointing too (242, 243). TAK-677 is a novel beta-3 agonist that was tested over four weeks in 65 healthy younger men and women with obesity and a BMI of 33.9 ± 2.1 (mean ± SD). Subjects were randomized to 3 groups and after 28 days of treatment with placebo, 0.2 mg or 1 mg in two divided doses daily, the 24-hour energy expenditure in a whole room calorimeter fell by 39 kcal/d in the placebo group and rose by 13 kcal/d with the higher dose of TAK-677.   Heart rate increased significantly by 8 beats/min in the higher dose group. This drug was not developed further because of the concerns for potential CV toxicity (242). The recent identification of brown adipose tissue by positron emission tomography in human beings may reawaken interest in the idea of enhancing thermogenesis.

 

Studies on the beta-3 adrenergic receptor demonstrate several things:

First, drugs developed based on biology of other species may not work in humans.

Second, predicting the in vivo effects of agonist drugs from in vitro data can be hazardous.

And third, the action on other (off target) receptors, the heart in this case, may vitiate the targeted biology, in this case energy expenditure (244).

 

Despite these disappointing results, thermogenic drugs for the treatment of obesity are still under investigation, including peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists and retinoids. Although much of this research is still in the early stages, the β-3 adrenergic receptor agonist (ARA) mirabegron, approved for the treatment of overactive bladder, has been studied in humans. Preclinical results suggest that β -3 ARAs could also improve obesity-associated metabolic diseases by increasing thermogenesis in BAT, lipolysis in white adipose tissue, or insulin sensitivity.  A small study of 14 women receiving 100 mg/d of mirabegron XR for 4 weeks demonstrated increased activity in BAT as well as improved insulin sensitivity (245).

 

Table 4. Clinical Studies with B-3 Adrenergic Agonists

Author (Ref No)

Year

Subjects

Length

Diet

Energy

Expend

Heart Rate

Weight Loss

Comments

 

 

 

 

 

 

Placebo

Drug

Placebo

Drug

 

Beecham Research Laboratories (BRL) 26836A

 

Zed (246)

1985

Obese (14F/2M)

6 wk

Restricted

 

--

--

-6.56 kg

-7.3%

-9.34 kg

-10.1%

Abstract; RCT; Initial weight 92.7 kg drug grp; 89.8 kg placebo grp.

Abraham (247)

1987

Obese

6 wk

Restricted

 

--

--

-232 g/d

-291 g/d

Abstract; Protein loss 17.1 g/d placebo; 8.9 g/d for BRL

Smith (248)

1987

Lean (12M)

1 d

Ad-lib

 

 

 

+0.3 kg

-0.2 kg

RCT; fasting insulin decreased

Chapman (249)

1988

Obese (43F#)

6 wk

1000 kcal/d

 

No Change

No Change

 

 

RCT; 50 mg/d; Tremor noted

Connacher (235)

1988

Obese

(32F/8M)

18 wk

800 kcal/d

REE up 11.6%

No Change

No Change

10.0 kg

15.4 kg

RCT; 200 mg/d 2 week then 400 mg/d for 16 wks.

Connacher (236)

1990

18 (Sex Not given)

Single dose

Ad-lib

 

 

 

 

 

Tremor increased

Connacher (233)

1992

Obese (12F)

3 wk

Ad-lib

No Δ VO2or RQ

No Change

No Change

 

 

100 mg tid improved insulin sensitivity and down-regulated adrenergic receptors.

Beecham Research Laboratories (BRL) 35135

 

Mitchell (238)

1989

Obese

(6F/4M)

10d

Wt Maintaining

 

 

 

No Change

No Change

AUC for glucose and insulin reduced Glucose Thermogenesis unchanged

Smith (250)

1990

T2D

 

 

 

 

 

 

 

Mild Tremor

Cawthorne (234)

1992

Lean M

 

 

Obese (6F/4M)

Single

 

 

10d

 

 

 

 

Wt Maintaining

Up 16% vs 4% placebo

 

 

 

 

Thermogenic response to glucose increased from 10.1% to 16.0% by BRL

Imperial Chemical Industries (ICI) D7114

 

Toubro (251)

1993

Lean

14d

 

No Change

 

 

 

 

Abstract- No effect on glucose disposal

Goldberg (239)

1995

Lean (16M)

14d

 

No Change in SEE

 

 

 

No Change

RCT Parallel arm

Hoffmann-LaRoche Ro 16-8714 (Ro 40-2148)

 

Henny (240)

1987

Lean M

Acute

 

REE Up with dose

 

Up by 2% 8% & 49%

 

 

3 doses; REE, HR and SBP increased with dose

Henny (252)

1988

Lean 6M

Obese 6

Acute

 

REE up in both groups

 

HR, SBP & FFA Up

 

 

Single dose comparison L vs Ob. Both up’d REE, HR, SBP & FFA

Jequier (228)

1992

 

 

 

 

 

 

 

 

Compared acute Epi, Dopamine and Ro16-8714.

Haesler (253)

1994

Obese 12F

14d

 

REE Not increased

 

 

 

 

Ro-2148. Parallel Group; 400 mg bid. Glucose thermogenesis up.

Lederle Laboratories CL 316,243 (BIA-243)

 

Wheeldon (254)

1994

Lean (8M)

Acute

 

 

 

 

 

 

Salbutamol & CL35135 with nadolol and Bispropol; Sal & CL has chronotropic and inotropic effects

Weyer (241)

1998

Lean (14M)

56d

Ad-lib

24h EE not changed

 

 

No Change

No Change

Parallel arm; 4 placebo, 10 CL; Insulin action increased

Lederle Laboratories L-796568

 

Van Baak (243)

2002

OW-OB (12M)

Acute

Ad-Lib

Increased 8% high dose

No Change

No Change

 

 

2 Center cross-over study; placebo, 250 & 1000 mg doses; SBP, glycerol & FFA increased; No change Temp, leptin, NE, DBP

Larsen (255)

2002

OW-OB (20M)

28d

Ad-lib

24h EE not changed

 

 

No Change

No Change

Parallel arm, 2 center RCT; RQ unchanged; GTT not changed; TG decreased

Takeda (TAK) 647

 

Redman (242)

2007

Obese

28d

Isocaloric

 

 

 

 

 

RCT; placebo & 2 doses

F=Female; M=Male; #= Post-menopausal; REE = Resting energy expenditure; RQ=respiratory quotient; tid=three times a day; bid=twice daily; RCT=randomized control trial; wk=week; d=day; Δ=change

 

CAPSINOIDS

 

Capsinoids are non-pungent compounds with molecular structures similar to capsaicin, which comes from red papers and gives them that “hot” taste. For this reason, capsinoids were thought to have thermogenic properties that could be harnessed in the management of obesity. This concept was tested in a clinical trial including 13 healthy subjects who received four doses of the capsinoids (1, 3, 6 and 12 mg) and placebo using a crossover, randomized, double-blind design. To test the thermogenic effect, resting metabolic rate was measured by indirect calorimetry for 45 min before and 120 min after ingesting each of the capsinoids or placebo. There were no significant effects of any dose on energy expenditure compared to placebo, and there was no effect on blood pressure or axillary temperature (256). Further development of these compounds was halted due to clinical ineffectiveness.

 

Peptides, Metabolic Inhibitors & Gastrointestinal Drugs (1994- )

 

The possibility that peptides might provide the basis for developing drugs to control food intake began well before 1994, but I have selected 1994 as the beginning of this period because it was the year that leptin was discovered—a discovery that made obesity a scientifically respectable field (6). Leptin became foundational for our current understanding of the physiological regulation of body weight and helped to unravel the genetic and molecular basis for the neurocircuitry implicated in the pathophysiologic changes that lead to unwanted weight gain and obesity. Following the discovery of leptin and advancement of the weight regulation model, obesity wasn’t “your fault” anymore. In this section we will discuss several peptide drugs, including cholecystokinin, human growth hormone, inhibitors of insulin release, human chorionic gonadotrophin, leptin, and ciliary neurotrophic factor.

 

CHOLECYSTOKININ

 

Cholecystokinin (CCK), also called pancreozymin, is a gastrointestinal peptide produced in and secreted from enteroendocrine “I” cells in the duodenum. CCK, along with gastrin, which is secreted from the “G” cells in the stomach, share five C-terminal amino acids. The cholecystokinin group of peptides are produced as a 150-amino acid precursor called pre-pro-cholecystokinin with several forms identified by the number of amino acids they contain, e.g., CCK58, CCK33, CCK22 and CCK8 with 58, 33, 22 or 8 amino acids respectively. Most CCK peptides have a sulfate group attached to a tyrosine located seven residues from the C-terminal end of the molecule. This modification is crucial for the ability of CCK to activate the cholecystokinin-1 receptor as the non-sulfated CCK peptides are inactive. When injected parenterally, CCK-8 produces a dose-related reduction in food intake in lean experimental animals and human beings with obesity (257-259). There are two CCK receptors:  CCK1 (CCKA) and CCK2 (CCKB). The former is located primarily in the gastrointestinal track and the latter in the brain. Peptide analogs of CCK provide one avenue for developing drugs that could reduce food intake (260, 261). Another approach to manipulating CCK is with benzodiazepines that act as CCK agonists (262). A third approach is to use antagonists to proteolytic degradation of CCK and CCK-releasing factors in the GI track.

 

CCK releases digestive enzymes from the pancreas and stimulates the release of bile from the gall bladder. Fatty acids and certain amino acids are the major stimulators of CCK release. CCK suppresses hunger by decreasing the rate of gastric emptying. It also stimulates the vagus nerve, an effect which is blocked by capsaicin. Vagotomy prevents the reduction in food intake produced by the peripheral injection of CCK, suggesting that afferent messages generated in the gastroduodenal/hepatic circuit are relayed to the brain by the vagus nerve (220). These vagal messages initiated by CCK activate several neuronal complexes in the brain including the nucleus of the tractus solitarius (NTS), the lateral parabrachial nucleus, and the central nucleus of the amygdala, as assessed by expression of the early gene product c-fos (263). The production of early satiety by CCK does not require an intact medial hypothalamus because it occurs in human beings with hypothalamic injury and obesity (264). In human studies CCK reduces food intake by 6–63% (average 27%) in lean subjects and 13–33% (average 21%) in individuals with obesity, with a small number of studies reporting GI side effects (220). However, animal studies suggest that suppressed food intake returns to baseline quickly (a true form of tolerance) and any initial weight loss is not sustained. Currently, no drugs appear to be in development using this pathway, suggesting limited effectiveness or potential side effects.

 

HUMAN GROWTH HORMONE  

 

Individuals who are obese secrete less human growth hormone (hGH) (265). This is important in relation to unwanted weight gain because this hormone enhances lipolysis (266), increases metabolic rate (267), and leads to changes in fat patterning in children with hypopituitarism treated with growth hormone (268). Early studies with hGH showed that it would lead to reduced protein loss in people with obesity (269). In adults with growth hormone deficiency, treatment with hGH reduces body fat (270), whereas effective treatment of patients with acromegaly who secrete excessive amounts of growth hormone reduces circulating growth hormone levels and is associated with an increase in body fat (271).

 

Most trials of human growth hormone in patients with obesity have been short term, lasting from 21 days to five weeks (272), but a few have lasted up to 39 weeks (273). Most of the subjects were women. Metabolic rate was increased in those patients when measured, and respiratory exchange rate was reduced, indicating that more fat was being burned (oxidized). Insulin-like growth factor I, the liver-derived hormone released by hGH, increased FFA levels, and the rate of fat loss relative to protein loss (272). However, a number of side effects were also noted (273) that reduce the enthusiasm for long-term treatment with hGH. In a long-term, randomized placebo-controlled trial lasting nine months, 15 men were treated with hGH daily and 15 with placebo injection (274). In these men, GH enhanced fat loss with a larger percentage of this loss coming from visceral fat than from the subcutaneous fat. In a review in 2008, Rixhon et al noted that treatment with growth hormone affects fat distribution, may or may not improve metabolic profile, but does not lead to much actual weight loss (275).

 

Human growth hormone is thus important for growth and maintaining a healthy body composition (increased lean mass, less visceral fat), but its value is obesity is limited by the fact that it does not produce weight loss.

 

MANIPULATION OF INSULIN SECRETION BY DIAZOXIDE OR OCTREOTIDE

 

Treatment with peripheral insulin in patients with type 1 diabetes with the goal of near normalization of glucose control is well known to produce weight gain (276). One hypothesis for the development of obesity is that dietary carbohydrate (glucose) stimulates insulin release, which in turn promotes obesity (277), although this hypothesis is thought by many to be overly simplistic (278). Even though insulin has been clearly established to be an important mediator of normal weight regulation through its central actions and that insulin resistance or deficiency leads to hyperphagia and weight gain (279, 280), a few studies with experimental animals and in small numbers of patients with obesity following hypothalamic injury have implicated hyperinsulinemia as a potential driver of weight gain, and that lowering insulin can reduce food intake and body fat (281, 282). There are at least two ways of reducing insulin secretion pharmacologically: the administration of diazoxide or the use of octreotide. Diazoxide lowers insulin secretion from the pancreatic beta cell and increases glucose release from the liver. Octreotide is an octapeptide that mimics the naturally occurring somatostatin, also called growth hormone inhibiting hormone. Its effects are mediated by SSTR2 and SSTR5 receptors, which inhibit the release of several hormones, including growth hormone, insulin and glucagon, and thus is non-specific in its effect.

 

The hypothesis that inhibiting insulin release could treat obesity was tested by Lustig et al. who treated patients with hypothalamic obesity using octreotide. In a randomized clinical trial of 18 patients, Lustig and colleagues demonstrated that octreotide could indeed suppress insulin levels, and at the same time resulted in stabilized body weight and BMI in this difficult to manage population with obesity (283). In a follow-up study, Lustig et al treated 172 (28M/144F) patients with evidence of insulin hypersecretion for six months with one of three doses of octreotide or placebo (284). The higher doses produced small but statistically significant weight loss, which appeared to be greater in those with higher insulin levels. The data were mixed, but those with the greatest decrease in insulin did show the largest reductions in weight (283, 284). A third study tested octreotide in 20 women with polycystic ovary syndrome who received a low-calorie diet for one month followed by 6 months of diet and either octreotide or placebo. There was no difference in weight loss, but there were improvements in hyperandrogenism and the insulin-IGF-I system (285). Because of its non-specific inhibition of hormonal secretion, poor efficacy in weight loss, and intolerable side effects in many patients (nausea, vomiting, and induction of type 2 diabetes due to inhibition of insulin secretion), octreotide has not been pursued further as a clinical therapy for weight management and cannot truly be considered a test of the “insulin as obesogenic hormone” hypothesis.

 

On the other hand, diazoxide has more specificity as an inhibitor of insulin secretion and has also been tested in patients with obesity. In a meta-analysis of seven studies, four with diazoxide and three with octreotide, Huang et al reported that suppression of insulin secretion in patients with obesity led to reduced body weight and fat mass and unchanged lean mass at the cost of slightly increased blood glucose (286). While this concept merits further development, like many complex physiological systems, insulin has several recognized roles in governing fat mass. In addition to its capacity to enhance peripheral fat storage, preclinical models have demonstrated that insulin acts as both a satiety factor and feed-back hormonal signal reflecting adipose tissue stores that inhibits appetite and enhances energy expenditure (279, 280). These functions of insulin, which have strong support in animal studies, plus the increased risk for causing type 2 diabetes when insulin secretion is pharmacologically suppressed, has dampened enthusiasm for this line of investigation.

 

HUMAN CHORIONIC GONADOTROPIN:  1954-2011

 

The story of the use of human Chorionic Gonadotropin (HCG) in the treatment of obesity involves several groups of actors. The first was Dr. Simeons who described the HCG protocols in 1954 and 1956. The second were the clinics that have used this hormone as a treatment for obesity. The third were the investigators who conducted clinical trials to test the effectiveness of HCG treatment plan. And the final actors were the US Government and its regulatory apparatus.

 

Human chorionic gonadotropin (HCG) is a peptide that comes from the placenta after implantation of a fetus. Its role is to maintain hormonal activity during part of pregnancy.  Concentrations of HCG in the blood and urine provide the basis for pregnancy tests. The biological function of HCG and its chemical composition is similar to that of luteinizing hormone produced in the pituitary. HCG maintains hormonal secretion from the corpus luteum during pregnancy. Some early experimental studies with HCG suggested it may have metabolic effects on adipose tissue, but these remain to be confirmed (287, 288).

 

The clinical use of human chorionic gonadotropin (HCG) in the treatment of obesity can be dated to a paper published in the prestigious medical journal The Lancet in 1954. A British Endocrinologist, A.T. Simeon’s (289, 290) described studies in India on pregnant women and on “fat boys” with pituitary problems (Fröhlich’s Syndrome) who were eating a calorie-deficient diet.  He noted that when treated with HCG, both groups lost weight and had a reduction in appetite.His clinical method subsequently appeared in a small booklet called Pounds and Inches that outlined his program in detail (291). This program involved a 500 total kcal per day diet along with daily injections of human chorionic gonadotrophin (hCG) lasting between 20 and 40 days.

 

There is little doubt that adhering to a 500 kcal/d diet will produce significant weight loss in a short period of time. The question was, however, whether the injections of HCG contributed pharmacologically to the effect or whether they were simply a placebo. In an early study, Carne compared 20 patients prescribed the 500 kcal/d diet half of whom received injections of saline and half HCG (292). They also compared a second group eating the same diet with half receiving shots of HCG and the other half receiving no injection. The authors concluded that patients receiving injections lost more weight than those not receiving injections, but that injections of HCG were not better than injections of saline. Other studies subsequently published came to the same conclusion: treatment with HCG was not significantly different from treatment with placebo. A young physician, Frank Greenway, MD working with me carried out one of these studies (293). We randomly assigned patients to receive “placebo injections” or injections of HCG. All patients were instructed in a 500 kcal/d diet. As expected on such a severe caloric restriction, all patients rapidly lost weight, but there was no difference in weight loss between those receiving HCG and those receiving placebo injections in this study.

 

Based on this and other studies, the US FDA ordered the following disclaimer in advertisements for HCG clinics.

“These weight reduction treatments include the injection of HCG, a drug which has not been approved by the Food and Drug Administration as safe and effective in the treatment of obesity or weight control. There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or "normal" distribution of fat, or that it decreases the hunger and discomfort associated with calorie-restrictive diets.”

 

Despite this negative clinical trial data, the popularity of treatment with HCG was so great that it became the basis for a group of clinics dispensing it along with the 500 kcal/d diet. Ten years after the FDA made its pronouncement, there is still no evidence that HCG increases weight loss. To investigate the use of this treatment, a Los Angeles Times reporter, Robert Steinbrook, wrote a story titled “Doctors Use of Obesity Treatment Debunked by FDA” (294). For this story, Steinbrook “randomly telephoned 40 medical weight-loss programs that advertised in Los Angeles yellow pages [and] found 19 that offered HCG shots, including the Lindora Medical Clinic, one of Southern California’s largest chains of weight-loss clinics.” In his article he said: “At Lindora medical clinics, the patient information booklet states that HCG works by “mobilizing your abnormal fat into the blood stream as nutrients. This permits you to accept a very low caloric intake so that you can lose weight rapidly and feel well and not be overly hungry.”  Steinbrook went on to say: “The FDA’s warning directly contradicts those assertions.”  In a telephone interview with Dr. Marshall Stamper, Lindora’s founder and owner Stamper said that “Most of the patients that come through the clinic use [HCG].” However, as Steinbrook noted in his story, “HCG shots have been condemned by the American Medical Association, the California Medical Association, and the Federal Trade Commission on the basis of studies in the Journal of the American Medical Association and elsewhere in the mid-1970s that concluded the shots were no more effective than salt-water placebo injections or diet alone.”  In his phone interview Dr. Stamper went on to say “They [patients] prefer it [HCG] to other methods,” “adding that he uses the shots himself on occasion for arthritis of his fingers, another condition for which the FDA has not approved HCG. We tell the patients point-blank that it doesn’t cause weight loss, but that they will do better on it. I feel the patients have definitely benefited. I feel it goes beyond the placebo effect,” Stamper said.

 

In 1995, a full ten years after Steinbrook’s story, HCG was still in use. A meta-analysis of studies with HCG published in 1995 (295) found that  studies of HCG were generally of poor quality and the authors of this review concluded that "there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight-loss or fat-redistribution, nor does it reduce hunger or induce a feeling of well-being.” (295)

 

Nonetheless, interest in the "HCG diet" continues into the 21st century as told in the story by Kevin Mark Trudeau published April 2007 and called The Weight Loss Cure "They" Don't Want You to Know About. The book describes a weight loss plan using HCG similar to the one published by Simeons in 1954 using human chorionic gonadotrophin (296).

 

Wikipedia describes Kevin Mark Trudeau as:

“….an American fraudster, author, salesman, and pool enthusiast, known for promotion of his books and resulting legal cases involving the Federal Trade commission (FTC). His ubiquitous late-night infomercials, which promoted unsubstantiated health, diet, and financial advice, earned him a fortune but eventually resulted in civil and criminal penalties for fraud, larceny, and contempt of court. In the early 1990s, Trudeau was convicted of larceny and credit card fraud. In 1998, he was accused of grossly misrepresenting the contents of his book, The Weight-Loss Cure “They” Don’t Want You to Know About. [The book uses the Simeon’s approach]. In a 2004 settlement, Trudeau agreed to pay a $500,000 fine and cease marketing of all products except his books, which are protected under the First Amendment. However, in 2011, he was fined $37.6 million for violating the 2004 settlement, and ordered to post a $2 million bond before engaging in any future infomercial advertising. In 2013, facing further prosecution for violations of the 2011 agreement and non-payment of the $37-million judgment, Trudeau filed for bankruptcy protection. His claims of insolvency were challenged by FTC lawyers, who maintained that he was hiding money in shell companies, and cited examples of continued lavish spending, such as $359 for a haircut. In November 2013, Trudeau was convicted of criminal contempt, and was sentenced to 10 years in federal prison. He will be eligible for release in 2022.  Infomercials starring Trudeau and promoting his books — under the auspices of a private California corporation of undisclosed ownership — continue to air regularly on United States television stations.” (297)

 

Finally, on December 6, 2011, the United States Food and Drug Administration (FDA) prohibited the sale of over-the-counter diet products like HCG and indicated that they were fraudulent.  Even later, on November 15, 2016, the American Medical Association (AMA) passed a policy statement saying that "The use of human chorionic gonadotropin (HCG) for weight loss is inappropriate." There is no scientific evidence that HCG is effective in the treatment of obesity. The authors stated “…the use of HCG should be regarded as an inappropriate therapy for weight reduction…” Yet, to this day, the internet still contains information about the HCG Diet, HCG Diet Cookbooks, and products claiming to contain HCG.

 

LEPTIN

 

The ‘obese’ mouse is a recessively inherited form of obesity that provided a major breakthrough in understanding the basic biology of food intake and regulation of body weight. This animal is obese because it lacks leptin, a hormone produced almost entirely in adipose tissue that was discovered in 1994 by positional cloning of the “ob” gene from the ‘obese’ mouse (6). This discovery revolutionized the field of obesity research by making it clear that obesity, in at least some cases, was a biochemical problem and not a problem of “will power.”

 

The principal site of action for leptin is in the brain, where activation of leptin receptors reduces food intake and increases energy expenditure, in part by increasing activity of the sympathetic nervous system. Several variants of the leptin receptor have been identified and cloned. Leptin inhibits hunger by reducing the production and release of neuropeptide Y (NPY) and agouti-related protein (AGRP), both potent stimulators of hunger, and by promoting satiety through synthesis of alpha melanocyte stimulating hormone (α-MSH), a hormone that suppresses food intake(298-300). Genetic deficiency in the leptin receptor, like the absence of leptin itself, is associated with a marked increase in food intake and massive obesity in both animals and humans (301, 302). Since leptin secretion is proportional to adipocyte cell size and number, as one might anticipate, circulating levels of leptin are highly correlated with the amount of body fat. In the cases of leptin deficient human beings and animals, leptin replacement cures their obesity by restoring normal appetite regulation and food intake and increasing the activity of the sympathetic nervous system (303).

 

Excitement following the discovery of leptin led to the hope that it might also cure “simple” (or polygenic) obesity once and for all. To test this, a randomized, double-blind clinical trial with leptin was performed. The results were a great disappointment when published in 1999 (304). There were 54 lean individuals with a mean weight of 72 kg and 73 subjects with obesity weighing on average 90 kg who were assigned to treatment with daily injections of leptin (r-met Hu Leptin) at doses of 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, or 0.3 mg/kg or placebo. The lean individuals maintained a eucaloric diet whereas the patients with obesity ate diets reduced by 500kcal/d below maintenance energy needs. All participants were treated for four weeks, and the subjects with obesity for an additional 20 weeks. There was a significant dose-related weight loss in the lean subjects at 4 weeks and in the individuals with obesity at 24 weeks.  At the end of four weeks, 60 of the 70 patients with obesity who remained in the study elected to continue for an additional 20 weeks. Among the subjects who completed the study (n = 53 lean at 4 weeks and n = 47 obese at the end of 20 weeks), the authors found a significant dose-response effect for weight loss from baseline at 4 weeks and from baseline in the obese subjects treated for 24 weeks, but the differences were relatively small (weight changes for obese subjects at 24 weeks were 21.7 kg for placebo; 20.7 kg at 0.01 mg/kg; 21.4 kg at 0.03 mg/kg; 22.4 kg at 0.10 mg/kg; and 27.1 kg at 0.3 mg/kg). Reactions at the site of injection were the most common adverse event, but only two subjects withdrew for this reason. Glycemic control was unchanged during the study.

 

In a second human study, daily injections of leptin at doses of 0, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg and 0.3 mg/kg daily were relatively ineffective in the treatment of obesity (305). This limited response to leptin in subjects with obesity and higher levels of circulating leptin, contrasted sharply to the dramatic weight loss when leptin was used in the rare individuals with leptin deficiency (303), in whom leptin was much more effective. These studies showed that human leptin could produce weight loss in human beings with obesity, but the weight loss was disappointingly small. This fact, along with the side effects and route of injection, as well as the probability that antibodies against native leptin would develop led to discontinuation of this drug for commercial uses in obesity. On the other hand, these findings opened the door to exploration of “downstream” neuronal pathways from the leptin receptor, where it is now thought that the basis for leptin resistance resides.

 

Although leptin failed as an agent for treatment of the patient with obesity, it did find a role in ameliorating many of the symptoms of lipodystrophy (306-309). During 4 months of therapy with leptin in patients with lipodystrophy, triglyceride levels decreased by 60%, liver volume was reduced by an average of 28%, and resting metabolic rate decreased significantly (306).

 

Leptin treatment has been shown to ameliorate many of the adaptive effects associated with calorie restriction, including attenuating the decreased 24-hour energy expenditure, and thyroid hormone levels (310, 311). Leptin also reversed many of the changes in the brain as assessed by functional magnetic resonance (fMRI) associated with hunger in subjects stabilized at 10% below their usual weight (312).  Leptin has been shown to help restore normal gonadal pulsatility and menses in women with leptin deficiency (313) and hypothalamic amenorrhea, typically due to extreme exercise or anorexia nervosa (314). While considered a failure as a single agent, the possibility that leptin may resurface in combination with some other peptide or oral agent remains open for the future.

 

CILIARY NEUROTROPHIC FACTOR

 

The receptor subunits for leptin share sequence similarities with the hypothalamic receptor for ciliary neurotrophic factor (CNTF), a neurocytokine that promotes neurotransmitter synthesis and neurite outgrowth in selected populations of brain cells (315). Leptin and CNTF both produce similar patterns of activation in brain cells. Treatment with CNTF in either ob/ob mice, which lack circulating leptin protein, or in db/db mice, which lack the leptin receptor, reduced the adiposity, hyperphagia, and hyperinsulinemia. CNTF was similarly effective in mice with diet-induced obesity. These findings suggest that this system may be a valuable target for drugs to manage obesity. Further support for this idea came from a published trial showing that CNTF produced weight loss in patients with amyotrophic lateral sclerosis (316).

 

A modified version of CNTF with a 15 amino-acid truncation of the C-terminal end and two amino acid substitutions was developed and tested in human beings with obesity (317). Phase 3 clinical trials for this modified ciliary neurotrophic factor were conducted in 2003 and demonstrated a small positive effect in some, but not all patients. A major problem was that nearly 70% of the participants developed antibodies against the recombinant CNTF after approximately three months of treatment. In the minority of subjects who did not develop the antibodies, weight loss averaged 12.5 pounds (5.7 kg) in one year, versus 4.5 pounds (2.0 kg) for the placebo-treated group. Development of neutralizing antibodies to peptide agents such as leptin and CNTF are pitfalls to this class of drugs (peptides) as they blunt the therapeutic responses.

 

Neuropeptide Y

 

Regulation of food intake in the brain involves a series of pathways located at the base of the brain in the arcuate and adjacent nuclei (298). This network involves secretion of peptides that increase food intake, including neuropeptide Y (NPY) and agouti-related peptide (AGRP) as well as the release of peptides that inhibit food intake, including α-MSH (derived from cleavage of pro-opiomelanocortin or POMC) and cocaine-amphetamine related peptide (CART). The effects of NPY are transmitted through 5 widely distributed receptors, Y-1, Y-2, Y-4, Y-5 and Y-6. Activation of NPY receptors Y-1 or Y-5 dramatically increases food intake in animals, and continued stimulation of the NPY receptor produces obesity, making an antagonist to these NPY receptors an attractive target for an anti-obesity drug.

 

Seeing this opportunity, Merck and Company developed MK-0557 which is a highly selective NPY-5 receptor antagonist with 98% receptor occupancy at 1.25 mg dose vs 3% for placebo using positron emission tomography. In the initial 12-week dose-ranging study weight losses were 0.7, 1.6, 2.2, 2.1 & 2.3 kg for placebo, 0.2, 1, 5 & 25 mg dose respectively (p=0.041) (318). Despite these small weight losses, a subsequent trial lasting 52-weeks was undertaken to evaluate it use in the prevention of weight regain. The placebo group had -1.1kg weight loss compared -2.2 kg in the group treated with 1 mg/d (319). This small, but statistically significant difference was not substantial enough for further drug development. While this study demonstrated that the NPY-5 receptor was involved in modulating food intake and body weight in human beings, the magnitude of weight loss was too small for further commercial development of this drug.

 

Melanocortin-4 Receptor Agonists 

 

The melanocortin-4 receptor (MC4R) plays a central role in the regulation of food intake (320, 321). Individuals with genetic defects in this receptor are obese and disabling this receptor in experimental animals produces obesity (322). This receptor thus appeared to be a good target for pharmaceutical intervention prompting Merck and Company to pursue it (323). Their target drug, MK-0493, went into clinical trials as a selective and novel melanocortin-4 receptor agonist. However single doses of 200 mg and 500 mg were disappointing, producing only a marginally significant effect on 24-hr food intake compared to placebo. Nonetheless in two subsequent weight loss trials (one following stepped titration), MK-0493 produced a small, but not statistically significant weight loss relative to baseline. These clinical studies suggest that an MC4R agonist alone may not be an easy clinical target. While this limited clinical response to this agonist led to a termination of the clinical development program at Merck, recent reports led the FDA to approve another agonist to the MC4 receptor, setmelanotide, which was shown to be effective in the treatment for 3 rare genetic forms of obesity representing neuro signaling defects upstream from the MC4R: leptin deficiency, dysfunction in the PCSK1 (encoding for prohormone convertase 1/3), and deficiency of POMC (324, 325).

 

Testosterone and Anabolic Steroids

 

Testosterone is the principal product of the male testis and is responsible for changes which occur in males during puberty, including masculinization, voice changes, and changes in distribution of fat and muscle. Testosterone can also be produced by the adrenal gland, the ovary, and by conversion of androstenedione in peripheral tissues with 25% of testosterone in women coming from the ovary, 25% from the adrenal gland, and 50% from peripheral conversion. Levels of testosterone are associated with masculine dominance and these levels decline slowly after their peak in mid-life.

 

Reports of disordered reproductive function in men with obesity appeared in the mid-1970s as abstracts. In one study of 10 men with massive obesity, total serum testosterone and free testosterone correlated negatively with body weight but did not correlate significantly with sex-hormone-binding-globulin (326). The effects of obesity are probably due to reduced release of gonadotrophins from the pituitary since there was a normal response of testosterone to injections of human chorionic gonadotropin (HCG) acting directly on the testis (326). When clomiphene, a drug which enhances the release of the pituitary gonadotrophins was given, it also produced an increased release of testosterone by enhancing release of gonadotrophins from the pituitary (326). In a recent review, low total testosterone and low serum sex hormone-binding globulin were noted to be highly prevalent in men with obesity (327). However, it was only those with low levels of free testosterone along with signs and/or symptoms of hypogonadism that should be considered androgen deficient and thus merit treatment (327). These alterations are reversible upon weight loss as summarized in pooled data from 9 analyses in which Grossmann showed a linear relationship between weight loss and the increase in total testosterone (328, 329). Whether low testosterone is a biomarker or a true risk factor for metabolic disturbances remains unclear (330).

 

Testosterone levels are positively related to the amount of visceral fat in women and negatively correlated with visceral fat in men (331, 332). This inverse relationship between testosterone and visceral fat suggested that visceral fat might be reduced by treatment with testosterone. This hypothesis was tested using men with low-normal levels of circulating testosterone (≤ 0.20 nmol/liter) and a BMI greater than 25 kg/m2 (333). In the first study, testosterone was given orally twice daily for 8 months in doses of 80 mg. The 11 men who received testosterone had a significant decrease in the amount of visceral fat as measured by computed tomography compared to the 12 men who received placebo. There were no changes in body weight, subcutaneous fat, or lean body mass, but insulin sensitivity was improved.

 

In a second study, 31 men were randomly allocated to three groups receiving either placebo, testosterone, or dihydrotestosterone (334). In this study, testosterone and dihydrotestosterone were given as a gel applied to the arms daily for 9 months. The placebo group received only the gel. The testosterone-treated group had a significant decrease in waist circumference and visceral fat. On the other hand, the group treated with dihydrotestosterone had an increase in visceral fat compared to placebo. Insulin sensitivity was also improved by treatment with testosterone.

 

These intriguing results with testosterone, led to two additional studies examining the effects of anabolic steroids in both men and women (335, 336). The idea was to emphasize the effects on muscle and fat and reduce the masculinizing effects of testosterone. The first study lasted 9-months and included 30 healthy men who were overweight with mean BMI values between 33.8 –34.5 kg/m2 and testosterone values between 2 and 5 ng/ml (336). During the first 3 months when oxandrolone, an oral anabolic steroid was given, there was a significantly greater decrease in subcutaneous fat and a greater fall in visceral fat than in the groups treated with placebo or testosterone enanthate injected every 2 wk. There was also a significant drop in HDL cholesterol levels, which is a known side effect of orally administered anabolic steroids. The anabolic steroid group was thus changed from an oral to an injectable drug, nandrolone decanoate. Surprisingly, the group treated with bi-weekly injections of testosterone did not replicate the earlier data with testosterone published by the Swedish investigators (333, 334).  Moreover, the biweekly injections of nandrolone failed to maintain the difference seen during daily oral treatment with oxandrolone. This suggests that frequent, if not daily, administration of steroid may be needed to obtain the effects on visceral fat.

 

In a second trial 30 post-menopausal women with obesity were treated for 9 months with the anabolic steroid nandrolone (335). During this time, they lost more fat and gained more lean mass than the comparison groups. Treatment with the anabolic steroid also produced a gain in visceral fat and a relatively greater loss of SC abdominal fat. The conclusion from the four studies is that visceral and total body fat can be manipulated separately, and that testosterone plays an important role in differential fat distribution in both men and women.

 

In older, obese hypogonadal men, adding testosterone for 6 months to lifestyle therapy does not further improve overall physical function. However, testosterone may attenuate the weight loss–induced reduction in muscle mass and hip bone mineral density (BMD) and may further improve aerobic capacity (337).

 

In summary, testosterone in men is related to their level of body fat and exogenous testosterone can influence both fat and muscle mass. Oral administration of testosterone or other steroids may have significant effects on circulating levels of lipids. The effects of obesity on testosterone may be related to changes in the central mechanisms that modulate the feedback of testosterone and luteinizing hormone levels, in which case weight loss benefits testosterone levels rather than vice versa. Ongoing studies are being conducted to determine if testosterone supplementation and the benefits on body composition are outweighed by increased risk for adverse cardiovascular events.

 

Dehydroepiandrosterone

 

Dehydroepiandrosterone [DHEA (3β-Hydroxyandrost-5-en-17-one)] and its sulfated derivate, DHEA-S are the most abundant steroid products of the human adrenal gland. At high levels of BMI, in the range of 40–60 kg/m2, there is a significant negative correlation of DHEA with BMI. Interestingly, the levels of DHEA and testosterone decline with age in both men and in women. Despite the high circulating levels of this steroid, no major function has been identified for it, although it can act as a weak androgen, a weak estrogen, and has effects in the central nervous system.

 

In contrast to human beings, most other animals have low levels of DHEA (338). When mice, rats, cats, and dogs are given DHEA in their diet they lost weight. This suggests that DHEA might be useful in treating patients with obesity (339-342). As a result, several clinical trials of DHEA have been completed in human beings. In a 28-day study with 10 volunteers of normal weight there was no effect on body weight or on insulin sensitivity as assessed by the euglycemic-hyperinsulinemic clamp even when the volunteers were given 1,600 mg/d of DHEA, a dose that is near the limit where hepatic toxicity becomes a risk (343). Another clinical study showed that DHEA had no effect on energy expenditure, body composition, or protein turnover (344). A third 28-day study in men with obesity also showed no improvement in body fat or insulin sensitivity (342). In women with obesity, there was likewise no change in body fat, but there was a decrease in insulin sensitivity (345). In one provocative trial, etiocholanedione, a metabolite of DHEA was tested in a 20 week double-blind cross-over study (346). Weight loss during treatment with etiocholandione was 2.8 kg compared to a weight loss of 0.21 kg (P<0.05) in the placebo group. This study has not been followed up and these compounds appear not to be under further study. All in all, a review of the subject by Clore (339) concluded that “a significant role for DHEA in the pharmacologic treatment of human obesity is unlikely.”

 

Conjugated Linoleic Acid

 

Dietary supplements containing ‘conjugated’ linoleic acid (CLA) have been widely promoted as weight loss agents. In this context, the word “conjugated” refers to the position of the double-bond between carbons 9-11 or 10-12 in the fatty acid chain of linoleic acid. In a meta-analysis of 13 randomized, controlled trials lasting up to 6 months, Larsen et al reported that there was little evidence that conjugated linoleic acid produced weight loss in human beings (347). One report suggests it may lower body fat without having an effect on body weight (348). Liver toxicity is one concern with the use of CLA with the trans-10, cis-12 isomeric form. One review said that this CLA isomer may adversely affect health by producing lipodystrophy and insulin resistance and by decreasing milk fat production in lactating women (347). Ultimately, Dwyer et al concluded that there is little evidence of benefit and there is a potential for harm when using CLA for weight reduction (349).

 

Hydroxycitrate

 

Hydroxycitric acid is a derivative of citric acid and is a component of some tropical plants including Garcia cambogia. One form of hydroxycitrate is a potent inhibitor of a final step in the tricarboxylic acid cycle (Krebs Cycle) involving the conversion of citrate to acetyl CoA and oxaloacetate. Studies in animals suggested that hydroxycitrate modulated lipid metabolism and thus might be useful in treating obesity (350). Garcinia cambogia is a significant plant source of hydroxycitrate. Two clinical trials with Garcinia cambogia have been published, but the results are not promising. In one randomized clinical trial there was no significant effect on body weight or fat mass (351). A more recent report suggests that either alone or with Green Tea Garcinia cambogia may cause liver damage (352) Clinically trivial differences in weight loss and potential liver toxicity  made this drug a bad bet for weight loss (353).

 

Drugs Acting on the Gastrointestinal Track

 

DRUGS THAT MODIFY DIGESTION OR ABSORPTION OF NUTRIENTS

 

Reducing absorption of ingested nutrients is one potential strategy for lowering body weight.   Drugs affecting metabolism and absorption of fat and carbohydrate have both been investigated to test this hypothesis. Orlistat is a drug approved around the world that uses this strategy by blocking intestinal lipases, thus leaving some “undigested” triglyceride in the GI tract. Because it is currently marketed, it will not be discussed further. Cetilostat is a second drug that blocks intestinal lipases. It has been tested in clinical trials and is approved for clinical use in Japan. Two other drugs, cholestyramine and neomycin have also been tested, but abandoned. 

 

Cetilstat A Blocker of Fat Digestion

 

Cetilistat, (ATL-962), like orlistat, is a gastrointestinal lipase inhibitor. A 5-day trial of cetilistat in 90 normal volunteers showed a three to seven-fold increase in fecal fat loss that was dose-dependent, but only 11% of subjects had more than one oily stool (354). This data suggested that cetilistat might have fewer gastrointestinal side-effects than orlistat.A subsequent 12-week study with 372 patients compared placebo with doses of 60, 120 or 240 mg of cetilistat given three times a day (355). Weight loss ranged between 3.5 and 4 kg compared with a 2 kg loss in the placebo-treated group. In a second phase II study, doses of 40, 80 and 120 mg three times a day were given to patients with type 2 diabetes (356) with a dose-related reduction in body weight and in hemoglobin A1c. Side-effects have reduced the enthusiasm for this drug.  However, it proved effective in vitro against the SARS-COVID-19 virus in a drug screen, which may give it a new life (357).

 

Cholestyramine a Binder of Sterols and Fatty Acids

 

Cholestyramine is a sequestrant that binds bile acids in the gastrointestinal track to prevent their reabsorption. As a strong ion exchange resin it can exchange its chloride anions with anionic bile acids and bind them strongly in the resin matrix, subsequently excreting the cholestyramine and adherent fat in the stool (358). Although originally developed for lowering cholesterol (Questran, Questran Light, Cholybar, and Olestyr), the idea that this drug could be used to enhance fat loss in the stools of patients with obesity as a strategy for weight loss was tested in two clinical studies. In the first, two patients with marked obesity received 36 g/d of cholestyramine for 9 days along with a 1200 kcal/d diet with 80% of the calories coming from fat. Although there was a statistically significant increase in fecal fat loss, it was disappointingly  (287).  A second study was conducted by Campbell et al in six patients with obesity using 30 g/d of cholestyramine (359). These results were also disappointing. Finally, cholestyramine was tried in an out-patient obesity clinic, where patients with obesity failed to lose significant amounts of weight (Bray Unpublished data). Thus, increasing fecal loss of fatty acids by binding them to resins produced clinically insignificant weight loss.

 

Neomycin as an Inhibitor of Fat Absorption

 

Neomycin is an antibiotic found in many topical medications, including creams, ointments, and eye drops. It was discovered in 1949 and approved for medical use in 1952. Like cholestyramine, it increases the loss of fat in the stools(358). In doses of 6-12 g/d it consistently produces steatorrhea (360), and in doses of 3 g/d it impaired fat absorption in 5 of 10 patients (361). Its use in obesity was limited by the fact that it alters the intestinal mucosa and is not safe in a chronic disease such as obesity (362), making it unsuitable for long-term use.

 

Olestra (Sucrose Polyester): An Indigestible Fat Replacement

 

Sucrose polyester (Olestra) is formed from sucrose by adding five or more fatty acids to a molecule of sucrose to produce a compound that has the physical characteristics of triglyceride, but which cannot be digested by pancreatic lipase. Short-term studies replacing dietary triglycerides with olestra showed two patterns of adaptation. Substitution of fat with sucrose polyester (olestra) in a single breakfast meal was followed by energy compensation over the next 24–36 hours in healthy young males (363). In contrast, substitution of dietary fat with sucrose polyester (olestra) in the noon or evening meal to lower digestible fat from 40% of intake to 30% of intake, was not followed by energy or nutrient compensation over the next 24 hours (364). Further lowering of digestible fat intake from 30% of intake to nearly 20% of energy intake over three meals in healthy subjects led them to feel less satiated at the end of the study and they compensated for nearly 75% of the energy deficit over the next day (365).  In longer term studies lasting either 2 or 10 weeks, substitution of sucrose polyester (olestra) for one-third of the dietary fat in a diet with 40% fat reduced energy intake by about 15% (366).

 

In each of the short-term experiments there was only partial compensation for the energy deficit, suggesting that when the energy density of the diet is changed surreptitiously, individuals continued to eat for the same mass of food, even though it provided less metabolizable energy. Weight loss in the two-week experiment was 1.5 kg and in the 10-week experiment it was more than 5 kg, a weight loss that was significantly greater than in the control group.  In a third study lasting nine months, 45 healthy men who were overweight were randomly assigned to one of three diets: a control diet with 33% of energy from fat, a fat-reduced diet containing 25% of energy from fat, and a diet where one-third of the dietary fat was replaced by olestra to achieve a diet containing 25% metabolizable energy from fat (367). Among the 36 men who completed the 9-month study, the sub-group receiving the sucrose polyester (olestra) as a replacement for regular dietary fat lost 6.27 ±1.66kg of body weight and 5.85 ±1.34 kg of body fat over the 9-month trial. This contrasted with the sub-group eating the control 33% fat diet who lost only half as much at 3.8 ± 1.34 kg of body weight and 3.45 ±1.0 kg of body fat. The sub-group eating the 25% low fat diet lost even less body weight (1.79 ± 0.81 kg) and body fat (1.68±0.75 kg). After 9 months it was clear that the men assigned to the fat-substituted diet had lost significantly more weight and fat than the men in the other two groups. In addition, the men eating the two regular fat diets (33% fat and 25% fat) asked for significantly more food than the men assigned to the olestra fat-substituted group, indicating higher levels of hunger (P < 0.05). In contrast, the men eating the olestra substituted fat-reduced diet asked for almost no extra foods suggesting that they were more satiated. The authors concluded that replacement of dietary fat with olestra reduces body weight and total body fat when compared with a 25% fat diet or a control diet containing 33% fat (367). Subjects eating the olestra-containing diet had substantial decreases in serum carotene, lycopene, lutein and zeaxanthin, which occurred by 12 weeks. Replacement with a multi-vitamin was sufficient to overcome these changes (368). Weight loss and the loss of fat also impacted cardiovascular risk factors with a significant effect of diet mainly on total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, all of which decreased in the olestra-substituted group but not the other two groups by 9 months (369). After adjustment for the percentage of fat loss during the trial, only the changes in triglycerides remained statistically significant (369).

 

Olestra was approved by the FDA as a food additive in 1996 and soon appeared in chips sold under the brand name “WOW.” Because of perceived or real side-effects, the use of olestra containing products declined and in 2002 Proctor-Gamble, the originator of olestra, sold its manufacturing facility in Cincinnati. Some products with olestra may still be available. In the end, while this food product produced beneficial effects, it never caught on with the public.

 

Fat emulsion: OlibraTM

 

Food and its digested products act on the intestine at various levels to secrete hormones that modulate food intake. One of these signals is the entry of fats and fatty acids into the ileum which activates both neural and humoral factors that inhibit gastric emptying, prolong gastric transit time, and can produce satiety. This mechanism is referred to as the “ileal brake.” Longer chain fatty acids (> 12 carbons) and free fatty acids, rather than triglycerides, are the most effective stimuli for the ileal brake. OlibraTM is a fat emulsion composed of fractionated palm and oat oil in the proportion of 95:5. The palm oil is emulsified by hydrophilic galactolipids derived from oat oil (Lipid Technologies Provider AB, Karishamn, Sweden). This product increases satiety and reduces food intake in some studies (370), but not in others (371). To test the clinical effectiveness of this fat emulsion, a phase-2 randomized double-blind controlled trial of 12 weeks duration was conducted in 74 men and women with obesity (372). In this study, “Olibra” had no significant effect on food intake, appetite or ratings of satiety and did not differentially affect, body weight, or body composition.

 

Amylase Blockers of Carbohydrate Digestion

 

Amylase is an enzyme found in the saliva and intestine that hydrolyzes dietary starch into simple sugars. Salivary α-amylase is encoded by a gene called AMY1. In epidemiological studies, low AMY1 gene expression was associated with obesity (373). Moreover, low serum concentrations of amylase have been associated with elevated BMI (374). In a weight loss study, individuals who were overweight or obese and carried the AMY1-AMY2 (rs11185098) genotype, which is associated with higher amylase activity, had greater weight loss during the 2-year POUNDS Lost dietary intervention study (375), suggesting that medications modifying starch digestion might be of potential value in the management of obesity.  

 

To test the effect of blocking starch digestion on body weight, a clinical trial with 59 people was designed to give some participants an amylase-starch (glucosidase) inhibitor called BAY e 4609 (Acarbose) or a placebo (376). Although insulin and glucose tolerance improved, the drug did not produce weight loss. A somewhat different conclusion was reached by William-Olsson et al (377) who treated 24 women with acarbose after they had already lost weight and found that it helped prevent weight regain. In a third study, Wolever et al. reported that after one-year, 354 individuals with type 2 diabetes who received acarbose lost 0.46 kg compared to a weight gain of 0.33 kg among those in the placebo group. Although statistically significant, this result was clinically small (378). In this case, despite the relation of the AMY-1 gene expression to weight change, α-amylase blockers produce either no effect or a clinically trivial effect on body weight.

 

Enterostatin A Peptide That Affects Fat Intake

 

Enterostatin is a penta-peptide produced by trypsin cleavage of pancreatic procolipase in the intestine. Procolipase is secreted from the pancreas in response to dietary fat. Enterostatin, is highly conserved across a number of species (379, 380) and selectively reduces fat intake in the rat by nearly 50% (381). The dose-response curve for enterostatin is U-shaped with an optimal inhibitory effect on feeding at 1 nmol. Higher and lower doses are less effective, and at high doses enterostatin actually stimulates food intake. Chronic infusion of enterostatin reduced body weight in animals (382), but parenteral enterostatin did not reduce food intake in human beings (383). In the end, limited effectiveness terminated development of this product.

 

SUMMARY AND PERSPECTIVE

 

This chapter provides a historical perspective on earnest but often misguided approaches advocated by providers in the treatment of obesity, as well as the scientific challenges and adverse patient outcomes that have plagued development of effective weight loss drugs. Besides the typical toxicities associated with any drug development program, including rashes, gastrointestinal distress, hepatic metabolism, and the development of antibodies against some peptides, a number of other specific toxicities have been particularly vexing. One example is off-target effects. This can occur when receptor activation (or inhibition) impacts more than one intra-cellular signaling system, such as when changes in blood pressure occur in response to sibutramine and tesofensine. Off-target effects can also occur when receptor specificity is low and more than one receptor within a drug class are affected. For example, drugs that either raise systemic levels of serotonin, or lack specificity for the serotonin receptor such as fenfluramine, will activate both the 5HT2c and 5HT2b receptors. Activation of the 5HT2c receptors lowered food intake whereas simultaneous activation of the 5HT2b receptor produces cardiac valvulopathy. Or an endocannaboid receptor antagonist may inhibit food intake and cause weight loss but may also affect mood centers and increase risk for suicidality. Finally, drugs that modulate brain neurotransmitters can result in different behaviors depending on where the drug is acting. For example, modulators of GABA activity, like topiramate, can simultaneously impact appetite and alter mood. Or dual or triple amine uptake inhibitors that can, on the one hand, reduce schizophrenic symptoms while increasing hunger signals and food intake. Food intake can be a pleasurable experience through activation of hedonic/pleasure circuitry involving dopamine, which has similarities to many addictive substances, including amphetamine. Many anorectic drugs have had to thread a small therapeutic window between improved appetite control and similar adverse behavioral effects.

 

The patient is equally as important in the management of obesity as the medication. Beside the biological effects alluded to above, patients often have unrealistic expectations about how much weight loss drugs can produce. When the treatment doesn’t meet their expectations, they can become frustrated and discontinue therapy even when health benefits from even modest weight loss occur. The second reality that often, and mistakenly, leads patients and providers to stop anti-obesity medication use is the weight plateau that usually occurs after 3-4 months (or up to one year in the case of GLP-1 receptor agonists) of continuous treatment. Ultimately a new weight plateau is to be expected since the body weight set point will still defend its fat stores. This does not indicate tolerance to the drug or that it stopped working, but more the limit of the therapeutic effectiveness expected for that drug. This is similar to the management of any chronic disease. An example would be initiating an angiotensin converting enzyme (ACE) inhibitor for hypertension. It is not expected that this one drug will result in normalization of BP in every patient or that, in taking the ACE inhibitor, the patient will be able to set and achieve a target blood pressure of their choosing. Instead, the medication is started and after appropriate follow-up, the physiological response is assessed and if deemed inadequate, adjustments are made in dose or combination therapy is initiated. Similar examples can be made for first line therapies for type 2 diabetes (metformin) and hyperlipidemia (statins).

 

Besides off-target effects and inter-individual variability in weight loss response, another barrier to effective obesity management is the cost of medications, especially with a chronic disease as highly prevalent as obesity. Until a medication or combination of medications is developed that can meet the patient’s weight loss goals and produce a large enough weight loss to make it cost-effective, challenges will remain in effectively treating patients with obesity.

 

REFERENCES

 

  1. Sarton G. The History of Science and the New Humanism. Colver lectures,. 1931, New York: H. Holt and company. 178 pages.
  2. Harari YN. Sapiens: A Brief History of Humankind. First U.S. edition. ed. 2015, New York: Harper. 443 pages.
  3. Conard NJ. A female figurine from the basal Aurignacian of Hohle Fels Cave in southwestern Germany. Nature.2009;459(7244):248-52. DOI: 10.1038/nature07995. PMID: 19444215.
  4. Weber GW, Lukeneder A, Harzhauser M, Mitteroecker P, Wurm L, Hollaus LM, Kainz S, Haack F, Antl-Weiser W, Kern A. The microstructure and the origin of the Venus from Willendorf. Sci Rep. 2022;12(1):2926. DOI: 10.1038/s41598-022-06799-z. PMID: 35228605.
  5. Bray GA. The Battle of the Bulge : A History of Obesity Research. 2007, Pittsburgh, Pa.: Dorrance Pub. Co. 847 pages.
  6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-32. DOI: 10.1038/372425a0. PMID: 7984236.
  7. Bray GA. Why do we need drugs to treat the patient with obesity? Obesity (Silver Spring). 2013;21(5):893-9. DOI: 10.1002/oby.20394. PMID: 23520198.
  8. Foxcroft L. Calories & Corsets: A History of Dieting Over 2,000 Years. 2011, London: Profile Books. 232 pages.
  9. Kryger MH. Sleep apnea. From the needles of Dionysius to continuous positive airway pressure. Arch Intern Med. 1983;143(12):2301-3. DOI: 10.1001/archinte.143.12.2301. PMID: 6360064.
  10. Papavramidou N, Christopoulou-Aletra H. Management of obesity in the writings of Soranus of Ephesus and Caelius Aurelianus. Obes Surg. 2008;18(6):763-5. DOI: 10.1007/s11695-007-9362-1. PMID: 18386109.
  11. Dorje G, Parfionovich Y. Tibetan Medical Paintings: Illustrations to the Blue Beryl Treatise of Sangye Gyamtso (1653-1705). 1992, New York: H.N. Abrams, Inc.
  12. Talbott JH. A Biographical History of Medicine: Excerpts and Essays on the Men and Their Work. 1970, New York,: Grune & Stratton. 1211 pages.
  13. Sarton G. Sarton on the History of Science. Essays by George Sarton. 1962, Cambridge,: Harvard University Press. 383 pages.
  14. Ullmann M. Islamic medicine. Islamic surveys. 1978, Edinburgh: Edinburgh University Press. 138 pages.
  15. Campbell D. Arabian Medicine and its Influence on the Middle Ages. Trübner's oriental series. 1926, London,: K. Paul, Trench, Trubner & co., ltd.
  16. Castiglioni A. A History of Medicine. 1941, New York,: A. A. Knopf. 1013 pages.
  17. Sigerist HE. A History of Medicine. Vol. 1. Primitive and Archaic Medicine. Vol. 2. Early Greek, Hindu, and Persian Medicine. Publication / Historical Library, Yale Medical Library. 1961, New York,: Oxford University Press.
  18. Major RH. A History of Medicine. 1954, Springfield, IL: Charles C Thomas.
  19. Gruner OC. A Treatise on the Canon of Medicine of Avicenna, Incorporating a Translation of the First Book. 1930, London,: Luzac & Co. 612 pages.
  20. Hopkins KD, Lehmann ED. Successful medical treatment of obesity in 10th century Spain. Lancet.1995;346(8972):452. DOI: 10.1016/s0140-6736(95)92830-8. PMID: 7623606.
  21. Irisarri Ád. El viaje de la reina: De cómo la intrépida reina Toda de Navarra realiza un viaje de Pamplona a Córdoba en el año mil. 6* ed ed. Novela histórica. 1998, Barcelona: Emecé Editores. 348 pages.
  22. Chao AM, Wadden TA, Ashare RL, Loughead J, Schmidt HD. Tobacco Smoking, Eating Behaviors, and Body Weight: A Review. Curr Addict Rep. 2019;6:191-199. DOI: 10.1007/s40429-019-00253-3. PMID: 33224710.
  23. Bonet T. A guide to the Practical Physician : Shewing from the most approved authors, both ancient and modern, the truest and safest way of curing all diseases, internal and external, whether by medicine, surgery, or diet. 1684, London: Thomas Flesher. 788 pages.
  24. Short T. A Discourse Concerning the Causes and Effects of Corpulency : Together with the Method for its Prevention and Cure. 1727, London: Oxford Arms in Warwick Lane. 80 pages.
  25. Flemyng M. A Discourse on the Nature, Causes, and Cure of Corpulency. Illustrated by a Remarkable Case, Read Before the Royal Society, November 1757. And Now First Published, by Malcolm Flemyng, M.D. 1760: L. Davis and C. Reymers.
  26. Wang ZM, Pierson RN, Jr., Heymsfield SB. The five-level model: a new approach to organizing body-composition research. Am J Clin Nutr. 1992;56(1):19-28. DOI: 10.1093/ajcn/56.1.19. PMID: 1609756.
  27. Report of a Committee of the Clinical Society of London Nominated December 14, 1883, to Investigate the Subject of Myxœdema. Trans Clinical Society of London. 1888;21(suppl):1-215.
  28. Kendall EC. A Method for the Decomposition of the Proteins of the Thyroid, with a Description of Certain Constituents. Journal of Biological Chemistry. 1915;20(4):501-509. DOI: 10.1016/s0021-9258(18)88214-x.
  29. Harington CR. Chemistry of Thyroxine: Constitution and Synthesis of Desiodo-Thyroxine. Biochem J.1926;20(2):300-13. DOI: 10.1042/bj0200300. PMID: 16743659.
  30. Putnam JJ. Cases of Myxedema and Acromegalia Treated with Benefit of Sheep’s Thyroid: Recent Observations respecting the pathology of the cachexias following disease of the thyroid: clinical relationships of Grave’s Disease and Acromegalia. The American Journal of the Medical Sciences. 1893;106(2):125-148.
  31. Yorke-Davies NE. Thyroid Tabloids in Obesity. Bmj. 1894;2(1749):42-43. DOI: 10.1136/bmj.2.1749.42.
  32. Wendelstadt. Ueber Entfettungscuren mit Schilddrüsenfütterung. Dtsch Med Wochenschr. 1894;20(50):934-935.
  33. Leichtenstern O. Ueber Myxödem und über Entfettungscuren mit Schilddrüsenfütterung1). Dtsch Med Wochenschr. 1894;20(50):932-933.
  34. Sajous CEdM. The Internal Secretions and the Principles of Medicine. 7th ed. 1916, Philadelphia: F.A. Davis.
  35. Strang JM, McClugage HB, Evans FA. Further studies in the dietary correction of obesity. Am J Clin Sci.1930;179:687-694.
  36. Short JJ. The Increased Metabolism of Obesity. Journal of the American Medical Association.1936;106(21):1776-1779. DOI: 10.1001/jama.1936.02770210002002.
  37. Evans FA. The Treatment of Obesity with Low Caloric Diets. Journal of the American Medical Association.1931;97(15):1063-1069. DOI: 10.1001/jama.1931.02730150019007.
  38. Lyon DM, Dunlop DM. The Treatment of Obesity: A Comparison of the Effects of Diet and of Thyroid Extract. QJM: An International Journal of Medicine. 1932;1(2):331-352. DOI: 10.1093/oxfordjournals.qjmed.a066590.
  39. Bayer LM, Gray H. Obesity treatment by diet, thyroid, and dinitrophenol: Result on 106 outpatients. American Journal of the Medical Sciences. 1935;189(1):86-90.
  40. Bray GA. Thyroid Hormones in the Treatment of Obesity. in Obesity in Perspective. (G.A. Bray, Ed.), Section IV, Vol 2, Part 2, Chapter. 55, Washington, D.C., U.S. Govt Printing Office, 1975. Washington DC: U.S. Govt. Print. Off. Pages 449-456.
  41. Rony HR. Obesity and Leanness. 2nd ed. 1940, Philadelphia: Lea & Febiger. 300 pages.
  42. Rynearson EH, Gastineau CF. Obesity. 1st ed. 1949, Springfield, IL: C. C. Thomas. 134 pages.
  43. Bram I. Therapeutic hyperthryroidism, in International clinics; a quarterly of clinical lectures. 1937, J.B. Lippincott.: Philadelphia. p. 48-61.
  44. Benedict FG, Miles WR, Roth P, Smith HM. Human Vitality and Efficiency Under Prolonged Restricted Diet. 1919, Washington,: Carnegie institution of Washington. 701 pages.
  45. Brown EG, Ohlson MA. Weight reduction of obese women of college age; clinical results and basal metabolism. J Am Diet Assoc. 1946;22:849-57. PMID: 20998120.
  46. Cutting WC. The Treatment of Obesity1. The Journal of Clinical Endocrinology & Metabolism. 1943;3(2):85-88. DOI: 10.1210/jcem-3-2-85.
  47. Means JH. Therapeutics of the Thyroid. Journal of the American Medical Association. 1935;105(1):24-28. DOI: 10.1001/jama.1935.92760270002009.
  48. Wilder RM. The treatment of obesity, in International clinics; a quarterly of clinical lectures. 1933, J.B. Lippincott.: Philadelphia. p. 24-28.
  49. Sevringhaus EL. Diagnostic and therapeutic problems of obesity. J. Mich. Med. Soc. 1943;42:530-536.
  50. Sevringhaus EL. Endocrine Therapy in General Practice. 5th ed. 1945, Chicago: Year Book Publishers, Inc. 223 pages.
  51. Barborka CJ. Obesity. Medical Clinics of North America. 1937;21(1):23-39. DOI: 10.1016/s0025-7125(16)37221-2.
  52. Bronstein IP, Halpern LJ, Brown AW. Obesity in children. The Journal of Pediatrics. 1942;21(4):485-496. DOI: 10.1016/s0022-3476(42)80242-5.
  53. Grulee CG. The American Journal of Diseases of Children. AMA Am J Dis Child. 1951;81(3):374-93. DOI: 10.1001/archpedi.1951.02040030384005. PMID: 14810171.
  54. Mason EH. The Treatment of Obesity. Can Med Assoc J. 1924;14(11):1052-6. PMID: 20315168.
  55. Lyon DM, Dunlop DM, Stewart CP. Respiratory quotient in obese subjects. Biochem J. 1932;26(4):1107-17. DOI: 10.1042/bj0261107. PMID: 16744913.
  56. Gross J, Pitt-Rivers R. The identification of 3:5:3'-L-triiodothyronine in human plasma. Lancet.1952;1(6705):439-41. DOI: 10.1016/s0140-6736(52)91952-1. PMID: 14898765.
  57. Chopra IJ, Solomon DH, Beall GN. Radioimmunoassay for measurement of triiodothyronine in human serum. J Clin Invest. 1971;50(10):2033-41. DOI: 10.1172/JCI106696. PMID: 4107265.
  58. Byerley LO, Heber D. Metabolic effects of triiodothyronine replacement during fasting in obese subjects. J Clin Endocrinol Metab. 1996;81(3):968-76. DOI: 10.1210/jcem.81.3.8772559. PMID: 8772559.
  59. Garrow JS. Energy balance and obesity in man. 2d ed. 1978, Amsterdam; New York New York: Elsevier/North-Holland Biomedical Press. xii, 243 p.
  60. Goodman NG. Triiodothyronine and placebo in the treatment of obesity. A study of fifty-five patients. Med Ann Dist Columbia. 1969;38(12):658-62 passim. PMID: 4902411.
  61. Hollingsworth DR, Amatruda TT, Jr., Scheig R. Quantitative and qualitative effects of L-triiodothyronine in massive obesity. Metabolism. 1970;19(11):934-45. DOI: 10.1016/0026-0495(70)90040-5. PMID: 4920912.
  62. Drenick EJ, Fisler JL. Prevention of recurrent weight gain with large doses of synthetic thyroid hormones. Curr Ther Res Clin Exp. 1970;12(9):570-6. PMID: 4989686.
  63. Bhasin S, Wallace W, Lawrence JB, Lesch M. Sudden death associated with thyroid hormone abuse. Am J Med. 1981;71(5):887-90. DOI: 10.1016/0002-9343(81)90392-2. PMID: 7304660.
  64. Krotkiewski M. Thyroid hormones in the pathogenesis and treatment of obesity. Eur J Pharmacol. 2002;440(2-3):85-98. DOI: 10.1016/s0014-2999(02)01420-6. PMID: 12007527.
  65. Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennstrom B, Mookhtiar K, Horvath R, Speelman J, Egan D, Baxter JD. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A. 2003;100(17):10067-72. DOI: 10.1073/pnas.1633737100. PMID: 12888625.
  66. Bleasdale EE, Thrower SN, Petroczi A. Would You Use It With a Seal of Approval? Important Attributes of 2,4-Dinitrophenol (2,4-DNP) as a Hypothetical Pharmaceutical Product. Front Psychiatry. 2018;9:124. DOI: 10.3389/fpsyt.2018.00124. PMID: 29731723.
  67. Perkins RG. A Study of the Munitions Intoxications in France. Public Health Reports (1896-1970).1919;34(43):2335-2374. DOI: 10.2307/4575357.
  68. Cutting WC, Tainter ML. Actions of dinitrophenol. Proceedings of the Society for Experimental Biology and Medicine. 1932;29:1268-1269.
  69. Cutting WC, Mehrtens HG, Tainter ML. Actions and Uses of Dinitrophenol. Journal of the American Medical Association. 1933;101(3):193-195. DOI: 10.1001/jama.1933.02740280013006.
  70. Colman E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul Toxicol Pharmacol.2007;48(2):115-7. DOI: 10.1016/j.yrtph.2007.03.006. PMID: 17475379.
  71. Tainter ML, Cutting WC, Stockton AB. Use of Dinitrophenol in Nutritional Disorders : A Critical Survey of Clinical Results. Am J Public Health Nations Health. 1934;24(10):1045-53. DOI: 10.2105/ajph.24.10.1045. PMID: 18014064.
  72. Tainter ML. Dinitrophenol in the Treatment of Obesity. Journal of the American Medical Association.1935;105(5):332-337. DOI: 10.1001/jama.1935.02760310006002.
  73. Horner WD. Cataract Following Di-Nitrophenol Treatment for Obesity. Archives of Ophthalmology.1936;16(3):447-461. DOI: 10.1001/archopht.1936.00840210121009.
  74. McGavack TH. Dinitrophenol and Reducing. Cal West Med. 1936;44(2):77-8. PMID: 18743565.
  75. Strang JM. An Evaluation of Dinitrophenol as an Aid in Weight Reduction. JAMA: The Journal of the American Medical Association. 1935;104(22):1957-1963. DOI: 10.1001/jama.1935.02760220003002.
  76. Council on Pharmacy and chemistry. Journal of the American Medical Association. 1935;105(1):31-33. DOI: 10.1001/jama.1935.02760270033012.
  77. Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011;7(3):205-12. DOI: 10.1007/s13181-011-0162-6. PMID: 21739343.
  78. Holborow A, Purnell RM, Wong JF. Beware the yellow slimming pill: fatal 2,4-dinitrophenol overdose. BMJ Case Rep. 2016;2016. DOI: 10.1136/bcr-2016-214689. PMID: 27045052.
  79. Ainsworth NP, Vargo EJ, Petroczi A. Being in control? A thematic content analysis of 14 in-depth interviews with 2,4-dinitrophenol users. Int J Drug Policy. 2018;52:106-114. DOI: 10.1016/j.drugpo.2017.12.012. PMID: 29331928.
  80. Geisler JG. 2,4 Dinitrophenol as Medicine. Cells. 2019;8(3). DOI: 10.3390/cells8030280. PMID: 30909602.
  81. Rasmussen N. America's first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present. Am J Public Health. 2008;98(6):974-85. DOI: 10.2105/AJPH.2007.110593. PMID: 18445805.
  82. Barger G, Dale HH. Chemical structure and sympathomimetic action of amines. J Physiol. 1910;41(1-2):19-59. DOI: 10.1113/jphysiol.1910.sp001392. PMID: 16993040.
  83. Hicks J. Fast Times: The Life, Death, and Rebirth of Amphetamine, in Science History Institute. 2012.
  84. Prinzmetal M. The Use of Benzedrine for the Treatment of Narcolepsy. Journal of the American Medical Association. 1935;105(25):2051-2054. DOI: 10.1001/jama.1935.02760510023006.
  85. Ulrich H, Trapp CE, Vidgoff B. The Treatment of Narcolepsy with Benzedrine Sulphate. Annals of Internal Medicine. 1936;9(9):1213-1221. DOI: 10.7326/0003-4819-9-9-1213.
  86. Lesses MF, Myerson A. Human Autonomic Pharmacology. New England Journal of Medicine. 1938;218(3):119-124. DOI: 10.1056/nejm193801202180307.
  87. Rasmussen N. Making the first anti-depressant: amphetamine in American medicine, 1929-1950. J Hist Med Allied Sci. 2006;61(3):288-323. DOI: 10.1093/jhmas/jrj039. PMID: 16492800.
  88. Bett WR. Benzedrine sulphate in clinical medicine; a survey of the literature. Postgrad Med J.1946;22(250):205-18. DOI: 10.1136/pgmj.22.250.205. PMID: 20997404.
  89. Benzedrine Sulfate—a Warning. Journal of the American Medical Association. 1938;110(12):901-902. DOI: 10.1001/jama.1938.02790120043013.
  90. Lesses MF. Benzedrine Sulfate. Journal of the American Medical Association. 1938;110(18):1507-1508. DOI: 10.1001/jama.1938.02790180095025.
  91. Myerson A. The Rationale for Amphetamine (Benzedrine) Sulphate Therapy. Am J Clin Sci. 1940;199(5):729-737.
  92. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol. 2013;27(6):479-96. DOI: 10.1177/0269881113482532. PMID: 23539642.
  93. Cohen PA, Goday A, Swann JP. The return of rainbow diet pills. Am J Public Health. 2012;102(9):1676-86. DOI: 10.2105/AJPH.2012.300655. PMID: 22813089.
  94. United States Congress Senate Committee on the Judiciary Subcommittee on Antitrust and Monopoly. Diet pill industry hearings before the Subcommittee on Antitrust and Monopoly of the Committee on the Judiciary, United States Senate, Ninetieth Congress, second session, pursuent to S. Res. 26. 1968, Washington, D.C.: U.S. G.P.O. 731 pages.
  95. Greenway F. A double-blind clinical evaluation of the anorectic activity of phenylpropanolamine versus placebo. Clin Ther. 1989;11(5):584-9. PMID: 2680083.
  96. Greenway FL. Clinical studies with phenylpropanolamine: a metaanalysis. Am J Clin Nutr. 1992;55(1 Suppl):203S-205S. DOI: 10.1093/ajcn/55.1.203s. PMID: 1530830.
  97. Morgan JP, Kagan DV, Brody JS. Phenylpropanolamine : risks, benefits, and controversies. Clinical pharmacology and therapeutics series. 1985, New York: Praeger. xxi, 426 p.
  98. Hoebel BG, Cooper J, Kamin MC, Willard D. Appetite suppression by phenylpropanolamine in humans. Obesity and Bariatric Medicine. 1975;4:l92-l99.
  99. Weintraub M. Phenylpropanolamine as an anorexiant agent in weight control: a review of published and unpublished studies, in Morgan JP, Kagan DV, Brody is, eds. Phenylpropanolamine. Risks, benefits, and controversies. New York: Praeger Scientific. 1985. p. 53-79.
  100. Schteingart DE. Effectiveness of phenylpropanolamine in the management of moderate obesity. Int J Obes Relat Metab Disord. 1992;16(7):487-93. PMID: 1323545.
  101. Scoville BA. Review of amphetamine-like drugs by the Food and Drug Administration: clinical data and value judgments, in Obesity in perspective : a conference. 1975, U.S. Govt. Print. Off.: Washington. p. 441–443.
  102. Weintraub M, Ginsberg G, Stein EC, Sundaresan PR, Schuster B, O'Connor P, Byrne LM. Phenylpropanolamine OROS (Acutrim) vs. placebo in combination with caloric restriction and physician-managed behavior modification. Clin Pharmacol Ther. 1986;39(5):501-9. DOI: 10.1038/clpt.1986.87. PMID: 3516509.
  103. Blackburn GL, Morgan JP, Lavin PT, Noble R, Funderburk FR, Istfan N. Determinants of the pressor effect of phenylpropanolamine in healthy subjects. JAMA. 1989;261(22):3267-72. PMID: 2716162.
  104. Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, Morgenstern LB, Wilterdink JL, Horwitz RI. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343(25):1826-32. DOI: 10.1056/NEJM200012213432501. PMID: 11117973.
  105. Samuel PD, Burland WL. Drug Treatment of Obesity, in Obesity in perspective : a conference. 1975, U.S. Govt. Print. Off.: Washington. p. 419-428.
  106. Heil GC, Ross ST. Chemical Agents Affecting Appetite, in Obesity in perspective : a conference. 1975, U.S. Govt. Print. Off.: Washington. p. 409-418.
  107. Bray GA. Treatment of obesity with drugs and invasive procedures, in Obesity in America. 1979, DHEW Publication No. (NIH) 79-359: Washington DC. p. 179-205.
  108. Final Report to the Director, Bureau of Drugs, by the Chairman, Consultants on Anorectic Drugs, in Obesity in perspective : a conference. 1975, U.S. Govt. Print. Off.: Washington. p. 409-418.
  109. Maier J, Mayer FP, Brandt SD, Sitte HH. DARK Classics in Chemical Neuroscience: Aminorex Analogues. ACS Chem Neurosci. 2018;9(10):2484-2502. DOI: 10.1021/acschemneuro.8b00415. PMID: 30269490.
  110. Colman E. Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Ann Intern Med. 2005;143(5):380-5. DOI: 10.7326/0003-4819-143-5-200509060-00013. PMID: 16144896.
  111. Kramer MS, Lane DA. Aminorex, dexfenfluramine, and primary pulmonary hypertension. J Clin Epidemiol.1998;51(4):361-4. DOI: 10.1016/s0895-4356(97)00289-8. PMID: 9539893.
  112. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104(23):2797-802. DOI: 10.1161/hc4801.100076. PMID: 11733397.
  113. Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation. 1999;100(8):869-75. DOI: 10.1161/01.cir.100.8.869. PMID: 10458725.
  114. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335(9):609-16. DOI: 10.1056/NEJM199608293350901. PMID: 8692238.
  115. Saxon DR, Iwamoto SJ, Mettenbrink CJ, McCormick E, Arterburn D, Daley MF, Oshiro CE, Koebnick C, Horberg M, Young DR, Bessesen DH. Antiobesity Medication Use in 2.2 Million Adults Across Eight Large Health Care Organizations: 2009-2015. Obesity (Silver Spring). 2019;27(12):1975-1981. DOI: 10.1002/oby.22581. PMID: 31603630.
  116. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001;39(1):32-41. DOI: 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID: 11071707.
  117. Underhill SM, Colt MS, Amara SG. Amphetamine Stimulates Endocytosis of the Norepinephrine and Neuronal Glutamate Transporters in Cultured Locus Coeruleus Neurons. Neurochem Res. 2020;45(6):1410-1419. DOI: 10.1007/s11064-019-02939-6. PMID: 31912366.
  118. Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J. 1968;1(5588):352-4. DOI: 10.1136/bmj.1.5588.352. PMID: 15508204.
  119. Langlois KJ, Forbes JA, Bell GW, Grant GF, Jr. A double-blind clinical evaluation of the safety and efficacy of phentermine hydrochloride (Fastin) in the treatment of exogenous obesity. Curr Ther Res Clin Exp.1974;16(4):289-96. PMID: 4208343.
  120. Willims RA, Foulsham BM. Weight reduction in osteoarthritis using phentermine. Practitioner.1981;225(1352):231-2. PMID: 7022428.
  121. Ryder JR, Kaizer A, Rudser KD, Gross A, Kelly AS, Fox CK. Effect of phentermine on weight reduction in a pediatric weight management clinic. Int J Obes (Lond). 2017;41(1):90-93. DOI: 10.1038/ijo.2016.185. PMID: 27773937.
  122. Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, Vercruysse F, Erondu N. Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial. Diabetes Care. 2017;40(5):632-639. DOI: 10.2337/dc16-2427. PMID: 28289041.
  123. Hendricks EJ, Srisurapanont M, Schmidt SL, Haggard M, Souter S, Mitchell CL, De Marco DG, Hendricks MJ, Istratiy Y, Greenway FL. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). 2014;38(2):292-8. DOI: 10.1038/ijo.2013.74. PMID: 23736363.
  124. Hendricks EJ, Greenway FL. A study of abrupt phentermine cessation in patients in a weight management program. Am J Ther. 2011;18(4):292-9. DOI: 10.1097/MJT.0b013e3181d070d7. PMID: 20592662.
  125. Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring).2011;19(12):2351-60. DOI: 10.1038/oby.2011.94. PMID: 21527891.
  126. Hendricks EJ, Rothman RB. Phentermine therapy for obesity does not elevate blood pressure. Diabetes Obes Metab. 2011;13(10):963-4. DOI: 10.1111/j.1463-1326.2011.01435.x. PMID: 21896124.
  127. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr.2012;95(2):297-308. DOI: 10.3945/ajcn.111.024927. PMID: 22158731.
  128. Ritchey ME, Harding A, Hunter S, Peterson C, Sager PT, Kowey PR, Nguyen L, Thomas S, Cainzos-Achirica M, Rothman KJ, Andrews EB, Anthony MS. Cardiovascular Safety During and After Use of Phentermine and Topiramate. J Clin Endocrinol Metab. 2019;104(2):513-522. DOI: 10.1210/jc.2018-01010. PMID: 30247575.
  129. Gorelik E, Gorelik B, Masarwa R, Perlman A, Hirsh-Raccah B, Matok I. The cardiovascular safety of antiobesity drugs-analysis of signals in the FDA Adverse Event Report System Database. Int J Obes (Lond).2020;44(5):1021-1027. DOI: 10.1038/s41366-020-0544-4. PMID: 32152496.
  130. Burland WL. A review of experience with fenfluramine, in Obesity in Perspective. Fogarty International Center Series of Preventive Medicine (GA Bray, Ed.). Section IV, Vol 2, Part 2, Capter 55. 1976, U.S. Govt. Print. Off.: Washington DC. p. 429-440 (DHEW Publicatioin #75-708).
  131. Garattini S, Bizzi A, Codegoni AM, Caccia S, Mennini T. Progress report on the anorexia induced by drugs believed to mimic some of the effects of serotonin on the central nervous system. Am J Clin Nutr. 1992;55(1 Suppl):160S-166S. DOI: 10.1093/ajcn/55.1.160s. PMID: 1728827.
  132. van Galen KA, Ter Horst KW, Serlie MJ. Serotonin, food intake, and obesity. Obes Rev. 2021;22(7):e13210. DOI: 10.1111/obr.13210. PMID: 33559362.
  133. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, Turner P. International trial of long-term dexfenfluramine in obesity. Lancet. 1989;2(8672):1142-5. DOI: 10.1016/s0140-6736(89)91499-2. PMID: 2572857.
  134. Douglas JG, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. Br Med J (Clin Res Ed). 1981;283(6296):881-3. DOI: 10.1136/bmj.283.6296.881. PMID: 6793158.
  135. Brenot F, Herve P, Petitpretz P, Parent F, Duroux P, Simonneau G. Primary pulmonary hypertension and fenfluramine use. Br Heart J. 1993;70(6):537-41. DOI: 10.1136/hrt.70.6.537. PMID: 8280518.
  136. Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch Intern Med. 1984;144(6):1143-8. PMID: 6375610.
  137. Weintraub M, Sundaresan PR, Madan M, Schuster B, Balder A, Lasagna L, Cox C. Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther. 1992;51(5):586-94. DOI: 10.1038/clpt.1992.69. PMID: 1587072.
  138. Stafford RS, Radley DC. National trends in antiobesity medication use. Arch Intern Med. 2003;163(9):1046-50. DOI: 10.1001/archinte.163.9.1046. PMID: 12742801.
  139. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581-8. DOI: 10.1056/NEJM199708283370901. PMID: 9271479.
  140. Ryan DH, Bray GA, Helmcke F, Sander G, Volaufova J, Greenway F, Subramaniam P, Glancy DL. Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine. Obes Res. 1999;7(4):313-22. DOI: 10.1002/j.1550-8528.1999.tb00414.x. PMID: 10440587.
  141. King DJ, Devaney N. Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers. Br J Clin Pharmacol. 1988;26(5):607-11. DOI: 10.1111/j.1365-2125.1988.tb05303.x. PMID: 3207566.
  142. Weintraub M, Rubio A, Golik A, Byrne L, Scheinbaum ML. Sibutramine in weight control: a dose-ranging, efficacy study. Clin Pharmacol Ther. 1991;50(3):330-7. DOI: 10.1038/clpt.1991.144. PMID: 1914367.
  143. Bray GA, Blackburn GL, Ferguson JM, Greenway FL, Jain AK, Mendel CM, Mendels J, Ryan DH, Schwartz SL, Scheinbaum ML, Seaton TB. Sibutramine produces dose-related weight loss. Obes Res. 1999;7(2):189-98. DOI: 10.1002/j.1550-8528.1999.tb00701.x. PMID: 10102256.
  144. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, Investigators S. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905-17. DOI: 10.1056/NEJMoa1003114. PMID: 20818901.
  145. Haslam D. Sibutramine: gone, but not forgotten. Practical Diabetes International. 2010;27(3):96-97. DOI: 10.1002/pdi.1453.
  146. Caterson ID, Finer N, Coutinho W, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Legler UF, Shepherd GM, Rode RA, Perdok RJ, Renz CL, James WP, Investigators S. Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Diabetes Obes Metab. 2012;14(6):523-30. DOI: 10.1111/j.1463-1326.2011.01554.x. PMID: 22192338.
  147. Astrup A, Meier DH, Mikkelsen BO, Villumsen JS, Larsen TM. Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease. Obesity (Silver Spring). 2008;16(6):1363-9. DOI: 10.1038/oby.2008.56. PMID: 18356831.
  148. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9653):1906-1913. DOI: 10.1016/S0140-6736(08)61525-1. PMID: 18950853.
  149. Huynh KD, Klose MC, Krogsgaard K, Drejer J, Byberg S, Madsbad S, Magkos F, Aharaz A, Edsberg B, Tfelt-Hansen J, Astrup A, Feldt-Rasmussen U. Weight Loss, Improved Body Composition and Fat Distribution by Tesomet in Acquired Hypothalamic Obesity. Journal of the Endocrine Society. 2021;5(Supplement_1):A64-A65. DOI: 10.1210/jendso/bvab048.130.
  150. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-56. DOI: 10.1056/NEJMoa0909809. PMID: 20647200.
  151. Smith SR, Garvey WT, Greenway FL, Zhou S, Fain R, Pilson R, Fujioka K, Aronne LJ. Coadministration of lorcaserin and phentermine for weight management: A 12-week, randomized, pilot safety study. Obesity (Silver Spring). 2017;25(5):857-865. DOI: 10.1002/oby.21811. PMID: 28440045.
  152. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J, Im K, Fanola CL, Qamar A, Brown C, Budaj A, Garcia-Castillo A, Gupta M, Leiter LA, Weissman NJ, White HD, Patel T, Francis B, Miao W, Perdomo C, Dhadda S, Bonaca MP, Ruff CT, Keech AC, Smith SR, Sabatine MS, Scirica BM, Committee C-TS, Investigators. Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients. N Engl J Med.2018;379(12):1107-1117. DOI: 10.1056/NEJMoa1808721. PMID: 30145941.
  153. Sharretts J, Galescu O, Gomatam S, Andraca-Carrera E, Hampp C, Yanoff L. Cancer Risk Associated with Lorcaserin - The FDA's Review of the CAMELLIA-TIMI 61 Trial. N Engl J Med. 2020;383(11):1000-1002. DOI: 10.1056/NEJMp2003873. PMID: 32905671.
  154. Itowi N, Nagai K, Nakagawa H, Watanabe T, Wada H. Changes in the feeding behavior of rats elicited by histamine infusion. Physiol Behav. 1988;44(2):221-6. DOI: 10.1016/0031-9384(88)90142-4. PMID: 3237828.
  155. Lecklin A, Tuomisto L, MacDonald E. Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats. Methods Find Exp Clin Pharmacol.1995;17(1):47-52. PMID: 7542717.
  156. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519-26. DOI: 10.1038/sj.npp.1300027. PMID: 12629531.
  157. Ratliff JC, Barber JA, Palmese LB, Reutenauer EL, Tek C. Association of prescription H1 antihistamine use with obesity: results from the National Health and Nutrition Examination Survey. Obesity (Silver Spring).2010;18(12):2398-400. DOI: 10.1038/oby.2010.176. PMID: 20706200.
  158. Barak N, Greenway FL, Fujioka K, Aronne LJ, Kushner RF. Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial. Int J Obes (Lond). 2008;32(10):1559-65. DOI: 10.1038/ijo.2008.135. PMID: 18698316.
  159. Stoa-Birketvedt G, Lovhaug N, Vonen B, Florholmen J. H2-receptor antagonist reduces food intake and weight gain in rats by non-gastric acid secretory mechanisms. Acta Physiol Scand. 1997;161(4):489-94. DOI: 10.1046/j.1365-201X.1997.00249.x. PMID: 9429656.
  160. Stoa-Birketvedt G, Paus PN, Ganss R, Ingebretsen OC, Florholmen J. Cimetidine reduces weight and improves metabolic control in overweight patients with type 2 diabetes. Int J Obes Relat Metab Disord. 1998;22(11):1041-5. DOI: 10.1038/sj.ijo.0800721. PMID: 9822940.
  161. Stoa-Birketvedt G. Effect of cimetidine suspension on appetite and weight in overweight subjects. BMJ.1993;306(6885):1091-3. DOI: 10.1136/bmj.306.6885.1091. PMID: 8388285.
  162. Rasmussen MH, Andersen T, Breum L, Gotzsche PC, Hilsted J. Cimetidine suspension as adjuvant to energy restricted diet in treating obesity. BMJ. 1993;306(6885):1093-6. DOI: 10.1136/bmj.306.6885.1093. PMID: 8388286.
  163. Garrow J. Does cimetidine cause weight loss? BMJ. 1993;306(6885):1084. DOI: 10.1136/bmj.306.6885.1084. PMID: 8495153.
  164. Smith R. Research misconduct: the poisoning of the well. J R Soc Med. 2006;99(5):232-7. DOI: 10.1258/jrsm.99.5.232. PMID: 16672756.
  165. Florholmen J, Leeds AR. Research misconduct: Dr Grethe Stoa Birketvedt not guilty of scientific misconduct. J R Soc Med. 2010;103(6):214. DOI: 10.1258/jrsm.2010.10k023. PMID: 20513898.
  166. Birketvedt GS, Thom E, Bernersen B, Florholmen J. Combination of diet, exercise and intermittent treatment of cimetidine on body weight and maintenance of weight loss. A 42 months follow-up study. Med Sci Monit.2000;6(4):699-703. PMID: 11208394.
  167. Gu XJ, Chen R, Sun CH, Zheng W, Yang XH, Wang SB, Ungvari GS, Ng CH, Golenkov A, Lok GKI, Li L, Chow IHI, Wang F, Xiang YT. Effect of adjunctive ranitidine for antipsychotic-induced weight gain: A systematic review of randomized placebo-controlled trials. J Int Med Res. 2018;46(1):22-32. DOI: 10.1177/0300060517716783. PMID: 28718688.
  168. Wong DT, Perry KW, Bymaster FP. Case history: the discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov. 2005;4(9):764-74. DOI: 10.1038/nrd1821. PMID: 16121130.
  169. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005;142(7):532-46. DOI: 10.7326/0003-4819-142-7-200504050-00012. PMID: 15809465.
  170. Avenell A, Brown TJ, McGee MA, Campbell MK, Grant AM, Broom J, Jung RT, Smith WC. What interventions should we add to weight reducing diets in adults with obesity? A systematic review of randomized controlled trials of adding drug therapy, exercise, behaviour therapy or combinations of these interventions. J Hum Nutr Diet. 2004;17(4):293-316. DOI: 10.1111/j.1365-277X.2004.00530.x. PMID: 15250841.
  171. Darga LL, Carroll-Michals L, Botsford SJ, Lucas CP. Fluoxetine's effect on weight loss in obese subjects. Am J Clin Nutr. 1991;54(2):321-5. DOI: 10.1093/ajcn/54.2.321. PMID: 1858696.
  172. Goldstein DJ, Rampey AH, Jr., Roback PJ, Wilson MG, Hamilton SH, Sayler ME, Tollefson GD. Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success. Obes Res. 1995;3 Suppl 4:481S-490S. DOI: 10.1002/j.1550-8528.1995.tb00216.x. PMID: 8697047.
  173. Wadden TA, Bartlett SJ, Foster GD, Greenstein RA, Wingate BJ, Stunkard AJ, Letizia KA. Sertraline and relapse prevention training following treatment by very-low-calorie diet: a controlled clinical trial. Obes Res.1995;3(6):549-57. DOI: 10.1002/j.1550-8528.1995.tb00189.x. PMID: 8653531.
  174. Sayler ME, Goldstein DJ, Roback PJ, Atkinson RL. Evaluating success of weight loss programs, with an application to fluoxetine weight reduction clinical trial data. Int J Obes Relat Metab Disord. 1994;18(11):742-51. PMID: 7866474.
  175. Jain AK, Kaplan RA, Gadde KM, Wadden TA, Allison DB, Brewer ER, Leadbetter RA, Richard N, Haight B, Jamerson BD, Buaron KS, Metz A. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res. 2002;10(10):1049-56. DOI: 10.1038/oby.2002.142. PMID: 12376586.
  176. Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O'Neil PM. Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial. Obes Res. 2002;10(7):633-41. DOI: 10.1038/oby.2002.86. PMID: 12105285.
  177. Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res. 2003;11(6):722-33. DOI: 10.1038/oby.2003.102. PMID: 12805393.
  178. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M, Group O-S. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004;28(11):1399-410. DOI: 10.1038/sj.ijo.0802783. PMID: 15486569.
  179. Toplak H, Hamann A, Moore R, Masson E, Gorska M, Vercruysse F, Sun X, Fitchet M. Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes (Lond). 2007;31(1):138-46. DOI: 10.1038/sj.ijo.0803382. PMID: 16703004.
  180. Gadde KM, Franciscy DM, Wagner HR, 2nd, Krishnan KR. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289(14):1820-5. DOI: 10.1001/jama.289.14.1820. PMID: 12684361.
  181. Gadde KM, Kopping MF, Wagner HR, 2nd, Yonish GM, Allison DB, Bray GA. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):1557-64. DOI: 10.1001/2013.jamainternmed.99. PMID: 23147455.
  182. Nogueiras R, Romero-Pico A, Vazquez MJ, Novelle MG, Lopez M, Dieguez C. The opioid system and food intake: homeostatic and hedonic mechanisms. Obes Facts. 2012;5(2):196-207. DOI: 10.1159/000338163. PMID: 22647302.
  183. Holtzman SG. Suppression of appetitive behavior in the rat by naloxone: lack of effect of prior morphine dependence. Life Sci. 1979;24(3):219-26. DOI: 10.1016/0024-3205(79)90222-4. PMID: 570626.
  184. Atkinson RL. Naloxone decreases food intake in obese humans. J Clin Endocrinol Metab. 1982;55(1):196-8. DOI: 10.1210/jcem-55-1-196. PMID: 7042740.
  185. Atkinson RL, Berke LK, Drake CR, Bibbs ML, Williams FL, Kaiser DL. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419-22. DOI: 10.1038/clpt.1985.197. PMID: 4042525.
  186. Hatsukami DK, Mitchell JE, Morley JE, Morgan SF, Levine AS. Effect of naltrexone on mood and cognitive functioning among overweight men. Biol Psychiatry. 1986;21(3):293-300. DOI: 10.1016/0006-3223(86)90050-8. PMID: 3947710.
  187. Maggio CA, Presta E, Bracco EF, Vasselli JR, Kissileff HR, Pfohl DN, Hashim SA. Naltrexone and human eating behavior: a dose-ranging inpatient trial in moderately obese men. Brain Res Bull. 1985;14(6):657-61. DOI: 10.1016/0361-9230(85)90115-7. PMID: 3896411.
  188. Malcolm R, O'Neil PM, Sexauer JD, Riddle FE, Currey HS, Counts C. A controlled trial of naltrexone in obese humans. Int J Obes. 1985;9(5):347-53. PMID: 3908352.
  189. Mitchell JE, Morley JE, Levine AS, Hatsukami D, Gannon M, Pfohl D. High-dose naltrexone therapy and dietary counseling for obesity. Biol Psychiatry. 1987;22(1):35-42. DOI: 10.1016/0006-3223(87)90127-2. PMID: 3790639.
  190. Novi RF, Lamberto M, Visconti P, Maurino M, Ardizzone A, Mantovan M, Meluzzi A, Francesetti G, Molinatti GM. [The role of opioid antagonists in the treatment of obesity. Results of a clinical trial with naltrexone]. Minerva Endocrinol. 1990;15(2):121-3. PMID: 2098653.
  191. de Zwaan M, Mitchell JE. Opiate antagonists and eating behavior in humans: a review. J Clin Pharmacol.1992;32(12):1060-72. PMID: 1487543.
  192. Pfohl DN, Allen JI, Atkinson RL, Knopman DS, Malcolm RJ, Mitchell JE, Morley JE. Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage. NIDA Res Monogr. 1986;67:66-72. PMID: 3092099.
  193. Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N. Brain dopamine is associated with eating behaviors in humans. Int J Eat Disord. 2003;33(2):136-42. DOI: 10.1002/eat.10118. PMID: 12616579.
  194. Terry P, Gilbert DB, Cooper SJ. Dopamine receptor subtype agonists and feeding behavior. Obes Res. 1995;3 Suppl 4:515S-523S. DOI: 10.1002/j.1550-8528.1995.tb00221.x. PMID: 8697052.
  195. Hoebel BG, Hernandez L, Schwartz DH, Mark GP, Hunter GA. Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications. Ann N Y Acad Sci. 1989;575:171-91; discussion 192-3. DOI: 10.1111/j.1749-6632.1989.tb53242.x. PMID: 2699187.
  196. Astrup A, Greenway FL, Ling W, Pedicone L, Lachowicz J, Strader CD, Kwan R, Ecopipam Obesity Study G. Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects. Obesity (Silver Spring). 2007;15(7):1717-31. DOI: 10.1038/oby.2007.205. PMID: 17636090.
  197. Cincotta AH, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care. 1996;19(6):667-70. DOI: 10.2337/diacare.19.6.667. PMID: 8725871.
  198. Andersen IB, Andreassen M, Krogh J. The effect of dopamine agonists on metabolic variables in adults with type 2 diabetes: A systematic review with meta analysis and trial sequential analysis of randomized clinical trials. Diabetes Obes Metab. 2021;23(1):58-67. DOI: 10.1111/dom.14183. PMID: 32869474.
  199. Keche Y. Bromocriptine mesylate: Food and Drug Administration approved new approach in therapy of non-insulin dependant diabetes mellitus with poor glycemic control. J Pharm Bioallied Sci. 2010;2(2):148-50. DOI: 10.4103/0975-7406.67000. PMID: 21814451.
  200. Di Marzo V, Deutsch DG. Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol Dis.1998;5(6 Pt B):386-404. DOI: 10.1006/nbdi.1998.0214. PMID: 9974173.
  201. Gelfand EV, Cannon CP. Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. Expert Opin Investig Drugs.2006;15(3):307-15. DOI: 10.1517/13543784.15.3.307. PMID: 16503766.
  202. Kirkham TC. Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol. 2005;16(5-6):297-313. DOI: 10.1097/00008877-200509000-00004. PMID: 16148436.
  203. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27(1):73-100. DOI: 10.1210/er.2005-0009. PMID: 16306385.
  204. Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63(4):908-14. DOI: 10.1124/mol.63.4.908. PMID: 12644592.
  205. Juan-Pico P, Fuentes E, Bermudez-Silva FJ, Javier Diaz-Molina F, Ripoll C, Rodriguez de Fonseca F, Nadal A. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium.2006;39(2):155-62. DOI: 10.1016/j.ceca.2005.10.005. PMID: 16321437.
  206. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, Group RI-ES. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389-97. DOI: 10.1016/S0140-6736(05)66374-X. PMID: 15836887.
  207. Rosenstock J, Hollander P, Chevalier S, Iranmanesh A, Group SS. SERENADE: the Study Evaluating Rimonabant Efficacy in Drug-naive Diabetic Patients: effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes. Diabetes Care. 2008;31(11):2169-76. DOI: 10.2337/dc08-0386. PMID: 18678611.
  208. Hollander PA, Amod A, Litwak LE, Chaudhari U, Group AS. Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes Care. 2010;33(3):605-7. DOI: 10.2337/dc09-0455. PMID: 20009090.
  209. O'Leary DH, Reuwer AQ, Nissen SE, Despres JP, Deanfield JE, Brown MW, Zhou R, Zabbatino SM, Job B, Kastelein JJ, Visseren FL, investigators A. Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. Heart.2011;97(14):1143-50. DOI: 10.1136/hrt.2011.223446. PMID: 21610270.
  210. Nissen SE, Nicholls SJ, Wolski K, Rodes-Cabau J, Cannon CP, Deanfield JE, Despres JP, Kastelein JJ, Steinhubl SR, Kapadia S, Yasin M, Ruzyllo W, Gaudin C, Job B, Hu B, Bhatt DL, Lincoff AM, Tuzcu EM, Investigators S. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008;299(13):1547-60. DOI: 10.1001/jama.299.13.1547. PMID: 18387931.
  211. Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, Cohen E, Gaudin C, Job B, Murphy JH, Bhatt DL, Investigators C. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet.2010;376(9740):517-23. DOI: 10.1016/S0140-6736(10)60935-X. PMID: 20709233.
  212. Lu D, Dopart R, Kendall DA. Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes. Cell Stress Chaperones.2016;21(1):1-7. DOI: 10.1007/s12192-015-0653-5. PMID: 26498013.
  213. Berlin I, Crespo-Laumonnier B, Turpin G, Puech AJ. The alpha-2 adrenoceptor antagonist yohimbine does not facilitate weight loss but blocks adrenaline induced platelet aggregation in obese subjects. Therapie.1989;44(4):301. PMID: 2595649.
  214. Heymsfield SB, Smith B, Dahle J, Kennedy S, Fearnbach N, Thomas DM, Bosy-Westphal A, Muller MJ. Resting Energy Expenditure: From Cellular to Whole-Body Level, a Mechanistic Historical Perspective. Obesity (Silver Spring). 2021;29(3):500-511. DOI: 10.1002/oby.23090. PMID: 33624441.
  215. Jimenez-Munoz CM, Lopez M, Albericio F, Makowski K. Targeting Energy Expenditure-Drugs for Obesity Treatment. Pharmaceuticals (Basel). 2021;14(5). DOI: 10.3390/ph14050435. PMID: 34066399.
  216. Astrup A, Lundsgaard C, Madsen J, Christensen NJ. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr. 1985;42(1):83-94. DOI: 10.1093/ajcn/42.1.83. PMID: 4014068.
  217. Malchow-Moller A, Larsen S, Hey H, Stokholm KH, Juhl E, Quaade F. Ephedrine as an anorectic: the story of the 'Elsinore pill'. Int J Obes. 1981;5(2):183-7. PMID: 7228474.
  218. Astrup A, Toubro S, Cannon S, Hein P, Madsen J. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind, placebo-controlled study. Metabolism. 1991;40(3):323-9. DOI: 10.1016/0026-0495(91)90117-f. PMID: 2000046.
  219. Dulloo AG. Ephedrine, xanthines and prostaglandin-inhibitors: actions and interactions in the stimulation of thermogenesis. Int J Obes Relat Metab Disord. 1993;17 Suppl 1:S35-40. PMID: 8384178.
  220. Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev. 1999;20(6):805-75. DOI: 10.1210/edrv.20.6.0383. PMID: 10605627.
  221. Astrup A, Breum L, Toubro S, Hein P, Quaade F. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord. 1992;16(4):269-77. PMID: 1318281.
  222. Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord. 1994;18(2):99-103. PMID: 8148931.
  223. Lee MR. The history of Ephedra (ma-huang). J R Coll Physicians Edinb. 2011;41(1):78-84. DOI: 10.4997/JRCPE.2011.116. PMID: 21365072.
  224. Elhadef K, Smaoui S, Fourati M, Ben Hlima H, Chakchouk Mtibaa A, Sellem I, Ennouri K, Mellouli L. A Review on Worldwide Ephedra History and Story: From Fossils to Natural Products Mass Spectroscopy Characterization and Biopharmacotherapy Potential. Evid Based Complement Alternat Med.2020;2020:1540638. DOI: 10.1155/2020/1540638. PMID: 32419789.
  225. Bass IS, Young AL. Dietary Supplement Health and Education Act : A Legislative History and Analysis. 1996, Washington D.C.: Food and Drug Law Institute. 319 pages.
  226. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Meredith T. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord.2002;26(5):593-604. DOI: 10.1038/sj.ijo.0802023. PMID: 12032741.
  227. Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagne J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA.2003;289(12):1537-45. DOI: 10.1001/jama.289.12.1537. PMID: 12672771.
  228. Jequier E, Munger R, Felber JP. Thermogenic effects of various beta-adrenoceptor agonists in humans: their potential usefulness in the treatment of obesity. Am J Clin Nutr. 1992;55(1 Suppl):249S-251S. DOI: 10.1093/ajcn/55.1.249s. PMID: 1345888.
  229. Stock MJ, Rothwell NJ. The role of brown fat in diet-induced thermogenesis. Int J Vitam Nutr Res.1986;56(2):205-10. PMID: 3460973.
  230. Strosberg AD. Structure and function of the beta 3-adrenergic receptor. Annu Rev Pharmacol Toxicol.1997;37:421-50. DOI: 10.1146/annurev.pharmtox.37.1.421. PMID: 9131260.
  231. Yen TT. Antiobesity and antidiabetic beta-agonists: lessons learned and questions to be answered. Obes Res.1994;2(5):472-80. DOI: 10.1002/j.1550-8528.1994.tb00095.x. PMID: 16353599.
  232. Arch JR, Wilson S. Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. Int J Obes Relat Metab Disord. 1996;20(3):191-9. PMID: 8653138.
  233. Connacher AA, Bennet WM, Jung RT, Rennie MJ. Metabolic effects of three weeks administration of the beta-adrenoceptor agonist BRL 26830A. Int J Obes Relat Metab Disord. 1992;16(9):685-94. PMID: 1356939.
  234. Cawthorne MA, Sennitt MV, Arch JR, Smith SA. BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Am J Clin Nutr. 1992;55(1 Suppl):252S-257S. DOI: 10.1093/ajcn/55.1.252s. PMID: 1345889.
  235. Connacher AA, Jung RT, Mitchell PE. Weight loss in obese subjects on a restricted diet given BRL 26830A, a new atypical beta adrenoceptor agonist. Br Med J (Clin Res Ed). 1988;296(6631):1217-20. DOI: 10.1136/bmj.296.6631.1217. PMID: 2898268.
  236. Connacher AA, Lakie M, Powers N, Elton RA, Walsh EG, Jung RT. Tremor and the anti-obesity drug BRL 26830A. Br J Clin Pharmacol. 1990;30(4):613-5. DOI: 10.1111/j.1365-2125.1990.tb03821.x. PMID: 1981320.
  237. MacLachlan M, Connacher AA, Jung RT. Psychological aspects of dietary weight loss and medication with the atypical beta agonist BRL 26830A in obese subjects. Int J Obes. 1991;15(1):27-35. PMID: 1672679.
  238. Mitchell TH, Ellis RD, Smith SA, Robb G, Cawthorne MA. Effects of BRL 35135, a beta-adrenoceptor agonist with novel selectivity, on glucose tolerance and insulin sensitivity in obese subjects. Int J Obes. 1989;13(6):757-66. PMID: 2695481.
  239. Goldberg GR, Prentice AM, Murgatroyd PR, Haines W, Tuersley MD. Effects on metabolic rate and fuel selection of a selective beta-3 agonist (ICI D7114) in healthy lean men. Int J Obes Relat Metab Disord.1995;19(9):625-31. PMID: 8574272.
  240. Henny C, Schutz Y, Buckert A, Meylan M, Jequier E, Felber JP. Thermogenic effect of the new beta-adrenoreceptor agonist Ro 16-8714 in healthy male volunteers. Int J Obes. 1987;11(5):473-83. PMID: 2892807.
  241. Weyer C, Tataranni PA, Snitker S, Danforth E, Jr., Ravussin E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans. Diabetes.1998;47(10):1555-61. DOI: 10.2337/diabetes.47.10.1555. PMID: 9753292.
  242. Redman LM, de Jonge L, Fang X, Gamlin B, Recker D, Greenway FL, Smith SR, Ravussin E. Lack of an effect of a novel beta3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study. J Clin Endocrinol Metab. 2007;92(2):527-31. DOI: 10.1210/jc.2006-1740. PMID: 17118998.
  243. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH. Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther.2002;71(4):272-9. DOI: 10.1067/mcp.2002.122527. PMID: 11956510.
  244. Arch JR. The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from beta3-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(2):225-40. DOI: 10.1007/s00210-008-0271-1. PMID: 18612674.
  245. O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Sater ZA, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Bergman RN, Herscovitch P, Chen KY, Cypess AM. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest.2020;130(5):2209-2219. DOI: 10.1172/JCI131126. PMID: 31961826.
  246. Zed CA, Harris GS, Harrison PJ, Robb GH. Anti-obesity activity of a novel β-adrenoceptor agonist (BRL 26830A) in diet restricted obese subjects. Int J Obes. 1985;9:231 (abstract).
  247. Abraham R, Zed C, Mitchell T, Parr J, Wynn V. The effect of a novel β-agonist BRL26830A on weight and protein loss in obese patients. Int J Obes. 1987;11:306A (Abstract).
  248. Smith SA, Cawthorne MA, Fay LC, McCullough DA, Mitchell TH. Effect of a novel β-adrenoceptor agonist on insulin sensitivity in lean healthy male volunteers. Diabetes. 1987;36:15A (Abstract).
  249. Chapman BJ, Farquahar DL, Galloway SM, Simpson GK, Munro JF. The effects of a new beta-adrenoceptor agonist BRL 26830A in refractory obesity. Int J Obes. 1988;12(2):119-23. PMID: 2898457.
  250. Smith SA, Sennitt MV, Cawthorne MA. BRL 35135: an orally active antihyperglycemic agent with weight reducing effects, in New Antidiabetic Drugs, C.J. Bailey and P.R. Flatt, Editors. 1990, Smith-Gordon and Company Limited London. p. 177–189.
  251. Toubro S, Astrup A. Randomised comparison of diets for maintaining obese subjects' weight after major weight loss: ad lib, low fat, high carbohydrate diet v fixed energy intake. BMJ. 1997;314(7073):29-34. DOI: 10.1136/bmj.314.7073.29. PMID: 9001476.
  252. Henny C, Buckert A, Schutz Y, Jequier E, Felber JP. Comparison of thermogenic activity induced by the new sympathomimetic Ro 16-8714 between normal and obese subjects. Int J Obes. 1988;12(3):227-36. PMID: 2899062.
  253. Haesler E, Golay A, Guzelhan C, Schutz Y, Hartmann D, Jequier E, Felber JP. Effect of a novel beta-adrenoceptor agonist (Ro 40-2148) on resting energy expenditure in obese women. Int J Obes Relat Metab Disord. 1994;18(5):313-22. PMID: 7914795.
  254. Wheeldon NM, McDevitt DG, McFarlane LC, Lipworth BJ. Beta-adrenoceptor subtypes mediating the metabolic effects of BRL 35135 in man. Clin Sci (Lond). 1994;86(3):331-7. DOI: 10.1042/cs0860331. PMID: 7908864.
  255. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A. Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr. 2002;76(4):780-8. DOI: 10.1093/ajcn/76.4.780. PMID: 12324291.
  256. Galgani JE, Ryan DH, Ravussin E. Effect of capsinoids on energy metabolism in human subjects. Br J Nutr.2010;103(1):38-42. DOI: 10.1017/S0007114509991358. PMID: 19671203.
  257. Corwin RL, Gibbs J, Smith GP. Increased food intake after type A but not type B cholecystokinin receptor blockade. Physiol Behav. 1991;50(1):255-8. DOI: 10.1016/0031-9384(91)90529-w. PMID: 1946726.
  258. Greenway FL, Bray GA. Cholecystokinin and satiety. Life Sci. 1977;21(6):769-72. DOI: 10.1016/0024-3205(77)90403-9. PMID: 916798.
  259. Kissileff HR, Gordon RJ, Thornton JC, Laferrere B, Albu J, Pi-Sunyer X, Geliebter A. Combined effects of cholecystokinin-8 and gastric distension on food intake in humans. Am J Physiol Regul Integr Comp Physiol.2019;317(1):R39-R48. DOI: 10.1152/ajpregu.00339.2018. PMID: 30916576.
  260. Moran TH, Sawyer TK, Seeb DH, Ameglio PJ, Lombard MA, McHugh PR. Potent and sustained satiety actions of a cholecystokinin octapeptide analogue. Am J Clin Nutr. 1992;55(1 Suppl):286S-290S. DOI: 10.1093/ajcn/55.1.286s. PMID: 1728841.
  261. Asin KE, Bednarz L, Nikkel AL, Gore PA, Jr., Nadzan AM. A-71623, a selective CCK-A receptor agonist, suppresses food intake in the mouse, dog, and monkey. Pharmacol Biochem Behav. 1992;42(4):699-704. DOI: 10.1016/0091-3057(92)90017-a. PMID: 1513850.
  262. Henke BR, Willson TM, Sugg EE, Croom DK, Dougherty RW, Jr., Queen KL, Birkemo LS, Ervin GN, Grizzle MK, Johnson MF, James MK. 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines: CCK-A agonists that demonstrate oral activity as satiety agents. J Med Chem. 1996;39(14):2655-8. DOI: 10.1021/jm960249k. PMID: 8709093.
  263. Hamamura M, Leng G, Emson PC, Kiyama H. Electrical activation and c-fos mRNA expression in rat neurosecretory neurones after systemic administration of cholecystokinin. J Physiol. 1991;444:51-63. DOI: 10.1113/jphysiol.1991.sp018865. PMID: 1822561.
  264. Boosalis MG, Gemayel N, Lee A, Bray GA, Laine L, Cohen H. Cholecystokinin and satiety: effect of hypothalamic obesity and gastric bubble insertion. Am J Physiol. 1992;262(2 Pt 2):R241-4. DOI: 10.1152/ajpregu.1992.262.2.R241. PMID: 1539732.
  265. Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, Pincus S, et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab.1995;80(11):3209-22. DOI: 10.1210/jcem.80.11.7593428. PMID: 7593428.
  266. Gertner JM. Effects of growth hormone on body fat in adults. Horm Res. 1993;40(1-3):10-5. DOI: 10.1159/000183761. PMID: 8300043.
  267. Bray GA. Calorigenic effect of human growth hormone in obesity. J Clin Endocrinol Metab. 1969;29(1):119-22. DOI: 10.1210/jcem-29-1-119. PMID: 5762314.
  268. Gertner JM. Growth hormone actions on fat distribution and metabolism. Horm Res. 1992;38 Suppl 2:41-3. DOI: 10.1159/000182592. PMID: 1292980.
  269. Bray GA, Raben MS, Londono J, Gallagher TF, Jr. Effects of triiodothyronine, growth hormone and anabolic steroids on nitrogen excretion and oxygen consumption of obese patients. J Clin Endocrinol Metab.1971;33(2):293-300. DOI: 10.1210/jcem-33-2-293. PMID: 4935638.
  270. Bengtsson BA, Eden S, Lonn L, Kvist H, Stokland A, Lindstedt G, Bosaeus I, Tolli J, Sjostrom L, Isaksson OG. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab.1993;76(2):309-17. DOI: 10.1210/jcem.76.2.8432773. PMID: 8432773.
  271. Brummer RJ, Lonn L, Kvist H, Grangard U, Bengtsson BA, Sjostrom L. Adipose tissue and muscle volume determination by computed tomography in acromegaly, before and 1 year after adenomectomy. Eur J Clin Invest. 1993;23(4):199-205. DOI: 10.1111/j.1365-2362.1993.tb00762.x. PMID: 8500511.
  272. Snyder DK, Clemmons DR, Underwood LE. Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition. J Clin Endocrinol Metab. 1988;67(1):54-61. DOI: 10.1210/jcem-67-1-54. PMID: 3379136.
  273. Thompson JL, Butterfield GE, Gylfadottir UK, Yesavage J, Marcus R, Hintz RL, Pearman A, Hoffman AR. Effects of human growth hormone, insulin-like growth factor I, and diet and exercise on body composition of obese postmenopausal women. J Clin Endocrinol Metab. 1998;83(5):1477-84. DOI: 10.1210/jcem.83.5.4826. PMID: 9589642.
  274. Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof K, Bjorntorp P, Sjostrom L, Bengtsson BA. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab. 1997;82(3):727-34. DOI: 10.1210/jcem.82.3.3809. PMID: 9062473.
  275. Rixhon M, Tichomirowa MA, Tamagno G, Daly AF, Beckers A. Current and future perspectives on recombinant growth hormone for the treatment of obesity. Expert Rev Endocrinol Metab. 2008;3(1):75-90. DOI: 10.1586/17446651.3.1.75. PMID: 30743787.
  276. Diabetes C, Complications Trial Research G, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86. DOI: 10.1056/NEJM199309303291401. PMID: 8366922.
  277. Ludwig DS, Ebbeling CB. The Carbohydrate-Insulin Model of Obesity: Beyond "Calories In, Calories Out". JAMA Intern Med. 2018;178(8):1098-1103. DOI: 10.1001/jamainternmed.2018.2933. PMID: 29971406.
  278. Hall KD. A review of the carbohydrate-insulin model of obesity. Eur J Clin Nutr. 2017;71(3):323-326. DOI: 10.1038/ejcn.2016.260. PMID: 28074888.
  279. Woods SC, Porte D, Jr., Bobbioni E, Ionescu E, Sauter JF, Rohner-Jeanrenaud F, Jeanrenaud B. Insulin: its relationship to the central nervous system and to the control of food intake and body weight. Am J Clin Nutr.1985;42(5 Suppl):1063-71. DOI: 10.1093/ajcn/42.5.1063. PMID: 3904396.
  280. Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab. 2013;24(2):76-84. DOI: 10.1016/j.tem.2012.11.004. PMID: 23265947.
  281. Bray GA, Gallagher TF, Jr. Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a reveiw of the literature. Medicine (Baltimore). 1975;54(4):301-30. DOI: 10.1097/00005792-197507000-00002. PMID: 1152672.
  282. Bray GA, York DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev. 1979;59(3):719-809. DOI: 10.1152/physrev.1979.59.3.719. PMID: 379887.
  283. Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, Rai SN, Lensing SY, Wu S, Xiong X. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2003;88(6):2586-92. DOI: 10.1210/jc.2002-030003. PMID: 12788859.
  284. Lustig RH, Greenway F, Velasquez-Mieyer P, Heimburger D, Schumacher D, Smith D, Smith W, Soler N, Warsi G, Berg W, Maloney J, Benedetto J, Zhu W, Hohneker J. A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion. Int J Obes (Lond). 2006;30(2):331-41. DOI: 10.1038/sj.ijo.0803074. PMID: 16158082.
  285. Gambineri A, Patton L, De Iasio R, Cantelli B, Cognini GE, Filicori M, Barreca A, Diamanti-Kandarakis E, Pagotto U, Pasquali R. Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(7):3854-62. DOI: 10.1210/jc.2004-2490. PMID: 15827099.
  286. Huang Z, Wang W, Huang L, Guo L, Chen C. Suppression of Insulin Secretion in the Treatment of Obesity: A Systematic Review and Meta-Analysis. Obesity (Silver Spring). 2020;28(11):2098-2106. DOI: 10.1002/oby.22955. PMID: 33150747.
  287. Bray GA. Drug therapy for the obese patient, in The Obese Patient. Major Problems in Internal Medicine, Vol 9. 1976, W.B. Saunders Company: Philadelphia. p. 353-410.
  288. Fleigelman R, Fried GH. Metabolic effects of human chorionic gonadotropin (HCG) in rats. Proc Soc Exp Biol Med. 1970;135(2):317-9. DOI: 10.3181/00379727-135-35043. PMID: 5479992.
  289. Simeons AT. Chorionic gonadotropin in geriatrics. J Am Geriatr Soc. 1956;4(1):36-40. DOI: 10.1111/j.1532-5415.1956.tb01142.x. PMID: 13286062.
  290. Simeons AT. The action of chorionic gonadotrophin in the obese. Lancet. 1954;267(6845):946-7. DOI: 10.1016/s0140-6736(54)92556-8. PMID: 13213083.
  291. Simeons ATW. Pounds and Inches: A New Approach to Obesity. 6th revised edition ed. 2010, Roma: Arti grafichi Scalia: Popular Publishing.
  292. Carne S. The action of chorionic gonadotrophin in the obese. Lancet. 1961;2(7215):1282-4. DOI: 10.1016/s0140-6736(61)91142-4. PMID: 13876697.
  293. Greenway FL, Bray GA. Human chorionic gonadotropin (HCG) in the treatment of obesity: a critical assessment of the Simeons method. West J Med. 1977;127(6):461-3. PMID: 595585.
  294. Steinbrook R. Doctors Use of Obesity Treatment Debunked by FDA, in Los Angeles Times Sunday. 1986: Los Angeles.
  295. Lijesen GK, Theeuwen I, Assendelft WJ, Van Der Wal G. The effect of human chorionic gonadotropin (HCG) in the treatment of obesity by means of the Simeons therapy: a criteria-based meta-analysis. Br J Clin Pharmacol.1995;40(3):237-43. DOI: 10.1111/j.1365-2125.1995.tb05779.x. PMID: 8527285.
  296. Trudeau K. The Weight Loss Cure "They" Don't Want You to Know About. 2008, Elk Grove Village, IL: Alliance Publishing. 255 pages.
  297. Kevin Mark Trudeau. July 10, 2021]; Available from: https://en.wikipedia.org/wiki/Kevin_Trudeau.
  298. Schwartz MW, Seeley RJ, Zeltser LM, Drewnowski A, Ravussin E, Redman LM, Leibel RL. Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev. 2017;38(4):267-296. DOI: 10.1210/er.2017-00111. PMID: 28898979.
  299. Schwartz MW, Porte D, Jr. Diabetes, obesity, and the brain. Science. 2005;307(5708):375-9. DOI: 10.1126/science.1104344. PMID: 15662002.
  300. Flier JS. Clinical review 94: What's in a name? In search of leptin's physiologic role. J Clin Endocrinol Metab.1998;83(5):1407-13. DOI: 10.1210/jcem.83.5.4779. PMID: 9589630.
  301. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903-8. DOI: 10.1038/43185. PMID: 9202122.
  302. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392(6674):398-401. DOI: 10.1038/32911. PMID: 9537324.
  303. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med.1999;341(12):879-84. DOI: 10.1056/NEJM199909163411204. PMID: 10486419.
  304. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16):1568-75. DOI: 10.1001/jama.282.16.1568. PMID: 10546697.
  305. Hukshorn CJ, Saris WH, Westerterp-Plantenga MS, Farid AR, Smith FJ, Campfield LA. Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J Clin Endocrinol Metab.2000;85(11):4003-9. DOI: 10.1210/jcem.85.11.6955. PMID: 11095423.
  306. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570-8. DOI: 10.1056/NEJMoa012437. PMID: 11856796.
  307. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345-50. DOI: 10.1172/JCI15001. PMID: 12021250.
  308. Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab. 2008;93(1):26-31. DOI: 10.1210/jc.2007-1856. PMID: 17940115.
  309. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53(1):27-35. DOI: 10.1007/s00125-009-1502-9. PMID: 19727665.
  310. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005;115(12):3579-86. DOI: 10.1172/JCI25977. PMID: 16322796.
  311. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. 2002;87(5):2391-4. DOI: 10.1210/jcem.87.5.8628. PMID: 11994393.
  312. Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest. 2008;118(7):2583-91. DOI: 10.1172/JCI35055. PMID: 18568078.
  313. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110(8):1093-103. DOI: 10.1172/JCI15693. PMID: 12393845.
  314. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987-97. DOI: 10.1056/NEJMoa040388. PMID: 15342807.
  315. Gloaguen I, Costa P, Demartis A, Lazzaro D, Di Marco A, Graziani R, Paonessa G, Chen F, Rosenblum CI, Van der Ploeg LH, Cortese R, Ciliberto G, Laufer R. Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc Natl Acad Sci U S A. 1997;94(12):6456-61. DOI: 10.1073/pnas.94.12.6456. PMID: 9177239.
  316. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology. 1996;46(5):1244-9. DOI: 10.1212/wnl.46.5.1244. PMID: 8628460.
  317. Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, Heshka S, Vicary C, Guler HP. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA. 2003;289(14):1826-32. DOI: 10.1001/jama.289.14.1826. PMID: 12684362.
  318. Erondu N, Gantz I, Musser B, Suryawanshi S, Mallick M, Addy C, Cote J, Bray G, Fujioka K, Bays H, Hollander P, Sanabria-Bohorquez SM, Eng W, Langstrom B, Hargreaves RJ, Burns HD, Kanatani A, Fukami T, MacNeil DJ, Gottesdiener KM, Amatruda JM, Kaufman KD, Heymsfield SB. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metab. 2006;4(4):275-82. DOI: 10.1016/j.cmet.2006.08.002. PMID: 17011500.
  319. Erondu N, Wadden T, Gantz I, Musser B, Nguyen AM, Bays H, Bray G, O'Neil PM, Basdevant A, Kaufman KD, Heymsfield SB, Amatruda JM. Effect of NPY5R antagonist MK-0557 on weight regain after very-low-calorie diet-induced weight loss. Obesity (Silver Spring). 2007;15(4):895-905. DOI: 10.1038/oby.2007.620. PMID: 17426325.
  320. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257(5074):1248-51.
  321. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-4.
  322. Ayers KL, Glicksberg BS, Garfield AS, Longerich S, White JA, Yang P, Du L, Chittenden TW, Gulcher JR, Roy S, Fiedorek F, Gottesdiener K, Cohen S, North KE, Schadt EE, Li SD, Chen R, Van der Ploeg LHT. Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment. J Clin Endocrinol Metab. 2018;103(7):2601-2612. DOI: 10.1210/jc.2018-00258. PMID: 29726959.
  323. Krishna R, Gumbiner B, Stevens C, Musser B, Mallick M, Suryawanshi S, Maganti L, Zhu H, Han TH, Scherer L, Simpson B, Cosgrove D, Gottesdiener K, Amatruda J, Rolls BJ, Blundell J, Bray GA, Fujioka K, Heymsfield SB, Wagner JA, Herman GA. Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy. Clin Pharmacol Ther. 2009;86(6):659-66. DOI: 10.1038/clpt.2009.167. PMID: 19741604.
  324. Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pepin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clement K, Farooqi IS, Van der Ploeg LHT. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-1329. DOI: 10.1016/j.molmet.2017.06.015. PMID: 29031731.
  325. Clement K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kuhnen P, Setmelanotide P, Investigators LPT. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-970. DOI: 10.1016/S2213-8587(20)30364-8. PMID: 33137293.
  326. Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab. 1977;45(6):1211-9. DOI: 10.1210/jcem-45-6-1211. PMID: 338622.
  327. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. DOI: 10.1210/jc.2018-00229. PMID: 29562364.
  328. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341-53. DOI: 10.1210/jc.2011-0118. PMID: 21646372.
  329. Kelly DM, Jones TH. Testosterone and obesity. Obes Rev. 2015;16(7):581-606. DOI: 10.1111/obr.12282. PMID: 25982085.
  330. Lapauw B, Kaufman JM. MANAGEMENT OF ENDOCRINE DISEASE: Rationale and current evidence for testosterone therapy in the management of obesity and its complications. Eur J Endocrinol. 2020;183(6):R167-R183. DOI: 10.1530/EJE-20-0394. PMID: 33105105.
  331. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab.1983;57(2):304-10. DOI: 10.1210/jcem-57-2-304. PMID: 6345569.
  332. Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, Sannerstedt R. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism.1990;39(9):897-901. DOI: 10.1016/0026-0495(90)90297-p. PMID: 2202881.
  333. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord. 1992;16(12):991-7. PMID: 1335979.
  334. Marin P, Holmang S, Gustafsson C, Jonsson L, Kvist H, Elander A, Eldh J, Sjostrom L, Holm G, Bjorntorp P. Androgen treatment of abdominally obese men. Obes Res. 1993;1(4):245-51. DOI: 10.1002/j.1550-8528.1993.tb00618.x. PMID: 16350577.
  335. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, Partington C. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women--a clinical research center study. J Clin Endocrinol Metab. 1996;81(6):2198-203. DOI: 10.1210/jcem.81.6.8964851. PMID: 8964851.
  336. Lovejoy JC, Bray GA, Greeson CS, Klemperer M, Morris J, Partington C, Tulley R. Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men. Int J Obes Relat Metab Disord. 1995;19(9):614-24. PMID: 8574271.
  337. Barnouin Y, Armamento-Villareal R, Celli A, Jiang B, Paudyal A, Nambi V, Bryant MS, Marcelli M, Garcia JM, Qualls C, Villareal DT. Testosterone Replacement Therapy Added to Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism. J Clin Endocrinol Metab. 2021;106(3):e1096-e1110. DOI: 10.1210/clinem/dgaa917. PMID: 33351921.
  338. Gabai G, Mongillo P, Giaretta E, Marinelli L. Do Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEAS) Play a Role in the Stress Response in Domestic Animals? Front Vet Sci. 2020;7:588835. DOI: 10.3389/fvets.2020.588835. PMID: 33195624.
  339. Clore JN. Dehydroepiandrosterone and body fat. Obes Res. 1995;3 Suppl 4:613S-616S. DOI: 10.1002/j.1550-8528.1995.tb00234.x. PMID: 8697065.
  340. Lardy H, Kneer N, Wei Y, Partridge B, Marwah P. Ergosteroids. II: Biologically active metabolites and synthetic derivatives of dehydroepiandrosterone. Steroids. 1998;63(3):158-65. DOI: 10.1016/s0039-128x(97)00159-1. PMID: 9558717.
  341. Svec F, Porter JR. The actions of exogenous dehydroepiandrosterone in experimental animals and humans. Proc Soc Exp Biol Med. 1998;218(3):174-91. DOI: 10.3181/00379727-218-44285. PMID: 9648935.
  342. Usiskin KS, Butterworth S, Clore JN, Arad Y, Ginsberg HN, Blackard WG, Nestler JE. Lack of effect of dehydroepiandrosterone in obese men. Int J Obes. 1990;14(5):457-63. PMID: 2143499.
  343. Nestler JE, Barlascini CO, Clore JN, Blackard WG. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab.1988;66(1):57-61. DOI: 10.1210/jcem-66-1-57. PMID: 2961787.
  344. Welle S, Jozefowicz R, Statt M. Failure of dehydroepiandrosterone to influence energy and protein metabolism in humans. J Clin Endocrinol Metab. 1990;71(5):1259-64. DOI: 10.1210/jcem-71-5-1259. PMID: 2146282.
  345. Mortola JF, Yen SS. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab. 1990;71(3):696-704. DOI: 10.1210/jcem-71-3-696. PMID: 2144295.
  346. Zumoff B, Strain GW, Heymsfield SB, Lichtman S. A randomized double-blind crossover study of the antiobesity effects of etiocholanedione. Obes Res. 1994;2(1):13-8. DOI: 10.1002/j.1550-8528.1994.tb00038.x. PMID: 16353603.
  347. Larsen TM, Toubro S, Astrup A. Efficacy and safety of dietary supplements containing CLA for the treatment of obesity: evidence from animal and human studies. J Lipid Res. 2003;44(12):2234-41. DOI: 10.1194/jlr.R300011-JLR200. PMID: 12923219.
  348. Riserus U, Smedman A, Basu S, Vessby B. Metabolic effects of conjugated linoleic acid in humans: the Swedish experience. Am J Clin Nutr. 2004;79(6 Suppl):1146S-1148S. PMID: 15159248.
  349. Dwyer JT, Allison DB, Coates PM. Dietary supplements in weight reduction. J Am Diet Assoc. 2005;105(5 Suppl 1):S80-6. DOI: 10.1016/j.jada.2005.02.028. PMID: 15867902.
  350. Sullivan AC, Triscari J, Hamilton JG, Miller ON. Effect of (-)-hydroxycitrate upon the accumulation of lipid in the rat. II. Appetite. Lipids. 1974;9(2):129-34. DOI: 10.1007/BF02532137. PMID: 4815800.
  351. Heymsfield SB, Allison DB, Vasselli JR, Pietrobelli A, Greenfield D, Nunez C. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial. JAMA. 1998;280(18):1596-600. DOI: 10.1001/jama.280.18.1596. PMID: 9820262.
  352. Vuppalanchi R, Bonkovsky HL, Ahmad J, Barnhart H, Durazo F, Fontana RJ, Gu J, Khan I, Kleiner DE, Koh C, Rockey DC, Phillips EJ, Li YJ, Serrano J, Stolz A, Tillmann HL, Seeff LB, Hoofnagle JH, Navarro VJ, Drug-Induced Liver Injury N. Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury. Clin Gastroenterol Hepatol. 2022;20(6):e1416-e1425. DOI: 10.1016/j.cgh.2021.08.015. PMID: 34400337.
  353. Onakpoya I, Hung SK, Perry R, Wider B, Ernst E. The Use of Garcinia Extract (Hydroxycitric Acid) as a Weight loss Supplement: A Systematic Review and Meta-Analysis of Randomised Clinical Trials. J Obes.2011;2011:509038. DOI: 10.1155/2011/509038. PMID: 21197150.
  354. Bryson A, de la Motte S, Dunk C. Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers. Br J Clin Pharmacol. 2009;67(3):309-15. DOI: 10.1111/j.1365-2125.2008.03311.x. PMID: 19220279.
  355. Kopelman P, Bryson A, Hickling R, Rissanen A, Rossner S, Toubro S, Valensi P. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond). 2007;31(3):494-9. DOI: 10.1038/sj.ijo.0803446. PMID: 16953261.
  356. Kopelman P, Groot Gde H, Rissanen A, Rossner S, Toubro S, Palmer R, Hallam R, Bryson A, Hickling RI. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical). Obesity (Silver Spring). 2010;18(1):108-15. DOI: 10.1038/oby.2009.155. PMID: 19461584.
  357. Yuan S, Chan JFW, Chik KKH, Chan CCY, Tsang JOL, Liang R, Cao J, Tang K, Chen LL, Wen K, Cai JP, Ye ZW, Lu G, Chu H, Jin DY, Yuen KY. Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system. Pharmacol Res. 2020;159:104960. DOI: 10.1016/j.phrs.2020.104960. PMID: 32473310.
  358. Goldsmith GA, Hamilton JG, Miller ON. Lowering of serum lipid concentrations: mechanisms used by unsaturated fats, nicotinic acid, and neomycin: excretion of sterols and bile acids. Arch Intern Med.1960;105:512-7. PMID: 13848368.
  359. Campbell UD, Juhl E, Quaade F. [Obesity therapy with cholestyramine]. Nord Med. 1970;84(51):1628-9. PMID: 5490740.
  360. Faloon WW, Paes IC, Woolfolk D, Nankin H, Wallace K, Haro EN. Effect of neomycin and kanamycin upon intestinal absortion. Ann N Y Acad Sci. 1966;132(2):879-87. DOI: 10.1111/j.1749-6632.1966.tb43008.x. PMID: 5227780.
  361. Hvidt S, Kjeldsen K. Malabsorption Induced by Small Doses of Neomycin Sulphate. JAMA: The Journal of the American Medical Association. 1963;186(3):229-229. DOI: 10.1001/jama.1963.03710030149127.
  362. Dobbins WO, 3rd, Herrero BA, Mansbach CM. Morphologic alterations associated with neomycin induced malabsorption. Am J Med Sci. 1968;255:63-77. DOI: 10.1097/00000441-196801000-00011. PMID: 5635294.
  363. Rolls BJ, Pirraglia PA, Jones MB, Peters JC. Effects of olestra, a noncaloric fat substitute, on daily energy and fat intakes in lean men. Am J Clin Nutr. 1992;56(1):84-92. DOI: 10.1093/ajcn/56.1.84. PMID: 1609767.
  364. Cotton JR, Burley VJ, Weststrate JA, Blundell JE. Fat substitution and food intake: effect of replacing fat with sucrose polyester at lunch or evening meals. Br J Nutr. 1996;75(4):545-56. DOI: 10.1079/bjn19960158. PMID: 8672407.
  365. Cotton JR, Weststrate JA, Blundell JE. Replacement of dietary fat with sucrose polyester: effects on energy intake and appetite control in nonobese males. Am J Clin Nutr. 1996;63(6):891-6. DOI: 10.1093/ajcn/63.6.891. PMID: 8644683.
  366. Roy HJ, Most MM, Sparti A, Lovejoy JC, Volaufova J, Peters JC, Bray GA. Effect on body weight of replacing dietary fat with olestra for two or ten weeks in healthy men and women. J Am Coll Nutr. 2002;21(3):259-67. DOI: 10.1080/07315724.2002.10719219. PMID: 12074254.
  367. Bray GA, Lovejoy JC, Most-Windhauser M, Smith SR, Volaufova J, Denkins Y, de Jonge L, Rood J, Lefevre M, Eldridge AL, Peters JC. A 9-mo randomized clinical trial comparing fat-substituted and fat-reduced diets in healthy obese men: the Ole Study. Am J Clin Nutr. 2002;76(5):928-34. DOI: 10.1093/ajcn/76.5.928. PMID: 12399262.
  368. Tulley RT, Vaidyanathan J, Wilson JB, Rood JC, Lovejoy JC, Most MM, Volaufova J, Peters JC, Bray GA. Daily intake of multivitamins during long-term intake of olestra in men prevents declines in serum vitamins A and E but not carotenoids. J Nutr. 2005;135(6):1456-61. DOI: 10.1093/jn/135.6.1456. PMID: 15930452.
  369. Lovejoy JC, Bray GA, Lefevre M, Smith SR, Most MM, Denkins YM, Volaufova J, Rood JC, Eldridge AL, Peters JC, Ole S. Consumption of a controlled low-fat diet containing olestra for 9 months improves health risk factors in conjunction with weight loss in obese men: the Ole' Study. Int J Obes Relat Metab Disord. 2003;27(10):1242-9. DOI: 10.1038/sj.ijo.0802373. PMID: 14513073.
  370. Burns AA, Livingstone MB, Welch RW, Dunne A, Reid CA, Rowland IR. The effects of yoghurt containing a novel fat emulsion on energy and macronutrient intakes in non-overweight, overweight and obese subjects. Int J Obes Relat Metab Disord. 2001;25(10):1487-96. DOI: 10.1038/sj.ijo.0801720. PMID: 11673771.
  371. Diepvens K, Steijns J, Zuurendonk P, Westerterp-Plantenga MS. Short-term effects of a novel fat emulsion on appetite and food intake. Physiol Behav. 2008;95(1-2):114-7. DOI: 10.1016/j.physbeh.2008.05.006. PMID: 18571210.
  372. Rebello CJ, Martin CK, Johnson WD, O'Neil CE, Greenway FL. Efficacy of Olibra: a 12-week randomized controlled trial and a review of earlier studies. J Diabetes Sci Technol. 2012;6(3):695-708. DOI: 10.1177/193229681200600326. PMID: 22768902.
  373. Falchi M, El-Sayed Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-Assarsson JC, Sudmant PH, Dorajoo R, Al-Shafai MN, Bottolo L, Ozdemir E, So HC, Davies RW, Patrice A, Dent R, Mangino M, Hysi PG, Dechaume A, Huyvaert M, Skinner J, Pigeyre M, Caiazzo R, Raverdy V, Vaillant E, Field S, Balkau B, Marre M, Visvikis-Siest S, Weill J, Poulain-Godefroy O, Jacobson P, Sjostrom L, Hammond CJ, Deloukas P, Sham PC, McPherson R, Lee J, Tai ES, Sladek R, Carlsson LM, Walley A, Eichler EE, Pattou F, Spector TD, Froguel P. Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet. 2014;46(5):492-7. DOI: 10.1038/ng.2939. PMID: 24686848.
  374. Nakajima K, Muneyuki T, Munakata H, Kakei M. Revisiting the cardiometabolic relevance of serum amylase. BMC Res Notes. 2011;4:419. DOI: 10.1186/1756-0500-4-419. PMID: 22004561.
  375. Heianza Y, Sun D, Wang T, Huang T, Bray GA, Sacks FM, Qi L. Starch Digestion-Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial. Diabetes. 2017;66(9):2416-2423. DOI: 10.2337/db16-1482. PMID: 28659346.
  376. Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med. 1995;98(5):443-51. DOI: 10.1016/S0002-9343(99)80343-X. PMID: 7733122.
  377. William-Olsson T. alpha-Glucosidase inhibition in obesity. Acta Med Scand Suppl. 1985;706:1-39. DOI: 10.1111/j.0954-6820.1986.tb19118.x. PMID: 3914827.
  378. Wolever TM, Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH. Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes. Int J Obes Relat Metab Disord. 1997;21(9):756-63. DOI: 10.1038/sj.ijo.0800468. PMID: 9376887.
  379. Erlanson-Albertsson C, York D. Enterostatin--a peptide regulating fat intake. Obes Res. 1997;5(4):360-72. DOI: 10.1002/j.1550-8528.1997.tb00565.x. PMID: 9285845.
  380. Erlanson-Albertsson C, Mei J, Okada S, York D, Bray GA. Pancreatic procolipase propeptide, enterostatin, specifically inhibits fat intake. Physiol Behav. 1991;49(6):1191-4. DOI: 10.1016/0031-9384(91)90350-w. PMID: 1896501.
  381. Okada S, York DA, Bray GA, Erlanson-Albertsson C. Enterostatin (Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake. Physiol Behav. 1991;49(6):1185-9. DOI: 10.1016/0031-9384(91)90349-s. PMID: 1896500.
  382. Lin L, York DA. Chronic ingestion of dietary fat is a prerequisite for inhibition of feeding by enterostatin. Am J Physiol. 1998;275(2):R619-23. DOI: 10.1152/ajpregu.1998.275.2.R619. PMID: 9688701.
  383. Rossner S, Barkeling B, Erlanson-Albertsson C, Larsson P, Wahlin-Boll E. Intravenous enterostatin does not affect single meal food intake in man. Appetite. 1995;24(1):37-42. DOI: 10.1016/s0195-6663(95)80004-2. PMID: 7741534.

Diabetes Mellitus After Solid Organ Transplantation

ABSTRACT

 

Post transplantation diabetes mellitus (PTDM), also known as New Onset Diabetes After Transplantation, is a common and important complication following solid organ transplantation. PTDM may arise from both transplant-related and traditional risk factors and has variably been reported to be associated with decreased patient and graft survival and other adverse outcomes including increased cardiovascular disease risk, infection, and graft rejection. This chapter reviews the nomenclature change for post-transplant diabetes, diagnostic criteria, risk factors, incidence after solid organ transplantation, and associated adverse effects. Screening for PTDM including pretransplant evaluation and early detection in the posttransplant period, and the unique aspects of diabetes management in the context of organ transplantation are also discussed.

 

NOMENCLATURES AND DIAGNOSIS OF POSTTRANSPLANTATION DIABETES MELLITUS: HISTORICAL PERSPECTIVES

 

Nomenclatures

 

Post transplantation diabetes mellitus (PTDM) was first described in kidney transplant recipients in 1964 (1). It was subsequently recognized as a complication of kidney transplantation in the 1970s. Over the years, PTDM has undergone changes in nomenclatures including steroid diabetes, post transplantation diabetes mellitus (PTDM), new onset diabetes mellitus (NODM), transplant-associated hyperglycemia (TAH), and new onset diabetes after transplantation (NODAT) (2, 3, 4, 5, 6). In 2014, the International Expert Panel consisting of transplant nephrologists, diabetologists, and clinical scientists recommended changing the terminology NODAT back to PTDM, excluding transient post transplantation hyperglycemia (7). Utilizing the term NODAT is thought to be misleading because it seemingly excludes patients with pretransplant diabetes. Pre-existing diabetes is often undiagnosed because of the effect of chronic kidney disease on insulin metabolism and clearance, and the lack of effective pretransplant screening. The term PTDM will be utilized for the remainder of this chapter.

 

Diagnosis

 

Historically, PTDM has been variably defined as having random glucose levels greater than 200 mg/dL, fasting glucose levels greater than 140 mg/dL, or the need for insulin or oral hypoglycemic agents in the posttransplant period (8). In 2003 the International Expert panel consisting of leaders from both the transplant and diabetes fields suggested that the definition and diagnosis of diabetes and impaired glucose tolerance should be based on the definition and diagnosis described by the World Health Organizations (9). In 2011, the American Diabetes Association (ADA) incorporated hemoglobin A1C (A1C) > 6.5% as a diagnostic criterion for diabetes mellitus in the general population based on the observed association between A1C level and the risk for future development of retinopathy (10). In 2014, the International Expert Panel recommended expanding screening tests for PTDM using postprandial glucose monitoring and A1C. However, A1C test is not recommended early after transplantation (arbitrarily defined as within 45 days after transplantation) because of potential confounding factors (7). A normal A1C does not exclude the diagnosis of PTDM in the presence of early posttransplant anemia and/or dynamic kidney allograft function. In a small single-center study consisting of 30 diabetic patients with CKD stage 3 b and 4, treatment with intravenous iron and erythropoietin stimulating agent (ESA) has been shown to result in a fall in A1C independent of glycemic changes (11). It is speculated that the fall in A1C level associated with either treatment is due to the formation of new erythrocytes in the circulation (causing a change in the proportion of young to old red blood cells), and an alteration in the red-cell glycation rates. A similar study in the transplant setting is lacking and warrants further exploration because intravenous iron and ESA therapy are commonly administered in the early posttransplant period. Although not widely used in clinical practice, oral glucose tolerance (OGTT) remains the gold standard for diagnosing PTDM. It should be noted that the algorithmic approach to the screening and diagnosis of PTDM is largely based on published kidney transplantation literature. Similar studies in the settings of liver, heart, and lung transplants are lacking. However, it is speculated that the principles are relevant to all forms of solid organ transplantation (7). The 2022 ADA criteria for prediabetes and diabetes are shown in Figure 1. 

Figure 1. The 2022 American Diabetes Association Diagnostic Criteria for Prediabetes and Diabetes.

1For A1C, FPG and 2-h OGTT, risk is continuous, extending below the lower limit of the range, becoming disproportionately greater at the higher end of the range. 2In the absence of unequivocal hyperglycemia, diagnosis of DM using A1C, FPG or 2-h OGTT requires two abnormal test results from the same sample or in two separate samples. 3Random plasma glucose is only diagnostic in patient with classic symptoms of hyperglycemia or hyperglycemic crisis (https://doi.org/10.2337/cd22-as01). OGTT, oral glucose tolerance test; A1C, hemoglobin A1C; NGSP, National Glycohemoglobin Standardization Program

 

INCIDENCE

 

PTDM has been reported to occur in 4% to 25% of kidney transplant recipients, 2.5% to 25% of liver transplant recipients, 4% to 40% of heart transplant recipients, and 30% to 35% of lung transplant recipients (9, 12-15). Higher incidences have also been reported. Variations in the reported incidence may be due in part to the prior lack of a standard definition, presence of both modifiable and nonmodifiable risks factors, duration of follow-up, type of organ transplants, and primary diagnostic indications for transplant. In one retrospective cohort study of 415 liver transplant recipients, PTDM occurred in 34.7%, 46.9%, and 56.2% of patients at 1, 3, and 5-year follow-up, respectively (15). The 33rd International Society of Heart and Lung Transplantation database demonstrated that approximately 29% of lung transplant recipients who survived 5 years post-transplantation developed PTDM, with the highest incidence occurring among those whose primary diagnosis for lung transplantation was cystic fibrosis. (16).

 

RISK FACTORS FOR PTDM

 

PTDM may arise from both transplant-related and traditional risk factors. The diabetogenic effect of various immunosuppressive agents have been well described. Corticosteroids may reduce peripheral insulin sensitivity, inhibit pancreatic production/secretion, and increase hepatic gluconeogenesis. The calcineurin inhibitors tacrolimus and cyclosporine decrease insulin secretion and synthesis. Sirolimus increases peripheral insulin resistance and impairs pancreatic beta-cell response. The antimetabolites azathioprine and mycophenolic acid derivatives (mycophenolate mofetil and mycophenolate sodium) are not diabetogenic. Belatacept is a humanized fusion protein that inhibits the costimulatory pathway. Its use in kidney transplant recipients has not been shown to increase PTDM risk. Transplant patients may have improved appetite and a more liberal diet which can lead to obesity. Risk factors for PTDM can be loosely categorized into those that are non-modifiable, potentially modifiable, and modifiable (8, 17-24).

 

Solid organ transplant recipients with specific end-organ diagnosis such as end-stage kidney disease due to polycystic kidney disease, end-stage lung disease due to cystic fibrosis, or end-stage liver disease due to hepatitis C infection or nonalcoholic steatohepatitis have been reported to be at increased risk for PTDM compared with those without such diagnosis (21). Donor liver steatosis has also been reported to be associated with an increased incidence of PTDM (22). Suggested risk factors for the development of PTDM are presented in Figure 2. A more extensive discussion of the studies evaluating PTDM risk factors is beyond the scope of this chapter. Interested readers are referred to reference Pham and colleagues (8).

 

Figure 2. Suggested Risk factors for PTDM

1Curative therapy for chronic hepatitis C can be achieved with interferon-free direct acting antiviral-based regimen. Stable transplant recipients with HCV viremia by PCR should be referred to Hepatology for treatment. In HCV-positive kidney transplant candidate with a living donor, pretransplant treatment of HCV infection should be considered. 2Posttransplantation CMV prophylaxis is preferred over preemptive therapy after heart and lung transplant. Either prophylaxis or preemptive therapy is recommended after kidney or liver transplant recipients. However, for programs or patients who are unable to meet the stringent logistic requirements required with preemptive therapy, prophylaxis therapy is recommended. 3Persistent hypomagnesemia can occasionally be seen despite aggressive replacement therapy because of ongoing calcineurin inhibitor-induced urinary magnesium wasting. 4Manipulation of immunosuppression should be weighed against the risk of acute rejection. 5Donor liver steatosis has also been reported to be associated with increased PTDM risk. PPAR, peroxisome proliferators activated receptor; IGT, impaired glucose tolerance; IFG, impaired fasting glucose

 

IMPACT OF PTDM ON OUTCOMES AFTER TRANSPLANTATION

 

Studies evaluating the association between PTDM and morbidity and mortality have yielded mixed results (25-33).

 

PTDM After Kidney Transplantation

 

Retrospective analysis of the United States Renal Data System consisting of more than 11,000 kidney transplant recipients demonstrated that PTDM was a strong, independent predictor of mortality (p < 0.0001), graft failure (unadjusted for graft loss due to rejection) (p < 0.0001), and death-censored graft failure (p < 0.0001) (18). One single-center study consisting of more than 700 kidney transplant recipients similarly demonstrated worse 10-year actuarial patient survival among patients with PTDM compared with those without PTDM (67.1% vs. 81.9%, respectively). Five- and 10-year graft survival rates were similar among patients with PTDM and those without PTDM (25). In contrast, in a multicenter longitudinal cohort study consisting of 632 kidney transplant recipients of deceased-donor kidneys, no association between PTDM and mortality or graft failure was observed at a median follow-up of 6 years post-transplantation (n=632) (26). Subgroup analyses showed that late onset PTDM (developing beyond 1-year post-transplantation) was associated with worse graft outcomes. A retrospective analysis of the UNOS/OPTN database (n > 37,000) similarly failed to demonstrate the negative impact of PTDM on transplant survival or cardiovascular mortality during a median follow up of 548 days (27). However, the study results were considered inconclusive because of the wide confidence intervals and relatively short duration of follow-up.   

 

PTDM After Liver Transplantation

 

Retrospective analysis of the UNOS/OPTN database consisting of > 13,000 liver transplant recipients demonstrated that the presence of both PTDM and acute rejection at 1-year posttransplant but not PTDM alone was associated with higher overall graft failure and mortality risk (27). However, it should be noted that UNOS database did not distinguish transient post transplantation hyperglycemia from established PTDM. A single-center retrospective cohort study (n=994) compared the incidence of major cardiovascular events (MCE) among four groups of liver transplant recipients 1) without diabetes (39%), 2) with pre-existing diabetes (24%), 3) with transient PTDM (16%), and 4) with sustained PTDM (20%). Sustained PTDM was found to be associated with a significant increase in mortality risk and a doubling of major cardiovascular events at a median follow up of 54.7 months (sub-distribution HR 1.95, 95% CI 1.20–3.18). A greater than threefold increased risk of death was observed among those who experienced MCE (sustained PTDM was defined as PTDM for at least 6 months after transplant). MCE was defined as a composite of cardiac arrest, fatal and nonfatal myocardial infarction, ischemic stroke, and symptomatic peripheral artery disease requiring a revascularization intervention) (30). In a retrospective cohort study of 415 adult liver transplant recipients, PTDM was found to be associated with higher rejection rates (31.9% vs. 21.8%, respectively; p=0.055) and a trend towards worse patient survival compared with no-PTDM at 5 year follow up (72.5% vs. 77.2%, respectively; p=0.460) (15). Although studies on the association between PTDM and patient and allograft outcomes after liver transplantation have yielded variable results, most studies demonstrated that PTDM after liver transplantation is associated with increased mortality risk (31).

 

PTDM After Heart Transplantation

 

Meta-analysis of observational studies in heart transplant recipients demonstrated that pre-existing diabetes was associated with a 37% increase in mortality risk (HR 1.37, CI 1.15-1.62) (32). Studies on the impact of PTDM on outcomes after heart transplantation are lacking. In one single-center South Korean study consisting of 391 isolated heart transplant recipients 1) without diabetes (n=257), 2) with pre-existing diabetes (n=46), and 3) with PTDM (n=88), the risk of death was found to be twofold higher among transplant recipients with pre-existing as well as post transplantation diabetes compared with their non-diabetic counterparts (33).

 

PTDM After Lung Transplantation

 

The 27th International Society for Heart and Lung Transplantation Registry consisting of more than 32,000 lung transplant recipients demonstrated that pre-existing diabetes was associated with a 21% increase in 5-year mortality risk (RR 1.21, p=0.0023) (34). Limited studies suggest that PTDM similarly adversely affects survival among lung transplant recipients. In a single-center prospective observational Australian study consisting of 210 patients who underwent their first single, bilateral, or heart-lung transplant between 2010-2013, hyperglycemia in both the early and late posttransplant periods (defined as first 4 months and beyond 4 months) was found to be associated with increased mortality risk. Of 210 patients, 80 had no DM, and 90 had persistent DM. Patients with preexisting DM (n=45) and PTDM (n=45) were classified together as “persistent DM”. In the whole cohort, each 18 mg/dL increase in mean fasting blood glucose (FBG) and random blood glucose and each 1% increase in mean A1C were associated with 18% (p=0.006), 38% (p< 0.001), and 46% (p=0.002) increase in mortality risk, respectively (median follow up of 3 years). Of interest, random blood glucose correlated with mortality in both the persistent DM and no DM groups (35%, p=0.012 and 109%, p=0.041, respectively). It was concluded that glycemic control strongly correlated with survival after lung transplant (35). The same group of investigators previously demonstrated that DM conferred a nearly fourfold increase in mortality risk compared with no DM. When patients were classified into subgroups including 1) no diabetes, 2) pre-existing DM, 3) PTDM, 4) DM diagnosed within 2 weeks of death, and 5) DM developing after transplant but death within 90 days of transplant, pre-existing DM and PTDM were associated with a 65% (p=0.003) and a 90% (p<0.001) increase in mortality risk, respectively (36).

 

Although studies on the impact of PTDM on outcomes after non-renal solid organ transplantation remain limited, PTDM appears to be associated with increased mortality risk regardless of the type of organ transplants (kidney, liver, heart, lung transplant) (21). Patients with PTDM may also develop many of the complications associated with diabetes similar to that observed in the general population. In a study of 4105 patients with PTDM, one or more diabetic complications arose in 58% including ketoacidosis (8%), hyperosmolarity (3%), renal complications (31%), ophthalmic complications (8%), neurological complications (16%), peripheral circulatory disorders (4%), and hypoglycemia/shock (7%). These complications occurred within a mean of 500-600 days of developing PTDM, indicating an accelerated pace for the development of complications (28). Moreover, PTDM patients had an increased rate of infections and sepsis compared with their non-diabetic counterparts.

 

DETECTION OF PTDM

 

Pretransplant Baseline Evaluation

 

Pretransplant Evaluation should include history of hyperglycemia, prediabetes, diabetes, and risk factors for PTDM including family history and hepatitis C virus. The 2004 International Consensus Guidelines suggest that a pretransplant baseline evaluation should include a complete medical and family history, including documentation of glucose history (37). Those with risk factors for metabolic syndrome can be screened further with laboratory testing. Patients with evidence of risk factors can be counseled of their risk for PTDM. Those with evidence of prediabetes can be counseled on lifestyle modifications including dietary modifications, thirty minutes of moderate intensity physical activity, and overall five to ten percent weight reduction (38). In HCV-positive kidney transplant candidates with a living donor, pretransplant treatment of HCV infection should be considered. With the advent of the interferon-free direct acting antiviral based regimen, treatment of hepatitis C in the posttransplant period is a reasonable alternative in selected prospective kidney transplant candidates without a living donor due to a considerably shorter waiting time for a deceased HCV-positive donor kidney (39). The choice of an immunosuppressive regimen should be tailored to each individual patient, weighing the risk of acute rejection against that for PTDM.

 

Early Detection of PTDM After Transplantation

 

New onset perioperative hyperglycemia is common and may develop in the context of high dose corticosteroid, as a consequence of posttransplant stress hyperglycemia, or both. Limited studies suggest that posttransplant stress hyperglycemia is an independent risk factor for subsequent diabetes (40). The 2014 International Consensus guidelines on PTDM screening is shown in Figure 3 (7). The expert panel suggested that patients with early post-transplant hyperglycemia (defined as hyperglycemia before 45 days after transplantation) should not be diagnosed as PTDM.

Figure 3. The 2014 International Consensus Guidelines on Screening, Diagnosis, and Management of PTDM

1Seldom performed in clinical practice (time-consuming/cost). 2 A1C cannot be accurately interpreted within the first 3 months after transplantation because anemia and impaired graft function can directly interfere with the A1C assay. Recent blood transfusion and dapsone may alter A1C level. 3A1C alone < 365 days may underestimate PTDM and require confirmatory testing. 4Within the past several years newer injectable antidiabetic agents have increasingly been used (however, it should also be noted that evidenced-based recommendations are lacking). PTDM, post-transplantation diabetes mellitus; OGTT, oral glucose tolerance test; A1C, hemoglobin A1C

 

At the authors’ institution, fasting and premeal home glucose monitoring is routinely recommended for patients with new-onset post transplantation hyperglycemia particularly those requiring insulin therapy in the immediate post transplantation period. Nonetheless, it should be noted that monitoring a 2- hour postprandial blood glucose may be a better indicator of diabetes, particularly in steroid-treated patients. Clinically stable patients with persistent post transplantation hyperglycemia for > 3 months should be screened for PTDM using A1C test. Although evidence-based screening guidelines for the early detection of PTDM are lacking, obtaining baseline A1C at 3 months after transplant, then at 6 months, 9 months, 12 months, and annually thereafter seems reasonable. If screening A1C is in the prediabetic range, patients should be counseled on dietary and lifestyle modification and A1C monitored every 3 months. While OGTT remains the gold standard for diagnosing PTDM, there remains insufficient evidence to recommend OGTT for all kidney transplant recipients (7). In addition, screening all patients with OGTT may be impractical in clinical practice and should be individualized and reserved for those with multiple risk factors (opinion-based) (40,41).

 

PREVENTION AND MANAGEMENT OF PTDM

 

Non-Pharmacological Preventive and Management Strategies

 

Studies in the general population demonstrated that lifestyle modification promoting reduced fat/energy diet, daily moderate intensity physical activity, and modest weight loss reduce the incidence of type 2 diabetes (42). Similar studies in the context of solid organ transplantation are limited. Small single-center studies showed that post transplantation weight gain is associated with persistent PTDM (43). In a small single center study consisting of 25 kidney transplant recipients with impaired glucose tolerance, reversal to normal glucose tolerance with lifestyle modification was observed in 13 patients after a median of 9 months with only one patient progressing to PTDM (44). In contrast, a single-center, randomized controlled trial designed to Compare the benefits of Active Versus passive lifestyle Intervention in kidney Allograft Recipients (CAVIAR) showed no improvement in surrogate markers of glucose metabolism (insulin secretion, insulin sensitivity, and disposition index) among patients randomized to active lifestyle intervention (lifestyle change with the guidance of a renal dietitian, n=66) compared with their passive lifestyle intervention counterparts at 6 month follow-up (leaflet advice alone, n=64). However, clinically, active versus passive lifestyle intervention resulted in weight loss (-2.47 kg, P=0.002) and reduction in fat mass (mean difference, -1.537 kg, P=0.123). A trend towards reduction in PTDM incidence (7.6% versus 15.6%, P = 0.123) was observed in the active intervention arm (45). 

 

Pharmacological Preventive and Management Strategies

 

In the immediate posttransplant period, the pancreatic β-cells are exposed to multiple hyperglycemic stressors including the transplant surgery itself, high-dose corticosteroids, and the introduction of cyclosporine or tacrolimus immunosuppression therapy. It has been suggested that early basal insulin therapy decreases PTDM through insulin-mediated protection of pancreatic beta-cells (46-47). In a randomized controlled trial, Hecking et al. demonstrated that early basal insulin therapy following detection of early post transplantation hyperglycemia (defined as < 3 weeks) reduced the subsequent odds of developing PTDM within the first year after transplantation by 73% (47). In an open-label, multicenter randomized trial comparing early post-operative basal insulin therapy vs. standard of care for the prevention of PTDM in kidney transplant recipients, early insulin therapy was similarly found to result in reduced odds for PTDM at 12 months (OR: 0.21 [95% CI, 0.07 to 0.62]) and at 24 months (OR 0.35 [95% CI, 0.14 to 0.87]) after adjustment for baseline differences including polycystic kidney disease. However, treatment resulted in significantly higher hypoglycemia rates (48). Currently, initiation of insulin therapy in the early post-transplantation period solely to prevent PTDM cannot be routinely recommended and awaits further study. The glucose threshold for starting insulin therapy remains to be defined. Insulin tapering or withdrawal and transitioning to noninsulin-based regimen can be considered after the first 1-3 month after transplant when insulin requirement is less than 15-20 units a day (opinion-based). The choice of individual agents should be based on the potential advantages and disadvantages of different classes of agents at the discretion of the clinicians (Figure 4).

Figure 4. The potential advantages and disadvantages of various classes of antihyperglycemic agents.

1 KDIGO guidelines: Reduce dose if estimated glomerular filtration rate (eGFR) < 45 cc/min/1.73 m2. Discontinue if eGFR < 30 cc/min/1.73m2. 2 From Parekh TM, Raji M, Lin YL, et al. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med. 2014;174(10):1605-1612. 3 Contraindicated in patients with personal history or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) type 2. 4 Sitagliptin may prolong QT interval particularly when used with cyclosporine.

 

Modification of Immunosuppression

 

Although clinical trials comparing the incidence of PTDM in cyclosporine versus tacrolimus-treated patients have yielded variable results, tacrolimus has more consistently been shown to have a greater diabetogenic effect than cyclosporine (49). Modification of immunosuppression including cyclosporine to tacrolimus conversion therapy or steroid avoidance, or withdrawal has variably been shown to improve glycemic control (8, 49-53). However, manipulation of immunosuppression is not without immunological risk. In a meta-analysis of controlled clinical trials to assess the safety and efficacy of early steroid withdrawal or avoidance, Pascual et al. showed that steroid avoidance or steroid withdrawal after a few days reduced PTDM incidence among cyclosporine but not tacrolimus-treated kidney transplant recipients (54). However, among cyclosporine-treated patients, acute rejection episodes were more frequently observed in steroid avoidance compared with conventional steroid treated groups. The same group of investigators demonstrated no significant beneficial effect of late steroid withdrawal (3 to 6 months after transplantation) on the incidence of PTDM (55). In the current era of immunosuppression, the beneficial effect of steroid avoidance or withdrawal on the incidence of PTDM has been questioned by experts in the field because rapid steroid taper and the use of lower target cyclosporine and tacrolimus levels are now common practice (7). The use of tacrolimus and mTOR inhibitor combination therapy may increase PTDM risk and should probably be avoided. Nonetheless, low dose calcineurin inhibitor (cyclosporine or tacrolimus) and mTOR inhibitor combination therapy seems justifiable in transplant recipients with a history of malignancies (such as skin cancers, renal cell carcinoma, or Kaposi sarcoma). Due to the lack of well-defined guidelines, modification of immunosuppression to alleviate the incidence of PTDM should be tailored to each individual patient. Reduction in immunosuppression should be weighed against the risk of acute rejection.

 

Management of Established PTDM in the Late Posttransplant Period

 

Although there may be differences in the pathogenesis and presentation of PTDM compared to type 2 diabetes mellitus, management of established PTDM in the late posttransplant period should follow the conventional approach and clinical guidelines as established by well-recognized organizations. The American Diabetes Association and European Association for the Study of Diabetes generally recommend an A1c target of < 7% (56). Lower A1C levels may be acceptable and even beneficial if it can be achieved safely without significant hypoglycemia or other treatment-related adverse effects. In contrast, less stringent A1C goals may be appropriate for patients with limited life expectancy or where the harms of treatment are greater than the benefits (57). Lifestyle modifications including weight reduction, dietary changes, and regular moderate cardiovascular activity should be employed. If glycemic control does not reach therapeutic targets, medical management with antidiabetic agents and ultimately insulin can be initiated.

 

Metformin has not been widely used in the setting of transplantation due to the concern for lactic acidosis in the presence of dynamic kidney allograft function particularly in the early post transplantation period. In contrast, the potential beneficial effects of metformin including weight neutral or weight loss, cardio protection, and lack of significant drug-drug interactions renders metformin an attractive treatment option for solid organ transplant recipients. There has been only one randomized clinical trial assessing the efficacy of metformin in the prevention of PTDM in kidney transplant recipients –The Transplantation and Diabetes (Transdiab) study (58). The Transdiab study is a single-center, open label, randomized controlled trial designed to assess the feasibility, gastrointestinal tolerability, and efficacy of metformin in patients with post transplantation impaired glucose tolerance. The latter is diagnosed using a 2-hour oral glucose tolerance test in the 4-12 weeks after transplant. Patients with eGFR < 30 mL/min/1.73 m2 were excluded from the study. Eligible patients with IFG were randomized to standard of care (n=9) or standard of care and metformin 500 mg twice daily (n=10). The efficacy of metformin was assessed by measuring fasting blood glucose and A1C at 3, 6, 9, and 12-month follow up. The study demonstrated similar tolerability and efficacy between the two groups. The former was evaluated by the gastrointestinal symptom rating scale at 3- and 12-months post randomization. At 12-month follow-up, 60% of patients in the metformin arm and 22% in the control arm returned to a normal OGGT (P=0.2). Both groups gained weight by the end of 12 months with the intervention group gaining 2.2 kg and the control group 6.7 kg (P=0.12). One patient discontinued metformin due to gastrointestinal symptoms and another patient required metformin dose reduction due to a metallic taste. One patient in the control group was started on metformin 500 mg twice daily by the treating physician 6 months after randomization due to elevated FBG and A1C. There were no episodes of lactic acidosis or serious adverse events in either arm. Although large randomized controlled trials to assess the risk and benefit ratio of metformin are needed before it can be endorsed as the oral antidiabetic agent of choice in PTDM, its use appears safe in kidney transplant recipients with mild to moderate renal impairment (eGFR 30-60 mL/min).

 

Experimental studies suggest that sulfonylureas are associated with β-cell apoptosis and β-cell exhaustion (59), raising theoretical concern about their use in PTDM, particularly in the early posttransplant period. In contrast, the anti-hyperglycemic dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitors have been shown to preserve pancreatic beta-cell function in diabetic animal models (60-61). 

 

Early clinical studies suggest that DPP-4 inhibitors are safe and effective in the treatment of PTDM in kidney transplant recipients (62-64). In a single-center study consisting of 71 stable kidney transplant recipients with PTDM newly diagnosed by an oral glucose tolerance test, Haidinger et al. demonstrated that patients treated with vildagliptin at baseline had significantly reduced HbA1C levels at 3, 6,12, and 18 months, whereas no improvement in glycemic control was observed among their sulfonylurea-treated counterparts (62). In a randomized controlled trial comparing vildagliptin with placebo in the treatment of PTDM, the same group of investigators demonstrated that treatment with vildagliptin significantly improved A1C levels within 3 months compared with placebo (65). In a systematic review and meta-analysis to assess the efficacy and safety of DDP-4 inhibitors in kidney transplant recipients with PTDM, DDP4-inhibitor use was found to have a favorable glycemic effect (assessed by A1C) compared with either placebo or oral anti-hyperglycemic agent (A1C= -0.993, p=0.001) at 6-month follow-up. No significant changes in eGFR or tacrolimus levels were observed in DDP-4 inhibitor-treated patients (66). 

 

Studies evaluating the safety and efficacy of DDP-4 inhibitors in non-renal solid organ transplant recipients remain lacking. In a small retrospective study of 30 stable heart transplant recipients with type 2 diabetes, vildagliptin was found to significantly reduce A1C level compared with their control counterparts. Mean A1C in the vildagliptin-treated patients was 7.4% ± 0.7% before versus 6.8% ± 0.8% after 8 months of therapy (P = 0.002 vs baseline). Mean A1C levels at baseline and at 8-month follow up in the control group were 7.0% ± 0.7% versus 7.3% ± 1.2%, respectively (P = 0.21) (67). No statistically significant changes in body weight, total cholesterol or triglyceride levels were seen in vildagliptin-treated patients. Furthermore, no significant changes in immunosuppressive drug levels or dosages were observed in either group. Whether vildagliptin is safe and effective in the treatment of PTDM after orthotopic heart transplantation warrants further exploration. In contrast, in a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the long-term cardiovascular efficacy and safety of saxagliptin in patients with type 2 DM at risk of cardiovascular events, saxagliptin administration was unexpectedly found to be associated with a significant 27% increase in hospitalizations for heart failure [the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, n =16,492) (68). However, subsequent post-hoc analyses of two large randomized placebo-controlled trials (EXAMINE and TECOS trials) showed no increase in heart failure risk in alogliptin- (69) or sitagliptin-treated patients (70) compared with their placebo-treated counterparts, suggesting that the increase in heart failure incidence observed with saxagliptin may be specific to the drug rather than a drug class effect. Nonetheless, based on early clinical study results, the FDA has issued a warning about the potential for increased risk for heart failure associated with the use of saxagliptin and alogliptin. Saxagliptin use in recipients of heart transplantation with PTDM is not recommended. Whether alogliptin is safe for use after heart transplantation awaits further studies.

 

GLP-1 agonists therapy may confer cardioprotective (liraglutide, dulaglutide, and semaglutide) and weight-loss benefits, counteracting the weight gain commonly seen in the setting of hyperglycemia and steroid therapy after transplantation (16, 71-72)

 

The novel sodium-glucose cotransporter type 2 inhibitor (SGLT2i) antidiabetic drug class inhibits glucose reabsorption in the proximal convoluted tubule resulting in glucosuria. The glucosuric effect of SGLT2i is attenuated in patients without hyperglycemia thereby lessening hypoglycemia risk. An experimental animal model of tacrolimus-induced diabetes demonstrated that empagliflozin improves hyperglycemia and suppressed the tacrolimus-induced twofold increase in the expression of SGLT2 receptors (73). Furthermore, empagliflozin was found to have a direct protective effect on tacrolimus-induced renal injury. The study findings suggest that SGLT2 inhibitor is a suitable therapeutic option for transplant recipients with tacrolimus induced PTDM.

 

Although initially approved for use as an antidiabetic agent, SGLT2i use was unexpectedly found to have cardio- and reno-protective effects in subjects with or without type 2 DM (74-76). The EMPEROR-Reduced randomized placebo-controlled trial designed to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function demonstrated a significant reduction in cardiovascular death, heart failure hospitalization, and total heart failure hospitalization among empagliflozin-treated patients compared with their placebo-treated counterparts at a median follow up of 16 months. A reduction in the composite kidney outcome (defined as sustained profound decline in eGFR, chronic dialysis, or transplant) was also observed among patients randomized to receive empagliflozin irrespective of baseline renal function (HR for patients with vs. without CKD: 0.53 vs. 0.46, respectively, p=0.78) (77). Whether the cardiorenal benefits of SGLT2i seen in the general population can be extrapolated to the transplant population awaits further studies. Limited prospective and retrospective studies in the setting of solid organ transplantation showed that SGLT2i has a modest effect on glycemic control and a favorable effect on weight reduction (78-80). In a single-center, prospective, double-blind study consisting of 44 kidney transplant recipients with PTDM randomized to receive either empagliflozin (n=22) or placebo (n=22) for 24 weeks, a significant reduction in A1C was observed among empagliflozin-treated patients compared with their placebo-treated counterparts (-0.2% vs. 0.1%, p=0.025). A significant reduction in body weight was also observed (-2.5 kg vs. +1.0 kg, respectively p=0.014). There were no significant differences in adverse events, immunosuppressive drug levels, or eGFR between the two treatment groups (78). A small retrospective single-center observational study consisting of 97 heart transplant recipients with PTDM demonstrated that empagliflozin-based treatment (n=20) resulted in a significant reduction in body weight (p=0.05), BMI (p=0.04), mean furosemide dose (p=0.05), and systolic and diastolic blood pressure (p=0.03) compared with control (non-empaglifloxin-based treatment, n=77) at 12-month follow-up. There was a statistically non-significant mean reduction in A1C of 0.6%. No serious adverse events were observed (80). Based on the study findings the investigators suggest that SGLT-2 inhibitors are suitable for use following heart transplantation (81). Reported adverse effects associated with SGLT2 use include increased risk for urinary tract infections, genital candidiasis, euglycemic diabetic ketoacidosis, and acute kidney injury. The latter presumably due to its effects on afferent arteriolar vasoconstriction and its natriuretic and diuretic effects. Distal limb amputation and Fournier gangrene associated with SGLT2i use have not consistently been demonstrated.

 

There have been no consensus treatment guidelines for PTDM. The choice of individual agents should be based on potential advantages and disadvantages of different classes of agents. Unless contraindicated, GLP1 receptor agonist may be considered in kidney transplant recipients with established CVD (or multiple CVD risk factors) whereas SGLT2i may be the preferred agent for those with a history of heart failure. SGLT2i use may have the added benefit of renoprotection independent of its glucose-lowering effects. Failure to achieve glycemic control despite multiple antihyperglycemic agent combination therapy generally requires initiation of insulin therapy. The 2014 international consensus guidelines on the screening, diagnosis, and management of early posttransplant hyperglycemia and PTDM is shown in Figure 3. Although evidenced-based recommendations are lacking, within the past several years newer injectable antidiabetic agents have increasingly been used. The authors’ suggested protocol for screening, diagnosis, and management of early post transplantation hyperglycemia and PTDM is shown in Figure 5 (practice varies among centers).

Figure 5. Suggested screening and management of PTDM (opinion-based)   

mo, month; AHA, American Heart Association; KDIGO, Kidney Disease Improving Global Outcomes

 

SUMMARY

 

PTDM is a common complication after solid organ transplantation and has variably been reported to be associated with increased morbidity and mortality. Risk stratification, intervention to minimize risk and early diagnosis may alleviate the incidence of PTDM and improve outcomes following solid organ transplantation. The 2014 International Consensus Guidelines suggest expanding screening tests for PTDM using postprandial glucose monitoring and HbA1C test. However, the latter should be used with caution in the early posttransplant period. A normal A1C does not exclude the diagnosis of PTDM in the presence of early posttransplant anemia and/or dynamic kidney allograft function. Whether intravenous iron therapy and/or the use of erythropoietin stimulating agent result in falsely low A1C levels remains to be studied. Currently early initiation of basal insulin therapy in patients with new onset hyperglycemia during the first post transplantation week to preserve β-cell function and progression to overt PTDM cannot be routinely recommended. Management of established late PTDM should follow the conventional approach and guidelines established for the general population. When lifestyle modification fails to achieve glycemic control, medical intervention is often necessary. The choice of one antihyperglycemic agent over the other should be based on the potential advantages and disadvantages of individual agents. Metformin appears safe in kidney transplant recipients with mild to moderate renal impairment (eGFR 30-60 mL/min). SGLT2 inhibitor has been suggested to be suitable for use following heart transplantation. Its use after kidney transplantation should be individualized. Similar to the general population, insulin therapy should be considered in individuals with suboptimal glycemic control despite multiple antihyperglycemic agent combination therapy.   

 

REFERENCES

 

  1. Starlz TE. Experience in renal transplantation. Philadelphia: Saunders 1964:111.
  2. Gunnarsson R, Arner P, Lundgren G, et al. Steroid diabetes after renal transplantation. A preliminary report. Scan Urol Nephrol Suppl 1977; 42:191-194.
  3. Araki M, Flechner SM, Ismail HR, et al. Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs. Transplantation 2006; 81(3): 335-341.
  4. Crutchlow MF, Bloom RD. Transplant-associated hyperglycemia: a new look at an old problem. Clin J Am Soc Nephrol 2007; 2(2):343-355.
  5. Bloom RD, Crutchlow MF. New-onset diabetes mellitus in the kidney recipients: diagnosis and management strategies. Clinical J Am Soc Nephrol 2008; 3: S38-48.
  6. Pham PT, Pham PVC, Lipshutz G. New onset diabetes mellitus after solid organ transplantation. Endocrinol Metab Clin North Am 2007; 36(4): 873-890.
  7. Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant. 2014; 14(9):1992-2000.
  8. Pham PT, Pham PM, Pham SV, Pham PA, Pham PC. New onset diabetes after transplantation (NODAT): an overview. Diabetes Metab Syndr Obes. 2011; 4:175-86.
  9. Davidson J, Wilkinson AH, Dantal J, et al. New-onset diabetes after transplantation: 2003 International Consensus Guidelines. Transplantation. 2003;7: SS3–SS24.
  10. American Diabetes Association. Standards of Medical Care in Diabetes 2011. Diabetes Care 2011; 34: S11.
  11. Ng JM, Cooke M, Bhandari S, et al. The effect of iron and erythropoietin treatment on the A1C of patients with diabetes and chronic kidney disease. Diabetes Care 2010; 33(11): 2310-2313.
  12. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation. 2001; 72:1066–1072.
  13. Knobler H, Stagnaro-Green A, Wallenstein S, et al. Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol. 1998; 26:30–33.
  14. Ye X, KuoH-T, Sampaio MS, Jiang Y, Bunnapradist S. Risk factors for the development of new-onset diabetes mellitus after transplant in adult lung transplant recipients. Clin Transplant. 2010; DOI 10. 1111:1–7
  15. Lieber SR, Lee RA, Jiang Y, et al. The Impact of PostTransplant Diabetes Mellitus on Liver Transplant Outcomes. Clin Transplant. 2019 Jun; 33 (6):e13554. doi: 10.1111/ctr.13554.
  16. Yusen RD, Edwards LB, Anne I Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart-Lung Transplant Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant. 2016 Oct;35(10):1170-1184. doi: 10.1016/j.healun.2016.09.001. Epub 2016 Sep 13.
  17. Cosio FG, Pesavento TE, Osei K, et al. Posttransplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kid Int 2001; 59(2): 732-737.
  18. Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J transplant 2003;3(2): 178-185.
  19. Martinez-Castelao A, Hernandez MD, Pascual J, et al. Detection and treatment of post kidney transplant hyperglycemia: a Spanish multicenter cross-sectional study. Transplant Proc 2005;37: 3813-3816.
  20. Quaglia M1, Terrazzino S, Musetti C, et al. The Role of TCF7L2 rs7903146 in Diabetes After Kidney Transplant: Results From a Single-Center Cohort and Meta-Analysis of the Literature. Transplantation 2016; 100(8): 1750-1758.
  21. Jenssen T, Hartmann A. Post-transplant diabetes mellitus in patients with solid organ transplants. Nat Rev Endocrinol 2019; 15(3): 172-188.
  22. Xue M, Lv C, Chen X, et al. Donor liver steatosis: A risk factor for early new-onset diabetes after liver transplantation. J Diabetes Investig. 2017 Mar;8(2):181-187. doi: 10.1111/jdi.12560.
  23. Elens L, Sombogaard F, Hesselink D, et al. Single-nucleotide polymorphism in P450 oxidoreductase and peroxisome proliferator-activated receptor are associated with the development of new onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics. 2013; 23:649-657 (21)
  24. El Essawy B, Kandeel F. Pre, peri and posttransplant diabetes mellitus. Current opinion Nephrol Hypertens. 2018; 28: 47-57 (22)
  25. Joss N, Staatz CE, Thomson AH, et al. Predictors of new onset diabetes after renal transplantation 2007;21(1): 136- 143.
  26. Malik RF, Jia Y, Mansour SG, et al. Post-transplant Diabetes Mellitus in Kidney Transplant Recipients: A Multicenter Study. Kidney360. 2021 Jun 2;2(8):1296-1307.
  27. Kuo H-T, Sampaio MS, Vincenti F, et al. Associations of pretransplant diabetes mellitus, New-Onset Diabetes Mellitus after Transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database. 2010;56(6): 1026-1028.
  28. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation. 2007;83(8):1027.
  29. Kuo HT, Lum E, Martin P, et al. Effect of diabetes and acute rejection on liver transplant outcomes, an analysis of the OPTN/UNOS database. Liver Transpl 2016; 22(16): 796-804
  30. Roccaro GA, Goldberg DS, Hwang WT, et al. Sustained post transplantation diabetes is associated with long-term major cardiovascular events following liver transplantation. Am J Transplant 2018; 18(1): 207-215
  31. Peláez-Jaramillo MJ, Cárdenas-Mojica AA, Gaete PV, Mendivil CO. Post-Liver Transplantation Diabetes Mellitus: A Review of Relevance and Approach to Treatment. Diabetes Ther. 2018 Apr;9(2):521-543. doi: 10.1007/s13300-018-0374-8
  32. Foroutan F, Alba AC, Guyatt G, et al. Predictors of 1-year mortality in heart transplant recipients: a systematic review and meta-analysis. Heart. 2018 Jan;104(2):151-160.
  33. Kim HJ, Jung SH, Kim JJ et al. New-onset diabetes mellitus after heart transplantation: incidence, risk factors, and impact on clinical outcome. Circ J 2017; 806-814
  34. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the international society of heart and lung transplantation: twenty-seventh official adult transplant report 2010. J Heart Lung Transplant 2010; 1105-1118
  35. Hackman KL, Snell GI, Bach LA. Poor glycemic control is associated with decreased survival in lung transplant recipients. Transplantation 2017; 2200-2205
  36. Hackman KL, Bailey MJ, Snell GI. Diabetes is a major risk factor for mortality after lung transplant. Am J Transplant 2014; 14: 438-445
  37. Wilkinson AH, Davidson J, Dotta F, et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant. 2005; 19:291–298.
  38. Nathan DM, Davidson MB, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance. Diabetes Care 2007; 30:753.
  39. Pham PT, Pham SV, Lee M, et al. Evaluation of the potential kidney transplant candidates. In: Pham PT, Pham PC. Quick Guide to Kidney Transplantation: From Initial Evaluation to Long-Term Post-Transplant Care. First Edition. Lippincott, Williams and Wilkins 2019; pp 40-58.
  40. Chakkera HA, Weil EJ, Pham PT, et al. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care 2013; 36: 1406-1412.
  41. Pham PT, Edling KL, Chakkera HA, et al. Screening strategies and predictive diagnostic tools for the development of newonset diabetes mellitus after transplantation: an overview. Diabetes Metab Syndr Obes. 2012; 5:379-87.
  42. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.
  43. Kim Y, Kim JR, Choi H, et al. Patients with persistent newonset diabetes after transplantation have greater weight gain after kidney transplantation. J Korean Med Sci. 2013 Oct;28(10):1431-4.
  44. Sharif A, Moore R, Baboolal K. Influence of lifestyle modification in renal transplant recipients with postprandial hyperglycemia. Transplantation 2008; 85: 353-358.
  45. Kuningas K, Driscoll J, Reena Mair R, et al. Comparing Glycemic Benefits of Active Versus Passive Lifestyle Intervention in Kidney Allograft Recipients: A Randomized Controlled Trial. Transplantation. 2020 Jul;104(7):1491-1499. doi: 10.1097/TP.0000000000002969.
  46. Hecking M, Werzowa J, Haidinger M, et al. Novel views on new-onset diabetes after transplantation: development, prevention and treatment. Nephrol Dial Transplant. 2013 Mar;28(3):550-66.
  47. Hecking M, Haidinger M, Doller D, et al. Early basal insulin therapy decreases new-onset diabetes after transplantation. J Am Soc Nephrol 2012; 23: 739-749.
  48. Schwaiger E, Krenn S, Kurnikowski A et al. Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial. J Am Soc Nephrol. 2021 Aug;32(8):2083-2098. doi: 10.1681/ASN.2021010127. 552.
  49. Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of post transplant diabetes in renal allograft recipients. Transplantation. 1987;44(3):376–381
  50. Heisel O, Heisel R, Balshaw R, et al. New onset diabetes in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004; 4(4): 583-595.
  51. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007 Jun;7(6):1506-14.
  52. Rathi M, Rajkumar V, Rao N, et al. Conversion from tacrolimus to cyclosporine in patients with new-onset diabetes after renal transplant: an open-label randomized prospective pilot study. Transplant Proc. 2015 May;47(4):1158-61.
  53. Wissing KM, Abramowicz D, Weekers L, et al. Prospective randomized study of conversion from tacrolimus to cyclosporine A to improve glucose metabolism in patients with posttransplant diabetes mellitus after renal transplantation. Am J Transplant. 2018;18(7):1726-1734.
  54. Pascual J, Royuela A, Galeano C, et al. Very early steroid withdrawal or avoidance for kidney transplant recipients: A systematic review. Nephroll Dial Transplant 2012; 27: 825- 832.
  55. Pascual J, Galeano C, Royuela A, et al. A systematic review on steroid withdrawal between 3 and 6 months after kidney transplantation. Transplantation 2010; 90: 343-349.
  56. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193.
  57. The 2022 American Diabetes Association. Standards of Medical Care in Diabetes-2022 Abridged for Primary Care Providers. http://doi.org/10.2337/cd22-as01
  58. Alnasrallah B, Goh TL, Chan LW, et al. Transplantation and diabetes (Transdiab): a pilot randomised controlled trial of metformin in impaired glucose tolerance after kidney transplantation. BMC Nephrol. 2019 Apr 29;20(1):147. doi: 10.1186/s12882-019-1321-2.
  59. Maedler K, Carr RD, Bosco D, et al. Sulfonylurea induced beta-cell apoptosis in cultured human islets. The J of Clin End and Metab 2005; 90: 501-506.
  60. Mu J, Petrov A, Eiermann GJ, Woods J, et al. Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 2009; 623(1-3): 148-154.
  61. Cho JM, Jang HW, Cheon H, et al. A novel dipeptidyl peptidase IV inhibitor DA-1229 ameliorates streptozocin induced diabetes by increasing β-cell replication and neogenesis. Diabetes Res Clin Pract 2011; 91(1): 72-79.
  62. Halden TAS, Asberg A, Vik K, et al. Short-term efficacy and safety of sitagliptin treatment in long-term stable renal recipients with new-onset diabetes after transplantation. Nephrol Dial Transplant 2014; 14: 115-123.
  63. Haidinger M, Werzowa J, Hecking M, et al. Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation. A randomized, double-blind, placebo controlled trial. Am J Transplant 2014; 14: 115-123
  64. Boerner BP, Miles CD, Shivaswamy V. Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation. Int J Endocrinol. 2014;2014:617638. doi: 10.1155/2014/617638. Epub 2014 Apr 10.
  65. Werzowa J, Hecking M, Haidinger M, et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial. Transplantation 2013; 95(3): 456-462.
  66. Abdelaziz TS, Ali AY1, Fatthy M. Efficacy and safety of Dipeptidyl Peptidase-4 Inhibitors in kidney transplant recipients with Post-transplant diabetes mellitus (PTDM)-a systematic review and Meta-Analysis. Curr Diabetes Rev. 2019 Mar 21. doi: 10.2174/1573399815666190321144310. [Epub ahead of print]
  67. Gueler I, Mueller S, Helmschrott M, et al. Effects of vildagliptin (Galvus®) therapy in patients with type 2 diabetes mellitus after heart transplantation. Drug Des Devel Ther. 2013 Apr 8;7:297-303.
  68. Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014 Oct 28;130(18):1579-1588. doi: 10.1161/CIRCULATIONAHA.114.010389. Epub 2014 Sep 4.
  69. Zannad F, Cannon CP. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015 May 23;385(9982):2067-76. doi: 10.1016/S0140-6736(14)62225-X. Epub 2015 Mar 10.
  70. McGuire DK, Van de Werf F, Armstrong PW, et al. Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2016 May 1;1(2):126-135. doi: 10.1001/jamacardio.2016.0103.
  71. Pinelli NR, Patel A, Salinitri FD. Coadministration of liraglutide with tacrolimus in kidney transplant recipients: a case series. Diabetes Care. 2013 Oct;36(10): e171-172.
  72. Sadhu AR, Schwartz SS, Herman ME. The rationale for use of incretins in the management of New Onset Diabetes after Transplantation (NODAT). Endocr Pract. 2015 Jul;21(7):814-822.
  73. Jin J, Jin L, Luo K, et al. Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury. Am J Transplant. 2017;17(10):2601-2616.
  74. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet. 2019 Jan 5;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X. Epub 2018 Nov 10.
  75. Zelniker TA, Braunwald E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Feb 4;75(4):422-434. doi: 10.1016/j.jacc.2019.11.031. Erratum in: J Am Coll Cardiol. 2020 Sep 22;76(12):1505. PMID: 32000955.
  76. Yang S, He W, Zhao L, Mi Y. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with kidney outcomes in patients with type 2 diabetes: A systematic review and network meta-analysis. PLoS One. 2022 Apr 14;17(4):e0267025. doi: 10.1371/journal.pone.0267025. PMID: 35421174; PMCID: PMC9009659.
  77. Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced. Circulation. 2021 Jan 26;143(4):310-321. doi: 10.1161/CIRCULATIONAHA.120.051685.
  78. Halden TAS, Kvitne KE, Karsten Midtvedt K, et al. Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care. 2019 Jun;42(6):1067-1074.
  79. Mahling M, Schork A, Nadalin S, et al. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibition in kidney transplant recipients with diabetes mellitus. Kidney Blood Press Res. 2019;44(5):984-992.
  80. Cehic MG, Christopher A, Muir CA, et al. Efficacy and Safety of Empagliflozin in the Management of Diabetes Mellitus in Heart Transplant Recipients. Transplant Direct.2019 May; 5(5): e450. doi: 10.1097/TXD.0000000000000885
  81. Cehic MG, Nundall N, Greenfield JR, et al. Management Strategies for Posttransplant Diabetes Mellitus after Heart Transplantation: A Review. J Transplant. 2018 Jan 29;2018:1025893. doi: 10.1155/2018/1025893. eCollection 2018

 

Pituitary Gigantism

ABSTRACT

 

Pituitary gigantism in a child is an extraordinarily rare condition that results from excessive production of growth hormone. It can present as early as infancy or not until adolescence. It may be congenital or acquired, occurring as a sporadic condition or in the context of a known syndrome in which hypersecretion of GH is a feature. Conditions in which GH excess occurs include Neurofibromatosis Type 1, McCune-Albright syndrome, Multiple Endocrine Neoplasia Type 1, Carney Complex, Isolated Familial Somatotropinomas, and X-Linked Acrogigantism. Therapeutic modalities for the treatment of pituitary gigantism are the same as those for acromegaly (adult-onset GH excess) and include surgery, medication, and radiation. Great strides have been made in identification of the molecular genetic basis for pituitary gigantism, affording novel insights into the mechanisms underlying normal and abnormal growth. Etiologies, phenotypic features, and diagnostic and treatment considerations are reviewed in this chapter.

 

ILLUSTRATIVE CASE

 

A 13 year 6-month-old boy presents for evaluation of rapid growth. Parents report that he was always tall as a child, but they have noticed that he is now taller than most classmates. He developed signs of puberty (body odor, pubic hair) a year ago coincident with the onset of rapid growth. His parents are concerned and want to make sure “everything is normal”. He is asymptomatic other than periodic headaches that developed during the last year.

 

He was born appropriate for gestational age (AGA) at term following an uncomplicated pregnancy. By 1 year of age he was noted to be tall for his age, but this was attributed to the tall stature of his parents. Father stands 6’2” and Mother is 5’8”. They are both healthy. He is an only child.

 

Upon review of his medical record he has a growth velocity of 19 cm/year (7.5 in/year) over the last calendar year; last year at the PCP the height was 160 cm, which is at 82.7% (0.9SDS)

 

He is currently at the 99.0 % for height at 179 cm/70.5 inches (+2.36 SDS) thus confirming the rapid gain in height. (See attached growth curves. Figure 1) On physical examination he is tall, but proportionate. Visual field testing shows normal vision in all fields. Thyroid examination is normal. There are no areas of skin hyperpigmentation and no obvious skeletal abnormalities other than acral enlargement. Pubic hair is Tanner stage 3 and testicular volumes are 10 and 12 cc.

Figure 1. Growth curves

Bone Age is 14 years yielding a predicted adult height of 193.1 cm (76 inches) which, at +2.35 SDS, is above his family genetic height potential. A random serum GH concentration in the morning is 15 ng/ml with a corresponding IGF1 level of 720 ng/ml. (normal range for age and pubertal status in a male: 123-701 ng/ml). Because of the excessive growth and elevated IGF1, a GH suppression test was conducted. GH concentration 120 min after 75g of glucose administered orally was 4 ng/ml. An MRI of the brain was ordered.

 

Approach

  

Statural growth is a dynamic process that varies in children during development. Unlike adults who reach a final height greater than 2 SDS for their genetic, sex, and ethnic population of origin, the definition of gigantism in children must include a growth pattern that diverges from normal. This would include the child who exceeds expected growth curve (moving up from established percentiles) or has a growth velocity exceeding the normal range for sex, pubertal stage, and age. Once the growth rate is determined to be significantly greater than normal, establishing biochemical evidence of growth hormone hypersecretion is critical to the evaluation. Measuring IGF1 levels and assessing the suppressibility of GH following a glucose load are the most useful biochemical tests. Prompt MRI imaging evaluating size, invasiveness, and extrasellar extension of a pituitary adenoma is key. Since close to 50% of patients with pituitary gigantism have a discernable genetic cause, genetic counseling and testing are helpful in management. The case is continued at the end of the chapter.

 

INTRODUCTION

 

The association between gigantism and acromegaly was recognized as early as the late 1880’s (1), when it was noted that pituitary giants invariably developed acromegalic features such as progressive enlargement of the head, face, hands, and feet (2). (See Appendix) The major difference between these two conditions is that pituitary gigantism results from excessive GH production during the period of active skeletal growth whereas acromegaly results from GH excess ensuing after epiphyseal fusion. A further distinction relates to the overall incidence of these disorders. While acromegaly is uncommon, occurring at an estimated worldwide annual rate of 2.8-4 cases per million (3), pituitary gigantism is extremely rare, with an estimated incidence of 8 per million person-years and the total number of reported cases thus far numbering only in the hundreds. Despite these disparities, a degree of clinical overlap is evident by the observation that 10% of patients with acromegaly have tall stature (4), indicating that the onset of GH excess pre-dated epiphyseal fusion in many.

 

GH hypersecretion may occur sporadically or within a constellation of abnormalities in the setting of several well- recognized syndromes. Conversely, a genetic predilection to the development of GH-secreting pituitary adenomas only may be present, as is the case in kindreds with isolated familial somatotropinomas. In recent years there has been increased recognition of the underlying molecular genetic abnormalities that lead to pituitary gigantism, one of which can be identified in approximately 50% of cases (5). Regardless of the underlying etiology, the clinical manifestations of chronic GH hypersecretion in childhood are indistinguishable, and the initial diagnostic evaluation standardized. The various categories and sources of GH excess along with their associated genetic abnormalities are discussed individually.

 

IDIOPATHIC SPORADIC FORMS OF PITUITARY GIGANTISM

 

Unlike in acromegalic adults, in whom discreet pituitary adenomas are present in the overwhelming majority (6), several different pathologic mechanisms underly childhood GH hypersecretion. These relate to the concept that pituitary gigantism represents a distinct entity, with different characteristics in terms of pituitary morphology and function. Supporting this view are reports of diffuse pituitary hyperplasia in the setting of early-onset gigantism in which congenital growth hormone releasing-hormone (GHRH) excess has been proposed as the inciting cause (7;8). Additionally, the nearly ubiquitous finding of combined GH and prolactin over-secretion in nearly all cases of early childhood gigantism, a feature not universally present in acromegaly, suggests separate pathologic processes. This dual hormonal secretion has been attributed to the presence of mammo-somatotrophs (9;10), which are rare in adults but predominate in fetal life. Even in cases of apparent pituitary microadenomas or macroadenomas arising during early childhood, this unique biochemical feature has been present (11;12). In contrast, prolactin levels are usually normal in cases of pituitary GH-secreting adenomas originating during adolescence, which may be thought of as existing within the spectrum of adult GH hypersecretion. Interestingly, a reversible transformation of pituitary somatotrophs into bi-hormonal mammo-somatotrophs when exposed to ectopic overproduction of GHRH has been observed, lending additional support to the concept that hypothalamic GHRH excess may play a pivotal role in the genesis of early-onset gigantism (13).

 

GH-secreting tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. As mentioned above, those composed of mammo-somatotrophs also produce prolactin whereas rare pluri-hormonal tumors composed of cells that resemble mammo-somatotrophs also produce TSH. Some pituitary neuroectodermal tumors (PitNETs) composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammo-somatotrophs, lactotroph, or thyrotrophs may also cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can also sometimes cause GH excess (14)

 

An additional cause of sporadic pituitary gigantism linked to CNS pathology is that which occurs in the setting of a hypothalamic gangliocytoma or neurocytoma. These rare tumors, comprised of large hypothalamic-like ganglion cells, produce GHRH (15;16) and are found in close proximity to pituitary growth hormone-secreting adenomas (17). Normalization of serum growth hormone levels following resection of the hypothalamic tumor in some patients further supports a central role for abnormal GHRH secretion in the development of gigantism or acromegaly in these cases (18).

 

SYNDROMIC AND FAMILIAL FORMS OF PITUITARY GIGANTISM

 

A second major category of childhood GH hypersecretion is that which occurs in the setting of a recognized syndrome. In these cases, gigantism may be the sole presenting feature or it may be detected during clinical follow-up for endocrine or nonendocrine problems. Alternatively, biochemical evidence of sub-clinical GH excess may be revealed through routine surveillance in a child known to be at risk for the development of gigantism. As is the case in sporadic GH hypersecretion, a variety of different morphologic abnormalities involving the pituitary gland may be found. Paracrine pituitary GHRH secretion has also been implicated by the discovery of GHRH expression from clusters of cells in the hyperplastic pituitaries of two boys from a family with hereditary early-onset gigantism (19). Syndromes that are associated with the development of childhood GH excess are reviewed below. Table 1 outlines the characteristics of the GH excess and other clinical features in these disorders.

 

Table 1. Clinical Characteristics in Syndromic and Familial Pituitary Gigantism

Disorder

Mode ofInheritance

Clinical Features

Frequency ofGigantism

Typical Age of Presentation

 

PituitaryMorphology

Screening

Neurofibromatosis -1

Autosomal Dominant or Sporadic

·       Optic gliomas

·       Café au lait skin pigmentation

Extremely rare

6 months on

Optic pathway tumor with normal to small pituitary

Not routine

McCune- AlbrightSyndrome

Sporadic

·       Precocious Puberty

·       Café au lait skin pigmentation

·       Fibrous bone dysplasia

·       Multiple endocrinopathies

15-20%

Early childhood on

Pituitary adenomas or diffuse pituitary hyperplasia or no visible abnormality

Annually

Multiple Endocrine Neoplasia Type 1

Autosomal Dominant or Sporadic

Pituitary, pancreatic and parathyroid adenomas

10-60%

10% by

age 40 but has occurred as early as age 5

Pituitary adenoma

Annually beginning at age 5

Multiple Endocrine Neoplasia Type 4

Autosomal Dominant or Sporadic

Pituitary, pancreatic and parathyroid adenomas

Unknown

Unknown

Pituitary adenoma

Not established

Carney Complex

Autosomal Dominant or Sporadic

Multiple endocrine tumors

Skin lentigines

Cardiac myxomas

Neural sheath tumors

10%

Usually 3rd & 4th decade

Pituitary adenoma or pituitary hyperplasia

Annually beginning post-pubertally

3PA Association

Autosomal Dominant or Sporadic

Pheochromocytoma, paraganglioma, pituitary adenoma

Unknown

Usually 3rd & 4th decade

Pituitary adenoma with intracytoplasmic vacuoles

As clinically indicated in unaffected family members

Isolated Familial Somatotropinomas

Autosomal Dominant or Sporadic

Isolated GH- secreting pituitary adenomas

100%

Before 3rd decade and as early as age 5

Pituitary adenoma

As clinically indicated in unaffected family members

X-linked Acrogigantism

Sporadic or X- linked

Isolated GH excess

100%

Early childhood with onset in late infancy or onset during adolescence

Pituitary adenoma or pituitary hyperplasia or both

As clinically indicated in unaffected family members

 

Neurofibromatosis-1 (NF-1)

 

  Beginning in the 1970’s, reports of gigantism occurring in young children with NF-1 have appeared in the medical literature (20). In these cases, excessive growth has been noted as early as 6 months of life (21).  Neuroimaging in these patients typically reveals an optic glioma (22), usually with infiltration into the medial temporal lobe. However, growth hormone excess has frequently been reported to be a transient phenomenon in children with NF-1, raising questions as to the necessity of treatment (23,24). Several investigations aimed at identifying the precise etiology of the gigantism in these children have been conducted, but in all cases in which tumor tissue has been available, immunostaining for GH, GHRH, and somatostatin has been uniformly negative (25;26). This, in conjunction with the known temporal lobe location of somatostatin-producing neurons, led to the hypothesis that GH excess in these patients was the result of a hypothalamic regulatory defect. Specifically, tumor infiltration of somatostatinergic pathways would presumably result in reduced somatostatin tone leading to overproduction of GHRH-mediated pituitary GH. Despite this plausible explanation, arginine-induced GH stimulation in a patient with gigantism in the setting of NF-1 showed an increase in GH secretion, contrary to the expected lack of response to arginine, which acts through somatostatin inhibition (27). Thus, the precise pathogenesis of gigantism in NF-1 remains unclear. Little information is available regarding the overall incidence of GH hypersecretion in patients with NF-1 and optic gliomas, although studies have suggested that it may occur in over 10% of affected patients, some of whom have concurrent central precocious puberty (28). Interestingly, all affected patients had a tumor involving the optic chiasm, without pituitary involvement. Optic pathway tumors are usually identified on magnetic resonance image scans as a contrast enhancing mass. (28). Interestingly, growth hormone excess has also been reported in children with sporadic optic pathway tumors without associated NF-1 (29). Figure 2 demonstrates the linear growth acceleration and figure 3 the café-au-lait pigmentation observed in a young boy with NF-1 and gigantism.

Figure 2. Growth acceleration seen in neurofibromatosis and gigantism.

Figure 3. Characteristic “coast of California” café au lait macules in a child with neurofibromatosis and gigantism.

McCune-Albright Syndrome (MAS)

 

MAS is a complex and heterogenous disorder in which GH excess typically arises in conjunction with additional endocrinopathies and other abnormalities. In the classic form, MAS displays the triad of precocious puberty, café-au-lait skin pigmentation, and fibrous dysplasia of bone. It has long been recognized, however, that individuals with MAS have a propensity to develop several additional endocrine disorders including gigantism or acromegaly (30).

 

  Elucidation of the molecular genetic defect in MAS in the early 1990’s (31) illuminated the mechanism underlying the abnormal hormone secretion. Activating mutations of Gsα, the stimulatory subunit of the heterotrimeric G-protein complex involved in intracellular signaling, are the basis for nearly all of the clinical manifestations of MAS (32). These mutations, which typically involve substitution of arginine at the 201 position with cysteine or histidine, result in unregulated signal transduction leading to increased intracellular cAMP accumulation and downstream gene transcription. All affected individuals are mosaic for the mutation, which may make confirmation with a molecular diagnosis challenging. The precise timing of the mutation during embryologic life, which occurs in a post-zygotic cell line, will ultimately determine the extent of abnormal cells and severity of the resultant clinical phenotype. The incidence of GH excess in classic MAS has been reported to be 15-21% (33.34) and may be more common in males (34). However, enhanced recognition of the frequency of atypical or forme fruste variants of MAS have the potential to increase the estimated frequency. Indeed, several historical reports of extreme gigantism where fibrous bone dysplasia was also present strongly suggest a diagnosis of MAS in these individuals, a hypothesis confirmed by molecular genetic analysis in at least one case (35.36). Subclinical growth hormone excess has also been reported in MAS, in which the only clinical manifestation may be the presence of normal stature as an adult (rather than short stature) in the context of a history of untreated precocious puberty. Additional phenotypic features in this subgroup of patients with MAS include a higher incidence of vision and hearing deficits, a rise in serum GH following a TRH test, and hyperprolactinemia (37). Growth hormone excess in MAS is typically accompanied by skull base fibrous dysplasia and is notorious for increasing craniofacial morbidity and macrocephaly (38). Early diagnosis and treatment have been found to decrease the risk of optic neuropathy in these patients (39).

 

A variety of pituitary morphologic abnormalities are found on histology and imaging in MAS patients with GH hypersecretion (40), ranging from discrete pituitary adenomas (41,42) to diffuse pituitary hyperplasia (7), to no discernible radiographic abnormality (43). Of note is the fact that the Gsα mutation found in MAS is identical to that implicated in the pathogenesis of sporadic GH-secreting pituitary adenomas, where it results in the formation of the GSP oncogene. Up to 40% of somatotroph adenomas in adults contain either an Arg201 activating mutation, or a related point substitution of glutamine at position 227 (44). Interestingly, these sporadic tumors, as well as those from patients with MAS and acromegaly, display the Gsα mutation exclusively from the maternal allele, providing evidence that the GNAS1 gene is subject to imprinting (45). Figure 4 demonstrates an area of classic café au lait skin pigmentation that crosses midline and has serrated edges in a patient with MAS.

Figure 4. Café au lait pigmentation in the typical “coast of Maine” configuration in an individual with McCune-Albright syndrome.

Multiple Endocrine Neoplasia-Type I (MEN1)

 

  MEN1 is a familial cancer syndrome characterized by autosomal dominant inheritance and multi-endocrine gland involvement. Although significant clinical heterogeneity exists in terms of specific tumor combinations, the most frequent manifestations of MEN1 are parathyroid, pancreatic, and pituitary adenomas (46). The gene for MEN1, which had previously been mapped to chromosomal locus 11q13, encodes the 610 amino acid nuclear protein, menin (47). Many different molecular genetic abnormalities within the menin gene have been identified in kindreds with MEN1, including nonsense, missense, deletion, insertion, and donor-splice mutations (48); genotype/phenotype correlations have not been observed. In all cases of MEN1, the development of neoplasia is thought to arise from a defect in normal tumor suppression via a 2-hit hypothesis. The first hit represents inheritance of a germline MEN1 mutation, leading to a heterozygous loss of the MEN1 gene in every cell (49). As menin is believed to function as a tumor suppressor protein, the second hit involves a somatic MEN1 mutation in one cell, with subsequent abnormal cellular transformation and clonal expansion. Indeed, somatic biallelic MEN1 mutations have been demonstrated to be present in at least 15% of sporadic pituitary adenomas, including somatotroph tumors (50). Anterior pituitary adenomas in individuals with known MEN1 have a reported prevalence of 10-60% and are thought to represent the first clinical manifestation of the disease in up to 25% of sporadic cases (51). Of these, the majority are prolactinomas, with GH-secreting adenomas developing in approximately 10% of individuals with MEN1 by age 40. The youngest reported case of gigantism in MEN1 occurred in a 5-year-old boy, who presented with growth acceleration and a GH-secreting mammo-somatotroph adenoma in the context of a family history of MEN1 (52). Molecular genetic analysis confirmed the germline and tumor tissue MEN1 mutations but failed to reveal an etiology for the accelerated presentation in this case. Nonetheless, current recommendations include screening for anterior pituitary hormone excess beginning at age 5 in all individuals with MEN1, as well as ascertaining MEN1 carrier status by germline mutation testing in several clinical situations (53). Interestingly, GH excess due to ectopic elaboration of GHRH from a pancreatic neuroendocrine tumor has also been reported in several individuals with MEN1 (54).

 

Multiple Endocrine Neoplasia-Type 4 (MEN4)

 

MEN4 is caused by germline mutations in the CDKN1B gene which encodes the putative tumor suppressor p27Kip1 (55). Affected patients are typically heterozygous for mutations in CDKN1B and exhibit a phenotype similar to that seen in MEN1. Because of the low number of individuals diagnosed with MEN4, screening protocols for patients and their family members have not yet been established (56).

 

Carney Complex (CNC)

 

Initially described in 1985 (57), CNC is a rare autosomal dominant disorder in which the cardinal features include multiple endocrine tumors, skin lentigines (spotty pigmentation), cardiac myxomas and neural sheath tumors. The condition shares characteristics with several other syndromes, including MEN1 (multiple endocrine tumors), MAS (endocrine hyperfunction and skin pigmentation) and Peutz-Jeghers syndrome (mucosal lentiginoses and gonadal tumors), but has a unique clinical and molecular genetic identity. Two distinct genetic abnormalities have been implicated in the pathogenesis of CNC. The first is found on 2p16 (58), although a specific candidate gene within this region has not been identified. The second involves mutations in the gene encoding the protein kinase A regulatory subunit (1α) (PRKAR1A) and explains 35-44% of both familial and sporadic cases of CNC (59). This protein, which is intricately involved in endocrine cell signaling pathways, is thought to function as a tumor suppressor. Supporting this theory has been the observation that tumors from patients with CNC (in which diminished levels of PRKAR1A are present) exhibit a 2-fold increase in cAMP responsiveness compared with control tumors (60).The identical mutation has also been found in some sporadic endocrine tumors. As with MEN1, a germline mutation is thought to be the inciting event for eventual development of the disease. The clinical presentation of CNC is extremely heterogeneous,as is the age at diagnosis. The development of GH excess is rare, occurring usually during the 3rd   and 4th decades of life, and typically found in only 10% of patients at the time of presentation (61). Thus, annual screening for GH hypersecretion is recommended only in post pubertal patients. As in cases of gigantism/acromegaly in the setting of MAS, diffuse pituitary hyperplasia (62) and concomitant hyperprolactinemia (63) are frequently seen in individuals with CNC and GH excess.

 

3PA Association

 

The constellation of paraganglioma, pheochromocytoma, and pituitary adenoma is termed 3PA Association and has been shown to be due to germline mutations in subunits of succinate dehydrogenase (56;64). Growth hormone excess typically occurs in the 3rd and 4th decades of life (65). To date, no pediatric patients with pituitary gigantism in the setting of the 3PA phenotype have been reported.

 

Familial Somatotropinomas

 

  It has long been recognized that isolated pituitary gigantism or acromegaly may occur in a familial pattern. This condition, “Familial Isolated Pituitary Adenomas” (FIPA), is defined as “the development of pituitary adenomas of any type in two or more members of a family in the absence of clinical and genetic evidence of other known syndromic diseases”.  At least 46 different affected kindreds have been reported (66). Unlike in MEN1 and CNC, GH excess tends to arise early in life, with 70% of those with the disorder diagnosed before the 3rd decade. Early childhood gigantism in this setting has also occurred, involving sisters with abnormal linear growth since age 5 (67) and a more virulent course than is seen in sporadic somatotropinomas has been suggested by a case series (68). Once assumed to represent a variant of MEN1, mutations within the menin gene as the etiology for FIPA were conclusively excluded (69;70). However, the precise molecular genetic basis for the development of pituitary GH-secreting adenomas in the majority of affected families has eluded detection. Initial investigation revealed loss of heterozygosity and linkage to a 9.7 Mb region of 11q13, suggesting the presence of an additional putative tumor suppressor gene in this region,distinct from that involved in MEN1. Subsequent studies identified inactivating mutations in the gene encoding aryl hydrocarbon receptor interacting protein (AIP) at 11q13.3 in 15%-25% of families with FIPA (71-73) making it the most common genetic defect found in these kindreds. Although the mechanism by which these mutations cause pituitary adenomas is unknown, the resulting phenotype is characterized by early-onset and aggressive disease. In an amazing case of medical sleuthing, a germline AIP mutation identified in DNA from the preserved teeth of an 18th century Irish giant was found to be an exact match for the mutation harbored by four contemporary Irish families with FIPA, indicating a common ancestor dating back more than 50 generations! Interestingly, a second potential locus for FIPA has been mapped to 2p12-16, very close to the region implicated in several kindreds with CNC (66). Additional molecular genetic analysis performed in these patients has included a search for germline mutations within the GHRH receptor gene, Gsα and Gi2α genes, all of which were normal. Similar to observations in MEN1, patients with FIPA have discreet pituitary adenomas, the majority of which are comprised solely of somatotrophs (75). However, prolactinomas, gonadotropinomas, and silent pituitary adenomas may occur in different members of the same kindred (76;77) . Macroadenomas with invasion into the cavernous sinus are common in the setting of FIPA, and treatment is notoriously difficult (77).

 

X-Linked Acrogigantism

 

An additional cause of familial gigantism and acromegaly is due to microduplication of Xq26.3 and termed X-linked acrogigantism (X-LAG). This genomic duplication was initially identified in 14 patients with gigantism and is associated with both sporadic and familial cases (78; 79). Of the four genes contained in the duplicated region, the growth hormone excess appears to result from an abnormality of GPR101, a gene that encodes for an orphan G-protein coupled receptor. This gene is markedly over-expressed in pituitary tissue from affected patients. The condition can result from either germline or somatic duplications in GPR101 and has a female predominance (80, 81). That more girls than boys have X-LAG might be related to their greater number of X chromosomes. However, a potentially lethal effect of an Xq26.3 microduplication on hemizygous male embryos is also a proposed explanation (82). Mosaicism for GPR101 duplication resulting in X-LAG has also been reported in sporadic cases involving boys (83). Patients harboring the Xq26.3 microduplication exhibit a distinct phenotype characterized by strikingly early gigantism with a median age of onset of 12 months. In addition to hypersecretion of GH, elevated circulating GHRH and prolactin have also been noted (84). Both pituitary adenomas and pituitary hyperplasia have been seen among cases testing positive for X-LAG. This discovery highlights new biological processes that will undoubtedly lead to novel insights regarding the central regulation of human growth.

 

A summary of the genetic abnormalities causing gigantism and their putative abnormalities is shown in figure 5.

Figure 5. Schematic of disorders leading to pituitary gigantism, genetic loci, and their putative targets. NF1: Neurofibromatosis type 1; XLAG: X-linked acrogigantism; MAS: McCune-Albright syndrome; CNC1: Carney complex type 1; FIPA: Familial isolated pituitary adenomatosis; MEN1: Multiple endocrine neoplasia syndrome type 1; MEN4: Multiple endocrine neoplasia syndrome type 4. The MEN syndromes display unrestrained cell replication due to lack of a tumor suppressor whereas the others affect the GH secretory pathway at the points shown. See text above for details.

CLINICAL AND BIOCHEMICAL FEATURES OF GIGANTISM

 

As would be predicted, linear growth acceleration is the cardinal feature of excessive GH production in a child or adolescent. However, the excessive linear growth observed in young children with gigantism may be accompanied or even preceded by macrocephaly and or increased weight for height. (9;11). In a large international study of patients with pituitary gigantism, the median onset of rapid growth was 13 years and occurred earlier in girls than in boys (85). Additional clinical features frequently encountered include frontal bossing, broad nasal bridge, prognathism, excessive sweating, voracious appetite, coarse facial features, and enlargement of the hands and feet. Bone age radiographs in these patients have been reported to be normal or advanced, even in the complete absence of sex steroid production. Figure 6 demonstrates the prognathism, coarse facial features and typical tall stature seen in a 12-year-old boy with gigantism, and Figure 7 illustrates enlargement of the hands in this same patient.

Figure 6. Twelve-year-old boy with pituitary gigantism measuring 6’5” with his mother. Note the coarse facial features and prominent jaw.

Figure 7. Enlarged hand of the same patient in comparison with the hand of an adult male with a height of 6’1”. The patient’s middle digit has a circumference of 9 centimeters.

The most consistent biochemical abnormality observed in patients with gigantism is an elevated IGF-1, which is known to exhibit an excellent correlation with 24-hour GH secretion (86). As previously mentioned, hyperprolactinemia is extremely common in early-onset GH hypersecretion. Depending on the individual situation, the additional pituitary screening evaluation may be normal, indicative of hypopituitarism, or central precocious puberty. Concurrent endocrinopathies may also be present, particularly in patients with syndromes such as MAS or MEN1. Rarely, alterations in glucose tolerance brought about by GH excess may result in the development of overt diabetes, leading to transient diabetic ketoacidosis (87-89) which may even be the presenting feature in rare instances (90). An additional physiologic effect of GH excess that may have clinical significance is that of increased erythropoiesis, as demonstrated by a case of acromegaly-induced polycythemia vera that resolved following surgical resection of the GH-secreting adenoma (91). The importance of GH in the regulation of red blood cell production has further been supported by the observation that pre- treatment hemoglobin concentrations in children with idiopathic growth hormone deficiency are lower than controls (92)

 

DIAGNOSTIC EVALUATION OF GH EXCESS

 

The gold standard for making the diagnosis of GH excess relies on the inability to suppress serum GH concentration following an oral glucose load. While the OGTT has been the diagnostic test of choice for many years, numeric guidelines for the expected degree of suppression in a normal individual have steadily decreased. This trend is the direct result of newer assays with an improved threshold of sensitivity for detection (93).  A normal response to a standardized glucose bolus (1.75 gm/kg up to 75 grams) utilizing the newer IRMA/ICMA assays is a GH level below 1 ng/ml (94). However, given the observation that recurrence of GH excess may be detected in patients with a GH nadir less than 1 ng/ml, and that healthy subjects nearly always suppress to below 0.14 ng/ml, some investigators have suggested that the 1 ng/ml cut-off is too liberal (95). The nadir in serum GH is typically occurs within the first 2 hours of the test. Occasionally, 24-hour integrated GH assessment may be helpful in cases in which an equivocal response to OGTT is seen (96). Despite the development of highly sensitive GH assays, generalizability of results across institutions or regions is hampered by significant heterogeneity in the availability of reference preparations and methods used by specific laboratories (97). Depending on the individual circumstance, measurement of peripheral GHRH may also be indicated to investigate the possibility of ectopic GHRH secretion. Once biochemical evidence of GH excess has been demonstrated, MRI scanning of the H-P region is obviously the next step. Figure 8 illustrates the typical appearance of a GH-secreting pituitary macroadenoma in an adolescent with gigantism.

Figure 8. Pituitary somatotroph macroadenoma in an adolescent with gigantism.

A potential pitfall in the evaluation of gigantism in adolescents is the fact that significant elevations of IGF-1 may be present during normal puberty (98). Moreover, growth hormone response to an oral glucose load in normal children has been found to be gender and pubertal-stage specific, with the highest nadir GH occurring in Tanner stage 2-3 girls (99). The effect of sex steroids on IGF-1 and GH suppression must also be considered when a diagnosis of gigantism is being considered in a child with concurrent precocious puberty, as may be the case in NF-1 or MAS. Adding to the possible diagnostic ambiguity is the fact that a significant percentage of normal tall adolescents fail to suppress serum GH in response to oral glucose testing (100). Therefore, both screening and definitive testing for GH excess should be performed in the context of high clinical suspicion, and IGF-1 levels interpreted according to age and pubertal stage-adjusted normal ranges (see figure 9).

Figure 9. Schematic evaluation of patients with suspected pituitary gigantism

TREATMENT

 

No large-scale studies evaluating various therapeutic approaches to the treatment of GH excess in pediatric patients are available. Therefore, the optimal treatment of gigantism has traditionally been extrapolated from the adult literature as well as case reports or small series involving children. As is the case in adults, the three separate modalities available for the treatment of children and adolescents are surgery, radiation, and medical therapy. Of these, the greatest recent advances by far have occurred in the realm of pharmacologic agents, resulting in an exciting armamentarium of drugs promising truly enhanced efficacy and excellent safety. Regardless of the individual treatment strategy, the goals of therapy remain the same, namely the restoration of GH and IGF-1 levels to normal (101). Of all parameters investigated, GH levels themselves appear to correlate best with overall morbidity and mortality in acromegaly (102). Table 2 summarizes the current therapeutic options as they pertain to pediatric patients, each of which is discussed below.

 

Table 2. Therapeutic Modalities in GH Excess in Pediatric Patients

 

Modality

Specific Options

Current Indications

Pediatric Experience

Surgery

Transphenoidal resection

Pituitary microadenoma or macroadenoma

Performed safely in children as young as 2 years old

 

Radiation

 

Conventional radiation

Adjuvant to surgical or medical therapy

Typically avoided if at all possible, but has been used as adjuvant therapy

Stereotactic radiosurgery,ex: gamma knife

Adjuvant therapy in patients with residual GH hypersecretion

No experience with use in children

Medical Therapy

Somatostatin analogues

·       Octreotide (Sandostatin)

·       Lanreotide

·       Primary therapy in cases of diffuse pituitary hyperplasia or severe bone disease

·       Adjuvant to surgery or radiation

·       Ectopic GH excess

Used safely in children with both sporadic and syndromic gigantism for extended periods of time alone and in combination with dopamine analogues

Depot somatostatin analogues

Sandostatin LAR

SR-lanreotide

·       Same as above

Safety and efficacy appear equivalent to non-depotpreparations

Dopamine agonists

·       Bromocriptine

Cabergoline

·       Adjuvant to somatostatin analogues and other therapies

·       Particularly useful when concurrenthyperprolactinemia is present

Used safely in children in combination with somatostatin analogues

GH receptor antagonists

Pegvisomant

·       Particularly useful for treatment of refractory disease

Has been used alone and in combination with somatostatin analogues Preliminary experience in children appears promising

 

Surgery

 

Transphenoidal resection is the treatment of choice for discreet pituitary microadenomas or macroadenomas (103), with the objective being preservation of pituitary function in association with the elimination of the GH excess, as evidenced by a rapid normalization of serum GH levels (often within one hour) and response to OGTT.  Not surprisingly, the expertise of the individual surgeon impacts the likelihood of success (104). However, while surgery cures the majority of patients with microadenomas, less than 50% of patients with macroadenomas are cured of their disease (105, 106). Moreover, extended post-operative follow-up has revealed a gradual return of GH excess over time in a substantial number of patients in whom the disease was previously deemed to be well controlled (107;108). In one large retrospective study of 208 patients with pituitary gigantism, long-term control of GH/IGF1 was achieved in only 39% (108). Experience with surgical treatment of gigantism in children and adolescents has been comparable to that observed in adults (109;110), and it has been employed safely in patients as young as 24 months (12). Although further investigation is needed, a potential role for pre-operative medical therapy has been suggested by studies indicating higher surgical remission rates and lower anesthesia risk following a several month course of a somatostatin analogue (111).

 

Radiation

 

Although traditionally included as a therapeutic option, significant problems exist with the use of conventional radiotherapy in gigantism or acromegaly. These include a low level of efficacy, delayed normalization of GH levels, and a high incidence of hypopituitarism. In the setting of MAS, radiation therapy for GH hypersecretion may contribute to malignant transformation of dysplastic bone tissue (112). Additional concerns particularly relevant to children include potential adverse neurocognitive effects and the possible development of hypothalamic obesity, both of which have been linked to cranial irradiation in pediatric patients (112;113). Therefore, radiation therapy would be considered a last resort. Improved precision and safety are observed with use of stereotactic radiosurgery in the form of the gamma knife technique, which has been successfully employed as adjuvant therapy in adults with acromegaly (112;114-116).

 

Medical Therapy

 

Although most commonly considered adjunctive to surgery or radiation, a primary role for medical therapy has always existed for those patients with diffuse pituitary hyperplasia or severe bony deformities precluding a surgical approach. As tremendous improvements in the pharmacologic agents available for use in GH excess continues to evolve (117), the number of patients offered medical therapy as first-line treatment will surely expand. The three currently existing classes of drugs for suppression of GH and IGF-1 levels are reviewed below.

 

SOMATOSTATIN ANALOGUES

 

Ever since their development in the mid-1980’s, long-acting analogues of somatostatin have held a pivotal place in the medical treatment of GH excess. These agents act by binding to somatostatin receptors within somatotroph adenomas (118). By far the greatest experience in the United States has been with octreotide, which is typically administered subcutaneously in three divided doses daily. Short-term administration of octreotide decreases GH levels within one hour in > 90% of patients with acromegaly (119), while sustained use normalizes GH and IGF-1 levels in up to 65% of patients (120). Experience with the use of octreotide in children has been similarly favorable, where it has been beneficial in the treatment of sporadic as well as syndromic gigantism (121;122). Continuous subcutaneous infusion of octreotide has also resulted in superior efficacy in controlling GH hypersecretion in a pubertal patient (123). Long-acting depot preparations of octreotide in the form of Sandostatin LAR and SR-lanreotide are also available, in which a slow release of drug is achieved through degradation of a polymer in which microspheres are encapsulated (124). This allows for monthly IM administration, resulting in a safety and efficacy profile that is comparable to or improved in contrast to traditional dosing (125). Both slow-release preparations have also been used in the treatment forms of GH excess due to ectopic GHRH secretion (126) and in MAS associated gigantism (127-129), and have been noted to have equivalent safety and efficacy (130). The development of novel somatostatin analogues has the potential to improve efficacy over existing agents (131). The major side effect of all the somatostatin analogues is an increased risk of biliary sludge and gallstones after sustained use, necessitating periodic ultrasound examinations in patients treated long-term (132).

 

DOPAMINE AGONISTS  

 

Although rarely effective alone, dopamine agonists have a valuable role as adjunctive agents in the treatment of GH excess. Due to their suppressive effects on prolactin, these drugs are particularly advantageous when hyperprolactinemia is also present, as is often the case in childhood-onset gigantism. Both bromocriptine and the more potent dopamine agonists such as cabergoline have been administered to children in combination with octreotide long-term with no apparent adverse effects (128).

 

GH RECEPTOR ANTAGONISTS    

 

The latest development in the realm of medical therapy has been the emergence of pegvisomant, a genetically engineered human GH analogue that acts as a highly selective GH antagonist (133). This is achieved through alterations in GH structure altering receptor binding compared to the native GH molecule (121), resulting in prevention of the normal extracellular dimerization of the growth hormone receptor. Administration of pegvisomant long-term to adults with acromegaly has been shown to result in normalization of serum IGF-1 levels in 97% of patients (134). Despite these extremely promising results, the implications of the nearly ubiquitous elevations in serum GH levels observed in conjunction with pegvisomant treatment initially created some concerns. Although early reports recounted an increase in tumor volume and abnormal liver enzymes in association with pegvisomant use (135;136), long-term follow has demonstrated that these complications are rare and that efficacy is very good (137;138). Combination therapy using pegvisomant along with a dopamine agonist or somatostatin analogue also appears promising (137). Thus far, preliminary experience with the use of pegvisomant alone or in combination with a somatostatin analogue for the treatment of gigantism in children also appears favorable (139). This approach resulted in successful normalization of IGFI levels in a 4 year old with NF-1 (140), a 12 year old with MAS (141), and a couple of children with persistent GH hypersecretion following surgical removal of a pituitary adenoma who had failed a somatostatin analogue (142;143). Even more reassuring is a report of long-term (up to 3.5 years) treatment using pegvisomant in 3 children with gigantism, all of whom experienced a decline in growth velocity and resolution of acromegalic features(144).

 

Treatment of Tall Stature

 

Medical treatment of children and adolescents with tall stature was more common in the past (145), particularly for girls, but is now strongly discouraged except in exceptional cases. This is because of increased cultural acceptance of tall stature and recognition of side effects of treatment, which include reduced fertility (146) and increased prevalence of depression (147) not related to adult height. Depending on the absolute height and the degree of growth potential remaining, one of the goals in the treatment of gigantism may be prevention of further linear growth in these exceptional cases. When this is the case, acceleration of epiphyseal fusion can be achieved with exogenous sex steroids (145). Short-term administration of both high dose testosterone and estrogen have been utilized for this purpose in children with gigantism, resulting in significant improvements in terms of adult height (148;149). However, such an approach would require great caution given reports of subfertility in women who were treated with high dose estrogen during adolescence with the goal of attenuating growth in the setting of constitutional tall stature (150;151).

 

CONCLUSION

 

The differential diagnosis of pituitary gigantism includes a significant number of heterogeneous disorders exhibiting a vast array of clinical and genetic features (66). In most cases, the history, physical examination and adjunctive biochemical, imaging, and/or molecular genetic testing will ultimately reveal the diagnosis. Albeit rare, pituitary gigantism affords the unique opportunity for a glimpse into the complex mechanisms of growth regulation. Thus, continued clinical and scientific investigation will enhance not only individual patient care, but also collective insight into the intricacies of the fundamental processes of human growth.

 

CASE OUTCOME

 

The MRI revealed a pituitary macroadenoma after which he underwent transsphenoidal surgery. Histopathological diagnosis was mammosomatotropic adenoma. Three months after surgery, IGF-1 normalized, nadir GH during OGTT suppressed to less than 1 ng/mL and no residual tumor was found on the MRI. Genetic testing identified a mutation in the AIP gene. This case points out the importance of early diagnosis of gigantism, as treatment delay increases long-term morbidity.

 

KEY LEARNING POINTS

 

  • Pituitary gigantism is rare but important condition resulting from excessive secretion of GH (and therefore IGF1) before fusion of epiphyseal growth plates leading to tall stature, acral enlargement, facial changes, headaches, and excessive sweating.
  • Excessive linear growth is the cardinal feature of excessive GH production in children and adolescents who have open epiphyseal growth plates.
  • There is a male preponderance (78%) in pituitary gigantism in contrast to the slight female predominance (54.5%) observed in acromegaly.
  • Once growth hormone (GH) hypersecretion has been established, prompt studies to examine pituitary anatomy and define the etiology via family history and genetic testing should be performed.
  • Normalization of GH and IGF-1 levels is the goal of therapy
  • Because nearly 50% of patients with pituitary gigantism have a known underlying genetic cause, these patients should receive genetic counseling and testing for mutations.
  • Somatotropinomas in pituitary gigantism are usually large (macroadenomas) and difficult to cure with surgery or medical therapy alone.
  • Patients with large tumors and multiple surgeries and radiotherapy are often left with multiple pituitary hormone deficiencies.

 

REFERENCES

1.       Dana C. L. Giants and Gigantism Scribner' Magazine 17,1719-185 (1895)  Giants and giantism - Digital Collections - National Library of Medicine (nih.gov)        
2.       Daughaday WH. Pituitary gigantism. Endocrinol Metab Clin North Am 1992; 21(3):633-647.

  1. Etxabe J, Gaztambide S, Latorre P, Vazquez JA. Acromegaly: an epidemiological study. J Endocrinol Invest 1993; 16(3):181-187.
  2. Sotos JF. Overgrowth. Hormonal Causes. Clin Pediatr (Phila) 1996; 35(11):579-590.
  3. Lodish MB, Trivellin G, Stratakis CA. Pituitary gigantism: update on molecular biology and management. Curr Opin Endocrinol Diabetes Obes 2016; 23(1):72-80.
  4. Melmed S. Acromegaly. N Engl J Med 1990; 322(14):966-977.
  5. Moran A, Asa SL, Kovacs K et al. Gigantism due to pituitary mammosomatotroph hyperplasia. N Engl J Med 1990; 323(5):322-327.
  6. Zimmerman D, Young WF, Jr., Ebersold MJ et al. Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation. J Clin Endocrinol Metab 1993; 76(1):216-222.
  7. Dubuis JM, Deal CL, Drews RT et al. Mammosomatotroph adenoma causing gigantism in an 8-year old boy: a possible pathogenetic mechanism. Clin Endocrinol (Oxf) 1995; 42(5):539-549.
  8. Felix IA, Horvath E, Kovacs K, Smyth HS, Killinger DW, Vale J. Mammosomatotroph adenoma of the pituitary associated with gigantism and hyperprolactinemia. A morphological study including immunoelectron microscopy. Acta Neuropathol (Berl) 1986; 71(1-2):76-82.
  9. Blumberg DL, Sklar CA, David R, Rothenberg S, Bell J. Acromegaly in an infant. Pediatrics 1989; 83(6):998-1002.
  10. Gelber SJ, Heffez DS, Donohoue PA. Pituitary gigantism caused by growth hormone excess from infancy. J Pediatr 1992; 120(6):931-934.
  11. Vidal S, Horvath E, Kovacs K, Lloyd RV, Smyth HS. Reversible transdifferentiation: interconversion of somatotrophs and lactotrophs in pituitary hyperplasia. Mod Pathol 2001; 14(1):20-28.
  12. Asa SL, Kucharczyk W, Ezzat S. Pituitary acromegaly: not one disease. Endocr Relat Cancer. 2017 Mar;24(3):C1-C4. doi: 10.1530/ERC-16-0496. Epub 2017 Jan 25. PMID: 28122798.
  13. Araki Y, Sakai N, Andoh T, Yoshimura S, Yamada H. Central neurocytoma presenting with gigantism: case report. Surg Neurol 1992; 38(2):141-145.
  14. Isidro ML, Iglesias DP, Matias-Guiu X, Cordido F. Acromegaly due to a growth hormone-releasing hormone-secreting intracranial gangliocytoma. J Endocrinol Invest 2005; 28(2):162-165.
  15. Asada H, Otani M, Furuhata S, Inoue H, Toya S, Ogawa Y. Mixed pituitary adenoma and gangliocytoma associated with acromegaly--case report. Neurol Med Chir (Tokyo) 1990; 30(8):628-632.
  16. Asa SL, Scheithauer BW, Bilbao JM et al. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor. J Clin Endocrinol Metab 1984; 58(5):796-803.
  17. Glasker S, Vortmeyer AO, Lafferty AR et al. Hereditary pituitary hyperplasia with infantile gigantism. J Clin Endocrinol Metab 2011; 96(12):E2078-E2087.
  18. Costin G, Fefferman RA, Kogut MD. Hypothalamic gigantism. J Pediatr 1973; 83(3):419-425.
  19. Drimmie FM, MacLennan AC, Nicoll JA, Simpson E, McNeill E, Donaldson MD. Gigantism due to growth hormone excess in a boy with optic glioma. Clin Endocrinol (Oxf) 2000; 53(4):535-538.
  20. Duchowny MS, Katz R, Bejar RL. Hypothalamic mass and gigantism in neurofibromatosis: treatment with bromocriptine. Ann Neurol 1984; 15(3):302-304.
  21. Josefson JL, Listernick R, Charrow J, Habiby RL. Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon. Horm Res Paediatr 2016; 86(1):35-38.
  22. Sani I, Albanese A. Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Glioma. Horm Res Paediatr 2017; 87(3):179-188.
  23. Fuqua JS, Berkovitz GD. Growth hormone excess in a child with neurofibromatosis type 1 and optic pathway tumor: a patient report. Clin Pediatr (Phila) 1998; 37(12):749-752.
  24. Manski TJ, Haworth CS, Duval-Arnould BJ, Rushing EJ. Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. Case report. J Neurosurg 1994; 81(4):595-600.
  25. Waguespack SG, Eugster EA, Pescovitz OH. Growth hormone (GH) excess in a child with neurofibromatosis type 1 (NF1) an optic pathway glioma. Pediatric Research 49[6 Suppl 2 of 2], 82A. 2001.Ref Type: Abstract
  26. Cambiaso P, Galassi S, Palmiero M et al. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am J Med Genet A 2017; 173(9):2353-2358.
  27. Josefson JL, Listernick R, Charrow J, Habiby RL. Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon. Horm Res Paediatr 2016; 86(1):35-38.
  28. Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab 2014; 99(6):1955-1969.
  29. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325(24):1688-1695.
  30. Lumbroso S, Paris F, Sultan C. McCune-Albright syndrome: molecular genetics. J Pediatr Endocrinol Metab 2002; 15 Suppl 3:875-882.
  31. Christoforidis A, Maniadaki I, Stanhope R. McCune-Albright syndrome: growth hormone and prolactin hypersecretion. J Pediatr Endocrinol Metab 2006; 19 Suppl 2:623-625.
  32. Yao Y, Liu Y, Wang L et al. Clinical characteristics and management of growth hormone excess in patients with McCune-Albright syndrome. Eur J Endocrinol 2017; 176(3):295-303.
  33. Tinschert S, Gerl H, Gewies A, Jung HP, Nurnberg P. McCune-Albright syndrome: clinical and molecular evidence of mosaicism in an unusual giant patient. Am J Med Genet 1999; 83(2):100-108.
  34. Vogl TJ, Nerlich A, Dresel SH, Bergman C. CT of the "Tegernsee Giant": juvenile gigantism and polyostotic fibrous dysplasia. J Comput Assist Tomogr 1994; 18(2):319-322.
  35. Akintoye SO, Chebli C, Booher S et al. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab 2002; 87(11):5104-5112.
  36. Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis 2012; 7 Suppl 1:S4.
  37. Boyce AM, Glover M, Kelly MH et al. Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess. J Clin Endocrinol Metab 2013; 98(1):E126-E134.
  38. Vortmeyer AO, Glasker S, Mehta GU et al. Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome. J Clin Endocrinol Metab 2012; 97(7):2404-2413.
  39. Dotsch J, Kiess W, Hanze J et al. Gs alpha mutation at codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCune-Albright syndrome. J Clin Endocrinol Metab 1996; 81(11):3839-3842.
  40. Zumkeller W, Jassoy A, Lebek S, Nagel M. Clinical, endocrinological and radiography features in a child with McCune-Albright syndrome and pituitary adenoma. J Pediatr Endocrinol Metab 2001; 14(5):553-559.
  41. Cuttler L, Jackson JA, Saeed uz-Zafar M, Levitsky LL, Mellinger RC, Frohman LA. Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. J Clin Endocrinol Metab 1989; 68(6):1148-1154.
  42. Shimon I, Melmed S. Genetic basis of endocrine disease: pituitary tumor pathogenesis. J Clin Endocrinol Metab 1997; 82(6):1675-1681.
  43. Mantovani G, Bondioni S, Lania AG et al. Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 2004; 89(6):3007-3009.
  44. Skogseid B, Rastad J, Oberg K. Multiple endocrine neoplasia type 1. Clinical features and screening. Endocrinol Metab Clin North Am 1994; 23(1):1-18.
  45. Guru SC, Goldsmith PK, Burns AL et al. Menin, the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci U S A 1998; 95(4):1630-1634.
  46. Bassett JH, Forbes SA, Pannett AA et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998; 62(2):232-244.
  47. Mutch MG, Dilley WG, Sanjurjo F et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat 1999; 13(3):175-185.
  48. Boggild MD, Jenkinson S, Pistorello M et al. Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 1994; 78(2):387-392.
  49. Carty SE, Helm AK, Amico JA et al. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 1998; 124(6):1106-1113.
  50. Stratakis CA, Schussheim DH, Freedman SM et al. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2000; 85(12):4776-4780.
  51. Brandi ML, Gagel RF, Angeli A et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86(12):5658-5671.
  52. Sala E, Ferrante E, Verrua E et al. Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype. Eur J Gastroenterol Hepatol 2013; 25(7):858-862.
  53. Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Front Horm Res 2013; 41:63-78.
  54. Lodish MB, Trivellin G, Stratakis CA. Pituitary gigantism: update on molecular biology and management. Curr Opin Endocrinol Diabetes Obes 2016; 23(1):72-80.
  55. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64(4):270-283.
  56. Stratakis CA, Carney JA, Lin JP et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996; 97(3):699-705.
  57. Kirschner LS, Carney JA, Pack SD et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26(1):89-92.
  58. Sandrini F, Stratakis C. Clinical and molecular genetics of Carney complex. Mol Genet Metab 2003; 78(2):83-92.
  59. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001; 86(9):4041-4046.
  60. Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA. Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the "complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex). J Clin Endocrinol Metab 2000; 85(10):3860-3865.
  61. Raff SB, Carney JA, Krugman D, Doppman JL, Stratakis CA. Prolactin secretion abnormalities in patients with the "syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex). J Pediatr Endocrinol Metab 2000; 13(4):373-379.
  62. O'Toole SM, Denes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22(4):T105-T122.

65      Denes J, Swords F, Rattenberry E et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab 2015; 100(3):E531-E541.

  1. Vasilev V, Daly AF, Trivellin G, et al. HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA). Endocr Relat Cancer. 2020 Aug;27(8):T77-T86.
  2. Matsuno A, Teramoto A, Yamada S et al. Gigantism in sibling unrelated to multiple endocrine neoplasia: case report. Neurosurgery 1994; 35(5):952-955.
  3. Nozieres C, Berlier P, Dupuis C et al. Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis 2011; 6:67.
  4. Gadelha MR, Prezant TR, Une KN et al. Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J Clin Endocrinol Metab 1999; 84(1):249-256.
  5. Jorge BH, Agarwal SK, Lando VS et al. Study of the multiple endocrine neoplasia type 1, growth hormone-releasing hormone receptor, Gs alpha, and Gi2 alpha genes in isolated familial acromegaly. J Clin Endocrinol Metab 2001; 86(2):542-544.
  6. Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 2013; 34(2):239-277.
  7. Daly AF, Vanbellinghen JF, Khoo SK et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 2007; 92(5):1891-1896.
  8. Martucci F, Trivellin G, Korbonits M. Familial isolated pituitary adenomas: an emerging clinical entity. J Endocrinol Invest 2012; 35(11):1003-1014.
  9. Chahal HS, Stals K, Unterlander M et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med 2011; 364(1):43-50.
  10. Gadelha MR, Une KN, Rohde K, Vaisman M, Kineman RD, Frohman LA. Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab 2000; 85(2):707-714.
  11. Raverot G, Arnous W, Calender A et al. Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features. J Endocrinol Invest 2007; 30(9):787-790.
  12. Cansu GB, Taskiran B, Trivellin G, Faucz FR, Stratakis CA. A novel truncating AIP mutation, p.W279*, in a familial isolated pituitary adenoma (FIPA) kindred. Hormones (Athens) 2016; 15(3):441-444.
  13. Trivellin G, Daly AF, Faucz FR et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371(25):2363-2374.
  14. Iacovazzo D, Korbonits M. Gigantism: X-linked acrogigantism and GPR101 mutations. Growth Horm IGF Res 2016; 30-31:64-69.
  15. Iacovazzo D, Caswell R, Bunce B et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun 2016; 4(1):56.
  16. Rodd C, Millette M, Iacovazzo D et al. Somatic GPR101 Duplication Causing X-Linked Acrogigantism (XLAG)-Diagnosis and Management. J Clin Endocrinol Metab 2016; 101(5):1927-1930.
  17. Beckers A, Lodish MB, Trivellin G, et al. X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer. 2015 Jun;22(3):353-67. doi: 10.1530/ERC-15-0038. Epub 2015 Feb 24.
  18. Daly AF, Yuan B, Fina F et al. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocr Relat Cancer 2016; 23(4):221-233.
  19. Daly AF, Lysy PA, Desfilles C et al. GHRH excess and blockade in X-LAG syndrome. Endocr Relat Cancer 2016; 23(3):161-170.
  20. Rostomyan L, Daly AF, Petrossians P et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 2015; 22(5):745-757.
  21. Barkan AL, Beitins IZ, Kelch RP. Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion. J Clin Endocrinol Metab 1988; 67(1):69-73.
  22. Ali O, Banerjee S, Kelly DF, Lee PD. Management of type 2 diabetes mellitus associated with pituitary gigantism. Pituitary 2007; 10(4):359-364.
  23. Alvi NS, Kirk JM. Pituitary gigantism causing diabetic ketoacidosis. J Pediatr Endocrinol Metab 1999; 12(6):907-909.
  24. Kuzuya T, Matsuda A, Sakamoto Y, Yamamoto K, Saito T, Yoshida S. A case of pituitary gigantism who had two episodes of diabetic ketoacidosis followed by complete recovery of diabetes. Endocrinol Jpn 1983; 30(3):329-334.
  25. Kuo SF, Chuang WY, Ng S et al. Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent. J Pediatr Endocrinol Metab 2013; 26(9-10):945-948.
  26. Grellier P, Chanson P, Casadevall N, Abboud S, Schaison G. Remission of polycythemia vera after surgical cure of acromegaly. Ann Intern Med 1996; 124(5):495-496.
  27. Eugster EA, Fisch M, Walvoord EC, DiMeglio LA, Pescovitz OH. Low hemoglobin levels in children with in idiopathic growth hormone deficiency. Endocrine 2002; 18(2):135-136.
  28. Chapman IM, Hartman ML, Straume M, Johnson ML, Veldhuis JD, Thorner MO. Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women. J Clin Endocrinol Metab 1994; 78(6):1312-1319.
  29. Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 1998; 83(8):2646-2652.
  30. Freda PU, Nuruzzaman AT, Reyes CM, Sundeen RE, Post KD. Significance of "abnormal" nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels. J Clin Endocrinol Metab 2004; 89(2):495-500.
  31. Patel YC, Ezzat S, Chik CL et al. Guidelines for the diagnosis and treatment of acromegaly: a Canadian perspective. Clin Invest Med 2000; 23(3):172-187.
  32. Bidlingmaier M, Strasburger CJ. Growth hormone assays: current methodologies and their limitations. Pituitary 2007; 10(2):115-119.
  33. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med 1997; 336(9):633-640.
  34. Misra M, Cord J, Prabhakaran R, Miller KK, Klibanski A. Growth hormone suppression after an oral glucose load in children. J Clin Endocrinol Metab 2007; 92(12):4623-4629.
  35. Holl RW, Bucher P, Sorgo W, Heinze E, Homoki J, Debatin KM. Suppression of growth hormone by oral glucose in the evaluation of tall stature. Horm Res 1999; 51(1):20-24.
  36. Giustina A, Barkan A, Casanueva FF et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000; 85(2):526-529.
  37. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 1994; 41(1):95-102.
  38. Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure'. Eur J Endocrinol 2005; 152(3):379-387.
  39. Gittoes NJ, Sheppard MC, Johnson AP, Stewart PM. Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon. QJM 1999; 92(12):741-745.
  40. Jane JA, Jr., Starke RM, Elzoghby MA et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab 2011; 96(9):2732-2740.
  41. Swearingen B, Barker FG, Katznelson L et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 1998; 83(10):3419-3426.
  42. Laws ER, Jr., Thapar K. Pituitary surgery. Endocrinol Metab Clin North Am 1999; 28(1):119-131.
  43. Rostomyan L, Daly AF, Petrossians P et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 2015; 22(5):745-757.
  44. Abe T, Tara LA, Ludecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery 1999; 45(1):1-10.
  45. Williams F, Hunter S, Bradley L et al. Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. J Clin Endocrinol Metab 2014; 99(4):1122-1131.
  46. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocr Pract 2011; 17 Suppl 4:1-44.
  47. Liu F, Li W, Yao Y et al. A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy. J Pediatr Endocrinol Metab 2011; 24(5-6):283-287.
  48. Sklar C, Boulad F, Small T, Kernan N. Endocrine complications of pediatric stem cell transplantation. Front Biosci 2001; 6:G17-G22.
  49. Attanasio R, Epaminonda P, Motti E et al. Gamma-knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 2003; 88(7):3105-3112.
  50. Castinetti F, Taieb D, Kuhn JM et al. Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 2005; 90(8):4483-4488.
  51. Swords FM, Allan CA, Plowman PN et al. Stereotactic radiosurgery XVI: a treatment for previously irradiated pituitary adenomas. J Clin Endocrinol Metab 2003; 88(11):5334-5340.
  52. Grasso LF, Pivonello R, Colao A. Investigational therapies for acromegaly. Expert Opin Investig Drugs 2013; 22(8):955-963.
  53. Patel YC, Greenwood M, Panetta R et al. Molecular biology of somatostatin receptor subtypes. Metabolism 1996; 45(8 Suppl 1):31-38.
  54. Ezzat S, Snyder PJ, Young WF et al. Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med 1992; 117(9):711-718.
  55. Newman CB, Melmed S, George A et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 1998; 83(9):3034-3040.
  56. Feuillan PP, Jones J, Ross JL. Growth hormone hypersecretion in a girl with McCune-Albright syndrome: comparison with controls and response to a dose of long-acting somatostatin analog. J Clin Endocrinol Metab 1995; 80(4):1357-1360.
  57. Schoof E, Dorr HG, Kiess W et al. Five-year follow-up of a 13-year-old boy with a pituitary adenoma causing gigantism--effect of octreotide therapy. Horm Res 2004; 61(4):184-189.
  58. Nanto-Salonen K, Koskinen P, Sonninen P, Toppari J. Suppression of GH secretion in pituitary gigantism by continuous subcutaneous octreotide infusion in a pubertal boy. Acta Paediatr 1999; 88(1):29-33.
  59. Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 2002; 87(7):3013-3018.
  60. Flogstad AK, Halse J, Bakke S et al. Sandostatin LAR in acromegalic patients: long-term treatment. J Clin Endocrinol Metab 1997; 82(1):23-28.
  61. Drange MR, Melmed S. Long-acting lanreotide induces clinical and biochemical remission of acromegaly caused by disseminated growth hormone-releasing hormone-secreting carcinoid. J Clin Endocrinol Metab 1998; 83(9):3104-3109.
  62. Ciresi A, Amato MC, Galluzzo A, Giordano C. Complete biochemical control and pituitary adenoma disappearance in a child with gigantism: efficacy of octreotide therapy. J Endocrinol Invest 2011; 34(2):162-163.
  63. Tajima T, Tsubaki J, Ishizu K, Jo W, Ishi N, Fujieda K. Case study of a 15-year-old boy with McCune-Albright syndrome combined with pituitary gigantism: effect of octreotide-long acting release (LAR) and cabergoline therapy. Endocr J 2008; 55(3):595-599.
  64. Zacharin M. Paediatric management of endocrine complications in McCune-Albright syndrome. J Pediatr Endocrinol Metab 2005; 18(1):33-41.
  65. Murray RD, Melmed S. A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. J Clin Endocrinol Metab 2008; 93(8):2957-2968.
  66. Hofland LJ, van der HJ, van Koetsveld PM et al. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab 2004; 89(4):1577-1585.
  67. Schmidt K, Leuschner M, Harris AG et al. Gallstones in acromegalic patients undergoing different treatment regimens. Clin Investig 1992; 70(7):556-559.
  68. Trainer PJ, Drake WM, Katznelson L et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 2000; 342(16):1171-1177.
  69. van der Lely AJ, Hutson RK, Trainer PJ et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001; 358(9295):1754-1759.
  70. Bernabeu I, Marazuela M, Lucas T et al. Pegvisomant-induced liver injury is related to the UGT1A1*28 polymorphism of Gilbert's syndrome. J Clin Endocrinol Metab 2010; 95(5):2147-2154.
  71. Buhk JH, Jung S, Psychogios MN et al. Tumor volume of growth hormone-secreting pituitary adenomas during treatment with pegvisomant: a prospective multicenter study. J Clin Endocrinol Metab 2010; 95(2):552-558.
  72. Higham CE, Atkinson AB, Aylwin S et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab 2012; 97(4):1187-1193.
  73. van der Lely AJ, Biller BM, Brue T et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab 2012; 97(5):1589-1597.
  74. Mangupli R, Rostomyan L, Castermans E et al. Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening. Pituitary 2016; 19(5):507-514.
  75. Main KM, Sehested A, Feldt-Rasmussen U. Pegvisomant treatment in a 4-year-old girl with neurofibromatosis type 1. Horm Res 2006; 65(1):1-5.
  76. Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol 2005; 153(2):195-201.
  77. Bergamaschi S, Ronchi CL, Giavoli C et al. Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy. Horm Res Paediatr 2010; 73(1):74-79.
  78. Daniel A, d'Emden M, Duncan E. Pituitary gigantism treated successfully with the growth hormone receptor antagonist, pegvisomant. Intern Med J 2013; 43(3):345-347.
  79. Goldenberg N, Racine MS, Thomas P, Degnan B, Chandler W, Barkan A. Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J Clin Endocrinol Metab 2008; 93(8):2953-2956.
  80. Drop SL, De Waal WJ, De Muinck Keizer-Schrama SM. Sex steroid treatment of constitutionally tall stature. Endocr Rev 1998; 19(5):540-558.
  81. Venn A, Bruinsma F, Werther G, et al.  Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility. Lancet. 2004 Oct 23-29;364(9444):1513-8.
  82. Bruinsma FJ, Venn AJ, Patton GC, et al. Concern about tall stature during adolescence and depression in later life. J Affect Disord. 2006 Apr;91(2-3):145-52. 
  83. Lu PW, Silink M, Johnston I, Cowell CT, Jimenez M. Pituitary gigantism. Arch Dis Child 1992; 67(8):1039-1041.
  84. Minagawa M, Yasuda T, Someya T, Kohno Y, Saeki N, Hashimoto Y. Effects of octreotide infusion, surgery and estrogen on suppression of height increase and 20K growth hormone ratio in a girl with gigantism due to a growth hormone-secreting macroadenoma. Horm Res 2000; 53(3):157-160.
  85. Albuquerque EV, Scalco RC, Jorge AA. MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature. Eur J Endocrinol 2017; 176(6):R339-R353.
  86. Hendriks AE, Drop SL, Laven JS, Boot AM. Fertility of tall girls treated with high-dose estrogen, a dose-response relationship. J Clin Endocrinol Metab 2012; 97(9):3107-3114.

APPENDIX  

Research into the function of the pituitary, and GH in particular, started with clinical observations and ana­tomical descriptions of people with gigantism and adults with acromegalic features (1). In 1884, the Swiss general physician Fritsche reported in great detail the history of a 44‑year-old man developing the characteristic features of acromegaly — a term later coined by Pierre Marie in 1886 (2) — and an enlarged pituitary, which was observed post-mortem (3). Minkowski proposed the connection between the pituitary and acromegaly before eosinophilic tumors of the anterior pituitary emerged as the anatomical basis of gigantism and acromegaly (4).

REFERENCES

  1. de Herder, W. W. Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary 12, 236–244 (2009).
  2. Marie, P. Sur deux cas d’acromégalie. Revue Med. Paris 6, 297–333 (1886).
  3. Fritsche, C. F. & Klebs, E. Ein Beitrag zur Pathologie des Riesenwuchses. Klinische und Pathologisch Anatomische Untersuchungen (Vogel, FCW, 1884).
  4. Minkowski, O. Übereinen fall von akromegalie. Berlin Klin. Wochenschr. 24, 371–374 (1887).

 

Hypocalcemia

CLINICAL RECOGNITION

 

Hypocalcemia can occur acutely over minutes to hours or chronically over weeks to months. Correspondingly, the signs and symptoms of hypocalcemia can develop acutely or chronically and can be life-threatening. The clinical manifestations of hypocalcemia are due to the increased neuromuscular tingling in the extremities and around the mouth. Chvostek’s and Trousseau’s signs can be elicited. When severe, tetany, convulsions, laryngospasm and bronchospasm can occur. Hypocalcemic symptoms are a result of both the absolute level of serum calcium and the rate of change in serum calcium concentration. Major signs and symptoms of hypocalcemia are summarized in Table 1.

 

Table 1. Signs/Symptoms of Hypocalcemia

I. Neuromuscular

.    Paresthesias - perioral and extremities

.    Muscle spasms

.    Laryngeal stridor, bronchospasm

.    Seizures

.    Cardiac arrhythmias

.   Coma

.   Chvostek’s sign

.   Trousseau’s sign (main d’accoucheur)

.   Tetany - Clinical or latent

.   Pseudotumor cerebri

.   Papilledema

II. Cardiovascular

.   Arrhythmias

.   Hypotension

.   Congestive heart failure

III. Other

.   Cataracts - subcapular, punctate

.   Extra-skeletal calcifications - Basal ganglia, Ligamentous and soft tissue

.   Dental enamel hypoplasia

.   Alopecia

.   Xeroderma

 

DIAGNOSIS AND DIFFERENTIAL

 

The major causes of hypocalcemia are summarized in Table 2.

 

Table 2. Major Causes of Hypocalcemia

Renal failure

Hypoparathyroidism (see Table 3)

Magnesium deficiency

Pancreatitis

Osteoblastic metastases

Hyperphosphatemia

Pseudohypocalcemia (e.g., hypoalbuminemia, gadolinium-contrast agents)

Massive transfusion of citrated blood products

Osteomalacia

Malabsorption

Vitamin D deficiency

Vitamin D receptor defect(s)

Calcium-sensing receptor (CaSR) constitutive activating mutations

Drugs (e.g., imatinib, bisphosphonates, denosumab, calcitonin)

 

Renal Failure

 

Hypocalcemia in chronic renal failure is due to two primary causes - increased serum phosphorus and decreased renal production of 1,25 (OH)2 vitamin D. The former causes hypocalcemia by complexing with serum calcium and depositing it into bone and other tissues.  The latter causes hypocalcemia by decreasing the GI absorption of calcium. 

Hypoparathyroidism

 

There are several causes of hypoparathyroidism, as summarized in Table 3. Neck surgery that removes or destroys the parathyroid glands is the most common cause of hypoparathyroidism.  These operations include: (1) thyroidectomy due to thyroid cancer or benign goiter, with inadvertent removal or destruction of parathyroid tissue; (2) parathyroidectomy, especially for multigland hyperplasia; and (3) laryngectomy. Post-surgical hypoparathyroidism can occur within hours after surgery or gradually over time when glands injured at surgery ultimately become non-functioning. 

 

Idiopathic hypoparathyroidism can occur in isolation or in association with other endocrine or autoimmune disorders (Table 4), typically with adrenal insufficiency. The parathyroid glands can be absent, remnant, or compromised by an immune destruction.  Anti-cytokine antibodies (e.g., against alpha interferons) or antibodies directed against parathyroid cell antigens (e.g., NALP5) may be present.   

 

Pseudohypoparathyroidism (PHP) is a genetic disorder characterized by target-organ unresponsiveness to PTH.  PHP mimics the hormone-deficient forms of hypoparathyroidism, with hypocalcemia and hyperphosphatemia, but PTH levels are elevated rather than low or absent.

 

Hypoparathyroidism can occur in an autoimmune setting (Table 4) associated with autoantibodies. The most commonly associated disorders are Addison disease and mucocutaneous candidiasis. Two of the 3 disorders in the triad are necessary for the diagnosis of APS1. These patients can be affected by other endocrinopathies or immune-mediated disorders (e.g., thyroid disease, diabetes mellitus, pernicious anemia, and ovarian failure).

 

TABLE 3.  Causes of Hypoparathyroidism

Postoperative - acute and chronic

Parathyroidectomy

      Thyroidectomy

      Cancer surgery – laryngeal, thyroid

Idiopathic

Isolated

            Associated with autoimmune polyendocrine 

            syndrome

Functional

            Magnesium deficiency (or excess)

            Newborn of mother with hyperparathyroidism

Pseudohypoparathyroidism (Types 1a, 1b, 2)

Genetic disease

            DiGeorge Syndrome - aplasia/dysgenesis of the parathyroids and thymus along with other features

            Activating mutation of the calcium-sensing receptor (CaSR) or of the G protein subunit G alpha 11

            PTH gene mutation

            GATA3 deficiency

            GCMB deficiency

            Mitochondrial DNA mutations

Infiltration of the glands

Iron deposits (Hemochromatosis, transfusions)

Copper deposits (Wilson’s Disease)

Radiation to neck

Metastases to the parathyroid glands from non-parathyroid tumors

Magnesium deficiency

Drugs (e.g., calcimimetics cinacalcet and etelcalcitide)

 

TABLE 4. Autoimmune Polyendocrine Syndrome Type 1 (APS1) Associated with Hypoparathyroidism

Mucocutaneous candidiasis

Addison disease

Hypothyroidism

Grave’s disease

Hypogonadism

Vitiligo

Alopecia

Malabsorption (steatorrhea)

Chronic active hepatitis

Pernicious anemia

Diabetes mellitus

Keratoconjunctivitis

 

Other Causes of Hypocalcemia

 

Magnesium deficiency causes hypocalcemia by interfering with the end-organ actions of PTH and/or by inhibiting its secretion. Pancreatitis causes hypocalcemia through sequestration of calcium by saponification with fatty acids. Osteoblastic metastases similarly take up blood calcium. Excessive transfusion of citrated blood products may transiently lower ionized calcium and cause symptoms until citrate is cleared by the liver. In hyperphosphatemia, high levels of blood phosphorus complexes with calcium, and the product can precipitate into organs and soft tissues. Causes include renal failure, administration of phosphate, rhabdomyolysis, tumor lysis, and some cases of tumoral calcinosis. Vitamin D deficiency (or resistance syndromes) contributes to the hypocalcemia of osteomalacia and malabsorption. Iatrogenic causes include cancer chemotherapy, notably certain tyrosine kinase inhibitors. Other drugs reported to cause hypocalcemia include inhibitors of bone resorption, loop diuretics, and agents that accelerate vitamin D metabolism, like anticonvulsants.  All inhibitors of bone resorption used to treat hypercalcemia (e.g., calcitonin, intravenous bisphosphonates, the receptor activator of nuclear factor kappa B ligand or RANK-L inhibitor denosumab) and the calcimimetics cinacalcet or etelcalcitide used to treat hyperparathyroidism can cause hypocalcemia.   

 

DIAGNOSTIC TESTING

 

The first step in assessing hypocalcemia is to confirm the results and rule out artifactually low calcium due to hypoalbuminemia. In hypoalbuminemic patients, ionized calcium can be measured, or total serum calcium can be corrected using the following formula: corrected Ca=measured Ca + (0.8) X (4- measured albumin). In critically ill patients with acid-base disturbances, measurement of ionized calcium is preferable due to altered calcium-albumin binding that can occur. Measuring serum phosphorus, PTH, creatinine, and 25 hydroxyvitamin D can usually identify the cause of the hypocalcemia. Interpreting PTH levels must be done in the context of serum calcium concentration. PTH can be low in hypoparathyroidism and hypomagnesemia and high when there is secondary (compensatory) hyperparathyroidism or pseudohypoparathyroidism. The PTH assay used should be an intact assay with reliable performance at the low end of the normal range. Patients with hypoparathyroidism may have a frankly low intact PTH or a low normal PTH that is inappropriate in the presence of hypocalcemia. Additional testing is done according to the clinical presentation and can include magnesium (hypomagnesemia), pancreatic enzymes (lipase), biochemical markers of bone turnover (osteoblastic metastases), ACTH/cortisol, and TSH (polyendocrine failure), and 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D (deficiency states).  Imaging can be useful for bone disease (osteomalacia, osteoblastic metastases).

 

TREATMENT

 

Acute Hypocalcemia

 

Hypocalcemia can be an endocrine emergency requiring rapid intervention. Patients with either severe hypocalcemia, usually <7.5 mg/dl, or with neurological manifestations or stridor (laryngo/bronchospasm) should receive intravenous calcium. Calcium gluconate (90 mg calcium per 10 mL) should be given as intravenous slow pushes, generally one vial over 10 minutes, repeated once with electrocardiographic monitoring. A chronic intravenous drip is then started if the patient is still symptomatic and oral treatment cannot act rapidly enough. The infusion rate should be guided by signs, symptoms, and calcium measurements checked every 1-2 hours, preferably ionized calcium levels. Magnesium deficiency should also be treated when present, since it can attenuate the effect of the treatment by calcium and vitamin D (see below). Oral calcium (e.g., 1-2 grams of elemental calcium) and a rapidly acting preparation of vitamin D (e.g., 0.5-1.0 micrograms of calcitriol in divided doses) should be started as soon as practical.  This is often limited by neck surgery. If necessary, intravenous calcium can be given for as long as necessary until oral therapy has taken effect. Patients taking cardiac drugs, especially digoxin, are predisposed to cardiotoxicity by the infusion of calcium, so an EKG should be used for cardiac monitoring. Treatment must be assessed with frequent serum ionized calcium levels. Several preparations of calcium for oral use are available. The most commonly used are calcium carbonate and calcium citrate (Table 5). Recombinant human PTH(1-84) has been recently approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder. However, in the United States this drug was removed from formularies because of rubber particulates discovered in the solution. Hopefully, this problem will be resolved soon. In the meantime, some clinicians are using other PTH preparations.

 

TABLE 5.  CALCIUM PREPARATIONS

Grams to provide 1 gm of elemental calcium

Carbonate                         2.5
Chloride                            3.7

Acetate                              4.0

Citrate                               5.0

Glycerolphosphate           5.7

Levulinate                         7.7
Lactate                              7.7

Orthophosphate                9.0

Gluconate                         11.1
Glubionate                        15.2

 

Hypomagnesemia should always be considered as a potential contributory cause of hypocalcemia, especially in post-operative and hospitalized patients. Low serum magnesium may reveal this, but the serum magnesium may be normal or low normal, since serum magnesium does not accurately reflect the stores of this primarily intracellular ion. Therefore, a therapeutic trial of magnesium, usually parenteral, may be needed to assess for magnesium deficiency.Oral magnesium is used for mild, chronic magnesium deficiency (e.g., daily dose of 200-300 mg). Many preparations are available including magnesium oxide, magnesium carbonate or magnesium sulfate. Parenteral magnesium (10% or 50% solutions of magnesium sulfate) is used for severe hypomagnesemia.  A common regimen is 2-4 mls IV of a 50% solution given over 10-15 minutes followed by similar amounts given daily. Several days of treatment are usually required to replete magnesium stores.

 

Chronic Hypocalcemia

 

The objective of chronic therapy for hypocalcemia is to keep the patient free of symptoms and to maintain serum calcium at approximately 8.0-9.0 mg/dL. With lower serum calcium levels, the patient may continue to experience symptoms over time. With serum calcium concentrations in the upper normal range, there may be significant hypercalciuria, especially when the hypocalciuric effect of PTH has been lost. This can predispose to nephrolithiasis, nephrocalcinosis, and renal damage.  When the calcium x phosphorus product rises to near 55 mg2/dL2 or greater, as it can in patients with hypoparathyroidism who also have a chronically elevated serum phosphorus level (due to the loss of PTH actions in the kidney), ectopic calcifications in other soft tissues like the brain (especially the basal ganglia), blood vessels, and eyes can occur.     

 

Calcium and vitamin D are used to treat most causes of chronic hypocalcemia, such as renal failure and hypoparathyroidism. Vitamin D is used to establish a baseline calcium level and calcium is added (or subtracted) for acute changes in calcium. Calcitriol is the preferred preparation of vitamin D because it is rapidly active and has a short half-life (i.e., rapidly reversible) in contrast to the other forms of vitamin D (Table 6). In patients with renal failure, treatment is directed at maintaining normal levels of calcium, phosphorus, and the calcium x phosphorus product and the intact PTH within an acceptable range for the chronic kidney disease. 1,25 dihydroxy-vitamin D or calcitriol or one of its analogs can be given orally or parenterally. Vitamin D2 or D3 may be used for nutritional deficiency. Recombinant human PTH(1-84) has been approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder. However, in the United States this drug was removed from formularies because of rubber particulates discovered in the solution. Hopefully, this problem will be resolved soon. In the meantime, some clinicians are using other PTH preparations.

 

Table 6. Vitamin D Preparations for Hypocalcemia Treatment

Name 

Daily dose

Time until normocalcemia

Duration of action

Vitamin D2 (Ergocalciferol)

400 units

4-8 weeks

2-6 months

Vitamin D3(Cholecalciferol)

Same as D2

Same as D2

Same as D2

1,25(OH2)D3 (Calcitriol)

0.25-0.5μg

2-5 days

1-2 days

 

FOLLOW-UP

 

The hypocalcemic patient should be periodically followed clinically (for signs and symptoms of recurrence) and biochemically (with serum calcium measurements, and less frequently with urinary calcium measurements). Other tests, such as magnesium and PTH, can be conducted as clinically indicated. Optimal therapy is best maintained by manipulating few variables, so patients on both vitamin D and calcium should hold vitamin D doses constant and change the oral intake of calcium when signs, symptoms, or measurements of calcium so dictate. Most patients can be treated with a reasonable degree of success, but some patients have frequent swings in symptoms, even though serum calcium levels are not abnormal.

 

GUIDELINE REFERENCES

 

Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, Van Biesen W, Dekkers OM.  European Society of Endocrinology Clinical Guideline:  treatment of chronic hypoparathyroidism in adults.  Eur J Endocrinol 173:  G1-G20, 2015. PMID: 26160136

 

Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke B, Thakker R, Khan A, Potts Jr JT.  Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 101: 2273-83, 2016. PMID: 26943719

 

Orloff LA, Wiseman SM, Bernet VJ, Fahey TJ 3rd, Shaha AR, Shindo ML, Snyder SK, Stack BC Jr, Sunwoo JB, Wang MB. American Thyroid Association Statement on Postoperative Hypoparathyroidism: Diagnosis, Prevention, and Management in Adults. Thyroid. 2018 Jul;28(7):830-841.

 

REFERENCES

 

Schafer AL, Shoback DM. Hypocalcemia: Diagnosis and Treatment. 2016 Jan 3. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905251

 

Hendy GN, Cole DEC, Bastepe M. Hypoparathyroidism and Pseudohypoparathyroidism. 2017 Feb 19. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905388

 

Hypercalcemia

CLINICAL RECOGNITION

 

Hypercalcemia can be defined as a serum calcium greater than 2 standard deviations above the normal mean in a reference laboratory. Calcium in the blood is normally transported:

partly bound to plasma proteins (about 45%), notably to albumin; partly bound to small anions such as phosphate and citrate (about 10%); partly in the free or ionized state (about 45%).

 

Only the ionized calcium is metabolically active i.e., subject to transport into cells, but most laboratories report total serum calcium concentrations. Hypercalcemia is therefore often defined as a total serum calcium (bound plus ionized) greater than 10.6 mg/dl (2.65 mM) or an ionized serum calcium greater than 5.3 mg/dl (1.3 mM) but values may vary between laboratories.

 

Dehydration, or hemoconcentration during venipuncture, may elevate total serum albumin whereas ionized calcium may remain normal. Consequently, a falsely elevated total serum calcium may be reported. Conversely when serum albumin levels are low, total serum calcium may be falsely low. To correct for an abnormally high or low serum albumin the following formula can be used:

 

Corrected calcium (mg/dL) = measured total serum calcium (mg/dL) + [4.0-serum albumin (g/dL) X 0.8] or Corrected calcium (mM) = measured total serum Ca (mM) + [40 - serum albumin (g/L) X 0.02]

 

Changes in blood pH can also alter the equilibrium constant of the albumin-calcium complex: Acidosis reduces binding and alkalosis enhances binding. Consequently, when major shifts in serum protein or pH are present it is prudent to directly measure the ionized calcium level in order to determine the presence of hypercalcemia.

 

Clinical Manifestations may be due to hypercalcemia or may be due to the causal disorder or may be due to both. Hypercalcemic manifestations will vary depending on whether the hypercalcemia is of acute onset and severe (greater than 12 mg/dL or 3 mM) or whether it is chronic and relatively mild. Patients may also tolerate higher serum calcium levels more readily if the onset is relatively gradual, but at concentrations above 14 mg/dL (3.5 mM) most patients are symptomatic. In both acute and chronic cases, the major manifestations affect gastrointestinal, renal and neuromuscular function (Table 1).

 

Table 1. Manifestations of Hypercalcemia

 

Acute

Chronic

Gastrointestinal

Anorexia, nausea, vomiting

Dyspepsia, constipation, pancreatitis

Renal

Polyuria, polydipsia

Nephrolithiasis, nephrocalcinosis

Neuro-muscular

Depression, confusion,
stupor, coma

Weakness

Cardiac

Short Q-T interval
bradycardia, first degree
atrioventricular block,
digitalis sensitivity

Hypertension

 

PATHOPHYSIOLOGY

 

Fluxes of calcium across the skeleton, the gut, and the kidney play a major role in maintaining calcium homeostasis. When the extracellular fluid (ECF) calcium is raised above the normal range, the calcium ion per se, by stimulating the G-protein coupled calcium sensing receptor (CaSR), can inhibit parathyroid hormone (PTH) release. Decreased PTH and CaSR stimulation will both facilitate reduced renal calcium reabsorption, and decreased PTH will result in reduced bone resorption and diminished release of calcium from bone. Decreased PTH and hypercalcemia will also reduce renal production of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], and decrease gut absorption of calcium. The net effect of the diminished renal calcium reabsorption, intestinal calcium absorption, and skeletal calcium resorption will be to reduce the elevated ECF calcium to normal. Consequently, decreased levels of PTH and decreased levels of 1,25(OH)2D should accompany hypercalcemia unless the PTH or 1,25(OH)2D is the cause of the hypercalcemia. The converse sequence of events occurs when the ECF calcium is reduced below the normal range.

 

A genetic relative of PTH, PTH-related peptide (PTHrP), can also resorb bone, when released from certain tumors. Both PTH and PTHrP act on osteoblastic cells to increase production of cytokines, notably receptor activator of nuclear factor kappa B ligand (RANKL) which increases production and activation of multinucleated osteoclasts which then resorb mineralized bone.

 

DIAGNOSIS AND DIFFERENTIAL (FIGURE 1)

Figure 1. Algorithm for Diagnosing the Cause of Hypercalcemia

 

Hypercalcemic disorders can be broadly grouped into Endocrine Disorders, Malignant Disorders, Inflammatory Disorders, Medication-Induced Hypercalcemia, and Immobilization as shown in Tables 2-8. Primary hyperparathyroidism (HPTH) and malignancy-associated hypercalcemia (MAH) account for the vast majority of hypercalcemic disorders. (For a more complete discussion of hypercalcemic disorders and the underlying pathophysiology, see reference 1)

 

Table 2. Endocrine Disorders Associated with Hypercalcemia

1. Endocrine Disorders with Excess PTH Production

Primary Sporadic Hyperparathyroidism (HPTH)

Adenoma (85-95%)

Hyperplasia (10-15%)

Carcinoma (<1%)

(80% of primary hyperparathyroidism is “asymptomatic”)

Primary Familial HPTH (Syndromic HPTH)

Multiple Endocrine Neoplasia, Type I (MEN1)- Autosomal dominant, MEN1 mutation (encodes menin)

Multiple Endocrine Neoplasia, Type II (also called MENIIA)- Autosomal dominant, RET mutation (encodes c-Ret)

Multiple Endocrine Neoplasia, Type IV (MENIV)- Autosomal dominant, CDKN1B mutation (encodes P27(Kip1))

Hyperparathyroidism – Jaw Tumor Syndrome-

   Autosomal dominant, CDC73/HRPT2 mutation (encodes parafibromin)

Non-Syndromic HPTH

Familial Hypocalciuric Hypercalcemia (FHH)
Heterozygotes and Neonatal Severe Primary Hyperparathyroidism (NSHPT) (homozygotes)
   FHH1:  CaSR mutation (encodes calcium sensing receptor)

   FHH2: GNA11 mutation (encodes G protein subunit α11)

   FHH3: AP2S1 mutation (encodes adaptor protein-2 sigma subunit)

Familial Isolated HPTH(Non-Syndromic)

  Mutations inf MEN1, CDC73/HRPT2 or CASR may account for a minority of kindreds with the FIHP phenotype upon initial ascertainment. Activating variants in GCM2 (encodes the transcription factor GCM2) have also been described.  

Tertiary HPTH

Chronic Kidney Disease

Phosphate Treatment of Hypophosphatemic Rickets/Osteomalacia

2. Endocrine Disorders without Excess PTH Production

Hyperthyroidism

Pheochromocytoma

VIPoma

Hypoadrenalism

Jansen’s Metaphyseal Chondrodysplasia- Due to activating mutation of PTHR1, the gene encoding the type1 PTH/PTHrP receptor

 

Table 3. Malignancy-Associated Hypercalcemia (MAH)

Accounts for about 90% of hypercalcemia in hospitalized patients.
Hypercalcemia is often acute and severe and usually a late manifestation of malignancy

1. MAH with Elevated PTHrP

Solid tumors (e.g. breast, lung, kidney, GI)

Hematologic malignancies (e.g. Non-Hodgkin’s lymphoma, adult T cell leukemia/lymphoma, chronic myelogenous, leukemia, chronic lymphocytic leukemia)

2. MAH with Elevation of Other Systemic Factors

1,25(OH)2D (e.g. Hodgkin’s Disease), cytokines (Multiple Myeloma and malignancies metastatic to bone), and rarely ectopic PTH production (e.g. ovarian, lung, thyroid and thymus)

 

Table 4. Granulomatous Disorders Causing Hypercalcemia

Due to extra-renal mononuclear cell 1,25(OH)2D production

1 Non-infectious (e.g. Sarcoidosis, Wegener’s granulomatosis, berylliosis)

2 Infectious (e.g. TB, histoplasmosis)

 

Table 5. Pediatric Syndromes

1. Williams Syndrome

2. Idiopathic Infantile Hypercalcemia
Due to loss-of-function of CYP24A1, encoding CYP24A1, the enzyme metabolizing 1,25(OH)2D, or due to loss-of-function of SLC34A1, encoding the renal proximal tubular sodium-phosphate cotransporter, Na/Pi-IIa.

 

Table 6. Viral Syndromes

Human Immunodeficiency Virus (HIV) infections

Cytomegalovirus (CMV) infections

 

Table 7. Medication-Induced

1. Thiazides

2. Lithium

3. Vitamin D

4. Vitamin A

5. Tamoxifen (during treatment of skeletal breast cancer metastases)

6. Aminophylline/theophylline

7. Aluminum Intoxication

8. Milk-Alkali Syndrome

 

Table 8. Immobilization

Immobilized patients continue to resorb bone whereas bone formation is inhibited. Consequently, immobilization may precipitate hypercalcemia and hypercalciuria in individuals with high bone turnover such as growing children, patients with Paget’s Disease or patients with primary HPTH or MAH.

 

DIAGNOSTIC TESTS NEEDED AND SUGGESTED

 

Laboratory testing should be guided by the results of a careful history and a detailed physical examination and should be geared toward assessing the extent of the alteration in calcium homeostasis and toward establishing the underlying diagnosis and determining its severity. Most patients with primary HPTH, the most common cause of hypercalcemia in the clinic, present with mild hypercalcemia discovered on a routine biochemical assessment. There may be a history of a recent or remote renal stone. Bone pain and fractures are rare although the patient may carry a diagnosis of osteoporosis based on a previous bone mineral density (BMD) measurement. A history of a documented peptic ulcer is rare in primary sporadic HPTH and should raise concern about MEN1. Although cardiovascular and neuropsychiatric manifestations have been described they appear to require more validation. Documentation of at least two elevated corrected (or ionized) serum calcium levels with concomitant elevated (or at least normal) serum PTH levels is required to establish the diagnosis (Figure 1). Lithium treatment has been associated with hypercalcemia, elevated or normal serum PTH, and increased renal calcium reabsorption. The presence of a family history of hypercalcemia or of kidney stones should raise suspicion of MEN1 or MEN2a (reference 3 and 4). If, in addition to primary HPTH in the proband, one or more first-degree relatives are found to have at least one of the three tumors characterizing MEN1 (parathyroid, pituitary, pancreas) or MEN2a (parathyroid, medullary thyroid carcinoma, pheochromocytoma) then it is highly likely that the disease is familial. The presence of ossifying fibromas of the mandible and maxilla, and renal lesions such as cysts and hamartomas in addition to HPTH would suggest HPTH-jaw tumor syndrome. In all patients with documented primary HPTH, a 24-hour urine calcium and creatinine level should be obtained to exclude familial hypocalciuric hypercalcemia (FHH). If the urine calcium to creatinine ratio is less than 0.01 and if testing serum and urine calcium in three relatives discloses hypercalcemia and relative hypocalciuria in other family members, then this diagnosis is likely and parathyroid surgery is to be avoided. If the urine calcium to creatinine ratio is greater than 0.01 then estimated glomerular filtration rate (eGFR) and a BMD test should be performed and guidelines for treatment of primary HPTH should be considered (see below).

 

Tertiary hyperparathyroidism with hypercalcemia and elevated PTH has been described in chronic kidney disease patients on hemodialysis, or in patients with hypophosphatemic syndromes (e.g., x-linked hypophosphatemic rickets) receiving long-term oral phosphate therapy without concomitant calcitriol.

 

If hypercalcemia is associated with very low or suppressed serum PTH levels, then malignancy would be an important consideration, either in association with elevated serum PTHrP or in its absence, in which case it is generally as a result of the production of other cytokines, often with osteolytic metastases. When malignancy-associated hypercalcemia is suspected then an appropriate malignancy screen should be done including skeletal imaging to identify skeletal metastases. As well appropriate general biochemical assessment such as a complete blood count and serum creatinine and specific biochemical assessment such as serum and urine protein electrophoresis to exclude multiple myeloma would be appropriate.

 

Detection of elevated serum 1,25(OH)2D levels in the absence of elevated serum PTH levels, suggests the need for a search for lymphoma or for non-infectious (e.g., sarcoidosis) or infectious granulomatous disease.

 

Hypercalcemia may also occur with thyrotoxicosis, pheochromocytoma, VIPoma, and hypoadrenalism. Increased PTHrP may be associated with neuroendocrine tumors. Serum PTH levels are suppressed in these disorders and 1,25(OH)2D levels are not elevated. Although these conditions may be suspected from clinical examination, detailed biochemical evaluation of these non-PTH associated endocrine disorders is required for confirmation.

 

Detection of elevated serum 25-hydroxyvitamin D [25(OH)D], should lead to a search for vitamin D intoxication. Vitamin A intoxication may also lead to hypercalcemia, but in the absence of elevated serum 25(OH)D, 1,25(OH)2D, or PTH. Hypercalcemia has been reported in association with human immunodeficiency virus (HIV), HTLV-III or cytomegalovirus (CMV) infections of the skeleton, presumably due to direct skeletal resorption. Use of foscarnet as an antiviral agent has also been associated with hypercalcemia. Transient hypercalcemia may accompany thiazide diuretic ingestion, possibly associated with dehydration, but prolonged hypercalcemia with thiazides requires a search for other causes. Hypercalcemia may be seen in patients with advanced breast cancer with skeletal metastases, at the initiation of treatment with tamoxifen. Aminophylline and theophylline used as bronchodilators have (rarely) been reported to be associated with hypercalcemia. The use of aluminum-containing phosphate binders in patients on chronic hemodialysis was associated with hypercalcemia in the past but, with the advent of other modes of therapy, this is rarely seen today. Similarly, the use of absorbable alkali (NaHCO3) along with large quantities of milk for ulcer treatment was a cause of hypercalcemia in the past but this therapy has been superseded today.

 

In the pediatric age group, hypercalcemia may include Jansens’s Metaphyseal Chondrodysplasia due to an activating mutation of the type 1 PTH/PTHrP receptor; neonatal severe hyperparathyroidism (NSHPTH) which may present with life-threatening hypercalcemia in neonates that are homozygous for inactivating mutations in CaSR; William’s Syndrome, an autosomal dominant disorder with hemizygous submicroscopic deletions of chromosome 7q11.23, characterized phenotypically by multiple congenital abnormalities, and in which hypercalcemia may occur possibly due to aberrant vitamin D metabolism; and idiopathic infantile hypercalcemia (IIH) in which hypercalcemia may be associated with increased 1,25(OH)2D.due to loss-of-function mutations in CYP24A1, the gene encoding the enzyme responsible for the first step in inactivation of 1,25(OH)2D. IIH may also be caused by loss-of-function mutations in SLC34A1, encoding the renal proximal tubular sodium-phosphate cotransporter, Na/Pi-IIa, leading to phosphaturia, phosphate depletion, suppression of the hormone fibroblast growth factor-23 (FGF-23), decreased CYP24A1,and increased 1,25(OH)2D production.

 

THERAPY

 

If the patient's serum calcium concentration is less than 12 mg/dL (3 mM) without symptoms of hypercalcemia then treatment of the hypercalcemia can be aimed solely at treatment of the underlying disorder. If the patient has symptoms and signs of acute hypercalcemia as described above and serum calcium is greater than 12 mg/dL (3 mM), then a series of urgent measures should be instituted (Table 9). These measures are almost always required with a serum calcium above 14 mg/dL (3.5 mM).

 

Table 9. Management of Acute Hypercalcemia

1. Hydration to Restore Euvolemia

0.9% saline (e.g. an initial rate of 200-300 mL/h subsequently adjusted to maintain a urine output at 100-150 mL/h). Use caution in patients with compromised cardiovascular or renal function.

2. Inhibition of Bone Resorption

Zoledronate 4 mg intravenously in 5 ml over 15 min or Pamidronate, 90 mg, intravenously in 500 ml of 0.9% saline or 5% dextrose in water over 4 hours.
Peak decrease in serum calcium after 4 days but may last for 8 weeks.
Flu-like syndrome or myalgias may occur

If bisphosphonates are contraindicated due to severe renal impairment, denosumab can be given instead (e.g. 0.3 mg/kg sc), with a second dose administered if the calcium is not lowered within approximately one week. Low serum 25(OH)D, if present, should be corrected before administering denosumab

Calcitonin, 4 to 8 IU/Kg im or sc, every 6-12 hours may be used with a bisphosphonate or denosumab because of its more rapid onset of action.
Peak decrease in serum calcium within 2-6 hours
Tachyphylaxis may occur after 24-48 hours
May use with a parenteral bisphosphonate for severe hypercalcemia because onset of calcium reduction is earlier

3. Calciuresis (when decreased renal excretion is suspected e.g. with excess PTH or PTHrP)

Loop diuretic e.g. furosemide, 10 to 20 mg IV
Administer only after rehydration

4. Glucocorticoids (when indicated)

e.g. hydrocortisone 200 to 300 mg intravenously over 24 hours for 3 to 5 days
For patients with responsive hematologic malignancies such as lymphoma or myeloma
For patients with vitamin D intoxication or granulomatous disease with increased 1,25(OH)2D

5. Dialysis

Patients refractory to other therapies
Patients with renal insufficiency
Either peritoneal dialysis or hemodialysis can be effective

6. Calcimimetics

The calcimimetic, cinacalcet, may be used in doses starting from 30 mg twice daily orally to as high as 90 mg 4 times daily for the treatment of hypercalcemia due to severe primary HPTH (especially if caused by a parathyroid carcinoma)

7. Mobilization

Mobilize as rapidly as possible after the acute episode

 

FOLLOW-UP

 

In the patient with primary sporadic HPTH who presents with kidney stones, fractures, or a low BMD (T-score less than -2.5) surgery would be indicated. In the patient with documented asymptomatic primary HPTH, follow-up should be done annually with measurement of serum calcium and serum creatinine (to determine estimated GFR). BMD should be repeated every one to two years. Guidelines below should be considered for recommending surgery in asymptomatic patients (table 10) (reference 2). The diagnosis of familial disease raises issues of management of HPTH in the proband and affected family members in view of the fact that familial HPTH generally is generally associated with multigland disease, whereas the sporadic disease is usually due to an adenoma. In HPTH jaw tumor syndrome there should be recognition of the high frequency of parathyroid carcinoma.

 

Table 10. Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism

Serum calcium

1.0 mg/dL elevation

Renal

24-h urine for FHH/stone risk
U Ca >400 mg/day
Creatinine clearance: <60 mL/min
Calcification on renal imaging

Bone

T-score < −2.5
Vertebral fracture on imaging

Age

<50

 

Management of other etiologies of hypercalcemia are generally directed toward the specific entity involved.

 

REFERENCES

 

  1. Goltzman D. Approach to Hypercalcemia. 2019 Oct 29. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905352
  2. Walker MD, Bilezikian JP. Primary Hyperparathyroidism. 2021 Apr 19. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905161
  3. Pieterman CRC, van Leeuwaarde RS, van den Broek MFM, van Nesselrooij BPM, Valk GD. Multiple Endocrine Neoplasia Type 1. 2021 Dec 22. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 29465925
  4. van Treijen MJC, de Vries LH, Hertog D, Vriens MR, Verrijn Stuart AA, van Nesselrooij BPM, Valk GD. Multiple Endocrine Neoplasia Type 2. 2022 Jan 2. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.
  5. Tsoli M, Dimitriadis GK, Androulakis II, Kaltsas G, Grossman A. Paraneoplastic Syndromes Related to Neuroendocrine Tumors. 2020 Sep 26. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905358

 

 

Primary Disorders of Phosphate Metabolism

ABSTRACT

 

Phosphorus is critical to many functions in human biology. Deprivation of phosphorus may manifest as disorders of the musculoskeletal system, reflecting its important role in energy metabolism and skeletal mineralization. Phosphorus excess can promote heterotopic mineralization and is associated with mortality, particularly in the setting of chronic kidney disease. Inorganic phosphorus, primarily occurring as phosphate (PO4), is highly regulated by transport systems in intestine and kidney, and is essential for the formation of a mineralized skeleton. Parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) are major hormonal regulators of phosphate homeostasis and membrane abundance of PO4 transporters. Tissue distribution of alpha-klotho permits a primary renal specificity for FGF23 actions. Disorders of phosphate metabolism that are encountered in clinical practice are described in this Endotext chapter, with an emphasis on pathophysiologic processes, diagnostic measures, and treatment. The identification of FGF23 as an important mediator of phosphate homeostasis has brought to light the underlying disease processes in many of these conditions, along with the possibility of novel, physiologic-based therapies.

 

INTRODUCTION

 

Phosphorus plays an important role in growth, development, bone formation, acid-base regulation, and cellular metabolism. Inorganic phosphorus exists primarily as the critical structural ion, phosphate (PO4), which serves as a constituent of hydroxyapatite, the mineral basis of the vertebrate skeleton, and at the molecular level, providing the molecular backbone of DNA. Its chemical properties allow its use as a biological energy store as adenosine triphosphate. Additionally, phosphorus influences a variety of enzymatic reactions (e.g., glycolysis) and protein functions (e.g., the oxygen-carrying capacity of hemoglobin by regulation of 2,3-diphosphoglycerate synthesis). Finally, phosphorus is an important signaling moiety, as phosphorylation and dephosphorylation of protein structures serves as an activation signal. Indeed, phosphorus is one of the most abundant components of all tissues, and disturbances in its homeostasis can affect almost any organ system. Most phosphorus within the body is in bone (600-700 g), while the remainder is largely distributed in soft tissue (100-200 g). The plasma contains 11-12 mg/dL of total phosphorus (in both organic and inorganic states) in adults. Inorganic phosphorus (Pi) primarily exists as phosphate (PO4), and is the commonly measured fraction, found in plasma at concentrations averaging 3-4 mg/dl in older children and adults. Plasma Pi concentrations values in children are higher, not infrequently as high as 8 mg/dl in small infants, and gradually declining steeply throughout the first year of life, and further in later childhood to adult values. The organic phosphorus component is primarily found in phospholipids. Although this fraction is not routinely assessed clinically, it comprises approximately two-thirds of the total plasma phosphorus (1). Thus, the term “plasma phosphorus” generally is used when referring to plasma inorganic Pi concentrations, and because plasma inorganic Pi is nearly all in the form of the PO4 ion, the terms phosphorus and phosphate are often interchangeably used in the clinical chemistry laboratory. It should be noted that this terminology can be confusing when using mass units (i.e., mg/dl) as the weight of the phosphorus content of the phosphate is reported, yet “serum phosphate” is often used in the clinic setting.  When using molar units the concentration of the phosphate and of the phosphorus are equivalent, and less confusion may arise.

 

Elaborate mechanisms have evolved to maintain phosphate balance, reflecting the critical role that phosphorus plays in cell and organism physiology. Adaptive changes are manifest by a variety of measurable responses, as modified by metabolic Pi need and exogenous Pi supply. Such regulation maintains the plasma and extracellular fluid phosphorus within a relatively narrow range and depends primarily upon gastrointestinal absorption and renal excretion as adjustable mechanisms to effect homeostasis. Although investigators have recognized a variety of hormones and transporter proteins which influence these various processes, in concert with associated changes in other metabolic pathways, the sensory system, the messenger and the mechanisms underlying discriminant regulation of Pi balance remain incompletely understood.

 

While long-term changes in Pi balance depend on these variables, short-term changes in Pi concentrations can occur due to redistribution between the extracellular fluid and either bone or cell constituents. Such redistribution results secondary to various mechanisms including: elevated levels of insulin and/or glucose; increased concentrations of circulating catecholamines; respiratory alkalosis; enhanced cell production or anabolism; and rapid bone remineralization.

 

REGULATION OF PHOSPHORUS HOMEOSTASIS

 

The majority of ingested phosphorus is absorbed in the small intestine. Active transport is mediated by sodium dependent transporter protein(s), and sodium-independent P-transport also occurs. Hormonal mechanisms regulating Pi homeostasis in the kidney are established in more detail. Indeed, the kidney has long been considered the dominant site of regulation of Pi balance, as renal tubular reclamation of filtered Pi occurs in response to complex regulatory mechanisms. Although the fate of Pi has generally been considered a matter of renal elimination, incorporation into organic forms in proliferating cells, or deposition into the mineral phase of bone as hydroxyapatite, the role of intestinal phosphate transport warrants further study. Indeed, it appears that presentation of Pi to the intestine can affect systemic phosphate handling before changes in serum Pi concentration are evident. Moreover, in the setting of severe phosphorus deprivation, the phosphate contained in bone mineral provides a source of phosphorus for the metabolic needs of the organism. The specific roles that the intestine and kidney play in this complex process are discussed below.

 

Gastrointestinal Absorption Of Phosphorus

 

Studies of Pi absorption in the intestine have yielded variable results, in part due to confounding influences of nutritional status, the effects of anesthesia on gut transit, species differences, and potential effects of studying whole organisms as opposed to isolated bowel segments. The small intestine is the dominant site of Pi absorption; in mice Pi is absorbed along the entire length of small bowel, but at the highest rate in the ileum. In rats, duodenum and jejunum provide the primary sites of Pi absorption, whereas very little occurs in ileum. This is felt to be more consistent with the pattern of Pi absorption in humans, however studies are subject to the confounding issues noted above. In normal adults net Pi absorption is a linear function of dietary Pi intake. For a dietary Pi range of 4 to 30 mg/kg/day, the net Pi absorption averages 60 to 65% of the intake (2). Intestinal Pi absorption occurs via two routes (Figure 1), a cellularly mediated sodium-dependent active transport mechanism, and sodium independent transport, which is not well characterized.  Mechanisms for the latter have been attributed in part to paracellular pathways (3), however recent findings suggest that for glucose, this pathway only accounts for 1-2% of passive glucose uptake in the intestine, far less that once speculated. Finally, the relative roles of these processes appear to be age dependent (4). Animal models suggest that weanling mice have both greater intestinal P transport (and greater expression of NaPi-IIb) than at other ages, presumably to support skeletal growth.

 

Controversy exists as to what proportion of intestinal Pi absorption is absorbed via sodium-dependent mechanisms and what proportion is sodium-independent. In this regard, the major Na+-dependent phosphate cotransporter identified in intestinal brush border membranes is NPT2b, a member of the SLC34 solute carrier family, also referred to as type II sodium-phosphate cotransporters (5). Earlier studies suggested that approximately 50% of intestinal P transport occurs by sodium-dependent mechanisms, and that most of this activity can be accounted for by the sodium-dependent transporter NPT2b. A lesser contribution to sodium-independent transport has been attributed to either type III transporters (PiT1 and PiT2, see below), and other unknown mechanisms. NPT2b is also expressed in lung, colon, testis/epididymis, liver, and in mammary and salivary glands, with most abundant expression in mammary glands (4). NPT2b is electrogenic, maintains a 3:1 stoichiometry of Na: Pi, prefers the divalent P species, and has a high affinity for Pi binding (6-10). Depending upon species and bowel segment, NPT2b transporters can be regulated by 1,25 dihydroxyvitamin D (­), FGF23 (¯), low Pi diet (­), and acute phosphate loading (­). Energy for the electrochemical uphill process is provided by the sodium gradient, which is maintained by sodium-potassium ATPase. The phosphate incorporated into intestinal cells by this mechanism is ferried from the apical pole to the basolateral pole likely through restricted channels such as the microtubules. Exit of Pi from the enterocyte across the basolateral membrane and into the circulation is a poorly understood process. More recently widely-expressed members of the SLC20 solute carrier family, the type III sodium-phosphate cotransporters PiT1 and PiT2, have been found to be variably expressed in the intestine (11), and PiT2 primarily in ileum.  Pit1 and Pit2 prefer to transport the monovalent Pi species (HPO4 -), and maintain a 2 Na: 1 P stoichiometry. These transporters may play a greater role in adaptive responses to intestinal Pi transport than previously recognized. PiT1 upregulates in response to phosphate deprivation, but in a relatively slow time frame, whereas expression of PiT2 and NPT2b upregulate within 24 hrs (12). In NPT2b-/- mice there is approximately 10% sodium-dependent Pi transport activity, suggesting that the type III transporters are of limited significance in the intestine in murine models. The process is further complicated by significant effects of alkaline pH as inhibitory to intestinal Pi transport, Moreover, the adaptation to P deprivation occurs with greater rates of transport occurring at more acidic pH (12) Given the variable nature and segment-specific regulation of NPT2b, the ultimate impact on overall phosphate homeostasis appears to be less well understood at the intestine than at the kidney. The presence of different classes of transporters in the intestine provide for Pi transport under a variety of different conditions such as variable pH, species of PO4 substrate, and Pi supply.  Indeed, recent work leads to speculation that much of the adaptive response to intestinal phosphate transport likely occurs by yet unrecognized transporters or transport processes (12).

Figure 1. Model of inorganic phosphate (HPO4=) transport in the intestine. At the luminal surface of the enterocyte the brush border membrane harbors sodium-dependent phosphate transporters of the NPT2b type. NPT2b transporters are electrogenic, have high affinity for Pi, and a stoichiometry of 3 Na ions: 1 phosphate. Energy for this transport process is provided by an inward downhill sodium gradient, maintained by transport of Na+ from the cell via a Na+/K+ ATPase cotransporter at the basolateral membrane. The HPO4= incorporated into the enterocytes by this mechanism is transferred to the circulation by poorly understood mechanisms. Type III sodium-dependent transporters are also expressed on the intestinal luminal surface (PiT1 and PiT2) and contribute to this process. Considerable HPO4= absorption occurs via a sodium-independent process(es) such diffusional absorption across the intercellular spaces in the intestine. Other processes have also been hypothesized.

As most diets contain an abundance of Pi, the quantity absorbed nearly always exceeds the need. Factors which may adversely influence the non-regulable, sodium-independent process are the formation of nonabsorbable calcium, aluminum or magnesium phosphate salts in the intestine and age, which reduces Pi absorption by as much as 50%.

 

Renal Excretion Of Phosphorus

 

The kidney responds rapidly to changes in serum Pi levels or to dietary Pi intake. The balance between the rates of glomerular filtration and tubular reabsorption (13) determines net renal handling of Pi. Pi concentration in the glomerular ultrafiltrate is approximately 90% of that in plasma, as not all of the plasma Pi is ultrafilterable (14). Since the product of the serum Pi concentration and the glomerular filtration rate (GFR) approximates the filtered load of Pi, a change in the GFR may influence Pi homeostasis if uncompensated by commensurate changes in tubular reabsorption.

 

The major site of phosphate reabsorption is the proximal convoluted tubule, at which 60% to 70% of reabsorption occurs (Figure 2). Along the proximal convoluted tubule, the transport is heterogeneous, with greatest activity in the S1 segment. Further, increasing, but not conclusive, data supports the existence of a Pi reabsorptive mechanism in the distal tubule. Currently, however, conclusive proof for tubular secretion of Pi in humans is lacking (15).

Figure 2. Distribution of Pi reabsorption and hormone-dependent adenylate cyclase activity throughout the renal tubule. The renal tubules consist of a proximal convoluted tubule (PCT), composed of an S1, S2 and S3 segment, a proximal straight tubule (PST), also known as the S3 segment, the loop of Henle, the medullary ascending limb (MAL), the cortical ascending limb (CAL), the distal convoluted tubule (DCT) and three segments of the collecting tubule: the cortical collecting tubule (CCT); the outer medullary collecting tubule (OMCT); and the inner medullary collecting tubule (IMCT). Pi reabsorption occurs primarily in the PCT but is present is the PST and DCT, sites at which parathyroid hormone (PTH) dependent adenylate cyclase is localized. In contrast, calcitonin alters Pi transport at sites devoid of calcitonin dependent adenylate cyclase, suggesting that Pi reabsorption in response to this stimulus occurs by a distinctly different mechanism.

At all three sites of Pi reabsorption, the proximal convoluted tubule, proximal straight tubule and distal tubule, PTH has been shown to decrease Pi reabsorption either by a cAMP-dependent process, or in some cases a cAMP-independent signaling mechanism. In contrast, calcitonin-sensitive adenylate cyclase maps to the medullary and cortical thick ascending limbs and the distal tubule (Figure 2) (16). Although calcitonin has been shown to inhibit Pi reabsorption in proximal convoluted and straight tubules by a cAMP-independent mechanism, the physiologic importance of this action is likely limited. It appears that the major regulators of renal tubular phosphate retention are PTH and the endocrine fibroblast growth factor, FGF23 (see below).

 

MECHANISM OF PHOSPHATE TRANSPORT

 

Investigations of the cellular events involved in Pi movement from the renal tubule luminal fluid to the peritubular capillary blood indicate that Pi reabsorption occurs principally by a unidirectional process that proceeds transcellularly. Entry of Pi into the tubular cell across the luminal membrane proceeds by way of a saturable active transport system that is sodium-dependent (analogous to the sodium-dependent co-transport in the intestine) (Figure 3). The rate of Pi transport is dependent on the abundance of transporters functioning in the membrane, and the magnitude of the Na+gradient maintained across the luminal membrane. This gradient depends on the Na+/ATPase or sodium pump on the basolateral membrane. The rate limiting step in transcellular transport is likely the Na+-dependent entry of Pi across the luminal membrane, a process with a low Km for luminal phosphate (~0.43M) which permits highly efficient transport.

Figure 3. Model of inorganic phosphate transcellular transport in the proximal tubule. At the brush border a Na+/H+ exchanger and NPT2 co-transporters operate. Nearly all proximal tubular reabsorption can be accounted for by the SLC34 (type II) family of sodium-dependent Pi transporters. In mice, NPT2a appears to be the more abundant transporter; it is electrogenic with a 3:1 (Na: PO4) stoichiometry, preferentially transporting the divalent phosphate anion. The lesser abundant NPT2c transporter is electroneutral with a 2:1 (Na: PO4) stoichiometry, but also prefers the divalent phosphate species. In humans NP2c appears to have a more significant role than in mice. The HPO4- that enters the cell across the luminal surface mixes with the intracellular pool of Pi and is transported across the basolateral membrane. This process is poorly understood, but anion exchange mechanisms have been suggested. A Na+/K+ ATPase located on the basolateral membrane pumps Na+ out of the cell maintaining the inward downhill Na gradient, which serves as the driving force for luminal entry of Na+.

The phosphate that enters the tubule cell plays a major role in governing various aspects of cell metabolism and function and is in rapid exchange with intracellular phosphate. Under these conditions the relatively stable free Pi concentration in the cytosol implies that Pi entry into the cell across the brush border membrane must be tightly coupled with either subcellular compartmentalization, organification, or exit across the basolateral membrane (Figure 3). The transport of phosphate across the basolateral membrane is poorly understood, however, several P transport pathways have been postulated, including Na+-Pi cotransport via type III Na-Pi cotransporters, passive diffusion, and anion exchange. The XPR1 transporter has been implicated in transport of phosphate out of cells but the significance of its role in total body P homeostasis is uncertain in humans (17). One animal study provides reasonable evidence for a critical role for this transporter in generalized tubular function (18). In any case, the basolateral Pi transport serves at least two functions: 1) complete transcellular Pi reabsorption when luminal Pi entry exceeds the cellular Pi requirements; and 2) basolateral Pi influx if apical Pi entry is insufficient to satisfy cellular requirements (19).

Pi entry into renal epithelium is primarily performed by the type II class of Na-Pi cotransporters (SLC34 family members), although recently the finding of type III transporters (SLC20 family members, PiT1 and PiT2) in kidney have raised the possibility of a potential role for this class as well (20).These two families of Na-Pi cotransporters share no significant homology in their primary amino acid sequence and as noted above, exhibit substantial variability in substrate affinity, pH dependence and tissue expression. The NPT2 class of transporters account for the bulk of regulated phosphate transport in kidney, and disruption of this regulation may result in significant disease, documenting their physiological importance (21, 22). As with intestinal Pi transport, physiologic differences between these families of Pi transporters provides for functional diversity allowing the body to transfer Pi between compartments in a variety of situations. Of the class II transporters NPT2a and NPT2c transporters are the predominant actors in the proximal renal tubule. NPT2a, the more abundant species in mice, is electrogenic with a 3:1 (Na: PO4) stoichiometry, preferentially transporting the divalent phosphate anion, and has a high affinity for Pi (all features of the NPT2b member of this family, the predominant intestinal sodium-dependent Pi transporter, see above). NPT2c differs from its type 2a/b family members in that is electroneutral with a 2:1 (Na: PO4) stoichiometry, but also prefers the divalent phosphate species. It has a much lower affinity for Pi, but is an efficient transporter due to its electroneutrality. An aspartic acid residue (Asp 224 in human NaPi-IIa) in a sodium binding site within a conserved amino acid cluster in the electrogenic transporters NPT2a and NPT2b, appears to be critical for electrogenicity. It is replaced with a glycine residue (Gly 196 in human NPT2c) in the electroneutral type IIc transporter (23).

Initial attention focused on NPT2a, as it was determined to be the most abundant Na-Pi cotransporter in kidney. Molecular and/or genetic suppression of NPT2a supports its role in mediating brush-border membrane Na-Pi cotransport. Intravenous injection of specific antisense oligonucleotides reduces brush-border membrane Na-Pi cotransport activity in accord with a decrease in NPT2a protein (24). In addition, disruption of the gene encoding NPT2a in mice (Slc34a1) leads to a 70% reduction in brush-border Na-Pi cotransport rate and complete loss of the protein (25, 26). However, the NPT2c transporter may have a relatively more important role for Pi transport in humans as compared to rodents, and appears to have a more widespread tissue distribution. The identification of a unique form of hypophosphatemia, Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) as a loss-of-function mutation in NPT2c has demonstrated an important physiologic role in humans for this transporter (27).

The roles of type III transporters in this process are not established at this time, and the previously described class of type I sodium-dependent phosphate transporters (of the SLC17 family) are not specific Pi transporters and do not appear to be central to the regulation of phosphate homeostasis.

REGULATION OF RENAL TUBULAR PHOSPHATE HANDLING

Several hormones and metabolic perturbations are able to modulate phosphate reabsorption by the kidney. Among these FGF23, PTH, PTHrP, calcitonin, atrial natriuretic peptide, acidosis, TGFb, glucocorticoids, hypercalcemia, and phosphate loading inhibit renal phosphate reclamation (for review, see reference 28). In contrast, IGF-1, growth hormone, insulin, thyroid hormone, EGF, alkalosis, hypocalcemia, and phosphate deprivation (depletion) stimulate renal phosphate reabsorption. The central role of FGF23 in this regard, revealed by the study of clinical disorders of renal phosphate wasting. Indeed, PTH and FGF23 are likely the two most important regulators of renal tubular phosphate handling, and are discussed in greater detail below. The common target for regulation by these factors is the renal proximal tubular cell. Effects of 1,25(OH)2D are less clearly delineated, and such effects in vivo may be mediated by PTH or FGF23.

PTH

Investigations of classical PTH effects on proximal tubule phosphate transport indicate that both the cAMP-protein kinase A (PKA) and the phospholipase C-protein kinase C (PKC) signal transduction pathways are able to modulate this process. The PTH mediated inhibition of phosphate reabsorption operates through the PKC system at low hormone concentrations (10-8 to 10-10 M) and via PKA at higher concentrations. The PKA pathway is the more important mediator of PTH’s role on P handling at the kidney. PTH, after interaction with its receptor, PTHR1, effects a rapid and irreversible endocytosis of NaPi-IIa transporters to the lysosomal compartment, where subsequent proteolytic degradation occurs (29). Stabilization of NPT2a is mediated by NHERF1 which is phosphorylated by PTH’s activation of the PKA and PKC pathways. NHERF3 also binds to NPT2a, but it does not appear to be necessary for apical retention of the transporter.

In contrast to NPT2a, NPT2c transporters are not targeted to lysosomes and their removal from the apical membrane may not be entirely irreversible (30, 31). Although recovery of NPT2a cotransport activity following PTH inhibition requires protein synthesis, this may not be the case for NPT2c. In addition, the abundance of NPT2a-specific mRNA is not changed by parathyroidectomy but is minimally decreased in response to PTH administration. These data implicate PTH as a regulator of renal Na-Pi cotransport in an acute time frame, and that the regulation is determined by changes in the abundance of NaPi-II proteins in the renal brush border membrane (32). Certain aspects of Pi homeostasis at the renal level, however, are not explained by actions of PTH. For instance, even in the setting where parathyroid glands have been removed, regulation of renal P transport by dietary P content still exists, implying that other mediators of this process are at work.

FGF23

FGF23 is the most recently identified important physiologic regulator of renal Pi excretion (33). This novel member of the fibroblast growth factor (FGF) family is produced by osteocytes and osteoblasts, thereby serving as a mechanism by which skeletal mineral demands can be communicated to the kidney, and influencing phosphate economy of the entire organism. In rodents and humans, after days of dietary phosphate loading, circulating FGF23 levels increase, and similarly, with dietary Pi deprivation, FGF23 levels decrease (34). FGF23 activates FGF receptors on the basolateral membrane of renal tubules resulting in removal of type II sodium-dependent Pi transporters from the apical surface of the tubular cell by a NHERF1 dependent process, similar to the mechanism described for PTH above. However, in contrast to PTH, FGF23 actions are mediated activation of ERK1/2 rather than the PTH driven PKA dependent pathway. Evidence also exists for decreased expression of type II sodium-dependent Pi via genomic mechanisms. FGF23 interacts with its receptor via a mechanism now identified as characteristic of the endocrine FGFs. FGF23 recognizes its cognate FGFR only in the presence of the co-receptor, alpha-klotho (35). Activation of this complex results in downstream ERK phosphorylation, and subsequently reduced expression of NaPi-IIa and NaPi-IIc, and CYP27B1 (1-hydroxylase), with an increase in expression of CYP24A1 (24-hydroxylase). This mechanism of signaling is apparent for the endocrine FGFs, FGF19 and FGF21, which require a separate member of the klotho family (beta-klotho) for specific tissue specific activation of FGFRs (for detailed review, see reference 36).

FGF23 contains a unique C-terminal domain, thought to be the site of the interaction with klotho. The FGF-like domain, N-terminal to a furin protease recognition site, is the basis for the interaction of FGF23 with FGFR. Alpha-klotho appears to be able to associate with “c” isoforms of FGFR1 and FGFR3, and also FGFR4 (35). Renal signaling is thought to occur via FGFR1c, thereby rendering the reduced expression of the apical membrane NaPi-II transporters. FGF23 also may play a role movement of transporters from the apical membrane; PTH may play a modulatory or necessary role for this effect (37). The physiologic importance of this system has been demonstrated in several ways. First, mice overexpressing FGF23 demonstrate increased renal Pi clearance and concomitant hypophosphatemia (38). Secondly, FGF23 null mice retain P at the kidney and are hyperphosphatemic (39). Thirdly, administration to mice of an FGF23 neutralizing antibody increases serum Pi (40).

Nevertheless, gaps in our understanding of this pathway remain. Alpha-klotho appears to be more abundantly expressed in distal renal tubules as compared to proximal tubular sites. Thus, the mechanism by which this pathway effects the transporters in the proximal tubule is unclear. Most recently klotho alone has been shown to increase expression of FGF23, and appears to be able to reduce renal tubular phosphate reabsorption, independent of FGF23 (41). These findings are consistent with a unique case of hypophosphatemia associated with a mutation in the klotho region resulting in overexpression of the protein and an abundance of circulating klotho (42). Finally, recent evidence indicating that it certain tissues (heart) FGF signaling may occur in the absence of alpha-klotho, although the physiologic significance of this finding is not certain (43).

The actions of FGF23 and other related proteins as mediators of disease are discussed in detail in the section on Pathophysiology of XLH (see below). Other potential regulators of renal Pi handling have been suggested. These include fragments of matrix extracellular glycoprotein (MEPE), secreted frizzled related protein-4 (sFRP4), stanniocalcin, and other FGFs, including FGF2, and FGF7 (44-47).

The Osteocyte As A Coordinating Center For Phosphate Homeostasis

Osteocytes are distributed throughout lamellar bone in an organized array with interconnections occurring through small tunneling caniculi (for review, see reference 48). Cellular processes extending from the cell body of the osteocyte pass through these caniculi and serve as a means of communication with other cells and to bony surfaces. Interestingly, many of the proteins involved in phosphate regulation are secreted by the osteocyte, including: 1) PHEX, which regulates FGF23 secretion, with loss-of-function resulting in elevated circulating FGF23; 2) DMP1, a SIBLING protein, in which loss-of-function also results in elevated circulating FGF23; 3) FGF23 itself, and 4) FGFR1 which appears to be activated in osteocytes resulting in elevated FGF23 expression. These observations have led to the consideration that the osteocyte may directly respond to phosphate nutritional status, and the osteocytic network throughout the skeleton may relay the mineral demands for bone maintenance to the kidney, where phosphate conservation is regulated. The osteocyte’s response to phosphate status does not appear to be an acute process, as that observed with the extracellular calcium sensing receptor system that regulates PTH secretion in PT glands. The coordination of certain specific matrix proteins may play a role in the local regulation of phosphate supply and mineralization. For instance, skeletal pyrophosphate (PPi) has been identified in increased abundance in the perilacunar bone of Hyp mice, suggesting a potential role of this potent inhibitor of mineralization in the skeletal pathophysiology of the disease (49). Others have demonstrated aberrations in osteopontin in skeletal matrix (50). It follows that genetic disruption of this pathway may result in the profound systemic disturbances observed in the diseases discussed herein.

In sum, repeated observations have confirmed that the balance between urinary excretion and dietary input of Pi is maintained in normal humans, in patients with hyper- and hypoparathyroidism, and under man conditions. This is predominantly due to the ability of the renal tubule to adjust Pi reabsorption rate according to the body’s Pi supply and demand. Thus, Pi reabsorption is increased under conditions of greater need, such as rapid growth, pregnancy, lactation and dietary restriction. Conversely, in times of surfeit, such as slow growth, chronic renal failure or dietary excess, renal Pi reabsorption is curtailed. Such changes in response to chronic changes in Pi availability are characterized by parallel changes in Na-phosphate cotransporter activity, the NPT2 mRNA level and NPT2 protein abundance. These changes are likely mediated by FGF23, as well as other possible factors. Removal of NPT2 cotransporters from the apical membrane of renal tubular cells is an acute process, mediated by PTH. The interaction of these two agents on the overall process may also be important. Indeed, ablation of PTH in a murine model of excess FGF23 abrogates hypophosphatemia. Likewise, suppression of PTH may reduce phosphate losses even with persistence of high FGF23 (51, 52), suggesting an interaction between the two pathways at the renal tubule (53).

CLINICAL DISORDERS OF PHOSPHATE METABOLISM

Primary disorders of phosphate homeostasis are listed in Table 1. Phosphate abnormalities may also occur in the setting of chronic kidney disease, as effects of therapeutic agents, and nutritional or intestinal absorption problems. Not surprisingly, since the kidney is the primary regulatory site for phosphate homeostasis, aberrant phosphate metabolism results most commonly from altered renal Pi handling. Moreover, the majority of the primary diseases are phosphate-losing disorders in which renal Pi wasting and hypophosphatemia predominate and osteomalacia and rickets are characteristic. Osteomalacia and rickets are disorders of calcification characterized by defects of bone mineralization in adults and bone and cartilage mineralization during growth. In osteomalacia, there is a failure to normally mineralize the newly formed organic matrix (osteoid) of bone. In rickets, a disease of children, there is not only abnormal mineralization of bone but defective cartilage growth plate calcification at the epiphyses as well. Apoptosis of chondrocytes in the hypertrophic zone is reduced, typically resulting in an expanded hypertrophic zone, delayed mineralization and vascularization of the calcification front, with an overall appearance of a widened and disorganized growth plate (54).

The remainder of this chapter reviews the pathophysiology of hypophosphatemic rachitic and osteomalacic disorders, and provides a systematic approach to the diagnosis and management of these diseases. The discussion will focus on disorders in which primary disturbances in phosphate homeostasis occur, emphasizing X-linked hypophosphatemic rickets/osteomalacia (XLH). Other FGF23-mediated disorders including autosomal dominant and autosomal recessive hypophosphatemic rickets (ADHR, ADHR, ARHR1, ARHR2, ARHR3), and tumor-induced osteomalacia (TIO) will be discussed. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Dent's disease will be described as examples of FGF23-independent hypophosphatemia.

Table 1. Primary Disorders of Phosphate Homeostasis

 

Gene

Mutation

FGF23-mediated                                                                                 Hypophosphatemia (XLH)                             

Autosomal dominant hypophosphatemic rickets (ADHR)       

Autosomal recessive hypophosphatemic rickets 1 (ARHR1)    

Autosomal recessive hypophosphatemic rickets 2 (ARHR2)    

Autosomal recessive hypophosphatemic rickets 2/Raine

       syndrome related hypophosphatemia (ARHR3)                    

McCune-Albright syndrome/fibrous dysplasia                           

Osteoglophonic dysplasia                                                         

Jansen metaphyseal chondrodysplasia                                    

Klotho overexpression                                                                         

Epidermal nevus syndrome (ENS)/Cutaneous Skeletal

        Hypophosphatemia Syndrome (CSHS)                     

Opsismodysplasia                                                                   

Tumor-induced osteomalacia (TIO)

 

PHEX

FGF23

DMP1

ENPP1

FAM20C

 

GNAS1

FGFR1

PTH1R

9;13 translocation

HRAS, NRAS

 

INPPL1  

 

LOF*

GOF*

LOF

LOF

LOF

 

GOF (somatic)

GOF

GOF

GOF

GOF (somatic)

 

LOF

FGF23-Independent

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) (NaPi-IIc deficiency)                                                   

Dent’s disease (X-linked recessive hypophosphatemic)                                                                          

NPT2a deficient Fanconi syndrome                                      

Fanconi-Bickel syndrome.                                                     

Hypophosphatemia with osteoporosis and nephrolithiasis   

 

SLC34A3

 

CLCNS

SLC34A1

SLC2A2

SLC34A1/SLC9A3R1

 

LOF

 

LOF

LOF

LOF

LOF

Hyperphosphatemia

Hyperphosphatemic tumoral calcinosis          

 

GALNT3, FGF23, KLOTHO

 

LOF

 

Mineralization Of Bone And Cartilage

Mineralization of bone is a complex process in which a calcium-phosphate mineral phase is deposited in a highly ordered fashion within the organic matrix (55). Apart from the availability of calcium and phosphorus, requirements for normal mineralization include: 1) adequate metabolic and transport function of chondrocytes and osteoblasts to regulate the concentration of calcium, phosphorus and other ions at the calcification sites; 2) the presence of collagen with unique type, number and distribution of cross-links, distinct patterns of hydroxylation and glycosylation and abundant phosphate content, which collectively facilitate deposition of mineral at gaps (or "hole zones") between the distal ends of collagen molecules; 3) a low concentration of mineralization inhibitors (such as pyrophosphates and proteoglycans) in bone matrix; and 4) maintenance of an appropriate pH of approximately 7.6 for deposition of calcium-phosphate complexes.

The abnormal mineralization in the hypophosphatemic disorders, is due most likely to the limited availability of phosphorus at calcification sites and, in some cases, paracrine inhibitory factors, which result in accumulation of unmineralized osteoid, a sine qua non for the diagnosis of osteomalacia. Since the resultant abundant osteoid is not unique to osteomalacia, establishing the diagnosis of osteomalacia requires dynamic histopathologic demonstration that abnormal mineralization, and not increased production, underlies the observed excess accumulation of osteoid (56, 57). Static histomorphometrical parameters seen in osteomalacia include an increase in osteoid volume and thickness, an increase in bone forming surface covered by incompletely mineralized osteoid, and a decrease in the mineralization front (the percentage of osteoid-covered bone-forming surface undergoing calcification). The critical dynamic parameter used to confirm that osteoid accumulation is due to osteomalacia is the mineral apposition rate.

Inadequate growth plate cartilage mineralization in rickets is primarily observed in the hypertrophic zone of chondrocytes. Irregular alignment and more extensive disorganization of the growth plate may be evident with increasing severity of disease. Calcification in the interstitial regions of this hypertrophic zone is defective. Grossly, these changes result in increased thickness of the epiphyseal plate, and an increase in transverse diameter that often extends beyond the ends of the bone and causes characteristic cupping or flaring.

Clinical Disorders: FGF23-mediated Hypophosphatemia

X-LINKED HYPOPHOSPHATEMIC RICKETS/OSTEOMALACIA

X-linked hypophosphatemic rickets/osteomalacia (XLH) was initially recognized in the 1930s as a form of “vitamin D resistant" and only later, as disorder of renal phosphate wasting. The disorder is inherited in X-linked dominant fashion and is manifest biochemically by a low renal threshold maximum for renal tubular phosphate reabsorption, consequent hypophosphatemia, and low, or inappropriate circulating levels of 1,25(OH)2D. Known biochemical characteristics of XLH and other hypophosphatemic disorders are shown in Table 2. Characteristic features of the disease include growth retardation, osteomalacia and rickets in growing children. The clinical expression of the disease is widely variable, ranging from mild skeletal abnormalities to severe bone disease. Most would agree that a wide spectrum of phenotypic severity occurs in both males (with a mutated gene on their only X chromosome) and females (who are heterozygous for the defective X-linked gene), although clinical experience suggests that females, particularly with certain mutations may express less severe disease (58). Bowing of the lower extremities is usually the first physical sign of the disorder, but is not often evident until 1-2 yrs of age, after the child is standing or walking (59). Biochemical evidence of disease can be detected shortly after birth, however may not become apparent until several weeks to months of age. Short stature generally becomes evident after the first year of life, as well (60), coincident with the timing of bow deformities. Growth abnormalities and limb deformities are both more evident in the lower extremities, since they represent the fastest growing body segment before puberty.


XLH, X-linked hypophosphatemia; ADHR, Autosomal dominant hypophosphatemic rickets; ARHR, Autosomal recessive hypophosphatemic rickets; TIO, Tumor-induced osteomalacia; XLHR, X-linked recessive hypophosphatemia (Dent's Disease); HHRH, Hereditary hypophosphatemic rickets with hypercalciuria. N, normal; , decreased; , increased, ( ), decreased relative to the serum phosphorus concentration; ?, unknown.

The majority of affected children exhibit clinical evidence of rickets (Figure 4), varying from enlargement of the wrists and/or knees to severe malalignment defects such as bowing or knock-knee deformities. (Figure 4). Such defects may result in waddling gait and leg length abnormalities (61). X-ray examination reveals expanded areas of non-mineralized cartilage in epiphyseal regions and lateral curvature of the femora and/or tibia. Strikingly absent are features observed in vitamin D deficiency rickets attributable to hypocalcemia, such as, tetany and convulsions. Muscle weakness and pain are not usually presentations of XLH in early childhood, but emerge later in life.

Figure 4. Radiograph of the lower extremities in a patient with X-linked hypophosphatemia. Bowing of the femurs is evident bilaterally. The distal femoral metaphysis is cupped, frayed and widened, radiographic features of an expanded and disorganized growth plate.

Additional signs of the disease may include delayed dentition and dental abscesses (62, 63), which are usually manifest clinically by pain and a gingival papule at the site of involvement. Radiographically there is an enlarged air compartment seen around the root of the affected tooth and an enlarged pulp chamber. Other dental findings that may play a role in the process include impaired mineralization of the dentine compartment of the tooth, and diminished cementum. Craniofacial structural anomalies may also result in crowding of teeth, requiring orthodontic management. Indeed, suture fusion of the cranial bones is aberrant, and craniosynostosis to some degree occurs frequently, and in severe cases require neurosurgical intervention.

 

Adults with XLH manifest a broad spectrum of disease. They may be asymptomatic or present with severe bone pain. On clinical examination they often display evidence of post-rachitic deformities, such as bowed legs or short stature. However, overt biochemical changes such as elevated serum alkaline phosphatase activity or other biomarkers of bone turnover may not be evident. Adult patients frequently demonstrate features of "active" osteomalacia, characterized radiographically by pseudofractures, coarsened trabeculation, rarified areas and/or non-union fractures, and although variably present, may have elevated serum alkaline phosphatase activity. Symptoms at presentation may reflect the end-result of chronic changes, and may not correlate with apparent current activity of the disease. In spite of marked variability in the clinical presentation of the disease, bone biopsy in affected children and adults nearly always reveals osteomalacia without osteopenia (Figure 5). Histomorphometry of biopsy samples usually demonstrates a reduced rate of formation, diffuse patchy hypomineralization, a decrease in mineralizing surfaces and characteristic areas of hypomineralization of the periosteocytic lacunae (64). Of note, as noted above, increased skeletal PPi identified in the perilacunar bone of Hyp mice, the syngeneic animal model of XLH, may serve to inhibit mineralization locally as well (49).

Figure 5. Section from an undecalcified bone biopsy in an untreated patient with X-linked hypophosphatemia. The Goldner stain reveals mineralized bone (blue/green) and an abundance of unmineralized osteoid (red) covering a substantial portion of the surfaces. The width of the osteoid seams is substantially increased.

Osteophytes and other findings of a mineralizing enthesopathy (65) occur frequently and may result in the most severe clinical symptomatology in adulthood. A great deal of the morbidity of XLH in adults arises from the high incidence of arthritis, calcified entheses, and osteophytes. Enthesopathy generally is first detectable radiographically by late in the second decade, or early in the third decade. Older subjects have more sites of involvement, and generally increasing involvement with age; the frequency of involvement appears to be greater in males. With progressive enthesopathy and bony overgrowth, excruciating pain may occur, particularly with fusion of the sacroiliac joint(s) and spinal stenosis (66). These manifestations do not appear to be affected for the better or worse with respect to exposure to currently available therapies (67).  It is peculiar that XLH represents a deficiency of mineralization at many skeletal sites, and pathologic ectopic mineralization elsewhere. This paradoxical situation raises the possibility that aberrant humoral factors, in addition to the ambient hypophosphatemia, may play a role in the discordant mineralization abnormalities observed.

 

Clinical Biochemistry

 

As previously noted, the primary biochemical abnormality of XLH is hypophosphatemia due to increased urinary phosphate excretion. Moreover, mild gastrointestinal phosphate malabsorption is present in the majority of patients, which may contribute to the evolution of the hypophosphatemia (Table 2) (68, 69).

 

In contrast, the serum calcium concentration in affected subjects is normal despite gastrointestinal malabsorption of calcium. However, as a consequence of this defect, urinary calcium is often decreased. The severe secondary hyperparathyroidism that occurs in vitamin D deficiency is not present as the degree of calcium malabsorption is not a severe in that condition. However, mildly elevated circulating levels of PTH occur in many patients naive to therapy, and thought to represent the inadequate production of 1,25(OH)2D. Other non-specific but typical findings include elevated serum alkaline phosphatase activity. Serum alkaline phosphatase activity, although usually elevated to 2-3 times the upper limit of normal in childhood, is generally less than the levels observed in nutritional rickets.  As noted above, circulating PTH levels may be normal to modestly elevated in naïve patients, but treatment with phosphate salts often aggravate this tendency such that persistent secondary hyperparathyroidism may occur. Because of variability in adulthood, this measure is not a reliable marker of disease involvement in the older age group. Prior to the initiation of therapy, serum 25-OHD levels are normal, and serum 1,25(OH)2D levels are in the low normal range (70, 71). The paradoxical occurrence of hypophosphatemia and normal serum calcitriol levels in affected subjects is consistent with aberrant regulation of both synthesis and clearance of this metabolite (due to increased 25-OHD-24-hydroxylase activity) (72, 73). Circulating levels of FGF23 are generally elevated in individuals with XLH, although overlap may occur. Thus, caution should be applied when using this measure as a strict diagnostic criterion for the diagnosis of XLH, as some subjects have been shown to have circulating FGF23 levels within the normal range, and commercially available assays (which recognize “intact” species or both intact and C-terminal species) do not always provide concordant results.

 

Genetics

 

With the recognition that hypophosphatemia is the definitive marker for XLH, Winters et al (74) and Burnett et al (75) discovered that this disease is transmitted as an X-linked dominant disorder. Analysis of data from 13 multigenerational pedigrees identified PHEX (for phosphate regulating gene with homologies to endopeptidases located on the X chromosome) as the gene disrupted in XLH (76). PHEX is located on chromosome Xp22.1, and encodes a 749-amino acid protein with three putative domains: 1) a small amino-terminal intracellular tail; 2) a single, short transmembrane domain; and 3) a large carboxyterminal extracellular domain, containing ten conserved cysteine residues and a HEXXH pentapeptide motif, which characterizes many zinc metalloproteases. Further studies have revealed that PHEX is homologous to the M13 family of membrane-bound metalloproteases, or neutral endopeptidases. M13 family members, including neutral endopeptidase 24.11 (NEP), endothelin-converting enzymes 1 and 2 (ECE-1 and ECE-2), the Kell blood group antigen (KELL), neprilysin-like peptide (NL1), and endothelin converting enzyme-like 1 (ECEL1), degrade or activate a variety of peptide hormones. In addition, like other neutral endopeptidases, immunofluorescent studies have revealed a cell-surface location for PHEX in an orientation consistent with a type II integral membrane glycoprotein (77). It has been demonstrated that certain missense variants in PHEX that substitute a highly conserved cysteine residue will interfere with normal trafficking of the molecule to the plasma membrane (78). Thus, it appears that one mechanism associated with the pathophysiology of XLH is to prevent PHEX from locating to the cell membrane. Other missense variants have been shown in in vitro studies to disrupt enzymatic function of the protein, alter its conformation, or disrupt cellular processing in other ways (79, 80).

 

Studies in rodents have demonstrated that Phex is predominantly expressed in bones (in osteoblasts/osteocytes) and teeth (in odontoblasts/ameloblasts) (81-84); mRNA, protein or both have also been found in lung, brain, muscle, gonads, skin and parathyroid glands. Subcellular locations appear to be the plasma membrane, endoplasmic reticulum and Golgi organelle. Immunohistochemistry studies suggest that Phex is most abundant on the cell surface of the osteocyte. In sum, the ontogeny of Phex expression suggests a possible role in mineralization in vivo.

 

Recently combined efforts of many investigators and genetic sequencing laboratories have documented over 850 pathogenic PHEX variants (85). Most of these (>70%) are predicted to generate a truncated PHEX protein. Overall, frameshift, splicing, copy-number, nonsense, and missense variants have been described, and are predicted to cause loss of function of the PHEX protein.  A recently updated on-line database of PHEX variants can be accessed at: https://www.rarediseasegenes.com/

 

The location of Phex expression in bone cells have led to the hypothesis that diminished PHEX/Phex expression in bone initiates the cascade of events responsible for the pathogenesis of XLH. In order to confirm this possibility, several investigators have used targeted over-expression of Phex in attempts to normalize osteoblast mineralization, in vitro, and rescue the Hyp phenotype in vivo (86-88). Results from these studies have not resulted in a complete skeletal rescue, raising questions as to the role of early developmental expression of PHEX, or at least the success of expression when targeted with osteocalcin or type I collagen promoters. Nevertheless, partial rescue of the mineralization defect in Hyp mice occurs, suggesting that local effects of the PHEX mutation may play some role in the mineralization process, but cannot completely restore the skeleton to normality. Of note, this partial rescue occurs in concert with a reduction in FGF23 levels, although not lowered to a truly normal range (88).

 

In sum, although a physiologic substrate for PHEX has not been identified, the consequence of loss-of-function of PHEX is an elevation in the circulating FGF23 level. Failure of targeted osteoblastic PHEX overexpression to completely rescue Hyp mice may reflect that critical sites (or developmental timing) for PHEX expression are not effectively generated with these models to effectively rescue the skeletal phenotype; this effect may be dependent upon the resultant capacity in these transgenic models of normal PHEX to reduce FGF23 production in mutant cells. ASARM peptides, fragments of SIBLING (small integrin binding ligand N-glycated) proteins, have been shown to inhibit mineralization and potentially play a role in modulation of renal P transport; these peptides have also been shown to be degraded by PHEX (89).  Other evidence has suggested that expression of osteopontin expression may be altered in the context of PHEX loss of function as well, (50).

 

Pathophysiology

 

Hypophosphatemia in XLH results from the impaired renal proximal tubule function of Pi reabsorption. For some time, XLH was thought to be a primary disorder of the renal tubule, however the consideration that humoral mediation of phosphate wasting in XLH was suggested by two novel clinical findings. First, the persistence of renal phosphate wasting after renal transplantation in a man with XLH indicated a new donor kidney continued to manifest the defect (90). Second, the clinical course of a similar phosphate-wasting syndrome, Tumor Induced Osteomalacia (also referred to as Oncogenic Osteomalacia), resolved upon removal of a tumor, suggesting that the tumor was the source of a mediating factor. Further evidence for humoral mediation was provided by classical parabiosis experiments, suggested that a cross-circulating factor could mediate renal phosphate wasting (91), and by renal cross-transplantation between Hyp and normal mice. These experiments demonstrated continued normal renal phosphate handling after transplantation of Hyp kidney to a normal host, as well as the failure to correct the mutant phenotype upon introduction of a normal kidney to a Hyp host (92). These findings, most consistent with humoral mediation of the Pi wasting in the disease, led to the search for candidate mediators of renal phosphate handling, and eventually to the discovery that FGF23 is an important regulator of renal phosphate homeostasis.  Subsequently mean circulating FGF23 concentrations were found to be greater in XLH patients than in unaffected control subjects, providing evidence for the role of this endocrine FGF in XLH.

 

Renal tubular wasting occurs on the basis of a decreased abundance of NPT2 transporters in the proximal convoluted tubule cells (93-95), and in turn, this reduction in NPT2 abundance is mediated by increased circulating levels of FGF23 (see above, Regulation of Renal Tubular Phosphate Handling). Increased FGF23 occurs in the context of disruption of PHEX, which, like FGF23, is primarily expressed in osteocytes, and FGF23 appears to be produced in a phosphate-sensitive manner.

 

It remains unclear as to how the loss-of-function of PHEX results in elevated FGF23 levels. The hypothesis that PHEX (a member of the M13 family of zinc-dependent type II cell surface membrane metalloproteinases) could serve as a processor of a phosphaturic hormone such as FGF23 has not been borne out, and the role PHEX plays in this pathway is not clear. Several other phosphate wasting disorders have been described (see below) in which elevated FGF23 occurs in the setting of (presumably) normal PHEX.  Such conditions include TIO, where overproduction of FGF23 results in a comparable Pi wasting phenotype. In Autosomal Dominant Hypophosphatemic Rickets (ADHR) specific mutations in FGF23 result in gain of function of the protein (96, 97). The specific mutations disrupt an RXXR protease recognition site, and thereby protect FGF23 from proteolysis, resulting in reduced clearance and elevating circulating levels of this protein, with coincident renal Pi wasting. In yet another genetic disorder, Autosomal Recessive Hypophosphatemic Rickets type I (98), due to homozygous loss of function mutations in dentin matrix protein-1 (DMP1), renal tubular Pi wasting occurs in the setting of increased FGF23 levels. DMP1 is a matrix protein of the SIBLING (small integrin binding ligand N-glycated) family, and, like PHEX and FGF23, has been primarily identified in osteocytes.

 

In Autosomal Recessive Hypophosphatemic Rickets type II, due to mutations in ENPP1, elevated FGF23 concentrations occur (99, 100). ENPP1 encodes a phosphatase with a critical local role in mineralization, serving to generate the mineralization inhibitor, pyrophosphate (PPi); loss of function of ENPP1 may result in Generalized Arterial Calcification of Infancy (GACI), a fatal disease of infants in which rampant vascular mineralization occurs (101). These findings have suggested the hypothesis that loss of the mineralization inhibitor PPi prompts a signal to compensate for the severe excess vascular mineralization, and increasing FGF23 levels results in an attempt to induce renal phosphate excretion and to limit further excessive mineralization. Nearly all patients who have survived GACI develop renal phosphate wasting and often consequent rickets (102).

 

Furthermore, FGF23 levels are elevated in mice with biallelic disruptions of DMP1 and with biallelic loss of ENPP1. Transgenic mice which overexpress FGF23, exhibit retarded growth, hypophosphatemia, decreased (or inappropriately normal) serum 1,25(OH)2D levels and rickets/osteomalacia, all features of XLH.   Indeed, murine models of all of these disorders (XLH, ADHR, TIO, and ARHR) similarly demonstrate elevated circulating FGF23 levels with concomitant renal phosphate wasting

 

In sum, enhanced FGF23 activity is common to several phosphate-wasting disorders. In particular, those disorders that share the combined defects of inappropriately low circulating levels of 1,25(OH)2D and renal tubular Pi wasting are associated with increased FGF23 levels. This coincidence of findings holds for XLH, ADHR, ARHR (types I, II, and III), and TIO, and are consistent with the notion that FGF23 is a both a direct regulator of Pi homeostasis at the renal level, a down-regulator of 1a-hydroxylase activity, responsible for the catalysis of 25-OH vitamin D to its active form, and stimulus for its clearance via the 24-hydroxylation pathway. The teleological appeal to this argument stems from the provision of 2 major Pi regulating hormones in the body: firstly, PTH (primarily responsive to serum Ca levels), which also serves to increase Ca levels via an increase in circulating 1,25(OH)2D, and secondly, FGF23 (primarily responsive to Pi), which counters PTH’s calcemic effect by reducing 1,25(OH)2D levels (Figure 6).

Figure 6. Scheme for the speculated pathophysiology of XLH, ARHR, TIO, and ADHR. Upper panel, osteocytes, comprising a network of connected cells embedded in mineralized bone are the cellular source of PHEX (which is mutated in XLH), DMP1 (which is mutated in ARHR), and FGF23 (which is found in high concentrations in all four of these hypophosphatemic disorders). It follows that loss of PHEX or DMP1 results in increased FGF23 production/secretion by mechanisms that are not currently understood. Circulating FGF23 concentrations may also occur secondary to the increased production associated with various tumors. Lower panel, circulating FGF23 interacts with an FGF receptor (presumably FGFR1) on the basolateral surface of the proximal renal tubular cell. Klotho, produced by the distal renal tubule in both membrane bound and secretory forms, is necessary for the FGF23/FGFR interaction. Signaling through this pathway results in a decrease in NPT2 mRNAs, thereby reducing the abundance of Pi cotransporters on the apical membrane as well as a more rapid action of translocating the transporter off of the apical membrane. Thus, impairment of renal tubular Pi reabsorption results. Likewise, synthesis of 1,25(OH)2D is impaired, while its clearance is augmented. In XLH and ARHR, increased production of FGF23 occurs in the skeleton; in TIO, increased production of FGF23 occurs in tumors; in ADHR, enhanced activity of FGF23 occurs as a result of the specific mutations that retard its metabolic clearance.

Other recent findings have provided support for the role of klotho in the FGF23-mediated hypophosphatemia pathway. An unusual patient with renal tubular Pi wasting and abnormally increased serum klotho has been described (42). Investigation revealed a translocation breakpoint disrupting the region upstream of that encoding klotho. Indeed, mice with disruption of the klotho gene manifest hyperphosphatemia and elevated circulating 1,25(OH)2D levels (103). The proof that klotho is distal to PHEX in this regulatory pathway was shown by crossing the klotho disrupted mice with Hyp (PHEX-deletion) mice. The double mutant (Hyp/Kl-/-) mice were hyperphosphatemic, with elevated 1,25(OH)2D levels, despite having extremely elevated circulating FGF23 levels due to PHEX loss-of-function (104).  The unexpected finding that overexpression of klotho can upregulate FGF23 production has also been reported (105).

 

Indeed, further evidence for the central role of FGF23 in the Pi-regulating process comes from the investigation of another group of rare disorders of Pi homeostasis in which renal Pi conservation is excessive in the setting of increased circulating Pi levels. This group of disorders, known as hyperphosphatemic tumoral calcinosis (HTC), is manifest clinically by precipitation of amorphous calcium-phosphate crystals in soft tissues. This phenomenon is thought to result from an increase in the ambient Ca x Pi solubility product, and occurs as a direct result of enhanced renal tubular reabsorption of Pi (106). In addition, circulating 1,25(OH)2D levels are inappropriately in the high-normal to high range. Thus, the precise converse of primary metabolic derangements occurs, as compared to the XLH-related group of diseases. Initially, HTC was been shown to directly result from loss of function mutations in GALNT3, a glycosylating enzyme important for appropriate O-glycosylation of proteins. This modification appears to be necessary for efficient Golgi secretion of full length FGF23 (107). Interestingly patients with HTC due to GALNT3 mutations have increased circulating levels of the inactive C-terminal fragment of FGF23, but low circulating levels of intact active form of FGF23 (108). Recent evidence implicates that variant post-translational modification of FGF23 can also be modulated by FAM20C: mutations in this gene can result in elevated FGF23 levels, renal phosphate wasting and hypophosphatemia, and referred to as Autosomal Recessive Hypophosphatemic Rickets, type III (ARHR3) and may have clinical features described as Raine syndrome (see table 1) (109, 110).

 

HTC may also occur in the setting of loss-of-function mutations of FGF23 (111). As with GALNT3-related HTC, these patients have low intact FGF23 level. Loss of function of klotho has also been described in a case of HTC, despite the finding of elevated FGF23 levels, thus rendering the FGF23 inactive at the renal proximal tubule (112). As with hypophosphatemia syndromes, animal models have confirmed the physiologic implications of these clinical scenarios:  FGF23 null mice develop a hyperphosphatemic, calcifying phenotype with elevated 1,25(OH)2D levels (39), similar to mice with disruption of the klotho gene (103, 113). As noted above, the klotho protein is now known to be an essential co-factor in FGFR1c activation when FGF23 serves as the activating ligand (35).

 

The overall physiologic importance of this regulating system requires further study. It is not clear how PHEX or DMP1 result in elevated FGF23 levels. The intriguing aspect of the osteocyte as a potential central cell in this pathway also bears further study.

 

Treatment

 

Decades ago, physicians employed pharmacological doses of vitamin D as the cornerstone for treatment of XLH. However, long-term observations indicate that this therapy fails to cure the disease and poses the serious problem of recurrent vitamin D intoxication and renal damage. Indeed, such treatment results only in incomplete healing of the rachitic abnormality, while hypophosphatemia and impaired growth remain. Similar unresponsiveness is typical with use of 25(OH)D.

 

With the recognition that phosphate depletion is an important contributor to impaired skeletal mineralization, physicians began to devise treatment strategies that employed oral phosphate supplementation to compensate for the renal phosphate wasting and thereby increasing the available Pi to the mineralizing skeleton. This strategy was somewhat successful in terms of improving skeletal lesions, although it was soon realized that pharmacologic amounts of vitamin D were necessary in combination with phosphate supplements to counter the exacerbation of hyperparathyroidism observed in this setting. Such combination therapy was found to be more effective than either administering vitamin D or phosphate alone. With the recognition that circulating 1,25(OH)2D levels are not appropriately regulated in XLH, the use of this metabolite in combination with phosphate was subsequently used to treat the disease (67, 114-116). The current treatment strategy directly addresses the combined calcitriol and phosphorus deficiency characteristic of the disorder. Although this combination therapy has become the conventional therapy for XLH, complete healing of the skeletal lesions is usually not the case, and late complications of the disease are persistent and often debilitating.

 

In children the goal of therapy is to improve growth velocity, normalize any lower extremity defects, and heal the attendant bone disease. Generally, the treatment regimen includes a period of titration to achieve a maximum dose of 1,25(OH)2D3 (Rocaltrol® or calcitriol), 20-50 ng/kg/day in two divided doses, and phosphorus, (20-50 mg/kg/day, to a maximum of 1-2 gms/day) in 3-5 divided doses.

 

Use of 1,25(OH)2D3/phosphorus combination therapy involves a significant risk of toxicity. Hypercalcemia, hypercalciuria, renal calcinosis, and hyperparathyroidism can be sequelae of unmonitored therapy. Detrimental effects on renal function were particularly common prior to the frequent monitoring now generally employed with this therapy. Indeed, hypercalcemia, severe nephrocalcinosis and/or diminished creatinine clearance necessitates appropriate dose adjustment, and in some cases discontinuation of therapy. Throughout the treatment course careful attention to renal function, as well as serum and urine calcium is extremely important. Nevertheless, the improved outcome of this therapeutic intervention compared to that achieved by previous regimens, justifies its use, albeit requires an aggressive clinical monitoring schedule.

 

While such combined therapy often improves growth velocity, refractoriness to the growth-promoting effects of treatment can be encountered in children who present with markedly short stature prior to 4 years of age. For that reason the use of recombinant growth hormone as additional treatment has been suggested (117), however this approach has not been universally recommended in view of the lack of definitive benefits in controlled studies, and a risk of resultant worsening of the disproportional stature (118), although others have not identified significant concerns in this regard (119).  A recent meta-analysis concluded there as insufficient evidence to support recommendation of its use (120)

 

Indications for therapy in adults with XLH are less clear. The occurrence of intractable bone pain and refractory non-union fractures often respond to treatment with calcitriol and phosphorus (121). However, data remain unclear regarding the effects of treatment on fracture incidence (which may not be increased in untreated patients). There does not appear to be any effect of this therapy on enthesopathy, however superior dentition appears to occur in the setting of higher medication exposure through adulthood as well as the entire life span (64). Muscle weakness and general well-being may occur with therapy in some adults. In sum, the decision to treat affected adults must be individualized. In general, it is beneficial to offer adults with significant symptomatology a trial of this therapy, but only if routine biochemical monitoring can be performed. Several detailed strategies for the management of children and adults with XLH are available (122-124).

 

A more recent development has been a more directed approach to the etiology of the renal phosphate loss. After demonstration of the efficacy of this strategy in the Hyp mouse model of XLH (40), trials of an antibody to the human FGF23 protein, burosumab (KRN23) have been conducted in children and adults (125-131) leading to its approval for use in both North America, several S. American countries, Europe, and other regions. The initial study using burosumab to treat in children with XLH resulted in improvement of radiographic features of rickets in concert with correction of abnormal biochemical indices after previous treated with conventional phosphate and active vitamin D therapy (127). Steady and stable correction of hypophosphatemia was attained with administration of the antibody every 2 weeks and a favorable safety profile was evident. The improved musculoskeletal status has been demonstrated to persist as seen in follow up extension studies for a total of 3 years (132). Moreover, one study has provided evidence that burosumab was superior to conventional therapy with calcitriol and phosphate in terms of skeletal improvement and growth (133).

 

AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS (ADHR)

 

Several studies have documented autosomal dominant inheritance of a hypophosphatemic disorder similar to XLH (134, 135). The phenotypic manifestations of this disorder include the expected hypophosphatemia due to renal phosphate wasting, lower extremity deformities, and rickets/osteomalacia. Affected patients also demonstrate normal serum 25(OH)D levels, while maintaining inappropriately normal serum concentrations of 1,25(OH)2D, in the presence of hypophosphatemia, all hallmarks of XLH (Table 2). PTH levels are normal. Long-term studies indicate that a few of the affected female patients demonstrate delayed penetrance of clinically apparent disease and an increased tendency for bone fracture, uncommon occurrences in XLH. In addition, among patients with the expected biochemical features documented in childhood, rare individuals lose the renal phosphate-wasting defect after puberty. As noted above, specific mutations in FGF23 in the 176-179 amino acid residue sequence are present in patients with ADHR (97). These mutations disrupt an RXXR furin protease recognition site, and the resultant mutant molecule is thereby protected from proteolysis, and resultant elevated circulating levels of FGF23 are the likely cause of the renal Pi wasting. Interestingly, circulating FGF23 levels can vary and reflect the activity of disease status (136).

 

Exploration of the waxing/waning severity of disease in ADHR has identified that iron may play a significant role in the regulation of circulating FGF23 (137).  Iron deficiency appears to upregulate FGF23 expression, and in normal individuals, processing of the intact protein to its inactive N- and C-terminal fragments is efficient, thereby compensating for the increased intact FGF23 production seen with iron deficiency. Thus. in normal individuals who become iron deficient normal circulating levels of intact FGF23 are maintained despite the increase in production. However, in ADHR, inefficient processing of FGF23, due to the lack of protease recognition at the usual amino acid 179/180 cleavage site, may not be able to compensate for increased FGF23 synthesis during periods of iron deficiency. Thus, the waxing and waning clinical severity observed in some cases of ADHR may be amenable to iron supplementation, and provide a straightforward approach to therapy. A recently reported case demonstrates that correction of serum iron levels to high normal levels allowed for discontinuation of conventional rickets medications (138)

 

An apparent forme fruste of ADHR (autosomal dominant) hypophosphatemic bone disease has many of the characteristics of XLH and ADHR, but recent reports indicate that affected children display no evidence of rachitic disease. Because this syndrome is described in only a few small kindreds, and radiographically evident rickets is not universal in children with familial hypophosphatemia, these families may have ADHR. Further observations are necessary to discriminate this possibility.

 

AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS (ARHR)

 

Families with phosphate wasting rickets inherited in an autosomal recessive manner have been described and demonstrate the same constellation of progressive rachitic deformities seen in both XLH and ADHR (98, 139).  Moreover, the biochemical phenotype is manifest by the same measures of hypophosphatemia, excess urinary Pi losses, and aberrant vitamin D metabolism (normal circulating 25-OHD and 1,25(OH)2D levels, despite ambient hypophosphatemia) as observed in both XLH and ADHR. In addition to the expected phenotypic features, and in contrast to XLH, spinal radiographs of patients with ARHR reveal noticeably sclerotic vertebral bodies. In addition to the enlarged pulp chamber characteristic of teeth in individuals with XLH, enamel hypoplasia can be evident in heterozygotes. Of particular interest is the identification of elevated levels of FGF23 in the affected individuals. Experience with long-term follow-up is not widespread in ARHR and therapeutic response or guidelines have not been definitively established.

 

The identification of a progressive mineralization defect associated with hypophosphatemia in DMP1 knockout mice led to the consideration of homozygous loss of function in this candidate gene as a cause of ARHR. Indeed, this was proven to be the case for the first families identified with the disorder. Thus, the role of the osteocyte product, DMP1, appears as either part of the PHEX-FGF23 pathway, or at least can affect circulating FGF23 levels, perhaps independently of PHEX. These observations reinforce the central role that the osteocyte plays in mineral homeostasis.

 

Moreover, hypophosphatemic rickets in association with renal Pi wasting has been recently described in the setting of the extremely rare disorder, generalized arterial calcification of infancy (GACI) (99-101). This disorder occurs with homozygous loss-of-function mutations of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). Loss-of-function of ENPP1 results in the inability to generate the mineralization inhibitor, pyrophosphate, thereby disrupting the restriction of heterotopic (e.g., vascular) mineralization. GACI is often fatal, but hypophosphatemia, identified in the setting of elevated FGF23 levels in an adult with a homozygous ENPP1 mutation raised this consideration of rickets in survivors of GACI (140). Moreover, the patient’s son was affected with both GACI and hypophosphatemia. The mechanism by which this enzyme influences renal tubular phosphate wasting is not evident, and further study is necessary to understand this intriguing problem. One speculated mechanism may reflect a bone cell response to a relatively hypermineralized (or high-phosphate/low pyrophosphate) milieu which results in a compensatory, prolonged secretion of FGF23. Such a mechanism may effectively signal the kidney to reduce the body’s mineral load, but apparently cannot be down-regulated to protect against excessive Pi losses. Although there has been concern that the treatment of rickets in patients affected with GACI patients may promote worsening of vascular calcification, no evidence to sustain this concern has emerged and one long term observational report suggests that treatment does not worsen this finding (141). A recent phenotyping study with long-term observations in this regard corroborates this initial impression (102).

 

TUMOR-INDUCED OSTEOMALACIA

 

Rickets and/or osteomalacia have been associated with various types of tumors (96). In many cases, the metabolic disturbances improved or completely disappeared upon removal of the tumor, indicating a causal role of the tumor. Affected patients generally present with bone and muscle pain, muscle weakness, rickets/osteomalacia, and occasionally recurrent fractures of long bones. Biochemistries include hypophosphatemia secondary to renal phosphate wasting and normal serum levels of calcium and 25(OH)D. Serum 1,25(OH)2D is often overtly low or is otherwise inappropriately normal in the setting of hypophosphatemia (Table 2). Aminoaciduria and/or glucosuria may be present. Radiographic abnormalities include generalized osteopenia, pseudofractures and coarsened trabeculae, as well as widened epiphyseal plates in children. The histologic appearance of trabecular bone in affected subjects most often reflects the presence of a low turnover osteomalacia.

 

The large majority of patients with this syndrome harbor tumors of mesenchymal origin, including primitive-appearing, mixed connective tissue lesions. These tumors are often classified as osteoblastomas, osteochondromas, non-ossifying fibromas and ossifying fibromas. In addition, tumors of epidermal and endodermal derivation have been implicated as causal of the disease. Indeed, the observation of tumor-induced osteomalacia concurrent with breast carcinoma, prostate carcinoma oat cell carcinoma, small cell carcinoma, multiple myeloma and chronic lymphocytic leukemia have been reported.

 

Although this syndrome is relatively rare compared to XLH, investigation of causative tumors eventually led to the identification and isolation of FGF23 (38, 142), the mediator of many heritable hypophosphatemic disorders, and the recognition that this protein is the central factor in a major regulatory system affecting Pi homeostasis. Moreover, the discovery represented the first disorder related to the endocrine subfamily of FGFs, acting at distant sites with specificity of site activity conferred by the family of klotho co-receptors. 

 

Regardless of the tumor cell type, the lesions at fault for the syndrome are often small, difficult to locate and present in obscure areas which include the nasopharynx, jaw, sinuses, the popliteal region and the suprapatellar area. In any case, a careful and thorough examination is necessary to document/exclude the presence of such a tumor. Indeed, CT and/or MRI scan of a clinically suspicious area should be undertaken. Recently newer imaging techniques such as octreotide scintigraphy or PET scans have been used to successfully identify tumors that remained unidentified by other means of localization. Newer agents with greater specificity for somatostatin receptors type 2 and type 5 appear to increase the sensitivity of PET scanning (143, 144), and co-registry with high resolution anatomic imaging has considerably advanced detection of small tumors.

 

Selective venous sampling has been suggested as a complementary approach to diagnosis. This technique may provide confirmation of local FGF23 secretion in suspicious areas identified by imaging (as to avoid unnecessary operations from false-positive imaging studies). The technique may serve to direct local imaging to anatomic regions defined by step-ups in FGF23 concentrations, but is limited by the relatively long half-life of FGF23, which may be misleading if the sampling is not in very close proximity to the offending tumor. Although useful in the settings mentioned above, the technique is not thought to be an optimal first-line approach in identification of TIO causing tumors (145).

 

Pathophysiology

 

TIO is a result of Pi wasting secondary to circulating factor(s) secreted by causal tumors. FGF23 has proven to be the primary factor identified in most patients where examination of serum levels or tumor material has occurred. Nevertheless, a variety of other factors have been considered as a potential part of the cascade that can lead to renal Pi wasting including: 1) FRP4 (frizzled related protein 4) (45), a secreted protein with phosphaturic properties, 2) FGF7, a paracrine FGF identified in TIO tumors that has been shown to directly inhibit renal Pi transport (47), 3) the SIBLING protein, MEPE (matrix extracellular phosphglycoprotein), which has been reported to generate fragments (ASARM peptide) with potential Pi wasting activity (44), 4) the SIBLING protein, DMP1, which has now been implicated in ARHR, and has been shown to be in particularly high abundance in TIO tumors (38, 98, 140, 146), and 5) the high molecular weight isoform of FGF2 (another paracrine FGF), which when expressed transgenically in mice, results in hypophosphatemic rickets (147). It is also possible that these or other tumor products may have direct effects on the mineralization function of the skeleton.

 

A novel genetic mechanism by which TIO tumors may develop autonomous FGF23 production involves a somatic chromosomal rearrangement which has been identified in a high proportion of TIO tumors (142). The rearrangement sequence predicts a fusion protein consisting of the N-terminal portion of fibronectin and the FGFR1 receptor. The extracellular fibronectin domain is proposed to promote dimerization and activation of the complex leading to downstream signaling resulting in FGF23 secretion. FGF23 itself is further proposed as an additive stimulus, amplifying FGF23 production as part of a feed-forward loop resulting in the substantial FGF23 production characteristic of TIO (148). More recently another rearrangement generating a fibronectin/FGF1 fusion protein has been described (149).

 

In contrast to these observations, other rare patients with TIO secondary to hematogenous malignancy manifest abnormalities that would suggest a different pathophysiologic mechanism. In these subjects a nephropathy induced with light chain proteinuria or other immunoglobulin derivatives appears to result in decreased renal tubular reabsorption of phosphate. Thus, light-chain nephropathy has been considered a possible mechanism for the TIO syndrome.

 

Treatment

 

The first and foremost treatment of TIO is complete resection of the tumor. However, recurrence of mesenchymal tumors, such as giant cell tumors of bone, or inability to resect completely certain malignancies, such as prostatic carcinoma, has resulted in development of alternative therapeutic intervention for the syndrome. In this regard, administration of 1,25(OH)2D alone or in combination with phosphorus supplementation has served as effective therapy for TIO. Doses of calcitriol required range from 1.5-3.0 µg/d, while those of phosphorus are 2-4 g/d. Although little information is available regarding the long-term consequences of such treatment, the high doses of medicine required raise the possibility that nephrolithiasis, nephrocalcinosis, and hypercalcemia may frequently complicate the therapeutic course. Indeed, hypercalcemia secondary to parathyroid hyperfunction has been documented in several subjects. Generally, these patients receive phosphorus as part of a combination regimen, exacerbating the path to parathyroid autonomy. Thus, as with treatment of XLH, careful assessment of parathyroid function, serum and urinary calcium, and renal function are essential to ensure safe and efficacious therapy.  Recent studies using burosumab, the antiFGF23 antibody, have demonstrated improvement in both biochemical indices and biopsy parameters of osteomalacia in inoperable TIO (150). 

 

OTHER FGF23 MEDIATED FORMS OF HYPOPHOSPHATEMIA

 

In widespread fibrous dysplasia of bone (due to mosaic activating mutations in GNAS), neurofibromatosis and cutaneous skeletal hypophosphatemic syndrome (associated with somatic mutations in HRAS and NRAS) (151), hypophosphatemic osteomalacia/rickets can result as a result of elevated circulating FGF23 levels (152). Indeed, variable degrees of decreased renal tubular phosphate reabsorption, as assessed by TMP/GFR assessments, occur in patients with fibrous dysplasia of bone. Other primary skeletal disorders in which elevated FGF23 levels have been reported include osteoglophonic dysplasia (due to mutations in the FGFR1 receptor) (153), Jansen metaphyseal chondrodysplasia, (due to activating mutations of the PTH1 receptor) (154), opsismodysplasia (155), and in FAM20C mutations (110). The mechanism(s) by which elevations in FGF23 occur in these settings is not certain at this time.

 

Clinical Disorders: FGF23-independent Hypophosphatemia

 

HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA (HHRH)

 

This rare autosomal recessive disease is marked by hypophosphatemic rickets with hypercalciuria (156). Initial symptoms of the disorder generally manifest between 6 months to 7 years of age and usually consist of bone pain and/or deformities of the lower extremities. Such deformities may include genu varum or genu valgum or anterior bowing of the femur and coxa vara. Additional disease features include short stature, and radiographic signs of rickets or osteopenia. In contrast to XLH, muscle weakness may be elicited as a presenting symptom.

 

Many of the distinguishing characteristics of HHRH stem from the fact that HHRH is not a disorder of FGF23-mediated hypophosphatemia. In fact, levels are often decreased compared to the normal population. Consequently, in contrast to the previously described disorders in which renal phosphate transport is limited, patients with HHRH exhibit increased 1,25(OH)2D production. The resultant elevated serum calcitriol levels enhance gastrointestinal calcium absorption, which in turn increases the filtered renal calcium load and inhibits PTH secretion. Collectively these events produce the hypercalciuria observed in affected patients (Table 2). Although initially not thought to be part of the syndrome, the propensity for kidney stones to occur has been reported in several patients.

 

In general, the severity of the bone mineralization defect correlates inversely with the prevailing serum Pi concentration. Relatives of patients with evident HHRH may exhibit an additional mode of disease expression (157). These subjects manifest hypercalciuria and hypophosphatemia, but the abnormalities are less marked and occur in the absence of discernible bone disease, which would suggest a mild phenotype in the heterozygous state with certain mutations.

 

After mutations in the candidate NaPi-IIa gene were excluded as causal to HHRH, the genetic defect was identified in NaPi-IIc (27, 158), previously thought to be of less importance than the type IIa transporter. As would be predicted by the isolated loss of function of a Pi transporter, reduced serum Pi and increased renal Pi losses occur, independent of FGF23 status. However, unlike the findings in XLH, Pi wasting does not coexist with limitations in 1,25(OH)2D production, and the system retains its capacity to increase 1,25(OH)2D levels in response to the ambient hypophosphatemia. Recently it has been suggested that specific mutations in NaPi-IIc may be associated with sodium wasting and potentially the tendency to form urinary tract stones (159).

 

Patients with HHRH have been treated successfully with high-dose phosphorus (1 to 2.5 g/day in five divided doses) alone. In response to therapy, bone pain disappears and muscular strength improves substantially. Moreover, the majority of treated subjects exhibit accelerated linear growth, and radiologic signs of rickets are completely absent within several months. Despite this favorable response, limited studies indicate that such treatment does not completely heal the associated osteomalacia. Indeed, there is no collective experience with long-term follow-up of this rare disorder, and the necessity and/or complications of long-term therapy are not well-established. Curiously an accompanying osteoporosis appears to occur in concert, a finding that is also quite different from the usual picture in XLH.

 

AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS WITH FANCONI SYNDROME AND PHOSPHATURIA ASSOCIATED WITH INFANTILE HYPERCALEMIA OF INFANCY

 

Although SLC34A3 (Na-Pi2c) mutations were identified as the mutated gene in the specific disorder of HHRH, homozygous loss-of-function mutations in SLC34A1 (Na-Pi2a) occur in yet another syndrome of autosomal recessive hypophosphatemic rickets accompanied by a generalized renal tubular disorder consistent with Fanconi syndrome (160). This disorder appears to occur with less frequency than HHRH, however in a recent search for genetic causes of idiopathic infantile hypercalcemia (IIH), loss-of-function mutations in SLC34A1 have been identified (161). Rickets is not a prominent feature of this disorder, but rather hypercalcemia, hypercalciuria, nephrocalcinosis and renal phosphate wasting. Resultant elevations in circulating 1,25(OH)2D levels lead to the hypercalcemia. It is important to distinguish this cause of IIH from those attributable to defects in CYP24A1 (vitamin D 24-hydroxylase) as therapy in cases attributable to NaPi2a deficiency should respond to phosphate supplementation whereas restriction of dietary calcium and vitamin D are recommended in cases due to CYP24A1 mutations.

 

DENT'S DISEASE (X-LINKED RECESSIVE HYPOPHOSPHATEMIA; XLRH)

 

The initial description of X-linked recessive hypophosphatemic rickets involved a family in which males presented with rickets or osteomalacia, hypophosphatemia, and a reduced renal threshold for phosphate reabsorption. In contrast to patients with XLH, affected subjects exhibited hypercalciuria, elevated serum 1,25(OH)2D levels (Table 1), and proteinuria of up to 3 g/day. Patients also developed nephrolithiasis and nephrocalcinosis with progressive renal failure in early adulthood. Female carriers in the family were not hypophosphatemic and lacked any biochemical abnormalities other than hypercalciuria. Three related syndromes have been reported independently: X-linked recessive nephrolithiasis with renal failure, Dent's disease, and low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis. These syndromes differ in degree from each other, but common themes include proximal tubular reabsorptive failure, nephrolithiasis, nephrocalcinosis, progressive renal insufficiency, and, in some cases, rickets or osteomalacia. Identification of mutations in the voltage-gated chloride-channel gene CLCN5 in all four syndromes has established that they are phenotypic variants of a single disease and are not separate entities (162,163). However, the varied manifestations that may be associated with mutations in this gene, particularly the presence of hypophosphatemia and rickets/osteomalacia, underscore that environmental differences, diet, and/or modifying genetic backgrounds may influence phenotypic expression of the disease.

 

INTESTINAL MALABSORPTION OF PHOSPHATE

 

Although primary disorders of intestinal phosphate absorption have not been considered of clinical significance, we have encountered a curious phenomenon of phosphate malabsorption in children with complex disorders associated with intestinal compromise, when fed amino-acid based elemental formula (164,165). Associated tube-feeding and use of antacid medications appear to be risk factors, and the phenomenon does not appear to occur when used for the labeled indication of milk protein allergy in children who are otherwise healthy (166). We have recommended that serum phosphorus levels be monitored periodically with the use of such formulas.

 

REFERENCES

 

  1. Yanagawa N, Nakhoul F, Kurokawa K, Lee DBN. Physiology of phosphorus metabolism. In: Narins RG, ed. Clinical disorders of fluid and electrolyte metabolism. 5th ed. New York: McGraw Hill,1994; 307-371.
  2. Lee DBN, Walling MW, Brautbar N . Intestinal phosphate absorption: Influence of vitamin D and non-vitamin D factors. Am J Physiol. 1986; 250: G369-G373.
  3. Cross HS, Debiec H, Peterlik M. Mechanism and regulation of intestinal phosphate absorption. Miner Electrolyte Metab. 1990;16:115-124.
  4. Marks J, Debnam ES, Unwin RJ. The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease. Curr Opin Nephrol Hypertens. 2013; 22:481-487.
  5. Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SCIntestinal npt2b plays a major role in phosphate absorption homeostasis. J Am Soc Nephrol. 2009; 20:2348–2358.
  6. Debiec H, Lorenc R. Identification of Na+,Pi-binding protein in kidney and intestinal brush-border membranes. Biochem J. 1988; 225:185-191.
  7. Katai K, Miyamoto K, Kishida S, Segawa H, Nii T, Tankaka H, Tani Y, Arai H, Tatsumi S, Morita K, Taketani Y, Takeda E. Regulation of intestinal Na+-dependent phosphate co-transporters by a low phosphate diet and 1,25-dihydroxyvitamin D3. Biochem J. 1999; 3:705-712.
  8. Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci USA. 1998; 95:14564-14569.
  9. Bai L, Collins JF, Ghishan FK. Cloning and characterization of a type III Na-dependent phosphate cotransporter from mouse intestine. Am J Physiol Cell Physiol. 2000; 279:C1135-C1143.
  10. Xu H, Bai L, Collins JF, Ghishan FK. Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)2 vitamin D3. Am J Physiol Cell Physiol. 2002; 282:C487-C493.
  11. Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol. 2009; 299:F285-F296.
  12. Candeal E, Caldas YA, Guillén N, Levi M, Sorribas V. Intestinal phosphate absorption is mediated by multiple transport systems in rats. Am J Physiol Gastrointest Liver Physiol. 2017; 312(4): G355-G366.
  13. Mizgala CL, Quamme GA. Renal handling of phosphate. Physiol Rev. 1985; 65:431-466.
  14. Harris CA, Sutton RA, Dirks JH. Effects of hypercalcemia on tubular calcium and phosphate ultrafilterability and tubular reabsorption in the rat. Am J Physiol. 1977; 233:F201-F206.
  15. Knox FG, Haramati A. Renal regulation of phosphate excretion. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York: Raven Press; 1981; 1381.
  16. Berndt TJ, Knox FG. Proximal tubule site of inhibition of phosphate reabsorption by calcitonin. Am J Physiol. 1984; 246:F927-F930.
  17. Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo A, Castro-Fernandez C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet. 2015; 47(6):579–581.
  18. Ansermet C, Moor MB, Centeno G, Auberson M, Hu DZ, Baron R, Nikolaeva S, Haenzi B, Katanaeva N, Gautschi I, Katanaev V, Rotman S, Koesters R, Schild L, Pradervand S, Bonny O, Firsov D. Renal fanconi syndrome and hypophosphatemic rickets in the absence of xenotropic and polytropic retroviral receptor in the nephron. J Am Soc Nephrol. 2017; 28(4):1073-1078.
  19. Schwab SJ, Klahr S, Hammerman MR.Na+ gradient-dependent Pi uptake in basolateral membrane vesicles from dog kidney. Am J Physiol. 1984; 246: F633-F639.
  20. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol. 2009; 296(4): F691-F699.
  21. Murer H, Forster I, Hernando N, Lambert G, Traebert M, Biber J. Post-transcriptional regulation of the proximal tubule Na+-phosphate transporter type II in response to PTH and dietary phosphate. Am J Physiol Renal Physiol. 1999; 277: F676-F684.
  22. Murer H, Forster I, Hilfiker H, Pfister M, Kaissling B, Lotscher M, Biber J. Cellular/molecular control of renal Na+/Pi cotransport. Kidney Int. 1988; 65:S2-S10.
  23. Bacconi A, Virkki LV, Biber J, Murer H, Forster IC. Renouncing electroneutrality is not free of charge: switching on electrogenicity in a Na+-coupled phosphate cotransporter. Proc Natl Acad Sci USA. 2005; 102(35):12606-12611.
  24. Oberbauer R, Schreiner GF, Biber J, Murer H, Meyer TW.In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides. Proc Natl Acad Sci USA. 1996; 93:4903-4906.
  25. Beck I, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt 2 in mice leads to severe renal phosphate wasting, hypercalciuria and skeletal annomalies. Proc Natl Acad Sci USA. 1998; 95:5372-5377.
  26. Hoag HH, Gauthier C, Martel I, Tenenhouse HS. Effects of Npt2 gene ablation and low Pi-diet on renal Na+-phosphate cotransport and cotransporter gene expression. J Clin Invest. 1999; 104:679-686.
  27. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan KN, Tenenhouse HS, Jüppner H. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Gen. 2006; 78:179-192.
  28. Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol. 2013; 75:535-550.
  29. Lötscher M, Scarpetta Y, Levi M, Halaihel N, Wang H, Zajicek HK, Biber J, Murer H, Kaissling B. Rapid downregulation of rat renal Na/P(i) cotransporter in response to parathyroid hormone involves microtubule rearrangement. J Clin Invest. 1999; 104(4):483-494.
  30. Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch. 2014; 466:139-153.
  31. Segawa H, Yamanaka S, Ito M, Kuwahata M, Shono M, Yamamoto T, Miyamoto K. Internalization of renal type IIc Na-Pi cotransporter in response to a high-phosphate diet. Am J Physiol Renal Physiol. 2005; 288:F587-F596.
  32. Foster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: a molecular perspective. Kidney Int. 2006; 70:1548-1559.
  33. Farrow EG, White KE. Recent advances in renal phosphate handling. Nat Rev Nephrol. 2010; 6(4):207-217.
  34. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab. 2006; 91:3144-3149.
  35. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006; 444:770-774.
  36. Belov AA, Mohammadi M. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol. 2013; 5:6.
  37. Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone. 2012; 51:621-628.
  38. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T . Cloning and characterization of FGF-23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA. 2001; 98:6500-6505.
  39. Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J. 2006; 6:720-722.
  40. Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, Fujita T, Wada M, Yamashita T, Fukumoto S, Shimada T. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009 Nov;24(11):1879-88.
  41. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Shawkat Razzaque M, Rosenblatt KP, Baum MG, Kuro-O M, Moe OW. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010; 24(9):3438-3450.
  42. Brownstein CA, Adler F, Nelson-Williams C, Iijma J, Imura A, Nabehsima Y, Carpenter TO, Lifton RP. A translocation causing increased α–Klotho level results in hypophosphatemic rickets and hyperparathyroidism. PNAS USA. 2008; 105:3455-3460.
  43. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, Li J, Shehadeh LA, Hare JM, David V, Martin A, Fornoni A, Di Marco GS, Kentrup D, Reuter S, Mayer AB, Pavenstädt H, Stypmann J, Kuhn C, Hille S, Frey N, Leifheit-Nestler M, Richter B, Haffner D, Abraham R, Bange J, Sperl B, Ullrich A, Brand M, Wolf M, Faul C. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015; 22(6):1020-32.
  44. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MH, Oudet CL. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics. 2000; 67:54-68.
  45. Berndt T, Craig TA, Howe AE, Vassiliadis J, Reczek D, Finnegan R, Jan de Beur SM, Schiavi SC, Kumar R.Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003; 112:785-794.
  46. Wagner GF, Dimattia GE. The stanniocalcin family of proteins. J Exp Zoolog, A Comp Exp Biol. 2006; 305:769-780.
  47. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R. FGF7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab. 2005; 90:1012-1020.
  48. Dallas SL, Prideaux M, Bonewald LF.The osteocyte: an endocrine cell ... and more. Endocr Rev. 2013; 34:658-690.
  49. Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice. PLoS Biol. 2016;14(4):e1002427.
  50. Hoac B, Østergaard M, Wittig NK, Boukpessi T, Buss DJ, Chaussain C, Birkedal H, Murshed M, McKee MD. Genetic ablation of osteopontin in osteomalacic Hyp mice partially rescues the deficient mineralization without correcting hypophosphatemia. J Bone Miner Res. 2020;35(10):2032-2048.
  51. Bai X, Miao D, Goltzman D, Karaplis AC. Early lethality in hyp mice with targeted deletion of Pth gene.Endocrinology. 2007; 148(10):4974-83.
  52. Carpenter TO, Olear EA, Zhang JH, Ellis BK, Simpson CA, Cheng D, Gundberg CM, Insogna KL. Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2014; 99(9):3103-11.
  53. Lanske B, Razzaque MS. Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int. 2014; 86(6):1072-4.
  54. Sabbagh Y, Carpenter TO, Demay M. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Nat Acad Sci. 2005; 102:9637-9642.
  55. Glimcher MJ .In: Aurbach GD ed. Handbook of physiology: endocrinology, parathyroid gland, sect 7, vol 7. Washington, D.C.: American Physiological Society. 1996; 21-32.
  56. Bordier PJ, Tun Chot S. Quantitative histology of metabolic bone disease. Clin Endocrinol Metab. 1972; 1:197-215.
  57. Frame B, Parfitt AM. Osteomalacia: current concepts. Ann Intern Med. 1978; 89:966-982.
  58. Mumm S, Huskey M, Cajic A, Wollberg V, Zhang F, Madson KL, Wenkert D, McAlister WH, Gottesman GS, Whyte MP. PHEX 3'-UTR c.*231A&gt;G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets. J Bone Miner Res. 2015; 30(1):137-43.
  59. Harrison HE, Harrison HC, Lifshitz F, Johnson AD. Growth disturbance in hereditary hypophosphatemia. Am J Dis Child. 1996; 112:290-297.
  60. Mao M, Carpenter TO, Whyte MP, Skrinar A, Chen CY, San Martin J, Rogol AD. Growth curves for children with X-linked Hypophosphatemia. J Clin Endocrinol Metab 105: 32439, 2020.
  61. Williams TF, Winters RW. Familial (hereditary) vitamin D-resistant rickets with hypophosphatemia. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease. 3rd ed. New York: McGraw-Hill. 1983; 1465-1485.
  62. Tracey WE, Campbell RA. Dentofacial development in children with vitamin D resistant rickets. J Am Dent Assoc. 1968; 76:1026-1031.
  63. Shields ED, Scriver CR, Reade T, Fujiwara TM, Morgan K, Ciampi A, Schwartz S. X-linked hypophosphatemia: the mutant gene is expressed in teeth as well as in kidney. Am J Human Gen. 1990; 46:434-442.
  64. Marie PJ, Glorieux FH. Relation between hypomineralized periosteocytic lesions and bone mineralization in vitamin D-resistant rickets. Calcif Tissue Int. 1983; 35:443-448.
  65. Polisson RP, Martinex S, Khoury M, Harrell RM, Lyles KW, Friedman N, Harrelson JM, Reisner E, Drezner MK. Calcificantion of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med. 1985; 313:1-6.
  66. Pierce DS, Wallace WM, Herndon CH. Long term treatment of vitamin D-resistant rickets. J Bone Joint Surg Am. 1964; 46:978-997.
  67. Connor J, Olear EA, Insogna KL, Katz L, Baker SD, Kaur RD, Simpson CA, Sterpka J, Dubrow R, Zhang JH, Carpenter TO. Conventional therapy in adults with X-linked hypophosphatemia: effects on enthesopathy and dental disease. J Clin Endocrinol Metab. 2015; 100:3625-3632.
  68. Steindijk R. On the pathogenesis of vitamin D resistant rickets and primary vitamin D resistant rickets. Helv Paediatr Acta. 1962; 17:65-85.
  69. Stickler GB External calcium and phosphorus balances in vitamin D-resistant rickets. J Pediatr. 1963; 63:942-948.
  70. Drezner MK, Lyles KW, Haussler MR, Harrelson JM. Evaluation of a role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia. J Clin Invest. 1980; 66:1020-1032.
  71. Haddad JG, Chyu KJ, Hahn TJ, Stamp TCB. Serum concentrations of 25-hydroxyvitamin D in sex linked hypophosphatemic vitamin D-resistant rickets. J Lab Clin Med. 1973; 81:22-27.
  72. Tenenhouse HS. Abnormal renal mitochondrial 25-hydroxyvitamin D3-1-hydroxylase activity in the vitamin D and calcium deficient X-linked Hyp mouse. Endocrinology. 1983; 113:816-818.
  73. Roy S, Martel J, Ma S, Tenenhouse HS. Increased renal 25-hydroxyvitamin D3-24-hydroxylase messenger ribonucleic acid and immunoreactive protein in phosphate-deprived Hyp mice: a mechanism for accelerated 1,25-dihydroxyvitamin D3 catabolism in X-linked hypophosphatemic rickets. Endocrinology. 1994; 134:1761-1767.
  74. Winters RW, Graham JB, Williams TF, McFalls VW, Burnett CH. A genetic study of familial hypophosphatemia and vitamin D-resistant rickets with a review of the literature. Medicine (Baltimore). 1958; 37:97-142.
  75. Burnett CH, Dent CE, Harper C, Warland BJ Vitamin D resistant rickets: analysis of 24 pedigrees and hereditary and sporadic cases. Am J Med. 1964; 36:222-232.
  76. Francis F, Henning S, Korn B, Reinhardt R, de Jong P, Poustka A, Lehrach H, Rowe PSN, Goulding JN, Summerfield T, Mountford R, Read AP, Popowska E, Pronicka E, Davies KE, O’Riordan JLH, Econs MJ, Nesbitt T, Drezner MK, Oudet C, Hanauer A, Strom TM, Meindl A, Lorenz B, Cagnoli M, Mohnike KL, Murken J, Meitinger T. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995; 11:130-136.
  77. Lipman ML, Dibyendu P, Hugh PJ, Bennett JE, Henderson ES, Yingnian S, Goltzman D, Daraplis AC. Cloning of human Pex cDNA: expression subcellular localization and endopeptidase activity. J Biol Chem. 1998; 273:13729-13737.
  78. Thompson DL, Roche PC, Drezner MK, Salisbury JL, Sabbagh Y, Tenenhouse HS, Grande JP, Poeschlia EM, Kumar R.Ontogeny of PHEX/PEX expression in the mouse embryo and studies on the subcellular localization of PHEX/PEX in osteoblasts. J Bone Miner Res. 2002; 17:311-320.
  79. Sabbagh, Y., Boileau, G., Campos, M., Carmona, A. K., & Tenenhouse, H. S. (2003). Structure and function of disease-causing missense mutations in the PHEX gene. TheJournal of Clinical Endocrinology and Metabolism, 88(5), 2213– 2222.
  80. Sabbagh, Y., Boileau, G., DesGroseillers, L., & Tenenhouse, H. S. (2001). Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Human Molecular Genetics, 10(15), 1539–1546.
  81. Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS. Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest. 1997; 99:1200-1209.
  82. Zoidis E, Zapf J, Schmid C. Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo. Mol Cell Endocrinol. 2000; 168:41-51.
  83. Ruchon AF, Tenenhouse HS, Marcinkiewicz M, Siegfried G, Aubin JE, DesGroseillers L, Crine P, Boileau G. Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. J Bone Miner Res. 2000; 15:1440-1450.
  84. Ruchon AF, Marcinkiewicz M, Siegfried G, Tenenhouse HS, DesGroseillers L, Crine P, Boileau G. Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. J Histochem Cytochem. 1998; 46:459-468.
  85. Sarafrazi S, Daugherty SC, Miller N, Boada P, Carpenter TO, Chunn L, Dill K, Econs MJ, Eisenbeis S, Imel EA, Johnson B, Kiel MJ, Krolczk S, Ramesan P, Truty R, Sabbagh Y. Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-Linked Hypophosphatemia (XLH). HumanMutation 43(2):143-157, 2022.
  86. Liu S, Guo R, Tu Q, Quarles LD. Overexpression of phex in osteoblasts fails to rescue the hyp-mouse phenotype. J Biol Chem. 2002; 277:3686-3697.
  87. Bai X, Miao D, Panda D, Grady S, McKee MD, Goltzman D, Karaplis AC. Partial rescue of the hyp phenotype by osteoblast-targeted PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) expression. Mol Endocrinol. 2002; 16:2913-2925.
  88. Boskey A, Frank A, Fujimoto Y, Spevak L, Verdelis K, Ellis B, Philbrick W, Carpenter T. The PHEX transgene corrects mineralization defects in 9-month-old hypophosphatemic mice. Calcif Tiss Int. 2009; 84:126-137.
  89. David V, Martin A, Hedge AM, Drezner MK, Rowe PS. ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol. 2011; 300(3):F783-91.
  90. Morgan JM, Hawley WL, Chenoweth AI, Retan WJ, Diethelm AG. Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch Intern Med. 1974; 134(3):549-52
  91. Meyer RA Jr, Meyer MH, Gray RW . Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J Bone Miner Res. 1989; 4:493-500.
  92. Nesbitt T, Coffman TM, Griffiths R, Drezner MK. Cross transplantation of kidneys in normal and hyp-mice: evidence that the hyp-mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest. 1992; 89:1453-1459.
  93. Tenenhouse HS, Beck L. Renal Na+-P cotransporter gene expression in X-linked Hyp and Gy mice. Kidney Int. 1996; 49:1027-1032.
  94. Tenenhouse HS, Martel J, Biber J, Murer H. Effect of P(i) restriction on renal Na(+)-P(i) cotransporter mRNA and immunoreactive protein in X-linked Hyp mice. Am J Physiol. 1995; 268: F1062-F1069.
  95. Tenenhouse HS, Martel J, Gauthier C, Segawa H, Miyamoto K. Differential effects of Npt2a gene ablation and X-linked Hyp mutation on renal expression of Npt2c. Am J Physiol Renal Physiol. 2003; 285(6):F1271-F1278.
  96. White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Jüppner H, Econs MJ. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001; 86:497-500.
  97. The ADHR Consortium. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF-23. Nat Genet. 2000; 26:345-348.
  98. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006; 38:1310-1315.
  99. Levy-Litan V, Hershkovitz E, Avizov L, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010; 86(2):273-278..
  100. Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010; 86(2):267-272.
  101. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Höhne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nürnberg P. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 2003; 34(4):379-381.
  102. Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, Gahl WA. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genet Med. 2021; 23(2):396-407.
  103. Yoskida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1 -hydroxylase gene. Endocrinology. 2002; 143:683-689.
  104. Brownstein C, Zhang J, Stillman A, Ellis B, Troiano N, Adams DJ, Gundberg CM, Lifton RP, Carpenter TO. Increased bone volume and correction of HYP mouse hypophosphatemia in the Klotho/HYP mouse. Endocrinology. 2010; 151: 492-501.
  105. Smith RC, O'Bryan LM, Farrow EG, Summers LJ, Clinkenbeard EL, Roberts JL, Cass TA, Saha J, Broderick C, Ma YL, Zeng QQ, Kharitonenkov A, Wilson JM, Guo Q, Sun H, Allen MR, Burr DB, Breyer MD, White KE. Circulating αKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest. 2012; 122:4710-4715.
  106. Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology. 2009; 150(6):2543-2550.
  107. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004; 36:579-81.
  108. Ichikawa S, Baujat G, Seyahi A, Garoufali AG, Imel EA, Padgett LR, Austin AM, Sorenson AH, Pejin Z, Topouchian V, Quartier P, Cormier-Daire V, Dechaux M, Malandrinou FCh, Singhellakis PN, Le Merrer M, Econs MJ.Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am J Med Genet A. 2010; 152A:896-903.
  109. Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014; 111:5520-5525.
  110. Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013; 28:1378-1385.
  111. Larsson T, Yu X, Davis SI, Draman MS, Mooney SD, Cullen MJ, White KE. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab. 2005; 90:2424-2427.
  112. Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007; 117(9):2684-2691.
  113. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI.Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390:45-51.
  114. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med. 1980; 303:1223-1231.
  115. Costa T, Marie P, Scriver CR, Cole DEC, Reade TM, Norgrady B, Glorieux FH, Delvin EE. X-linked hypophosphatemia: effect of calcitriol on renal handling of phosphate, serum phosphate and bone mineralization. J Clin Endocrinol Metab. 1981; 52:463-477.
  116. Harrell RM, Lyles KW, Harrelson JM, Freedman NE, Drezner MK . Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia: induction and maintenance with phosphorus and calcitriol. J Clin Invest. 1985; 75:1858-1864.
  117. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G 2001 Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets. J Pediatr. 1985; 138:236-243.
  118. Haffner D, Wuhl E, Blum WF, Schaefer F, Mehls O. Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr. 1995; 154:610-613.
  119. Zivicnjak M, Schnabel D, Staude H, et al. Three-Year Growth Hormone Treatment in Short Children with X-Linked Hypophosphatemic Rickets: Effects on Linear Growth and Body Disproportion. J Clin Endocrinol Metab.2011; 96(12):E2097-E2105.
  120. Smith S, Remmington T.Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database Syst Rev. 2021 Oct 7;10(10):CD004447.
  121. Sullivan W, Carpenter TO, Glorieux F, Travers R, Insogna K. A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy on symptomatic adults with X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 1992; 75:879-885.
  122. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011; 26(7):1381-1388.
  123. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019 Jul;15(7):435-455.
  124. Laurent MR, De Schepper J, Trouet D, Godefroid N, Boros E, Heinrichs C, Bravenboer B, Velkeniers B, Lammens J, Harvengt P, Cavalier E, Kaux JF, Lombet J, De Waele K, Verroken C, van Hoeck K, Mortier GR, Levtchenko E, Vande Walle J. Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium. Front Endocrinol (Lausanne). 2021 Mar 19;12:641543. doi: 10.3389/fendo.2021.641543. eCollection 2021.
  125. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M.Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014; 124:1587-1597.
  126. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, Peacock M, Carpenter TO. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab. 2015; 100, 2565-2573.
  127. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, Padidela R, Van't Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018 May 24;378(21):1987-1998.
  128. Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Mar;7(3):189-199.
  129. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA.Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427.
  130. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA, Weber T, Pitukcheewanont P, Cheong HI, Jan de Beur S, Imanishi Y, Ito N, Lachmann RH, Tanaka H, Perwad F, Zhang L, Chen CY, Theodore-Oklota C, Mealiffe M, San Martin J, Carpenter TO; AXLES 1 Investigators. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018 Aug;33(8):1383-1393.
  131. Insogna KL, Rauch F, Kamenický P, Ito N, Kubota T, Nakamura A, Zhang L, Mealiffe M, San Martin J, Portale AA. Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial. J Bone Miner Res. 2019 Dec;34(12):2183-2191.
  132. Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM, Padidela R, Van't Hoff W, Gottesman GS, Chen A, Skrinar A, Scott Roberts M, Carpenter TO. Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):813-824.
  133. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019 Jun 15;393(10189):2416-2427.
  134. Harrison HE, Harrison HC. Rickets and osteomalacia. In: disorders of calcium and phosphate metabolism in childhood and adolescence. Philadelphia: WB Saunders. 1979; 141-256.
  135. Econs M, McEnery P. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate wasting disorder. J Clin Endocrinol Metab. 1997; 82:674-681.
  136. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007; 22(4):520-526.
  137. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011; 96: 3541-3549.
  138. Kapelari K, Köhle J, Kotzot D, Högler W. Iron supplementation associated with loss of phenotype in autosomal dominant hypophosphatemic rickets. J Clin Endocrinol Metab. 2015; 100(9):3388-92.
  139. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Jüppner H, Strom TM. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006; 38:1248-1250..
  140. Rutsch F, Böyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, Davies JH, Loirat C, Strom TM, Schnabel D, Nürnberg P, Terkeltaub R; GACI study group hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008; 1(2):133-140.
  141. Ferreira CR, Ziegler SG, Gupta A, Groden C, Hsu KS. Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification. Am J Med Genet A. 2016; 170A(5):1308-11.
  142. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular P transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001; 284:977-981.
  143. Breer S, Brunkhorst T, Beil FT, Peldschus K, Heiland M, Klutmann S, Barvencik F, Zustin J, Gratz KF, Amling M. 68Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT. Bone. 2014; 64:222-227.
  144. El-Maouche D, Sadowski SM, Papadakis GZ, Guthrie L, Cottle-Delisle C, Merkel R, Millo C, Chen CC, Kebebew E, Collins MT. 68Ga-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia. J Clin Endocrinol Metab. 2016 ;101(10):3575-3581.
  145. Andreopoulou P, Dumitrescu CE, Kelly MH, Brillante BA, Cutler Peck CM, Wodajo FM, Chang R, Collins MT. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. J Bone Miner Res. 2011; 26:1295-1302.
  146. Jan De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D, Estes S, Manavalan P, Petroziello J, Madden SL, Cho JY, Kumar R, Levine MA, Schiavi SC. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res. 2002; 17:1102-1110.
  147. Xiao L, Naganawa T, Lorenzo J, Carpenter TO, CoffinJD, Hurley MM. Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and Klotho. J Biol Chem. 2010; 285:2843-2846.
  148. Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Mariño-Enríquez A, Chen CC, Folpe AL, Chang YL, Liang CW. Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol. 2015; 235:539-545.
  149. Lee JC, Su SY, Changou CA, Yang RS, Tsai KS, Collins MT, Orwoll ES, Lin CY, Chen SH, Shih SR, Lee CH, Oda Y, Billings SD, Li CF, Nielsen GP, Konishi E, Petersson F, Carpenter TO, Sittampalam K, Huang HY, Folpe AL. Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol. 2016; 29:1335-1346.
  150. Jan de Beur SM, Miller PD, Weber TJ, Peacock M, Insogna K, Kumar R, Rauch F, Luca D, Cimms T, Roberts MS, San Martin J, Carpenter TO. Burosumab for the Treatment of Tumor-Induced Osteomalacia. J Bone Miner Res. 2021;36(4):627-635.
  151. de Castro LF, Ovejero D, Boyce AM. Eur J Endocrinol. DIAGNOSIS OF ENDOCRINE DISEASE: Mosaic disorders of FGF23 excess: Fibrous dysplasia/McCune-Albright syndrome and cutaneous skeletal hypophosphatemia syndrome. 2020 May;182(5):R83-R99. doi: 10.1530/EJE-19-0969
  152. Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, Kelley PK, Jüppner H, Gottschalk M, Tifft CJ, Gafni RI, Boyce AM, Cowen EW, Bhattacharyya N, Guthrie LC, Gahl WA, Golas G, Loring EC, Overton JD, Mane SM, Lifton RP, Levy ML, Collins MT, Choate KA. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet. 2014; 23:397-407.
  153. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet. 2005; 76(2):361-367.
  154. Brown WW, Jüppner H, Langman CB, Price H, Farrow EG, White KE, McCormick KLHypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 2009; 94(1):17-20.
  155. Fradet A, Fitzgerald J. INPPL1 gene mutations in opsismodysplasia. J Hum Genet. 2017;62(2):135-140.
  156. Tieder M, Modai D, Samuel R, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985; 312:611-617.
  157. Tieder M, Modai D, Shaked U, et al. Idiopathic hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med. 1987; 316:125-129.
  158. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006; 78:193-201.
  159. Jaureguiberry G, Carpenter TO, Forman S, Jüppner H, Bergwitz C. A novel missense mutation in SLC34A3 that causes HHRH identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol. 2008; 295: F371-F379.
  160. Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K: A loss-of-function mutation in NaPi-IIa and renal fanconi's syndrome. N Engl J Med. 2010; 362:1102-1109.
  161. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol. 2016; 27(2):604-14.
  162. Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA, Thakker RV. Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies. J Clin Invest. 1997; 91:2351-2357.
  163. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 1998; 53:3-17.
  164. Gonzalez Ballesteros LF, Ma NS, Gordon RJ, Ward L, Backeljauw P, Wasserman H, Weber DR, DiMeglio LA, Gagne J, Stein R, Cody D, Simmons K, Zimakas P, Topor LS, Agrawal S, Calabria A, Tebben P, Faircloth R, Imel EA, Casey L, Carpenter TO. Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children. Bone. 2017; 97, 287-292.
  165. Eswarakumar AS, Ma NS, Ward LM, Backeljauw P, Wasserman H, Weber DR, DiMeglio LA, Imel EA, Gagne J, Cody D, Zimakas P, Topor LS, Agrawal S, Calabria A, Tebben P, Faircloth RS, Gordon R, Casey L, Carpenter TO. Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation. Clin Pediatr (Phila). 2020;59(12):1080-1085.
  166. Harvey BM, Eussen SRBM, Harthoorn LF, Burks AW. Mineral Intake and Status of Cow's Milk Allergic Infants Consuming an Amino Acid-based Formula. J Pediatr Gastroenterol Nutr. 2017; 65(3):346-349.

Severe Hypothyroidism in the Elderly

CLINICAL RECOGNITION

 

Elderly patients with severe hypothyroidism often present with variable symptoms that may be masked or potentiated by co-morbid conditions. Characteristic symptoms may include fatigue, weight gain, cold intolerance, hoarseness, constipation, and myalgias. Neurologic symptoms may include ataxia, depression, and mental status changes ranging from mild confusion to overt dementia. Clinical findings that may raise suspicion of thyroid hormone deficiency include hypothermia, bradycardia, goitrous enlargement of the thyroid, cool dry skin, myxedema, delayed relaxation of deep tendon reflexes, a pericardial or abdominal effusion, hyponatremia, and hypercholesterolemia.

 

DIAGNOSIS AND DIFFERENTIAL

 

Autoimmune (Hashimoto’s) thyroiditis with destruction of functioning tissue is the most common endogenous cause of hypothyroidism in elderly patients. Checkpoint inhibitors that are used to treat a variety of malignancies can induce a rapidly progressing form of autoimmune thyroiditis. Unrecognized or untreated cases can progress to a state of pronounced thyroid hormone deficiency over weeks to months. Administration of radioactive iodine to treat hyperthyroidism ascribed to Graves’ disease usually causes permanent hypothyroidism. Surgery performed to remove thyroid cancer or an enlarged multinodular goiter inevitably leads to overt hypothyroidism. External beam radiation used to treat lymphoid malignancies and head and neck cancer can lead to rapid or delayed development of hypothyroidism. Pituitary dysfunction that inhibits secretion of TSH may be caused by growth of a mass in the sella turcica or may develop as a complication of surgery performed to remove a tumor. 

 

Table 1: Causes of Hypothyroidism in the Elderly

Primary hypothyroidism

Autoimmune (Hashimoto’s) thyroiditis

Amiodarone induced hypothyroidism

Lithium induced hypothyroidism

Post-ablative hypothyroidism

Post-surgical hypothyroidism

Radiation-induced hypothyroidism
Thyroiditis induced by checkpoint inhibitors, tyrosine kinase inhibitors, interferon alpha, or CAMPATH

Central hypothyroidism

Pituitary or hypothalamic dysfunction

Decreased absorption of levothyroxine

Celiac disease

Drugs: iron sulfate, bile acid resins, sucralfate, calcium

Accelerated metabolism of thyroid hormone

Increased deiodinase activity (consumptive hypothyroidism)

Drugs: phenytoin, phenobarbital, carbamazepine, rifampin

 

DIAGNOSTIC TESTS NEEDED AND SUGGESTED

 

Laboratory tests that demonstrate an elevated TSH level in tandem with a low free or total T4 level confirm a diagnosis of primary hypothyroidism. Commonly used drugs including ASA and phenytoin lower total T4 levels and may cause interference with FT4 assays. Anti-thyroid peroxidase and anti-thyroglobulin antibody levels may be checked to confirm the presence of autoimmune thyroiditis, but this usually isn’t necessary as it is the presumptive diagnosis in patients who haven’t been treated with other predisposing therapies. A low free or total T4 level detected in tandem with a low or inappropriately normal TSH level may raise suspicion of central hypothyroidism. This may prompt further biochemical evaluation of other pituitary hormones and anatomic imaging of the pituitary and hypothalamus. Serious illness in the elderly is often accompanied by the non-thyroidal illness (euthyroid sick) syndrome that presents with a normal or low total T4 level, a low total T3 level, and an inappropriately low or normal TSH level. Recognition of this syndrome requires exclusion of other causes of hypothyroidism or pituitary dysfunction. Appropriate treatment of this condition is controversial. Subclinical hypothyroidism, with a normal range freeT4 level and elevated TSH level is not infrequent in elderly patients, and if due to autoimmune thyroiditis, often progresses to overt hypothyroidism.

 

THERAPY

 

Levothyroxine (T4) is the principal thyroid hormone preparation used to treat hypothyroidism. Regimens that include liothyronine (T3) have not been shown to be any more efficacious and run the risk of triggering atrial arrhythmias in susceptible individuals. Most adults require a full replacement dose of 1.6 mcg per kilogram of body weight. The major concern in elderly patients with known or suspected cardiovascular disease is to avoid exacerbating underlying conditions. In these circumstances levothyroxine should be started at a low dose of 12.5-25 mcg daily. If this dose does not provoke ischemic symptoms or an atrial arrhythmia, it can be increased in 25 mcg increment at 4-week intervals. Patients who develop hypothyroidism after treatment of hyperthyroidism can be treated with full replacement doses from the outset. Agents that may block absorption of levothyroxine include iron sulfate, bile acid resins, sucralfate, and supplemental forms of calcium. Doses should be separated from ingestion of these agents by at least 4 hours. Higher than anticipated doses may be required in patients treated with other agents that increase metabolism of levothyroxine including phenytoin, phenobarbital, carbamazepine, and rifampin.

Appropriate treatment of subclinical hypothyroidism is open to debate. Some clinicians feel that treatment is indicated with any confirmed and unexplained elevation of TSH above normal but most clinicians do not initiate replacement therapy in elderly patients until the TSH level is > 10uU/ml on several occasions.

 

FOLLOW-UP

 

When treating primary hypothyroidism, a TSH level should be checked 6 weeks after starting a dose or 4 weeks after changing a dose of levothyroxine. Doses should be adjusted to maintain a TSH level within the reference range. Maintenance of a slightly elevated TSH level may be acceptable in cases where treatment to a full replacement dose triggers ischemic symptoms or atrial arrhythmias. When treating central hypothyroidism, doses should be adjusted to maintain a free T4 level in the upper half of the reference range. The TSH level is unreliable in this setting and should not be used to guide treatment.

 

GUIDELINES

 

Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24(12):1670-751

 

Jeffrey R. Garber, Rhoda H. Cobin, Hossein Gharib, James V. Hennessey, Irwin Klein, Jeffrey I. Mechanick, Rachel Pessah-Pollack, Peter A. Singer, and Kenneth A. Woeber. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028.

 

REFERENCES

 

Kim MI. Hypothyroidism in Older Adults. 2020 Jul 14. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.

 

Feldt-Rasmussen U. Treatment of hypothyroidism in elderly patients and in patients with cardiac disease. Thyroid. 2007 Jul;17(7):619-24.

 

Wiersinga WM. Adult Hypothyroidism.2014 Mar 28. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–

 

Akamizu T, Amino N. Hashimoto’s Thyroiditis. 2017 Jul 17. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.