Cushing's Syndrome for USMLE Step 3

Cushing's Syndrome for the USMLE Step 3 Exam

Excess Cortisol: Cushing's syndrome occurs due to prolonged exposure to high levels of cortisol, leading to metabolic, cardiovascular, and immunosuppressive effects.
ACTH-Dependent vs. ACTH-Independent:
ACTH-Dependent: Excess ACTH stimulates adrenal cortisol production.
Cushing's Disease: Caused by a pituitary adenoma secreting ACTH. This is the most common cause of endogenous Cushing’s syndrome.
Ectopic ACTH Production: Tumors, especially small-cell lung cancer, secrete ACTH, leading to elevated cortisol.
ACTH-Independent: Autonomous cortisol production occurs from adrenal sources.
Adrenal Tumors: Adenomas or carcinomas in the adrenal glands can autonomously secrete cortisol.
Exogenous Steroids: The most common cause of Cushing's syndrome overall, due to long-term glucocorticoid therapy.

General Appearance:
Central Obesity: Truncal obesity with thin extremities.
Moon Facies: A round, full face due to fat deposition.
Buffalo Hump: Fat accumulation over the upper back.
Skin Changes:
Purple Striae: Wide, purplish stretch marks on the abdomen, breasts, or thighs.
Thin Skin and Easy Bruising: Cortisol inhibits collagen production, causing fragile skin.
Hirsutism and Acne: Increased androgens can lead to excess hair growth and acne, particularly in women.
Muscle and Bone:
Proximal Muscle Weakness: Cortisol-induced muscle catabolism leads to weakness, particularly in the thighs and upper arms.
Osteoporosis: Cortisol decreases bone formation, leading to osteoporosis and increased fracture risk.
Metabolic Effects:
Hyperglycemia: Cortisol promotes gluconeogenesis and insulin resistance, often resulting in diabetes mellitus.
Hypertension: Enhanced sodium retention and increased catecholamine sensitivity raise blood pressure.
Dyslipidemia: Elevated LDL and triglyceride levels.
Psychiatric Effects:
Mood Disorders: Depression, anxiety, and irritability are common.
Immune Suppression: Increased risk of infections due to cortisol’s immunosuppressive effects.

Screening Tests:
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 indicate Cushing's syndrome.
Low-Dose Dexamethasone Suppression Test: 1 mg dexamethasone is given at night, and cortisol is measured the next morning. Failure to suppress cortisol suggests Cushing's syndrome.
ACTH Levels:
High ACTH: Indicates ACTH-dependent Cushing’s (pituitary adenoma or ectopic ACTH production).
Low ACTH: Suggests an adrenal cause (adenoma or carcinoma).

Imaging:
Pituitary MRI: Used to identify a pituitary adenoma in suspected Cushing’s disease.
CT or MRI of the Adrenal Glands: To detect adrenal adenomas or carcinomas.
Chest/Abdominal Imaging: Used to locate ectopic ACTH-secreting tumors.

Surgery:
Cushing’s Disease (Pituitary Adenoma): Transsphenoidal surgery to remove the adenoma is the first-line treatment.
Adrenal Tumors: Adrenalectomy for adenomas or carcinomas.
Ectopic ACTH-Producing Tumors: Resection of the tumor, if feasible.
Medical Therapy:
Steroidogenesis Inhibitors: Drugs like ketoconazole or metyrapone are used to reduce cortisol production in patients who cannot undergo surgery or have refractory disease.
Mifepristone: A glucocorticoid receptor antagonist used to manage hyperglycemia in patients with inoperable Cushing’s.
Adjunctive Treatment:
Osteoporosis Management: Calcium, vitamin D, and bisphosphonates to improve bone density.
Hypertension and Hyperglycemia: Antihypertensive and antidiabetic treatments are often necessary.

Cardiovascular Complications: Chronic hypertension, dyslipidemia, and hyperglycemia increase the risk of cardiovascular events.
Osteoporosis: Increased fracture risk due to long-term bone loss.
Infections: Cortisol suppresses the immune system, increasing the likelihood of infections.
Adrenal Insufficiency: May occur after surgery or abrupt cessation of glucocorticoid therapy.

Key Points

Pathophysiology: Cushing’s syndrome results from excess cortisol, commonly due to exogenous steroid use or a pituitary adenoma (Cushing’s disease).
Etiology: ACTH-dependent causes include Cushing’s disease and ectopic ACTH secretion, while ACTH-independent causes include adrenal adenomas and exogenous steroid use.
Clinical Features: Patients typically present with central obesity, moon facies, purple striae, proximal muscle weakness, hyperglycemia, and hypertension.
Diagnosis: Includes 24-hour urine free cortisol, low-dose dexamethasone suppression test, ACTH levels, and imaging studies.
Treatment: First-line treatment is surgical resection for tumors, with medical therapy available for inoperable or refractory cases.
Complications: Cardiovascular disease, osteoporosis, and infections are significant risks associated with untreated or poorly managed Cushing’s syndrome.