ADRENAL DISORDERS
Addison’s disease
Antonia M Brooke
John P Monson
Abstract
Addison’s disease or primary adrenocortical failure is a rare condition,
most commonly caused in the UK by autoimmune destruction of the ad-
renal glands. The insidious onset of symptoms over many months means
there is often a delay in diagnosis and patients can first present in adrenal
crisis. The diagnosis is made by the finding of a low serum cortisol at
09.00 hours in the presence of an elevated adrenocorticotropic hormone
(ACTH) concentration, or by a poor cortisol response to exogenous ACTH
on provocation testing. Replacement with hydrocortisone and fludrocorti-
sone should approximate physiological levels as closely as possible and
be regularly monitored.
Keywords Addison’s; adrenal; autoimmune; dehydroepiandrosterone;
fludrocortisone; hydrocortisone; tuberculosis
Addison’s disease (AD), first described by Thomas Addison (1855),
denotes primary adrenocortical failure.1 Most of the original cases
described were caused by tuberculosis (TB), but the most common
aetiology is now autoimmunity. AD remains rare; the prevalence is
about 120/million.2 A delay in diagnosis is common because of
failure to recognize the insidious onset of symptoms; a survey from
the US National Adrenal Disease Foundation revealed that 60% of
patients with AD had sought medical attention from two or more
physicians before the diagnosis was considered.
Anatomy and pathophysiology
The adrenals are Y-shaped glands (each limb measuring <5 mm)
located at the superior poles of the kidneys. They comprise a
cortex (90%) surrounding the medulla (10%) (Figure 1). The
cortex secretes:
 the glucocorticoid cortisol from the zona fasciculata
 androgens (e.g. dehydroepiandrosterone, DHEA) from the
zona reticularis
 mineralocorticoids (aldosterone) from the zona glomerulosa,
predominantly under the control of the renineangiotensin
system (although 5e10% of total aldosterone production is
mediated by adrenocorticotropic hormone, ACTH).
AD involves all three zones of the adrenal cortex. Overt symp-
toms do not usually appear until more than 90% of the gland has
Antonia M Brooke MD MRCP MA MBBS is a Consultant in Endocrinology at
The Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Competing interests: none declared.
John P Monson MD FRCP FRCPI is Emeritus Professor of Clinical
Endocrinology at St Bartholomew’s and The Royal London Hospital,
London, UK. Competing interests: Consultant to Viropharma.
MEDICINE 41:9
What’s new?
C Addison’s disease has recently been shown to be associated
with a twofold increased risk of mortality compared to the
general population
C A new, modified-release, once-daily hydrocortisone preparation
(PlenadrenÒ) may help adherence, mimic normal daytime
physiology more closely and reduce overall cortisol exposure
C Additional androgen treatment, usually in the form of dehy-
droepiandrosterone, offers psychological benefit to some
patients although long-term data are unavailable
been destroyed. Glucocorticoids, mineralocorticoids and andro-
gens are all reduced, in contrast to the situation in secondary
adrenal failure (ACTH deficiency), in which mineralocorticoid
secretion is relatively preserved. Immune destruction leads to
fibrosis with a mononuclear cell infiltrate, occasional plasma
cells and, rarely, germinal centres.
Aetiology
In developed countries, about 75e80% of cases of AD are caused
by autoimmune destruction.3 TB is the second most common
cause. Other causes are rare (Table 1).4 Patients with autoim-
mune AD are at a 50e60% risk of developing another autoim-
mune disorder (10% of patients develop type 1 diabetes
mellitus). There is an association with human leukocyte antigen
(HLA) DR3 and HLA DR4.
Determination of the cause may be guided by age at presen-
tation and gender.
 At birth, adrenal haemorrhage (from anoxia) is the most
common cause.
 In young females, an autoimmune basis is more likely
(three times more common than in males).
 Infection and metastases should be considered in males
and the elderly.
 Although adrenal metastases are relatively common, hor-
monal insufficiency is unusual.
 Fungal infections are more common in the immunocom-
promised; up to 5% of patients with AIDS have adrenal
insufficiency at a late stage.
Clinical features
Patients can present with an insidious onset of non-specific
symptoms (Table 2) or during an adrenal crisis, depending on
the acuteness of the hormonal deficit and any intercurrent
illness.5 Primary adrenal failure is suggested by hyperpigmenta-
tion (from elevation of melanocyte-stimulating hormone and
ACTH) in the buccal mucosa, nailbeds and areas that are exposed
to light and pressure.
Investigations and diagnosis
Biochemical abnormalities
At presentation, patients are often hyponatraemic, hyperkalaemic
and acidotic.6 Mineralocorticoid deficiency leads to sodium
depletion, reduced extracellular fluid volume and hypotension,
522 Ó 2013 Elsevier Ltd. All rights reserved.
 ADRENAL DISORDERS

Causes of primary adrenal deficiency

Adrenal destruction
Autoimmune
C Isolated
C Autoimmune polyglandular syndrome 1 (autosomal recessive,
equally common in males and females, chronic mucocutaneous
candidiasis, acquired hypoparathyroidism (90%), Addison’s
disease (60%))
C Autoimmune polyglandular syndrome 2 (autosomal recessive,
autosomal dominant and polygenic, more common in females,
Addison’s disease (100%), autoimmune disease of the thyroid
(Schmidt’s syndrome), immune-mediated diabetes mellitus
(Carpenter’s syndrome))
Infections
C Tuberculosis
C Fungal (histoplasma, cryptococcus)
C Opportunistic (cytomegalovirus in acquired immunodeficiency
syndrome)
Metastases
C Lung, breast, kidney
C Lymphoma
Haemorrhage
C WaterhouseeFriderichsen syndrome (meningococcal
septicaemia)
Infiltrations
C Amyloidosis, haemochromatosis
Others
C Adrenoleukodystrophy
Adrenal dysgenesis
C Congenital adrenal hypoplasia
C Mutations in SF1
Figure 1 Cross-section of the adrenal gland. c, capsule; a, arteriole; n,
Impaired steroidogenesis
nerve fibres; gc, ganglionic cells; zg, zona glomerulosa; s, sinusoids; zf,
C Congenital adrenal hyperplasia
zona fasciculata; ma, medullary artery; i, isolated islets of chromaffin
cells; zr, zona reticularis; m, medulla. Mitochondrial disorders iatrogenic
C Adrenal suppressors (e.g. ketoconazole, etomidate)
C Enzyme inducers (e.g. phenytoin, rifampicin)
and results in a raised plasma renin. This can precede cortisol
deficiency by several years. Reduced renal water clearance com- Table 1
pounds the hyponatraemia. Hyperkalaemia develops as a result of
reduced renal potassium and hydrogen ion excretion, and type IV
renal tubular acidosis ensues. Low plasma glucose (from reduced distinguish primary from secondary adrenal failure; 1 mg is given
glycogen stores) is common, although severe hypoglycaemia is IM and serum cortisol measured at 0, 6 and 24 hours. In AD, there
rare in adults. Reversible hypercalcaemia may occur. is no increase after 6 hours, whereas in secondary adrenal failure a
continuous increase is seen.
Serum cortisol
The diagnosis is made by documenting low (or normal) serum Investigations for the cause
cortisol in the presence of elevated plasma ACTH. A serum Once primary adrenal insufficiency has been diagnosed, the
cortisol of less than 100 nmol/litre at 09.00 hours is diagnostic of cause should be established. Adrenal antibodies to enzymes of
deficiency and a serum cortisol above 550 nmol/litre makes the the adrenal cortex (e.g. 21-OH, P450scc, 17-OH) are found in
diagnosis unlikely. more than 90% of patients with recent-onset adrenal autoim-
munity (but in screening for autoimmunity only 20% of those
Tetracosactide test with positive antibodies will develop Addison’s disease).
The diagnosis is confirmed by a suboptimal cortisol response to If there is a clinical suspicion of TB, chest and abdominal
synthetic ACTH. Tetracosactide (SynacthenÒ), 250 mg intramus- radiography should be performed looking for apical shadowing
cularly (IM) or intravenously, is given at 09.00 hours and serum and adrenal calcification. Computed tomography of the adrenals
cortisol measured at 0, 30 and 60 minutes. A normal response is a is necessary only when metastases, an infiltrative process or TB
peak of more than 550 nmol/litre; occasionally, false-negative are suspected. Adrenal failure may be associated with modest
results are obtained. Depot tetracosactide can also be used to and reversible elevation of serum thyroid-stimulating hormone.

MEDICINE 41:9 523 Ó 2013 Elsevier Ltd. All rights reserved.

 ADRENAL DISORDERS
Symptoms, signs and investigations
Symptoms Signs
Anorexia Hyperpigmentation
Weight loss (>90% of patients) Postural hypotension Hyperkalaemia (65%)
Fatigue Dehydration
Muscle weakness and myalgia (generalized) Vitiligo  goitre
Weight loss Pyrexia of unknown origin Elevated 09.00 hours ACTH
Gastrointestinal (abdominal pain, diarrhoea, vomiting) (Occasionally)
Dizziness
Headache
Depression and behavioural changes
Reduced libido, reduced axillary hair
Sweating
Salt craving
ACTH, adrenocorticotropic hormone; CT, computed tomography; ESR, erythrocyte sedimentation rate.
Table 2
Management
The aims of treatment are to replace the deficient hormones and
treat any reversible causes of adrenal disease.
Glucocorticoids
Glucocorticoid replacement is usually given three times daily,
with the largest dose (10e20 mg) taken before getting out of bed
to mimic the physiological peak just before waking, followed by
5 mg at midday and 5 mg at 18.00 hours. An increase of up to
50% is often required in pregnancy. A new once-daily dual
release preparation of hydrocortisone (PlenadrenÒ) is now
available. This reduces overall cortisol exposure, which may
improve glycaemic control in the 10% of patients with co-
existent type 1 diabetes mellitus, and may improve adherence.7,8
Mineralocorticoids
The aim of treatment with fludrocortisone is to achieve normal
sodium homoeostasis as shown by normal or slightly elevated
plasma renin activity. A commencing dose of 0.1 mg daily is
appropriate for most patients but doses up to 0.1 mg twice daily
may be required. Measurement of plasma renin activity is
mandatory to avoid excessive mineralocorticoid replacement.
Over-treatment may result in hypertension and, rarely, oedema.
Adrenal androgens
Compared to the general population, patients with AD report a
reduced quality of life. DHEA replacement may improve self-
esteem, mood and fatigue scores, and libido in some female
patients,9 which may be testosterone-driven. The long-term
benefits remain to be established.
Management during intercurrent illness
Endogenous adrenal secretion is increased in critically ill and
perioperative patients with healthy adrenal glands. In those with
adrenal insufficiency, glucocorticoid doses should be doubled
MEDICINE 41:9 524
Investigations
Hyponatraemia (90%)
Hypoglycaemia
Hypercalcaemia
Low 09.00 hours cortisol and response to ACTH stimulation
Elevated renin and low/normal aldosterone
Elevated urea
Elevated thyroid-stimulating hormone
Eosinophilia, lymphocytosis, raised ESR
Normochromic anaemia
Adrenal autoantibodies
Chest and abdominal radiography, CT (for calcification)
during significant febrile illnesses.10 Patients should keep an
ampoule of hydrocortisone in their refrigerator for IM injection,
in case of diarrhoea and vomiting at home. In a crisis, an infusion
of sodium chloride 0.9%, and hydrocortisone, 100 mg IM
6-hourly or an intravenous infusion (1e4 mg/hour), should be
administered. It is unnecessary to replace mineralocorticoids
when giving high doses of hydrocortisone, which have a signif-
icant mineralocorticoid effect as a result of saturation of renal
11b-hydroxysteroid dehydrogenase type 2 activity.
Patient education
Every patient should wear a MedicAlert bracelet (or necklace), be
given written information (including about patient support
groups), carry a steroid card and be aware of the need to increase
glucocorticoid doses in the event of severe intercurrent illness.11
AD has recently been associated with a twofold increase in
standardized mortality ratio, related mainly to cardiovascular,
malignant and infectious diseases.12 While the cause for this is
unknown, optimizing replacement therapy to mimic normal
physiology as closely as possible should always be a key goal.A
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3 Martorell PM, Roep BO, Smit JWA. Autoimmunity in Addison’s dis-
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(accessed 15 May 2009).
Ó 2013 Elsevier Ltd. All rights reserved.
 ADRENAL DISORDERS
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MEDICINE 41:9
Practice points
C Addison’s disease is rare. The most common cause in the UK is
autoimmune destruction of the adrenals, followed by infiltra-
tion of the glands by tuberculosis
C Patients with autoimmune Addison’s disease have a 60%
chance of developing another autoimmune disease
C Symptoms of cortisol deficiency are insidious in onset, but
skin hyperpigmentation can help differentiate between primary
and secondary adrenal failure
C Addison’s disease should be considered in any patient with
unexplained hyponatraemia or hyperkalaemia and 09.00 hours
cortisol should be measured
C Treatment with hydrocortisone and fludrocortisone should be
monitored closely to ensure response resembles normal
physiology, and dosage should be increased in times of severe
illness or pregnancy
525 Ó 2013 Elsevier Ltd. All rights reserved.