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At the heart of general practice since 1960

How not to miss Addison's disease

Endocrinologists Dr Trevor Howlett, Professor Simon Pearce and colleagues on the key signs and symptoms of this autoimmune disease

Endocrinologists Dr Trevor Howlett, Professor Simon Pearce and colleagues on the key signs and symptoms of this autoimmune disease

Worst outcomes if missed

Untreated Addison's disease is universally fatal and the patient may die quite rapidly from adrenal crisis.

In adrenal crisis, hypovolaemic shock, cardiac arrest, stroke or other circulatory complications can occur even in young, fit patients. Complications from hypoxia may leave the patient permanently disabled. Children with adrenal crisis are particularly susceptible to hypoglycaemia, which can cause permanent brain damage.

Where the patient has severe hyponaetremia, incautious correction can lead to cerebral oedema or extrapontine central pontine myelinolysis.

Epidemiology

Autoimmune Addison's disease affects about one in 10,000, with an upper estimate of about 8,400 diagnosed cases

in the UK. In common with other autoimmune and inflammatory diseases – such as type 1 diabetes and asthma – there is evidence of increasing incidence in westernised societies. Diagnosis can occur at any age, from five to 80. Almost half of all diagnoses occur outside the most common age of onset (30 to 50 years).

Symptoms and signs

41225513As well as overwhelming exhaustion, patients with adrenal failure typically report nausea, loss of appetite and dizziness on standing. Muscle weakness with cramps, abdominal, joint or back pains are often present. A preference for salty foods and increased thirst are common.

Key signs are:

• deepening skin pigmentation

• low blood pressure

• postural hypotension.

There is a wide range of symptoms but few patients report the full complement. Psychosis is occasionally documented. Minor depression and tearfulness may be observed along with chronic exhaustion.

Differential diagnosis

41225514Some of the early signs overlap with type 1 diabetes, although in adrenal failure the blood glucose should be normal or even low. Excessive fatigue and sleepiness, increased thirst and urination, and unexplained weight loss are common to both conditions.

In early stage autoimmune (primary) adrenal disease, the predominant signs are usually those of mineral corticoid deficiency (postural dizziness, increasing thirst and urination, salt cravings), with increasing pigmentation as a consequence of the rise in pituitary ACTH level, which is in response to declining circulating glucocorticoid levels.

In early-stage pituitary disease, signs of glucocorticoid deficiency will predominate, notably anorexia, weight loss and muscle weakness.

Hypoglycaemia may be present in children, but skin pigmentation usually remains unchanged in secondary adrenal insufficiency or displays an alabaster-like pallor.

Hypothyroidism occurs alongside autoimmune Addison's in more than 40% of patients, although one usually predates the other. Starting thyroid replacement without glucocorticoid therapy exacerbates hypoadrenal symptoms and may precipitate adrenal crisis.

Elevated TSH may be an indicator of hypoadrenalism in an ill patient with extreme fatigue but without the typical features of hypothyroidism.

Adrenal destruction triggered by disseminated infections such as TB, fungal infection or histoplasmosis is more common in regions such as the Indian subcontinent and Latin America.

Mucocutaneous hyperpigmentation is more frequently observed here. HIV is a growing cause of adrenal failure.

Diabetes occurs alongside autoimmune Addison's in about 10% of cases. In established diabetes, a marked reduction in the insulin requirement can be a warning sign of developing hypoadrenalism.

First-line investigations

Patients showing signs of adrenal crisis – typically, persistent vomiting with profound muscle weakness, hypotension, headache, extreme sleepiness or even coma – should be admitted as an emergency and if possible stabilised by a saline infusion before transfer. If admission is delayed or if the patient is in extremis with strong clinical suspicion of hypoadrenalism, then consider a 100mg hydrocortisone injection before transportation to hospital.

If the patient is stable, the GP may:

• Take blood pressure sitting and standing. Postural hypotension usually results in a 20-point drop in blood pressure on standing.

• Question the patient to establish if they frequently drop their keys, struggle to climb stairs or get up from a sitting or squatting position.

• Inspect oral mucosa for patchy hyperpigmentation. This generally occurs in areas of increased friction. It may also be visible where clothes rub against the skin. Hyperpigmentation may be a soft, muddy brown colour or darker, depending on the patient's natural level of melanocytes.

• Measure electrolytes (low Na, high K), blood glucose, 9am cortisol.

The diagnosis is highly likely if 9am cortisol is less than 100nmol/l – unless the patient is already on oral or inhaled steroids. The diagnosis is unlikely if cortisol is greater than 400nmol/l – but not excluded if the patient is acutely unwell at the time. For values between 100nmol/l and 400nmol/l the diagnosis can only be excluded by a short Synacthen (ACTH stimulation) test.

Second-line investigations

Whenever there is a real suspicion of adrenal insufficiency, the GP is encouraged to refer the patient to a specialist endocrinology unit for a Synacthen test. The urgency of this referral will depend on the clinical context. If the patient is hypotensive and vomiting, or where the 9am cortisol is less than 100nmol/l, an immediate referral is required.

Associated investigations may include:

• Plasma renin (must be drawn at the processing lab)

• Plasma ACTH

• Serum DHEA-S

• Thyroid function tests

• Organ-specific antibodies.

Where pituitary involvement is suspected, further investigations of the hypothalamic-pituitary-adrenal axis may be necessary.

Dr Trevor Howlett is consultant physician and endocrinologist at Leicester Royal Infirmary

Professor Simon Pearce is professor of endocrinology at the Institute of Human Genetics, Newcastle University

Professor Wiebke Arlt is professor of medicine, Division of Medical Sciences, Birmingham University

Professor John Monson is consultant physician and emeritus professor of clinical endocrinology, St Bartholomew's Hospital, London

Professor John Wass is professor of endocrinology at the Churchill Hospital, Oxford

Competing interests None declared

Further reading

•Arlt W, Allolio B, Adrenal insufficiency, Lancet 2003; 361 (9372): 1881-93

•On-line endocrinology textbook: www.endotext.org/adrenal

•Parker K and Kovacs W, ‘Addison's disease (adrenal insufficiency)' in Wass JAH, Shalet SM, Oxford Textbook of Endocrinology and Diabetes, OUP 2002, 837-844

•Online case reports of adrenal insufficiency diagnosis: www.endocrine-abstracts.org/

•Online patient information and support; patient perspectives on the pre-diagnosis illness: www.addisons.org.uk

Further information

• For GPs and their patients: Addison's Disease Self-Help Group – www.addisons.org.uk

Calcified adrenal gland (upper right) in Addison's patient Calcified adrenal gland Key questions Red herrings

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