Elevated Parathyroid Hormone Concentrations Research Articles

Variable Bone Phenotypes in Patients with Pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. PHP is divided into several subtypes with different yet overlapping phenotypes. Research on the bone status in patients with PHP is sparse and has yielded inconsistent results. This review was performed to summarize the current knowledge on the bone phenotypes and possible mechanisms of PHP. Patients with PHP exhibit highly variable bone phenotypes and increased concentrations of bone turnover markers. Long-standing elevation of the parathyroid hormone concentration may lead to hyperparathyroid bone diseases, including rickets and osteitis fibrosa. Compared with normal controls, patients with PHP may exhibit similar, increased, or decreased bone mineral density. Higher bone mineral density has been found in patients with PHP type 1A than in normal controls, whereas decreased bone mass, osteosclerosis, and osteitis fibrosa cystica have been reported in patients with PHP type 1B, indicating more variable bone phenotypes in PHP type 1B. Bone tissues show partial sensitivity to parathyroid hormone in patients with PHP, leading to heterogeneous reactions to parathyroid hormone in different individuals and even in different regions of bone tissues in the same individual. Regions rich in cancellous bone are more sensitive and show more obvious improvement after therapy. Active vitamin D and calcium can significantly improve abnormal bone metabolism in patients with PHP.

Non-oxidized PTH (n-oxPTH) is associated with graft loss in kidney transplant recipients

Elevated parathyroid hormone (PTH) concentrations were reported to be associated with chronic renal allograft failure. However, measurements of PTH are challenging, because PTH can occur either as non-oxidized (n-ox) or oxidized (ox) PTH. Only n-ox PTH is a PTH receptor agonist. The intact PTH (iPTH) concentrations measured routinely in clinical practice, however, equals non-oxidized PTH (n-oxPTH) plus oxidized PTH (oxPTH). In CKD patients, the majority of the circulating PTH is oxidized. We measured iPTH, oxPTH and n-oxPTH at study entry in 600 kidney transplant recipients (KTRs). They were followed for graft loss for 3 years. Graft loss was defined as need for initiation of renal replacement therapy. Thirty-eight patients had graft loss during the 3 years follow-up. OxPTH correlated very well with iPTH (R2 = 0.997, p < 0.0001), whereas the correlation between n-oxPTH and iPTH was much weaker (R2 = 0.762, p < 0.0001). Compared to KTRs without graft loss, KTRs with graft loss had significantly higher levels of iPTH, oxPTH, and n-oxPTH (p < 0.0001 in all cases). After adjusting for confounding factors in cox proportional hazards analysis, only n-oxPTH, but not oxPTH neither iPTH, was significantly associated with graft loss (Hazard ratio (HR): 1.02, 95% CI: 1.01–1.03, p = 1.84 × 10−3). The very close correlation between oxPTH and iPTH measurements suggests that conventional iPTH measurements most likely describe oxidative stress rather than PTH bioactivity. Only non-oxidized PTH but not oxidized PTH nor intact PTH is associated with graft loss in stable kidney transplant recipients.

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.

MON-539 Mice Harboring a Germline Heterozygous AP2S1 Mutation, Arg15Leu, Are a Model for Familial Hypocalciuric Hypercalcemia Type 3 (FHH3)

Familial hypocalciuric hypercalcemia (FHH) is a disorder of calcium homeostasis comprising three reported genetic variants: FHH types 1 and 2 are due to germline loss-of-function mutations of the calcium-sensing receptor (CaSR) and G-protein subunit α-11 (Gα11), respectively, whereas, FHH type 3 (FHH3) is mainly caused by germline heterozygous loss-of-function mutations affecting the Arg15 residue (Arg15Cys, Arg15His or Arg15Leu) of the adaptor-related protein complex 2-sigma subunit (AP2σ), which is encoded by the AP2S1 gene, and regulates CaSR endocytosis and endosomal signaling. FHH is considered to be an asymptomatic disorder characterised by mild-to-moderate hypercalcemia, normal or mildly elevated parathyroid hormone (PTH) concentrations and low urinary calcium excretion. However, some FHH3 patients, especially those harboring the Arg15Leu AP2S1 mutation, have marked and symptomatic hypercalcemia, thereby indicating that FHH3 may represent a more severe clinical disorder. To further evaluate the impact of the Arg15Leu AP2S1 mutation on calcium homeostasis, we utilised CRISPR/Cas9-mediated gene editing to generate C57BL/6J mice harboring the germline Arg15Leu mutation. Plasma and 24-hour urine samples were collected for biochemical analysis, and bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DEXA). All studies were conducted in mice aged 12-15 weeks (n = 10-12 mice per genotype), and in accordance with institutional welfare guidelines. Wild-type (Ap2s1+/+), heterozygous (Ap2s1+/L15) and homozygous (Ap2s1L15/L15) mice were born as expected for a Mendelian pattern of inheritance, however, Ap2s1L15/L15 mice died within 48 hours of birth. In contrast, male and female Ap2s1+/L15mice were viable and biochemical analysis showed marked hypercalcemia (plasma albumin-adjusted calcium = 2.77±0.02 mmol/L) compared to wild-type (WT) mice (plasma albumin-adjusted calcium = 2.13±0.03 mmol/L, p<0.0001), and this finding was associated with significant hypophosphatemia and hypermagnesemia. Male and female Ap2s1+/L15mice also had significant elevations of plasma PTH (157±14 pmol/L) compared to WT mice (63±10 pmol/L, p<0.0001). Furthermore, urine analysis showed that Ap2s1+/L15mice were significantly hypocalciuric (fractional excretion of calcium (FECa) = 0.016±0.002) compared to WT mice (FECa =0.029±0.002, p<0.01), whilst, DEXA analysis demonstrated that Ap2s1+/L15mice have significantly reduced BMD. Thus, these studies have established a mouse model for FHH3, which highlights the importance of the AP2σ protein in the parathyroid and renal regulation of mineral and bone homeostasis. In addition, these findings demonstrate that the germline heterozygous Arg15Leu AP2S1 mutation causes a severe form of FHH characterized by marked hypercalcemia, hyperparathyroidism and reduced BMD.

Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) invitro and invivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells invitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Parathyroid carcinoma: a case report

Parathyroid carcinoma (PC) is an uncommon cause of primary hyperparathyroidism (pHPT). The tumor is mostly functioning with following high serum calcium and parathyroid hormone (PTH) levels. Consideration of PC in differential diagnosis of pHPT is important because the mortality and the prognosis depend on early recognition and surgical approach. A case of PC in 51-year old female patient with persistent pHPT is reported. A patient, referred with anterior cervical hematoma, dysphagia, underwent neck ultrasound, barium X-ray swallow test and neck computed tomography. On the posterior surface of left thyroid lobe, close to the esophagus the heterogenic lesion with irregular margins was found. The preoperative calcemia was slightly elevated. The patient underwent cervical exploration with parathyroidectomy. Histological exam showed parathyroid lesion with immunohistochemical confirmation of PC. After 2months follow-up there are no signs of a residual-recurrent disease. Although laboratory tests revealed pHPT preoperatively, no clinical effects of elevated calcium and PTH concentration levels were presented. As histological features are not specific for the differential diagnosis between the parathyroid adenoma and PC, the immunohistochemistry remains the only useful tool for the definite diagnosis.

High parathyroid hormone levels are associated with poor balance in older persons: A cross-sectional study

ObjectivesA high level of parathyroid hormone (PTH) was recently identified as a risk factor for falling. As balance instability is one of the major risk factors for falls, we aimed to investigate whether high PTH concentrations are associated with poor balance in older persons. Study designCross-sectional study with 127 community-dwelling older adults (75% female), aged 65–96 years, at the Falls and Fracture Clinic, Western Health-Sunshine Hospital, Melbourne, Australia. Patients with clinical conditions that could affect balance (e.g. Meniere’s disease), denosumab users, and those with advanced kidney failure were excluded. Main outcome measuresWe assessed dynamic balance by timed “up and go” (TUG)and four-square step tests, and by gait parameters; and static balance by posturography on a force platform. Blood tests provided values of PTH, vitamin D, calcium, albumin, and creatinine. Standard questionnaires were applied to assess clinical condition, medications and nutritional status, and to screen for depression. ResultsFor dynamic balance, elevated PTH concentrations resulted in increased time to complete the TUG test (β = 0.13; 95%CI: 0.01–0.26), indicating worse performance. For static balance, increased PTH was associated with increased instability in the center of pressure while standing with eyes closed on a hard surface (β = 0.38; 95%CI: 0.03–0.73). Both models were controlled for vitamin D, renal function, nutritional and depressive status, age, sex, and number of medications. ConclusionIncreasing concentrations of PTH in this population of older persons had an independent negative association with both static and dynamic balance, which could place them at risk of falls. However, longitudinal studies are still required.

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

SummaryFamilial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.Learning points:Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.Large deletions or duplications in the CASR gene can be detected by the MLPA technique.Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

Effects of growth hormone treatment on growth plate, bone, and mineral metabolism of young rats with uremia induced by adenine.

BackgroundIn a model of growth retardation secondary to chronic kidney disease (CKD) induced by adenine, this study explores the effects of growth hormone (GH) therapy on growth plate and mineral metabolism.MethodsWeaning female rats receiving a 0.5% adenine diet during 21 days, untreated (AD) or treated with GH (ADGH) for 1 week, were compared with control rats receiving normal diet, either ad libitum or pair-fed with AD animals. AD and ADGH rats had similarly elevated serum concentrations of urea nitrogen, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).ResultsUremia induced by adenine caused growth retardation and disturbed growth cartilage chondrocyte hypertrophy. We demonstrated marked expression of aquaporin 1 in the growth plate, but its immunohistochemical signal and the expression levels of other proteins potentially related with chondrocyte enlargement, such as Na-K-2Cl cotransporter, insulin-like growth factor 1 (IGF-1), and IGF-1 receptor, were not different among the four groups of rats. The distribution pattern of vascular endothelial growth factor was also similar. AD rats developed femur bone structure abnormalities analyzed by micro-computerized tomography.ConclusionGH treatment accelerated longitudinal growth velocity, stimulated the proliferation and enlargement of chondrocytes, and did not modify the elevated serum PTH or FGF23 concentrations or the abnormal bone structure.

Postprandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor.

What is the central question of this study? Does a previously hypothesized signalling mechanism, believed to detect postprandial increases in intestinal phosphate and that can stimulate the kidneys to rapidly excrete phosphate, operate under physiological conditions? What is the main finding and its importance? Contrary to earlier reports, rapid signalling between the small intestine and kidney mediated by a gut-derived phosphaturic factor in response to a physiological intestinal phosphate load is not supported by the present findings; moreover, hyperphosphataemia and increased parathyroid hormone concentrations are likely to be the underlying factors responsible for the phosphaturia following a supraphysiological intestinal phosphate load. To date, the role of the small intestine in the regulation of postprandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) concentration; however, these early studies used duodenal luminal phosphate concentrations in the molar range, and therefore, the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative 'intestinal phosphatonin'. Instillation of 1.3m phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH concentration; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10mm) phosphate load had no effect on plasma phosphate concentration, PTH concentration or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different concentrations of phosphate. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between the gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis.

Genetic Variants Associated with Circulating Parathyroid Hormone.

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Prevalence and prognostic implications of vitamin D deficiency in chronic kidney disease.

Vitamin D is an important nutrient involved in bone mineral metabolism, and vitamin D status is reflected by serum total 25-hydroxyvitamin D (25[OH]D) concentrations. Vitamin D deficiency is highly prevalent in patients with chronic kidney disease (CKD), and nutritional vitamin D supplementation decreases elevated parathyroid hormone concentrations in subgroups of these patients. Furthermore, vitamin D is supposed to have pleiotropic effects on various diseases such as cardiovascular diseases, malignancies, infectious diseases, diabetes, and autoimmune diseases. Indeed, there is cumulative evidence showing the associations of low vitamin D with the development and progression of CKD, cardiovascular complication, and high mortality. Recently, genetic polymorphisms in vitamin D-binding protein have received great attention because they largely affect bioavailable 25(OH)D concentrations. This finding suggests that the serum total 25(OH)D concentrations would not be comparable among different gene polymorphisms and thus may be inappropriate as an index of vitamin D status. This finding may refute the conventional definition of vitamin D status based solely on serum total 25(OH)D concentrations.

Normocalcemic hyperparathyroidism: A new clinical type of primary hyperparathyroidism

Normocalcemic hyperparathyroidism: A new clinical type of primary hyperparathyroidism Primary hyperparathyroidism is the third most common endocrine disorder and the most common cause of hypercalcemia in the outpatient setting. After the introduction of automated serum calcium measurements in the 1970s, its prevalence increased significantly. In addition, the clinical phenotype had shifted from a symptomatic disorder to a less symptomatic or even asymptomatic state. This clinical profile has been called asymptomatic primary hyperparathyroidism. A newer presentation of primary hyperparathyroidism has been described over the past decade, in which parathyroid hormone is elevated but total and ionized serum calcium concentrations are consistently normal, in the absence of secondary causes for elevated parathyroid hormone concentration. This new condition has been called normocalcemic primary hyperparathyroidism. This review presents the current data in relation to this newly described type of primary hyperparathyroidism.

Impact of vitamin D replacement in patients with normocalcaemic and hypercalcaemic primary hyperparathyroidism and coexisting vitamin D deficiency.

Vitamin D deficiency is increasingly recognized in patients with primary hyperparathyroidism but some clinicians are reluctant to replace vitamin D due to concerns with aggravating hypercalcaemia. We investigated the impact of vitamin D repletion in asymptomatic patients with normocalcaemic and hypercalcaemic primary hyperparathyroidism. This is a retrospective analysis of 111 patients with elevated parathyroid hormone concentrations (>6.4 pmol/L) referred to our endocrine clinic between January and December 2012; we identified 39 patients with primary hyperparathyroidism and vitamin D deficiency, i.e. 25 hydroxy vitamin D <20 µg/L. Patients were categorized into normocalcaemic (n = 23) and hypercalcaemic (n = 16) groups and the impact on biochemical parameters was recorded after at least six months treatment with either 1600 or 3200 units daily of cholecalciferol. Both normocalcaemic and hypercalcaemic groups showed a rise in 25 hydroxy vitamin D concentrations after replacement (p <0.0001). Parathyroid hormone concentrations fell in the normocalcaemic group (p = 0.08) but individually, five patients showed a rise (8-38% of baseline). In the hypercalcaemic group, parathyroid hormone remained static but the adjusted calcium concentration fell significantly (p = 0.006) except in two patients who showed mild rises (3 and 6%, respectively). There was no deterioration in renal function or calcium-related adverse events in any of the groups. Our study supports the safety of vitamin D replacement in patients with mild asymptomatic primary hyperparathyroidism and coexistent vitamin D deficiency. Repletion does not aggravate hypercalcaemia and may limit disease progression. Patients with normocalcaemic primary hyperparathyroidism need further characterization from longitudinal studies.

Adenoma Localization for Recurrent or Persistent Primary Hyperparathyroidism Using Dynamic Four-Dimensional CT and Venous Sampling

PurposeTo determine if parathyroid venous sampling (PVS) combined with four-dimensional (4D) computed tomography (CT) improves sensitivity and accuracy of identification of parathyroid adenoma in patients with recurrent or persistent primary hyperparathyroidism (pHPT) and negative technetium-99m methoxyisobutyl isonitrile (99mTc-MIBI) and ultrasound (US) scans. Materials and MethodsBoth PVS and 4D CT were performed in 28 patients with recurrent or persistent pHPT and negative 99mTc-MIBI and US examinations. Localization by 4D CT alone and in combination with PVS and lateralization by PVS alone were retrospectively assessed for correlation with surgical results. Suspected adenomas on 4D CT were said to correlate with PVS if venous drainage identified on CT corresponded to sites of elevated parathyroid hormone concentration on PVS. Lesions difficult to identify on 4D CT were lesions < 1 cm in longest dimension. Results of 4D CT were classified as positive, negative, or equivocal. ResultsSurgery was performed in 22 of 28 patients. Surgery identified 23 parathyroid adenomas, 1 carcinoma, and 2 hyperplastic glands in 20 patients. 4D-CT alone localized 11 lesions in 10 patients. PVS helped localize 13 additional lesions in nine more patients and clarified two lesions that were equivocal on 4D CT. Comparing 4D CT alone with 4D CT plus PVS, the sensitivity increased from 50% to 95% (P = .004), and accuracy increased from 55% to 91% (P = .022). PVS lateralization had a sensitivity of 93.3%, positive predictive value of 66.7%, and accuracy of 63.6%. ConclusionsPVS significantly improves 4D CT localization of parathyroid adenomas in patients undergoing repeat surgery for pHPT with negative 99mTc-MIBI and US.

Commentary on Silent Renal Stones in Primary Hyperparathyroidism: Prevalence and Clinical Features

Commentary on Silent Renal Stones in Primary Hyperparathyroidism: Prevalence and Clinical Features

Vitamin D deficiency during winter months among an adult, predominantly urban, population in Northern Poland.

Vitamin D is vital in the regulation of the calcium-phosphate metabolism, has a direct impact on the musculoskeletal system, and also affects numerous other systems. Widespread vitamin D deficiency and its detrimental effect on health have been reported globally. Data concerning vitamin D status in Polish adult population is scarce. Ambulatory patients of an outpatient clinic in Gdańsk were included in the study. Serum concentrations of 25(OH) D, parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium and phosphorus were determined. In a questionnaire declared UVB exposure, dietary vitamin D and calcium intake, and health status of the subjects were assessed. Non- and parametric tests, logistic regression and population attributable risk were applied in data analysis. 448 adults were examined from February to mid-April 2012, 305 women and 143 men, aged 19 to 86 (mean 46.3 ± 14.9 years). Mean 25-hydroxyvitamin D concentration was 14.3 ± 6.6 ng/mL. 84.4% of subjects were vitamin D deficient (25(OH)D < 20 ng/mL); 13.2% presented insufficient (20-30 ng/mL), and 2.5% (or 11 subjects) sufficient 25(OH)D concentrations. Significantly higher 25(OH)D concentrations were found in subjects who reported more UVB exposure, supplemented vitamin D orally and those who declared more physical activity. 21% of subjects had elevated serum PTH concentration (i.e. > 62 pg/mL); mean parathormone was 48.6 ± 25.2 pg/mL. A linear correlation was found between the logarithm of PTH and logarithm of 25(OH)D concentrations (r = -0.21, p < 0.001). Results obtained here demonstrate the necessity of implementing a monitoring and prophylaxis programme of vitamin D deficiency in Poland.

Predictive Parameters of Accelerated Muscle Loss in Men—MINOS Study

BackgroundAging-related muscle loss is a public health problem. We investigated the association of lifestyle and hormonal factors with a prospectively assessed muscle loss in older men. MethodsAmong 608 home-dwelling men, aged 60-85 (mean 68) years, lifestyle and health status were evaluated through a questionnaire. Appendicular skeletal muscle mass was estimated using dual-energy x-ray absorptiometry and calculated as the sum of lean mass of the 4 limbs. Free testosterone concentration was calculated using concentrations of total testosterone and sex hormone-binding globulin. Longitudinal data were analyzed by hierarchical models. ResultsAverage muscle loss was 0.63 ± 0.05%/year. The results of our multivariable adjusted analyses showed that muscle loss was higher in men whose leisure physical activity was <15 hours/week versus ≥15 hours/week (−0.76 vs −0.57%/year). Age-related acceleration of muscle loss was greater in men with lower total testosterone levels (<10 vs ≥10 nmol/L: −0.10 vs −0.07%/year/year of age at baseline [age]). Men with lower free testosterone (<75 vs ≥75 pmol/L) had greater age-related acceleration of muscle loss (−0.12 vs −0.08%/year/age). Higher parathyroid hormone concentrations were associated with greater age-related acceleration of muscle loss (≥45 vs <45 pg/mL −0.14 vs −0.12%/year/age). Men with type 2 diabetes had higher age-related acceleration of muscle loss versus men without diabetes (−0.08 vs −0.03%/year/age) (All P values are <.05). ConclusionIn elderly men, low leisure physical activity, type 2 diabetes, low total and free testosterone, and elevated parathyroid hormone concentrations are associated with greater age-related acceleration of muscle loss. These factors are likely to represent real determinants of aging-related muscle loss in men.

Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human ‘knockout’

Loss-of-function calcium-sensing receptor (CAR) mutations cause elevated parathyroid hormone (PTH) secretion and hypercalcaemia. Although full Car deletion is possible in mice, most human CAR mutations result from a single amino acid substitution that maintains partial function. However, here, we report a case of neonatal severe hyperparathyroidism (NSHPT) in which the truncated CaR lacks any transmembrane domain (CaR(R392X)), in effect a full CAR 'knockout'. The infant (daughter of distant cousins) presented with hypercalcaemia (5.5-6 mmol/l corrected calcium (2.15-2.65)) and elevated PTH concentrations (650-950 pmol/l (12-81)) together with skeletal demineralisation. NSHPT was confirmed by CAR gene sequencing (homozygous c.1174C-to-T mutation) requiring total parathyroidectomy during which only two glands were located and removed, resulting in normalisation of her serum PTH/calcium levels. The R392X stop codon was inserted into human CAR and the resulting mutant (CaR(R392X)) expressed transiently in HEK-293 cells. CaR(R392X) expressed as a 54 kDa dimeric glycoprotein that was undetectable in conditioned medium or in the patient's urine. The membrane localisation observed for wild-type CaR in parathyroid gland and transfected HEK-293 cells was absent from the proband's parathyroid gland and from CaR(R392X)-transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity. Intriguingly, the patient remained normocalcaemic throughout childhood (2.5 mM corrected calcium, 11 pg/ml PTH (10-71), age 8 years) but exhibited mild asymptomatic hypocalcaemia at age 10 years, now treated with 1-hydroxycholecalciferol and Ca2+ supplementation. Despite representing a virtual CAR knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.

Calcium and phosphate homeostasis in hyperthyroid cats – associations with development of azotaemia and survival time

To evaluate calcium and phosphate homeostasis in hyperthyroid cats and determine if plasma parathyroid hormone and fibroblast growth factor-23 are associated with the presence of -azotaemic chronic kidney disease and/or have prognostic significance. Retrospective cohort study. Logistic regression analysis and Cox regression analysis were performed to identify if parathyroid hormone and fibroblast growth factor-23 were predictors of development of azotaemia following treatment and survival time, respectively. Two hundred and seven hyperthyroid cats were included. Elevated plasma parathyroid hormone concentrations, hyperphosphataemia, decreased plasma fibroblast growth factor-23 concentrations and hypocalcaemia were documented; however, all parameters returned to reference intervals following treatment of hyperthyroid cats without azotaemic chronic kidney disease. After adjustment for plasma creatinine concentration, baseline plasma parathyroid hormone and fibroblast growth factor-23 concentrations were not predictors of the development of azotaemia following treatment. Baseline plasma fibroblast growth factor-23 concentrations were associated with all-cause mortality; however, this association was not maintained after adjustment for packed cell volume. Changes in plasma parathyroid hormone and fibroblast growth factor-23 concentrations which occur in hyperthyroid cats are not mediators of progression of chronic kidney disease; however, fibroblast growth factor-23 would appear to have some prognostic significance in hyperthyroidism.