Plasma Parathyroid Hormone Concentrations Research Articles

Vitamin D metabolism in critically ill patients with acute kidney injury: a prospective observational study

BackgroundVitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease. Whether acute kidney injury (AKI) is associated with altered Vitamin D metabolism is unknown. We aimed to compare the longitudinal profiles of serum 25(OH)D and 1,25(OH)2D concentrations in critically ill patients with and without moderate to severe AKI and explore the impact of renal recovery and parathyroid hormone (PTH).MethodsIn this prospective, observational study in two centres in the UK, critically ill patients with and without AKI underwent serial measurement of serum 25(OH)D and 1,25(OH)2D and plasma PTH concentrations for 5 days. Linear mixed model analysis and sensitivity analyses were performed.ResultsSerial data of 137 patients were analysed. Seventy-one patients had AKI stage II/III of whom 23 recovered kidney function during the 5-day study period; 66 patients did not have AKI at enrolment of whom 14 developed new AKI. On day of enrolment, patients’ serum 25(OH)D concentrations were low (median 18 nmol/L) but there was no significant difference between patients with and without AKI. Median serum 1,25(OH)2D levels were significantly lower in patients with AKI II/III (41 pmol/L [IQR 26, 58]) compared to similarly unwell patients without AKI (54 pmol/L [IQR 33, 69]) during the 5-day period. Recovery of kidney function in patients with AKI was associated with a rise in 1,25(OH)2D concentrations. Plasma PTH results were impacted by serum calcium and magnesium levels but not associated with 1,25(OH)2D levels.ConclusionsCritically ill patients with moderate-to-severe AKI have significantly lower serum 1,25(OH)2D concentrations than similarly sick patients without AKI but there was no difference in serum 25(OH)D concentrations. Recovery of AKI was associated with a rise in serum 1,25(OH)2D concentrations. More research is needed to investigate the health benefits and safety of supplementation with active vitamin D in critically ill patients with moderate-to-severe AKI.Trial registration Clinicaltrials.gov (NCT02869919), registered on 16 May 2016.

The Relationship Between Atrial Fibrillation and Parathyroid Hormone in Heart Failure Outpatients.

Background Atrial fibrillation (AF) is a common arrhythmia in heart failure (HF). Plasma concentrations of para-thyroid hormone (PTH) have been shown to increase in HF. The relationship between PTH concentrations and the presence of AF in HF is, however, unknown. This study analyzed the relationship between plasma PHT concentrations and AF in patients with systolic HF.Material and methods 131 consecutive, stable HF patients, who were admitted to the HF outpatient clinic, were included in this prospective, observational study. Patients were classified as those with AF (n = 36) and those in sinus rhythm (SR, n = 95).Results PTH concentrations were markedly higher in patients with AF compared to the patients in SR [85 (15-320) vs. 112 (30-326) U / ml, p=0.007]. PTH, creatinine clearance, hemoglobin, creatinine, age, and left ventricular ejection fraction were found to be related to AF by univariate analysis; though, multivariate logistic regression analysis showed that only PTH concentration was independently related to AF.Conclusion PTH concentrations can be used to indicate AF in patients with systolic HF.

Short-term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23).

Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24-hydroxylase (Cyp24a1), thereby inactivating 1,25(OH)2 D3 . Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesized that fasting can induce FGF23 synthesis through the production of ketone bodies. UMR106 cells and isolated neonatal rat ventricular myocytes (NRVM) were treated with ketone body β-hydroxybutyrate. Mice were fasted overnight, fed ad libitum, or treated with β-hydroxybutyrate. Proteins and further blood parameters were determined by enzyme-linked immunoassay (ELISA), western blotting, immunohistochemistry, fluorometric or colorimetric methods, and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). β-Hydroxybutyrate stimulated FGF23 production in UMR106 cells in a nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB)-dependent manner, and in NRVMs. Compared to fed animals, fasted mice exhibited higher β-hydroxybutyrate and FGF23 serum levels (based on assays either detecting C-terminal or intact, biologically active FGF23 only), cardiac, pancreatic, and thymic Fgf23 and renal Cyp24a1 expression, and lower 1,25(OH)2 D3 serum concentration as well as renal Slc34a1 and αKlotho (Kl) expression. In contrast, Fgf23 expression in bone and serum phosphate, calcium, plasma parathyroid hormone (PTH) concentration, and renal Cyp27b1 expression were not significantly affected by fasting. Short-term fasting increased FGF23 production, as did administration of β-hydroxybutyrate, effects possibly of clinical relevance in view of the increasing use of FGF23 as a surrogate parameter in clinical monitoring of diseases. The fasting state of patients might therefore affect FGF23 tests.

Primary hyperparathyroidism, a machine learning approach to identify multiglandular disease in patients with a single adenoma found at preoperative Sestamibi-SPECT/CT.

Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients. This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy. A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights. The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight. Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.

Bioactive, full-length parathyroid hormone delivered using an adeno-associated viral vector.

Delivering the parathyroid hormone (PTH) gene has been attempted preclinically in a handful of studies, but delivering full-length PTH (1-84) using adeno-associated viral (AAV) vectors has not. Given the difficulty in achieving therapeutic levels of secreted proteins using gene therapy, this study seeks to determine the feasibility of doing so with PTH. An AAV vector was used to deliver human PTH driven by a strong promoter. We demonstrate the ability to secrete full-length PTH from various cell types in vitro. PTH secretion from hepatocytes was measured over time and a fluorescent marker was used to compare the secretion rate of PTH in various cell types. Potency was measured by the ability of PTH to act on the PTH receptors of osteosarcoma cells and induced proliferation. PTH showed potency in vitro by inducing proliferation in two osteosarcoma cell lines. In vivo, AAV was administered systemically in immunocompromised mice which received xenografts of osteosarcoma cells. Animals that received the highest dose of AAV-PTH had higher liver and plasma concentrations of PTH. All dosing groups achieved measurable plasma concentrations of human PTH that were above the normal range. The high-dose group also had significantly larger tumors compared to control groups on the final day of the study. The tumors also showed dose-dependent differences in morphology. When looking at endocrine signaling and endogenous bone turnover, we observed a significant difference in tibial growth plate width in animals that received the high-dose AAV as well as dose-dependent changes in blood biomarkers related to PTH. This proof-of-concept study shows promise for further exploration of an AAV gene therapy to deliver full-length PTH for hypoparathyroidism. Additional investigation will determine efficacy in a disease model, but data shown establish bioactivity in well-established models of osteosarcoma.

Ionized hypercalcemia in cats with azotemic chronic kidney disease (2012-2018).

BackgroundHypercalcemia is associated with chronic kidney disease (CKD) in cats, but studies assessing the physiologically relevant ionized calcium fraction are lacking.ObjectivesTo describe the prevalence and incidence rate of ionized hypercalcemia, and to explore predictor variables to identify cats at risk of ionized hypercalcemia in a cohort of cats diagnosed with azotemic CKD.AnimalsOne hundred sixty‐four client‐owned cats with azotemic CKD.MethodsVariables independently associated with ionized hypercalcemia at diagnosis of azotemic CKD were explored by binary logistic regression. Cats that were normocalcemic at diagnosis of azotemic CKD were followed over a 12‐month period or until ionized hypercalcemia occurred and baseline predictor variables for ionized hypercalcemia explored using Cox proportional hazards and receiver operating characteristic curve analysis.ResultsIonized hypercalcemia (median, 1.41 mmol/L; range, 1.38‐1.68) was observed in 33/164 (20%) cats at diagnosis of azotemic CKD and was associated with male sex, higher plasma total calcium and potassium concentrations, and lower plasma parathyroid hormone concentrations. Twenty‐five of 96 initially normocalcemic (26%) cats followed for minimum 90 days developed ionized hypercalcemia (median, 1.46 mmol/L; range, 1.38‐1.80) at a median of 140 days after diagnosis of azotemic CKD (incidence rate, 0.48 per feline patient‐year). Only body condition score was independently associated with incident ionized hypercalcemia.Conclusions and Clinical ImportanceThe occurrence of ionized hypercalcemia is high in cats with CKD. Continued monitoring of blood ionized calcium concentrations is advised.

Mathematical Models of Parathyroid Gland Biology: Complexity and Clinical Use.

Altered parathyroid gland biology is a major driver of chronic kidney disease-mineral bone disorder (CKD-MBD) in patients with chronic kidney disease. CKD-MBD is associated with a high risk of vascular calcification and cardiovascular events. A hallmark of CKD-MBD is secondary hyperparathyroidism with increased parathyroid hormone (PTH) synthesis and release and reduced expression of calcium-sensing receptors on the surface of parathyroid cells and eventually hyperplasia of parathyroid gland cells. The KDIGO guidelines strongly recommend the control of PTH in hemodialysis patients. Due to the complexity of parathyroid gland biology, mathematical models have been employed to study the interaction of PTH regulators and PTH plasma concentrations. Here, we present an overview of various model approaches and discuss the impact of different model structures and complexities on the clinical use of these models.

FC026: Chronic High Phosphate Level Impairs Cardiac Health

Abstract BACKGROUND AND AIMS Patients with chronic kidney disease (CKD) suffer from disturbed mineral metabolism in which the chronic phosphate load leads to the elevation of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Persistent hyperphosphatemia predisposes to cardiovascular events and increased morbidity and mortality rates. It is discussed that even in the general population, consumption of highly processed food increases phosphate level, which in turn may increase cardiovascular risk. Here, we aim to elucidate the pathological mechanisms of how chronic high phosphate intake mediates cardiac remodeling and dysfunction, respectively. METHOD Male C57BL/6 wild type mice received a high phosphate diet containing 2% inorganic phosphate (HPD) or a 0.8% normal phosphate diet (NPD) for 6 months. Echocardiographic analysis and ex-vivo measurements in cardiomyocytes using IonOptix system were assessed to evaluated cardiac function and contractility. Bulk RNA sequencing of whole heart tissue followed by pathway analysis was done to identify affected relevant signaling pathways, which were verified by in vitro studies using neonatal rat ventricular myocytes (NRVM). RESULTS Chronic phosphate overload resulted in increased level of serum and urinary phosphate and high plasma PTH and FGF23 concentrations. HPD caused impaired heart function as shown by reduced ejection fraction, increased end-systolic volumes and enlarged systolic left ventricular internal diameter accompanied by impaired left ventricular relaxation as seen in Doppler echocardiography. Histological analysis showed increased cardiomyocyte area and length in HPD-fed mice compared with NPD demonstrating cellular hypertrophy. RNA sequencing revealed differentially expressed genes of calcium signaling pathways in the HPD group. Besides, immunoblot analysis of whole heart tissue showed altered Phospholamban activity after 6 months of HPD compared with NPD, indicating altered calcium pump in cardiomyocytes. Preliminary analysis of sarcomere movements and changes of intracellular calcium levels in single cardiomyocytes isolated from NPD and HPD mice after 6 months suggested impaired contractility. Detailed results will be presented here. In vitro stimulation of isolated NRVM with high phosphate induced a hypertrophic growth response, verifying a direct effect of high phosphate on the heart. CONCLUSION HPD in mice causes a dilated cardiac phenotype including cellular hypertrophy, altered contractility and differentially expressed genes involved in calcium signaling pathways, indicating that a chronic high phosphate load is harmful for the heart also in the general population.

Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2.

Adaptor protein 2 (AP2), a heterotetrameric complex comprising AP2α, AP2β2, AP2μ2 and AP2σ2 subunits, is ubiquitously expressed and involved in endocytosis and trafficking of membrane proteins, such as the calcium-sensing receptor (CaSR), a G-protein coupled receptor that signals via Gα11. Mutations of CaSR, Gα11 and AP2σ2, encoded by AP2S1, cause familial hypocalciuric hypercalcaemia types 1–3 (FHH1–3), respectively. FHH3 patients have heterozygous AP2S1 missense Arg15 mutations (p.Arg15Cys, p.Arg15His or p.Arg15Leu) with hypercalcaemia, which may be marked and symptomatic, and occasional hypophosphataemia and osteomalacia. To further characterize the phenotypic spectrum and calcitropic pathophysiology of FHH3, we used CRISPR/Cas9 genome editing to generate mice harboring the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, and had marked hypercalcaemia, hypermagnesaemia, hypophosphataemia, and increases in alkaline phosphatase activity and fibroblast growth factor-23. Plasma 1,25-dihydroxyvitamin D was normal, and no alterations in bone mineral density or bone turnover were noted. Homozygous (Ap2s1L15/L15) mice invariably died perinatally. Co-immunoprecipitation studies showed that the AP2S1 p.Arg15Leu mutation impaired protein–protein interactions between AP2σ2 and the other AP2 subunits, and also with the CaSR. Cinacalcet, a CaSR positive allosteric modulator, decreased plasma calcium and parathyroid hormone concentrations in Ap2s1+/L15 mice, but had no effect on the diminished AP2σ2-CaSR interaction in vitro. Thus, our studies have established a mouse model that is representative for FHH3 in humans, and demonstrated that the AP2S1 p.Arg15Leu mutation causes a predominantly calcitropic phenotype, which can be ameliorated by treatment with cinacalcet.

Parathyroid hormone may play a role in the pathophysiology of primary hypertension.

Parathyroid hormone has been related with the risk of hypertension, but the matter remains controversial. We examined the association of parathyroid hormone with central blood pressure and its determinants in 622 normotensive or never-treated hypertensive subjects aged 19–72 years without diabetes, cardiovascular or renal disease, or cardiovascular medications. The methods were whole-body impedance cardiography and analyses of pulse wave and heart rate variability. Cardiovascular function was examined in sex-specific tertiles of plasma parathyroid hormone (mean concentrations 3.0, 4.3 and 6.5 pmol/L, respectively) during head-up tilt. Explanatory factors for haemodynamics were further investigated using linear regression analyses. Mean age was 45.0 (s.d. 11.7) years, BMI 26.8 (4.4) kg/m2, seated office blood pressure 141/90 (21/12) mmHg, and 309 subjects (49.7%) were male. Only five participants had elevated plasma parathyroid hormone and calcium concentrations. Highest tertile of parathyroid hormone presented with higher supine and upright aortic diastolic blood pressure (P < 0.01) and augmentation index (P < 0.01), and higher upright systemic vascular resistance (P < 0.05) than the lowest tertile. The tertiles did not present with differences in pulse wave velocity, cardiac output, or measures of heart rate variability. In linear regression analyses, parathyroid hormone was an independent explanatory factor for aortic systolic (P = 0.005) and diastolic (P = 0.002) blood pressure, augmentation index (P = 0.002), and systemic vascular resistance (P = 0.031). To conclude, parathyroid hormone was directly related to central blood pressure, wave reflection, and systemic vascular resistance in subjects without cardiovascular comorbidities and medications. Thus, parathyroid hormone may play a role in the pathophysiology of primary hypertension.

An examination of multiple explanations forsecondary hyperparathyroidism .

Seven theories address the evolution of secondary hyperparathyroidism (SHPT) as chronic kidney disease (CKD) progresses. The tradeoff-in-the-nephron hypothesis states that the plasma parathyroid hormone ([PTH]) concentration rises because an increased phosphate concentration in the cortical distal nephron ([P]CDN) reduces the ionized calcium concentration in that segment. In the present study, we compared this hypothesis to its predecessors. We studied 30 patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 (mean 29.5). To examine historic theories, we performed regressions of [PTH] on plasma concentrations of ionized calcium, phosphorus, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and fibroblast growth factor 23, and on calcium excreted per volume of filtrate (ECa/Ccr). To assess the tradeoff-in-the-nephron hypothesis, we examined regressions of [PTH] on 100/eGFR and phosphorus excreted per volume of filtrate (EP/Ccr). Regressions pertinent to historic theories yielded significant direct relationships between [PTH] and both ECa/Ccr and [FGF23], but neither association supported the theory to which it pertained. [PTH] varied directly with 100/eGFR and with EP/Ccr, a surrogate for [P]CDN. EP/Ccr correlated strongly with 100/eGFR. The only theory of SHPT that our data support is the tradeoff-in-the-nephron hypothesis. Other theories are not supported.

Association Between Plasma Intact Parathyroid Hormone Levels and the Prevalence of Atrial Fibrillation in Patients With Chronic Kidney Disease - The Fukuoka Kidney Disease Registry Study.

Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD).Methods and Results:The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-Q4) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016). Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

Studies of mice deleted for Sox3 and uc482: relevance to X-linked hypoparathyroidism.

Hypoparathyroidism is genetically heterogeneous and characterized by low plasma calcium and parathyroid hormone (PTH) concentrations. X-linked hypoparathyroidism (XLHPT) in two American families is associated with interstitial deletion-insertions involving deletions of chromosome Xq27.1 downstream of SOX3 and insertions of predominantly non-coding DNA from chromosome 2p25.3. These could result in loss, gain, or movement of regulatory elements, which include ultraconserved element uc482, which could alter SOX3 expression. To investigate this, we analysed SOX3 expression in EBV-transformed lymphoblastoid cells from three affected males, three unaffected males, and four carrier females from one XLHPT family. SOX3 expression was similar in all individuals, indicating that the spatiotemporal effect of the interstitial deletion-insertion on SOX3 expression postulated to occur in developing parathyroids did not manifest in lymphoblastoids. Expression of SNTG2, which is duplicated and inserted into the X chromosome, and ATP11C, which is moved telomerically, were also similarly expressed in all individuals. Investigation of male hemizygous (Sox3−/Y and uc482−/Y) and female heterozygous (Sox3+/− and uc482+/−) knockout mice, together with wild-type littermates (male Sox3+/Y and uc482+/Y, and female Sox3+/+ and uc482+/+), revealed Sox3−/Y, Sox3+/−, uc482−/Y, and uc482+/− mice to have normal plasma biochemistry, compared to their respective wild-type littermates. When challenged with a low calcium diet, all mice had hypocalcaemia, and elevated plasma PTH concentrations and alkaline phosphatase activities, and Sox3−/Y, Sox3+/−, uc482−/Y, and uc482+/− mice had similar plasma biochemistry, compared to wild-type littermates. Thus, these results indicate that absence of Sox3 or uc482 does not cause hypoparathyroidism and that XLHPT likely reflects a more complex mechanism.

Association between 25-Hydroxyvitamin D, Parathyroid Hormone, Vitamin D and Calcium Intake, and Bone Density in Healthy Adult Women: A Cross-Sectional Analysis from the D-SOL Study.

There is still limited data on the association between 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and bone health in healthy younger adults, particularly in Latin America. This cross-sectional analysis aimed to investigate the associations of 25(OH)D and plasma PTH concentrations with bone parameters, and potential confounders, in women living in a high (England) or low (Brazil) latitude country. Bone was assessed by either peripheral quantitative computed tomography (pQCT) (England) or dual-energy x-ray absorptiometry (DXA) scan (Brazil), serum 25(OH)D concentrations by high performance liquid chromatography tandem mass spectrometry (HPLC-MS) and PTH by the chemiluminescent method. In participants living in England, total volumetric bone mineral density (vBMD) was significantly higher in women <29 years compared to ≥30 years, and total and cortical vBMD values at the 66% site were negatively correlated with weight and body mass index (BMI). In participants living in Brazil, age was positively correlated with bone mineral density (BMD) at the femur and bone mineral content (BMC), and weight, BMI, and body fat were correlated with BMD (lumbar spine and femur) and BMC. PTH concentrations were negatively correlated with 25(OH)D concentrations, and the prevalence of secondary hyperparathyroidism was 28.6% (n = 14) in participants with concentrations <25 nmol/L and 12.2% (n = 41) with concentrations between 25 and 49.9 nmol/L, compared to 6.3% (n = 79) in those with concentrations ≥50 nmol/L. In conclusion, weight and BMI were significantly correlated with bone parameters in both groups and age was significantly correlated with BMD at the femoral neck for women living in Brazil only. Although 25(OH)D concentrations were not correlated to bone parameters at any sites, in either country, PTH concentrations showed a significant correlation with total vBMD at the 66% site for women living in England. Secondary hyperparathyroidism was more common amongst those with deficient and insufficient vitamin D status.

TRENDS IN PARATHYROID HORMONE PLASMA CONCENTRATION IN CRITICALLY ILL PATIENTS: PROSPECTIVE OBSERVATIONAL STUDY

Introduction: There is no data in the literature regarding trends in parathormone serum concentration assessment in critically ill patients. The aim: To assess the parathyroid hormone plasma concentrations and kinetics in critically ill patients admitted to the intensive care unit due to multiorgan failure. Materials and methods: Thirty multiorgan failure (at least circulatory and respiratory failure) patients were included. Patients who met any of the following criteria were excluded: acute liver failure, end stage renal disease, hypercalcemia, parathyroid gland disease, severe vitamin D deficiency, admission from another ICU or readmission, age younger than 18 years, or lack of consent from relatives. We performed the parathyroid hormone plasma measurements in 12-hour time intervals. Results: The initial parathyroid hormone plasma concentration levels in the study group were rather variable and medians exceeded laboratory reference values. Especially in the acute kidney injury subpopulation treated with continuous renal replacement therapy these trends were emphasized. The initial parathyroid hormone plasma concentration levels in this group significantly exceeded laboratory reference values in 80% of patients. After initial spike we observed subsequent drop between second and third measurement. The distribution of plasma levels was rather variable between second and third measurement in this group of patients. Conclusions: The parathyroid hormone plasma concentration levels in the critically ill patients are variable. In the acute kidney injury subpopulation treated with continuous renal replacement therapy after initial significant spike we observed subsequent drop between second and third measurement.

Detrimental Impact of Interferon-Based Regimens for Chronic Hepatitis C on Vitamin D/Parathyroid Hormone Homeostasis

Background: Both the anti-infective and anti-inflammatory properties of vitamin D, an essential hormone of calcium homeostasis, have ample support in the literature. The high rates of vitamin D deficiency among patients with chronic hepatitis C are also well known. That supplementation with vitamin D may boost sustained viral response rates in vitamin D deficient, hepatitis C virus (HCV) infected patients undergoing Interferon-alpha (IFN) treatment, on the other hand, is controversial. Surprisingly, studies considering in this latter setting what are the effects of IFN treatment (with or without vitamin D supplementation) on the other major regulator of mineral metabolism, i.e. the Parathyroid hormone (PTH), are lacking. Aim: Evaluate the impact of interferon-based treatment against HCV (±cholecalciferol supplementation) on vitamin D and PTH homeostasis. Methods: A series of 40 consecutive patients received pegylated IFN plus ribavirin to treat chronic hepatitis C. At the discretion of their physician, some of them (N. = 27) received vitamin D supplementation while others did not (N. = 13). All had measured plasma 25-hydroxycholecalciferol and PTH concentrations at baseline, at completion of the 4th (TW4) and 12th treatment week (TW12) and at 24 weeks after the end of therapy (SVR24). Results: Plasma PTH concentration increased significantly from baseline during treatment, raising to 44.8 [30.7-57.2] pg/mL at TW4 (p=0.01), 47.0 [37.1-63.2] pg/mL at TW12 (p=0.006) to return to baseline levels in the follow-up (34.5 [27.6-43.0]; p=0.16). The proportion of patients who satisfied criteria for hyperparathyroidism was higher at TW12 (N=10, 25%) than at TW4 (N=6, 15%). There was no statistical correlation between vitamin D and PTH blood levels (ρ=-0.07; p=0.65). Conclusion: An increase in plasma PTH occurs systematically during IFN treatment of HCV patients and cannot be prevented by vitamin D supplementation.

Short communication: Effect of dietary phosphorus deprivation in late gestation and early lactation on the calcium homeostasis of periparturient dairy cows

Environmental concerns with P of animal origin polluting surface waters are leading to legal incentives aimed at reducing the dietary P content of dairy cow rations to the lowest possible level that does not negatively affect health and productivity. The objective of the present study was to determine the effect of feeding rations with low dietary P content in late gestation on the Ca homeostasis of the periparturient dairy cow. Eighteen multiparous dairy cows were either fed a P-deficient (0.15% P in dry matter antepartum and 0.20% P in dry matter postpartum) but otherwise balanced ration or a control ration with adequate P content (0.28% P in dry matter antepartum and 0.44% P in dry matter postpartum) during the last 4 wk of gestation until d 10 postpartum. Blood was obtained before initiation of P-deprivation (baseline) and -10, -2, +1, +3, and +10 d relative to parturition to be analyzed for plasma concentrations of Ca [Ca] and inorganic phosphate [Pi]. In addition, plasma concentrations of parathyroid hormone [PTH], the bone resorption marker CrossLaps [CTX], 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were determined in a subset of samples. Feeding a P-deficient diet for 4 wk antepartum positively affected the Ca homeostasis of periparturient cows. Clinical hypocalcemia occurred in 3/9 control and 0/9 P-deprived cows. [Calcium], [PTH], and plasma concentrations of vitamin D metabolites did not differ between groups until parturition, whereas [Pi] was decreased and [CTX] significantly increased in P-deprived animals. At parturition [PTH] was significantly greater in control cows compared with P-depleted cows. The P-deprived cows had significantly higher [Ca] than control cows on d +1 (2.46 ± 0.11 vs. 2.27 ± 0.41 mmol/L) and +2 (2.61 ± 0.13 vs. 2.35 ± 0.25 mmol/L). Plasma [CTX] was significantly higher in P-deprived than in control cows on d +2. Bone resorption and the typical increase in 1,25-dihydroxyvitamin D in periparturient P-deprived cows seemed to occur despite the smaller rise of [PTH], suggesting either greatly increased sensitivity to PTH or bone mobilization independent of PTH. Future studies must explore potentially negative effects of P-deprivation antepartum on health and productivity of the dairy cow in the following lactation.

Calcium metabolism-related hormonal changes in layers experimentally infected with Salmonella Gallinarum

The present study was conducted to investigate the calcium metabolism-related hormonal changes in layers experimentally infected with Salmonella Gallinarum. A total of 20 18-week-old ISA brown layers were purchased from a commercial poultry farm in Kujama farm, Kaduna State, Nigeria. The birds were allowed to acclimatize for a period of 4 weeks prior to commencement of the experiment. On the day of infection with Salmonella Gallinarum, the birds were randomly divided into two groups, infected and control, of 10 birds each. To establish the infection, each bird in the infected group was orally administered 0.5 ml of the inoculum containing 9 × 108 CFU/ml. Similarly, birds in the control group were each administered 0.5 ml normal saline only. Following the inoculation, all experimental birds were closely monitored for clinical signs of fowl typhoid. Blood samples were collected from each group and was dispensed into heparinized bottles for plasma separation at day zero (day 0), 2, 4, 7, 14, 21, 28, 35, and 42 post-infection (pi) and was used for determination of hormones and electrolyte parameters. By day 7 post-infection, all birds in the infected group showed clinical signs typical of fowl typhoid, namely weakness, ruffled feathers, huddling together, somnolence, greenish-yellow diarrhea, weight loss, drop in egg production, decrease in feed and water consumption, and mortality rate (50%). There were, however, significant decrease in plasma calcium and phosphorus concentrations and significant increase in plasma estrogen and parathyroid hormone concentration in the Salmonella Gallinarum-infected layers. In conclusion, the decrease in plasma calcium and phosphorus concentrations observed in the Salmonella Gallinarum experimentally infected layers was a consequence of hepatic, renal, and gastrointestinal lesions and not due to endocrine dysfunction as plasma levels of the hormones did not suggest so.

About an aggressive bone lesion.

Key Clinical MessageWe report here a case of hyperparathyroidism with disseminated brown tumors mimicking malignancy. The important clinical teaching of our case is that hyperparathyroidism can take various aspects. Plasma parathyroid hormone concentration should be measured in all patients with multiple bone lesions.

Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation.

Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin–adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.