Familial hypocalciuric hypercalcaemia: observations on vitamin D metabolism and parathyroid function

Abstract

Serum vitamin D metabolites, the renal tubular maximum reabsorptive rate for phosphate (TMP/ GFR) nephrogenic cyclic AMP (NcAMPI, and CaE (urinary calcium excretion per litre of glomerular filtrate) were measured in 14 adults with familial hypocalciuric hypercalcaemia (FHH). The findings were compared with analyses in 14 patients with surgically proven primary hyperparathyroidism matched for serum calcium, creatinine clearance and vitamin D status (assessed by serum concentrations of 25 hydroxyvitamin D). Vitamin D metabolites were also measured in 16 normocalcaemic relatives of patients with FHH. The serum concentration of 24,25 dihydroxycholecalciferol was appropriate for the prevailing 25 hydroxyvitamin D and no difference was found between groups. The serum concentration of 1,25 dihydroxycholecalciferol was significantly greater in primary hyperparathyroidism (P < 0.0005) compared with patients with FHH and their normocalcaemic relatives. TMP/GFR was reduced in both primary hyperparathyroidism (0.53 \m=+-\0.12 mmol/l GF, mean \m=+-\sem) and FHH (0.86 \m=+-\0.14mmol/l GF). Patients with primary hyperparathyroidism showed an increase in NcAMP output in the urine (38.5 \m=+-\16 mmol/l GF) which was significantly greater (P < 0.0001) than the normal NcAMP (13.5 \ m=+-\9.2 nmol/l GF) found in FHH. CaE was low in FHH indicating increased renal tubular reabsorption of calcium.It is concluded that there is no abnormality of vitamin D metabolism in FHH comparable with the changes observed in primary hyperparathyroidism. It is suggested that the biochemical abnormalities in FHH cannot be explained solely upon an increased sensitivity of the renal tubules to the effects of endogenous parathyroid hormone. Foley et al. (1972) first drew attention to a familial form of hypercalcaemia in which, unlike other causes of hypercalcaemia, the urinary excretion of calcium is characteristically low. This condition, -known as familial benign hypercalcaemia or as familial hypocalciuric hypercalcaemia (FHH) (Marx et al. 1977) -is inherited as an autosomaldominant, and closely resembles primary hyper¬ parathyroidism, for which it is commonly mistaken. Clinical experience of FHH is limited, but there is general agreement that with few exceptions the condition is benign. Some patients have presented with acute pancreatitis which has endangered life (Davies et al. 1981). The role of parathyroid hor¬ mone in the pathogenesis of FHH is uncertain; immunoassayable parathyroid hormone (iPTH) can often be detected in the serum, sometimes in increased amounts. The parathyroid glands can appear normal at exploration of the neck, but in some patients all the glands are found to be enlar¬ ged and hyperplastic (Davies et al. 1981).The differentiation of FHH from primary hyperparathyroidism is important because surgical treatment is unsatisfactory and seldom indicatd (Adams 1982). Unfortunately, no single routine biochemical test clearly distinguishes the individual patient with FHH from one with asymptomatic or uncomplicated primary hyperparathyroid...

Plasma 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone in familial hypocalciuric hypercalcemia and primary hyperparathyroidism

“…Finally, a pre-existing vitamin D insufficiency could theoretically predispose to the development of PHPT (6). Vitamin D metabolism has been explored only in a small number of FHH patients (17)(18)(19). We have recently reported on the ability of the calcium/creatinine clearance ratio (CCCR) and other variables of renal calcium excretion to discriminate between FHH and PHPT (20), as described by Marx et al and others (1,(21)(22)(23)(24)(25)(26).…”

Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism

“…With these methodologic limitations, serum PTH levels were normal in 92 out of 106 subjects (87%) with FHH from 16 separate studies prior to the mid-1980s. 1,[30][31][32]49,61,62,[70][71][72] Up to one-fourth of patients with FHH may have serum intact PTH values above the upper limit of normal, even when using the sandwich second generation immunoradiometric assay (Figure 24.2). [68][69][70] For example, intact PTH levels were 23.4 ± 1.7 pg/ml (2.43 ± 0.2 pmol/liter, mean ± SE) in 20 normal subjects, 28.3 ± 3.6 pg/ml (2.98 ± 0.4 pmol/liter) in 26 subjects with FHH, and 80 ± 1.5 pg/ml (8.4 ± 1.6 pmol/liter) in 12 patients with hyperparathyroidism.…”

Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

“…Multiple comparisons between serum concentrations of 1,25(OH) 2 D in FBH and PH patients at basal conditions have been performed (20)(21)(22)(23)(24). The results showed similar (21,22) or significantly lower serum levels of 1,25(OH) 2 D in FBH patients compared with PH patients (20,23,24).…”

“…FBH is typically caused by inactivating mutations of the calcium-sensing receptor (CASR) gene, resulting in inappropriate secretion of PTH and in a markedly enhanced resorption of urinary calcium through mechanisms that are both dependent on and independent of PTH (10)(11)(12)(13)(15)(16)(17)(18)(19)(20). Multiple comparisons between serum concentrations of 1,25(OH) 2 D in FBH and PH patients at basal conditions have been performed (20)(21)(22)(23)(24). The results showed similar (21,22) or significantly lower serum levels of 1,25(OH) 2 D in FBH patients compared with PH patients (20,23,24).…”