Addison's Disease (Primary Adrenal Insufficiency)
Summary
Addison's disease is primary adrenal insufficiency caused by destruction or dysfunction of the adrenal cortex, resulting in deficiency of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). In the UK, autoimmune adrenalitis accounts for 80% of cases. The condition is rare but potentially life-threatening, particularly during adrenal crisis. Classic features include fatigue, weight loss, hyperpigmentation (due to elevated ACTH), and postural hypotension. Diagnosis is confirmed by the short Synacthen test. Lifelong replacement with hydrocortisone and fludrocortisone is required, along with education on sick-day rules to prevent adrenal crisis.
Key Facts
- Definition: Primary adrenal insufficiency — destruction/dysfunction of adrenal cortex
- Prevalence: ~5 per 100,000 (rare but serious)
- Main Cause (UK): Autoimmune adrenalitis (80%)
- Key Biochemistry: Low cortisol, High ACTH, Low Na⁺, High K⁺
- Diagnostic Test: Short Synacthen test (SST) — cortisol fails to rise
- Treatment: Hydrocortisone + fludrocortisone + sick-day education
Clinical Pearls
"Addisonian Pigmentation": Hyperpigmentation (especially creases, buccal mucosa, scars) is due to elevated ACTH and MSH (from shared proopiomelanocortin precursor). This distinguishes primary from secondary adrenal insufficiency.
"Sick Day Rules Save Lives": Patients MUST double or triple hydrocortisone during febrile illness, injury, or surgery. Failure to do so can precipitate life-threatening adrenal crisis.
Salt Craving is a Clue: Patients often crave salty foods due to aldosterone deficiency and sodium loss. This symptom is frequently overlooked but highly suggestive.
Why This Matters Clinically
Addison's disease is easily missed due to non-specific symptoms (fatigue, weight loss) but is fatal if untreated during crisis. Early recognition, proper testing (Short Synacthen Test), lifelong replacement, and patient education are essential.
Incidence & Prevalence
- Prevalence: 5 per 100,000 (rare)
- Incidence: ~0.5-1 per 100,000 per year
- Trend: Increasing (better detection, increased autoimmune disease)
Demographics
| Factor | Details |
|---|---|
| Age | Peak 30-50 years; can occur at any age |
| Sex | Female:Male 2-3:1 (autoimmune) |
| Ethnicity | More common in those with other autoimmune diseases |
| Geography | TB more common cause in developing countries |
Risk Factors
Autoimmune (80% in UK):
- Other autoimmune conditions (type 1 DM, thyroid disease, vitiligo, coeliac)
- Family history of autoimmune disease
- Female sex
Other Causes:
| Cause | Notes |
|---|---|
| Tuberculosis | Most common worldwide; adrenal calcification on CT |
| Adrenal haemorrhage | Waterhouse-Friderichsen (meningococcal sepsis) |
| Metastatic cancer | Lung, breast, melanoma |
| Adrenoleukodystrophy | X-linked; young males; VLCFA testing |
| Drugs | Ketoconazole, etomidate, rifampicin |
| HIV/AIDS | Opportunistic infections |
Mechanism
Step 1: Adrenal Cortex Destruction
- Autoimmune: Antibodies against 21-hydroxylase enzyme
- TB: Caseating granulomas destroy cortex
- Other: Haemorrhage, metastases, infiltration
Step 2: Hormone Deficiencies
| Hormone | Zone | Deficiency Effect |
|---|---|---|
| Cortisol | Zona fasciculata | Fatigue, hypoglycaemia, poor stress response |
| Aldosterone | Zona glomerulosa | Sodium loss, potassium retention, hypotension |
| DHEA | Zona reticularis | Reduced libido, axillary/pubic hair loss (women) |
Step 3: Loss of Feedback → High ACTH
- Low cortisol removes negative feedback on hypothalamus/pituitary
- ACTH and MSH rise (both from POMC precursor)
- MSH causes hyperpigmentation
Primary vs Secondary Adrenal Insufficiency
| Feature | Primary (Addison's) | Secondary (Pituitary) |
|---|---|---|
| ACTH | High (no feedback) | Low (pituitary failure) |
| Hyperpigmentation | Present | Absent |
| Mineralocorticoid | Deficient | Usually preserved (RAAS) |
| Cause | Adrenal destruction | Pituitary tumour, steroid withdrawal |
Symptoms
Chronic (Insidious Onset):
Acute (Adrenal Crisis):
Signs
Red Flags
[!CAUTION] Adrenal Crisis Red Flags — Life-threatening emergency:
- Hypotension not responding to fluids
- Shock, collapse
- Severe hyperkalaemia
- Hypoglycaemia
- Altered consciousness
- Abdominal pain with hypotension (can mimic acute abdomen)
Treatment: IV hydrocortisone 100mg STAT, IV 0.9% saline
Structured Approach
General:
- Nutritional status (often underweight)
- Vital signs including postural BP
- Hydration status
Specific:
- Skin: Hyperpigmentation (creases, buccal, scars)
- BP: Postural drop
- Hair: Axillary/pubic hair loss (women)
- Associated conditions: Vitiligo, thyroid
Special Tests
| Feature | Technique | Significance |
|---|---|---|
| Postural Hypotension | BP lying → standing | Drop >20 systolic = positive |
| Palmar Crease Pigmentation | Compare to dorsum | Darker creases in Addison's |
| Buccal Mucosa | Examine cheeks, gums | Dark patches |
| Scar Pigmentation | Old scars darker | Characteristic of primary AI |
| Vitiligo | Depigmented patches | Associated autoimmune |
First-Line
| Test | Expected Finding | Notes |
|---|---|---|
| U&E | Low Na⁺, High K⁺ | Classic pattern |
| Glucose | May be low | Cortisol needed for gluconeogenesis |
| FBC | Normocytic anaemia; eosinophilia | Cortisol normally suppresses eosinophils |
| 9am Cortisol | Low (<100 nmol/L highly suggestive) | >500 excludes AI |
| ACTH | High (primary) vs Low (secondary) | Distinguishes primary from secondary |
Short Synacthen Test (SST)
Gold Standard Diagnostic Test:
| Time | Action |
|---|---|
| 0 min | Take baseline cortisol; give Synacthen 250mcg IM/IV |
| 30 min | Measure cortisol |
Interpretation:
- Normal: Cortisol rises to ≥450-500 nmol/L at 30 minutes
- Addison's: Cortisol fails to rise adequately
Further Investigations
| Test | Purpose |
|---|---|
| Adrenal antibodies (21-hydroxylase) | Confirms autoimmune cause (present in 80%) |
| CT Adrenals | TB (calcification), haemorrhage, tumour, metastases |
| Very long chain fatty acids | Adrenoleukodystrophy (young males) |
| TFTs | Associated autoimmune thyroid disease |
| Glucose / HbA1c | Associated type 1 DM |
| Renin / Aldosterone | Assessment of mineralocorticoid axis |
Management Algorithm
ADDISON'S DISEASE MANAGEMENT
↓
┌─────────────────────────────────────────────────────┐
│ ACUTE ADRENAL CRISIS │
│ (Life-Threatening Emergency) │
│ │
│ • IV access, take blood (cortisol, ACTH, U&E, glucose)│
│ • Hydrocortisone 100mg IV/IM IMMEDIATELY │
│ • IV 0.9% saline (1L in first hour, then guided) │
│ • Treat hypoglycaemia (IV dextrose if needed) │
│ • Monitor and ITU if severe │
│ • Identify and treat trigger (infection common) │
│ • Continue hydrocortisone 50-100mg IV 6-hourly │
│ • (No fludrocortisone needed — high-dose HC has │
│ mineralocorticoid activity) │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ CHRONIC REPLACEMENT │
│ │
│ GLUCOCORTICOID: │
│ • Hydrocortisone 15-25mg/day in divided doses │
│ • Typical: 10mg AM, 5mg noon, 5mg evening │
│ OR 10mg AM, 5mg noon, 2.5mg evening │
│ • Aim to mimic circadian rhythm (largest dose AM) │
│ │
│ MINERALOCORTICOID: │
│ • Fludrocortisone 50-200mcg once daily (morning) │
│ • Titrate to: BP, K⁺, renin levels │
│ │
│ DHEA (Women): │
│ • Consider DHEA 25-50mg if fatigue/low libido persist│
│ • Not universally available/prescribed │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ PATIENT EDUCATION (Essential) │
│ │
│ • Steroid card (carry at all times) │
│ • MedicAlert bracelet/pendant │
│ • Emergency hydrocortisone injection kit │
│ - Teach patient/family to administer │
│ • SICK DAY RULES: │
│ - Minor illness (cold, fever): DOUBLE HC dose │
│ - Severe illness/vomiting: TRIPLE dose / IM HC │
│ - Surgery/major stress: IV HC cover │
│ • Never stop steroids abruptly │
└─────────────────────────────────────────────────────┘
Monitoring
- Clinical: Symptoms, weight, BP
- Biochemistry: U&E (sodium, potassium), renin (titrate fludrocortisone)
- Annual review: Screen for associated autoimmune conditions (TFTs, glucose)
Adrenal Crisis
| Feature | Details |
|---|---|
| Triggers | Infection, trauma, surgery, non-compliance, steroid cessation |
| Presentation | Hypotension, shock, confusion, abdominal pain, vomiting |
| Treatment | IV hydrocortisone 100mg + IV saline + identify trigger |
| Mortality | High if untreated; low with prompt treatment |
Long-Term Complications
- Cardiovascular risk (glucocorticoid effects, BP management)
- Osteoporosis (excess glucocorticoid replacement)
- Associated autoimmune diseases (thyroid, T1DM, vitiligo)
Treatment-Related
- Over-replacement: Cushingoid features, osteoporosis, weight gain
- Under-replacement: Fatigue, crisis risk, hypotension
Natural History
Untreated Addison's disease is fatal. With appropriate lifelong replacement therapy and education, patients can lead normal lives with near-normal life expectancy.
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Life expectancy | Near-normal with good compliance |
| Quality of life | Most patients do well |
| Crisis risk | ~8% annual risk of crisis (reduced with education) |
| Mortality in crisis | Low with prompt treatment; high if delayed |
Prognostic Factors
Good Prognosis:
- Early diagnosis
- Good education and compliance
- Access to healthcare
- Carrying steroid card/emergency kit
Poorer Prognosis:
- Delayed diagnosis
- Poor compliance
- Inadequate sick-day education
- Living alone without support
Key Guidelines
-
Endocrine Society Clinical Practice Guideline: Diagnosis and Treatment of Primary Adrenal Insufficiency (2016) — Comprehensive guidance on diagnosis, replacement, and crisis management.
-
Society for Endocrinology Emergency Guidelines: Adrenal Crisis (2016) — UK emergency protocol.
Landmark Studies
Arlt & Allolio (2003) — Lancet review
- Comprehensive review of adrenal insufficiency
- Key finding: Established modern approach to diagnosis and management
- Clinical Impact: Standard reference for replacement strategies
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Short Synacthen Test | 1b | Established diagnostic standard |
| Hydrocortisone replacement | 2a | Cohort studies, guidelines |
| Fludrocortisone | 2a | Established practice |
| Sick-day rules | 2b | Observational studies showing crisis prevention |
What is Addison's Disease?
Addison's disease is a condition where your adrenal glands (small glands above your kidneys) don't make enough of certain hormones — mainly cortisol and aldosterone. These hormones are essential for handling stress, regulating blood pressure, and maintaining salt balance.
Why does it matter?
Without these hormones, you can become very unwell, especially during times of stress like illness, injury, or surgery. If not treated, Addison's disease can be life-threatening. However, with proper treatment and education, people with Addison's can live completely normal lives.
How is it treated?
You will need to take replacement hormones every day for the rest of your life:
-
Hydrocortisone tablets: Replaces cortisol. Usually taken 2-3 times a day, with the largest dose in the morning to mimic your body's natural pattern.
-
Fludrocortisone tablets: Replaces aldosterone. Usually taken once daily.
-
Sick day rules: When you're unwell (fever, vomiting, infection), you need to double or triple your hydrocortisone dose. If you're very unwell or can't keep tablets down, you may need an injection.
-
Emergency kit: You should have an emergency hydrocortisone injection kit and know how to use it (or have family/friends who can).
-
Steroid card and MedicAlert: Always carry your steroid card and consider wearing a MedicAlert bracelet so that medical staff know about your condition if you're unable to tell them.
What to expect
- With proper treatment, you can live a normal, active life
- You'll need regular check-ups (usually yearly)
- You must never stop your medication suddenly
- Learning the sick-day rules is very important
When to seek help
Seek emergency help immediately if:
- You feel very weak or faint
- You have severe vomiting and can't keep tablets down
- You collapse or feel you might collapse
- You have severe abdominal pain with feeling unwell
Tell them you have Addison's disease and may need emergency hydrocortisone.
Primary Guidelines
- Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. PMID: 26760044
Key Studies
-
Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881-1893. PMID: 12788587
-
Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275(2):104-115. PMID: 24330030
Further Resources
- Addison's Disease Self-Help Group (UK): addisons.org.uk
- Society for Endocrinology: endocrinology.org
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate guidelines and specialists for patient care.