Cushing Syndrome

Risk factors

• Chronic glucocorticoid therapy (most common overall cause)
• Pituitary adenoma (Cushing disease) — usually microadenoma <10 mm
• Ectopic ACTH — small-cell lung cancer, bronchial carcinoid, medullary thyroid, pheochromocytoma, pancreatic NET
• Adrenal adenoma or carcinoma
• McCune-Albright (somatic GNAS), Carney complex (PRKAR1A)
• Familial: MEN1, FIPA

Pathophysiology

Sustained elevation of cortisol drives gluconeogenesis (insulin resistance), proteolysis (muscle wasting, thin skin, striae), lipolysis with central redistribution (truncal obesity, dorsocervical fat, moon facies), mineralocorticoid receptor activation when excess cortisol overwhelms renal 11-beta-HSD2, most marked in severe hypercortisolism such as ectopic ACTH (hypertension, hypokalemia, metabolic alkalosis with suppressed renin and low aldosterone), suppression of GnRH (hypogonadism), bone resorption (osteoporosis), and immune suppression (infection risk).

Clinical presentation

Differential diagnosis

• Exogenous glucocorticoid use — Most common cause; ask about inhaled, topical, joint injections, herbal/over-the-counter; suppressed ACTH AND cortisol
• Pseudo-Cushing (alcohol, depression, obesity, poorly controlled diabetes) — Mild biochemical hypercortisolism that normalizes after treating the underlying condition; dexamethasone-CRH test or midnight salivary cortisol help distinguish
• Polycystic ovary syndrome — Hirsutism, irregular menses, central obesity — but normal cortisol; ovarian US, free testosterone, DHEAS
• Metabolic syndrome — Central obesity, HTN, dyslipidemia, insulin resistance — no purple striae, proximal myopathy, or biochemical hypercortisolism
• Familial glucocorticoid resistance — Elevated cortisol without Cushingoid features; ACTH elevated; very rare

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Suspicion of Cushing syndrome] --> B[Exclude exogenous steroids first]
  B --> C["Screen: ≥2 of 3 abnormal<br/>• Late-night salivary cortisol<br/>• 24-h urine free cortisol<br/>• 1 mg dex suppression"]
  C --> D{Screens positive?}
  D -->|No| E[Not Cushing syndrome]
  D -->|Yes| F[Measure ACTH]
  F --> G{ACTH suppressed?}
  G -->|Yes| H["ACTH-independent (ACTH <5 pg/mL)<br/>Adrenal CT/MRI"]
  H --> I[Adrenalectomy]
  G -->|No, normal/high| J[ACTH-dependent<br/>Pituitary MRI]
  J --> K{"Adenoma ≥10 mm with<br/>concordant CRH/desmopressin test?"}
  K -->|Yes| M[Cushing disease<br/>Transsphenoidal surgery]
  K -->|No lesion or small lesion| L["Bilateral IPSS<br/>(central:peripheral ACTH gradient)"]
  L -->|Gradient| M
  L -->|No gradient| N["Ectopic ACTH<br/>CT chest/abdomen, Ga-68 DOTATATE PET"]
  N --> O["Identify and resect source<br/>(SCLC, bronchial carcinoid)"]

Treatment

Complications

• Cardiovascular disease, stroke (excess mortality)
• Osteoporosis and fragility fracture
• Diabetes mellitus, hypertension, dyslipidemia
• Hypercoagulability (VTE risk)
• Infection (especially opportunistic if severe immunosuppression)
• Psychiatric: depression, psychosis, suicide
• Post-treatment adrenal insufficiency — lifelong glucocorticoid replacement may be needed; risk of crisis
• Nelson syndrome after bilateral adrenalectomy in Cushing disease

PANCE pearls

• ALWAYS rule out exogenous steroid exposure first — including inhaled, topical, intra-articular, and over-the-counter supplements adulterated with steroids.
• Wide (>1 cm) PURPLE/violaceous striae and proximal myopathy are the most specific clinical features.
• Late-night salivary cortisol is the easiest first screening test; loss of the circadian nadir is highly sensitive.
• Cushing disease (pituitary) suppresses with high-dose dexamethasone; ectopic ACTH does NOT. Bilateral IPSS is the gold standard and the next step when pituitary MRI is negative or equivocal.
• After successful surgery, expect transient secondary adrenal insufficiency — patients require hydrocortisone replacement until HPA axis recovers (months).
• Cyclical Cushing is rare but real — multiple negative tests don't exclude the diagnosis; repeat during symptomatic period.
• Adrenal incidentaloma: every patient gets a 1 mg overnight DST; post-DST cortisol >1.8 mcg/dL without overt Cushing features = mild autonomous cortisol secretion (MACS, ESE/ENSAT 2023) — screen for hypertension and diabetes, confirm ACTH independence and degree of cortisol excess (e.g., 24-h UFC), and individualize surgery. Metanephrines are needed only if the mass is not a lipid-rich adenoma (>10 HU).

References

• Endocrine Society 2008/2015 — Diagnosis of Cushing's Syndrome (Nieman et al., J Clin Endocrinol Metab 2008) and Treatment of Cushing's Syndrome (2015)
• Pituitary Society 2021 — Consensus on Diagnosis and Management of Cushing's Disease (Fleseriu et al., Lancet Diabetes Endocrinol 2021)
• ESE/ENS@T 2018 — European Society of Endocrinology Clinical Practice Guideline on Adrenocortical Carcinoma (Fassnacht et al., Eur J Endocrinol 2018)
• ESE/ENSAT 2023 — European Society of Endocrinology Clinical Practice Guidelines on the Management of Adrenal Incidentalomas, in collaboration with ENSAT (Fassnacht M et al., Eur J Endocrinol 2023;189(1):G1-G42)