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PubMed2004

Macrophage inflammatory protein-1alpha induces hypercalcemia in adult T-cell leukemia.

UNLABELLED: Hypercalcemia is observed in >80% of ATL. Serum MIP-1alpha levels were elevated in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without hypercalcemia. We propose that serum MIP-1alpha is a clinical hallmark for hypercalcemia in ATL. INTRODUCTION: High serum cytokines levels are not always associated with hypercalcemia in patients with adult T-cell leukemia (ATL), suggesting that other factors are involved in the pathogenesis of ATL patients with hypercalcemia. This study was designed to determine the role of macrophage inflammatory protein-1alpha (MIP-1alpha), a chemokine recently described as an osteoclast stimulatory factor, in ATL-associated hypercalcemia. MATERIALS AND METHODS: We measured serum interleukin (IL)-1beta, IL-6, TNF-alpha, parathyroid hormone-related protein (PTHrP), and MIP-1alpha levels in ATL patients by enzyme-linked immunosorbent assays. FACScan was used to measure the expression of RANKL on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral blood mononuclear cells (PBMCs) was evaluated by TRACP staining. RESULTS: High serum MIP-1alpha levels were noted in all 24 ATL patients with hypercalcemia and in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1alpha and calcium in ATL patients decreased after effective chemotherapy, emphasizing the role of MIP-1alpha in ATL hypercalcemia. ATL cells spontaneously produced MIP-1alpha. MIP-1alpha significantly enhanced human monocyte (precursor cells of osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell-induced osteoclast formation from PBMCs was inhibited by anti-MIP-1alpha antibody and osteoprotegerin. CONCLUSION: Our results suggest that MIP-1alpha can induce RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the hypercalcemic effect of MIP-1alpha in ATL. We propose that MIP-1alpha is the clinical hallmark of hypercalcemia in ATL and could be a potentially useful therapeutic target.

Carrier Proteins↗
PubMedDate not supplied

Reversible hypercalcemia and hyperparathyroidism associated with lithium therapy: case report and review of literature.

OBJECTIVE: To present a case of reversible hypercalcemia and hyperparathyroidism associated with lithium therapy and to discuss the pathophysiology and management of this condition. METHODS: The clinical and laboratory findings in a patient with lithium-induced hypercalcemia are presented. A PubMed search for associated English language articles (with use of the key words lithium, hypercalcemia, and hyperparathyroidism) was conducted, and the relevant literature to date was reviewed. An approach to the management of patients with lithium-induced hypercalcemia is suggested. RESULTS: A 56-year-old man was referred for management of incidentally discovered hypercalcemia. The serum parathyroid hormone (PTH) level was increased; serum phosphorus and 24-hour urine calcium excretion were both normal. For 5 years, he had been treated with lithium carbonate for bipolar affective disorder. The laboratory features were consistent with lithium-induced primary hyperparathyroidism. Discontinuation of lithium treatment resulted in normalization of serum calcium and PTH levels. Review of the literature suggests that hypercalcemia and hyperparathyroidism are common consequences of lithium therapy. CONCLUSION: Hypercalcemia associated with lithium-induced hyperparathyroidism is a common, but underrecognized, complication of lithium therapy. Most patients have mild asymptomatic hypercalcemia. The long-term consequences of mild lithium-induced hypercalcemia are unknown. After discontinuation of lithium, the hypercalcemia may not always resolve; thus, parathyroidectomy may be necessary in some cases. Measurement of the serum calcium and PTH levels before and periodically after the initiation of lithium treatment is advisable. The appropriate monitoring of patients with lithium-induced hypercalcemia and decisions regarding parathyroidectomy are unclear. The decision to continue lithium therapy in the presence of hypercalcemia should be individualized.

Bipolar Disorder↗
PubMed1988

Reliability of QT intervals as indicators of clinical hypercalcemia.

Reliability of corrected QT intervals (QoTc, QaTc, and QeTc) as indicators of clinical hypercalcemia was assessed in 14 hypercalcemic patients. Hypercalcemia was severe to extreme (serum calcium 14.9 to 22.8 mg/dl) in 11, moderate (13.4 mg/dl) in 1, and mild (12.2 and 11.8 mg/dl) in 2 patients. QT intervals during hypercalcemia were compared with those during normocalcemia either before or after development of hypercalcemia. QeTc interval showed neither significant correlation with serum calcium nor any consistent pattern of change with development of hypercalcemia or normalization of serum calcium. In contrast, QoTc and QaTc intervals shortened with development of hypercalcemia and returned toward normal with normalization of serum calcium in all the patients, and showed significant correlation with serum calcium (QoTc: r = -0.77, p less than 0.001, n = 35; QaTc: r = 0.82, p less than 0.001, n = 35). QaTc was short (less than 0.30 s) in all the ECGs in severe and moderate hypercalcemia and in 2 of the 5 ECGs in mild hypercalcemia. Combination of short QoTc (less than 0.18 s) and short QaTc was found to be highly specific for, and was present in 65% of ECGs, in moderate and severe hypercalcemia. Combination of normal QoTc (greater than 0.18 s) and normal QaTc (greater than 0.30 s) was not observed in moderate or severe hypercalcemia. We conclude that QoTc and QaTc intervals are reliable indicators of clinical hypercalcemia.

Adult↗
PubMed1985

Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes.

Autosomal dominant familial hypocalciuric hypercalcemia was found in a kindred with neonatal severe primary hyperparathyroidism, previously judged to be an autosomal recessive trait. Mild hypercalcemia was documented in eight members representing three generations. Mild hypercalcemia was documented at an age as early as one week. In seven adults presumed to be heterozygotes, urinary calcium levels were in the same range as for familial hypocalciuric hypercalcemia. An additional adult member (who previously underwent parathyroidectomy for neonatal severe primary hyperparathyroidism) showed an abnormality in renal clearance of calcium and sodium characteristic of combined familial hypocalciuric hypercalcemia and surgical hypoparathyroidism. Parathyroidectomy in three hypercalcemic members did not cause normocalcemia. Unlike other kindreds with familial hypocalciuric hypercalcemia in whom hypercalcemia is consistent over time and moderate in heterozygotes, this kindred was characterized by heterozygotes showing hypercalcemia that was intermittent and mild. The consanguineous parents of the two previously described severely affected neonates were judged to be heterozygotes for familial hypocalciuric hypercalcemia. In conclusion, (1) a gene presenting as familial hypocalciuric hypercalcemia can be expressed as hypercalcemia that is intermittent and very mild in heterozygotes; (2) such a gene can cause neonatal severe primary hyperparathyroidism in homozygotes.

Adolescent↗
PubMed1990

Overview of cancer-related hypercalcemia: epidemiology and etiology.

Hypercalcemia is one of the most serious metabolic disorders associated with cancer. The incidence and clinical circumstances associated with hypercalcemia vary in different types of cancer. Hypercalcemia is the most frequent metabolic complication of breast cancer and is usually related to widespread osteolytic metastases; however, local and systemic humoral factors mediating bone resorption have been described. In some patients with breast cancer, hypercalcemia results from treatment with estrogens, antiestrogens, androgens, or progestins. Coexisting primary hyperparathyroidism rarely confounds the diagnosis. In patients with lung cancer, the incidence of hypercalcemia varies with histology and is often unrelated to bone metastases. Hypercalcemia may occur either late or early in the disease but is seldom a presenting symptom. In patients with cancers of the head and neck region, hypercalcemia is most often associated with advanced recurrent and terminal disease, presumably humorally mediated. In renal cell carcinoma, hypercalcemia is also an adverse prognostic indicator, commonly mediated by humoral factors. On the other hand, almost all patients with multiple myeloma have extensive osteolytic bone destruction and hypercalcemia is frequently a presenting symptom. Hypercalcemia is uncommon in most lymphomas; however, it is usually a prominent feature of adult T-cell lymphomas and also occurs in some large cell, diffuse B-cell lymphomas. Awareness of the setting in which hypercalcemia of malignancy occurs will lead to its prompt diagnosis and institution of appropriate therapy.

Humans↗
PubMed2006

Tamoxifen flare hypercalcemia: an additional support for gallium nitrate usage.

In 12 of 93 hypercalcemic patients with metastatic advanced breast cancer treated with tamoxifen the most common life-threatening metabolic complication of flare hypercalcemia developed. All the hypercalcemic patients had osteolytic or mixed lytic and blastic bone metastases. In patients with advanced breast cancer, hypercalcemia develops within the first few weeks of initiation of tamoxifen therapy. In our study group, calcium levels were measured frequently in both serum and urine samples by a semi-autoanalyzer and an autoanalyzer, using standard methods. Elevation of calcium levels was noticed in the tamoxifen-receiving hypercalcemic breast cancer patients, and levels returned to normal when tamoxifen was withdrawn. The median duration of flare hypercalcemia was 9 days (range, 4-16 days). The median calcium value was 13.6 mg/dl (range, 11.7-15.8). The diagnosis of tamoxifen flare hypercalcemia was based on the normal pretreatment serum or urine calcium values and the occurrence of hypercalcemia within the first few weeks of tamoxifen initiation. There are no specific treatment recommendations for hormone flare hypercalcemia, except for tamoxifen withdrawal, which is usually temporary, and the introduction of a low dose of an antihypercalcemic drug. We evaluated the effect of such a drug, gallium nitrate, on flare hypercalcemia. All the patients were treated with hydration, and 6 patients, whose calcium level was above 13.6 mg/dl, were treated with a moderate dose of gallium nitrate (200 mg/m(2) per kg) for 5 consecutive days, they achieved normocalcemia and continued with tamoxifen. The median time from hormonal drug initiation to flare hypercalcemia was 17.5 days, and median duration was 9 days. The above result indicates that the serious metabolic complication of hypercalcemia develops due to the iatrogenic effect of tamoxifen, but it can be controlled with an antihypercalcemic drug, gallium nitrate, while continuing tamoxifen therapy. It seems that the use of gallium nitrate in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature tamoxifen discontinuance or withdrawal.

Adult↗
PubMed2001

[Tumor-induced hypercalcemia. Review of bisphosphonate treatment].

INTRODUCTION: The incidence of tumor-induced hypercalcemia is between 10 to 20%. New treatments justify this review article. CURRENT KNOWLEDGE AND KEY POINTS: Tumor-induced hypercalcemia (half of all hypercalcemia) is divided into two groups: hematological tumors (10%), and solid tumors (90%), with osteolytic hypercalcemia and humoral hypercalcemia of malignancy (HHM: mediators include PTHrP). The two most common causes of tumor-induced hypercalcemia are lung cancer and breast cancer. Tumor-induced hypercalcemia most commonly disturbs gastrointestinal, neurological, renal and cardiovascular functions. These symptoms may be erroneously attributed to the underlying malignancy or its therapy. Prognosis of tumor-induced hypercalcemia is very poor, with median survival being about 3 months. Bisphosphonates have emerged as the standard treatment of tumor-induced hypercalcemia. The intravenous administration of isotonic saline is the first step in the management of tumor-induced hypercalcemia. Specific treatment of cancer remains essential to prevent TIH relapse. FUTURE PROSPECTS AND PROJECTS: New bisphosphonates have appeared, the most potent known bisphosphonate today is zoledronate.

Diagnosis, Differential↗
PubMed2001

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.

Adult↗
PubMed2003

Current management strategies for hypercalcemia.

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials. Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication. Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days). The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.

Bone Diseases↗
PubMed1994

[A case of temporary severe disequilibrium hypercalcemia].

The patient, a 69-year-old woman, was admitted to Osaka City University Hospital on July 25, 1992, for severe hypercalcemia. Laboratory data on admission revealed severe hypercalcemia of 14.9 mg/dl and renal dysfunction with serum creatinine of 2.9 mg/dl. As reflected by increased urinary excretions of pyridinoline and deoxypyridinoline and suppressed serum levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, increased bone resorption seemed to be a main factor for the development of hypercalcemia. The development of hypercalcemia seemed to be acute because of (i) her severe symptoms caused by hypercalcemia and (ii) impaired renal function which improved after normalization of serum calcium. Following combination therapy of saline infusion and furosemide, there was a gradual decrease and later normalization of serum calcium together with serum creatinine. Even 8 months after discontinuation of the therapy for hypercalcemia, the serum calcium level has remained within the normal range. Measurement of serum factors which have hypercalcemia effects such as PTH, parathyroid hormone-related peptide and cytokines (interleukin-1 alpha, interleukin-1 beta, interleukin-2, interleukin-6 and tumor necrosis factor-alpha) were all within the normal range. In summary, hypercalcemia in this patient was regarded as a kind of disequilibrium hypercalcemia due to a combination of increased bone resorption and decreased renal capacity to excrete calcium. Furthermore, since it was temporary and has not recurred despite no treatment, her hypercalcemia developed due to imbalance in calcium regulation but not due to any organic disease.

Acute Disease↗
PubMed1994

A case of temporary severe disequilibrium hypercalcemia.

We report a rare case of temporary and severe hypercalcemia: the patient, a 69-year-old woman, was admitted to Osaka City University Hospital on July 25, 1992, for severe hypercalcemia. The laboratory data on admission revealed severe hypercalcemia (14.9 mg/dl) and renal dysfunction with increased serum creatinine level (2.9 mg/dl). The urinary excretion of pyridinoline and deoxypyridinoline was increased, and serum levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D were decreased. The data suggested that increased bone resorption was a probable main factor in the development of the hypercalcemia. The development of hypercalcemia seemed to be of acute onset because of (1) her severe symptoms caused by hypercalcemia and (2) impaired renal function which was improved after normalization of serum calcium level. Combination therapy with saline infusion and furosemide was administered, and there was a gradual decrease and subsequent normalization of serum calcium level along with serum creatinine. Even 8 months after discontinuation of the therapy for hypercalcemia, the serum calcium level remained within the normal range. The measured values of serum factors which are suspected to have a hypercalcemic effect, such as PTH, parathyroid hormone-related peptide and the cytokines (interleukin-1 alpha, interleukin-1 beta, interleukin-2, interleukin-6 and tumor necrosis factor-alpha) were all within the normal range. In summary, the hypercalcemia in this patient was regarded to be a type of disequilibrium hypercalcemia due to a combination of increased bone resorption and decreased renal capacity to excrete calcium. Furthermore, since it was temporary and did not recur even in the absence of treatment, the hypercalcemia was concluded to have developed due to an imbalance in calcium regulation rather than as a result of organic disease.

Aged↗
PubMed1994

[Hypercalcemia in malignancy].

Malignant tumors are often complicated by hypercalcemia (malignancy associated hypercalcemia: MAHC) which causes various clinical symptoms. Hypercalcemia may occasionally lead to death. Unfortunately, many physicians caring for patients with malignant diseases are not aware of this danger. Hypercalcemia is seen in about 15% of patients with solid tumors. This condition is more frequent in some malignant proliferative hematological diseases. In patients with multiple myeloma, the incidence of hypercalcemia is about 20%. The rate of complication by hypercalcemia is as high as 80% in patients with adult T cell leukemia. The symptoms of hypercalcemia include anorexia, easy fatigability, nausea, and vomiting. These symptoms are often mistaken for adverse effects of anticancer drugs or as signs of aggravation of malignant disease. If abnormal thirst and polydipsia are noted in patients with malignant disease, a diagnosis of MAHC should always be considered because these two symptoms are highly characteristic of hypercalcemia. Caution should be exercised when CNS symptoms such as unstable emotions or somnolence are noted. These symptoms in patients with MAHC may lead to death, if untreated. The corrected serum calcium level should always be monitored in patients with malignant disease, so that a possible diagnosis of MAHC may not be overlooked when these symptoms appear. MAHC is caused by the bone resorption stimulating factor (BRSF), which is produced and secreted by the tumor cells. BRSF may act systemically to cause increased bone resorption, resulting in hypercalcemia. MAHC occurring in this manner is called the 'humoral hypercalcemia of malignancy (HHM)'. BRSF produced by multiple myeloma or bone metastasis enhances bone resorption through local osteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin↗
PubMed1995

[Hypercalcemia and squamous cell carcinoma of the upper respiratory-digestive tracts. Incidence and prognosis].

We performed a retrospective analysis on all head and neck cancers with hypercalcemia seen between January 1988 and June 1993 at the Centre Oscar-Lambret, cancer center of northern France. Hypercalcemia, non albumin-corrected, higher than 2.60 mmol/l was observed in 173 of 3,394 consecutive patients (5%). Median age of patients with hypercalcemia was 53 years and 97% of these patients were males. All patients with hypercalcemia had advanced or recurrent and/or metastatic squamous cell carcinoma of head and neck (SCCHN); 31 of them were not pretreated. There was no significant difference in histology between patients with or without hypercalcemia, but hypercalcemia was most commonly associated with lesions of the oropharynx (p = 0.00001). The median of calcemia was of 2.83 mmol/l (2.61-4.70). Gastrointestinal and neurologic symptoms respectively occurred in 24% and in 14% of patients and bone metastases in 25% of patients. Median survival after the first determination of hypercalcemia was of 7 weeks (0-128) for the overall group of 173 patients and of 12 weeks (1-128) for those 31 patients with hypercalcemia at initial diagnosis. Prognosis associated factors were: efficacy of antitumour treatment, performance status and hypercalcemia superior or not to 3 mmol/l. We concluded that hypercalcemia in head and neck cancer is usually a late manifestation associated with advanced, recurrent and/or metastatic disease and carries a poor prognosis. The prolongation of survival can be obtained in some patients if an effective antitumour treatment is feasible.

Adult↗
PubMed1982

Hypercalcemia associated with gynecologic malignancies: biochemical characterization.

Fasting calcium excretion, renal phosphorus threshold, plasma 1,25 dihydroxyvitamin D, immunoreactive PTH, nephrogenous cyclic AMP excretion, and tumor burden were assessed in nine patients with gynecologic neoplasms and hypercalcemia. Gynecologic neoplasms were responsible for hypercalcemia in seven of 34 (20.5%) consecutive patients with malignancy-associated hypercalcemia. The tumor burden in each patient was large. Three of four endometrial carcinomas contained squamous elements. All patients displayed biochemical evidence of nonparathyroid humorally mediated hypercalcemia (bone resorption). Treatment of hypercalcemia did not appear to diminish production of the humoral calcemic factor but eradication of tumor eliminated biochemical evidence of the humoral syndrome. It can be concluded that (1) gynecologic neoplasms are a frequent cause of malignancy-associated hypercalcemia, (2) humoral mechanisms appeared to be responsible for the hypercalcemia in 100% of the patients in this series, (3) squamous features occur with unexpected frequency in hypercalcemic endometrial carcinoma, (4) the presence of hypercalcemia connotes a large tumor burden, and (5) treatment directed at the neoplasm (but not treatment directed at hypercalcemia) may eliminate evidence of ectopic calcemic hormone production.

Adolescent↗
PubMed1991

Evaluation of bone resorption and renal tubular reabsorption of calcium and phosphate in malignant and nonmalignant hypercalcemia.

Tubular reabsorption of calcium (Ca) is becoming recognized as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specific treatment. Bone resorption (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nonmalignant hypercalcemia, BRI was markedly increased in vitamin D intoxication, sarcoidosis, and immobilization. In primary hyperparathyroidism (PHP), BRI was moderately increased. TRCaI was abnormally elevated in PHP, but normal in vitamin D intoxication, sarcoidosis, and immobilization. In malignant hypercalcemia, TmPi/GFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PHP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPi/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation in tubular Ca reabsorption in half the patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%. Increased TRCaI is restricted to some types of tumor, whereas decreased TmPi/GFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a significant increase in mean TRCaI was only observed in PHP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.

Absorption↗
PubMed2000

Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy.

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1.25(OH)2D3. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1.25(OH)2D3 with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1.25(OH)2D3 by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1.25(OH)2D3 in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1.25(OH)2D3 in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.

Adult↗
PubMed1985

Effects of acute hypercalcemia on exocrine pancreatic secretion in the cat.

To investigate the effects of acute hypercalcemia on exocrine pancreatic secretion, anesthetized cats were given calcium intravenously. Increasing hypercalcemia (3.7-6.3 mmol/L) evoked a dose-dependent increase in enzyme output that was 12 times greater than in normocalcemic controls (p less than 0.001) and was 60% of subsequent maximal stimulation with intravenous cholecystokinin (CCK). The effect of hypercalcemia on enzyme secretion was abolished when CCK was administered 60 min before calcium and at a dose to cause maximal enzyme output. Atropine did not prevent the calcium-induced increase in enzyme secretion. Pancreatic fluid and bicarbonate outputs were not influenced by hypercalcemia during intravenous administration of small amounts of secretin, but were increased by addition of CCK to the secretin infusion. Hypercalcemia did not induce macroscopic or light-microscopic changes in pancreatic morphology. Plasma levels of both CCK and gastrin were increased (p less than 0.01) during hypercalcemia, with and without precalcium administration of CCK; atropine significantly inhibited (p less than 0.05), but did not abolish the calcium-induced releases of both peptides. These data suggest that in the anesthetized cat, acute hypercalcemia induced by intravenous calcium infusion stimulates pancreatic secretion of enzymes, but not fluid and bicarbonate. Acute hypercalcemia also causes release of CCK and, as shown previously, gastrin. The findings suggest that the stimulatory effect of hypercalcemia on pancreatic enzyme secretion is not dependent on intact cholinergic pathways and is probably not exclusively mediated by release of CCK or gastrin.

Acute Disease↗
PubMed2006

Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.

Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.

Adolescent↗