Match each clinical presentation of hypercalcemia and its associated laboratory profile wi… — USMLE Step 2 CK

Match each clinical presentation of hypercalcemia and its associated laboratory profile with the most likely underlying pathophysiologic mechanism.

A $35$ -year-old asymptomatic woman has a serum calcium of $11.2$ mg/dL, intact PTH of $75$ pg/mL (normal: $10$ - $65$ pg/mL), and $24$ -hour urine calcium of $45$ mg/day (normal: $100$ - $300$ mg/day).Inactivating mutation of the calcium-sensing receptor in the parathyroid glands and kidneys
A $55$ -year-old man with recurrent nephrolithiasis has a serum calcium of $11.5$ mg/dL, intact PTH of $82$ pg/mL, and $24$ -hour urine calcium of $350$ mg/day.Autonomous parathyroid hormone secretion from a monoclonal proliferation of chief cells
A $65$ -year-old man with a $40$ -pack-year smoking history and a central lung mass has a serum calcium of $13.2$ mg/dL, phosphorus of $2.1$ mg/dL, and intact PTH of $8$ pg/mL.Ectopic production of a peptide that activates the PTH-1 receptor
A $42$ -year-old woman with chronic cough and bilateral hilar lymphadenopathy has a serum calcium of $11.8$ mg/dL, intact PTH of $12$ pg/mL, and significantly elevated $1,25$ -dihydroxyvitamin D levels.Unregulated extrarenal $1$ -alpha-hydroxylase activity by activated tissue macrophages

Answer

The 35-year-old with low urine calcium has Familial Hypocalciuric Hypercalcemia (FHH). The 55-year-old with high urine calcium has primary hyperparathyroidism. The 65-year-old with a lung mass has humoral hypercalcemia of malignancy. The 42-year-old with hilar lymphadenopathy has sarcoidosis-induced hypercalcemia.

Correctly matching these presentations requires a systematic approach to hypercalcemia. PTH is elevated in primary hyperparathyroidism (adenoma) and FHH (CaSR mutation), separated by high versus low urine calcium, respectively. PTH is suppressed in malignancy (ectopic PTHrP) and granulomatous disease (macrophage 1-alpha-hydroxylase).

Step-by-Step Solution

Evaluate the intact parathyroid hormone (PTH) level in each patient relative to the serum calcium.

Patients 1 and 2 have PTH-dependent hypercalcemia (PTH is inappropriately normal or elevated). Patients 3 and 4 have PTH-independent hypercalcemia (PTH is appropriately suppressed <20 pg/mL).

Categorizing hypercalcemia into PTH-dependent and PTH-independent is the essential first branch point in the diagnostic algorithm.

Analyze the 24-hour urine calcium in the two patients with PTH-dependent hypercalcemia.

Patient 1 has hypocalciuria (consistent with an inactivating CaSR mutation/FHH). Patient 2 has hypercalciuria (consistent with autonomous parathyroid adenoma).

Primary hyperparathyroidism and FHH can present with identical serum calcium and PTH profiles. Urine calcium distinguishes them.

Differentiate the underlying mechanisms for the two patients with PTH-independent hypercalcemia using clinical context and additional markers.

Patient 3's lung mass and suppressed PTH suggest ectopic PTHrP production. Patient 4's hilar lymphadenopathy and elevated 1,25-dihydroxyvitamin D suggest macrophage-mediated 1-alpha-hydroxylase activity in sarcoidosis.

Identifying the specific non-parathyroid mediator of hypercalcemia clarifies the underlying systemic disease or malignancy.

Key Concept

The diagnostic evaluation of hypercalcemia relies on analyzing intact PTH levels followed by ancillary tests (24-hour urine calcium, PTHrP, 1,25-vitamin D) to identify the precise pathophysiologic mechanism.

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