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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Primary adrenal insufficiency (Addison's): destruction of adrenal cortex — low cortisol AND aldosterone. Autoimmune in >80% of UK cases
- Secondary: pituitary ACTH deficiency (most commonly from withdrawal of exogenous steroids). Aldosterone preserved (RAAS intact)
- Classic triad: fatigue, weight loss, hyperpigmentation (primary only — from high ACTH/MSH). Also: postural hypotension, hyponatraemia
- Diagnosis: morning cortisol (<100 nmol/L strongly suggestive; >500 excludes). Short Synacthen test (250 mcg IM/IV): cortisol <450 nmol/L at 30 min = adrenal insufficiency
- Treatment: hydrocortisone 15–25 mg/day in divided doses + fludrocortisone 50–200 mcg/day (primary only) + sick day rules education
- Adrenal crisis = medical emergency: IV/IM hydrocortisone 100 mg stat, IV 0.9% saline, treat precipitant. All patients carry steroid emergency card and injection kit (NICE NG243)
Overview
Adrenal insufficiency is the inadequate production of adrenal cortex hormones (cortisol, aldosterone, adrenal androgens). Primary adrenal insufficiency (Addison's disease) results from destruction or dysfunction of the adrenal cortex itself. In the UK, autoimmune adrenalitis accounts for >80% of cases — often associated with other autoimmune conditions (autoimmune polyglandular syndromes: T1DM, autoimmune thyroiditis, vitiligo, pernicious anaemia). Worldwide, tuberculosis remains an important cause. Secondary adrenal insufficiency results from deficient pituitary ACTH secretion — most commonly caused by chronic exogenous glucocorticoid use and subsequent withdrawal. Tertiary adrenal insufficiency involves hypothalamic CRH deficiency. In secondary/tertiary forms, aldosterone production is preserved because it is primarily regulated by the renin-angiotensin-aldosterone system, not ACTH.
Epidemiology
Primary adrenal insufficiency affects approximately 100–140 per million population in the UK. It has a slight female predominance (F:M 1.5:1). Peak onset is 30–50 years. Secondary adrenal insufficiency is more common (150–280 per million) — the most frequent cause is iatrogenic HPA axis suppression from exogenous glucocorticoid therapy (oral, inhaled, topical, intra-articular). Risk of secondary adrenal insufficiency increases with dose, duration, and potency of steroid therapy. Any patient on >5 mg prednisolone daily for >4 weeks (or equivalent) is at risk of HPA axis suppression.
Clinical Features
Symptoms
Fatigue and lethargy — often the earliest and most prominent symptom
Weight loss and reduced appetite
Dizziness and postural hypotension (from mineralocorticoid and cortisol deficiency)
Nausea, vomiting, abdominal pain, diarrhoea
Salt craving (aldosterone deficiency — primary only)
Myalgia and arthralgia
Adrenal crisis: collapse, severe hypotension, confusion, abdominal pain, vomiting, hypoglycaemia
Signs
Hyperpigmentation: skin creases, buccal mucosa, scars, pressure areas (PRIMARY only — from excess ACTH/MSH)
Postural hypotension (systolic drop ≥20 mmHg on standing)
Dehydration
Loss of axillary and pubic hair in women (adrenal androgen deficiency)
Vitiligo (associated autoimmune condition)
Shock (in adrenal crisis): hypotension, tachycardia, reduced GCS
Investigations
First-line
9 AM serum cortisol<100 nmol/L strongly suggests adrenal insufficiency. >450 nmol/L makes it very unlikely. 100–450 = perform Synacthen test
Short Synacthen test (SST)Give tetracosactide (Synacthen) 250 mcg IM/IV. Measure cortisol at 0 and 30 min. Peak cortisol <450 nmol/L = adrenal insufficiency (NICE NG243 threshold)
U&EsHyponatraemia (common), hyperkalaemia (primary only — aldosterone deficiency), raised urea (dehydration)
Second-line
Plasma ACTHHIGH in primary (adrenal failure → loss of negative feedback). LOW/normal in secondary (pituitary failure). Take 9 AM sample simultaneously with cortisol
Plasma renin and aldosteroneHigh renin + low aldosterone = primary. Normal in secondary (RAAS intact)
Adrenal autoantibodies (21-hydroxylase)Positive in autoimmune Addison's (>80% of UK cases)
Blood glucoseHypoglycaemia — cortisol is a counter-regulatory hormone
Specialist
CT adrenalsSmall atrophic adrenals (autoimmune), calcified adrenals (TB), enlarged adrenals (infiltration, haemorrhage, metastases)
Screen for associated autoimmune conditionsTFTs, coeliac serology, vitamin B12, glucose — autoimmune polyglandular syndrome
MRI pituitaryIf secondary adrenal insufficiency suspected — assess for pituitary tumour/empty sella
Management
NICE NG243 (Adrenal insufficiency), 20241
Glucocorticoid replacement
- Hydrocortisone: 15–25 mg/day in 2–3 divided doses (e.g. 10 mg on waking, 5 mg midday, 5 mg late afternoon)
- Mimic physiological cortisol rhythm: largest dose in the morning, avoid late evening dose (disrupts sleep)
- Alternative: prednisolone 3–5 mg daily (some patients prefer once-daily dosing)
- Modified-release hydrocortisone (Plenadren): once daily, mimics diurnal rhythm
2
Mineralocorticoid replacement (PRIMARY only)
- Fludrocortisone: 50–200 mcg once daily
- Monitor: BP (sitting and standing), U&Es, plasma renin (aim for upper normal renin to avoid overreplacement)
- Not needed in secondary adrenal insufficiency (aldosterone production is intact)
3
Sick day rules and stress dosing (CRITICAL)
- Febrile illness, vomiting, diarrhoea, significant physical stress: DOUBLE oral hydrocortisone dose ("stress dose")
- If unable to take oral: IM hydrocortisone 100 mg (emergency injection kit must be available at all times)
- Surgery/major stress: IV hydrocortisone 100 mg bolus then 50 mg 6–8 hourly
- All patients MUST carry: NHS Steroid Emergency Card, medical alert jewellery, emergency IM hydrocortisone kit
- Educate patient AND family/carers in IM injection technique (NICE NG243)
4
Adrenal crisis — emergency management
- Medical emergency — mortality ~5%
- IM/IV hydrocortisone 100 mg STAT (do NOT delay for investigations)
- IV 0.9% saline: aggressive fluid resuscitation (1 L in first hour)
- Check and correct hypoglycaemia (IV dextrose if needed)
- Continue IV hydrocortisone 50 mg 6-hourly until able to take oral
- Identify and treat precipitant: infection (most common trigger), missed doses, surgery, trauma
- At hydrocortisone doses >50 mg/day, separate fludrocortisone is not needed (sufficient mineralocorticoid activity)
Complications
- Adrenal crisis: Life-threatening — triggered by infection, missed doses, surgery, trauma. Presents with collapse, hypotension, hypoglycaemia, hyponatraemia. Treat with IM/IV hydrocortisone 100 mg + IV saline
- Osteoporosis: From glucocorticoid replacement (aim for lowest effective dose). Monitor with DEXA
- Cardiovascular: Increased cardiovascular mortality despite replacement — possibly from non-physiological cortisol dosing pattern
- Associated autoimmune diseases: Autoimmune polyglandular syndrome type 1 (Addison + hypoparathyroidism + candidiasis) or type 2 (Addison + autoimmune thyroid + T1DM — Schmidt syndrome). Regular screening required
- Impaired quality of life: Persistent fatigue common even with adequate replacement — may relate to absent adrenal androgen production (DHEA)
UKMLA Exam Tips
- 1Primary vs secondary: hyperpigmentation + hyperkalaemia + high ACTH = PRIMARY. No pigmentation + normal K⁺ + low ACTH = SECONDARY
- 2Short Synacthen test: cortisol <450 nmol/L at 30 min = adrenal insufficiency. This tests adrenal RESERVE, not just baseline
- 3Most common cause of secondary adrenal insufficiency = chronic steroid use and withdrawal. Always ask about steroids
- 4Hyponatraemia is common in BOTH primary and secondary (cortisol deficit → impaired free water excretion). Hyperkalaemia is PRIMARY only
- 5Adrenal crisis management: IM hydrocortisone 100 mg — do NOT delay for cortisol blood test. Treat first, confirm later
- 6Sick day rules: double the dose. Vomiting? Give IM hydrocortisone. This MUST be taught to every patient
- 7Waterhouse-Friderichsen syndrome: bilateral adrenal haemorrhage in meningococcal sepsis → acute adrenal failure
practicetest your knowledge on addison's diseaseApply what you've learnt with UKMLA-style questions from the iatroX Q-Bank — endocrine and beyond.
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Addison's Disease and Adrenal Insufficiency: guidance by region
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