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Updated: Feb 19 2023

Cushing Syndrome / Disease

  • Snapshot
    • A 61-year-old obese man with well-controlled hypertension on a diuretic, hyperlipidemia, diabetes and current smoker (35 pack-year history) presents to his primary care physician for fatigue. He also notes that he has been having increasing cough, shortness of breath, and poor appetite. On evaluation, he is found to be hypertensive reaching 190/110 mmHg and noted to have facial flushing, purple abdominal striae, and a buffalo hump.
  • Introduction
    • Clinical definition
      • a condition that refers to the manifestations of chronic hypercortisolism
      • 2 broad categories
        • exogenous
          • iatrogenic exogenous glucocorticoid administration (reviewed separately)
        • endogenous
          • pituitary adrenocorticotropic hormone (ACTH) overproduction (Cushing disease)
          • adrenal glucocorticoid overproduction
          • ectopic ACTH overproduction
    • Associated conditions
      • multiple endocrine neoplasia type 1 (ACTH-secreting pituitary adenoma, though most are prolactin-secreting adenomas)
  • Epidemiology
    • Demographics
      • 5:1 female-to-male ratio for adrenal or pituitary source
        • peak age 25-50 years of age
      • male predominance for ectopic source secondary to lung cancer
        • peak age 70-80 years of age
  • Etiology
    • ACTH-dependent (ACTH is elevated)
      • etiologies
        • pituitary overproduction:
          • ACTH-secreting tumor (usually an adenoma)
        • ectopic production:
          • ACTH-secreting malignancy of a neuroendocrine origin such as small-cell lung cancer
    • ACTH-independent (ACTH is normal or low)
      • cortisol overproduction --> negative feedback --> lowers ACTH --> atrophy of normal adrenal tissue
      • etiologies
        • exogenous intake (usually patients prescribed systemic glucocorticoids for inflammatory conditions)
          • most common cause of Cushing's syndrome
          • may cause bilateral adrenal atrophy
        • adrenal overproduction (by adrenal adenoma, carcinoma or nodular hyperplasia)
          • may cause atrophy of the contralateral adrenal gland (imaging may show one adrenal gland enlarged by a tumor and one atrophied adrenal gland)
  • Presentation
    • Symptoms
      • depression and psychological changes
      • oligomenorrhea
      • decreased libido
      • proximal muscle weakness
      • acne
      • excessive hair growth
      • symptoms of diabetes (polydipsia and polyuria)
      • weight gain
    • Physical exam
      • hypertension
      • central obesity
      • muscle wasting
      • thin skin that easily bruises
      • purple striae
      • hirsutism
      • moon facies
      • buffalo hump
      • hyperpigmentation if high ACTH
  • imaging
    • Adrenal computed tomography (CT) scan or magnetic resonance imaging (MRI)
      • evaluate for adrenal tumor as possible etiology of low ACTH Cushing syndrome
    • Chest and/or abdominal CT
      • evaluate for ectopic ACTH-producing tumor
  • Studies
    • Diagnostic testing
      • diagnostic approach
        • medication review to rule out exogenous etiology
        • initial screening tests are very sensitive
          • if normal, rules out the diagnosis
          • if abnormal, does not determine etiology of Cushing
        • to determine etiology, follow up with ACTH level, high-dose dexamethasone suppression, corticotropin-releasing hormone (CRH) stimulation, and imaging
        • ancillary lab studies to evaluate for associated imbalances
      • studies
        • overnight low-dose dexamethasone suppression test
          • initial screening
          • very sensitive
        • cortisol (initial screening)
          • 24-hour urinary free cortisol (more sensitive, but logistically difficult to collect)
          • serum morning cortisol level (more convenient)
        • serum morning ACTH-level
        • high-dose dexamethasone suppression test
          • performed after the diagnosis of Cushing syndrome is made, to distinguish between pituitary (Cushing disease) and non-pituitary causes
          • determines if pituitary or ectopic
        • corticotropin-releasing hormone (CRH) stimulation test
          • determines if pituitary or ectopic
        • ancillary
          • chemistry panel
            • associated metabolic alkalosis, hypokalemia, and hyperglycemia
          • lipid panel
            • associated hyperlipidemia
          • complete blood count
            • associated leukocytosis
        • chemistries
          • hypokalemia and metabolic alkalosis from mineralocorticoid activity
  • Differential
    • Pseudo-Cushing syndrome
      • distinguishing factor
        • hypercortisolemia is secondary to other factors and when resolved, Cushingoid features resolve as well
        • examples include obesity, polycystic ovarian syndrome, diabetes, and chronic alcoholism
    • Diagnostic criteria
      • overnight low-dose dexamethasone suppression test
        • if serum cortisol is < 5 ug/dL, Cushing can be excluded
        • if serum cortisol is > 5 ug/dL, Cushing is diagnosed
      • 24-hour urinary free cortisol
        • greater than 3x the normal value is consistent with diagnosis
      • ACTH level
        • ↓ serum ACTH ( < 5 pg/mL) is consistent with iatrogenic Cushing and adrenal Cushing
        • ↑ serum ACTH (< 5 pg/mL) is consistent with pituitary or ectopic Cushing
      • high-dose dexamethasone suppression test
        • > 50% suppression is consistent with pituitary Cushing disease
        • < 50% suppression is consistent with ectopic Cushing
      • corticotropin-releasing hormone (CRH) stimulation test
        • ↑ ACTH and cortisol is consistent with pituitary Cushing disease
        • no response is consistent with ectopic Cushing
      • imaging
        • identified adrenal, chest, or abdominal neoplasm
  • Treatment
    • Management approach
      • resectable lesions
        • localize lesion with subsequent resection
        • may require temporary postoperative glucocorticoid replacement for HPA axis suppression from chronic hypercortisolemia
      • nonresectable lesions
        • ketoconazole and metyrapone
          • blocks cortisol production
        • mifepristone
          • blocks the cortisol receptor
        • pasireotide or cabergoline
          • somatostatin analog
    • Pituitary Cushing
      • transsphenoidal adenomectomy of the pituitary
      • may require replacement of other lost functions
    • Adrenal Cushing
      • adrenalectomy
        • if bilateral, requires lifelong glucocorticoid and mineralocorticoid replacement
    • Ectopic Cushing
      • treat the underlying neuroendocrine tumor, may consist of surgical resection, chemotherapy, radiation, and other targeted therapies
    • Hypertension
      • eplerenone and spironolactone (potassium sparing diuretics)
  • Complications
    • Panhypopituitarism, if large pituitary adenoma
    • Adrenal insufficiency, if bilateral adenectomy is performed
    • Nelson syndrome, if bilateral adenectomy is performed
    • Death, if a malignant lesion
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