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Addison Disease in Adults: Diagnosis and Management
Ali J. Chakera, MBChB, MRCP, Bijay Vaidya, PhD, FRCP
Department of Endocrinology, Royal Devon & Exeter Hospital, Exeter, UK.
ABSTRACT Addison disease is a rare but potentially fatal disorder of the adrenal glands. Its manifestations are often confused with many common disorders, and a high index of suspicion is required for the diagnosis. Optimum steroid replacement and patient education are vital for good quality of life and to prevent acute adrenal crisis in this condition. © 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123, 409-413 KEYWORDS: Addison disease; Adrenal; Glucocorticoid; Hypoadrenalism; Mineralocorticoid
Addison disease, or primary adrenal insufﬁciency, is a chronic disorder of the adrenal cortex resulting in inadequate production of glucocorticoid and mineralocorticoid.1 It is a relatively rare disease with a prevalence of about 140 per million and an annual incidence about 4 per million in Western populations.2 Addison disease is a potentially lethal condition if left untreated, yet its diagnosis is often missed or delayed. Furthermore, recent studies have shown that treated patients with Addison disease have a perception of reduced health-related quality of life2 and remain at risk of premature death.3
The most common cause of Addison disease in developed countries is autoimmune adrenalitis (Table 1). This can occur in isolation or as a part of the autoimmune polyendocrinopathy syndromes (type 1 and type 2). In autoimmune polyendocrinopathy syndrome type 1, Addison disease occurs in association with autoimmune hypoparathyroidism, chronic mucocutaneous candidiasis, and other autoimmune disorders, including type 1 diabetes, chronic active hepatitis, primary gonadal failure, and autoimmune thyroid disease.
Funding: The work of Dr. Vaidya was partly supported by the Peninsula Collaboration for Leadership in Applied Health Research and Care (PenCLAHRC) Funding. Conﬂict of Interest: None. Authorship: Both authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Bijay Vaidya, PhD, Department of Endocrinology, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK. E-mail address: email@example.com
In autoimmune polyendocrinopathy syndrome type 2, Addison disease occurs in association with type 1 diabetes or autoimmune thyroid disease. Other autoimmune disorders, such as primary gonadal failure, pernicious anemia, and vitiligo also might be present. Several infective agents can affect the adrenal gland, resulting in adrenal failure. Tuberculosis remains the most common cause of Addison disease worldwide. Adrenoleukodystrophy is an important cause of Addison disease in men. It is caused by accumulation of very longchain fatty acids in the adrenal gland as well as in the central and peripheral nervous system. Adrenal failure may precede neurological manifestations in this disorder.
Addison disease presents insidiously with nonspeciﬁc symptoms that easily can be mistaken for other more prevalent conditions (Table 2). For example, its common symptoms, chronic fatigue, malaise, and anorexia may mimic a depressive illness. Likewise, unintentional weight loss, nausea, vomiting, and vague abdominal pain may be confused with symptoms of a gastrointestinal or eating disorder. Symptoms of postural hypotension (syncope, postural dizziness) and hypoglycemia are late manifestations of the disease. Pigmentation of skin and mucous membranes, when present, is a cardinal sign of Addison disease. Several biochemical abnormalities may provide a clue to the diagnosis of Addison disease (Table 2). In a patient with unexplained hyponatremia, adrenal insufﬁciency must be excluded before making the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. Likewise, in a patient with unexplained hyperkalemia, Addison disease
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most common form caused by mutations in the cytochrome P-450c21 (CYP21) gene. Some patients with Addison disease show a raised serum thyrotropin level at presentation. This involves injecting 250 g of synacthen (tetracosactrin. which may lead to a misdiagnosis of an acute abdomen. dementia. muscle weakness. mutations in the melanocortin 2 receptor [MC2R] gene) and type 2 (normal stature. mucocutaneous candidiasis. and abdominal pain. Autosomal recessive. adrenocortical insufﬁciency. alacrimia. retinal degeneration. Genetic defect unknown. Furthermore. X-linked recessive. other autoimmune disorders. Associated with meningococcal septicemia (Waterhouse. other autoimmune disorders. Bilateral adrenalectomy or drugs (ketoconazole. Associated with antiphospholipid syndrome. unexplained recurrent hypoglycemic episodes in a patient with type 1 diabetes should also raise a suspicion of Addison disease. Autosomal recessive. 30. Malignant: metastasis or lymphoma. X-linked recessive. genital abnormalities. May 2010 INVESTIGATIONS Diagnosing Addison Disease A morning serum cortisol level higher than 500 nmol/L (18 g/dL) usually excludes Addison disease. Mutations in the dosage-sensitive sex-reversal adrenal hypoplasia critical region on the x-chromosome protein 1 (DAX-1) gene. Acute adrenal crisis is usually precipitated by infection or other forms of severe physiological stress. metaphyseal dysplasia. Ophthalmoplegia. alacrimia syndrome (AAAS) gene. Elevated plasma very long-chain fatty acids. mutations in the melanocortin 2 receptor accessory protein [MRAP] gene). No 5. testicular failure. The diagnosis of Addison disease must be considered in a hypothyroid patient whose symptoms worsen after starting thyroxine. Mutations in the ATP-binding cassette subfamily D member 1 (ABCD1) gene. Autosomal recessive. Vol 123. Ambiguous external genitalia. Often associated with immunodeﬁciency.1 Table 1 Causes Important Causes of Addison Disease Key Associated Features Hypoparathyroidism. lactic acidosis. etomidate. Autosomal recessive. . vomiting.410 must be considered as a possibility before treating the patient with insulin and dextrose infusion. Autoimmunity Autoimmune polyendocrinopathy syndrome type 1 Autoimmune polyendocrinopathy syndrome type 2 Isolated autoimmune Addison disease Infective Tuberculosis Fungal Acquired immune deﬁciency syndrome Genetic Adrenoleukodystrophy Congenital adrenal hyperplasia Adrenal hypoplasia congenita Familial glucocorticoid deﬁciency IMAGe syndrome Allgrove syndrome (Triple A syndrome) Kearns-Sayre syndrome (Mitochondrial Addison disease) Miscellaneous Inﬁltration Hemorrhage Infarction Iatrogenic Neurological deﬁcit. Blood samples for serum cortisol are taken at 0. sensory deafness. cardiomyopathy. Intact mineralocorticoid function. An increase in serum cortisol level 30 or 60 minutes after the synacthen injection to above 500 nmol/L (18 g/dL) is considered a normal response. About half of patients with Addison disease present acutely with adrenal crises. Type 1 (tall stature. Salt wasting or hypertension in some forms. coccidioidomycosis. Autoimmune thyroid disease.1 This is a life-threatening emergency characterized by severe dehydration and circulatory shock. synthetic analogue of adrenocorticotrophic hormone [ACTH]) intramuscularly or intravenously. deafness. Achalasia. most patients will need a short synacthen test for conﬁrmation or exclusion of Addison disease. Mutations in the autoimmune regulator-1 (AIRE-1) gene. — Signs of active tuberculosis often absent. aminoglutethimide. Several forms due to mutations in different genes. mitotane). Intra-uterine growth retardation. mental retardation. Systemic infection with histoplasmosis. Nonmalignant: amyloidosis. hemochromatosis or sarcoidosis.1 However.Fredrickson syndrome) or anticoagulation. Mutations in the achalasia. and 60 minutes. autoimmune diabetes. Hypogonadotropic hypogonadism. Often associated with cytomegalovirus adrenalitis. Adrenal calciﬁcation. The American Journal of Medicine. cryptococcosis. Deletions in mitochondrial DNA. while a level below 165 nmol/L (6 g/dL) is suggestive of adrenal insufﬁciency. Many patients also have nausea.
If the cortisol response to synacthen is inadequate. There may be clues in the history and examination. . Signs and Investigations that Point to Addison Disease Signs Hyperpigmentation of skin and mucous membranes Low blood pressure Postural hypotension Laboratory results Hyponatremia Hyperkalemia Hypoglycaemia Raised urea Metabolic acidosis Hypercalcemia Raised thyroid-stimulating hormone Normocytic anemia Fatigue Malaise Loss of appetite Nausea and vomiting Abdominal pain Weight loss Postural dizziness “Funny turns” – may be due to postural hypotension or hypoglycemia Myalgia Joint pain Salt craving Loss of libido (particularly in women) although the threshold cortisol level may vary according to local laboratory reference ranges. Investigating the Cause of Addison Disease Once a diagnosis of Addison disease is conﬁrmed. For example. VLCFA very long-chain fatty acid. whereas patients with secondary adrenal insufﬁciency due to pituitary or hypothalamic disorders have a low or inappropriately normal plasma ACTH level. APS1 autoimmune polyendocrinopathy syndrome type 1. Plasma renin activity is elevated in Addison disease and is sometimes a useful investigation to distinguish between Addison disease and secondary adrenal insufﬁciency.Chakera and Vaidya Table 2 Symptoms Addison Disease 411 Symptoms. APS2 autoimmune polyendocrinopathy syndrome type 2. ACTH adrenocorticotrophic hormone. a presence of another autoimmune condition (eg. PTH parathyroid hormone. A raised plasma ACTH level conﬁrms the diagnosis of Addison disease. further investigations are needed to elucidate the underlying cause (Figure). vitiligo) will point to autoimmune Figure Algorithm to determine the cause of Addison disease in adults. plasma ACTH level should be measured.
resulting in excess glucocorticoid levels overnight. common cold. cardiothoracic surgery) Other Pregnancy Physical exercise Psychologically stressful situation (eg. or both (eg. May 2010 other glucocorticoids. Intravenous injections 50 mg every 8 h or continuous intravenous infusion 150 mg/24 h. patients should increase the dose of hydrocortisone to mimic the normal physiological response (Table 3). If unable to take orally. gastroenteritis) Serious medical illness (eg. phenobarbitone. hemorrhage. thin skin. and patients starting on such drugs may need to increase the dose of hydrocortisone. prednisolone. the dose of hydrocortisone is maintained on the basis of clinical assessment. If the cause still remains unclear. hypertension. it is important to screen for other features of autoimmune polyendocrinopathy syndromes. In patients with autoimmune Addison disease. dexamethasone. rifampicin. colonoscopy) Major surgery (eg. Intercurrent illness Minor febrile illness (eg. Long-acting glucocorticoids. The American Journal of Medicine. In men with negative adrenal antibodies. for example.412 Addison disease. There are no satisfactory biochemical tests to assess the adequacy of glucocorticoid replacement. Fludrocortisone is the only available agent for mineralocorticoid replacement. and prednisolone have the advantage of a once-daily dosing schedule but have the drawback of losing the diurnal pattern. give a dose of 50 mg parenterally during the second stage. Some drugs (eg. although Table 3 Conditions Recommendations for an Increased Dose Hydrocortisone in Patients with Addison Disease in Different Conditions Increment in Hydrocortisone Dose Double the dose. and other forms of stress. and phenytoin) increase hepatic metabolism of glucocorticoids. easy bruising. both adrenal cortex antibodies and 21-hydroxylase antibodies should be measured. 5 mg at around noon. severe sepsis. In Addison disease. which may show evidence of metastasis. Admission to hospital for intravenous hydrocortisone. given in 2 or 3 divided doses. Dose increment usually not necessary. antituberculous drugs in Addison disease due to tuberculosis. Ideally. plasma very long-chain fatty acids should be checked to exclude adrenoleukodystrophy.4 21-hydroxylase antibodies are more sensitive than adrenal cortex antibodies in the diagnosis of autoimmune Addison disease. neurological manifestations in a young man should raise a suspicion of adrenoleukodystrophy. and 5 mg early evening. examination. standard replacement dose of hydrocortisone is 15-25 mg a day. Taper down to the maintenance dose over 2-3 days after the illness. In practice. taking an account of patient’s wellbeing.1 A typical starting regime would consist of hydrocortisone 10 mg on waking. dental extraction. weight loss and pigmentation). taper down to the maintenance dose over 2-3 days. Intravenous injections 50 mg every 8 h or continuous intravenous infusion 150 mg/24 h.* Double the dose on the day. . Hydrocortisone is most commonly used for glucocorticoid replacement. adrenal calciﬁcation in longstanding tuberculosis). The usual starting dose is 100 g a day. but may need to give parenterally if unable to take oral medication because of nausea. a computed tomographic scan of the adrenal glands should be carried out. Dose increment not necessary. Some forms of Addison disease also will require speciﬁc treatment for the underlying cause. Dose increment not necessary for gentle exercise. During intercurrent illnesses. pancreatitis) or major trauma Surgery Minor surgery or invasive diagnostic procedure (eg. and dexamethasone are occasionally used. infarction. gastroscopy. viral chest infection) Persistent vomiting or diarrhea. Increase the dose by 5 mg before strenuous exercise. and glucose intolerance) or under-replacement (eg. The presence of adrenal antibodies indicates autoimmune Addison disease. Mineralocorticoid Replacement.* Following uncomplicated procedure. Hypertension and presence of ankle edema suggest over- MANAGEMENT Routine Management of Addison Disease Routine treatment of Addison disease involves replacement of the glucocorticoid and mineralocorticoid hormones. double the dose. weight gain. perioperative periods. and presence of any signs of over-replacement (eg. During labor. or infection (for example. No 5. intra-abdominal surgery. interview) *No need to replace mineralocorticoid at these doses of hydrocortisone as high dose hydrocortisone has mineralocorticoid activity. Glucocorticoid Replacement. herniorrhaphy. including cortisone. inﬁltration. Likewise. myocardial infarction. Vol 123. The dose is adjusted (usually 50-200 g a day) according to clinical response.
If acute adrenal crisis is suspected in an undiagnosed patient. Leonsson-Zachrisson M. Management Controversy: Dehydroepiandrosterone Replacement Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate are androgens secreted by the adrenal cortex . J Clin Endocrinol Metab. postural hypotension. Lovas K. Patients should carry a steroid card and a medic alert bracelet with details of the diagnosis. Elamin MB. Falorni A. 2006. the treatment should not be delayed to carry out diagnostic tests. an infection) should be sought and treated. Allolio B. J Clin Endocrinol Metab. Patient education is critical for the successful management of Addison disease. Oden A. J Clin Endocrinol Metab. Lancet. 2009. Rostami-Hodjegan A. Patient Education.6 which might improve quality of life and other outcomes in patients with this condition. Skinningsrud B. and serum thyrotropin (thyroid dysfunction). 94:4882-4890. 2. et al. 2009. et al. and check the regularity of menstrual cycle in women (premature ovarian failure). and reinforce patient education. Alkatib AA. Arlt W. The recommended initial dose of hydrocortisone is 100 mg.94:1548-1554. with subsequent doses of 100-200 mg over 24 hours divided into 3 or 4 doses. Johannsson G. Endogenous cortisol secretion starts at around 3 AM. 5. Debono M. In patients with autoimmune Addison disease. while salt craving. you also should screen annually for associated autoimmune disorders with full blood count (pernicious anemia). Bergthorsdottir R.91:4849-4853. Italian addison network study: update of diagnostic criteria for the etiological classiﬁcation of primary adrenal insufﬁciency. 2009. Premature mortality in patients with Addison’s disease: a populationbased study. De Bellis A. as suppressed and elevated plasma renin activity indicate over-replacement and underreplacement.Chakera and Vaidya Addison Disease 413 and are decreased in Addison disease. A promising advance in the management of Addison disease is development of a modiﬁed-release hydrocortisone tablet that can mimic the circadian rhythm of endogenous cortisol production. Clinical.1 The precipitating cause (for example. 6. peaking in the morning after waking. et al. and hyperkalemia are signs of under-replacement. fasting glucose (diabetes mellitus). Laureti S. 2004. Ghobadi C. Cosma M. respectively. and genetic features of autoimmune primary adrenal insufﬁciency: observations from a Norwegian Registry. An assessment of plasma renin activity also is helpful in optimizing the dose of ﬂudrocortisone. They and their family members should be taught to give intramuscular hydrocortisone injections during emergencies. J Clin Endocrinol Metab. Erichsen MM. et al. FUTURE DEVELOPMENT Current regimes of glucocorticoid replacement in Addison disease are a poor surrogate for the homeostasis of endogenous cortisol production. A meta-analysis of randomized controlled trials of DHEA treatment in women with Addison disease has shown evidence of a nominal beneﬁcial effect on health-related quality of life. Patients with Addison disease should be reviewed annually to assess well-being. Patients may need several liters of normal saline to maintain their blood pressure. immunological. Information on management of steroid replacement during sickness can prevent acute adrenal crisis. Management of an Adrenal Crisis An adrenal crisis is a life-threatening medical emergency that requires urgent hospital admission for treatment with intravenous hydrocortisone and crystalloid.89: 1598-1604.5 More long-term efﬁcacy and safety data are needed before DHEA replacement can be advocated in routine clinical practice. monitor whether the glucocorticoid and mineralocorticoid replacement is adequate. Modiﬁed-release hydrocortisone to provide circadian cortisol proﬁles. and gradually wanes to nothing by midnight. 2003. replacement. 4. J Clin Endocrinol Metab.361:18811893.94:3676-3681. Adrenal insufﬁciency. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufﬁciency. 3. References 1. Follow-up.
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