Addison's Disease

Background

Addison's disease is a rare disorder that is caused by failure of the adrenal gland. The adrenal gland is important in producing steroids, both corticosteroids and mineralocorticoids. If the adrenal gland does not produce these hormones, the loss leads to devastating effects in nearly every organ system, and eventually death. Patients may first experience weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin. Some critical functions of the steroids include maintainence of blood pressure, regulation of insulin, and regulation of the breakdown of proteins, carbohydrates, and fats

OUTLINE

Epidemiology

Disease Associations

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE/PREVALENCE 1/100,000

AGE All ages

SEX Both

Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal.

Perry R, Kecha O, Paquette J, Huot C, Van Vliet G, Deal C.

Endocrinology Service, Sainte-Justine Hospital, 3175 Sainte-Catherine Road, Montreal, Quebec, Canada H3T 1C5.

J Clin Endocrinol Metab. 2005 Jun;90(6):3243-50. . Abstract quote

Primary adrenal insufficiency (PAI) in the pediatric population (0-18 yr) is most commonly attributed to congenital adrenal hyperplasia (CAH), which occurs in about 1 in 15,000 births, followed by Addison's disease, with an assumed autoimmune etiology. However, molecular advances have increased the number of possible diagnoses.

The objective of this study was to determine the incidence and etiologies of PAI in our pediatric population. All patients with a diagnosis of PAI followed by the Endocrinology Service at our institution between September 1981 and September 2001 were studied. One hundred three patients (48 boys) were identified, primarily by the Endocrinology Clinic case registry. CAH was the most frequent etiology (71.8%). However, non-CAH etiologies accounted for 28.2%, of which 55% were nonautoimmune in etiology. Importantly, the CAH sex ratio was 1:1, despite the absence of biochemical screening for this condition in Quebec newborns.

Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) developed adrenal insufficiency 4 yr earlier than those with non-autoimmune disease. Finally, we review the rare etiologies of PAI and propose an algorithm to aid in targeted genetic testing.

DISEASE ASSOCIATIONS CHARACTERIZATION

ADRENOLEUKO-DYSTROPHY

The importance of testing for adrenoleucodystrophy in males with idiopathic Addison's disease.

Ronghe MD, Barton J, Jardine PE, Crowne EC, Webster MH, Armitage M, Allen JT, Steward CG.

Department of Haematology/Oncology, Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK.
Arch Dis Child 2002 Mar;86(3):185-9 Abstract quote
X linked adrenoleucodystrophy (X-ALD) is considered to be a rare cause of Addison's disease, although several small series suggest a high incidence in young Addisonian males. A survey in the south west of England identified 12 male patients diagnosed with Addison's disease in the period 1987-99. In 10 of these (83%) X-ALD was the underlying cause; the other two were of autoimmune aetiology.

Five boys had developed Addison's disease subsequent to the diagnosis of X-ALD. Of the remaining five, in three boys the diagnosis of X-ALD was considerably delayed (by six months to two years from that of Addison's disease) and in two it was only made as a result of this survey.

We also identified a patient who presented with Addison's disease at the age of 5 years but was only diagnosed as having X-ALD at the age of 34 years; in the interim his diagnosis of adrenomyeloneuropathy had been missed. Our experience highlights the absolute necessity of measuring very long chain fatty acids in all males with idiopathic Addison's disease.

AUTOIMMUNE POLYENDOCRINE SYNDROMES

Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction.

Betterle C, Dal Pra C, Mantero F, Zanchetta R.

Chair of Clinical Immunology and Allergy, Department of Medical and Surgical Sciences, University of Padova, I-35128, Padova, Italy.
Endocr Rev 2002 Jun;23(3):327-64 Abstract quote
Recent progress in the understanding of autoimmune adrenal disease, including a detailed analysis of a group of patients with Addison's disease (AD), has been reviewed. Criteria for defining an autoimmune disease and the main features of autoimmune AD (history, prevalence, etiology, histopathology, clinical and laboratory findings, cell-mediated andhumoral immunity, autoantigens and their autoepitopes, genetics, animal models, associated autoimmune diseases, pathogenesis, natural history, therapy) have been described. Furthermore, the autoimmune polyglandular syndromes (APS) associated with AD (revised classification, animal models, genetics, natural history) have been discussed.

Of Italian patients with primary AD (n = 317), 83% had autoimmune AD. At the onset, all patients with autoimmune AD (100%) had detectable adrenal cortex and/or steroid 21-hydroxylase autoantibodies. In the course of natural history of autoimmune AD, the presence of adrenal cortex and/or steroid 21-hydroxylase autoantibodies identified patients at risk to develop AD.

Different risks of progression to clinical AD were found in children and adults, and three stages of subclinical hypoadrenalism have been defined. Normal or atrophic adrenal glands have been demonstrated by imaging in patients with clinical or subclinical AD. Autoimmune AD presented in four forms: as APS type 1 (13% of the patients), APS type 2 (41%), APS type 4 (5%), and isolated AD (41%). There were differences in genetics, age at onset, prevalence of adrenal cortex/21-hydroxylase autoantibodies, and associated autoimmune diseases in these groups. "Incomplete" forms of APS have been identified demonstrating that APS are more prevalent than previously reported.

A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17alpha-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed. In addition, the prevalence, characteristic autoantigens, and autoantibodies of minor autoimmune diseases associated with AD have been described.

Imaging of adrenal glands, genetic tests, and biochemical analysis have been shown to contribute to early and correct diagnosis of primary non-autoimmune AD in the cases of hypoadrenalism with undetectable adrenal autoantibodies. An original flow chart for the diagnosis of AD has been proposed.

CELIAC DISEASE

Coeliac disease and autoimmune Addison's disease: a clinical pitfall.

O'Leary C, Walsh CH, Wieneke P, O'Regan P, Buckley B, O'Halloran DJ, Ferriss JB, Quigley EM, Annis P, Shanahan F, Cronin CC.

Department of Medicine, National University of Ireland, Cork, Ireland.

QJM 2002 Feb;95(2):79-82 Abstract quote
BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association.

DESIGN: Prospective screening of patients with confirmed Addison's disease.

METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening.

RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption.

DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.

HISTOPLASMOSIS

A case of Histoplasma capsulatum causing granulomatous liver disease and Addisonian crisis.

Wong P, Houston S, Power B, Lalor E, Bain VG.

Division of Gastroenterology, McGill University, Montreal, Quebec.
Can J Gastroenterol 2001 Oct;15(10):687-91 Abstract quote
A 56-year-old man with persistently elevated liver enzyme levels, fatigue, lethargy and a 9.0 kg weight loss over six months underwent a percutaneous liver biopsy that demonstrated multiple granulomas. Screening serologies were positive for histoplasmosis, and he was started on itraconazole treatment. He returned to hospital the same night with coffee-ground emesis and in Addisonian crisis requiring parenteral steroids and intensive care unit support. An abdominal computed tomography scan revealed bilaterally enlarged, nonenhancing adrenal glands suggestive of infarcts, presumed secondary to histoplasmosis.

Treatment was initiated with amphotericin B, and Histoplasma capsulatum was cultured from his urine and cerebrospinal fluid. A serum immunodiffusion test was also positive for both H and M bands, indicating active infection with Histoplasmosis species. His serum and urine samples were also weakly positive for the antigen. Despite complications of renal failure, pneumonia and congestive heart failure, he recovered with medical therapy and was discharged home to complete a prolonged course of itraconazole therapy.

While hepatic granulomas often reflect an occult disease process, the cause may remain undiscovered in 30% to 50% of patients despite exhaustive investigations. H capsulatum is an uncommon cause of granulomatous liver disease, and with its protean clinical presentation, a high index of suspicion is needed to make the diagnosis and avoid the potentially high fatality rate associated with disseminated infection.

LYMPHOMA

Adrenal lymphoma and Addison's disease: report of a case.

Lu JY, Chang CC, Chang YL.

College of Medicine, National Taiwan University, Taipei.

J Formos Med Assoc 2002 Dec;101(12):854-8 Abstract quote
Addison's disease due to adrenal lymphoma usually manifests as bilateral adrenal enlargement.

We report a patient with Addsion's disease in whom the initial overt primary adrenal insufficiency was accompanied by an only slightly enlarged right adrenal gland. The 80-year-old man presented with nausea, anorexia, weight loss, and hyperpigmentation of the skin and buccal mucosa. Addison's disease was diagnosed based on this clinical presentation and laboratory findings of low cortisol and high adrenocorticotropin levels.

Computerized tomography (CT) of the adrenal glands revealed a small right adrenal tumor. His family refused to allow percutaneous or surgical biopsy to determine the nature of the tumor. His general condition improved after steroid supplementation. However, about 1 year later, dizziness, fever, night sweats, and edema of the lower legs developed, and adrenal CT scanning revealed that the left adrenal gland had enlarged and now exceeded the size of the right one. Left adrenalectomy was performed and pathology showed a diffuse large B-cell lymphoma. Staging work-up using whole-body CT scanning suggested a stage IIIb lymphoma. Chemotherapy was given, but the disease still progressed and the patient died 4 months after diagnosis.

Primary adrenal lymphoma should be considered in the differential diagnosis of Addison's disease, even if only slight enlargement of the adrenal glands is found initially.

MYELODYSPLASIA

Myelodysplastic syndrome accompanied by Addison's disease and multiple autoimmune phenomena: steroid therapy resolved cytopenias and all immune disorders.

Funato K, Kuriyama Y, Uchida Y, Suzuki A, Miyazawa K, Ohyashiki K.

First Department of Internal Medicine, Tokyo Medical University.
Intern Med 2001 Oct;40(10):1041-4 Abstract quote
We report here a patient with myelodysplastic syndromes (MDS), which was complicated with several autoimmune disorders and asymptomatic immunologic abnormalities.

An 82-year-old woman with refractory anemia (RA) rapidly developed thrombocytopenia with the appearance of symptoms such as purpura, fatigue, anorexia, and weight loss.

Furthermore, clinical examinations revealed that she also had Addison's disease, rheumatoid arthritis, and autoimmune hematological diseases such as thrombocytopenia and hemolytic anemia. However, the cytopenia and all autoimmune disorders were remarkably improved after she received steroid therapy.

OSTEOPOROSIS

Long-term follow-up of bone mineral density in Addison's disease.

Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F.

Services of Endocrinology, University Hospital 12 de Octubre and Hospital Gregorio Maranon, Madrid, Spain.

Clin Endocrinol (Oxf) 2003 May;58(5):617-20 Abstract quote
BACKGROUND AND AIMS: There is conflicting evidence regarding the long-term effects of long-term glucocorticoid replacement therapy (GRT) on bone mineral density (BMD) in patients with chronic adrenal insufficiency. Our aim was to evaluate bone turnover and changes in BMD in patients on GRT.

PATIENTS AND METHODS: We have studied 25 subjects (six men, 19 women; aged 62.4 +/- 11.3 years, duration of disease 21.7 +/- 11.7 years, fasting cortisol 63 +/- 36 nmol/l) on GRT (hydrocortisone 30 mg/day or prednisone 7.5 mg/day). BMD was assessed at the lumbar spine (LS; L2-L4), proximal femur (PF) and ultra distal radius (UR) by dual energy X-ray absorptiometry (DXA). The rates of bone loss were calculated using previous DXA measurements at the LS (48 and 60 months earlier). Serum calcium, phosphate alkaline phosphatase (ALP), bone ALP, serum osteocalcin (BGP), intact parathyroid hormone (PTH) and 25(OH) vitamin D were also measured.

RESULTS: BMD [Z-score; 95% confidence interval (95% CI)] was normal at the LS: (-1.15-+0.07); PF: (-0.90-+0.22) and UDR (-0.77-+0.36). No significant differences were found according to the type of replacement therapy or sex. No significant bone loss (g/cm2; 95% CI) was detected at the LS: (-0.021-+0.023). Fifty-six per cent of patients met osteoporotic criteria; a greater proportion of patients treated with prednisone had osteoporosis compared with those an hydrocortisone. All bone markers were in their normal ranges.

CONCLUSIONS: Patients on long-term therapy do not show accelerated bone loss at the lumbar spine. Nevertheless, a considerable proportion of patients, mainly those treated with prednisone, showed densitometric osteoporosis.

TUBERCULOSIS

A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis.

Lam KY, Lo CY.

Faculty of Medicine, University of Hong Kong, Hong Kong.
Clin Endocrinol (Oxf) 2001 May;54(5):633-9 Abstract quote
OBJECTIVE: Tuberculosis is potentially fatal and adrenal gland involvement is uncommonly reported. The aims of the current study were to define the characteristics of tuberculosis in hospitalized patients and to analyse the features of adrenal tuberculosis.

DESIGN: Retrospective analysis of autopsies and adrenalectomies.

PATIENTS: 13,762 patients (13492 at autopsies and 270 at adrenalectomy).

MEASUREMENTS: The presence of active tuberculosis, the predisposing factors, the pathological features and organs of involvement were examined.

RESULTS: Active tuberculosis was present in 871 patients (6.5% of all 13492 autopsies). It was first diagnosed in 70% of these patients during autopsy. Cancers and a history of recent major operations were the 2 main concomitant factors in the patients with tuberculosis. Extra-pulmonary tuberculosis was seen in 261 patients (30%). The five most common extra-pulmonary sites of tuberculosis were the liver, spleen, kidney, bone and adrenal gland. Adrenal tuberculosis was seen in 52 of the 871 patients (6%) with active tuberculosis at autopsy and in 3 patients at adrenalectomy. The adrenal gland was the only organ involved by active tuberculosis in 14 of these 55 patients (25%; 35 men, 20 women). Tuberculosis was evident on macroscopic examination of the adrenal glands in 46% of the patients. On histological examination, caseous necrosis and granulomatous inflammation with Langhan's giant cells were seen in 71% and 40% of patients, respectively. Seven patients presented with signs and symptoms of Addison's disease due to bilateral adrenal involvement. Langhan's giant cells were frequently seen in histological sections and bilateral enlargement of the adrenal glands was often noted. Fine needle aspiration cytology was not useful for diagnosing adrenal tuberculosis.

CONCLUSION: Unexpected and extra-pulmonary tuberculosis such as adrenal tuberculosis has been a common problem. A high index of suspicion, correct diagnosis and proper treatment are essential for the management of tuberculosis.

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

HLA SUBTYPES

Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features.

Myhre AG, Undlien DE, Lovas K, Uhlving S, Nedrebo BG, Fougner KJ, Trovik T, Sorheim JI, Husebye ES.

Department of Pediatrics, Akershus Central Hospital, N-1474 Nordbyhagen, Norway.
J Clin Endocrinol Metab 2002 Feb;87(2):618-23 Abstract quote
Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison's disease) in industrialized countries.

We have investigated a large Norwegian cohort of patients with Addison's disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6-85 yr (mean 45 yr) with, either isolated Addison's disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03).

Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2) and DRB1*04-DQA1*03-DQB1*0302 (DR4-DQ8) haplotypes were positively correlated to Addison's disease, whereas the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB1*04 subtype DRB1*0404 was increased among Addison patients relative to controls.

We verify that autoimmunity is the main cause of Addison's disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison's disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).

TREATMENT CHARACTERIZATION

GENERAL Steroid replacement
Treatment of underlying disease process

DHEA

Dehydroepiandrosterone replacement in addison's disease.

Kim SS, Brody KH.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98105, USA.
Eur J Obstet Gynecol Reprod Biol 2001 Jul;97(1):96-7 Abstract quote
Addison's disease is a rare endocrine disorder which can be life-threatening. It can also interfere with the normal development of adrenarche, resulting in the absence of pubic and axillary hair growth.

We report a case of satisfactory restoration of adrenarche through DHEA administered in conjunction with the standard glucocortisone and fluorocortisone replacement.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated June 8, 2005

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DISEASE ASSOCIATIONS	CHARACTERIZATION
ADRENOLEUKO-DYSTROPHY
The importance of testing for adrenoleucodystrophy in males with idiopathic Addison's disease. Ronghe MD, Barton J, Jardine PE, Crowne EC, Webster MH, Armitage M, Allen JT, Steward CG. Department of Haematology/Oncology, Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK.	Arch Dis Child 2002 Mar;86(3):185-9 Abstract quote X linked adrenoleucodystrophy (X-ALD) is considered to be a rare cause of Addison's disease, although several small series suggest a high incidence in young Addisonian males. A survey in the south west of England identified 12 male patients diagnosed with Addison's disease in the period 1987-99. In 10 of these (83%) X-ALD was the underlying cause; the other two were of autoimmune aetiology. Five boys had developed Addison's disease subsequent to the diagnosis of X-ALD. Of the remaining five, in three boys the diagnosis of X-ALD was considerably delayed (by six months to two years from that of Addison's disease) and in two it was only made as a result of this survey. We also identified a patient who presented with Addison's disease at the age of 5 years but was only diagnosed as having X-ALD at the age of 34 years; in the interim his diagnosis of adrenomyeloneuropathy had been missed. Our experience highlights the absolute necessity of measuring very long chain fatty acids in all males with idiopathic Addison's disease.
AUTOIMMUNE POLYENDOCRINE SYNDROMES
Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Chair of Clinical Immunology and Allergy, Department of Medical and Surgical Sciences, University of Padova, I-35128, Padova, Italy.	Endocr Rev 2002 Jun;23(3):327-64 Abstract quote Recent progress in the understanding of autoimmune adrenal disease, including a detailed analysis of a group of patients with Addison's disease (AD), has been reviewed. Criteria for defining an autoimmune disease and the main features of autoimmune AD (history, prevalence, etiology, histopathology, clinical and laboratory findings, cell-mediated andhumoral immunity, autoantigens and their autoepitopes, genetics, animal models, associated autoimmune diseases, pathogenesis, natural history, therapy) have been described. Furthermore, the autoimmune polyglandular syndromes (APS) associated with AD (revised classification, animal models, genetics, natural history) have been discussed. Of Italian patients with primary AD (n = 317), 83% had autoimmune AD. At the onset, all patients with autoimmune AD (100%) had detectable adrenal cortex and/or steroid 21-hydroxylase autoantibodies. In the course of natural history of autoimmune AD, the presence of adrenal cortex and/or steroid 21-hydroxylase autoantibodies identified patients at risk to develop AD. Different risks of progression to clinical AD were found in children and adults, and three stages of subclinical hypoadrenalism have been defined. Normal or atrophic adrenal glands have been demonstrated by imaging in patients with clinical or subclinical AD. Autoimmune AD presented in four forms: as APS type 1 (13% of the patients), APS type 2 (41%), APS type 4 (5%), and isolated AD (41%). There were differences in genetics, age at onset, prevalence of adrenal cortex/21-hydroxylase autoantibodies, and associated autoimmune diseases in these groups. "Incomplete" forms of APS have been identified demonstrating that APS are more prevalent than previously reported. A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17alpha-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed. In addition, the prevalence, characteristic autoantigens, and autoantibodies of minor autoimmune diseases associated with AD have been described. Imaging of adrenal glands, genetic tests, and biochemical analysis have been shown to contribute to early and correct diagnosis of primary non-autoimmune AD in the cases of hypoadrenalism with undetectable adrenal autoantibodies. An original flow chart for the diagnosis of AD has been proposed.
CELIAC DISEASE
Coeliac disease and autoimmune Addison's disease: a clinical pitfall. O'Leary C, Walsh CH, Wieneke P, O'Regan P, Buckley B, O'Halloran DJ, Ferriss JB, Quigley EM, Annis P, Shanahan F, Cronin CC. Department of Medicine, National University of Ireland, Cork, Ireland.	QJM 2002 Feb;95(2):79-82 Abstract quote BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association. DESIGN: Prospective screening of patients with confirmed Addison's disease. METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening. RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption. DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.
HISTOPLASMOSIS
A case of Histoplasma capsulatum causing granulomatous liver disease and Addisonian crisis. Wong P, Houston S, Power B, Lalor E, Bain VG. Division of Gastroenterology, McGill University, Montreal, Quebec.	Can J Gastroenterol 2001 Oct;15(10):687-91 Abstract quote A 56-year-old man with persistently elevated liver enzyme levels, fatigue, lethargy and a 9.0 kg weight loss over six months underwent a percutaneous liver biopsy that demonstrated multiple granulomas. Screening serologies were positive for histoplasmosis, and he was started on itraconazole treatment. He returned to hospital the same night with coffee-ground emesis and in Addisonian crisis requiring parenteral steroids and intensive care unit support. An abdominal computed tomography scan revealed bilaterally enlarged, nonenhancing adrenal glands suggestive of infarcts, presumed secondary to histoplasmosis. Treatment was initiated with amphotericin B, and Histoplasma capsulatum was cultured from his urine and cerebrospinal fluid. A serum immunodiffusion test was also positive for both H and M bands, indicating active infection with Histoplasmosis species. His serum and urine samples were also weakly positive for the antigen. Despite complications of renal failure, pneumonia and congestive heart failure, he recovered with medical therapy and was discharged home to complete a prolonged course of itraconazole therapy. While hepatic granulomas often reflect an occult disease process, the cause may remain undiscovered in 30% to 50% of patients despite exhaustive investigations. H capsulatum is an uncommon cause of granulomatous liver disease, and with its protean clinical presentation, a high index of suspicion is needed to make the diagnosis and avoid the potentially high fatality rate associated with disseminated infection.
LYMPHOMA
Adrenal lymphoma and Addison's disease: report of a case. Lu JY, Chang CC, Chang YL. College of Medicine, National Taiwan University, Taipei.	J Formos Med Assoc 2002 Dec;101(12):854-8 Abstract quote Addison's disease due to adrenal lymphoma usually manifests as bilateral adrenal enlargement. We report a patient with Addsion's disease in whom the initial overt primary adrenal insufficiency was accompanied by an only slightly enlarged right adrenal gland. The 80-year-old man presented with nausea, anorexia, weight loss, and hyperpigmentation of the skin and buccal mucosa. Addison's disease was diagnosed based on this clinical presentation and laboratory findings of low cortisol and high adrenocorticotropin levels. Computerized tomography (CT) of the adrenal glands revealed a small right adrenal tumor. His family refused to allow percutaneous or surgical biopsy to determine the nature of the tumor. His general condition improved after steroid supplementation. However, about 1 year later, dizziness, fever, night sweats, and edema of the lower legs developed, and adrenal CT scanning revealed that the left adrenal gland had enlarged and now exceeded the size of the right one. Left adrenalectomy was performed and pathology showed a diffuse large B-cell lymphoma. Staging work-up using whole-body CT scanning suggested a stage IIIb lymphoma. Chemotherapy was given, but the disease still progressed and the patient died 4 months after diagnosis. Primary adrenal lymphoma should be considered in the differential diagnosis of Addison's disease, even if only slight enlargement of the adrenal glands is found initially.
MYELODYSPLASIA
Myelodysplastic syndrome accompanied by Addison's disease and multiple autoimmune phenomena: steroid therapy resolved cytopenias and all immune disorders. Funato K, Kuriyama Y, Uchida Y, Suzuki A, Miyazawa K, Ohyashiki K. First Department of Internal Medicine, Tokyo Medical University.	Intern Med 2001 Oct;40(10):1041-4 Abstract quote We report here a patient with myelodysplastic syndromes (MDS), which was complicated with several autoimmune disorders and asymptomatic immunologic abnormalities. An 82-year-old woman with refractory anemia (RA) rapidly developed thrombocytopenia with the appearance of symptoms such as purpura, fatigue, anorexia, and weight loss. Furthermore, clinical examinations revealed that she also had Addison's disease, rheumatoid arthritis, and autoimmune hematological diseases such as thrombocytopenia and hemolytic anemia. However, the cytopenia and all autoimmune disorders were remarkably improved after she received steroid therapy.
OSTEOPOROSIS
Long-term follow-up of bone mineral density in Addison's disease. Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Services of Endocrinology, University Hospital 12 de Octubre and Hospital Gregorio Maranon, Madrid, Spain.	Clin Endocrinol (Oxf) 2003 May;58(5):617-20 Abstract quote BACKGROUND AND AIMS: There is conflicting evidence regarding the long-term effects of long-term glucocorticoid replacement therapy (GRT) on bone mineral density (BMD) in patients with chronic adrenal insufficiency. Our aim was to evaluate bone turnover and changes in BMD in patients on GRT. PATIENTS AND METHODS: We have studied 25 subjects (six men, 19 women; aged 62.4 +/- 11.3 years, duration of disease 21.7 +/- 11.7 years, fasting cortisol 63 +/- 36 nmol/l) on GRT (hydrocortisone 30 mg/day or prednisone 7.5 mg/day). BMD was assessed at the lumbar spine (LS; L2-L4), proximal femur (PF) and ultra distal radius (UR) by dual energy X-ray absorptiometry (DXA). The rates of bone loss were calculated using previous DXA measurements at the LS (48 and 60 months earlier). Serum calcium, phosphate alkaline phosphatase (ALP), bone ALP, serum osteocalcin (BGP), intact parathyroid hormone (PTH) and 25(OH) vitamin D were also measured. RESULTS: BMD [Z-score; 95% confidence interval (95% CI)] was normal at the LS: (-1.15-+0.07); PF: (-0.90-+0.22) and UDR (-0.77-+0.36). No significant differences were found according to the type of replacement therapy or sex. No significant bone loss (g/cm2; 95% CI) was detected at the LS: (-0.021-+0.023). Fifty-six per cent of patients met osteoporotic criteria; a greater proportion of patients treated with prednisone had osteoporosis compared with those an hydrocortisone. All bone markers were in their normal ranges. CONCLUSIONS: Patients on long-term therapy do not show accelerated bone loss at the lumbar spine. Nevertheless, a considerable proportion of patients, mainly those treated with prednisone, showed densitometric osteoporosis.
TUBERCULOSIS
A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Lam KY, Lo CY. Faculty of Medicine, University of Hong Kong, Hong Kong.	Clin Endocrinol (Oxf) 2001 May;54(5):633-9 Abstract quote OBJECTIVE: Tuberculosis is potentially fatal and adrenal gland involvement is uncommonly reported. The aims of the current study were to define the characteristics of tuberculosis in hospitalized patients and to analyse the features of adrenal tuberculosis. DESIGN: Retrospective analysis of autopsies and adrenalectomies. PATIENTS: 13,762 patients (13492 at autopsies and 270 at adrenalectomy). MEASUREMENTS: The presence of active tuberculosis, the predisposing factors, the pathological features and organs of involvement were examined. RESULTS: Active tuberculosis was present in 871 patients (6.5% of all 13492 autopsies). It was first diagnosed in 70% of these patients during autopsy. Cancers and a history of recent major operations were the 2 main concomitant factors in the patients with tuberculosis. Extra-pulmonary tuberculosis was seen in 261 patients (30%). The five most common extra-pulmonary sites of tuberculosis were the liver, spleen, kidney, bone and adrenal gland. Adrenal tuberculosis was seen in 52 of the 871 patients (6%) with active tuberculosis at autopsy and in 3 patients at adrenalectomy. The adrenal gland was the only organ involved by active tuberculosis in 14 of these 55 patients (25%; 35 men, 20 women). Tuberculosis was evident on macroscopic examination of the adrenal glands in 46% of the patients. On histological examination, caseous necrosis and granulomatous inflammation with Langhan's giant cells were seen in 71% and 40% of patients, respectively. Seven patients presented with signs and symptoms of Addison's disease due to bilateral adrenal involvement. Langhan's giant cells were frequently seen in histological sections and bilateral enlargement of the adrenal glands was often noted. Fine needle aspiration cytology was not useful for diagnosing adrenal tuberculosis. CONCLUSION: Unexpected and extra-pulmonary tuberculosis such as adrenal tuberculosis has been a common problem. A high index of suspicion, correct diagnosis and proper treatment are essential for the management of tuberculosis.

Epidemiology
Disease Associations
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Treatment
Commonly Used Terms
Internet Links

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
HLA SUBTYPES
Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features. Myhre AG, Undlien DE, Lovas K, Uhlving S, Nedrebo BG, Fougner KJ, Trovik T, Sorheim JI, Husebye ES. Department of Pediatrics, Akershus Central Hospital, N-1474 Nordbyhagen, Norway.	J Clin Endocrinol Metab 2002 Feb;87(2):618-23 Abstract quote Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison's disease) in industrialized countries. We have investigated a large Norwegian cohort of patients with Addison's disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6-85 yr (mean 45 yr) with, either isolated Addison's disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03). Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB103-DQA105-DQB102 (DR3-DQ2) and DRB104-DQA103-DQB10302 (DR4-DQ8) haplotypes were positively correlated to Addison's disease, whereas the DRB101-DQA10101-DQB10501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB104 subtype DRB1*0404 was increased among Addison patients relative to controls. We verify that autoimmunity is the main cause of Addison's disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison's disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).

TREATMENT	CHARACTERIZATION
GENERAL	Steroid replacement Treatment of underlying disease process
DHEA
Dehydroepiandrosterone replacement in addison's disease. Kim SS, Brody KH. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98105, USA.	Eur J Obstet Gynecol Reprod Biol 2001 Jul;97(1):96-7 Abstract quote Addison's disease is a rare endocrine disorder which can be life-threatening. It can also interfere with the normal development of adrenarche, resulting in the absence of pubic and axillary hair growth. We report a case of satisfactory restoration of adrenarche through DHEA administered in conjunction with the standard glucocortisone and fluorocortisone replacement.