European Journal of Internal Medicine 12 (2001) 344–349 www.elsevier.com / locate / ejim Original article Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements * Jean-Paul Casez, Rahel Pfammatter, Quan-Vinh Nguyen, Kurt Lippuner, Philippe Jaeger Policlinic of Medicine, University Hospital, 3010 Berne, Switzerland Received 20 March 2000; received in revised form 24 October 2000; accepted 31 October 2000 Abstract Background: Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTH-rP) are two potent hypercalcemic hormones that act on the same targets. Autonomous secretion of the former is involved in primary hyperparathyroidism (PHPT), whereas the latter is responsible for humoral hypercalcemia of malignancy (HHM). Methods: From 250 consecutive, hypercalcemic serum samples sent to our laboratory for assessment of intact PTH, we were able to obtain clinical information, as well as an additional plasma sample for PTH-rP measurement, in 134 patients. At the time of sampling, patients could be classified into seven groups: cancer without known bone metastases (CaNoMeta, n 5 36), cancer with bone metastases (CaMeta, n 5 9), no evidence of cancer (noEvCa, n 5 71), sarcoidosis (Sarc, n 5 3), end-stage renal disease (ESRD, n 5 12), vitamin D overdose (VIT-D, n 5 2), and hyperthyroidism (Thyr, n 5 1). Results: In the CaNoMeta group, 29 / 36 patients had elevated PTH-rP levels, 9 / 36 patients had inappropriately elevated PTH levels, and 5 / 36 had elevated levels of both hormones. In the CaMeta group, three of the nine patients had inappropriately elevated PTH levels, two of them with concomitantly elevated PTH-rP levels. In the NoEvCa group, 63 / 71 patients had an inappropriate elevation of PTH levels and were diagnosed as having PHPT. Four of the 71 patients had elevated levels of both PTH and PTH-rP; three of them were in poor health and died within a short period of time. All of the ESRD patients had very high PTH and normal PTH-rP levels, except for one woman with high PTH-rP and undetectable PTH levels; she died from what later turned out to be a recurrent bladder carcinoma. In the Sarc,Vit-D, and Thyr groups, both PTH and PTH-rP levels were normal. Conclusions: (1) Elevated PTH-rP levels are a common finding in cancer patients without bone metastases. Intact PTH, however, should always be measured in hypercalcemic patients with malignancy because concurrent primary hyperparathyroidism is not rare. (2) Primary hyperparathyroidism accounts for hypercalcemia in 90% of patients without evidence of cancer whose PTH-rP levels may also be found to be elevated in a few cases, even some with surgically demonstrated parathyroid adenoma.  2001 Elsevier Science B.V. All rights reserved. Keywords: Parathyroid hormone; Parathyroid hormone-related protein; Hypercalcemia; Malignancy; Primary hyperparathyroidism 1. Introduction failure, chronic renal failure, thiazide diuretics, sarcoidosis or other granulomatous diseases, Milk-alkali syndrome, Hypercalcemia is a frequent finding in clinical practice. Addison’s disease, and Paget’s disease [1]. All of these Its causes are manifold and include primary hyperpara- possible causes must be considered in a given patient thyroidism, malignant disease, hyperthyroidism, immobili- presenting with hypercalcemia. However, in practice, 90% zation, vitamin D and vitamin A overdose, familial hypo- of cases are due either to primary hyperparathyroidism calciuric hypercalcemia, diuretic phase of acute renal (PHPT) or to malignancy [2]. Therefore, the differential diagnosis of these two causes is of paramount importance. The term humoral hypercalcemia of malignancy (HHM) ´ *Corresponding author. Division de Nephrologie, Centre Hospitalier describes patients with certain cancers in whom the blood Universitaire Vaudois, CH-1011 Lausanne, Switzerland. Tel.: 141-21- calcium concentration is elevated in the absence of skeletal 314-1130; fax: 141-21-314-1139. E-mail address: phillippe.jaeger@freesurf.ch (P. Jaeger). metastases [3]. Patients with HHM resemble those with 0953-6205 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0953-6205(01)00124-8