PLASMA INTACT PARATHYROID-HORMONE (PTH) AND PTH-RELATED PEPTIDE IN FAMILIAL BENIGN HYPERCALCEMIA - GREATER RESPONSIVENESS TO ENDOGENOUS PTH THAN IN PRIMARY HYPERPARATHYROIDISM

The cause of hypercalcemia in familial benign hypercalcemia (FBH; also called familial hypocalciuric hypercalcemia) is unclear, although it is PTH dependent. It is also uncertain how plasma PTH levels are related to the severity of biochemical abnormalities in FBH. Because the PTH-related peptide (PTHrP) has many PTH-like actions, it might have a role in the hypercalcemia of FBH. Thus, we studied 29 patients with FBH from 11 families, 29 age- and sex-matched controls, and 42 patients with primary hyperparathyroidism (1-degrees-HPT), measuring PTH with a highly sensitive two-site immunochemiluminometric assay and the hypercalcemic tumor factor PTH-related peptide (PTHrP) with an extraction/concentration RIA. Plasma PTH values were elevated in 86% of 1-degrees-HPT patients (36 of 42), but in only 20% of FBH patients (6 of 29). Plasma PTHrP was elevated in 1 FBH patient, and the group mean value was normal. Plasma PTH was positively correlated with calcium (Ca) in 1-degrees-HPT (r = 0.66; P < 0.0001) and in FBH (r = 0.53; P < 0.004), but the slopes of the regressions were markedly different: 1-degrees-HPT, 6.72; FBH, 1.61 (P < 0.0001). There was a negative correlation between PTH and phosphorus (P) in 1-degrees-HPT (r = -0.39; P < 0.01) and in FBH (r = -0.41; P < 0.03), but, again, the slopes differed greatly: 1-degrees-HPT, -6.57; FBH, -1.95 (P < 0.0001). There were no correlations between PTHrP and Ca or between PTH and PTHrP. The sums and products of PTH and PTHrP were not better correlated with Ca than PTH alone. Thus, PTH values are lower at given Ca and P levels in patients with FBH than in those with 1-degrees-HPT, suggesting that PTH is more effective in raising Ca and lowering P in FBH than in 1-degrees-HPT. The enigma of FBH remains: what molecular defect can simultaneously cause parathyroid cell insensitivity to Ca, enhanced renal tubular reabsorption of Ca, increased renal rejection of P, and enhanced or retained sensitivity to PTH?