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UPDATE IN OFFICE MANAGEMENT

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 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

must be considered as a possibility before treating the pa- INVESTIGATIONS


tient with insulin and dextrose infusion. Some patients with
Addison disease show a raised serum thyrotropin level at Diagnosing Addison Disease
presentation. The diagnosis of Addison disease must be A morning serum cortisol level higher than 500 nmol/L
considered in a hypothyroid patient whose symptoms (18 ␮g/dL) usually excludes Addison disease, while a
worsen after starting thyroxine. Furthermore, unexplained level below 165 nmol/L (6 ␮g/dL) is suggestive of adre-
recurrent hypoglycemic episodes in a patient with type 1 nal insufficiency.1 However, most patients will need a
diabetes should also raise a suspicion of Addison disease. short synacthen test for confirmation or exclusion of
About half of patients with Addison disease present Addison disease. This involves injecting 250 ␮g of syn-
acutely with adrenal crises.1 This is a life-threatening emer- acthen (tetracosactrin; synthetic analogue of adrenocor-
gency characterized by severe dehydration and circulatory ticotrophic hormone [ACTH]) intramuscularly or intra-
shock. Many patients also have nausea, vomiting, and ab- venously. Blood samples for serum cortisol are taken at
dominal pain, which may lead to a misdiagnosis of an acute 0, 30, and 60 minutes. An increase in serum cortisol level
abdomen. Acute adrenal crisis is usually precipitated by 30 or 60 minutes after the synacthen injection to above
infection or other forms of severe physiological stress. 500 nmol/L (18 ␮g/dL) is considered a normal response,1

Table 1 Important Causes of Addison Disease

Causes Key Associated Features


Autoimmunity
Autoimmune polyendocrinopathy Hypoparathyroidism, mucocutaneous candidiasis, other autoimmune disorders. Autosomal
syndrome type 1 recessive. Mutations in the autoimmune regulator-1 (AIRE-1) gene.
Autoimmune polyendocrinopathy Autoimmune thyroid disease, autoimmune diabetes, other autoimmune disorders.
syndrome type 2
Isolated autoimmune Addison disease —
Infective
Tuberculosis Signs of active tuberculosis often absent. Adrenal calcification.
Fungal Systemic infection with histoplasmosis, cryptococcosis, coccidioidomycosis. Often
associated with immunodeficiency.
Acquired immune deficiency Often associated with cytomegalovirus adrenalitis.
syndrome
Genetic
Adrenoleukodystrophy Neurological deficit, dementia, testicular failure. Elevated plasma very long-chain fatty
acids. X-linked recessive. Mutations in the ATP-binding cassette subfamily D member 1
(ABCD1) gene.
Congenital adrenal hyperplasia Ambiguous external genitalia. Salt wasting or hypertension in some forms. Autosomal
recessive. Several forms due to mutations in different genes, most common form caused
by mutations in the cytochrome P-450c21 (CYP21) gene.
Adrenal hypoplasia congenita Hypogonadotropic hypogonadism. X-linked recessive. Mutations in the dosage-sensitive
sex-reversal adrenal hypoplasia critical region on the x-chromosome protein 1 (DAX-1)
gene.
Familial glucocorticoid deficiency Intact mineralocorticoid function. Autosomal recessive. Type 1 (tall stature; mutations in
the melanocortin 2 receptor [MC2R] gene) and type 2 (normal stature; mutations in the
melanocortin 2 receptor accessory protein [MRAP] gene).
IMAGe syndrome Intra-uterine growth retardation, metaphyseal dysplasia, genital abnormalities. Genetic
defect unknown.
Allgrove syndrome (Triple A Achalasia, alacrimia, mental retardation, deafness. Autosomal recessive. Mutations in the
syndrome) achalasia, adrenocortical insufficiency, alacrimia syndrome (AAAS) gene.
Kearns-Sayre syndrome Ophthalmoplegia, retinal degeneration, muscle weakness, cardiomyopathy, lactic acidosis,
(Mitochondrial Addison disease) sensory deafness. Deletions in mitochondrial DNA.
Miscellaneous
Infiltration Malignant: metastasis or lymphoma.
Nonmalignant: amyloidosis, hemochromatosis or sarcoidosis.
Hemorrhage Associated with meningococcal septicemia (Waterhouse- Fredrickson syndrome) or
anticoagulation.
Infarction Associated with antiphospholipid syndrome.
Iatrogenic Bilateral adrenalectomy or drugs (ketoconazole, etomidate, aminoglutethimide, mitotane).
Chakera and Vaidya Addison Disease 411

Table 2 Symptoms, Signs and Investigations that Point to Addison Disease

Symptoms Signs Laboratory results


Fatigue Hyperpigmentation of skin and mucous Hyponatremia
Malaise membranes Hyperkalemia
Loss of appetite Low blood pressure Hypoglycaemia
Nausea and vomiting Postural hypotension Raised urea
Abdominal pain Metabolic acidosis
Weight loss Hypercalcemia
Postural dizziness Raised thyroid-stimulating hormone
“Funny turns” – may be due to Normocytic anemia
postural hypotension or
hypoglycemia
Myalgia
Joint pain
Salt craving
Loss of libido (particularly in women)

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

Figure Algorithm to determine the cause of Addison disease in adults. ACTH ⫽


adrenocorticotrophic hormone; APS1 ⫽ autoimmune polyendocrinopathy syndrome type
1; APS2 ⫽ autoimmune polyendocrinopathy syndrome type 2; PTH ⫽ parathyroid hor-
mone; VLCFA ⫽ very long-chain fatty acid.
412 The American Journal of Medicine, Vol 123, No 5, May 2010

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

Conditions Increment in Hydrocortisone Dose


Intercurrent illness
Minor febrile illness (eg, common cold, viral chest infection) Double the dose. Taper down to the maintenance dose over 2-3 days
after the illness.
Persistent vomiting or diarrhea, or both (eg, gastroenteritis) Admission to hospital for intravenous hydrocortisone.
Serious medical illness (eg, severe sepsis, myocardial Intravenous injections 50 mg every 8 h or continuous intravenous
infarction, pancreatitis) or major trauma infusion 150 mg/24 h.*
Surgery
Minor surgery or invasive diagnostic procedure (eg, dental Double the dose on the day.
extraction, herniorrhaphy, gastroscopy, colonoscopy)
Major surgery (eg, intra-abdominal surgery, cardiothoracic Intravenous injections 50 mg every 8 h or continuous intravenous
surgery) infusion 150 mg/24 h.* Following uncomplicated procedure, taper
down to the maintenance dose over 2-3 days.
Other
Pregnancy Dose increment usually not necessary, but may need to give
parenterally if unable to take oral medication because of nausea.
During labor, double the dose. If unable to take orally, give a dose
of 50 mg parenterally during the second stage.
Physical exercise Dose increment not necessary for gentle exercise. Increase the dose
by 5 mg before strenuous exercise.
Psychologically stressful situation (eg, examination, Dose increment not necessary.
interview)
*No need to replace mineralocorticoid at these doses of hydrocortisone as high dose hydrocortisone has mineralocorticoid activity.
Chakera and Vaidya Addison Disease 413

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.

Patient Education. Patient education is critical for the


successful management of Addison disease. Information on
management of steroid replacement during sickness can FUTURE DEVELOPMENT
prevent acute adrenal crisis. Patients should carry a steroid
Current regimes of glucocorticoid replacement in Addison
card and a medic alert bracelet with details of the diagnosis.
disease are a poor surrogate for the homeostasis of endog-
They and their family members should be taught to give
intramuscular hydrocortisone injections during emergencies. enous cortisol production. Endogenous cortisol secretion
starts at around 3 AM, peaking in the morning after waking,
Follow-up. Patients with Addison disease should be re- and gradually wanes to nothing by midnight. A promising
viewed annually to assess well-being, monitor whether the advance in the management of Addison disease is develop-
glucocorticoid and mineralocorticoid replacement is ade- ment of a modified-release hydrocortisone tablet that can
quate, and reinforce patient education. In patients with au- mimic the circadian rhythm of endogenous cortisol produc-
toimmune Addison disease, you also should screen annually tion,6 which might improve quality of life and other out-
for associated autoimmune disorders with full blood count comes in patients with this condition.
(pernicious anemia), fasting glucose (diabetes mellitus), and
serum thyrotropin (thyroid dysfunction), and check the reg-
ularity of menstrual cycle in women (premature ovarian References
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Premature mortality in patients with Addison’s disease: a population-
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is 100 mg, with subsequent doses of 100-200 mg over 24 4. Falorni A, Laureti S, De Bellis A, et al. Italian addison network
hours divided into 3 or 4 doses.1 The precipitating cause (for study: update of diagnostic criteria for the etiological classification
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Management Controversy:
J Clin Endocrinol Metab. 2009;94:3676-3681.
Dehydroepiandrosterone Replacement 6. Debono M, Ghobadi C, Rostami-Hodjegan A, et al. Modified-release
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