Hypercalcaemia: calcium levels, PTH and PTH-related protein could help diagnose the cause.

Clinical bottom line (level 4)

  1. Roughly half of patients with hypercalcaemia had primary parathyroidism and half had a malignancy.
  2. Patients with hypercalcaemia above 3.0 mmol/l were at increased risk of having cancer (LR+3.2) .
  3. Patients with an abnormal PTH have primary hyperparathyroidism. Patients with a normal PTH were much less likely to have it (~5%).
  4. Patients with detectable PTH-related protein in their blood were at increased risk for having cancer (LR+8.7) .
Ratcliffe et al: Lancet 1992; 339: 164-167
Expires October 2004

The study

Setting: acute hospital, geriatric hospital, 118 general practices, UK

121 patients (aged ?, ?% male) corrected calcium > 2.65 mmol/l on two samples (56% inpatients)

Excluded if
  • hypercalcaemia could not be confirmed (death, refusal)



    • Non-independent unblinded reference standard, applied in all patients from a consecutive ?appropriate spectrum.
    Reference standard:
    • clinical diagnosis and results of all investigations
    Diagnostic test:
    • corrected calcium (measured calcium (mmol/l) + 0.02 [40 - albumin (g/l)])
    • parathyroid hormone level (PTH): positive if > 4.0 pmol/l or within reference range (0.9 to 4.0 pmmol/l) that was high in relation to calcium
    • PTH-related protein: positive if any detected

    The evidence


    differential diagnosis number of patients prevalence
    (95% CI)
    primary hyperparathyroidism 56 46%
    (37% to 55%)
    solid malignancy 46 38%
    (29% to 47%)
    haematological malignancy 10 8.3%
    (3.4% to 13%)
    unknown cause 9 7.4%
    (2.8% to 12%)


    diagnostic test malignancy no malignancy LR+
    (95% CI)    		 post-test probability LR-
    (95% CI)    		 post-test probability
    corrected calcium >3.00 25 9 3.2
    (1.7 to 6.3)     		74% 0.64
    (0.50 to 0.83)     		36%
    total 56 63


    diagnostic test primary hyperparathyroidism no primary hyperparathyroidism LR+
    (95% CI)    		 post-test probability LR-
    (95% CI)    		 post-test probability
    abnormal PTH 63 1 58
    (8.3 to 400)     		98% 0.0
    (0.0 to 0.048)     		0%
    total 63 58


    diagnostic test malignancy no malignancy LR+
    (95% CI)    		 post-test probability LR-
    (95% CI)    		 post-test probability
    PTH-related protein detected 45 6 8.7
    (4.0 to 19)     		88% 0.22
    (0.13 to 0.37)     		16%
    total 56 65

    • Seven patients had both primary hyperparathyroidism and a malignancy.

    Comments

    1. PTH-related protein shares sequence homology with PTH and is released by tumours. It may account for hypercalcaemia of malignancy.
    2. The reference standard was not independent or blinded making for bias: consequently the results are probably better than in reality.

    Citation

    1. Ratcliffe WA, Hutchesson AC, Bundred NJ, et al: role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet 1992; 339: 164-167
    Contributor: Chris Ball and Clare Wotton, October 2000
    Reviewer:

    Clinical Question.
    Patient hypercalcaemia
    Intervention or Exposure calcium levels, PTH, PTH-related protein
    Outcome diagnosis of cause