Abnormal Calcium Metabolism Research Articles

Hyperthermie maligne anesthésique

Our knowledge about malignant hyperthermia (MH) has been markedly improved since 10 years, primarily due to molecular genetics. Susceptibility to MH is based on an abnormal calcium metabolism within the skeletal muscle fibre. This is most probably caused by a defective calcium release channel in the sarcoplasmic reticulum, e.g. the ryanodine receptor. This defect is due to genetic mutations essentially located into the RYR1 gene. Mortality of MH crisis has been dramatically decreased since the widespread use of capnograph in operating theatre and the immediate infusion of dantrolene sodium. However, incomplete and non typical forms of MH do exist, and require further testing for MH susceptibility for the probant and his (her) family. The reference test is currently the in vitro contracture test (IVCT), which exposes muscle strips to incremental concentration of halothane and caffeine. Genetic analysis has emerged as a viable supplement to IVCT. Safe anesthesia for MH susceptible patients must avoid the use of volatile agents and succinylcholine. Central core disease and maybe exercise-induced rhabdomyolysis have an increased risk for MH susceptibility.

Understanding hypercalcemia

PREVIEWHypercalcemia is a common metabolic condition encountered in both inpatient and outpatient settings. This article, the first of two parts, provides an overview of normal and abnormal calcium metabolism. A discussion of the various causes of hypercalcemia, as well as signs and symptoms, is included. The second article, which will appear in an upcoming issue of POSTGRADUATE MEDICINE, reviews the diagnostic evaluation of the patient with an elevated serum calcium concentration and presents appropriate therapeutic strategies.

Examination of megalin in renal tubular epithelium from patients with Dent disease

Dent disease is characteristic for the urinary loss of low-molecular-weight proteins and calcium, leading to renal calcification and, in some patients, chronic renal failure. This disorder is caused by loss-of-function mutations in the renal chloride channel gene, CLCN5. The animal model of this disease has demonstrated the possible role of disturbed megalin expression, which is a member of the low-density lipoprotein receptor family and is associated with renal reabsorption of a variety of proteins, in Dent disease. We examined the expression of megalin in the renal tubular epithelium of two unrelated patients with Dent disease. One patient, whose CLCN5 gene was completely deleted, showed significantly decreased staining of megalin compared with controls, while there was no change in another patient with partial deletion of the gene. These results demonstrated that mutation of CLCN5 in some patients with Dent disease may impair the expression of megalin, resulting in abnormal calcium metabolism, manifested as hypercalciuria and nephrocalcinosis.

Physiopathologie de la Sclérose Latérale Amyotrophique : approches thérapeutiques

The finding in 1993 of a mutation of the copper zinc super oxyde dismutase (SOD1) provides a major breakthrough in the understanding of the etiopathogenic mechanism of amyotrophic lateral sclerosis. Various mechanisms are commonly implied in the motor neurons degeneration. Excitotoxicity and calcium metabolism abnormalities are one of the most frequently confirmed hypotheses. It allowed proposing riluzole which remains the only one drug proved to be active in the disease. The role of growth factors remains controversial and all therapeutic trials performed with these molecules remained negative. Oxidative stress abnormalities are demonstrated by number of studies but their direct therapeutic application remains to be demonstrated. Apoptosis and the role of mitochondria has been definitely confirmed and open a new therapeutic avenue for the next few years.

Calcium Metabolism in the Morbidly Obese

Morbidly obese patients are known to have abnormal calcium metabolism compared with the non-obese, but the clinical significance of this is unknown. Since surgical treatment of obesity may itself cause hyperparathyroidism, it is important to understand the preoperative physiology of these patients. 213 consecutive patients (M 37 : F 176, ages 21-68) presenting for surgical treatment of morbid obesity between October 2000 and June 2002 were prospectively evaluated. Preoperative levels of serum calcium corrected for albumin, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured. We recorded the prevalence of abnormalities in study parameters and correlated them with PTH levels. Hyperparathyroidism (PTH >65 pg/ml) was present in 25.0% of subjects. By contrast, abnormalities of serum calcium were rare. The prevalence of hypocalcemia was 3.5%, and of hypercalcemia was 0.5%. Only 4.3% of patients had increased levels of alkaline phosphatase. 21.1% of patients had abnormally low levels of 25-hydroxyvitamin D (median 15 ng/ml), and 23.1% had increased levels of 1,25-dihydroxyvitamin D (median 49 pg/ml). PTH was positively correlated with BMI (r=.30, P=<.001) and 25-dihydroxyvitamin D (r=.27, P=.01), and was negatively correlated with alkaline phosphatase (r=.21, P=.02). There was no correlation between PTH and calcium, 1,25-dihydoxyvitamin D, age, or sex. Parathyroid hormone levels are increased in the morbidly obese and are positively correlated with BMI. Recognition of preoperative hyperparathyroidism is important because of the risk of attributing postoperative hyperparathyroidism to the effects of surgery. Further studies are needed to elucidate the cause of elevated PTH in these patients.

Factors influencing metacarpal bone mineral density in adults with cerebral palsy.

Several studies have examined bone mineral density (BMD) and related factors in children with cerebral palsy, but there are no such studies of adults with cerebral palsy. We evaluated BMD in 123 institutionalized adults (51 men aged 21-41 years and 72 premenopausal women aged 24-46 years) with cerebral palsy, and examined the associations of BMD with mobility level, use of anticonvulsant drugs, and abnormal calcium metabolism status. Hand radiographs were used to measure BMD of the second metacarpal bone (mBMD). Body weight (kg), height (m), and body mass index (BMI) were recorded. Serum calcium, phosphate, and alkaline phosphatase were measured. Abnormal calcium metabolism, defined as calcium <8.5 mg/dl, phosphate <2.6 mg/dl, or alkaline phosphatase >260 U/l, was identified in 28% of the men and 31% of the women. Multiple regression analysis showed that the use of anticonvulsant drugs was significantly associated with lower mBMD in both sexes. Higher alkaline phosphatase level was significantly associated with lower mBMD in men. Mobility level (ambulation) was significantly associated with higher mBMD in women. Neither age nor BMI correlated with mBMD. Our findings indicated poor bone health status in adults with cerebral palsy and the existence of several factors that could affect bone metabolism in these patients.

Mineralization of the basal ganglia: implications for neuropsychiatry, pathology and neuroimaging

This article examines the evidence for and against the existence of basal ganglia mineralization as a defined clinico–pathological entity. In reviewing the literature on basal ganglia mineralization, this article emphasizes evidence derived from different neuroimaging modalities, genetics, metabolic studies, postmortem series and their possible neuropsychiatric correlates. Relevant articles were collected through Medline and Index Medicus searches. Researchers have encountered multiple difficulties in accepting basal ganglia mineralization as a distinct entity. This syndrome lacks set clinical criteria or a unique etiology; not surprisingly, numerous articles have applied varied definitions. Because many of the reported cases have not been examined postmortem, both the extent and nature of their mineralization remains uncertain. Furthermore, researchers have considered small foci of basal ganglia mineralization a normal phenomenon of aging. However, when brain deposits are extensive, they are associated with a set of age-dependent, progressive clinical symptoms. They include cognitive impairment, extrapyramidal symptoms and psychosis. Most cases are related to abnormalities of calcium metabolism, but rare familial cases of idiopathic origin have been reported. Overabundant mineralization of the brain is judged pathological based on its amount, distribution and accompanying clinical symptoms. Although its relation with calcium dysregulation is well known, modern studies have emphasized abnormalities of iron and dopamine metabolism. The authors suggest that these metabolic abnormalities may link basal ganglia mineralization to psychotic symptomatology.

Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls.

Abnormalities of calcium and vitamin D metabolism in cystic fibrosis (CF) are well documented. We tested the hypothesis that alterations in calcium metabolism are related to vitamin D deficiency, and that bone resorption is increased relative to accretion in patients with CF. Calcitropic hormones, electrolytes, osteocalcin (OC) and bone alkaline phosphatase (BAP), (markers of bone mineralisation), urinary deoxypyridinoline [total (t) Dpd, a marker of bone resorption] and lumbar spine bone mineral density (LS BMD), expressed as a z-score, were measured in 149 (81 M) CF and 141 (61 M) control children aged 5.3-10.99 years, adolescents aged 11-17.99 years and adults aged 18-55.9 years. Data were analysed by multiple regression to adjust for age. In patients, FEV(1)% predicted and CRP (as disease severity markers), genotype and pancreatic status (PS) were recorded. The distribution of PTH differed between groups ( P<0.0001), with CF levels both below and above the control range. 25OH vitamin D (25OHD) was not different in control and CF subjects ( P=0.06). Active hormonal vitamin D (1,25(OH)(2)D) was lower in the CF group ( P<0.0001), not explained by 25OHD or disease severity, as was serum magnesium ( P<0.0001). OC was decreased in CF adults ( P=0.004), and tDpd increased in CF adolescents ( P=0.003) and adults ( P=0.03). The ratio of OC to tDpd (a measure of bone coupling) was similar in CF and control children, but decreased in CF adolescents ( P=0.04) and adults ( P=0.02), suggesting decreased overall bone accrual in CF adolescents and uncoupling of bone balance in adults. 1,25(OH)2D was weakly correlated with OC in CF children ( r=0.43, P=0.01), and with tDpd in CF and control adolescents ( r=0.33, P=0.05 and r=0.36, P=0.02, respectively); thus there was limited evidence of association of calcitropic hormones, which had an abnormal pattern in all age groups, with bone turnover. There was no association between calcitropic hormones or bone turnover markers and LS BMD z-score. Despite vitamin D sufficiency, abnormalities of calcium metabolism and bone turnover markers were still apparent and bone accretion was decreased relative to resorption in the CF adolescent and adult groups. These changes were not fully explained by disease severity or genotype, but are consistent with reports of decreased BMD and unique bone histomorphometry in older subjects with CF.

Pathophysiology and clinical features of adynamic bone disease

Adynamic bone disease is characterized by an extremely low bone turnover bone due to the lack of osteoid formation. An abnormal calcium metabolism refractory to hypocalcemia lies behind the development of adynamic bone. Extraskeletal calcification is often seen in patients with adynamic bone disease. Hypoparathyroidism appeared to be an life prognosis limiting factor in dialysis patients. Most of them are considered to be with adynamic bone disease.

Ectopic calcification in Klotho mice

We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as klotho. The most characteristic phenotypes seem to be caused by abnormalities in calcium metabolism. Furthermore the klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus in the brain, and the main cells of the parathyroid gland. Klotho plays a critical role for the regulation of calcium and phosphorus homeostasis by negatively regulating the synthesis of active vitamin D. The deficiency of the klotho gene results in degradation of cells by the activation of calcium dependent proteolysis in kidney, lung, heart and other tissues. Importantly, the increased activation of calcium- dependent proteolysis occurs in tissues of old mice together with the down regulation of klotho gene expression.

Sarcoidosis of the Thyroid and Kidneys and Calcium Metabolism

In sarcoidosis, the thyroid and the kidneys are infrequently affected. Clinically recognizable thyroid involvement occurs in < 1% of sarcoidosis patients. Hyperthyroidism, myxodema, and thyroid occur with an equal frequency. It is important to distinguish sarcoidosis of the thyroid from other infections and disorders of the gland. Renal involvement may present as granulomatous infiltration of the renal parenchyma, glomerulonephritis, renal arteritis, and nephrocalcinosis or renal stones. The latter are due to abnormalities of calcium metabolism. Hypercalcemia occurs in about 10 to 13% of sarcoidosis patients; hypercalciuria is three times more frequent. Calcium abnormalities may precede, follow, or occur at any time during the course of sarcoidosis. An endogenous overproduction of 1,25-dihydroxyvitamin D [1,25-(OH (2))-D (3)] by granulomatous tissue and activated macrophages results in an increase of intestinal absorption of calcium. Corticosteriods, chloroquine, and hydroxychloroquine subdue 1,25-(OH (2))-D (3) production and correct hypercalcemia and hypercalciuria.

High serum retinyl esters are not associated with reduced bone mineral density in the Third National Health And Nutrition Examination Survey, 1988-1994.

Hypervitaminosis A is sometimes associated with abnormalities of calcium metabolism and bone mineral status. A recent study found a negative association between reported dietary vitamin A intake and bone mineral density (BMD). Some segments of the U.S. population have high fasting serum retinyl ester concentrations, a physiological marker that may reflect high and possibly excessive vitamin A intake. We examined the association between fasting serum retinyl esters and BMD in the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III), a large, nationally representative sample of the U.S. population. BMD was measured for the femoral neck, trochanter, intertrochanter, and total hip on all nonpregnant participants aged > or = 20 years; 5,790 participants also had complete data on fasting serum retinyl esters and covariates including age, body mass index (BMI), smoking, alcohol consumption, dietary supplement use, diabetes, physical activity, and, among women, parity, menopausal status, and the use of oral contraceptives or estrogen-replacement therapy. The sample included non-Hispanic white, non-Hispanic black, and Mexican American men and women. We examined the association between fasting serum retinyl esters and BMD at each site, controlling for covariates with multiple linear regression. We examined the association with osteopenia and osteoporosis with multiple logistic regression. Although the prevalences of high fasting serum retinyl esters concentration and low BMD were both substantial in this sample, there were no significant associations between fasting serum retinyl esters and any measure of bone mineral status.

Bone metabolic markers and diagnosis of abnormal bone and calcium metabolism

Bone metabolic markers increase in blood or urine, when bone formation or bone resorption accelerates. Reference values of bone metabolic markers are determined in male or female, and in pre- or post-menopause, respectively. Values of bone metabolic markers in most patients with primary osteoporosis were distributed within a reference value, mean+/-1.96 SD. When measured values exceeded a reference values, we should survey a possibility of abnormal calcium or bone metabolism such as primary hyperparathyroidism, renal osteodystrophy, hyperthyroidism and Paget's disease of bone or bone metastasis associated with malignant tumor.

Bone mineral density in women with essential hypertension

Recent studies have reported the abnormalities in calcium metabolism at the systemic level in human hypertension as well as in experimental hypertension. Because bone is the largest store of calcium in the body, the bone calcium content and mineralization may represent the entire calcium balance. The present study was undertaken to investigate the bone mineral density (BMD) in women with essential hypertension by means of the dual-energy X-ray absorptiometric (DXA) method. The DXA analysis showed a significant decrease in BMD in female hypertensive subjects compared with normotensive subjects. In addition, the BMD was inversely correlated with systolic blood pressure in women. The 24-h urinary calcium excretion was significantly greater in female hypertensive subjects than in female normotensive subjects. Furthermore, the greater the urinary calcium excretion, the lower the BMD in women. The values of serum total calcium, total magnesium, ionized calcium, and 1, 25(OH) 2 vitamin D were not different between hypertensive and normotensive subjects. The results of the present study demonstrated that DXA provided an index of whole calcium balance, and suggest that high blood pressure might be associated with reduced BMD in female hypertension.

Association between a polymorphism of the transforming growth factor-beta1 gene and genetic susceptibility to ossification of the posterior longitudinal ligament in Japanese patients.

A study was conducted to determine the association between polymorphism of the transforming growth factor-beta1 (TGF-beta1) gene and ossification of the posterior longitudinal ligament (OPLL) prevalence. To examine whether the T869-->C polymorphism of the TGF-beta1 gene is associated with genetic susceptibility to OPLL in Japanese subjects. In the posterior longitudinal ligament, OPLL is associated with abnormal calcium metabolism. Several candidate genes are associated with the prevalence of OPLL. In the ossified matrix and chondrocytes of adjacent cartilaginous areas of OPLL, TGF-beta1 is overexpressed. The TGF-beta1 genotype was identified with an allele-specific polymerase chain reaction method in 319 Japanese subjects (46 subjects with OPLL and 273 control subjects). There was a significant association between the T869-->C genotype and the prevalence of OPLL in the cervical spine. Multivariable logistic regression analysis, adjusted for gender, age, height, and body weight, showed that the frequency of the C allele was significantly higher in subjects with OPLL than in control subjects. The T869-->C polymorphism of the TGF-beta1 gene is a genetic determinant of a predisposition to OPLL, with the C allele representing a risk factor for genetic susceptibility to OPLL in Japanese subjects. Therefore, TGF-beta1 genotyping may be useful in the prevention of OPLL.

Hypercalcemia in granulomatous disorders: a clinical review.

Hypercalcemia occurs in most granulomatous disorders. High serum calcium levels are seen in about 10% of patients with sarcoidosis; hypercalciuria is about three times more frequent. Tuberculosis, fungal granulomas, berylliosis, and lymphomas are other conditions that are associated with disorders of calcium metabolism. These abnormalities of calcium metabolism are due to dysregulated production of 1,25-(OH2)D3 (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation. Undetected hypercalcemia and hypercalciuria can cause nephrocalcinosis, renal stones, and renal failure. Corticosteroids cause prompt reversal of the metabolic defect. Chloroquine, hydroxychloroquine, and ketoconazole are the drugs that should be used if the patient fails to respond or develops dangerous side effects to corticosteroid therapy.

Calcium metabolism in sarcoidosis and its clinical implications.

: To examine the clinical implications of disturbed calcium metabolism in sarcoidosis and how the pathophysiology affects management strategies. : The literature concerning calcium metabolism in sarcoidosis was reviewed. : Dysregulated calcium metabolism is a well-recognized complication of sarcoidosis, resulting in hypercalcaemia (prevalence 5-10%), hypercalcuria (40-62%) and reduced bone density (40-55%). Extrarenal synthesis of calcitriol [1,25(OH)(2)D(3)] is central to the pathogenesis of abnormal calcium homeostasis, but alterations in parathyroid hormone (PTH) activity and the expression of PTH-related peptide have also been demonstrated. The immunosuppressive properties of calcitriol suggest that the raised levels seen in sarcoidosis could represent an adaptive response to the undefined antigen that causes sarcoidosis. : The mechanisms of abnormal calcium metabolism in sarcoidosis need to be understood when treating hypercalcaemia, hypercalcuria and corticosteroid-induced osteoporosis. Studies are required to determine if the currently available therapies for osteoporosis are safe and effective in sarcoidosis.

Left atrial calcification in a hemodialysis patient with cor triatriatum

Myocardial calcification is a rare manifestation of abnormal calcium metabolism seen in some patients with chronic renal failure. This report describes the transesophageal echocardiographic and spiral computed tomography (CT) findings in a young hemodialysis female with severe secondary hyperparathyroidism. These findings included calcification of the multiperforated membrane of a cor triatriatum and the wall of the left atrium.

Diminished Expression of Sarcoplasmic Reticulum Ca2+-ATPase and Ryanodine Sensitive Ca2+Channel mRNA in Streptozotocin-induced Diabetic Rat Heart

Y. Teshima, N. Takahashi, T. Saikawa, M. Hara, S. Yasunaga, S. Hidaka and T. Sakata. Diminished Expression of Sarcoplasmic Reticulum Ca2+-ATPase and Ryanodine Sensitive Ca2+Channel mRNA in Streptozotocin-induced Diabetic Rat Heart. Journal of Molecular and Cellular Cardiology (2000) 32, 655–664. The diabetic heart has an abnormal intracellular calcium ([Ca2+]i) metabolism. However, the responsible molecular mechanisms are unclear. The present study aimed to investigate mRNAs expressed in the proteins which regulate heart [Ca2+]i metabolism in streptozotocin (STZ)-induced diabetic rats. Expression of sarcoplasmic reticulum Ca2+-adenosine triphosphatase (SR Ca2+-ATPase) mRNA was significantly less in the heart 3 weeks after STZ injection than that in the age-matched controls. Together with the down-regulation of SR Ca2+-ATPase, expression of ryanodine sensitive Ca2+channel (RYR) mRNA was also decreased 12 weeks after STZ injection. Insulin supplementation fully restored the decreased mRNAs expression of SR Ca2+-ATPase and RYR. The diminished expression and restoration with insulin supplementation of SR Ca2+-ATPase was further confirmed at the protein level. In contrast, expression of mRNAs coding the L-type Ca2+channel, Na+-Ca2+exchanger, or phospholamban were not affected 3 or 12 weeks after STZ injection. These results can be taken to indicate that the down-regulation of SR Ca2+-ATPase and RYR mRNAs is a possible underlying cause of cardiac dysfunction in STZ-induced diabetic rats.

High Blood Pressure and Bone-Mineral Loss in Elderly White Women: A Prospective Study

There is evidence from animal, clinical, and epidemiological studies that high blood pressure is associated with abnormal calcium metabolism. Calcium loss apparently is followed by activation of parathyroid function and loss of calcium from bones. A defect in renal calcium handling may be responsible. If sustained for many years, ongoing mineral loss may increase the risk of osteoporosis. This prospective study examined the relationship between blood pressure and bone mineral loss in 3676 white women older than 65 years (average age, 73 years) who were followed up for an average of 3.5 years. Bone densitometry was repeated 3 to 5 years after initial assessment. The participants were generally in good health. More than 15 percent were receiving hormone replacement therapy (HRT). Approximately 17 percent of women were receiving regular antihypertensive therapy at the time of follow-up. Loss of bone mineral at the femoral neck averaged 0.5 percent per year. Both absolute and relative bone loss at this site were significantly related to age and baseline systolic blood pressure. Smokers had relatively high bone loss, whereas women receiving HRT had less than expected. Ongoing change in bone mineral density increased significantly with increasing systolic blood pressure, even after excluding women taking antihypertensive drugs. This association was not influenced by age. Diastolic blood pressure correlated with bone loss only in women younger than 75 years. Elderly white women with high blood pressure are at increased risk of losing bone mineral at the femoral neck. Because a high salt intake promotes urinary calcium excretion, less dietary salt should not only lower the blood pressure but also encourage positive calcium balance and, it is hoped, lessen the risk of hip fracture. Lancet 1999;354:971–975