Cushings syndrome
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Cushing's Syndrome
Definition
Cushing's syndrome is the clinical state resulting from chronic exposure to excess glucocorticoids, regardless of the source. When hypercortisolism is specifically caused by an ACTH-secreting pituitary adenoma, it is termed Cushing's disease - a subset of Cushing's syndrome.
- Campbell Walsh Wein Urology, p. 3134
Pathophysiology & The HPA Axis
The zona fasciculata of the adrenal cortex secretes ~20 mg of cortisol daily under regulation of the hypothalamic-pituitary-adrenal (HPA) axis:
- Hypothalamus releases CRH (corticotropin-releasing hormone)
- Anterior pituitary secretes ACTH (from POMC cleavage)
- Adrenal cortex produces cortisol
- Cortisol completes a negative feedback loop by suppressing CRH and ACTH
Cortisol secretion follows a circadian rhythm - peak in the morning, nadir around 11 PM. Even small disruptions in this rhythm are considered pathological.
Etiology & Classification
| Type | Cause | % of Endogenous Cases |
|---|---|---|
| Exogenous | Iatrogenic glucocorticoid use (oral, topical, inhaled) | Most common overall |
| Cushing's Disease (ACTH-dependent) | Pituitary corticotroph adenoma | ~68-70% of endogenous |
| Ectopic ACTH syndrome (ACTH-dependent) | Non-pituitary tumors (small cell lung CA, carcinoid, etc.) | ~10-12% |
| Adrenal adenoma (ACTH-independent) | Autonomous cortisol secretion | ~10% |
| Adrenal carcinoma (ACTH-independent) | Autonomous cortisol secretion | ~8% |
| AIMAH / PPNAD | Bilateral adrenal hyperplasia | Rare |
ACTH-dependent causes account for 80-85% of endogenous Cushing's syndrome.
- Campbell Walsh Wein Urology, p. 3135-3136
- Henry's Clinical Diagnosis and Management, p. 1806
Key features of ectopic ACTH syndrome (vs. pituitary Cushing's disease):
- More rapid onset
- Greater proximal limb weakness, skin pigmentation, hypokalemia, hypertension, and glycosuria
- Plasma ACTH usually >20 pg/mL (at times >50 pg/mL)
- Not suppressed by dexamethasone
Clinical Features
Classic features described by Harvey Cushing (1932):
Metabolic/Body Composition:
- Central (truncal) obesity - "buffalo hump," supraclavicular fat pads
- Moon face (facial plethora)
- Weight gain with thin extremities
Skin:
- Purple/violaceous striae over abdomen and extremities
- Skin fragility, easy bruising
- Acne, hirsutism
- Hyperpigmentation (especially in ectopic ACTH - due to high ACTH stimulating melanocyte receptors)
Musculoskeletal:
- Proximal muscle weakness (myopathy) - can be the presenting complaint to neurologists
- Osteoporosis, pathological fractures, kyphosis
Cardiovascular/Metabolic:
- Hypertension
- Hyperglycemia / diabetes mellitus
- Hypokalemia (especially ectopic ACTH)
- Dyslipidemia
Endocrine/Reproductive:
- Amenorrhea, impotence
- Growth retardation in children
Neuropsychiatric:
- Depression, anxiety, cognitive dysfunction
- Rarely psychosis
Diagnosis
Diagnosis proceeds in two phases: (1) confirm hypercortisolism, then (2) determine the cause.
Phase 1 - Screening Tests (any one of three)
| Test | Principle | Notes |
|---|---|---|
| 24-hour urinary free cortisol (UFC) | Measures unbound cortisol filtered by glomerulus; integrated over 24 hrs | Upper normal ~110-138 nmol/24h (40-50 µg/day); values >4x ULN are diagnostic. May be falsely normal in ~10-15% of cases; unreliable in GFR <30 mL/min |
| Overnight low-dose dexamethasone suppression test (LD-DST) | 1 mg dexamethasone at midnight; cortisol measured at 8 AM. Failure to suppress = Cushing's | Dexamethasone corresponds to 3-4x physiologic glucocorticoid; not detected by cortisol assay |
| Late-night salivary cortisol (LNSC) | Takes advantage of loss of diurnal rhythm - cortisol fails to suppress at night even in mild Cushing's | Practical for outpatient use; 2 separate collections recommended |
- Henry's Clinical Diagnosis and Management, p. 1811-1814
- Campbell Walsh Wein Urology, p. 3137-3138
Phase 2 - Localizing the Cause
Once hypercortisolism is confirmed:
- Plasma ACTH level
- ACTH suppressed (undetectable/low) → ACTH-independent (adrenal cause) → proceed to adrenal imaging (CT)
- ACTH elevated/normal → ACTH-dependent → proceed to pituitary MRI
- High-dose dexamethasone suppression test (8 mg)
- Suppresses urinary cortisol by ≥90% → Cushing's disease (pituitary)
- No suppression → ectopic ACTH or adrenal source
-
CRH stimulation test - helps distinguish pituitary from ectopic ACTH
-
Inferior petrosal sinus sampling (IPSS) - gold standard for distinguishing pituitary Cushing's disease from ectopic ACTH when imaging is equivocal
-
Imaging: MRI pituitary (most adenomas are microadenomas <1 cm); CT/MRI abdomen for adrenal; whole-body imaging for ectopic source
Treatment
Treatment is dictated by the underlying cause.
Cushing's Disease (Pituitary Adenoma)
- First-line: Transsphenoidal pituitary microsurgery - curative in ~70-90% of microadenomas
- If surgery fails: repeat surgery, stereotactic radiosurgery, or bilateral adrenalectomy
- Nelson syndrome (progressive pituitary tumor growth after bilateral adrenalectomy) occurs in 8-29% of cases - prophylactic radiotherapy is controversial
Ectopic ACTH Syndrome
- Resect the primary tumor - possible in only ~10% of patients
- For unresectable tumors: bilateral adrenalectomy with lifelong steroid replacement
- Up to 35% of cases have no identifiable primary tumor
ACTH-Independent (Adrenal) Cushing's
- Unilateral adrenalectomy for solitary adenoma/carcinoma
- Bilateral adrenalectomy for AIMAH and PPNAD with lifelong replacement
Medical Therapy (bridge to surgery or when surgery not possible)
Steroidogenesis inhibitors:
- Metyrapone - most commonly used
- Ketoconazole
- Aminoglutethimide
- Etomidate (IV, for severe/urgent cases)
- Mitotane (adrenolytic - primarily for adrenal carcinoma)
- Mifepristone (glucocorticoid receptor antagonist)
Exogenous Cushing's
- Taper and discontinue glucocorticoid therapy when clinically possible
- Adrenal insufficiency during taper must be anticipated
Key Distinguishing Points
| Feature | Cushing's Disease | Ectopic ACTH | Adrenal Tumor |
|---|---|---|---|
| ACTH level | Elevated | Very elevated | Suppressed (low) |
| Dexamethasone suppression | Partial (high-dose) | No suppression | No suppression |
| Pigmentation | Mild | Pronounced | Absent |
| Hypokalemia | Mild | Severe | Absent/mild |
| Onset | Gradual | Rapid | Variable |
Pseudo-Cushing's Syndrome
A condition of HPA axis overactivity without true Cushing's syndrome. Seen in:
- Major depression
- Alcoholism
- Poorly controlled diabetes
- Morbid obesity
- Anxiety disorders
Mild UFC elevation can occur; distinguished by CRH + dexamethasone testing (Liddle test).
- Henry's Clinical Diagnosis and Management, p. 1814
Sources: Campbell Walsh Wein Urology (3-Volume Set), Adams and Victor's Principles of Neurology, 12th ed., Henry's Clinical Diagnosis and Management by Laboratory Methods, Tietz Textbook of Laboratory Medicine, 7th ed.
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