Impaired Parathyroid Hormone Research Articles

Evaluation of T helper17 as skeletal homeostasis factor in peripheral blood mononuclear cells and T helper cells of end-stage renal disease cases with impaired parathyroid hormone.

Chronic renal failure is mainly connected with high and low parathyroid hormone (PTH) levels and immunological impairments. The present study aimed to evaluate T helper 17 (Th17) cells as a crucial modulator of the immune system and skeletal homeostasis in hemodialysis patients with impaired intact PTH (iPTH). In this research, blood samples were taken from ESRD patients with high (> 300 pg/mL), normal (150-300 pg/mL), and low (< 150 pg/mL) serum intact parathyroid hormone (iPTH( levels (n = 30 in each group). The frequency of Th17 (CD4+ IL17+) cells was evaluated by flow cytometry in each group. The expression levels of Th17 cell-related master transcription factors, cytokines in peripheral blood mononuclear cells (PBMC), and Th cells, and the level of the mentioned cytokines were determined in the supernatant of PBMCs. The number of Th17 cells remarkably increased in subjects with high iPTH against low and normal iPTH. Also, RORɣt and STAT3 levels were significantly higher in high iPTH ESRD patients than in other groups in the expression of mRNA and protein levels. These findings are confirmed by evaluating the IL-17 and IL-23 in the supernatant of cultured PBMCs and isolated Th cells. Our findings indicated that increased serum PTH levels in hemodialysis cases may be involved in increasing the differentiation of CD4 + cells to Th17 cells in PBMC.

Spectrum of Disorders associated with Tetany.

Awareness regarding the etiological spectrum of tetany is poor among physicians. Because of poor awareness, tetany is underdiagnosed and undertreated. Databases like PubMed, PubMed Central, Scopus, and Google Scholar are searched to identify peer-reviewed articles on tetany. Case reports, case series, and original articles are analyzed to identify different causes of tetany prevalent in the community. Different causes found are analyzed and tabulated, and finally, a flowchart is made on the approach for diagnosing different underlying pathologies of tetany. Both metabolic and respiratory alkalosis are important causes of tetany because of reduced ionized calcium levels. Gitelman syndrome (GS) is associated with metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria, and frequently causes normocalcemic tetany. Recurrent vomiting and primary hyperaldosteronism also cause tetany due to metabolic alkalosis. Hyperventilation syndrome (HVS) leads to respiratory alkalosis and is a frequent cause of tetany. Hyperventilation-induced tetany is also seen after spinal anesthesia and in respiratory disorders like asthma. Vitamin D deficiency (VDD), primary hypoparathyroidism, and pseudohypoparathyroidism (PHP) (1a, 1b, and 2) cause hypocalcemic tetany. Hypomagnesemia causes hypocalcemia and tetany due to peripheral parathyroid hormone resistance and impaired parathyroid hormone secretion. Drugs causing tetany include bisphosphonates, denosumab, cisplatin, antiepileptics, aminoglycosides, diuretics, etc. Tetany is also seen in acute pancreatitis, dengue, falciparum malaria, hyperemesis gravidarum, tumor lysis syndrome (TLS), massive blood transfusion, etc. Conclusion: The spectrum of disorders associated with tetany is diverse. Awareness of different causes will help early and proper diagnosis of tetany.

ODP100 Hypoparathyroidism in the Setting of COVID-19: Increasingly Common Phenomenon

Abstract Background Acquired hypoparathyroidism (HPT) in adults is most commonly caused by post-surgical or autoimmune damage to the parathyroid glands. Genetic defects causing abnormal gland development, impaired parathyroid hormone (PTH) production or action are rare and typically diagnosed in childhood. Recent literature suggests surprisingly high prevalence of hypocalcemia in patients with SARS-CoV-2 infection and this finding is associated with poor outcomes. [1] We present a case of new onset HPT in a patient admitted with respiratory failure due to COVID-19. Case presentation A 63-year-old woman with history of obesity, GERD, asthma, presented to the ED with fever, cough, dyspnea, and diarrhea. She was found to have low O2 saturation, CXR revealed multifocal interstitial and airspace opacities. Her PCR SARS-CoV-2 test was positive and she was admitted to ICU. She was incidentally found to have severe hypocalcemia Ca 5.2 mg/dL (8.5 - 10.3 mg/dL), ionized Ca 2.46 mg/dL (4.50 - 5.10 mg/dL), albumin 3.7 g/dL (3.5 - 5. 0 g/dL). She denied any history of neck surgery, radiation or trauma and personal or family history of autoimmune or calcium disorders. Her calcium levels were normal over the past 4 years. She denied symptoms of hypocalcemia prior to presentation and reported leg cramps and finger numbness in the ED. Further work-up revealed PTH 13 pg/mL (15 - 65 pg/mL), 25-OH vitamin D 16 ng/mL (30 - 80 ng/mL), Mg 1.2 mg/dL (1.4 - 2.5 mg/dL), phosphorus 4.9 mg/dL (2.3 - 4.5 mg/dL), bicarbonate 26 mmol/L (22 - 32 mmol/L). Patient was started on Ca (IV and PO), Mg, and vitamin D replacement. PTH reassessment on days 6, 14, and 19 showed persistently low/inappropriately normal PTH (22, 14, and 8 pg/mL respectively) despite normalization of magnesium levels. Patient was discharged on Ca, Mg, and vitamin D supplementation with follow-up in Endocrinology clinic for further evaluation of her hypoparathyroidism progression. Conclusion SARS-CoV-2 infection causes a hypersensitive immune reaction and widespread inflammation. Emerging evidence suggests that this cytokine-mediated reaction and hypoxia associated with COVID-19 can affect the parathyroid glands, resulting in impaired PTH secretion. Furthermore, direct parathyroid tissue invasion and destruction by means of entry via angiotensin-converting enzyme 2 receptors has also been proposed [2]. Hypocalcemia in our patient could be multifactorial, however we believe that COVID-19 induced HPT was the leading mechanism. We hope that further research explores this hypothesis and elucidates the underlying pathophysiology.

Kidney Failure Alters Parathyroid Pin1 Phosphorylation and Parathyroid Hormone mRNA-Binding Proteins, Leading to Secondary Hyperparathyroidism.

Secondary hyperparathyroidism (SHP) is a common complication of CKD that increases morbidity and mortality. In experimental SHP, increased parathyroid hormone (PTH) expression is due to enhanced PTH mRNA stability, mediated by changes in its interaction with stabilizing AUF1 and destabilizing KSRP. The isomerase Pin1 leads to KSRP dephosphorylation, but in SHP parathyroid Pin1 activity is decreased and hence phosphorylated KSRP fails to bind PTH mRNA, resulting in high PTH mRNA stability and levels. The up- and downstream mechanisms by which CKD stimulates the parathyroid glands remain elusive. Adenine-rich high-phosphate diets induced CKD in rats and mice. Parathyroid organ cultures and transfected cells were incubated with Pin1 inhibitors for their effect on PTH expression. Mass spectrometry was performed on both parathyroid and PTH mRNA pulled-down proteins. CKD led to changes in rat parathyroid proteome and phosphoproteome profiles, including KSRP phosphorylation at Pin1 target sites. Furthermore, both acute and chronic kidney failure led to parathyroid-specific Pin1 Ser16 and Ser71 phosphorylation, which disrupts Pin1 activity. Pharmacologic Pin1 inhibition, which mimics the decreased Pin1 activity in SHP, increased PTH expression ex vivo in parathyroid glands in culture and in transfected cells through the PTH mRNA-protein interaction element and KSRP phosphorylation. Kidney failure leads to loss of parathyroid Pin1 activity by inducing Pin1 phosphorylation. This predisposes parathyroids to increase PTH production through impaired PTH mRNA decay that is dependent on KSRP phosphorylation at Pin1-target motifs. Pin1 and KSRP phosphorylation and the Pin1-KSRP-PTH mRNA axis thus drive SHP.

Novel PTH Gene Mutations Causing Isolated Hypoparathyroidism.

Parathyroid hormone (PTH) gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously. Through describing 2 novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism. Proband case reports were compiled with extended family analysis. The probands in both kindreds presented before age 10 days with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, whereas these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Methylation analysis was performed of CpG dinucleotides within 3 GNAS differentially methylated regions; whole-genome sequencing; and PTH infusion with analysis of nephrogenous 3',5'-cyclic adenosine 5'-monophosphate. Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys), and proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G > A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH. PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations.

Hypocalcemia in COVID-19 is associated with low vitamin D levels and impaired compensatory PTH response.

BackgroundHypocalcemia has been identified as a major distinctive feature of COVID-19, predicting poor clinical outcomes. Among the mechanisms underlying this biochemical finding, high prevalence of vitamin D (VD) deficiency in COVID-19 patients reported so far in several studies was advocated. However, robust data in favor of this hypothesis are still lacking. Therefore, aim of our study was to investigate the role of hypovitaminosis D and parathyroid hormone (PTH) levels in the development of hypocalcemia in COVID-19 patients.MethodsPatients admitted to IRCCS Ospedale San Raffaele for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing calcium and VD metabolism. Serum levels of total calcium (tCa), ionized calcium (Ca2+), 25-OH-VD, and PTH were evaluated at admission. We defined VD deficiency as VD below 20 ng/mL, hypocalcemia as tCa below 2.2 mmol/L or as Ca2+ below 1.18 mmol/L, and hyperparathyroidism as PTH above 65 pg/mL.ResultsA total of 78 patients were included in the study. Median tCa and Ca2+ levels were 2.15 and 1.15 mmol/L, respectively. Total and ionized hypocalcemia were observed in 53 (67.9%) and 55 (70.5%) patients, respectively. VD deficiency was found in 67.9% of patients, but secondary hyperparathyroidism was detected in 20.5% of them, only. tCa levels were significantly lower in patients with VD deficiency and regression analyses showed a positive correlation between VD and tCa.ConclusionsIn conclusion, we confirmed a high prevalence of hypocalcemia in COVID-19 patients and we showed for the first time that it occurred largely in the context of marked hypovitaminosis D not adequately compensated by secondary hyperparathyroidism.

A Distinct Variant of Pseudohypoparathyroidism (PHP) First Characterized Some 41 Years Ago Is Caused by the 3-kbSTX16 Deletion.

ABSTRACTIn 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Calcium: More Than Bone? Implications for Clinical Practice and Theory

Serum calcium is routinely screened, but rarely scrutinized in the context of normal, physiologic functioning. This brief review strives to explore the implications of serum calcium, suggests guidelines for its interpretation, and discusses the implications of high, low, and “normocalcemia” in the clinical setting. We find that serum Ca 2+ concentrations are a valuable prognostic indicator in routine metabolic workups and advocate for greater attention, on behalf of the provider, to variations in a patient’s calcemic status. Variations in calcemic status are primarily tied to malignancy, impaired parathyroid hormone (PTH) secretion, defects in vitamin D synthesis, insulin-like growth factor 1 (IGF-1) fluctuation, genetic syndromes (DiGeorge syndrome) and calcium-sensing receptor ( CaSR ) mutation. Prognostic implications for high and low serum Ca 2+ include, but are not limited to, increased thromboembolic and major adverse cardiovascular event (MACE) risk, cardiac remodeling, hypertension, cognitive decline, and insulin resistance. J Clin Med Res. 2021;13(5):253-257 doi: https://doi.org/10.14740/jocmr4505

Calcium: More Than Bone? Implications for Clinical Practice and Theory.

Serum calcium is routinely screened, but rarely scrutinized in the context of normal, physiologic functioning. This brief review strives to explore the implications of serum calcium, suggests guidelines for its interpretation, and discusses the implications of high, low, and “normocalcemia” in the clinical setting. We find that serum Ca2+ concentrations are a valuable prognostic indicator in routine metabolic workups and advocate for greater attention, on behalf of the provider, to variations in a patient’s calcemic status. Variations in calcemic status are primarily tied to malignancy, impaired parathyroid hormone (PTH) secretion, defects in vitamin D synthesis, insulin-like growth factor 1 (IGF-1) fluctuation, genetic syndromes (DiGeorge syndrome) and calcium-sensing receptor (CaSR) mutation. Prognostic implications for high and low serum Ca2+ include, but are not limited to, increased thromboembolic and major adverse cardiovascular event (MACE) risk, cardiac remodeling, hypertension, cognitive decline, and insulin resistance.

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

SAT-LB309 Amphotericin B Induced Hypocalcemia in a Patient With Severe Hypercalcemia Due to Acute T-Cell Leukemia/Lymphoma

Seasonality of vitamin D concentrations and the incidence of vitamin D deficiency in children and adolescents from central Poland.

Vitamin D3 [25(OH)D] deficiency is asignificant problem in Polish children. In many regions of the world, 25(OH)D concentrations show seasonal variation and differences between boys and girls, due to seasonal differences in insolation, as well as different sociological and cultural factors. The aim of the study was to assess the seasonal variations of 25(OH)D concentrations and the incidence of vitamin D deficiency in children from central Poland. The analysis comprised 1275 children, age 3-18 (11.2 ±4.0) years, with disorders of growing and/or puberty, obesity, and other complaints that could be related to endocrine diseases, except for ones with calcium-phosphorus imbalance, impaired parathyroid hormone secretion, and diseases that may influence vitamin D supply. Seasonal variability of 25(OH)D concentrations was observed with maximal levels in August and minimal in January and close relationship between 25(OH)D levels and insolation in the previous two months. In all the quarters, 25(OH)D concentrations were lower in girls than in boys and in older vs. younger children. The median value of 25(OH)D concentrations was below the lower limit of optimal range during the whole year. High incidence of 25(OH)D deficiency was observed (from 10.7% in August to 80.4% in January) together with low proportion of normal 25(OH)D levels (from 3.6% in January to 42.1% in August). Our results are consistent with previous reports on inadequate vitamin D supplementation in Polish children and adolescents, pointing out the necessity to implement current recommendations concerning vitamin D supplementation and the need for further studies on the consequences vitamin D deficiency for health of children and adolescents, with special attention to the pleiotropic effects of vitamin D.

Low magnesium diet aggravates phosphate-induced kidney injury.

Magnesium is known to protect against phosphate-induced tubular cell injuries in vitro. We investigated in vivo effects of magnesium on kidney injuries and phosphate metabolism in mice exposed to a high phosphate diet. Heminephrectomized mice were maintained on a high phosphate/normal magnesium diet or a high phosphate/low magnesium diet for 6 weeks. We compared renal histology, phosphaturic hormones and renal α-Klotho expression between the two diet groups. High phosphate diet-induced tubular injuries and interstitial fibrosis were remarkably aggravated by the low-magnesium diet. At 1 week after high phosphate feeding when serum creatinine levels were similar between the two groups, the low magnesium diet suppressed not only fecal phosphate excretion but also urinary phosphate excretion, resulting in increased serum phosphate levels. Parathyroid hormone (PTH) levels were not appropriately elevated in the low magnesium diet group despite lower 1,25-dihydroxyvitamin D and serum calcium levels compared with the normal magnesium diet group. Although fibroblast growth factor 23 (FGF23) levels were lower in the low magnesium diet group, calcitriol-induced upregulation of FGF23 could not restore the impaired urinary phosphate excretion. The low magnesium diet markedly downregulated α-Klotho expression in the kidney. This downregulation of α-Klotho occurred even when mice were fed the low phosphate diet. A low magnesium diet aggravated high phosphate diet-induced kidney injuries. Impaired PTH secretion and downregulation of renal α-Klotho were likely to be involved in the blunted urinary phosphate excretion by the low magnesium diet. Increasing dietary magnesium may be useful to attenuate phosphate-induced kidney injury.

Simulated Interventions to Ameliorate Age-Related Bone Loss Indicate the Importance of Timing.

Bone remodeling is the continuous process of bone resorption by osteoclasts and bone formation by osteoblasts, in order to maintain homeostasis. The activity of osteoclasts and osteoblasts is regulated by a network of signaling pathways, including Wnt, parathyroid hormone (PTH), RANK ligand/osteoprotegrin, and TGF-β, in response to stimuli, such as mechanical loading. During aging there is a gradual loss of bone mass due to dysregulation of signaling pathways. This may be due to a decline in physical activity with age and/or changes in hormones and other signaling molecules. In particular, hormones, such as PTH, have a circadian rhythm, which may be disrupted in aging. Due to the complexity of the molecular and cellular networks involved in bone remodeling, several mathematical models have been proposed to aid understanding of the processes involved. However, to date, there are no models, which explicitly consider the effects of mechanical loading, the circadian rhythm of PTH, and the dynamics of signaling molecules on bone remodeling. Therefore, we have constructed a network model of the system using a modular approach, which will allow further modifications as required in future research. The model was used to simulate the effects of mechanical loading and also the effects of different interventions, such as continuous or intermittent administration of PTH. Our model predicts that the absence of regular mechanical loading and/or an impaired PTH circadian rhythm leads to a gradual decrease in bone mass over time, which can be restored by simulated interventions and that the effectiveness of some interventions may depend on their timing.

Retromer in Osteoblasts Interacts With Protein Phosphatase 1 Regulator Subunit 14C, Terminates Parathyroid Hormone's Signaling, and Promotes Its Catabolic Response

Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function. VPS35 is expressed in osteoblast (OB)-lineage cells. VPS35-deficiency in OBs impaired PTH(1–34)-promoted PTH1R translocation to the trans-Golgi network, enhanced PTH(1–34)-driven signaling, and reduced PTH(1–34)'s catabolic response in culture and in mice. Further mechanical studies revealed that VPS35 interacts with not only PTH1R, but also protein phosphatase 1 regulatory subunit 14C (PPP1R14C), an inhibitory subunit of PP1 phosphatase. PPP1R14C also interacts with PTH1R, which is necessary for the increased endosomal PTH1R signaling and decreased PTH(1–34)'s catabolic response in VPS35-deficient OB-lineage cells. Taken together, these results suggest that VPS35 deregulates PTH1R-signaling likely by its interaction with PTH1R and PPP1R14C. This event is critical for the control of PTH(1–34)-signaling dynamics, which may underlie PTH-induced catabolic response and adequate bone remodeling.

Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1-Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism.

Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-) mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-) mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.

Gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation.

Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130(f/f)) and littermate controls (Dmp1Cre.gp130(w/w)) were treated with hPTH(1-34) (30 μg/kg 5× per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130(w/w) mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130(f/f) femora compared with Dmp1Cre.gp130(w/w). Furthermore, lentiviral-Cre infection of gp130(f/f) primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH.

659 Hypoparathyroidism and Pseudo-Hypoparathyroidim: About 9 Cases

IntroductionHypoparathyroidism(HP) is an uncommon disorder of calcium metabolism characterized by hypocalcemia and hyperphosphatemia due to impaired parathyroid hormone (PTH) secretion. The pseudo-hypoparathyroidism(PHP) is characterized by a high level of PTH...

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Tight regulation of calcium levels is required for many critical biological functions. The Ca2+-sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone

Chronic hypomagnesemia is closely associated with hypocalcemia, which is caused by impaired parathyroid hormone (PTH) secretion or the refractoriness of bone and renal tubules to PTH. The dominant mechanism of acute-onset, hypomagnesemia-induced hypocalcemia is currently unclear. An 83-year-old man who had undergone chemotherapy with carboplatin for prostate cancer suffered from acute diarrhea and finger paresthesia. Laboratory data confirmed hypocalcemia as well as hypomagnesemia. Urinary calcium levels were not measured. However, the urinary fractional excretion of Mg (FE(Mg)) was elevated. Despite elevated PTH levels, the renal tubular maximal reabsorption rate of phosphate to GFR (TmP/GFR) was elevated, and bone formation and resorption markers were suppressed. A magnesium loading test revealed a clear magnesium deficiency. After administration of magnesium, bone marker levels were increased, and TmP/GFR was reduced to normal levels, despite the persistent elevation of PTH. Serum calcium levels eventually increased to approximately the reference range. Clinical histories and these observations both suggest that when patients with hypomagnesemia-induced hypocalcemia rapidly lose magnesium through complications such as diarrhea, the primary cause may be the refractoriness of bone and renal tubules to PTH, rather than impaired PTH secretion.

Vitamin D Deficiency Before Bariatric Surgery: Should Supplement Intake Be Routinely Prescribed?

Before bariatric surgery, we demonstrate a 96% rate of vitamin D deficiency in morbidly obese French patients: should supplement intake be routinely prescribed? We conducted a prospective observational study to demonstrate the prevalence of vitamin D deficiency in morbidly obese patients awaiting bariatric surgery. Clinical and biological data were collected on 50 successive patients. Data showed vitamin D deficiency in 96% (25-OH vitamin D = 31 ± 13 nmol/l), with a cut-point of 50 nmol/l. Secondary hyperparathyroidism was found in 44% of patients with hypovitaminosis D (parathyroid hormone (PTH), 59 ± 24 pg/ml). Impaired PTH level concerned 89% of this group, considering the cut-point at 30 pg/ml. No significant correlation appeared between vitamin D and calcium or phosphate levels. Before surgery, we demonstrated a higher incidence of vitamin D deficiency in morbidly obese French patients as compared to the general population. The incidence was also higher than previous American studies. Screening for hypovitaminosis D may routinely be considered in morbid obesity. Long-term observation is, however, needed to assess the advantages and potential side effects of systematic vitamin D supplements.