Cushing's Syndrome for the ABIM

Cushing's Syndrome for the America Board of Internal Medicine Exam

Excess Cortisol Production: Cushing's syndrome results from prolonged exposure to elevated levels of cortisol, a glucocorticoid produced by the adrenal cortex. Cortisol plays a crucial role in regulating metabolism, immune response, and stress adaptation.
ACTH-Dependent vs. ACTH-Independent:
ACTH-Dependent Cushing's Syndrome: Caused by excess adrenocorticotropic hormone (ACTH) production, which stimulates the adrenal glands to produce cortisol. This is the most common cause.
Cushing's Disease: The most common form of ACTH-dependent Cushing's, caused by a pituitary adenoma secreting excess ACTH.
Ectopic ACTH Syndrome: Non-pituitary tumors (e.g., small-cell lung carcinoma) produce ectopic ACTH.
ACTH-Independent Cushing's Syndrome: Caused by excess cortisol production by the adrenal glands, independent of ACTH.
Adrenal Adenoma or Carcinoma: Adrenal tumors can autonomously secrete cortisol.
Exogenous Steroid Use: The most common overall cause of Cushing's syndrome is iatrogenic, due to long-term glucocorticoid therapy.

General Appearance:
Central Obesity: Excess cortisol promotes fat redistribution, resulting in truncal obesity with thin extremities.
Moon Facies: A round, full face due to fat deposition.
Buffalo Hump: Fat accumulation in the upper back.
Skin and Hair:
Thin Skin: Cortisol inhibits fibroblast function, leading to thin, fragile skin with easy bruising.
Purple Striae: Wide, violaceous stretch marks, typically found on the abdomen, breasts, or thighs.
Hirsutism: Excess hair growth, especially in women, due to increased androgen production.
Acne: Common due to cortisol-induced androgenic activity.
Musculoskeletal:
Muscle Weakness: Cortisol induces muscle protein catabolism, leading to proximal muscle weakness.
Osteoporosis: Cortisol impairs bone formation, leading to increased fracture risk.
Metabolic Effects:
Hyperglycemia and Diabetes: Cortisol increases gluconeogenesis and insulin resistance, contributing to hyperglycemia and type 2 diabetes.
Dyslipidemia: Increased LDL and triglyceride levels.
Hypertension: Cortisol enhances the vasoconstrictive effects of catecholamines and increases sodium retention, leading to hypertension.
Psychiatric Effects:
Mood Disorders: Depression, anxiety, and irritability are common.
Cognitive Impairment: Patients may experience memory and concentration difficulties.
Immune Suppression: Cortisol suppresses immune function, increasing susceptibility to infections.

Initial Screening Tests:
24-Hour Urine Free Cortisol: Measures cortisol excreted in the urine over 24 hours. Elevated levels confirm hypercortisolism.
Late-Night Salivary Cortisol: Cortisol should normally be low at night. Elevated late-night cortisol is a sensitive marker for Cushing's syndrome.
Low-Dose Dexamethasone Suppression Test: 1 mg of dexamethasone is given at night, and serum cortisol is measured the next morning. In normal individuals, dexamethasone suppresses cortisol production. Lack of suppression (cortisol >5 µg/dL) indicates hypercortisolism.
ACTH Levels:
ACTH-Dependent: Elevated ACTH levels point to either Cushing's disease (pituitary adenoma) or ectopic ACTH production.
ACTH-Independent: Suppressed ACTH levels suggest an adrenal source of cortisol (e.g., adrenal adenoma or carcinoma).
High-Dose Dexamethasone Suppression Test:
Cushing's Disease: Cortisol production is suppressed with high doses of dexamethasone.
Ectopic ACTH Syndrome or Adrenal Tumor: Cortisol levels remain elevated despite high-dose dexamethasone.

Imaging:
Pituitary MRI: Used to identify a pituitary adenoma in suspected Cushing's disease.
CT Scan or MRI of Adrenal Glands: Used to detect adrenal tumors in ACTH-independent Cushing's syndrome.
Chest and Abdominal Imaging: For patients with ectopic ACTH production, imaging of the chest or abdomen may help locate the source.

Pseudocushing's Syndrome: Conditions like alcoholism, depression, or obesity may cause transient hypercortisolism but are not true Cushing's syndrome.
Exogenous Glucocorticoid Use: Prolonged use of glucocorticoid therapy (e.g., prednisone) can mimic endogenous Cushing's syndrome.

Treatment of Underlying Cause:
Pituitary Tumor (Cushing's Disease): Transsphenoidal surgery to remove the pituitary adenoma is the treatment of choice.
Ectopic ACTH-Secreting Tumors: Surgical resection of the tumor, if localized, is preferred. If surgery is not possible, medications may be required to control cortisol levels.
Adrenal Tumors: Adrenalectomy is indicated for adrenal adenomas or carcinomas.
Medical Therapy:
Steroidogenesis Inhibitors: Drugs like ketoconazole, metyrapone, and mitotane inhibit cortisol production in cases where surgery is not feasible or as a pre-surgical adjunct.
Mifepristone: A glucocorticoid receptor antagonist used to control hyperglycemia in patients with Cushing's syndrome.
Pasireotide: A somatostatin analog used in Cushing's disease when surgery is not successful or feasible.
Adjunctive Management:
Osteoporosis Treatment: Calcium, vitamin D supplementation, and bisphosphonates may be needed to reduce fracture risk.
Hypertension and Diabetes Management: Antihypertensives and antidiabetic medications are often necessary to control secondary complications.
Exogenous Cushing's Syndrome:
Glucocorticoid Tapering: Gradually tapering the dose of exogenous steroids is essential to allow the hypothalamic-pituitary-adrenal (HPA) axis to recover. Sudden withdrawal can lead to adrenal insufficiency.

Cardiovascular Disease: Long-term hypertension, dyslipidemia, and hyperglycemia increase the risk of atherosclerosis and cardiovascular events.
Osteoporosis and Fractures: Chronic cortisol excess leads to significant bone loss.
Infections: Immunosuppression increases the risk of infections, particularly opportunistic infections.
Adrenal Insufficiency: If treatment is too aggressive or if glucocorticoid therapy is abruptly stopped, patients may develop adrenal insufficiency, leading to fatigue, hypotension, and electrolyte imbalances.

Key Points

Pathophysiology: Cushing's syndrome results from prolonged exposure to elevated cortisol levels. The most common cause is exogenous glucocorticoid use, followed by pituitary adenomas (Cushing's disease).
Etiology: Can be ACTH-dependent (pituitary adenoma, ectopic ACTH secretion) or ACTH-independent (adrenal adenoma, carcinoma, or exogenous glucocorticoids).
Clinical Features: Central obesity, moon facies, buffalo hump, purple striae, hypertension, hyperglycemia, osteoporosis, and mood changes.
Diagnosis: Initial testing includes 24-hour urine free cortisol, late-night salivary cortisol, and dexamethasone suppression test. ACTH levels differentiate between ACTH-dependent and independent causes.
Treatment: Management depends on the underlying cause, with transsphenoidal surgery for Cushing's disease, adrenalectomy for adrenal tumors, and medical therapy for inoperable or refractory cases.
Complications: Cardiovascular disease, osteoporosis, immunosuppression, and adrenal insufficiency are significant risks associated with untreated or inadequately treated Cushing's syndrome.