First-Line Investigation in Hypercalcemia

Once hypercalcemia is confirmed on a repeat, ideally albumin-corrected (or ionised), calcium measurement, the single most useful initial test to determine its cause is the serum intact parathyroid hormone (iPTH) level. This is because the diagnostic evaluation of hypercalcemia is fundamentally built around separating PTH-dependent causes from PTH-independent causes, and iPTH is the test that makes this distinction.

Why Serum iPTH Is the First Step

• If iPTH is elevated or inappropriately normal in the presence of high calcium, this points to primary hyperparathyroidism (or, less commonly, tertiary hyperparathyroidism / familial hypocalciuric hypercalcemia), which together account for the majority of cases seen in outpatients.
• If iPTH is suppressed (low), this indicates a PTH-independent cause, prompting a search for malignancy (PTHrP-mediated, osteolytic metastases, myeloma), vitamin D excess, granulomatous disease, thyrotoxicosis, immobilization, or milk-alkali syndrome.
• Because this single test bifurcates the entire differential diagnosis, it is universally recommended as the first-line/initial investigation once hypercalcemia is biochemically confirmed.

Why the Other Options Are Not First-Line

• 24-hour urinary calcium excretion: This test is used after PTH-dependent hypercalcemia is suspected, mainly to distinguish primary hyperparathyroidism (high or normal urinary calcium) from familial hypocalciuric hypercalcemia (low urinary calcium, calcium/creatinine clearance ratio <0.01). It is a second-tier test, not the initial one.
• Serum phosphate levels: Phosphate is low in PTH-mediated hypercalcemia and can be a supportive clue, but it lacks the specificity to independently drive the diagnostic pathway and is only interpreted alongside the PTH result, not before it.
• Serum vitamin D levels: Checking 25-hydroxyvitamin D (and 1,25-dihydroxyvitamin D in select cases) is useful when a PTH-independent cause is being worked up (e.g., vitamin D intoxication or granulomatous disease raising 1,25-OH vitamin D), but this comes only after iPTH has been shown to be suppressed. It is not the initial screening test.

Therefore, the correct first investigation of choice in the diagnostic evaluation of hypercalcemia is Serum intact PTH (iPTH) level, as it directs all subsequent testing by classifying the hypercalcemia as PTH-dependent or PTH-independent.