ABSTRACT

 

Anaerobic bacteria are present as part of the normal microbial flora in the human body. These bacteria turn virulent whenever the host defense mechanisms are compromised. Diabetes and glucocorticoid abuse are the two common endocrine conditions that predisposes individuals to anaerobic infections. Anaerobic infections are common in tropical countries and can affect any tissue or gland resulting in severe organ dysfunction. Microbial endocrinology deals with the bidirectional interaction between the hormones and the microbes. The interaction is influenced by the virulence factors released from the microbes, inflammatory mediators, and the hormonal dysfunction. In this chapter, we shall discuss the various anaerobic bacterial infections relevant in endocrinology practices.

 

INTRODUCTION

 

The term “anaerobic” broadly denotes intolerance to oxygen. Anaerobic bacteria are the commonest bacteria in the bacterial flora present on the skin and mucous membranes (1). They are broadly divided into three types based on their relation to oxygen and growth potential as shown in figure 1.

Figure 1. Types of anaerobic bacteria

 

Virtually all anaerobic infections are derived from the normal bacterial flora of the body. The virulence characteristics of the organisms are kept in check by the defense mechanisms and a breach in the same may lead to infection. The risk of anaerobic infection is determined by the balance between the inoculum, virulence characteristics, and the host defenses. Previously, anaerobic infections were considered to be less prevalent due to the lack of identification techniques and the fastidious nature of the bacteria (2). Increased awareness, antibiotic misuse resulting in changing microbiome, ease of culture and diagnostic techniques helped in demonstrating that anaerobic infections also are frequent in clinical practice.

 

Microbial endocrinology is a term coined in 1992, to describe the bi-directional interplay between microbes and endocrine hormones (3). Endocrine glands are located deep in the human body with the exception of the thyroid gland. Most of the endocrine glands have a thick capsule protecting them from the contagious spread of infection. The endocrine glandular tissue is highly vascular, thereby not conducive for the growth of anaerobic bacteria. However, anaerobes can overcome the host defenses resulting in infection and breaks in the anatomic barrier can occur due to surgery, trauma, or the disease process itself from within. The predisposing factors for anaerobic infections include diabetes, immunosuppression, malignancy, neutropenia, and decreased redox potential in the tissues.

 

INTERPLAY BETWEEN ANAEROBIC BACTERIA AND HORMONES

 

The taxonomy of anaerobes has changed recently due to the improvement in diagnostic techniques. The development of advanced culture methods, next generation sequencing technology, and metagenomics has improved the understanding of anaerobic bacteria (4). Previously, the antibiotic susceptibility pattern of most of the anaerobes was not clear due to the difficulties in culture methods. Advanced diagnostic techniques like DNA hybridization, mass spectrometry, multiplex PCR, and oligonucleotide array technologies helped in improving the classification as well as the understanding of antibiotic susceptibility patterns of these bacteria. A simple taxonomical classification of anaerobic bacteria useful in clinical practice is shown in figure 2.

Figure 2. Types of anaerobic bacteria

 

Estrogen and Vaginal Flora

 

The healthy vaginal flora consists of Lactobacillus species and estrogen plays an important role in maintaining this flora (5). Estrogen increases vaginal epithelial activity resulting in a thickened layer of epithelium with glycogen deposition. The Lactobacilli breaks the glycogen into lactic acid and hydrogen peroxide locally, resulting in the vaginal pH being maintained in acidic range (< 4.5) to prevent the growth of anaerobic bacteria. Bacterial vaginosis is a common infection in women due to a shift of the vaginal microbiome from Lactobacillus flora to a mixture of facultative and obligatory anaerobic bacteria. The typical microorganisms include Gardnerella vaginalis, Mycoplasma hominis, and Atopobium vaginae. Postmenopausal females have a higher risk of bacterial vaginosis due to the precipitous decline in the concentration of estradiol. Evidence shows that topical estrogen therapy in these women normalize the vaginal flora and reduce the risk of anaerobic infections (6).

 

Adrenal Hormone and Anaerobes

 

Exposure to any form of stress elevates sympathetic nervous system activity and releases adrenaline and noradrenaline from the adrenal medulla. Prolonged stress induces a shift in immunity from Th1 linked cellular immunity to Th2 linked humoral immunity. In addition to many host tissues, microbes also respond to the catecholamines and increase their virulent characteristics (7). The hormonal communication between bacteria and humans involves the presence of interkingdom signaling receptors. Bacterial cell membrane bound histidine kinases (QseC and QseE) act as adrenergic sensors to detect the local hormone concentrations. QseC also modulate the expression of many genes that increase the virulence and inflammation. This is one of the mechanisms that interlink the immune-endocrine interactive pathway mediated by stress hormones.

 

Stress induced alterations in the anaerobes of the gingival flora led to the observation that noradrenaline and adrenaline act as environmental cues for bacteria (8). The spectrum of biological effects of the stress hormones on gingival flora could range from halitosis to atherosclerotic plaque rupture leading to acute coronary syndrome. These hormones affect the growth of Fusobacterium, Propionibacterium, and Prevotella and the hormonal effects are mostly species or strain specific. The biological adverse effects are mediated by changes in biofilms, bacterial adaptation techniques, bacterial adherence, and release of the cytotoxic enzymes.

 

DIABETES AND ANAEROBIC INFECTIONS

 

Diabetes mellitus (DM) is the most common metabolic and endocrine disorder that predisposes an individual to the development of infections. The defective immune responses seen in patients with DM could exacerbate the risk of anaerobic infections. Though many superficial and deep infections are common in patients with DM, few amongst them are unique in their description. The unique anaerobic infections seen in patients with DM include emphysematous cholecystitis and emphysematous pyelonephritis. Malignant otitis externa is also unique to DM but is mostly polymicrobial in origin.

 

Diabetic Foot Disease

 

Diabetic foot disease is the commonest cause of lower limb amputation in clinical practice. The lifetime risk for a diabetic foot disease is about 25% in certain patients with diabetes. The infections are usually polymicrobial in nature and lead to considerable morbidity and occasional mortality. Anaerobic infections are more common in wounds that are deep seated and are often resistant to the antibiotics and conservative measures (9). Peptostreptococcus and Bacteroides species are the two common anaerobic bacteria of the diabetic foot. Anaerobic bacteria could be either primary or secondary colonizers in the etiology of diabetic foot ulcers. The ischemic and necrotic wounds have a higher rate of anaerobic infection due to the associated low blood supply and low redox potential that facilitate the growth of these bacteria. There is an ethnic variation in the bacterial etiology of diabetic foot infections. Anaerobic osteomyelitis is typically seen associated with diabetic foot ulcers and presents with a chronic non-healing ulcer of the leg. Early surgical debridement, antibiotic therapy with a spectrum against anaerobes, foot revascularization along with proper foot care are the guiding principles in the management of diabetic foot disease. 

 

Fournier’s Gangrene

 

Fournier’s gangrene (FG), first described in 1883, is a rare necrotizing infection of the perineal and genital skin due to both aerobic and anaerobic organisms (10). There is a male preponderance and the disease is mostly described in middle age and elderly patients. The predisposing factors for FG include diabetes mellitus, immunosuppression, and alcoholism. Recently SGLT2 inhibitors have been linked with an increased risk of FG. The condition leads to microthrombi of the small subcutaneous vessels leading to local necrosis and gangrene which is a fertile nidus for anaerobic bacteria to spread rapidly in the subcutaneous tissues. Initially, the patient presents with cellulitis of the scrotal skin and progression of symptoms may lead to severe sepsis and death. The reported mortality rates with FG are about 25 – 30% and the management includes extensive surgical debridement along with broad spectrum antibiotics and hemodynamic supportive measures.

 

Necrotizing Fasciitis

 

Necrotizing fasciitis (NF) is a life-threatening soft tissue infection that causes local tissue destruction, necrosis, and severe sepsis (11). FG is also a form of NF restricted to the genital area. NF is divided into four types based on the etiological organisms. Type 1 NF is polymicrobial in origin including anaerobes, whereas, type 2 NF is due to either Streptococcus or Staphylococcus. Type 3 and 4 are less common and are due to Vibrio species and fungi respectively. The predisposing factors include DM, malignancy, immunosuppression, alcohol abuse, and systemic chronic debilitating disease. Initial presentation mimics that of cellulitis and early clues to the NF are pain and systemic features out of proportion to the local swelling and the presence of hemorrhagic bullae. Patients with diabetes and NF tend to have polymicrobial infections, severe renal impairment, delayed diagnosis. and multiple co-morbid ailments in comparison to NF patients without diabetes (12). Management principles are similar to FG and include surgical debridement, broad spectrum antibiotics, and supportive measures.

 

Periodontitis

 

Infection of the tissues surrounding the teeth are known as periodontitis and is usually caused by the anaerobic gram-negative bacteria. This is more common in patients with type 2 DM and this complication is often known as the “Sixth” complication of diabetes. The links between diabetes and periodontitis are mediated by oxidative stress, advanced glycation end products leading to immune dysfunction, inflammatory marker release, and increased tissue destruction (13). Periodontitis also exacerbates insulin resistance due to the release of cytokines and chemokines. DM is characterized by periapical bone destruction, poor wound healing, and also has a direct effect on the dental pulp integrity. Periodontitis is an independent marker of mortality in patients with T2DM and it is essential to treat these two conditions simultaneously for better outcomes.

 

ORGAN SPECIFIC ANAEROBIC INFECTIONS

 

Endocrine glands are usually resistant to localized infections due to their location, high vascularity, and in some glands the presence of a protective capsule preventing the local spread of infection. However, these natural barriers are broken in certain conditions leading to the development of infections.

 

Thyroid Gland

 

The thyroid gland is resistant to bacterial infection due to the high iodine content, blood supply, and thick capsule. Acute suppurative thyroiditis (AST) is a complication due to the anaerobic bacterial infection of the thyroid gland (14). Porphyromonas, Propionibacterium and Streptococcus are the common bacteria that have been reported to lead to AST. Many of these bacteria live as commensals in the gingival epithelium. These patients usually present with a tender neck mass and systemic features of inflammation, similar to the presentation of subacute thyroiditis (SAT). It is essential to differentiate between AST and SAT, as glucocorticoids worsen the former and are indicated in the later condition. The majority of the AST patients are euthyroid, whereas, the SAT presents with features of thyrotoxicosis. AST is seen involving the left side of thyroid gland, whereas, SAT involves both sides similarly. Ultrasonography and aspiration cytology aid in the confirmation of the diagnosis. Therapy consists of appropriate antimicrobial drugs and surgical drainage of an abscess if present.

 

Pituitary Gland

 

The intrasellar location and the high rate of blood flow per gram makes the pituitary gland resistant to the development of local infections. However, a few case reports have described anaerobic abscesses in the sella that could be due to blood stream infection (15). The patients present with features of a pituitary mass including local compression and hormonal dysfunction. Surgical drainage of the abscess along with prolonged anti-anaerobic therapy is essential for recovery. There may be residual hormonal dysfunction in patients necessitating long-term hormonal replacement.

 

Adrenal Gland

 

Adrenal gland infections are very rare in clinical practice and are usually predisposed by the presence of a blood collection in the gland. The presenting features include fever with chills, abdominal pain, and occasionally features of adrenal deficiency. The infection is mostly due to the aerobic bacilli, but polymicrobial infections are not uncommon. Recent reports suggest the beneficial role of metagenomic next generation sequencing (mNGS) that helps in the early identification of the anaerobic infection (16). mNGS technology helps in identification of multiple anaerobic bacteria simultaneously and the results are available in less than 48 hr, unlike conventional culture which takes more than a week. Management is similar to any other organ involvement with pus drainage and prolonged antibiotics.

 

INFERTILITY AND ANAEROBIC INFECTIONS

 

Infertility affects about 10 – 15% of couples and infections constitute one of the major contributory factors for infertility (17). Female and male factors account for about 40% of etiologies exclusively, whereas, both partners along with an idiopathic etiology account for the remaining 20%. Anaerobic infections constitute one of the common infectious causes of infertility, albeit, predominantly in females.

 

Female Infertility

 

Pelvic inflammatory disease (PID) is the commonest cause leading to female infertility due to tubal adhesions, mucosal damage, and tubal occlusion. PID is caused by multiple organisms which include Chlamydia, Neisseria, and anaerobes. Bacterial vaginosis is a major contributory factor in the pathogenesis of PID as evidenced by the identification of the similar microbial flora (18). Bacteria ascend the genital tract via the endocervical and endometrial epithelia including the lymphatics. Lower abdominal pain and vaginal discharge are the two common symptoms of PID. Early identification of PID, prompt antibiotic therapy, and surgical drainage of the pus result in the cure without residual tubal complications. Patients with recurrent abortions have also been shown to have vaginal colonization with Gardnerella vaginalis and facultative anaerobes (18). This indicates an association between the altered vaginal microflora, local and systemic inflammation, change in the immune mediators, chemokines and cytokines, impaired implantation, placentation, and blood vessel transformation culminating into the recurrent abortions.

 

Male Infertility

 

Anaerobic infections affect semen quality and the total sperm concentration leading to male infertility. The semen samples from sub-fertile men are characterized by the presence of a large number of pus cells and multiple bacteria (19). Anaerobic bacteria affect the ability of the sperm to penetrate the cervical mucosa by the release of microbial toxins. Anaerobic infections are not routinely identified with the standard methods of culture and should be ruled out in all patients with unexplained oligoasthenospermia along with the presence of pus cells in the semen. Positive microbial cultures, however do not convey the exact location of the infection as the semen consists of secretions from the multiple glands including the prostate. A classic four specimen technique could be helpful in the localization of the infection and these patients require long term antibiotic therapy.

 

GUT ANAEROBES AND METABOLIC DISORDERS

 

Gut microbes are essential for the host immune system and help in digestion and maintenance of local tissue integrity. The intestinal bacteria mediate their beneficial effects by breaking dietary constituents into various short chain fatty acids which act as beneficial signals in metabolism and immunomodulation (21). Though it’s very difficult to characterize the entire gut microbiome, parameters such as alpha species diversity, ratio between the beneficial (Akkermansia, Bifidobacterium, Lactobacillus etc.) and the harmful (Enterococcus, Bacteroides, Lachnospiraceae etc.) bacteria are used in laboratory evaluation. Recent reports have emerged that the gut microbiome plays an important role in the etiopathogenesis of metabolic disorders including type 2 DM and obesity.

 

Diet and environmental factors play an important role in shaping the gut microbiome. The diversity in the gut microbiota could also be a contributory factor in the prevalence of the metabolic disorders between different ethnic populations (22). Increasing use of the antibiotics, environmental pollution, and consumption of refined products have led to alterations in the microbial flora with a shift from a healthy flora to an unhealthy one. Proinflammatory molecules secreted from intestinal bacteria translocate to the blood stream triggering metabolic endotoxemia, which is described as the leaky gut syndrome. The gut-blood barrier is often broken with the colonization of the anaerobic bacteria in the gut replacing the normal flora.  

 

The microflora in individuals is a key determinant in directing the response to antibiotics and probiotics. The fecal samples of Japanese patients with T2DM showed lower bacterial counts of obligatory anaerobes and higher content of facultative anaerobes in comparison to the control population. There is also a higher percentage of gut bacteria in the circulation, thereby confirming the leaky-gut hypothesis (23).  Apart from metabolic disorders, the gut dysbiosis has not been shown to affect other endocrine disorders.

 

ENDOCRINE ISSUES WITH THE ANTIMICROBIALS USED AGAINST ANAEROBES

 

Antimicrobials are the cornerstone of therapy against the anaerobic infections. In a few cases, the antibiotic therapy is supplemented with the surgical drainage of the pus. The therapy is often prolonged due to the slow growth rate of the anaerobes, polymicrobial nature of the infection, and the development of antibiotic resistance (24). The commonly used antimicrobials against anaerobic infections include metronidazole, carbapenems, quinolones, beta-lactams, chloramphenicol, tigecycline, and clindamycin. Many of these drugs have no significant endocrine side-effects except for the dysglycemia with the use of quinolones. Other endocrine effects due to the protracted use of these drugs are summarized in the table 1.

 

Table 1. Endocrine Side-Effects of Antimicrobials used Against Anaerobic Infection
Drug	Endocrine side-effects
Metronidazole	Altered gut microbiome Anterior pituitary inhibition
Quinolones	Dysglycemia, Reduced absorption of levothyroxine Seizures in thyrotoxicosis patients
Beta-lactams	Fractures
Tigecycline	Hypoglycemia
Chloramphenicol	Inhibition of thyroid hormones production
Clindamycin & Carbapenems	Nil

 

CONCLUSION

 

Anaerobic infections are common in clinical practice and diabetes is the most common endocrine condition predisposing for these infections. Anaerobic organisms have hormonal interactions with gonadal and adrenal hormones and the field of microbial endocrinology is expanding rapidly. Organ specific anaerobic infections may lead to endocrine dysfunction in the form of infertility, glandular abscess, and hypofunction of the involved endocrine axis. A high index of clinical suspicion is essential to identify anaerobic infections especially in the tropical countries. The principles of management are prolonged antibiotic therapy along with drainage of the pus. Systemic supportive therapy and extensive debridement is essential in life threatening anaerobic infections like necrotizing fasciitis.

 

REFERENCES

 

1. Brook I. Spectrum and treatment of anaerobic infections. J Infect Chemother. 2016 Jan;22(1):1-13.
2. Vena A, Muñoz P, Alcalá L, Fernandez-Cruz A, Sanchez C, Valerio M, Bouza E. Are incidence and epidemiology of anaerobic bacteremia really changing? Eur J Clin Microbiol Infect Dis. 2015 Aug;34(8):1621-9.
3. Lyte M, Ernst S. Catecholamine induced growth of gram-negative bacteria. Life Sci. 1992;50(3):203-12.
4. Lavigne JP, Sotto A, Dunyach-Remy C, Lipsky BA. New Molecular Techniques to Study the Skin Microbiota of Diabetic Foot Ulcers. Adv Wound Care (New Rochelle). 2015 Jan 1;4(1):38-49.
5. Wilson JD, Lee RA, Balen AH, Rutherford AJ. Bacterial vaginal flora in relation to changing oestrogen levels. Int J STD AIDS. 2007 May;18(5):308-11. 
6. Tidbury FD, Langhart A, Weidlinger S, Stute P. Non-antibiotic treatment of bacterial vaginosis-a systematic review. Arch Gynecol Obstet. 2021 Jan;303(1):37-45. 
7. Boyanova L. Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria. Anaerobe. 2017 Apr;44:13-19.
8. Jentsch HF, März D, Krüger M. The effects of stress hormones on growth of selected periodontitis related bacteria. Anaerobe. 2013 Dec;24:49-54. 
9. Charles PG, Uçkay I, Kressmann B, Emonet S, Lipsky BA. The role of anaerobes in diabetic foot infections. Anaerobe. 2015 Aug;34:8-13. 
10. Montrief T, Long B, Koyfman A, Auerbach J. Fournier Gangrene: A Review for Emergency Clinicians. J Emerg Med. 2019 Oct;57(4):488-500.
11. Shimizu T, Tokuda Y. Necrotizing fasciitis. Intern Med. 2010;49(12):1051-7.
12. Tan JH, Koh BT, Hong CC, Lim SH, Liang S, Chan GW, Wang W, Nather A. A comparison of necrotising fasciitis in diabetics and non-diabetics: a review of 127 patients. Bone Joint J. 2016 Nov;98-B(11):1563-1568. 
13. Lima SM, Grisi DC, Kogawa EM, Franco OL, Peixoto VC, Gonçalves-Júnior JF, Arruda MP, Rezende TM. Diabetes mellitus and inflammatory pulpal and periapical disease: a review. Int Endod J. 2013 Aug;46(8):700-9. 
14. Sun JH, Chang HY, Chen KW, Lin KD, Lin JD, Hsueh C. Anaerobic thyroid abscess from a thyroid cyst after fine-needle aspiration. Head Neck. 2002 Jan;24(1):84-6. 
15. Neelon FA, Mahaley MS Jr. Chiasmal syndrome due to intrasellar abscess. Arch Intern Med. 1976 Sep;136(9):1041-3. 
16. Jin W, Miao Q, Wang M, Zhang Y, Ma Y, Huang Y, Wu H, Lin Y, Hu B, Pan J. A rare case of adrenal gland abscess due to anaerobes detected by metagenomic next-generation sequencing. Ann Transl Med. 2020 Mar;8(5):247.
17. Rhoton-Vlasak A. Infections and infertility. Prim Care Update Ob Gyns. 2000 Sep 1;7(5):200-206.
18. Hay PE. Bacterial vaginosis and miscarriage. Curr Opin Infect Dis. 2004 Feb;17(1):41-4.
19. Kuon RJ, Togawa R, Vomstein K, Weber M, Goeggl T, Strowitzki T, Markert UR, Zimmermann S, Daniel V, Dalpke AH, Toth B. Higher prevalence of colonization with Gardnerella vaginalis and gram-negative anaerobes in patients with recurrent miscarriage and elevated peripheral natural killer cells. J Reprod Immunol. 2017 Apr;120:15-19.
20. Eggert-Kruse W, Rohr G, Ströck W, Pohl S, Schwalbach B, Runnebaum B. Anaerobes in ejaculates of subfertile men. Hum Reprod Update. 1995 Sep;1(5):462-78.
21. Hills RD Jr, Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR. Gut Microbiome: Profound Implications for Diet and Disease. Nutrients. 2019 Jul 16;11(7):1613. 
22. Escobar JS, Klotz B, Valdes BE, Agudelo GM. The gut microbiota of Colombians differs from that of Americans, Europeans and Asians. BMC Microbiol. 2014 Dec 14;14:311.
23. Sato J, Kanazawa A, Ikeda F, Yoshihara T, Goto H, Abe H, Komiya K, Kawaguchi M, Shimizu T, Ogihara T, Tamura Y, Sakurai Y, Yamamoto R, Mita T, Fujitani Y, Fukuda H, Nomoto K, Takahashi T, Asahara T, Hirose T, Nagata S, Yamashiro Y, Watada H. Gut dysbiosis and detection of "live gut bacteria" in blood of Japanese patients with type 2 diabetes. Diabetes Care. 2014 Aug;37(8):2343-50. 
24. Brook I. Antimicrobials therapy of anaerobic infections. J Chemother. 2016 Jun;28(3):143-50. 

ABSTRACT

 

The adrenal gland in conjunction with the pituitary gland is one of the major components of the endocrine system and regulates blood volume, blood pressure, serum electrolytes, and stress responses. Dysfunction of the adrenal glands may be related to diseases of the adrenal glands or pituitary gland. Adrenal disorders may present either due to structural or functional abnormalities. In the tropical countries, adrenal insufficiency is primarily due to adrenal infection by tuberculosis, adrenal mycosis infections, and adrenal hemorrhages. HIV (Human immunodeficiency virus) related adrenal problems are also common. Adrenal dysfunction due to pituitary disorders still occur frequently in tropical region and include Sheehan’s syndrome, vasculotoxic snake bite, and thalassemia. Adrenal hormone excess typically occurs secondary to exogenous glucocorticoid use. Adrenal disorders that occur in the developed world occur with similar frequencies in tropical regions.

INTRODUCTION  

Adrenal glands are one of the major peripheral organs necessary for homeostasis including maintenance of blood volume, blood pressure, and serum electrolytes. Disorders of adrenal glands are common in clinical practice. Adrenal dysfunction in tropical countries often occurs due to specific etiologies that differ from the typical causes of adrenal dysfunctions that commonly occur in other parts of the world (Table 1). 

Table 1. Classification of Adrenal Disease in the Tropics

Adrenal insufficiency: Primary:  1)     Adrenal Tuberculosis 2)     Adrenal Mycosis 3)     Adrenal Haemorrhage Secondary: 1)     Sheehan’s Syndrome 2)     Vasculotoxic Snake Bite 3)     Thalassemia’s Both Primary and Secondary: 1)    HIV

Adrenal Hormone excess syndromes: 1.    Exogenous Glucocorticoid hormone excess syndromes 2.  Licorice induced syndrome of apparent mineralocorticoid excess

PRIMARY ADRENAL INSUFFICIENCY  

The causes of primary adrenal insufficiency that are more frequent in tropical regions include infection of the adrenal glands by tuberculosis or mycotic infections. In addition, autoimmune Addison’s disease or adrenal failure as a component of polyglandular syndromes are equally prevalent in tropical regions as is in other parts of the world. 

Adrenal Gland Tuberculosis

Adrenal gland tuberculosis or Tuberculous adrenalitis is the result of infection of adrenal gland by mycobacterium tuberculosis. The infection causes a destructive lesion of the adrenal cortex with uncertain chances of recovery and remains one of the most important causes of Addison’s disease in the tropical countries (1). In fact, the adrenal glands are the most common endocrine organs to be involved in tuberculosis (2). Adrenal gland tuberculosis occurs almost always secondarily due to the hematogenous spread of the bacilli to the gland with the primary focus in lung. Adrenal failure or Addison’s disease clinically manifest when at least 90% of the gland has been destroyed (1,2,3). Though classically the adrenal cortex is involved, the medulla also may be involved in many cases of adrenal tuberculosis (3,4).

PATHOPHYSIOLOGY 

It is interesting to know why the adrenal glands are susceptible to infections. In fact, adrenal gland infections are common in response to a distant infection elsewhere in the body and in disseminated infection. Autopsy examination revealed that the prevalence of adrenal tuberculosis is about 6% in patients with active tuberculosis (4). However, subclinical adrenal dysfunction may be present in about 60-70% of patients with active tuberculosis (5). In any of these situations, there is an exaggerated response of the hypothalamo-pituitary-adrenal axis to produce excess cortisol in response to the stress of infection. This stress induced hypercortisolemia shifts the balance in the Th1/Th2 cell ratio towards a Th2 response (6). This T cell dysfunction (which is primarily responsible for cell mediated immunity) and low DHEA levels increases the host susceptibility to infection to mycobacterium tuberculosis and other organisms (6). Low DHEAS levels have been documented in tuberculosis (1,6). In addition, endotoxin released in response to the hyperactive HPA axis can cause pathological changes in the adrenal glands to increase the susceptibility to infection (7). The intrinsically rich vascularity of the adrenal glands promotes all of these pathophysiological events.

Histopathologically, four classic patterns have been described in adrenal tuberculosis (3). These are:  granuloma (caseating or non-caseating), enlargement of the gland with destruction by inflammatory granuloma, mass lesions due to cold abscesses, and adrenal atrophy due to fibrosis related to chronic infection. Caseating granuloma is the commonest one and this is identified in about 70% of cases (4). However, granuloma with typical presence of Langhan’s giant cell are less common and identified in less than 50% of cases (4), probably due to anti-inflammatory effects of local glucocorticoids. Calcification of the gland is a common but it is present in other chronic infections of the adrenal glands (3). In about 25 % cases the infection may be unilateral (1).

PRESENTATION

Typical symptoms of adrenal gland tuberculosis in a patient with diagnosed tuberculosis (whether or not on anti-tubercular chemotherapy) are mucocutaneous pigmentation in association with chronic ill health, vomiting, postural hypotension, and anorexia (3). The features are similar to Addison’s disease due to other conditions. As the features of progressively evolving adrenal hypofunction are mostly nonspecific, a high index of suspicion is necessary in subjects with diagnosed active tuberculosis especially when pigmentation is absent. However clinical manifestations may take months to years to become apparent.

The patient may also present rarely with frank adrenal crisis with hypotension, hyponatremia, hyperkalemia, and low serum cortisol levels. The crisis may even be precipitated after administration of rifampicin which increases the hepatic metabolism of cortisol in the background of subclinical adrenal dysfunction (8). 

Adrenal tuberculosis may also present as an adrenal incidentaloma. Nonspecific abdominal pain, weight loss, dizziness, and vomiting may lead to imaging of the abdomen which may reveal an incidental adrenal mass often with calcification. The differential diagnosis of Addison’s disease with adrenal enlargement includes (apart from tuberculosis) malignancy, fungal infections, hemorrhage, amyloidosis, sarcoidosis, etc. (3).

Subclinical adrenal dysfunction is also very common and should be actively sought in all cases of active tuberculosis (5).

INVESTIGATIONS

Laboratory Studies

Common laboratory findings include anemia, hyponatremia, and hyperkalemia. In the presence of a positive Mantoux test in association with typical clinical manifestations of adrenal hypofunction, adrenal tuberculosis must be ruled out. Adrenal insufficiency should be ruled out by using a standard protocol. Serum cortisol levels <5 µg/dL and a plasma ACTH more than 2-fold the upper limit of the reference range is suggestive of primary adrenal insufficiency (9). The serum cortisol may remain in the low-normal to mid-normal range in many cases.  However, a standard dose (250 µg) intravenous cosyntropin (Synacthen) stimulation test establishes the diagnosis of adrenal insufficiency when the peak level of cortisol remains below 18 µg/d (9). Random cortisol levels, though useful during an acute crisis, is not usually sufficient to rule out adrenal insufficiency (9). Documentation of subclinical adrenal dysfunction may reveal mineralocorticoid deficiency alone (as demonstrated by raised plasma rennin activity) when stimulated cortisol is within the normal range (8).

Imaging of Adrenal Glands

CT scan of the abdomen is the most important non-invasive investigation with a very good spatial resolution to diagnose adrenal tuberculosis. The findings are usually bilateral and vary with the duration of the disease before diagnosis (1, 3). The most common early findings during the initial 2 years include a mass lesion with smooth adrenal contour preserved. The glands may show central or patchy hypodensity corresponding to areas of caseous necrosis (3). On contrast administration there is peripheral rim enhancement. Calcification is not a common feature in early tuberculosis (3).

With chronic infection, the adrenal glands become small and shrunken, often with associated calcifications and the margins become irregular (3). Though prevalence and intensity of calcification increases with the duration of tuberculosis, this is not a specific finding and may be associated with other conditions.

Though MRI is also done in many cases, this imaging modality has limitations to assess calcification. However, T1 weighted image shows hypointense or isointense areas and T2 weighted image shows hyperintense areas because of necrosis (3).

Percutaneous FNA/ TB PCR 

 For confirmation of adrenal tuberculosis tissue diagnosis is required. CT scan guided fine needle aspiration from the adrenal gland is necessary to obtain adequate tissue specimens (3, 10). Pathological and microbiological confirmation is necessary, especially where there is isolated adrenal involvement. However, it should be remembered that PCR and culture of these specimens for tuberculosis bacilli are not consistently positive (3). Hence a combination of histopathology, PCR, and culture may be necessary to confirm the diagnosis (3). However, routine search for pulmonary tuberculosis with necessary investigations is mandatory.

TREATMENT

Treatment of adrenal insufficiency in tuberculosis requires administration of both glucocorticoids and mineralocorticoids. As the medulla is frequently involved, patients may require higher doses for maintenance of blood pressure. At the same time, rifampicin used in the anti-tubercular regimen is a potent hepatic enzyme inducer and accelerates cortisol metabolism. This also may necessitate a higher dose of glucocorticoids for adequate treatment. However, aldosterone is less likely to be involved. Adrenal crisis is also reported to occur following the administration of rifampicin (11).

Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes and blood glucose. Patients should be also be monitored for over treatment with glucocorticoids with weight gain, blood pressure, decreasing bone mineral density, and other manifestations of Cushing’s syndrome. All subjects should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situations such as fever, infection, vomiting, trauma, etc.

PROGNOSIS FOR ADRENAL FUNCTION RECOVERY

Chances of adrenal recovery with anti-tuberculosis therapy are uncertain and unpredictable. When the disease is diagnosed late, the glandular destruction is usually significant and the gland becomes atrophic, and anti-tuberculosis therapy does not lead to a recovery of adrenal function (12, 13). If therapy is started early before the gland is destroyed recovery may occur (14, 15). It is also suggested that if the gland size remains the same on subsequent follow up CT scans, it is prudent to follow up the patient for adrenal function recovery.

Adrenal Mycosis

HISTOPLASMOSIS 

Adrenal Histoplasmosis caused by the dimorphic fungus Histoplasma capsulatum, is a recognized cause of adrenal insufficiency. Though this opportunistic pathogen is known to affect immunocompromised individuals predominantly (16), it can rarely infect immunocompetent individuals (16, 17).  This is the most fungal infection of the adrenal glands (16, 18).

Involvement of the adrenals can occur during disseminated infection or many years after disease resolution (18). Adrenal involvement can vary from an asymptomatic milder form to a very severe form that presents with extensive bilateral granulomatous involvement of the entire adrenal gland with calcified lesions culminating in acute adrenal insufficiency (18, 19). Rarely the involvement can be unilateral (17). The common differential diagnosis includes tuberculosis, other fungal infections, adrenal metastasis, primary adrenal malignancy, and primary adrenal lymphoma (16). In immunocompetent individuals it commonly presents with a unilateral or bilateral adrenal mass with constitutional symptoms.

The hypothesis for why histoplasmosis involves the adrenal glands with increased frequency includes the local high levels of glucocorticoids in association with a relative paucity of reticulo-endothelial cells within the adrenal gland (6). The gland is destroyed by direct infection that leads to local ischemia and infarction due to perivasculitis, and caseation (6).

Diagnosis depends on imaging studies with pathological confirmation. CT scan of the adrenal glands typically reveals symmetric enlargement with central hypodensity and characteristic peripheral rim like enhancement (20). Frequently calcification is also present, particularly during the healing phase (20). Percutaneous ultrasound or CT guided fine-needle aspiration or biopsy is necessary for tissue diagnosis (18). The characteristic cytopathological findings are the presence of numerous small oval yeast like structures inside the cytoplasm of macrophages (16). On a necrotic background, this yeast like structures inside the macrophages is surrounded by a clear ring of space resembling a capsule. However, the gold standard for diagnosis is documentation of the organism in the culture of pathological specimen (16). Bhansali et al reported a high uptake in adrenal glands in FDG-PET scan in patients with adrenal histoplasmosis (17). 

Treatment for adrenal histoplasmosis depends on the severity of the infection and the condition of the patient. For severe infection in critically ill patient’s amphotericin B is used initially followed by long-term therapy with oral itraconazole (16). Parenteral liposomal amphotericin B is given 3mg/kg body weight for 2 weeks (17). The duration of therapy with itraconazole varies from six months to two years depending on the patient’s condition. For mild to-moderate histoplasmosis, the recommended treatment is itraconazole. The recommended dose is 200 mg twice daily given for 12 months (16). When itraconazole is used, liver enzymes should be monitored on a regular basis (18).  Treatment for adrenal insufficiency follows the same principles as described earlier.

Though the remission rate from adrenal histoplasmosis is high with long-term oral itraconazole, adrenal insufficiency rarely resolves and reversal of adrenal dysfunction can be seen only in some patients after prolonged antifungal therapy (21).  However, histoplasma in adrenals is reported to persist even 7 years after antifungal therapy (22). 

OTHER FUNGAL INFECTIONS

Paracoccidioidomycosis Brasiliensis

Paracoccidioidomycosis brasiliensis is a dimorphic fungus and can cause chronic, progressive, suppurative and granulomatous disease which can lead to adrenal insufficiency (3). The disease is endemic in Latin America. Humans are the accidental host for the organism and females are rarely affected (23). Smoking and alcohol increase the risk. The lungs are the usual portals of entry. Juvenile forms of the disease are also known (23). Apart from frank adrenal crisis, it can present as progressive constitutional symptoms, hyperpigmentation, and low blood pressure with postural drop and bilateral adrenal enlargement in imaging studies with frank adrenal calcification detected by CT scans (24, 25). Histopathology with GMS stain shows multiple budding yeast with steering wheels appearance which is consistent with Paracoccidioides brasiliensis (24). However, confirmation of the organism by culture material is the gold standard for diagnosis. Serology for antibody detection is also useful in the diagnosis. Diagnosis and treatment of adrenal insufficiency is not different than described above for histoplasmosis. P. brasiliensis primarily causes adrenal destruction by embolic infection of small vessels by large fungal cells and granuloma formation (3). Subjects who receive early antifungals with itraconazole over a 1–2-year period may have a full recovery of adrenal function by preventing fungal embolism in adrenal gland vasculature and reducing ischemic necrotic destruction of the gland (3). Hence an early diagnosis is crucial for preventing the progression of adrenal dysfunction. However, persistence of high antibody titer against paracoccidioidomycosis at the end of treatment or during follow-up is a frequent finding in subjects with paracoccidioidomycosis.

Blastomyces Dermatitidis

Blastomyces dermatitidis is also a dimorphic fungus, which has a strong affinity for the adrenal gland for reasons described earlier. Overt adrenal insufficiency is less common and adrenal Blastomyces dermatitidis typically presents as bilateral adrenal incidentaloma during radiological investigations for other reasons (3). The portal of entry is through the lungs and when there is lymphohematogenous dissemination the disease spreads to other organs (26). In situations when it presents as adrenal insufficiency, the presentation, investigations, and management are similar to those described above. Diagnosis is by fine-needle aspiration guided by ultrasound or CT scan followed by cytologic and histologic examinations. However, the gold standard is fungal culture showing thick-walled, broad-based budding yeast cells (27). Treatment is with long term oral itraconazole. In patients with severe manifestations initial treatment with liposomal amphotericin B for 2 weeks could be used.

Cryptocoocus Neoformans

Cryptocoocus neoformans is an encapsulated yeast-like fungus which infects primarily immunodeficient hosts, particularly subjects infected with HIV or lymphohematogenous malignancies (28). In immunocompromised hosts it usually affects the central nervous system and lungs.  However immune-competent individuals may also suffer adrenal cryptococcosis (29). Adrenal dysfunction is uncommon until almost the whole of adrenal gland is infiltrated with C. neoformans and caseating granulomas. Cryptococcosis is diagnosed by fine-needle aspiration biopsy of the adrenal mass. The serum cryptococcal antigen titer is highly elevated. Treatment is with antifungal therapy with fluconazole and amphotericin B. Adrenal enlargement by Cryptococcus may be completely reversible without any abnormality after antifungal treatment (30). Cases not responsive to anti-fungal therapy have been reported to improve after unilateral or bilateral adrenalectomy (28, 29).

Miscellaneous

Pneumocystis jirovecii (previously known P. carinii) occurs in individuals with advanced HIV due to defects in cell mediated immunity. Spread to other organs including the adrenal glands is also possible (3). Adrenal failure associated with coccidioidomycosis and rarely candidiasis has also been reported.

Adrenal Hemorrhage; the Waterhouse Friderichsen Syndrome

This is a condition in which patient presents with acute hypotension and shock due to adrenal insufficiency arising from acute adrenal hemorrhage. The syndrome is typically related to infection with Neisseria meningitides infection (3). However, this is also known to occur in septicemia due to infections with Staphylococcus aureus, Streptococcus spp, Haemophilus influenzae, Corynebacterium diphtheria, etc. (3). Hence this is more common in the tropical region.  The condition is hypothesized to be due to interplay between endotoxemia and elevated ACTH. The adrenal gland is anatomically prone to hemorrhage as it has three separate arterial supplies and does not have proportional venous drainage (3). In endotoxemia, elevated ACTH increases the blood supply several fold in this compromised anatomical setting. At the same time increased adrenaline secretion in relation to stress leads to constriction of adrenal veins, which further increases this imbalance between arterial supply and venous drainage. Management includes immediate fluid replacement and parenteral glucocorticoids apart from the management of the underlying infection.

SECONDARY ADRENAL INSUFFICIENCY 

Adrenal insufficiency secondary to disorders of pituitary gland is also very common in developing countries in tropical regions.  Secondary adrenal insufficiency caused by pituitary tumors and apoplexy, pituitary surgery, radiation therapy, hypophysitis, various genetic disorders, and withdrawal of exogenous steroids are equally common in tropical regions but certain other disorders like Sheehan’s syndrome, thalassemia, and vasculotoxic snake bite induced pituitary failure are more common in tropical regions.

Sheehan’s Syndrome 

Sheehan’s syndrome consists of various degrees of pituitary insufficiency, which develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. The important pathogenetic/predisposing factors include a small sella, increased pituitary volume, vasospasm induced by postpartum hemorrhage, thrombosis, and probable pituitary autoimmunity (31). In developed countries there has been a drastic reduction in the incidence of Sheehan’s syndrome. This is primarily due to the remarkable improvement in obstetric care and availability of rapid blood transfusion. However, this remains as a major cause of hypopituitarism in the other parts of the world.

CLINICAL FEATURES

Most commonly the disorder presents as a lactation failure in the post-partum state and non-resumption of menses following child birth, which was complicated by massive post-partum hemorrhage leading to hypotension and shock. However, it may very rarely occur without massive bleeding or after normal delivery. Patients may present in the emergency with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, and vomiting with a typical history of failure to resume menses and lactation failure following child birth (31). Apart from anterior pituitary hormone deficiency, symptoms like anemia, pancytopenia, osteoporosis, cognitive impairment, and poor quality of life are also present in these patients (31,32).  Very rarely diabetes insipidus may occur. However, the mean age of the participants may be as late as 40 years or more and the mean interval between inciting event to diagnosis may be as high as 10 years or more (33).

Adrenal insufficiency due to ACTH deficiency is reported to occur in up to 100% of cases (in fact deficiency of all anterior pituitary hormones occur in a variable percentage of patients and may be up to 100%) (32). Weakness, fatigue, and postural drop are common manifestations. Hyponatremia is particularly common in Sheehan’s syndrome, which may be due to glucocorticoids deficiency coupled with increased AVP release as a consequence of reduced blood pressure and cardiac output resulting from glucocorticoid deficiency (32).

DIAGNOSIS

The basal pituitary hormonal levels and those after dynamic tests are beyond the purview of this chapter. However adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a cosyntropin stimulated cortisol level <18 mcg/dl. Documentation of growth hormone deficiency does not require a dynamic test in presence of other pituitary hormone deficiencies. Only low age specific and assay specific IGF-1 assay may be sufficient to document adult growth hormone deficiency (AGHD) (34).

The preferred radiological imag­ing is an MRI of hypothalamic pituitary area.  CT scan may also be helpful. MRI findings in Sheehan’s syndrome usually vary with the stages of the disease. In earlier stages of the disease there may be an enlarged pituitary gland with central hypodensity (suggestive of infarction). However, an empty sella (complete or partial) is considered to be a characteristic of Sheehan’s syndrome in established cases (32).

TREATMENT

The acute adrenal crisis in Sheehan’s syndrome is treated with intravenous glucocorticoids. In other patients’ glucocorticoids should be started orally with hydrocortisone 15-25 mg daily in 2-3 divided doses with the higher dose in the morning and a lower dose in the evening (35). Mineralocorticoids are not necessary in general (35). Once daily prednisolone may also be used at a dose of 2.5-5 mg once daily in the early morning. As GH deficiency decreases cortisol clearance, it may necessary to increase the dose of glucocorticoid for those who receive GH treatment (35). Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes, and blood glucose. Patients should be also be monitored for an overdose of glucocorticoids with weight gain, blood pressure, decreased bone mineral density, and other symptoms and signs of Cushing’s syndrome. All subjects with Sheehan’s syndrome should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Subjects with Sheehan’s syndrome should also be treated with levothyroxine, combined oral contraceptives according to guideline, calcium and vitamin D supplements, and growth hormone therapy (if possible) according to the protocol of adult growth hormone deficiency.

Viscerotropic Snake Bite

Snakebite is a major public health problem in tropical regions and is considered as one of the most neglected tropical diseases. The development of a Sheehan-like syndrome with chronic hypopituitarism following Russell viper envenomation is fairly common. Hypoadrenalism due to ACTH deficiency is the commonest abnormality (36). However acute hypopituitarism with predominant glucocorticoids deficiency has also been reported (37).

The venom of vipers is vasculotoxic in nature and the clinical features of viper venomation include local cellulitis and tissue necrosis, bleeding manifestations, disseminated intravascular coagulation, shock, and acute kidney injury (AKI) (38). Hypopituitarism is particularly common following vasculotoxic snake bite in subjects who develop AKI requiring hemodialysis. Hypopituitarism can develop as early as 7 days following snake bites and should be evaluated for particularly in younger subjects, especially those requiring increasing number of sessions of hemodialysis and in subjects with abnormal 20 min WBCT (whole blood clotting test) at presentation (36,39). On the other hand, the time of onset/presentation of hypopituitarism following snake bite may be as long as up to 24 years (40). Acute hypopituitarism is thought to occur due to acute damage to the pituitary gland at the time of the precipitating event, but a gradual/slower progression of pituitary damage may occur over years due to other unknown mechanisms (36).

Those who survive acute snake bite may later present with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, vomiting and amenorrhea in females (36).

Variable degrees of hypopituitarism may be present. Cortisol deficiency is reported to be the commonest abnormality. Secondary adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a co-syntropin stimulated cortisol level <18 mcg/dl (36). Documentation of growth hormone deficiency is done as mentioned in section of Sheehan’s Syndrome (34).

The preferred radiological imag­ing is the MRI of hypothalamic pituitary area which may show partial or complete empty sella or evidences of old hemorrhage. However, these changes are not present in all cases (41).

Treatment of secondary adrenal insufficiency and other hormone deficiencies are similar to described above. All subjects with hypopituitarism on glucocorticoids supplements should carry a ‘steroid card’ and should be advised on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Thalassemia Major

Thalassemia’s are inherited autosomal recessive disorders of hemoglobin synthesis. Thalassemia major is the most severe form of beta thalassemia which involves the beta chain of hemoglobin. Organ dysfunction in thalassemia is principally attributed to excessive iron overload and suboptimal chelation. The precise underlying mechanism of iron overload induced organ dysfunction is not very unclear. The current management of thalassemia includes regular transfusion programs and chelation therapy. Pre-marital counselling and assessment with HPLC to assess the asymptomatic carrier has reduced its prevalence significantly in the developed world. However, this is still a major problem in many parts of the world.  Prevalence of adrenal insufficiency is variable and depends on the severity of iron overload. This secondary hemochromatosis can disrupt adrenal function by affecting the hypothalamic-pituitary-adrenal axis at the hypothalamic or pituitary level (42). In more severe cases primary adrenal failure may supervene due to iron deposition in the adrenal glands (42). Additionally, an extramedullary hematopoietic tumor has been reported in HbE thalassemia and beta thalassemia as non-hormone secretory unilateral or bilateral adrenal enlargement resembling adrenal myelolipoma (43). 

Biochemical adrenal insufficiency is reported to occur from   0% to 45% of subjects with thalassemia major (42), but adrenal crisis or clinical adrenal insufficiency is extremely uncommon and mostly they are asymptomatic. However, subclinical cortisol deficiency is not uncommon. In this context it should be remembered that mild symptoms of adrenal insufficiency like asthenia, weight loss, or postural drops are frequently overlooked as these features are common in thalassemia subjects with low levels of hemoglobin (42).                           

The unique finding in subjects with thalassemia is the dissociation between adrenal androgen levels with cortisol and aldosterone levels. This paradox is reflected by frequent documentation of low serum DHEA, DHEA-sulfate, androstenedione, and testosterone levels in the presence of normal serum cortisol and aldosterone levels (44). Absence of adrenarche occurring in most adolescents with thalassemia major is probably explained by this phenomenon (45). 

Diagnosis of adrenal dysfunction in thalassemia is similar to other causes of secondary adrenal insufficiency. If the morning cortisol is not unequivocally low, synacthen stimulation test should be done with either the low dose (1 µg) or the standard high dose (250 µg). A peak cortisol level of >18 µg/dL after 30-60 min of intravenous synacthen excludes adrenal insufficiency. Alternately an insulin tolerance test with a similar cut-off may also be done.

Treatment of clinical adrenal insufficiency is similar to that described above. Subjects with subclinical adrenal insufficiency require only steroid coverage during periods of stress.

HIV AND ADRENAL DYSFUNCTION

Endocrine manifestations of HIV infection may include adrenal dysfunction, hypothyroidism, hypogonadism, insulin resistance and diabetes etc. Changes in the HPA (hypothalamic-pituitary-adrenal) axis are the most frequent abnormality (46). Adrenal dysfunction in HIV infection may be a consequence of concomitant systemic illness, opportunistic infections, and neoplasm (47).

Probably the most frequent adrenal abnormality is a stress induced elevation in serum cortisol and ACTH (46). This may be due to activation of the HPA axis due to HIV infection itself or pro-inflammatory cytokines (e.g., IL-1β, IL-6 and TNF-α) (46). Alternately a peripheral increase in the conversion of cortisone to cortisol due to activation of 11-β HSD type 1 in adipose tissue or decrease in cortisol metabolism may be responsible for increased cortisol with subnormal ACTH (46). Tissue hypersensitivity to glucocorticoids is also reported in subjects with HIV-1 infection, which may result in hippocampal atrophy, altered secretion of cytokine/interleukins, etc. (48).

On the other hand, subclinical or clinical adrenal dysfunction can happen in about 10-20% of subjects with advanced disease and multiple co-morbidities when about 80-90% of the gland is destroyed (46). The involvement and destruction by HIV, opportunistic infections, or malignancies in the adrenal glands or the hypothalamus and/or pituitary area can result in either primary or secondary adrenal sufficiency (47).

The opportunistic infections include cytomegalovirus (CMV), Mycobacterium avium-intracellular and M. tuberculosis, fungal infections (such as Histoplasma, Cryptococcus, and Pneumocystis jirovecii), and Toxoplasma gondii (47). Of these opportunistic infections, CMV infection is known to be the commonest etiology with earlier literature reporting Cytomegalovirus adrenalitis in nearly 80 % of cases of HIV infection (46). However, due to improvements in active management of HIV by HAART (highly active anti- retroviral therapy), the prevalence of adrenal insufficiency has decreased over the last two decades.

Medications used for the treatment of HIV infection and its complication may also result in adrenal dysfunction. For example:  Rifampicin used for mycobacterial infection is a known hepatic Cytochrome P 450 (CYP) enzyme inducer and can lower serum cortisol levels by enhanced cortisol metabolism. Ketoconazole used to treat severe mycotic infections inhibits adrenal steroid synthesis and can lead to glucocorticoid deficiency or even adrenal crisis in patients with impaired adrenal reserve (49). Interestingly, ART-related lipodystrophy (dorsocervical fat pad enlargement and visceral adiposity) may mimic Cushing’s syndrome but it is typically not associated with hypercortisolism (49). On the contrary, some protease inhibitors (e.g., ritonavir) used in ART are reported to decrease metabolism of endogenous and exogenously co-administered glucocorticoids, resulting in an iatrogenic Cushing's syndrome.

Tumors of the adrenal gland in HIV infected patients include Kaposi’s sarcoma and high-grade non-Hodgkin’s lymphoma. Kaposi’s sarcoma is secondary to co-infection with the oncogenic human herpes virus type 8 (HHV8) and non-Hodgkin’s lymphoma could be secondary to Epstein-Barr virus (EBV).

Assessment for symptoms of adrenal involvement requires a high degree of suspicion as constitutional symptoms of HIV may mask the features of adrenal insufficiency.  Morning serum cortisol should be done in all cases suspected for adrenal dysfunction. Stress induced hypercortisolemia does not require any further testing and low serum cortisol <5 μg/dl with an elevated ACTH level requires treatment with glucocorticoids and mineralocorticoids. In other cases, synthacthen stimulated cortisol is used to determine the course of treatment. Stimulated cortisol <18 μg/dl, especially if associated with elevated plasma ACTH, should be treated as adrenal insufficiency. Asymptomatic subjects with stimulated serum cortisol <18 μg/dl should be advised to take stress doses of glucocorticoids only as mentioned before.

Diagnosis and management of adrenal disorders in a patient with HIV infection does not differ from that in immunocompetent persons in general.

ADRENAL HORMONE EXCESS SYNDROMES

Glucocorticoid Excess Syndromes 

The primary cause of Cushing’s syndrome, more common in tropical regions, is exogenous glucocorticoids. The background etiology for exogenous steroid usage includes: nephrotic syndrome, rheumatoid arthritis and other collagen vascular disease, bronchial asthma, Graves’ orbitopathy, etc.  Glucocorticoids used as inhalational agent for bronchial asthma, in creams and ointments for eczematous skin lesions may also be responsible. Endogenous steroid excess (Cushing’s disease, ectopic ACTH syndromes, adrenal tumors) are equally common in tropical regions as in other areas of the world.

Often it is a challenge to suspect exogenous glucocorticoid use based on the patient’s history, especially in situations when glucocorticoids were not being used for a therapeutic purpose. Subjects presenting with features suggestive of Cushing’s syndrome should therefore mandatorily undergo testing for basal morning cortisol (with paired ACTH if possible) to rule out exogenous glucocorticoid use. A suppressed morning cortisol and plasma ACTH strongly suggests the diagnosis (50). One important caveat is that prednisolone may cross react with some cortisol assays giving false positive results in some chemiluminescent assay (51). Additionally, if the patient is receiving hydrocortisone, the result will also be fallacious to interpret. It is not uncommon in tropical regions that some form of glucocorticoids is being used in disguise as an alternative medicine for joint pain, respiratory problems, fever, or even as a weight gain therapy for young lean subjects. Hence a more detailed evaluation of the history with leading questions and scrutiny of all past records of medicine, including that of the alternative medicines, may sometimes reveal the offending agent. 

The clinical features that suggest exogenous Cushing’s syndrome are lack of pigmentation and the absence of hypertension and hirsutism (as exogenous Cushing’s syndrome does not contain mineralocorticoids and androgens as opposed to endogenous Cushing’s syndrome). Patients with exogenous Cushing’s syndrome are prone to develop glaucoma, osteoporosis, psychiatric disturbances, etc. (50).

Once diagnosed, these subjects should be advised to withdraw the offending agents and should be given hydrocortisone in the lowest possible dose for preventing adrenal crisis. The withdrawal of hydrocortisone subsequently after 3 months depends on the morning cortisol, after stopping the previous evening dose and subjecting the patient to short synacthen test to assess the recovery of HPA axis. Those with morning cortisol between 5 -18 µ/dl should be advised stress coverage only. For bone protection, all subjects with exogenous Cushing’s syndrome should receive bisphosphonate therapy unless contraindicated (52). Adequate calcium supplements with cholecalciferol should also be used.

For subjects receiving glucocorticoids for therapeutic purpose, it is essential to maintain bone protection, check for secondary diabetes and hypertension, and prevent gastric ulceration. Withdrawal (if at all possible) should be performed very slowly. When the therapeutic steroid reaches the lowest possible dose to prevent crisis, it is converted to equivalent dose of hydrocortisone and the same principle is used as described before.

Licorice Induced Syndrome Of Apparent Mineralocorticoid Excess 

Licorice root extracts are used as a herbal medicine for several conditions like cough, peptic ulceration, etc. Licorice is also used as a sweetener and mouth freshener particularly in tropical regions (53). Licorice possesses some glucocorticoid activity, antiandrogen effect, estrogenic activity, and mineralocorticoid like activity. Subjects consuming excessive licorice may develop hypertension and hypokalemia (53). Sometimes this is severe enough to cause a cardiac arrhythmia. While screening for primary aldosteronism for subjects presenting with hypertension and hypokalemia, plasma aldosterone and plasma rennin activity are found to be suppressed in patients using licorice (53). 

                                                                                                                                                                           The active ingredient of liquorice is glycyrrhizic acid, which is hydrolyzed into glycyrrhetinic acid in vivo. Glycyrrhetinic acid has a very low affinity for the mineralocorticoid receptor but is a potent competitive inhibitor of the enzyme 11β-HSD type 2 which is preferentially expressed in kidney (54). Hence it may cause acquired 11β-HSD type 2 deficiency. The physiological role of the enzyme 11β-HSD type 2 is to inactivate cortisol to cortisone and thereby preventing access of cortisol to mineralocorticoid receptor. Cortisol and aldosterone have equipotent stimulating activity on mineralocorticoid receptor (54). Hence any situation associated with suppressed 11β-HSD type 2 activities may lead to overstimulation of mineralocorticoid receptors by cortisol, leading to hypertension with hypokalemia and metabolic alkalosis. After correction of hypokalemia, the screening test reveals suppressed aldosterone and plasma rennin activity (54). The hypertension is primarily due to sodium and water retention. A careful history for licorice ingestion clinches the diagnosis.

Treatment consists of avoidance of licorice products. In the interim period patients should be treated with oral potassium and spironolactone after the completion of screening of aldosterone rennin ratio (ARR). Withdrawal of licorice, even after prolonged use or ingestion of large amounts, leads to a complete resolution of the symptoms of acquired apparent mineralocorticoid excess (55).

REFERENCES

1. Upadhyay J, Sudhindra P, Abraham G, Trivedi N. Tuberculosis of the adrenal gland: a case report and review of the literature of infections of the adrenal gland. Int J Endocrinol. 2014;2014:876037. doi: 10.1155/2014/876037. Epub 2014 Aug 6. PMID: 25165474; PMCID: PMC4138934.
2. Kelestimur F. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest. 2004 Apr;27(4):380-6. doi: 10.1007/BF03351067. PMID: 15233561.
3. Vinnard C, Blumberg EA. Endocrine and Metabolic Aspects of Tuberculosis. Microbiol Spectr. 2017 Jan;5(1):10.1128/microbiolspec.TNMI7-0035-2016. doi: 10.1128/microbiolspec.TNMI7-0035-2016. PMID: 28233510; PMCID: PMC5785104.
4. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf). 2001 May;54(5):633-9. doi: 10.1046/j.1365-2265.2001.01266.x. PMID: 11380494.
5. Neogi S, Mukhopadhyay P, Sarkar N, Datta PK, Basu M, Ghosh S. Overt and Subclinical Adrenal Insufficiency in Pulmonary Tuberculosis. Endocr Pract. 2020 Dec 14:S1530-891X(20)48391-0. doi: 10.1016/j.eprac.2020.11.012. Epub ahead of print. PMID: 33645514.
6. Paolo WF Jr, Nosanchuk JD. Adrenal infections. Int J Infect Dis. 2006 Sep;10(5):343-53. doi: 10.1016/j.ijid.2005.08.001. Epub 2006 Feb 17. PMID: 16483815; PMCID: PMC7110804.
7. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003;9(1):3-24. doi: 10.1179/096805103125001298. PMID: 12691614.
8. Denny N, Raghunath S, Bhatia P, Abdelaziz M. Rifampicin-induced adrenal crisis in a patient with tuberculosis: a therapeutic challenge. BMJ Case Rep. 2016 Nov 29;2016:bcr2016216302. doi: 10.1136/bcr-2016-216302. PMID: 27899384; PMCID: PMC5175016.
9. Stefan R. Bornstein, Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis, David J. Torpy, Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 2, 1 February 2016, Pages 364–389, https://doi.org/10.1210/jc.2015-1710
10. Liatsikos EN, Kalogeropoulou CP, Papathanassiou Z, Tsota I, Athanasopoulos A, Perimenis P, Barbalias GA, Petsas T. Primary adrenal tuberculosis: role of computed tomography and CT-guided biopsy in diagnosis. Urol Int. 2006;76(3):285-7. doi: 10.1159/000091637. PMID: 16601397.
11. Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab. 1984 Dec; 59(6):1204-6. doi: 10.1210/jcem-59-6-1204. PMID: 6490796.
12. Bhatia E, Jain SK, Gupta RK, Pandey R. Tuberculous Addison's disease: lack of normalization of adrenocortical function after anti-tuberculous chemotherapy. Clin Endocrinol (Oxf). 1998 Mar;48(3):355-9. doi: 10.1046/j.1365-2265.1998.00409.x. PMID: 9578827.
13. Laway, B.A., Mir, S.A., Ganie, M.A. et al. Nonreversal of adrenal hypofunction after treatment of adrenal tuberculosis. Egypt J Intern Med 27, 42–44 (2015). https://doi.org/10.4103/1110-7782.155860
14. Penrice J, Nussey SS. Recovery of adrenocortical function following treatment of tuberculous Addison's disease. Postgrad Med J. 1992 Mar; 68(797):204-5. doi: 10.1136/pgmj.68.797.204. PMID: 1589379; PMCID: PMC2399240.
15. Kelestimur F. Recovery of adrenocortical function following treatment of tuberculous Addison's disease. Postgrad Med J (1993) 69, 832-34
16. Roxas MCA, Sandoval MAS, Salamat MS, Matias PJ, Cabal NP, Bartolo SS. Bilateral adrenal histoplasmosis presenting as adrenal insufficiency in an immunocompetent host in the Philippines. BMJ Case Rep. 2020 May 12;13(5):e234935. doi: 10.1136/bcr-2020-234935. PMID: 32404324; PMCID: PMC7228487.
17. Bhansali A, Das S, Dutta P, Walia R, Nahar U, Singh SK, Vellayutham P, Gopal S. Adrenal histoplasmosis: unusual presentations. J Assoc Physicians India. 2012 Oct;60:54-8. PMID: 23777028.
18. Jayathilake WAPP, Kumarihamy KWMPP, Ralapanawa DMPUK, Jayalath WATA, "A Rare Presentation of Possible Disseminated Histoplasmosis with Adrenal Insufficiency Leading to Adrenal Crisis in an Immunocompetent Adult: A Case Report", Case Reports in Medicine, vol. 2020, Article ID 8506746, 5 pages, 2020. https://doi.org/10.1155/2020/8506746
19. Vyas S, Kalra N, Das PJ, Lal A, Radhika S, Bhansali A, Khandelwal N. Adrenal histoplasmosis: An unusual cause of adrenomegaly. Indian J Nephrol. 2011 Oct;21(4):283-5. doi: 10.4103/0971-4065.78071. PMID: 22022092; PMCID: PMC3193675.
20. Mukherjee JJ, Villa ML, Tan L, Lee KO. Bilateral adrenal masses due to histoplasmosis. J Clin Endocrinol Metab. 2005 Dec; 90(12):6725-6. doi: 10.1210/jc.2005-1868. PMID: 16330806.
21. Robinson LJ, Lu M, Elsayed S, Joy TR. Bilateral adrenal histoplasmosis manifesting as primary adrenal insufficiency. CMAJ. 2019 Nov 4;191(44):E1217-E1221. doi: 10.1503/cmaj.190710. PMID: 31685665; PMCID: PMC6834444.
22. Kothari D, Chopra S, Bhardwaj M, Ajmani AK, Kulshreshtha B. Persistence of histoplasma in adrenals 7 years after antifungal therapy. Indian J Endocrinol Metab. 2013 May;17(3):529-31. doi: 10.4103/2230-8210.111679. PMID: 23869317; PMCID: PMC3712391.
23. de Oliveira FM, Fragoso MCBV, Meneses AF, Vilela LAP, Almeida MQ, Palhares RB, de Arruda Mattos TV, Scalissi NM, Viana Lima J. Adrenal insufficiency caused by Paracoccidioidomycosis: three case reports and review. AACE Clin Case Rep. 2019 Mar 13;5(4):e238-e243. doi: 10.4158/ACCR-2018-0632. PMID: 31967043; PMCID: PMC6873835.
24. Cataño J, Porras J. Adrenal Paracoccidioidomycosis. Am J Trop Med Hyg. 2020 Sep;103(3):935-936. doi: 10.4269/ajtmh.20-0083. PMID: 32896237; PMCID: PMC7470546.
25. Tobón AM, Agudelo CA, Restrepo CA, Villa CA, Quiceno W, Estrada S, Restrepo A. Adrenal function status in patients with paracoccidioidomycosis after prolonged post-therapy follow-up. Am J Trop Med Hyg. 2010 Jul; 83(1):111-4. doi: 10.4269/ajtmh.2010.09-0634. PMID: 20595488; PMCID: PMC2912586.
26. Kumar A, Sreehari S, Velayudhan K, Biswas L, Babu R, Ahmed S, Sharma N, Kurupath VP, Jojo A, Dinesh KR, Karim S, Biswas R. Autochthonous blastomycosis of the adrenal: first case report from Asia. Am J Trop Med Hyg. 2014 Apr;90(4):735-9. doi: 10.4269/ajtmh.13-0444. Epub 2014 Feb 3. PMID: 24493676; PMCID: PMC3973522.
27. Rimondi AP, Bianchini E, Barucchello G, Panzavolta R. Addison's disease caused by adrenal blastomycosis: a case report with fine needle aspiration (FNA) cytology. Cytopathology. 1995 Aug;6(4):277-9. doi: 10.1111/j.1365-2303.1995.tb00480.x. PMID: 8520008.
28. Matsuda Y, Kawate H, Okishige Y, Abe I, Adachi M, Ohnaka K, Satoh N, Inokuchi J, Tatsugami K, Naito S, Nomura M, Takayanagi R. Successful management of cryptococcosis of the bilateral adrenal glands and liver by unilateral adrenalectomy with antifungal agents: a case report. BMC Infect Dis. 2011 Dec 14; 11:340. doi: 10.1186/1471-2334-11-340. PMID: 22166121; PMCID: PMC3254187.
29. Ito M, Hinata T, Tamura K, Koga A, Ito T, Fujii H, Hirata F, Sakuta H. Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual. Intern Med. 2017; 56(10):1259-1264. doi: 10.2169/internalmedicine.56.7356. Epub 2017 May 15. PMID: 28502948; PMCID: PMC5491828.
30. Muraoka Y, Iwama S, Arima H. Normalization of Bilateral Adrenal Gland Enlargement after Treatment for Cryptococcosis. Case Rep Endocrinol. 2017; 2017:1543149. doi: 10.1155/2017/1543149. Epub 2017 Mar 26. PMID: 28458934; PMCID: PMC5385225.
31. Keleştimur F. Sheehan's syndrome. Pituitary. 2003;6(4):181-8. doi: 10.1023/b:pitu.0000023425.20854.8e. PMID: 15237929.
32. Karaca Z, Laway BA, Dokmetas HS, Atmaca H, Kelestimur F. Sheehan syndrome. Nat Rev Dis Primers. 2016 Dec 22; 2:16092. doi: 10.1038/nrdp.2016.92. PMID: 28004764.
33. Mandal S, Mukhopadhyay P, Banerjee M, Ghosh S. Clinical, endocrine, metabolic profile, and bone health in Sheehan’s syndrome. Indian J Endocr Metab 2020; 24:338-42.
34. Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ; HyposCCS Advisory Board; U.S. HypoCCS Study Group. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab. 2002 Feb; 87(2):477-85. doi: 10.1210/jcem.87.2.8216. PMID: 11836272.
35. Kilicli F, Dokmetas HS, Acibucu F. Sheehan's syndrome. Gynecol Endocrinol. 2013 Apr;29(4):292-5. doi: 10.3109/09513590.2012.752454. Epub 2012 Dec 18. PMID: 23245206.
36. Bhat S, Mukhopadhyay P, Raychaudhury A, Chowdhury S, Ghosh S. Predictors of hypopituitarism due to vasculotoxic snake bite with acute kidney injury. Pituitary. 2019 Dec; 22(6):594-600. doi: 10.1007/s11102-019-00990-8. PMID: 31556012
37. Rajagopala S, Thabah MM, Ariga KK, Gopalakrishnan M. Acute hypopituitarism complicating Russell's viper envenomation: case series and systematic review. QJM. 2015 Sep;108(9):719-28. doi: 10.1093/qjmed/hcv011. Epub 2015 Jan 27. PMID: 25630907.
38. Shivaprasad C, Aiswarya Y, Sridevi A, Anupam B, Amit G, Rakesh B, Annie PA, Anish K. Delayed hypopituitarism following Russell's viper envenomation: a case series and literature review. Pituitary. 2019 Feb; 22(1):4-12. doi: 10.1007/s11102-018-0915-1. PMID: 30317419.
39. Benjamin JM, Chippaux JP, Sambo BT, Massougbodji A. Delayed double reading of whole blood clotting test (WBCT) results at 20 and 30 minutes enhances diagnosis and treatment of viper envenomation. J Venom Anim Toxins Incl Trop Dis. 2018 May 16; 24:14. doi: 10.1186/s40409-018-0151-1. PMID: 29796013; PMCID: PMC5956810
40. Tun-Pe, Phillips RE, Warrell DA, Moore RA, Tin-Nu-Swe, Myint-Lwin, Burke CW. Acute and chronic pituitary failure resembling Sheehan's syndrome following bites by Russell's viper in Burma. Lancet. 1987 Oct 3;2(8562):763-7. doi: 10.1016/s0140-6736(87)92500-1. PMID: 2888987.
41. Naik BN, Bhalla A, Sharma N, Mokta J, Singh S, Gupta P, Rai A, Subbiah S, Bhansali A, Dutta P (2018) Pituitary dysfunction in survivors of Russell’s viper snake bite envenomation: A prospective study. Neurol India 66(5):1351
42. De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, Karimi M, Yassin MA, El Awwa A, Stoeva I, Raiola G, Galati MC, Bedair EM, Fiscina B, El Kholy M. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab. 2013 Jan;17(1):8-18. doi: 10.4103/2230-8210.107808. PMID: 23776848; PMCID: PMC3659911.
43. Saraogi RK, Chowdhury S, Mukherjee S, Roy S, Chatterjee P. Adrenal extramedullary haematopoietic tumor in HbE Thalassemia. BMJ 2002; 18(7). South Asia Edition.
44. Tiosano D, Hochberg Z. Endocrine complications of thalassemia. J Endocrinol Invest. 2001 Oct; 24(9):716-23. doi: 10.1007/BF03343916. PMID: 11716158.
45. De P, Mistry R, Wright C, Pancham S, Burbridge W, Gangopadhayay K, Pang T, Das D. A Review of Endocrine Disorders in Thalassaemia. OJEMD 2014; 4(2).
46. Bhatia E. Adrenal disorders in people with HIV: The highs and lows. Indian J Med Res. 2018 Feb; 147(2):125-127. doi: 10.4103/ijmr.IJMR_1087_17. PMID: 29806599; PMCID: PMC5991116.
47. Eledrisi MS, Verghese AC. Adrenal insufficiency in HIV infection: a review and recommendations. Am J Med Sci. 2001 Feb; 321(2):137-44. doi: 10.1097/00000441-200102000-00005. PMID: 11217816.
48. Bakari Adamu Girei, Sani-Bello Fatima. Endocrine Manifestations of HIV Infection.2013. http://dx.doi.org/10.5772/52684
49. Unachukwu CN, Uchenna DI, Young EE. Endocrine and metabolic disorders associated with human immune deficiency virus infection. West Afr J Med. 2009 Jan;28(1):3-9. doi: 10.4314/wajm.v28i1.48415. PMID: 19662737.
50. Hopkins RL, Leinung MC. Exogenous Cushing's syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005 Jun;34(2):371-84, ix. doi: 10.1016/j.ecl.2005.01.013. PMID: 15850848.
51. http://www.meditecno.pt/Upload/Product/Archive/lkco1.pdf . Last accessed on 14.4.2021
52. Patt H, Bandgar T, Lila A, Shah N. Management issues with exogenous steroid therapy. Indian J Endocrinol Metab. 2013 Dec; 17(Suppl 3):S612-7. doi: 10.4103/2230-8210.123548. PMID: 24910822; PMCID: PMC4046616.
53. Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. 2004 Oct; 48(5):687-96. doi: 10.1590/s0004-27302004000500015. Epub 2005 Mar 7. PMID: 15761540.
54. Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med. 1991 Oct 24;325(17):1223-7. doi: 10.1056/NEJM199110243251706. PMID: 1922210.
55. Gallacher SD, Tsokolas G, Dimitropoulos I. Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department. Clin Med (Lond). 2017 Feb; 17(1):43-45. doi: 10.7861/clinmedicine.17-1-43. PMID: 28148579; PMCID: PMC6297599.

 

ABSTRACT

 

Snakebite envenoming (SBE) is a life-threatening medical emergency encountered in tropical parts of Asia, Africa, and Latin America. Toxins in the venom cause local damage and multi-organ dysfunction, predominantly affecting neurological, hematological, and vascular systems. Endocrine anomalies are less frequently reported and often masked by more severe disorders. Anterior pituitary insufficiency is the most common endocrine manifestation and mainly observed after Russell’s viper (Daboia russelii and D. siamensis) bite. SBE-induced hypopituitarism can manifest early or have a delayed presentation. Primary adrenal insufficiency, hyponatremia, hypokalemia, hyperkalemia, and hyperglycemia are also described. These complications are uncommon and under-reported, as SBE occurs in remote areas and medical facilities for endocrine assessment might not be available. Timely identification and management of these problems are critical for optimum medical outcome.

 

INTRODUCTION

 

Snakebite envenoming (SBE) occurs predominantly in rural parts of Asia, Africa, and Latin America (1,2). The World Health Organization (WHO) included SBE in the priority list of neglected tropical diseases in 2018. According to the WHO, 4.5–5.4 million people get bitten by snakes annually, but many cases are not reported as people living in remote areas with limited healthcare access are affected. Clinical illness from SBE develops in 1.8–2.7 million, and the annual mortality is around 81,000 to 138,000 (3).

 

Toxins in snake venom can cause local tissue destruction, neurological damage, hemorrhagic tendency, renal failure, and cardiovascular compromise. Endocrine dysfunctions are uncommon but can have ominous consequences if not recognized. Anterior pituitary insufficiency (API) after Russell’s viper (RV) envenomation (RVE) is the most common endocrine manifestation of SBE. Electrolyte disturbances and hyperglycemia are the other complications described (4). Timely recognition and appropriate management of endocrine derangements like hypocortisolism and electrolyte imbalances can save lives.

 

SPECIES OF SNAKES AND SNAKE VENOM

 

The medically relevant poisonous snakes usually belong to the Elapidae and Viperidae families. Rare cases of envenoming from Atractaspididae and Colubridae families are also described. The common Elapidae snakes include cobras, mambas, kraits, coral snakes, death adders, and sea snakes. The Viperidae snakes of significance are vipers, including RV, adders, asps, and pit vipers. The general notion that Elapidae envenomation results in neuroparalytic manifestation and Viperidae bite induce local reaction and vasculotoxicity does not always hold.

 

Snake venoms contain mixtures of polypeptides, amines, carbohydrates, lipids, phospholipids, nucleosides, and minerals. The principal constituents are proteins belonging to the four families: phospholipase A2, metalloprotease, serine protease, and three-finger peptides. Additional secondary protein families include cysteine-rich secretory proteins, l-amino acid oxidases, kunitz peptides, C-type lectins/snaclecs, disintegrins, and natriuretic peptides (5).

 

Snake venom toxicity can be classified into three main categories: vasculotoxic, neurotoxic, and cytotoxic. Various proteins with enzymatic properties such as phospholipase A2, hyaluronidases, peptidases, and metalloprotease can cause local tissue destruction. Phospholipase A2, metalloproteases, and other protein components can cause neurotoxicity, damage the coagulation cascade, induce muscle necrosis, and sometimes exert cardiotoxic and nephrotoxic effects (6). Cardiac compromise and acute kidney injury (AKI) can also emerge as secondary complications. Endocrine disorders after SBE are uncommon and pathophysiologic mechanisms are incompletely understood.

 

ANTERIOR PITUITARY INSUFFICIENCY

 

Anterior pituitary insufficiency (API) is the most well-recognized endocrine manifestation of SBE. Most cases are from Sri Lanka, India, and Myanmar and occur after RVE (Daboia russelii and D. siamensis).

 

Etiology

 

Wolff first narrated SBE-induced hypopituitarism in 1958 after bite from Bothrops jararacussu (7). The first description of API following RVE in the Indian subcontinent came from Eapen et al. (8). Although RV is found in many south Asian countries, most accounts of RVE-induced API are almost exclusively from Myanmar, India, and Sri Lanka (9–16). It could be related to the geographic variation in venom composition among the same snake species. The incidence of API in a study from northern India was 14.6% (6/41) among patients admitted with vasculotoxic snakebites (presumed RVE) (12).

 

Pathophysiology

 

The pituitary gland is a highly vascular structure enclosed in a bony cavity called the sella tursica. The low-pressure hypothalamic-pituitary portal system originating from the superior hypophyseal artery provides blood supply to the anterior pituitary. The hypophyseal portal system is susceptible to compressive effects from an enlarged or engorged gland and renders the anterior pituitary vulnerable to vascular insults after stimulation from any cause.

 

Sheehan’s syndrome and RVE-induced hypopituitarism share similar pathophysiology (16,17). In Sheehan’s syndrome, hemorrhagic infarction of the pregnancy-induced hyperplastic gland occurs during severe postpartum bleeding-related hypovolemic shock (18). Predisposition to vascular damage in RVE could result from gland engorgement due to a generalized increase in capillary permeability as in capillary leak syndrome (19–21). Additionally, the toxins in RV venom can stimulate pituitary cells as suggested by in-vitro studies, further increasing the susceptibility to damage (22).

 

The vascular supply to an engorged and stimulated gland might be compromised due to microthrombi deposition or hemorrhage from disseminated intravascular coagulation (DIC) (16,23), circulatory or hypovolemic shock (14), thrombotic occlusion of major vessels including cerebral venous thrombosis (24,25), and increased intracranial pressure (14). Autoimmune damage has been postulated to contribute to delayed pituitary injury in Sheehan’s syndrome (26,27). The role of similar immune-mediated damage in the development of delayed hypopituitarism after RVE has not been studied.

 

Clinical Features

 

ACUTE HYPOPITUITARISM

 

Acute onset API has been observed after RVE in several series and can present as early as the first day (11,12,15). In one series of nine patients, API occurred after a median interval of nine days (range 2-14 days) (15). The usual manifestations of RVE include local reaction, coagulopathy, neuromuscular paralysis, and AKI (28,29). Circulatory shock, another feature of RVE, is multifactorial in etiology (14). In the acute phase, adrenal insufficiency (AI) dominates the clinical presentation of API. The symptoms of AI often get masked by other systemic effects of RVE. Clinical clues could be refractory hypotension and the presence of hypoglycemia or hyponatremia.

 

Central hypothyroidism may coexist with secondary AI and is diagnosed if serum thyroid-stimulating hormone (TSH) is low or normal along with decreased serum thyroxine levels. TSH can also get suppressed due to sick euthyroid syndrome and glucocorticoid administration. The diagnosis of central hypothyroidism is difficult to discern in the acute phase, and a follow-up test after recovery is necessary for confirmation. Reassessment of hypothalamic-pituitary-adrenal (HPA) and additional evaluation of the gonadotrophic and growth hormone (GH) secretion should be performed after 4-6 weeks. Acute hypopituitarism is sometimes transient, but the typical outcome is a permanent disease (12,13).

 

DELAYED HYPOPITUITARISM

 

API is often diagnosed years after RVE (30–33). The symptoms depend on the hormone axis involved and the extent of hormone deficiency (34). Delayed hypopituitarism often presents as secondary amenorrhea and infertility in females. In males, hypogonadotropic hypogonadism usually manifests as loss of libido and erectile dysfunction. Loss of secondary sexual characteristics can be present in both genders.

 

Standard features of secondary hypothyroidism include cold intolerance, weight gain, constipation, dry skin, and hoarseness. Secondary AI presents as fatigue, loss of appetite, and orthostatic dizziness (34). Involvement in early childhood can cause stunted growth and delayed or absent puberty (31). In a case series of delayed API, secondary hypothyroidism and hypogonadotropic hypogonadism were present in all the cases (8/8); and GH and secondary AI were present in 75% (6/8) (30). Table 1 depicts the recent case series describing API.

 

Predictors of Hypopituitarism

 

The presence of acute kidney injury (AKI) most consistently correlates with the development of API after RVE (13,30). Bhat et al. found that in patients (n=51) with vasculotoxic snakebite-associated AKI, the risk factors for API were younger age, the number of hemodialysis sessions, and 20-min whole blood clotting time (13). There was a history of AKI in 75% of cases of delayed hypopituitarism in another series (30). In a study describing nine patients with acute API, the predictors were multi-organ dysfunction, lower platelet counts, and more bleeding with a requirement for transfusions (15). However, coagulopathy, AKI, hemodialysis, and clinical severity scores failed to show any association with hypopituitarism in a prospective study (12).

 

Table 1. Case Series of Hypopituitarism After Snakebite Envenoming
Author, year	Region	Snake species	No. of patients	Onset,  Time	Clinical features/ hormone axes involved/ comments
Tun Pe, 1987(10)	Myanmar	Not defined	Snakebite – 220 Acute API – 3 PH (on autopsy) – 4   Delayed  API – 11	Acute: 21 hr - 9 d   Delayed: 2 wk - 24 yr	Acute - C, GH, PRL   Delayed Symptomatic - 7 Asymptomatic – 4
Proby, 1989 (35)	Myanmar	RV	Acute API (probable) – 20   Delayed API – 11/12	Acute, NA   Delayed – 8 - 226 wk	C - 10/15 T - 19/20 G -12/17
Golay, 2014 (11)	West Bengal, India	Vasculotoxic snakebite	API - 9/96 cases of snakebite associated AKI	Acute and delayed, 2 wk - 10 yr	C - 6/9 G, GH, T - 9/9 1 empty sella, rest normal
Rajagopala, 2014 (15)	Puducherry, India	Vasculotoxic snakebite	9/989 cases	Acute, 2-14 d	Hypoglycemia (100%), hypotension (67%) C - 9/9 Partial empty sella in 6/9
Naik, 2018 (12)	India	Vasculotoxic snakebite	9/41 cases	Acute (10%), Mean - 32 hr	Primary AI - 2/6, C, GH, G - 6/6 PRL - 2/6
White, 2019 (36)	Myanmar	RV (85.4%), Rest - cobra, krait, green pit viper, others	20/948 cases	Acute (2%)	Coagulopathy - 68.9%,  AKI - 72.2%
Gopalkrishnan, 2018 (14)	India	RV, saw-scaled viper	SB - 248 AI – 12 API - 4	Acute	C -19/48 Autopsy - 52. PH or ischemic necrosis - 46% Bilateral adrenal hemorrhage - 26%, Adrenal ischemic necrosis – 6%
Shivaprasad, 2018 (30)	Karnataka, India	RV	Delayed API - 8	Delayed, 5-11 yr	C, GH - 6/8 T, G - 8/8
Bhat, 2019 (13)	West Bengal, India	Vasculotoxic snakebite	API - 11/51 at 7 d and 13/33 at 3 mn after snakebite associated AKI	Acute and delayed, 7 d – 3 mn	C – 12/13 PRL – 9/13 G – 9/13 GH – 5/13 T – 4/13

RV - Russell’s viper, C - cortisol, GH - growth hormone, G - gonadotropin, PRL - prolactin, T - thyroid, API – anterior pituitary insufficiency, AI - adrenal insufficiency, PH – pituitary hemorrhage, AKI – acute kidney injury, SB- snake bite

 

Diagnosis

 

ACUTE HYPOPITUITARISM

 

It is challenging to diagnose API during the acute phase. The indicators associated with API are summarized in table 2. The assessment of the HPA axis is required to decide the necessity for glucocorticoid replacement. Hypocortisolism in the acute phase is diagnosed from random cortisol or with the cosyntropin stimulation test. In remote areas, if a delay is anticipated in obtaining the cortisol report, hydrocortisone replacement should be started in suspected cases. The different criteria that have been used to diagnose hypocortisolism in the acute phase are (a) fasting serum cortisol < 3 μg/dL (83 nmol/L) (13), (b) random serum cortisol < 5 μg/dL (138 nmol/L) in suspected pituitary apoplexy (37), (c) random serum cortisol < 10 μg/dL (275 nmol/L) in a critically ill patient (14), (d) post-cosyntropin peak cortisol < 18 μg/dl (500 nmol/L), and (e) post-cosyntropin delta cortisol < 9 μg/dL (250 nmol/L) (38). Note in very ill patients serum cortisol levels can be artifactually low secondary to a decrease in cortisol binding protein.

 

The interpretation of the thyroid function test can be problematic in the acute phase. Low luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin might be indicative but not diagnostic of API. The gonadal axis and sex hormone secretion (testosterone in males and estradiol in females) is usually suppressed during any severe illness. The pituitary function should be reassessed after 4-6 weeks of recovery. The MRI findings reveal a normal gland on imaging in acute cases (11,12,15). Pituitary hemorrhage has been demonstrated in autopsy findings but is seldom observed in imaging studies (15).

 

Table 2. Features Suggestive Of or Associated with Acute Hypopituitarism after Russell’s Viper Bite
Clinical features	Laboratory results	Imaging
Persistent or unexplained hypotension	Hypoglycemia	Pituitary hemorrhage or infarct on MRI
Acute kidney injury	Hyponatremia
Capillary leak syndrome
Disseminated intravascular coagulation

 

DELAYED HYPOPITUITARISM

 

Acute hypopituitarism may progress to chronic disease or manifest insidiously years later (11,12,30). It may be prudent to perform periodic surveillance to rule out the development of API following RVE. Hypogonadism has been described in 100% of cases, central hypothyroidism in 96.4%, secondary AI in 82%, and GH deficiency in 77% (30). Central diabetes insipidus (CDI) is very rare and discussed next. The clinical presentation depends on the age, the hormone axes involved, and the mode of onset. The tests recommended for the diagnosis of pituitary hormone deficiency are outlined in table 3. However, facilities for the dynamic tests may not be available in remote areas where SBE is prevalent (34). MRI usually reveals a normal pituitary during the initial year, but partial or complete empty sella may be found later on (4). 

 

Table 3. Investigations for Diagnosis of Chronic Anterior Pituitary Insufficiency
Hormone	Tests	Interpretation/comments
ACTH	Cortisol, ACTH between 8- 9 AM	Serum cortisol values < 3 μg/dL (83 nmol/L) at 8–9 AM on 2 occasions strongly suggest AI in an appropriate clinical setting. Intermediate levels (3-18 μg/dl; 83 – 497 nmol/L) require cosyntropin stimulation test. Concomitant normal or low ACTH levels indicate secondary AI.
	Cosyntropin (Synacthen) stimulation test	Cosyntropin injection 250 μg (i.v. or i.m.) followed by serum cortisol at 30 min and 60 min. Peak cortisol < 18 μ/dl (500 nmol/L) is suggestive of AI.
	Insulin tolerance test	Serum cortisol < 20 μg/dL (550 nmol/L) at the time of insulin induced hypoglycemia < 40 mg/dL (2.2 mmol/L). Extreme caution required, not practiced in many centers.
TSH	T4 (total or free), TSH	Low T4 with low or normal TSH suggests the diagnosis of central hypothyroidism
GH	IGF-1	Low IGF-1 suggestive but not diagnostic.
	GH stimulation test	Adults: Insulin tolerance test, arginine, GHRH stimulation test, Macimorelin stimulation test, glucagon stimulation test. Children: Clonidine stimulation test in addition to tests used for adults.
Gonadotrophin (Males)	LH, FSH, testosterone (total), SHBG	Low total testosterone (<300 ng/dl (10.41 nmol/L)) between 8–9 AM, preferably on 2 occasions along with low or normal LH, FSH is suggestive of gonadotrophin deficiency. SHBG and free or bioavailable testosterone measurement should be considered in borderline cases.
Gonadotrophin (Females)	LH, FSH, estradiol	Low estradiol in the setting of low or normal LH and FSH in the appropriate clinical setting (amenorrhea/ oligomeorrhea) suggests gonadotrophin deficiency.
Prolactin	Prolactin	Low levels found in hypopituitarism

 ACTH – adrenocorticotrophic hormone, AI – adrenal insufficiency, TSH – thyroid-stimulating hormone, T4 – thyroxine, GH - growth hormone, IGF-1 – insulin-like growth factor 1, LH – luteinizing hormone, FSH – follicle-stimulating hormone, SHBG – sex-hormone binding globulin

 

Management

 

Acute hypopituitarism typically occurs in critically ill patients with severe envenomation from RV. Intravenous hydrocortisone is required if AI is suspected or diagnosed. Thyroxine supplementation for hypothyroidism should be started only after correcting AI. There is a risk of precipitating adrenal crisis because of the accelerated metabolic clearance of cortisol, if thyroxine is administered before treatment of AI (39). Monitoring of electrolytes, and slow correction of hyponatremia when present, in order to prevent central pontine myelinolysis, are important adjuncts.

 

If oral intake is proper and the patient is hemodynamically stable, intravenous hydrocortisone can be substituted by oral glucocorticoids. Hormonal evaluation of the entire pituitary axes should be performed after 4-6 weeks of recovery. Replacement of deficient hormones as per standard practice should be instituted if API persists (34).

 

Post-mortem Findings

 

Pituitary hemorrhage and ischemic necrosis have been described in autopsy studies of 43% (36/84) cases of RVE in Myanmar (40). Areas of ischemic necrosis with hemorrhage at the center were observed in studies from India (15). Deposition of fibrin microthrombi in the pituitary and other organs, including the kidney, suggests a possible role of DIC in the pathogenesis of API (23). 

 

DIABETES INSIPIDUS

 

Involvement of the posterior pituitary gland is exceedingly rare in SBE. There are only a few case reports of central diabetes insipidus (CDI) after RVE (13,31,41,42). The posterior pituitary receives direct arterial supply from the inferior hypophyseal artery and is resistant to vascular damage. On the other hand, the anterior gland is susceptible to vascular compromise as it is supplied by the low-pressure hypophyseal-portal system (43). Moreover, CDI occurs when more than 80% of arginine vasopressin (AVP)-producing hypothalamic magnocellular neurons are lost. The posterior pituitary acts as a storage and secretory organ, and persistent CDI ensues only in the presence of significant damage to the hypothalamus (44). Polyuria, a cardinal feature of CDI, may be obscured due to concomitant hypocortisolism and manifest only after glucocorticoid replacement (45). CDI should be treated with nasal or oral desmopressin.

 

ADRENAL DISORDERS

 

Etiopathogenesis

 

Secondary AI from hypopituitarism is the classically described adrenal disorder resulting from SBE. Primary AI is exceptionally uncommon, though adrenal hemorrhage (AH) has been described in imaging studies and autopsy findings. There are cases of AH occurring after RVE and saw scale viper (Echis carinatus) bite (40,46,47).

 

The pathophysiology of AH is related to DIC and has been postulated to resemble Waterhouse–Friderichsen syndrome (48). The adrenal gland is a highly vascular structure that derives its arterial supply from three arteries but is drained by only one adrenal vein and has a dense internal network of capillaries (49). The causal factors behind predisposition to AH after RVE are summarized in table 4 (14,50,51).

 

Table 4. Factors Predisposing to Hemorrhage after Russell’s Viper Envenomation

Intrinsic predisposition of adrenal vascular structure due to arterial supply by 3 vessels but drainage by one vein

Rich subcapsular plexus with limited drainage by venules forming a “dam”

Disseminated intravascular coagulation and hemorrhagic toxins in the venom increase bleeding tendency

Formation of microthrombi in venules impair venous drainage and cause pooling of blood

Pooling of blood due to capillary leak syndrome

Stress-induced trophic effect of adrenocorticotrophic hormone induces adrenal cortical hyperplasia and increase vascularity

Stress-induced catecholamine secretion causes adrenal venous constriction resulting in pooling of blood in the adrenal gland

 

Diagnosis And Treatment

 

AH has been described in 36% of cases in an autopsy series, though primary AI is rare (40). Refractory hypotension, hypoglycemia, hyponatremia and hyperkalemia should raise suspicion of primary AI. The presence of associated secondary AI can confound the diagnosis. Bilateral AH with transient AI has been described following RVE. The hemorrhage and adrenal function resolved in weeks (47). Cases depicting chronic AI have been published after vasculotoxic SBE (12). Diagnosis and treatment are similar to secondary AI; the primary differentiating point is elevated plasma ACTH. Mineralocorticoid supplementation may be additionally required in primary AI.

 

HYPERGLYCEMIA

 

Etiopathogenesis

 

Hyperglycemia, an infrequent endocrine complication after SBE, has been described following both elapid (Bungarus multicinctus multicinctus) and viper envenomation (Vipera ammodytes ammodytes, European viper spp) (52–54). In rat models, common krait (Bungarus caeruleus) venom produces hyperglycemia (55). Intraperitoneal injection of saw-scaled viper (Echis carinatus) venom in rats suppressed plasma insulin and depleted liver glycogen stores (56). The hyperglycemic effect of Egyptian cobra (Naja haje) was also associated with concomitant depletion of liver and kidney glycogen stores. The mechanism of hyperglycemia is presumed to be triggered by a massive surge of catecholamines, a phenomenon observed after scorpion envenomation and in pheochromocytoma (4,57). Scorpion toxins stimulate sodium and inhibit potassium channels leading to intense and persistent excitation of the autonomic nervous system and release of neurotransmitters from the adrenal medulla, activating parasympathetic (early hours) and sympathetic nerve endings (4–48 hours). Catecholamine-mediated activation of the alpha receptors inhibits insulin secretion and contributes to hyperglycemia (54,58).

 

Clinical Features and Management

 

In a series of 83 children, viper envenomation resulted in hyperglycemia starting 4 hours after the bite, was moderate in severity, and usually transient. Moreover, hyperglycemia at presentation was a marker of high-grade envenomation (54). Severe hyperglycemia up to 480 mg/dl (26.7 mmol/L) occurred in a 45-day baby after two hours of bite from a nose-horned viper (V. a. ammodytes). (53). A retrospective study from Taiwan found hyperglycemia in 15% (7/44) patients of Bungarus multicinctus envenomation. Only one of them had persistent diabetes after recovery (52). Acute pancreatitis can result from the bite of the adder (Vipera berus), but associated hyperglycemia was not observed (59,60). Insulin and other antihyperglycemic drugs should be administered for management of hyperglycemia as and when necessary.

 

ELECTROLYTE DISTURBANCES

 

Hyponatremia

 

ETIOPATHOGENESIS

 

Envenomation by Malayan krait (Bungarus candidus), banded krait (Bungarus fasciatus)), and vipers can result in hyponatremia (61–68). Hyponatremia sometimes occur secondary to anterior pituitary insufficiency (API) after vasculotoxic envenoming but it has also been reported in the absence of API (4). Initial descriptions suggested that the syndrome of inappropriate antidiuretic hormone secretion (SIADH) could be responsible for hyponatremia (64). However, subsequent accounts revealed that urinary salt loss from natriuretic peptides in venom, rather than SIADH, is the pathogenic mechanism. The urinary salt loss is secondary to venom-derived natriuretic peptides, similar to endogenous natriuretic peptides, and acts on the renal tubules to decrease sodium and water reabsorption (69). Cerebral salt wasting has also been postulated to cause hyponatremia (61). An unusually high prevalence of hyponatremia (89%) was observed in a series of 14 patients with berg adder (Bitis atropos) bite in South Africa (67). Many-banded krait (Bungarus multicinctus) envenomation caused hyponatremia in 42% of cases (63).

 

Natriuretic peptides are found in the venom of Elapidae species such as Bungarus candidus,  Bungarus multicinctus, Dendroaspi sangusticeps, Oxyuranus microlepidotus, Pseudonaja textillis, and Pseudechis australis and a few Viperidae species e.g. Hypnale hypnale,  Psudocerastus persicus, and Macrovipera lebetina (66).

 

CLINICAL FEATURES

 

The presentation of hyponatremia depends on the severity and acuteness of onset. The clinical profile ranges from asymptomatic hyponatremia to varying alteration in sensorium to frank coma (61,62). Seizures occur in severe cases (62). Usually there are associated systemic features but isolated hyponatremia, hypovolemia, urinary salt loss, and generalized tonic-clonic seizures, following hump-nosed pit viper bite (Hypnale hypnale) has been described (66). In a case series of 42 patients admitted in Vietnam, 31 people (73.8%) had hyponatremia, the lowest values occurring an average of two days after the bite. Approximately 42–50% of patients who did not receive antivenom developed significant hyponatremia (< 130 mmol/L) 2–3 days post-bite. (70).  Another series of 78 cases of krait bite from Thailand reported hyponatremia in 17.6%, with severe hyponatremia (< 120 mmol/L) developing in four pediatric patients, two of whom developed seizures (71).

 

MANAGEMENT

 

Hyponatremia resulting from natriuretic peptides should be corrected by intravenous saline administration. SIADH is not the cause of hyponatremia, and fluid restriction is not recommended. If chronic hyponatremia is suspected, the correction rate should not exceed 10-12 meq/L in any 24 hours to avoid osmotic demyelination (72). If primary or secondary AI is the cause of hyponatremia, glucocorticoid supplementation is necessary.

 

Hypokalemia

 

ETIOPATHOGENESIS

 

Hypokalemia results from both elapid (73,74) and viper envenomation (75–77). Patients with hypokalemia after RV, common krait (Bungarus caeruleus), and Balkan adder (Vipera berus) bite demonstrated low trans-tubular potassium gradient (TTKG) ruling out renal potassium loss. The intracellular redistribution of potassium has been suggested as the likely pathophysiological mechanism, as gastrointestinal loss was also unlikely. Beta-adrenergic stimulation from toxin-mediated autonomic dysfunction leads to the intracellular shift of potassium and is the likely cause of hypokalemia (74,75). Concomitant hypomagnesemia and high urinary magnesium excretion were also observed in patients with hypokalemia, following Viperidae bite, presumably resulting from the direct toxic action of venom on the renal tubules (77). A high incidence (71%) of hypokalemia (<3.5 mmol/l) was found in a series of 210 patients from Sri Lanka during the first 48 hours. It was accompanied by metabolic acidosis but not respiratory alkalosis (78).

 

CLINICAL FEATURES AND MANAGEMENT

 

Hypokalemia manifests as muscular cramps or weakness, constipation, abdominal bloating, polyuria, and sometimes cause life-threatening complications like arrhythmias, rhabdomyolysis, hypokalemic paralysis, diaphragmatic palsy, and respiratory failure (75). The treatment strategy is similar to that of hypokalemic periodic paralysis. Rebound hyperkalemia is a potential complication during recovery. Potassium should be replaced orally or intravenously, along with appropriate monitoring. Magnesium deficit should be corrected if present (79).

 

Hyperkalemia

 

ETIOPATHOGENESIS

 

Hyperkalemia can complicate envenomation by nose-horned viper (Vipera ammodytes ammodytes), European viper (Vipera berus), and hump-nosed viper (Hypnale hypnale) (53,80–83). Severe envenomation from these snakes causes hyperkalemia secondary to rhabdomyolysis and AKI, and can be fatal (53,80). Hyperkalemia was present in 7% of cases of SBE in 258 patients from Thailand (77).

 

Type 4 renal tubular acidosis (T4RTA) is another possible cause of hyperkalemia. It was described during the recovery phase of bite by hump-nosed viper (81,82). Renal biopsy from these patients showed tubular atrophy and focal segmental glomerulosclerosis pattern (81). The underlying cause could be thrombotic microangiopathy caused by toxins in venom leading to patchy cortical necrosis with delayed or partial recovery of renal functions (83).

 

CLINICAL FEATURES AND MANAGEMENT

 

Hyperkalemia associated with rhabdomyolysis and AKI can cause life-threatening arrhythmias. The presence of hyperkalemia along with hyperchloremic metabolic acidosis and low trans-tubular potassium gradient (TTKG) is suggestive of T4RTA and has been described in victims of hump-nosed viper bites during recovery from AKI. Fludrocortisone has been used successfully in such cases. T4RTA, in most cases, was transient (82). Hyperkalemia associated with rhabdomyolysis and AKI will require potassium lowering therapy and, in severe cases, dialysis.

Table 5. Summary of Snakebite Envenoming Induced Endocrine Dysfunctions
Endocrine manifestation	Pathophysiology	Onset of symptoms	Clinical features	Management
Acute hypopituitarism	Hemorrhagic infarction of the anterior pituitary (pathogenesis similar to Sheehan’s syndrome)	Hours to days	Hypotension not responding to standard therapy, hypoglycemia, hyponatremia	Glucocorticoid +/- thyroxine replacement
Delayed hypopituitarism	Sequalae of vascular insult to pituitary during acute phase	Months to years	Amenorrhea, hypogonadism, hypothyroidism, secondary adrenal insufficiency, growth hormone deficiency	Replacement of deficient hormones
Diabetes Insipidus	Very rare, possible vascular insult during acute phase	Immediate or delayed	Polyuria, polydipsia	Desmopressin
Adrenal insufficiency	Hemorrhage with or without infarction in the adrenals secondary to coagulopathy	Hours to days	Hypotension and circulatory collapse	Glucocorticoid +/- mineralocorticoid replacement
Hyperglycemia	Massive catecholamine surge	First 4-6 hours	Children more than adults	Standard treatment of hyperglycemia
Hyponatremia	Venom derived natriuretic peptides – renal salt wasting	First 2-3 days	Asymptomatic to varying alteration in sensorium to coma, seizures	Intravenous saline
	Pituitary or adrenal insufficiency			Glucocorticoid replacement
Hypokalemia	Intracellular redistribution of potassium secondary to autonomic dysfunction.	Within first 24 hours	Muscle cramps, constipation, abdominal bloating, paralysis, respiratory failure, arrhythmia	Replacement of potassium with precaution to avoid rebound hyperkalemia
	Venom-mediated renal tubular damage
Hyperkalemia	Venom mediated thrombotic microangiopathy in the kidneys leading to type 4 renal tubular acidosis	Weeks	Arrhythmia	Fludrocortisone
	Rhabdomyolysis or kidney injury related	Days		Supportive, dialysis in severe cases

 

CONCLUSION

 

Endocrine dysfunctions associated with SBE are rare. However, missing the diagnosis can have life-threatening consequences. Acute or delayed anterior pituitary insufficiency is the most common manifestation. Establishing the diagnosis of hypocortisolism and timely glucocorticoid initiation in acute hypopituitarism are critical. Reports of adrenal dysfunction are scarce, though adrenal hemorrhage following RVE has been described more often in autopsy series. Electrolyte abnormalities should be anticipated and managed appropriately. Awareness and appropriate treatment of endocrine dysfunctions in resource-limited settings are necessary for optimal outcome.

 

REFERENCES

 

1. Feasey N, Wansbrough-Jones M, Mabey DCW, Solomon AW. Neglected tropical diseases. Br Med Bull. 2010 Mar 1;93(1):179–200.
2. Williams DJ, Faiz MA, Abela-Ridder B, Ainsworth S, Bulfone TC, Nickerson AD, et al. Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007059.
3. Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primer. 2017 Sep 14;3:17063.
4. Bhattacharya S, Krishnamurthy A, Gopalakrishnan M, Kalra S, Kantroo V, Aggarwal S, et al. Endocrine and Metabolic Manifestations of Snakebite Envenoming. Am J Trop Med Hyg. 2020 Oct;103(4):1388–96.
5. Tasoulis T, Isbister GK. A Review and Database of Snake Venom Proteomes. Toxins. 2017 18;9(9).
6. Ferraz CR, Arrahman A, Xie C, Casewell NR, Lewis RJ, Kool J, et al. Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis. Front Ecol Evol. 2019 Jun 19;7:218.
7. Wolff H. Insuficiência hipofisária anterior por picada de ofídio. Arq Bras Endocrinol Metab. 1958;7:25–47.
8. Animal, Plant, and Microbial Toxins - Volume 1—Biochemistry | Akira Ohsaka | Springer [Internet]. [cited 2021 May 2]. Available from: https://www.springer.com/gp/book/9781468408881
9. Myint-Lwin, Warrell DA, Phillips RE, Tin-Nu-Swe, Tun-Pe, Maung-Maung-Lay. Bites by Russell’s viper (Vipera russelli siamensis) in Burma: haemostatic, vascular, and renal disturbances and response to treatment. Lancet Lond Engl. 1985 Dec 7;2(8467):1259–64.
10. Tun-Pe, Phillips RE, Warrell DA, Moore RA, Tin-Nu-Swe, Myint-Lwin, et al. Acute and chronic pituitary failure resembling Sheehan’s syndrome following bites by Russell’s viper in Burma. Lancet Lond Engl. 1987 Oct 3;2(8562):763–7.
11. Golay V, Roychowdhary A, Dasgupta S, Pandey R. Hypopituitarism in patients with vasculotoxic snake bite envenomation related acute kidney injury: a prospective study on the prevalence and outcomes of this complication. Pituitary. 2014 Apr;17(2):125–31.
12. Naik BN, Bhalla A, Sharma N, Mokta J, Singh S, Gupta P, et al. Pituitary dysfunction in survivors of Russell’s viper snake bite envenomation: A prospective study. Neurol India. 2018 Oct;66(5):1351–8.
13. Bhat S, Mukhopadhyay P, Raychaudhury A, Chowdhury S, Ghosh S. Predictors of hypopituitarism due to vasculotoxic snake bite with acute kidney injury. Pituitary. 2019 Dec;22(6):594–600.
14. Gopalakrishnan M, Vinod KV, Dutta TK, Shaha KK, Sridhar MG, Saurabh S. Exploring circulatory shock and mortality in viper envenomation: a prospective observational study from India. QJM Mon J Assoc Physicians. 2018 Nov 1;111(11):799–806.
15. Rajagopala S, Thabah MM, Ariga KK, Gopalakrishnan M. Acute hypopituitarism complicating Russell’s viper envenomation: case series and systematic review. QJM Mon J Assoc Physicians. 2015 Sep;108(9):719–28.
16. Antonypillai CN, Wass J a. H, Warrell DA, Rajaratnam HN. Hypopituitarism following envenoming by Russell’s vipers (Daboia siamensis and D. russelii) resembling Sheehan’s syndrome: first case report from Sri Lanka, a review of the literature and recommendations for endocrine management. QJM Mon J Assoc Physicians. 2011 Feb;104(2):97–108.
17. Burke CW. The anterior pituitary, snakebite and Sheehan’s syndrome. Q J Med. 1990 Apr;75(276):331–3.
18. Diri H, Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F. Sheehan’s syndrome: new insights into an old disease. Endocrine. 2016 Jan;51(1):22–31.
19. Kendre PP, Jose MP, Varghese AM, Menon JC, Joseph JK. Capillary leak syndrome in Daboia russelii bite-a complication associated with poor outcome. Trans R Soc Trop Med Hyg. 2018 Feb 1;112(2):88–93.
20. Lingam TMC, Tan KY, Tan CH. Capillary leak syndrome induced by the venoms of Russell’s Vipers (Daboia russelii and Daboia siamensis) from eight locales and neutralization of the differential toxicity by three snake antivenoms. Comp Biochem Physiol Toxicol Pharmacol CBP. 2021 Sep 9;250:109186.
21. Rucavado A, Escalante T, Camacho E, Gutiérrez JM, Fox JW. Systemic vascular leakage induced in mice by Russell’s viper venom from Pakistan. Sci Rep. 2018 Oct 31;8(1):16088.
22. Hart GR, Proby C, Dedhia G, Yeo TH, Joplin GF, Burrin JM. Burmese Russell’s viper venom causes hormone release from rat pituitary cells in vitro. J Endocrinol. 1989 Aug;122(2):489–94.
23. Than-Thannull, Francis N, Tin-Nu-Swe  null, Myint-Lwin  null, Tun-Pe  null, Soe-Soe  null, et al. Contribution of focal haemorrhage and microvascular fibrin deposition to fatal envenoming by Russell’s viper (Vipera russelli siamensis) in Burma. Acta Trop. 1989 Jan;46(1):23–38.
24. Hung D-Z, Wu M-L, Deng J-F, Yang D-Y, Lin-Shiau S-Y. Multiple thrombotic occlusions of vessels after Russell’s viper envenoming. Pharmacol Toxicol. 2002 Sep;91(3):106–10.
25. Das SK, Khaskil S, Mukhopadhyay S, Chakrabarti S. A patient of Russell’s viper envenomation presenting with cortical venous thrombosis: an extremely uncommon presentation. J Postgrad Med. 2013 Sep;59(3):235–6.
26. Goswami R, Kochupillai N, Crock PA, Jaleel A, Gupta N. Pituitary autoimmunity in patients with Sheehan’s syndrome. J Clin Endocrinol Metab. 2002 Sep;87(9):4137–41.
27. De Bellis A, Kelestimur F, Sinisi AA, Ruocco G, Tirelli G, Battaglia M, et al. Anti-hypothalamus and anti-pituitary antibodies may contribute to perpetuate the hypopituitarism in patients with Sheehan’s syndrome. Eur J Endocrinol. 2008 Feb;158(2):147–52.
28. Kularatne S a. M. Epidemiology and clinical picture of the Russell’s viper (Daboia russelii russelii) bite in Anuradhapura, Sri Lanka: a prospective study of 336 patients. Southeast Asian J Trop Med Public Health. 2003 Dec;34(4):855–62.
29. Hung D-Z, Wu M-L, Deng J-F, Lin-Shiau S-Y. Russell’s viper snakebite in Taiwan: differences from other Asian countries. Toxicon Off J Int Soc Toxinology. 2002 Sep;40(9):1291–8.
30. Shivaprasad C, Aiswarya Y, Sridevi A, Anupam B, Amit G, Rakesh B, et al. Delayed hypopituitarism following Russell’s viper envenomation: a case series and literature review. Pituitary. 2019 Feb;22(1):4–12.
31. Golay V, Roychowdhary A, Pandey R, Pasari A, Praveen M, Arora P, et al. Growth retardation due to panhypopituitarism and central diabetes insipidus following Russell’s viper bite. Southeast Asian J Trop Med Public Health. 2013 Jul 4;44(4):697–702.
32. Ratnakaran B, Punnoose VP, Das S, Kartha A. Psychosis in Secondary Empty Sella Syndrome following a Russell’s Viper Bite. Indian J Psychol Med. 2016;38(3):254–6.
33. Yerawar C, Punde D, Pandit A, Deokar P. Russell’s viper bite and the empty sella syndrome. QJM Mon J Assoc Physicians. 2021 Jul 28;114(4):255–7.
34. Chung T-T, Koch CA, Monson JP. Hypopituitarism. 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.; 2000 [cited 2021 Oct 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK278989/
35. Proby C, Tha-Aung, Thet-Win, Hla-Mon, Burrin JM, Joplin GF. Immediate and long-term effects on hormone levels following bites by the Burmese Russell’s viper. Q J Med. 1990 Apr;75(276):399–411.
36. White J, Alfred S, Bates D, Mahmood MA, Warrell D, Cumming R, et al. Twelve month prospective study of snakebite in a major teaching hospital in Mandalay, Myanmar; Myanmar Snakebite Project (MSP). Toxicon X. 2019 Jan;1:100002.
37. Hannoush ZC, Weiss RE. Pituitary Apoplexy. 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.; 2000 [cited 2021 Oct 27]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK279125/
38. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017 Dec;45(12):2078–88.
39. Higham CE, Johannsson G, Shalet SM. Hypopituitarism. The Lancet. 2016 Nov 12;388(10058):2403–15.
40. Thein CM, Byard RW. Characteristics and relative numbers of lethal snake bite cases in medicolegal practice in central Myanmar - A five year study. J Forensic Leg Med. 2019 Apr;63:52–5.
41. Krishnan MN, Kumar S, Ramamoorthy KP. Severe panhypopituitarism and central diabetes insipidus following snake bite: unusual presentation as torsades de pointes. J Assoc Physicians India. 2001 Sep;49:923–4.
42. Gupta UC, Garg OP, Kataria ML. Cranial diabetes insipidus due to viper bite. J Assoc Physicians India. 1992 Oct;40(10):686–7.
43. Anderson JR, Antoun N, Burnet N, Chatterjee K, Edwards O, Pickard JD, et al. Neurology of the pituitary gland. J Neurol Neurosurg Psychiatry. 1999 Jun 1;66(6):703–21.
44. Christ-Crain M, Bichet DG, Fenske WK, Goldman MB, Rittig S, Verbalis JG, et al. Diabetes insipidus. Nat Rev Dis Primer. 2019 Aug 8;5(1):1–20.
45. Garrahy A, Moran C, Thompson CJ. Diagnosis and management of central diabetes insipidus in adults. Clin Endocrinol (Oxf). 2019 Jan;90(1):23–30.
46. Lakhotia M, Pahadiya HR, Singh J, Gandhi R, Bhansali S. Adrenal hematoma and right hemothorax after echis carinatus bite: an unusual manifestation. Toxicol Int. 2014 Dec;21(3):325–7.
47. Senthilkumaran S, Menezes RG, Hussain SA, Luis SA, Thirumalaikolundusubramanian P. Russell’s Viper Envenomation-Associated Addisonian Crisis. Wilderness Environ Med. 2018 Dec;29(4):504–7.
48. Fox B. Disseminated intravascular coagulation and the Waterhouse-Friderichsen syndrome. Arch Dis Child. 1971 Oct;46(249):680–5.
49. Gagnon R. The venous drainage of the human adrenal gland. Rev Can Biol. 1956 Feb;14(4):350–9.
50. Tan GXV, Sutherland T. Adrenal congestion preceding adrenal hemorrhage on CT imaging: a case series. Abdom Radiol N Y. 2016 Feb;41(2):303–10.
51. Senthilkumaran S, Menezes RG, Hussain SA, Luis SA, Thirumalaikolundusubramanian P. Russell’s Viper Envenomation-Associated Addisonian Crisis. Wilderness Environ Med. 2018 Dec;29(4):504–7.
52. Mao Y-C, Liu P-Y, Chiang L-C, Liao S-C, Su H-Y, Hsieh S-Y, et al. Bungarus multicinctus multicinctus Snakebite in Taiwan. Am J Trop Med Hyg. 2017 Jun 7;96(6):1497–504.
53. Lukšić B, Culić V, Stričević L, Brizić I, Poljak NK, Tadić Z. Infant death after nose-horned viper (Vipera ammodytes ammodytes) bite in Croatia: A case report. Toxicon Off J Int Soc Toxinology. 2010 Dec;56(8):1506–9.
54. Claudet I, Grouteau E, Cordier L, Franchitto N, Bréhin C. Hyperglycemia is a risk factor for high-grade envenomations after European viper bites (Vipera spp.) in children. Clin Toxicol Phila Pa. 2016;54(1):34–9.
55. Kiran KM, More SS, Gadag JR. Biochemical and clinicopathological changes induced by Bungarus coeruleus venom in a rat model. J Basic Clin Physiol Pharmacol. 2004;15(3–4):277–87.
56. Al-Saleh SSM. The effect of Echis carinatus crude venom and purified protein fractions on carbohydrate metabolism in rats. Cell Biochem Funct. 2002 Mar;20(1):1–10.
57. Bouaziz M, Bahloul M, Kallel H, Samet M, Ksibi H, Dammak H, et al. Epidemiological, clinical characteristics and outcome of severe scorpion envenomation in South Tunisia: multivariate analysis of 951 cases. Toxicon Off J Int Soc Toxinology. 2008 Dec 15;52(8):918–26.
58. Bahloul M, Turki O, Chaari A, Bouaziz M. Incidence, mechanisms and impact outcome of hyperglycaemia in severe scorpion-envenomed patients. Ther Adv Endocrinol Metab. 2018 Jul;9(7):199–208.
59. Pande R, Khan H. Acute pancreatitis following adder bite in the UK: a case report. Ann R Coll Surg Engl. 2010 Sep;92(6):e25–6.
60. Kjellström BT. Acute pancreatitis after snake bite. Case report. Acta Chir Scand. 1989 May;155(4–5):291–2.
61. Kumar Keyal N, Shrestha R, Thapa S, Adhikari P. Krait Snake Bite Presenting as a Cerebral Salt Wasting. Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med. 2019 Jul;23(7):347–8.
62. Höjer J, Tran Hung H, Warrell D. Life-threatening hyponatremia after krait bite envenoming – A new syndrome. Clin Toxicol. 2010 Nov 1;48(9):956–7.
63. Hung HT, Höjer J, Du NT. Clinical features of 60 consecutive ICU-treated patients envenomed by Bungarus multicinctus. Southeast Asian J Trop Med Public Health. 2009 May;40(3):518–24.
64. Trinh KX, Khac QL, Trinh LX, Warrell DA. Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam. Toxicon Off J Int Soc Toxinology. 2010 Nov;56(6):1070–5.
65. Tongpoo A, Sriapha C, Pradoo A, Udomsubpayakul U, Srisuma S, Wananukul W, et al. Krait envenomation in Thailand. Ther Clin Risk Manag. 2018;14:1711–7.
66. de Silva U, Sarathchandra C, Senanayake H, Pilapitiya S, Siribaddana S, Silva A. Hyponatraemia and seizures in Merrem’s hump-nosed pit viper (Hypnale hypnale) envenoming: a case report. J Med Case Reports. 2018 Aug 2;12(1):213.
67. van der Walt AJ, Muller GJ. Berg adder (Bitis atropos) envenoming: an analysis of 14 cases. Clin Toxicol Phila Pa. 2019 Feb;57(2):131–6.
68. Wium CA, Marks CJ, Du Plessis CE, Müller GJ. Berg adder (Bitis atropos): An unusual case of acute poisoning. South Afr Med J Suid-Afr Tydskr Vir Geneeskd. 2017 Nov 27;107(12):1075–7.
69. Vink S, Jin AH, Poth KJ, Head GA, Alewood PF. Natriuretic peptide drug leads from snake venom. Toxicon Off J Int Soc Toxinology. 2012 Mar 15;59(4):434–45.
70. Trinh KX, Khac QL, Trinh LX, Warrell DA. Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam. Toxicon Off J Int Soc Toxinology. 2010 Nov;56(6):1070–5.
71. Tongpoo A, Sriapha C, Pradoo A, Udomsubpayakul U, Srisuma S, Wananukul W, et al. Krait envenomation in Thailand. Ther Clin Risk Manag. 2018;14:1711–7.
72. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Mar;170(3):G1-47.
73. Gawarammana IB, Mudiyanselage Kularatne SA, Kularatne K, Waduge R, Weerasinghe VS, Bowatta S, et al. Deep coma and hypokalaemia of unknown aetiology following Bungarus caeruleus bites: Exploration of pathophysiological mechanisms with two case studies. J Venom Res. 2010 Dec 14;1:71–5.
74. Kularatne S a. M. Common krait (Bungarus caeruleus) bite in Anuradhapura, Sri Lanka: a prospective clinical study, 1996-98. Postgrad Med J. 2002 May;78(919):276–80.
75. Jeevagan V, Katulanda P, Gnanathasan CA, Warrell DA. Acute pituitary insufficiency and hypokalaemia following envenoming by Russell’s viper (Daboia russelii) in Sri Lanka: Exploring the pathophysiological mechanisms. Toxicon Off J Int Soc Toxinology. 2013 Mar 1;63:78–82.
76. Malina T, Krecsák L, Jelić D, Maretić T, Tóth T, Siško M, et al. First clinical experiences about the neurotoxic envenomings inflicted by lowland populations of the Balkan adder, Vipera berus bosniensis. Neurotoxicology. 2011 Jan;32(1):68–74.
77. Aye K-P, Thanachartwet V, Soe C, Desakorn V, Thwin K-T, Chamnanchanunt S, et al. Clinical and laboratory parameters associated with acute kidney injury in patients with snakebite envenomation: a prospective observational study from Myanmar. BMC Nephrol. 2017 Mar 16;18(1):92.
78. Sellahewa K. Lessons from four studies on the management of snake bite in Sri Lanka. Ceylon Med J. 1997 Mar;42(1):8–15.
79. Kardalas E, Paschou SA, Anagnostis P, Muscogiuri G, Siasos G, Vryonidou A. Hypokalemia: a clinical update. Endocr Connect. 2018 Apr;7(4):R135–46.
80. Denis D, Lamireau T, Llanas B, Bedry R, Fayon M. Rhabdomyolysis in European viper bite. Acta Paediatr Oslo Nor 1992. 1998 Sep;87(9):1013–5.
81. Weerakkody RM, Lokuliyana PN, Lanerolle RD. Transient distal renal tubular acidosis following hump nosed viper bite: Two cases from Sri Lanka. Saudi J Kidney Dis Transplant. 2016 Sep 1;27(5):1018.
82. Karunarathne S, Udayakumara Y, Govindapala D, Fernando H. Type IV renal tubular acidosis following resolution of acute kidney injury and disseminated intravascular coagulation due to hump-nosed viper bite. Indian J Nephrol. 2013;23(4):294–6.
83. Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, et al. Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon Off J Int Soc Toxinology. 2012 Jul;60(1):61–5.

 

ABSTRACT

 

Fungi are ubiquitous microbes and form a fraction of the symbiotic human microbiome. Transition from normal commensals to opportunistic mycoses can occur in immunocompromised hosts. Endemic mycoses are caused by fungi that are acquired from environmental sources. Fungal infections can be classified based on the depth of tissue invasion. Superficial diseases are limited to skin, nails, and mucous membrane while systemic dissemination can affect multiple organs including endocrine glands. Fungal involvement of the adrenals, pituitary, thyroid, pancreas, and gonads is well recognized. On the other hand, individual with diabetes mellitus and Cushing’s syndrome are susceptible to fungal disease as a result of immune dysfunction. Mucormycosis, candidiasis, and dermatophytosis occur more commonly in diabetes. Exogenous as well as endogenous Cushing’s syndrome is another endocrine disorder that predisposes to systemic fungal diseases. High index of suspicion is necessary to recognise these infections as clinical manifestations can be masked due to the anti-inflammatory properties of glucocorticoids. Autoimmune polyendocrine syndrome type I (APS-1) is a unique genetic disease where autoimmune damage predisposes to chronic mucocutaneous candidiasis (CMC) and a multitude of endocrine anomalies. Antifungal agents like azoles and polyenes can adversely affect the normal functioning of various endocrine pathways. Errors in diagnosis and treatment of the fungal infections of the endocrine glands can be critical. Equally important is to identify the various fungal diseases occurring in diabetes and other endocrine disorders. Conditions that predispose to fungal diseases such as diabetes and immunosuppressed states in organ-transplant recipients are becoming increasingly prevalent. Understanding of the critical interplay between the endocrine system and fungal pathogens are imperative for optimal patient outcomes in modern medicine.

INTRODUCTION

 

Fungi are classified as a separate kingdom that consists of single-celled or complex multicellular organisms. They are heterotrophs and unlike autotrophic plants, fungi lack chlorophyll and cannot synthesize their own food. They acquire nutrients from the surrounding media by osmosis.

 

Fungi are ubiquitous, transient, or persistent human colonizers which form the fungal microbiota or mycobiome. The human microbiota consists of a diverse array of microorganisms such as viruses, bacteria, fungi, protozoa, and parasites that reside in and around the human body. Fungi comprise ≤0.1% of the total human microbiota, but it still plays a crucial role in human health and disease (1).

 

Fungal species have complex interactions with the human host, which can be viewed as a spectrum of symbiotic relationships. The association can be mutualistic where it is advantageous to both, or commensal where only one profits but the other is unharmed.  On the other hand, the connection can be parasitic where the fungi are benefitted with a damaging effect on the human host, or amensalistic where one organism is harmed but the other remains unaffected. These human fungal symbionts can transition from commensalism to parasitism within the body. Immune dysfunction is one of the common factors that influence this conversion. Endocrine diseases like diabetes mellitus, Cushing’s syndrome, and autoimmune polyglandular syndrome type 1 (APS1) are prone to fungal infections due to immune dysfunction.

 

The prevalence of superficial fungal infection is 20-25% (2). On the other hand, fungal infections tend to spread in individuals with low immunity such as patients with cancer or acquired immunodeficiency syndrome (AIDS) and recipients of immunosuppressive drugs. The reported incidence of invasive fungal disease is 5.9 cases per thousand per year (3). The dissemination may affect various endocrine glands leading to their dysfunction, the adrenal gland being the one most commonly involved. Endocrine system involvement in fungal infections would extend to the adverse effect of various antifungal therapy too. Azoles are the most frequently described class affecting the endocrine system and, adrenal glands and gonads are their primary targets.

 

The diverse aspects of this complex relationship between fungi and the endocrine system are described in this chapter.

 

TYPES OF FUNGAL INFECTION

 

Fungal infections have been classified based on both anatomic location and epidemiology. They can also be classified on the basis of morphological structure of the fungus.

 

Anatomical Categories

 

MUCOCUTANEOUS INFECTIONS

 

Mucocutaneous infections is a heterogeneous group characterized by infections of the skin, mucous membranes, and the nails. These infections are confined to the cutaneous surface, with little propensity for systemic dissemination. The effect can vary from mild to severe depending on the extent of involvement but are rarely fatal.

 

DEEP ORGAN INFECTIONS

Fungal infections can sometimes cause deep tissue involvement and have the potential for hematogenous and systemic spread. Dissemination of fungal infections is usually observed in immunocompromised conditions. If untreated, deep organ or systemic fungal affection can be fatal.

 

Epidemiological Categories

 

ENDEMIC MYCOSES

 

Endemic mycoses include infections caused by fungi that do not belong to the normal human microbiota but rather are acquired from environmental sources. In endemic mycosis, deep organ infection is almost exclusively caused by inhalation, whereas cutaneous disease is most often caused by direct contact with soil but can also occasionally result from hematogenous dissemination. Dermatophytid fungi are mainly acquired by environmental contact however, human-to-human transmission has been reported. Examples of endemic mycoses include coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis, penicilliosis, phaeohyphomycosis, sporotrichosis, and adiaspiromycosis.

 

OPPORTUNISTIC MYCOSES

 

Opportunistic fungi can be normal human microbiota components, but in the immunocompromised state, these organism transition from harmless commensals to invasive pathogens. These fungi invade the host from the usual sites of colonization, typically the mucous membranes or the gastrointestinal tract. Typical examples are candidiasis, aspergillosis, mucormycosis (zygomycosis), cryptococcosis, scedosporiosis, trichosporonosis, fusariosis, and pneumocystosis. Fungi that are reported to affect the various endocrine glands are shown in table 1.

 

Table 1. Fungi Affecting Specific Endocrine Glands
Type of fungus	Organs affected
Aspergillosis	Pituitary, Thyroid, Pancreas, Adrenal
Zygomycosis	Thyroid
Candidiasis	Pituitary, Thyroid, Pancreas, Testis
Cryptococcosis	Thyroid, Pancreas, Adrenal, Testis
Histoplasmosis	Thyroid, Adrenal, Ovaries,
Blastomycosis	Testis, Ovaries
Coccidioidomycosis	Thyroid, Adrenal,
Paracoccidioidomycosis	Thyroid, Adrenal
Pneumocystis jirovecii	Pituitary, Thyroid, Parathyroid, Pancreas, Adrenal

 

Based on Morphology

 

YEASTS

 

Yeast are found as single rounded cells or as budding organisms. Examples are Saccharomyces cerevisiae, Candida albicans, and Leucosporidium frigidum.

 

MOLDS

 

Molds grow in filamentous forms called hyphae both at room temperature and in invaded tissue. The common molds are aspergillus (A. fumigatus, A flavus, and A brasiliensis), penicillium and rhizopus.

 

DIMORPHIC

 

Dimorphic fungi grow as yeasts or large spherical structures in the tissue but as filamentous forms at room temperature in the environment. These include histoplasma (H. capsulatum), blastomyces (B. dermatitidis), paracoccidioides (P. brasiliensis), coccidioides (C. immitis), penicillium (P. marneffei), and sporothrix (S schenckii).

FUNGAL DISEASES OF MAJOR ENDOCRINE GLANDS

 

Fungal infections are more prevalent in the immunocompromised state (table 2). There is a tendency for fungal infections to disseminate in such cases and affect endocrine organs like the pituitary, thyroid, parathyroid, pancreas, adrenal glands, and gonads. The involvement of these endocrine glands may lead to deficient hormone secretion. The clinical manifestations, diagnosis, and management of fungal infection of the major endocrine glands are discussed below.

 

Table 2. Conditions Predisposing to Systemic Fungal Infections

A.    Endocrine diseases 1.     Diabetes mellitus 2.     Cushing’s syndrome 3.     Autoimmune polyendocrine syndrome-1 4.     STAT5b deficiency (Congenital Insulin-like Growth Factor-1 Deficiency) B.    Immunosuppressed states 1.     Cancer 2.     Acquired immunodeficiency syndrome 3.     Acute leukemia 4.     Hematopoietic stem cell transplant recipients 5.     Solid-organ transplant recipients 6.     Recipients of immunosuppressive drugs in conditions like connective tissue diseases

 

Pituitary Fungal Infections

 

ETIOLOGY

 

Pituitary infections or abscesses are rare and account for less than 1% of pituitary lesions (4). Even among them, fungal infections are extremely unusual and occur predominantly in immunocompromised states. The mode of spread could be hematogenous, extension from adjacent structures like meninges, sphenoid sinus, cavernous sinus, and skull base, or iatrogenic during transsphenoidal procedures. Fungal infection of the pituitary can occur in the presence of underlying lesions like pituitary adenoma, Rathke’s cleft cyst, etc. Cushing’s syndrome, resulting from an adrenocorticotrophic hormone (ACTH) secreting pituitary adenoma, itself causes immunosuppression and further predisposes to fungal disease (5). Aspergillus is the most frequently reported fungal infection of the pituitary (6–8). Other fungi described to infect the pituitary include candida (9,10), Pneumocystis jirovecii (in HIV/AIDS) (11,12), and coccidia (13). In a review of 13 cases of pituitary aspergillus infection, five were immunosuppressed (14).

 

CLINICAL FEATURES

 

The clinical presentation of fungal infection of the pituitary can be variable (table 3).  Symptoms from mass effects such as headache, visual disturbances (due to optic chiasma compression), and ophthalmoplegia are the usual presenting features. Features suggestive of infection, such as fever, leukocytosis, and meningismus were absent in most of the reported cases (8,15,16). Aspergillus is known to cause angioinvasion and vasculitis, and thus can be additionally associated with features arising from cerebrovascular infarcts (8,14). Pituitary insufficiency can acutely manifest as hypotension and shock primarily from secondary hypoadrenalism (9). Gonadotrophin and other hormone secretion can be affected as a delayed sequalae,  but such reports are very rare (17). Pituitary stalk compression can induce hyperprolactinemia (18). Diabetes insipidus (DI) occur more frequently than seen with pituitary adenomas (10).

 

Table 3. Clinical Profile of Recently Reported Cases of Pituitary Aspergillus Infection
Author, year	Clinical setting	Symptoms	Diagnosis	Management/ outcome
Moore, 2016 (8)	74-year old male, CAD, CKD, AHA hypertension	Right eye pain, headaches, 10 months of worsening left hemiparesis	Imaging - right ICA occlusion, acute right pontine stroke, smaller infarcts in the right MCA territory	Fatal outcome, autopsy findings revealed fungal hyphae in pituitary
Choi, 2021(15)	75-year old male, DM, hypertension, lung aspergillosis	Headache, visual disturbance, hyponatremia	MRI - bilateral sphenoid sinusitis and pituitary involvement, transsphenoidal biopsy demonstrated invasive aspergillus	Endoscopic debridement of sinuses. Oral voriconazole given, gradual improvement
Saffarian,2018 (16)	60-year old male DM, hypertension, sphenoid aspergilloma	Headache, progressive visual loss, 4thcranial nerve palsy	MRI findings, endoscopy by nasal approach demonstrated aspergillus in biopsy	Endoscopic drainage, intravenous amphotericin, responded to treatment
Ouyang, 2015 (18)	55-year old female, no comorbidities	Headache, dizziness, and decreased visual acuity	MRI - sellar and sphenoid sinus mass Prolactin - 815 ng/mL	Transnasal, transsphenoidal removal of the mass and oral voriconazole – resolution of symptoms
Vijay-vargiya, 2013 (14)	68-year old female, kidney transplant recipient	Headache, left temporal hemianopsia, ptosis.	MRI – sellar mass Intraoperative frozen section showed organisms consistent with aspergillus	Transsphenoidal resection, voriconazole, Developed ACA ischemic stroke, died.

CAD – coronary artery disease, AHA – autoimmune hemolytic anemia, ICA – internal carotid artery, MCA – middle cerebral artery, ACA – anterior cerebral artery, DM – diabetes mellitus, MRI – magnetic resonance imaging

 

DIAGNOSIS

 

Fungal pituitary infections usually present with symptoms of headache, visual disturbance, and ophthalmoplegia and are often misdiagnosed as tumors (14). Identification of a mass in the sellar region in an immunocompromised state should raise suspicion of fungal etiology.  T1-weighted magnetic resonance imaging (MRI) of fungal abscess of pituitary shows nonspecific isointensity or hypointensity (4). Pituitary abscess of any etiology including fungal may demonstrate peripheral rim enhancement and calcifications on T2-weighted images. Low signals due to iron deposition are however indicative of fungal involvement (19). Involvement of the adjacent sinuses is another pointer for fungal disease (15,16). It is difficult to distinguish fungal pituitary infections from intrasellar bacterial infections and tumors, and the diagnosis is often confirmed during surgery or autopsy. Histopathological examination can reveal hyphae and fungal spores. Silver impregnation stains such as Grocott or Gomori methenamine silver, fungal culture, or fungal polymerase chain reaction (PCR) can confirm the diagnosis (4). Serum 1,3-β-D-glucan is positive in a broad range of invasive fungal infections, including candida (19). Serum galactomannan is however, a specific marker for invasive aspergillosis (20).

 

TREATMENT

 

Treatment includes antifungal therapy and drainage of the abscess by transsphenoidal endoscopic approach (14). Craniotomy is discouraged due to fear of intracranial dissemination. Deficiency of pituitary hormones may necessitate replacement (9). Voriconazole is the preferred therapeutic agent for aspergillus infection. Other medical options are liposomal amphotericin B, posaconazole, isavuconazole, and echinocandins (21). The recommended dose of voriconazole for central nervous system (CNS) aspergillosis is intravenous loading with 6 mg/kg every 12 hour for two doses followed by 4 mg /kg every 12 hour. The oral loading dose is 400 mg every 12 hour for two doses, followed by 200 mg twice daily (22). Oral treatment may be required for months. The exact duration of therapy is not established and depends on the clinical parameters. Antifungal therapy for other varieties of fungus should be administered as per standard practice. Mortality rates are high in disseminated disease with vascular invasion, immunosuppressed state, and in cases of a delayed diagnosis (14).

 

Thyroid Disorders

 

ETIOLOGY

 

Infections of the thyroid are rare as its rich blood supply, iodine content, and capsule are protective against microbial invasion (23). Fungi form a small subset among the microbial pathogens infecting the thyroid. A. fumigatus is the predominant fungi in general, whereas P. jirovecii is the most common cause of fungal thyroiditis in patients with AIDS (24,25). Table 4 enumerates the fungal infections reported to infect the thyroid. These infections are primarily seen in immunocompromised patients and usually is a part of disseminated infection. Both hematogenous and lymphatic spread can occur.  Direct invasion of the thyroid by fungal infection is also reported. Mycotoxin secreted by the fungus may affect thyroid function, however the evidence in humans is not definitive (26).

 

Table 4. Predisposing Conditions Where Fungus Affects the Thyroid Gland
Type of fungus	Predisposing condition
Aspergillus	Organ transplant (27,28), AML (29), ALL (30),  MDS (31), NHL (32), SLE (24,33), cryoglobulinemic vasculitis (34), AIDS, normal immune status with MNG (35)
Pneumocystis	AIDS (25), Thymic alymphoplasia (36)
Candida	ALL (37), AML (38)
Coccidiodes	SLE on corticosteroids (39), sarcoidosis on corticosteroids, PAN on corticosteroids (40)
Histoplasmosis	NHL (41)

AML – acute myeloid leukemia, ALL – acute lymphoblastic leukemia, MDS – myelodysplastic syndrome, NHL- Non-Hodgkin’s Lymphoma, SLE- systemic lupus erythematosus, AIDS – acquired immunodeficiency syndrome, MNG – multinodular goiter, PAN – polyarteritis nodosa

 

CLINICAL FEATURES

 

Fungal infection of the thyroid usually occurs in presence of underlying critical illness. The symptoms of thyroid infection can get masked by the primary disease. Thyroid involvement can be often detected post-mortem in cases of disseminated fungal disease (42). Common clinical presentations include pain, swelling of the thyroid gland, and fever, often mimicking subacute thyroiditis. In severe cases, thyroid enlargement may cause dysphagia and respiratory distress due to esophageal and tracheal obstruction, respectively (25,42,43). Fungal thyroiditis typically follows the course of a brief phase of thyrotoxicosis followed by hypothyroidism. Recovery of thyroid function generally takes place in weeks to months. Sick euthyroid syndrome, which sometimes occurs in disseminated fungal infections, may confound thyroid function testing. The clinical presentation of different varieties of fungal infections is similar.

 

Aspergillus

 

A review of 28 cases of aspergillus thyroiditis by Tan et al. revealed that 12 (43%) patients had a primary thyroid infection. The rest had aspergillus infection elsewhere (usually lungs and airways). Fever, dyspnea, and neck swelling were the usual presentation. Dysphagia and airway obstruction resulted from mass effect and was fatal in two cases. The overall mortality rate was high (64%) (24).

 

Pneumocystis

 

Zavascki et al. described 15 cases of P. jirovecii thyroiditis. Most of the cases were reported in individuals with AIDS. It should be suspected if neck pain and swelling occur in presence of a CD4 count < 200/µL. Compressive symptoms such as odynophagia, dysphagia, dysarthria, and hoarseness have been reported. Extra-thyroid disease was present in 53% (8/15) of cases and documented usually on post-mortem studies. Most of the cases were euthyroid, three were hypothyroid, and one developed transient thyrotoxicosis (25).

 

Others

 

There are reports of infection of the thyroid with candida, histoplasma, coccidiodes, and, paracoccidiodes in immunocompromised hosts (37–41). The different varieties of fungal thyroiditis are clinically indistinguishable from each other.

 

DIAGNOSIS

 

Thyroid infection should be suspected in immunocompromised hosts who present with swelling and pain in the region of the thyroid gland. The thyroid involvement not uncommonly remains asymptomatic and gets detected post-mortem (42). Imaging of the neck by ultrasonography can be useful to define the morphology of the lesion. Computed tomography of the chest additionally identifies fungal lesions in the lungs, the usual site of primary or secondary infection. Fungal staining and culture of the lesion obtained by fine needle aspiration (FNA) of the thyroid gland can confirm the diagnosis. Results of thyroid function testing can be normal or may reveal thyrotoxicosis or hypothyroidism.

 

TREATMENT

 

Antifungal therapy is the mainstay of treatment. Voriconazole is the first line agent for invasive aspergillus infection. Adding echinocandin (capsofungin or antidulafungin) along with voriconazole may provide marginally better outcomes in patients who are immunocompromised (44,45). Cotrimoxazole is the preferred therapy for pneumocystis infection. The choice of antifungal therapy depends on the type of fungus and the prevalent pattern of antifungal resistance. Surgical debridement may be required especially if there is a possibility of tracheal compression due to mass effect. Symptomatic treatment may be required in the thyrotoxic phase resulting from acute damage to the gland. The thyroid gland fails to recover in a minority of patients. They should be treated with thyroid hormone replacement. Outcome of fungal thyroiditis has improved over the last two decades with advances in antifungal therapy (43).  

 

Disorders of Calcium Metabolism

 

Fungal infections can alter calcium and vitamin D metabolism. The common metabolic bone disorders are described in the following section.

 

MONOCYTE 1α HYDROXYLASE MEDIATED HYPERCALCEMIA

 

Etiology and Pathogenesis

 

Conversion to the active 1,25-dihydroxyvitamin D [1,25(OH)₂D] from 25-hydroxyvitamin D [25(OH)D] occurs primarily in the kidney. The renal enzyme 25(OH)D-1α hydroxylase (CYP27B1) responsible for the conversion, is tightly regulated by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), and the serum 1,25(OH)₂D concentration. The activated mononuclear cells and macrophages also exhibit 25(OH)D-1α-hydroxylase activity. The 1,25(OH)₂D synthesized in these cells normally exert a paracrine effect on growth and differentiation of cells. In granulomatous disorders, such as sarcoidosis, tuberculosis, and fungal infections, the 1,25(OH)₂D production in monocytes is dysregulated resulting in hypercalcemia. The monocyte 25(OH)D-1α-hydroxylase is resistant to the regulatory mechanisms and the lack of calcium-mediated negative feedback predisposes to hypercalcemia  (46). PTH-independent hypercalcemia is described in chronic fungal infections, such as histoplasmosis, coccidioidomycosis, para-coccidioidomycosis, candidiasis, cryptococcosis, and pneumocystis.

 

Clinical Profile

 

The fungal infections associated with 1α-hydroxylase mediated hypercalcemia can occur in both immunocompromised and immunocompetent hosts. In a review summarizing 16 cases of histoplasmosis induced hypercalcemia, 68.7% (11/16) were immunosuppressed. The common presentations were with polyuria, constipation, altered sensorium, and renal insufficiency (47). Hypercalcemia is also reported in cryptococcus and pneumocystis infections in individuals with HIV/AIDS (48–50). Hypercalcemia can be an early marker of pneumocystis pneumonia in renal transplant recipients (51,52).  

 

Laboratory Features

 

Patients present with elevated serum calcium and phosphate levels, suppressed PTH values, normal 25(OH)D, and increased 1,25(OH)₂D concentrations. Serum angiotensin-converting enzyme (ACE) levels can be elevated (47).

 

Treatment

 

Hypercalcemia resolves with resolution of the infection after institution of successful antifungal therapy. Hydration, calcitonin, and bisphosphonates can be considered to lower calcium till the effect of antifungal medication occurs (47). Steroids can be used in resistant cases but should be initiated only under appropriate antifungal coverage. Fatalities have been reported when the cases have been misdiagnosed as sarcoidosis and steroids initiated without antifungal drugs (53,54). Some cases show transient worsening of hypercalcemia probably mediated by immune reconstitution inflammatory syndrome (55). Also, initiation of antiretroviral therapy in patients with HIV/AIDS infected with cryptococcus, might cause hypercalcemia. This may be due to restoration of granulomatous host response (56).

 

PARATHYROID HORMONE REALTED PROTEIN (PTHrP) MEDIATED HYPERCALCEMIA

 

Coccidioidomycosis infection is associated with hypercalcemia. However, the mechanism of hypercalcemia in coccidioidomycosis is not related to autonomous 1,25(OH)₂D production. It could be due to osseous coccidioidomycosis in some cases, but in the majority of cases it occurs without bony lesions. Serum PTH levels and 1,25(OH₂)D levels were either suppressed or normal (57).  Expression of PTHrP by the granulomatous tissue has been documented in coccidioidomycosis. The serum PTHrP levels are elevated in cases with hypercalcemia and presumed to be the possible mechanism. The PTHrP levels return to normal along with resolution of hypercalcemia after successful antifungal treatment  (58).

 

OTHER DISORDERS OF CALCIUM METABOLISM

 

Histoplasmosis-induced hypercalcemia has been postulated to result from excess expression and secretion of osteopontin by histiocytes in granulomas (59). Osteopontin can activate osteoclasts and subsequently lead to bone resorption (60). However, currently there is insufficient evidence to support this hypothesis. 

 

Hypoparathyroidism has also been described in HIV/AIDS with pneumocystis infiltrating the parathyroid glands. It causes hypocalcemia and hyperphosphatemia (61).

 

Fungal Infection of the Adrenal Gland

 

The adrenal gland is the commonest endocrine organ to be affected by infections including mycosis. Adrenal fungal infection can be asymptomatic and get detected as an incidental finding during radiological imaging, or can manifest with symptoms of adrenal insufficiency (62,63).

 

ETIOLOGY AND PATHOGENESIS

 

Unlike the other endocrine organs, isolated adrenal involvement can be seen as a manifestation of endemic mycoses in immunocompetent hosts by histoplasmosis, paracoccidioidomycosis, blastomycosis, and other fungal organisms (64–66). The susceptibility to develop primary adrenal infection or disseminated fungal disease is however more often seen in the immunocompromised individuals with HIV/AIDS, or in those receiving immunosuppressive therapy such as solid organ transplant recipients (67). Predisposition of the adrenal glands to fungal infections is postulated to be due to suppression of cell-mediated local immunity caused by high local glucocorticoid levels (68). More often than isolated involvement, the adrenal gland is involved as a part of disseminated infection. Histoplasmosis and paracoccidioidomycosis are the commonest fungal infections reported to have adrenal disease at autopsy (67,69).

 

Affinity for different adrenal zones might vary for different fungal infections. Paracoccidioides species has affinity for zona reticularis as well as zona glomerulosa leading to decreased dehydroepiandrosterone sulfate and aldosterone levels, respectively (59,70,71). The large fungal cells cause embolic infection of the small vessels of the gland subsequently leading to endovasculitis, granuloma formation and caseous necrosis (67,72). In patients with histoplasmosis, zona fasciculata and reticularis are preferentially affected owing to the presence of high concentration of cortisol (73). Vasculitis of downstream medullary vessels starting from zona fasciculata induce glandular destruction and subsequent caseation necrosis  (68,74).

 

CLINICAL FEATURES

 

The spectrum of manifestations of fungal adrenal involvement can vary from asymptomatic cases detected incidentally to frank adrenal crisis. Occasionally, adrenal involvement can get masked by the disseminated fungal disease or the underlying immunocompromised state (67). Many of the patients despite bilateral adrenal infection do not develop adrenal insufficiency, as destruction of more than 90% of adrenal cortex is required for the disease to manifest (59). Some studies have observed lower prevalence of adrenal involvement in immunocompromised hosts, presumably due to the inability to launch a granulomatous response in the gland (75,76).

 

Addison’s disease is most frequently reported with histoplasmosis and paracoccidioidomycosis, given their high affinity for adrenal glands. In a review of 252 cases of adrenal histoplasmosis, adrenal hypofunction was confirmed in 41.3%. Almost all the cases were secondary to chronic disseminated pulmonary histoplasmosis although isolated adrenal involvement has also been reported (77). A study of 546 cases of paracoccidioidomycosis from Brazil documented adrenal involvement in only 5% (n = 27) (78). Another review revealed partial adrenal insufficiency in 33–40% of cases, and frank symptoms in 3–10% cases (79).  Patients with diminished adrenal reserve often require glucocorticoid supplementation during periods of stress or after initiating antifungal agents known to affect steroidogenesis. There are reports of blastomycosis, pneumocystis, and cryptococcus causing adrenal insufficiency as well (80–82). The clinical features of primary adrenal insufficiency include fatigue, loss of appetite, weight loss, orthostatic hypotension, and hyperpigmentation (66,83).

 

DIAGNOSIS

 

Fungal infection of the adrenal glands can be asymptomatic and detected incidentally on abdominal imaging. Radiographically bilateral symmetric adrenal enlargement is seen with histoplasmosis whereas paracoccidioidomycosis and blastomycosis cause asymmetric and occasionally unilateral involvement (81,84–86). Other radiographical features include peripheral enhancement, central hypoattenuation, preserved contour, and calcifications (66,67). These features help to differentiate from other disorders such as metastatic disease where the adrenal contour is distorted and autoimmune adrenalitis, where the glands are atrophic (66,67,87,88).

 

The laboratory findings such as hyponatremia and hyperkalemia are often seen but the diagnosis of adrenal insufficiency is confirmed with the short Synacthen test (SST) or cosyntropin test (250 ug of Synacthen, im or iv) in chronic and stable cases. In a patient with suspected Addisonian crisis, a blood sample collected for estimation of serum cortisol and adrenocorticotrophic hormone (ACTH) before initiating glucocorticoid replacement can be helpful. A formal evaluation by SST can be performed later. Simultaneous estimation of plasma renin and aldosterone to determine mineralocorticoid reserve can be considered. (66).

 

The confirmation of fungal etiology might necessitate fungal staining or culture of the biopsied material. In disseminated disease, a more accessible site like skin lesion or affected lymph node can be biopsied instead of the adrenal gland.

 

MANGEMENT AND PROGNOSIS

 

Initiation of antifungal therapy at the earliest is essential to salvage adrenal function. Recovery has been reported in a few cases with histoplasmosis and paracoccidioidomycosis (59). However, frequently adrenal insufficiency is irreversible and lifelong glucocorticoid replacement is required. Mineralocorticoid replacement with fludrocortisone may additionally be necessary (83). Onset of  adrenal insufficiency in paracoccidioidomycosis can occur after initiation of antifungal therapy from the fibrosis that occurs during recovery (79,89).

 

Fungal Infection of the Pancreas

 

The pancreas is normally resistant to fungal infection. Fungal affection of the pancreas usually occurs in an inflamed gland in the presence of underlying necrosis. Although rare, the prevalence of fungal pancreatitis is on the rise.

 

ETIOLOGY AND PATHOGENESIS

 

Candida (C. albicans and C. glabrata) is the most common etiology responsible for fungal pancreatic infections (90). Pneumocystis, aspergillosis, and cryptococcosis have also been reported to affect the pancreas (91–93). The risk factors for fungal infection are necrotizing pancreatitis, use of broad-spectrum antibiotics, abdominal surgery, prolonged total parenteral nutrition, indwelling catheters, and an immunosuppressed state. The mode of spread could be translocation from the gut, hematogenous spread, or external seeding (90).

 

CLINICAL COURSE AND MANAGEMENT

 

The clinical features of fungal infection of the pancreas are non-specific. Abdominal pain, fever, and a palpable abdominal mass can occur (94). Most cases of fungal pancreatitis occur on the backdrop of recent necrotizing pancreatitis (90,94). In a study of 92 patients with necrotizing pancreatitis, 22 (24%) had evidence of candida infection in the surgical necrosectomy material (95). Candida was demonstrated in 27% of aspirates from walled-off necrosis occurring after acute pancreatitis (96).  Rare cases of recurrent pancreatitis from candida have also been described (97,98).

 

Fungal culture and staining of percutaneous aspirates, or necrosed tissue obtained during surgery, are necessary to establish the diagnosis. Antifungal therapy and surgical drainage and debridement are the mainstay of therapy. Mortality rates are higher if candida infection is present (95).

 

 

Fungal Infection of the Testis

 

ETIOLOGY AND PATHOGENESIS

 

Fungal epididymo-orchitis can occur in isolation or as a part of disseminated infection. The fungi reported to infect testis and epididymis include candida, blastomycosis, histoplasma, aspergillus, and cryptococcus (99–103). Both C. albicans and C. glabatra can cause epididymo-orchitis by retrograde transport from infection in the urinary tract. Risk factors comprise diabetes mellitus, instrumentation of the urinary tract, urinary obstruction, or recent antibiotic usage (104). The majority of blastomycosis infections were associated with systemic diseases (105). Granulomatous epididymo-orchitis can also occur as a part of disseminated histoplasmosis in immunocompromised state (106).  

 

CLINICAL COURSE AND MANAGEMENT

 

Most patients present with unilateral or bilateral pain and swelling of the scrotum. Onset can be acute or insidious with duration of symptoms lasting for days to months (104). In contrast, bacterial infection is almost always unilateral with an acute onset of scrotal swelling, redness, and pain. Some fungal infections may remain asymptomatic and get detected on autopsy (102). Fungal epididymo-orchitis is also recognized as a cause of azoospermia and infertility (107). This is mainly due to direct gonadal invasion but can also be due to anti-sperm effects induced by fungi and by secreted mycotoxins (59). C. guilliermondii and C. albicans can affect sperm viability and motility (108). Antifungal agents are the mainstay of treatment. Surgery may be required in some cases.

 

Fungal Infection of the Ovary

 

ETIOLOGY AND PATHOGENESIS

 

Pelvic inflammatory disease (PID) refers to infection of the upper genital tract usually occurring in reproductive age females. A tubo-ovarian abscess (TOA) is a sequela of PID. It is a complex adnexal mass resulting from ascent of the infection through the fallopian tube (109). Though the common causative organisms are bacteria such as Chlamydia trachomatis and Neisseria gonorrhoeae, fungal infections are also recognized as an important etiological agent (110). It can also be a part of disseminated infection (111–113). C. albicans as well as other candida species such as C. glabrata and C. keyfr have been described to cause TOA (114–116). Intrauterine devices, diabetes, and morbid obesity are the typical risk factors (114,117). There are rare reports of female genital coccidioidomycosis (112,113,118).

 

CLINICAL COURSE AND MANAGEMENT

 

The usual presentation is that of a pelvic infection not responding to conventional antibiotics (117). Presenting symptoms can be dysmenorrhea, menstrual irregularities, menorrhagia, anovulation, and infertility. Occasional patients present with severe lower abdominal pain, fever and vomiting (116).  

 

Fusarium toxin zearalenone and its metabolite zearalenol can be present as a contaminant in cereals and usually enter the food chain as pesticide. It is a non-steroidal estrogen mycotoxin with strong affinity for estrogen receptors (119). The resulting hyperestrogenism has the potential to cause infertility by suppressing luteinizing hormone (LH) and progesterone secretion and also can have a carcinogenic effect on the breast (120).

 

FUNGAL INFECTIONS OCCURING IN ENDOCRINE DISORDERS

 

Individuals with certain endocrine disorders such as diabetes mellitus and Cushing’s syndrome are predisposed to fungal infections as a result of the associated immune dysfunction. Both pathogenic and opportunistic fungi can cause infection in these conditions. APS1 is an endocrine syndrome characterized by CMC (121). The common fungal infections occurring in individuals with endocrine dysfunction are discussed below. Other fungal infections like coccidioidomycosis and aspergillosis are also known to occur at a higher frequency in individuals with diabetes.

 

Fungal Infections in Patients with Diabetes

 

Diabetes is known to affect both innate and adaptive immunity. Hyperglycemia also induces critical alterations in cytokine signaling (122). Fungal infections in general occur at a slightly increased frequency in diabetes, especially if glycemic control is poor. However, certain fungal infections like mucocutaneous candidiasis and invasive mucormycosis have a strong association with diabetes (123).

 

CANDIDIASIS

 

Infection with candida is common in individuals with diabetes (124) . Genital candidiasis is often an indicator for undetected or poorly controlled diabetes. Increased hydrolytic enzyme activity and hydrophobicity along with altered biofilm formation have been proposed as possible mechanisms that favor candida infection in diabetes (125,126). The common sites and clinical characteristics of candida infection in diabetes are summarized in table 5.

 

Table 5. Candida Infections in Diabetes
Site	Usual species	Predisposing factors	Clinical features	Diagnosis	Treatment
Oral candidiasis	C. albicans C. glabrata C. tropicalis C. krusei C. dubliniensis C. parapsilosis (124)	Uncontrolled hyperglycemia, dentures, xerostomia, inhaled corticosteroids (127)	Types of lesions: Pseudo-membranous Hyperplastic Erythematous Atrophic (denture stomatitis) Angular cheilitis Median rhomboid glossitis (128)	Compatible clinical findings; Confirmation by Gram stain or KOH preparation or fungal culture of the scrapings (129)	Oral hygiene Topical: Clotrimazole, miconazole, nystatin, amphotericin B suspension Oral: Fluconazole, itraconazole (129)
Vulvo-vaginal candidiasis	C. albicans C. glabrata (124)	Uncontrolled hyperglycemia, pregnancy and hyper-estrogenemic state, SGLT2 inhibitor therapy, immunosuppression (130)	Thick white cottage cheese-like discharge, itching, pain, redness, burning, edema and dyspareunia	Clinical findings, Vaginal swab – acidic pH, KOH or fungal staining, fungal culture in selected cases	Glycemic control Vaginal: Clotrimazole, miconazole, tioconazole, terconazole, butoconazole Oral: Fluconazole (150 mg single dose ) (131)
Balanoposthitis	C. albicans C. glabrata	Uncontrolled hyperglycemia,  SGLT2 inhibitor therapy, uncircumcised men, immunosuppression (132,133)	Sore, pruritic erythematous rash with small papules, erosions or dry dull areas with glazed appearance (134)	Clinical findings, KOH or fungal stain of scrapings in rare cases	Glycemic control Topical: Clotrimazole, miconazole Oral: Fluconazole (150 mg single dose), Itraconazole
Esophageal candidiasis	C. albicans,  C. dubliniensis (124)	Old age, HIV/AIDS, corticosteroid use, COPD, PPI use, esophageal dysmotility (135)	Odynophagia, dysphagia, retrosternal pain, usually associated with oral thrush (136)	Endoscopy - white mucosal plaque-like lesions. Biopsy – confirmatory. Culture rarely required (136)	Initial therapy: Oral fluconazole Second-line therapy: Itraconazole, voriconazole isavuconazole, echinocandin, liposomal amphotericin B
Urinary tract candidiasis	C. albicans, C. glabrata, C. tropicalis (137)	Hyperglycemia, urinary retention and stasis, renal transplantation, long-term urinary catheterization, hospitalization (138)	Asymptomatic, symptoms of lower and upper urinary tract involvement mimic bacterial infection (139)	Urinalysis and culture of urine, Imaging when indicated (139)	Asymptomatic candiduria needs treatment in neutropenic patients, before urological procedures. First line: Fluconazole Second line: Flucytosine, amphotericin B (138)
Onychomycosis	C. albicans, C. parapsilosis C. tropicalis (124)	Age, nail disorders, frequent exposure to moisture (124)	Nail discoloration, subungual hyperkeratosis, onycholysis, splitting, and nail plate destruction	Clinical findings, KOH preparations, fungal cultures, histopathologic examination with a PAS stain and PCR testing (140)	Oral itraconazole treatment of choice. Terbinafine might also be efficacious (141)
Systemic candidiasis	C. albicans, C. parapsilosis, C. krusei, C. tropicalis, C. glabrata (142)	New onset hemodialysis, use of TPN, or receipt of broad-spectrum antibiotic (143)	Can vary from minimal fever to a full-blown sepsis	Blood culture. 1,3-β-d-glucan assay may assist in the diagnosis	Preferred therapy Echinocandin: anidulafungin, capsofungin, micofungin Alternative: Amphotericin B Step down therapy: Fluconazole if susceptibility results support (144)

KOH - potassium hydroxide, SGLT2 - Sodium-glucose cotransporter-2, COPD – chronic obstructive pulmonary disease, PPI – proton-pump inhibitor, PAS – Periodic Acid Schiff, PCR – polymerase chain reaction, TPN – total parenteral nutrition.

 

MUCORMYCOSIS

 

Mucormycosis refers to a group of infections caused by fungi of the order Mucorales present ubiquitously in the environment. Individuals with uncontrolled diabetes or those who are immunosuppressed are characteristically affected. The most common presentation is rhino-orbital-cerebral mucormycosis, though pulmonary, gastrointestinal, cutaneous, and renal infection can also occur (145). Several cases of mucormycosis have been reported recently following SARS COV-2 disease (146). Around 40% of the patients had received corticosteroids within the month before the diagnosis of mucormycosis. Diabetes with ketoacidosis (DKA) is 50% more likely to develop mucormycosis than without DKA. The prognosis is poor and mortality rates remain high. The rhino-orbital-cerebral form is characteristically associated with diabetes and detailed below.

 

Pathogenic Organisms

 

The pathogenic fungi belonging to order Mucorale customarily associated with human infections are Rhizopus, Mucor,and Lichtheimia (formerly Absidia and Mycocladus). The rarer pathogens include Rhizomucor, Cunninghamella, Apophysomyces, and Saksenaea (147).  Infection occurs presumably from inhalation of spores.

 

Pathogenesis

 

Patients with diabetes, defects in phagocytic function (such as neutropenia or glucocorticoid treatment), and/or elevated levels of free iron which supports fungal growth in serum and tissues are prone to mucormycosis. DKA is a risk factor for developing rhino-orbital-cerebral mucormycosis, as acidosis leads to dissociation of iron from sequestering proteins, which aids increased fungal survival and virulence (148). Moreover, the ketoacid -hydroxybutyrate facilitates fungal adherence and penetration into tissues, by increased expression of fungal receptors (149). Apart from ketoacidosis, hyperglycemia itself may contribute to the risk of mucormycosis by four possible mechanisms: (i) disruption of normal iron sequestration due to hyper-glycation of iron-sequestering proteins; (ii) phagocytic dysfunction; (iii) enhanced expression of a mammalian cell receptor (GRP78) that binds to Mucorales, enabling tissue penetration; (iv) enhanced expression of CotH, a Mucorales-specific protein that binds to  GRP78 and mediates host cell invasion (150). The risk factors for mucormycosis are summarized in table 6.

 

Table 6. Risk Factors for Mucormycosis

Uncontrolled diabetes mellitus especially if associated with ketoacidosis

Underlying malignancy receiving chemotherapy or immunotherapy

Solid organ transplant

Hematopoietic stem cell transplant

Treatment with deferoxamine

Iron overload

Corticosteroid therapy

Trauma or burns

Malnutrition

Coronavirus disease 2019

 

Clinical Features

 

Rhino-orbital-cerebral mucormycosis is the most common form of the disease whereas lung, gastrointestinal, renal, and cutaneous involvement are less frequent (145). Initial symptoms of rhino-orbital-cerebral mucormycosis include eye or facial pain and facial numbness followed by conjunctival suffusion and blurring of vision. Facial erythema with or without edema may be present. Fever occurs in only half of the cases (151). Black, necrotic eschar develops over the palate or in the nasal mucosa. In untreated cases, infection spreads from the ethmoid sinus to the orbit which involvement of extra-ocular muscles. It results in proptosis, typically with chemosis. Infection might further extend from the orbit to the frontal lobe of the brain via hematogenous route or contiguous dissemination. It may extend to cavernous sinus as well via venous drainage (147). The clinical features are summarized in table 7.

 

Table 7. Clinical Features of Rhino-Orbital-Cerebral Mucormycosis
Site	Symptoms	Signs
Paranasal sinuses	Nasal congestion, purulent nasal discharge or post-nasal drip, loss of smell, headache, pain over the sinuses	Swelling, redness, ulceration and blackening of overlying skin and nasal mucosa
Systemic features	Fever	Fever
Orbit	Red eyes, pain, visual blurring, loss of vision, bulging of eyes	Periorbital swelling, chemosis, proptosis, loss of visual acuity
Cavernous sinus	Headache, periorbital swelling and pain, diplopia, and visual loss	Periorbital swelling, chemosis, ptosis, proptosis, restricted or painful eye movement, diminished facial sensation
Palate	Ulceration, pain, swelling	Ulceration, eschar formation
Central nervous system	Headache, drowsiness, seizures, hemiparesis, obtundation, coma	Focal seizures, hemiparesis, altered sensorium
Vascular invasion	Black eschars over skin, nasal mucosa, palate and involved areas, symptoms related to stroke	Black eschars (from cutaneous necrosis), focal neurological deficit (also from mycotic aneurysm)

 

Diagnosis

 

Clinical features, mycological, and histological investigations and imaging with CT or MRI are necessary for establishing the diagnosis and assessing the extent of spread. If sinusitis is suspected, endoscopy should be performed. Histopathological examination of infected tissue demonstrates characteristic wide, thick walled, ribbon like, aseptate hyphal elements that branch at right angles. Fungal culture of specimens is strongly recommended for genus and species identification, and for antifungal susceptibility testing (145). PCR-based technique and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) can assist to confirm fungal etiology if cultures are negative (145,152). MRI of the cranium including the sinuses and orbit should be done to delineate the extent of involvement (145). CT scan can help to assess the extent of bony erosion and can be considered if MRI is not readily available.

 

Treatment and Prognosis

 

Surgical debridement of the necrotic tissue in combination with intravenous lipid preparations of amphotericin B are the mainstay of therapy. It is also important to restore euglycemia and correct acidosis as soon as possible. The recommended dose of lipid formulation amphotericin B is 5mg/kg/day. There is evidence to support a higher dose of 10 mg/kg/day in cases of CNS involvement. There is no consensus on total duration of therapy but it usually takes weeks to months for completely cure these infections. It is critically important to monitor for adverse effects of amphotericin B especially nephrotoxicity and electrolyte imbalance. Posaconazole or isavuconazole can be considered as oral step down therapy, as salvage therapy, or if amphotericin B related adverse effects precludes its further use (145). Repeat surgery may be necessary if the infection progresses. Prognosis is poor especially if there is associated CNS involvement.

 

DERMATOPHYTES

 

Dermatophytosis are caused by filamentous fungi belonging to the genera Microsporum, Epidermophyton, and Trichophyton. Dermatophytes cause infection of skin, hairs, and nails and derive nutrition from keratin present in these tissues. Dermatophytosis is known to occur commonly in individuals with diabetes. Infection of the hair is referred to as tinea capitis (scalp) and tinea barbae (beard). Infection of the body surface in general is called tinea corporis while that of groin is known as tinea cruris.

 

Skin infection with dermatophytes occurring over the feet is called tinea pedis. It can cause micro-fissuring that may predispose to secondary bacterial infection and subsequently to diabetic foot. The other form of dermatophyte infection affecting feet is onychomycosis or tinea unguium (153). Tinea pedis and onychomycosis are commonly causes by the anthropophilic dermatophytes T. rubrum, T. interdigitale and E. floccosum (154). Uremic patients on hemodialysis more often have dystrophic nail changes and are at increased risk of developing onychomycosis (155). Dystrophic nails in onychomycosis look thick, brittle and discolored, often with a yellow shade. It may also lead to separation of the nail plate from the nail bed (onycholysis). Paronychial inflammation of the nail edge surrounding skin is a characteristic feature (156). Early recognition and treatment of tinea pedis and onychomycosis can prevent ominous complications like diabetic foot.

 

Clinical features along with KOH preparation of scrapings from affected area are usually adequate to establish the diagnosis. Treatment mainly includes topical and oral agents with activity against dermatophytes. The commonly applied topical agents includes azoles, allylamines, butenafine, ciclopirox, and tolnaftate. Oral therapy usually involves use of terbinafine, itraconazole or fluconazole (157).

 

Fungal Infections in Cushing’s Syndrome

 

The susceptibility of individuals with Cushing’s syndrome to fungal infection is well recognized. Both endogenous and exogenous hypercortisolism are associated with opportunistic fungal diseases. Hypercortisolism induces immune dysfunction by multiple mechanisms (158).  The major defects induced by excess cortisol are depicted in table 8. Among the subtypes of endogenous Cushing’s syndrome, fungal infections are more commonly seen in the syndrome of ectopic ACTH secretion. Propensity for fungal infections in exogenous Cushing’s syndrome depends on both, the intensity of glucocorticoid therapy and relative virulence of the offending fungus. With respect to glucocorticoids, it depends on administration route, dose, potency, and duration of treatment (159). The commonly reported fungal infections in Cushing’s syndrome are discussed below.

 

Table 8. Hypercortisolemia-Induced Immune Dysfunctions Increasing Susceptibility to Fungal Infections
Cell/Mediator	Dysfunction
Innate immunity
Neutrophils	Impaired neutrophil adherence to endothelium
Monocytes and macrophages	Decreased circulating monocytes Decreased degranulation capacity Decreased phagocyte function
Natural Killer cells	Suppressed cytotoxic activity
Adaptive immunity
T Cells	Lymphopenia due to a reduction in CD4+ subset
	Influences the Th1/Th2 balance
	Induces apoptosis in mature T lymphocytes
Cytokines
Cytokines	Down-regulates multiple cytokines by inactivating key proinflammatory transcription factors (e.g., NF kappa B)

CD - cluster of differentiation, Th – T helper cells, NF – nuclear factor

 

CANDIDIASIS

 

In immunocompromised states such as Cushing’s syndrome, candida species may cause superficial infections like cutaneous candidiasis, oropharyngeal candidiasis, esophagitis, or vulvovaginitis. Cases of candida endophthalmitis have also been described (160). It may also disseminate in the bloodstream to cause candidemia. Glucocorticoid may augment biological fitness of candida species, by enhancing its adhesion to epithelial cells. C. albicans is the most common species reported though infection with C. glabrata, C. parapsilosis and C. tropicalis can also occur (159).

 

ASPERGILLUS

 

Aspergillus is associated with invasive fungal infection in endogenous Cushing’s syndrome as well as in those receiving exogenous glucocorticoids (161) . Most common species to cause invasive infection are A. fumigatus, followed by A. flavus, A. terreus, and A. niger. The usual portal of entry for aspergillus is typically the pulmonary tract. However, later it might get disseminated systemically and severe cases requiring emergency bilateral adrenalectomy for control of hypercortisolism has been reported (162). Apart from immune dysfunction, glucocorticoids can induce alterations in the biology of aspergillus species to increase its invasiveness. For example A. fumigatus and A. flavusshowed increased growth on in-vitro exposure to pharmacological doses of hydrocortisone (163).

 

PNEUMOCYSTIS

P.  jirovecii is usually seen in immunocompromised patients. Severe P. jirovecii pneumonia even leading to fatal outcome are described in cases of endogenous Cushing’s syndrome (164). The infection is often unmasked once treatment for hypercortisolism is commenced. The restoration of immune response with lowering of cortisol levels presumably induce the inflammatory changes and result in manifest disease (165,166). A review of 15 cases of P. jirovecii pneumonia, reiterated the same observation of immune reconstitution related worsening of symptoms after treatment initiation. In 13 of these cases symptoms were triggered after cortisol-lowering therapy was started. Interestingly, all but one if these patients had ectopic Cushing’s syndrome. All the cases were characterized by severe hypercortisolemia and the outcome was fatal in 11 cases (167). Patients with Cushing’s syndrome, especially those with severe hypercortisolemia might benefit from prophylaxis with cotrimoxazole before beginning cortisol-lowering therapy.

 

CRYPTOCOCCOSIS

C. neoformans is another opportunistic infection where Cushing’s syndrome is a predisposing factor. The route of entry is inhalational. It may cause pneumonitis or disseminate systemically to cause more severe infections, such as meningitis and meningoencephalitis (168). Fatal cases have been reported (169,170). The presence of coexisting diabetes might further increase the risk of infection (171).

 

Glucocorticoid-induced immunosuppression has a few unique characteristics noted with cryptococcosis. For example, alveolar macrophage capacity to attach to and ingest is diminished by cortisone acetate, which potentially may lead to dissemination of the fungus (172). Moreover, chemotactic activity of cerebrospinal fluid toward polymorphonuclear (PMN) leucocytes and monocytes, is substantially reduced by glucocorticoid administration. This leads to lack of PMN leucocyte influx in cerebrospinal fluid and subsequent inability to eradicate fungi like C. neoformans with tropism for the CNS. Glucocorticoid-induced abnormalities of microglial cells further intensify this attenuation. Thus, individuals with hypercortisolemia are predisposed to cryptococcal meningitis (173).

 

HISTOPLASMOSIS

 

Pulmonary histoplasmosis has been reported in association with endogenous Cushing’s syndrome (174). Patients receiving glucocorticoids may develop primary or reactivated infections by endemic fungi (175). There are reports of pulmonary histoplasmosis after prolonged glucocorticoid therapy from non-endemic countries as well (176). H. capsulatum, the usual pathogen in most cases of histoplasmosis, enters through the respiratory tract and causes pulmonary histoplasmosis but can also disseminate to cause systemic infection. Pathological features of histoplasmosis are atypical in patients treated with glucocorticoids. Discrete granuloma formation is prevented by the anti-inflammatory properties of glucocorticoids (175).

 

OTHER FUNGAL INFECTIONS

 

Other fungal infections reported with hypercortisolemia are C. immitis, mucor, fusarium and blastomyces (159). Besides the heightened risk of fungal inspection in hypercortisolemia, the other concerning issue is masking of the signs and symptoms of infections due to the anti-inflammatory properties of glucocorticoids. Recognition of infections may be delayed in presence of hypercortisolemia, and a high index of suspicion is required for early diagnosis. Treatment of fungal infection must include prompt correction of hypercortisolism and aggressive antifungal therapy.

 

Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1

 

Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by the classical triad of chronic mucocutaneous candidiasis (CMC), autoimmune hypoparathyroidism, and Addison’s disease. Two of the three classic features should be present to establish the diagnosis of APS1. However, there is a risk of the development of autoimmune diseases affecting almost every organ. APS1 is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) with ectodermal dysplasia occurring in a third of the patients. Ectodermal dystrophy is not related to candidiasis (121). CMC commonly occurs sporadically secondary to AIDS, diabetes, and immunosuppressive treatment (177). C. albicans is the predominant pathogen but infection with other candida species is also described.

 

PATHOGENESIS

 

APS1 is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, located on the short arm of chromosome 21. The functioning of following pathways can be altered in APS1, though the specific contribution in increasing susceptibility to candida infection is not well defined.

1. Defects in AIRE gene are associated with autoantibodies to interleukin (IL) 17A, IL17F and IL22, which are key cytokines for the function of the T-helper (Th) 17 cell subset. Loss of function of these cytokines increase susceptibility to candida infections (177).
2. Autoimmunity to mediators involved in antigen presentation by B cells may be an additional factor responsible for susceptibility. This is further corroborated by the response to rituximab (anti-CD 20 antibody that prevents B cell function) to certain components of the disease in individuals with AIRE deficiency (178).

• A defect in Dectin-1, a β-glucan receptor, has been shown to diminish tumor necrosis factor α production in APS-1. Innate immune response is affected as a result (179).

 

CLINICAL SPECTRUM

 

CMC is the most common component of APS-1. It has been reported in 80-100% of cases in different series (121,177). Onset of CMC is usually in the first decade and cases can be seen in the very first year of life. Mouth, nails and, less frequently, skin, vagina and the esophagus are affected. The infection tends to be persistent or recurrent. Severity of the infection in variable, however disseminated disease is rare (177).

 

The oral mucosa is the usual site of infection. All spectra of infection starting from localized ulceration, and redness in mild cases to involvement of entire mouth is described. White or grey membrane covering the tongue or mucosa are visible in the hyperplastic form. Cracks (angular cheilitis or perlèche) occurring at the angle of the mouth is common. The atrophic form has areas of leukoplakia, which is a significant risk factor for carcinoma of the oral mucosa. The finger nails are the other site which is commonly affected. There can be an associated paronychia. Onychomycosis in CMC is particularly resistant to treatment (121,180).

 

TREATMENT

 

Oral fluconazole is the preferred therapy. Some patients require suppressive treatment with fluconazole 100 mg three times a week. Emergence of resistance remains a possibility with suppressive therapy. Alternatives for fluconazole refractory disease includes itraconazole, Posaconazole, or voriconazole. Rare cases of systemic disease not responding to azoles might require a lipid formulation of amphotericin B or echinocandins (144).

 

ADVERSE ENDOCRINE EFFECTS OF ANTIFUNGAL AGENTS

 

The antifungal drugs such as polyenes, azoles and echinocandins can impact the function of endocrine glands. Azoles are recognized for their adverse effect on adrenal cortex and the gonads. The other drugs are also known to cause endocrine dysfunction though less frequently. These important adverse endocrine consequences of the different antifungal agents are discussed below.

 

Azoles

 

The azoles are the one of the most frequently administered systemic antifungal agents. They can be divided into two groups on the basis of their structure. Ketoconazole, which belongs to the imidazole group, is associated with multiple endocrine adverse effect, but seldom used orally as an antifungal agent currently. The newer azoles belonging to the triazole group include fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. Endocrine dysfunction also occurs with the triazoles but is less frequent (181).

 

ADRENAL GLAND

 

The azoles exert their antifungal effect by inhibiting the cytochrome P450 (CYP450) enzyme lanosterol 14-α-demethylase (CYP51) mediated conversion of lanosterol to ergosterol, a critical constituent of fungal cell wall.  Mammals do not have this enzyme, but azoles can block the synthesis of glucocorticoids, mineralocorticoids, and sex steroids by blocking CYP450 dependent enzymes involved in steroidogenesis (182).

 

Ketoconazole

 

Ketoconazole is a dose-dependent reversible inhibitor of cholesterol desmolase, 17,20-lyase, 11β-hydroxylase, 17α-hydroxylase, and 18-hydroxylase (183). Ketoconazole at doses of more than 200 mg daily can impair glucocorticoid synthesis. Overt adrenal insufficiency is relatively infrequent however it can be seen with doses of 600 to 1200 mg/day, which are often used in the medical management of Cushing’s syndrome (59,184,185). Apart from inhibiting enzymes involved in steroidogenesis, ketoconazole is also a dose-dependent, reversible, competitive antagonist at the glucocorticoid receptor level (186). The inhibitory effect of ketoconazole on adrenal steroid synthesis has been utilized for  the medical management of Cushing’s  syndrome (187).

 

Fluconazole and Posaconazole

 

Adrenal insufficiency has been reported with the imidazole derivatives itraconazole, fluconazole, voriconazole, and posaconazole (188–192). Primary adrenal insufficiency induced by fluconazole has been observed in critically ill patient as a result of CYP450 inhibition (193). Fluconazole has been employed for the medical management of Cushing’s syndrome (194). Posaconazole-induced primary adrenal insufficiency resulting from a similar mechanism has been described (190,192).

 

Itraconazole and Voriconazole

 

Itraconazole and voriconazole (also ketoconazole) are potent inhibitors of CYP3A4, the enzyme that partially metabolizes glucocorticoids. The resultant decrease in glucocorticoid clearance produces supraphysiological levels of glucocorticoid from inhaled, nasal or oral steroids (195). The clinical profile resembles that of an iatrogenic Cushing’s syndrome later progressing to secondary or central adrenal insufficiency consequent to suppression of the hypothalamic-pituitary-adrenal (HPA) axis (196). Secondary adrenal insufficiency following combined use of glucocorticoids and itraconazole or voriconazole have been described (188,191). Steroids that are predominantly metabolized by the CYP3A4 pathway include methylprednisolone, fluticasone, budesonide and triamcinolone. It may be prudent to consider alternative glucocorticoids such as prednisolone, beclomethasone, or flunisolide that are not predominantly metabolized by CYP3A4 enzymes when voriconazole or itraconazole is being administered (190,191).

 

Pseudohyperaldosteronism

 

Posaconazole and itraconazole has been associated with a syndrome of mineralocorticoid excess manifested by low-renin low-aldosterone hypertension and hypokalemia (197). Two distinct mechanisms are implicated in the pathogenesis with significant interindividual differences. Posaconazole can inhibit the enzyme 11 β-hydroxylase (CYP11B1) and prevent the conversion of 11-deoxycortisol to cortisol. Diminished cortisol synthesis triggers adrenal steroidogenesis as a result of loss of feedback inhibition of the HPA axis and causes accumulation of 11-deoxycortisol (and 11-deoxycorticosterone). Even though aldosterone production is reduced due to posaconazole-induced aldosterone synthase (CYP11B2) inhibition, very high levels of 11-deoxycortisol and 11-deoxycorticosterone can overcome that and produce a state of mineralocorticoid excess (197,198). The other mechanism incriminated is blockage of the peripheral cortisol metabolizing enzyme 11 β-hydroxysteroid dehydrogenase 2 (11β-HSD2) leading to an increased ratio of active to inactive cortisol metabolite. Elevated ratios of cortisol to corticosterone and their tetrahydro-metabolites are observed in such individuals (198). There are few case reports of itraconazole and several reports of posaconazole-induced pseudohyperladosteronism (199–202). Therapeutic options include lowering the dose of azoles or changing to alternatives like isavuconazole (198).

 

GONADS

 

Male Sexual Dysfunction

 

Inhibition of 17,20-lyase by ketoconazole impairs production of testosterone in the male gonads (203). The effect can be seen even at a single dose of 200mg, however lower testosterone levels and longer duration of suppression can be seen with an increasing dose (204). Oligospermia and azoospermia as well as decreased libido and impotence have been reported at doses more than 800mg/day (181). Reversible gynecomastia is another manifestation seen due to increase in the estradiol:testosterone ratio partially attributed to displacement of estrogen from sex-hormone binding globulin by the drug (205).

 

Ketoconazole also binds to androgen receptors thereby blocking androgen signaling (206). Antiandrogenic properties of ketoconazole have been used in the treatment of prostate cancer, autonomous Leydig cell hyperactivity in children with precocious puberty, and topical therapy for androgenetic alopecia (207–209).

 

Fluconazole in contrast to ketoconazole does not affect testosterone synthesis (210). A single case of posaconazole induced gynecomastia has been reported. Inhibition of the CYP11B1 enzyme by the drug stimulates compensatory adrenal steroidogenesis. Increased peripheral conversion of adrenal androgens to estrogen was presumed to induce gynecomastia after posaconazole use. The other possible hypothesis could be reduced catabolism of estrogen in the liver due to blocking of CYP3A4 and CYP3A7 (211).

 

Female Reproductive Dysfunction

 

Ketoconazole reduces estrogen levels in females. Reduction of estrogen levels could be due to aromatase inhibition or androgen synthesis blockade. Estrogen precursor deprivation from decreased androgen synthesis is likely to be the predominant mechanism (59). In animal studies, ovarian progesterone production is impaired thereby preventing uterine implantation (212). Ketoconazole has been used in treatment of polycystic ovarian syndrome and ovarian hyperthecosis, given its ability to substantially block ovarian androgen synthesis (213). Itraconazole when co-prescribed with simvastatin, induced metrorrhagia in a 69-year old lady, presumably occurring as result of low-estrogen breakthrough bleeding (214). Itraconazole can also enhance estrogen metabolism interfering with efficacy of oral contraceptives (215). Fluconazole on the other hand can increase estrogen levels by inhibiting its metabolism and is not associated with risk of contraceptive failure (216).

 

HYPONATREMIA

 

Voriconazole use has been associated with severe hyponatremia. The median time to onset of hyponatremia is 6-26 days (217). Severe hyponatremia, volume depletion, elevated antidiuretic hormone (ADH), and plasma renin activity along with high urinary sodium suggestive of salt-losing nephropathy were observed after voriconazole administration (218). Syndrome of inappropriate ADH secretion (SIADH) has been implicated as another possible mechanism and euvolemia is the critical distinguishing feature from salt-losing nephropathy (219). The toxic effect of voriconazole is concentration-dependent and therapeutic drug monitoring has been found to be useful for prevention and dose adjustment for hyponatremia (220). The risk of hyponatremia increased with trough concentrations > 7 mg/L and the dose should be modified to maintain levels below that threshold (181). An interesting observation was predisposition to develop voriconazole induced hyponatremia among Asians, in whom polymorphism of CYP2C19 is more common (221). CYP2C19 is the enzyme that metabolizes voriconazole and dosing depending on genotype has been proposed as a means to avert its adverse effects including hyponatremia (222,223).

 

FLUORIDE-INDUCED PERIOSTITIS

 

There are several reports of voriconazole-induced periostitis presumably related to excess fluoride released from the three fluorine atoms present in the molecule (224–228). A 400 mg tablet of voriconazole contains approximately 65 mg of fluoride, however only 5% of the fluoride is generated from the drug in free form (181,224). The other fluorinated azoles fluconazole and posaconazole contain two atoms of fluorides and have not been associated with fluorosis and periostitis (225).

 

A review summarizing 98 cases of periostitis, reported the median age to be 59 years with onset of symptoms between 6 weeks to 8 years after drug exposure. Presenting features are muscle and bone pain. Affection of almost any skeletal site has been described (229). Ribs and ulna are the most common site of involvement. The other involved sites include tibia, clavicle, femur, radius, fibula, scapula, and humerus (224,229).

 

The serum fluoride and alkaline phosphatase levels are significantly higher in those with periostitis compared to those without (224). The plain radiograph reveals multiple areas of periosteal thickening along with formation of new bones which may take the form of an exostoses or can be fluffy. The radiological findings are analogous to periostitis deformans observed in fluoride intoxication (230).  Bone scan shows increased tracer uptake but unlike hypertrophic osteoarthropathy tend to be asymmetric (224). Discontinuation of voriconazole usually results in improvement in the majority of cases. Substitution by a non-fluorinated azole such as itraconazole can be considered when continued antifungal coverage is necessary. Replacement by posaconazole has also been beneficial (228). 

 

OTHER ENDOCRINE ABNORMALITIES

 

High dose ketoconazole (1200mg/day) may rarely cause hypothyroidism by interference with iodine and thyroid peroxidase (231). Ketoconazole is also an inhibitor of 25(OH)D-1α hydroxylase (CYP27B1) leading to decreased 1,25(OH)₂D levels (232). Hypercalcemia induced by sarcoidosis, tuberculosis and other granulomatous disorders respond to treatment with ketoconazole (233,234). Both ketoconazole and fluconazole are treatment options for idiopathic infantile hypercalciuria that occurs from CYP24A1 (24-hydroxylase) gene mutations (235,236). The effects of ketoconazole on enzymes regulating vitamin D has also been explored for treatment of prostate cancer (208,237).   

 

There are rare reports of pancreatitis with fluconazole, itraconazole, and voriconazole (181). Voriconazole, ketoconazole, and fluconazole have been implicated as a cause of hypoglycemia (238,239). The hypoglycemia could be due to hyperinsulinemia resulting from decreased degradation of insulin (240). The metabolism of sulfonylureas can be inhibited by fluconazole thereby increasing the risk of hypoglycemia in individuals receiving both these drugs (241,242).

 

Polyenes

 

The polyenes currently in medical use are nystatin and amphotericin B. Use of nystatin is limited to topical application. Amphotericin B deoxycholate is associated with higher risk of toxicity as compared to its lipid preparation. The lipid formulations of amphotericin B are expensive but the risk of adverse effect is less. Electrolyte abnormalities resulting from tubular damage is the predominant endocrine dysfunction described with amphotericin B. Rare cases of pancreatitis have occurred with liposomal amphotericin B (243).  

 

TUBULAR DAMAGE

 

Clinical manifestations of amphotericin B induced nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic acidosis resulting from distal renal tubular acidosis, and polyuria due to nephrogenic diabetes insipidus (DI) (244–246). The mechanism for DI involves a decrease in aquaporin 2 expression in the kidney medulla, that makes the collecting tubules insensitive to ADH (244). Although the risk of nephrogenic DI with lipid preparations of  amphotericin B is significantly less, cases have still been described (247). Nephrogenic DI can be managed by amiloride plus hydrochlorothiazide, or indomethacin (248).

 

Nephrogenic DI can also be induced by hypokalemia caused by amphotericin B (249). Hypokalemia is more common with amphotericin B deoxycholate but is also recognized  with lipid preparations of amphotericin B (250). Amphotericin B can induce apoptosis of renal tubular cells and also enhance tubular permeability by damage to lining epithelium (251). Renal magnesium loss can also result from amphotericin B. PTH secretion is  affected by hypomagnesemia and that may subsequently lead to hypocalcemia (252). Monitoring and supplementing potassium and magnesium is an important adjunct to prevent adverse consequences of amphotericin B therapy (253).

 

Echinocandins

 

Capsofungin, micofungin and antidulafungin are the three echinocandins currently in clinical use.  These agents, unlike azoles or amphotericin B, do not usually cause adverse endocrine effects. Micafungin is rarely reported to cause pancreatitis (254). Caspofungin has been reported to induce hypercalcemia in an infant by an undefined mechanism (255).

 

Other Agents

 

Oral potassium iodide is used in treatment of cutaneous sporotrichosis (256). It may precipitate thyrotoxicosis in patients with incipient Graves’ disease or multinodular goiter in areas of relative iodine deficiency (Jod-Basedow disease).  Hypothyroidism can occur in those with excessive autoregulation on prolonged exposure (Wolff-Chaikoff effect) (257).

 

CONCLUSION

 

Although fungi are ubiquitous within the environment, very few are considered true pathogens and affect healthy individuals only in limited circumstances. The majority of fungi are opportunistic and immune dysfunction in endocrine disorders increase susceptibility to fungal infection. On the other hand, fungal diseases especially in immunocompromised host can disseminate and affect various endocrine glands thereby impairing their function. Antifungal therapies too contribute to endocrine adverse effects. Moreover, in few endocrinological conditions like Cushing’s syndrome, signs and symptoms of fungal infection can be masked due to effect of hypercortisolemia. A high index of suspicion is mandated in such cases, as delayed or missed diagnosis could dramatically influence the outcome. An understanding of the complex relationship between fungal infection and endocrine disorders is necessary in modern-day medicine as both these conditions are increasingly prevalent.

 

REFERENCES

 

1. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59–65.
2. Havlickova B, Czaika VA, Friedrich M. Epidemiological trends in skin mycoses worldwide. Mycoses. 2008 Sep;51 Suppl 4:2–15.
3. Bitar D, Lortholary O, Le Strat Y, Nicolau J, Coignard B, Tattevin P, et al. Population-based analysis of invasive fungal infections, France, 2001-2010. Emerg Infect Dis. 2014 Jul;20(7):1149–55.
4. Pekic S, Miljic D, Popovic V. Infections of the Hypothalamic-Pituitary Region. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 [cited 2021 Mar 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK532083/
5. Catarino D, Ribeiro C, Gomes L, Paiva I. Corticotroph adenoma and pituitary fungal infection: a rare association. Endocrinol Diabetes Metab Case Rep. 2020 Mar 25;2020.
6. Al-Mendalawi MD. Pituitary aspergillosis: A report and review of the literature. Neurol India. 2018 Oct;66(5):1525.
7. Iplikcioglu AC, Bek S, Bikmaz K, Ceylan D, Gökduman CA. Aspergillus pituitary abscess. Acta Neurochir (Wien). 2004 May;146(5):521–4.
8. Moore LA, Erstine EM, Prayson RA. Pituitary aspergillus infection. J Clin Neurosci Off J Neurosurg Soc Australas. 2016 Jul;29:178–80.
9. Strickland BA, Pham M, Bakhsheshian J, Carmichael J, Weiss M, Zada G. Endoscopic Endonasal Transsphenoidal Drainage of a Spontaneous Candida glabrata Pituitary Abscess. World Neurosurg. 2018 Jan;109:467–70.
10. Heary RF, Maniker AH, Wolansky LJ. Candidal pituitary abscess: case report. Neurosurgery. 1995 May;36(5):1009–12; discussion 1012-1013.
11. Sano T, Kovacs K, Scheithauer BW, Rosenblum MK, Petito CK, Greco CM. Pituitary pathology in acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1989 Sep;113(9):1066–70.
12. Bartlett JA, Hulette C. Central nervous system pneumocystosis in a patient with AIDS. Clin Infect Dis Off Publ Infect Dis Soc Am. 1997 Jul;25(1):82–5.
13. Scanarini M, Rotilio A, Rigobello L, Pomes A, Parenti A, Alessio L. Primary intrasellar coccidioidomycosis simulating a pituitary adenoma. Neurosurgery. 1991 May;28(5):748–51.
14. Vijayvargiya P, Javed I, Moreno J, Mynt MA, Kotapka M, Zaki R, et al. Pituitary aspergillosis in a kidney transplant recipient and review of the literature. Transpl Infect Dis Off J Transplant Soc. 2013 Oct;15(5):E196-200.
15. Choi E, Kim SB, Kim JH, Yoon YK. Lung aspergilloma with pituitary invasive aspergillosis presenting as headache and hyponatraemia. BMJ Case Rep. 2021 Jan 27;14(1).
16. Saffarian A, Derakhshan N, Taghipour M, Eghbal K, Roshanfarzad M, Dehghanian A. Sphenoid Aspergilloma with Headache and Acute Vision Loss. World Neurosurg. 2018 Jul;115:159–61.
17. Stalldecker G, Molina HA, Antelo N, Arakaki T, Sica RE, Basso A. [Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis]. Medicina (Mex). 1994;54(3):248–52.
18. Ouyang T, Zhang N, Wang L, Jiao J, Zhao Y, Li Z, et al. Primary Aspergillus sellar abscess simulating pituitary tumor in immunocompetent patient. J Craniofac Surg. 2015 Mar;26(2):e86-88.
19. Hong W, Liu Y, Chen M, Lin K, Liao Z, Huang S. Secondary headache due to aspergillus sellar abscess simulating a pituitary neoplasm: case report and review of literature. SpringerPlus. 2015;4:550.
20. Fontana C, Gaziano R, Favaro M, Casalinuovo I, Pistoia E, Di Francesco P. (1-3)-β-D-Glucan vs Galactomannan Antigen in Diagnosing Invasive Fungal Infections (IFIs). Open Microbiol J. 2012 Aug 24;6:70–3.
21. Patterson TF, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016 Aug 15;63(4):e1–60.
22. Miceli MH. Central Nervous System Infections Due to Aspergillus and Other Hyaline Molds. J Fungi [Internet]. 2019 Aug 30 [cited 2021 Mar 21];5(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787746/
23. Shrestha RT, Hennessey J. Acute and Subacute, and Riedel’s Thyroiditis. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 [cited 2021 Mar 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK285553/
24. Tan J, Shen J, Fang Y, Zhu L, Liu Y, Gong Y, et al. A suppurative thyroiditis and perineal subcutaneous abscess related with aspergillus fumigatus: a case report and literature review. BMC Infect Dis. 2018 Dec 27;18(1):702.
25. Zavascki AP, Maia AL, Goldani LZ. Pneumocystis jiroveci thyroiditis: report of 15 cases in the literature. Mycoses. 2007 Nov;50(6):443–6.
26. Mori T, Matsumura M, Yamada K, Irie S, Oshimi K, Suda K, et al. Systemic aspergillosis caused by an aflatoxin-producing strain of Aspergillus flavus. Med Mycol. 1998 Apr;36(2):107–12.
27. Cicora F, Mos F, Paz M, Roberti J. Successful treatment of acute thyroiditis due to Aspergillus spp. in the context of disseminated invasive aspergillosis in a kidney transplant patient. Nefrol Publicacion Of Soc Espanola Nefrol. 2013;33(4):618–9.
28. Solak Y, Atalay H, Nar A, Ozbek O, Turkmen K, Erekul S, et al. Aspergillus thyroiditis in a renal transplant recipient mimicking subacute thyroiditis. Transpl Infect Dis Off J Transplant Soc. 2011 Apr;13(2):178–81.
29. Badawy SM, Becktell KD, Muller WJ, Schneiderman J. Aspergillus thyroiditis: first antemortem case diagnosed by fine-needle aspiration culture in a pediatric stem cell transplant patient. Transpl Infect Dis Off J Transplant Soc. 2015 Dec;17(6):868–71.
30. Phulware RH, Gupta B, Sahoo B, Agarwal S, Mathur S. Aspergillus thyroiditis: In an immunocompromised young adult. Diagn Cytopathol. 2019 Apr;47(4):362–4.
31. Santiago M, Martinez JH, Palermo C, Figueroa C, Torres O, Trinidad R, et al. Rapidly growing thyroid mass in an immunocompromised young male adult. Case Rep Endocrinol. 2013;2013:290843.
32. Kishi Y, Negishi M, Kami M, Hamaki T, Miyakoshi S, Ueyama J, et al. Fatal airway obstruction caused by invasive aspergillosis of the thyroid gland. Leuk Lymphoma. 2002 Mar;43(3):669–71.
33. Marui S, de Lima Pereira AC, de Araújo Maia RM, Borba EF. Suppurative thyroiditis due to aspergillosis: a case report. J Med Case Reports. 2014 Nov 21;8:379.
34. Nicolè S, Lanzafame M, Cazzadori A, Vincenzi M, Mangani F, Colato C, et al. Successful Antifungal Combination Therapy and Surgical Approach for Aspergillus fumigatus Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports. Mycopathologia. 2017 Oct;182(9–10):839–45.
35. Erdem H, Uzunlar AK, Yildirim U, Yildirim M, Geyik MF. Diffuse infiltration of Aspergillus hyphae in the thyroid gland with multinodular goiter. Indian J Pathol Microbiol. 2011 Dec;54(4):814–6.
36. Rahimi SA. Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Pathol. 1974 Mar;97(3):162–5.
37. Niles D, Boguniewicz J, Shakeel O, Margolin J, Chelius D, Gupta M, et al. Candida tropicalis Thyroiditis Presenting With Thyroid Storm in a Pediatric Patient With Acute Lymphocytic Leukemia. Pediatr Infect Dis J. 2019 Oct;38(10):1051–3.
38. Fernandez JF, Anaissie EJ, Vassilopoulou-Sellin R, Samaan NA. Acute fungal thyroiditis in a patient with acute myelogenous leukaemia. J Intern Med. 1991 Dec;230(6):539–41.
39. Berry CZ, Goldberg LC, Shepard WL. Systemic lupus erythematosus complicated by coccidioidomycosis. JAMA. 1968 Oct 28;206(5):1083–5.
40. Smilack JD, Argueta R. Coccidioidal infection of the thyroid. Arch Intern Med. 1998 Jan 12;158(1):89–92.
41. Goldani LZ, Klock C, Diehl A, Monteiro AC, Maia AL. Histoplasmosis of the thyroid. J Clin Microbiol. 2000 Oct;38(10):3890–1.
42. Goldani LZ, Zavascki AP, Maia AL. Fungal thyroiditis: an overview. Mycopathologia. 2006 Mar;161(3):129–39.
43. Nguyen J, Manera R, Minutti C. Aspergillus thyroiditis: a review of the literature to highlight clinical challenges. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2012 Dec;31(12):3259–64.
44. Lee D-G, Lee H-J, Yan JL, Lin SS-F, Aram JA. Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis. Mycoses. 2019 Oct;62(10):969–78.
45. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20;162(2):81–9.
46. Goltzman D. Approach to Hypercalcemia. 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.; 2000 [cited 2021 May 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK279129/
47. Gurram PR, Castillo NE, Esquer Garrigos Z, Vijayvargiya P, Abu Saleh OM. A Dimorphic Diagnosis of a Pleomorphic Disease: An Unusual Cause of Hypercalcemia. Am J Med. 2020 Nov;133(11):e659–62.
48. Spindel SJ, Hamill RJ, Georghiou PR, Lacke CE, Green LK, Mallette LE. Case report: vitamin D-mediated hypercalcemia in fungal infections. Am J Med Sci. 1995 Aug;310(2):71–6.
49. Ahmed B, Jaspan JB. Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia. Am J Med Sci. 1993 Nov;306(5):313–6.
50. Huang J-C, Kuo M-C, Hwang S-J, Hwang D-Y, Chen H-C. Vitamin D-mediated hypercalcemia as the initial manifestation of pulmonary cryptococcosis in an HIV-uninfected patient. Intern Med Tokyo Jpn. 2012;51(13):1793–6.
51. Hamroun A, Lenain R, Bui Nguyen L, Chamley P, Loridant S, Neugebauer Y, et al. Hypercalcemia is common during Pneumocystis pneumonia in kidney transplant recipients. Sci Rep. 2019 Aug 29;9(1):12508.
52. Giordani MC, Villamil Cortez SK, Diehl M, Barcan LA, Rosa-Diez G, Groppa SR, et al. Hypercalcemia as an Early Finding of Opportunistic Fungal Pneumonia in Renal Transplantation: A Case Series Report. Transplant Proc. 2020 May;52(4):1178–82.
53. Walker JV, Baran D, Yakub N, Freeman RB. Histoplasmosis with hypercalcemia, renal failure, and papillary necrosis. Confusion with sarcoidosis. JAMA. 1977 Mar 28;237(13):1350–2.
54. Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med. 1985 May;78(5):881–4.
55. Chalhoub E, Elhomsy G, Brake M. Hypercalcemia in histoplasmosis aggravated with antifungal treatment. J Med Liban. 2012 Sep;60(3):165–8.
56. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis Off Publ Infect Dis Soc Am. 2004 Jan 1;38(1):154–5.
57. Caldwell JW, Arsura EL, Kilgore WB, Reddy CM, Johnson RH. Hypercalcemia in patients with disseminated coccidioidomycosis. Am J Med Sci. 2004 Jan;327(1):15–8.
58. Fierer J, Burton DW, Haghighi P, Deftos LJ. Hypercalcemia in disseminated coccidioidomycosis: expression of parathyroid hormone-related peptide is characteristic of granulomatous inflammation. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012 Oct;55(7):e61-66.
59. Lionakis MS, Samonis G, Kontoyiannis DP. Endocrine and Metabolic Manifestations of Invasive Fungal Infections and Systemic Antifungal Treatment. Mayo Clin Proc. 2008 Sep;83(9):1046–60.
60. Reinholt FP, Hultenby K, Oldberg A, Heinegård D. Osteopontin--a possible anchor of osteoclasts to bone. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4473–5.
61. Siddiqi A, Goh BT, Brown CL, Hillman RJ, Monson JP. Hypothyroidism and hypoparathyroidism associated with Pneumocystis carinii infection in a patient with AIDS. Int J STD AIDS. 1998 Feb;9(2):108–10.
62. Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am. 2016 Mar;30(1):207–27.
63. Kauffman CA. Endemic mycoses: blastomycosis, histoplasmosis, and sporotrichosis. Infect Dis Clin North Am. 2006 Sep;20(3):645–62, vii.
64. Sharma B, Nehara HR, Bhavi VK, Maan P, Saran S. Adrenal histoplasmosis in immunocompetent individuals a case series from the North-Western part of India, Rajasthan province: An emerging endemic focus. Indian J Med Microbiol. 2020 Dec;38(3 & 4):485–8.
65. Pereira GH, Lanzoni VPB, Beirão EM, Timerman A, Melhem M de SC. DISSEMINATED FUNGAL INFECTION WITH ADRENAL INVOLVEMENT: REPORT OF TWO HIV NEGATIVE BRAZILIAN PATIENTS. Rev Inst Med Trop Sao Paulo. 2015 Dec;57(6):527–30.
66. Alexandraki KI, Grossman A. Adrenal Insufficiency. 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.; 2000 [cited 2021 May 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK279122/
67. Paolo WF, Nosanchuk JD. Adrenal infections. Int J Infect Dis. 2006 Sep;10(5):343–53.
68. Frenkel JK. Role of corticosteroids as predisposing factors in fungal diseases. Lab Investig J Tech Methods Pathol. 1962 Nov;11:1192–208.
69. Roubsanthisuk W, Sriussadaporn S, Vawesorn N, Parichatikanond P, Phoojaroenchanachai M, Homsanit M, et al. Primary adrenal insufficiency caused by disseminated histoplasmosis: report of two cases. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2002 Jun;8(3):237–41.
70. Leal AMO, Magalhães PKR, Martinez R, Moreira AC. Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis. J Infect Dis. 2003 Jan 1;187(1):124–7.
71. Del Negro G, Melo EH, Rodbard D, Melo MR, Layton J, Wachslicht-Rodbard H. Limited adrenal reserve in paracoccidioidomycosis: cortisol and aldosterone responses to 1-24 ACTH. Clin Endocrinol (Oxf). 1980 Dec;13(6):553–9.
72. Cherri J, Freitas MA, Llorach-Velludo MA, Piccinato CE. Paracoccidioidomycotic aortitis with embolization to the lower limbs. Report of a case and review of the literature. J Cardiovasc Surg (Torino). 1998 Oct;39(5):573–6.
73. Disseminated Histoplasmosis and Rare Adrenal Involvement: Evidence of Absence or Absence of Evidence. Front Cell Infect Microbiol [Internet]. 2021 Mar 15 [cited 2021 May 23];11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005706/
74. Goodwin RA, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore). 1980 Jan;59(1):1–33.
75. Gupta A, Ghosh A, Singh G, Xess I. A Twenty-First-Century Perspective of Disseminated Histoplasmosis in India: Literature Review and Retrospective Analysis of Published and Unpublished Cases at a Tertiary Care Hospital in North India. Mycopathologia. 2017 Dec;182(11–12):1077–93.
76. Sifuentes-Osornio J, Corzo-León DE, Ponce-de-León LA. Epidemiology of Invasive Fungal Infections in Latin America. Curr Fungal Infect Rep. 2012 Mar;6(1):23–34.
77. Carvalho FP de F de, Curiati JAE, Mauad T, Incerti MM, Jacob Filho W. Bilateral adrenal [corrected] nodules due to histoplasmosis in an elderly. Braz J Infect Dis Off Publ Braz Soc Infect Dis. 2007 Feb;11(1):160–2.
78. Peçanha PM, Batista Ferreira ME, Massaroni Peçanha MA, Schmidt EB, Lamas de Araújo M, Zanotti RL, et al. Paracoccidioidomycosis: Epidemiological and Clinical Aspects in 546 Cases Studied in the State of Espírito Santo, Brazil. Am J Trop Med Hyg. 2017 Sep;97(3):836–44.
79. Bocca AL, Amaral AC, Teixeira MM, Sato PK, Sato P, Shikanai-Yasuda MA, et al. Paracoccidioidomycosis: eco-epidemiology, taxonomy and clinical and therapeutic issues. Future Microbiol. 2013 Sep;8(9):1177–91.
80. Sharma N, Ahlawat RS, Singh H, Sharma C, Anuradha S. Pneumocystis jirovecii infection of bilateral adrenal glands in an immunocompetent adult: a case report. J R Coll Physicians Edinb. 2019 Sep;49(3):222–4.
81. Kumar A, Sreehari S, Velayudhan K, Biswas L, Babu R, Ahmed S, et al. Autochthonous blastomycosis of the adrenal: first case report from Asia. Am J Trop Med Hyg. 2014 Apr;90(4):735–9.
82. Ito M, Hinata T, Tamura K, Koga A, Ito T, Fujii H, et al. Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual. Intern Med Tokyo Jpn. 2017;56(10):1259–64.
83. Koene RJ, Catanese J, Sarosi GA. Adrenal hypofunction from histoplasmosis: a literature review from 1971 to 2012. Infection. 2013 Aug;41(4):757–9.
84. Porntharukchareon T, Khahakaew S, Sriprasart T, Paitoonpong L, Snabboon T. Bilateral Adrenal Histoplasmosis. Balk Med J. 2019 Dec;36(6):359–600.
85. Ahuja A, Mathur SR, Iyer VK, Sharma SK, Kumar N, Agarwal S. Histoplasmosis presenting as bilateral adrenal masses: cytomorphological diagnosis of three cases. Diagn Cytopathol. 2012 Aug;40(8):729–31.
86. de Morais RQ, Salomon MFB, Corbiceiro WCH, de Melo ASA, Corrêa DG. Imaging contribution for the diagnosis of disseminated paracoccidioidomycosis. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2020 Dec;101:206–9.
87. Gupta P, Bhalla A, Sharma R. Bilateral adrenal lesions. J Med Imaging Radiat Oncol. 2012 Dec;56(6):636–45.
88. Dhamija E, Panda A, Das CJ, Gupta AK. Adrenal imaging (Part 2): Medullary and secondary adrenal lesions. Indian J Endocrinol Metab. 2015;19(1):16–24.
89. Gaspar GG, Cocio TA, Guioti-Puga F, Nascimento E, Fabro AT, Kress MR von Z, et al. Paracoccidioidomycosis due to Paracoccidioides lutzii complicated with adrenal injury and pulmonary arterial hypertension. Rev Inst Med Trop São Paulo [Internet]. [cited 2021 May 24];62. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669275/
90. Shanmugam N, Isenmann R, Barkin JS, Beger HG. Pancreatic fungal infection. Pancreas. 2003 Aug;27(2):133–8.
91. Karam MB, Mosadegh L. Extra-pulmonary Pneumocystis jiroveci infection: a case report. Braz J Infect Dis Off Publ Braz Soc Infect Dis. 2014 Dec;18(6):681–5.
92. Guice KS, Lynch M, Weatherbee L. Invasive aspergillosis: an unusual cause of hemorrhagic pancreatitis. Am J Gastroenterol. 1987 Jun;82(6):563–5.
93. Cappell MS, Hassan T. Pancreatic disease in AIDS--a review. J Clin Gastroenterol. 1993 Oct;17(3):254–63.
94. Trikudanathan G, Navaneethan U, Vege SS. Intra-abdominal fungal infections complicating acute pancreatitis: a review. Am J Gastroenterol. 2011 Jul;106(7):1188–92.
95. Isenmann R, Schwarz M, Rau B, Trautmann M, Schober W, Beger HG. Characteristics of infection with Candida species in patients with necrotizing pancreatitis. World J Surg. 2002 Mar;26(3):372–6.
96. Sahar N, Kozarek RA, Kanji ZS, Chihara S, Gan SI, Irani S, et al. The microbiology of infected pancreatic necrosis in the era of minimally invasive therapy. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2018 Jul;37(7):1353–9.
97. Tange K, Yokota T, Sunago K, Aono M, Ochi H, Takechi S, et al. A rare case of acute pancreatitis caused by Candida Albicans. Clin J Gastroenterol. 2019 Feb;12(1):82–7.
98. Chung RT, Schapiro RH, Warshaw AL. Intraluminal pancreatic candidiasis presenting as recurrent pancreatitis. Gastroenterology. 1993 May;104(5):1532–4.
99. Giannopoulos A, Giamarellos-Bourboulis EJ, Adamakis I, Georgopoulou I, Petrikkos G, Katsilambros N. Epididymitis caused by Candida glabrata: a novel infection in diabetic patients? Diabetes Care. 2001 Nov;24(11):2003–4.
100. Seo R, Oyasu R, Schaeffer A. Blastomycosis of the epididymis and prostate. Urology. 1997 Dec;50(6):980–2.
101. Botero-García CA, Faccini-Martínez ÁA, Uribe E, Calixto O-J, Pérez-Díaz CE, Osejo-Diago PP, et al. Epididymo-orchitis caused by Histoplasma capsulatumin a Colombian patient. Rev Soc Bras Med Trop. 2017 Dec;50(6):868–70.
102. Hood SV, Bell D, McVey R, Wilson G, Wilkins EG. Prostatitis and epididymo-orchitis due to Aspergillus fumigatus in a patient with AIDS. Clin Infect Dis Off Publ Infect Dis Soc Am. 1998 Jan;26(1):229–31.
103. James CL, Lomax-Smith JD. Cryptococcal epididymo-orchitis complicating steroid therapy for relapsing polychondritis. Pathology (Phila). 1991 Jul;23(3):256–8.
104. Jenkin GA, Choo M, Hosking P, Johnson PD. Candidal epididymo-orchitis: case report and review. Clin Infect Dis Off Publ Infect Dis Soc Am. 1998 Apr;26(4):942–5.
105. Eickenberg H-Unull, Amin M, Lich R. Blastomycosis of the genitourinary tract. J Urol. 1975 May;113(5):650–2.
106. Tichindelean C, East JW, Sarria JC. Disseminated histoplasmosis presenting as granulomatous epididymo-orchitis. Am J Med Sci. 2009 Sep;338(3):238–40.
107. Fijak M, Pilatz A, Hedger MP, Nicolas N, Bhushan S, Michel V, et al. Infectious, inflammatory and ‘autoimmune’ male factor infertility: how do rodent models inform clinical practice? Hum Reprod Update. 2018 Jul;24(4):416–41.
108. Nagy B, Sutka P. Demonstration of antibodies against Candida guilliermondii var. guilliermondii in asymptomatic infertile men. Mycoses. 1992 Oct;35(9–10):247–50.
109. Lareau SM, Beigi RH. Pelvic inflammatory disease and tubo-ovarian abscess. Infect Dis Clin North Am. 2008 Dec;22(4):693–708.
110. Curry A, Williams T, Penny ML. Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention. Am Fam Physician. 2019 Sep 15;100(6):357–64.
111. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010 Apr;23(2):367–81.
112. Chowfin A, Tight R. Female genital coccidioidomycosis (FGC), Addison’s disease and sigmoid loop abscess due to Coccidioides immites; case report and review of literature on FGC. Mycopathologia. 1999;145(3):121–6.
113. Bæk O, Astvad K, Serizawa R, Wheat LJ, Brenøe PT, Hansen A-BE. Peritoneal and genital coccidioidomycosis in an otherwise healthy Danish female: a case report. BMC Infect Dis. 2017 Jan 31;17(1):105.
114. To V, Gurberg J, Krishnamurthy S. Tubo-Ovarian Abscess Caused by Candida Albicans in an Obese Patient. J Obstet Gynaecol Can JOGC J Obstet Gynecol Can JOGC. 2015 May;37(5):426–9.
115. Toy EC, Scerpella EG, Riggs JW. Tuboovarian abscess associated with Candida glabrata in a woman with an intrauterine device. A case report. J Reprod Med. 1995 Mar;40(3):223–5.
116. Okmen F, Ekici H, Ari SA. Case Report of a Tubo-ovarian Abscess Caused by Candida kefyr. J Obstet Gynaecol Can JOGC J Obstet Gynecol Can JOGC. 2018 Nov;40(11):1466–7.
117. Hsu W-C, Lee Y-H, Chang D-Y. Tuboovarian abscess caused by Candida in a woman with an intrauterine device. Gynecol Obstet Invest. 2007;64(1):14–6.
118. Bylund DJ, Nanfro JJ, Marsh WL. Coccidioidomycosis of the female genital tract. Arch Pathol Lab Med. 1986 Mar;110(3):232–5.
119. Tatay E, Meca G, Font G, Ruiz M-J. Interactive effects of zearalenone and its metabolites on cytotoxicity and metabolization in ovarian CHO-K1 cells. Toxicol Vitro Int J Publ Assoc BIBRA. 2014 Feb;28(1):95–103.
120. Minervini F, Giannoccaro A, Cavallini A, Visconti A. Investigations on cellular proliferation induced by zearalenone and its derivatives in relation to the estrogenic parameters. Toxicol Lett. 2005 Dec 15;159(3):272–83.
121. Sperling MA, Angelousi A, Yau M. Autoimmune Polyglandular Syndromes. 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.; 2000 [cited 2021 May 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK279152/
122. Zhou K, Lansang MC. Diabetes Mellitus and Infections. 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.; 2000 [cited 2021 May 31]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK569326/
123. Higa M. [Clinical epidemiology of fungal infection in diabetes]. Nihon Rinsho Jpn J Clin Med. 2008 Dec;66(12):2239–44.
124. Rodrigues CF, Rodrigues ME, Henriques M. Candida sp. Infections in Patients with Diabetes Mellitus. J Clin Med [Internet]. 2019 Jan 10 [cited 2021 May 31];8(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352194/
125. Tsang CSP, Chu FCS, Leung WK, Jin LJ, Samaranayake LP, Siu SC. Phospholipase, proteinase and haemolytic activities of Candida albicans isolated from oral cavities of patients with type 2 diabetes mellitus. J Med Microbiol. 2007 Oct;56(Pt 10):1393–8.
126. Mba IE, Nweze EI. Mechanism of Candida pathogenesis: revisiting the vital drivers. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2020 Oct;39(10):1797–819.
127. Rautemaa R, Ramage G. Oral candidosis--clinical challenges of a biofilm disease. Crit Rev Microbiol. 2011 Nov;37(4):328–36.
128. Axéll T, Samaranayake LP, Reichart PA, Olsen I. A proposal for reclassification of oral candidosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Aug;84(2):111–2.
129. Millsop JW, Fazel N. Oral candidiasis. Clin Dermatol. 2016 Aug;34(4):487–94.
130. Unnikrishnan AG, Kalra S, Purandare V, Vasnawala H. Genital Infections with Sodium Glucose Cotransporter-2 Inhibitors: Occurrence and Management in Patients with Type 2 Diabetes Mellitus. Indian J Endocrinol Metab. 2018;22(6):837–42.
131. Dovnik A, Golle A, Novak D, Arko D, Takač I. Treatment of vulvovaginal candidiasis: a review of the literature. Acta Dermatovenerol Alp Pannonica Adriat. 2015;24(1):5–7.
132. Nyirjesy P, Sobel JD. Genital mycotic infections in patients with diabetes. Postgrad Med. 2013 May;125(3):33–46.
133. Nyirjesy P, Sobel JD, Fung A, Mayer C, Capuano G, Ways K, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin. 2014 Jun;30(6):1109–19.
134. Kalra S, Chawla A. Diabetes and balanoposthitis. JPMA J Pak Med Assoc. 2016 Aug;66(8):1039–41.
135. Weerasuriya N, Snape J. Oesophageal candidiasis in elderly patients: risk factors, prevention and management. Drugs Aging. 2008;25(2):119–30.
136. Mohamed AA, Lu X-L, Mounmin FA. Diagnosis and Treatment of Esophageal Candidiasis: Current Updates. Can J Gastroenterol Hepatol. 2019;2019:3585136.
137. Yismaw G, Asrat D, Woldeamanuel Y, Unakal C. Prevalence of candiduria in diabetic patients attending Gondar University Hospital, Gondar, Ethiopia. Iran J Kidney Dis. 2013 Mar;7(2):102–7.
138. Alfouzan WA, Dhar R. Candiduria: Evidence-based approach to management, are we there yet? J Mycol Medicale. 2017 Sep;27(3):293–302.
139. Kauffman CA. Diagnosis and management of fungal urinary tract infection. Infect Dis Clin North Am. 2014 Mar;28(1):61–74.
140. Saunte DML, Piraccini BM, Sergeev AY, Prohić A, Sigurgeirsson B, Rodríguez-Cerdeira C, et al. A survey among dermatologists: diagnostics of superficial fungal infections - what is used and what is needed to initiate therapy and assess efficacy? J Eur Acad Dermatol Venereol JEADV. 2019 Feb;33(2):421–7.
141. Gupta AK, Gregurek-Novak T, Konnikov N, Lynde CW, Hofstader S, Summerbell RC. Itraconazole and terbinafine treatment of some nondermatophyte molds causing onychomycosis of the toes and a review of the literature. J Cutan Med Surg. 2001 Jun;5(3):206–10.
142. Pfaller MA, Jones RN, Doern GV, Fluit AC, Verhoef J, Sader HS, et al. International surveillance of blood stream infections due to Candida species in the European SENTRY Program: species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents. SENTRY Participant Group (Europe). Diagn Microbiol Infect Dis. 1999 Sep;35(1):19–25.
143. Borg-von Zepelin M, Kunz L, Rüchel R, Reichard U, Weig M, Gross U. Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005. J Antimicrob Chemother. 2007 Aug;60(2):424–8.
144. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016 Feb 15;62(4):e1-50.
145. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019 Dec;19(12):e405–21.
146. Ravani SA, Agrawal GA, Leuva PA, Modi PH, Amin KD. Rise of the phoenix: Mucormycosis in COVID-19 times. Indian J Ophthalmol. 2021 Jun;69(6):1563–8.
147. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012 Feb;54 Suppl 1:S23-34.
148. Artis WM, Fountain JA, Delcher HK, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes. 1982 Dec;31(12):1109–14.
149. Ibrahim AS, Kontoyiannis DP. Update on mucormycosis pathogenesis. Curr Opin Infect Dis. 2013 Dec;26(6):508–15.
150. Morales-Franco B, Nava-Villalba M, Medina-Guerrero EO, Sánchez-Nuño YA, Davila-Villa P, Anaya-Ambriz EJ, et al. Host-Pathogen Molecular Factors Contribute to the Pathogenesis of Rhizopus spp. in Diabetes Mellitus. Curr Trop Med Rep. 2021 Jan 22;1–12.
151. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol. 1994 Aug;39(1):3–22.
152. Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Med Mycol. 2018 Apr 1;56(suppl_1):93–101.
153. Lipner SR, Scher RK. Onychomycosis: Treatment and prevention of recurrence. J Am Acad Dermatol. 2019 Apr;80(4):853–67.
154. Nenoff P, Krüger C, Ginter-Hanselmayer G, Tietz H-J. Mycology - an update. Part 1: Dermatomycoses: causative agents, epidemiology and pathogenesis. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2014 Mar;12(3):188–209; quiz 210, 188–211; 212.
155. Falodun O, Ogunbiyi A, Salako B, George AK. Skin changes in patients with chronic renal failure. Saudi J Kidney Dis Transplant Off Publ Saudi Cent Organ Transplant Saudi Arab. 2011 Mar;22(2):268–72.
156. Westerberg DP, Voyack MJ. Onychomycosis: Current trends in diagnosis and treatment. Am Fam Physician. 2013 Dec 1;88(11):762–70.
157. Ely JW, Rosenfeld S, Seabury Stone M. Diagnosis and management of tinea infections. Am Fam Physician. 2014 Nov 15;90(10):702–10.
158. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The Immune System in Cushing’s Syndrome. Trends Endocrinol Metab TEM. 2020 Sep;31(9):655–69.
159. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet Lond Engl. 2003 Nov 29;362(9398):1828–38.
160. Lee EK, Kim JH, Yu HG. Candida albicans endophthalmitis in a patient with a non-functioning pituitary adenoma evolving into Cushing׳s disease: A case report. Med Mycol Case Rep. 2014 Oct;6:37–41.
161. Kansagara DL, Tetrault J, Hamill C, Moore C, Olson B. Fatal factitious Cushing’s syndrome and invasive aspergillosis: case report and review of literature. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2006 Dec;12(6):651–5.
162. Joubert M, Reznik Y, Verdon R. “Rescue” bilateral adrenalectomy in paraneoplastic Cushing’s syndrome with invasive Aspergillus fumigatus infection. Am J Med Sci. 2007 Dec;334(6):497–8.
163. Ng TT, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp.: implications for pathogenesis. Microbiol Read Engl. 1994 Sep;140 ( Pt 9):2475–9.
164. Arlt A, Harbeck B, Anlauf M, Alkatout I, Klöppel G, Fölsch UR, et al. Fatal pneumocystis jirovecii pneumonia in a case of ectopic Cushing’s syndrome due to neuroendocrine carcinoma of the kidney. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc. 2008 Oct;116(9):515–9.
165. Oosterhuis JK, van den Berg G, Monteban-Kooistra WE, Ligtenberg JJM, Tulleken JE, Meertens JHJM, et al. Life-threatening Pneumocystis jiroveci pneumonia following treatment of severe Cushing’s syndrome. Neth J Med. 2007 Jun;65(6):215–7.
166. Gabalec F, Zavrelová A, Havel E, Cerman J, Radocha J, Svilias I, et al. Pneumocystis pneumonia during medicamentous treatment of Cushing’s syndrome--a description of two cases. Acta Medica (Hradec Kralove). 2011;54(3):127–30.
167. van Halem K, Vrolijk L, Pereira AM, de Boer MGJ. Characteristics and Mortality of Pneumocystis Pneumonia in Patients With Cushing’s Syndrome: A Plea for Timely Initiation of Chemoprophylaxis. Open Forum Infect Dis [Internet]. 2017 Jan 30 [cited 2021 Jun 7];4(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414011/
168. Lu L, Zhao YY, Yang HB, Tian XL, Xu ZJ, Lu ZL. Cushing’s disease with pulmonary Cryptococcus neoformans infection in a single center in Beijing, China: A retrospective study and literature review. J Formos Med Assoc Taiwan Yi Zhi. 2019 Jan;118(1 Pt 2):285–90.
169. Fujikawa H, Araki M. Disseminated cryptococcosis in a patient with adrenocortical carcinoma and Cushing’s syndrome. J Infect Chemother Off J Jpn Soc Chemother. 2020 Dec;26(12):1301–4.
170. Lacativa PGS, Donangelo I, Wagman MB, Sieiro Neto L, Caldas CR, Violante AHD, et al. [Pseudotumoral pulmonary cryptococcosis in association with Cushing’s syndrome]. Arq Bras Endocrinol Metabol. 2004 Apr;48(2):318–23.
171. Thangakunam B, Christopher DJ, Kurian S, Thomas R, James P. ENDOGENOUS EXCESS CORTISOL PRODUCTION AND DIABETES MELLITUS AS PREDISPOSING FACTORS FOR PULMONARY CRYPTOCOCCOSIS: A CASE REPORT AND LITERATURE REVIEW. Lung India Off Organ Indian Chest Soc. 2008;25(4):155–7.
172. Gross NT, Chinchilla M, Camner P, Jarstrand C. Anticryptococcal activity by alveolar macrophages from rats treated with cortisone acetate during different periods of time. Mycopathologia. 1996;136(1):1–8.
173. Nidhi A, Meena A, Sreekumar A, Daga MK. Corticosteroid-induced cryptococcal meningitis in patient without HIV. BMJ Case Rep. 2017 Jan 4;2017.
174. Kosseifi SG, Nassour DN, Shaikh MA, Sarubbi FA, Jordan RM, Peiris AN. Nodular pulmonary histoplasmosis in Cushing’s disease: a case report and literature review. Tenn Med J Tenn Med Assoc. 2007 Dec;100(12):44–6.
175. Dismukes WE, Royal SA, Tynes BS. Disseminated histoplasmosis in corticosteroid-treated patients. Report of five cases. JAMA. 1978 Sep 29;240(14):1495–8.
176. Jung EJ, Park DW, Choi J-W, Choi WS. Chronic Cavitary Pulmonary Histoplasmosis in a Non-HIV and Immunocompromised Patient without Overseas Travel History. Yonsei Med J. 2015 May 1;56(3):871–4.
177. Humbert L, Cornu M, Proust-Lemoine E, Bayry J, Wemeau J-L, Vantyghem M-C, et al. Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1. Front Immunol. 2018;9:2570.
178. Gavanescu I, Benoist C, Mathis D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13009–14.
179. Pedroza LA, Kumar V, Sanborn KB, Mace EM, Niinikoski H, Nadeau K, et al. Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-α production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1. J Allergy Clin Immunol. 2012 Feb;129(2):464–72, 472.e1-3.
180. Eyerich K, Eyerich S, Hiller J, Behrendt H, Traidl-Hoffmann C. Chronic mucocutaneous candidiasis, from bench to bedside. Eur J Dermatol EJD. 2010 Jun;20(3):260–5.
181. Benitez LL, Carver PL. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs. 2019 Jun;79(8):833–53.
182. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest. 1983 May;71(5):1495–9.
183. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med. 1987 Sep 24;317(13):812–8.
184. Best TR, Jenkins JK, Murphy FY, Nicks SA, Bussell KL, Vesely DL. Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy. Am J Med. 1987 Mar 23;82(3 Spec No):676–80.
185. Khosla S, Wolfson JS, Demerjian Z, Godine JE. Adrenal crisis in the setting of high-dose ketoconazole therapy. Arch Intern Med. 1989 Apr;149(4):802–4.
186. Duret C, Daujat-Chavanieu M, Pascussi J-M, Pichard-Garcia L, Balaguer P, Fabre J-M, et al. Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329–39.
187. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015 Aug;36(4):385–486.
188. Skov M, Main KM, Sillesen IB, Müller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J. 2002 Jul;20(1):127–33.
189. Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J. 2006 Sep;82(971):e23.
190. Miller A, Brooks LK, Poola-Kella S, Malek R. Posaconazole-Induced Adrenal Insufficiency in a Case of Chronic Myelomonocytic Leukemia. Case Rep Endocrinol. 2018;2018:2170484.
191. Duman AK, Fulco PP. Adrenal Insufficiency With Voriconazole and Inhaled/Intranasal Corticosteroids: Case Report and Systematic Review. J Pharm Pract. 2017 Aug;30(4):459–63.
192. Araque DP, Zuniga G, Ayala AR. PRIMARY ADRENAL INSUFFICIENCY SECONDARY TO CHRONIC POSACONAZOLE USE. AACE Clin Case Rep. 2020 Apr;6(2):e62–4.
193. Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med. 2001 Mar;29(3):668–70.
194. Zhao Y, Liang W, Cai F, Wu Q, Wang Y. Fluconazole for Hypercortisolism in Cushing’s Disease: A Case Report and Literature Review. Front Endocrinol. 2020;11:608886.
195. Lebrun-Vignes B, Archer VC, Diquet B, Levron JC, Chosidow O, Puech AJ, et al. Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol. 2001 May;51(5):443–50.
196. Varis T, Kivistö KT, Backman JT, Neuvonen PJ. Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol. 1999 Jul;85(1):29–32.
197. Beck KR, Odermatt A. Antifungal therapy with azoles and the syndrome of acquired mineralocorticoid excess. Mol Cell Endocrinol. 2021 Mar 15;524:111168.
198. Thompson GR, Beck KR, Patt M, Kratschmar DV, Odermatt A. Posaconazole-Induced Hypertension Due to Inhibition of 11β-Hydroxylase and 11β-Hydroxysteroid Dehydrogenase 2. J Endocr Soc. 2019 Jul 1;3(7):1361–6.
199. Hoffmann WJ, McHardy I, Thompson GR. Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation. Mycoses. 2018 May;61(5):337–9.
200. Boughton C, Taylor D, Ghataore L, Taylor N, Whitelaw BC. Mineralocorticoid hypertension and hypokalaemia induced by posaconazole. Endocrinol Diabetes Metab Case Rep. 2018;2018.
201. Agarwal N, Apperley L, Taylor NF, Taylor DR, Ghataore L, Rumsby E, et al. Posaconazole-Induced Hypertension Masquerading as Congenital Adrenal Hyperplasia in a Child with Cystic Fibrosis. Case Rep Med. 2020;2020:8153012.
202. Barton K, Davis TK, Marshall B, Elward A, White NH. Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme. Clin Kidney J. 2018 Oct;11(5):691–3.
203. Sikka SC, Swerdloff RS, Rajfer J. In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology. 1985 May;116(5):1920–5.
204. Pont A, Williams PL, Azhar S, Reitz RE, Bochra C, Smith ER, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982 Nov;142(12):2137–40.
205. Pont A, Goldman ES, Sugar AM, Siiteri PK, Stevens DA. Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia. Arch Intern Med. 1985 Aug;145(8):1429–31.
206. Eil C. Ketoconazole binds to the human androgen receptor. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 1992 Aug;24(8):367–70.
207. Hugo Perez BS. Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men. Med Hypotheses. 2004;62(1):112–5.
208. Patel V, Liaw B, Oh W. The role of ketoconazole in current prostate cancer care. Nat Rev Urol. 2018 Oct;15(10):643–51.
209. Almeida MQ, Brito VN, Lins TSS, Guerra-Junior G, de Castro M, Antonini SR, et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin Endocrinol (Oxf). 2008 Jul;69(1):93–8.
210. Hanger DP, Jevons S, Shaw JT. Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob Agents Chemother. 1988 May;32(5):646–8.
211. Thompson GR, Surampudi PN, Odermatt A. Gynecomastia and hypertension in a patient treated with posaconazole. Clin Case Rep. 2020 Sep 28;8(12):3158–61.
212. Cummings AM, Hedge JL, Laskey J. Ketoconazole impairs early pregnancy and the decidual cell response via alterations in ovarian function. Fundam Appl Toxicol Off J Soc Toxicol. 1997 Dec;40(2):238–46.
213. Pepper G, Brenner SH, Gabrilove JL. Ketoconazole use in the treatment of ovarian hyperandrogenism. Fertil Steril. 1990 Sep;54(3):438–44.
214. P B, Sj G, D G, A C. Iatrogenic metrorrhagia after the use of itraconazole for onychomycosis. Indian J Pharmacol [Internet]. 2017 Dec [cited 2021 Jun 11];49(6). Available from: https://pubmed.ncbi.nlm.nih.gov/29674803/
215. Pillans PI, Sparrow MJ. Pregnancy associated with a combined oral contraceptive and itraconazole. N Z Med J. 1993 Oct 13;106(965):436.
216. Hilbert J, Messig M, Kuye O, Friedman H. Evaluation of interaction between fluconazole and an oral contraceptive in healthy women. Obstet Gynecol. 2001 Aug;98(2):218–23.
217. Levine MT, Chandrasekar PH. Adverse effects of voriconazole: Over a decade of use. Clin Transplant. 2016 Nov;30(11):1377–86.
218. Teranishi J, Nagatoya K, Kakita T, Yamauchi Y, Matsuda H, Mori T, et al. Voriconazole-associated salt-losing nephropathy. Clin Exp Nephrol. 2010 Aug;14(4):377–80.
219. Isobe K, Muraoka S, Sugino K, Yamazaki Y, Kikuchi N, Hamanaka N, et al. [Case of pulmonary aspergillosis associated with inappropriate antidiuretic hormone syndrome caused by voriconazole therapy]. Nihon Kokyuki Gakkai Zasshi. 2007 Jun;45(6):489–93.
220. Xu R-A, Zheng S-L, Xiao L-L, Cai X-D, Lai X-X, Lin G-Y, et al. Therapeutic drug monitoring in voriconazole-associated hyponatremia. Med Mycol Case Rep. 2013 Jun 19;2:134–6.
221. Matsumoto K, Ikawa K, Abematsu K, Fukunaga N, Nishida K, Fukamizu T, et al. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents. 2009 Jul;34(1):91–4.
222. Ho S, Rawlins M, Ingram P, Boan P. Voriconazole-induced hyponatraemia associated with homozygous CYP2C19*2 genotype. J Chemother Florence Italy. 2017 Oct;29(5):325–6.
223. Lin X-B, Li Z-W, Yan M, Zhang B-K, Liang W, Wang F, et al. Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients. Br J Clin Pharmacol. 2018 Jul;84(7):1587–97.
224. Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, et al. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014 Nov 1;59(9):1237–45.
225. Thompson GR, Bays D, Cohen SH, Pappagianis D. Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles. Antimicrob Agents Chemother. 2012 Jan;56(1):563–4.
226. Wermers RA, Cooper K, Razonable RR, Deziel PJ, Whitford GM, Kremers WK, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011 Mar 1;52(5):604–11.
227. Skiles JL, Imel EA, Christenson JC, Bell JE, Hulbert ML. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2011 Nov 10;29(32):e779-782.
228. Poinen K, Leung M, Wright AJ, Landsberg D. A vexing case of bone pain in a renal transplant recipient: Voriconazole-induced periostitis. Transpl Infect Dis Off J Transplant Soc. 2018 Oct;20(5):e12941.
229. Adwan MH. Voriconazole-induced periostitis: a new rheumatic disorder. Clin Rheumatol. 2017 Mar;36(3):609–15.
230. Chitkara M, Rackoff PJ, Beltran LS. Multiple painless masses: periostitis deformans secondary to fluoride intoxication. Skeletal Radiol. 2014 Apr;43(4):529–30, 555–6.
231. Tanner AR. Hypothyroidism after treatment with ketoconazole. Br Med J Clin Res Ed. 1987 Jan 10;294(6564):125.
232. Glass AR, Eil C. Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 1986 Sep;63(3):766–9.
233. G S, S B, Gi B, G DN. Ketoconazole decreases the serum ionized calcium and 1,25-dihydroxyvitamin D levels in tuberculosis-associated hypercalcemia. Am J Dis Child 1960 [Internet]. 1993 Mar [cited 2021 Jun 13];147(3). Available from: https://pubmed.ncbi.nlm.nih.gov/8438806/
234. Ar G, Jm C, W E, J L, Rw G, C E. Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis. J Endocrinol Invest [Internet]. 1990 May [cited 2021 Jun 13];13(5). Available from: https://pubmed.ncbi.nlm.nih.gov/2166103/
235. Sayers J, Hynes AM, Srivastava S, Dowen F, Quinton R, Datta HK, et al. Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clin Kidney J. 2015 Aug;8(4):453–5.
236. Nguyen M, Boutignon H, Mallet E, Linglart A, Guillozo H, Jehan F, et al. Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment. J Pediatr. 2010 Aug;157(2):296–302.
237. Peehl DM, Seto E, Feldman D. Rationale for combination ketoconazole/ vitamin D treatment of prostate cancer. Urology. 2001 Aug;58(2 Suppl 1):123–6.
238. Ghatak T, Singh RK, Baronia AK. Enteral voriconazole induced hypoglycemia: A potentially life threatening complication. Indian J Pharmacol. 2012;44(1):138–9.
239. Lobo BL, Miwa LJ, Jungnickel PW. Possible ketoconazole-induced hypoglycemia. Drug Intell Clin Pharm. 1988 Aug;22(7–8):632.
240. Lyoen M, Rostain F, Grimault A, Minello A, Sgro C. VFEND® (voriconazole)-associated hypoglycaemia without identified drug interaction. Fundam Clin Pharmacol. 2013 Oct;27(5):570–1.
241. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivistö KT. Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther. 2001 Apr;69(4):194–200.
242. Gunaratne K, Austin E, Wu PE. Unintentional sulfonylurea toxicity due to a drug-drug interaction: a case report. BMC Res Notes. 2018 May 21;11(1):331.
243. Stuecklin-Utsch A, Hasan C, Bode U, Fleischhack G. Pancreatic toxicity after liposomal amphotericin B. Mycoses. 2002 Jun;45(5–6):170–3.
244. Kim SW, Yeum CH, Kim S, Oh Y, Choi KC, Lee J. Amphotericin B decreases adenylyl cyclase activity and aquaporin-2 expression in rat kidney. J Lab Clin Med. 2001 Oct;138(4):243–9.
245. Metzger NL, Varney Gill KL. Nephrogenic diabetes insipidus induced by two amphotericin B liposomal formulations. Pharmacotherapy. 2009 May;29(5):613–20.
246. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009 Dec 31;26(4):223–7.
247. Canada TW, Weavind LM, Augustin KM. Possible liposomal amphotericin B-induced nephrogenic diabetes insipidus. Ann Pharmacother. 2003 Jan;37(1):70–3.
248. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol. 2015 Oct;11(10):576–88.
249. Ishikawa S. Amphotericin B-induced nephrogenic diabetes insipidus. Intern Med Tokyo Jpn. 2005 May;44(5):403.
250. Kobayashi R, Keino D, Hori D, Sano H, Suzuki D, Kishimoto K, et al. Analysis of Hypokalemia as a Side Effect of Liposomal Amphotericin in Pediatric Patients. Pediatr Infect Dis J. 2018 May;37(5):447–50.
251. Zager RA, Bredl CR, Schimpf BA. Direct amphotericin B-mediated tubular toxicity: assessments of selected cytoprotective agents. Kidney Int. 1992 Jun;41(6):1588–94.
252. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med. 1984 Sep;77(3):471–4.
253. Johansen HK, Gøtzsche PC. Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev [Internet]. 2014 Sep 4 [cited 2021 Jun 13];2014(9). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457843/
254. Sato K, Hayashi M, Utsugi M, Ishizuka T, Takagi H, Mori M. Acute pancreatitis in a patient treated with micafungin. Clin Ther. 2007 Jul;29(7):1468–73.
255. Smith PB, Steinbach WJ, Cotten CM, Schell WA, Perfect JR, Walsh TJ, et al. Caspofungin for the treatment of azole resistant candidemia in a premature infant. J Perinatol Off J Calif Perinat Assoc. 2007 Feb;27(2):127–9.
256. Xue S, Gu R, Wu T, Zhang M, Wang X. Oral potassium iodide for the treatment of sporotrichosis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006136.
257. Costa RO, de Macedo PM, Carvalhal A, Bernardes-Engemann AR. Use of potassium iodide in Dermatology: updates on an old drug. An Bras Dermatol. 2013;88(3):396–402.

 

ABSTRACT

 

Bacteria are microscopic organisms that are ubiquitous in the environment and human body. Some bacteria exhibit symbiotic relationship with the human body, while other bacteria are harmful and cause various diseases. Bacteria may infect the endocrine glands either by direct invasion or local or hematogenous spread. Suppurative bacterial infections can involve the pituitary, thyroid, adrenals, and gonads. In the majority of cases, specific risk factors predispose the endocrine glands to such infections. This in turn may lead to temporary or permanent endocrine dysfunction. There may also be states of hormone excess following bacterial infections. This is particularly noted in cases of bacterial thyroiditis. Permanent endocrine dysfunction following bacterial infections will warrant life-long hormone replacement therapy. In acute stages of infection, intravenous or oral antibiotics are the cornerstone of management. The choice of antibiotic is guided by culture and sensitivity report. Sometimes, however, empirical antibiotic therapy may need to be continued as no organism may be isolated on culture. Empirical therapy should provide coverage for gram positive, gram negative, and anaerobic bacteria. If there is abscess formation in any endocrine gland, it may require aspiration and drainage. In this chapter, we have discussed the risk factors, bacteriology, clinical presentation, diagnosis, and management of common bacterial infections involving endocrine glands.

INTRODUCTION

 

The incidence of bacterial infections of endocrine glands is low when compared to that in other organs of the body. The endocrine glands that may be affected by bacterial infections are: pituitary, thyroid, adrenals and gonads. Bacterial infection of parathyroid glands is extremely rare. Certain risk factors may predispose the glands for infection.

 

In general, bacteria may be classified as gram positive, gram negative, and miscellaneous categories. The classification of medically important bacteria is highlighted in another chapter of the Endotext (1). Among all the bacteria, Mycobacterium tuberculosis remains the most common agent involving the endocrine glands (2). Mycobacterium tuberculosis is a weakly gram positive highly aerobic bacterium that can cause tuberculosis in any organ of the body. This organism can affect the adrenal glands and lead to primary adrenal insufficiency. In developing countries, tuberculosis remains the most common cause of primary adrenal insufficiency. Tuberculosis can also affect pituitary, thyroid, and gonads. In this chapter, we are discussing only adrenal tuberculosis, since tuberculosis of the Endocrine system has been covered in great details in another chapter (3). Apart from Mycobacterium tuberculosis, the other common bacteria that may affect the endocrine system are Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitides, Escherichia coli, Chlamydia trachomatis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Treponema pallidum, and Yersinia enterocolitica among others. We have tried to present a spectrum of bacterial infections of various endocrine glands including their clinical presentation, investigations, management, long-term prognosis, and follow up.

 

BACTERIAL INFECTIONS OF PITUITARY

 

Infections of the pituitary gland are rare but may cause clinical problems because of the non-specific nature of the presentation (4). Among the various infectious agents, bacterial infections including Mycobacterial infections seem to be the most common. The various bacterial agents causing infection of the pituitary gland are summarized in the table 1. The common bacterial infections of the pituitary gland are described below.

 

Table 1.  Bacterial Agents Causing Infection of Pituitary-Hypothalamus
Bacterial class	Organism
Gram positive bacteria	Staphylococcus aureus, Streptococcus pneumoniae
Gram negative bacteria	E coli, Pseudomonas aeruginosa, Neisseria meningitides
Spirochaete	Treponema pallidum
Mycobacterium	Mycobacterium tuberculosis

 

Pituitary Abscess

 

EPIDEMIOLOGY AND RISK FACTORS

 

Pituitary abscesses are a very rare clinical entity and account for less than 1% of pituitary lesions (4). The first case of pituitary surgery involving an abscess was described in 1848. Since then, there have been around 300 such cases reported in the literature (4, 5). Risk factors include underlying pituitary diseases such as a pituitary adenoma, Rathke’s cyst, craniopharyngioma, lymphocytic hypophysitis, immunocompromised states (uncontrolled diabetes mellitus, tuberculosis, HIV infection, after solid organ transplantation, chemotherapy, radiotherapy), history of surgical exploration in pituitary hypothalamic region, and spread of local infection from meninges and paranasal sinuses (5-7). Rarely, abscess may develop in a normal pituitary gland (6, 8). 

 

BACTERIOLOGY

 

In the majority of cases, culture is negative in pituitary abscess, with only 19.7% cases showing growth of bacteria (9).The most common organisms isolated are Streptococci and Staphylococci. Other bacterial organisms are Escherichia coli, Mycobacteria, Neisseria, and anaerobes (6, 10). As culture is negative in most of the cases, it is important for empirical antibiotic therapy to cover gram positive, gram negative and anaerobic bacteria. Rarely, a fungal etiology is seen.

 

CLINICAL PRESENTATION

 

Clinical presentation can be classified with respect to chronicity as: acute (within days to weeks), subacute (less than a month) and chronic (more than a month). Acute and subacute abscesses have fulminant presentation while chronic abscess has a more indolent course (5). In the initial stages, patients present with headache (67%), fever, meningismus, and malaise. With progression of the disease, neurological symptoms like altered sensorium, seizures, and coma can occur.

 

Extension of infection in nearby areas can lead to visual dysfunction (45%), extra ocular movement defects, and other cranial nerve palsies (4, 8, 9, 11).

 

Both anterior and posterior pituitary hormonal hypofunction can be seen with a pituitary abscess. In the largest series of pituitary abscesses with 60 cases over 23 years, anterior pituitary hormone deficiencies were reported in 81.8% patients whereas diabetes insipidus was reported in 47.9% of the patients. In the same study, 9.3% had isolated hypogonadism, 3.7% had isolated ACTH deficiency, 1.8% had isolated hypothyroidism, and 1.8% hypothyroidism and ACTH deficiency (9).

 

DIAGNOSIS

 

The investigation of choice for the diagnosis of pituitary abscess is MRI (Magnetic Resonance Imaging) with proper sellar cuts. On T1 weighted images, pituitary abscess appears iso-intense to hypo-intense while on T2 weighted images, it is iso-intense to hyper-intense. There is a characteristic rim of enhancement after gadolinium injection around the abscess site (9, 11). Diffusion-weighted imaging (DWI) shows high signal intensity with a decrease in the apparent diffusion coefficient in the region of pus collection (9, 11).

 

MANAGEMENT

 

Trans-nasal trans-sphenoidal surgery and drainage of the abscess is the treatment of choice. The sphenoid sinus may require exploration if extrasellar invasion is suspected. Along with surgical exploration, the patient should be started on intravenous antibiotics empirically with ceftriaxone (alternatives are cefotaxime and cefepime) along with metronidazole for anaerobic coverage. In case of suspicion for Staphylococcus aureus, vancomycin should be added (9, 12). Further intensification or alteration of antibiotics is subjected to clinical improvement and culture and sensitivity reports. Microbiological etiology may not be identified in the majority of cases. Hence, it is imperative to give proper broad-spectrum coverage empirically.

 

PROGNOSIS AND FOLLOW-UP

 

With current standard of care, mortality rate is 10 % and chance of recurrence is <13%. In about 25% of cases hormonal recovery occurs. After recovering from a pituitary abscess, these patients should be followed up by serial MRI at 3, 6 and 12 months (12). Monitoring for anterior and posterior pituitary hormone deficiency should be done in any patient with a pituitary abscess. Replacement with corticosteroid, thyroid, gonadal, and growth hormone therapy may be required if the patient develops deficiency of any of these hormones. Replacement with vasopressin therapy may be required if patient develops central diabetes insipidus following a pituitary abscess.

 

Hypopituitarism Caused by Treponema Pallidum Infection

 

Syphilis caused by Treponema pallidum (a spirochete) may involve the pituitary- hypothalamic region causing syphilitic gumma with non-caseating granulomas (13, 14). It is more common in patients with underlying human immune deficiency virus (HIV) infection. Diagnosis can be made by demonstration of the spirochete in the samples of sellar tissues following trans sphenoidal surgery. Immunological diagnosis can be made by measuring titers of anti-Treponemal antibody in the serum. Treatment consists of intravenous followed by oral antibiotics (13-15). Penicillin is the drug of choice for syphilis. In patients who are allergic to penicillin, doxycycline is a good alternative.

 

BACTERIAL INFECTIONS OF THE THYROID

 

It is rare for bacteria to invade the normal thyroid gland because of the rich vascular supply, good lymphatic drainage, separation of thyroid gland from other structures by fascial planes, high iodine content, and production of hydrogen peroxide inside the gland (16). Both iodine and hydrogen peroxide have bactericidal properties.

 

Acute Suppurative Thyroiditis

 

EPIDEMIOLOGY AND RISK FACTORS      

 

Acute suppurative thyroiditis is rare and is usually due to bacterial infection of the thyroid gland. In severe cases, it can lead to abscess formation and spread to surrounding structures leading to acute obstruction of the respiratory tract. More than 90% of the patients are less than 40 years of age, with females being more commonly affected than males (17, 18). The incidence of acute suppurative thyroiditis lies between 0.1% and 0.7% of all thyroidal illnesses(19). In children acute suppurative thyroiditis is usually due to persistent pyriform sinus and almost always affects the left lobe and is often recurrent (20-22).  Risk factors for acute suppurative thyroiditis are summarized in table 2 (23).

 

Table 2. Risk Factors for Acute Suppurative Thyroiditis

Common risk factors

Pyriform sinus fistula – more common in children and young adults and associated with recurrent disease

Immunocompromised status – AIDS, blood malignancies, uncontrolled diabetes (more common risk factor overall)

Other risk factors

Thyroglossal cyst

Patent foramen cecum

Congenital brachial fistula

Spread of adjacent suppurative infection into thyroid

Anterior esophageal perforation

Underlying thyroid disorders like chronic autoimmune thyroiditis, goiter, and thyroid malignancy

Fine need aspirations/biopsy of thyroid

Dental abscess/ treatment

Systemic autoimmune disorders

 

BACTERIOLOGY

 

Although bacterial agents account for the majority of cases, acute suppurative thyroiditis can also be caused by fungal (immunosuppressive status), parasitic, and tubercular etiology. Common bacterial organisms include Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis, and Streptococcus pneumoniae. Rarely other causative bacteria include Klebsiella species, Hemophilus influenzae, Streptococcus viridans, Arcanobacterium haemolyticum, Eikenella corrodens, Salmonella species, and Enterobacteriaceae. In the context of immunosuppressed states like HIV-AIDS, acute suppurative thyroiditis can be caused by Mycobacterium tuberculosis, atypical mycobacteria, Salmonella species, Nocardia species and Treponema pallidum (19, 24).

 

CLINICAL PRESENTATION

 

Acute suppurative thyroiditis due to bacterial etiology has a very rapid onset and progression of symptoms if not addressed. The common manifestations are fever, neck pain, and dysphagia. Thyroid gland may be tender on palpation and sometimes there may be swelling with fluctuation suggestive of localized pus collection (25). Very rarely infection can spread to nearby anatomical structures resulting in a more dramatic presentation with stridor due to laryngeal involvement requiring urgent tracheostomy (26). It is important to differentiate this condition from subacute thyroiditis which also presents with systemic symptoms and neck pain (Table 3) (see below).

 

DIAGNOSIS AND MANAGEMENT

 

Laboratory investigations are consistent with acute inflammation characterized by leukocytosis with shift to left, elevated erythrocyte sedimentation rate, raised C- reactive protein (CRP), and other acute inflammatory markers (23). In cases of severe disease, blood cultures may be positive. Ultrasonography of the thyroid may reveal an abscess. The latter requires aspiration and pus should be sent for microbiological diagnosis. Typical findings of acute suppurative thyroiditis on ultrasound are perithyroidal hypoechoic space, effacement of the plane between the thyroid and surrounding tissues, and unilateral presentation [Fig 1] (27). Computed Tomography (CT) offers better spatial resolution and can be used in cases where ultrasound is not showing characteristic findings or when there is involvement of nearby soft tissue structures. Barium swallow studies may be required to diagnose a pyriform sinus, especially in children when there are recurrent episodes of suppurative thyroiditis (28).

Aspiration or surgical drainage of pus with intravenous empirical broad-spectrum antibiotics (especially in sick patients) is the cornerstone of management for acute suppurative thyroiditis. If the patient is immunocompromised, antifungal therapy should be added to initial therapy. In case of extensive involvement of nearby structures, surgical debridement of involved areas may be needed. With respect to culture sensitivity, antibiotic therapy can be modified and once clinical improvement occurs, patients can be switched to oral antibiotics. If there is presence of pyriform fistula, it should be treated either surgically (removal of entire tract with thyroidectomy) or by ablation (21, 29).

 

Subacute Thyroiditis

 

Subacute thyroiditis (also termed as granulomatous, giant cell, or deQuervain’s thyroiditis), is usually due to a viral illness following respiratory illness. Rarely, bacterial infections like Mycobacterium tuberculosis, Treponema pallidum, or Yersinia enterocolitica may cause subacute thyroiditis. Tuberculous thyroiditis is discussed in another chapter (2). Differentiating features of subacute thyroiditis and suppurative thyroiditis are presented in table 3 (19, 30, 31).

 

Table 3. Differentiating Acute Suppurative Thyroiditis and Subacute Thyroiditis
Features	Acute suppurative thyroiditis	Sub-acute thyroiditis
Etiology	Usually bacterial in origin	Usually follows viral upper respiratory tract infection
Presentation	Rapidly evolving, patient can be very toxic with extensive involvement	Presents with systemic symptoms over days to week
Age	Children, 20 to 40 years	20 to 60 years
Sex	Slight female preponderance	More common in females
Fever	72%	54%
Neck pain	70%	77%
Neck tenderness	Usually, unilateral (Left sided involvement due to persistent pyriform sinus)	Bilateral and migratory
Redness over skin	Common	Not present
Swelling with fluctuation suggestive of abscess formation	Common	Not present
History of sore throat	Absent	Present
Clinical features of thyrotoxicosis	Not common	Common in the initial phase
Laboratory
Leukocytosis	82%	25 to 50 %
Raised ESR	90%	85%
Abnormal thyroid function test	44%	60%
FNAC	Pus	Giant cells, granulomas
Ultrasound Thyroid	Hypoechoic areas with abscess formation, usually unilateral	Ill-defined hypoechoic areas, usually in bilateral lobes
RAIU study	Normal	Decreased in the initial thyrotoxic phase
18 F FDG PET	Increased uptake	Increased uptake
CT scan	Useful when ultrasound is doubtful and when infection extends into peri thyroid tissue	Not useful
Treatment	Antibiotics & drainage of pus	NSAIDS, glucocorticoids in severe cases and sequential follow up of thyroid function tests.

FNAC- fine needle aspiration cytology; RAIU- radioactive iodine uptake; NSAIDS-Non steroidal anti-inflammatory drugs

 

BACTERIAL INFECTIONS OF ADRENALS

 

Tuberculosis of Adrenals

 

Tuberculosis of the adrenal glands is the most common cause of primary adrenal insufficiency in developing countries. An autoimmune etiology remains common in developed countries. Tuberculous infection of the adrenal gland occurs from hematogenous spread from pulmonary or genitourinary sites (32). Adrenals are the most common endocrine gland involved in tuberculosis (2). The symptoms are usually non-specific with generalized weakness, easy fatiguability, loss of weight, loss of appetite, pain in abdomen, and gradually progressive darkening of complexion (Fig 2). These symptoms and signs of adrenal insufficiency do not occur until more than 90% of the glands are destroyed (33). Patient can have low grade fever if the tuberculosis is active and cough and hemoptysis if associated pulmonary involvement is present. In the majority of the cases, the tuberculosis infection may not be active with only a past history of pulmonary tuberculosis (33). Untreated patients may present with adrenal crisis during times of stress. Laboratory investigations reveal low serum cortisol and high plasma adrenocorticotrophic hormone (ACTH). Sometimes, ACTH stimulation test (short synacthen test) may be needed. Adrenal insufficiency is ruled out if serum cortisol level one hour post synacthen (ACTH) stimulation is more than 500-550 nmol/L (14-20 ug/dL depending on the assay). Electrolyte abnormalities noted in adrenal insufficiency are hyponatremia and hyperkalemia. Computed tomography shows bilateral enlarged adrenal masses with areas of necrosis and caseation. In long standing cases, there may be evidence of calcifications (33). Diagnosis is confirmed by adrenal biopsy showing caseating granulomas with acid fast bacilli. Other methods like culture and molecular techniques can be used for diagnosing tuberculosis in biopsy samples. Anti-tubercular treatment (ATT) along with both glucocorticoid and mineralocorticoids remain the treatment of choice. ATT consists of isoniazid - INH (5 mg/kg /d), rifampicin (10 mg/kg /d), pyrazinamide (30 mg/kg /d), and ethambutol (20 mg/kg/d) for 3 to 6 months, subsequently isoniazid and rifampicin for 6 to 12 months (34). In case of multi drug resistant tuberculosis, ATT may be altered with respect to the pattern of resistance. It may require second line medications and longer duration of therapy. Patients usually require lifelong replacement therapy with glucocorticoids and mineralocorticoids.

 

Apart from Mycobacterium tuberculosis, in the context of HIV-AIDS and other immunocompromised states, Mycobacterium avium intracellular and Mycobacterium chelonae may also cause primary adrenal insufficiency.

Adrenal Abscess

 

An adrenal abscess is a rare clinical condition with very few cases reported in the literature. Organisms that are implicated are Mycobacterium, anaerobes, Salmonella, Nocardia, and E coli. Treatment includes drainage of abscess and antibiotic therapy (35-40). The choice of antibiotic is guided by culture and sensitivity report. In culture negative cases, broad spectrum antibiotics with coverage for gram positive, gram negative, and anaerobic organisms should be considered.

 

Waterhouse-Friderichsen Syndrome

 

Waterhouse-Friderichsen syndrome (WFS) or purpura fulminans is an uncommon clinical entity associated with bilateral adrenal hemorrhage in the setting of severe bacterial sepsis, which was first reported by Rupert Waterhouse and Carl Friderichsen (41). The initial version of this syndrome was classically described with Neisseria meningitidis sepsis. But later it was found that a similar clinical picture was seen with other bacterial infections such as Streptococcus pneumoniae, Hemophilus influenzae, Escherichia coli, Staphylococcus aureus, Group A beta-hemolytic Streptococcus, Capnocytophaga canimorsus, Enterobacter cloacae, Pasteurella multocida, Plesiomonas shigelloides,Neisseria gonorrhoeae, Moraxella duplex, Rickettsia rickettsia, Bacillus anthracis, Treponema pallidum,and Legionella pneumophila (42-44).

 

Adrenal glands are predisposed to hemorrhage because around 50-60 small adrenal branches from 3 main adrenal arteries form a subcapsular plexus that drains into the medullary sinusoids through only a few venules (43). Therefore, an increase in adrenal venous pressure due to any cause may lead to hemorrhage. These bacteria may invade the adrenals directly or may produce endotoxins to cause adrenal necrosis and hemorrhage. There is also evidence of microthrombi within the adrenals along with disseminated intravascular coagulation (DIC). Pathologically, organisms are hardly demonstrated in the adrenal specimens (45). The patients are usually sick and present with profound adrenal crisis and shock.  A petechial rash is usually present on the trunk, lower limbs, and mucous membrane and its severity correlates with the degree of thrombocytopenia (44). Treatment involves admission to an intensive care unit and resuscitation with intravenous fluids, intravenous glucocorticoids, and appropriate antibiotics.

 

BACTERIAL INFECTIONS OF GONADS

 

Bacterial Infections of Testes

 

EPIDEMIOLOGY

 

Infection of the epididymis can occur in both children and adults. In severe cases, the inflammation can spread further into testis and present as epididymo-orchitis. If the duration of illness is less than 6 weeks, it is termed as acute epididymo-orchitis, whereas duration more than 6 weeks is termed as chronic. In children, it usually occurs between two and thirteen years of age, whereas in adults, it is common between twenty and thirty years of age (46).

 

BACTERIOLOGY

 

Causative organisms in younger males less than 35 years of age are Neisseria gonorrhoeae and Chlamydia trachomatis. In older men, causative organisms include Escherichia coli, other coliforms, and Pseudomonas. Rare bacterial causes include Ureaplasma species, Mycoplasma genitalium, Mycobacterium tuberculosis, and Brucella species (47-49). Risk factors for epididymitis include urinary tract infections, sexually transmitted diseases, bladder outlet obstruction, prostate enlargement, and urinary tract surgeries or urogenital procedures. In homosexual men, an enteric bacterial etiology is common (46, 50).

 

CLINICAL PRESENTATION

 

Acute epididymitis presents as localized testicular pain. On palpation, there may be swelling in the posterior part of the testis that represents an enlarged testis and inflamed epididymis. More advanced cases present with secondary testicular pain and swelling (epididymo-orchitis). There could be redness of scrotum and hydrocele (reactive fluid collection secondary to infection) (Fig 3). A positive Prehn sign (manual elevation of the scrotum relieves pain) is more often seen with epididymitis than testicular torsion (46).

 

 

DIAGNOSIS AND MANAGEMENT

 

In all cases of acute epididymo-orchits, it is important to rule out acute surgical conditions like testicular torsion and Fournier’s gangrene. All patients should undergo routine urine microscopy, urine for culture and sensitivity, and a urine nucleic acid amplification test (NAAT) for N. gonorrhoeae and C. trachomatis. NAAT is helpful in diagnosing infections where urine cultures are negative (51). Management depends on the severity of illness, history suggestive of sexually transmitted diseases, and reports of NAAT (summarized in table 4) (46, 52).

 

Table 4. Management of Acute Epididymo-Orchitis
Clinical scenario	Likely organisms	Choice of empirical antibiotic therapy *
Children < 14 years	Various possibilities – secondary to anatomical issues	Treatment based on urine culture results and referral to urologist.
Individuals at risk of sexually transmitted diseases but do not practice anal intercourse	N. gonorrhoeae and C. trachomatis	Single injection of ceftriaxone 500mg intramuscular and oral Doxycycline 100mg twice daily for 10 days.    Alternative for doxycycline – Azithromycin Alternative for ceftriaxone- Gentamycin
Individuals at risk of sexually transmitted diseases but do practice anal intercourse	N. gonorrhoeae, C. trachomatis and enteric pathogens	Single injection of ceftriaxone 500mg intramuscular and oral Doxycycline 100mg twice daily for 10 days plus oral levofloxacin 500 mg once daily for 10 days
Individuals at lower risk of sexually transmitted diseases Recent urinary tract surgery or instrumentation	Enteric pathogens	Oral levofloxacin 500 mg once daily for 10 days

*Further treatment should be adjusted based culture and NAAT results; severe cases may require hospitalization and intravenous antibiotics.

 

Bacterial Infections of Ovaries

 

Isolated infection of ovaries is not common. It is usually part of pelvic inflammatory disease. In severe cases, it may present as tubo-ovarian abscess. Tubo-ovarian abscesses are often polymicrobial and typically contain a predominance of anaerobic bacteria. Common organisms include Escherichia coli, Bacteroides fragilis, other Bacteroides species, Pepto-streptococci, and anaerobic streptococci (53). Diagnosis is based on history, physical examination, ultrasound suggesting tubo -ovarian mass or abscess, and microbiological diagnosis. Treatment consists of admission, intravenous antibiotic therapy, and aspiration of abscess if needed. Patients who do not respond, will need surgical intervention (54).

 

OTHER LINKS BETWEEN BACTERIA AND ENDOCRINE DISORDERS

 

Yersinia enterocolitica has been implicated in the pathogenesis of autoimmune thyroid disease (55). Immunoglobulins from patients with Yersinia infection inhibit binding of TSH to thyrocytes (56). This could be explained by structural similarity between Yersinia outer membrane proteins (YOP) and epitopes of the TSH receptor (55, 56).

 

Role of gut microbiome has recently implicated in the metabolic syndrome, obesity, and diabetes (57). Many metabolites produced by gut microbes get absorbed into the circulation. They may act on specific receptors to regulate metabolism (58, 59). Also, some bacterial components can act as endocrine factors controlling metabolism(58).

 

CONCLUSION

 

Bacterial infections of the endocrine glands are rare. Pituitary abscesses usually occur in the setting of underlying pathology of the pituitary gland.  It is commonly caused by Streptococci and Staphylococci. MRI of the sella demonstrates a characteristic rim of enhancement after gadolinium injection. Treatment of pituitary abscess is trans-sphenoidal surgery and intravenous antibiotics. Culture is positive in only 19.7% of cases. Acute suppurative thyroiditis is commonly caused by Streptococci and Staphylococci. Important risk factor for acute suppurative thyroiditis in children is pyriform fistula, whereas in adults, it is more common in immunocompromised states. Acute suppurative thyroiditis appear as hypoechoic area on ultrasound. It is treated by ultrasound guided drainage of the abscess and antibiotic therapy. Acute suppurative thyroiditis should be differentiated from subacute thyroiditis. Primary adrenal bacterial infections other than tuberculosis are rare. Waterhouse-Friderichsen syndrome (WFS) is an uncommon clinical entity associated with bilateral adrenal hemorrhage in the setting of severe bacterial sepsis. It is classically described with Neisseria meningitides, but may be associated with other bacteria as well. Toxins produced by bacteria can cause necrosis, hemorrhage, and microthrombi within the adrenal gland leading to WFS. Infection of the epididymis can occur in both children and adults. Sometimes, the inflammation spreads further into testis and presents as epididymo-orchitis. Common bacterial agents causing epididymo-orchitis are N. gonorrhoeae and C.trachomatis. Enteric pathogens should be suspected if there is history of homosexual practice. Management depends on the severity of illness, history of suggestive sexually transmitted diseases, and reports of NAAT (urine nucleic acid amplification test).

 

ACKNOWLEDGEMENTS

 

Dr. Lovekesh Bhatia, Department of Radiodiagnosis, Aadhar Health Institute, Hisar, India

Dr. Vinita Jain, Department of Pediatrics, Aadhar Health Institute, Hisar, India

 

REFERENCES

 

1. Nagendra L, Boro H, Mannar V. Bacterial Infections in Diabetes. 2022 Apr 5. 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.; 2000.
2. Gupta S, Ansari MAM, Gupta AK, Chaudhary P, Bansal LK. Current Approach for Diagnosis and Treatment of Adrenal Tuberculosis-Our Experience and Review of Literature. Surg J (N Y). 2022 Mar 3;8(1):e92-e97.
3. Jacob JJ, Paul PAM. Infections in Endocrinology: Tuberculosis. 2021 Mar 14. 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.; 2000.
4. Machado MJ, Ramos R, Pereira H, Barbosa MM, Antunes C, Marques O, Almeida R. Primary pituitary abscess: case report and suggested management algorithm. Br J Neurosurg. 2021 Aug 24:1-4.
5. Pekic S, Miljic D, Popovic V. Infections of the Hypothalamic-Pituitary Region. 2021 Aug 9. 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.; 2000.
6. Cabuk B, Caklılı M, Anık I, Ceylan S, Celik O, Ustün C. Primary pituitary abscess case series and a review of the literature. Neuro Endocrinol Lett. 2019 Oct;40(2):99-104.
7. Pekic S, Popovic V. Alternative causes of hypopituitarism: traumatic brain injury, cranial irradiation, and infections. Handb Clin Neurol. 2014;124:271-90.
8. Adams D, Kern PA. A case of pituitary abscess presenting without a source of infection or prior pituitary pathology. Endocrinol, Diabetes & Metabol Case Reports [Internet]. 2016 Aug 16 [cited 2022 May 10];2016.
9. Gao L, Guo X, Tian R, Wang Q, Feng M, Bao X, Deng K, Yao Y, Lian W, Wang R, Xing B. Pituitary abscess: clinical manifestations, diagnosis and treatment of 66 cases from a large pituitary center over 23 years. Pituitary. 2017 Apr;20(2):189-194.
10. Ling X, Zhu T, Luo Z, Zhang Y, Chen Y, Zhao P, et al. A review of pituitary abscess: our experience with surgical resection and nursing care. Transl Cancer Res. 2017 Aug;6(4):852–9.
11. Vates GE, Berger MS, Wilson CB. Diagnosis and management of pituitary abscess: a review of twenty-four cases. J Neurosurg. 2001 Aug;95(2):233-41.
12. Bloomer ZW, Knee TS, Rubin ZS, Hoang TD. Case of an atypical pituitary abscess. BMJ Case Rep. 2021 Nov 30;14(11):e246776. 
13. Bricaire L, Van Haecke C, Laurent-Roussel S, Jrad G, Bertherat J, Bernier M, Gaillard S, Groussin L, Dupin N. The Great Imitator in Endocrinology: A Painful Hypophysitis Mimicking a Pituitary Tumor. J Clin Endocrinol Metab. 2015 Aug;100(8):2837-40.
14. Benzick AE, Wirthwein DP, Weinberg A, Wendel GD Jr, Alsaadi R, Leos NK, Zeray F, Sánchez PJ. Pituitary gland gumma in congenital syphilis after failed maternal treatment: a case report. Pediatrics. 1999 Jul;104(1):e4. 
15. Spinner CD, Noe S, Schwerdtfeger C, Todorova A, Gaa J, Schmid RM, Busch DH, Neuenhahn M. Acute hypophysitis and hypopituitarism in early syphilitic meningitis in a HIV-infected patient: a case report. BMC Infect Dis. 2013 Oct 17;13:481.
16. Har-el G, Sasaki CT, Prager D, Krespi YP. Acute suppurative thyroiditis and the branchial apparatus. Am J Otolaryngol. 1991 Jan-Feb;12(1):6-11. 
17. Touihmi S, Rkainilham, Mehdaoui A, El boussaadni Y, Oulmaati A. Acute suppurative thyroiditis with abscess. J Pediatr Surg Case Rep. 2021 Feb;65:101757.
18. Bukvic B, Diklic A, Zivaljevic V. Acute suppurative klebsiella thyroiditis: a case report. Acta Chir Belg. 2009 Mar-Apr;109(2):253-5.
19. 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 Mar;20(3):247-55.
20. Madana J, Yolmo D, Kalaiarasi R, Gopalakrishnan S, Saxena SK, Krishnapriya S. Recurrent neck infection with branchial arch fistula in children. Int J Pediatr Otorhinolaryngol. 2011 Sep;75(9):1181-5. 
21. 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 Nov;78(11):1953-7.
22. Zhang P, Tian X. Recurrent neck lesions secondary to pyriform sinus fistula. Eur Arch Otorhinolaryngol. 2016 Mar;273(3):735-9
23. Lafontaine N, Learoyd D, Farrel S, Wong R. Suppurative thyroiditis: Systematic review and clinical guidance. Clin Endocrinol (Oxf). 2021 Aug;95(2):253-264
24. Falhammar H, Wallin G, Calissendorff J. Acute suppurative thyroiditis with thyroid abscess in adults: clinical presentation, treatment and outcomes. BMC Endocr Disord. 2019 Dec 3;19(1):130.
25. Dunham B, Nicol TL, Ishii M, Basaria S. Suppurative thyroiditis. Lancet. 2006 Nov 11;368(9548):1742.
26. Minhas SS, Watkinson JC, Franklyn J. Fourth branchial arch fistula and suppurative thyroiditis: a life-threatening infection. J Laryngol Otol. 2001 Dec;115(12):1029-31.
27. 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 Oct;21(10):1075-80.
28. Furukawa M, Kano M, Takiguchi T, Umeda R. Piriform sinus fistula as a route of infection in acute suppurative thyroiditis. Auris Nasus Larynx. 1986;13(2):107-12.
29. 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 Jul;19(7):789-93. 
30. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003 Jun 26;348(26):2646-55.
31. Shrestha RT, Hennessey J. Acute and Subacute, and Riedel’s Thyroiditis. 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.; 2000-.
32. Del Borgo C, Urigo C, Marocco R, Belvisi V, Pisani L, Citton R, et al. Diagnostic and therapeutic approach in a rare case of primary bilateral adrenal tuberculosis. J Med Microbiol. 2010 Dec;59 (Pt 12):1527-1529
33. Kelestimur F. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest. 2004 Apr;27(4):380-6.
34. Laway BA, Khan I, Shah BA, Choh NA, Bhat MA, Shah ZA. Pattern of adrenal morphology and function in pulmonary tuberculosis: response to treatment with antitubercular therapy. Clin Endocrinol (Oxf). 2013 Sep;79(3):321-5.
35. Regino CA, Gómez JP, Mosquera-Klinger G. Endoscopic Ultrasound-Guided Transgastric Puncture and Drainage of an Adrenal Abscess in an Immunosuppressed Patient. Clin Endosc. 2022 Mar;55(2):302-304. 
36. O'NEILL JA Jr, HALL WH. ISOLATED ADRENAL ABSCESS SECONDARY TO SALMONELLA. Arch Surg. 1965 Mar;90:454-6.
37. Midiri M, Finazzo M, Bartolotta TV, Maria MD. Nocardial adrenal abscess: CT and MR findings. Eur Radiol. 1998;8(3):466-8.
38. Yokoyama S, Sekioka A, Utsunomiya H, Hara S, Takahashi T, Yoshida A. Adrenal abscess as a complication of Escherichia coli sepsis in neonates: A case report. J Pediatr Surg Case Rep. 2013 Sep;1(9):328–30.
39. Jin W, Miao Q, Wang M, Zhang Y, Ma Y, Huang Y, et al. A rare case of adrenal gland abscess due to anaerobes detected by metagenomic next-generation sequencing. Ann Transl Med. 2020 Mar;8(5):247. 
40. Rumińska M, Witkowska-Sędek E, Warchoł S, Dudek-Warchoł T, Brzewski M, Pyrżak B. Adrenal abscess in a 3-week-old neonate - a case report. J Ultrason. 2015 Dec;15(63):429-37.
41. Varon J, Chen K, Sternbach GL. Rupert Waterhouse and Carl Friderichsen: adrenal apoplexy. J Emerg Med. 1998 Jul-Aug;16(4):643-7. 
42. Hamilton D, Harris MD, Foweraker J, Gresham GA. Waterhouse-Friderichsen syndrome as a result of non-meningococcal infection. J Clin Pathol. 2004 Feb;57(2):208-9. 
43. Karki BR, Sedhai YR, Bokhari SRA. Waterhouse-Friderichsen Syndrome. [Updated 2021 Dec 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
44. Kalinoski T. Waterhouse-Friderichsen Syndrome with Bilateral Adrenal Hemorrhage Associated with Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia in an Adult Patient with History of Intravenous Drug Use. Am J Case Rep. 2022 Apr 14;23:e936096.
45. Guarner J, Paddock CD, Bartlett J, Zaki SR. Adrenal gland hemorrhage in patients with fatal bacterial infections. Mod Pathol. 2008 Sep;21(9):1113-20.
46. McConaghy JR, Panchal B. Epididymitis: An Overview. Am Fam Physician. 2016 Nov 1;94(9):723-726. 
47. Tracy CR, Steers WD, Costabile R. Diagnosis and management of epididymitis. Urol Clin North Am. 2008 Feb;35(1):101-8; vii. 
48. Doble A, Taylor-Robinson D, Thomas BJ, Jalil N, Harris JR, Witherow RO. Acute epididymitis: a microbiological and ultrasonographic study. Br J Urol. 1989 Jan;63(1):90-4. 
49. Hawkins DA, Taylor-Robinson D, Thomas BJ, Harris JR. Microbiological survey of acute epididymitis. Genitourin Med. 1986 Oct;62(5):342-4.
50. Kaver I, Matzkin H, Braf ZF. Epididymo-orchitis: a retrospective study of 121 patients. J Fam Pract. 1990 May;30(5):548-52.
51. Wampler SM, Llanes M. Common scrotal and testicular problems. Prim Care. 2010 Sep;37(3):613-26, x.
52. Trojian TH, Lishnak TS, Heiman D. Epididymitis and orchitis: an overview. Am Fam Physician. 2009 Apr 1;79(7):583-7.
53. Kairys N, Roepke C. Tubo-Ovarian Abscess. 2021 Jul 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
54. Munro K, Gharaibeh A, Nagabushanam S, Martin C. Diagnosis and management of tubo-ovarian abscesses. Obstet Gynecol. 2018 Jan;20(1):11–9.

         Mar;93(3):674-6.

56. Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol. 2014 Jun;170(6):R241-52. 
57. Li R, Li Y, Li C, Zheng D, Chen P. Gut Microbiota and Endocrine Disorder. Adv Exp Med Biol. 2020;1238:143-164.
58. Rastelli M, Cani PD, Knauf C. The Gut Microbiome Influences Host Endocrine Functions. Endocr Rev. 2019 Oct 1;40(5):1271-1284
59. Cani PD, Knauf C. How gut microbes talk to organs: The role of endocrine and nervous routes. Mol Metab. 2016 May 27;5(9):743-52.

ABSTRACT

 

Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is responsible for the largest number of deaths worldwide caused by a single organism. Over 25% of the world population is infected with M. tuberculosis, though active infections account only for a small percentage. Though some degree of endocrine dysfunction is invariable in all patients with TB, clinically significant endocrinopathy other than glucose intolerance is rare. This chapter reviews endocrine dysfunction and endocrinopathies associated with TB infection related to the adrenal, thyroid and pituitary glands. Additionally, functional derangement of sodium and calcium homeostasis is also covered. Adrenal involvement can be found in up to 6% of patients with active TB, however isolated adrenal involvement is seen only in a fourth of these. The most common clinical manifestation is Addison’s disease (AD). Clinical manifestations of AD appear only after 90% of the adrenal cortices have been compromised. Thyroid tuberculosis (TTB) is very rare, even in countries with a high prevalence of TB. TB has been seen to involve the thyroid in 0.1 to 1% of patients. Primary pituitary TB (in the absence of systemic involvement and/or constitutional symptoms) is extremely rare, and secondary pituitary TB is more commonly encountered in clinical practice. Pituitary TB should be considered in the differential of a suprasellar mass especially in developing countries, as the condition is potentially curable with treatment. Hyponatremia has been commonly seen in patients admitted to the hospital with TB. The commonest cause of hyponatremia is the syndrome of inappropriate antidiuresis (SIAD). Other causes include untreated primary or secondary adrenal insufficiency, volume depletion, hyponatremia associated with volume excess and hypoalbuminemia and rare cases of cerebral salt wasting seen with tuberculous meningitis. The prevalence of hypercalcemia in patients with TB has ranged from 2-51% in various studies. The primary determinant in the development of hypercalcemia among patients with TB appears to be their Vitamin D status and nutritional calcium intake.

 

INTRODUCTION

 

Mycobacterium tuberculosis the etiological agent of tuberculosis (TB) was directly responsible for 1.3 million deaths in 2019. A majority of these deaths happen in patients without human immunodeficiency virus (HIV) co-infection making M. tuberculosis the pathogen responsible for the largest number of deaths in the world by a single organism. Additionally, TB is among the top ten causes of death worldwide (1).

 

Most cases of primary TB infections are clinically, bacteriologically, and radiologically inapparent. This primary infection in 5-10% patients leads to active disease after a period of latency within 2 years of contracting the infection. In another 5% the disease becomes active much later in life after a decline in general immunity. It is thought that over 25% of the world’s current population is infected with M. tuberculosis though active infections account only for a small percentage. In the year 2019 over 10 million patients were newly diagnosed with clinical TB. South East Asia accounted for over 44% of these along with Africa (25%), Western Pacific (18%), Eastern Mediterranean (8.2%), Americas (2.9%) and Europe (2.5%). The eight countries of India (26%), Indonesia (8.5%), China (8.4%), Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%) account for two thirds of the world’s newly diagnosed cases last year (1).

 

As previously noted most active TB infections are reactivation of latent primary TB though a small but significant percentage of patients have active TB related to new exogenous re-infection. The most common primary site of adult active TB are the highly aerated upper lobes of the lungs. The defining pathology includes the presence of granulomas containing epithelioid cells, Langhan’s giant cells surrounded by lymphocytes with a center of caseous necrosis and varying degrees of fibrosis. This chapter focuses on the endocrinology of tuberculous infection (2, 3).

 

ALTERED IMMUNE-NEUROENDOCRINE COMMUNICATION IN TUBERCULOSIS        

 

The two-way communication between the immune system and the neuroendocrine system is well known and documented. An activated immune cascade can affect all the endocrine systems of the body. Adrenal steroids are the primary hormones that modify immune responses. The up-regulation of the hypothalamic-pituitary adrenal (HPA) axis by inflammation related to infections is primarily mediated by the action of inflammatory cytokines on the hypothalamic releasing factors. Cytokines like Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) stimulate the secretion of corticotrophin releasing hormone (CRH) from the hypothalamus leading to corticotrophin (ACTH) secretion from the pituitary. The action of ACTH on the adrenal cortex leads to secretion of both cortisol and dehydroepiandrosterone (DHEA). Cortisol inhibits the T- lymphocyte mediated Th1 response while DHEA antagonizes the cortisol action on Th1 response. This intense immune-endocrine response to acute infection leads to early mobilization of the immune cells and a robust immune response by the host against the offending pathogen (4, 5).

 

However, in TB the chronic persistent activation of the immune-endocrine axis leads to misuse of the immune-endocrine axis and can exacerbate damage to the host. Primarily the prolonged activation of the HPA and resultant increase in glucocorticoid (GC) secretion leads to a change in the T-lymphocyte response from Th1 to Th2 response (6). Beyond this GCs can interfere with gene expression of certain transcription factors like nuclear factor kappa-β(NF-κβ) (7), inhibit the proliferation of effector T cells and cause an increased rate of apoptosis of the regulatory T cells (8). Clinical studies in patients with TB have shown increased circulating levels of cytokines like IL-6, IL-10, interferon-α (IFN-α) and cortisol. However, DHEA levels have been consistently shown to be well below normal levels. In summary, GCs appear to have an adverse effect on the anti-TB immune response while DHEA appears to have a favorable effect. This balance is adversely impacted with the chronic inflammation seen in TB.

 

Some of these changes in immune-endocrinology have also been implicated in the morbidity associated with TB. In vitro studies suggest that negative immune response to mycobacterial antigens was associated with increased IL-6 production which in turn was associated with lower body weights among patients with TB. Higher circulating IL-6 was also associated with loss of appetite (9). The increased circulating GCs additionally mobilize peripheral lipid stores and inhibit protein synthesis and favor loss of lean body mass. Hypothalamic CRH secretion also appear to have direct catabolic effects on the body other than its effect mediated through increased GC secretion (10). Among the adipocyte hormones there is a decrease in leptin and increased secretion of adipocytokines in TB. In an acute infection the above adaptive response appears to be useful by directing limited energy stores to the immune response away from the body’s physiological needs. However, in chronic infections like TB these changes lead to a chronic metabolic deficit leading to cachexia which in turn then affects the further ongoing immune response and disease outcome (11, 12).  

 

Some of these alterations in the immune-endocrine axis in M. tuberculosis infection are summarized in Figure 1.

ENDOCRINOPATHIES IN PATIENTS WITH TUBERCULOSIS        

 

Though some degree of endocrine dysfunction is invariable in all patients with TB, clinically significant endocrinopathies other than glucose intolerance is rare. In a small study of 50 patients hospitalized with sputum-positive pulmonary TB in South Africa the commonest endocrine dysfunction noted was a low free T3 state as part of sick euthyroid syndrome in over 90% of patients. The other common endocrine dysfunction noted in the study was a 72% prevalence of hypogonadotropic hypogonadism among male patients and a 64% prevalence of hyponatremia of whom almost half of them (17/50) had documented syndrome of inappropriate diuresis (SIAD). No patients in this study had clinically significant adrenal insufficiency and one patient had hypercalcemia (13).

 

In disseminated TB, seeding of the various endocrine glands with mycobacteria and formation of tubercules is common. In an autopsy study performed in over 100 patients who succumbed to disseminated TB done in the eighties, 53% had involvement of the adrenals, 14% had seeding into the thyroid gland, 5% had direct involvement of the testes, and 4% had seeding into the pituitary gland. Among these 100 patients only one had antemortem clinical adrenal insufficiency (14).

 

The full spectrum of possible endocrine abnormalities seen with tuberculosis is summarized in Table 1.

 

Table 1. Endocrine Abnormalities Seen with Mycobacterium Tuberculosis Infection and with Anti-Tubercular Therapy
Hypothalamus	Diabetes Insipidus
Pituitary	1.     Sellar mass lesion 2.     Tuberculous abscess 3.     Sellar Tuberculoma 4.     Thickened stalk with pituitary interruption syndrome 5.     Isolated hyperprolactinemia 6.     Incidental partial or complete hypopituitarism  7.     Isolated hypogonadotropic hypogonadism 8.     Pituitary dysfunction seen with Tuberculous meningitis
Thyroid	1.     Tubercular thyroiditis 2.     Cold abscess of the thyroid 3.     Chronic fibrosing thyroiditis 4.     Sick euthyroid syndrome 5.     Para-amino-salicylic acid (PAS) related goiter 6.     Ethionamide and rifampicin related thyroid dysfunction
Parathyroid	Inflammation
Pancreas	1.     Stress hyperglycemia 2.     Frank diabetes 3.     Pancreatic abscess
Testes	1.     Isolated TB orchitis 2.     TB epididymitis 3.     Epididymo-orchitis  4.     Primary gonadal failure
Ovaries	1.     Tubo-ovarian abscess 2.     Tubal blockage 3.     Unexplained infertility
Water Metabolism	1.     Hyponatremia 2.     Syndrome of inappropriate anti-diuresis (SIAD) 3.     Cerebral salt wasting (CSW)
Vitamin D-Calcium Metabolism	1.     Parathyroid hormone independent hypercalcemia 2.     Vitamin D deficiency/hypocalcemia related to isoniazid and rifampicin
Adrenals	1.     Tubercular adrenalitis 2.     Addison’s disease 3.     Reversible adrenal insufficiency 4.     Isolated DHEA deficiency

 

In this chapter we will review endocrine dysfunction and endocrinopathies associated with TB infection related to the adrenal, thyroid and pituitary glands. Additionally, functional derangement of sodium, and calcium homeostasis will be covered. Glucose intolerance, diabetes and tuberculosis is a large area of public health and will not covered in this chapter.

 

ADRENALS AND TUBERCULOSIS

 

TB can involve both adrenal glands primarily or the involvement may be part of disseminated TB. Both conditions may present with primary adrenal insufficiency (Addison’s Disease). Anti-tuberculous therapy (ATT)-related enzyme induction abnormalities can also lead to adrenal dysfunction and in some cases unmask subclinical adrenal insufficiency. Chronic steroid therapy used in the treatment of some types of tuberculous infection can lead to suppression of HPA axis and secondary adrenal insufficiency. Finally, it is important to remember that pituitary involvement in central nervous system (CNS) TB can sometimes lead to isolated corticotropin deficiency with adrenal insufficiency or it can be part of generalized hypopituitarism 

 

Tuberculosis and Addison’s Disease

 

Thomas Addison in 1855 first described chronic adrenal failure, or Addison’s disease (AD), due to Mycobacterium tuberculosis infection involving both the adrenal glands. In his paper describing AD, 6/11 patients had tuberculous involvement of the adrenal glands. In 1930, Guttman reported a large series of 566 cases with AD, of which 70% was due to tuberculous adrenalitis (15). In 1956 only 25% of AD was related to TB infection (16). The decreasing incidence of tubercular adrenal failure in Western literature was highlighted in a recent large study of 615 cases of AD from Italy in 2011; in this series only 9% of cases were due to TB (17).

 

This decline in the number of patients with AD related to TB has not been seen in countries endemic for TB like India and South Africa. In India, tuberculous etiology was found in 47% of patients with AD, and of them 85% had enlargement of one or both adrenal glands on imaging (18). The differences between AD due to TB and those with idiopathic AD is summarized in Table 2. In South Africa, 32% of patients with AD had tubercular etiology (19). The most common cause of AD worldwide, however, is autoimmune adrenalitis.

 

Table 2. Differences in Clinical Presentation of Tubercular Addison’s Disease (AD) versus Idiopathic AD (18)
Clinical Features	Tubercular	Idiopathic	p-value
Mean age (in years)	42	35	NS
Durations of symptoms before diagnosis (in months)	14	21	NS
Sex Ratio (M: F)	10:1	14:8	< 0.05
Presentation as crisis (%)	40%	23%	NS
Evidence of other autoimmune disease (%)	10%	27%	< 0.05
Evidence of extra-adrenal TB (%)	55%	9%	< 0.05
Adrenal Cytoplasmic Antibodies (%)	17%	50%	< 0.05

 

PATHOPHYSIOLOGY OF TUBERCULAR ADRENALITIS            

 

Adrenal TB develops from hematogenous or lymphatic spread, hence is often associated with extra-adrenal infection. The rich vascularity of the adrenal gland and high levels of local corticosteroids that suppress cell mediated immunity create an ideal microenvironment for the growth of Mycobacterium tuberculosis (20). Adrenal involvement can be found in up to 6% of patients with active TB, however isolated adrenal involvement is seen only in a fourth of these (1.5-3% of cases with tubercular infection) (21, 22). Clinical manifestations of AD appear only after 90% of the adrenal cortices have been compromised (23).

 

The patterns of adrenal gland involvement in TB are summarized below and in Figure 2 (24):

1. Chronic infection of the adrenal gland, with clinical manifestations of primary adrenal insufficiency appearing years after initial infection. Pathologically these patients have small atrophic fibrous glands with or without calcification.
2. Isolated adrenal gland involvement early in the course of disease usually within 2 years of the primary infection. Pathologically these patients most commonly present with bilateral adrenal enlargement because of mass lesions secondary to production of cold abscesses within the adrenal glands. Milder enlargement can be seen in patients with extensive granulomas within the adrenal gland. Lastly, patients with isolated adrenal tuberculosis may also present with normal sized glands with granulomatous inflammation seen microscopically. Calcifications maybe seen in these cases as well.
3. Secondary adrenal insufficiency due to prolonged steroid therapy in disseminated TB or tubercular involvement of the pituitary or hypothalamus.
4. Subclinical steroid deficiency unmasked by ATT-related enzyme induction.

CLINICAL FEATURES

 

Adrenal TB can be found in any age, however is more commonly seen in adults. Rare cases have also been described in the pediatric age group (25, 26). Thomas Addison’s first description of AD showed a constellation of symptoms like “general languor and debility, remarkable feebleness of heart’s action, and a peculiar change in the color of the skin.” Classic manifestations of AD in the form of malaise or fatigue, anorexia, weight loss, nausea, vomiting, muscle and joint pain, orthostatic hypotension, skin hyperpigmentation and salt craving are often present. Mineralocorticoid deficiency leads to postural hypotension, while hyperpigmentation occurs due to activation of the melanocortin 1 receptors (MC1R) in turn because of high ACTH levels (27). In some patients, however, hyperpigmentation can be absent due to reduced stimulation of MC1R from adrenocorticotropin hormone (ACTH), resulting in an alabaster-like appearance (27). A prior history of TB may also be provided in some patients.

 

RADIOLOGIC FINDINGS

 

Computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) are useful non-invasive tools in the diagnosis of adrenal TB. CT has been regarded as the modality of choice for diagnosing adrenal TB, and should include both non-contrast and contrast-enhanced techniques. Adrenal involvement is usually bilateral (28), and findings vary according to course of disease.

 

• Early stage: In the first two years, CT shows noncalcified enlarged adrenals with areas of lucency reflecting caseous necrosis, and a peripheral rim of contrast-enhanced parenchyma. Contours of the adrenal glands are generally preserved.
• Late stage: As disease progresses, the adrenals normalize in size, then shrink, and have calcific foci with irregular margins. Calcifications are best visualized on non-contrast CT scans. These may be either diffuse, focal or punctate in nature (22). These findings correlate with long-standing fibrosis and dystrophic calcification seen with tuberculous granulomas.

 

LABORATORY FINDINGS

 

Common findings in patients with adrenal TB include hyponatremia, hyperkalemia and normochromic anemia (27). Hyponatremia can occur due to decreased inhibitory control of vasopressin secretion, resulting in mild SIAD (29). The Mantoux (tuberculin) test usually is strongly positive and erythrocyte sedimentation rate (ESR) is elevated.

 

• In primary AD, baseline serum ACTH levels are higher than 100 pg/ml, plasma renin levels are elevated and serum aldosterone levels are low. In secondary AD, ACTH levels will be low or inappropriately normal, while mineralocorticoid secretion will be normal (27).
• Serum DHEAS will also be low in patients with both primary and secondary AD (27).
• Adrenal insufficiency can be demonstrated by low morning plasma cortisol with a reduced response to synthetic ACTH (27). Impaired ACTH-stimulated cortisol responses have also been observed with lower baseline cortisol levels, and both higher and lower cortisol responses to ACTH stimulation in patients with isolated pulmonary TB without adrenal involvement (24). Injectable tetracosactide hexa-acetate, ACTH 1-24 (Synacthen®) (SST), is not marketed or easily available in many developing countries in the world including India. An alternative ACTH which is injectable long-acting porcine sequence, ACTH 1-39 (Acton Prolongatum®) (APST), is easily available and much cheaper. In a study done recently in India by Nair et al in 20 patients with established adrenal insufficiency and 27 controls, the area under the curve of APST (at 120 min) was 0.986 when compared to the standard SST, thus proving its high accuracy. A serum cortisol cut off value of 19.5 µg/dL at 120-min following APST showed a sensitivity of 100% and specificity of 88% (30).

 

PATHOLOGY OF ADRENAL TUBERCULOSIS

 

Macroscopic involvement of the adrenal gland can be seen in up to 46% of patients with adrenal TB. Bilateral involvement is seen in nearly 70% of patients, however they may not be equally affected. Mean combined weight of adrenal gland ranges from 10-37 gm (mean 17 gm) (31). Caseous necrosis can be seen grossly within a large cavity or within multiple scattered tubercles.

 

Histopathologically, destruction of both the cortex and the medulla is seen with the following patterns of adrenal gland involvement (24):

1. Presence of granulomas, with or without necrosis. The granulomas show epithelioid cell collections with typical Langhan’s giant cells and an admixture of lymphocytes and plasma cells. Ziehl-Neelsen stain is very useful for detecting acid fast bacilli (AFB) within the necrotic areas, as well as within the granulomas.
2. Glandular enlargement with destruction of parenchyma by necrotizing granulomas.
3. Mass lesion secondary to formation of cold abscesses. In these cases, CT-guided fine needle aspiration cytology (FNAC) is helpful for demonstration of AFB, polymerase chain reaction (PCR), and culture for Mycobacterium tuberculosis In most cases, a combination of histopathology, PCR and culture may be required to confirm the diagnosis.
4. Adrenal atrophy secondary to fibrosis resulting from long-standing tuberculous infection (32).

 

DIFFERENTIAL DIAGNOSIS

 

The differential diagnosis for adrenal enlargement includes primary or metastatic tumors, lymphomas, fungal infections like cryptococcus and histoplasma, amyloidosis, sarcoidosis, hemangiomas and adrenal cortical hyperplasia (24, 28). Tissue sampling for microbiological (PCR and culture) and pathological analysis should adequately distinguish between them.

 

TREATMENT

 

Treatment for active adrenal TB is similar to the regimen followed for extrapulmonary TB with use of multidrug ATT. Rifampicin induces hepatic enzymes that increase the metabolism of glucocorticoids; hence higher doses of replacement glucocorticoids may be required. Rarely, Rifampicin may trigger an adrenal crisis.

 

In cases of chronic disease, adrenal gland function is unlikely to recover due to massive destruction of the gland (20, 28). However, a few authors report improvement in adrenal function when patients are given ATT early in the course of disease (33-35). This may be in part due to the remarkable regenerative capacity of the adrenal cortex to undergo hyperplasia and hypertrophy during active infection (20).

 

Hormone replacement for primary and secondary adrenal insufficiency related to TB follow the same principles as autoimmune or idiopathic primary AD or secondary adrenal insufficiency. In addition to appropriate glucocorticoid replacement mineralocorticoid replacement may be required. Care must be taken to educate patients about stress dosing and the need for parenteral steroids when the patient may not be able to take or absorb oral glucocorticoids. 

 

THYROID AND TUBERCULOSIS

 

The thyroid gland is an uncommon site for infection by M. tuberculosis. Thyroid TB (TTB) is therefore very rare, even in places with a high prevalence of TB. The primary presentation of TTB is as a mass or a goiter. Overt hormonal dysfunction is very uncommon in TTB. However, in patients with tuberculosis affecting any organ clinically insignificant abnormalities in thyroid function tests are very common. ATT also causes both structural and functional thyroid dysfunction. Pre-operative diagnosis of TTB can be made only with a high index of suspicion while evaluating thyroid nodules especially in communities with a high prevalence of TB (36).

 

Epidemiology

 

1. tuberculosis has been documented to be involved in the thyroid gland of 0.1 to 1% of patients who underwent thyroid tissue sampling for any indication (37-39). In an autopsy series of patients with advanced disseminated TB occurring in the pre- and post-antibiotic era, 14% had evidence of thyroid gland involvement (14). In a large cohort of 2,426 patients from Morocco, only eight had evidence of TB (0.32%). These were in the form of goiter or as a solitary thyroid nodule. In a study from India, thyroid involvement has been seen in 0.43% of specimens obtained from FNAC (40), while among Turkish patients undergoing thyroidectomy, 0.25 - 0.6% showed thyroid involvement by M. tuberculosis (41, 42).

 

Pathogenesis

 

Thyroid involvement in TB is very uncommon. A few postulated intrinsic properties of the thyroid which are proposed not to allow Mycobacterium tuberculosis bacilli to survive include (24, 36):

• Presence of iodine-containing colloid possessing bacteriostatic activity.
• High blood flow within the thyroid gland with the presence of intracellular iodine.
• Increased phagocytosis within the gland, seen in hyperthyroidism.
• Rich lymphatic supply to the thyroid.
• Thyroid hormones themselves exercise anti-TB roles.

 

TTB can be primary or secondary

1. Primary TTB is involvement of the thyroid gland alone, with no evidence of TB elsewhere in the body.
2. Secondary TTB is usually the result of hematogenous, lymphatic and/or direct spread from an active tubercular focus involving the cervical lymph nodes or larynx. Secondary TTB is much more commonly encountered than primary TTB, and TTB may go undiagnosed in many cases especially where clinical signs are non-specific (24).

 

Clinical Features

 

TTB occurs slightly more commonly in women as compared to men (M: F = 1:1.4) and occurs over a wide age range of 14 to 83 years, median age of 40 ± 16 years for men and 43 ± 17 years for women (36).

 

TTB can manifest as a localized swelling with cold abscess mimicking carcinoma, as multinodular goiter, as a solitary thyroid nodule without cystic component, or very rarely as an acute abscess. The various presentations are summarized in Figure 3. Rarely TTB may present as a goiter or a chronic fibrosing thyroiditis. Presence of cervical lymphadenopathy may raise suspicion of malignancy (36). Clinical presentation is often subacute, but may be acute in cases of abscess (43). Pain associated with swelling, thyroid tenderness, fever and localized extra-thyroidal findings such as dysphagia, dysphonia or recurrent laryngeal nerve palsy are less common in TTB as compared to patients with acute bacterial thyroiditis (24). However, some patients with TTB may present with pyrexia of unknown origin. Table 3 documents with differences in clinical presentation between TTB and bacterial thyroiditis.

 

Table 3. Clinical Features that Help Differentiate Between Tuberculous Thyroiditis and Bacterial Thyroiditis
Clinical Features	Tuberculous Thyroiditis	Bacterial Thyroiditis
Pain	-	+++
Pyrexia	+1	+++
Duration of illness (mean duration) (Ref;24)	105 days	18 days
Dysphagia	++	+++
Dysphonia	++	+++
Recurrent Laryngeal Nerve Palsy (Hoarseness)	++	+++
History of previous thyroid illness	-	+
Tenderness over the gland	-	+++
Leukocytosis	-	++
Elevated Erythrocyte Sedimentation Rate (ESR)	+++	+

1Rare reports of presentation as pyrexia of unknown origin

 

Most patients with TTB are euthyroid and do not have pre-existing thyroid disease. Very rarely TTB can be associated with hypothyroidism, with a period of subclinical hyperthyroidism preceding the hypothyroidism (44). Myxedema can occur in cases with extensive destruction of the thyroid gland by disseminated TB, which can also be fatal (45). Past history of TB may be elicited in some cases, and patients may have history of cervical lymphadenopathy (43).

 

Radiological and Laboratory Findings

 

Chest X-ray, ESR, and tuberculin skin test should be performed in all cases of suspected TTB. The diagnosis is made only after FNAC or histopathological examination of the surgical specimen when FNAC is negative (43). Sputum AFB may rarely assist in diagnosis in cases with associated pulmonary TB.

 

Ultrasonography usually shows a heterogenous, hypoechoic mass similar to a neoplastic nodule. Anechoic areas with internal echoes may be seen in abscesses. Contrast-enhanced CT scan can determine the location of the necrotic lesions (46).

 

On MRI the normal thyroid is homogenously hyperintense relative to the neck muscles on both T1 and T2-weighted images. TTB may show intermediate signal intensity due to granulomatous inflammation, however, this appearance is also seen in thyroid carcinoma. Abscesses appear hypointense on T1 and hyperintense on T2-weighted images, and may show peripheral rim of contrast enhancement (47).

 

Thyroid function tests (TFT) are usually normal in patients with TTB. Thyrotoxicosis in the initial stage of rapid release of thyroid hormone, and myxedema in the later stage of thyroid gland destruction have also been noted, and patients may have abnormal TFT accordingly (24). Only 5.2% of patients with TTB have abnormal TFT (36).

 

Pathology of Thyroid TB

 

In most cases, TTB can be diagnosed on FNAC which typically shows epithelioid cell granulomas with Langhan’s giant cells, peripheral lymphocytic infiltration and purulent caseous necrosis. The yield of AFB by the Zeihl Neelsen stain is more with FNAC samples than in biopsies. The aspirates can be sent for TB culture or PCR. TB-PCR is much more sensitive in detecting M. tuberculosis deoxyribonucleic acid (DNA) from FNA samples, and is an alternative to rapid diagnosis of TB in AFB-negative cases (40). The diagnosis is substantiated by histopathology which typically shows granulomas, Langhan’s giant cells and necrosis (Figure 4). Few cases show dense lymphocytic infiltrate with prominent germinal centers, resembling lymphocytic or Hashimoto thyroiditis (Figure 5).

Five pathological varieties of TTB have been described (36):

1. Multiple miliary lesions throughout the thyroid gland
2. Goiter with caseation necrosis
3. Cold abscess
4. Chronic fibrosing tuberculosis
5. Acute abscess

 

Differential Diagnosis

 

TTB, although rare, should be considered in the list of differentials for solitary or multinodular thyroid nodules, and abscesses (36). Reidel’s thyroiditis may mimic chronic fibrosing tuberculosis clinically, however histopathology clinches the diagnosis (42).

 

Treatment

 

ATT remains the cornerstone of treatment. Surgery has a limited role with drainage of abscess, avoiding total destruction of gland and subsequent hypothyroidism. However inadvertent total thyroidectomies are performed as the pre-operative diagnosis is commonly a malignancy. In cases were TB was diagnosed prior to surgery, ATT is well tolerated with resolution of symptoms, reduction in thyroid mass symptoms, and with favorable reversal of thyroid hormonal dysfunction. Standard ATT schedules are followed. Thyroid hormone levels should be monitored before, during, and after treatment. Despite strict ATT, recurrence and failure rate is 1% due to resistance to ATT drugs (48).

 

Functional and Structural Alterations of Thyroid Functions with Active Tuberculosis and with Anti-tubercular Therapy

 

Among hospitalized patients with TB without any evidence of involvement of the thyroid gland sick euthyroid syndrome with low free T3 is common. The estimates vary between 63-92% and probably is the commonest endocrinopathy seen in patients with TB (13,49). As with other unwell patients the degree of reduction in Free T3 serves both as a marker for severity of the disease and mortality. In the study by Chow et al, all patients who survived the hospitalization had normal TFT within one month of initiation of ATT. In community dwelling patients with TB, the prevalence of thyroid dysfunction is unclear.

 

Thyroid hormones are metabolized in the liver and the kidneys. In the liver, the enzyme CYP3A4 belonging to the hepatic cytochrome P450 family is responsible for the metabolism. Rifampicin is a potent activator of the P450 system and this leads to an increase in T4 turnover. In most adults with normal a hypothalmo-pituitary-thyroid axis this increase in turnover is compensated by an increase in the production of thyroid hormones and a slight increase in thyroid volume. This may be noted biochemically as a slight increase in free T3 and total T3 levels after rifampicin administration. There are no changes in free T4 and TSH concentrations (50). Among patients with pre-existing thyroid disease with a limited capacity to increase production of thyroid hormones, the rifampicin-mediated increase in free T4 turnover might lead to the need for an increase in thyroid hormone replacement therapy. In a retrospective cohort of patients on levothyroxine replacement therapy, the addition of rifampicin as part of ATT led to a need for a 26% increase in dose in patients on thyroid hormone replacement therapy and a 50% increase in patients on suppressive therapy post thyroidectomy for differentiated thyroid cancer (51).

 

Older anti-tubercular agents have more profound effects on thyroid physiology. Studies by Munkner et al demonstrated an association between the use of p-amino salicylic acid (PAS) and the development of goiter (52). PAS and ethionamide were also associated with significant risk of developing hypothyroidism (53, 54). However, these agents are currently not used as first line agents. It is prudent to monitor TFTs 6-8 weeks after initiation of any of these three agents in patients who have pre-existing thyroid dysfunction.

 

PITUITARY AND TUBERCULOSIS

 

Direct involvement of the pituitary gland by Mycobacterium Tuberculosis is very rare. Some of the earliest published reports of pituitary TB include von Rokitansky who noted tubercles in the hypophysis as early as 1844, Letchworth in 1924 who reported a case of primary pituitary tuberculoma on autopsy examination, and Coleman and Meredith documented a case of pituitary TB in 1940 (55, 56).

 

The spectrum of involvement (Figure 6) of the pituitary gland with TB includes sellar, parasellar, and stalk tuberculomas and sellar tubercular abscesses. Patients with tuberculous meningitis exhibit a range of functional pituitary dysfunction even in the absence of any evidence of direct invasion/extension of the disease into the sella. Among survivors of tubercular meningitis hypopituitarism was noted 10 years after the primary disease. Hypothalamic pituitary dysfunction such as isolated hypogonadotropic hypogonadism may accompany cachexia and weight loss that can complicate more extensive disease. Infiltrative tubercular disease of the stalk can produce pituitary interruption syndrome including isolated diabetes insipidus and hyperprolactinemia.

 

In most cases the diagnosis of tuberculosis of the pituitary is established on histopathology, often in the absence of confirmatory culture studies or positive acid-fast stains (57). Although the diagnosis is difficult on clinical and radiological examination, pituitary TB should be considered in the differential of a suprasellar mass especially in developing countries, as the condition is potentially curable with ATT (58, 59).

 

Sellar Tuberculoma/Abscess

 

EPIDEMIOLOGY  

 

The incidence of pituitary TB is very low. In an autopsy series of 3,533 cases, only 2 of 89 intracranial tuberculomas involved the sella turcica, while in another autopsy series of 14,160 cases, only 2 cases of TB were encountered involving the anterior pituitary lobe (50).  In patients with late generalized TB, the incidence of pituitary involvement is 4% (14). Nearly 70% of pituitary TB reported worldwide has been reported from the Indian subcontinent, probably attributable to the higher prevalence of TB in this location (60). In the largest series from India, 18 cases of sellar TB were diagnosed based on histopathology from 1148 pituitary surgeries (60).

 

PATHOGENESIS

 

Pituitary TB can arise either from hematogenous seeding, in the presence or absence of miliary disease, or from direct extension from the brain, meninges or sinuses. TB can either involve the pituitary gland alone, or involve the adjacent and/or distant organs as well (60). Both the adenohypophysis and neurohypophysis may be involved by TB. Supra-sellar extension is common in pituitary TB with only rare cases confined to the sella (57). 

 

CLINICAL FEATURES

 

Pituitary TB occurs at a mean age of 34.1 ± 13.6 years (age range 6 to 68 years), and is more common in women (F:M = 2.7:1). Young children are at high risk of progression of TB including CNS disease. Clinical presentation is often indolent. Duration of symptoms average 4 months (60, 61).

 

Pituitary involvement, either as a sellar abscess or tuberculoma presents primarily with symptoms of a sellar mass. The common presentations clinically are gradual onset of headache (85.2%), visual loss (48.1%) (Figure 7), seizures and cranial nerve palsies. Patients with infiltration of the stalk by tuberculomas may present with central diabetes insipidus with polyuria (8.6%) or menstrual abnormalities related to hyperprolactinemia like amenorrhea in women (37.3%) and galactorrhea (23.7%) (60, 61). Growth retardation and hypogonadism are rare findings in children with pituitary TB (61). Hyperphagia resulting in obesity or weight gain has also rarely been documented which may occur due to the loss of sensitivity of the appetite-regulating network in the hypothalamus to afferent peripheral humoral signals (62). Apoplexy, characterized by acute infarction and/or hemorrhage in the pituitary gland, is an uncommon presentation of pituitary TB (63). Systemic and constitutional symptoms may or may not be present; low grade fever may be seen in 14.8% of patients. Other organs may show evidence of TB in 26.9% (60, 64). Tuberculous meningitis may be associated in a few cases.

RADIOLOGICAL FINDINGS

 

The diagnosis of primary pituitary TB is challenging and often difficult. Radiologically pituitary TB can mimic pituitary adenoma, arachnoid cyst, pyogenic abscess, metastasis, or craniopharyngioma. MRI typically shows a sellar mass which may extend into the suprasellar region, involving the optic nerves and inter-carotid space (Figure 8). T1-weighted MR images appear isointense. T2-weighted images show central hyperintensity corresponding to caseous necrosis, and gadolinium contrast imaging may show thick ring enhancement in the periphery with central hypointense areas. Meningeal enhancement with enhancement of the thickened pituitary stalk may favor non-adenoma etiology. Additional findings like sellar/suprasellar calcification and sellar floor erosion have also been described (57, 63-65).

MR spectroscopy can detect elevated lipid peaks in a tuberculoma at 0.9, 1.3, 2.0 and 2.8 ppm, and a phosphoserine peak at 3.7 ppm. Lipid resonance at 0.9 and 1.3 ppm occur due to methylene and terminal methyl groups on fatty acids found in caseous necrosis (66)

 

LABORATORY FINDINGS

 

Panhypopituitarism may be encountered on evaluation of anterior pituitary hormones like thyroid stimulating hormone (TSH), early morning cortisol, growth hormone, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

 

Testing for HIV and immunocompromised states should be considered in the appropriate clinical setting. Positive tuberculin test and elevated ESR may be seen in patients with systemic involvement.

 

PATHOLOGY OF PITUITARY TUBERCULOSIS

 

The most common pattern of tuberculous involvement of the pituitary on histopathological examination is granulomas without caseation necrosis (59.6%) as show in Figure 9A. Granulomas may be miliary or may coalesce together to form a conglomerate mass. Reticulin stain helps demonstrate loss of normal reticulin pattern of the pituitary (Figure 9B). The granulomas are composed of epithelioid cells, Langhan’s giant cells, and lymphocytes (Figure 9C-D). Immunohistochemistry (IHC) with CD68 can help confirm the presence of epithelioid histiocytes in cases of unequivocal morphology, while CD3, CD20 and CD138 can highlight a mixture of T-lymphocytes, B-lymphocytes and plasma cells, respectively (Figure 10A-D). Pus and caseation necrosis are seen less commonly, and in these cases the yield of AFB is greater than with cases without necrosis. As with other sites, demonstration of AFB on biopsy material is very low. In such cases growth of M. Tuberculosis organisms on culture and TB PCR aid in diagnosis.

DIFFERENTIAL DIAGNOSIS

 

Sarcoidosis must be considered in the differential of non-caseating granulomatous hypophysitis, and shows naked granulomas without infiltrating lymphocytes. IgG4-related disease typically shows increase in plasma cells of the IgG4 subtype with storiform fibrosis. Histiocytic lesions like Langerhans cell histiocytosis (LCH) usually involve the infundibulum and typically show presence of Langerhans’s histiocytes with eosinophils. LCH is more common in children and young adults. Other inflammatory lesions involving the pituitary stalk are lymphocytic infundibuloneurohypophysitis (LINH), Wegener’s granulomatosis, and pituitary stalk parasitosis (67). Fungal granulomas involving the hypophyseal region can be ruled out by performing fungal stains on tissue sections (60).

 

TREATMENT

 

Transsphenoidal approach is preferred for surgery and is used for diagnosis and decompression of adjacent structures. Typical intra-operative findings are firm to hard, non-suckable greyish tissue with thickening of the dura. Pituitary TB can be managed conservatively if the diagnosis is confirmed with cerebrospinal fluid TB PCR and other tests.

ATT may be given for up to 18 months and patients should be on periodic follow up with assessment of hormonal profile. Lifelong replacement of hormones may be required in some patients (68). Recurrence of TB in lymph nodes despite completion of 18 months of ATT has been reported to occur due to resistance of M.tuberculosis bacilli to Rifampicin (69).

 

Pituitary Dysfunction in Patients with Tuberculous Meningitis (TBM)

 

In an Indian study of 75 patients with tuberculous meningitis, common pituitary functional abnormalities included hyperprolactinemia (49%), cortisol insufficiency (43%), central hypothyroidism (31%) and multiple hormone deficiencies (29%) (70). Prevalence of functional pituitary abnormalities seen in TBM in multiple studies from India is summarized in Table 4 (71, 72).  In addition, there may be hyponatremia.

 

Table 4. Pituitary Involvement in Patients with Tuberculous Meningitis
	Delhi (70)	Chandigarh (71)	Lucknow (72)
Number of patients	75	63	115
Any Involvement of Pituitary		84.2%	53.9%
Single Axis Involvement		39.8%	30.4%
More than one axis (Panhypopituitarism)	29.3%	44.4%	23.5%
Hypogonadotropic Hypogonadism	NR	38.1%	33.9%
Hyperprolactinemia	49.3%	49.2%	22.6%
Secondary Adrenal insufficiency	42.7%	42.9%	13%
Central hypothyroidism	30.7%	9.5%	17.4%
Isolated Growth hormone deficiency	NR	NR	7.8%
Syndrome of Inappropriate anti-diuresis	NR	NR	9.%
Diabetes Insipidus	Nil	Nil	Nil

NR- Not reported

 

Even among patients who survive tuberculous meningitis, pituitary dysfunction may persist. A study done by Lam in Hong Kong showed growth hormone deficiency to be the most common finding in patients younger than 21 years of age with tuberculous meningitis after 10 years of surviving tuberculous meningitis (73). 

 

WATER IMBALANCE AND TUBERCULOSIS

 

Hyponatremia has been commonly seen in patients admitted to the hospital with TB. Though data about the prevalence of hyponatremia among community treated patients with uncomplicated pulmonary TB is sparse, among inpatients admitted with TB, hyponatremia has been seen in 10-76% of patients (74-78). The commonest cause of hyponatremia is the SIAD. Other causes include untreated primary or secondary adrenal insufficiency, volume depletion, hyponatremia associated with volume excess, and hypoalbuminemia and rare cases of cerebral salt wasting seen with tuberculous meningitis (79) (Figure 11). Hypernatremia is rarely encountered and usually signifies involvement of the hypothalamus or the pituitary stalk leading to diabetes insipidus.

Syndrome of Inappropriate Antidiuresis (SIAD)

 

In the absence of adrenal deficiency, patients with non-CNS TB who are adequately hydrated (euvolemic) the hyponatremia is almost always a consequence of retention of free water despite low serum osmolality (inappropriate antidiuresis). Wiess and Katz first noted the association between active untreated TB and syndrome of inappropriate antidiuresis (SAID). In four patients with active TB and hyponatremia they noted excessive urinary sodium excretion. When these four patients were put on fluid restriction there was an improvement in the serum sodium levels. All patients who survived also had gradual normalization of serum sodium levels and SAID with treatment of TB (80).

 

Three different mechanisms have been proposed for the development of SIAD in patients with tuberculosis without evidence of adrenal involvement.

1. The first proposed mechanism in common with other pulmonary diseases is the stimulation of baroreceptors by chronic hypoxemia that can accompany extensive pulmonary TB. There is release of anti-diuretic hormone (ADH) in response to baroreceptor stimulation which leads on to SIAD (81).
2. The second possible mechanism proposed is a shift of the “osmostat” towards the left as seen in patients with decreased effective circulating volume leading to ADH release at lower serum osmolality. Investigators have noted higher circulating ADH levels in the serum despite hyponatremia which subsequently declined when free water was administered. The intact response to hypoosmolality suggested that the osmoregulation set up in the hypothalamus was functioning normally but at a lower osmolar threshold for ADH release (82).
3. The third mechanism proposed is the ectopic secretion of ADH by the tubercular granuloma. This mechanism was proposed by the authors of a case where a patient with well-established diabetes insipidus developed SIAD and hyponatremia after contracting pulmonary tuberculosis (83).

 

Patients with CNS TB have a higher prevalence of hyponatremia compared to those with pulmonary infections. In adult patients with TBM the prevalence of a low sodium state has varied from 45-65% in different studies (84-86). In children with TBM the prevalence varied from 38-71% in different studies (87-89). In children with TBM and hyponatremia there appears to be an association with mortality and increased intracranial pressures (87, 90). A recent review from India compiled data from over 11 studies comprising a total of 642 patients with TBM and found the prevalence of hyponatremia to be 44%. Unlike non-CNS TB the commonest etiology of hyponatremia among patients with CNS TB is cerebral salt wasting (CSW) rather than SIAD (36% vs 26%) (86). The other less common causes of hyponatremia encountered in TBM include the following

1. Dehydration and hypovolemic hyponatremia due to anorexia, vomiting, nausea and diarrhea
2. Drug induced including use of diuretics, osmotic agents like mannitol and anti-seizure medications like carbamazepine and phenytoin.
3. Secondary adrenal insufficiency and rarely primary adrenal insufficiency

 

CLINICAL PRESENTATION AND TREATMENT OF SIAD ASSOCIATED WITH TUBERCULOSIS        

 

Most patients with SIAD and TB are asymptomatic and do not require any treatment. The hyponatremia accompanying SIAD self corrects itself when ATT is started (82). Fluid restriction is only required in symptomatic patients or in patients with severe hyponatremia. Prior to restricting fluids in patients with non-CNS TB it is important to rule out dehydration either by assessing volume status clinically, assessing volume status with urine spot sodium levels, or measuring central venous pressures in unwell patients. In patients with CNS TB, it is important to rule out CSW prior to initiating fluid restriction. Hypertonic saline infusions are limited to patients with life threatening symptoms like seizures and deep coma attributable to hyponatremia (86). Care should be taken to correct hyponatremia at a rate not faster than 8-10 mEq/L in 24 hours to avoid central pontine myelinolysis.  

 

Cerebral Salt Wasting (CSW)

 

CSW refers to changes in renal salt handling that accompanies CNS disorders which leads to natriuresis and hypovolemia. The accompanying dehydration and decrease in effective circulating volume triggers ADH release via baroreceptors. The action of ADH on collecting tubules then leads to selective water resorption and relative water excess and hyponatremia despite overall hypovolemia. The putative renal natriuretic triggers include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide. In TBM the most likely natriuretic trigger is BNP (91). What induces BNP release in patients with TBM is less well characterized. The putative mechanisms that trigger BNP release include sympathoadrenal activation, increase in intracranial pressure, and vasospasm in cerebral arteries (92). In patients with CNS TB statistically CSW is more likely to be the cause of hyponatremia and should always be ruled out prior to labelling them as SIAD and starting fluid restriction. A simple diagnostic criterion proposed by Kalita et al (86) includes meeting all the 3 essential criteria and meeting at least 3 out of 5 additional supportive criteria to label the patient has having CSW. Table 5 lists the clinical and biochemical differences between SIAD and CSW.

 

Essential Criteria (meets all three)

1. Polyuria (>3 liters of urine in 24 hours over 2 days)
2. Documented hyponatremia
3. Exclusion of other cause of natriuresis like adrenal insufficiency, salt losing nephropathies, use of diuretics, hepatic and cardiac failure.

 

Additional criteria (meet 3 out of 5)

1. Clinical evidence of hypovolemia and dehydration
2. Documented negative fluid balance either by careful weight monitoring or by strict intake and output records
3. Urine spot Sodium > 40 mEq/L
4. Central Venous Pressure (CVP) < 6 cm of water
5. Laboratory evidence of dehydration including an increase in hemoglobin and hematocrit, increase in blood urea nitrogen and increase in albumin than previously.

 

Table 5. Differentiation Between Syndrome of Inappropriate Anti-Diuresis (SIAD) and Cerebral Salt Wasting (CSW)
Parameter	SIAD	CSW
Extracellular Volume	Increased	Decreased
Body Weight	Increased	Decreased
Fluid Balance	Positive	Negative
Tachycardia	-	+
Hypotension	-	+
Hematocrit/Albumin/Blood Urea Nitrogen	Normal	Increased
Central Venous Pressure	Normal or slightly high	Decreased

 

TREATMENT OF CSW ASSOCIATED WITH TBM

 

The primary treatment for CSW is fluid replacement with or without oral salt loading for as long as polyuria continues. Isotonic fluids are preferred for replacement. If the patient has a central venous line then the central venous pressure (CVP) measurements would guide the fluid replacements. In the absence of a CVP line fluid balance is needed by either meticulous intake and output charting or use of daily weight measurements.

 

In patient’s refractory to fluid replacement and oral salt loading, oral fludrocortisone (OFC) has been tried as there is an inhibition of the renin-angiotensin-aldosterone system (RAAS) system in CSW. A recent randomized control trial was conducted in 36 patients with CSW associated with TBM. Half of them received OFC (0.4-1mg/day) plus fluid and oral salt and the other half received only fluids and oral salt. The patients who received OFC in addition had quicker normalization of serum sodium levels (4 days vs 15 days; p 0.04) and lesser cerebral infarctions related to vasospasm (6% vs 33%; p 0.04). However, OFC use was associated with severe hypokalemia and significant hypertension in 2 patients each and in one patient there was an episode of pulmonary edema. OFC had to be withdrawn in 2/18 patients because of these serious adverse events. There was no difference in mortality or disability at 3 and 6 months among patients who received OFC vs the patients who did not (93).

 

CALCIUM ABNORMALITIES IN TUBERCULOSIS

 

Hypercalcemia in Patients with Tuberculosis

 

Hypercalcemia has been known to be associated with a number of granulomatous diseases. The three commonest granulomatous diseases causing hypercalcemia include sarcoidosis, TB, and fungal infection (94). The prevalence of hypercalcemia in patients with TB has ranged from 2-51% in studies done from South Africa (2%), Hong Kong (6%), India (10.6%), Sweden (25%), Malaysia (27.5%), Greece (25% & 48%) and Australia (51%) (13, 95-101). In contrast, prospective studies from the United Kingdom, Belgium, and Turkey did not show any hypercalcemia among patients with newly diagnosed tuberculosis (102-104). The primary determinant in the development of hypercalcemia among patients with TB appears to be their Vitamin D status and nutritional calcium intake. In populations with high nutritional calcium intake and adequate sunlight exposure like in Greece and Australia the prevalence of hypercalcemia is highest. Among countries with good sunlight exposure but poor nutritional calcium intake like most Asian countries there is a more modest prevalence of hypercalcemia. The countries with good nutritional calcium intake but poor sunlight exposure and low Vitamin D levels appear to have the lowest prevalence of hypercalcemia. This has been elegantly explained by Chan et al (105). However, some outliers like the higher prevalence in Sweden and moderate prevalence in India are not completely explained by this hypothesis alone.

 

In a recent paper looking at retrospective records of patients admitted with TB at a tertiary care hospital in Vellore almost 20% of patients were found to have albumin-adjusted hypercalcemia. The authors looked at the risk factors for hypercalcemia by comparing them with the patients without hypercalcemia assuming that background nutritional calcium intake and Vitamin D levels were similar. The primary risk factors for the development of hypercalcemia within this group was presence of renal dysfunction or frank renal failure, use of diuretics, disseminated tuberculosis, and presence of co-morbidities like diabetes and hypertension (106).

 

MECHANISM OF HYPERCALCEMIA WITH TUBERCULOSIS

 

The definitive mechanism that causes hypercalcemia among patients with TB is still unclear. Alternative etiologies for hypercalcemia including adrenal insufficiency, primary hyperparathyroidism, primary hyperthyroidism, milk alkali syndrome have been ruled out in many of the case series. Biochemically several investigators have shown an increase in the levels of 1,25-dihydroxy vitamin D along with low or normal levels of 25-hydroxy vitamin D levels. This suggests an increase in the conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D (107). This conversion is mediated by the enzyme 1-α-hydroxylase found in the kidney. However, hypercalcemia is even reported in patients with chronic renal failure and among those with absent kidneys (108, 109). This suggests a non-renal site of enzymatic activity. 

 

The tubercular granuloma is suggested as the site for the extra renal 1-α-hydroxylase activity (110). Activated macrophages can express 1-α-hydroxylase activity and in patients with active TB activated macrophages retrieved by broncho-alveolar lavage were able to synthesize 1,25 dihydroxy vitamin D in vitro studies (111). The macrophage production of 1-α-hydroxylase is probably important for the immune response to tuberculous infection. The binding of active Vitamin D (1,25-dihydroxy vitamin D) to Vitamin D receptors within the immune cells stimulates autophagy and production of cytokines that contribute to the clearance of the mycobacterium from the body (112, 113). In addition, active Vitamin D contributes to the downregulation of the inflammatory response of the body to reduce damage to bystander host tissues (114). The increased intestinal absorption of calcium and observed hypercalcemia may be an unintended consequence of this immune-protective phenomenon.

 

This also explains why patients with low levels of substrate (25-hydroxy vitamin D) for the enzyme or among those with poor calcium intake there is less likelihood of the development of hypercalcemia.

 

CLINICAL PRESENTATION

 

Most patients with hypercalcemia related to TB infection are asymptomatic. Rarely patients develop symptoms related to hypercalcemia including polyuria, anorexia, nausea, weakness and lethargy, more serious CNS symptoms like delirium.

 

Patients may develop hypercalcemia later in the course of TB after commencement of therapy with improvements in nutritional and albumin status and improvement in nutritional calcium intake. 

 

TREATMENT

 

A Cochrane review of Vitamin D supplementation in patients with TB did not show any benefits in terms of improved outcomes but there was also no increased risk of developing hypercalcemia (115). Most patients have gradual resolution of hypercalcemia on ATT over 1 to 7 months (96).

Hypocalcemia in Patients Treated with Rifampicin and Isoniazid

Hypocalcemia was noted for the first time in United Kingdom during a randomized control trial of anti-tubercular chemotherapy after several months of therapy. Fourteen out of the 325 patients on the trial developed hypocalcemia. In this trial none of the 325 patients was noted to have hypercalcemia. On the whole as a group the mean calcium levels dropped significantly during the course of the treatment trial. The mechanism is proposed to be the action of both Rifampicin and Isoniazid on vitamin D metabolism (102).

 

When isoniazid is given to normal subjects there is a brisk decline in the levels of active Vitamin D (1,25 dihydroxy vitamin D). There is slower decline in the levels of 25-hydroxy vitamin D accompanied by a compensatory increase in the levels of parathyroid hormones. In the same study isoniazid was shown to inhibit cytochrome p450 related hepatic mixed function oxidase and it is assumed that since the renal 1-α Hydroxylase is also related to cytochrome P450 system there would be decreased conversion of 25-hydroxy vitamin D to 1,25 dihydroxy vitamin D (116).

 

On the other hand, rifampicin is an inducer of hepatic hydroxylase which should in theory lead to an increase in active Vitamin D levels. However, when rifampicin was given to normal volunteers there was a fall in 25-hydroxy vitamin D levels with no changes to the levels of 1,25-dihydroxy vitamin D. The possible explanation for this decline is likely to be that the higher metabolic turnover of active Vitamin D induced by rifampicin is not compensated by an increase in dermal production or increased nutritional provision of vitamin D (117). Regardless, in treatment regimens that include both rifampicin and isoniazid there is a very real possibility of the development of not just hypocalcemia but unmasking of rickets and osteomalacia especially when the patient is poorly nourished.

CONCLUSIONS

 

TB can involve almost all endocrine glands as a primary disease-causing destruction and loss of function. In enclosed spaces like the pituitary fossa and neck the granuloma/tuberculoma/cold abscess can replace vital structures and cause symptoms related to a mass. This chapter did not cover direct tubercular involvement of the ovaries, testes, and the pancreas.

 

Additionally, a whole range of functional hormone abnormalities can accompany the effect on chronic inflammation on the immune-endocrine pathways. Metabolic derangement in calcium and water metabolism are covered in detail. Abnormalities in glucose metabolism are not covered because of the vast amount of information now available on the public health aspects of TB and diabetes mellitus.

 

Fortunately, most abnormalities are self-limited and resolve with successful ATT. However, one needs to consider the rare possibility of a hormonal emergency like an adrenal crisis, hypercalcemic emergency, or pituitary apoplexy in the context of TB.

 

REFERENCES

 

1. World Health Organization. Global Tuberculosis Report 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf (Accessed 28 Nov 2020)
2. Lyon SM, Rossman MD. Pulmonary tuberculosis. Microbiol Spectr (2017) 5:TNMI7–0032. doi: 10.1128/microbiolspec.TNMI7-0032-2016
3. Ndlovu H, Marakalala MJ. Granulomas and inflammation: host-directed therapies for tuberculosis. Front Immunol (2016) 7:434.
4. Besedovsky H, del Rey A. Immune-neuro-endocrine interactions: facts and hypothesis. Endocr Rev (1996) 17:64–95. doi:10.1210/edrv-17-1-64
5. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev (1999) 79:1–71
6. Straub RH, Schuld A, Mullington J, Haack M, Schölmerich J, Pollmächer T. The endotoxin-induced increase of cytokines is followed by an increase of cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects. J Endocrinol (2002) 175:467–74.
7. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NFκB activity through induction of IκB synthesis. Science (1995) 270:286–90.
8. Pandolfi J, Baz P, Fernández P, Discianni Lupi A, Payaslián F, Billordo LA, et al. Regulatory and effector T-cells are differentially modulated by dexamethasone. Clin Immunol (2013) 149:400–10.
9. van Lettow M, van der Meer JWM, West CE, van Crevel R, Semba RD. Interleukin-6 and human immunodeficiency virus load, nut not plasma leptin concentration, predict anorexia and wasting in adults with pulmonary tuberculosis in Malawi. J Clin Endocrinol Metab (2005) 90:4771–6.
10. Kellendonk C, Eiden S, Kretz O, Schütz G, Schmidt I, Tronche F, et al. Inactivation of the GR in the nervous system affects energy accumulation. Endocrinology (2002) 143:2333–40.
11. Plata-Salaman CR. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition (2000) 16:1009–12.
12. D’Attilio L, Santucci N, Bongiovanni B, Bay ML and Bottasso O (2018) Tuberculosis, the Disrupted Immune-Endocrine Response and the Potential Thymic Repercussion as a Contributing Factor to Disease Physiopathology. Front. Endocrinol. 9:214.
13. Post FA, Soule SG, Willcox PA, Levitt NS. The spectrum of endocrine dysfunction in active pulmonary tuberculosis. Clin Endocrinol (Oxf). 1994 Mar;40(3):367-71.
14. Slavin RE, Walsh TJ, Pollack AD. Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine (Baltimore). 1980 Sep;59(5):352-66.
15. Guttman P. Addison’s disease: A statistical analysis of 566 cases and a study of pathology. Arch Pathol 1930; 10:742-5.
16. Sanford JP, Favour CB. The interrelationships between Addison's disease and active tuberculosis: a review of 125 cases of Addison's disease. Ann Intern Med. 1956 Jul;45(1):56-72.
17. Betterle C, Morlin L. Autoimmune Addison’s Disease. Endocr Dev 2011; 20:171-72.
18. Agarwal G, Bhatia E, Pandey R, Jain SK. Clinical profile and prognosis of Addison's disease in India. Natl Med J India. 2001 Jan-Feb;14(1):23-5.
19. Soule S. Addison's disease in Africa--a teaching hospital experience. Clin Endocrinol (Oxf). 1999 Jan;50(1):115-20.
20. Roy A, Bhattacharjee R, Goswami S, Thukral A, Chitra S, Chakraborty PP, et al. Evolving adrenal insufficiency. Indian J Endocr Metab 2012;16:S367-70.
21. Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Med 1984;63:25-55.
22. Huang YC, Tang YL, Zhang XM, Zeng NL, Li R, Chen TW. Evaluation of primary adrenal insufficiency secondary to tuberculous adrenalitis with computed tomography and magnetic resonance imaging: Current status. World J Radiol 2015;28:336-42.
23. Maitra A. The endocrine system. In: Kumar V, Abbas AK, Aster AC, editors. Robbins and Cotran Pathologic Basis of Disease. Philadelphia; Elsevier. 9th edition. 2015. P. 1073-139.
24. Vinnard C, Blumberg EA. Endocrine and metabolic aspects of tuberculosis. Microbiol Spectr 2017;5:1-19.
25. Chhangani NP, Sharma P. Addison’s disease. Indian Ped 2003; 40:904-5.
26. Sharma S, Joshi R, Kalelkar R, Agrawal P. Tuberculous adrenal abscess presenting as adrenal insufficiency in a 4-year-old boy. J Tropical Ped 2018;0:1-4.
27. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015:3;216-26.
28. Herndon J, Nadeau AM, Davidge-Pitts CJ, Young WF, Bancos I. Primary adrenal insufficiency due to bilateral infiltrative disease. Endocrine 2018;62:721-8.
29. Erichsen MM, Lovas K, Skinningsrud B, Wolff AB, Undlien DE, Svatberg J, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab 2009;94:4882-4890.
30. Nair A, Jayakumari C, George GS, Jabbar PK, Das DV, Jessy SJ, Aneesh TS. Long acting porcine sequence ACTH in the diagnosis of adrenal insufficiency. Eur J Endocrinol. 2019 Dec;181(6):639-645.
31. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol 2001;54:633-9.
32. Friedman F. The pathology of the adrenal gland in Addison’s disease with special reference to adrenocortical contraction. J name to be found 1948;42:181-200.
33. Annear TD, Baker GP. Tuberculous Addison’s disease. A case apparently cured by chemotherapy. Lancet 1961;2:577-8.
34. Penrice J, Nussey SS. Recovery of adrenocortical function following treatment of tuberculous Addison’s disease. Postgrad Med J 1992;68:204-5.
35. Kelestimur F. Recovery of adrenocortical function following treatment of tuberculous Addison’s disease. Postgrad Med J 1993;69:832-4.
36. Bulbuloglu E, Ciralik H, Okur E, Ozdemir G, Ezberci F, Cetinkaya A. Tuberculosis of the thyroid gland: review of the literature. World J Surg 2006;30:149-55.
37. Rankin FW, Graham AS. Tuberculosis of the thyroid gland. Ann Surg 1932;94:625-48.
38. Das DK, Pant CS, Chachra KL, Gupta AK. Fine needle aspiration cytology diagnosis of tuberculous thyroiditis. A report of eight cases. Acta Cytol 1992;36:517-22.
39. Mondal A, Patra DK. Efficacy of fine needle aspiration cytology in the diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otol 1995;109:36-8.
40. Gupta N, Sharma K, Barwad A, Sharma M, Rajwanshi A, Dutta P, et al. Thyroid tuberculosis – role of PCR in diagnosis of a rare entity. Cytopathol 2011;22:392-6.
41. Ozekinci S, Mizrak B, Saruhan G, Senturk S. Histopathologic diagnosis of thyroid tuberculosis. Thyroid 2009;19:983-6.
42. Akbulut S, Sogutcu N, Arikanoglu Z, Bakir S, Ulku A, Yagmur Y. Thyroid tuberculosis in Southeastern Turkey: is this the resurgence of a stubborn disease? World J Surg 2011;35:1847-52.
43. Majid U, Islam N. Thyroid tuberculosis: a case series and a review of the literature. J Thyroid Res 2011;vol?:1-4. doi:10.4061/2011/359864
44. Luiz HV, Pereira BD, Silva TN, Veloza A, Matos A, Matos C, et al. Thyroid tuberculosis with abnormal thyroid function – case report and review of the literature. Endocr Pract 2013;19:e44-e49.
45. Barnes P, Weatherstone R. Tuberculosis of the thyroid: two case reports. Br J Dis Chest 1979;73:187-91.
46. Kang BC, Lee SW, Shim SS, Choi HY, Baek SY, Cheon YJ. US and CT findings of tuberculosis of the thyroid: three case reports. Clin Imaging 2000;24:283-6.
47. Madhusudhan KS, Seith A, Khadgawat R, Das P, Mathur S. Tuberculosis of the thyroid gland: magnetic resonance imaging appearances. Singapore Med J 2009;50:e235-e238.
48. El Malki HO, El Absi M, Mohsine R…. Tuberculosis of the thyroid. Diagnosis and treatment. Ann Chir 2002;127:385-7.
49. Chow CC, Mak TW, Chan CH, Cockram CS. 1995. Euthyroid sick syndrome in pulmonary tuberculosis before and after treatment. Ann Clin Biochem 32:385–391.
50. Christensen HR, Simonsen K, Hegedus L, Hansen BM, Dossing M, Kampmamn JP, et al. Influence of rifampicin on thyroid gland volume, thyroid hormones, and antipyrine metabolism. Acta Endocrinol (Copenh). 1989; 121: 406–410.
51. Kim HI, Kim TH, Kim H, Kim YN, Jang HW, Chung JH, et al. (2017) Effect of Rifampin on Thyroid Function Test in Patients on Levothyroxine Medication. PLoS ONE 12(1): e0169775
52. Munkner T. Studies on goiter due to para-aminosalicylic acid. Scand J Respir Dis. 1969;50(3):212-26.
53. Chhabra N, Gupta N, Aseri M L, Mathur SK, Dixit R. Analysis of thyroid function tests in patients of multidrug resistance tuberculosis undergoing treatment. J Pharmacol Pharmacother 2011;2:282-5
54. Munivenkatappa S, Anil S, Naik B, et al. Drug-Induced Hypothyroidism during Anti-Tuberculosis Treatment of Multidrug-Resistant Tuberculosis: Notes from the Field. Journal of Tuberculosis Research. 2016 Sep;4(3):105-110.
55. Letchworth TW. Tuberculoma of the pituitary body. Br Med J 1924;1127.
56. Kirshbaum JD, Levy HA. Tuberculoma of hypophysis with insufficiency of anterior lobe: a clinical and pathological study of two cases. Arch Intern Med 1941;68:1095-104.
57. Ben Abid F, Abukhattab M, Karim H, Agab M, Al-Bozom I, Ibrahim WH. Primary pituitary tuberculosis revisited. Am J Case Rep 2017;18:391-4.
58. Sunil K, Menon R, Goel N, Sanghvi D, Bandgar T, Joshi SR, et al. Pituitary tuberculosis. J Assoc Physicians India 2007;55:453-6.
59. Dutta P, Bhansali A, Singh P, Bhat MH. Suprasellar tubercular abscess presenting as panhypopituitarism: a common lesion in an uncommon site with a brief review of literature. Pituitary 2006;6:73-7.
60. Sharma MC, Arora R, Mahapatra AK, Sarat-Chandra P, Gaikwad SB, Sarkar C. Intrasellar tuberculoma – an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 2000;102:72-7.
61. Cellen S, Whittaker E, Eisenhut M, Grandjean L. Cerebral tuberculomas in a 6-year-old girl causing central diabetes insipidus. BMJ Case Rep 2018. DOI: 10.1136/bcr-2018-226590.
62. Dayal D, Muthuvel B, Sodhi KS. Obesity as the presenting feature of sellar-suprasellar tuberculoma. Indian J Endocr Metab 2018;22:176-7.
63. Srisukh S, Tanpaibule T, Kiertiburanakul S, Boongird A, Wattanatranon D, Panyaping T, et al. Pituitary tuberculoma: a consideration in the differential diagnosis in a patient manifesting with pituitary apoplexy-like syndrome. ID Cases 2016;5:63-6.
64. Roka YB, Roka N, Pandey SR. Primary pituitary tubercular abscess: a case report. J Nepal Med Assoc 2019;57:206-8.
65. Mittal P, Dua S, Saggar K, Gupta K. Magnetic resonance findings in sellar and suprasellar tuberculoma with hemorrhage. Surg Neurol Int 2010;1:73.
66. Saini KS, Patel AL, Shaikh WA, Magar LN, Pungaonkar SA. Magnetic resonance spectroscopy in pituitary tuberculoma. Singap Med J 2007;48:783-6.
67. Doknic M, Miljic D, Pekic S, Stojanovic M, Savic D, Manojlovic-Gacic E, et al. Single center study of 53 consecutive patients with pituitary stalk lesions. Pituitary 2018. DOI: 10.1007/s11102-018-0914-2.
68. Agrawal VM, Giri PJ. Tuberculosis: a common infection with rare presentation, isolated sellar tuberculoma with panhypopituitarism. J Neurosci Rural Pract 2019;10:327-30.
69. Antony G, Dasgupta R, Chacko G, Thomas N. Pituitary tuberculoma with subsequent drug-resistant tuberculous lymphadenopathy: an uncommon presentation of a common disease. BMJ Case Rep 2017.
70. Dhanwal DK, Vyas A, Sharma A, Saxena A. Hypothalamic pituitary abnormalities in tubercular meningitis at the time of diagnosis. Pituitary 2010;13:304-10.
71. Mohammed H, Goyal MK, Dutta P, Sharma K, Modi M, et al. Hypothalamic and pituitary dysfunction is common in tubercular meningitis: A prospective study from a tertiary care center in Northern India. J Neurol Sci. 2018 Dec 15;395:153-158.
72. More A, Verma R, Garg RK et al. A study of neuroendocrine dysfunction in patients of tuberculous meningitis. J Neurol Sci. 2017 Aug 15;379:198-206.
73. Lam KS, Shamm MM, Tam SC, Ng MM, Ma HT. Hypopituitarism after tuberculous meningitis in childhood. Ann Intern Med1993; 118:701-6.
74. Chung DK, Hubbard WW. 1969. Hyponatremia in untreated active pulmonary tuberculosis. Am Rev Respir Dis 99:595–597.
75. Morris CD, Bird AR, Nell H. 1989. The haematological and biochemical changes in severe pulmonary tuberculosis. Q J Med 73:1151–1159
76. Jonaidi Jafari N, Izadi M, Sarrafzadeh F, Heidari A, Ranjbar R, Saburi A. 2013. Hyponatremia due to pulmonary tuberculosis: review of 200 cases. Nephrourol Mon 5:687–691
77. Dash M, Sen RK, Behera BP, Sahu SS. Prevalence of hyponatremia in pulmonary tuberculosis. Int J Adv Med 2020;7:63-6.
78. Khan K, Rasool N, Mustafa F, Tariq R. Hyponatremia Due to Pulmonary Tuberculosis in Indian Population. Int J Sci Stud 2017;5(5):98-101.
79. Chaya BE, Rajesh KN, Mohan K, Mahesh DM. Hyponatremia in tuberculosis: Focus on brain instead of adrenals. Neurol India 2018;66:1515-6.
80. Weiss H, Katz S. Hyponatremia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1965 Oct;92(4):609-16.
81. Anderson RJ, Pluss RG, Berns AS, Jackson JT, Arnold PE, Schrier RW, McDonald KE. 1978. Mechanism of effect of hypoxia on renal water excretion. J Clin Invest 62:769–777.
82. Hill AR, Uribarri J, Mann J, Berl T. 1990. Altered water metabolism in tuberculosis: role of vasopressin. Am J Med 88:357–364.
83. Lee P, Ho KK. 2010. Hyponatremia in pulmonary TB: evidence of ectopic antidiuretic hormone production. Chest 137:207–208.
84. Roca B, Tornador N, Tornador E. 2008. Presentation and outcome of tuberculous meningitis in adults in the province of Castellon, Spain: a retrospective study. Epidemiol Infect 136:1455–1462.
85. Misra UK, Kalita J, Bhoi SK, Singh RK. A study of hyponatremia in tuberculous meningitis. J Neurol Sci. 2016 Aug 15; 367:152-7.
86. Misra UK, Kalita J and Tuberculous Meningitis International Research Consortium. Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis [version 1; peer review: 2 approved] Wellcome Open Research 2019, 4:189 https://doi.org/10.12688/wellcomeopenres.15502.1 (accessed November 2020)
87. Cotton MF, Donald PR, Schoeman JF, Aalbers C, Van Zyl LE, Lombard C. 1991. Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in tuberculous meningitis. Pediatr Infect Dis J 10:837–842.
88. Inamdar P, Masavkar S, Shanbag P. Hyponatremia in children with tuberculous meningitis: A hospital-based cohort study. J Pediatr Neurosci. 2016;11(3):182-187.
89. Singh BS, Patwari AK, Deb M: Serum sodium and osmolal changes in tuberculous meningitis. Indian Pediatr. 1994; 31(11): 1345–50.
90. Cotton MF, Donald PR, Schoeman JF, Van Zyl LE, Aalbers C, Lombard CJ. 1993. Raised intracranial pressure, the syndrome of inappropriate antidiuretic hormone secretion, and arginine vasopressin in tuberculous meningitis. Childs Nerv Syst 9:10–15.
91. Berendes E, Walter M, Cullen P, et al.: Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet. 1997; 349(9047): 245–59.
92. Lenhard T, Külkens S, Schwab S: Cerebral salt-wasting syndrome in a patient with neuroleptic malignant syndrome. Arch Neurol. 2007; 64(1): 122–25
93. Misra UK, Kalita J, Kumar M: Safety and Efficacy of Fludrocortisone in theTreatment of Cerebral Salt Wasting in Patients with Tuberculous Meningitis: A Randomized Clinical Trial. JAMA Neurol. 2018; 75(11): 1383–91.
94. Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab. 2005 Nov;90(11):6316-22.
95. Shek CC, Natkunam A, Tsang V, Cockram CS, Swaminathan R. Incidence, causes and mechanism of hypercalcaemia in a hospital population in Hong Kong. Q J Med. 1990 Dec;77(284):1277-85.
96. Sharma SC. Serum calcium in pulmonary tuberculosis. Postgrad Med J. 1981 Nov;57(673):694-6.
97. Lind L, Ljunghall S. Hypercalcemia in pulmonary tuberculosis. Ups J Med Sci. 1990;95(2):157-60
98. Liam CK, Lim KH, Srinivas P, Poi PJ. Hypercalcaemia in patients with newly diagnosed tuberculosis in Malaysia. Int J Tuberc Lung Dis. 1998 Oct;2(10):818-23.
99. Kitrou MP, Phytou-Pallikari A, Tzannes SE, Virvidakis K, Mountokalakis TD. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med. 1982 Feb;96(2):255.
100. Roussos A, Lagogianni I, Gonis A, Ilias I, Kazi D, Patsopoulos D, Philippou N. Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respir Med. 2001 Mar;95(3):187-90.
101. Need AG, Phillips PJ, Chiu F, Prisk H. Hypercalcaemia associated with tuberculosis. Br Med J. 1980 Mar 22;280(6217):831.
102. A controlled trial of six months chemotherapy in pulmonary tuberculosis. First Report: results during chemotherapy. British Thoracic Association. Br J Dis Chest. 1981 Apr;75(2):141-53.
103. Keleştimur F, Güven M, Ozesmi M, Paşaoğlu H. Does tuberculosis really cause hypercalcemia? J Endocrinol Invest. 1996 Nov;19(10):678-81.
104. Fuss M, Karmali R, Pepersack T, Bergans A, Dierckx P, Prigogine T, Bergmann P, Corvilain J. Are tuberculous patients at a great risk from hypercalcemia? Q J Med. 1988 Nov;69(259):869-78.
105. Chan TY. Differences in vitamin D status and calcium intake: possible explanations for the regional variations in the prevalence of hypercalcemia in tuberculosis. Calcif Tissue Int. 1997 Jan;60(1):91-3.
106. John SM, Sagar S, Aparna JK, Joy S, Mishra AK. Risk factors for hypercalcemia in patients with tuberculosis. Int J Mycobacteriol 2020;9:7-11
107. Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med. 1979 Mar;90(3):324-8.
108. Felsenfeld AJ, Drezner MK, Llach F. Hypercalcemia and elevated calcitriol in a maintenance dialysis patient with tuberculosis. Arch Intern Med. 1986 Oct;146(10):1941-5.
109. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med. 1984 Dec 27;311(26):1683-5.
110. Isaacs RD, Nicholson GI, Holdaway IM. Miliary tuberculosis with hypercalcaemia and raised vitamin D concentrations. Thorax. 1987 Jul;42(7):555-6.
111. Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25(OH)2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest. 1990 May;85(5):1588-93.
112. Facchini L, Venturini E, Galli L, de Martino M, Chiappini E. 2015. Vitamin D and tuberculosis: a review on a hot topic. J Chemother 27:128–138.
113. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV,Kwiatkowski D. 1998. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage like cell line. Infect Immun 66:5314–5321.
114. Coussens AK, Wilkinson RJ, Hanifa Y, et al. 2012. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci U S A 109: 15449–15454.
115. Sinclair D, Abba K, Grobler L, Sudarsanam TD. Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD006086.
116. Brodie MJ, Boobis AR, Hillyard CJ, et al: Effect of Isoniazid on vitamin D metabolism and hepatic monooxygenase activity. Clin Pharmacol Ther 1981; 30:363-370.

Brodie MJ, Boobis AR, Dollery CT, et al: Rifampicin and vitamin D metabolism. Clin Pharmacol Ther 1980; 27:810-814.

ABSTRACT

 

Protozoa are parasitic organisms that are among the most important pathogens worldwide. They are classified into four groups and in infected persons, the disease process may be asymptomatic. Of the four groups, Flagellates and Sporozoa are implicated in the causation of endocrine dysfunction and metabolic abnormalities. The disease condition caused by the flagellates include Giardiasis, Leishmaniasis, and Trypanosomiasis and all cause endocrine abnormalities that range from growth retardation, hypogonadism, adrenal insufficiency, thyroid dysfunction which is largely a resultant effect of the sick euthyroid syndrome, and the syndrome of inappropriate ADH secretion. The Sporozoan disease that notably give rise to metabolic abnormalities is malaria especially severe malaria which is commonly caused by P Falciparum infection. Hypoglycemia is one of the defining criteria for severe malaria and in Africa where malaria is endemic the reported prevalence rate of hypoglycemia in children is as high as 60%. Other abnormalities which are infrequently reported requiring treatment albeit temporarily are hyperglycemia, hypocalcemia, and diabetes insipidus. Adrenal insufficiency when is present is a poor prognostic factor in severe malaria. Toxoplasmosis is acquired or vertically transmitted and may present with neuroendocrine manifestations and adrenal insufficiency resulting from infiltration of the affected endocrine organs with the parasites.

 

PROTOZOA

 

A parasite is an organism that lives on or in a host organism and gets its food from or at the expense of its host. The three main classes of parasites that can cause disease in humans include helminths, protozoa, and ectoparasites.

 

Protozoa are microscopic, one-celled organisms that can be free-living or parasitic in nature. Their ability to multiply in humans contributes to their survival and also permits serious infections to develop from just a single organism. Transmission of protozoa that live in a human’s intestine to another human typically occurs through a fecal-oral route and for those that live in the blood or tissue of human’s transmission to other humans is via an arthropod vector (1). Protozoa that are infectious to humans are classified into four groups based on their mode of movement;

 

Mastigophora – the flagellates, e.g., Giardia, Leishmania, Trypanosoma

Sporozoa – organisms whose adult stage is not motile e.g., Plasmodium, Cryptosporidium, Toxoplasma gondii,

Ciliophora – the ciliates, e.g., Balantidium

Sarcodina – the ameba, e.g., Entamoeba

 

MASTIGOPHORA  

 

Mastigophora is a phylum of protozoans of the Kingdom Protista, consisting mainly of free-living flagellated unicellular organisms that reproduce by binary fission and whose habitat includes fresh and marine waters. Leishmania and Trypanosoma live in the blood, lymph, and tissue spaces and are typically transmitted from one host to another by blood feeding arthropods.

 

Giardiasis 

 

This is a diarrheal illness that is caused by Giardia (also known as Giardia intestinalis, Giardia lamblia, or Giardia duodenalis). It is a microscopic parasite and is the most common cause of protozoa associated diarrhea worldwide. The prevalence rate of Giardiasis is higher in developing countries than in the developed countries of the world with Giardia species being endemic in areas of the world that have poor sanitation and high-risk groups including immunocompromised individuals (2-3).

 

MODE OF TRANSMISSION

 

The parasite is found on surfaces or in soil, food, or water that has been contaminated with feces from infected humans or animals. Infection is transmitted commonly through ingestion of infectious G lamblia cysts. In the intestine, excystation occurs and trophozoites are released into the feces. A summary of the transmission of the parasite is shown in Figure 1.

Giardia infrequently is transmitted sexually specifically through oral-anal practices. The incubation period is 3-35 days but 7-10 days on the average.

CLINICAL PRESENTATION

 

The clinical manifestations include acute or chronic diarrheal disease, but the infection may be asymptomatic even in children. In a Nigeria Study (3) that evaluated stool samples of children aged between 0-5 years, about half-(41%) were positive for G. lamblia. The extraintestinal manifestations of Giardiasis include allergic presentations resulting from immune system activation, and long-term consequences such as ocular pathologies, arthritis, allergies, growth failure, muscular, and metabolic complications (4-5).

 

ENDOCRINE AND METABOLIC ABNORMALITIES

 

The complications relating to endocrine and metabolic dysfunction include growth failure and hypothyroidism. The Nigerian Report described above showed a positive association between asymptomatic giardiasis and malnutrition. The relation between Giardiasis and growth failure is explained mainly by malabsorption leading to protein energy malnutrition and micronutrient deficiencies. Other than nutritional status, other contributory factors to growth stunting in children include sanitary and socio-economic conditions, loss of intestinal surface area, and maldigestion (4-5).

 

Giardia infection has no direct effect or impact on thyroid function but has been reported to indirectly affect thyroid status. Worsening of hypothyroidism related to malabsorption of levothyroxine tablets occasioned by the presence of Giardia infection has been documented in the literature (6-7).

 

DIAGNOSIS AND MANAGEMENT

 

The diagnosis is made by demonstration of cysts or trophozoites in stool samples. Other means of diagnosis include small bowel biopsy and stool ELISA. The mainstay of treatment is metronidazole. Patients with stunted growth often experience catch- up growth following treatment of giardiasis.

 

Leishmaniasis  

 

Leishmaniasis is a poverty related protozoal disease caused by the Leishmania donovani complex. There are 3 main forms of leishmaniases – visceral (also known as kala-azar, the most serious form of the disease), cutaneous (the most common), and mucocutaneous. The clinical spectrum of leishmaniasis ranges from a self-resolving cutaneous ulcer to a mutilating mucocutaneous disease and even to a lethal systemic illness. In Nigeria cutaneous leishmaniasis is the commonly occurring type and has been noted to occur in Northern Nigeria especially in areas bordering the Niger Republic.

 

Types of Leishmaniasis

MODE OF TRANSMISSION

 

Leishmania spp. is a parasite with a dimorphic life cycle that is controlled by the passage from vector to host .All three forms of Leishmaniasis are transmitted by the bite of infected female sand fly. The vector phase of the life cycle begins when the vector ingests blood containing the parasites with the parasites undergoing differentiation and ultimately becoming promastigotes and pass into the proboscis where where they can inoculate the host during feeding of the vector (8). These human and vector stages of Leishmania are shown in Figure 2. Infiltration of the reticuloendothelial system by amastigotes leads to the biochemical and clinical features of the disease.

 

Vertical transmission of visceral leishmaniasis may occur during pregnancy while cutaneous leishmaniasis may be transmitted through physical contact. Transmission via contaminated needles, blood transfusion, sexual intercourse and vertical transmission are modes of transmission that are documented albeit infrequently (8).

CLINICAL PRESENTATION

 

Visceral Leishmaniasis (VL) may present with fever, malnutrition, weight loss , hepatosplenomegaly and death if treatment is delayed or sub-optimal. Cutaneous Leishmaniasis presents with skin ulceration and nodules and the Mucocutaneous form of Leishmaniasis with skin and mucous involvement.

 

ENDOCRINE AND METABOLIC ABNORMALITIES

 

Evidence of involvement of several endocrine organs- pituitary, adrenal, thyroid, and sex glands- via histopathologic studies have been documented in VL (9). However abnormal endocrine function tests in some instances without clinical manifestations have been documented.

 

Reports from Africa and Europe show that thyroid function may be affected in VL but the abnormalities detected are most likely a result of euthyroid sick syndrome (ESS) or non-thyroidal illness (NTI) with no clinical presentation of thyroid disease (10-12). VL has been reported to present with primary adrenal insufficiency in with clinically overt features and in some cases biochemical evidence without clinical features may occur. Primary adrenal insufficiency (AI) was reported in VL in a patient without HIV infection and a patient with concomitant HIV infection and was attributable to parasitic infiltration of the organ (13-14). A Brazilian Series reported a prevalence rate of AI to be about 50% in persons with VL (12). In the Brazilian Report (12) that compared hormonal parameters between persons with chronic leishmaniasis and control subjects, the following were noted in some of the subjects with leishmaniasis; a) features of pituitary dysfunction characterized by low TSH, low T4, and low T3 levels (ESS/NTI), b) elevated ACTH with normal cortisol levels, c) high FSH, LH, and low testosterone levels. Other endocrine abnormalities include low parathyroid hormone (PTH) and decreased total and ionized calcium levels.

 

An unusual presentation of VL is adrenal cysts which has been reported to come to clinical attention because of the mass effect (15-16). The Syndrome of inappropriate ADH secretion (SIADH) is often reported in VL with hyponatremia documented as a significant contributory factor to mortality of the disease (17). The endocrine and metabolic abnormalities of Leishmaniasis and potential mechanisms underlying their occurrence are shown in Table 1. 

 

Table 1. Endocrine and Metabolic Dysfunction in Visceral Leishmaniasis
Endocrine Gland	Hormonal Status	The Level of Abnormality	Underlying Mechanism	Presentations
Thyroid Gland	Low TSH, Low T3, Low T4   High TSH, Low T4, Low T3	Hypothalamic/Pituitary Axis	ESS/NTI Malnutrition in VL may lead to suppressed TSH and subsequent low TH production. Parasitism of the pituitary gland.	No clinical features of thyroid disease
	Low T4, High TSH	Primary hypothyroidism /Thyroid gland	Primary thyroid insufficiency due to the infiltration of the thyroid gland causing thyroiditis
Adrenal Gland	Low Cortisol, High ACTH	Primary adrenal insufficiency	Parasitic Infiltration of the adrenal cortex	Mucosal pigmentation, chronic diarrhea, weight loss
	High ACTH, Normal Cortisol	Primary adrenal insufficiency	Parasitic Infiltration of the adrenal cortex	These patients have normal cortisol levels but were unable to mount an adequate response to stress
	High ACTH, high cortisol	Hypothalamus, Pituitary	Stress Response
Parathyroid gland	Low PTH, Hypocalcemia	Renal (interstitial nephritis) and GIT	Hypomagnesaemia resulting from increased renal loss. GIT loss from possible malabsorption and frequent diarrhea.
Posterior pituitary gland	Syndrome of inappropriate ADH secretion (SIADH)	Hypothalamo-Pituitary Axis	Volume depletion from vomiting leading to increased serum osmolality and resultant Vasopressin release from the PPG. Intense inflammatory response from multiple organ involvement leads to activation of HPA axis and Vasopressin release.	Hyponatremia, elevated urinary osmolality and reduced serum osmolality
Gonads	High FSH, High LH and low testosterone	Primary hypogonadism	Parasitism of the testes, reduced testicular size with fewer Sertoli and Leydig cells. Malnutrition may be contributory to the low testosterone level	Delayed Puberty Erectile dysfunction

 

DIAGNOSIS AND TREATMENT

 

A combination of clinical symptoms and laboratory parameters clinches the diagnosis. The laboratory tests involve the detection of the parasites in samples taken from the base of the ulcer and dermal scrapings- Wright ‘s stain detects round or ovoid parasite in the cytoplasm of macrophages.

 

Polymerase chain reaction for detection of the parasite in peripheral blood and bone marrow samples IS diagnostic. Other tests to support the diagnosis is the Leishman test, which essentially refers to observation of a delayed tuberculin type of reaction following an Intradermal injection of leishmanial antigen.

 

The mainstay of treatment is the pentavalent antimony compounds. Other pharmacotherapies include amphotericin B, oral miltefosine, pentamidine, and antibiotics. Treatment is individualized, thus persons with associated endocrine/metabolic dysfunction are treated on a case-by-case basis.

 

Trypanosomiasis  

 

This is an anthropozoonosis caused by a protozoan hemoflagellate. Trypanosoma cruzi in American trypanosomiasis, also known as Chagas disease, is transmitted to human host by a tick. Human African trypanosomiasis (HAT) also known as sleeping sickness is caused by Trypanosoma brucei gambiense in West and Central Africa andTrypanosoma brucei rhodosiense in East Africa is transmitted to human hosts by bites of infected tsetse flies.

MODE OF TRANSMISSION

 

In HAT the tsesefly (glossina specie) injects metacyclic trypomastogotes into the skin and these pass into the blood stream and are subsequently carried to other parts of the body and body fluids. The tsetsefly becomes infected when it bites an infected person. Trypanosoma brucei gambiense may also be acquired congenitally from an infected mother.

 

Chagas disease is transmitted by a group of blood-feeding insects known as kissing bugs or triatomid bugs. The pathogen normally circulates between bugs and wild animals in sylvatic habitats; infected bugs in domestic habitats can transmit Chagas to humans and domestic animals (dogs, guinea pigs). Details of the life cycle and transmission of the pathogen is shown in Figure 4.

CLINICAL PRESENTATION

 

Trypanosomiasis may cause acute illness but on the other hand the infection may be asymptomatic. Chagas disease (CD) presents in three phases: acute, indeterminate, and chronic. The acute phase occurs immediately following infection and is usually asymptomatic in most people but when symptomatic, presentation is essentially those of malaise and skin lesions. The indeterminate phase is usually asymptomatic but may progress to a chronic phase where organ systems mainly the heart and sometimes the gastrointestinal tract are affected.

 

HAT is characterized by an early hyper-hemolytic phase in which the trypanosomes are restricted to the blood and the lymphatic system and also characterized by organomegaly and lymphadenopathy. This is followed by a late phase or the meningo-encephalitic stage characterized by neuro-psychiatric and endocrinal disorders.

 

ENDOCRINE AND METABOLIC ABNORMALITIES   

 

These occur infrequently and includes systemic neuroendocrine manifestations in the sympathetic and parasympathetic ganglia. In HAT, documented endocrine abnormalities include adrenal insufficiency, hypothyroidism, and hypogonadism in the absence of autoantibodies (18). Some authors have reported thyroid dysfunction specifically hypothyroidism in untreated HAT (19).

 

Adrenal insufficiency in trypanosomiasis may be primary or secondary and this is seen especially in untreated cases (20). The adrenal may serve as a reservoir for the T. cruzi infection and some investigators have noted a correlation between Chagasic myocarditis and infection within the central vein of the adrenal gland (21).

 

Secondary hypogonadism in both sexes had also been demonstrated in some reports which clearly showed that in the majority of the cases, the pathology was not at the level of the pituitary gland but rather an extra pituitary origin (22). Clearly, primary hypogonadism was not demonstrated to be a contributory factor to cases of hypogonadism in persons with trypanosomiasis.

 

Metabolic abnormalities are infrequently reported however a case of spurious hypoglycemia (23) has been documented in which hypoglycemia was attributable to invitro utilization of glucose by the parasite. The metabolic and endocrine abnormalities are shown in Table 2.

 

Table 2. Endocrine and Metabolic Dysfunction in Trypanosomiasis
Endocrine Gland	Hormone /Hormonal status	The level of abnormality	Possible reason	Clinical Presentation
Thyroid Gland	Low TSH, Low T3 Low T4   High TSH, Low T4, Low T3	Secondary hypothyroidism   Primary hypothyroidism	Elevated plasma cytokines related to untreated HAT Parasitic thyroiditis
HPA Axis	Subnormal Cortisol response to ACTH           Subnormal cortisol response to ACTH   Subnormal ACTH and cortisol response to (CRT) test	Primary Adrenal Insufficiency               Secondary adrenal insufficiency	Parasitic invasion of the adrenal gland. Iatrogenic: Suramin in doses exceeding the quantity employed in the treatment of trypanosomiasis inhibits adrenocortical hormone synthesis. Adaptation of the HPA state to the cytokines released due to inflammatory status of the underlying disease
Glucose metabolism	Low glucose levels	Spurious Hypoglycemia     Clinical hypoglycemia	Invitro utilization of glucose by trypanosome   Iatrogenic: Pentamidine
HPG Axis	In Men: Low Testosterone, Low LH and FSH   Positive response of testosterone to GnRH/LHRH stimulation     In women: Low Estradiol, low basal LH and FSH levels and positive response to GnRH/ LHRH	Secondary hypogonadism           Tertiary hypogonadism           Tertiary hypogonadism	Most likely due to inflammatory status of the underlying disease       Mechanism not known but may be due to cytokine release           Mechanism not known but may be due to cytokine release	Loss of libido, Impotence         Impotence               Amenorrhea

 

DIAGNOSIS  

 

Diagnosis of HAT involves a three-tiered approach for infections due to T.b. Gambiense and a two-tiered approach for that due to T.b. rhodosiense. The three steps for gambiense HAT include a screening test, diagnostic confirmation, and stage determination while that for rhodesiense HAT are diagnostic confirmation and stage determination. Screening is for gambiense HAT involves serology - CATT (Card Agglutination Test for Trypanosomiasis), which detects the presence of specific antibodies in the patient’s blood or serum. Diagnostic confirmation is done to detect the presence of trypanosomes in lymph node aspirates, chancre smear, or in blood. Stage determination is via the detection of trypanosomes (after centrifugation) and white cell count in the cerebrospinal fluid (lumbar puncture):Hemolymphatic stage is characterized by the absence of trypanosomes AND ≤ 5 white cells/mm³ and the Meningoencephalitic stage is defined by evidence of trypanosomes OR > 5 white cells/mm³.

 

Diagnosis of Chagas disease is via identification of Trypanosoma cruzi by direct microscopy of fresh blood or blood concentrated by the microhematocrit method. Serological tests for anti-Trypanosoma cruzi antibodies are performed for cases of suspected disease but no definitive diagnosis by microscopy.

 

PHARMACOTHERAPY FOR TRYPANOSMIASIS

 

Acute or chronic Chagas disease can be treated with either benznidazole or nifurtimox for those without cardiac or GIT complications. Drugs employed in the management of HAT include Nifurtimox, Eflornithine, Melarsoprol, Pentamidine, and Prednisolone (24).

 

SPOROZOANS

 

Sporozoans are a group of non-flagellated, non-ciliated and non-amoeboid protists that are responsible for diseases such as malaria and toxoplasmosis.

 

Malaria

 

Malaria is an infection caused by single-celled parasites that enter the blood through the bite of an Anopheles mosquito. These parasites, called plasmodia, belong to at least five species; P falciparum, P vivax, P ovale, P malariae and P knowlesi. Plasmodium parasites spend several parts of their life cycle inside humans and another part inside mosquitoes. During the human part of their life cycle, Plasmodium parasites infect and multiply inside liver cells and red blood cells.

 

Malaria infection begins when an infected female Anopheles mosquito bites a person, injecting Plasmodium parasites, in the form of sporozoites, into the bloodstream and then to the liver. In the liver, asexual multiplication of the sporozoites take place and these are released from the liver as merozoites which invade the red blood cells and multiply within the red cells until the cells burst and the released merozoites invade more red cells with the cycle repeating itself and causing fever. Some of the merozoites leave the cycle of asexual multiplication and instead of replicating within the cells develop into sexual forms of the parasites known as gametocytes. Following the bite of an infected person, gametocytes are ingested by the mosquito and develop into gametes which ultimately become sporozoites which travel to the mosquito’s salivary glands (25).

CLINICAL PRESENTATION

 

Uncomplicated malaria presents with fever, headache, and generalized malaise. Severe malaria refers to the demonstration of asexual forms of the malaria parasites (commonly P falciparum) in a patient with a potentially fatal manifestations or complications of malaria. Severe malaria is characterized by altered mentation, severe hemolysis, some metabolic abnormalities, and organ complications.

 

ENDOCRINE AND METABOLIC ABNORMALITIES

 

Hypoglycemia is commonly documented in severe malaria and hyperglycemia although infrequently reported is seen in severe malaria as well as uncomplicated malaria. Hypocalcemia is also reported in severe malaria as well as in cases of uncomplicated malaria.

 

Hypoglycemia may be iatrogenic due to quinine administration or due to increased glucose turnover secondary to increased glucose uptake resulting from anaerobic glycolysis and alterations in glucose production in severe malaria (26). Nigeria Reports have hypoglycemia (blood glucose <2.2mmol/L) documented in 60% of children diagnosed with severe malaria (27). Hyperglycemia on the other hand infrequently occurs in persons with malaria and it may present in uncomplicated malaria or severe malaria due to P falciparum infection. The causes of hyperglycemia sometimes necessitate the temporary use of insulin and is multifactorial. These include release of counter-regulatory hormones in response to the stress of the underlying malaria disease condition and pro inflammatory cytokines which increase blood glucose (28). Other proposed reasons for hyperglycemia are reduced sensitivity to insulin and increased gastric and small intestine permeability for sucrose in malaria patients (29-30).

 

Hypocalcemia is reported in severe malaria as well as in cases of uncomplicated malaria. It has been shown that there is an inverse relationship between parasite load and calcium levels with calcium levels returning to normal following treatment and parasite clearance (31). Altered magnesium metabolism and disturbed parathyroid gland function have been documented as possible reasons for hypocalcemia in malaria (32).

 

The pituitary-thyroid axis may be depressed in severe malaria and this is most likely attributable to adaptations of the pituitary-thyroid axis to the underlying illness. A Report has noted suppressed T4 and TSH levels with a poorly responsive pituitary gland to TRH stimulation as evidenced by low TSH levels following stimulation (33-34).  Another possible mechanism underlying the secondary hypothyroidism is parasitic sequestration within the hypothalamo-pituitary portal system (35).

 

Clinical and biochemical parameters of central diabetes insipidus which in some cases warranted treatment has been reported in severe malaria. The suggested mechanism is obstruction of the neurohypophyseal microvasculature (36-37).

 

Primary and secondary adrenal insufficiency which may present with subnormal cortisol levels and in some cases overt features of hypocortisolemia may be seen in severe malaria. Primary adrenal insufficiency may be due to necrosis or impaired circulation due to sequestration of parasites. Some reports have results suggestive of cytokines playing a role in modulating the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Other potential mechanisms for secondary adrenal insufficiency are erythrocyte sequestration within the hypothalamic -pituitary portal system, altered setpoint for cortisol inhibition of ACTH, and production of a peptide like mammalian somatostatin which has been found to inhibit ACTH secretion in vitro (38-39).

 

DIAGNOSIS AND TREATMENT

 

Direct microscopy employed on thin and thick blood films enable parasite detection, species identification, quantification, and monitoring of parasitemia. Serology via the rapid diagnostic tests which detects the parasite antigen can be employed.

Severe malaria regardless of the infecting specie is treated with intravenous Artesunate and interim oral treatment, artemether -lumefantrine. Other oral antimalarial drugs are Atovaquone-proguanil, Quinine. and Mefloquine.

 

Toxoplasmosis

 

Toxoplasmosis is an infection with Toxoplasma gondii, an obligate intracellular protozoon, which is ingested in the form oocysts in material contaminated by feces from infected cats. Oocysts may also be transported to food by flies and cockroaches.

 

TRANSMISSION  

 

It is primarily an intestinal parasite in cats and has a wide host of intermediate hosts including sheep and mice and exists in three forms: oocysts, tachyzoites, and bradyzoites. Oocysts are only produced in the definitive host – the cat. When passed in the feces and then ingested, the oocysts can infect humans and other intermediate hosts where they develop into tachyzoites- rapidly multiplying trophozoite form of T. gondii. They divide rapidly in cells, causing tissue destruction and spreading the infection. The transmission of toxoplasmosis is shown in Figure 5. Tachyzoites in pregnant women are capable of infecting the fetus. Eventually tachyzoites localize to muscle tissues and the CNS where they convert to tissue cysts, or bradyzoites which is the dormant stage. This is thought to be a response to the host immune reaction. Ingestion of cysts in contaminated meat is also a source of

infection, as bradyzoites transform back into tachyzoites upon entering a new host.

CLINICAL PRESENTATION

 

Toxoplasmosis is often asymptomatic or associated with mild self-limiting symptoms except in immunocompromised persons and sometimes in cases that are congenitally transmitted via the transplacental route (congenital toxoplasmosis).

 

CNS toxoplasmosis is one of the most common and important opportunistic infections in patients who are immunocompromised -the clinical manifestations are often nonspecific, with the most common presenting symptoms being headache, lethargy, fever, and focal neurologic signs. In congenital toxoplasmosis (CT), chorioretinitis is the most common manifestation and may cause seizure, hydrocephalus, and psychomotor delay.

 

ENDOCRINE AND METABOLIC ABNORMALITIES

 

Endocrine defects in toxoplasmosis are usually neuroendocrine in nature and may occur in congenital toxoplasmosis as well as acquired toxoplasmosis. Endocrine manifestations of   Toxoplasmosis include hypogonadotropic hypogonadism, precocious puberty, short stature, and diabetes insipidus. Documented hormonal abnormalities in persons with congenital toxoplasmosis result from hypothalamo-pituitary dysfunction and include growth hormone, gonadotropin, and ADH deficiency (40-41) (Figure 6).

Hypogonadotropic hypogonadism may occur transiently as a result of the modulation of the hypothalamus-pituitary axis by cytokines. Trypanosomiasis which is seen as a ring enhancing lesions in the brain during MRI imaging is an organic cause of the neuroendocrine abnormalities noted in some series (42-44).

 

Toxoplasmosis has been suggested as a possible risk factor for type 2 diabetes mellitus. Some Researchers have suggested that Toxoplasma gondii directly effects pancreatic cells through beta cell destruction (45-46).

 

DIAGNOSIS AND TREATMENT  

 

Diagnosis is made via direct detection of the parasites in body fluid and tissue samples.

Serology and molecular techniques are also employed in the diagnosis. Imaging preferable MRI is of use in suspected CNS involvement. Pyrimethamine, Sulfadiazine and Trimethorprin, and sulfamethoxazole are pharmacotherapies for managing toxoplasmosis.

 

BALANTIDIASIS

 

Balantidiasis is a disease caused by Balantidium coli, a ciliated protozoan and the only ciliate known to be capable of infecting humans. It is transmitted via contaminated water or food through cysts often associated with swine, the primary reservoir host. Endocrine and metabolic dysfunction or abnormalities are not documented in Balantidiasis.

 

SARCODINA

 

Amoebiasis is a diarrhea illness caused by infection with Entamoeba histolytica and is acquired by fecal-oral transmission. In some instances, extraintestinal diseases may occur but endocrine and metabolic dysfunction are not known to occur.

 

CONCLUSION

 

Protozoal infections are rare but significant causes of metabolic and endocrine abnormalities. The possibility of protozoal infections as possible causes of these abnormalities should be sought out in regions where these infections are prevalent especially after exclusion of other commonly occurring causes.

 

REFERENCES

 

1. Mousa HA. The Hidden Scene behind the High prevalence of Giardiasis and other infectious diseases in developing countries. J Infect Dis Ther 2014; 2:e106. doi:10.4172/2332-0877.
2. Werner Espelage , Matthias an der Heiden, Klaus Stark, Katharina Alpers. Characteristics and risk factors for symptomatic Giardia lamblia infections in Germany. BMC Public Health. 2010;10:41. doi: 10.1186/1471-2458-10-41.
3. Inabo HI, Yau B, Yakubu SE Asymptomatic Giardiasis and Nutritional Status of Children in Two Local Government Areas in Kaduna State, Nigeria. Sierra Leone Journal of Medical Research; 2011;3:157-162.

4       Jeffrey R. Donowitz, Masud Alam, Mamun Kabir, Jennie Z. Ma, Forida Nazib, James A. Platts-Mills, Luther A. Bartelt, Rashidul Haque, William A. Petri, Jr, A Prospective Longitudinal Cohort to Investigate the Effects of Early Life Giardiasis on Growth and All Cause Diarrhea, Clinical Infectious Diseases, 2016;63(6) 792–797.

5. Simsek Z, Zeyrek FY, Kurcer MA Effect of Giardia infection on growth and psychomotor development of children aged 0-5 years. Journal of Tropical Pediatrics 2004;50(2):90-3.
6. Radaeli Rde F, Diehl LA. Increased levothyroxine requirement in a woman with previously well-controlled hypothyroidism and intestinal giardiasis. Arq Bras Endocrinol Metabol 2011;55:81-4.
7. Seppel T, Rose F, Schlaghecke R. Chronic intestinal giardiasis with isolated levothyroxine malabsorption as reason for severe hypothyroidism - implications for localization of thyroid hormone absorption in the gut. Exp Clin Endocrinol Diabetes. 1996;104:180-2.
8. Miroslava Avila-García, Javier Mancilla, Enrique Segura-Cervantes and Norma Galindo-Sevilla (March 19th 2014). Transmission to Humans, Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment, David M. Claborn, IntechOpen, DOI: 10.5772/57271.https://www.intechopen.com/books/leishmaniasis-trends-in-epidemiology-diagnosis-and-treatment/transmission-to-humans
9. Meleney HE. The histopathology of kala-azar in the hamster, monkey and man. Am J Pathol. 1925;1:147–168.
10. Nahid R. Yousif, Rimaz E. Gurashi, Mohamed A. El Tahir, Safa Wadidi. Abd El Karim A. Abdrabo. Evaluation of Thyroid Function among Visceral Leishmaniasis Sudanese Patients. African Journal of Medical Sciences, 2018; 3 (8) .
11. Al-Ezzy AI, Abood WN. Correlation of Rk39-Specific Antibodies and Thyroid Function in Patients with Visceral Leishmaniasis. Eurasian J Med. 2016;48(3):181-185.
12. Frederico Araujo Lima Verde, Francisco Agenor Araujo Lima Verde, Augusto Saboia Neto, Paulo César Almeida, Emir Mendonça Lima Verde. Hormonal Disturbances in Visceral Leishmaniasis (Kala-Azar) Am J Trop Med Hyg. 2011; 84(5): 668–673.
13. Mondain-Miton V, Toussaint-Gari M, Hofman P, Marty P, Carles M, De Salvador F, et al. Atypical leishmaniasis in a patient infected with human immunodeficiency virus, Clin Infect Dis 1995;21:663-665.
14. Kaneria MV, Jagtap S, Modi C, Kamath S. Atypical presentation of Visceral Leishmaniasis. JAPI 2005;53
15. Brandonisio O, Fumarola L, Spinelli R, Gradoni L. Unusual presentation of leishmaniasis as an adrenal cystic mass. Eur J Clin Microbiol Infect Dis. 2002 ;21(9):682-3.
16. Brenner DS, Jacobs SC, Drachenberg CB, Papadimitriou JC. Isolated visceral leishmaniasis presenting as an adrenal cystic mass. Arch Pathol Lab Med. 2000 ;124(10):1553-6.
17. Daher EF, Soares DS, Filho SL, et al. Hyponatremia and risk factors for death in human visceral leishmaniasis: new insights from a cross-sectional study in Brazil. BMC Infect Dis. 2017;17(1):168.
18. Reincke M, Arlt W, Heppner C, Petzke F, Chrousos GP, Allolio B. Neuroendocrine dysfunction in African trypanosomiasis. The role of cytokines. Ann N Y Acad Sci. 1998 ;840:809-21.
19. Reincke M, Allolio B, Petzke F, Heppner C, Mbulamber D, Vollmer D et al. Thyroid dysfunction in African trypanosomiasis: a possible role for inflammatory cytokines. Clin Endocrinol (Oxf) 1993;39(4): 455-461
20. Reincke M, Allolio B, Petzke F, Heppner C, Mbulamber D, Vollmer D et al. Impairment of Adrenocortical Function Associated with Increased Plasma Tumor Necrosis Factor-Alpha and Interleukin-6 Concentrations in African Trypanosomiasis. Neuroimmunomodulation 1994;1:14–22.
21. Paolo WF, Nosanchuk JD. Adrenal Infections International journal of infectious diseases. 2006; 10(5): 343-353)
22. Boersma A, Noireau F, Hublart M. Gonadotropic axis and Trypanosoma brucei gambiense infection, Annales de la Société belge de médecine tropicale 1989;69(2):127-35.
23. Nieman, Roger E., et al. “Severe African Trypanosomiasis with Spurious Hypoglycemia.” The Journal of Infectious Diseases, 1989; 159:360-362.
24. Pan American Health Organization. Guidelines for diagnosis and treatment of Chagas disease. Washington, D.C. 2019.
25. Baer K, Klotz C, Kappe SH, et al. Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature. PLoS Pathogens. 2007;(11):e171.
26. Planche T, Dzeing A, Ngou-Milama E, Kombila M, Stacpoole PW. Metabolic complications of malaria. Curr Top Microbiol Immunol 2005;295:105-36.
27. Osonuga OA, Osonuga Ifabunmi, Derkyi-Kwarteng L. Prevalence of hypoglycemia among severe malaria children in rural Africa population, Asian Pacific Journal of Tropical Disease 2011; 1(3):192–194.
28. Kiely A, McClenaghan NH, Flatt PR, Newsholme P. Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta-cell line. J Endocrinol. 2007 ;195(1):113-23.
29. Singh Y, Joshi SC, Satyawali V, Gupta A. A case of severe falciparum malaria presenting with hyperglycemia. J Med Trop 2014;16:39-41
30. Singh Yatendra, Joshi Subhash C., Satyawali Vivekanand, Gupta Abhisek .A case of severe falciparum malaria presenting with hyperglycemia. Journal of Medicine in the Tropics 2014:16:39-41.
31. Prabha MR, Pereira P, Chowta N, Hegde BM. Clinical implications of hypocalcemia in malaria. Indian J Med Res. 1998;108:62-5..
32. Singh PS, Singh N. Tetany with Plasmodium falciparum infection. J Assoc Physicians India. 2012;60:57-8. .
33. Feinsod FM, Heinrich G Malaria infection presenting with symptoms of thyroid insufficiency and amenorrhoea. Trans R Soc Trop Med Hyg 1981;75(1):117-8.
34. Davis,TM, Supanaranond W, Pukrittayakamee S,Krishna S,  Hart GR,  Burrin JR, et al. The pituitary-thyroid axis in severe falciparum malaria: evidence for depressed thyrotroph and thyroid gland function.  Trans R Soc Trop Med Hyg 1990;84(3):330-5.
35. Selvaraj V. Hypopituitarism: A rare sequel of cerebral malaria – Presenting as delayed awakening from general anesthesia. Anesth Essays Res. 2015; 9(2): 287–289.
36. Premji R, Roopnarinesingh N, Cohen J, Sen S. Cerebral Malaria: An Unusual Cause of Central Diabetes Insipidus 2016 |Article ID 2047410 | https://doi.org/10.1155/2016/2047410.
37. Grimwade K, French N, Mthembu D, Gilks C. Polyuria in association with Plasmodium falciparum malaria in a region of unstable transmission. Trans R Soc Trop Med Hyg. 2004 ;98(4):255-60.
38. Timothy M. E. Davis, Li Thi Anh Thu, Tran Quang Binh, Ken Robertson, John R. Dyer, Phan Thi Danh, Desiree Meyer, Miles H. Beaman, Trinh Kim Anh. The hypothalamic-pituitary-adrenocortical Axis in Severe Falciparum Malaria: Effects of Cytokines, The Journal of Clinical Endocrinology & Metabolism, 1997; 82, (9):3029–3033.
39. Mohapatra MK, Barihar PK, Mohapatra A.Adrenal insufficiency in severe falciparum malaria: its outcome and prediction by discriminant score. IJCMR 2019;6(9):148-155.
40. Mohamed, S., Osman, A., Al Jurayyan, N.A. et al. Congenital toxoplasmosis presenting as central diabetes insipidus in an infant: a case report. BMC Res Notes 2014;( 7): 184 https://doi.org/10.1186/1756-0500-7-184
41. Suresh Babu, P.S., Nagendra, K., Sarfaraz Navaz, R. et al. Congenital toxoplasmosis presenting as hypogonadotropic hypogonadism. Indian J Pediatr 2007; 74: 577–579.
42. Massa G, Vanderschueren-Lodeweyckx M, Van Vliet G, Craen M, de Zegher F, Eggermont E. Hypothalamo-pituitary dysfunction in congenital toxoplasmosis. Eur J Pediatr. 1989 ;148(8):742-4.
43. Oktenli C, Doganci L, Ozgurtas T, Araz RE, Tanyuksel M, Musabak U. Transient hypogonadotrophic hypogonadism in males with acute toxoplasmosis: suppressive effect of interleukin-1b on the secretion of GnRH.Human Reproduction 2004;19(4):859-866
44. Setian N, Andrade RSF, Kuperman H, Della Manna T, Dichtchekenian V, and Damiani D. Precocious Puberty: An Endocrine Manifestation in Congenital Toxoplasmosis. Journal of Pediatric Endocrinology and Metabolism. 2002;15:9, https://doi.org/10.1515/JPEM.2002.15.9.1487
45. Hamidreza Majidiani, Sahar Dalvand, Ahmad Daryani, Ma de la Luz Galvan-Ramirez, Masoud Foroutan-Rad. Is chronic toxoplasmosis a risk factor for diabetes mellitus? A systematic review and meta-analysis of case–control studies. The Brazilian Journal of Infectious Diseases, 2016;20(6):605-609.
46. Shahnaz Shirbazou, Ali Delpisheh, Rahim Mokhetari, and Ghafor Tavakoli. Serologic Detection of Anti Toxoplasma gondii Infection in Diabetic Patients. Iran Red Crescent Med J. 2013 15(8): 701–703.

ABSTRACT

Helminths are parasitic worms that can infect humans. They are broadly classified as flatworms (including Cestodes and Trematodes) and roundworms (nematodes). These worms infect organs such as intestines, liver, skin, as well as other tissues. These infections are more common in underdeveloped parts of the world affecting almost one-sixth of the world population. These infections can lead to a variety of endocrine manifestations. A decreased risk of developing type 2 diabetes mellitus has been observed in affected populations. Helminths modulate the host immunity towards a type 2 immune response which is anti-inflammatory in nature. An increase in T regulatory cells has also been seen which reduces T cell response to infections.  By virtue of these changes, chronic inflammation is suppressed in adipose tissues - this phenomenon may explain the protective effect in type 2 diabetes mellitus. A reduction in insulin resistance independent of BMI has been observed in animal as well as human studies. Hepatic lipid production can be reduced by the soluble egg antigen from certain schistosomes. The immunomodulatory effects of helminth infections can also protect against autoimmune endocrine conditions such as type 1 diabetes mellitus and Graves' disease. These observations may reflect the well-known "hygiene hypothesis". Thyroid nodules and hypothyroidism can occur in helminth infections. Insights into thyroid physiology, including thyroid hormone receptors and de-iodination pathways, have been obtained from studies in helminths. Certain helminth infections can impair osteoclast maturation suggesting potential implications for osteoporosis. Similarities between human and helminth bone morphogenetic protein pathways have been observed. Adrenal masses as well as adrenal insufficiency, have been observed in helminth infections. Infertility has frequently been reported with Schistosomiasis due to inflammation in the genital tracts. An estrogen like compound may be produced by schistosomes which can lead to hypogonadism in males. The helminth, Caenorhabditis elegans can serve as a model for studies on Kallman syndrome as the KAL-1 gene appears to be functionally conserved in this helminth.  A reduction in IGF-1 levels may be seen in adults infected with helminths. Apart from these manifestations, novel insights regarding endocrine disease mechanisms as well endocrine physiology can be derived from studies on helminths.

INTRODUCTION

The term helminth refers to parasitic worms which are broadly classified as flatworms (including Cestodes and Trematodes) and roundworms (nematodes) (1). These infections may be soil-transmitted and present as intestinal infections while others may invade different tissues such as blood vessels or other organs. These parasitic worms are endemic in several parts of the world, specifically in underdeveloped and parts of developing countries (1). It is estimated that approximately one-sixth of the world’s population is affected by helminth infections  (2). Helminths employ complex mechanisms to evade host immunity. They induce malnutrition in the host while simultaneously ensuring an adequate supply of nutrients for their own growth and reproduction.

Table 1. Classification of Helminths
PHYLUM	Affected Organ	Examples
Platyhelminths	Intestine	Cestodes -Taenia, Echinococcus
	Liver	Trematodes- Schistosoma, Fasciola
Nematodes	Intestine	Ascaris, Enterobius, Necator, Ancylostoma, Trichuris, Strongyloides
	Cutaneous	Strongyloides
	Tissues	Onchocerca, Loa, Wuchereria

 

These immunological and metabolic interactions between helminth and the host may modulate the pathophysiology of several endocrine disorders including diabetes, thyroid disorders, and gonadal disorders apart from others. A discussion of each of these groups of disorders is presented below.

DIABETES MELLITUS

Diabetes mellitus is among the most common endocrine disorders with its rapidly growing prevalence earning it the designation of a pandemic. While type 1 diabetes mellitus is an autoimmune disease, type 2 diabetes is mediated by insulin resistance which is of multifactorial origin with genetics, environmental factors, and inflammation all playing their part. Among these factors, it has been noticed that areas with a high prevalence of soil-transmitted helminth infections have a relatively lower prevalence of diabetes (3). Although several other factors may also be operational in such areas, there are several proposed mechanisms by which helminth infections may influence diabetes and its pathogenesis.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus has been described as a chronic inflammatory disorder. Chronic inflammation in adipose tissues has been shown to be among the factors underlying this disease. The inflammatory process in adipose tissue involves infiltration by inflammatory cells such as lymphocytes, macrophages, and neutrophils.  Eosinophils on the other hand appear to have an anti-inflammatory effect. Apart from infiltration, several phenotypic changes occur in these cells which tip the balance towards inflammation. These include the predominance of T helper type 1 (Th1) and T helper type 17 (Th17) instead of the T helper type 2 (Th2) and the regulatory T cells (Tregs). The Th1 and Th17 cells promote the macrophage activation into classically activated macrophages (CAM) which in turn secrete inflammatory markers such as tumor necrosis factor-alpha (TNF-α), interleukin 6 and 12(IL6, IL12). TNF-α has been shown to interfere with insulin signaling. On the other hand, Th2 and T reg cells secrete IL-3 and IL 4 which stimulate the formation of alternatively activated macrophages (AAM) which are anti-inflammatory and express IL-10. Adipokines such as leptin, lipocalin 2, retinol-binding protein (RBP4), resistin, angiopoietin-like protein 2 (ANGPTL2), IL-6, IL-1, CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 5 (CXCL5) are also pro-inflammatory while adiponectin may have anti-inflammatory actions.

Helminth infections are associated with induction of type 2 immune response which involves increased activation of Th2 cells, eosinophilia, and production of IgE. The Th2 response in turn manifests as increased secretion of IL-4, IL-5, IL-9, IL-10, IL-13 which are anti-inflammatory. This also promotes the induction of anti-inflammatory AAMs.  Similarly, helminth infections are associated with an increase in T reg cells which mediate a state of T cell hypo-responsiveness. These changes on one hand limit the damage to host tissues by uncontrolled inflammation in response to helminth antigens and on the other hand prevent the clearance of the helminth from the host. The T cell hypo-responsiveness to parasite antigens can spill over to other antigens as well and this phenomenon has been invoked to explain the reduced prevalence of certain allergic and autoimmune disorders in helminth infected populations. Therefore, it has been hypothesized that since the immunological changes associated with helminth infections are anti-inflammatory in nature, they can reduce chronic inflammation in adipose and other tissues, thereby mitigating insulin resistance and the resultant type 2 diabetes.

The above hypothesis is supported by epidemiological data. In a study from China, previous schistosome infection was associated with a lower prevalence of obesity and metabolic syndrome as compared to those without such infection (4). Another study, which used ultrasonography to document chronic liver disease caused by schistosomiasis, found that metabolic syndrome prevalence was reduced to half of that seen in those without evidence of schistosomiasis (5). Serological evidence of chronic Strongyloides stercoralis infection was associated with a 61% lower risk of developing type 2 diabetes as compared to those who did not have this infection, despite adjustment for parameters such as age, BMI, and hypertension (6). In Indonesia, higher insulin sensitivity was demonstrated in patients who had infections with soil-transmitted helminths as evidenced by lower BMI and HOMA-IR levels (7). A randomized controlled trial to demonstrate the effect of ongoing helminth infection on insulin sensitivity has been conducted (8). This trial randomized households in an area endemic for helminth infection to receive albendazole or placebo over a period of time. In this trial, treatment of helminth infected subjects with albendazole lead to an increase in insulin resistance along with a reduction in IgE and eosinophil counts. However, at the community level, insulin resistance remained unchanged (9).

While the mechanisms of the reduction in type 2 diabetes have not been concretely studied in humans, animal studies provide support for the role of immunomodulation. Infections with Schistosoma mansoni, Nippostrongylus brasiliensis, and Litomosoides sigmodontis have been shown to increase eosinophils and AAMs in mice with diet-induced obesity (10–12). These animals had improved insulin sensitivity and glucose tolerance - this effect was lost in eosinophil deficient mice. S. mansoni soluble egg antigen and egg-derived ὠ-1 antigens stimulate innate lymphoid type 2 cells which produce IL-5 and IL-13 cytokines necessary for sustaining eosinophils and AAMs (13). L. sigmodontis Ag-treated obese mice had greater numbers of CD4+Foxp3+ Tregs in white adipose tissues as compared to controls indicating the upregulation of these cells as a mechanism of reducing insulin resistance (12).

Apart from these immunomodulatory mechanisms, the effect on body weight and gut microbiota are also potential mechanisms. The soluble egg antigen of S. japonicum, has been shown to reduce hepatic expression of microRNA 802 (miR802) which suppresses hepatic lipid production by upregulating the AMPK pathway. This has been proposed to be a future therapeutic target in obesity (14). However, the effect of helminth infection on insulin sensitivity has been shown to be independent of BMI in mice (10). This echoes the study on Australian aboriginals where the findings persisted despite adjusting for BMI (6).

Similarly, data on gut microbiota changes is scanty and conflicting. A few studies show an increase in gut bacterial diversity after helminth infection (15,16). Other authors have not found any significant changes in gut microbiota (17). While the mechanisms require further elucidation in both animal as well as human studies, there seems to be sufficient evidence to support the role of helminth infections in modulating the pathophysiology of type 2 diabetes.

Type 1 Diabetes Mellitus

Regarding type 1 diabetes, the type 2 immune response and suppressive regulatory environment induced by helminths may induce a protective effect. The incidence of type 1 diabetes has been increasing rapidly in developed countries and these regions are relatively less affected by helminth infections (18). The hygiene hypothesis has been invoked to explain this phenomenon (19). There are very few human studies which directly look at helminth infection and amelioration of type 1 diabetes risk. Enterobiasis did not reduce risk of type 1 diabetes in a population based study (19). Several animal studies do support the protective role of helminth infection. Axenic Caenorhabditis elegans antigen can protect against type 1 diabetes in the non-obese diabetes (NOD) mouse model (20). Trehalose produced by some helminths can alter intestinal microbiota leading to induction of CD8+ T cells which protect against type 1 diabetes in mice models (21). The severity of type 1 diabetes in mice models is ameliorated by recombinant Schistosoma japonicum cystatin and fructose-1,6-bisphosphate aldolase (22). Interestingly, children with schistosomiasis appear to have islet cell antibodies and defects in insulin secretion when compared to non infected siblings of children with insulin-dependent diabetes mellitus (23). Future studies may further shed light on this interesting topic.

THYROID DISORDERS

There appears to be a bidirectional relationship between the thyroid gland and helminth infections. On one hand, helminths appear to possess several proteins which are analogous to those involved in human thyroid physiology while on the other hand helminths can play a role in several thyroid diseases.

Thyroid hormone receptors which were earlier thought to be found only in chordates have been found to be present in S. mansoni (24). Two homologues of mammalian thyroid receptor (TR) has been isolated and characterized in S. mansoni (25), The thyroid hormone receptor beta from S. japonicum has also been characterized and evaluated as a vaccine candidate for this infection (26). Similarly, a nuclear hormone receptor has been identified in S. stercoralis which has some resemblance with steroid/thyroid hormone receptor found in humans (27). A transthyretin like protein has also been identified in Schistosoma dublin and Caenorhabditis elegans, although its function is unclear (28). Thyroid hormones may be essential for helminth growth and multiplication. In mice infected with Schistosoma mansoni, thyroid hormone therapy led to parasite multiplication and an increase in size whereas iodine deficient or thyroid hormone receptor knockout mice had lesser parasite numbers and smaller sized worms (29).

Some novel insights into thyroid physiology have also come from studies in helminths. Studies on the nematode Caenorhabditis have helped elucidate the mechanisms behind toxic effects of excess iodine - the dual oxidase maturation factor (DOXA-1) being among the implicated factors (30). Similarly, helminth studies have shown that iodotyrosine deiodinase may also have a role in regulating potassium channels in muscles (31).

Hypothyroidism and Thyroid Nodules

With respect to thyroid disorders, hypothyroidism and thyroid nodules appear to have some associations with helminth infections. S. stercoralis has been associated with hypothyroidism in one case report (32). Fasciola gigantica infection in buffaloes has been shown to lead to lymphocytic thyroiditis and hypothyroidism (33).

Hydatid cyst disease can mimic thyroid nodules and is often diagnosed by fine needle aspiration cytology (34). Cysticerosis may also present as a thyroid nodule (35). Similarly, microfilaria have also been found in fine needle aspirations from the thyroid (36). Schistosomiasis may interfere with technetium pertechnetate uptake in various tissues including the thyroid as demonstrated in mice- this may have implications for thyroid scan performed in infected humans (37).

Hyperthyroidism

Graves' disease, which is the most common cause of hyperthyroidism, may be affected by helminth infections. Considering that helminths affect host immune response and Graves' disease is an autoimmune process, such an association is not unexpected. Graves' disease is characterized by autoantibodies to the TSH receptor which leads to gland enlargement, hyperthyroidism, as well as extrathyroidal manifestations such as orbitopathy and dermopathy.  Animal models of Graves' disease have been developed which involve introduction of TSH receptor complementary DNA. It has been shown in such a mouse model that prior infection with S. mansoni may lead to a sustained Th2 type immune response towards the parasite egg antigens. This Th2 type immune response prevented the development of Graves' disease when mice were immunized with non-replicative recombinant adenovirus expressing the human TSHR. However, if given after disease onset, the Schistosoma infection could not cure the disease. Graves’ disease was once thought to be a Th2-type immune response, but recent studies have described a Th1-type as well as a Th2-type response suggesting that reversal of an activated immune response to the TSH receptor is not possible (38).  Based on similar findings with other infections, a hygiene hypothesis for Graves disease has also been proposed (39). 

BONES AND CALCIUM METABOLISM

There is limited information regarding calcium metabolism and bone health in helminth infections. Hydatid cyst disease involving the vertebrae has been described recently  and pathological hip fracture has also been reported (40,41). However, this is likely to represent direct involvement of the bone rather than alterations in bone metabolism.

Inflammatory arthritis is associated with secondary osteoporosis. The Th2 type immune response seen with helminth infections may attenuate inflammatory arthritis. N. brasiliensis was able to inhibit arthritis and bone loss in two experimental models of inflammatory arthritis (42). In vitro osteoclast differentiation has been shown to be inhibited by excretory/ secretory products from Heligmosomoides polygyrus bakeri, a murine helminth (43).  C-terminal sequence of Fasciola helminth defense molecule-1 (C-FhHDM-1) has been shown to reduce RANKL secretion as well as prevents both the formation of osteoclasts and acidification of lysosomes in animal models [6]. These features may be beneficial in osteoporotic states. However, in a study on pregnant mice, Heligmosomoides bakeri infection in late pregnancy and lactation led to a decrease in maternal bone mineral density and was associated with an increase in levels of inflammatory cytokines (IL-1 beta and IL-6) (44).

There may be several similarities between human and helminth physiology with respect to certain metabolic pathways. Homologues of  osteonectin, also called SPARC [Secreted Protein Acidic and Rich in Cysteine]), have been found in C. elegans while S. mansoni has homologues of TGF-beta receptor (45,46). More recently, it has been found that bone morphogenetic protein signaling may be conserved between humans and helminths, especially C. elegans. Secreted Modular Calcium-binding protein-1 (SMOC-1) gene identified in Caenorhabditis elegans may promote BMP signaling leading to the growth of the helminth (47,48). While BMP pathway plays several roles in human physiology including bone growth, the implications of these discoveries in helminths are still unclear.

 ADRENALS

Helminth infections in the adrenal with presentation as an adrenal mass have been reported in the literature.  Paragonimus westermani has been reported in a patient who had a lung cavity and an adrenal mass (49). Echinococcus multilocularis can infrequently present as a right adrenal mass detected incidentally (50). Adrenal schistosomiasis has also been reported (51). F. gigantica can cause adrenal insufficiency in animals (33). Acute adrenal insufficiency accompanied by adrenal hemorrhage has also been reported with S. stercoralis (52).

Activation of the hypothalamic-pituitary-adrenal axis leading to immunosuppression has been shown in mouse studies with Angiostrongylus cantonensis (53). While chronic immunosuppressive  therapy can lead to hyperinfection with helminths like S. stercoralis (54,55), adrenalectomized mice appeared to have higher worm burden and worm fecundity rates when infected with S mansoni (56). Previous mouse studies have shown adrenal hypertrophy and higher cortisol levels in S. mansoni infection (57). In vitro treatment of S. mansoni with adrenal hormones suggests that DHEA has a toxic effect with cercariae being more susceptible than schistosomula and adults (58).

GONADS

The manifestations of helminth infections with respect to gonads include hypogonadism and infertility. 

Hypogonadism

1. mansoni infection has been associated with low normal testosterone and elevated estrogen levels in males although hepatic dysfunction may also play a role in these abnormalities (59). Patients infected with Loa loa and Mansonella perstans filariasis are more likely to have low testosterone and elevated gonadotropins as compared to control subjects (60). Further research in this area revealed that an estradiol-related compound was present in schistosome worm extracts (61). Later, the same authors confirmed the presence of this estradiol-related compound by mass spectrometry and also demonstrated that this compound has an antagonistic activity on the estrogen receptor and leads to a reduced expression of the estrogen receptor (62). Schistosome eggs can also convert estrogens to catechol-estrogens which in turn can be metabolized to active quinones. These quinones can cause DNA modifications and are implicated in the pathogenesis of malignancies related to schistosomiasis (63). These hormonal changes explain the pathogenesis of hypogonadism in schistosomiasis.

 Infertility

Schistosomiasis has been well recognized as a cause of infertility especially in females. Apart from hypogonadism caused by alterations in the estrogen axis, schistosomiasis can affect the genital tract leading to infertility. Genital involvement occurs in the form of granulomatous inflammation, fibrosis, and adhesion formation. The manifestations of this infection in females include tubal blockage, tubal pregnancy, tubal abortions, hemoperitoneum, preterm births, and miscarriages (64). Males can also have direct testicular inflammation along with, blockage of the genital ductal system and venous drainage leading to infarction. However, the involvement of male genital tract has been reported infrequently (65). Female infertility has also been reported with enterobiasis (66). Filarial involvement of male genitalia leading to hydrocele is well recognized (67). Male sterility can occur in such cases (68).

Some insights into genetic hypogonadism may come from helminth studies. The gene responsible for Kallman syndrome, KAL-1, appears to have a functionally conserved homologue in C. elegans. This gene plays a role in morphogenesis by influencing migration of epidermal cells in C. elegans. This discovery has established C. elegans as a model for study of Kallman syndrome for which a mouse model has proved to be elusive [33].

GROWTH

Children with helminth infections may have impaired growth- a phenomenon that can easily be attributed to malnutrition. However, helminth infections in adults are associated with significantly lower free IGF-1 which showed improvement after anti-helminth treatment(69). IGF-BP3 levels remain unchanged. Thus, direct effects on the GH-IGF-1 axis may occur in these infections.

CONCLUSION 

Table 2. Endocrine Manifestations of Helminth Infections

May protect against development of type 2 and type 1 diabetes mellitus

Hypothyroidism and thyroid nodules

May protect against Graves' disease

May protect against osteoporosis

Adrenal masses and acute adrenal insufficiency

Hypogonadism and infertility

Growth failure via reduction in IGF-1levels

 

In conclusion, helminths appear to play an important role in several endocrine disorders in endemic areas. Apart from contributing to the pathogenesis of disease, they may have a protective effect in some metabolic disorders. Novel insights regarding endocrine disease mechanisms as well endocrine physiology can be derived from studies using helminths. This is an interesting area for research which should encourage both helminthologists as well as endocrinologists.

REFERENCES

1. Bethony J, Brooker S, Albonico M, Geiger S, Loukas A, D D, Pj H. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367(9521):1521–32.
2. Pullan RL, Smith JL, Jasrasaria R, Brooker SJ. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit. Vectors 2014;7(1):37.
3. de Ruiter K, Tahapary DL, Sartono E, Soewondo P, Supali T, Smit JWA, Yazdanbakhsh M. Helminths, hygiene hypothesis and type 2 diabetes. Parasite Immunol. 2017;39(5):e12404.
4. Chen Y, Lu J, Huang Y, Wang T, Xu Y, Xu M, Li M, Wang W, Li D, Bi Y, Ning G. Association of Previous Schistosome Infection With Diabetes and Metabolic Syndrome: A Cross-Sectional Study in Rural China. J. Clin. Endocrinol. Metab. 2013;98(2):E283-7.
5. Shen S-W, Lu Y, Li F, Shen Z-H, Xu M, Yao W-F, Feng Y-B, Yun J-T, Wang Y-P, Ling W, Qi H-J, Tong D-X. The potential long-term effect of previous schistosome infection reduces the risk of metabolic syndrome among Chinese men. Parasite Immunol. 2015;37(7):333–339.
6. Hays R, Esterman A, Giacomin P, Loukas A, McDermott R. Does Strongyloides stercoralis infection protect against type 2 diabetes in humans? Evidence from Australian Aboriginal adults. Diabetes Res. Clin. Pract. 2015;107(3):355–361.
7. Wiria AE, Hamid F, Wammes LJ, Prasetyani MA, Dekkers OM, May L, Kaisar MMM, Verweij JJ, Guigas B, Partono F, Sartono E, Supali T, Yazdanbakhsh M, Smit JWA. Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity. PloS One 2015;10(6):e0127746.
8. Tahapary DL, de Ruiter K, Martin I, van Lieshout L, Guigas B, Soewondo P, Djuardi Y, Wiria AE, Mayboroda OA, Houwing-Duistermaat JJ, Tasman H, Sartono E, Yazdanbakhsh M, Smit JWA, Supali T. Helminth infections and type 2 diabetes: a cluster-randomized placebo controlled SUGARSPIN trial in Nangapanda, Flores, Indonesia. BMC Infect. Dis. 2015;15(1):133.
9. Tahapary DL, de Ruiter K, Martin I, Brienen EAT, van Lieshout L, Cobbaert CM, Soewondo P, Djuardi Y, Wiria AE, Houwing-Duistermaat JJ, Sartono E, Smit JWA, Yazdanbakhsh M, Supali T. Effect of Anthelmintic Treatment on Insulin Resistance: A Cluster-Randomized, Placebo-Controlled Trial in Indonesia. Clin. Infect. Dis. 2017;65(5):764–771.
10. Hussaarts L, García-Tardón N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, Ozir-Fazalalikhan A, Berbée JFP, Willems van Dijk K, van Harmelen V, Yazdanbakhsh M, Guigas B. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 2015;29(7):3027–3039.
11. Yang Z, Grinchuk V, Smith A, Qin B, Bohl JA, Sun R, Notari L, Zhang Z, Sesaki H, Urban JF, Shea-Donohue T, Zhao A. Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity. Infect. Immun. 2013;81(6):1905–1914.
12. Berbudi A, Surendar J, Ajendra J, Gondorf F, Schmidt D, Neumann A-L, Wardani APF, Layland LE, Hoffmann LS, Pfeifer A, Hoerauf A, Hübner MP. Filarial Infection or Antigen Administration Improves Glucose Tolerance in Diet-Induced Obese Mice. J. Innate Immun. 2016;8(6):601–616.
13. Hams E, Bermingham R, Wurlod FA, Hogan AE, O’Shea D, Preston RJ, Rodewald H-R, McKenzie ANJ, Fallon PG. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism. FASEB J. 2016;30(2):824–835.
14. Ni Y, Xu Z, Li C, Zhu Y, Liu R, Zhang F, Chang H, Li M, Sheng L, Li Z, Hou M, Chen L, You H, McManus DP, Hu W, Duan Y, Liu Y, Ji M. Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism. Theranostics 2021;11(3):1079–1099.
15. Lee SC, Tang MS, Lim YAL, Choy SH, Kurtz ZD, Cox LM, Gundra UM, Cho I, Bonneau R, Blaser MJ, Chua KH, Loke P. Helminth Colonization Is Associated with Increased Diversity of the Gut Microbiota. PLoS Negl. Trop. Dis. 2014;8(5):e2880.
16. Kay G, Millard A, Sergeant M, Midzi N, R G, T M, A I, N N, F M, M P. Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. PLoS Negl. Trop. Dis. 2015;9(6):e0003861.
17. Cooper P, Walker AW, Reyes J, Chico M, Salter SJ, Vaca M, Parkhill J. Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota. PLOS ONE 2013;8(10):e76573.
18. Zaccone P, Hall SW. Helminth infection and type 1 diabetes. Rev. Diabet. Stud. RDS 2012;9(4):272–286.
19. Bager P, Vinkel Hansen A, Wohlfahrt J, Melbye M. Helminth infection does not reduce risk for chronic inflammatory disease in a population-based cohort study. Gastroenterology 2012;142(1):55–62.
20. Jackson-Thompson B, Torrero M, Mitre B, Long J, Packiam M, Mitre E. Axenic Caenorhabditis elegans antigen protects against development of type-1 diabetes in NOD mice. J. Transl. Autoimmun. 2020;3:100065.
21. Shimokawa C, Kato T, Takeuchi T, Ohshima N, Furuki T, Ohtsu Y, Suzue K, Imai T, Obi S, Olia A, Izumi T, Sakurai M, Arakawa H, Ohno H, Hisaeda H. CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes. Nat. Commun. 2020;11(1):1922.
22. Yan K, Wang B, Zhou H, Luo Q, Shen J, Xu Y, Zhong Z. Amelioration of type 1 diabetes by recombinant fructose-1,6-bisphosphate aldolase and cystatin derived from Schistosoma japonicum in a murine model. Parasitol. Res. 2020;119(1):203–14.
23. Soliman AT, El-Nawawy AA, El-Azzouni OF, Amer EA, Demian SR, El-Sayed MH. High prevalence of islet cell antibody and defective insulin release in children with schistosomiasis. J. Trop. Pediatr. 1996;42(1):46–49.
24. Wu W, Niles EG, LoVerde PT. Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni. BMC Evol. Biol. 2007;7:150.
25. Wu W, LoVerde PT. Nuclear hormone receptors in parasitic Platyhelminths. Mol. Biochem. Parasitol. 2019;233:111218.
26. Qiu C, Liu S, Hong Y, Fu Z, Wei M, Ai D, Lin J. Molecular characterization of thyroid hormone receptor beta from Schistosoma japonicum and assessment of its potential as a vaccine candidate antigen against schistosomiasis in BALB/c mice. Parasit. Vectors 2012;5:172.
27. Siddiqui AA, Stanley CS, Skelly PJ, Berk SL. A cDNA encoding a nuclear hormone receptor of the steroid/thyroid hormone-receptor superfamily from the human parasitic nematode Strongyloides stercoralis. Parasitol. Res. 2000;86(1):24–29.
28. Richardson SJ, Hennebry SC, Smith BJ, Wright HM. Evolution of the thyroid hormone distributor protein transthyretin in microbes, C. elegans, and vertebrates. Ann. N. Y. Acad. Sci. 2005;1040:448–451.
29. Saule P, Adriaenssens E, Delacre M, Chassande O, Bossu M, Auriault C, Wolowczuk I. Early variations of host thyroxine and interleukin-7 favor Schistosoma mansoni development. J. Parasitol. 2002;88(5):849–855.
30. Zhaofa X, Jintao L, Yu L, Long M. The BLI-3/TSP-15/DOXA-1 dual oxidase complex is required for iodide toxicity in Caenorhabditis elegans. G3 Bethesda 2014;5(2):195–203.
31. de la Cruz IP, Ma L, Horvitz HR. The Caenorhabditis elegans Iodotyrosine Deiodinase Ortholog SUP-18 Functions through a Conserved Channel SC-Box to Regulate the Muscle Two-Pore Domain Potassium Channel SUP-9. PLoS Genet. 2014;10(2):e1004175.
32. Yue S, Min L. [Strongyloides stercoralis infection with hypothyroidism: one case report]. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2017;29(3):393–394.
33. Ganga G, Varshney JP, Sharma RL, Varshney VP, Kalicharan null. Effect of Fasciola gigantica infection on adrenal and thyroid glands of riverine buffaloes. Res. Vet. Sci. 2007;82(1):61–67.
34. Dissanayake PI, Chennuri R, Tarjan G. Fine-needle aspiration diagnosis of primary hydatid disease of the thyroid; first reported case in the USA. Diagn. Cytopathol. 2016;44(4):334–337.
35. Gupta S, Sodhani P. Clinically unsuspected thyroid involvement in cysticercosis: a case report. Acta Cytol. 2010;54(5 Suppl):853–856.
36. Yenkeshwar PN, Kumbhalkar DT, Bobhate SK. Microfilariae in fine needle aspirates: a report of 22 cases. Indian J. Pathol. Microbiol. 2006;49(3):365–369.
37. Góes VC, Neves RH, Arnóbio A, Bernardo-Filho M, Machado-Silva JR. Streptozotocin (STZ) and schistosomiasis mansoni change the biodistribution of radiopharmaceutical sodium (99m)Tc-pertechnetate in mice. Nucl. Med. Biol. 2016;43(9):581–586.
38. Nagayama Y, Watanabe K, Niwa M, McLachlan SM, Rapoport B. Schistosoma mansoni and alpha-galactosylceramide: prophylactic effect of Th1 Immune suppression in a mouse model of Graves’ hyperthyroidism. J. Immunol. 2004;173(3):2167–2173.
39. Nagayama Y, McLachlan SM, Rapoport B, Oishi K. Graves’ hyperthyroidism and the hygiene hypothesis in a mouse model. Endocrinology 2004;145(11):5075–5079.
40. Meinel TR, Gottstein B, Geib V, Keel MJ, Biral R, Mohaupt M, Brügger J. Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature. Lancet Infect. Dis. 2018;18(3):e87–e98.
41. Salman F, Khan MI, Hussain I, Abdullah HMA. Pathological fracture of femoral neck in a middle-aged woman: a rare presentation of primary hydatid cyst disease in humans. BMJ Case Rep. 2018;2018:bcr-2017-222980.
42. Chen Z, Andreev D, Oeser K, Krljanac B, Hueber A, Kleyer A, Voehringer D, Schett G, Bozec A. Th2 and eosinophil responses suppress inflammatory arthritis. Nat. Commun. 2016;7:11596.
43. Sarter K, Kulagin M, Schett G, Harris NL, Zaiss MM. Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites. Autoimmunity 2017;50(3):151–157.
44. Odiere MR, Scott ME, Weiler HA, Koski KG. Protein deficiency and nematode infection during pregnancy and lactation reduce maternal bone mineralization and neonatal linear growth in mice. J. Nutr. 2010;140(9):1638–1645.
45. Schwarzbauer JE, Spencer CS. The Caenorhabditis elegans homologue of the extracellular calcium binding protein SPARC/osteonectin affects nematode body morphology and mobility. Mol. Biol. Cell 1993;4(9):941–952.
46. Beall MJ, Pearce EJ. Human transforming growth factor-beta activates a receptor serine/threonine kinase from the intravascular parasite Schistosoma mansoni. J. Biol. Chem. 2001;276(34):31613–31619.
47. DeGroot MS, Shi H, Eastman A, McKillop AN, Liu J. The Caenorhabditis elegans SMOC-1 Protein Acts Cell Nonautonomously To Promote Bone Morphogenetic Protein Signaling. Genetics 2019;211(2):683–702.
48. Schultz RD, Bennett EE, Ellis EA, Gumienny TL. Regulation of extracellular matrix organization by BMP signaling in Caenorhabditis elegans. PloS One 2014;9(7):e101929.
49. Kwon YS, Lee HW, Kim HJ. Paragonimus westermani infection manifesting as a pulmonary cavity and adrenal gland mass: A case report. J. Infect. Chemother. Off. J. Jpn. Soc. Chemother. 2019;25(3):200–203.
50. Spahn S, Helmchen B, Zingg U. Alveolar echinococcosis of the right adrenal gland: a case report and review of the literature. J. Med. Case Reports 2016;10(1):325.
51. Poderoso WLS, Santana WB de, Costa EF da, Cipolotti R, Fakhouri R. Ectopic schistosomiasis: description of five cases involving skin, one ovarian case and one adrenal case. Rev. Soc. Bras. Med. Trop. 2008;41(6):668–671.
52. Mutreja D, Sivasami K, Tewari V, Nandi B, Nair GL, Patil SD. A 36-year-old man with vomiting, pain abdomen, significant weight loss, hyponatremia, and hypoglycemia. Indian J. Pathol. Microbiol. 2015;58(4):500–505.
53. Chen A-L, Sun X, Wang W, Liu J-F, Zeng X, Qiu J-F, Liu X-J, Wang Y. Activation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to the immunosuppression of mice infected with Angiostrongylus cantonensis. J. Neuroinflammation 2016;13(1):266.
54. Jones N, Cocchiarella A, Faris K, Heard SO. Pancreatitis associated with Strongyloides stercoralis infection in a patient chronically treated with corticosteroids. J. Intensive Care Med. 2010;25(3):172–174.
55. Darlong J. Strongyloides hyper infection in a steroid dependent leprosy patient. Lepr. Rev. 2016;87(4):536–542.
56. Morales-Montor J, Mohamed F, Damian RT. Schistosoma mansoni: the effect of adrenalectomy on the murine model. Microbes Infect. 2004;6(5):475–480.
57. Antonios SN, Ismail HI, el-Nouby KA, Khalifa EA. Morphometric and histochemical study of the adrenal cortex in experimental schistosomiasis mansoni. J. Egypt. Soc. Parasitol. 2001;31(1):13–20.
58. Morales-Montor J, Mohamed F, Ghaleb AM, Baig S, Hallal-Calleros C, Damian RT. In vitro effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on Schistosoma mansoni. J. Parasitol. 2001;87(5):1132–1139.
59. Saad AH, Abdelbaky A, Osman AM, Abdallah KF, Salem D. Possible role of Schistosoma mansoni infection in male hypogonadism. J. Egypt. Soc. Parasitol. 1999;29(2):307–323.
60. Lansoud-Soukate J, Dupont A, De Reggi ML, Roelants GE, Capron A. Hypogonadism and ecdysteroid production in Loa loa and Mansonella perstans filariasis. Acta Trop. 1989;46(4):249–256.
61. Botelho MC, Crespo M, Almeida A, Vieira P, Delgado ML, Araujo L, Machado JC, Correia da Costa JM. Schistosoma haematobium and Schistosomiasis mansoni: production of an estradiol-related compound detected by ELISA. Exp. Parasitol. 2009;122(3):250–253.
62. Botelho MC, Soares R, Vale N, Ribeiro R, Camilo V, Almeida R, Medeiros R, Gomes P, Machado JC, Correia da Costa JM. Schistosoma haematobium: Identification of new estrogenic molecules with estradiol antagonistic activity and ability to inactivate estrogen receptor in mammalian cells. Exp. Parasitol. 2010;126(4):526–535.
63. Cardoso R, Lacerda PC, Costa PP, Machado A, Carvalho A, Bordalo A, Fernandes R, Soares R, Richter J, Alves H, Botelho MC. Estrogen Metabolism-Associated CYP2D6 and IL6-174G/C Polymorphisms in Schistosoma haematobium Infection. Int. J. Mol. Sci. 2017;18(12):2560.
64. Ribeiro AR, Luis C, Fernandes R, Botelho MC. Schistosomiasis and Infertility: What Do We Know? Trends Parasitol. 2019;35(12):964–971.
65. Kini S, Dayoub N, Raja A, Pickering S, Thong J. Schistosomiasis-induced male infertility. Case Rep. 2009;2009:bcr0120091481.
66. Dezsényi B, Sárközi L, Kaiser L, Tárkányi K, Nikolova R, Belics Z. Gynecological and obstetrical aspects of Enterobius vermicularis infection. Acta Microbiol. Immunol. Hung. 2018;65(4):459–465.
67. Mand S, Debrah AY, Klarmann U, Mante S, Kwarteng A, Batsa L, Marfo-Debrekyei Y, Adjei O, Hoerauf A. The role of ultrasonography in the differentiation of the various types of filaricele due to bancroftian filariasis. Acta Trop. 2011;120 Suppl 1:S23-32.
68. Panda DK, Mohapatra DP. Bancroftian filariasis associated with male sterility. BMJ Case Rep. 2018;2018:bcr-2017-223236.
69. Kurniawan F, Tahapary DL, de Ruiter K, Yunir E, Biermasz NR, Smit JWA, Supali T, Sartono E, Yazdanbakhsh M, Soewondo P. Effect of anthelmintic treatment on serum free IGF-1 and IGFBP-3: a cluster-randomized-controlled trial in Indonesia. Sci. Rep. 2020;10(1):19023.

 

 

ABSTRACT

Bacteria are microscopic single-celled organisms that exist in millions inside and outside the human body. Some bacteria are harmful and can cause a multitude of diseases in human beings. Diabetes mellitus, being a global pandemic, serves as an important cause of susceptibility to bacterial infections. Uncontrolled hyperglycemia is associated with impaired innate and adaptive immune responses that predispose to bacterial infections. In addition, chronic complications of diabetes like neuropathy (sensorimotor and autonomic) and peripheral vascular disease can lead to skin ulcerations with secondary bacterial infections. Diabetes also increases the incidence of infection related mortality. The relationship of diabetes and bacterial infections can be reciprocal, with certain infections like periodontitis exacerbating insulin resistance. Abnormalities in the bacterial flora of the gastrointestinal tract can play a role in the development of diabetes. Bacteria can infect any organ in the human body, the most common sites of infection in diabetes being the urinary tract, respiratory tract, skin, and soft tissues. Certain bacterial infections are very specific for diabetes like emphysematous pyelonephritis, emphysematous cholecystitis, and malignant otitis externa. Different antibiotic regimens (empirical and culture-specific) have been recommended for different bacterial infections, depending upon the site and severity. Our chapter gives an overview of the various bacteria, important from the standpoint of diabetes. We have also discussed the epidemiology and pathogenesis of bacterial infections in diabetes. In addition, we have highlighted the spectrum of bacterial infections and their management in diabetes. Stringent glycemic control, vaccination, adequate foot care practices, source control are some of the preventive measures to avoid bacterial infections in diabetes. Adequate knowledge about the spectrum and management of bacterial infections is important to prevent morbidity and mortality in diabetes.

INTRODUCTION

Diabetes is on the rise worldwide, with a global prevalence in adults in 2019 being 9.3% of the world population. In total numbers, this reflects a population of 463 million people with diabetes worldwide in 2019, with a projection of an increase to 700 million adults by 2045. A further 1.1 million children and adolescents under the age of 20, live with type 1 diabetes (1). The association between diabetes and bacterial infections is well recognized clinically and further adds to the morbidity associated with diabetes and its complications (2).

 

Patients with diabetes have a two-fold higher risk of community-acquired bacterial infections such as pneumococcal, streptococcal, and enterobacterial infections as compared with patients without diabetes (3-5). Urinary tract infections are more frequent in patients with diabetes. Janifer et al reported a high prevalence of 42.8% in 1157 South Indian subjects with type 2 diabetes (6). In a large retrospective cohort study in England comparing 102,493 patients with diabetes mellitus vs. n = 203,518 matched control subjects, incidence rate ratios (IRR) for infection-related hospitalizations were 3.71 (95% CI, 3.27 to 4.21) in those with type 1 diabetes mellitus and 1.88 (95% CI, 1.83 to 1.92) in those with type 2 diabetes mellitus (7). Diabetes is also associated with an average twofold higher risk of infection related mortality compared with individuals without diabetes (8).

 

Increased incidence and severity of bacterial infections in diabetes has been linked to an impaired innate and adaptive immune responses within the hyperglycemic environment (9).

Apart from hyperglycemia, other chronic complications of diabetes may also predispose patients to infections. For example, neuropathy in combination with peripheral vascular disease in diabetes can lead to ulcerations in the skin and secondary infections (10).

There is a bidirectional relationship between diabetes and bacterial infections. While diabetes increases the susceptibility to bacterial infections and its complications, chronic infections such as periodontitis is associated with increased pro inflammatory cytokines which can exacerbate insulin resistance and worsen glycemic control (11). There is a recent growing evidence that abnormalities in the microbiota composition can have a major role in the development of diabetes (12).

 

Awareness regarding the complex inter relationships between diabetes and associated bacterial infections is important for prevention and prompt treatment. A wide spectrum of bacterial infections such as malignant otitis externa, emphysematous pyelonephritis, emphysematous cholecystitis tend to be more common in diabetics than in others, and other infections may be more severe in diabetics than in nondiabetics (13). Infections may also be the first manifestation of long-standing unrecognized diabetes (14). The following figure illustrates the classification of medically important bacteria (15).

Fig 1. Classification of medically important bacteria

 

EPIDEMIOLOGY OF COMMON BACTERIAL INFECTIONS IN DIABETES

Epidemiology of common bacterial infections in diabetes with associated pathogens is shown in Table 1.

Table 1. Epidemiology of Common Bacterial Infections in Diabetes with Associated Pathogens
	Epidemiology	Pathogens	Ref
Bacterial meningitis	Relative Risk = 2.2 (95% CI, 1.9–2.6) in diabetes compared to patients without diabetes	S pneumonia Listeria monocytogenes	16
Malignant otitis externa	Odds ratio of prior diabetes in Malignant otitis externa is 10.07 (95% CI, 8.15-12.44)	Pseudomonas aeruginosa	17,18
Periodontitis	Odds Ratio = 1.34 (95% CI, 1.07–1.74) for periodontitis in diabetes  compared to patients without diabetes	Staphylococcus species Streptococcus species Bacillus species E. Coli	19,20
Community Acquired pneumonia (CAP)	Relative risk = 1.64 (95% CI 1.55–1.73) for CAP in patients with diabetes	Streptococcus pneumoniae Legionella Haemophilus influenza	21,22
Hospital Acquired pneumonia	Incidence Rate Ratio = 1.21, (95% CI,1.03–1.42) for postoperative pneumonia in diabetes	Pseudomonas species Staphylococcus aureus	23, 24
Infective endocarditis	Odds ratio =1.9 (95% confidence interval 1.8-2.1)	Streptococcus viridans Staphylococus aureus Enterococcus species	25,26
Emphysematous Cholecystitis (EC)	60% of patients with EC had diabetes	Clostridium perfringens Escherichia coli	27,28
Pyogenic liver abscess	Relative Risk = 3.6 (95% CI 2.9-4.5) in diabetes	Klebsiella pneumoniae	29,30
Urinary tract Infections	In patients with type 1 DM, adjusted odds ratio = 1.96 (95 % CI, 1.49–2.58) In patients  with type 2 diabetes, adjusted Odds ratio = 1.24 (95 % CI, 1.10–1.39)	Escherichia coli   Other Enterobacteriaceae such as Klebsiella spp., Proteus spp., Enterobacter spp., and Enterococci	31,32
Bacterial skin and mucous membrane infections	In patients with type 1 DM, adjusted odds ratio = 1.59 (95 % CI, 1.12–2.24) In patients  with type 2 diabetes, adjusted Odds ratio = 1.33 (95 % CI, 1.15–1.54)	Folliculitis        Group A streptococcus                          Staphylococcus Aureus     Furunculosis     Streptococcus pneumoniae Cellulitis	31, 33
Osteomyelitis of foot	20% of diabetic foot infections were associated with osteomyelitis.	More often poly-microbial   Gram positive : Staphylococcus aureus, Staphylococcus epidermidis, Streptococci, Enterobacteriaceae   Gram Negative : Escherichia coli, Klebsiella pneumonia,  Proteus, Pseudomonas aeruginosa	34,35

GLYCEMIC CONTROL AND RISK OF INFECTIONS

Poor glycemic control increases the risk of infections in diabetes. A recent study examined the association between glycemic control in 85,312 patients with diabetes mellitus aged 40–89 years and the incidence of infection (36).  Infection rates rose steadily with HbA1c, which was particularly evident among those with HbA1c >11% (36).

 INCREASED INCIDENCE OF INFECTIONS IN DIABETES: PATHOPHYSIOLOGY

Infections are an important concern in individuals with diabetes due to the immune system’s failure to fight off invading pathogens (37). Diabetes progression itself is associated with immune dysfunction; autoimmunity in T1DM and low-grade chronic inflammation in T2DM (38).

 

Numerous studies have investigated the diabetes-related mechanisms that impair the host’s defence against pathogens. These mechanisms include a complex interplay between the host’s innate immunity and adaptive immunity (39, 40, 41). As noted earlier, chronic complications of diabetes can also predispose to infections (10).

The proposed mechanisms for increased susceptibility to infections in diabetes are depicted in figure 2.

Fig 2. Complex interactions between immune dysregulation (both innate and adaptive) from glycemic status, organism specific factors and diabetic complications plays major role in development of diabetes related infections.

Innate immunity

Cellular innate immunity is affected in uncontrolled diabetes. The steps involved in pathogen elimination by polymorphonuclear (PMN) leucocytes are:

(a) PMN adhesion to vascular endothelium, initially via the cell surface adhesion molecule L-selectin and then integrins

(b) transmigration through the vessel wall down a chemotactic gradient

(c) phagocytosis and microbial killing (2).

Hyperglycemia induces an increase in intracellular calcium concentration thereby reducing adenosine triphosphate (ATP) levels, which in turn leads to reduced phagocytic ability of polymorphonuclear cells. Correction of hyperglycemia leads to a significant reduction in intracellular calcium levels, an increase in ATP content, and improved phagocytosis (42). The hyperglycemic environment also inhibits glucose-6-phosphate dehydrogenase (G6PD) with resultant increase in apoptosis of polymorphonuclear leukocytes, and reduced polymorphonuclear leukocyte transmigration through the endothelium. Superoxide production is reduced in parallel with increasing glycemic exposure and consequently results in decreased microbial killing (2). Hyperglycemia is associated with increased formation of advanced glycation end products (AGE). AGE albumin has been shown to bind to the receptor for AGE (RAGE) present on neutrophils. This binding inhibits transendothelial migration and Staphylococcus aureus induced production of reactive oxygen species (ROS), resulting in impaired bacterial killing (43). Hyperglycemia also adversely affects the humoral component of innate immunity. Deficiency of C4 complement as well as decreased complement activation has been demonstrated in diabetes. This results in decreased opsonisation and phagocytosis of microbes. (44,45). Increased duration of cytokine response, increased pro-inflammatory cytokine gene expression and impaired local cytokine production leads to a dysregulated cytokine response in uncontrolled diabetes further increasing susceptibility to severe infections (46, 47, 48). 

Adaptive Immunity

There are two broad classes of adaptive immunity responses—antibody responses and cell-mediated immune responses, which are carried out by B cells and T cells respectively. In antibody responses, B cells are activated to secrete immunoglobulins which bind to the invading microbial antigens and block their binding to receptors on host cells. Antibody binding also marks invading pathogens for destruction by the phagocytes (49). Decreased levels of circulating immunoglobulins (IgG antibodies) as well as increased non enzymatic glycation of IgG antibodies leading to quantitative and qualitative defects in the humoral responses have been demonstrated in uncontrolled diabetes (50,51).

 

In cell-mediated immune responses, the second class of adaptive immune response, T cells which are activated by certain cytokines and antigen presenting cells, react directly against a foreign antigen that is presented to them on the surface of a host cell or themselves secrete cytokines that activate macrophages to destroy the invading microbes after phagocytosis (47). Dysregulation between anti-inflammatory and proinflammatory cytokines and defects at the level of antigen presenting cells in uncontrolled diabetes leads to dysfunction of T cells (52, 53). The role of immune systems and pathogenesis of bacterial infections is depicted in figure 3.

Fig 3. Pathogenesis of bacterial infections in diabetes. Describes role of various components of innate and adaptive immunity in pathogenesis of bacterial infection in diabetes; G6PD-Glucose 6 phosphate dehydrogenase; PMN-Polymorphonuclear cells; NADPH – Nicotinamide adenine dinucleotide phosphate; ROS- Reactive oxygen species; ATP -Adenosine triphosphate; AGEs- Advanced glycation end products; RAGE-Receptor for advanced glycation end products. 

Chronic Complications of Diabetes Predisposing to Infections

Over 50% of men and women with diabetes have bladder dysfunction which may impair voiding and increase the risk for urinary tract infections (54). The presence of renal disease and urinary incontinence in women are also predisposing factors for urinary tract infections. Diabetic cystopathy secondary to autonomic nervous dysfunction in long standing diabetes is characterized by a loss of sensation of bladder distension leading to decreased frequency of voiding and increased post-void residual urine volume. The possibility that voiding disorders may contribute to UTI should be considered in all diabetic patients (55).  

 

Peripheral diabetic neuropathy contributes to motor, autonomic, and sensory components of neuropathic foot ulcers. Damage to motor neurons of the foot musculature may lead to an imbalance of flexors and extensors, anatomic deformities, and eventual skin ulcerations. Damage to autonomic nerves impairs sweat gland function in the foot leading to a decreased ability to moisturize skin, resulting in epidermal cracks and skin breakdown. Lastly, the affected sensory component results in a loss of sensation of foot and reduced awareness of minor injuries (56). With ischemia, often as a result of related peripheral arterial disease, neuropathy can result in impaired barrier defences, skin ulcers with poor healing, and an increased risk of secondary infections and gangrene (57).

 

Pulmonary autonomic neuropathy in diabetes reduces mucociliary clearance and predisposes the lung to infections. Furthermore, hyperglycemia and insulin resistance impair collective surfactant D-mediated host defences of the lung in diabetes. Loose junctions between airway epithelial cells, which increase the transepithelial glucose gradient along with an increase in the glucose concentration of the airway surface liquid due to hyperglycemia, may dampen the airway defence against infection, resulting in lung bacterial overgrowth in diabetes (58).

SPECTRUM OF BACTERIAL INFECTIONS

Head and Neck Infections

BACTERIAL MENINGITIS

The majority of bacterial meningitis cases in adults is caused by Streptococcus pneumoniae. Listeria monocytogenes meningitis is more often found in elderly patients (>60 years) and those with acquired immune-deficiencies, such as diabetes. Immunodeficiency associated with diabetes is also a predisposing factor for pneumococcal and Haemophilus influenzae meningitis. Patients with bacterial meningitis and diabetes mellitus are older, have more comorbidities, frequently present with altered mental status and have higher mortality. In patients with diabetes, empirical antibiotics should include Cefotaxime/ ceftriaxone plus amoxicillin/ampicillin/ penicillin G (16, 59, 60).

MALIGNANT OTITIS EXTERNA

 Malignant otitis externa (MOE) is an invasive, potentially life-threatening infection of the external ear and skull base. MOE affects immunocompromised individuals and its presentation in an otherwise healthy individual should prompt an investigation for diabetes mellitus or other immune-deficiencies. In most cases, the causative agent of MOE is Pseudomonas aeruginosa. Typical patients with MOE are elderly individuals who have diabetes and severe, unremitting otalgia, aural fullness, otorrhea, and conductive hearing loss. Headache, temporomandibular joint pain, and decreased oral intake secondary to trismus may also be present. Findings of pain disproportionate to the examination, otorrhea, and granulation tissue along the floor of the ear canal at the bony–cartilaginous junction are usually the first nonspecific signs and symptoms of MOE. Important principles of treatment include aggressive control of diabetes and culture directed antibiotic therapy for at least 6-8 weeks. Although surgical intervention is no longer standard of care for MOE, it does require biopsy and culture, and may require local debridement of granulation tissue and bony sequestration or drainage of associated abscess. Long-term monotherapy with oral ciprofloxacin (750 mg twice daily) has been proposed as the preferred initial antibiotic regimen. However, microbial resistance to ciprofloxacin has been described and numerous studies have proposed carbapenem or third- generation cephalosporins as the initial empirical treatment. Recurrence rates of 15% to 20% have been reported for MOE (18, 61, 62). The risk factors for malignant otitis externa and its pathogenesis in diabetes are depicted in figure 4.

Fig 4. Risk factors for Malignant Otitis Externa and its pathogenesis in diabetes

PERIODONTITIS

Periodontitis is a complex chronic inflammatory condition in which inflammation in the periodontal tissues is stimulated by the long-term presence of the subgingival biofilm (figure 5). Periodontitis is a slowly progressing disease but the tissue destruction that occurs is largely irreversible. In the early stages, the condition is typically asymptomatic, is not usually painful, and many patients are unaware until the condition has progressed enough to result in tooth mobility. Advanced periodontitis is characterized by gingival erythema and edema, gingival bleeding, gingival recession, tooth mobility, suppuration from periodontal pockets, and tooth loss. In a randomized clinical trial, intensive periodontal treatment was associated with better glycemic control (A1C 8.3% vs 7.8% in control subjects and intensive treatment group respectively). Oral and periodontal health should be promoted as integral components of diabetes management (63, 64).

Fig 5. Chronic periodontitis with gingival inflammation in a patient with poorly controlled diabetes

DEEP NECK SPACE INFECTIONS/ABSCESS

Patients with diabetes are susceptible to spreading deep neck infections with a high frequency of complications, including tracheostomy and prolonged hospital stay. Odontogenic infections and upper airway infections are the leading reported causes of deep neck infections and the most common organism isolated is Klebsiella pneumoniae.  Early open surgical drainage remains the most appropriate method of treating deep neck abscesses. The choice of empirical antimicrobial agents in diabetic patients should take into account the agents effective against Klebsiella pneumoniae (65).

Respiratory Infections

COMMUNITY ACQUIRED PNEUMONIA

Patients with diabetes are at high risk of hospitalization due to community acquired pneumonia (CAP) (figure 6). Atypical clinical features like impaired consciousness and more severe pneumonia at admission are reported in patients with diabetes. Acute onset of disease, cough, purulent sputum, and pleuritic chest pain are less frequent among patients with diabetes. S. pneumonia, Legionella, and H influenza are frequent causative organisms of pneumonia in diabetes (22). Studies have also reported increased incidence of Klebsiella and pneumococcal pneumonia (3, 66). Independent risk factors for mortality in patients with diabetes and CAP are advanced age, bacteremia, septic shock at admission, and gram-negative pneumonia (22). The American Thoracic Society guidelines recommend combination therapy with amoxicillin/ clavulanic acid/ cephalosporin and macrolide/ doxycycline or monotherapy with respiratory fluoroquinolone for initial outpatient treatment in patients with diabetes. Beta lactam + macrolide or beta-lactam + fluoroquinolone is recommended in cases of severe in-patient pneumonia. Coverage for Pseudomonas aeruginosa is recommended in case of prior respiratory isolation, recent hospitalization with parenteral antibiotics treatment, and locally validated risk factors for Pseudomonas aeruginosa (67). The American Diabetes Association recommends vaccination against pneumococcal strains with one dose of PPSV23 (pneumococcal polysaccharide vaccine) between the ages of 19–64 years and another dose after 65 years of age. The PCV13 (pneumococcal conjugate vaccine) is no longer routinely recommended for patients over 65 years of age because of the declining rates of pneumonia due to these strains. All children are recommended to receive a four-dose series of PCV13 by 15 months of age. For children with diabetes who have incomplete series by ages 2–5 years, a catch-up schedule is recommended to ensure that these children have four doses. Children with diabetes between 6–18 years of age are also advised to receive one dose of PPSV23, preferably after receipt of PCV13 (68).

Fig 6. Radiographs of lower respiratory tract infection. A- Postero-anterior view radiograph of chest showing right middle lobe and left lower lobe consolidation in a patient with diabetes. B- Postero-anterior view radiograph of chest showing right lower lobe consolidation in a patient with diabetes

Cardiovascular Infections  

INFECTIVE ENDOCARDITIS

Infective endocarditis (IE) in diabetes is associated with poorer outcomes (figures 7 and 8). Diabetes mellitus was associated with increased mortality, acute heart failure, stroke, atrioventricular block, septic shock, and cardiogenic shock. The clinical profile of native valve infective endocarditis (NVIE) patients with diabetes is reported to be different compared to those without diabetes. Patients with diabetes had higher rates of comorbidities, and IE risk factors such as older age, and hemodialysis. They were less likely to have structural heart disease (valvular heart disease and congenital heart disease) and intravenous drug abuse. Patients with diabetes had higher rates of staphylococcus species, enterococci, and gram-negative microorganisms reflecting the increased health care utilization in DM patients, exposing them to nosocomial infections (26). Ampicillin with flucloxacillin or oxacillin with gentamicin is recommended as initial empirical therapy in community acquired native valves or late prosthetic valves (≥ 12 months post-surgery) endocarditis. Vancomycin with gentamicin and rifampicin is recommended in early PVE (<12 months post-surgery) or nosocomial and non-nosocomial healthcare associated endocarditis (69).

Fig 7. Two-dimensional Echocardiography of a patient with diabetes showing aortic root abscess (red arrowhead) and vegetations attached to aorto-mitral continuity (blue arrowhead), suggestive of infective endocarditis

 

Fig 8. Two-dimensional echocardiography in a patient with diabetes, showing large vegetation (blue arrowhead) attached to the posterior mitral leaflet, suggestive of infective endocarditis

Gastrointestinal Infections  

EMPHYSEMATOUS CHOLECYSTITIS

Emphysematous cholecystitis (EC) is an uncommon but serious biliary tract infection that occurs in increased frequency with male preponderance among diabetics. The common causative organisms are Clostridium perfringens and E. coli (28). Clinical findings of EC may be indistinguishable from those of uncomplicated cholecystitis although occasional crepitus may be present in some patients. The emphysematous infection is diagnosed by radiographic demonstration of gas on plain films or by CT. The treatment of choice is rapid surgical removal of the gallbladder and broad-spectrum antimicrobial therapy. Mortality caused by this infection is substantially higher than that of uncomplicated cholecystitis, ranging 15% to 25% compared with less than 4 percent (13).

LIVER ABSCESS

Diabetes is a strong, potentially modifiable risk factor for pyogenic liver abscess (figure 9). Pyogenic liver abscess patients with diabetes are older, with isolate of Klebsiella. pneumoniae being the predominant pathogen and require an increased use of combined antibiotic therapy with carbapenems. However, these patients have fewer abdominal surgeries and fewer E. coli infections as compared to patients without diabetes. In addition, poorly controlled glycemia in pyogenic liver abscess patients is associated with high incidence of fever and abscesses in both the lobes of the liver (29, 30).

Fig 9. Contrast enhanced axial (A) and sagittal (B) CT images showing multifocal well defined hypodense lesions involving both lobes of liver suggestive of liver abscesses in a patient with diabetes 

Urinary Tract Infections

The urinary tract is the most frequent site of infection in patients with diabetes (8, 70, 71). The spectrum of urinary tract infections in these patients ranges from asymptomatic bacteriuria (ASB) to lower UTI (cystitis), pyelonephritis, and severe urosepsis. Serious complications of UTI, such as emphysematous cystitis and pyelonephritis (figure 10), renal abscesses and renal papillary necrosis, are all encountered more frequently in type 2 diabetes than in the general population (72, 73).

Figure 10. Emphysematous pyelonephritis. Non contrast CT abdomen of a 45-year-old female with emphysematous pyelonephritis showing bilateral enlarged kidney with evidence of abscess formation on either side (black arrowheads) and air pockets in left kidney

 

The most common pathogens isolated from diabetic patients with UTI are E. coli, other Enterobacteriaceae such as Klebsiella spp., Proteus spp., Enterobacter spp., and Enterococci. Patients with diabetes are more prone to have resistant pathogens as the cause of their UTI, including extended-spectrum β-lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant Enterococci. (32, 74).

 

As a general rule, treatment of UTI in diabetic patients is similar to that of UTI in non-diabetic patients. Antibiotic choice should be guided by local susceptibility patterns of uropathogens. First-line treatment recommendations for various types of UTI are detailed in Table 2 (74).

 

Table 2. First Line Antibiotics for Various Types of UTI in Diabetes
Type of urinary tract infection (UTI)	Gender	Antibiotic treatment	Route	Dosage	Duration of treatment
Asymptomatic bacteriuria	Male and female	None
Acute cystitis	Female	Nitrofurantoin	Per oral	100 mg BD/TDS	5 days
Complicated lower UTI  (catheter associated UTI)	Male and female	Ciprofloxacin	Per oral	200-500 mg BD	7-14 days
		Ofloxacin	Per oral	200 mg BD	7-14 days
		Trimethoprim-Sulfamethoxazole	Per oral	960 mg BD	7-14 days
		Cefuroxime	Per oral	500 mg BD	7-14 days
Uncomplicated pyelonephritis	Female	Ciprofloxacin	Intravenous	400 mg BD	7 days
		Ciprofloxacin	Per oral	500 mg BD	7 days
		Ofloxacin	Intravenous	400 mg BD	7 days
		Gentamicin	Intravenous	5 mg/kg OD	7 days
		Cefuroxime	Intravenous	750 mg TDS	7-14 days
		Cefuroxime	Per oral	500 mg BD	7-14 days
Complicated pyelonephritis/urosepsis	Male and female	Ciprofloxacin	Intravenous	400 mg BD	10-14 days
		Ofloxacin	Intravenous	400 mg BD	10-14 days
		Gentamicin	Intravenous	5 mg/kg OD	10-14 days
		Amikacin	Intravenous	15 mg/kg OD	10-14 days
		Piperacillin-Tazobactum	Intravenous	4.5 g TDS	10-14 days
		Ertapenem	Intravenous	1 g OD	10-14 days

OD-once daily, BD-twice daily, TDS-thrice daily

Skin and Soft Tissue Infections 

Skin and soft tissue infections (SSTI) cause a substantial morbidity in patients with diabetes (75). SSTIs commonly seen in diabetes include cellulitis, abscess, decubitus ulcer, folliculitis, impetigo, carbuncle and furuncle, and surgical site infections. SSTI-associated complications such as gangrene, osteomyelitis, bacteremia, sepsis, and SSTI-associated hospitalizations are higher in patients with diabetes compared to those without diabetes (76).

FOOT INFECTIONS IN DIABETES

Foot infections in diabetes remain the most frequent complication requiring hospitalization and the most common precipitating event leading to lower extremity amputation (figure 11) (77-79).

Fig 11.  A-Trophic changes in the bilateral feet of a patient with diabetes with clawing of toes, thickened toe nails, loss of hair and shiny skin texture. B-Infected foot ulcer with slough in the plantar aspect of heel of a patient with diabetes. C-Another infected foot ulcer involving the entire sole in a patient with diabetes, the ulcer shows presence of granulation tissue along with oozing of pus and slough

 

Outcomes in patients presenting with an infected foot ulcer are poor. In one large prospective study at the end of one year, the ulcer had healed in only 46% (and it later recurred in 10% of these), while 15% had died and 17% required a lower extremity amputation (80). There are various validated classification systems to assess the severity and prognosis of foot ulcers and infection. One such scoring system is the SINBAD system which grades area, depth, sepsis, arteriopathy, and denervation plus site as either 0 or 1 point creating an easy to use scoring system that can achieve a maximum of 6 points (81). The IWGDF (International Working Group on the Diabetic Foot) infection classification is recommended to characterize and guide infection management in diabetic foot infections. The IWGDF/IDSA (Infectious Diseases Society of America) classification consists of four grades of severity for diabetic foot infection (Table 3) (82, 83).

 

Table 3. IWGDF/IDSA Classification for Foot Infections
Clinical classification of infection, with definitions	IWGDF classification
Uninfected No systemic or local symptoms or signs of infection
	1 (Uninfected)
Infected ·       At least, 2 of these items are present ·       Local swelling or induration ·       Erythema >0.5 cm around the wound ·       Local tenderness or pain ·       Local increased warmth ·       Purulent discharge And no other cause(s) of an inflammatory response of the skin (eg. trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis or venous stasis)
Infection with no systemic manifestation involving: ·       only the skin or subcutaneous tissue (not any deeper tissues) and ·       any erythema present does not extend >2 cm around the wound	2 (mild infection)
Infection with no systemic manifestation involving: ·       erythema extending ≥ 2 cm from the wound margin, and/or ·       tissue deeper than skin and subcutaneous tissue (e.g., tendon, muscle, joint, bone)	3 (moderate infection)
Any foot infection with associated systemic manifestations (of the systemic inflammatory response syndrome [SIRS]), as mentioned by ≥2 of the following: ·       Temperature >38 degree celsius or <36 degree Celsius ·       Heart rate >90 beats/ minute ·       Respiratory rate >20 breaths/minute or PaCO2 <4.3 kPa (32 mm Hg) ·       White blood cell count >12,000/mm3 or <4000/mm3 or >10% immature (band) forms	4 (Severe infection)
Infection involving bone (osteomyelitis)	Add ‘O’ after 3 or 4

 

The empirical antibiotic choice is guided by the history, clinical examination, severity of infection, likely etiological agent, and previous antimicrobial sensitivity pattern. Studies from temperate climates in North America and Europe have consistently demonstrated that the most common pathogens in diabetic foot infections are aerobic gram-positive cocci, especially Staphylococus aureus, and to a lesser extent, streptococci and coagulase-negative staphylococci. More recent studies of diabetic foot infections from patients in tropical/subtropical climates (mainly Asia and northern Africa) have shown that aerobic gram-negative bacilli are often isolated, either alone or in combination with gram-positive cocci. Empirical treatment aimed at Pseudomonas aeruginosa, which usually requires either an additional or broad-spectrum agent should be considered in tropical/subtropical climates or if Pseudomonas aeruginosa has been isolated from previous cultures of the affected patient. Obligate anaerobes can play a role in diabetic foot infections, especially in ischemic limbs and in case of abscesses. Empirical treatment of these pathogens, e.g., with an imidazole (metronidazole), or beta-lactam with beta lactamase inhibitor, should be considered for diabetic foot infection associated with ischemia or a foul-smelling discharge. THE IWGDF guidelines on empirical antibiotic therapy for diabetic foot infections are outlined in table 4 (83).

 

Table 4. Empirical Antibiotic Therapy Recommended by IWGDF Guidelines for Diabetic Foot Infections
Severity of infection	Additional factors	Usual pathogen(s)	Potential empirical regimens
Mild	No complicating features	Gram positive cocci	Semi synthetic penicillin; 1st generation cephalosporins
	Beta lactam allergy or intolerance	Gram positive cocci	Clindamycin;Fluroquinolone;Trimethoprim-sulfamethoxazole;Macrolide;Doxycycline
	Recent antibiotic exposure	Gram positive cocci + Gram negative rods	β-lactamase inhibitor-amoxicillin/clavulanate; Trimethorpim-sulfamethoxazole; Fluoroquinolone
	High risk for MRSA	MRSA	Linezolid; Trimethoprim-sulfamethoxazole; doxycycline; macrolide
Moderate or severe	No complicating features	Gram positive cocci ± Gram negative rods	β-lactamase inhibitor-amoxicillin/clavulanate; second or third generation cephalosoporins
	Recent antibiotic exposure	Gram positive cocci ± Gram negative rods	β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; 3rd generation cephalosporins; group I carbapenems (depends on prior therapy)
	Macerated ulcer or warm climate	Gram negative rods including pseudomonas	β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; semi synthetic penicillins + ceftazidime; semi synthetic penicillins + ciprofloxacin; group 2 carbapenems
	Ischemic limb/necrosis/gas forming	Gram positive cocci ± Gram negative rods ± Anaerobes	β-lactamase inhibitor or 2; group 1 or 2 carbapenems; 2nd or 3rd generation cephalosporins + clindamycin or metronidazole
	MRSA risk factors	MRSA	Consider adding or substituting with glycopeptides; linezolid; daptomycin; fusidic acid; trimethoprim-sulfamethoxazole ± rifampicin; doxycycline
	Risk factors for resistant gram negative rods	ESBL (Extended spectrum beta lactamase producing bacteria)	Carbapenem; Aminoglycoside and Colistin; Fluoroquinolone

MRSA-Methicillin resistant Staph aureus ; 1^st generation cephalosporins-Cefadroxil, cefazolin, cephalexin; 2^nd generation cephalosporins-Cefotetan, cefoxitin, cefuroxime, cefprozil; 3^rd generation cephalosporins-Cefixime, cefotaxime, cefpodoxime; β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; group 1 carbapenem: ertapenem; group 2 carbapenem: imipenem, meropenem, doripenem

FOURNIER’S GANGRENE

Fournier's gangrene (FG) is a fulminant form of infective necrotising fasciitis of the perineal, genital, or perianal regions, which commonly affects men with diabetes (figure 12) (84). Diabetes mellitus is reported to be present in 20%–70% of patients with Fournier’s gangrene (85). FG shows vast heterogeneity in clinical presentation, from insidious onset and slow progression to rapid onset and fulminant course, the latter being the more common presentation. The local signs and symptoms are usually dramatic with significant pain and swelling. The patient also has pronounced systemic signs; usually out of proportion to the local extent of the disease. Crepitus of the inflamed tissues is a common feature because of the presence of gas forming organisms. As the subcutaneous inflammation worsens, necrotic patches start appearing over the overlying skin and progress to extensive necrosis (86).

 

There has been an associated increased incidence of FG with the use of SGLT2 inhibitors in diabetes. The US Food and Drug Administration (FDA) has identified 55 cases of FG in patients receiving SGLT2 inhibitors between 2013 and 2019, out of which 39 were men and 16 were women (87). Time to onset of FG after initiation of SGLT2-inhibitors varied considerably, ranging from 5 days to 49 months (87). All patients were sick and had surgical debridement. Three patients died (87).  SGLT2-inhibitors cause glycosuria that can enhance the growth of bacterial flora in the urogenital milieu. This in turn increases the risk of urogenital infections, including FG. All types of SGLT2-inhibitors have been associated with FG. The FDA has issued a warning about the risk of FG to be added to the prescribing information of all SGLT2-inhibitors and to the patient medication guide.

 

Cultures from the wounds commonly show poly microbial infections by aerobes and anaerobes, which include coliforms, klebsiella, streptococci, staphylococci, clostridia, bacteroides, and corynebacteria (88). FG has a high mortality rate of 40% (85) and warrants an aggressive multimodal approach, which includes haemodynamic stabilisation, broad spectrum antibiotics and surgical debridement (86).

Fig 12. Fournier’s gangrene. Redness, swelling of the scrotum, penis and perineal tissues with necrosis and sloughing of the overlying skin

NECROTIZING FASCIITIS

Necrotizing fasciitis (NF) has been defined as a severe soft-tissue infection that causes extensive necrosis of subcutaneous tissue and fascia, relatively sparing the muscle and skin tissue (figure 13) (89). Based on bacterial culture results, NF is classified into the following categories: type I, which consists of synergistic polymicrobial infection; type II, representing infections caused by group A Streptococcus alone or combined with Staphylococcus; and type III, which comprises infections caused by Vibrio species (90).  Diabetic NF patients are reported to be more susceptible to polymicrobial and monomicrobial Klebsiella pneumoniae infections, which should be considered when choosing empirical antibiotics for these patients (91).

Fig 13. A and B Necrotizing fasciitis; black necrotic tissue and slough seen invading the subcutaneous tissues and fascia

INFECTION MIMICS IN DIABETES

Charcot Neuroarthropathy   

Charcot neuroarthropathy is a limb-threatening, destructive process that occurs in patients with neuropathy associated with medical diseases such as diabetes mellitus. Clinicians treating diabetic patients should be aware that the early signs of acute Charcot neuroarthropathy, such as pain, warmth, edema mimic foot infection. Early detection and prompt treatment can prevent joint and bone destruction, which, if untreated, can lead to morbidity and high-level amputation. The differentiation between acute presentations of Charcot’s joint and osteomyelitis is often difficult because the two conditions have many features in common. However, the lack of systemic sepsis or fever, significant hyperglycemia and leukocytosis may direct the diagnosis towards neuropathic joint (92, 93).

INFECTIONS AS A RISK FACTOR FOR DIABETES

Infections have been documented as a predisposing factor for Type 2 Diabetes Mellitus. Recent studies have revealed H. pylori infections to be significantly higher among diabetic patients than in non-diabetic patients (94, 95). Evidence suggests that advanced periodontitis also compromises glycemic control. Furthermore, periodontal treatment has been associated with improvement in glycemic control (63, 64). Abnormalities in the microbiota composition can have a major role in the development of obesity and diabetes. A reduced microbial diversity is associated with inflammation, insulin-resistance, and adiposity.  A rise in the Firmicutes/Bacteroidetes ratio is found to be related to a low-grade inflammation and to an increased capability of harvesting energy from food. Changes in some metabolites, such as short-chain fatty acids (SCFAs), produced by gut microbiota, and decreased amounts of the Akkermansia muciniphila are associated with the presence of type 2 diabetes (12). Increased pro inflammatory cytokine response in infections leads to insulin resistance. Even pathogen products, such as lipopolysaccharide and peptidoglycans, can cause insulin resistance leading to development of diabetes (96).

CONCLUSION

Awareness regarding the spectrum and severity of infections, in diabetes, is essential for prevention and prompt treatment. Strict glycemic control, proper choice of antibiotics and source control form the cornerstones of management. Preventive measures like vaccination and foot care practises go a long way in reducing infection related morbidity and mortality in diabetes.

REFERENCES

1. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. 2017. 
2. Peleg AY, Weerarathna T, McCarthy JS, Davis TM. Common infections in diabetes: Pathogenesis, management and relationship to glycaemic control. Diabetes Metab Res Rev. 2007; 23:3–13.
3. Thomsen RW, Hundborg HH, Lervang HH, et al. Risk of community-acquired pneumococcal bacteremia in patients with diabetes: a population-based case-control study. Diabetes Care 2004; 27:1143–7.
4. Thomsen RW, Riis AH, Kjeldsen S, et al. Impact of diabetes and poor glycaemic control on risk of bacteremia with haemolytic streptococci groups A, B, and G. J Infect 2011;63:8–16.
5. Thomsen RW, Hundborg HH, Lervang HH, et al. Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteremia: a 10-year population based study among adults. Clin Infect Dis 2005; 40:628–31
6. Janifer J, Geethalakshmi S, Satyavani K, Viswanathan V. Prevalence of lower urinary tract infection in South Indian type 2 diabetic subjects. Indian J Nephrol. 2009 Jul; 19(3):107.
7. Carey IM, Critchley JA, DeWilde S, Harris T, Hosking FJ, Cook DG. Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study. Diabetes Care. 2018 Mar 1;41(3):513-21.
8. Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care. 2003 Feb 1;26(2):510-3.
9. Frydrych LM, Fattahi F, He K, Ward PA, Delano MJ. Diabetes and sepsis: risk, recurrence, and ruination. Front Endocrinol (Lausanne).2017 Oct 30;8:271.
10. Shaw JE, Boulton AJ. The pathogenesis of diabetic foot problems: an overview. Diabetes. 1997 Sep 1;46(Supplement 2):S58-61.
11. Mirza BA, Syed A, Izhar F, Ali Khan A. Bidirectional relationship between diabetes and periodontal disease: review of evidence. J Pak Med Assoc. 2010 Sep 1;60(9):766-8.
12. Pascale A, Marchesi N, Govoni S, Coppola A, Gazzaruso C. The role of gut microbiota in obesity, diabetes mellitus, and effect of metformin: new insights into old diseases. Curr Opin Pharmacol. 2019 Dec 1;49:1-5.
13. Calvet HM, Yoshikawa TT. Infect Dis Clin North Am. 2001 Jun 1;15(2):407-21.
14. Clive S, Cockram C, Wong BCK. Diabetes and Infections. Textbook of Diabetes. Holt RI, Cockram C, Flyvbjerg A, Goldstein BJ (editors). John Wiley & Sons; 2017 Mar 6. 799-820.
15. Harvey RA, Champe PC, Fisher BD, Strohl WA. Microbiology. Philadelphia: Lippincott Williams & Wilkins. 2007
16. Van Veen KE, Brouwer MC, Van Der Ende A, Van De Beek D. Bacterial meningitis in diabetes patients: a population-based prospective study. Sci Rep. 2016 Nov 15;6(1):1-7.
17. Yang TH, Xirasagar S, Cheng YF, Wu CS, Kao YW, Shia BC, Lin HC. Malignant Otitis Externa is Associated with Diabetes: A Population-Based Case-Control Study. Ann Otol Rhinol Laryngol. 2020 Jun;129(6):585-90.
18. Carlton DA, Perez EE, Smouha EE. Malignant external otitis: the shifting treatment paradigm. Am J Otolaryngol. 2018;39(1):41-45.
19. Wang TT, Chen TH, Wang PE, Lai H, Lo MT, Chen PY, Chiu SY. A population- based study on the association between type 2 diabetes and periodontal disease in 12,123 middle-aged Taiwanese (KCIS no. 21). J Clin Periodontol. 2009;36(5):372–9.
20. Ali T, Rumnaz A, Urmi UL, Nahar S, Rana M, Sultana F, Iqbal S, Rahman MM, Rahman NA, Islam S, Haque M. Type-2 Diabetes Mellitus Individuals Carry Different Periodontal Bacteria. Pesqui. Bras. Odontopediatria Clín. Integr. 2021 Apr 2;21.
21. Brunetti VC, Ayele HT, Yu OH, Ernst P, Filion KB. Type 2 diabetes mellitus and risk of community-acquired pneumonia: a systematic review and meta-analysis of observational studies. CMAJ Open. 2021 Jan;9(1):E62.
22. Di Yacovo S, Garcia-Vidal C, Viasus D, Adamuz J, Oriol I, Gili F, Vilarrasa N, García-Somoza MD, Dorca J, Carratala J. Clinical features, etiology, and outcomes of community-acquired pneumonia in patients with diabetes mellitus. Medicine (Baltimore). 2013 Jan;92(1):42-50.
23. Akbar DH. Bacterial pneumonia: comparison between diabetics and non-diabetics. Acta Diabetol. 2001 Jun 1;38(2):77-82.
24. López-de-Andrés A, Perez-Farinos N, de Miguel-Díez J, Hernández-Barrera V, Jiménez-Trujillo I, Méndez-Bailón M, de Miguel-Yanes JM, Jiménez-García R. Type 2 diabetes and postoperative pneumonia: an observational, population-based study using the Spanish hospital discharge database, 2001-2015. PLoS One. 2019 Feb 6;14(2):e0211230.
25. Movahed MR, Hashemzadeh M, Jamal MM. Increased prevalence of infectious endocarditis in patients with type II diabetes mellitus. J Diabetes Complications. 2007 Nov 1;21(6):403-6.
26. Abe T, Eyituoyo HO, De Allie G, Olanipekun T, Effoe VS, Olaosebikan K, Mather P. Clinical outcomes in patients with native valve infective endocarditis and diabetes mellitus. World J Cardiol. 2021 Jan 26;13(1):11.
27. Abengowe CU, McManamon PJ. Acute emphysematous cholecystitis. Can Med Assoc J. 1974 Nov 16;111(10):1112.
28. Safwan M, Penny SM. Emphysematous cholecystitis: a deadly twist to a common disease. J Diagn Med Sonogr. 2016 May;32(3):131-7.
29. Thomsen RW, Jepsen P, Sørensen HT. Diabetes mellitus and pyogenic liver abscess: risk and prognosis. Clin Infect Dis. 2007 May 1;44(9):1194-201.
30. Li W, Chen H, Wu S, Peng J. A comparison of pyogenic liver abscess in patients with or without diabetes: a retrospective study of 246 cases. BMC Gastroenterol. 2018 Dec;18(1):1-9.
31. Muller LM, Gorter KJ, Hak E, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41:281–8.
32. Geerlings SE, Meiland R, van Lith EC, Brouwer EC, Gaastra W, Hoepelman AI. Adherence of type 1-fimbriated Escherichia coli to uroepithelial cells: more in diabetic women than in control subjects.Diabetes Care. 2002 Aug; 25(8):1405-9
33. Atreja A, Kalra S. Infections in diabetes. J Pak Med Assoc. 2015 Sep 1;65(9):1028-30.
34. Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe- to-bone test for diagnosing diabetic foot osteomyelitis: reliable or relic? Diabetes Care. 2007 Feb;30(2):270-4
35. Giurato L, Meloni M, Izzo V, Uccioli L. Osteomyelitis in diabetic foot: a comprehensive overview. World J Diabetes. 2017 Apr 15;8(4):135.
36. Critchley JA, Carey IM, Harris T, DeWilde S, Hosking FJ, Cook DG. Glycemic control and risk of infections among people with type 1 or type 2 diabetes in a large primary care cohort study. Diabetes Care. 2018 Oct 1;41(10):2127-35.
37. American Diabetes Association. AD Standards of medical care in diabetes--2013.Diabetes Care. 2013;36 (Suppl. 1):S11–S66.
38. Pearson-Stuttard J, Blundell S, Harris T, Cook DG, Critchley J. Diabetes and infection: assessing the association with glycaemic control in population-based studies. Lancet Diabetes Endocrinol. 2016;4:148–158
39. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab. 2012 Mar;16(Suppl1):S27.
40. Schuetz P, Castro P, Shapiro NI. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care. 2011 Mar 1;34(3):771-8.
41. Gan YH. Host susceptibility factors to bacterial infections in type 2 diabetes. PLoS Pathog. 2013 Dec 26;9(12):e1003794.
42. Alexiewicz JM, Kumar D, Smogorzewski M, Klin M, Massry SG. Polymorpho- nuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. Ann Intern Med. 1995;123:919–924.
43. Collison KS, Parhar RS, Saleh SS, Meyer BF, Kwaasi AA, et al. (2002) RAGE- mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukoc Biol. 71: 433–444.
44. Stoeckle M, Kaech C, Trampuz A, Zimmerli W. The role of diabetes mellitus in patients with bloodstream infections. Swiss Med Wkly. 2008;138:512-9. 

45. Ilyas R, Wallis R, Soilleux EJ, Townsend P, Zehnder D, et al. (2010) High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus. Immunobiology 216: 126–131.
46. Geerlings SE, Brouwer EC, VanKessel KC, Gaastra W, Stolk RP, Hoepelman AI. Cy- tokine secretion is impaired in women with diabetes mellitus. Eur J Clin Invest 2000;30:995–1001
47. Graves DT, Naguib G, Lu H, Leone C, Hsue H, Krall E. Inflammation is more persistent in type 1 diabetic mice. J Dent Res. 2005;84:324–328
48. Stegenga ME, van der Crabben SN, Dessing MC, et al. Effect of acute hyper- glycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cyto- kine production and neutrophil function in humans. Diabet Med. 2008;25:157–164.
49. Alberts A, Johnson A, Lewis J, Raff M, Roberts K, Walter P. The Adaptive Immune System. Molecular Biology of the Cell. New York: Garland Science; 2002.
50. Liberatore RR Jr, Barbosa SF, Alkimin MG, et al. Is immunity in diabetic patients influencing the susceptibility to infections? Immunoglobulins, complement and phagocytic function in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2005;6:206–212
51. Lapolla A, Tonani R, Fedele D, et al. Non- enzymatic glycation of IgG: an in vivo study. Horm Metab Res. 2002;34:260– 264
52. Spatz M, Eibl N, Hink S, et al. Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells. Cell Immunol. 2003; 221:15–26
53. Rubinstein R, Genaro AM, Motta A, Cremaschi G, Wald MR. Impaired immune responses in streptozotocin-induced type I diabetes in mice. Involvement of high glucose. Clin Exp Immunol. 2008;154: 235–246.
54. Frimodt-moller C. Diabetic cystopathy : epidemiology and related disorders. Ann Intern Med. 1980; 92: 318-321.
55. Fünfstück R, Nicolle LE, Hanefeld M, Naber KG. Urinary tract infection in patients with diabetes mellitus. Clin Nephrol. 2012 Jan 1;77(1):40.
56. Aumiller WD, Dollahite HA. Pathogenesis and management of diabetic foot ulcers. JAAPA. 2015 May 1;28(5):28-34.
57. American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec 1;26(12):3333-41.
58. Kolahian S, Leiss V, Nürnberg B. Diabetic lung disease: fact or fiction? Rev Endocr Metab Disord. 2019 Sep;20(3):303-19.
59. van de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek AT, Leib SL, Mourvillier B, Ostergaard C, Pagliano P, Pfister HW. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May 1;22:S37-62.
60. Pomar V, de Benito N, Mauri A, Coll P, Gurguí M, Domingo P. Characteristics and outcome of spontaneous bacterial meningitis in patients with diabetes mellitus. BMC Infect Dis. 2020 Dec;20:1-9.
61. Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am. 2008 Jun 1;41(3):537-49.
62. Ciorba A, Cultrera R, Di Laora A, Grilli A, Bianchini C, Aimoni C. Malignant otitis externa in the antibiotic resistance era: key to successful treatment. B-ENT. 2018. 14:119-123
63. Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, Taylor R. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012 Jan;55(1):21-31.
64. D'Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, Masi S, Tsakos G, Hurel S, Hingorani AD, Donos N. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018 Dec 1;6(12):954-65.
65. Huang TT, Tseng FY, Liu TC, Hsu CJ, Chen YS. Deep neck infection in diabetic patients: comparison of clinical picture and outcomes with nondiabetic patients. Otolaryngol Head Neck Surg. 2005 Jun;132(6):943-7.
66. Saibal MA, Rahman SH, Nishat L, Sikder NH, Begum SA, Islam MJ, Uddin KN. Community acquired pneumonia in diabetic and non-diabetic hospitalized patients: presentation, causative pathogens and outcome. Bangladesh Med Res Counc Bull. 2012;38(3):98-103.
67. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
68. American Diabetes Association. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021 Jan;44(Supplement 1):S40-52.
69. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM. 2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC) endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075-128.
70. Patterson JE, Andriole VT. Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am. 1997;11(3):735–750.
71. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus.N Engl J Med. 1999;341(25):1906–1912
72. Mnif MF, Kamoun M, Kacem FH, et al. Complicated urinary tract infections associated with diabetes mellitus: pathogenesis, diagnosis and management.Indian J Endocrinol Metab. 2013;17(3):442–445.
73. Kofteridis DP, Papadimitraki E, Mantadakis E, et al. Effect of diabetes mellitus on the clinical and microbiological features of hospitalized elderly patients with acute pyelonephritis. J Am Geriatr Soc. 2009;57(11):2125–2128.
74. Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes Metab Synd Obes. 2015;8:129.
75. Lipsky BA, Tabak YP, Johannes RS, Vo L, Hyde L, Weigelt JA. Skin and soft tissue infections in hospitalised patients with diabetes: culture isolates and risk factors associated with mortality, length of stay and cost. Diabetologia. 2010 May;53(5):914-23.
76. Suaya JA, Eisenberg DF, Fang C, Miller LG. Skin and soft tissue infections and associated complications among commercially insured patients aged 0–64 years with and without diabetes in the US. PLoS One. 2013 Apr 10;8(4):e60057.
77. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabet Med 2018;35:78-88.
78. Lavery LA, Armstrong DG, Murdoch DP, Peters EJ, Lipsky BA. Validation of the Infectious Diseases Society of America's diabetic foot infection classification system. Clin Infect Dis 2007;44:562-5.
79. Tan TW, Shih CD, Concha-Moore KC, et al. Disparities in outcomes of patients admitted with diabetic foot infections. PLoS One 2019;14:e0211481.
80. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabet Med 2018;35:78-88.
81. Ince P, Abbas ZG, Lutale JK, Basit A, Ali SM, Chohan F, et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care. 2008;31(5):964-7.
82. Monteiro‐Soares M, Russell D, Boyko EJ, Jeffcoate W, Mills JL, Morbach S, Game F, International Working Group on the Diabetic Foot (IWGDF). Guidelines on the classification of diabetic foot ulcers (IWGDF 2019). Diabetes Metab Res Rev. 2020 Mar;36:e3273.
83. Lipsky BA, Senneville É, Abbas ZG, Aragón‐Sánchez J, Diggle M, Embil JM, Kono S, Lavery LA, Malone M, van Asten SA, Urbančič‐Rovan V. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).Diabetes Metab Res Rev. 2020 Mar;36:e3280.
84. Smith G L, Bunker C B, Dineeen M D. Fournier's gangrene.Br J Urol 1998 Mar;81(3):347-55.
85. Morpurgo E, Galandiuk S. Fournier's gangrene. Surg Clin North Am. 2002 Dec 1;82(6):1213-24.
86. Thwaini A, Khan A, Malik A, Cherian J, Barua J, Shergill I, Mammen K. Fournier’s gangrene and its emergency management. Postgrad Med J. 2006 Aug 1;82(970):516-9.
87. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Intern Med. 2019 Jun 4;170(11):764-769.
88. Yaghan RJ, Al-Jaberi TM, Bani-Hani I. Fournier's gangrene. Dis Colon Rectum. 2000 Sep 1;43(9):1300-8.
89. Lin C, Yeh FL, Lin JT, Ma H, Hwang CH, Shen BH, et al. Necrotizing fasciitis of the head and neck: an analysis of 47 cases.Plast Reconstr Surg. 2001;107(7):1684–93.
90. Giuliano A, Lewis F, Jr, Hadley K, Blaisdell FW. Bacteriology of necrotizing fasciitis.Am J Surg. 1977;134(1):52–7.
91. Cheng NC, Tai HC, Chang SC, Chang CH, Lai HS. Necrotizing fasciitis in patients with diabetes mellitus: clinical characteristics and risk factors for mortality. BMC Infect Dis. 2015 Dec;15(1):1-9.
92. Jain R, Brown M, Boynton EL. Not another Diabetic Foot Infection: A Case Report of Charcot's Joint. Can J Plastic Surg. 1996 Dec;4(4):1-6.
93. Varma AK. Charcot neuroarthropathy of the foot and ankle: a review. J Foot Ankle Surg. 2013 Nov 1;52(6):740-9.
94. Mabeku LB, Ngamga ML, Leundji H. Helicobacter pylori infection, a risk factor for Type 2 diabetes mellitus: a hospital-based cross-sectional study among dyspeptic patients in Douala-Cameroon. Sci Rep. 2020 Jul 22;10(1):1-1.
95. Bener A, Ağan AF, Al-Hamaq AO, Barisik CC, Öztürk M, Ömer A. Prevalence of Helicobacter pylori infection among type 2 diabetes mellitus. Adv Biomed Res. 2020;9:27.
96. Chakraborty S, Bhattacharyya R, Banerjee D. Infections: a possible risk factor for type 2 diabetes. Adv Clin Chem. 2017 Jan 1;80:227-51.