Addison Disease
Primary adrenal insufficiency due to destruction of the adrenal cortex. Commonest cause in the UK is autoimmune adrenalitis (~80%). Characterised by cortisol and aldosterone deficiency with elevated ACTH. Presents with fatigue, weight loss, hyperpigmentation, and hypotension. Requires lifelong glucocorticoid and mineralocorticoid replacement.
Key Facts
Primary adrenal insufficiency: destruction of adrenal cortex → deficiency of cortisol, aldosterone, and adrenal androgens; elevated ACTH Commonest UK cause: autoimmune adrenalitis (~80%); associated with other autoimmune conditions (autoimmune polyendocrine syndromes — T1DM, thyroid disease, vitiligo, pernicious anaemia) Other causes: TB (commonest worldwide), adrenal metastases, adrenal haemorrhage (Waterhouse-Friderichsen — meningococcal sepsis), drugs (ketoconazole, etomidate), adrenoleukodystrophy Clinical features: fatigue, weight loss, hyperpigmentation (ACTH-driven — palmar creases, buccal mucosa, scars, skin folds), postural hypotension, nausea, abdominal pain, salt craving Diagnosis: Short Synacthen test (gold standard): 250μg IV/IM Synacthen → cortisol at 0 and 30 minutes; failure to rise >450 nmol/L at 30 min confirms adrenal insufficiency Treatment: hydrocortisone 15-25 mg/day in 2-3 divided doses (e.g., 10mg morning, 5mg midday, 5mg evening) + fludrocortisone 50-200μg OD (mineralocorticoid replacement) Sick-day rules: DOUBLE hydrocortisone dose during illness/stress; IM hydrocortisone 100mg if vomiting/unable to take oral; carry steroid emergency card and MedicAlert bracelet
Overview
Key Facts
Addison disease is rare but potentially fatal if undiagnosed. Hyperpigmentation is the distinguishing feature from secondary adrenal insufficiency. All patients need sick-day rules education and emergency hydrocortisone.
Epidemiology
Prevalence ~100-140 per million. F:M 2:1. Peak diagnosis age 30-50 years.
Aetiology
UK: autoimmune (~80%), TB (~10-15%), other (metastases, haemorrhage, infiltrative, drugs). Autoimmune polyendocrine syndrome type 1 (APS-1): Addison + chronic mucocutaneous candidiasis + hypoparathyroidism (AIRE gene mutation). APS-2 (more common): Addison + autoimmune thyroid disease ± T1DM.
Pathophysiology
Destruction of >90% of adrenal cortex → cortisol deficiency (zona fasciculata), aldosterone deficiency (zona glomerulosa), DHEA deficiency (zona reticularis). Loss of cortisol negative feedback → elevated ACTH → hyperpigmentation (ACTH is cleaved from POMC, which also produces MSH). Aldosterone deficiency → sodium wasting, hyperkalaemia, hypotension, metabolic acidosis.
Clinical Presentation
Symptoms
- Fatigue, weakness (universal)
- Weight loss, anorexia
- Nausea, vomiting, abdominal pain
- Dizziness, postural hypotension
- Salt craving (aldosterone deficiency)
- Myalgia, arthralgia
- Depression
Signs
- Hyperpigmentation: palmar creases, buccal mucosa, scars, nipples, skin folds, sun-exposed areas (ACTH excess — NOT present in secondary adrenal insufficiency)
- Postural hypotension (systolic drop >20 mmHg)
- Weight loss
- Vitiligo (associated autoimmune condition)
Biochemical Features
- Hyponatraemia (~90%), hyperkalaemia (~65%), hypoglycaemia
- Mildly raised urea (dehydration), raised calcium (sometimes)
- Eosinophilia, lymphocytosis
Red Flags
- Acute collapse with hypotension, hyponatraemia, hyperkalaemia → adrenal crisis (see separate topic)
- Unexplained hyperpigmentation with fatigue and weight loss → urgent Synacthen test
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Secondary adrenal insufficiency | NO hyperpigmentation, NO hyperkalaemia (aldosterone preserved); pituitary cause | SST, pituitary MRI |
| Chronic fatigue syndrome | Fatigue, normal bloods | Exclusion |
| Depression | Low mood, anhedonia | PHQ-9, normal cortisol |
| Anorexia nervosa | Weight loss, body image distortion | History, BMI |
| Coeliac disease | Weight loss, diarrhoea, fatigue | tTG antibodies |
Diagnosis / Investigation
Definitive
- Short Synacthen test: IM/IV Synacthen 250μg; measure cortisol at 0 and 30 minutes; peak cortisol <450 nmol/L = adrenal insufficiency; baseline cortisol <100 nmol/L highly suggestive
- 9am cortisol: screening; <100 nmol/L = likely insufficient; >450 nmol/L = likely sufficient; intermediate → SST needed
Confirm Primary vs Secondary
- ACTH level: HIGH in Addison (primary); LOW/normal in secondary
- Renin and aldosterone: renin HIGH, aldosterone LOW in Addison (not affected in secondary)
Aetiology
- Adrenal antibodies (21-hydroxylase antibodies): positive in ~90% of autoimmune Addison
- CT adrenals: TB → calcified adrenals; metastases → enlarged adrenals
- Very long chain fatty acids (VLCFA): young men → adrenoleukodystrophy
Associated Conditions
- TFTs (autoimmune thyroid), HbA1c (T1DM), B12 (pernicious anaemia), coeliac screen
Management
Glucocorticoid Replacement
- Hydrocortisone 15-25 mg/day in divided doses: e.g., 10mg on waking, 5mg midday, 5mg late afternoon (mimics circadian rhythm)
- Alternatively: prednisolone 3-5 mg/day in 1-2 doses
- Monitor: clinical wellbeing, weight, BP; avoid over-replacement (Cushingoid features, osteoporosis)
Mineralocorticoid Replacement
- Fludrocortisone 50-200μg OD
- Monitor: postural BP, electrolytes, renin (aim for high-normal renin)
DHEA (Optional)
- DHEA 25-50mg OD: consider in women with persistent low mood/fatigue despite adequate cortisol replacement
Sick-Day Rules (Essential)
- Minor illness (cold, fever): DOUBLE hydrocortisone dose
- Vomiting/unable to take oral: IM hydrocortisone 100mg
- Major surgery/trauma: IV hydrocortisone 100mg QDS
- Carry steroid emergency card, MedicAlert bracelet, emergency IM hydrocortisone injection kit
Patient Education
- Never stop steroids abruptly
- Inform all healthcare providers (dentist, surgeon, anaesthetist)
- Annual flu vaccination
Referral Criteria
- Endocrinology: all patients with new Addison disease
- Screen for associated autoimmune conditions
Prognosis
With adequate replacement therapy, life expectancy approaches normal. Mortality risk ~2× population rate (mainly from adrenal crisis, cardiovascular disease, infection). Adrenal crisis: mortality ~0.5 per 100 patient-years. Risk factors for poor outcomes: inadequate replacement, delayed diagnosis, poor sick-day rule adherence. Quality of life often impaired despite adequate biochemical replacement.
Other Relevant Information
Primary vs Secondary Adrenal Insufficiency
| Feature | Primary (Addison) | Secondary |
|---|---|---|
| ACTH | HIGH | LOW |
| Hyperpigmentation | YES | NO |
| Aldosterone | LOW (needs fludrocortisone) | NORMAL (no fludrocortisone) |
| Hyperkalaemia | YES | NO |
| Cause | Adrenal destruction | Pituitary/hypothalamic |
Autoimmune Polyendocrine Syndromes
| Type | Features | Genetics |
|---|---|---|
| APS-1 | Addison + mucocutaneous candidiasis + hypoparathyroidism | AIRE gene (AR) |
| APS-2 | Addison + autoimmune thyroid ± T1DM | HLA-DR3/DR4 |