Cushing's Syndrome for USMLE Step 2

Cushing's Syndrome for the USMLE Step 2 Exam

Excess Cortisol Production: Cushing's syndrome is caused by prolonged exposure to elevated cortisol levels, resulting in a wide range of metabolic, cardiovascular, and immunosuppressive effects.
ACTH-Dependent vs. ACTH-Independent:
ACTH-Dependent: Cortisol excess results from increased adrenocorticotropic hormone (ACTH) production.
Cushing's Disease: Caused by a pituitary adenoma secreting ACTH, this is the most common endogenous cause.
Ectopic ACTH Syndrome: Non-pituitary tumors (e.g., small-cell lung carcinoma) secrete ectopic ACTH.
ACTH-Independent: Caused by excessive cortisol production independent of ACTH.
Adrenal Adenoma/Carcinoma: Adrenal tumors can autonomously secrete cortisol.
Exogenous Glucocorticoids: Long-term steroid use is the most common cause of Cushing's syndrome.

General Appearance:
Central Obesity: Fat redistribution leads to truncal obesity with thin extremities.
Moon Facies: Rounded, full face due to fat accumulation.
Buffalo Hump: Fat pad on the upper back.
Skin and Hair:
Purple Striae: Wide, purplish stretch marks, typically on the abdomen and thighs.
Thin Skin: Increased bruising and poor wound healing due to impaired collagen synthesis.
Hirsutism and Acne: Increased androgen activity, especially in women.
Musculoskeletal:
Proximal Muscle Weakness: Muscle catabolism from cortisol leads to weakness, especially in the upper arms and thighs.
Osteoporosis: Increased risk of fractures due to decreased bone density from cortisol’s effects on bone metabolism.
Metabolic Effects:
Hyperglycemia and Insulin Resistance: Cortisol promotes gluconeogenesis and insulin resistance, often leading to diabetes mellitus.
Hypertension: Cortisol increases sodium retention and potentiates the vasoconstrictive effects of catecholamines.
Dyslipidemia: Elevated LDL and triglyceride levels.
Immune and Psychiatric Effects:
Immune Suppression: Increased susceptibility to infections.
Psychiatric Symptoms: Depression, anxiety, irritability, and cognitive dysfunction are common.

Screening Tests:
24-Hour Urine Free Cortisol: Measures the total cortisol excreted 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 dexamethasone is given at night, and serum cortisol is measured the next morning. Lack of suppression suggests hypercortisolism.
ACTH Levels:
High ACTH: Suggests ACTH-dependent Cushing’s (pituitary adenoma or ectopic ACTH).
Low ACTH: Indicates ACTH-independent Cushing’s (adrenal adenoma or carcinoma).

Imaging:
Pituitary MRI: Used to detect a pituitary adenoma in suspected Cushing’s disease.
CT or MRI of the Adrenal Glands: To assess for adrenal tumors.
Chest or Abdominal CT: For ectopic ACTH production, imaging helps identify the tumor.

Surgery:
Pituitary Adenoma (Cushing’s Disease): Transsphenoidal surgery is the first-line treatment.
Adrenal Tumors: Adrenalectomy is indicated for adrenal adenomas or carcinomas.
Ectopic ACTH-Producing Tumors: Tumor resection if localized; if not, medical management is needed.
Medical Therapy:
Steroidogenesis Inhibitors: Ketoconazole, metyrapone, or mitotane to reduce cortisol production.
Mifepristone: A glucocorticoid receptor antagonist used in cases of refractory Cushing’s or inoperable disease.
Adjunctive Treatment: Management of osteoporosis (e.g., bisphosphonates), hypertension (e.g., ACE inhibitors), and hyperglycemia (e.g., insulin or oral hypoglycemics) is crucial.

Cardiovascular Disease: Long-term hypertension, hyperglycemia, and dyslipidemia increase the risk of myocardial infarction and stroke.
Osteoporosis: Increased fracture risk due to bone loss.
Infections: Cortisol’s immunosuppressive effects predispose patients to infections.
Adrenal Insufficiency: May develop if cortisol-lowering therapy is too aggressive or after adrenalectomy.

Key Points

Pathophysiology: Cushing's syndrome is caused by prolonged cortisol excess, most commonly due to exogenous steroid use or a pituitary adenoma (Cushing’s disease).
Etiology: It can be ACTH-dependent (Cushing’s disease, ectopic ACTH secretion) or ACTH-independent (adrenal adenomas, exogenous steroids).
Clinical Features: Central obesity, moon facies, purple striae, muscle weakness, hyperglycemia, hypertension, and osteoporosis are key findings.
Diagnosis: Initial screening involves 24-hour urine free cortisol, dexamethasone suppression tests, and ACTH levels. Imaging is used to locate the source of cortisol excess.
Treatment: Surgery is the primary treatment for tumors, while medical therapy is used for inoperable or refractory cases.
Complications: Cardiovascular disease, osteoporosis, and infections are major risks associated with untreated or inadequately managed Cushing’s syndrome.