Download Report

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
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
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 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 protected]
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2009.12.017
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.
PRESENTATION
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
410
The American Journal of Medicine, Vol 123, No 5, May 2010
must be considered as a possibility before treating the patient 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 emergency characterized by severe dehydration and circulatory
shock. Many patients also have nausea, vomiting, and abdominal 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.
Table 1
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 adrenal insufficiency.1 However, most patients will need a
short synacthen test for confirmation or exclusion of
Addison disease. This involves injecting 250 ␮g of synacthen (tetracosactrin; synthetic analogue of adrenocorticotrophic hormone [ACTH]) intramuscularly or intravenously. 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
Important Causes of Addison Disease
Causes
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
Key Associated Features
Hypoparathyroidism, mucocutaneous candidiasis, other autoimmune disorders. Autosomal
recessive. Mutations in the autoimmune regulator-1 (AIRE-1) gene.
Autoimmune thyroid disease, autoimmune diabetes, other autoimmune disorders.
—
Signs of active tuberculosis often absent. Adrenal calcification.
Systemic infection with histoplasmosis, cryptococcosis, coccidioidomycosis. Often
associated with immunodeficiency.
Often associated with cytomegalovirus adrenalitis.
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.
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.
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.
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).
Intra-uterine growth retardation, metaphyseal dysplasia, genital abnormalities. Genetic
defect unknown.
Achalasia, alacrimia, mental retardation, deafness. Autosomal recessive. Mutations in the
achalasia, adrenocortical insufficiency, alacrimia syndrome (AAAS) gene.
Ophthalmoplegia, retinal degeneration, muscle weakness, cardiomyopathy, lactic acidosis,
sensory deafness. Deletions in mitochondrial DNA.
Malignant: metastasis or lymphoma.
Nonmalignant: amyloidosis, hemochromatosis or sarcoidosis.
Associated with meningococcal septicemia (Waterhouse- Fredrickson syndrome) or
anticoagulation.
Associated with antiphospholipid syndrome.
Bilateral adrenalectomy or drugs (ketoconazole, etomidate, aminoglutethimide, mitotane).
Chakera and Vaidya
Table 2
Addison Disease
411
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
although the threshold cortisol level may vary according
to local laboratory reference ranges. If the cortisol response to synacthen is inadequate, plasma ACTH level
should be measured. A raised plasma ACTH level confirms the diagnosis of Addison disease, whereas patients
with secondary adrenal insufficiency 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 insufficiency.
Investigating the Cause of Addison Disease
Once a diagnosis of Addison disease is confirmed, 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 autoimmune 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 hormone; VLCFA ⫽ very long-chain fatty acid.
412
The American Journal of Medicine, Vol 123, No 5, May 2010
Addison disease. Likewise, neurological manifestations
in a young man should raise a suspicion of adrenoleukodystrophy.
The presence of adrenal antibodies indicates autoimmune Addison disease. Ideally, both adrenal cortex antibodies 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 polyendocrinopathy 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 adrenal glands should be carried out, which may show evidence
of metastasis, infiltration, hemorrhage, infarction, or infection (for example, adrenal calcification 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 specific
treatment for the underlying cause, for example, antituberculous drugs in Addison disease due to tuberculosis.
Glucocorticoid Replacement. Hydrocortisone is most
commonly used for glucocorticoid replacement, although
Table 3
other glucocorticoids, including cortisone, prednisolone,
and dexamethasone are occasionally used. Long-acting glucocorticoids, 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 hydrocortisone 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 assess the adequacy of glucocorticoid replacement. In practice, the dose of hydrocortisone is maintained on the basis of
clinical assessment, taking an account of patient’s wellbeing, 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-
Recommendations for an Increased Dose Hydrocortisone in Patients with Addison Disease in Different Conditions
Conditions
Intercurrent illness
Minor febrile illness (eg, common cold, viral chest infection)
Persistent vomiting or diarrhea, or both (eg, gastroenteritis)
Serious medical illness (eg, severe sepsis, myocardial
infarction, pancreatitis) or major trauma
Surgery
Minor surgery or invasive diagnostic procedure (eg, dental
extraction, herniorrhaphy, gastroscopy, colonoscopy)
Major surgery (eg, intra-abdominal surgery, cardiothoracic
surgery)
Other
Pregnancy
Physical exercise
Psychologically stressful situation (eg, examination,
interview)
Increment in Hydrocortisone Dose
Double the dose. Taper down to the maintenance dose over 2-3 days
after the illness.
Admission to hospital for intravenous hydrocortisone.
Intravenous injections 50 mg every 8 h or continuous intravenous
infusion 150 mg/24 h.*
Double the dose on the day.
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.
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.
Dose increment not necessary for gentle exercise. Increase the dose
by 5 mg before strenuous exercise.
Dose increment not necessary.
*No need to replace mineralocorticoid at these doses of hydrocortisone as high dose hydrocortisone has mineralocorticoid activity.
Chakera and Vaidya
Addison Disease
replacement, while salt craving, postural hypotension, and
hyperkalemia are signs of under-replacement. An assessment of plasma renin activity also is helpful in optimizing
the dose of fludrocortisone, as suppressed and elevated
plasma renin activity indicate over-replacement and underreplacement, 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 reviewed annually to assess well-being, monitor whether the
glucocorticoid and mineralocorticoid replacement is adequate, and reinforce patient education. In patients with autoimmune 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 regularity 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 dehydroepiandrosterone sulphate are androgens secreted by the adrenal cortex
413
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
beneficial effect on health-related quality of life.5 More
long-term efficacy 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 endogenous 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 development of a modified-release hydrocortisone tablet that can
mimic the circadian rhythm of endogenous cortisol production,6 which might improve quality of life and other outcomes in patients with this condition.
References
1. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361:18811893.
2. Erichsen MM, Lovas K, Skinningsrud B, et al. Clinical, immunological,
and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian Registry. J Clin Endocrinol Metab. 2009;
94:4882-4890.
3. Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G.
Premature mortality in patients with Addison’s disease: a populationbased study. J Clin Endocrinol Metab. 2006;91:4849-4853.
4. Falorni A, Laureti S, De Bellis A, et al. Italian addison network
study: update of diagnostic criteria for the etiological classification
of primary adrenal insufficiency. J Clin Endocrinol Metab. 2004;89:
1598-1604.
5. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and
meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency.
J Clin Endocrinol Metab. 2009;94:3676-3681.
6. Debono M, Ghobadi C, Rostami-Hodjegan A, et al. Modified-release
hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol
Metab. 2009;94:1548-1554.