Hypercalcaemia Cause Interpreter: PTH, FHH, PTHrP & Vitamin D
Hypercalcaemia Cause Interpreter: PTH, FHH, PTHrP & Vitamin D
Find the cause of a high calcium. Read the PTH taken with it against your own reference interval — suppressed, inappropriately normal or raised — to split PTH-dependent from PTH-independent hypercalcaemia. Then ask the familial hypocalciuric hypercalcaemia (FHH) question with the calcium:creatinine clearance ratio, or work through PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and a myeloma screen.
Why is the calcium high?
PTH against your interval, CCCR, PTHrP, vitamin D, myeloma → causeA 44-year-old woman with a calcium of 2.72 mmol/L, stable for years. PTH 6.1 pmol/L (interval 1.6–6.9). CCCR 0.006. Kidney function normal, no lithium or thiazide.
The order
2. PTH in the same sample, against your interval: below the lower limit → PTH-independent; at or above it → PTH-dependent
3. PTH-dependent: kidney function, lithium and thiazides, then calcium:creatinine clearance ratio — below 0.01 favours FHH; 0.01–0.02 overlap; above 0.02 FHH less likely
4. PTH-independent: PTHrP, myeloma screen, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D
- CCCR
- (24-h urine calcium × serum creatinine) ÷ (serum calcium × 24-h urine creatinine), all in the same units
- inappropriately normal
- a PTH inside the reference interval when calcium is high; normal parathyroids would have switched off
Worked example
A 44-year-old woman with a calcium of 2.72 mmol/L, stable for years. PTH 6.1 pmol/L (interval 1.6–6.9). CCCR 0.006. Kidney function normal, no lithium or thiazide.
Calcium confirmed high → PTH 6.1 is inside 1.6–6.9 → inappropriately normal → PTH-dependent
No kidney disease, lithium or thiazide
CCCR 0.006 is below 0.01 → favours FHH
CASR genetic testing and family screening before any referral for parathyroidectomy
Reading the PTH when the calcium is high
| PTH against your interval | Meaning | Next step |
|---|---|---|
| Below the lower limit (suppressed) | Parathyroids responding normally; something else drives the calcium | PTHrP, myeloma screen, 1,25- and 25-hydroxyvitamin D |
| Within the interval (inappropriately normal) | PTH-dependent: normal glands would have switched off | CCCR for FHH; vitamin D; surgery criteria |
| Above the upper limit (raised) | PTH-dependent | As above; also consider CKD (tertiary) and lithium |
The calcium:creatinine clearance ratio
| Ratio | Reading | Source |
|---|---|---|
| Below 0.01 | Favours FHH — found in 70–80% of people with FHH | Fifth International Workshop, 2022 |
| 0.01 to 0.02 | Overlap — about 40% of patients with either disease | Fifth International Workshop, 2022 |
| 0.020 or below | Genetic testing for FHH proposed | Christensen 2008 |
| Above 0.02 | FHH less likely | Above the overlap zone; not a confirmatory threshold |
Suppressed or not suppressed is the only question the PTH has to answer
Calcium regulates PTH through the calcium-sensing receptor on the parathyroid cells: when calcium rises, PTH secretion falls. So in a patient with hypercalcaemia the normal response is a suppressed PTH, and that makes the PTH result the single most useful test. The clinically meaningful split is not normal against abnormal but suppressed against not suppressed. A PTH inside the reference interval is not reassuring when the calcium is high — it is inappropriately normal, because healthy glands would have switched off — and the Fifth International Workshop notes that PTH is often within the interval in primary hyperparathyroidism. That is why the page reads your PTH against your own interval rather than a fixed number: assays and intervals differ by manufacturer and by unit (see the PTH unit converter).
When PTH is not suppressed, primary hyperparathyroidism is by far the commonest cause, but one condition must be excluded before anyone operates: familial hypocalciuric hypercalcaemia. FHH resets the calcium-sensing receptor so that a higher calcium is read as normal, and the kidney retains calcium accordingly. Parathyroidectomy does not help. The calcium:creatinine clearance ratio is the screening test: below 0.01 favours FHH, but about 40% of patients with either disease fall between 0.01 and 0.02, and 0.02 is the top of that overlap zone rather than a line that confirms primary hyperparathyroidism. Genetic testing settles it. Thiazides and lithium lower urinary calcium and can mimic FHH, and advanced kidney disease makes the ratio meaningless.
When PTH is suppressed, the cause is elsewhere. In hospital that is most often cancer, through PTHrP or through bone destruction; then myeloma, calcitriol made by granulomas or lymphoma, and vitamin D taken in excess. The page works through those four and lists the rarer causes when all four are negative.
How high the calcium is, and how urgently to treat it, is a separate question answered by the hypercalcaemia severity classifier. When primary hyperparathyroidism is the answer, the primary hyperparathyroidism surgery criteria interpreter applies the 2022 surgical criteria. This page supports clinical judgement and does not replace it.
Frequently asked questions
Why is a normal PTH abnormal in hypercalcaemia?
Because a high calcium should switch the parathyroids off. A PTH inside the reference interval when calcium is high is inappropriately normal and means PTH-dependent hypercalcaemia, usually primary hyperparathyroidism or FHH.
What calcium:creatinine clearance ratio suggests FHH?
Below 0.01, which the Fifth International Workshop says is present in 70 to 80% of people with FHH. Between 0.01 and 0.02 the two diseases overlap, and genetic testing decides.
What causes hypercalcaemia with a suppressed PTH?
Most often malignancy, through PTHrP or bone destruction. Then myeloma, calcitriol from granulomatous disease or lymphoma, vitamin D excess, thyrotoxicosis, immobilisation, vitamin A excess and milk-alkali syndrome.
Can thiazides or lithium mimic FHH?
Yes. Both lower urinary calcium and so lower the clearance ratio. Lithium also raises the calcium level at which PTH switches off. Stop them if it is safe and retest.
Related calculators
References
- Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and management of primary hyperparathyroidism: summary statement and guidelines from the Fifth International Workshop. J Bone Miner Res. 2022;37(11):2293–2314.
- Goltzman D. Approach to hypercalcemia. In: Endotext. MDText.com; NCBI Bookshelf NBK279129. Updated March 2026.
- Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf). 2008;69(5):713–720.
Medical Disclaimer: The tools and content provided here are for educational and reference purposes only. They are not intended to substitute for professional medical advice, diagnosis, or treatment. Clinical decisions should always be based on the comprehensive assessment of a qualified healthcare professional.