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Infectious causes of adrenal insufficiency.

Abstract: More than 150 years ago, Thomas Addison first described the clinical features and pathogenesis of adrenal insufficiency. At that time, tuberculosis was the most common cause of this disease. The pathway to diagnosis and treatment of Addison's disease has been well described. However, determining the cause of the disorder remains a challenge. It is important to consider recently described infectious agents in the pathogenesis of Addison's disease. Mycobacterial, bacterial, viral, and fungal infections may lead to the development of adrenal insufficiency. Skin, pulmonary, and imaging findings can aid the clinician in making a prompt diagnosis of specific infections, which is crucial because early identification of infectious causes of Addison's disease may enable recovery of adrenal function. This review describes the clinical presentations of the multiple infectious causes of adrenal insufficiency.

Key Words: adrenal insufficiency, clinical manifestations, infectious causes

Addison's disease is a primary adrenocortical deficiency that is a result of damage to the adrenal cortex. Overt clinical features of hypoadrenalism develop when 80 to 90% of both adrenal cortices are destroyed. It is a relatively uncommon disease in Western countries and remains underdiagnosed, leading to unnecessary morbidity and mortality. Symptoms of Addison's are often nonspecific and may include weakness, fatigue, hypoglycemia, weight loss, hypotension, hyponatremia, hyperkalemia, and generalized hyperpigmentation of the skin. (1) Autoimmune disease is the predominant cause of primary adrenal failure in Western countries. However, other causes of adrenal insufficiency include amyloidosis, sarcoidosis, Wilson's disease, adrenal hemorrhage or infarction, adrenoleukodystrophy, adrenomyeloneurnpathy, congenital adrenal hyperplasia or hypoplasia, and specific medications. (2) Infection is an often-overlooked cause of Addison's disease, and delay in diagnosis and treatment may adversely affect patient outcome. Although the diagnosis and management of Addison's disease have been well documented in the literature, adrenal insufficiency secondary to infectious agents has received less attention. Infections that may lead to adrenal insufficiency may be classified as mycobacterial, bacterial, viral, and fungal.

Mycobacterial Agents

In many areas of the world, tuberculosis remains the major cause of Addison's disease. Today, it is a relatively rare cause of adrenal insufficiency in Western countries but should nonetheless be considered in the differential diagnosis, especially in the setting of altered immune status. Most cases of adrenal tuberculosis are found 10 to 15 years after the initial infection, and bilateral adrenal calcification is the most common radiologic feature. (1) It is important to consider the diagnosis of adrenal insufficiency in patients with a history of tuberculosis and nonspecific signs and symptoms. Recovery of adrenal function is possible after appropriate antituberculous therapy, but usually it does not occur. (1)

Atypical mycobacterial species have also been linked to adrenal insufficiency. Mycobacterium avium-intracellulare can be found in the soil, particularly in the southeastern United States. Infection with this organism can be associated with adrenal dysfunction, especially in patients with acquired immunodeficiency syndrome (AIDS). Autopsy studies have shown that as many as 12% of the adrenal glands in patients with AIDS may be infected with this organism. (3) Treatment with clarithromycin, ethambutol, and rifabutin as well as steroids is indicated. Although the widespread dissemination of Mycobacterium avium-intracellulare can cause Addison's disease in some patients with AIDS, it is also possible to find adrenal gland infiltration by the organism alone without evidence of glandular dysfunction. (4)

Bacterial Agents

Acute adrenal insufficiency can occur as a result of bilateral adrenal infarction caused by hemorrhage, which is most commonly associated with the Waterhouse-Friderichsen syndrome. Most often, this syndrome is secondary to meningococcal infection, although Pseudomonas aeruginosa, Group A Streptococcus, Haemophilus influenzae, and Pasteurella multocida also have been implicated. (5) The onset of Waterhouse-Friderichsen syndrome is usually abrupt, and patients present with lever, chills, nausea, vomiting, myalgia, arthralgia, and a generalized rash. The rash begins as erythematous macules and then progresses rapidly to petechiae and, in severe cases, purpura. Adrenal necrosis is thought to be secondary to intravascular changes involving the adrenal cortical vessels caused by endotoxins, stress, and hypotension. (6) Blood cultures may grow Neisseria meningitidis, and intensive treatment with IV antibiotics and corticosteroids may lead to recovery.

Viral Agents

Addison's disease can occur in patients with AIDS with greater frequency than previously surmised. (3) Cytomegalovirus (CMV) infection is the most common pathogen underlying adrenal insufficiency in this population. CMV infection of the adrenal gland can present at any stage of AIDS, but often it is seen in patients with a particularly low CD4 lymphocyte count, and it may occur without evidence of disseminated CMV disease. (7) The symptoms of adrenal insufficiency are often missed and are attributed to AIDS-related features rather than to Addison's disease. Treatment of CMV itself is generally not warranted, unless there is evidence of CMV disease elsewhere. However, it is critical to treat the underlying human immunodeficiency virus infection with antiretroviral agents to attempt immune restitution. Such reconstitution is essential to the patient who is infected with pathogens such as CMV or Mycobacterium avium-intracellulare.

Fungal Agents

Pneumocyslis carinii, a fungus whose natural habitat is the lung, is primarily an opportunistic pathogen that infects immunocompromised individuals. Rarely, infection can lead to Addison's disease in patients with normal immune function. A needle biopsy of the patient's adrenal glands may reveal P. carinii infection, and direct immunofluorescence using monoclonal antibodies against P. carinii cells may be positive. (8) Anti-Pneumocystis treatment with trimethoprimsulfamethoxazole or pentamidine isethionate is indicated.

Disseminated disease with Histoplasma capsulatum, a dimorphic fungus that is most endemic to the midwestern and south-central United States, often presents as malaise, weight loss, painless oral ulcers, levers, and chills. The adrenal glands are involved in more than 80% of patients, and approximately 5 to 10% of patients develop clinical adrenal insufficiency. (9) Patients may present with multisystem involvement, including abnormal liver function tests. Computed tomographic scans of patients with histoplasmosis and adrenal gland involvement may show bilateral enlargement with a low, attenuated center and increased density of the gland perimeter. (9) Treatment with amphotericin B or itraconazole is indicated. Interestingly, there may be recovery of adrenal function.

Addison's disease secondary to Blastomyces dermatitidis, a dimorphic fungus that is most endemic to the southeastern and south-central United States, has been a well-known entity for more than a century. Symptoms may be nonspecific, and infection usually involves the respiratory system. Adrenal gland cytology can confirm the presence of B. dermatitidis. (10) Treatment with itraconazole or amphotericin B is indicated. Paracoccidioidomycosis (ie, South American blastomycosis) is another important fungal cause of Addison's disease, especially in Brazil and other developing countries. Usually, this organism involves the lungs, skin, and lymph nodes. Adrenal involvement is also regularly recorded, and postmortem studies show adrenal abnormalities in 44 to 80% of cases, with two-thirds occurring bilaterally. (11) Addison's disease may become evident before treatment of paracoccidioidomycosis, and the patient's history of paracoccidioidomycosis infection may be remote. An adrenal gland biopsy may reveal yeasts of Paracoccidioides brasiliensis, and adrenal gland calcification may be seen on the computed tomographic scan. (12) Treatment with sulfa drugs or various imidazole derivatives is recommended. Several studies have shown fall clinical and functional recovery of adrenal glands after long-term therapy with antifungal agents and steroids. (13)

Addison's disease also has been linked to infection by Coccidioides immitis, a dimorphic fungus endemic to the southwestern United States, some areas of Central and South America, and parts of Mexico. Infection occurs secondary to inhalation of Arthroconidia. Only 3% of patients develop disseminated disease that may result in adrenal insufficiency. (14) Therapy with steroids and an azole agent or amphotericin B is indicated.

Adrenal glands are occasionally involved in disseminated cryptococcosis. Cryptococcus neoformans, an encapsulated yeastlike fungus, is found abundantly in pigeon excrement. Approximately 75% of patients with cryptococcal disease in the United States are immunocompromised. (15) It is not uncommon for dissemination of C. neojormans to involve the adrenal glands. Computed tomography most often shows bilaterally enlarged adrenal glands, whereas magnetic resonance imaging scans may show adrenal masses that are hypointense relative to the liver and the kidneys. (16) A fine-needle aspiration biopsy of the adrenal glands may be used to confirm the diagnosis. Treatment with IV amphotericin B along with flucytosine is optimal, and this therapy can be followed with fluconazole. Generalized candidiasis, toxoplasmosis, syphilis, and African trypanosomiasis causing adrenal insufficiency also have been postulated as possible infectious causes. (12, 17)

Conclusions

Many infectious agents can affect adrenal gland function and cause adrenal insufficiency. These agents, which are listed in Table 1, include mycobacterial, bacterial, viral, and fungal etiologies. In addition to prompt intervention for Addison's disease, treatment of concurrent infections may enable the recovery of adrenal function. Clinicians should suspect an infectious etiology in the presence of altered immune status, skin and radiographic manifestations, including enlarged adrenal glands. A computed tomography-guided fine-needle aspiration biopsy may be indicated for diagnostic purposes.

Key Points

* Infections secondary to mycobaeterial, bacterial, viral, and fungal agents may lead to adrenal insufficiency.

* Early identification of infectious causes of Addison's disease may enable the recovery of adrenal function.

* The multiple infectious causes of adrenal insufficiency have distinct clinical manifestations.
Table 1. Infectious agents and clinical manifestations at time of
Addison's disease diagnosis (a)

Infectious agent Possible coexisting
 skin abnormalities

TB +PPD

MAC Rare: in setting of AIDS,
 may mimic Kaposi's
 sarcoma
Meningococcus Petechial rash
CMV Decreased skin turgor
Pneumocystis carinii None
Histoplasma capsulatum Indurated ulcers of
 mouth, tongue, and
 nose
Blastomyces dermatiditis Wartlike lesions

Paracoccidioides hrasiliensis Mucocutancous lesions
Cryptococcus neoformans Nodular lesions with
 ulceration
Coccidiodes immitis Skin nodules

Infectious agent Potential CXR findings

TB Variable
MAC Possible cavitary lesions or localized
 infiltrate
Meningococcus Pulmonary edema

CMV Interstitial infiltrates
Pneumocytsis carinii Interstitial infiltrates
Histoplasma capsulatum Variable (granulomatous disease,
 discrete nodules, or miliary
 pattern, or CXR may be clear)
Blastomyces dermatiditis Pulmonary infiltrates mimicking
 lobar pneumonia or mass lesion
Paracoccidioides hrasiliensis Bilateral patchy infiltrates
Cryptococcus neoformans Variable (well-circumscribed, dense
 infiltrate or diffuse pneumonic
 infiltrate, or CXR may be clear)
Coccidiodes immitis Reticulonodular infiltrate

Infectious agent Adrenal gland Disseminated
 appearance on CT scan disease

TB Asymmetric adrenal Yes
 enlargement and
 calcification
MAC N/A Yes

Meningococcus Enlarged and poorly Yes
 defined adrenal
 glands
CMV N/A Yes
Pneumocvvis carinii Bilateral adrenal Yes
 enlargement
Histoplasma capsulatum Nonenhancing (consis- Yes
 tent with infarct or
 necrosis) bilateral-
 ly enlarged adrenals
Blastomyces dermatiditis Bilateral asymmetric Yes
 enlargement
Paracoccidioides hrasiliensis Bilateral adrenal Yes
 enlargement
Cryptococcus neoformans Bilateral adrenal Yes
 enlargement
 Bilateral adrenal
Coccidiodes immitis enlargement Yes

(a) CXR, chest s-ray; CT, computed tomographic: TB, tuberculosis + PPD,
positive for purified protein derivative; MAC, Myobacterium
avium-intracellulare; AIDS, acquired immunodeficiency syndrome: N/A,
not available: CMV, cytomegalovirus.


References

(1.) Orth DN. Adrenal insufficiency. Curt Ther Endocrinol Metab 1994;5: 124-130.

(2.) Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab 2001;86:2909-2922.

(3.) Birchall D, Comty C. Addison's disease in the acquired immunodeficiency syndrome. Med J Aust 1993;159:359-360 (letter).

(4.) Guenthner EE, Rabinowe $1,, Van Niel A, et al. Primary Addison's disease in a patient with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:847-848.

(5.) Karakousis PC, Page KR, Varello MA, et al. Waterhouse-Friderichsen syndrome after infection with Group A Streptococcus. Mayo Clin Proc 2001;76:1167-1170.

(6.) Agraharkar M, Fahlen M, Siddiqui M, et al. Waterbouse-Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis. Am J Kidney Dis 2000;36:396-400.

(7.) Pinching AJ. Cytomegalovirus infection in the acquired immune deficiency syndrome. J Antimicrob Chemother 1989;23(Suppl E):31-36.

(8.) Agarwal J, Agarwal G, Ayyagari A, et al. Isolated Pneumocystis carinii infection of adrenal glands causing Addison's disease in a non-immunocompromised adult. Endocr Pathol 2001;12:87-91.

(9.) Wong P, Houston S, Power B, et al. A ease of Histoplasma capsulatum causing granulomatous liver disease and Addisonian crisis. Can J Gastroenterol 2001;15:687-691.

(10.) Rimondi AP, Bianchini E, Baruchello G, et al. Addison's disease caused by adrenal blastomycosis: A case report with fine needle aspiration (FNA) cytology. Cytopathologv 1995;6:277-279.

(11.) Colombo AL, Faical S, Kater CE. Systematic evaluation of the adrenocortical function in patients with paracoccidioidomycosis. Mycopathologia 1994; 127:89-93.

(12.) Faical S, Borri ML, Hauache OM, et al. Addison's disease caused by Paracoccidioides brasiliensis: Diagnosis by needle aspiration biopsy of the adrenal gland. A JR Am J Roentgenol 1996;166:461 462 (letter).

(13.) Do Valle AC, Guimaraes MR, Cuba J, et al. Recovery of adrenal function after treatment of paracoccidioidomycosis. Am J Trop Med Hyg 1993;48:626-629.

(14.) Chowfin A, Tight R. Female genital coccidioidomycosis (FGC), Addison's disease and sigmoid loop abscess due to Coccidioides immitis: Case report and review of literature on FGC. Mycopathologia 1999;145:121-126.

(15.) Confusion and hypotension in a 42-year-old woman. Am J Med 1997; 103:441-447.

(16.) Takeshita A, Nakazawa H, Akiyama H, et al. Disseminated cryptococcosis presenting with adrenal insufficiency and meningitis resistant to prolonged antifungal therapy but responding to bilateral adrenalectomy. Intern Med 1992;31:1401-1405.

(17.) Alteras I, Cojocaru I, Balanescu A. Generalized candidiasis associated with Addison's disease. Mykosen 1969;12:575-577.

From the Divisions of Infectious Diseases and Endocrinology, Department of Medicine, James H. Quillen Veterans Affairs Medical Center and James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

We received no financial support and have no commercial or proprietary interest in any drug, device, or equipment mentioned in this article.

Reprint requests to Alan N. Peiris, MD, PhD, Department of Endocrinology. James H. Quillen College of Medicine. East Tennessee State University. P.O. Box 70622, Johnson City, TN 37614.

Accepted March 7, 2003.
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Author:Peiris, Alan N.
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Sep 1, 2003
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