Cushing’s syndrome

Addison’s Disease

1. Introduction and Overview

Definition:

Addison’s disease (primary adrenal insufficiency) is a chronic disorder characterized by the inadequate secretion of glucocorticoids (cortisol) and often mineralocorticoids (aldosterone) due to the destruction or dysfunction of the adrenal cortex.

Epidemiology:

• Prevalence: ~5–10 cases per million annually.

• Sex: Slightly more common in females.

• Age: Typically manifests between 30–50 years of age.

• Geographic Variations: Autoimmune adrenalitis is more common in developed countries, whereas infections like tuberculosis predominate in developing regions.

Relevance:

Addison’s disease can be life-threatening due to adrenal crises if undiagnosed or untreated, requiring lifelong management.

2. Etiology

Primary Causes:

1. Autoimmune Adrenalitis (70–90%):

   • Most common cause in developed countries.

   • May occur in isolation or as part of autoimmune polyendocrine syndromes (APS).

2. Infections:

   • Tuberculosis: Leading cause in developing countries.

   • Fungal infections (e.g., histoplasmosis, cryptococcosis).

   • HIV-associated adrenalitis.

3. Other Causes:

   • Adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome in sepsis).

   • Metastases to the adrenal glands (e.g., from lung or breast cancer).

   • Congenital adrenal hyperplasia (enzyme defects).

Secondary Causes:

• Iatrogenic: Long-term corticosteroid therapy leading to suppression of the hypothalamic-pituitary-adrenal (HPA) axis (secondary adrenal insufficiency).

Risk Factors:

• Family history of autoimmune disorders.

• Past infections like tuberculosis.

• Adrenal hemorrhage due to anticoagulant use.

3. Pathophysiology

Normal Physiology:

• The adrenal cortex secretes:

  • Glucocorticoids (cortisol): Regulate metabolism and stress response.

  • Mineralocorticoids (aldosterone): Maintain electrolyte balance and blood pressure.

  • Androgens: Minor contribution to sexual development.

Mechanisms of Disease:

1. Destruction of the Adrenal Cortex:

   • Autoimmune antibodies target adrenal cortex enzymes (e.g., 21-hydroxylase).

   • Infections or metastases lead to glandular destruction.

2. Hormonal Deficiency:

   • Cortisol deficiency impairs stress response and metabolism.

   • Aldosterone deficiency disrupts sodium-potassium homeostasis, causing hypotension and hyperkalemia.

4. Clinical Features

Symptoms:

1. Chronic Presentation:

   • Fatigue, weight loss, anorexia.

   • Hyperpigmentation (due to ACTH stimulation of melanocytes).

   • Abdominal pain, nausea, and vomiting.

   • Salt craving (due to aldosterone deficiency).

2. Acute Adrenal Crisis:

   • Severe hypotension, dehydration, shock.

   • Hypoglycemia, confusion, fever.

Signs:

1. General Appearance:

   • Hyperpigmentation in sun-exposed areas, scars, and mucosa.

   • Muscle wasting and weight loss.

2. Vitals:

   • Hypotension (especially postural).

   • Tachycardia.

Stages and Progression:

• Initial vague symptoms progressing to full-blown adrenal crisis in stress situations (e.g., surgery, infections).

Differentiating Features:

• Distinguish from secondary adrenal insufficiency (lack of hyperpigmentation, normal aldosterone levels).

5. Diagnostic Approach

Clinical Diagnosis:

• History of unexplained fatigue, hyperpigmentation, and salt craving.

• Examination findings like hypotension and pigmentation.

Laboratory Investigations:

1. Baseline Tests:

   • Electrolytes: Hyponatremia, hyperkalemia.

   • Glucose: Hypoglycemia.

   • Cortisol Levels: Morning serum cortisol <5 µg/dL is suggestive.

2. ACTH Levels:

   • Elevated in primary adrenal insufficiency.

   • Low or normal in secondary causes.

Functional Testing:

• ACTH Stimulation Test (Synacthen Test):

  • Cortisol fails to rise >18 µg/dL after ACTH administration in Addison’s disease.

Imaging Studies:

1. CT of the Adrenals:

   • Small and atrophic adrenals in autoimmune adrenalitis.

   • Enlarged or calcified glands in infections or metastases.

2. MRI Brain: To evaluate pituitary causes in secondary insufficiency.

Diagnostic Criteria:

• Confirmed low cortisol with elevated ACTH and abnormal ACTH stimulation test.

6. Management

Medical Management:

1. Chronic Management:

   • Glucocorticoid Replacement:

     • Hydrocortisone (15–25 mg/day in divided doses).

     • Alternatives: Prednisolone or dexamethasone.

   • Mineralocorticoid Replacement:

     • Fludrocortisone (0.05–0.2 mg/day).

   • Androgen Replacement (if needed):

     • Dehydroepiandrosterone (DHEA) for improved quality of life.

2. Stress Dose Adjustments:

   • Double or triple glucocorticoid dose during infections, surgery, or trauma.

Surgical Management:

• Not applicable unless underlying tumor or infection requires intervention.

Emergency Management:

1. Acute Adrenal Crisis:

   • Immediate Hydrocortisone: IV bolus 100 mg, followed by continuous infusion or 50 mg every 6–8 hours.

   • Fluids: IV normal saline with dextrose to correct hypovolemia and hypoglycemia.

   • Monitor and correct electrolytes.

7. Prognosis

Natural History:

• Fatal if untreated due to cardiovascular collapse during adrenal crises.

Outcomes with Treatment:

• Lifelong hormone replacement provides excellent quality of life.

• Risk of adrenal crisis persists, requiring vigilance.

Long-Term Impacts:

• Patients may experience fatigue and reduced physical performance despite adequate treatment.

8. Complications

Primary Disease Complications:

1. Adrenal Crisis: Life-threatening hypotension, shock, and hypoglycemia.

2. Electrolyte Imbalance: Chronic hyponatremia and hyperkalemia.

Therapeutic Complications:

• Over-replacement with glucocorticoids causing Cushingoid features.

• Mineralocorticoid excess leading to hypertension and hypokalemia.

9. Prevention

Primary Prevention:

• Screening in high-risk populations (e.g., family history of autoimmune disorders).

• Prompt treatment of infections like tuberculosis.

Secondary Prevention:

• Early diagnosis through ACTH stimulation testing in symptomatic individuals.

Tertiary Prevention:

• Patient education to recognize and prevent adrenal crises.

10. Patient Education

Disease Understanding:

• Explain the chronic nature of the condition and the need for lifelong therapy.

Self-Monitoring:

• Recognize signs of adrenal insufficiency or crisis.

Lifestyle Advice:

• Carry a medical alert card/bracelet.

• Maintain a balanced diet with adequate salt intake.

Adherence to Treatment:

• Regularly take prescribed glucocorticoids and mineralocorticoids.

When to Seek Help:

• Signs of adrenal crisis: severe weakness, confusion, or shock.

11. Recent Research and Advances

• Novel Glucocorticoid Formulations: Modified-release hydrocortisone for more physiological cortisol replacement.

• Autoimmune Pathways: Ongoing research on immunotherapy to prevent adrenal destruction.

• Genetic Insights: Advances in identifying genetic predispositions in autoimmune adrenalitis.

12. Case Studies

Example:

A 45-year-old man presents with fatigue, hyperpigmentation, and recurrent nausea. Tests reveal low cortisol, elevated ACTH, and failure to respond to ACTH stimulation. Diagnosis of Addison’s disease is made, and he is successfully managed with hydrocortisone and fludrocortisone.

13. References

1. Hahner S, et al. "Adrenal Insufficiency." Lancet Diabetes Endocrinol., 2015.

2. Endocrine Society Clinical Practice Guidelines for Adrenal Insufficiency (2021).

3. Harrison’s Principles of Internal Medicine, 21st Edition.