Pro-FHH: A Risk Equation to Facilitate the Diagnosis of Parathyroid-Related Hypercalcemia

Context: Parathyroid-related hypercalcemia is due to primary hyperparathyroidism (PHPT) or to familial hypocalciuric hypercalcemia (FHH). PHPT can lead to complications that necessitate parathyroidectomy. FHH is a rare genetic disease resembling PHPT; surgery is ineffective. A reliable method for distinguishing FHH from PHPT is needed.

Objective: To develop an easy-to-use tool to predict if a patient has PHPT.

Design: Retrospective analysis of two prospective cohorts. Development of an unsupervised risk equation (Pro-FHH).

Setting: University hospitals in Paris, France, and Aarhus, Denmark.

Participants: Patients (Paris: 65 with FHH, 85 with PHPT; Aarhus: 38 with FHH, 55 with PHPT) were adults with hypercalcemia and PTH concentration within normal range.

Main Outcome Measures: Performance of Pro-FHH to predict PHPT.

Results: Pro-FHH takes into account plasma calcium, PTH, and serum osteocalcin concentrations, and calcium-to-creatinine clearance ratio calculated from 24-hour urine collection (24h-CCCR). In the Paris cohort, area under the receiver operating characteristic curve (AUROC) of Pro-FHH was 0.961, higher than that of 24h-CCCR. With a cutoff value of 0.928, Pro-FHH had 100% specificity and 100% positive predictive value for the diagnosis of PHPT; it correctly categorized 51 of 85 patients with PHPT; the remaining 34 were recommended to undergo genetic testing. No patients with FHH were wrongly categorized. In an independent cohort from Aarhus, AUROC of Pro-FHH was 0.951, higher than that of 24h-CCCR.

Conclusion: Pro-FHH effectively predicted whether a patient has PHPT. A prospective trial is necessary to assess its usefulness in a larger population and in patients with elevated PTH concentration.