Chapter 13 - Nicolas C. Nicolaides,MD, Evangelia Charmandari,MD George P. Chrousos, MD
Division of Endocrinology and Metabolism (N.C.N., E.C., G.P.C.), Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens, 11527, Greece ; and First Department of Pediatrics (E.C., G.P.C.), University of Athens Medical School, “Aghia Sophia” Children’s Hospital, Athens, 11527, Greece
January 22, 2011
TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE
Adrenal insufficiency is a disorder first described by Thomas Addison in 1855, which is characterized by impaired adrenocortical function and decreased production of glucocorticoids, mineralocorticoids and/or adrenal androgens ( 1 ). Adrenal insufficiency can be caused by diseases affecting the adrenal cortex (primary), the pituitary gland and the secretion of adrenocorticotropic hormone (ACTH) (secondary), or the hypothalamus and the secretion of corticotropic-releasing hormone (CRH) (tertiary). This chapter will provide a brief overview of the etiology, clinical manifestations, diagnosis and treatment of adrenal insufficiency.
The etiology of primary adrenal insufficiency has changed over time. Prior to 1920, the most common cause of primary adrenal insufficiency was tuberculosis, while since 1950, the majority of cases have been ascribed to autoimmune adrenalitis, either in isolation or in the context of complex polyglandular syndromes ( 2 ).
Autoimmune adrenalitis : This condition is the result of an autoimmune process that destroys the adrenal cortex. Both humoral and cell-mediated immune mechanisms directed at the adrenal cortex are involved. The adrenals appear small and atrophic and the surrounding capsule is thickened. Antibodies that react with several steroidogenic enzymes, as well as all three zones of the adrenal cortex are detected in 60-75% of patients with autoimmune primary adrenal insufficiency, but only rarely in patients with other causes of adrenal insufficiency or normal subjects ( 3 , 4 ). Considerable progress has been made in identifying genetic factors that predispose to the development of autoimmune adrenal insufficiency ( 5 ). In addition to the well-known association of the HLA genotype DR3/4-DQB1*0302 with type 1 diabetes mellitus and adrenal insufficiency, a strong susceptibility for the latter was also found for the DR3-DQ2/DRB1*0404-DQ8 genotype, which predicted early onset of primary adrenal insufficiency ( 6 ). Moreover, a polymorphism of another major histocompatibility complex gene MICA5.1 was found to predispose subjects to the development of adrenal insufficiency ( 7 ). However, the role of these genetic factors in clinical practice has not been established.
Autoimmune adrenalitis may present in isolation or may be accompanied by other diseases. Approximately 50% of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders ( 8 , 9 ), whereas patients with the more common autoimmune endocrine disorders, such as type 1 diabetes mellitus, chronic autoimmune thyroiditis, or Graves' disease, rarely develop adrenal insufficiency. The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune syndromes type I and II ( 10-12 ) ( Table 1 ).
Table 1. Etiology of Adrenal Insufficiency
Primary Adrenal Insufficiency
Autoimmune (polyglandular failure)
Sarcoidosis, amyloidosis, hemochromatosis
Hemorrhage (meningococcemia, anticoagulants, trauma)
Congenital adrenal hyperplasia
Congenital adrenal hypoplasia
Congenital unresponsiveness to ACTH (glucocorticoid deficiency, ACTH resistance)
Aquired immynodeficiency syndrome
Steroid synthesis inhibitors (e.g., metyrapone, ketoconazole, aminoglutethimide)
Adrenolytic agents (o,p’DDD, suramin)
Glucocorticoid antagonists (RU 486)
Secondary and Tertiary Adrenal Insufficiency
Following discontinuation of exogenous glucocorticoids or ACTH
Following the cure of Cushing’s syndrome
Pituitary and hypothalamic lesions
Congenital aplasia, hypoplasia, dysplasia, ectopy
Pituitary-hypothalamic hemorrhage (apoplexy)
Acquired isolated ACTH deficiency
Familial corticosteroid-binding-globulin deficiency
Infectious adrenalitis : Many infectious agents may attack the adrenal gland and result in adrenal insufficiency, including tuberculosis (tuberculous adrenalitis), disseminated fungal infections and HIV-associated infections, such as adrenalitis due to cytomegalovirus and mycobacterium avium complex ( 13-15 ).
Hemorrhagic infarction: Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency ( 16 , 17 ). The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen shows bilateral adrenal enlargement. Several coagulopathies and the heparin-induced thrombocytopenia syndrome have been associated with adrenal vein thrombosis and hemorrhage, while the primary antiphospholipid syndrome has been recognized as a major cause of adrenal hemorrhage ( 2 ). Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection ( 18 ).
Adrenoleukodystrophy : This is an X-linked recessive disorder affecting 1 in 20.000 males ( 5 ). Adrenoleukodystrophy is characterized by spastic paralysis and adrenal insufficiency, usually beginning in infancy or childhood, and is caused by mutations in the ABCD1 gene, resulting in defective beta oxidation of very long chain fatty acids (VLCFAs) within peroxisomes. The abnormally high concentrations of VLCFAs in many organs, including the adrenal cortex, result in the clinical manifestations of this disorder ( 19 ).
Drug-induced adrenal insufficiency : Drugs that may cause adrenal insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with limited pituitary and/or adrenal reserve, include aminoglutethimide (antiepileptic) ( 20 ), etomidate (anesthetic-sedative) ( 21 , 22 ), ketoconazole (antimycotic) ( 23 ) and metyrapone ( 24 ). Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, and rifampicin can also cause adrenal insufficiency in patients with limited pituitary or adrenal reserve, as well as those who are on replacement therapy with glucocorticoids ( 25 ). Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib) have been shown in animal studies to cause adrenal dysfunction and hemorrhage ( 26 ) .
Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits ( Table 1 ). The most common cause of secondary adrenal insufficiency is exogenous glucocorticoid administration therapy. On the other hand, tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. The most common causes of tertiary adrenal insufficiency are abrupt cessation of high-dose glucocorticoid therapy and treatment of Cushing's syndrome ( 27 ).
In primary adrenal insufficiency, all the above mentioned causes result in gradual destruction of the adrenal cortex. However, the clinical manifestations of the condition appear when the loss of the adrenocortical tissue of both glands is higher than 90% ( 2 ). In the initial phase of chronic gradual destruction, the adrenal reserve is decreased and although the basal steroid secretion is normal, the secretion in response to stress is suboptimal. Consequently, any major or even minor stressor can precipitate an acute adrenal crisis. With further loss of adrenocortical tissue, even basal steroid secretion is decreased, leading to the clinical manifestations of the disease. Low plasma cortisol concentrations result in the increase of production and secretion of ACTH due to decreased negative feedback inhibition ( 2 ). The elevated plasma ACTH concentrations are responsible for the well-recognised hyperpigmentation observed in these patients.
ACTH deficiency leads to decreased secretion of cortisol and adrenal androgens, while mineralocorticoid production remains normal. In the early stages, basal ACTH secretion is normal, while that of stress-induced is impaired ( 2 ). With further loss of basal ACTH secretion, there is atrophy of zonae fasciculata and reticularis of the adrenal cortex. Therefore, basal cortisol secretion is decreased but aldosterone secretion by the zona glomerulosa is preserved.
The clinical manifestations of adrenal insufficiency depend upon the extent of loss of adrenal function and whether mineralocorticoid production is preserved. The onset of adrenal insufficiency is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis ( 27 , 28 ).
Adrenal Crisis: Adrenal crisis or acute adrenal insufficiency may complicate the course of chronic primary adrenal insufficiency, and may be precipitated by a serious infection, acute stress, bilateral adrenal infarction or hemorrhage. It is rare in patients with secondary or tertiary adrenal insufficiency. The main clinical manifestation of adrenal crisis is shock, but patients may also have nonspecific symptoms, such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, confusion or coma. Hypoglycemia is rare in acute adrenal insufficiency, but more common in secondary adrenal insufficiency. Hypoglycemia is a common manifestation in children and thin women with the disorder. Hyperpigmentation due to chronic ACTH hypersecretion and weight loss are indicative of long-standing adrenal insufficiency, while additional symptoms and signs relating to the primary cause of adrenal insufficiency may also be present.
The major factor precipitating an adrenal crisis is mineralocorticoid deficiency and the main clinical problem is hypotension. Adrenal crisis can occur in patients receiving appropriate doses of glucocorticoid if their mineralocorticoid requirements are not met ( 29 ), whereas patients with secondary adrenal insufficiency and normal aldosterone secretion rarely present in adrenal crisis. However, glucocorticoid deficiency may also contribute to hypotension by decreasing vascular responsiveness to angiotensin II, norepinephrine and other vasoconstrictive hormones, reducing the synthesis of renin substrate, and increasing the production and effects of prostacyclin and other vasodilatory hormones ( 30 , 31 ).
Chronic Primary Adrenal Insufficiency: Patients with chronic primary adrenal insufficiency may have symptoms and signs of glucocorticoid, mineralocorticoid, and androgen deficiency. By contrast, patients with secondary or tertiary adrenal insufficiency usually have normal mineralocorticoid function. The onset of chronic adrenal insufficiency is often insidious and the diagnosis may be difficult in the early stages of the disease.
The most common clinical manifestations of chronic primary adrenal insufficiency include general malaise, fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain or diarrhea, which may alternate with constipation, hypotension, electrolyte abnormalities (hyponatremia, hyperkalemia, metabolic acidosis), hyperpigmentation, autoimmune manifestations (vitiligo), decreased axillary and pubic hair, and loss of libido and amenorrhea in women ( 27 , 28 ).
Secondary or Tertiary Adrenal Insufficiency: The clinical features of secondary or tertiary adrenal insufficiency are similar to those of primary adrenal insufficiency. However, hyperpigmentation is not present because ACTH secretion is not increased. Also, given that the production of mineralococorticoids by the zona glomerulosa is mostly preserved, dehydration and hyperkalemia are not present, and hypotension is less prominent. Hyponatremia and increased intravascular volume may be the result of “inappropriate” increase in vasopressin secretion. Hypoglycemia is more common in secondary adrenal insufficiency possibly due to concomitant growth hormone insufficiency and in isolated ACTH deficiency. Clinical manifestations of a pituitary or hypothalamic tumor, such as symptoms and signs of deficiency of other anterior pituitary hormones, headache or visual field defects, may also be present ( 27 , 28 ).
The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder ( 27 , 28 ).
Cortisol Secretion : The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (04:00h – 08:00h) and increase further with stress. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency ( 32 ), while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may be low-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency.
ACTH Secretion : Inappropriately low serum cortisol concentrations in association with increased plasma ACTH concentrations determined simultaneously are suggestive of primary adrenal insufficiency. On the other hand, inappropriately low baseline morning cortisol and ACTH concentrations indicate secondary or tertiary disease. Given that basal cortisol and ACTH secretion may be normal in partial adrenal insufficiency, stimulation tests of adrenocortical reserve must be performed in order to establish the diagnosis.
Short ACTH stimulation tests: The short ACTH stimulation test assesses the capacity of the adrenal cortex to respond to ACTH and should be performed in all patients suspected of having adrenal insufficiency. It involves the intravenous administration of synthetic ACTH (1-24) (cosyntropin), which has the full biologic potency of native ACTH (1-39) , and subsequent measurement of serum cortisol concentrations at regular intervals.
i) High-Dose ACTH stimulation test: This test consists of determining serum cortisol responses immediately before and 30 and 60 minutes after the intravenous administration of 250 µg of cosyntropin. This dose of cosyntropin results in pharmacologic (supra-physiologic) plasma ACTH concentrations for the 60 min duration of the test, which are often too high to detect cases of chronic partial and mild pituitary ACTH deficiency ( 33 ). Therefore, this test may miss mild cases of adrenal insufficiency. Also, in early acute secondary or tertiary adrenal insufficiency, as in Sheehan syndrome, the test is not reliable, because it takes several days for the adrenal cortex to atrophy. The advantage of the high-dose ACTH stimulation test is that the cosyntropin can be injected intravenously or intramuscularly, since pharmacologic plasma ACTH concentrations can still be achieved by either route ( 34 ).
A rise in serum cortisol concentration at 30 minutes to a peak of 18 to 20 µg/dL (500 to 550 nmol/L) or more is considered a normal response to high-dose ACTH stimulation test ( 35-37 ) and excludes the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency. However, if secondary adrenal insufficiency is of recent onset, the adrenal glands will have not yet atrophied, and will still be capable of responding to ACTH stimulation normally. In these cases, a low-dose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis ( 38 -40 ).
ii) Low-Dose ACTH stimulation test: This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. This test should be performed at 14:00h, when the endogenous secretion of ACTH is at its lowest. The results might not be valid if it is performed at another time. At 14:00h, a blood sample is collected for determination of basal cortisol concentrations. The low dose of ACTH (1-24) (500 nanograms ACTH(1-24)/1.73 m 2 ) is then administered as an intravenous bolus. In normal subjects, this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia ( 40 ). Subsequently, blood samples are collected at +10 min, +15 min, +20 min, +25 min, +30 min, +35 min, +40 min and +45 min after stimulation for determination of serum cortisol concentrations ( 28 ). A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard high-dose test ( 38-42 ). The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency ( 43-46 ).
In addition to serum cortisol concentrations, recent studies have demonstrated that salivary cortisol concentrations perform equally well when measured in the high-dose ACTH stimulation test in patients with secondary adrenal insufficiency ( 47 ).
Prolonged ACTH Stimulation Tests: Prolonged ACTH stimulation tests are rarely performed because the history and physical examination, the CRH test (see below) and/or the determination of cortisol and ACTH concentrations in association with the low-dose ACTH test may provide all necessary information. Prolonged stimulation with exogenous ACTH is used to differentiate between primary and secondary or tertiary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH.
i) Eight-hour ACTH stimulation test: This test consists of administering 250 µg (40 IU) of cosyntropin intravenously as an infusion over eight hours, and determining serum cortisol, and 24-hour urinary cortisol and 17-hydroxycorticoid (17-OHCS) concentrations before and after the infusion. In normal subjects, the 24-hour urinary 17-OHCS excretion increases 3- to 5-fold above the baseline. Serum cortisol concentrations reach 20 g/dL (550 nmol/L) at 30 to 60 min, and exceed 25 g/dL (690 nmol/L) at 6-8 hours post-initiation of the infusion.
ii) Two-day ACTH Stimulation Test: The two-day ACTH stimulation test is similar to the eight-hour infusion test, except that 250 µg of ACTH (1-24) are infused for over 24 hours on two (or three) consecutive days ( 48 ). This test may be helpful in distinguishing primary from secondary/tertiary adrenal insufficiency. In primary adrenal insufficiency there is no or a minimal response of plasma or urinary cortisol and urinary 17-OHCS. Increases of these values in the 2-3 days of the test are indicative of a secondary/tertiary cause of adrenal insufficiency.
CRH Stimulation Test: This test is used to differentiate between secondary and tertiary adrenal insufficiency. In both conditions, cortisol concentrations are low at baseline and remain low after CRH administration. In patients with secondary adrenal insufficiency, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response ( 49 , 50 ).
Additional investigations required to identify the cause of adrenal insufficiency vary depending on whether the disease is primary, secondary or tertiary.
Adrenal insufficiency is a potentially life-threatening condition. Treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis ( 51, 52 ).
Treatment of adrenal crisis: Adrenal crisis is a life-threatening emergency that requires immediate treatment. If the diagnosis is suspected blood samples should be obtained for measurement of cortisol concentrations.
Initial treatment: The aim of initial management in adrenal crisis is to treat hypotension, i.e., to correct hypovolemia, and to reverse the electrolyte abnormalities and cortisol deficiency. Large volumes of normal saline solution should be given intravenously. The glucocorticoid deficiency should be treated by immediate intravenous administration of dexamethasone sodium phosphate or hydrocortisone sodium succinate. Dexamethasone may be preferred because it has long-duration of action and does not interfere with the measurements of serum or urinary steroids during subsequent ACTH stimulation tests. Once the initial treatment is offered, the cause of the adrenal crisis should be sought and treated.
Subsequent treatment: Once the patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy.
Treatment of Chronic Adrenal Insufficiency: One of the important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy, the need to increase the dose of glucocorticoid during minor or major stress and to inject hydrocortisone, methylprednisolone or dexamethasone in emergencies.
Emergency precautions: Patients should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card, which should provide information on the diagnosis, the medications and daily doses, and the physician involved in the patient’s management. Patients should also have supplies of dexamethasone sodium phosphate and should be educated about how and when to administer them.
Glucocorticoid replacement therapy: Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be given in two to three divided doses. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses ( 53 ), as well as impaired quality of life ( 54 , 55 ) were observed in patients treated with hydrocortisone. A longer-acting synthetic glucocorticoid, such as prednisolone, prednisone or dexamethasone, may be employed but should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess, such as loss of lean body mass and bone density, and gain of visceral fat. The usual oral replacement dosages are 5-7.5 mg of prednisolone or prednisone or 0.25-0.75 mg of dexamethasone once daily.
Glucocorticoid replacement during minor illness or surgery: During minor illness or surgical procedures, the dosage of glucocorticoid can be increased up to three times the usual maintenance dosage for three days. Depending on the nature and severity of the illness, additional treatment may be required.
Glucocorticoid replacement during major illness or surgery: During major illness or surgery, high doses of glucocorticoid up to 10 times the daily production rate are required to avoid an adrenal crisis. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. This dose can be halved the second postoperative day, and the maintenance dose can be resumed the third postoperative day.
Mineralocorticoid replacement therapy: Mineralocorticoid replacement therapy is required to prevent sodium loss, intravascular volume depletion and hyperkalemia. It is given in the form of fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.1 mg daily. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range, while patients receiving hydrocortisone, which has some mineralocorticoid activity, may require lower doses. The mineralocorticoid dose may have to be increased in the summer, particularly if patients are exposed to temperatures above 29ºC (85ºF).
Androgen replacement: In women, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Although the physiologic role of these androgens in women has not been fully elucidated, their replacement is being increasingly considered in the treatment of adrenal insufficiency ( 56 , 57 ) but remains controversial ( 58 ). Dehydroepiandrosterone may be beneficial in females with hypopituitarism in whom there was significant improvement in pubic hair development ( 59 ).
Treatment of chronic secondary and tertiary adrenal insufficiency: In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary.
Critical illness-related corticosteroid insufficiency (“relative adrenal insufficiency”) is a syndrome characterized by dysfunction of the HPA axis that occurs during critical illness ( 60 ). Investigated mostly in cases of sepsis and septic shock ( 61-64 ), this syndrome is the consequence of adrenal insufficiency combined with glucocorticoid resistance. Strong inflammatory signals, such as cytokines (tumor necrosis- α ) or other peptides, known as corticostatins, compete with ACTH for binding on its cognate receptor, thus resulting in decreased cortisol production and secretion ( 65 ). Furthermore, other neuropeptides, signaling molecules, components of oxidative stress and the impaired adrenal blood flow contribute to adrenal insufficiency. On the other hand, some inflammatory factors may cause glucocorticoid resistance at the level of target cell, affecting vital steps of the glucocorticoid receptor signaling ( 66 ). Since the diagnosis of tissue glucocorticoid resistance remains difficult, efforts have been made in order to establish a diagnostic workup for this syndrome. The American College of Critical Care Medicine suggests that the diagnosis is best made by a delta total serum cortisol of < 9 μ g/dL following intravenous administration of ACTH (1-24) in a dose of 250 μ g or a random total cortisol level of < 10 μ g/dL ( 60 ). Moreover, the consensus statement recommends that hydrocortisone therapy should be given in patients with septic shock, particularly those who respond poorly to fluid resuscitation and vasopressing agents ( 60 ).