What is the definition, pathophysiology, clinical features, investigation, and treatment of primary adrenal insufficiency, also known as Addison's disease?

Primary Adrenal Insufficiency (Addison's Disease): Comprehensive Overview

Definition

Primary adrenal insufficiency (PAI), also known as Addison's disease, is a life-threatening endocrine disorder characterized by inadequate production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) due to destruction of the adrenal cortex, regardless of the underlying cause. 1

• Prevalence is approximately 10-15 per 100,000 population, making it a rare condition 1, 2
• Prior to the 1940s, PAI was universally fatal; corticosteroid synthesis transformed it into a treatable chronic condition 1

Pathophysiology

The disease results from disruption of the hypothalamic-pituitary-adrenal (HPA) axis due to adrenal cortex damage, leading to cortisol deficiency (affecting metabolism, immune function, and stress responses) and aldosterone deficiency (causing dysregulation of sodium and potassium homeostasis). 3

Etiology by Region and Frequency:

• Autoimmune adrenalitis: Predominant cause in Europe (~85% of cases), where the immune system destroys adrenal cortical cells 1, 2, 4
• Infectious causes: Tuberculosis (Mycobacterium tuberculosis) can infiltrate and impair the adrenal glands 3
• Hemorrhagic damage: Secondary to severe stress, trauma, or coagulopathies 3
• Metastatic neoplasms: Can involve and destroy the adrenal glands 3
• Genetic disorders: Adrenoleukodystrophy affects both cerebral white matter and adrenal cortex 3
• Iatrogenic: Adrenalectomy or medications inhibiting steroidogenesis 3

Associated Autoimmune Conditions:

Approximately 50% of patients with autoimmune PAI develop other co-existing autoimmune diseases during their lifetime 1, 2, 4:

• Autoimmune Polyendocrine Syndrome Type-1 (APS-1): Defined by two of three components: PAI, hypoparathyroidism, and chronic mucocutaneous candidiasis; caused by AIRE gene mutations 1, 2
• Autoimmune Polyendocrine Syndrome Type-2 (APS-2): Most commonly PAI with primary hypothyroidism, but can include Graves' disease, autoimmune gastritis with vitamin B12 deficiency, and type 1 diabetes 1, 2
• Other associations: Premature ovarian insufficiency, vitiligo, and coeliac disease 1

Clinical Features

Chronic Presentation (Insidious Onset Over Months to Years):

The clinical manifestations are often nonspecific, requiring high clinical suspicion to avoid missing a life-threatening adrenal crisis. 4

• Hyperpigmentation: Especially in areas subjected to friction, sun-exposed areas, palmar creases, and mucous membranes (due to elevated ACTH) 3, 4
• Fatigue and weakness: Persistent, debilitating myasthenia 3, 4
• Gastrointestinal symptoms: Anorexia, nausea, vomiting, abdominal pain 5, 4
• Weight loss: Unintentional 3, 4
• Orthostatic hypotension: Due to volume depletion 3, 4
• Salt craving: Characteristic symptom 2, 4
• Neuropsychiatric manifestations: Depression, psychosis, lack of energy 3
• Muscle and joint pain 4

Laboratory Abnormalities at Presentation:

• Hyponatremia: Present in 90% of newly diagnosed cases (caused by sodium loss in urine and impaired free water clearance) 1, 2
• Hyperkalaemia: Present in approximately 50% of cases (caused by aldosterone deficiency, impaired glomerular filtration, and acidosis) 1, 2
• Hypercalcaemia: Mild to moderate in 10-20% of patients 1
• Hypoglycaemia: Particularly in children, rarely in adults; can cause seizures 1
• Anaemia, mild eosinophilia, lymphocytosis 1
• Increased liver transaminases 1

Important caveat: The classical combination of hyponatremia and hyperkalaemia is NOT reliable for diagnosis, as sodium is often only marginally reduced and potassium is elevated in only half of patients. 1 In the presence of severe vomiting, hypokalaemia and alkalosis may be present instead. 1

Acute Presentation (Adrenal Crisis):

Adrenal crisis is a life-threatening emergency characterized by hypotension, shock, volume depletion, and potentially death. 5

• Precipitating factors: Gastrointestinal diseases, infections, stressful events (major pain, surgery, strenuous physical activity, heat, pregnancy), and withdrawal of glucocorticoid therapy 5
• Mortality rate: 0.5 per 100 patient-years 5
• Remains a significant cause of premature death despite available treatments 1

Investigation

Diagnostic Algorithm (Two-Step Approach):

Step 1: Confirm Adrenal Insufficiency 1

The initial diagnostic test is paired measurement of serum cortisol and plasma ACTH. 1, 2

• Diagnostic criteria in acute illness (suspected acute adrenal crisis):

  • Serum cortisol <250 nmol/L with elevated ACTH is diagnostic of primary PAI 1, 2
  • Serum cortisol <400 nmol/L with elevated ACTH raises strong suspicion of PAI 1

• Diagnostic criteria in non-acute settings:

  • Serum cortisol usually below normal range with clearly increased plasma ACTH 1
  • However, approximately 10% of patients present with normal cortisol concentrations despite clearly elevated ACTH when case history is suggestive 6

• In equivocal cases: Perform synacthen (tetracosactide) stimulation test (0.25 mg IM or IV); peak serum cortisol <500 nmol/L confirms diagnosis 1, 2

Additional laboratory findings:

• Increased plasma renin activity (PRA) 1
• Low serum aldosterone 1
• Low dehydroepiandrosterone sulphate (DHEAS) 1
• TSH levels may be mildly elevated (4-10 IU/L) due to lack of cortisol's inhibitory effect 1

Important confounders: Exogenous steroid use (oral prednisolone, dexamethasone) and inhaled steroids (fluticasone) may confound interpretation of low serum cortisol levels. 1

Step 2: Establish Etiology 1

• First-line: Measure serum 21-hydroxylase (anti-adrenal) autoantibodies 1
• If antibodies negative: Perform CT imaging of adrenal glands 1
• In male patients: Assay very long-chain fatty acids to check for adrenoleukodystrophy 1
• In children/young persons with PAI plus hypoparathyroidism and/or candidiasis: Consider APS-1; confirm with anti-interferon omega antibodies or AIRE gene mutational analysis 1

Critical principle: Treatment of suspected acute adrenal insufficiency should NEVER be delayed by diagnostic procedures. 1

Treatment

Chronic Replacement Therapy:

All patients with PAI require lifelong hormone replacement with both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis. 2, 3

Glucocorticoid Replacement:

Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids. 2

• Hydrocortisone: 15-25 mg per day divided into 2-3 doses (current recommended starting dose is 20 mg/day) 2, 7
• Cortisone acetate: Starting dose 25 mg/day divided into 2-3 doses 7
• Dosage adjustment: Based on clinical assessment (weight, blood pressure, symptoms, well-being) rather than laboratory values 2

Important consideration: Available drugs do not restore normal diurnal variations in serum hormone levels, resulting in grossly unphysiological replacement therapy. 7 Many patients complain of fatigue, weariness, and reduced stress tolerance despite standard therapy. 7

Mineralocorticoid Replacement:

Fludrocortisone is the standard mineralocorticoid replacement. 8

• Standard dose: 0.1 mg daily (FDA-approved for partial replacement therapy in PAI) 8
• Dosage range: 0.1 mg three times weekly to 0.2 mg daily 8
• Dose adjustment: If transient hypertension develops, reduce to 0.05 mg daily 8
• Combination therapy: Preferably administered with hydrocortisone (10-30 mg daily in divided doses) or cortisone (10-37.5 mg daily in divided doses) 8

Management of Adrenal Crisis:

Adrenal crisis requires immediate treatment without delay for diagnostic confirmation. 2, 5

Treatment protocol:

1. Immediate hydrocortisone: 100 mg IV or IM bolus 2
2. Continued hydrocortisone: 100 mg every 6-8 hours until recovery 2
3. Fluid resuscitation: Rapid infusion of isotonic (0.9%) sodium chloride solution, initially at 1 L/hour until hemodynamic improvement 2
4. Monitoring support: Continuous vital signs and electrolyte monitoring 5
5. Antibiotics: If infection is suspected as precipitating factor 5

Stress-Dose Glucocorticoids:

During times of stress (illness, invasive surgical procedures, major pain, strenuous physical activity, heat, pregnancy), glucocorticoid doses must be increased because adrenal gland destruction prevents adequate physiologic response. 5, 4

• Failure to increase doses during acute stress can lead to adrenal crisis and increased morbidity/mortality 5

Patient Safety Measures:

All patients must wear Medic Alert identification jewelry and carry a steroid/alert card. 1, 2

• The emergency card has high value in reducing morbidity and mortality of adrenal crisis 5
• Patients require structured education programs to ensure self-monitored dose adjustments can be made as needed 6
• Education on precocious identification of stressor situations and adjusting glucocorticoid dosage is essential for preventing adrenal crisis 5

Follow-Up and Monitoring:

Annual follow-up should include: 2

• Assessment of health and well-being
• Measurement of weight and blood pressure
• Monitoring of serum electrolytes
• Screening for development of new autoimmune disorders (up to 50% develop another autoimmune disorder during lifetime) 4
• Assessment for complications of glucocorticoid therapy (osteoporosis, cardiovascular complications) 1

Long-Term Complications and Quality of Life:

Despite treatment, patients face several challenges 1:

• Risk of therapy-related osteoporosis and cardiovascular complications
• Reduced quality of life and ability to work in many patients
• Concerns about fertility in women due to increased risk of autoimmune premature ovarian insufficiency
• Sexual dysfunction due to lack of androgens

Note on DHEA replacement: Replacement of dehydroepiandrosterone 20-50 mg has been advocated for adrenal androgen depletion, but evidence for benefit is weak. 7