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Cushing Disease and Cushing Syndrome

Basics

  • Definition: Excessive cortisol exposure from exogenous (steroids) or endogenous sources (pituitary, adrenal, ectopic).
  • Cushing disease: Excess ACTH secretion from pituitary adenoma; most common endogenous cause.
  • Systems affected: Endocrine/metabolic, musculoskeletal, skin/exocrine, cardiovascular, neuropsychiatric.
  • Pediatric: Rare; often presents with growth failure and weight gain.
  • Pregnancy: May exacerbate disease.

Epidemiology

  • Incidence: 2 to 8 per million annually (endogenous causes)
  • Prevalence: 10-15 per million
  • Age: 20-50 years most common
  • Female predominance
  • 2-5% prevalence in difficult-to-control diabetic patients with obesity and hypertension

Etiology and Pathophysiology

  • Cortisol from adrenal zona fasciculata; catabolic hormone released under stress
  • Excess cortisol leads to hyperglycemia, insulin resistance, immunosuppression, neurocognitive and bone disorders
  • Causes:
  • Exogenous glucocorticoids (most common)
  • Endogenous ACTH-dependent: pituitary adenoma (Cushing disease), ectopic ACTH tumors
  • ACTH-independent: adrenal tumors
  • Genetic associations: MEN syndrome, McCune-Albright syndrome

Risk Factors

  • Prolonged corticosteroid use

Associated Conditions

  • Psychiatric disorders, diabetes, hypertension, hypokalemia, infections, dyslipidemia, osteoporosis, poor physical fitness

Diagnosis

History

  • Weight gain (95%)
  • Decreased libido (90%)
  • Menstrual irregularity (80%)
  • Depression/emotional lability (50-80%)
  • Easy bruising (95%)
  • Diabetes/glucose intolerance (90%)

Physical Exam

  • Central obesity (95%)
  • Facial plethora (90%)
  • Moon face (90%)
  • Thin skin (85%)
  • Hypertension (75%)
  • Hirsutism (75%)
  • Proximal muscle weakness (90%)
  • Purple striae
  • Supraclavicular fat pads, buffalo hump
  • Acne
  • Growth retardation in children (70-80%)

Differential Diagnosis

  • Obesity
  • Type 2 diabetes mellitus
  • Hypertension
  • Polycystic ovarian disease
  • Pseudo-Cushing syndrome (alcoholism, physical stress, depression)

Diagnostic Tests

  • Screening:
  • Midnight salivary cortisol (2 measurements)
  • 1 mg overnight dexamethasone suppression test
  • 24-hour urinary free cortisol (UFC)
  • Interpretation:
  • Loss of diurnal cortisol rhythm in Cushing syndrome (not in pseudo-Cushing)
  • UFC requires adequate collection; avoid excess fluids
  • Low-dose dexamethasone suppression: cortisol <1.8 µg/dL excludes Cushing (limited specificity)
  • Localization:
  • Morning ACTH:
    • <10 pg/mL → ACTH-independent (adrenal)

    • 20 pg/mL → ACTH-dependent

    • 10-20 pg/mL → CRH stimulation test
  • High-dose dexamethasone suppression: suppression suggests pituitary source
  • Imaging:
  • Pituitary MRI for ACTH-dependent
  • Adrenal CT for ACTH-independent
  • Chest CT or Dotatate PET/CT for ectopic ACTH tumors
  • Octreotide scintigraphy for occult tumors

Treatment

  • Primary: Surgical resection of underlying tumor (transsphenoidal surgery for pituitary adenoma)
  • Medical:
  • Used adjunctively or when surgery contraindicated
  • Metyrapone, ketoconazole, mitotane inhibit adrenal steroidogenesis
  • Etomidate IV for rapid control in severe cases
  • Mifepristone for hyperglycemia control in non-surgical candidates
  • Pasireotide (somatostatin analog) for pituitary tumors; watch for hyperglycemia
  • Osilodrostat (CYP11B1/11B2 inhibitor) effective in cortisol suppression
  • Emerging agents: retinoic acid, silibinin, roscovitine (pituitary tumor-directed)

Ongoing Care

  • Monitor resolution of symptoms over 2-12 months post-treatment
  • Treat residual hypertension, glucose intolerance, osteoporosis
  • Children: monitor bone density and growth
  • Educate on diet, weight monitoring, infection risk, emotional changes

Prognosis

  • Chronic with cyclic exacerbations and rare remission
  • 20% recurrence for adrenal tumors
  • Poor prognosis for ectopic ACTH tumors (e.g., small-cell lung carcinoma)
  • Post-surgical cortisol drop predicts remission
  • Some patients require prolonged steroid replacement therapy

Complications

  • Untreated disease: fatal cardiovascular, thromboembolic, infectious complications

ICD10: - E24.9 Cushing’s syndrome, unspecified - E24.0 Pituitary-dependent Cushing’s disease - E24.2 Drug-induced Cushing’s syndrome

Clinical Pearls: - Cushing disease is caused by pituitary ACTH-secreting tumor - Cushing syndrome results from excess corticosteroids, endogenous or exogenous - Pseudo-Cushing states mimic clinical/lab features but lack true cortisol excess - Characteristic features include facial plethora, moon face, dorsocervical fat pads, purple striae, thin skin, fragility fractures, and muscle weakness