Overview
Addison's Disease
1. Introduction & Epidemiology
Summary
Addison's Disease is primary failure of the adrenal cortex, leading to life-threatening deficiency of Glucocorticoids (Cortisol) and Mineralocorticoids (Aldosterone).
- Primary: The gland itself is destroyed (High ACTH).
- Secondary: Pituitary failure (Low ACTH). This is NOT Addison's (Aldosterone remains intact).
Clinical Summary Table
| Domain | Details |
|---|---|
| Pathology | Autoimmune destruction of Adrenal Cortex. Deficient Cortisol + Aldosterone. |
| Presentation | Weight loss, Pigmentation (Tan), Hypotension, Salt Craving. |
| Investigation | SST (Gold Standard), 9am Cortisol, ACTH (High). |
| Management | Hydrocortisone + Fludrocortisone. |
| Emergency | 100mg IV Hydrocortisone + Fluids immediately. |
Glossary for Patients
- Adrenal Cortex: The outer shell of the adrenal gland.
- Cortisol: The stress hormone (essential for life).
- Aldosterone: The salt hormone (keeps blood pressure up).
- Crisis: A life-threatening crash in blood pressure due to lack of cortisol.
- Meds: You replace what is missing.
Epidemiology
- Prevalence: 1 in 10,000 (Rare but critical).
- Demographics: Autoimmune form affects Women > Men (2:1). Peak age 30-50.
- Mortality: Patients still die from missed Adrenal Crisis.
The "Spot Diagnosis"
Classic Appearance: "The Healthy Tan". A patient who looks tanned (hyperpigmented) but feels incredibly weak, dizzy, and nauseous.
Red Flags (Adrenal Crisis)
- Hypotension: Resistent to fluids (needs Dopamine/Steroids).
- Abdo Pain: Severe, mimicking acute abdomen.
- Confusion: Due to hypoglycaemia/hyponatraemia.
2. Pathophysiology
The Gland is Gone.
- Cortisol Loss:
- Metabolic: Loss of gluconeogenesis -> Hypoglycaemia.
- Vascular: Loss of vascular tone -> Hypotension.
- Immune: Disinhibition of inflammation (paradoxically prone to death from cytokine storm).
- Aldosterone Loss:
- Kidney: Can't retain Sodium. Can't excrete Potassium.
- Result: Hyponatraemia (Salt Wasting) + Hyperkalaemia + Dehydration.
- ACTH Excess:
- Lack of feedback inhibition causes the pituitary to scream.
- POMC: The precursor molecule (Pro-opiomelanocortin) is cleaved into ACTH AND MSH (Melanocyte Stimulating Hormone).
- Result: Deep skin pigmentation.
Physiological Drill Down: The Circadian Rhythm
- Normal: Cortisol peaks at 8-9am (The "Wake Up" surge) and falls to a nadir at midnight (Sleep).
- Addison's: Flatline (Low/Zero) all day.
- Replacement Challenge: Pills (taken 2-3 times a day) create unnatural peaks and deep troughs. This mismatch causes the "afternoon crash" and "insomnia" seen in many patients.
- Goal: To replicate the curve as closely as possible (mimetic therapy).
Pathology Drill Down: Why the Tan?
The POMC Connection
- Low Cortisol -> Pituitary makes massive amounts of POMC (Pro-opiomelanocortin).
- Cleavage: POMC is chopped into ACTH (to whip the adrenal) and MSH (Melanocyte Stimulating Hormone).
- MSH Effect: Binds to melanocortin-1 receptors in skin -> Melanin production.
- Sign: "Sun tan in winter", especially in scars, gingiva (gums), and pressure points (elbows/knuckles).
2. Aetiology (Causes)
| Cause | Mechanism | Notes |
|---|---|---|
| Autoimmune (80%) | 21-Hydroxylase Antibodies destroy the cortex. | Often part of APS-2 (Thyroid/Diabetes). |
Drill Down: 21-Hydroxylase Antibodies
- Target: The enzyme responsible for cortisol synthesis in the Zona Fasciculata.
- Specificity: >90% specific for Autoimmune Addison's.
- Predictive Value: Presence of antibodies predicts overt disease in "at risk" populations (e.g. Type 1 Diabetics) years before symptoms start.
Pathology Drill Down: Autoimmune Adrenalitis
- Macroscopic: The glands are shrunken, fibrotic, and difficult to find at autopsy ("Atrophic").
- Microscopic: Lymphocytic infiltration of the cortex. The medulla is spared (Adrenaline is still made).
- Comparison: In TB/Metastases, the glands are enlarged (calcified or tumorous).
| TB (Tuberculosis) | Granulomatous destruction. | Most common cause worldwide (developing countries). | | Adrenal Haemorrhage | Waterhouse-Friderichsen Syndrome (Meningococcal Sepsis). | Acute catastrophic failure. | | Metastases | Bilateral infiltration (Lung/Breast/Renal cancer). | Adrenals are a common met site. | | Genetic | Adrenoleukodystrophy (ALD). | X-linked. Affects young males. |
Drill Down: Adrenoleukodystrophy (ALD)
The one you miss.
- Genetics: X-linked recessive (ABCD1 gene).
- Mechanism: Accumulation of Very Long Chain Fatty Acids (VLCFA).
- Presentation: Young boy with "Addison's" + Behavioural change/Dementia.
- Action: Check VLCFA in any male with antibody-negative Addison's.
Waterhouse-Friderichsen Syndrome (The Catastrophe)
- Cause: Neisseria meningitidis (Meningoccal Sepsis).
- Pathology: DIC causes thrombosis and massive bilateral haemorrhage into the adrenal glands.
- Presentation: Purpuric rash, shock, coma.
- Outcome: "Adrenal Apoplexy". Instant loss of all cortisol support during massive sepsis. Nearly always fatal without steroids.
TB Addison's (The Global Killer)
- Pathology: Mycobacterium tuberculosis infects the glands causing Caseous Necrosis.
- Imaging: CT shows Adrenal Calcification (unlike autoimmune where glands are atrophied/small).
- Treatment: Anti-TB therapy (RIPE).
- Warning: Rifampicin accelerates cortisol metabolism (CYP450 inducer). You must INCREASE steroid dose during TB treatment or you will precipitate a crisis.
3. Clinical Presentation
Symptoms (The "Slow Burn")
History Taking: The Key Questions
Physical Signs
Technique Drill Down: Postural BP
- Lie Down: Measure BP after 5 mins supine.
- Stand Up: Measure BP immediately on standing, and at 3 mins.
- Positive: Systolic drop >20mmHg OR Diastolic drop >10mmHg.
- Addison's: Often profound drop with reproduction of dizziness.
Clinical Vignette: The "Gastro" Trap
Patient: 24F, presents with "D&V" (Diarrhoea & Vomiting). History: Feeling tired for months. Weight loss 5kg. Exam: Tanned skin (she says she uses sunbeds... or does she?). BP 90/50. The Trap: Diagnosed as "Gastroenteritis" and sent home. Outcome: Relentless vomiting -> Hypovolaemic Shock -> Cardiac Arrest (Hyperkalaemia). Lesson: Any "Gastro" with hypotension or pigmentation needs Electrolytes checking.
Clinical Vignette 2: The "Post-Op" Crash
Patient: 45M, undergoes routine knee replacement. History: Diagnosed with Addison's 10 years ago. Event: Surgeon forgot to write up IV Hydrocortisone cover. Outcome: BP drops to 60/40 in recovery. Unresponsive to fluids. Rescue: Anaesthetist spots the Medic Alert bracelet -> Giving 100mg Hydrocortisone -> BP normalises in 20 mins. Lesson: The adrenal glands can't wake up for surgery. You MUST replace them.
Clinical Vignette 3: The "Morning Sickness" Error
Patient: 30F, 10 weeks pregnant. Known Type 1 Diabetic. Complaint: Hyperemesis Gravidarum (Severe vomiting). Trap: Vomiting is assumed to be pregnancy-related. Clue: Her insulin requirements have DROPPED massively (Hypoglycaemia). Cortisol opposes insulin. If Cortisol is low, Insulin works too well. Dx: Addison's Disease (APS-2). Action: Stabilise with IV Hydrocortisone.
Fatigue
Profound, progressive.
Weight Loss
Anorexia ("I can't eat").
Salt Craving
Drinking pickle juice/soy sauce.
Nausea/Vomiting
A sign of impending crisis.
Dizziness
Postural drop.
4. Investigations
Acute (Crisis)
Do NOT wait for results. Treat first.
- Labs: Hyponatraemia (Low Na), Hyperkalaemia (High K), Hypoglycaemia (Low Glucose), High Urea (Dehydration).
Diagnosis (Stable Patient)
- Morning Cortisol (9am):
- <100 nmol/L: Highly suggestive.
- >450 nmol/L: Unlikely.
Diagnostic Pitfalls: Hyperpigmentation
It's not always Addison's.
| Condition | Clue | Test |
|---|---|---|
| Haemochromatosis | "Bronze Diabetic". Liver disease. | Ferritin high. |
| Acanthosis Nigricans | Velvety texture (neck/axilla). Insulin resistance. | HbA1c. |
| Drug Induced | Minocycline (Blue-grey). | Medication history. |
| Nelson's Syndrome | History of Adrenalectomy. | ACTH very high. |
Reviewer's Note: The "Orange" Patient
Carotenaemia: Patients who drink excessive carrot juice/eat pumpkins can turn orange. Diff: Sclera (whites of eyes) are white (unlike Jaundice). Diff: Palmar creases are orange but not brown (unlike Addison's). Action: Ask about diet.
- Short Synacthen Test (SST): The Gold Standard.
- Method: Give 250mcg ACTH (Synacthen) IM/IV. Measure Cortisol at 0 and 30 mins.
- Normal: Cortisol rises >450 nmol/L.
- Addison's: Flatline response (Gland is dead).
- Addison's: Flatline response (Gland is dead).
Drill Down: The Short Synacthen Test (SST)
- Preparation: Stop hydrocortisone for 24 hours before test (Prednisolone needs 48-72h wash out).
- Pass: Peak Cortisol >450 nmol/L = Adrenals are working.
- Fail: Peak Cortisol <450 nmol/L = Adrenal Insufficiency.
- Note: OCP (Estrogen) raises CBG (Cortisol Binding Globulin) -> Falsely high total cortisol. Stop OCP 6 weeks before, or use higher cutoff (>800).
- ACTH Level:
- High: Primary (Addison's).
- Low: Secondary (Pituitary).
- Autoantibodies: Anti-21-Hydroxylase (positive in >80% of autoimmune cases).
When to Refer (Triage)
| Scenario | Action | Urgency |
|---|---|---|
| Suspected Crisis | Admit to ED immediately. | Emergency (0 hours). |
| High Suspicion (Pigmented + Hypotensive) | Same Day Medical Assessment (SDEC). | Urgent (24 hours). |
| Low Suspicion (Fatigue only) | 9am Cortisol in Primary Care. | Routine. |
| Positive SST | Refer to Endocrinology. | Urgent (2 weeks). |
5. Management
1. The Adrenal Crisis (Emergency)
Protocol: > 1. Hydrocortisone: 100mg IV Bolus immediately. > 2. Fluids: 1L 0.9% Saline stat (They are volume depleted). > 3. Glucose: If hypoglycaemic. > 4. Maintenance: Hydrocortisone 50-100mg IV q6h.
Emergency Drill Down: The "Golden Hour"
| Action | Detail | Reason |
|---|---|---|
| Cannulate | Two large bore (grey/orange). | Need rapid fluid resus. |
| Draw Bloods | U&E, Cortisol, ACTH, Glucose. | DO NOT WAIT FOR RESULTS. |
| Inject Steoids | 100mg Hydrocortisone IV (or IM). | Saving the life takes priority over diagnosis. |
| Fluids | 1L Saline over 30-60 mins. | Treating hypovolaemic shock. |
| Glucose | 10% Dextrose if hypo. | Hypoglycaemia kills fast. |
- Dose: 15-25mg daily. Split dosing (e.g. 10mg waking, 5mg lunch, 5mg early evening).
Memory Aid: The 5 S's of Adrenal Crisis ( Emergency)
- Salt: 0.9% Saline (Treats hyponatraemia/volume).
- Sugar: Dextrose (Treats hypoglycaemia).
- Steroids: 100mg Hydrocortisone.
- Support: Oxygen, HDU admission.
- Search: Find the trigger (Sepsis? Missed dose?).
Algorithm: The Resuscitation Sequence
- ABC: Airway secure? Breathing? Circulation (Shocked?).
- Access: 2x large bore cannulas. Take bloods but DON'T WAIT.
- Drugs:
- Hydrocortisone 100mg IV.
- 0.9% Saline 1000ml stat.
- Re-assess: Is BP rising?
- Next Steps: Check Glucose. If <4.0mmol/L -> 100ml 10% Dextrose.
- ICU: If requiring noradrenaline or vasopressors.
Common Triggers for Crisis
- Infection: Gastro/Pneumonia (Most common).
- Missed Doses: "I felt sick so I stopped taking pills". (Fatal error).
- Surgery/Trauma: Without extra cover.
- Thyroxine: Starting Thyroxine in undiagnosed Addison's precipitates crisis (Increases metabolic clearance of cortisol).
2. Maintenance Therapy (Replacement)
Mimic Nature.
- Glucocorticoid: Hydrocortisone.
- Dose: 15-25mg daily. Split dosing (e.g. 10mg waking, 5mg lunch, 5mg early evening).
- Goal: Energy levels, avoid evening dose (insomnia).
- Mineralocorticoid: Fludrocortisone.
- Dose: 50-200mcg daily.
- Monitor: BP, Sodium, Potassium, Renin levels.
- Limit: Only used if QoL remains poor despite optimal Gluc/Mineral replacement.
The Multidisciplinary Team (MDT)
- Endocrinologist: Oversights annual review.
- Endocrine Nurse Specialist: The most important contact. Teaches injection technique and runs sick day education.
- GP: Prescribes repeats. Handles minor infections.
- Patients: Values peer support (ADSHG).
Drug Table: The "Extras"
| Drug | Role | Monitoring | Notes |
|---|---|---|---|
| Fludrocortisone | Replaces Aldosterone (Salt retention). | Renin: Aim for upper limit of normal. BP: No drop on standing. K+: Normal. | High dose -> Hypertension + Hypokalaemia. |
| DHEA | Replaces Adrenal Androgens. | Skin: Acne/Oily skin. Mood: Libido/Energy. | Controversial. Trial for 6 months then stop if no benefit. |
Surgical & Stress Dosing Guide
Adrenals can't surge, so we must surge for them.
- Minor Procedure (Dental, Endoscopy): Double oral dose for 24 hours.
- Moderate Surgery (Hernia, Appendectomy): 50-100mg IV Hydrocortisone at induction -> Orals as soon as eating.
- Major Surgery (Cardiac, bowel): 100mg IV at induction -> 50-100mg IV q6h for 24-48 hours -> Taper.
- Labour/Delivery: 50-100mg IV at onset of active labour -> 50mg q6h.
Special Populations: Pregnancy
- First Trimester: Nausea/hyperemesis is DANGEROUS. Low threshold for IV steroids.
- Dose Adjustment: Usually increase Hydrocortisone by 20-50% in 3rd trimester (increased cortisol binding globulin).
- Fludrocortisone: Keep dose same (Progesterone acts as anti-mineralocorticoid, so need is balanced).
- Labour: Is a major stress event. Needs IV coverage.
Pregnancy Roadmap
| Stage | Action | Reason |
|---|---|---|
| Pre-Conception | Optimise TSH and HbA1c (if APS-2). | Ensure fertility. |
| Trimester 1 | Cover Hyperemesis with IV steroids. | Vomiting = Crisis. |
| Trimester 2 | Monitor BP/Symptoms. | Usually stable. |
| Trimester 3 | Increase Hydrocortisone by 20-40%. | CBG rises. Fetus needs cortisol. |
| Labour | 100mg IV at onset + 50mg q6h. | Major stress. |
| Post-Partum | Rapid taper to pre-pregnancy dose. | Avoid over-replacement. |
Special Populations: Paediatrics
- Presentation: Often vague "fail to thrive" or poor school performance.
- Growth: Poor linear growth despite weight gain (if overtreated) or weight loss (if untreated).
- Hypoglycaemia: More common in children.
- Puberty: Adrenal androgens (DHEA) drive pubic/axillary hair. A girl with no pubic hair by age 13 -> Check Adrenals.
6. Sick Day Rules (Patient Education)
The most important part of management.
Rule 1: The "Double Dose"
- Trigger: Fever >38°C, antibiotics, minor procedure.
- Action: Double the daily dose of Hydrocortisone immediately. Keep doubled until fever resolves.
Rule 2: The "Emergency Injection"
- Trigger: Vomiting or Diarrhoea (Meds not absorbed). Or Major Trauma.
- Action: Inject 100mg Hydrocortisone IM immediately. Call Ambulance covering note ("I am in Adrenal Crisis").
Sick Day Action Guide
| Situation | Action | Dose |
|---|---|---|
| Mild Cold/Sniffles | No Change. | Standard. |
| Fever >8°C | Double Dose. | 20+10+10mg (approx). |
| Antibiotics Prescribed | Double Dose. | Until infection clears. |
| Vomiting Once | Take another dose immediately. | If vomited again -> Inject. |
| Persistent Vomiting | INJECT 100mg IM. | Call 999. Do not wait. |
| Colonoscopy Prep | Admit for IV steroids + fluids. | Oral meds won't be absorbed. |
The Emergency Injection Kit (Must Haves)
| Item | Details |
|---|---|
| Drug | Hydrocortisone Sodium Succinate 100mg (Powder). |
| Water | Water for injection (Ampoule). |
| Syringe | 2ml or 5ml. |
| Needles | Green (Draw up) and Blue (Inject IM). |
| Instruction | Printed card showing "How to Inject". |
| Expiry | Check date annually. |
7. Complications
- Adrenal Crisis: Mortality 5-10%.
- Overtreatment: Cushing's Syndrome, Osteoporosis, Diabetes.
- Autoimmune Polyendocrine Syndromes (APS):
- APS-1: Addison's + Hypoparathyroid + Candidiasis.
- APS-2: Addison's + Type 1 Diabetes + Thyroid Disease.
Psychological Impact ("Brain Fog")
- Cognitive: Difficulty concentrating is a very common complaint.
- Mood: Depression and anxiety are prevalent, partly due to the burden of chronic disease.
- Steroids: High doses can cause irritability/insomnia. Low doses cause flattening/fatigue. Finding the "Sweet Spot" is hard.
Drill Down: Autoimmune Polyendocrine Syndromes (APS)
| Type | Genetics | Features | Onset |
|---|---|---|---|
| APS Type 1 | AIRE gene. Autosomal Recessive. | Triad: Addison's, Hypoparathyroidism, Chronic Candidiasis. | Childhood (rare). |
| APS Type 2 | Polygenic (HLA). | Addison's + Hypothyroid (Schmidt's) + T1DM (Carpenter's). | Adult (common). |
| Screening: All Addison's patients need annual TSH, HbA1c, and B12 (Pernicious Anaemia link). |
Genetics Drill Down: The HLA Link
- Risk Genes: HLA-DR3 and HLA-DR4.
- Mechanism: Determine which antigens are presented to T-cells.
- Overlap: These are the same risk alleles as Type 1 Diabetes and Coeliac Disease (Explaining the Clustering).
Future Horizons
- Plenadren: Modified-release hydrocortisone. Mimics the circadian curve better than pills (spike and trough). Proven to improve metabolic profile.
- Continuous Subcutaneous Hydrocortisone Infusion (CSHI): An "Insulin pump" for cortisol. Used in brittle Addison's.
- Stem Cell Therapy: Regenerating the adrenal cortex (Experimental).
Socioeconomic Impact
- Employment: Fatigue often limits ability to work full time.
- Insurance: "Critical Illness" cover often excludes Addison's (seen as manageable).
- Travel: Fear of crisis abroad limits travel.
Cost of Care
- Cheap: Hydrocortisone and Fludrocortisone are generic and cheap.
- Expensive: Plenadren (Modified release) is very expensive (£££) vs standard hydrocortisone (£).
- Hidden: Cost of ICU admissions for missed crises.
Evidence Check: Plenadren vs Standard
- Study: The Dual Release Hydrocortisone Trial.
- Result: Small reduction in weight, BP, and HbA1c. Improved QoL scores.
- Verdict: Use if standard therapy fails to control sugars/weight or severe fatigue exists.
8. Patient Handout
Support & Resources
- Addison's Disease Self-Help Group (ADSHG): The gold standard for patient support. Provides "Emergency Injection Kits" and training.
- Pituitary Foundation: Also covers adrenal insufficiency.
- MedicAlert: Essential jewellery.
Frequently Asked Questions
- "Will I die?": Not if you take your meds. Life expectancy is near normal with good management.
- "Can I exercise?": Yes, but you may need extra salt (and fluids) for marathons.
- "Is it genetic?": Usually sporadic (APS-2 has some familial link, APS-1 is genetic).
Lifestyle & Diet
- Licorice: Avoid excessive "real" licorice (blocks 11-beta-HSD2). Can mimic mineralocorticoid excess but messes with replacement balance.
- Salt: You are a "Salt Waster". Do NOT restrict salt. Add salt to food, especially in summer.
- Alcohol: Hypoglycaemia risk is higher. Eat carbs while drinking.
Dietary Tips for Stability
- Potassium: Do NOT restrict potassium (unless you have renal failure), but be aware that Fludrocortisone helps you excrete it. Hyperkalaemia is a risk only in Acute Crisis or missed doses.
- Caffeine: Some patients find it exacerbates the "jittery" feeling of steroids.
- Timing: Take meds with food to protect the stomach (Gastritis risk).
Travel Advice (The "Survival Kit")
- Customs Letter: Carry a doctor's letter stating you need needles/syringes for life-saving medication.
- Double Supply: Keep one set in hand luggage, one in hold.
- Time Zones: Adjust steroid timing to destination time gradually.
- Hot Climates: You sweat more -> Lose more salt -> Need more Fludrocortisone.
MedicAlert Wording
"Adrenal Insufficiency. Steroid Dependent. In emergency: Inject 100mg Hydrocortisone IM/IV. Do NOT stop steroids."
Driving Advice
- Hypoglycaemia: Serious risk (Group 2 drivers may have restrictions).
- Fatigue: Do not drive if feeling crisis symptoms.
Key Learning Points (The Pearls)
- Don't Wait: If you suspect crisis, inject first, think later. Hydrocortisone never killed anyone in a single dose.
- Double Up: Sick day rules save lives.
- Salt Craving: It's real. Patients drink soy sauce.
- The Tan: It's not a healthy glow.
- Medic Alert: Non-negotiable.
Safety Net (When to call 999)
- Vomiting: If you vomit <1 hour after meds -> Take again. If vomit twice -> Inject & Call.
- Dizziness: Unable to stand up.
- Confusion: Family members notice you are "not right".
Evidence Check: Mortality and QoL
- Mortality: Increased 2-fold compared to general population, largely due to Adrenal Crisis and Infection.
- Quality of Life: Generally lower than healthy controls. High levels of fatigue and anxiety reported.
- Bone Health: Risk of Osteoporosis is higher due to glucocorticoid over-replacement.
8. References
- Bornstein SR, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016. [PMID: 26760044]
- Husebye ES, et al. Adrenal Insufficiency. Lancet. 2021. [PMID: 33587817]
- Bancos I, et al. Diagnosis and Management of Adrenal Insufficiency. Lancet Diabetes Endocrinol. 2015. [PMID: 25533777]
- Betterle C, et al. Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes. Endocrinol Metab Clin North Am. 2002. [PMID: 12055986]
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