Endocrine: Hypercortisolism (Cushing Syndrome)

Definition

• Excess Cortisol from Exogenous Administration or Endogenous Production

Causes

• Exogenous Steroids (Iatrogenic/Factitious) – #1 Most Common Cause Overall
• Endogenous Causes:
  • ACTH-Dependent Causes:
    • Cushing Disease/Pituitary ACTH Adenoma (65-70% Most Common Endogenous Cause & #2 Overall)
    • Ectopic ACTH Secretion (10-15%)
      • Most Common Source: Squamous Cell Lung Cancer
    • Ectopic CRH Secretion (< 1%)
    • Exogenous ACTH Administration (<1%)
  • ACTH-Independent Causes:
    • Adrenal Adenoma/Carcinoma (18-20%)
    • Adrenal Hyperplasia
      • Primary Pigmented Nodular Adrenocortical Disease (< 1%)
      • Bilateral Macronodular Adrenal Hyperplasia (< 1%)

Presentation

• Abnormal Glucose Intolerance
• Hypertension
• Weight Gain:
  • Central Obesity
  • Round “Moon” Face (Fat Accumulation in Cheeks)
  • “Buffalo Hump” (Dorsal Fat Pad)
• Skin Changes:
  • Purple Striae
  • Acne
  • Easy Bruising/Ecchymosis
  • Hyperpigmentation – If Due to Excess ACTH (Pituitary Adenoma or Ectopic Production)
    • ACTH Converted to MSH (Melanocyte Stimulating Hormone)
• Reproductive:
  • Menstrual Irregularity
  • Decreased Libido
  • Hirsutism
• Pain:
  • Abdominal Pain
  • Headache
  • Back Ache
• Musculoskeletal:
  • Proximal Muscle Weakness
  • Osteoporosis
• Psychologic Changes:
  • Lethargy
  • Depression
  • Anxiety
  • Irritability

Diagnosis

• First Exclude Exogenous Steroids Before Starting Testing
• #1 Screen: 24-Hour Urine Cortisol (Best Screening Test)
  • Other Screening Tests:
    • Low-Dose Dexamethasone Suppression Test
    • Late-Night Salivary or Serum Cortisol
• #2 Determines ACTH Dependence: Plasma ACTH Level
  • Low ACTH (< 5 pg/mL): Indicates ACTH Independence (Adrenal Source)
  • High ACTH (> 20 pg/mL): Indicates ACTH Dependence (Extra-Adrenal Source)
  • *If Intermediate (5-20 pg/mL): Likely Dependent but Consider CRH Stimulation Test
• #3 Determine ACTH Source if Dependent: High-Dose Dexamethasone Suppression Test
  • Cortisol Suppressed: Indicates a Pituitary Tumor
  • Cortisol Not Suppressed: Indicates an Ectopic ACTH Source
  • *If Indeterminate: Consider Inferior Petrosal Sinus Sampling (IPSS) to Directly Measure Pituitary ACTH Secretion
• Radiographic Localization/Definition:
  • Adrenal Source: CT Adrenal Glands
  • Pituitary Tumor: Pituitary MRI
  • Ectopic ACTH: CT Chest (#1) & CT Abdomen

Treatment

• Exogenous Steroids: Tapered Steroid Withdrawal
  • Abrupt Discontinuation Will Cause Adrenal Insufficiency
• Cushing Disease (Pituitary ACTH Adenoma): Transsphenoidal Resection
  • If Unresectable: Medical Management or Radiation Therapy
• Ectopic ACTH or CRH Secretion: Resect Primary Tumor
  • Options If Unresectable: Medical Management or Bilateral Adrenalectomy
• ACTH-Independent (Adrenal Source): Adrenalectomy
  • *See Endocrine: Adrenalectomy
  • Extent:
    • Adrenal Adenoma: Unilateral Adrenalectomy
    • Adrenal Hyperplasia: Bilateral Adrenalectomy
  • If Unresectable or Not Surgical Candidate: Medical Management

Specific Treatment Considerations

• Medical Management:
  • Adrenal Enzyme Inhibitors (Ketoconazole, Metyrapone or Etomidate)
  • Mitotane (Adrenal Enzyme Inhibitor & Adrenal Lytic)
• Surgical Approach:
  • Laparoscopic Adrenalectomy is Preferred if Able
  • Open (Anterior) Approach if Large > 6-7 cm