Cushing Syndrome

Detailed Overview

Endogenous hypercortisolism is classified as ACTH-dependent (e.g., Cushing disease from a pituitary adenoma, ectopic ACTH from small cell lung cancer) or ACTH-independent (e.g., adrenal adenoma/carcinoma). Chronic hypercortisolism leads to altered fat distribution, catabolism of protein in skin and muscle, and metabolic disturbances like impaired glucose tolerance. Early diagnosis is crucial to prevent complications such as severe hypertension, osteoporosis, and recurrent infections.

Epidemiology & Demographics

Incidence of endogenous Cushing syndrome is 2-3 per 1 million people annually. The median age of onset is 41.4 years. It is three times more common in females than in males. Cushing disease accounts for 70% of endogenous cases.

Etiological Mechanism

Exogenous etiology involves iatrogenic corticosteroid therapy. Endogenous causes include corticotroph pituitary adenomas (Cushing disease, 70%), ectopic ACTH secretion (10-15%, often bronchial carcinoids or small cell lung cancer), and primary adrenal tumors (15-20%, adrenal adenomas or carcinomas).

Primary Causes

Long-term prednisone use (e.g., for asthma or RA), pituitary microadenoma secreting ACTH, ectopic ACTH-producing tumors, macronodular or micronodular adrenal hyperplasia.

• Chronic glucocorticoid use: Long-term therapy with oral, inhaled, or intra-articular steroids.
• Female gender: Higher predilection for ACTH-secreting pituitary adenomas.

Excess cortisol binds to glucocorticoid receptors, upregulating gluconeogenesis and glycogenolysis, leading to hyperglycemia. It stimulates lipolysis centrally but promotes central adipogenesis. High cortisol exerts mineralocorticoid activity by overwhelming 11-beta-hydroxysteroid dehydrogenase type 2, causing renal sodium retention and potassium wasting. Protein catabolism leads to muscle wasting and thinning of the dermis. Furthermore, cortisol inhibits osteoblast function and decreases intestinal calcium absorption, driving osteoporosis.

Characteristic Clinical Presentation

• Weight gain: Central obesity, predominantly involving the face, neck, and trunk.
• Proximal muscle weakness: Difficulty rising from a chair or climbing stairs due to myopathy.
• Menstrual irregularities: Oligomenorrhea or amenorrhea due to suppression of the HPG axis.
• Psychological changes: Lethargy, depression, paranoia, or frank psychosis.

Physical Examination Signs

• Plethoric 'moon' facies
• Dorsocervical fat pad ('buffalo hump')
• Wide (>1 cm) violaceous striae on abdomen and flanks
• Facial plethora and hirsutism
• Spontaneous ecchymoses (easy bruising)

• Osteoporosis: Vertebral compression fractures occurring in up to 50% of untreated patients.
• Cardiovascular disease: Hypertension, dyslipidemia, and hypercoagulability leading to myocardial infarction or DVT/PE.
• Diabetes Mellitus: Steroid-induced hyperglycemia necessitating insulin therapy.

Diagnostic Criteria & Guidelines

Requires at least two abnormal first-line tests: 1) 24-hour urine free cortisol (UFC) > normal range (usually >50 mcg/24h) for assay, 2) Late-night salivary cortisol (LNSC) > 145 ng/dL, or 3) 1-mg overnight dexamethasone suppression test (ODST) showing 8 AM serum cortisol > 1.8 mcg/dL (50 nmol/L).

Differential Diagnosis

• Pseudo-Cushing syndrome (PCOS, severe depression, alcoholism)
• Simple obesity
• Metabolic syndrome

Laboratory Tests & Biomarkers

• 24-hour UFC: > 3x upper limit of normal
• Serum ACTH: < 5 pg/mL suggests adrenal cause; > 20 pg/mL suggests pituitary/ectopic.
• Basic Metabolic Panel: Hypokalemia (<3.5 mEq/L) and hyperglycemia.

Imaging Modalities & Findings

• Pituitary MRI: Delayed enhancement of a microadenoma (<10 mm) after gadolinium.
• Adrenal CT: Unilateral lipid-poor/rich mass (adenoma/carcinoma) or bilateral adrenal hyperplasia.

• Mild/Subclinical
  Normal or slightly elevated midnight salivary cortisol with subtle clinical signs, often incidentally found adrenal mass.
• Overt
  Classic signs (striae, myopathy) with confirmed hypercortisolism on multiple biochemical tests.
• Severe/Complicated
  Hypercortisolism complicated by opportunistic infections, severe hypokalemia, or uncontrolled severe hypertension/diabetes.

Second-Line & Adjunctive Therapy

Medical therapy if surgery is contraindicated or fails: Ketoconazole 200 mg PO TID up to 1200 mg/day, Metyrapone 250 mg PO QID, or Mifepristone 300 mg PO daily for hyperglycemia. Pituitary irradiation (radiosurgery) for recurrent Cushing disease.

Surgical & Procedural Management

Transsphenoidal surgery (TSS) for Cushing disease (remission rate 70-90%). Bilateral adrenalectomy as definitive therapy for occult or unresectable ectopic ACTH or failed TSS, requiring lifelong glucocorticoid and mineralocorticoid replacement.

Recommended Lifestyle Changes

• Diet rich in calcium and vitamin D (1000-1200 mg Ca, 800 IU Vit D).
• Low sodium diet (<2 g/day) to help manage hypertension and edema.
• Weight-bearing exercise to preserve bone density.

Patient Counseling & Advice

Warn patients of postoperative adrenal insufficiency symptoms (fatigue, nausea, hypotension). Remind them that physical changes (e.g., striae, body fat redistribution) may take 6-12 months to resolve after cure.

Follow-Up & Monitoring Schedule

Measure morning serum cortisol and ACTH on post-op days 1-3. Long-term monitoring: 24-hr UFC, LNSC, or 1-mg DST every 6-12 months. DEXA scan every 1-2 years.

Preventive Strategies

Strict indication and minimal effective dose/duration for exogenous corticosteroid prescriptions. Alternate-day dosing for chronic steroid requirement if possible.

Untreated endogenous Cushing syndrome has a 5-year mortality of 50%. With surgical cure, 10-year survival normalizes, but patients maintain higher cardiovascular risk profiles for years.