Addison's Disease (Primary Adrenal Insufficiency)

1. Clinical Overview

Summary

Addison's disease is primary adrenal insufficiency (PAI) caused by destruction or dysfunction of the adrenal cortex, resulting in deficiency of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens (DHEA/DHEAS). The condition was first described by Thomas Addison in 1855 in his seminal publication on the constitutional effects of disease of the suprarenal capsules. [1]

In developed countries, autoimmune adrenalitis accounts for approximately 80-90% of cases, while tuberculosis remains the leading cause in regions with high TB prevalence. [2,3] The hallmark biochemical abnormality is elevated adrenocorticotropic hormone (ACTH) due to loss of negative feedback, which drives the characteristic hyperpigmentation through melanocyte-stimulating hormone (MSH) co-secretion from the proopiomelanocortin (POMC) precursor.

Diagnosis is confirmed by the short Synacthen test (SST), demonstrating failure of cortisol to rise following synthetic ACTH stimulation. Lifelong physiological replacement with hydrocortisone and fludrocortisone is essential, along with comprehensive patient education on "sick-day rules" to prevent the potentially fatal complication of adrenal crisis. [4]

Key Facts

Clinical Pearls

"Addisonian Pigmentation": Hyperpigmentation in sun-exposed areas, palmar creases, buccal mucosa, and recent scars is pathognomonic. It results from elevated ACTH and α-MSH (both cleaved from POMC). This finding distinguishes primary from secondary adrenal insufficiency, where ACTH is low and pigmentation is absent. [8]

"The Salt Craving Clue": Up to 64% of patients report intense salt craving due to aldosterone deficiency and renal sodium wasting. This symptom is frequently overlooked but highly suggestive when present with fatigue and weight loss. [9]

"Sick Day Rules Save Lives": The majority of adrenal crises occur due to inadequate glucocorticoid dosing during intercurrent illness. Patients MUST be educated to double or triple hydrocortisone during febrile illness, and to use parenteral hydrocortisone if vomiting. [7]

"The 3 Ps of Adrenal Crisis": Profound weakness, Postural hypotension, and Pigmentation — think primary adrenal insufficiency.

Why This Matters Clinically

Addison's disease exemplifies a condition that is easily missed due to non-specific early symptoms (fatigue, weight loss, nausea) but is fatal if untreated during crisis. The annual rate of adrenal crisis is approximately 6-8 per 100 patient-years, with mortality of 0.5% per crisis episode. [7] Early recognition, appropriate diagnostic testing, lifelong hormone replacement, and comprehensive patient education are the pillars of excellent care.

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2. Epidemiology

Incidence & Prevalence

Contemporary epidemiological studies demonstrate increasing recognition of primary adrenal insufficiency:

The apparent increase in incidence likely reflects improved diagnostic awareness and increased prevalence of autoimmune diseases rather than a true increase in disease occurrence. [5]

Demographics

Risk Factors

Autoimmune Adrenalitis (80-90% in Developed Countries)

Major Risk Factors:

• Pre-existing autoimmune disease (odds ratio 3-5×)
• First-degree relative with autoimmune endocrinopathy
• Female sex
• HLA associations: DRB104:04, DRB103:01, DQB1*03:02 [6]

Associated Autoimmune Conditions (Autoimmune Polyglandular Syndromes):

Non-Autoimmune Causes (10-20%)

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3. Pathophysiology

Adrenal Cortex Anatomy and Zones

The adrenal cortex comprises three distinct zones with specific steroidogenic functions:

Molecular Mechanism of Autoimmune Adrenalitis

Exam Detail: Step 1: Autoimmune Targeting

Autoimmune adrenalitis involves T-cell mediated destruction of the adrenal cortex. The primary autoantigen is 21-hydroxylase (CYP21A2), an enzyme essential for cortisol and aldosterone synthesis. Antibodies against 21-hydroxylase are detected in 86-90% of patients with autoimmune PAI and may predate clinical disease by years. [6]

Immunological Features:

• CD4+ and CD8+ T-lymphocyte infiltration of adrenal cortex
• Complement-fixing antibodies against adrenocortical cells
• HLA class II associations (particularly DRB1*04:04)
• Shared epitopes with other autoimmune conditions (APS-1, APS-2)

Step 2: Progressive Cortical Destruction

Clinical symptoms typically manifest when > 90% of adrenal cortex is destroyed. The zona glomerulosa (aldosterone) may be affected earlier or later than the zona fasciculata (cortisol), leading to variable presentations:

• Isolated glucocorticoid deficiency (early): Fatigue, weight loss, ACTH elevation
• Combined deficiency (later): Added hyponatraemia, hyperkalaemia, hypotension

Step 3: Loss of Negative Feedback

Low circulating cortisol removes negative feedback at:

• Hypothalamus (CRH secretion increases)
• Anterior pituitary (ACTH secretion increases)

ACTH is cleaved from proopiomelanocortin (POMC) along with:

• α-melanocyte-stimulating hormone (α-MSH)
• β-endorphin

Elevated α-MSH binds to melanocortin-1 receptors (MC1R) on melanocytes, stimulating eumelanin synthesis → hyperpigmentation.

Hormonal Deficiencies and Clinical Correlates

Primary vs Secondary vs Tertiary Adrenal Insufficiency

Pathophysiology of Adrenal Crisis

Adrenal crisis represents acute decompensation in a patient with limited adrenal reserve. It is most commonly precipitated by:

1. Intercurrent illness (infection, gastroenteritis) — increased cortisol demand
2. Non-compliance with replacement therapy
3. Inadequate sick-day dosing
4. Surgery/trauma without stress-dose steroids
5. Vomiting (unable to absorb oral medication)

Physiological cascade:

• Inadequate cortisol → impaired vascular tone → hypotension
• Inadequate cortisol → reduced gluconeogenesis → hypoglycaemia
• Inadequate aldosterone → sodium wasting, potassium retention → hyponatraemia, hyperkalaemia
• Volume depletion → cardiovascular collapse

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4. Clinical Presentation

Symptoms

Clinical presentation is typically insidious, developing over weeks to months. A high index of suspicion is required as symptoms are non-specific.

Chronic Symptoms (Frequency Based on Case Series)

Acute Presentation (Adrenal Crisis)

Clinical Pearl: Adrenal Crisis Mimics Acute Abdomen: Severe abdominal pain with vomiting and hypotension can lead to unnecessary laparotomy. Always consider adrenal crisis in unexplained shock, especially with hyperpigmentation, hyponatraemia, or hyperkalaemia.

Signs

General Inspection

• Unwell, fatigued appearance
• Weight loss (may be profound)
• Dehydrated
• Postural instability

Characteristic Signs

Associated Autoimmune Stigmata

Examine for features of associated conditions:

• Thyroid: Goitre, thyroid eye signs, pretibial myxoedema
• Vitiligo: Depigmented patches
• Diabetes: Acanthosis (if associated with insulin resistance in treatment)
• Alopecia: Patchy or total hair loss

Red Flags — Adrenal Crisis

[!CAUTION] Life-Threatening Emergency — Immediate Action Required:

• Hypotension (SBP less than 90 mmHg) not responding to IV fluids
• Shock, cardiovascular collapse
• Severe hyperkalaemia (K⁺ > 6.5 mmol/L)
• Hypoglycaemia (glucose less than 3.0 mmol/L)
• Altered consciousness, confusion, coma
• Severe hyponatraemia (less than 120 mmol/L)
• Severe abdominal pain with hypotension (may mimic surgical abdomen)

Immediate Treatment:

• Hydrocortisone 100 mg IV/IM STAT (do not wait for results)
• IV 0.9% saline 1L in first hour (adjust to clinical response)
• Monitor glucose — give IV dextrose if hypoglycaemic
• Identify and treat precipitant (commonly infection)
• Admit to high-dependency/intensive care if severe

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5. Clinical Examination

Structured Approach

1. General Observation (from end of bed):

• Skin: Overall pigmentation (compare to patient's baseline if possible)
• Vital signs: Tachycardia, postural hypotension
• Hydration: Dry mucous membranes, reduced skin turgor

2. Hands and Arms:

• Palmar crease hyperpigmentation (compare to dorsum of hand)
• Nail beds: May be pigmented
• Skin creases and scars: Darker than surrounding skin
• Hair: Reduced axillary hair (females)

3. Face and Mouth:

• Sun-exposed areas: Hyperpigmented
• Buccal mucosa: Dark patches on cheeks, gums, tongue
• Lips: Hyperpigmented

4. Neck:

• Thyroid: Assess for goitre (associated autoimmune thyroid disease)
• Scars: Thyroidectomy, adrenalectomy

5. Trunk:

• Nipple areolae: Hyperpigmented
• Old surgical scars: Hyperpigmented
• Vitiligo patches

6. Cardiovascular:

• Blood pressure: Lying and standing (assess for postural drop)
• Heart sounds: Usually normal

7. Abdomen:

• Tenderness (may be present in crisis)
• No specific organomegaly (unless associated condition)

Special Tests

OSCE Examination Checklist

ADDISON'S DISEASE EXAMINATION
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
□ General: Underweight, unwell, pigmented
□ Vital signs: Postural BP, heart rate

HANDS:
□ Palmar crease hyperpigmentation
□ Nail bed pigmentation
□ Axillary hair (females)

FACE:
□ Buccal mucosa pigmentation
□ Lip pigmentation
□ Sun-exposed skin

TRUNK:
□ Nipple areolae
□ Scar pigmentation
□ Vitiligo

CARDIOVASCULAR:
□ Postural hypotension

ASSOCIATED CONDITIONS:
□ Thyroid examination
□ Vitiligo
□ Alopecia areata

COMPLETE BY:
□ "I would like to check blood glucose"
□ "I would like to see recent U&E results"
□ "I would examine for signs of precipitating infection"

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6. Investigations

First-Line (Screening) Investigations

Interpretation of 9 AM Cortisol

Short Synacthen Test (SST) — Gold Standard

The short Synacthen test (also called ACTH stimulation test or cosyntropin test) is the gold standard for diagnosing adrenal insufficiency. [4,12]

Protocol:

Interpretation:

Note: Different assays may use slightly different cut-offs (450-550 nmol/L). Check local laboratory reference ranges.

Exam Detail: SST Interpretation Pearls:

1. Primary vs Secondary AI: SST confirms AI but does not distinguish primary from secondary. Use concurrent ACTH level:

   • ACTH elevated (> 2× ULN) = Primary AI
   • ACTH low/normal = Secondary AI

2. Low-Dose SST (1 μg): Some centres use 1 μg Synacthen for greater sensitivity in detecting partial AI. Not universally adopted.

3. Timing Considerations:

   • Best performed in morning (8-9 AM) when cortisol is at peak
   • Can be performed at any time in emergencies

4. False Negatives in Secondary AI: In recent-onset secondary AI (e.g., pituitary surgery), the adrenals may still respond normally to exogenous ACTH. Insulin tolerance test (ITT) may be needed.

5. In Crisis: Do NOT delay treatment to perform SST. Take a random cortisol and ACTH, then treat immediately. SST can be performed later during recovery.

Further Investigations

To Confirm Aetiology

CT Adrenal Findings by Aetiology

Screening for Associated Autoimmune Conditions

Recommendation: Screen all patients with autoimmune PAI annually for thyroid dysfunction (TSH) and periodically for other autoimmune conditions. [4]

Investigation Algorithm

SUSPECTED ADDISON'S DISEASE
         ↓
┌─────────────────────────────────────┐
│ Initial Investigations:              │
│ • U&E, glucose, FBC, calcium         │
│ • 9 AM cortisol + ACTH (paired)      │
└─────────────────────────────────────┘
         ↓
    ┌────────────────────────────────┐
    │ 9 AM Cortisol Result:          │
    ├────────────────────────────────┤
    │ less than 100 nmol/L → Highly suggestive│
    │ 100-400 nmol/L → Indeterminate │
    │ > 500 nmol/L → AI excluded      │
    └────────────────────────────────┘
         ↓ (if less than 500)
┌─────────────────────────────────────┐
│ SHORT SYNACTHEN TEST (SST)          │
│ 250 μg Synacthen IM/IV              │
│ Measure cortisol at 30 min          │
│                                     │
│ • ≥450-550 nmol/L = Normal          │
│ • less than 450 nmol/L = Adrenal insufficiency│
└─────────────────────────────────────┘
         ↓
    ┌────────────────────────────────┐
    │ ACTH Level:                     │
    ├────────────────────────────────┤
    │ Elevated → PRIMARY AI (Addison's)│
    │ Low/Normal → SECONDARY AI       │
    └────────────────────────────────┘
         ↓
┌─────────────────────────────────────┐
│ AETIOLOGY WORKUP:                   │
│ • 21-Hydroxylase antibodies         │
│ • CT adrenals                       │
│ • VLCFA (young males)               │
│ • Autoimmune screen (TSH, HbA1c,    │
│   coeliac serology, B12)            │
└─────────────────────────────────────┘

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7. Differential Diagnosis

Conditions Mimicking Addison's Disease

Key Differentiating Points

Primary vs Secondary Adrenal Insufficiency:

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8. Classification

Autoimmune Polyglandular Syndromes (APS)

Autoimmune adrenalitis often occurs as part of autoimmune polyglandular syndromes:

Causes of Primary Adrenal Insufficiency — Classification

1. Autoimmune (80-90% in developed countries)

• Isolated autoimmune adrenalitis
• APS-1 (APECED)
• APS-2 (Schmidt syndrome)

2. Infectious

• Tuberculosis (most common globally)
• Fungal (histoplasmosis, coccidioidomycosis)
• CMV adrenalitis (HIV/AIDS)
• MAC (HIV/AIDS)

3. Infiltrative/Metastatic

• Metastatic carcinoma (lung, breast, melanoma)
• Lymphoma
• Amyloidosis
• Haemochromatosis
• Sarcoidosis

4. Haemorrhagic

• Waterhouse-Friderichsen syndrome (meningococcal sepsis)
• Anticoagulant therapy
• Trauma
• Post-surgical

5. Genetic

• Adrenoleukodystrophy (X-linked)
• Congenital adrenal hyperplasia
• Adrenal hypoplasia congenita (DAX1 mutation)
• Triple A syndrome (Allgrove)

6. Iatrogenic

• Bilateral adrenalectomy
• Drug-induced (ketoconazole, etomidate, mitotane)

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9. Management

Management Algorithm

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
                    ADDISON'S DISEASE MANAGEMENT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

┌─────────────────────────────────────────────────────────────────┐
│  ACUTE: ADRENAL CRISIS — LIFE-THREATENING EMERGENCY            │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  IMMEDIATE (within minutes):                                    │
│  1. IV access — take bloods: cortisol, ACTH, U&E, glucose, FBC  │
│  2. HYDROCORTISONE 100 mg IV/IM STAT                            │
│     (Do NOT delay for investigations)                           │
│  3. IV 0.9% SALINE — 1 litre in first hour                      │
│     (Then guided by clinical response)                          │
│  4. IV DEXTROSE if hypoglycaemic                                │
│                                                                 │
│  ONGOING:                                                       │
│  • Hydrocortisone 50-100 mg IV every 6-8 hours                  │
│  • Continue IV fluids (may need 2-4L in first 24 hours)         │
│  • Cardiac monitoring (hyperkalaemia risk)                      │
│  • Treat precipitant (commonly infection)                       │
│  • ITU/HDU if haemodynamically unstable                         │
│                                                                 │
│  Note: Fludrocortisone NOT needed acutely                       │
│  (High-dose HC has mineralocorticoid activity)                  │
│                                                                 │
│  TRANSITION TO ORAL:                                            │
│  • When stable and eating: convert to oral HC                   │
│  • Taper over 3-4 days to maintenance dose                      │
│  • Add fludrocortisone when HC less than 50 mg/day                       │
└─────────────────────────────────────────────────────────────────┘
                              ↓
┌─────────────────────────────────────────────────────────────────┐
│  CHRONIC: LIFELONG REPLACEMENT THERAPY                          │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  GLUCOCORTICOID REPLACEMENT:                                    │
│                                                                 │
│  HYDROCORTISONE (First-line) [4,13]                             │
│  • Total daily dose: 15-25 mg/day (typically 15-20 mg)          │
│  • Divided into 2-3 doses to mimic circadian rhythm:            │
│                                                                 │
│    ┌──────────────────────────────────────────────────────┐     │
│    │ REGIMEN A (3 doses):                                 │     │
│    │ • 10 mg on waking (6-8 AM)                           │     │
│    │ • 5 mg at midday (12-1 PM)                           │     │
│    │ • 5 mg late afternoon (4-6 PM)                       │     │
│    │ Total: 20 mg/day                                     │     │
│    ├──────────────────────────────────────────────────────┤     │
│    │ REGIMEN B (3 doses, lower):                          │     │
│    │ • 10 mg on waking                                    │     │
│    │ • 5 mg at midday                                     │     │
│    │ • 2.5 mg late afternoon                              │     │
│    │ Total: 17.5 mg/day                                   │     │
│    ├──────────────────────────────────────────────────────┤     │
│    │ REGIMEN C (2 doses):                                 │     │
│    │ • 15 mg on waking                                    │     │
│    │ • 5 mg early afternoon                               │     │
│    │ Total: 20 mg/day                                     │     │
│    └──────────────────────────────────────────────────────┘     │
│                                                                 │
│  • Give largest dose on waking (mimics cortisol peak)           │
│  • Avoid evening doses (interferes with sleep)                  │
│  • Do NOT give with grapefruit juice (CYP3A4)                   │
│                                                                 │
│  ALTERNATIVES:                                                  │
│  • Modified-release hydrocortisone (Plenadren): 20-25 mg OD     │
│    - Better cortisol profile; improves QoL in some [14]         │
│    - More expensive; not universally available                  │
│  • Prednisolone: 3-5 mg daily (rarely used; less physiological) │
│                                                                 │
├─────────────────────────────────────────────────────────────────┤
│  MINERALOCORTICOID REPLACEMENT:                                 │
│                                                                 │
│  FLUDROCORTISONE [4]                                            │
│  • Dose: 50-200 micrograms once daily (typically 100 mcg)       │
│  • Give in the morning with hydrocortisone                      │
│  • Titrate to:                                                  │
│    - Blood pressure (avoid hypertension)                        │
│    - Serum potassium (aim normal range)                         │
│    - Plasma renin activity (aim upper normal)                   │
│  • Most patients need 100 mcg; range 50-200 mcg                 │
│                                                                 │
├─────────────────────────────────────────────────────────────────┤
│  DHEA REPLACEMENT (Optional):                                   │
│                                                                 │
│  • Consider DHEA 25-50 mg daily in FEMALES if:                  │
│    - Persistent fatigue despite optimised HC/FC                 │
│    - Reduced libido                                             │
│    - Impaired well-being                                        │
│  • Evidence is mixed; 2016 guideline: trial for 6 months [4,15] │
│  • Not available on NHS prescription (patient purchase)         │
│  • Monitor for androgenic side effects (acne, hirsutism)        │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘
                              ↓
┌─────────────────────────────────────────────────────────────────┐
│  SICK DAY RULES — CRITICAL PATIENT EDUCATION                    │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  ⚠️  SICK DAY RULES PREVENT ADRENAL CRISIS [7,16]               │
│                                                                 │
│  ┌────────────────────────────────────────────────────────────┐ │
│  │ SITUATION                      │ HYDROCORTISONE ACTION     │ │
│  ├────────────────────────────────┼───────────────────────────┤ │
│  │ Minor illness (cold, mild      │ DOUBLE total daily dose   │ │
│  │ infection without fever)       │ until recovered           │ │
│  ├────────────────────────────────┼───────────────────────────┤ │
│  │ Moderate illness (fever > 38°C, │ TRIPLE total daily dose   │ │
│  │ significant infection)         │ until recovered           │ │
│  ├────────────────────────────────┼───────────────────────────┤ │
│  │ Vomiting/diarrhoea (cannot     │ IM HYDROCORTISONE 100 mg  │ │
│  │ keep tablets down)             │ STAT → seek medical help  │ │
│  ├────────────────────────────────┼───────────────────────────┤ │
│  │ Major stress (trauma, severe   │ IM/IV HYDROCORTISONE      │ │
│  │ illness, surgery)              │ 100 mg → hospital         │ │
│  └────────────────────────────────┴───────────────────────────┘ │
│                                                                 │
│  KEY MESSAGES:                                                  │
│  • NEVER stop hydrocortisone suddenly                           │
│  • If vomiting, switch to IM injection — do not wait            │
│  • Return to normal dose when fully recovered                   │
│  • If unsure, take MORE not less                                │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘
                              ↓
┌─────────────────────────────────────────────────────────────────┐
│  ESSENTIAL PATIENT EQUIPMENT & IDENTIFICATION                   │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  MANDATORY:                                                     │
│  □ Steroid emergency card (carry at ALL times)                  │
│  □ MedicAlert bracelet/necklace or equivalent                   │
│  □ Emergency hydrocortisone injection kit:                      │
│    • Hydrocortisone 100 mg powder + Water for Injection         │
│    • Patient and family/carer trained in administration         │
│                                                                 │
│  DOCUMENTATION:                                                 │
│  □ Written sick-day rules                                       │
│  □ Emergency contact numbers                                    │
│  □ GP and endocrinologist contact details                       │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

Surgical/Procedural Steroid Cover

Patients with Addison's disease require stress-dose glucocorticoids for surgery and invasive procedures:

Key Principle: Always give hydrocortisone cover; withhold usual fludrocortisone until oral intake and lower HC doses resume (HC has mineralocorticoid activity at high doses). [17]

Special Populations

Pregnancy [18]

Elderly

• May require lower hydrocortisone doses (reduced clearance)
• Higher risk of osteoporosis with over-replacement
• Be vigilant for atypical crisis presentations

Children

• Weight-based dosing: Hydrocortisone 8-10 mg/m²/day in 3 divided doses
• Growth monitoring (over-replacement suppresses growth)
• School and carer education essential

Monitoring

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10. Complications

Adrenal Crisis

Adrenal crisis is the most serious complication and is a medical emergency. [7]

Long-Term Complications

Treatment-Related Complications

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11. Prognosis & Outcomes

Natural History

Untreated Addison's disease is invariably fatal, typically from adrenal crisis during intercurrent illness or stress. Thomas Addison's original patients all died within months to years of diagnosis. [1]

Outcomes with Modern Treatment

Prognostic Factors

Favourable Prognosis:

• Early diagnosis before first crisis
• Excellent patient education and understanding
• Regular follow-up and monitoring
• Access to emergency hydrocortisone
• Carries identification (steroid card, MedicAlert)
• Supportive family/social network

Poorer Prognosis:

• Delayed diagnosis with crisis presentation
• Poor understanding of sick-day rules
• Non-compliance with medication
• Living alone without support
• Concurrent serious illness
• Elderly patients
• Limited healthcare access

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12. Evidence & Guidelines

Key Guidelines

Landmark Studies

Arlt & Allolio (2003) — Lancet Review [2]

• Comprehensive review establishing modern understanding of adrenal insufficiency
• Defined approach to diagnosis, replacement, and complications
• Clinical Impact: Foundational reference for current management paradigms

Hahner et al. (2015) — JCEM [7]

• Prospective study of adrenal crisis frequency and outcomes
• Crisis rate: 6-8 per 100 patient-years
• Clinical Impact: Demonstrated importance of patient education and prevention strategies

Johannsson et al. (2012) — JCEM [14]

• RCT of modified-release hydrocortisone (Plenadren) vs conventional HC
• Improved metabolic profile and quality of life
• Clinical Impact: Established role for modified-release preparations

Evidence Strength Summary

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13. Exam-Focused Sections

Common Exam Questions (MRCP, PLAB)

1. "What are the causes of primary adrenal insufficiency?"
2. "How would you investigate a patient with suspected Addison's disease?"
3. "How would you differentiate primary from secondary adrenal insufficiency?"
4. "What is your emergency management of adrenal crisis?"
5. "What are the sick-day rules for patients with Addison's disease?"
6. "How would you manage a patient with Addison's disease undergoing surgery?"
7. "What biochemical abnormalities would you expect in Addison's disease?"

Viva Points

Viva Point: Opening Statement: "Addison's disease is primary adrenal insufficiency characterised by destruction of the adrenal cortex, leading to deficiency of cortisol, aldosterone, and adrenal androgens. In developed countries, autoimmune adrenalitis accounts for 80-90% of cases. [2,4]"

Key Facts to Quote:

• Prevalence: ~140 per million; incidence 4-6 per million per year [5]
• Autoantibody: 21-hydroxylase antibodies in 90% of autoimmune cases [6]
• Diagnostic test: Short Synacthen test — cortisol should rise to > 450-500 nmol/L at 30 minutes
• Treatment: Hydrocortisone 15-25 mg/day in divided doses + fludrocortisone 50-200 mcg OD [4]
• Crisis rate: 6-8 per 100 patient-years, reduced with education [7]

Structured Approach to Diagnosis: "I would approach this systematically. First, I would take a detailed history focusing on fatigue, weight loss, salt craving, postural symptoms, and associated autoimmune conditions. On examination, I would look for hyperpigmentation of palmar creases and buccal mucosa, postural hypotension, and features of associated conditions. Investigations would include U&E showing hyponatraemia and hyperkalaemia, 9 AM cortisol and ACTH, and a Short Synacthen test. If confirmed, I would investigate the aetiology with 21-hydroxylase antibodies and CT adrenals."

Model Answers

Q: How do you distinguish primary from secondary adrenal insufficiency?

"The key distinguishing features are:

1. ACTH level: Elevated in primary AI (loss of negative feedback from low cortisol), low in secondary AI (pituitary failure)

2. Hyperpigmentation: Present in primary AI (elevated ACTH/MSH from POMC), absent in secondary AI

3. Mineralocorticoid deficiency: Present in primary AI (aldosterone deficiency), preserved in secondary AI (RAAS system intact, independent of ACTH)

4. Hyperkalaemia: Present in primary AI (aldosterone deficiency), absent in secondary AI

5. Aetiology: Primary AI is due to adrenal pathology (autoimmune, TB, etc.); secondary AI is due to pituitary or hypothalamic pathology (tumour, surgery, Sheehan's, etc.)

A paired cortisol and ACTH at 9 AM is the key initial investigation to distinguish these."

Q: What is your emergency management of adrenal crisis?

"Adrenal crisis is a medical emergency requiring immediate treatment. My approach would be:

1. Do not delay treatment for investigations — if clinically suspected, treat immediately

2. Immediate actions:

   • IV access and take bloods (cortisol, ACTH, U&E, glucose, FBC)
   • Hydrocortisone 100 mg IV or IM STAT
   • IV 0.9% saline — 1 litre in the first hour, then guided by response
   • IV dextrose if hypoglycaemic

3. Ongoing management:

   • Hydrocortisone 50-100 mg IV every 6-8 hours
   • Continue IV fluids (may need 2-4L in first 24 hours)
   • Cardiac monitoring for hyperkalaemia
   • Identify and treat the precipitant (most commonly infection)
   • Consider ITU/HDU if haemodynamically unstable

4. Fludrocortisone is NOT needed acutely — high-dose hydrocortisone has adequate mineralocorticoid activity

5. Transition to oral when stable and eating, with gradual taper to maintenance doses."

Common Mistakes (What Fails Candidates)

❌ Mistakes that lose marks:

• Forgetting that hyperpigmentation is absent in secondary AI
• Not knowing the SST protocol (250 μg Synacthen, measure at 30 min)
• Stating wrong cortisol cut-off (should be 450-500 nmol/L, not 550)
• Forgetting to mention fludrocortisone in chronic management
• Not knowing sick-day rules
• Missing the need for steroid card and emergency injection kit
• Waiting for investigation results before treating crisis

❌ Dangerous errors:

• Delaying hydrocortisone in crisis to wait for results
• Forgetting stress-dose steroids for surgery
• Allowing patients to stop steroids abruptly

MCQ-Style Questions

Q1. A 35-year-old woman presents with fatigue, weight loss, and hyperpigmentation of her palmar creases. Blood tests show: Na⁺ 128, K⁺ 5.8, cortisol 85 nmol/L at 9 AM. What is the next best investigation?

A) MRI pituitary
B) CT adrenal glands
C) Short Synacthen test
D) 24-hour urinary free cortisol
E) Insulin tolerance test

Answer: C) Short Synacthen test

Explanation: The clinical picture and 9 AM cortisol less than 100 nmol/L are highly suggestive of adrenal insufficiency. The Short Synacthen test is the gold standard diagnostic test. ACTH should also be measured to distinguish primary from secondary. CT adrenals would be appropriate once diagnosis is confirmed to investigate aetiology.

Q2. A patient with known Addison's disease develops gastroenteritis with vomiting. She takes hydrocortisone 20 mg/day and fludrocortisone 100 mcg/day. What advice should she be given?

A) Continue usual doses and drink fluids
B) Double the hydrocortisone dose
C) Triple the hydrocortisone dose
D) Take IM hydrocortisone 100 mg and attend hospital
E) Stop fludrocortisone until better

Answer: D) Take IM hydrocortisone 100 mg and attend hospital

Explanation: Vomiting means oral medication cannot be reliably absorbed. She should use her emergency hydrocortisone injection (IM 100 mg) and seek medical attention. This is a core sick-day rule. [7,16]

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14. Patient/Layperson Explanation

What is Addison's Disease?

Addison's disease is a condition where your adrenal glands (small glands that sit on top of your kidneys) don't make enough of certain vital hormones. The main hormones affected are:

• Cortisol — helps your body respond to stress, control blood sugar, and fight infection
• Aldosterone — helps control your blood pressure and balance of salt and water in your body

Without these hormones, you can become very unwell, especially during times of stress like illness, injury, or surgery.

What Causes It?

In most cases (about 8 out of 10 people in the UK), the body's own immune system mistakenly attacks the adrenal glands. This is called "autoimmune" disease. Other causes include tuberculosis (more common in other parts of the world), infections, or rarely, cancer spreading to the adrenal glands.

What Are the Symptoms?

Symptoms often develop gradually over weeks to months and include:

• Extreme tiredness and weakness
• Weight loss and loss of appetite
• Feeling sick or being sick
• Dizziness when standing up
• Craving salty foods
• Darkening of the skin, especially in skin creases, inside the mouth, and on scars
• Muscle aches and pains

How Is It Diagnosed?

Your doctor will do blood tests to check your cortisol levels and other hormones. The main test is called the "Short Synacthen Test" — this involves giving you an injection that should make your adrenal glands produce cortisol. If your glands are damaged, they won't respond properly.

How Is It Treated?

You will need to take replacement hormones every day for the rest of your life:

1. Hydrocortisone tablets (replaces cortisol)

• Usually 2-3 times a day
• The largest dose is taken in the morning to copy your body's natural pattern

2. Fludrocortisone tablets (replaces aldosterone)

• Usually once daily in the morning

Sick-Day Rules — Very Important!

When you're unwell, your body needs more cortisol. You MUST increase your hydrocortisone dose:

Never stop your hydrocortisone suddenly — this could make you very unwell.

What You Should Always Have

• Steroid emergency card — carry it with you at all times
• MedicAlert bracelet or necklace — so medical staff know about your condition if you can't tell them
• Emergency hydrocortisone injection kit — you and your family/friends should know how to use this

When to Seek Emergency Help

Go to A&E immediately if you:

• Feel very weak or faint
• Are vomiting and can't keep tablets down
• Collapse or feel you might collapse
• Have severe abdominal pain with feeling very unwell
• Have confusion or drowsiness

Tell them you have Addison's disease and may need emergency hydrocortisone.

Living with Addison's Disease

• With proper treatment, you can live a full, normal, and active life
• You'll need regular check-ups (usually every 6-12 months)
• Most people do well and have normal life expectancy
• Learning about your condition and the sick-day rules is very important

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15. References

Primary Guidelines

1. Addison T. On the constitutional and local effects of disease of the suprarenal capsules. London: Samuel Highley. 1855. [Historical text]

2. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881-1893. doi:10.1016/S0140-6736(03)13492-7 PMID: 12788587

3. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23(3):327-364. doi:10.1210/edrv.23.3.0466 PMID: 12050123

4. 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. doi:10.1210/jc.2015-1710 PMID: 26760044

5. Erichsen MM, Løvås K, Skinningsrud B, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882-4890. doi:10.1210/jc.2009-1368 PMID: 19858318

6. Winqvist O, Karlsson FA, Kämpe O. 21-Hydroxylase, a major autoantigen in idiopathic Addison's disease. Lancet. 1992;339(8809):1559-1562. doi:10.1016/0140-6736(92)91829-w PMID: 1351548

7. Hahner S, Spinnler C, Gasperi M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407-416. doi:10.1210/jc.2014-3191 PMID: 25419882

8. Findling JW, Raff H. Clinical review: Cushing's syndrome--important issues in diagnosis and management. J Clin Endocrinol Metab. 2006;91(10):3746-3753. doi:10.1210/jc.2006-0997 PMID: 16868050

9. Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):217-223. doi:10.1097/MED.0b013e328338f608 PMID: 20375886

10. Olafsson AS, Sigurjonsdottir HA. Increasing Prevalence of Addison Disease: Results from a Nationwide Study. Endocr Pract. 2016;22(1):30-35. doi:10.4158/EP15754.OR PMID: 26401579

11. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294(24):3131-3134. doi:10.1001/jama.294.24.3131 PMID: 16380592

12. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008;93(11):4245-4253. doi:10.1210/jc.2008-0710 PMID: 18697863

13. Mah PM, Jenkins RC, Rostami-Hodjegan A, et al. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2004;61(3):367-375. doi:10.1111/j.1365-2265.2004.02106.x PMID: 15355454

14. Johannsson G, Nilsson AG, Bergthorsdottir R, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012;97(2):473-481. doi:10.1210/jc.2011-1926 PMID: 22112807

15. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(10):3676-3681. doi:10.1210/jc.2009-0672 PMID: 19773400

16. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency. Anaesthesia. 2020;75(5):654-663. doi:10.1111/anae.14963 PMID: 32017015

17. Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust. 2008;188(7):409-413. doi:10.5694/j.1326-5377.2008.tb01686.x PMID: 18393745

18. Lebbe M, Arlt W. What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy? Clin Endocrinol (Oxf). 2013;78(4):497-502. doi:10.1111/cen.12097 PMID: 23173890

19. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. 2006;91(12):4849-4853. doi:10.1210/jc.2006-0076 PMID: 16968806

20. 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. doi:10.1111/joim.12162 PMID: 24330030

Further Resources

• Addison's Disease Self-Help Group (UK): addisons.org.uk
• Society for Endocrinology: endocrinology.org
• Patient.info Addison's Disease: patient.info/hormones/addisons-disease

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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.