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Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.

Plasma concentrations of PTH are much lower for a given calcium or phosphorus level in patients with familial benign hypercalcemia (FBH, or familial hypocalciuric hypercalcemia) than in those with primary hyperparathyroidism; these and other data suggest that there might be tissue hypersensitivity to PTH in FBH. To test this hypothesis, we have used cultured dermal fibroblasts from abdominal skin biopsies of six patients with FBH and six age- and sex-matched controls as surrogate PTH-responsive tissues. Cells in 24-well plastic plates were exposed to vehicle, human PTH-(1-34) (10(-10)-10(-7) M), prostaglandin E2 (10(-6) M), or isoproterenol (10(-4) M) for 10 min in the presence of isobutylmethylxanthine, and cellular cAMP was determined by RIA. All cells responded to PTH with dose-dependent increases in cAMP, and all responded strongly to prostaglandin E2 and isoproterenol. There were no consistent or significant differences between control and FBH fibroblasts in maximal responses to the three agonists, and half-maximal stimulation was achieved with about 10(-9) M PTH in both normal and FBH cells. These data are not consistent with increased tissue sensitivity to PTH in FBH.

In an earlier 8-day study, we showed increased immunoreactive PTH (iPTH) levels in young adults fed high phosphorus (P), low calcium (Ca) diets assembled from common grocery foods, a dietary pattern characteristic of teens and young adults. Because animals fed high P, low Ca diets developed secondary hyperparathyroidism and, ultimately, osteopenia, perhaps the typical teen diet may reduce peak bone mass and contribute to osteoporotic fracture later in life. To determine if the elevation in iPTH levels and action persists with chronic intake of this typical diet, we studied the 24-h mineral and hormone responses of 15 young women (18-25 yr of age) to either high P, low Ca or control diets. Each subject served as her own control, first consuming a basal diet (800 mg Ca, 900 mg P) for 28 days; 10 women were then switched to the high P, low Ca test diet (400 mg Ca, 1700 mg P) for 28 days, while the remaining 5 women in the control group continued eating the basal diet. On days 28 and 56, all subjects were studied as inpatients for 24 h, with blood drawn every 4 h and collection of fasting and 24-h urine. Serum iPTH (midregion) and serum intact PTH (2-site immunoradiometric assay) increased significantly [maximal increases of 26% (P less than 0.002) and 36% (P less than 0.004), respectively] after 4 weeks of consuming the test diet, and there was no change in the control group. In contrast to our 8-day study, plasma levels of 1,25-dihydroxyvitamin D did not change in either group. Our findings suggest that this common dietary pattern in young adult women causes persistent alterations in calcium-regulating hormones that could be unfavorable to achieving maximal positive bone balance.

Cimetidine, an antagonist to histamine H2-receptors, reportedly lowers serum calcium and/or serum immunoreactive parathyroid hormone (iPTH) concentrations in some patients with primary and secondary (azotemic) hyperparathyroidism. We administered the drug orally (300 mg every 6 h) to five normal volunteers and four azotemic patients with secondary hyperparathyroidism who were not undergoing chronic hemodialysis. The normal persons and one azotemic patient took the drug for 5 weeks, and the remaining azotemic patients took it for 1 week. Before treatment, all patients had elevated levels of serum iPTH (two different assay systems), with or without elevated serum calcium concentrations, and increased urinary excretion of cAMP (per 100 ml glomerular filtrate). Cimetidine treatment caused no changes in serum calcium, phosphorus, or iPTH or in urinary cAMP (expressed as nanomoles per g creatinine). Serum creatinine, however, increased significantly in patients (P less than 0.02) and control subjects (P less than 0.025), which yielded statistically significant but spurious increases of urinary cAMP when expressed per 100 ml glomerular filtrate. We conclude that short term cimetidine administration has no effect on parathyroid function in normal persons or those with azotemic hyperparathyroidism. Because of its confusing effect on serum creatinine and a possible (albeit rare) adverse effect on renal function, the drug should be used with caution in azotemic patients not yet requiring chronic dialysis.

We studied in vitro the presence of histamine and the effect of histamine and its antagonists on cAMP accumulation in parathyroid tissue (parathyroid adenoma or hyperplasia) from patients with primary hyperparathyroidism. Parathyroid adenomatous tissue contained 11.2 +/- 2.9 ng histamine/g wet weight (approximately 2 X 10(-5) M), as determined by a specific radioenzyme assay. Histamine caused a prominent increase in cAMP accumulation in parathyroid tissue slices in a dose-dependent manner, with half-maximal stimulation being achieved at 5 X 10(-6) M and maximal stimulation occurring at 10(-4) M histamine. The histamine H2 receptor antagonists, cimetidine and metiamide, caused profound inhibition of histamine-stimulated cAMP accumulation in the parathyroid tissue. Pyrilamine, an H1 antagonist, also inhibited histamine-stimulated cAMP accumulation. Isoproterenol, a beta-adrenergic agonist, elicited marked elevation of cAMP, and its stimulatory effect was blocked by propranolol, but the effects of histamine on cAMP levels in parathyroid tissue were not blocked by propranolol. Histamine significantly stimulated (an increase of 50%) the release of immunoreactive parathyroid hormone. The present observations demonstrate that parathyroid adenomatous tissue has a relatively high content of histamine, and the release of immunoreactive parathyroid hormone from this tissue. The effects of antagonists suggest that histamine stimulates cAMP accumulation in the parathyroid adenomatous tissue by an action on both H2 and H1 histamine receptors.

PDN-21, the carboxyl-terminal flanking peptide encoded by the calcitonin (CT) gene, has been found in plasma of patients with medullary thyroid carcinoma and reportedly is cosecreted with CT. To test whether PDN-21 and CT are cosecreted in normal subjects, we developed a RIA for PDN-21 and measured immunoreactive CT and PDN-21 in whole plasma and silica or C18 cartridge extracts of plasma (exCT, exPDN-21) before and after calcium (Ca) infusion (2 mg Ca/kg over 5 min) in nine normal men and nine normal women. Plasma CT and immunoreactive PDN-21 levels were often below the assay detection limits. In contrast, basal exCT and exPDN-21 were detectable in all plasma samples, and the concentrations of both were significantly higher in men than in women [basal exCT (mean +/- SE): men, 4.8 +/- 0.3 ng/L; women, 2.4 +/- 0.3 (P less than 0.001); basal exPDN-21: men, 4.7 +/- 0.3 ng/L; women, 3.3 +/- 0.3 (P less than 0.01)]. Ca infusion sharply increased CT and PDN-21 concentrations in both sexes, but the increments were greatest in men [mean (+/-SE) increment of exCT: men, 37.2 +/- 3.9 ng/L; women, 15.7 +/- 4.3 (P less than 0.002); mean increment of exPDN-21: men, 29.7 +/- 4.7 ng/L; women, 11.0 +/- 3.1 (P less than 0.005)]. The molar concentrations of exCT and exPDN-21 were closely correlated (r = 0.97; P less than 0.001). With our antiserum, the extraction-concentration technique for measurement of PDN-21 had increased sensitivity and decreased nonspecific interference compared to the whole plasma assay. We conclude that CT and PDN-21 are cosecreted from normal thyroid C-cells under the control of extracellular fluid Ca, and that men have greater secretory capacity for both peptides than women. Plasma PDN-21 may serve alternatively to CT as a marker for C-cell activity.

An acute increase in serum calcium stimulates calcitonin (CT) secretion, but the effects of chronic hypercalcemia are controversial. Histopathological studies have shown C-cell hyperplasia in primary hyperparathyroidism (1 degree HPT), although circulating levels of CT have been variously reported to be normal, elevated, or depressed. We reexamined this relationship using CT RIA in conjunction with a silica extraction technique that conveys improved sensitivity and specificity for monomeric CT. Nine men and seven women with surgically documented 1 degree HPT were studied preoperatively before and after a short calcium infusion (2 mg Ca/kg, for 5 min), as were 72 normal men and 76 normal women. Basal whole plasma immunoreactive CT and silica-extractable CT concentrations in 1 degree HPT were indistinguishable from normal, regardless of sex. In addition, the whole plasma and silica-extractable CT responses to calcium stimulation were normal or blunted in patients with 1 degree HPT. We conclude that hypercalcemia resulting from 1 degree HPT is not associated with augmented CT secretion in response to an iv calcium infusion.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

We compared serum concentrations of immunoreactive PTH and plasma levels of vitamin D metabolites in 11 patients with adenomatous primary hyperparathyroidism and 32 individuals with the syndrome of familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH). Serum immunoreactive PTH was elevated in the hyperparathyroid group but indistinguishable from control in FHH, despite comparable degrees of hypercalcemia. Plasma 25-hydroxyvitamin D concentrations were normal in both groups, but plasma 1,25-dihydroxyvitamin D levels in FHH were significantly lower than control (P less than 0.0025) or hyperparathyroid (P less than 0.01) values. FHH is pathogenetically distinct from primary hyperparathyroidism and should not be thought of simply as a variant of that condition.

The reported effects of PTH on urinary excretion of cations are highly variable. We investigated dose and time relationships for urinary clearance of calcium (Ca), magnesium (Mg), sodium (Na), and potassium (K) after infusions of synthetic bovine PTH fragment 1-34 [bPTH-(1-34)] in seven normal subjects. The bPTH-(1-34) was given over 15 min on widely separated days at doses of 10, 30, 75, 150, and 300 U/70 kg. The 75, 150, and 300 U/70 kg doses produced a biphasic excretory pattern for all four ions, with increased clearance from 0-30 min and enhanced reabsorption at 60-120 min. Lower doses produced only retention of Ca, Mg, and Na, but even 10 U bPTH-(1-34)/70 kg caused a marked biphasic excretory pattern of K. These data explain why in previous studies PTH increased, decreased, or had no effect on the excretion of divalent and monovalent cations and emphasize the importance of short, clearly defined urine collection intervals for in vivo studies of PTH action of the kidney.

Recent reports that cimetidine, a blocker of histamine H2 receptors, lowered serum calcium and/or immunoreactive parathyroid hormone (PTH) concentrations in primary or secondary hyperparathyroidism prompted us to administer the drug (300 mg, orally, every 6 h) to two patients with hyperparathyroidism accompanying familial multiple endocrine neoplasia type 1. The patients were hypercalcemic (10.9--11.2 mg/dl), hypophosphatemic (2.0--2.4 mg/dl), and hypercalciuric (greater than or equal to 410 mg/24 h), with elevated urinary cAMP and phosphate clearance and inappropriately high serum immunoreactive PTH levels. Multiple observations of these variables over 5 weeks of cimetidine treatment showed no systematic changes; in particular, serum and urinary calcium did not change, and there was no evidence of a decreased PTH effect on the kidneys. The data offer no support for the treatment of familial hyperparathyroidism with cimetidine.