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Addison's disease

SNOMED: 363732003804 words•Updated 03/03/2026

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Exam Tips

Classic triad for primary adrenal failure: hypotension, hyponatraemia/hyperkalaemia, and hyperpigmentation with high ACTH.
In crisis, do not wait for dynamic tests: give hydrocortisone and IV saline immediately.
Primary vs secondary clue: hyperpigmentation and marked mineralocorticoid deficiency point to primary disease.
Starting levothyroxine in unrecognized adrenal insufficiency can precipitate crisis; assess adrenal status if hypothyroid symptoms behave atypically.
Most common UK/Western cause is autoimmune adrenalitis; always screen for associated autoimmune endocrinopathies.

Definition

Addison’s disease is primary adrenal insufficiency caused by failure or destruction of the adrenal cortex, leading to deficient cortisol and usually aldosterone production (often with reduced adrenal androgens). Loss of cortisol feedback increases ACTH, which contributes to characteristic hyperpigmentation, and the condition is life-threatening without lifelong steroid replacement and emergency stress-dose planning.

Pathophysiology

In UK/Western practice, most cases are autoimmune adrenalitis, with progressive cortical destruction affecting zona fasciculata, glomerulosa, and reticularis. Cortisol deficiency impairs vascular tone, gluconeogenesis, and stress responses; aldosterone deficiency causes renal sodium loss, hypovolaemia, hyponatraemia, hyperkalaemia, and postural hypotension; androgen deficiency may reduce libido and axillary/pubic hair in women. Reduced negative feedback raises pituitary ACTH (and related POMC peptides), driving skin/mucosal hyperpigmentation. During infection, surgery, trauma, or vomiting illness, fixed adrenal reserve cannot meet increased cortisol demand, precipitating adrenal crisis (shock, altered consciousness, severe electrolyte/metabolic disturbance). See Figure reference: HPA axis negative-feedback diagram in standard endocrinology texts.

Risk Factors

Autoimmune disease (especially autoimmune thyroid disease, type 1 diabetes, pernicious anaemia, vitiligo, coeliac disease) and autoimmune polyendocrine syndromes (APS-1, APS-2)
Personal/family autoimmunity or known 21-hydroxylase autoimmunity
Past or current tuberculosis, HIV, CMV, fungal infection, or meningococcal disease affecting adrenal glands
Adrenal metastases, infiltrative disease (amyloidosis, haemochromatosis)
Iatrogenic adrenal damage (bilateral adrenalectomy, adrenal haemorrhage including anticoagulant-associated haemorrhage)
Immune checkpoint inhibitor therapy
Genetic causes (for example congenital adrenal hyperplasia, adrenoleukodystrophy; particularly relevant in children)

Clinical Features

Symptoms

Progressive fatigue, lethargy, reduced exercise tolerance
Weight loss and anorexia
Nausea, vomiting, abdominal pain, diarrhoea
Dizziness/light-headedness on standing (postural symptoms)
Salt craving and increased thirst
Muscle weakness
Mood change (low mood, anxiety, poor concentration)
In women: reduced libido and loss of axillary/pubic hair

Signs

Hyperpigmentation (including buccal mucosa, palmar creases, scars; may be subtle on darker skin)
Hypotension or postural hypotension
Volume depletion/dehydration
Hyponatraemia and hyperkalaemia on biochemistry
Hypoglycaemia (particularly in children)
In adrenal crisis: shock/collapse, clamminess, confusion or reduced consciousness, feverish/cold peripheries, seizures

Investigations

Serum cortisol (8-9 am):Low morning cortisol supports adrenal insufficiency; if crisis suspected, do not delay treatment for testing.

Short Synacthen test (250 micrograms ACTH stimulation, specialist pathway):Inadequate cortisol rise confirms adrenal insufficiency.

Plasma ACTH:Raised ACTH with low cortisol indicates primary adrenal insufficiency (Addison’s disease).

Urea and electrolytes:Hyponatraemia, hyperkalaemia, possible pre-renal azotaemia from volume depletion.

Glucose:Low or low-normal glucose; hypoglycaemia more common in children and during crisis.

Plasma renin and aldosterone:High renin with low/inappropriately normal aldosterone supports mineralocorticoid deficiency.

Adrenal autoantibodies (21-hydroxylase antibodies):Positive in autoimmune Addison’s disease.

Autoimmune/associated condition screen (for example TFTs, HbA1c/glucose, B12, coeliac serology):May identify autoimmune polyendocrine overlap.

Adrenal imaging (CT) when non-autoimmune cause suspected:May show haemorrhage, calcification/infection (e. g. TB), infiltrative disease, or metastases.

Management

Lifestyle Modifications

Provide steroid emergency card/medical alert identification and clear sick-day rules (increase glucocorticoid during intercurrent illness).
Teach self-management: never stop steroids abruptly, keep rescue hydrocortisone injection available, and seek urgent care for persistent vomiting/diarrhoea or collapse.
Regular endocrinology follow-up with blood pressure, weight, symptoms, electrolytes, and renin-guided mineralocorticoid titration.
Pre-conception and pregnancy planning with specialist endocrine-obstetric input.

Pharmacological Treatment

Glucocorticoid replacement (chronic)

Hydrocortisone oral usually 15-25 mg/day in 2-3 divided doses (largest dose on waking, smaller dose at lunch, optional late-afternoon dose)

Aim for physiologic replacement; overtreatment increases risk of weight gain, hypertension, diabetes, osteoporosis, and excess mortality. Undertreatment risks fatigue and adrenal crisis. Do not stop abruptly.

Mineralocorticoid replacement (primary adrenal insufficiency)

Fludrocortisone oral typically 50-200 micrograms once daily

Monitor BP, postural symptoms, sodium/potassium, and plasma renin. Use caution in heart failure, significant renal impairment, oedema, or uncontrolled hypertension.

Adrenal crisis emergency treatment (immediate)

Hydrocortisone 100 mg IV or IM stat, then 200 mg over 24 hours (continuous IV infusion) or 50 mg IV/IM every 6 hours
% sodium chloride IV (rapid rehydration; add dextrose if hypoglycaemic)

Treat first, investigate later if unstable. Delay increases mortality. Monitor glucose, electrolytes, haemodynamics, and precipitating cause (e. g. sepsis).

Androgen replacement (selected patients, specialist use)

Dehydroepiandrosterone (DHEA) 25-50 mg once daily in women with persistent low mood/libido despite optimized standard replacement

Consider only after endocrine review; monitor for androgenic adverse effects (acne, hirsutism). Avoid in pregnancy unless specialist-directed.

Complications

Adrenal crisis (life-threatening shock, severe dehydration, seizures, stroke, cardiac arrest)
Recurrent hospital admissions during intercurrent illness if stress dosing is delayed
Persistent reduced quality of life (fatigue, mood symptoms, reduced daily function)
Pregnancy-related adverse outcomes if inadequately controlled (miscarriage, preterm birth, fetal growth restriction)
Premature ovarian insufficiency in women with autoimmune Addison’s disease
Complications from over-replacement (cardiometabolic and bone risk)

Prognosis

Untreated Addison’s disease is fatal. With appropriate lifelong replacement and emergency planning, many patients live well, but mortality remains higher than the general population, with adrenal crisis a major preventable cause of death; avoiding both under-replacement and chronic glucocorticoid excess is central to long-term outcomes.