13.3 Cushing's Syndrome: Aetiology, Screening & Localisation

The adrenal gland comprises an outer mesodermal cortex (zona glomerulosa producing mineralocorticoids, zona fasciculata producing glucocorticoids, and zona reticularis producing androgens) and an inner neural crest-derived medulla (chromaffin cells producing catecholamines). Understanding adrenal physiology, diagnostic suppression/stimulation testing, and hypertensive endocrinopathies is essential for MRCP(UK) Part 1.

---

1. Cushing's Syndrome: Etiology, Screening & Localization

Classification & Pathophysiology

Cushing's syndrome describes the constellation of clinical features caused by prolonged, inappropriate systemic glucocorticoid excess:

• Exogenous Glucocorticoids: By far the most prevalent cause overall. Characterized by bilateral adrenocortical atrophy, suppressed endogenous ACTH, and undetectable baseline cortisol.
• Endogenous ACTH-Dependent (~80% of endogenous cases):
  • Cushing's Disease (~70%): ACTH-secreting pituitary adenoma (predominantly microadenomas $< 10\text{ mm}$). More common in females (4:1 female-to-male ratio).
  • Ectopic ACTH Secretion (~10%): Non-pituitary neuroendocrine tumors. Most commonly small cell lung carcinoma (SCLC, ~50%), bronchial carcinoid ($~10\text{–}15%$), pancreatic neuroendocrine tumors, thymic tumors, or medullary thyroid carcinoma. Ectopic ACTH often presents rapidly with severe hypokalaemic metabolic alkalosis, profound proximal muscle wasting, hyperpigmentation, and cachexia, rather than classical centripetal obesity.
  • Ectopic CRH Secretion ($< 1%$): Extremely rare.
• Endogenous ACTH-Independent (~20% of endogenous cases):
  • Adrenocortical Adenoma (~10–15%): Autonomous cortisol secretion from a unilateral benign adrenal tumor with contralateral cortical atrophy.
  • Adrenocortical Carcinoma (~5%): Highly aggressive malignant tumor, frequently co-secreting androgens (manifesting as rapid virilization, hirsutism, and severe abdominal mass effects).
  • Primary Pigmented Nodular Adrenocortical Disease (PPNAD / Carney Complex) and Bilateral Macronodular Adrenal Hyperplasia (BMAH).

Clinical Features

Cardinal clinical signs with the highest discriminatory diagnostic value include proximal myopathy (severe muscle wasting, inability to climb stairs or stand from a squatting position), wide purple/violaceous striae ($> 1\text{ cm}$ width on abdomen, flanks, or breasts), facial plethoric mooning, dorsocervical fat pad ('buffalo hump'), supraclavicular fat pads, thin fragile skin with spontaneous ecchymoses/easy bruising, impaired wound healing, osteopenia/vertebral collapse, neuropsychiatric disturbances (depression, emotional lability, psychosis), systemic hypertension, and secondary type 2 diabetes.

Tiered Diagnostic Strategy

Establishing a diagnosis requires three sequential steps: (1) Confirm hypercortisolism, (2) Determine ACTH dependency, and (3) Localize the anatomical source.

Step 1: Confirming Glucocorticoid Excess (Screening)

At least two concordant positive screening tests are required to confirm Cushing's syndrome:

1. Overnight 1 mg Dexamethasone Suppression Test (ONDST): 1 mg dexamethasone orally at 23:00; serum cortisol measured at 08:00–09:00 the following morning. Diagnostic cut-off: Failure to suppress serum cortisol to $< 50\text{ nmol/L}$ ($< 1.8\text{ mcg/dL}$) indicates autonomous cortisol production. (False positives occur with CYP3A4 inducers [phenytoin, carbamazepine, rifampicin], high oestrogen/pregnancy elevating cortisol-binding globulin, severe depression, obesity, and alcohol excess [pseudo-Cushing's]).
2. 24-Hour Urinary Free Cortisol (UFC): Measures unbound cortisol filtered by the glomeruli over 24 hours. Requires at least 2–3 collections; levels $> 3 \times$ the upper reference limit confirm hypercortisolism.
3. Late-Night Salivary Cortisol: Saliva collected at 23:00–24:00 using a cotton swab. Loss of the normal midnight physiological nadir is highly sensitive ($> 95%$).

Step 2: Differentiating ACTH Dependency

Morning plasma ACTH (measured on ice at 09:00):

• Plasma ACTH $< 10\text{ pg/mL}$ ($< 2\text{ pmol/L}$): ACTH-Independent. Autonomous adrenal secretion suppresses pituitary corticotrophs. Next step: High-resolution adrenal CT or MRI to identify an adrenal adenoma, carcinoma, or bilateral nodular hyperplasia.
• Plasma ACTH $\ge 20\text{ pg/mL}$ ($> 4.4\text{ pmol/L}$) (or inappropriately normal in the presence of hypercortisolism): ACTH-Dependent. Indicates either a pituitary corticotroph adenoma or ectopic ACTH secretion.

Step 3: Localizing ACTH-Dependent Sources

Distinguishing a pituitary adenoma from an ectopic neuroendocrine tumor:

• High-Dose Dexamethasone Suppression Test (HDDST): 8 mg dexamethasone orally overnight (or 2 mg 6-hourly for 48 hours). Pituitary adenomas retain partial negative feedback: serum cortisol suppresses by $> 50%$ of baseline. Ectopic ACTH tumors are fully autonomous: serum cortisol fails to suppress ($< 50%$ suppression).
• Corticotropin-Releasing Hormone (CRH) Test: 100 mcg IV human or ovine CRH. Pituitary adenomas express CRH receptors and respond with an exaggerated rise in ACTH ($> 50%$) and cortisol ($> 20%$). Ectopic tumors lack functional CRH receptors and show no biochemical response.
• Inferior Petrosal Sinus Sampling (IPSS): The gold standard diagnostic investigation for ACTH-dependent Cushing's when pituitary MRI is negative, indeterminate, or shows a microadenoma $< 6\text{ mm}$. Bilateral microcatheters sample ACTH simultaneously from the inferior petrosal sinuses (draining the pituitary) and a peripheral vein, before and after peripheral CRH administration:
  • Central-to-Peripheral ACTH Ratio: Baseline ratio $> 2.0$, or post-CRH peak ratio $> 3.0$, unequivocally confirms a pituitary source (Cushing's disease).
  • Ratio $< 2.0$ at baseline and $< 3.0$ post-CRH indicates ectopic ACTH secretion, directing whole-body thoracic/abdominal CT, gallium-68 DOTATATE PET-CT, or octreoscan imaging.

---