Cushing's Syndrome, basics

Cushing's Syndrome = non-physiologic hypercortisolism from any cause

Pathophysiology

• ACTH-dependent
• Cushing’s disease: (2nd most common!) ACTH secreting pituitary adenoma causing bilateral adrenal hyperplasia
• Ectopic ACTH secretion: associated with malignancy, most commonly SCLC; also neuroendocrine thymic and pancreatic tumors
• Rare: ectopic CRH secretion
• ACTH-independent
• Iatrogenic: (most common!) 2/2 prescribed glucocorticoids - oral, topical, inhaled; also megestrol acetate and ritonavir
• Adrenocortical adenomas and carcinomas: primary adrenal cortisol hypersecretion
• Rare: primary adrenal familial forms, ectopic cortisol secretion

Clinical Presentation  - ROS: positive?

• Appearance: central obesity, moon facies, buffalo hump, striae, hyperpigmentation
• CV: HTN, VTE
• MS: proximal myopathy, osteoporosis
• Heme: easy bruising, immune suppression
• Endo: diabetes, hirsutism and menstrual irregularity in women
• Psych: depression, agitation/irritability, anxiety

Diagnosis

• Dexamethasone suppression test
• Exogenous steroid inhibits endogenous cortisol production via stimulation of negative feedback loop
• Low-dose, 1 mg: initial screening, tests integrity of negative feedback loop
• High-dose, 8 mg: localizes ACTH source
• CRH stimulation test
• Administer IV CRH, assess ACTH/cortisol levels
• Increased ACTH/cortisol levels with pituitary source vs no change with other etiologies
• Inferior petrosal sinus sampling (gold standard)
• Catheterize inferior petrosal veins, measure central:peripheral ATCH gradient after CRH administration
• Increased central:peripheral gradient suggests pituitary source vs no difference with ectopic source
• Serum ACTH, cortisol
• Imaging: pituitary MRI, chest/abd CT

Treatment 

• Iatrogenic: stop offending agent
• Cushing’s disease: transphenoidal surgery
• Other: medical tx (cabergoline, pasireotide), pituitary irradiation
• Ectopic ACTH secretion: remove tumor
• Nonresectable tumors: suppress cortisol synthesis with ketoconazole, metyrapone, etomidate
• Adrenalectomy: medical or surgical
• Primary adrenal disease: adrenalectomy