Adrenal Insufficiency for USMLE Step 3

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Adrenal Insufficiency for the USMLE Step 3 Exam

Primary Adrenal Insufficiency (Addison’s Disease): Results from direct adrenal cortex damage, leading to reduced production of cortisol, aldosterone, and adrenal androgens. Cortisol deficiency impairs glucose metabolism and blood pressure regulation, while aldosterone deficiency leads to hyponatremia, hyperkalemia, and hypotension.
Secondary Adrenal Insufficiency: Caused by reduced adrenocorticotropic hormone (ACTH) secretion from the pituitary, leading to decreased cortisol production. Aldosterone production is preserved, as it is regulated by the renin-angiotensin-aldosterone system (RAAS).
Tertiary Adrenal Insufficiency: Results from reduced corticotropin-releasing hormone (CRH) secretion from the hypothalamus, usually secondary to chronic glucocorticoid use, which suppresses the hypothalamic-pituitary-adrenal (HPA) axis.

Primary Adrenal Insufficiency:
Autoimmune Adrenalitis: The most common cause in developed countries. The immune system destroys the adrenal cortex, leading to cortisol and aldosterone deficiencies.
Infections: Tuberculosis and fungal infections (e.g., histoplasmosis) can damage the adrenal glands.
Adrenal Hemorrhage: Waterhouse-Friderichsen syndrome (caused by meningococcemia) or anticoagulation therapy can result in adrenal hemorrhage.
Metastatic Disease: Cancers such as lung or breast cancer can spread to the adrenal glands.
Secondary Adrenal Insufficiency:
Chronic Glucocorticoid Use: Long-term glucocorticoid use suppresses ACTH production, leading to adrenal atrophy.
Pituitary Tumors or Surgery: Damage to ACTH-producing cells causes secondary adrenal insufficiency.
Tertiary Adrenal Insufficiency:
Most commonly caused by chronic glucocorticoid therapy, which suppresses CRH and ACTH production.

Primary Adrenal Insufficiency (Addison's Disease):
Fatigue, Weakness, and Anorexia: Due to cortisol deficiency.
Hypotension: Caused by both cortisol and aldosterone deficiencies.
Hyperpigmentation: Increased ACTH stimulates melanocytes, causing darkening of the skin, especially in areas exposed to friction.
Hyponatremia and Hyperkalemia: Due to aldosterone deficiency, causing sodium loss and potassium retention.
Hypoglycemia: Cortisol deficiency impairs gluconeogenesis.
Secondary and Tertiary Adrenal Insufficiency:
Similar symptoms to primary adrenal insufficiency but without hyperpigmentation or significant electrolyte disturbances, as aldosterone production is preserved.

Morning Serum Cortisol: A low level (<5 µg/dL) suggests adrenal insufficiency.
ACTH Levels:
Primary Adrenal Insufficiency: High ACTH levels indicate that the adrenal glands are not responding to ACTH stimulation.
Secondary/Tertiary Adrenal Insufficiency: Low or normal ACTH levels indicate pituitary or hypothalamic dysfunction.
ACTH Stimulation Test (Cosyntropin Test): Synthetic ACTH is administered to measure cortisol response.
Primary Adrenal Insufficiency: Cortisol remains low despite ACTH administration.
Secondary/Tertiary Adrenal Insufficiency: Cortisol may increase, depending on the degree of adrenal atrophy.
Electrolytes: Hyponatremia and hyperkalemia suggest primary adrenal insufficiency.

Primary Adrenal Insufficiency:
Glucocorticoid Replacement: Hydrocortisone or prednisone is used to replace cortisol. Dosing should mimic the natural diurnal rhythm.
Mineralocorticoid Replacement: Fludrocortisone is used to replace aldosterone and manage sodium/potassium balance.
Secondary and Tertiary Adrenal Insufficiency:
Glucocorticoid Replacement: Hydrocortisone or prednisone is administered. Mineralocorticoid replacement is generally not necessary.
Acute Adrenal Crisis:
Emergency Treatment: High-dose intravenous hydrocortisone and fluid resuscitation with normal saline are required to manage hypotension, hyponatremia, and hyperkalemia.

Adrenal Crisis: A life-threatening emergency precipitated by infection, surgery, or trauma, characterized by severe hypotension, shock, and electrolyte imbalances.
Chronic Symptoms: Untreated adrenal insufficiency can lead to chronic fatigue, weakness, weight loss, and poor quality of life.

Key Points

Pathophysiology: Primary adrenal insufficiency affects both cortisol and aldosterone, while secondary and tertiary forms affect cortisol only, with preserved aldosterone.
Etiology: Primary adrenal insufficiency is caused by autoimmune disease, infections, or adrenal hemorrhage. Secondary and tertiary forms are due to chronic glucocorticoid use or pituitary/hypothalamic dysfunction.
Clinical Features: Primary adrenal insufficiency presents with fatigue, hyperpigmentation, hypotension, hyponatremia, and hyperkalemia. Secondary/tertiary forms lack hyperpigmentation and significant electrolyte imbalances.
Diagnosis: Low morning cortisol, abnormal ACTH stimulation test, and electrolyte abnormalities in primary disease.
Treatment: Glucocorticoid and mineralocorticoid replacement in primary adrenal insufficiency; glucocorticoids alone for secondary/tertiary forms. Adrenal crisis requires urgent intervention.