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Cushing's Syndrome for USMLE Step 1

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Cushing's Syndrome for the USMLE Step 1 Exam
  • Pathophysiology
    • Excess Cortisol: Cushing's syndrome is caused by prolonged exposure to high levels of cortisol, leading to metabolic and systemic effects.
    • ACTH-Dependent vs. ACTH-Independent:
    • ACTH-Dependent: Excess ACTH stimulates the adrenal glands to produce cortisol.
    • Cushing's Disease: Pituitary adenoma secreting excess ACTH is the most common cause of endogenous Cushing’s syndrome.
    • Ectopic ACTH Production: Non-pituitary tumors (e.g., small-cell lung carcinoma) secrete ectopic ACTH.
    • ACTH-Independent: Caused by autonomous cortisol secretion from adrenal sources.
    • Adrenal Adenoma/Carcinoma: Adrenal tumors produce cortisol independent of ACTH.
    • Exogenous Glucocorticoids: Long-term use of corticosteroids is the most common cause of Cushing’s syndrome.
  • Clinical Features
    • Central Obesity: Fat redistribution causes truncal obesity with thin extremities.
    • Moon Facies: A rounded face due to fat deposition.
    • Buffalo Hump: Fat accumulation over the upper back.
    • Skin Changes:
    • Purple Striae: Wide, violaceous stretch marks on the abdomen, thighs, or breasts.
    • Thin Skin and Easy Bruising: Cortisol inhibits collagen production, leading to fragile skin.
    • Hirsutism and Acne: Due to excess androgen production in some cases.
    • Muscle Weakness: Proximal muscle wasting due to protein catabolism.
    • Bone Health: Osteoporosis occurs due to cortisol's inhibitory effects on bone formation.
    • Metabolic Effects:
    • Hyperglycemia: Increased gluconeogenesis and insulin resistance.
    • Hypertension: Due to enhanced vasoconstriction and sodium retention.
    • Immune Suppression: Increased risk of infections due to cortisol's immunosuppressive effects.
    • Psychiatric Symptoms: Depression, anxiety, and irritability are common.
  • Diagnosis
    • Initial Screening:
    • 24-Hour Urine Free Cortisol: Measures cortisol excretion over 24 hours. Elevated levels confirm hypercortisolism.
    • Late-Night Salivary Cortisol: Cortisol should be low at night. Elevated levels suggest Cushing’s syndrome.
    • Low-Dose Dexamethasone Suppression Test: 1 mg of dexamethasone is administered at night, and serum cortisol is measured the next morning. In normal individuals, cortisol is suppressed; lack of suppression suggests Cushing’s syndrome.
    • ACTH Levels:
    • High ACTH: Suggests ACTH-dependent Cushing's (pituitary adenoma or ectopic ACTH).
    • Low ACTH: Indicates an adrenal cause (adenoma or carcinoma).
    • High-Dose Dexamethasone Suppression Test:
    • Cushing’s Disease: Cortisol production is suppressed with high doses of dexamethasone.
    • Ectopic ACTH or Adrenal Tumors: Cortisol remains elevated despite high-dose dexamethasone.
Cortisol test cushings
    • Imaging:
    • Pituitary MRI: Used to identify pituitary adenomas.
    • Adrenal CT/MRI: Used to detect adrenal tumors.
    • Chest/Abdomen CT: To locate ectopic ACTH-secreting tumors.
  • Differential Diagnosis
    • Pseudocushing's Syndrome: Alcoholism, depression, or obesity can cause transient hypercortisolism.
    • Exogenous Glucocorticoid Use: Chronic corticosteroid use can mimic Cushing's syndrome.
  • Management
    • Surgical Treatment:
    • Cushing’s Disease: Transsphenoidal surgery to remove the pituitary adenoma is the treatment of choice.
    • Adrenal Tumors: Adrenalectomy is indicated for adrenal adenomas or carcinomas.
    • Ectopic ACTH-Secreting Tumors: Resection of the tumor, if localized.
    • Medical Therapy:
    • Steroidogenesis Inhibitors: Ketoconazole or metyrapone to inhibit cortisol production when surgery is not feasible or as an adjunctive therapy.
    • Mifepristone: A glucocorticoid receptor antagonist used to control hyperglycemia in Cushing’s syndrome.
    • Pasireotide: A somatostatin analog used in refractory cases of Cushing’s disease.
    • Adjunctive Management:
    • Osteoporosis Treatment: Calcium, vitamin D, and bisphosphonates may be necessary.
    • Management of Hypertension and Diabetes: Antihypertensives and antidiabetic agents are often needed.
  • Complications
    • Cardiovascular Disease: Hypertension, hyperlipidemia, and hyperglycemia increase the risk of cardiovascular events.
    • Osteoporosis: Increased risk of fractures due to bone loss.
    • Immunosuppression: Increased risk of infections.
    • Adrenal Insufficiency: Can occur after surgical removal of the adrenal glands or withdrawal from glucocorticoid therapy.
Key Points
  • Pathophysiology: Cushing's syndrome is caused by prolonged cortisol exposure, most commonly from exogenous steroid use or a pituitary adenoma.
  • Etiology: It can be ACTH-dependent (Cushing’s disease, ectopic ACTH) or ACTH-independent (adrenal tumors, exogenous glucocorticoids).
  • Clinical Features: Central obesity, moon facies, purple striae, muscle weakness, hyperglycemia, hypertension, and osteoporosis.
  • Diagnosis: Includes 24-hour urine free cortisol, dexamethasone suppression tests, ACTH levels, and imaging studies.
  • Treatment: Depends on the cause; surgical resection for tumors and medical therapy to control cortisol production or effects.
  • Complications: Cardiovascular disease, osteoporosis, and infections are major concerns.

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