What part of the adrenal glands is affected in Addison's disease and how does it relate to the symptoms?

Addison's Disease: Adrenal Pathophysiology and Symptom Correlation

In Addison's disease, the adrenal cortex is destroyed (usually by autoimmune mechanisms), leading to deficiencies in cortisol and aldosterone production, which directly causes the characteristic symptoms of fatigue, hypotension, salt craving, and hyperpigmentation. 1, 2

Adrenal Anatomy and Pathology in Addison's Disease

Addison's disease (primary adrenal insufficiency) specifically affects the adrenal cortex, which is the outer layer of the adrenal gland. The adrenal cortex is responsible for producing three main types of hormones:

1. Glucocorticoids (cortisol)

   • Produced in the zona fasciculata
   • Regulates metabolism, stress response, and immune function

2. Mineralocorticoids (aldosterone)

   • Produced in the zona glomerulosa
   • Controls sodium retention and potassium excretion

3. Adrenal androgens

   • Produced in the zona reticularis
   • Contributes to secondary sexual characteristics

In Addison's disease, all three zones of the adrenal cortex are progressively destroyed, most commonly by an autoimmune process where the body's immune system attacks the adrenal tissue 2, 3. The adrenal medulla (inner portion that produces adrenaline) is typically not directly affected.

How Adrenal Destruction Links to Symptoms

Cortisol Deficiency Symptoms

• Fatigue and weakness: Cortisol helps regulate energy metabolism
• Weight loss and decreased appetite: Impaired metabolism and gastrointestinal function
• Low blood sugar (hypoglycemia): Cortisol normally helps maintain blood glucose levels
• Muscle and joint pain: Related to altered metabolism and electrolyte imbalances
• Poor stress response: Inability to mount appropriate physiological responses to illness or stress

Aldosterone Deficiency Symptoms

• Low blood pressure and orthostatic hypotension: Reduced sodium retention leads to decreased blood volume
• Salt craving: Body's attempt to compensate for sodium loss
• Increased urination: Inability to reabsorb sodium in kidneys
• Dehydration: Result of sodium and water loss
• Electrolyte imbalances: Typically low sodium (hyponatremia) and high potassium (hyperkalemia)

Adrenal Androgen Deficiency

• Reduced body hair (particularly in women): Less significant in men due to testicular androgen production
• Decreased libido: More noticeable in women than men

Characteristic Hyperpigmentation

• Darkening of the skin: Occurs due to elevated ACTH (adrenocorticotropic hormone) levels
• Most noticeable in sun-exposed areas, palmar creases, oral mucosa, and recent scars: These areas have higher concentrations of melanocytes
• ACTH increases when cortisol levels fall (negative feedback loop disruption), and ACTH has melanocyte-stimulating properties 4

Diagnostic Considerations

The diagnosis of Addison's disease requires a high index of suspicion due to its rarity (prevalence of approximately 1 in 20,000) and often subtle initial presentation 5. Key laboratory findings include:

• Low morning cortisol levels
• Elevated ACTH levels (distinguishing primary from secondary adrenal insufficiency)
• Abnormal electrolytes (low sodium, high potassium)
• Positive ACTH stimulation test: The gold standard confirmatory test 2

Treatment Approach

Treatment involves hormone replacement therapy:

• Glucocorticoid replacement: Typically hydrocortisone 15-25 mg daily in divided doses (2/3 in morning, 1/3 in afternoon) 2, 6
• Mineralocorticoid replacement: Fludrocortisone 0.1 mg daily (range 0.05-0.2 mg) 2, 7
• Stress dosing: Increased glucocorticoid doses during illness, surgery, or other stressors 1, 2

Important Clinical Pitfalls

• Delayed diagnosis due to nonspecific early symptoms
• Inadequate stress dosing during illness or procedures
• Failure to recognize adrenal crisis (a medical emergency requiring immediate hydrocortisone 100 mg IV and fluid resuscitation)
• Insufficient patient education about emergency management
• Overlooking associated autoimmune conditions (up to 50% of patients develop another autoimmune disorder) 2, 5

Patients should wear medical alert identification and carry emergency hydrocortisone for injection to prevent life-threatening adrenal crisis 2.