The roles of parathyroid hormone (PTH) and calcitonin (CT) in the pathogenesis of familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) are uncertain. Thus we performed studies in 26 patients with FBH, 12 patients with primary hyperparathyroidism (HPT), and 20 normal volunteers, to answer these questions: are plasma levels of intact or biologically active PTH frequently elevated in FBH? Is plasma intact PTH nonsuppressible during calcium infusion? Is there blunting of the C cell CT response to calcium infusion as occurs in primary HPT? We used three methods for measurement of PTH: a mid region-specific radioimmunoassay (iPTH, antiserum GP-1M), an extraction-concentration bioassay (bioPTH, stimulation of cAMP generation in osteoblastlike cells), and a two-site immunoradiometric assay (IRMA) for intact PTH. PTH levels were significantly elevated in primary HPT by all three methods, but mean PTH was normal in FBH and 85-92% of values overlapped the normal range. During 5 minute calcium infusions (2 mg Ca2+ per kg) iPTH values fell little, but bioPTH and intact PTH fell sharply in all three groups. Mean calcium-induced decreases of intact and bioPTH were indistinguishable from normal in FBH, but PTH levels generally remained elevated at 5 minutes in primary HPT. In FBH basal and postinfusion CT levels were normal. The data show that, in the majority of patients with FBH, PTH concentrations and bioactivity in blood are within the normal range and are suppressed rapidly to very low levels with further increases of calcium. The data suggest that the abnormality of parathyroid function in FBH differs from that in primary HPT.(ABSTRACT TRUNCATED AT 250 WORDS)
One group has reported hypocalcemic individuals in families affected with familial benign hypercalcemia (FBH), suggesting either that FBH is merely an extreme of normality or that hypocalcemia is independently inherited in that kindred. To test these hypotheses, we examined the distributions of serum total calcium (Ca) values in 260 normal adults and 171 adult individuals in 21 FBH kindreds. We excluded from analysis the 21 adult probands, leaving 85 apparently affected persons (Ca, greater than 10.1 mg/dL or greater than 2.52 mmol/L) and 65 apparently unaffected individuals (Ca, less than or equal to 10.1 mg/dL or less than or equal to 2.52 mmol/L). Five FBH family members were hypocalcemic (less than 8.9 mg/dL or less than 2.22 mmol/L); of these, 3 had hypoproteinemia or hypoalbuminemia, 1 had surgical hypoparathyroidism, and 1 was pregnant (and thus excluded from further analysis). Histogram analysis suggested a bimodal distribution of Ca in the FBH families, and familial serum Ca levels were significantly elevated (P less than 0.001, rank sum). When only apparently unaffected family members were compared with normal individuals with serum Ca of 10.1 mg/dL or 2.52 mmol/L or less, the distributions were virtually identical. Our results indicate that hypocalcemia in members of families with FBH is of sporadic nongenetic origin. Furthermore, FBH is not an extreme of the normal distribution, but, instead, a clear disturbance with its own distribution about a supranormal mean serum calcium value.
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