Divalent cation metabolism. Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = -0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.