What can mimic Addison's disease?

Multiple conditions can mimic one or more symptoms of adrenal insufficiency (chronic fatigue syndrome, depression, hypothyroidism, fibromyalgia, chronic dyspepsia, etc.).

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Worst outcomes if missed

Adrenal crisis is a life-threatening emergency occurring with a frequency of 6-8/100 patient years – so each patient with Addison’s will have, on average, four adrenal crises in a lifetime. Unless it is treated very promptly, it is fatal.

Epidemiology

Causes

Autoimmune-mediated destruction of adrenal tissue is the most common cause of primary adrenal insufficiency and can occur in isolation (30-40%) or in combination with other autoimmune diseases, such as autoimmune thyroid disease, primary gonadal failure, type 1 diabetes, vitiligo, chronic atrophic gastritis and coeliac disease. Other causes of primary adrenal insufficiency include bilateral infection (tuberculosis, CMV), infiltration (lymphoma, metastasis) or genetic causes (congenital adrenal hyperplasia).

Symptoms and signs

Most of the patients with Addison’s are often initially misdiagnosed or diagnosed with a significant delay. Presenting signs and symptoms in patients with adrenal insufficiency are often non-specific and may comprise of fatigue, weakness, weight loss, nausea, poor appetite, and light headedness. More specific signs and symptoms are skin hyperpigmentation, due to enhanced activation of skin melanocortin receptors by high ACTH levels, salt craving and postural hypotension due to mineralocorticoid deficiency.

Differential diagnoses

Most of the cases of adrenal insufficiency are due to exogenous glucocorticoid exposure . The next most common is pituitary pathology. In these situations, baseline ACTH concentrations are low, in contrast with elevated ACTH levels in primary adrenal insufficiency. Multiple conditions can mimic one or more symptoms of adrenal insufficiency (chronic fatigue syndrome, depression, hypothyroidism, fibromyalgia, chronic dyspepsia, etc.). However, adrenal insufficiency should always be excluded prior to attributing the patient’s symptoms to a different or co-existent disorder. Am I over-treating my patient or under-treating? (Signs of iatrogenic Cushing’s syndrome, hypertension, orthostasis, electrolytes, renin) Am I missing common associated conditions? (yearly TFTs and screening of other autoimmune conditions)

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Investigations

Baseline morning cortisol and ACTH should be performed initially (elevated ACTH levels are consistent with primary adrenal insufficiency), followed by a short synacthen stimulation test. Both tests are required, as often adrenal insufficiency cannot be diagnosed based on baseline cortisol and ACTH alone. A cut-off of 550 nmol/L (20µg/dl) is used to define failure to respond appropriately to ACTH stimulation. Timing is important – cortisol has a circadian rhythm and is highest in the morning. In primary adrenal insufficiency, investigations will also reveal an elevated plasma renin concentration and electrolyte abnormalities (hyponatremia and hyperkalemia), while in secondary adrenal insufficiency the mineralocorticoid axis is preserved. Five red herrings No associated autoimmune history – autoimmune adrenalitis can be an isolated finding in 30-40% of all cases. Patient on synthetic oestrogen therapy/pregnant patient – total cortisol concentrations are higher due to increased CBG. Ongoing fatigue mistakenly blamed on insufficient glucocorticoid supplementation, leading to supraphysiological daily dose and its consequences (iatrogenic Cushing’s syndrome, osteoporosis, metabolic derangements and fatigue). Normal sodium and potassium levels – this can be present in some cases.

Therapy and monitoring

Hydrocortisone 15-25 mg (total daily dose) in two to three divided doses. Clinical monitoring for symptoms and signs of under- or over-supplementation (weight loss or gain, fatigue, skin thinning or easy bruising). No biochemical monitoring exists. Fludrocortisone 50-300 mcg (total daily dose), taken in the morning. Clinical monitoring includes measurement of orthostatic vitals and signs of lower extremity oedema. Biochemical monitoring includes measurement of sodium, potassium and renin during each visit. The aim for renin is mid-high normal range. Dehydroepiandrosterone (DHEA) supplementation 25-50mg (total daily dose) – the adrenal androgen precursor. Women with adrenal insufficiency invariably suffer from androgen deficiency which can contribute to low energy levels and cause loss of libido. Clinical monitoring – watch for acne and hirsutism. Biochemical monitoring – DHEAS concentrations 24 hours after last dose, goal mid-normal range.

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Prevention of adrenal crisis

Re-enforce sick day rules during every visit:

Sick day rule one – double hydrocortisone in times of sickness, fever, antibiotic use. Sick day rule two – administer parenteral hydrocortisone 100mg in times of inability to take oral hydrocortisone, such as vomiting. Every patient should carry a few vials of hydrocortisone and syringes. The patient is taught to self-administer hydrocortisone intramuscularly (1ml solution containing 100mg hydrocortisone) at the onset of symptoms without delay. This provides coverage for six to eight hours and prevents symptoms due to adrenal crisis, however, a hospital admission might still be warranted for treatment and supportive management of underlying illness, such as severe gastroenteritis. Provide a steroid card, adrenal crisis information sheet and encourage wearing medical bracelet/necklace. Provide sufficient amount of hydrocortisone and supplies for intramuscular hydrocortisone injection (100 mg vials of hydrocortisone, syringes, needles).

Arrange for an education session on how to self-administer intramuscular hydrocortisone.

Dr Irina Bancos and Professor Wiebke Arlt are endocrinologists at the University of Birmingham.

Professor John Wass is professor of endocrinology at the University of Oxford

Addison’s Disease Self Help Group provides information an on-line support. Patient Information materials are also available to all GP surgeries/health clinics from www.addisonsl.org.uk.