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 insufciency, is a
chronic disorder of the adrenal cortex resulting in inade-
quate 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 le-
thal 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 life
2
and remain at risk
of premature death.
3
CAUSES
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 polyen-
docrinopathy 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 disor-
ders, including type 1 diabetes, chronic active hepatitis,
primary gonadal failure, and autoimmune thyroid disease.
In autoimmune polyendocrinopathy syndrome type 2, Ad-
dison 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 long-
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.
PRESENTATION
Addison disease presents insidiously with nonspecic
symptoms that easily can be mistaken for other more prev-
alent conditions (Table 2). For example, its common symp-
toms, chronic fatigue, malaise, and anorexia may mimic a
depressive illness. Likewise, unintentional weight loss, nau-
sea, vomiting, and vague abdominal pain may be confused
with symptoms of a gastrointestinal or eating disorder.
Symptoms of postural hypotension (syncope, postural diz-
ziness) 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 insufciency must be
excluded before making the diagnosis of syndrome of in-
appropriate antidiuretic hormone secretion. Likewise, in a
patient with unexplained hyperkalemia, Addison disease
Funding: The work of Dr. Vaidya was partly supported by the Pen-
insula Collaboration for Leadership in Applied Health Research and Care
(PenCLAHRC) Funding.
Conict 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, De-
partment of Endocrinology, Royal Devon & Exeter Hospital, Exeter EX2
5DW, UK.
E-mail address: bijay.vaidya@pms.ac.uk
0002-9343/$ -see front matter 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2009.12.017
must be considered as a possibility before treating the pa-
tient with insulin and dextrose infusion. Some patients with
Addison disease show a raised serum thyrotropin level at
presentation. The diagnosis of Addison disease must be
considered in a hypothyroid patient whose symptoms
worsen after starting thyroxine. Furthermore, unexplained
recurrent hypoglycemic episodes in a patient with type 1
diabetes should also raise a suspicion of Addison disease.
About half of patients with Addison disease present
acutely with adrenal crises.
1
This is a life-threatening emer-
gency characterized by severe dehydration and circulatory
shock. Many patients also have nausea, vomiting, and ab-
dominal pain, which may lead to a misdiagnosis of an acute
abdomen. Acute adrenal crisis is usually precipitated by
infection or other forms of severe physiological stress.
INVESTIGATIONS
Diagnosing Addison Disease
A morning serum cortisol level higher than 500 nmol/L
(18 g/dL) usually excludes Addison disease, while a
level below 165 nmol/L (6 g/dL) is suggestive of adre-
nal insufciency.
1
However, most patients will need a
short synacthen test for conrmation or exclusion of
Addison disease. This involves injecting 250 g of syn-
acthen (tetracosactrin; synthetic analogue of adrenocor-
ticotrophic hormone [ACTH]) intramuscularly or intra-
venously. Blood samples for serum cortisol are taken at
0, 30, and 60 minutes. 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,
1
Table 1 Important Causes of Addison Disease
Causes Key Associated Features
Autoimmunity
Autoimmune polyendocrinopathy
syndrome type 1
Hypoparathyroidism, mucocutaneous candidiasis, other autoimmune disorders. Autosomal
recessive. Mutations in the autoimmune regulator-1 (AIRE-1) gene.
Autoimmune polyendocrinopathy
syndrome type 2
Autoimmune thyroid disease, autoimmune diabetes, other autoimmune disorders.
Isolated autoimmune Addison disease
Infective
Tuberculosis Signs of active tuberculosis often absent. Adrenal calcication.
Fungal Systemic infection with histoplasmosis, cryptococcosis, coccidioidomycosis. Often
associated with immunodeciency.
Acquired immune deciency
syndrome
Often associated with cytomegalovirus adrenalitis.
Genetic
Adrenoleukodystrophy Neurological decit, 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 deciency 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
syndrome)
Achalasia, alacrimia, mental retardation, deafness. Autosomal recessive. Mutations in the
achalasia, adrenocortical insufciency, alacrimia syndrome (AAAS) gene.
Kearns-Sayre syndrome
(Mitochondrial Addison disease)
Ophthalmoplegia, retinal degeneration, muscle weakness, cardiomyopathy, lactic acidosis,
sensory deafness. Deletions in mitochondrial DNA.
Miscellaneous
Inltration 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).
410 The American Journal of Medicine, Vol 123, No 5, May 2010
although the threshold cortisol level may vary according
to local laboratory reference ranges. If the cortisol re-
sponse to synacthen is inadequate, plasma ACTH level
should be measured. A raised plasma ACTH level con-
rms the diagnosis of Addison disease, whereas patients
with secondary adrenal insufciency due to pituitary or
hypothalamic disorders have a low or inappropriately
normal plasma ACTH level. Plasma renin activity is
elevated in Addison disease and is sometimes a useful
investigation to distinguish between Addison disease and
secondary adrenal insufciency.
Investigating the Cause of Addison Disease
Once a diagnosis of Addison disease is conrmed, further
investigations are needed to elucidate the underlying
cause (Figure). There may be clues in the history and
examination. For example, a presence of another autoim-
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.
Table 2 Symptoms, Signs and Investigations that Point to Addison Disease
Symptoms Signs Laboratory results
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)
Hyperpigmentation of skin and mucous
membranes
Low blood pressure
Postural hypotension
Hyponatremia
Hyperkalemia
Hypoglycaemia
Raised urea
Metabolic acidosis
Hypercalcemia
Raised thyroid-stimulating hormone
Normocytic anemia
411 Chakera and Vaidya Addison Disease
Addison disease. Likewise, neurological manifestations
in a young man should raise a suspicion of adrenole-
ukodystrophy.
The presence of adrenal antibodies indicates autoim-
mune Addison disease. Ideally, both adrenal cortex antibod-
ies and 21-hydroxylase antibodies should be measured.
4
21-hydroxylase antibodies are more sensitive than adrenal
cortex antibodies in the diagnosis of autoimmune Addison
disease. In patients with autoimmune Addison disease, it is
important to screen for other features of autoimmune poly-
endocrinopathy syndromes. In men with negative adrenal
antibodies, plasma very long-chain fatty acids should be
checked to exclude adrenoleukodystrophy. If the cause still
remains unclear, a computed tomographic scan of the adre-
nal glands should be carried out, which may show evidence
of metastasis, inltration, hemorrhage, infarction, or infec-
tion (for example, adrenal calcication in longstanding
tuberculosis).
MANAGEMENT
Routine Management of Addison Disease
Routine treatment of Addison disease involves replacement
of the glucocorticoid and mineralocorticoid hormones.
Some forms of Addison disease also will require specic
treatment for the underlying cause, for example, antituber-
culous drugs in Addison disease due to tuberculosis.
Glucocorticoid Replacement. Hydrocortisone is most
commonly used for glucocorticoid replacement, although
other glucocorticoids, including cortisone, prednisolone,
and dexamethasone are occasionally used. Long-acting glu-
cocorticoids, dexamethasone, and prednisolone have the
advantage of a once-daily dosing schedule but have the
drawback of losing the diurnal pattern, resulting in excess
glucocorticoid levels overnight.
In Addison disease, standard replacement dose of hydro-
cortisone is 15-25 mg a day, given in 2 or 3 divided doses.
1
A typical starting regime would consist of hydrocortisone
10 mg on waking, 5 mg at around noon, and 5 mg early
evening. There are no satisfactory biochemical tests to as-
sess the adequacy of glucocorticoid replacement. In prac-
tice, the dose of hydrocortisone is maintained on the basis of
clinical assessment, taking an account of patients well-
being, and presence of any signs of over-replacement (eg,
hypertension, weight gain, thin skin, easy bruising, and
glucose intolerance) or under-replacement (eg, weight loss
and pigmentation).
During intercurrent illnesses, perioperative periods, and
other forms of stress, patients should increase the dose of
hydrocortisone to mimic the normal physiological response
(Table 3). Some drugs (eg, rifampicin, phenobarbitone, and
phenytoin) increase hepatic metabolism of glucocorticoids,
and patients starting on such drugs may need to increase the
dose of hydrocortisone.
Mineralocorticoid Replacement. Fludrocortisone is the
only available agent for mineralocorticoid replacement. The
usual starting dose is 100 g a day. The dose is adjusted
(usually 50-200 g a day) according to clinical response.
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
infarction, pancreatitis) or major trauma
Intravenous injections 50 mg every 8 h or continuous intravenous
infusion 150 mg/24 h.*
Surgery
Minor surgery or invasive diagnostic procedure (eg, dental
extraction, herniorrhaphy, gastroscopy, colonoscopy)
Double the dose on the day.
Major surgery (eg, intra-abdominal surgery, cardiothoracic
surgery)
Intravenous injections 50 mg every 8 h or continuous intravenous
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,
interview)
Dose increment not necessary.
*No need to replace mineralocorticoid at these doses of hydrocortisone as high dose hydrocortisone has mineralocorticoid activity.
412 The American Journal of Medicine, Vol 123, No 5, May 2010
replacement, while salt craving, postural hypotension, and
hyperkalemia are signs of under-replacement. An assess-
ment of plasma renin activity also is helpful in optimizing
the dose of udrocortisone, as suppressed and elevated
plasma renin activity indicate over-replacement and under-
replacement, respectively.
Patient Education. Patient education is critical for the
successful management of Addison disease. Information on
management of steroid replacement during sickness can
prevent acute adrenal crisis. Patients should carry a steroid
card and a medic alert bracelet with details of the diagnosis.
They and their family members should be taught to give
intramuscular hydrocortisone injections during emergencies.
Follow-up. Patients with Addison disease should be re-
viewed annually to assess well-being, monitor whether the
glucocorticoid and mineralocorticoid replacement is ade-
quate, and reinforce patient education. In patients with au-
toimmune Addison disease, you also should screen annually
for associated autoimmune disorders with full blood count
(pernicious anemia), fasting glucose (diabetes mellitus), and
serum thyrotropin (thyroid dysfunction), and check the reg-
ularity of menstrual cycle in women (premature ovarian
failure).
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. Patients may
need several liters of normal saline to maintain their blood
pressure. The recommended initial dose of hydrocortisone
is 100 mg, with subsequent doses of 100-200 mg over 24
hours divided into 3 or 4 doses.
1
The precipitating cause (for
example, an infection) should be sought and treated. If acute
adrenal crisis is suspected in an undiagnosed patient, the
treatment should not be delayed to carry out diagnostic tests.
Management Controversy:
Dehydroepiandrosterone Replacement
Dehydroepiandrosterone (DHEA) and dehydroepiandros-
terone sulphate are androgens secreted by the adrenal cortex
and are decreased in Addison disease. A meta-analysis of
randomized controlled trials of DHEA treatment in women
with Addison disease has shown evidence of a nominal
benecial effect on health-related quality of life.
5
More
long-term efcacy and safety data are needed before DHEA
replacement can be advocated in routine clinical practice.
FUTURE DEVELOPMENT
Current regimes of glucocorticoid replacement in Addison
disease are a poor surrogate for the homeostasis of endog-
enous cortisol production. Endogenous cortisol secretion
starts at around 3 AM, peaking in the morning after waking,
and gradually wanes to nothing by midnight. A promising
advance in the management of Addison disease is develop-
ment of a modied-release hydrocortisone tablet that can
mimic the circadian rhythm of endogenous cortisol produc-
tion,
6
which might improve quality of life and other out-
comes in patients with this condition.
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413 Chakera and Vaidya Addison Disease