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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
Addison disease, or primary adrenal insufficiency, is a In autoimmune polyendocrinopathy syndrome type 2, Ad-
chronic disorder of the adrenal cortex resulting in inade- dison disease occurs in association with type 1 diabetes or
quate production of glucocorticoid and mineralocorticoid.1 autoimmune thyroid disease. Other autoimmune disorders,
It is a relatively rare disease with a prevalence of about 140 such as primary gonadal failure, pernicious anemia, and
per million and an annual incidence about 4 per million in vitiligo also might be present.
Western populations.2 Addison disease is a potentially le- Several infective agents can affect the adrenal gland,
thal condition if left untreated, yet its diagnosis is often resulting in adrenal failure. Tuberculosis remains the most
missed or delayed. Furthermore, recent studies have shown common cause of Addison disease worldwide.
that treated patients with Addison disease have a perception Adrenoleukodystrophy is an important cause of Addison
of reduced health-related quality of life2 and remain at risk disease in men. It is caused by accumulation of very long-
of premature death.3 chain 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.
CAUSES
The most common cause of Addison disease in developed
countries is autoimmune adrenalitis (Table 1). This can PRESENTATION
occur in isolation or as a part of the autoimmune polyen- Addison disease presents insidiously with nonspecific
docrinopathy syndromes (type 1 and type 2). In autoimmune symptoms that easily can be mistaken for other more prev-
polyendocrinopathy syndrome type 1, Addison disease occurs alent conditions (Table 2). For example, its common symp-
in association with autoimmune hypoparathyroidism, chronic toms, chronic fatigue, malaise, and anorexia may mimic a
mucocutaneous candidiasis, and other autoimmune disor- depressive illness. Likewise, unintentional weight loss, nau-
ders, including type 1 diabetes, chronic active hepatitis, sea, vomiting, and vague abdominal pain may be confused
primary gonadal failure, and autoimmune thyroid disease. with symptoms of a gastrointestinal or eating disorder.
Symptoms of postural hypotension (syncope, postural diz-
ziness) and hypoglycemia are late manifestations of the
Funding: The work of Dr. Vaidya was partly supported by the Pen-
insula Collaboration for Leadership in Applied Health Research and Care disease. Pigmentation of skin and mucous membranes,
(PenCLAHRC) Funding. when present, is a cardinal sign of Addison disease.
Conflict of Interest: None. Several biochemical abnormalities may provide a clue to
Authorship: Both authors had access to the data and a role in writing the diagnosis of Addison disease (Table 2). In a patient with
the manuscript. unexplained hyponatremia, adrenal insufficiency must be
Requests for reprints should be addressed to Bijay Vaidya, PhD, De-
partment of Endocrinology, Royal Devon & Exeter Hospital, Exeter EX2 excluded before making the diagnosis of syndrome of in-
5DW, UK. appropriate antidiuretic hormone secretion. Likewise, in a
E-mail address: bijay.vaidya@pms.ac.uk patient with unexplained hyperkalemia, Addison disease
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2009.12.017
410 The American Journal of Medicine, Vol 123, No 5, May 2010
although the threshold cortisol level may vary according investigation to distinguish between Addison disease and
to local laboratory reference ranges. If the cortisol re- secondary adrenal insufficiency.
sponse to synacthen is inadequate, plasma ACTH level
should be measured. A raised plasma ACTH level con- Investigating the Cause of Addison Disease
firms the diagnosis of Addison disease, whereas patients Once a diagnosis of Addison disease is confirmed, further
with secondary adrenal insufficiency due to pituitary or investigations are needed to elucidate the underlying
hypothalamic disorders have a low or inappropriately cause (Figure). There may be clues in the history and
normal plasma ACTH level. Plasma renin activity is examination. For example, a presence of another autoim-
elevated in Addison disease and is sometimes a useful mune condition (eg, vitiligo) will point to autoimmune
Addison disease. Likewise, neurological manifestations other glucocorticoids, including cortisone, prednisolone,
in a young man should raise a suspicion of adrenole- and dexamethasone are occasionally used. Long-acting glu-
ukodystrophy. cocorticoids, dexamethasone, and prednisolone have the
The presence of adrenal antibodies indicates autoim- advantage of a once-daily dosing schedule but have the
mune Addison disease. Ideally, both adrenal cortex antibod- drawback of losing the diurnal pattern, resulting in excess
ies and 21-hydroxylase antibodies should be measured.4 glucocorticoid levels overnight.
21-hydroxylase antibodies are more sensitive than adrenal In Addison disease, standard replacement dose of hydro-
cortex antibodies in the diagnosis of autoimmune Addison cortisone is 15-25 mg a day, given in 2 or 3 divided doses.1
disease. In patients with autoimmune Addison disease, it is A typical starting regime would consist of hydrocortisone
important to screen for other features of autoimmune poly- 10 mg on waking, 5 mg at around noon, and 5 mg early
endocrinopathy syndromes. In men with negative adrenal evening. There are no satisfactory biochemical tests to as-
antibodies, plasma very long-chain fatty acids should be sess the adequacy of glucocorticoid replacement. In prac-
checked to exclude adrenoleukodystrophy. If the cause still tice, the dose of hydrocortisone is maintained on the basis of
remains unclear, a computed tomographic scan of the adre- clinical assessment, taking an account of patient’s well-
nal glands should be carried out, which may show evidence being, and presence of any signs of over-replacement (eg,
of metastasis, infiltration, hemorrhage, infarction, or infec- hypertension, weight gain, thin skin, easy bruising, and
tion (for example, adrenal calcification in longstanding glucose intolerance) or under-replacement (eg, weight loss
tuberculosis). and pigmentation).
During intercurrent illnesses, perioperative periods, and
other forms of stress, patients should increase the dose of
MANAGEMENT hydrocortisone to mimic the normal physiological response
(Table 3). Some drugs (eg, rifampicin, phenobarbitone, and
Routine Management of Addison Disease phenytoin) increase hepatic metabolism of glucocorticoids,
Routine treatment of Addison disease involves replacement and patients starting on such drugs may need to increase the
of the glucocorticoid and mineralocorticoid hormones. dose of hydrocortisone.
Some forms of Addison disease also will require specific
treatment for the underlying cause, for example, antituber- Mineralocorticoid Replacement. Fludrocortisone is the
culous drugs in Addison disease due to tuberculosis. only available agent for mineralocorticoid replacement. The
usual starting dose is 100 g a day. The dose is adjusted
Glucocorticoid Replacement. Hydrocortisone is most (usually 50-200 g a day) according to clinical response.
commonly used for glucocorticoid replacement, although Hypertension and presence of ankle edema suggest over-
Table 3 Recommendations for an Increased Dose Hydrocortisone in Patients with Addison Disease in Different Conditions
replacement, while salt craving, postural hypotension, and and are decreased in Addison disease. A meta-analysis of
hyperkalemia are signs of under-replacement. An assess- randomized controlled trials of DHEA treatment in women
ment of plasma renin activity also is helpful in optimizing with Addison disease has shown evidence of a nominal
the dose of fludrocortisone, as suppressed and elevated beneficial effect on health-related quality of life.5 More
plasma renin activity indicate over-replacement and under- long-term efficacy and safety data are needed before DHEA
replacement, respectively. replacement can be advocated in routine clinical practice.