Match each patient's clinical presentation and laboratory evaluation to the most likely un… — USMLE Step 2 CK

Match each patient's clinical presentation and laboratory evaluation to the most likely underlying diagnosis or pathophysiologic mechanism.

A $44$ -year-old woman with weight gain and bruising; evaluation shows elevated $24$ -hour urine free cortisol, plasma ACTH of $3 \text{ pg/mL}$ (normal $10-60 \text{ pg/mL}$ ), and lack of cortisol suppression following an $8\text{-mg}$ overnight dexamethasone test.Autonomous adrenocortical cortisol hypersecretion
A $35$ -year-old woman with amenorrhea and proximal muscle weakness; evaluation shows elevated $24$ -hour urine free cortisol, plasma ACTH of $70 \text{ pg/mL}$ (normal $10-60 \text{ pg/mL}$ ), and $>50\%$ cortisol suppression following an $8\text{-mg}$ overnight dexamethasone test.ACTH-secreting pituitary adenoma
A $65$ -year-old man with a $40$ -pack-year smoking history and severe hypokalemia; evaluation shows markedly elevated $24$ -hour urine free cortisol, plasma ACTH of $450 \text{ pg/mL}$ (normal $10-60 \text{ pg/mL}$ ), and lack of cortisol suppression following an $8\text{-mg}$ overnight dexamethasone test.Paraneoplastic syndrome due to malignancy
A $52$ -year-old woman with rheumatoid arthritis presenting with central obesity, thinning skin, and osteopenia; evaluation shows a morning serum cortisol of $2\ \mu\text{g/dL}$ (normal $5-25\ \mu\text{g/dL}$ ) and plasma ACTH of $<5 \text{ pg/mL}$ (normal $10-60 \text{ pg/mL}$ ).Suppression of the hypothalamic-pituitary-adrenal axis by exogenous agents

Answer

Patient 1 matches autonomous adrenocortical cortisol hypersecretion. Patient 2 matches ACTH-secreting pituitary adenoma. Patient 3 matches paraneoplastic syndrome due to malignancy. Patient 4 matches suppression of the hypothalamic-pituitary-adrenal axis by exogenous agents.

The diagnostic workup for Cushing syndrome follows a rigorous stepwise approach. First, hypercortisolism is confirmed. Next, a plasma ACTH level determines if the cause is ACTH-independent (suppressed ACTH, typically adrenal) or ACTH-dependent (normal to high ACTH, typically pituitary or ectopic). For ACTH-dependent cases, a high-dose dexamethasone suppression test helps distinguish between a pituitary adenoma (which usually suppresses) and ectopic ACTH secretion (which typically does not suppress). Finally, exogenous glucocorticoids mimic Cushing syndrome clinically but suppress the entire HPA axis, resulting in undetectable ACTH and low endogenous cortisol.

Step-by-Step Solution

Analyze the 24-hour urine free cortisol and morning serum cortisol levels to confirm the presence of endogenous hypercortisolism or hypocortisolism.

Patients 1, 2, and 3 have elevated urine free cortisol, confirming endogenous Cushing syndrome. Patient 4 has low morning cortisol despite physical signs of Cushing syndrome.

Establishing endogenous cortisol excess is the necessary first step in the algorithm to rule out physiological or iatrogenic variants.

Evaluate the plasma ACTH level to determine if the hypercortisolism is ACTH-dependent or ACTH-independent.

Patient 1 has suppressed ACTH (ACTH-independent). Patients 2 and 3 have normal/elevated ACTH (ACTH-dependent). Patient 4 has suppressed ACTH in the setting of low endogenous cortisol.

ACTH levels accurately differentiate primary adrenal causes from pituitary or ectopic causes.

Assess the response to the high-dose (8-mg) dexamethasone suppression test for the ACTH-dependent cases.

Patient 2 suppresses >50%, indicating a pituitary source (Cushing disease). Patient 3 does not suppress, indicating an ectopic ACTH source.

Pituitary adenomas generally retain a degree of negative feedback response to high-dose synthetic glucocorticoids, whereas ectopic tumors typically do not.

Key Concept

The diagnostic evaluation of Cushing syndrome relies on establishing hypercortisolism, differentiating ACTH-dependent from ACTH-independent causes via plasma ACTH levels, and utilizing the high-dose dexamethasone suppression test to locate the source of ACTH.

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