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At least 19 recordsLinked to original sources

PubMed1989

Changes in T wave morphology during hypercalcemia and its relation to the severity of hypercalcemia.

The effect of hypercalcemia on T wave morphology, polarity, and amplitude was studied in 14 patients with a primary diagnosis of malignant lymphoma (8 patients), adult T-cell leukemia (5 patients), and Hodgkin's disease (1 patient). Hypercalcemia was severe to extreme in 11 (14.9-22.8 mg/dl), moderate in 1 (13.4 mg/dl), and mild in 2 (11.8 and 12.2 mg/dl) patients. Ten of the 11 patients (91%) with severe hypercalcemia showed inverted, biphasic, and notched T waves, mainly in the chest leads. Notched T waves were observed in all 10 of these patients in anterior to lateral, mid to lateral, or lateral chest leads. Biphasic and/or inverted T waves in anterior or anterior to midchest leads were present in 4 of these 10 patients who had extreme hypercalcemia (greater than 16 mg/dl). Changes in T wave morphology were not observed in moderate or mild hypercalcemia. T wave amplitude showed significant inverse correlation with serum calcium (T mV vs Ca, r = -0.60, p less than 0.001; T/R ratio vs Ca, r = -0.68, p less than 0.001; n = 35). Decrease in T wave amplitude was marked in severe hypercalcemia (p less than 0.0001) and moderate hypercalcemia, but there was no change in mild hypercalcemia. Changes in T wave morphology, polarity, and amplitude either appeared with development of hypercalcemia or disappeared with normalization of serum calcium level. It was concluded that in addition to shortening the QT interval, severe to extreme hypercalcemia can cause development of inverted, biphasic, or notched T wave with a marked decrease in amplitude of T waves.

Adult↗

PubMed1984

Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia).

The histologic characteristics of the parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia) are disputed, some finding parathyroid hyperplasia and others finding no abnormalities. To further investigate this issue, the histologic appearance of 82 parathyroid glands from 47 control patients (surgical and autopsy) were compared with those of 28 glands from 23 patients with familial hypocalciuric hypercalcemia who had undergone surgery for suspected primary hyperparathyroidism. Median and mean weights of 23 parathyroid glands from 12 patients with familial hypocalciuric hypercalcemia were 50 mg and 60 mg, respectively, with a range from 5 to 181 mg. Eighty-three percent of individual glands were within extreme normal limits for weight (less than 75 mg). Percent parenchymal area in familial hypocalciuric hypercalcemia was slightly but significantly less than control values (62 +/- 2 versus 71 +/- 2 percent, respectively; (p = 0.009). Conversely, percent fat was higher in familial hypocalciuric hypercalcemia than control values (30 +/- 3 versus 21 +/- 2 percent, respectively; p = 0.015). Stromal area was 8 +/- 1 percent in each group. Although 15 to 20 percent of parathyroid glands in familial hypocalciuric hypercalcemia exceeded normal size, most were indistinguishable from normal by size, weight, and microscopic appearance. The significantly reduced percent parenchyma in glands from patients with familial hypocalciuric hypercalcemia further suggests that the condition is not uniformly accompanied by typical parathyroid hyperplasia and should not be thought of as merely a variant of the latter.

Adenoma↗

PubMed1989

[Mechanism of hypercalcemia associated with malignancy: interactions between induction of hypercalcemia and autonomous growth in VX2 cancer cells].

Hypercalcemia is one of well-recognized paraneoplastic syndromes and occurs occasionally in patients with oral cancers. Because bone is the richest source of calcium in the body, it has been proposed that humoral bone resorbing factors which are released by tumors are responsible for the pathogenesis of hypercalcemia. In the present study, partial purification and identification of bone resorbing humoral factors were carried out employing VX2 squamous cell carcinoma which has been known to induce hypercalcemia in rabbits. In addition, extra- and intra-cellular mechanisms which are operating to confer autonomous growth on VX2 cancer cells were also studied. VX2 carcinoma induced marked hypercalcemia not only in rabbits but also in nude mice in parallel with tumor enlargement. Administration of indomethacin (INDO), a prostaglandin (PG) synthesis inhibitor, before onset of the hypercalcemia prevented an elevation of serum calcium levels and growth of the tumor. INDO, however, failed to decrease serum calcium levels and tumor growth when administered after development of the hypercalcemia and tumor enlargement. These results indicate that not only PGs but other humoral factors are involved in the pathogenesis of the hypercalcemia seen in VX2 cancer-bearing animals. VX2 cancer cells in culture retained their cancerous phenotypic properties, synthesized PGE2, PGF2 alpha and 6-keto PGF1 alpha and secreted highly levels of PGE2, a powerful bone resorber, into the culture medium in a time- and cell density-dependent manner. The culture supernatants also contained a trypsin- and heat-sensitive bone risorbing factor (BRF) with a molecular weight of approximately 20kD. BRF was presumed to be similar to parathyroid hormone related protein (PTHrP) from its biological and biochemical behaviors. Both PGE2 and PTHrP promoted VX2 cell growth, thus suggesting that these two substances are autocrine growth factors for VX2 cells. Calcium stimulated VX2 cell growth and secretion of PGE2 and BRF (PTHrP) in a concentration-dependent fashion. Stimulation of VX2 cell proliferation by PGE2 and PTHrP was closely correlated with a transient elevation of intracellular free calcium ion ([Ca2+]i). [Ca2+]i elevated transiently in response to PGE2 and PTHrP was shown to be supplied by influx of extracellular free calcium ion ([Ca2+]e) through calcium channel present in plasma membrane. Involvement of protein kinase C in autocrine growth stimulation of VX2 cells by PGE2 and PTHrP was unclear. These results demonstrate that PGE2 and PTHrP secreted by VX2 cancer cells not only induce hypercalcemia but promote VX2 cell growth as autocrine growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families.

Familial benign hypercalcemia (hypocalciuric hypercalcemia) was diagnosed in 125 members of 21 families. The syndrome was generally characterized by autosomal dominant inheritance of symptomless, nonprogressive hypercalcemia with normal serum immunoreactive parathyroid hormone concentrations, parathyroid glands that had normal gross and histologic features, relatively low urinary excretion of calcium, and failure to achieve normocalcemia after subtotal parathyroidectomy. Affected persons had normal longevity and no discernible increase in other medical problems except gallstones. The parathyroid glands were not seen using high-resolution ultrasonography. Plasma calcitonin and calcitriol levels were normal or low. Skeletal mass was normal as assessed by photon absorptiometry of the radius and lumbar spine, and fractures were not more frequent. Familial benign hypercalcemia or hypocalciuric hypercalcemia is a distinctive heritable syndrome that should always be considered in the differential diagnosis of asymptomatic hypercalcemia.

Adolescent↗

PubMed1975

Hypercalcemia and neoplasia. Biologic, biochemical, and ultrastructural studies of a hypercalcemia-producing Leydig cell tumor of the rat.

A localized, transplantable testicular tumor of the Fischer rat regularly produces hypercalcemia and increased phosphorus clearance in host animals. Light and electron microscopic examinations of the tumor indicate that it is of Leydig origin. There is no evidence that the tumor secretes any biologically active sex steroids, judges by weights of target tissues, when the tumor is grown in castrated or spayed rats. No radioactive steroid hormone formation in vitro was detected using 1-14C-acetate as a precursor although 14C was incorporated into the "C27" sterol fraction. Mass (micrograms) amounts of sex steroids were not detected after purifying large amounts of tumor extracts. The phytosterols, beta-sitosterol, stigmasterol, campesterol, were tentatively identified in tumor extracts but were also found in other tissues and in tumors not associated with hypercalcemia. Administered in vivo, human chorionic gonadotropin caused an acute rise in serum calcium in 3 to 5 hours in tumor-bearing hypercalcemic rats. Only trophic hormones with luteinizing hormone activity were found to compete with 125I-human chorionic gonadotropin for binding to the tumor homogenate in vitro indicating the tumor possessed luteinizing hormone receptors. When the tumor was transplanted intrasplenically, hypercalcemia did not occur unless adhesions formed, suggesting that the tumor hormone was rapidly metabolized by the liver and was probably of small molecular weight. Secretory granules, usually thought to be associated with peptide hormone secretion, were not detected at the ultrastructure level. Cortisol, conjugated estrogen, and an inhibitor of sterol biosynthesis (AY-9944) were effective in lowering the elevated serum calcium. Definitive identification of the agent causing lethal hypercalcemia has not been accomplished. The available data suggest it is not parathyroid hormone or vitamin D. The Leydig cell origin of the tumor, its response to human chorionic gonadotropin in vivo, the lack of secretory granules at the ultrastructural level, and biologic characteristics, all lead to the speculation that the secretory product of the tumor is a new hormonal substance, possibly a steroid precursor or related substance not previously described or is a known substance of small molecular weight whose calcium-mobilizing properties have not been fully characterized. This transplantable tumor may represent a model for one form of neoplastic hypercalcemia occurring in man and may have important implications in the general area of calcium and phosphorus homeostasis.

Animals↗

PubMed1989

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy.

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.

Adult↗

PubMed1984

High-resolution parathyroid ultrasonography in familial benign hypercalcemia (familial hypocalciuric hypercalcemia).

Familial benign hypercalcemia, or familial hypocalciuric hypercalcemia (FHH), is frequently confused with primary hyperparathyroidism, but the consistent failure of subtotal parathyroidectomy to normalize serum calcium levels in FHH makes accurate distinction from familial hyperparathyroidism imperative. Because ultrasonography frequently demonstrates enlargement of the parathyroid glands in hyperparathyroidism, we examined 14 hypercalcemic adults (who had not undergone operation) from seven kindreds with FHH by using a high-resolution real-time scanner. We compared our results with those from 156 patients (who had undergone scanning preoperatively) with surgically confirmed hyperparathyroidism. Enlargement of the parathyroid glands was detected ultrasonographically in 137 of 156 (88%) of the total group of patients with hyperparathyroidism and in 17 of 24 patients (71%) with hyperparathyroidism who had hypercalcemia (serum calcium, 10.6 to 11.0 mg/dl) comparable to that of the FHH group (mean value, 10.7 mg/dl). In contrast, the single possible parathyroid lesion seen in the FHH group was substantially smaller (4 mm) than the smallest (7 mm, 75 mg) abnormal gland reliably detected by ultrasonography in the group with hyperparathyroidism and was conceivably normal in size. Patients with FHH have a dramatic absence of ultrasonographic parathyroid enlargement. High-resolution parathyroid ultrasonography may be of ancillary diagnostic benefit in patients with familial hypercalcemia.

Adult↗

PubMed1982

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

The VX2 carcinoma-bearing rabbit is an animal model for tumor-induced hypercalcemia, thought to be due to increased bone destruction effected by prostaglandin E2. The present experiments suggest that the pathophysiology of the hypercalcemia differs from that previously proposed. Tumor was transplanted intramuscularly into 2.5- to 3-kg male New Zealand White rabbits, which were conditioned to a 1.5% calcium diet and treated with daily subcutaneous injections of dichloromethane diphosphonate (10 mg . kg-1 . day-1), a potent inhibitor of bone resorption, or 0.9% NaCl (2 ml . kg-1 . day -1). The diphosphonate had no significant effect on plasma Ca2+ in either group. After day 31, half the animals of each group were fed a calcium-free diet. This normalized the plasma Ca2+ in each VX2-bearing rabbit within 3 to 4 days but had little effect in control rabbits. In a second series of experiments, VX2-bearing rabbits maintained on standard rabbit chow were treated for 11 days with parenteral indomethacin (30--60 mg/day) or 0.9% NaCl. Although indomethacin normalized the markedly elevated urinary excretion of prostaglandin E2, both treatment groups became severely hypercalcemic. Dietary calcium restriction promptly restored to normal the plasma Ca2+ concentration. In a third series of experiments, rabbits were fed standard rabbit chow and treated with oral indomethacin (40 mg/day) while control-rabbits were pair fed in identical chow. Transplantation of VX2 tumor into both groups caused hypercalcemia. We conclude that the hypercalcemia produced by this tumor strain is indomethacin resistant and dependent on an increase in gastrointestinal calcium absorption, not on skeletal calcium mobilization.

Animals↗

PubMed1986

Infantile hypercalcemia with subcutaneous fat necrosis. Report of a case with studies on the pathogenesis of hypercalcemia.

A case of hypercalcemia in neonatal subcutaneous fat necrosis, which was successfully treated with a low Ca and vitamin D-free formula, is described. Low 1,25(OH)2D and severe calciuria, which were considered to result from hypercalcemia itself as well as parathyroid suppression, were noted during the hypercalcemic phase. The oral Ca load test was repeatedly normal, suggesting that intestinal hyperabsorption of Ca was not a cause of the hypercalcemia. Later recurrence of calciuria without hypercalcemia was noted concomitant with softening of indurated calcified necrotic tissue. In this patient, cerebral infarction on the left side was detected by CT scanning.

Cerebral Infarction↗

PubMed1985

Pancreatic islet cell carcinoma with hypercalcemia. Primary hyperparathyroidism or humoral hypercalcemia of malignancy.

A 60-year-old woman presented with hypercalcemia and was found to have metastatic pancreatic islet cell carcinoma. Although clinical features were very suggestive of hyperparathyroidism, her parathyroid hormone levels were not elevated and no abnormal parathyroid tissue was detected by thallium-technetium or computed tomographic scanning techniques. Her hypercalcemia appeared to be due to a humoral factor--distinct from parathyroid hormone--that mimics the action of parathyroid hormone almost exactly. The various tools that may be used to differentiate primary hyperparathyroidism from the humoral hypercalcemia of malignancy are reviewed.

Adenoma, Islet Cell↗

PubMed1982

Hypercalcemia in association with a Leydig cell tumor in the rat: a model for tumor-induced hypercalcemia in man.

The etiology of tumor-induced hypercalcemia was investigated in a transplantable Leydig cell tumor of the Fischer rat. In this model, serum calcium rose from a baseline of 10.4 +/0 0.3 mg/dl to 12.5 + 0.4 mg/dl at day 10 and 16.4 +/- 1.3 mg/dl (p less than 0.001) at day 13 post transplant. Urinary calcium also increased from 1.52 +/- 0.17 mg/d to 3.52 + 0.72 mg/d (Day 12, p less than 0.01). Serum phosphate decreased from a baseline of 7.5 +/- 0.3 mg/dl to 5.5 +/- 0.6 mg/dl at day 13 (p less than 0.05). At day 13 serum immunoreactive parathyroid hormone levels fell 76% from baseline (p less than 0.01). Calcitonin increased from 59 +/- 2 pg/ml to 88 +/- 9 pg/ml (p less than 0.02). The plasma prostaglandin E metabolite, 13,14-dihydro-15-keto-PGE2 increased from 407 +/- 103 pg/ml to 647 +/-62 pg/ml (p less than 0.05) and the active Vit D compound 1,25(OH)2D increased from 94.8 +/- 5.2 pg/ml to 162.3 +/- 11.8 pg/ml (p less than 0.01). Urinary cyclic AMP did not decrease in parallel with the parathyroid hormone level and, in fact, increased from 146 +/- 3 nmol/d to 172 +/- 27 nmol/d (NS). Administration of the cyclooxygenase inhibitor indomethacin (20 mg/Kg/d) or hydrocortisone (50 mg/Kg/d) did not prevent the development of hypercalcemia. This model is similar to many patients with humoral hypercalcemia of malignancy who demonstrate suppression of parathyroid hormone with elevated urinary cyclic AMP excretion and may prove useful in the understanding of the responsible mechanisms.

Animals↗

PubMed1984

Vitamin D metabolism in familial benign hypercalcemia (hypocalciuric hypercalcemia) differs from that in primary hyperparathyroidism.

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.

Adult↗

PubMed1986

[Hypercalcemia in childhood. A boy with asymptomatic hypocalciuric hypercalcemia].

The diagnostic work-up of a patient with (familial) hypocalciuric hypercalcemia (FHH) is discussed. The patient showed no clinical signs of hypercalcemia. There were no indications of vitamin D intoxication. In the first degree family members no hypercalcemia was found. Physical examination was normal. In contrast to hyperparathyroidism, FHH is usually symptomless. Furthermore, FHH is characterized by a normal chloride/phosphate ratio, a normal, but relatively high, serum parathyroid hormone level, a relatively low urinary calcium excretion, a calcium-creatinine clearance ratio less than 0.01 and a normal cyclic AMP excretion.

Calcium↗

PubMed1985

Adult T-cell leukemia complicated by hypercalcemia. Report of three autopsy cases with special reference to the etiologic factor of hypercalcemia.

Three autopsy cases of adult T-cell leukemia (ATL) complicated by a severe hypercalcemia are presented. In two of them, the hypercalcemia itself was the direct cause of death. There was no evidence of an increase of serum PTH in all three cases. Prostaglandins were within normal range in two of them. By a bioassay, a bone-resorbing factor, osteoclast activating factor (OAF)-like substance, was demonstrated in the culture medium of leukemic cells from one patient. Also, various degrees of osteoclastic activation were found in the bones of all three patients by the postmortem examination. It may be that the hypercalcemia occurring in cases of ATL is partly caused by the humoral factor, which is released from leukemic cells and activates a bone resorption by osteoclasts. Similar cases in which a significant activation of osteoclasts was practically demonstrated by histopathologic examination in addition to the detection of a bone-resorbing factor have been rarely reported.

Adult↗

PubMed1983

Hypercalcemia and diffuse osteolytic lesions in the acute phase of chronic myelogenous leukemia. A possible relation between lymphoid transformation and hypercalcemia.

A patient with blastic crisis of chronic myelogenous leukemia (CML) is presented. The acute phase was localized in the lymph nodes and bones, causing severe osteolytic lesions and hypercalcemia. The blast cells were undifferentiated in light microscopy and by histochemical stains. As viewed under electron microscopy, a considerable proportion of the blast cells were of myeloid origin, while immunologic markers and cytogenetics indicated a lymphoid origin. It seems plausible that the patient had a mixed myeloid-lymphoid blast crisis, but that the lymphoid blasts were responsible for the severe osteolytic lesions and the hypercalcemia.

Acute Disease↗

PubMed1984

Bone mineral density and skeletal fractures in familial benign hypercalcemia (hypocalciuric hypercalcemia).

To determine whether familial benign hypercalcemia, or familial hypocalciuric hypercalcemia (FHH), has adverse effects on the skeleton, we measured bone mineral density (BMD) in 31 affected persons from 14 families (16 women and 15 men), ranging in age from 19 to 68 years. Forearm BMD was measured by single-photon absorptiometry, and spinal BMD was measured by dual-photon absorptiometry. In addition, we systematically queried 82 hypercalcemic and 52 normocalcemic family members about skeletal fractures. Both men and women with FHH had normal BMD (expressed as grams per square centimeter) in the lumbar spine, distal radius, and midradius. Osteoporotic-type fractures (vertebrae, hip, and distal radius) were virtually absent in both affected and unaffected family members. Detailed evaluation of larger numbers of of older affected persons may be necessary to resolve this issue definitively, but we conclude provisionally that FHH has no important adverse effects on skeletal health.

Adult↗

PubMed1991

Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer.

A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against synthetic PTHrP-(1-40) and recombinant PTHrP-(1-84) as standard. The detection limit is 2 pmol/L, and intra- and interassay coefficients of variation are 4.8% and 13.6%, respectively. This assay does not detect PTH even at concentrations of up to 2000 pmol/L. Cross-reactivity studies using various synthetic PTHrP peptides localize the antibody-binding epitope between residues 20 and 29. Hypercalcemic patients with a range of solid tumors and no evidence of bone metastases on radionuclide scanning (n = 27) all had detectable PTHrP levels (range, 2.8-51.2 pmol/L). Of 17 patients with solid tumors (other than breast) and bone metastases, 11 (64%) also had detectable PTHrP levels (range, 4.9-47.5 pmol/L). Twenty samples from breast cancer patients with hypercalcemia, 19 with evidence of bone metastases, and 1 with a negative bone scan were assayed, and detectable PTHrP levels were found in 13 (65%; range, 3.8-61.6 pmol/L). Patients with squamous cell carcinomata and normal serum calcium levels (n = 11) had no detectable PTHrP or levels close to the detection limit of the assay (range, less than 2 to 3.7 pmol/L). Plasma levels in normal volunteers were below the detection limit of the assay in all but 1 of 38 normal subjects. Patients with chronic renal failure on hemodialysis (n = 18) and patients with primary hyperparathyroidism (n = 14) all had undetectable PTHrP in this assay. This assay allows positive identification of patients with PTHrP-mediated hypercalcemia and, therefore, should be useful in the clinical investigation of the hypercalcemic patient. Furthermore, it has allowed detection of circulating PTHrP in hypercalcemic breast cancer patients with bone metastases, indicating a significant role for PTHrP in this disease.

Adult↗

PubMed1991

Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. The Hypercalcemia Study Group.

In a prospective, randomized, double-blind, multicenter study, 202 patients with cancer from 19 medical centers were treated for hypercalcemia of malignancy with daily intravenous infusions of etidronate disodium (136 patients) or saline alone (66 patients) for 3 consecutive days. Patients also received up to 3.25 L of saline daily during the treatment period. Of 157 patients for whom data could be evaluated for efficacy, 63% (72/114) of etidronate-treated and 33% (14/43) of saline-treated patients had a normalization of total serum calcium levels. When serum calcium levels were adjusted for albumin (147 assessable patients), 24% of the etidronate- and 7% of the saline-treated patients responded to treatment. No serious side effects or treatment-related deaths occurred. When accompanied by adequate hydration and diuresis, intravenous etidronate was safe and more effective than hydration and diuresis alone in controlling hypercalcemia of malignancy.

Double-Blind Method↗