Familial hypocalciuric hypercalcaemia: evidence for continued enhanced renal tubular reabsorption of calcium following total parathyroidectomy

A patient with familial hypocalciuric hypercalcaemia (FHH) is reported. Seven years after total parathyroidectomy he remained hypocalcaemic, with biochemical evidence of hypoparathyroidism (enhanced renal tubular reabsorption of phosphate, low nephrogenic cyclic AMP excretion, and reduced serum concentration of 1,25-dihydroxycholecalciferol in the presence of normal renal function and normal serum 25-hydroxyvitamin D levels). Iv infusions of calcium were given before and 6 years after total parathyroidectomy. The renal tubular reabsorption of calcium was compared in these two situations. No difference was found. Before and after parathyroidectomy there was enhanced renal tubular reabsorption of calcium. It is concluded that the enhanced renal tubular reabsorption of calcium in FHH is independent of parathyroid hormone. Total parathyroidectomy corrects the hypercalcaemia in FHH by a reduction in the input of calcium into the extra-cellular fluid from gut and or bone perhaps as a result of reduced renal synthesis of 1,25-dihydroxycholecalciferol.     

Altered parathyroid set point to calcium in familial hypocalciuric hypercalcaemia

Changes in calcium concentration were induced by an infusion of disodium-EDTA or calcium in 2 members of a family suffering from hypocalciuric hypercalcaemia ( FHH ) associated with interstitial lung disease. These changes in calcium demonstrated an inverse linear relationship with the changes in serum parathyroid hormone (PTH). Infusion of EDTA in control subjects and in patients with an adenoma or hyperplasia of the parathyroid glands also showed inverse relationships between calcium and PTH. The correlation between serum calcium and serum PTH was significant over the range observed during the induced hypo- and/or hypercalcaemia in controls and in patients with FHH or adenoma. The regressions were, however, shifted relative to each other: in comparison with controls, the FHH was displaced upwards and to the right, although not as far as the adenomas. These findings suggest the existence of an elevated set point for extracellular calcium (or calciostat ) in FHH .     

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 age- and sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.     

Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis

OBJECTIVE  Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium-sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis.
PATIENTS AND METHODS  Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy-terminators. Mutations were confirmed and demonstrated to co-segregate with FHH by restriction enzyme analysis.
RESULTS  Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co-segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls.
CONCLUSIONS  Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium-sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.     

Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism

Objectives Bone metabolism is only superficially described in familiar hypocalciuric hypercalcaemia (FHH). We describe and compare biochemical and osteodensitometric variables in FHH and primary hyperparathyroidism (PHPT) and assess whether they can improve the diagnostic discrimination between the groups. Design Cross‐sectional. Patients Sixty‐six FHH patients with known calcium‐sensing receptor (CASR) gene mutations and 147 PHPT patients. Measurements We determined calcium, creatinine, phosphate, magnesium, parathyroid hormone (PTH), 25OHD, 1,25(OH)₂D and alkaline phosphatase (AP) in plasma, NTx/creatinine ratio in urine and calculated the calcium/creatinine clearance ratio (CCCR). We performed dual energy X‐ray absorptiometry at the lumbar spine, hip, forearm and whole body. Results When compared with normal controls, the FHH patients had increased levels of PTH and AP with normal U‐NTx and regional Z‐scores. Increased phenotypic expression of CASR mutations in terms of hypercalcaemia was associated with higher lumbar spine bone mineral density, but not with bone markers. FHH were younger and leaner than the PHPT patients. They had comparable plasma Ca²⁺ and 25OHD, but lower levels of PTH, 1,25(OH)₂D, AP and U‐NTx. They had higher Z‐scores in the hip and in the forearm. We achieved the best discrimination between groups by multiplying CCCR with AP, 1,25(OH)₂D and PTH, but the difference between the area under the curves by receiver operating characteristic analysis remained insignificant. Conclusion Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations. A multiplicative model including CCCR, AP, 1,25(OH)₂D and PTH insignificantly improved the power of the CCCR to differentiate between FHH and PHPT. However, we still recommend CASR gene analysis in patients with a CCCR <0·020.     

Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia

OBJECTIVE: Heterozygous inactivating mutations of the calcium-sensing receptor (CaR) gene cause familial hypocalciuric hypercalcaemia (FHH), a generally benign disorder characterized by mild to moderate PTH-dependent hypercalcaemia. We aimed to identify the causative CaR mutations in three families with FHH and examine the correlation between type of mutation and biochemical and/or functional phenotypes. PATIENTS, DESIGN AND MEASUREMENTS: The CaR gene from FHH family members was assessed for mutations by direct DNA sequencing and mutations were confirmed by restriction enzyme analysis. Functional studies on two missense mutations were conducted by introducing them by site-directed mutagenesis into the CaR cloned into a mammalian expression vector, and assessing calcium responsiveness using an inositol phosphate (IP) assay in HEK293 cells. Biochemical data from patients heterozygous for each type of mutant were correlated with functionality. RESULTS: Two novel nonsense mutations (R25stop and K323stop) and one novel missense mutation (G778D) were identified. The G778D mutant receptor and another mutation identified in an earlier study (L174R) demonstrated a complete lack of Ca2+ responsiveness using the IP assay. When cotransfected with wild-type receptor, the mutant receptors demonstrated a dominant-negative effect on wild-type receptor response, with L174R having a more pronounced effect than G778D. Significantly more severe hypercalcaemia and a trend towards higher PTH levels were observed in patients heterozygous for CaR mutants with a stronger dominant-negative effect. CONCLUSIONS: Naturally occurring CaR mutations with differences in dominant-negative effect on wild-type receptor demonstrate differences in biochemical severity in FHH.     

Renal tubular sodium reabsorption and oxygen consumption in the hypothyroid dog

The degree to which an insufficiency of thyroid hormone (TH) affects renal tubular sodium reabsorption (RNa) and oxygen consumption (QO₂) in vivo, was investigated in a mature mammalian kidney. The results suggest that TH influences renal QO₂ as a result of alterations in renal hemodynamics and the renal tubular handling of sodium. Changes in GFR played a major role in the regulation of RNa and QO₂. This is suggested by the comparison of hypothyroid animals with and without renal compensatory hypertrophy. In the latter group a twofold lower GFR was associated with parallel changes in RNa and QO₂. However, in going from euthyroid (E) to hypothyroid (H) conditions, the decrease in RNa of 31 ± 4% was greater than the reduction in GFR of 25 ± 3% (p < .05). Thus, a decrease in RNa of 6 ± 2% under hypothyroid conditions could not be attributed to the changes in GFR. The normal renal stoichiometry between RNa and QO₂ in hypothyroid animals indicates that the above changes in RNa were accompanied by comparable changes in QO₂. The decrease in RNa in hypothyroid animals was not associated with a significant change in kidney weight (E:48.2 ± 4.0gm., n = 5 and H:45.4 ± 1.4gm, n = 5; pN.S.) The results suggest that an adaptive response to changes in GFR is the predominant cause of the decrease in RNa and renal QO₂ under hypothyroid conditions. A modest reduction in renal tubular sodium reabsorptive capacity in hypothyroid animals is probably secondary to a direct effect of TH on active sodium transport.     

Familial hypocalciuric hypercalcaemia: a study of four kindreds

Four kindreds with hereditary hypercalcaemia have been investigated. Thirty-seven of 72 subjects examined had hypercalcaemia with an autosomal dominant pattern of inheritance. Hypercalcaemic patients had total serum calcium of 2.91 +/- 0.12 mmol l-1. Serum parathyroid hormone (PTH) was normal while daily urinary calcium excretion was subnormal (below 2.5 mmol) in 45%. Comparison with an age-matched group of patients with primary hyperparathyroidism gave a small overlap regarding serum human PTH, urinary calcium and the ratio between calcium clearance and creatinine clearance. Family screening therefore is of diagnostic importance. Twelve subjects had been subjected to parathyroid surgery before the correct diagnosis was settled, none of the cases had an adenoma. Three patients became normocalcaemic and the others had persistent hypercalcaemia. One male non-abuser had seven episodes of acute pancreatitis before surgery and none after. The findings in all four kindreds are compatible with familial hypocalciuric hypercalcaemia (FHH). This hereditary disorder of unknown aetiology, therefore, also exists in Scandinavia. It is of importance to consider FHH in the differential diagnosis of hypercalcaemia, since this disorder usually has a benign prognosis if untreated.     

Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods

Background Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented. Aim To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards. Design Follow‐up approach (direct design). Materials We included 54 FHH patients (17 males and 37 females, aged 18–75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19–86 years). All PHPT patients became normocalcaemic following successful neck exploration. Results Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0·923 ± 0·021 (SE)), than the 24‐h calcium/creatinine excretion ratio (AUC = 0·903 ± 0·027) and the 24‐h calcium excretion (AUC = 0·876 ± 0·029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut‐off points. Based on the ROC curve, the optimal cut‐off point for diagnosing FHH using CCCR was < 0·0115, which yielded a diagnostic specificity of 0·88 and a sensitivity of 0·80. Overlap analysis revealed that a cut‐off point for CCCR at < 0·020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients. Conclusion Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two‐step diagnostic procedure, where the first step is based on the CCCR with a cut‐off at < 0·020, and the second step is CASR gene analysis in patients with FHH or PHPT.     

Renal action of progesterone: effect on calcium reabsorption

Recently, the kidney has been reported to be the site of receptors for progesterone. Although the exact segment of the nephron has not been precisely determined, the cortical collecting tubule was suspected, since the hormone displaces bound 3H aldosterone. The aim of the present study was to investigate the effect of progesterone on calcium (Ca(2+)) transport by the renal luminal membranes and to determine the site and mechanisms of action. Incubation of proximal tubules from rabbit kidney with progesterone did not influence Ca(2+) or Na(+) transport by the luminal membranes. In the distal tubules (DT), a 5 min treatment with 10(-11) M of the hormone enhanced 0.5 mM 45Ca uptake from 0.60+/-0.02 to 0.84+/-0.08 pmol/microg per 10 s (P<0.05) in the absence of Na(+) and from 0.26+/-0.02 to 0.41+/-0.02 pmol/microg per 10 s (P<0.01) in the presence of 100 mM Na(+). The dose-response curve showed a biphasic action with a peak at 10(-11) M. Ca(2+) uptake by DT membranes presents dual kinetics. The hormone enhanced the Vmax value of the high affinity component from 0.41+/-0.05 to 0.57+/-0.06 pmol/microg per 10 s (P<0.05). In contrast, incubation of DT with 10(-8) M progesterone decreased 1 mM Na(+) uptake from 0.68+/-0.03 to 0.53+/-0.07 pmol/microg per 10 s (P<0.05). Finally, 10(-11) M progesterone also enhanced Ca(2+) uptake by the DT membranes through a direct nongenomic mechanism.     

Familial hypocalciuric hypercalcaemia and pancreatitis: no causal link proven

A case of a patient with pancreatitis and familial hypocalciuric hypercalcaemia is presented and the literature linking FHH and pancreatitis is reviewed. The case for a causal link between the two conditions is not proven and seems unlikely. In view of this we strongly challenge the recommendation of total parathyroidectomy in such cases.     

The tubular maximum for calcium reabsorption: a normal range in children

OBJECTIVE: We aimed to establish a normal range for the tubular maximum rate of reabsorption of calcium corrected for glomerular filtration rate. DESIGN: A prospective survey was used. PATIENTS: One hundred and ten normal children aged 2-14 years were studied. MEASUREMENTS: Total plasma calcium, ultrafiltrable calcium and parathyroid hormone. Urinary calcium, sodium and creatinine excretion. RESULTS: The normal range was found to be 1.87-3.39 mmol/l of glomerular filtrate with a geometric mean value of 2.40 mmol/l. There was a significant inverse relationship between the tubular maximum for calcium and the urinary sodium excretion. No significant relationship was found between the tubular maximum for calcium and the level of parathyroid hormone in this group of normal children. CONCLUSIONS: The normal range seen in children is higher than that seen in adults with a higher mean value. This normal range should be useful in the assessment of renal calcium handling in children with disorders of calcium homeostasis.