Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism

Abstract

A B S T R A C T Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait comprising hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium. We evaluated the role of parathyroid hormone in the relative hypocalciuria of FHH and characterized the renal transport of calcium in this disorder using three previously hypercalcemic FHH patients with surgical hypoparathyroidism and three controls with surgical hypoparathyroidism. Intravenous infusion of calcium chloride in two patients with FHH and in three controls increased serum calcium from a mean basal of 5.0 to a mean peak of 6.8 meq/liter in two FHH patients and from 4.2 to 5.7 in three control subjects. Urinary calcium in a third FHH patient was studied without calcium infusion during recovery from hypercalcemia of vitamin D intoxication. At all serum concentrations of calcium, calcium clearance was lower in FHH than in controls; at base-line serum calcium, the ratio of calcium clearance to inulin clearance (CCa/CIN) in FHH subjects was 32% of that in controls and decreased to 19% during hypercalcemia. Calcium infusion increased the ratio of sodium clearance to inulin clearance in controls from a base line of 0.020 to 0.053 at peak concentrations of calcium in serum, but did not affect this parameter in FHH (0.017 at baseline serum calcium vs. 0.019 at peak). When calcium infusion studies were performed (in two patients with FHH and one control) during administration of acetazolamide, a drug whose principal renal action causes inhibition of proximal transport of solute, CCa/CIN in the patients with FHH was 29 and 7% of that of the control at base-line and peak serum calcium, respectively. In contrast, ethacrynic acid, a diuretic that acts in the ascending limb of the loop of Henle, increased CCa/CIN more in the FHH patients than in the control subject; CCa/CIN was 65% at baseline and 47% at peak serum calcium, compared with that of the control subject. The greater calciuric response to ethacrynic acid than to acetazolamide or calcium infusion alone in FHH indicates that a major renal locus of abnormal calcium transport in this disorder may be the ascending limb of the loop of Henle.Decreased clearance of calcium in patients with FHH and hypoparathyroidism when compared with hypoparathyroid controls indicates that relative hypocalciuria in FHH is not dependent on hyperparathyroidism. Since the parathyroid glands in FHH are not appropriately suppressed by calcium, this implies that FHH represents a disorder of abnormal transport of, and/or response to, extracellular calcium in at least two organs, parathyroid gland and kidney.

The calcium-sensing receptor and related diseases

“…Additional evidence of the role of CASR in regulating Ca 2+ and Mg 2+ transport in CTAL is found in subjects with mutations in the CASR gene. In subjects with FHH due to an inactivating mutation in the CASR there is a PTH-independent increase in tubular Ca 2+ reabsorption (48), while in ADH subjects there is increased urinary calcium excretion (31).…”

Calcium Mediates the Phosphaturia in Hypercalcemia of Malignancy

“…1). Although there is no direct evidence of a calcium receptor effect on phosphate transport, it is found that subjects with benign hypocalciuric hypercalcemia due to insensitivity of the calcium receptor show less phosphaturia than patients with the same degree of hypercalcemia due to primary hyperparathyroidism [11]. It will further support our hypothesis that management of hypercalcemia would improve TRP.…”

Muscle function and quality of life are not impaired in familial hypocalciuric hypercalcemia: a cross-sectional study on physiological effects of inactivating variants in the calcium-sensing receptor gene (CASR)

“…The degree of hypercalcemia depends on how severely the variant affects the function of CaSR (6). Similarly, in the renal tubules, calcium reabsorption is increased causing a relatively low renal calcium excretion (7,8,9). Recently, similar phenotypes have been shown to be attributable to mutations in the G protein alpha 11 (Ga11(GNA11)) gene (FHH type 2) and adaptor protein 2 sigma 1 (AP2S1) gene (FHH type 3) with loci placed on chromosomes 19p and 19q respectively (10).…”

“…However, in the case of FHH, PTX is not only unnecessary but also inappropriate, as it does not cure FHH-associated hypercalcemia (3,9). When FHH is not considered as an alternative diagnosis, failed PTX may lead to a suspicion of persistent PHPT with the risk of subsequent neck explorations, postoperative hypoparathyroidism, and recurrent laryngeal nerve palsy.…”