Hypercalcemia: read the whole pattern

Visual summary

Six common hypercalcemia mechanisms compared across calcium, phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, PTH and PTHrP, with caveats for kidney dysfunction and normal ALP in myeloma. — · Download PNG · Download Markdown · Read text and evidence
Ca, phosphate, alkaline phosphatase, both vitamin D metabolites, PTH and PTHrP.

Teaching text

Start with PTH in the context of calcium

A PTH inside its reference interval is not necessarily appropriate: high calcium should suppress it. A clearly suppressed PTH directs the workup toward PTH-independent causes. Use the assay and clinical context rather than a universal cutoff.

The vitamin D tests answer different questions

25-hydroxyvitamin D reflects stores and exposure. 1,25-dihydroxyvitamin D is the active hormone; an elevated value with suppressed PTH can suggest extrarenal production. A low 25-hydroxy level does not exclude calcitriol-driven hypercalcemia.

Phosphate and alkaline phosphatase are supporting clues

AKI and CKD can raise phosphate and blur a typical phosphaturic pattern. Total alkaline phosphatase includes liver and bone sources; normal ALP does not exclude myeloma or lytic bone disease. These tests help interpret a mechanism but cannot identify one alone.

The table is a pattern guide, not an order set

Not every patient needs all seven tests at once. Confirm calcium, assess symptoms and volume, interpret PTH, then choose PTHrP, vitamin D metabolites and monoclonal-protein testing as indicated. Mixed mechanisms and drug exposures can coexist.

Additional causes remain part of the differential

Thiazides can unmask primary hyperparathyroidism; lithium can shift calcium sensing. Vitamin A excess, immobilization, thyrotoxicosis, adrenal insufficiency and pediatric syndromes require the appropriate history and targeted tests. None has a single obligatory seven-test signature.

Typical patterns, not diagnostic requirements. N = the laboratory reference interval; ↑ = increased; ↓ = decreased.
Mechanism	Ca	PO₄	Alk Phos	1,25(OH)₂D	25(OH)D	PTH	PTHrP	Interpretation
Primary hyperparathyroidism	↑	↓ or N	N or ↑	N or ↑	Variable	↑ or inappropriately N	Not elevated	PTH should be suppressed by high calcium; check urine calcium in the appropriate setting.
PTHrP-mediated malignancy	↑	↓ or N	Variable	↓ or N	Variable	↓	↑	PTHrP mimics some PTH effects. An abnormal SPEP is not required.
Calcitriol-mediated disease	↑	N or ↑	Variable	↑	N or ↓	↓	Usually not elevated	Consider lymphoma or granulomatous disease; the lab pattern does not identify which.
Vitamin D₂/D₃ excess	↑	N or ↑	N or ↓	N or ↑	Markedly ↑	↓	Not elevated	Excess nutritional vitamin D raises 25(OH)D; active-vitamin-D medications are a different exposure.
Osteolytic malignancy / myeloma	↑	Variable	Variable; often N in myeloma	↓ or N	Variable	↓	Usually not elevated	ALP can remain normal despite lytic lesions; evaluate monoclonal protein when indicated.
Calcium–alkali syndrome	↑	↓ or N; affected by kidney function/intake	Usually N	↓ or N	Variable	↓	Not elevated	Calcium/alkali exposure, alkalosis and AKI; medication history matters.
Tertiary hyperparathyroidism	↑	Often ↑ in advanced CKD; may fall after transplant	Variable	Variable; often low in advanced CKD	Variable	Markedly ↑	Not elevated	Longstanding secondary HPT becomes autonomous; CKD alone does not prove this diagnosis.
Familial hypocalciuric hypercalcemia	Usually mildly ↑	N or ↓	Usually N	Variable	Variable	N or mildly ↑	Not elevated	Lifelong/familial pattern and relative hypocalciuria; CKD, low vitamin D and thiazides confound urine calcium.

Continue learning

Read the connected teaching · Summary-day capstone · Bring the lecture to the bedside