Presentation and management of hypoparathyroidism in a paediatric patient - a case report.

Hypoparathyroidism occurs due to insufficient parathyroid gland activity leading to abnormal calcium and phosphate levels. The presentation of hypoparathyroidism is rare in adults and mostly encountered in the paediatric population. We present a case of a 3.5-month-old male infant with the presenting complaint of an episode of afebrile generalized tonic-clonic seizure. Haematological, urinary, cerebro-spinal fluid and radiological investigations were unremarkable but a biochemical profile revealed hypocalcaemia, hyperphosphataemia and lowered vitamin D3 levels. Parathyroid hormone profile showed a decreased level, confirming diagnosis of hypoparathyroidism. Intravenous administration of calcium and magnesium in combination with oral activated vitamin D3 and phosphate binders managed to resolve symptoms and maintain normal levels. The rationale of this case is to confirm the necessity of early diagnosis to prevent irreversible sequelae of hypocalcaemia and regular monitoring of treatment to avoid side-effects of medication.

A 15-year experience: intraoperative parathyroid hormone assay for the management of primary hyperparathyroidism in a UK endocrine surgical unit.

PURPOSE: This study aims to evaluate the outcomes of first-time parathyroidectomy for primary hyperparathyroidism using intraoperative PTH (IOPTH) assay in the light of the UK National Institute for Health and Care Excellence (NICE) guidelines for the management of primary hyperparathyroidism. METHOD: This is a retrospective cohort analysis of a prospectively maintained database of endocrine surgery in a tertiary centre. Preoperative radiological localisation (concordance and accuracy), intraoperative PTH parameters and adjusted serum calcium at minimum 6-month follow-up were analysed. The accuracy of IOPTH to predict post-operative normocalcaemia and the number needed to treat (NNT) within the cohort when IOPTH was utilised were determined. Differences between groups were evaluated with Chi-squared and Fisher's exact test. RESULTS: Between January 2004 and September 2018, 849 patients (75.4% women), median age 64 years (IQR 54-72), were analysed. The median preoperative adjusted serum calcium was 2.80mmol/l (IQR 2.78-2.90), and the median preoperative PTH was 14.20pmol/l (IQR 10.70-20.25). The overall first-time cure (normocalcaemia) rate was 96.4%. The sensitivity, specificity, positive predictive value and negative predictive values of IOPTH were 96.8%, 83.2%, 97.6% and 78.8%, respectively, with an accuracy of 95.1%. For patients with concordant scans (48.3%), a targeted approach without IOPTH would have achieved a cure rate of 94.1% compared with 98.0% using IOPTH (p<0.01) CONCLUSION: The use of IOPTH assay significantly improved the rate of normocalcaemia at 6 months. The low NNT to benefit from IOPTH, particularly those patients with a single positive scan, and the inevitable reduction in the potential costs incurred from failure and reoperation justify its utilisation.

Attenuation of Alzheimer's brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model. METHODS: 5XFAD mice, an early onset ß-amyloid (Aß)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1-34 (50 µg/Kg), 5 days/week, starting at 2-month old (MO) for 2-3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aß and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope. RESULTS: A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aß-associated brain pathologies, including Aß and Aß deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice. CONCLUSIONS: These results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34's therapeutic potential for patients with not only osteoporosis but also AD.

Effect of magnesium on vascular calcification in chronic kidney disease patients: a systematic review and meta-analysis.

PURPOSE: To evaluate the effects of magnesium (Mg) supplementation on vascular calcification (VC) in patients with chronic kidney disease (CKD). METHODS: PubMed, Embase, Cochrane Library, Medline, Web of Science, CNKI, VIP, and WanFang databases were searched from build to July 2022. Randomized controlled trials (RCT) and non-RCT related to whether Mg supplementation inhibits VC in patients with CKD were included. The literature was screened according to inclusion and exclusion criteria, and quality evaluation and data collection were performed. Meta-analysis was performed using Review Manager 5.4 software. RESULTS: 8 RCTs and 1 non-RCT studies with a total of 496 patients were eventually included. Compared to control groups, Mg supplementation increased serum Mg levels (SMD = 1.26, 95% CI: -0.70 to 1.82, p < 0.001), but it was not statistically significant in alleviating the degree of VC, increasing T50, and reducing serum phosphorus (P) levels in patients with CKD (all p > 0.05). Oral Mg reduced left (WMD=-0.06, 95% CI. -0.11 to -0.01, p = 0.03) and right (WMD=-0.07, 95% CI: -0.13 to -0.01, p = 0.02) carotid intima-media thickness (cIMT). Additionally, calcium (Ca) (SMD=-0.43, 95% CI: -0.74 to -0.11, p = 0.008) and parathyroid hormone (PTH) (SMD=-0.43, 95% CI: -0.75 to -0.11, p = 0.008) levels were reduced by increasing dialysate Mg concentration. CONCLUSIONS: Mg supplementation increased serum Mg levels and reduced Ca, PTH, and cIMT, but it did not reduce VC scores in patients with CKD. This still requires further studies with larger samples to evaluate the effect of Mg supplementation on VC.

Parathyroidectomy for adults with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT), a disorder in which the parathyroid glands produce excessive amounts of parathyroid hormone, is most common in older adults and postmenopausal women. While most people with PHPT are asymptomatic at diagnosis, symptomatic disease can lead to hypercalcaemia, osteoporosis, renal stones, cardiovascular abnormalities and reduced quality of life. Surgical removal of abnormal parathyroid tissue (parathyroidectomy) is the only established treatment for adults with symptomatic PHPT to prevent exacerbation of symptoms and to be cured of PHPT. However, the benefits and risks of parathyroidectomy compared to simple observation or medical therapy for asymptomatic and mild PHPT are not well established. OBJECTIVES: To evaluate the benefits and harms of parathyroidectomy in adults with PHPT compared to simple observation or medical therapy. SEARCH METHODS: We searched CENTRAL, MEDLINE, LILACS, ClinicalTrials.gov and WHO ICTRP from their date of inception until 26 November 2021. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing parathyroidectomy with simple observation or medical therapy for the treatment of adults with PHPT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. cure of PHPT, 2. morbidity related to PHPT and 3. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. health-related quality of life and 3. hospitalisation for hypercalcaemia, acute renal impairment or pancreatitis. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We identified eight eligible RCTs that included 447 adults with (mostly asymptomatic) PHPT; 223 participants were randomised to parathyroidectomy. Follow-up duration varied from six months to 24 months. Of the 223 participants (37 men) randomised to surgery, 164 were included in the analyses, of whom 163 were cured at six to 24 months (overall cure rate 99%). Parathyroidectomy compared to observation probably results in a large increase in cure rate at six to 24 months follow-up: 163/164 participants (99.4%) in the parathyroidectomy group and 0/169 participants in the observation or medical therapy group were cured of their PHPT (8 studies, 333 participants; moderate certainty).  No studies explicitly reported intervention effects on morbidities related to PHPT, such as osteoporosis, osteopenia, kidney dysfunction, urolithiasis, cognitive dysfunction or cardiovascular disease, although some studies reported surrogate outcomes for osteoporosis and cardiovascular disease. A post-hoc analysis revealed that parathyroidectomy, compared to observation or medical therapy, may have little or no effect after one to two years on bone mineral density (BMD) at the lumbar spine (mean difference (MD) 0.03 g/cm2,95% CI -0.05 to 0.12; 5 studies, 287 participants; very low certainty). Similarly, compared to observation, parathyroidectomy may have little or no effect on femoral neck BMD after one to two years (MD -0.01 g/cm2, 95% CI -0.13 to 0.11; 3 studies, 216 participants; very low certainty). However, the evidence is very uncertain for both BMD outcomes. Furthermore, the evidence is very uncertain about the effect of parathyroidectomy on improving left ventricular ejection fraction (MD -2.38%, 95% CI -4.77 to 0.01; 3 studies, 121 participants; very low certainty). Four studies reported serious adverse events. Three of these reported zero events in both the intervention and control groups; consequently, we were unable to include data from these three studies in the pooled analysis. The evidence suggests that parathyroidectomy compared to observation may have little or no effect on serious adverse events (RR 3.35, 95% CI 0.14 to 78.60; 4 studies, 168 participants; low certainty).  Only two studies reported all-cause mortality. One study could not be included in the pooled analysis as zero events were observed in both the intervention and control groups. Parathyroidectomy compared to observation may have little or no effect on all-cause mortality, but the evidence is very uncertain (RR 2.11, 95% CI 0.20 to 22.60; 2 studies, 133 participants; very low certainty). Three studies measured health-related quality of life using the 36-Item Short Form Health Survey (SF-36) and reported inconsistent differences in scores for different domains of the questionnaire between parathyroidectomy and observation. Six studies reported hospitalisations for the correction of hypercalcaemia. Two studies reported zero events in both the intervention and control groups and could not be included in the pooled analysis. Parathyroidectomy, compared to observation, may have little or no effect on hospitalisation for hypercalcaemia (RR 0.91, 95% CI 0.20 to 4.25; 6 studies, 287 participants; low certainty). There were no reported hospitalisations for renal impairment or pancreatitis. AUTHORS' CONCLUSIONS: In accordance with the literature, our review findings suggest that parathyroidectomy, compared to simple observation or medical (etidronate) therapy, probably results in a large increase in cure rates of PHPT (with normalisation of serum calcium and parathyroid hormone levels to laboratory reference values). Parathyroidectomy, compared with observation, may have little or no effect on serious adverse events or hospitalisation for hypercalcaemia, and the evidence is very uncertain about the effect of parathyroidectomy on other short-term outcomes, such as BMD, all-cause mortality and quality of life. The high uncertainty of evidence limits the applicability of our findings to clinical practice; indeed, this systematic review provides no new insights with regard to treatment decisions for people with (asymptomatic) PHPT. In addition, the methodological limitations of the included studies, and the characteristics of the study populations (mainly comprising white women with asymptomatic PHPT), warrant caution when extrapolating the results to other populations with PHPT. Large-scale multi-national, multi-ethnic and long-term RCTs are needed to explore the potential short- and long-term benefits of parathyroidectomy compared to non-surgical treatment options with regard to osteoporosis or osteopenia, urolithiasis, hospitalisation for acute kidney injury, cardiovascular disease and quality of life.

[Extended release calcifediol and paricalcitol in the treatment of secondary hyperparathyroidism: a network meta-analysis of indirect comparison].

Introduction: Secondary hyperparathyroidism (SHPT) is a common and major complication of chronic kidney disease (CKD) among patients on dialysis and in patients with CKD stage G3 to G5. SHPT in CKD is caused by disturbances in metabolic parameters. Paricalcitol (PCT), other active vitamin D analogous (doxercalciferol and alfacalcidol), and active vitamin D (calcitriol) have been commonly used to treat SHPT in non-dialysis CKD (ND-CKD) for several years. However, recent studies indicate that these therapies adversely increase serum calcium, phosphate, and fibroblast growth factor 23 (FGF-23) levels. Extended release calcifediol (ERC) has been developed as an alternative treatment for SHPT in ND-CKD. The present meta-analysis compares the effect of ERC against PCT in the control of PTH and calcium levels. Methods: A systematic literature review was conducted, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to identify studies for inclusion in the Network Meta-Analysis (NMA). Results: 18 publications were eligible for inclusion in the network meta-analysis and 9 articles were included in the final NMA. The estimated PTH reduction from PCT (-59.5 pg/ml) was larger than the PTH reduction from ERC (-45.3 pg/ml), but the difference in treatment effects did not show statistical significance. Treatment with PCT caused statistically significant increases in calcium vs. placebo (increase: 0.31 mg/dl), while the marginal increase in calcium from treatment with ERC (increase: 0.10 mg/dl) did not reach statistical significance. Conclusions: The evidence suggests that both PCT and ERC are effective in reducing levels of PTH, whereas calcium levels tended to increase from treatment with PCT. Therefore, ERC may be an equally effective, but more tolerable treatment alternative to PCT.

Extreme Elevation of Baseline Intraoperative Parathyroid Hormone Measurements: Should Usual Protocols Apply?

INTRODUCTION: Intraoperative parathyroid hormone (IOPTH) monitoring is routinely used to facilitate minimally invasive parathyroidectomy. Many IOPTH protocols exist for predicting biochemical cure. Some patients are found to have extremely high baseline IOPTH levels (defined in this study as >500 pg/mL), which may affect the likelihood of satisfying certain final IOPTH criteria. We aimed to discover whether clinically significant differences exist in patients with extremely high baseline IOPTH and which IOPTH protocols are most appropriately applied to these patients. MATERIALS AND METHODS: This is a retrospective review of 237 patients who underwent parathyroidectomy with IOPTH monitoring for primary hyperparathyroidism (pHPT) from 2016 to 2020. Baseline IOPTH levels, drawn prior to manipulation of parathyroid glands, were grouped into categories labeled "elevated" (>65-500 pg/mL) and "extremely elevated" (>500 pg/mL). Final IOPTH levels were analyzed to determine whether there was a >50% decrease from baseline and whether a normal IOPTH value was achieved. 6-wk postoperative calcium levels were also examined. RESULTS: Of the patients in this cohort, 76% were in the elevated group and 24% in the extremely elevated group. Male sex and higher preoperative PTH levels were correlated with higher baseline IOPTH levels. Patients with extremely elevated baseline IOPTH were less likely to have IOPTH fall into normal range at the conclusion of the case (P = 0.019), and final IOPTH levels were higher (P < 0.001), but the IOPTH was equally likely to decrease >50% from baseline. There was no difference in the mean postoperative calcium levels between the two groups at 6-wk or at longer term follow-up (mean 525 d). CONCLUSIONS: Detection of baseline IOPTH levels >500 pg/mL during parathyroidectomy performed for pHPT is not uncommon. IOPTH in patients with extremely elevated baseline levels were less likely to fall into normal range, but follow-up calcium levels were equal, suggesting that applying more stringent IOPTH criteria for predicting biochemical cure may not be appropriate for this population.

Different outcomes following parathyroidectomy in patients with uremic tumoral calcinosis: two case reports.

BACKGROUND: Uremic tumoral calcinosis (UTC) is a rare complication in hemodialysis patients, whose mechanism remains incompletely understood. We report two cases with UTC who experienced completely different patterns of regression following parathyroidectomy, although there were no significant differences in serum calcium levels, parathyroid hormone, or phosphorus production between the two patients. CASE PRESENTATION: Case 1 had a substantial improvement in soft tissue calcification. However, in Case 2, one calcified mass was partially absorbed, while the others were aggravated with severe microvascular calcification and subcutaneous extravascular calcification. Whole-exome sequencing data revealed five mutation sites associated with atherosclerosis. CONCLUSION: The different outcomes in UTC patients after PTX are rare. Further studies are required to elucidate the mechanism of paradoxical changes occurring in patients with UTC after parathyroidectomy.

Mitochondrial ß-oxidation of adipose-derived fatty acids by osteoblasts fuels parathyroid hormone-induced bone formation.

The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues, like adipose, that can supply energy-dense macronutrients. In the case of intermittent parathyroid hormone (PTH) treatment, a strategy used to reduce fracture risk, bone formation is preceded by a change in systemic lipid homeostasis. To investigate the requirement for fatty acid oxidation by osteoblasts during PTH-induced bone formation, we subjected mice with osteoblast-specific deficiency of mitochondrial long-chain ß-oxidation as well as mice with adipocyte-specific deficiency for the PTH receptor or adipose triglyceride lipase to an anabolic treatment regimen. PTH increased the release of fatty acids from adipocytes and ß-oxidation by osteoblasts, while the genetic mouse models were resistant to the hormone's anabolic effect. Collectively, these data suggest that PTH's anabolic actions require coordinated signaling between bone and adipose, wherein a lipolytic response liberates fatty acids that are oxidized by osteoblasts to fuel bone formation.

Regional modular responses in different bone compartments to the anabolic effect of PTH (1-34) and axial loading in mice.

Beneficial effects of intermittent parathyroid hormone (PTH) on bone mass and architecture are described to either simply add to, or to synergise with those of mechanical loading. We evaluate whether interaction with in vivo loading is reinforced by PTH dosing regimen and exhibits compartment-specific sensitivities. Female 12-week-old C57Bl6 mice received daily (7/7) or interrupted 5 day/week (5/7) PTH for 3 weeks (two vehicle groups). All mice had six loading episodes (12N) applied to right tibia (left, non-loaded) for the last 2 weeks. Micro-CT scans were used to evaluate mass and architecture in almost the entire cortical and proximal trabecular regions. Epiphyseal cortical, trabecular and marrow space volumes, and bony growth-plate bridge incidence were evaluated. Statistical analyses employed a linear mixed-effects model at each percentile and 2-way ANOVA with post-hoc test for epiphyses and bridging. We found that daily PTH enhances cortical mass and modifies shape along almost the entire tibia and that these effects are partly mitigated by brief interruption in treatment. Mechanical loading alone augments cortical mass and modifies shape but only in a region proximal to the tibiofibular junction. The effect of combining load and daily PTH dosing is solely additive for cortical bone mass with no significant load: PTH interaction, but exhibits clear synergy with interrupted PTH treatment. Daily, not interrupted PTH stimulates trabecular bone gains, yet load:PTH interaction is present at limited regions with both daily and interrupted treatment. PTH treatment, but not loading, modifies epiphyseal bone but, in contrast, only loading modifies bridge number and areal density. Our findings demonstrate impressive local effects on tibial mass and shape of combined loading and PTH that are sensitive to dosing regimen and exert their effects modularly. These findings emphasise a need to clarify PTH dosing regimens and that advantages could be accrued by aligning treatment accordingly to patient requirements and life-style.

Rescue of High Glucose Impairment of Cultured Human Osteoblasts Using Cinacalcet and Parathyroid Hormone.

Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca2+-sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased alkaline phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling.

The association of parathyroid hormone with serum 25-hydroxyvitamin during pregnancy.

It is currently debated whether vitamin D requirements during pregnancy differ from those during non-gravid states. In current analyses, we aimed to determine the best model for the association between PTH and serum 25-hydroxyvitamin D (25(OH)D) and the threshold for circulating 25(OH)D at which serum parathyroid hormone (PTH) is suppressed. This multicenter prospective cross-sectional study was conducted on 227 Iranian pregnant women aged 15-45 years in their third trimester of pregnancy. The locally weighted smoothing scatter plot (LOWESS) was used to determine the curvilinear shape of the 25(OH)D/PTH relationship. Linear and non-linear methods were employed to determine the best fit and cut-point for serum 25(OH)D concentration. The median serum 25(OH)D and corresponding serum PTH concentration were 17⋅26 (13⋅44-23⋅08) ng/ml and 19⋅46 (15⋅08-25⋅04) pg/ml in our study population, respectively. The LOWESS curve suggested a non-linear and monotonic with a negative slope relation between PTH (pg/ml) and serum 25(OH)D (ng/ml). The optimal model for the association between PTH and serum 25(OH)D was a one-term fractional polynomial (FP1) (AIC = 1640⋅463). The FP1 analysis identified the 25(OH)D threshold of 12⋅48 ng/ml at which serum PTH rapidly rose. The expected degree of PTH stimulation seems to have a linear trend as 25(OH)D falls below 40 ng/ml. 25(OH)D (ng/ml) and PTH (pg/ml) had a non-linear and monotonic relationship with a negative slope. Our data suggest that a 25(OH)D threshold of 12⋅48 ng/ml is sufficient for parathyroid hormone suppression, which could be used to screen for deficient individuals.

Allolobophora caliginosa coelomic fluid and extract alleviate glucocorticoid-induced osteoporosis in mice by suppressing oxidative stress and regulating osteoblastic/osteoclastic-related markers.

Allolobophora calignosa (Ac) is a folk medicine for millennia, as it possesses many biological activities. This study aimed to investigate the chemo-preventive activity of A.calignosa coelomic fluid (AcCF) and A.calignosa extract (AcE) on glucocorticoid-induced osteoporosis (GIOP) in mice. Characterization and in vitro biological activity of AcE and AcCF has been assessed. Male CD-1 mice were subcutaneously received dexamethasone (DEX) (1 mg/kg, 5 times/week) and concurrently intraperitoneally treated with either AcCF (20 mg/kg) or AcE (45 mg/kg) every other day for 28 days. Serum and bone homogenates were subjected for qPCR and biochemical analysis. AcE and AcCF treatment significantly increased bone mineral density (BMD), bone mineral content (BMC), calcium (Ca), phosphorus (P), and calcitonin levels, whereas activity of serum alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), serum acidic phosphatase (ACP), bone acidic phosphatase (BACP) and parathyroid hormone (PTH) levels were significantly reduced compare with untreated GIOP mice. Treatment with AcE and AcCF modulates oxidative stress and downregulated Rank and Mmp9 expression, as well as increased glycosaminoglycan content in the organic bone matrix, resulting in osteoclastogenesis inhibition. Overall, AcCF and AcE show a chemo-preventive activity against GIOP by inhibiting oxidative stress and regulating expression and/or activity of osteoblast/osteoclast-related markers.

Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone.

Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(-6 to +84). Synthetic pro[P1]PTH(-6 to +34) and pro[S1]PTH(-6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(-6 to +34), pro[P1]PTH(-6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(-6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.

The Role of Consumption of Molybdenum Biofortified Crops in Bone Homeostasis and Healthy Aging.

Osteoporosis is a chronic disease and public health issue in aging populations. Inadequate intake of micronutrients increases the risk of bone loss during an adult's lifespan and therefore of osteoporosis. The aim of the study was to analyze the effects of consumption of biofortified crops with the micronutrient molybdenum (Mo) on bone remodeling and metabolism in a population of adults and seniors. The trial enrolled 42 senior and 42 adult people randomly divided into three groups that consumed lettuce biofortified with molybdenum (Mo-biofortified group) or without biofortification (control group) or molybdenum in a tablet (Mo-tablet group) for 12 days. We chose an experimental period of 12 days because the bone remodeling marker levels are influenced in the short term. Therefore, a period of 12 days allows us to determine if there are changes in the indicators. Blood samples, obtained at time zero and at the end of the study, were compared within the groups adults and seniors for the markers of bone resorption, C-terminal telopeptide (CTX) and bone formation osteocalcin, along with the markers of bone metabolism, parathyroid hormone (PTH), calcitonin, albumin-adjusted calcium, vitamin D, phosphate and potassium. Consumption of a Mo tablet did not affect bone metabolism in the study. Consumption of Mo-biofortified lettuce significantly reduced levels of CTX and PTH and increased vitamin D in adults and seniors while levels of osteocalcin, calcitonin, calcium, potassium and phosphate were not affected. The study opens up new considerations about the role of nutrition and supplementation in the prevention of chronic diseases in middle-aged and older adults. Consumption of Mo-biofortified lettuce positively impacts bone metabolism in middle-aged and older adults through reduced bone resorption and improved bone metabolism while supplementation of Mo tablets did not affect bone remodeling or metabolism. Therefore, Mo-biofortified lettuce may be used as a nutrition intervention to improve bone homeostasis and prevent the occurrence of osteoporosis in the elderly.

Preoperative, Intraoperative, and Postoperative Parathyroid Pathology: Clinical Pathologic Collaboration for Optimal Patient Management.

Parathyroid disease typically presents with parathyroid hyperfunction as result of neoplasia or a consequence of non-neoplastic systemic disease. Given the parathyroid gland is a hormonally active organ with broad physiologic implications and serologically accessible markers for monitoring, the diagnosis of parathyroid disease is predominantly a clinical pathologic correlation. We provide the current pathological correlates of parathyroid disease and discuss preoperative, intraoperative, and postoperative pathology consultative practice for optimal patient care.

Changes and Influencing Factors of Urinary Phosphorus Excretion in Patients with Different Stages of Chronic Kidney Disease.

BACKGROUND: The aim of the study was to explore the changes and the possible influencing factors of phosphorus excretion in chronic kidney disease (CKD) patients. METHODS: A database with 204 patients who met the CKD diagnostic criteria was established. Clinical data, including 24-hour urine phosphorus excretion (24-hour UPE), were collected. The demographic and clinical characteristics of CKD patients in different stages and the changes in serum phosphorus (P) and 24-hour UPE with renal function were studied. After exploring the factors influencing 24-hour UPE by multiple linear regression analysis, the effects of gender on 24-hour UPE was assessed. RESULTS: Among 204 patients, there were significant differences in serum calcium (Ca), P, 24-hour UPE, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D [25(OH)-VD] among different CKD stages. Twenty-four-hour UPE fluctuated greatly, but serum P was relatively stable, which was > 1.46 mmol/L at an estimated glomerular filtration rate (eGFR) < 10 mL/minute/1.73 m2. Male gender (ß = 3.42, p < 0.00) and eGFR (ß = 0.06, p < 0.00) were related to 24-hour UPE, while age, body weight, albumin (ALB), iPTH, and serum P were not related to 24-hour UPE according to regression analysis. There were significant differences in 24-hour UPE and serum P between males and females. CONCLUSIONS: Urinary phosphorus excretion decreased with decreasing renal function in CKD patients. Urinary phosphorus excretion might be affected by eGFR and gender.

Predictive value of characteristics of resected parathyroid glands for persistent secondary hyperparathyroidism during parathyroidectomy.

BACKGROUND: Parathyroidectomy (PTX), an effective treatment for refractory secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, still has a high persistent rate. This study aimed to analyze the predictive value of characteristics of resected parathyroid glands for postoperative persistent SHPT. METHODS: The clinical data of patients with persistent SHPT and successful PTX controls who had or underwent total parathyroidectomy with forearm autotransplantation (TPTX + AT) was retrospectively collected. The characteristics including the number, minimum weight, maximum weight and total weight of resected parathyroid glands from each patient were recorded. Characteristics and cutoff value of resected parathyroid glands for the prediction of persistent SHPT were analyzed. RESULTS: A total of 227 patients (62 persistent SHPT patients and 165 successful PTX controls) were enrolled in the study. Forty-one (66%) persistent SHPT cases related to supernumerary parathyroid and the remaining 21 (34%) cases related to residual undetected parathyroid. In addition, ectopic parathyroid was found in 8 patients (13%) before PTX. The average number of resected glands in the persistent SHPT group and successful PTX group was 3.53 ± 0.72 and 3.93 ± 0.25 respectively (p < 0.001). There was significance in the number of patients with different resected parathyroid glands between two groups (p < 0.001). When the resected gland number was 4, minimum weight of the parathyroid was noted to be heavier in the persistent SHPT group than that in the successful PTX group (0.52 ± 0.31 g vs. 0.38 ± 0.19 g, p < 0.001). For persistent SHPT prediction, cutoff value of minimum weight was 0.535 g, with sensitivity of 46% and specificity of 82% (AUC = 0.611; p = 0.029). CONCLUSIONS: Major reason for the persistent SHPT is the existence of supernumerary parathyroid glands or resection of less than 4 glands. When 4 glands were resected, a minimum total parathyroid gland weight heavier than 0.535 g implied the potential presence of a missed supernumerary parathyroid gland, which also contributed to the persistent SHPT.

24,25-Dihydroxy Vitamin D and Vitamin D Metabolite Ratio as Biomarkers of Vitamin D in Chronic Kidney Disease.

The appropriate management of vitamin D deficiency and hyperparathyroidism is essential to prevent metabolic bone disorder (MBD) and cardiovascular diseases in chronic kidney disease (CKD). Recently, the 24,25-dihydroxyvitamin D [24,25(OH)2D] and vitamin D metabolite ratio (VMR), i.e., the ratio of 24,25(OH)2D to 25-hydroxyvitamin D [25(OH)D], have emerged as biomarkers of vitamin D level. We analyzed the usefulness of vitamin D biomarkers for the evaluation of MBD in patients with CKD. We analyzed blood and urine samples from 208 outpatients with CKD stage G2-G5. 25(OH)D showed a poor correlation with the estimated glomerular filtration rate (eGFR). Conversely, the 24,25(OH)2D level and VMR were significantly correlated with eGFR and the intact parathyroid hormone level. In conclusion, 24,25(OH)2D and VMR have the potential to be vitamin D biomarkers for the detection of MBD in CKD patients.