Elevated Plasma Calcium Research Articles

Primary hyperparathyroidism: diagnostic features and surgical outcomes.

Primary hyperparathyroidism is characterized by elevated plasma calcium levels due to inappropriate secretion of parathyroid hormone (PTH) in most cases by an adenomatous or hyperplastic parathyroid. We present a retrospective analysis of a large cohort of patients operated on of parathyroidectomy in our center analyzing their diagnostic characteristics, intraoperative match and surgical outcomes. We included patients with benign parathyroid disease who underwent parathyroidectomy associated or not with hemi- or total thyroidectomy at the Sant'Anna University Hospital of Ferrara between September 2003 and September 2022. In our study 371 patients fulfilled the inclusion criteria. The most widely used preoperative imaging method was ultrasound, followed by 99mTc-sestamibi scintigraphy. In most cases, preoperative imaging correctly localized the affected parathyroid. Considering the intraoperative site of the pathologically affected parathyroid, the majority of pathological parathyroids were located in the lower districts of the neck and a smaller percentage in the upper, intermediate, and ectopic sites. Postoperative complications were infrequent. The main challenge in parathyroid surgery lies in the difficulty in localizing the pathological parathyroid at the surgical site, which can lengthen the surgical time by increasing comorbidities. Currently, the results on pathological parathyroid localization are good. Technology needs to be developed toward greater diagnostic accuracy and minimally invasive surgical approaches.

719 CIRCULATING SORTILIN LEVELS ARE INCREASED IN PATIENTS RECEIVING LONG-TERM WARFARIN AND ITS INHIBITION ATTENUATES WARFARIN-INDUCED VASCULAR CALCIFICATION

Abstract Long-term use of the vitamin K antagonist (VKA) warfarin, has been shown to accelerate vascular and valvular calcification both in rodents and in humans. Increasing evidence suggests that vascular endothelium contributes to calcification via endothelial-mesenchymal transition (EndMT). However, additional research is warranted to elucidate the signaling mechanisms involved. In the last decade, a prominent role for sortilin has been demonstrated in cardiovascular calcification. Moreover, we recently demonstrated that the increase of sortilin in the endothelium promotes endothelial dysfunction, a known initiator of EndMT. Thus, we aim to investigate a potential contribution of sortilin in vascular calcification induced by warfarin. For this purpose, human endothelial cells and aortic rings from wild type C57BL/6J mice were cultured in promineralization medium in the presence of therapeutic levels of warfarin. Plasma sortilin and calcium levels were measured in 19 patients under VKA therapy who were stratified into short-term (3-12 months) or long-term group (24-45 months) based on VKA treatment duration. Increased protein expression of sortilin was found both in the endothelial and in the medial smooth muscle layers of aortic rings. Sortilin immunostaining was found to co-localize with α-SMA in the endothelium of warfarin-treated aortic rings, a hallmark of EndMT. Interestingly, pharmacological inhibition of sortilin with AF38469 reduced calcification and prevented loss of expression of the endothelial marker von Willebrand Factor (vWF) induced by warfarin treatment in human endothelial cells and mouse aortas. Finally, along with elevated plasma calcium levels, patients receiving long-term VKA showed increased circulating sortilin levels when compared to short term VKA-treated patients. Our data provide evidence for a potential role for endothelial-derived sortilin in regulating vascular calcification promoted by warfarin, and suggest that targeting circulating sortilin may be beneficial for the prevention of warfarin-associated cardiovascular calcification.

Vitamin D and Cardiovascular Disease: An Update

In the clinical setting, administration of high daily or bolus doses of vitamin D is often solely based on 25-hydroxyvitamin D [25(OH)D] testing. This review summarizes the evidence of the effect of vitamin D on cardiovascular disease (CVD). Meta-analyses of randomized controlled trials (RCTs) have demonstrated that CVD risk markers, such as lipid parameters, inflammation markers, blood pressure, and arterial stiffness, are largely unaffected by vitamin D supplementation. Similar results have been obtained regarding CVD events and mortality from (meta)-analyses of RCTs, even in subgroups with 25(OH)D concentrations <50 nmol/l. Likewise, Mendelian randomization studies have indicated that the genetic reduction of the 25(OH)D concentration does not increase CVD risk. Some studies do not exclude the possibility of adverse vitamin D effects, such as elevated plasma calcium concentration and an increased CVD risk at a 25(OH)D concentration >125 nmol/l. Based on a conservative benefit-risk management approach, vitamin D doses beyond the nutritionally recommended amounts of 600 to 800 IE daily currently cannot be advised for the prevention of CVD events.

MON-139 SODIUM THIOSULPHATE IN CALCIPHYLAXIS; A SINGLE-CENTRE AUDIT

Calciphylaxis is a rare and debilitating disease caused by progressive microvascular necrosis of skin resulting in ulcers. The pathophysiology is unclear but mural calcification is central to the disease process. Patients are usually hyperphosphataemic, have hyperparathyroidism and an elevated plasma calcium and phosphate product. Prognosis is poor with one-year survival estimated between 45-80%.There is little evidence to guide treatment; parathyroidectomy and vitamin K2 supplementation have been used with some success. One of the most commonly used treatment strategies is intravenous sodium thiosulphate, an agent thought to dissolve the intramural calcium and thus reduce inflammation. The aim of this audit is to examine the prescribing practices and patterns in the Gold Coast Health Service haemodialysis population. An audit of the Gold Coast Health Service pharmacy dispensing of intravenous sodium thiosulphate was conducted between 2014-2018. Patients with end-stage renal disease, defined as being established on haemodialysis or planned to commence within 6 months, were included. Nine patients were identified and their demographic, dialysis history, duration of treatment, biochemistry and mortality data was collated from electronic health records. One third of the patients were female. The average age at time of diagnosis was 63 years. The average time from start of dialysis to diagnosis was 3.51 years (range 22-3869 days). The average treatment duration was 131 days. Time from diagnosis to death averaged 217 days. Three patients had complete resolution of lesions and treatment was discontinued. The mean calcium phosphate product was 3.92 mmol2/L2 at time of diagnosis and mean PTH was 50.78 micromol/L. Sodium thiosulphate may slow, and in some cases cure, an otherwise aggressive and debilitating syndrome. Delay in administering this medication may be to the detriment of patients, however prospective, randomised data is required.

Safety and Health Benefits of Novel Dietary Supplements Consisting Multiple Phytochemicals, Vitamins, Minerals and Essential Fatty Acids in High Fat Diet Fed Rats

ABSTRACTThe objective was to determine safety and efficacy of health supplements “Beyond Tangy Tangerine,” a multivitamin/mineral complex and combination of multivitamin/mineral complex, “Osteofx,” a bone healthy supplement and “Ultimate Essential Fatty Acids” in Sprague Dawley rats consuming high-fat diets. Initially a pilot study was conducted which confirmed palatability and acceptability of supplements. In a second study, rats (n = 15/group) were randomized to Control; Multivitamin/mineral complex (2 g/kg BW) or Combination (2 g Multivitamin/mineral complex, 1.5 g Bone healthy supplement and 0.34 g Essential fatty acids/kg BW). No differences were observed in BW change, feed intake, organ weights or bone mineral composition with supplementations compared to control. Multivitamin/mineral complex supplementation decreased abdominal white adipose tissue weights (WAT) (p = .005), total (p = .033) and fat mass (p = .040), plasma IL-6 (p = .016) and ALKP (p = .038) and elevated plasma calcium (p < .001), phosphorus (p = .038), total protein (p = .002), albumin (p = .014) and globulin (p = .018), compared to control. Similarly, combination supplementation reduced WAT (p < .001), total (p = .023) and fat mass (p = .045), plasma triglycerides (p = .018), IL-6 (p = .002) and ALKP (p < .001) with increases in plasma calcium (p = .031), phosphorus (p < .001) compared to control. Results indicate that consuming either supplement can be considered safe and improves overall health by reducing inflammation, abdominal fat mass and plasma triglycerides, as well as promote bone health.

Increased trabecular volumetric bone mass density in Familial Hypocalciuric Hypercalcemia (FHH) type 1: a cross-sectional study.

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56years, 69% females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca(2+) levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.

Vitamin D Deficiency and Exogenous Vitamin D Excess Similarly Increase Diffuse Atherosclerotic Calcification in Apolipoprotein E Knockout Mice

BackgroundObservational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice.MethodsMice were fed atherogenic diets with normal vitamin D content (1.5IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography.ResultsVitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm2) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions.ConclusionVitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

Elevated plasma magnesium and calcium may be associated with shorter telomeres in older South Australian women.

Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structure and its DNA hexamer (TTAGGG)n repeat sequence is critical for protecting the ends of chromosomes from degradation and in maintaining overall chromosomal stability. Currently, there are limited data on the influence that nutrition has on telomere length. Recent studies have suggested that micronutrients may influence telomere length. Here we examined the relationship between telomere length in lymphocytes and plasma calcium, magnesium, selenium and zinc status in a healthy cohort of younger and older adults. We report a negative association between telomere length and both plasma calcium and magnesium levels, (r=-0.47, P=0.03 and r=-0.61, P=0.001 respectively), in older females; Intriguingly Ca/Mg ratio was positively associated with telomere length (r=0.55, P=0.007). These relationships were not observed in the younger adults, nor in the older males. In conclusion, our study provides preliminary evidence suggesting that levels of plasma magnesium and calcium may impact on telomere length in lymphocytes in older women.

Hypocalcemic Role Of Calcitonin In Female Mastacembelus Armatus (lacepede), During Reproductive Cycle

On the basis of various histological changes the ovarian cycle of Mastacembelus armatus can be divided in to five different phases i.e. resting, maturation, prespawning, spawning and postspawning phases. Seasonal cyclic changes in the plasma calcium and calcitonin level were found associated with this ovarian cycle. An increase in their level occurs during maturation phase with a corresponding increase in the gonadosomatic index reaching the peak during prespawning phase and spawning phase. On the other hand a significant decrease was noted during postspawning and resting phase. Histological changes in the ultimobranchial gland also revealed the seasonal variation in its activity. It exhibits various signs of hyperactivity like Maximum increase in the population of secretory cells, decrease in size of lumen and dilation of blood vessels during prespawning and spawning phase. Disruptive follicular organization was noted during resting and post spawning phase. 17-â estradiol administration resulted in hypercalcemia and increase in plasma calcitonin level in M. armatus fed with calcium deficient food. Therefore it can be concluded that UBG is mainly concerned with reproductive physiology of the fish M. Armatus by lowering down elevated plasma calcium level accompanied through extra intestinal routes during ovarian maturation.

Muscle function and quality of life are not impaired in familial hypocalciuric hypercalcemia: a cross-sectional study on physiological effects of inactivating variants in the calcium-sensing receptor gene (CASR)

Familial hypocalciuric hypercalcemia (FHH) is often due to inactivating variants in the calcium-sensing receptor (CASR) gene causing chronically elevated plasma calcium levels with inappropriately normal or elevated parathyroid hormone levels. In patients with primary hyperparathyroidism, the state of hyperparathyroid hypercalcemia is associated with reduced muscle strength and impaired quality of life (QoL). To study whether FHH affects muscle function, postural stability, and QoL. In a cross-sectional study, we investigated muscle strength (handgrip, elbow flexion/extension, and knee flexion/extension), balance function, physical activity, and QoL in 50 patients with FHH and in a similar number of age- and gender-matched population-based healthy controls. All but one of the FHH cases had genetically verified inactivating variants in the CASR gene. Studied subjects (n=100, 68% females) had a mean age of 56.0 years. Muscle strength as assessed by measuring maximum force and maximum force production did not differ between the groups. Neither did groups differ in terms of QoL, physical activity, or postural stability, as assessed during normal standing with eyes open, normal standing with eyes closed, semi-tandem standing, or tandem standing. Adjustment for vitamin D status (plasma 25-hydroxyvitamin D levels) and BMI did not change results. Despite a state of chronic hypercalcemia, muscle strength, balance function, and QoL are not impaired in patients with FHH. Our findings are reassuring for patients with FHH as they should not be considered as having a severe disease.

Bone Involvement in Primary Hyperparathyroidism and Changes After Parathyroidectomy

Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands and has primary effects on kidney and bone. During the pathologic growth of one or more parathyroid glands, the plasma level of PTH increases and causes primary hyperparathyroidism (PHPT). This disease is normally characterized by hyperparathyroid hypercalcemia. In PHPT a continuously elevated PTH stimulates the kidney and bone causing a condition with high bone turnover, elevated plasma calcium, and increased fracture risk. If bone resorption is not followed by a balanced formation of new bone, irreversible bone loss may occur in these patients. Medical treatment can help to minimize the loss of bone but the cure of PHPT is by parathyroidectomy. After operation, bone mineral density increases during the return to normal bone metabolism. Supplementation with calcium and vitamin D after operation may improve the normalization to normal bone metabolism with a secondary reduction in fracture risk.

TEI-A00114: A new vitamin D3 analogue that inhibits neutrophil recruitment in an acute lung injury hamster model while showing reduced hypercalcemic activity

While searching for vitamin D3 analogues which inhibit neutrophil recruitment in the lung without elevating plasma calcium level, we found that (5Z,7E)-(1S,3R)-20(R)-[(5E)-(2S)-2-hydroxy-2-methyl-cyclopentanone-5-ylidene]methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol (TEI-A00114) had the best efficacy and calcemic action. TEI-A00114 has a vitamin D receptor affinity 2.5-fold weaker and a vitamin D binding protein affinity 330.9-fold weaker than those of 1α,25(OH)2D3. The estimated effective doses for 40% inhibition (ED40) via peroral and intratracheal administration are 7.6 and 0.4μg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED40 was calculated as 0.2μg/kg. The estimated 40% inhibitory concentration (IC40) of TEI-A00114 on interleukin (IL)-8 production induced by lipopolysaccharide and on IL-1β in human whole blood cells in vitro were 9.8×10−8 or 1.8×10−9M, respectively. These levels of TEI-A00114’s activities are equal to those of 1α,25(OH)2D3. On the other hand, the calcemic action of TEI-A00114, which was evaluated at day 14 after sequential peroral quaque die administration, was 89-fold weaker (molar ratio) than that of 1α,25(OH)2D3. These results indicate that TEI-A00114 has a dissociated profile between inhibition of neutrophil recruitment in the lung and calcemic action, suggesting its suitability over 1α,25(OH)2D3 as a candidate for the treatment of acute lung injury.

Diet influences salinity preference of an estuarine fish, the killifishFundulus heteroclitus

Understanding the interplay among the external environment, physiology and adaptive behaviour is crucial for understanding how animals survive in their natural environments. The external environment can have wide ranging effects on the physiology of animals, while behaviour determines which environments are encountered. Here, we identified changes in the behavioural selection of external salinity in Fundulus heteroclitus, an estuarine teleost, as a consequence of digesting a meal. Fish that consumed high levels of dietary calcium exhibited a higher preferred salinity compared with unfed fish, an effect that was exaggerated by elevated dietary sodium chloride. The mean swimming speed (calculated as a proxy of activity level) was not affected by consuming a diet of any type. Constraining fish to water of 22 p.p.t. salinity during the digestion of a meal did not alter the amount of calcium that was absorbed across the intestine. However, when denied the capacity to increase their surrounding salinity, the compromised ability to excrete calcium to the water resulted in significantly elevated plasma calcium levels, a potentially hazardous physiological consequence. This study is the first to show that fish behaviourally exploit their surroundings to enhance their ionoregulation during digestion, and to pinpoint the novel role of dietary calcium and sodium in shaping this behaviour. We conclude that in order to resolve physiological disturbances in ion balance created by digestion, fish actively sense and select the environment they inhabit. Ultimately, this may result in transient diet-dependent alteration of the ecological niches occupied by fishes, with broad implications for both physiology and ecology.

The influence of extracellular and intracellular calcium on the secretion of renin

Changes in plasma, extracellular, and intracellular calcium can affect renin secretion from the renal juxtaglomerular (JG) cells. Elevated intracellular calcium directly inhibits renin release from JG cells by decreasing the dominant second messenger intracellular cyclic adenosine monophosphate (cAMP) via actions on calcium-inhibitable adenylyl cyclases and calcium-activated phosphodiesterases. Increased extracellular calcium also directly inhibits renin release by stimulating the calcium-sensing receptor (CaSR) on JG cells, resulting in parallel changes in the intracellular environment and decreasing intracellular cAMP. In vivo, acutely elevated plasma calcium inhibits plasma renin activity (PRA) via parathyroid hormone-mediated elevations in renal cortical interstitial calcium that stimulate the JG cell CaSR. However, chronically elevated plasma calcium or CaSR activation may actually stimulate PRA. This elevation in PRA may be a compensatory mechanism resulting from calcium-mediated polyuria. Thus, changing the extracellular calcium in vitro or in vivo results in inversely related acute changes in cAMP, and therefore renin release, but chronic changes in calcium may result in more complex interactions dependent upon the duration of changes and the integration of the body's response to these changes.

Pathophysiology of Renal Calcium Handling in Acromegaly: What Lies behind Hypercalciuria?

Hypercalciuria is frequent in patients with acromegaly, but it is unclear how GH/IGF-I regulate renal calcium handling. Elevated fasting plasma calcium levels despite increased glomerular filtration suggest enhanced renal calcium reabsorption. The aim of this study was to investigate the impact of acromegaly on phosphocalcium metabolism. We conducted a prospective sequential study at a tertiary referral medical center and clinical investigation center (www.ClinicalTrials.gov Identifier: NCT00531908). Sixteen consecutive patients (five females/11 males) with acromegaly received a single iv infusion of 25 mg of furosemide to induce an acute increase in calcium and magnesium delivery to distal tubular segments during a high-sodium diet with stable dietary calcium, magnesium, and phosphate intake. Baseline plasma and urine electrolytes, plasma calciotropic hormones, and furosemide-induced changes in the fractional excretion and tubular reabsorption of Na, Ca, and Mg were measured before and 6 months (range, 1-12) after effective treatment of acromegaly. Serum IGF-I concentrations normalized in all the patients after acromegaly treatment. Compared with controlled acromegaly, active acromegaly was associated with higher fasting plasma (P = 0.0002) and urinary calcium (P = 0.0003) levels, lower PTH levels (P = 0.0075), higher calcitriol levels (P = 0.0137), higher phosphatemia (P<0.0001) and tubular phosphate reabsorption (P = 0.0002), and a lower calciuric (P = 0.0327) but not magnesiuric response to furosemide related to higher baseline and postfurosemide tubular calcium (P = 0.0034 and P = 0.0081, respectively), but not magnesium reabsorption. The IGF-I-mediated and PTH-independent increase in calcitriol synthesis in acromegaly is responsible for both absorptive hypercalciuria and increased fasting plasma calcium linked to enhanced distal tubular calcium reabsorption, as shown by the selectively diminished calciuric response to furosemide.

Differential expression of PTHrP and its receptor in pituitary gland and gills in estradiol-treated gilthead sea bream ( Sparus auratus, L.)

In the gilthead sea bream ( Sparus auratus) 17β-estradiol (E 2) plays an important role in the synthesis of vitellogenin. During vitellogenesis, vitellogenin as a nutritional precursor protein is loaded with calcium, which requires elevated plasma calcium levels. This is accomplished via E 2-dependent processes. Reports have shown that hypercalcemic effects of E 2 are possibly mediated by another hypercalcemic factor, viz. parathyroid hormone related protein (PTHrP). To further investigate the possibility of PTHrP as a mediator of E 2-induced hypercalcemia, we investigated the local expression levels of the pthrp mRNA and of the gene coding for the PTHrP receptor, PTH1R ( pth1r) in two tissues involved in the calcium regulation (gills, pituitary gland) of the sea bream treated with E 2. Compared to control, treatment with E 2 resulted in: significantly increased total calcium and plasma PTHrP levels ( P < 0.01), a down-regulation of pthrp mRNA in the pituitary gland ( P < 0.01), and up-regulation of expression levels for both pthrp and pth1r in the branchial system ( P < 0.05). These findings provide direct evidence for a mediating role of PTHrP in E 2 induced hypercalcemia, and in addition support the idea for the presence of two independent systems, an endocrine pituitary PTHrP system and a peripheral paracrine branchial PTHrP system.

Bone Involvement in Primary Hyperparathyroidism and Changes After Parathyroidectomy.

Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands and has primary effects on kidney and bone. During the pathological growth of one or more parathyroid glands, the plasma level of PTH increases and causes primary hyperparathyroidism (PHPT). This disease is normally characterised by hyperparathyroid hypercalcaemia. In PHPT a continuously elevated PTH stimulates the kidney and bone causing a condition with high bone turnover, elevated plasma calcium and increased fracture risk. If bone resorption is not followed by a balanced formation of new bone, irreversible bone loss may occur in these patients. Medical treatment can help to minimise the loss of bone but the cure of PHPT is by parathyroidectomy. After operation, bone mineral density increases during the return to normal bone metabolism. Supplementation with calcium and vitamin D after operation may improve the normalisation to normal bone metabolism with a secondary reduction in fracture risk.

Vitamin D and the Parenteral Nutrition Patient

Vitamin D is a prohormone produced in the skin epidermis when irradiated with sunlight or ultraviolet light B. It is also absorbed from food or supplements. Vitamin D must be converted to 25-hydroxyvitamin D3 (circulating form) and finally to the hormone, 1a,25-dihydroxyvitamin D3, before it can function. This hormone acts through a single nuclear receptor. The details of these conversions and molecular biology of the action of vitamin D3 are summarized. The physiologic functions of vitamin D have been expanded beyond the mineralization of the skeleton to include modulation of the immune system, terminal differentiation in several tissues, suppression of malignant cells, and anabolic activity in the skeleton and in the renal-cardiovascular system. Epidemiologic studies have associated vitamin D deficiency with an increased risk of colorectal and breast cancers and an increased risk of autoimmune diseases, such as multiple sclerosis, type 1 diabetes, and cardiovascular events. Thus, vitamin D is essential not only for the skeleton but also many other organ systems. Recommendations for 25-hydroxyvitamin D3 levels for PN patients are presented.

Familial hypocalciuric hypercalcemia revealed by chondrocalcinosis

BackgroundCalcium pyrophosphate dihydrate crystal deposition disease (CPPD-CDD) has been associated to hypercalcemia. Familial hypocalciuric hypercalcemia (FHH) is a rare but important consideration in the differential diagnosis of hypercalcemia. This autosomal dominantly inherited condition is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH level. The disease is caused by inactivating mutations in the calcium-sensing receptor gene. Case reportWe describe a 77-year-old Italian man with arthritis secondary to CPPD-CDD and hypercalcemia. Clinical and biochemical data (s-Ca: 2.94mmol/L; PTH: 5.9 pmol/L; 24 h urinary calcium: 69.6mg; calcium/creatinine clearance: 0.004) suggested the diagnosis of FHH. Mild hypocalciuric hypercalcemia was also found in five of seven relatives confirming the diagnosis, of these one showed chondrocalcinosis. ConclusionsIt is important to screen for FHH using fractional urinary excretion of calcium in subjects with CPPD-CDD associated to hypercalcemia, this approach may prevent unnecessary parathyroidectomy.

Molecular Genetic Analysis of the Calcium Sensing Receptor Gene in Patients Clinically Suspected to Have Familial Hypocalciuric Hypercalcemia: Phenotypic Variation and Mutation Spectrum in a Danish Population

The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene. We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations. A total of 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype-phenotype relationships were established in 66 mutation-positive index patients and family members. We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4), and PTH were measured. We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F, and p.G553R. The present data add 19 novel mutations to the catalog of inactivating CASR mutations and illustrate a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.