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Malachi J McKenna Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland

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Barbara F Murray Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland

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Myra O'Keane Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland

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Mark T Kilbane Metabolism Laboratory, Department of Endocrinology, School of Medicine and Medical Sciences, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland

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Background

The Institute of Medicine 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D specified higher intakes for all age groups compared to the 1997 report, but also cautioned against spurious claims about an epidemic of vitamin D deficiency and against advocates of higher intake requirements. Over 40 years, we have noted marked improvement in vitamin D status but we are concerned about hypervitaminosis D.

Objective

We sought to evaluate the 25-hydroxyvitamin D (25OHD) trend over 20 years.

Design

We retrieved all results of serum 25OHD from 1993 to 2013 (n=69 012) that was trimmed to one sample per person (n=43 782). We conducted a time series analysis of the monthly averages for 25OHD using a simple sequence chart and a running median smoothing function. We modelled the data using univariate auto-regressive integrated moving average (ARIMA) and forecast 25OHD levels up to 2016.

Results

The time series sequence chart and smoother function demonstrated a steady upward trend with seasonality. The yearly average 25OHD increased from 36.1 nmol/l in 1993 to 57.3 nmol/l in 2013. The ARIMA model was a good fit for the 25OHD time series; it forecasted monthly average 25OHD up to the end of 2016 with a positive stationary R 2 of 0.377.

Conclusions

Vitamin D status improved over the past 40 years, but there remains a dual problem: there are groups at risk of vitamin D deficiency who need public health preventative measures; on the other hand, random members of the population are taking unnecessarily high vitamin D intakes for unsubstantiated claims.

Open access
Maria Luisa Brandi Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Fondazione Italiana Ricerca sulle Malattie dell’Osso (FIRMO Onlus), Florence, Italy

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Stefania Bandinelli Geriatric Unit, Azienda Sanitaria Toscana Centro, Florence, Italy

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Teresa Iantomasi Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Francesca Giusti Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Eleonora Talluri Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Giovanna Sini Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Fabrizio Nannipieri Clinical Research, Abiogen Pharma, Pisa, Italy

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Santina Battaglia Clinical Research, Abiogen Pharma, Pisa, Italy

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Riccardo Giusti Clinical Research, Abiogen Pharma, Pisa, Italy

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Colin Gerard Egan CE Medical Writing SRLS, Pisa, Italy

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Luigi Ferrucci Longitudinal Study Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA

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Objective

This study aimed to evaluate the association between the endocrine-disrupting chemical, bisphenol A (BPA) on circulating levels of 25-hydroxy vitamin D (25(OD)D) and other vitamin D metabolites in an elderly population in Italy.

Methods

This was a retrospective analysis of the InCHIANTI Biobank in Italy. The association between vitamin D metabolites namely 1,25(OH)D, 25(OH)D, parathyroid hormone (PTH) and BPA levels were evaluated. Multiple regression models were used to examine the association between predictor variables with 1,25(OH)D or 25(OH)D levels.

Results

Samples from 299 individuals aged 72.8 ± 15.7 years were examined. Mean levels of BPA, 1,25(OH)D and 25(OH)D were 351.2 ± 511.6 ng/dL, 43.7 ± 16.9 pg/mL and 20.2 ± 12.1 ng/mL, respectively. One hundred eighty individuals (60.2%) were deficient (<20 ng/mL) in 25(OH)D and this population also presented higher BPA levels (527.9 ± 1289.5 ng/dL vs 86.9 ± 116.8 ng/dL, P  < 0.0001). Univariate analysis revealed that BPA levels were negatively correlated with both 1,25(OH)D (r= −0.67, P  < 0.0001) and 25(OH)D (r= −0.69, P  < 0.0001). Multivariate regression revealed that PTH (β: −0.23, 95% CI: −0.34, −0.13, P  < 0.0001) and BPA (β: −0.25, 95% CI: −0.3, −0.19, P  < 0.0001) remained significantly associated with 25(OH)D levels while BPA was also associated with 1,25(OH)D levels (β: −0.19, 95% CI: −0.22, −0.15, P  < 0.0001). Receiver operating characteristic curve analysis showed that a BPA concentration of >113 ng/dL was the best cut-off to predict individuals deficient in 25(OH)D (area under the curve: 0.87, 95% CI: 0.82–0.90, P  < 0.0001).

Conclusion

The strong negative association between BPA and vitamin D in this elderly population warrants further investigation, particularly since this population is already at greatest risk of hypovitaminosis and fracture.

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Eliana Piantanida Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Daniela Gallo Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Giovanni Veronesi Department of Medicine and Surgery, University of Insubria, Varese, Italy
Research Center in Epidemiology and Preventive Medicine (EPIMED), University of Insubria, Varese, Italy

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Eugenia Dozio Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Eugenia Trotti Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Adriana Lai Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Silvia Ippolito Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Jessica Sabatino Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Maria Laura Tanda Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Antonio Toniolo Department of Biotechnology and Life Science, University of Insubria, Varese, Italy

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Marco Ferrario Department of Medicine and Surgery, University of Insubria, Varese, Italy
Research Center in Epidemiology and Preventive Medicine (EPIMED), University of Insubria, Varese, Italy

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Luigi Bartalena Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Objective

The aim of this observational study was to clarify the link between vitamin D status and metabolic syndrome (MetS) in people with visceral obesity.

Design and methods

One hundred ninety-six consecutive patients (152 women; mean age 51 ± 13 years) with visceral obesity (mean body weight 103 ± 20 kg, mean waist circumference (WC) 119 ± 13 cm) were enrolled at the Obesity Outpatient Clinic of the University of Insubria in Varese. Anthropometric measurements were recorded. Laboratory tests, including vitamin D (25(OH)D)), fasting blood glucose (FBG), lipid profile, liver and kidney function tests were assessed. Vitamin D status was defined according to the European Society of Endocrinology guidelines, MetS to the 2009 harmonized definition.

Results

An inverse association emerged among 25(OH)D, body mass index (BMI) (P = 0.001) and WC (all P = 0.003). Serum 25(OH)D levels were inversely related to FBG and systolic blood pressure (SBP) (respectively, P = 0.01 and 0.02). Median serum 25(OH)D levels were 13.3 ng/mL (CI 95% 12; 15) in MetS and 16 ng/mL (CI 95% 14; 18) (P = 0.01) in non-MetS patients. Among patients with MetS, lower 25(OH)D concentrations were related to higher risk of hypertension (HT) (odds ratio (OR) 1.7, CI 95%, 0.7;4) and hyperglycemia (IFG)/type 2 diabetes (OR 5.5, CI 95% 2; 14).

Conclusion

Vitamin D status and MetS are inversely correlated in visceral obesity, particularly with regard to glucose homeostasis and BP. More extensive studies are required to investigate the potential for causality.

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Rasmus Reinke Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Stefano Christian Londero Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Martin Almquist Department of Surgery, Lund University Hospital, Lund, Sweden

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Lars Rejnmark Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

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Lars Rolighed Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Objective

Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy operations for Graves’ disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves’ disease.

Design

Retrospective cohort study from a single institution.

Methods

We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves’ disease.

Results

We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012–2014 to 6% in 2020–2021. For patients with Graves’ disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015–2016 to 2% (1 out of 56) in 2020–2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012–2014 to 10% (10 out of 51) in 2020–2021.

Conclusion

Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery.

Significance statement

Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoperative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves’ disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

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Marc Blondon Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Emmanuel Biver Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Olivia Braillard Division of Primary Care Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Marc Righini Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Pierre Fontana Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Alessandro Casini Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

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Objective

Vitamin D deficiency is associated with increased risks of arterial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assays and fibrin clot structure.

Methods

In this prospective cohort study, we enrolled adult outpatients attending the Primary Care Division of the Geneva University Hospitals with a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD) <25 nmol/L), excluding obese patients or with a recent acute medical event. We evaluated changes in coagulation times, thrombin generation assay, clot formation and clot lysis time, 25-OHD and parathormone before and 1–3 months after cholecalciferol oral supplementation with one-time 300,000 IU then 800 IU daily. Paired t-tests with a two-sided alpha of 0.05 compared absolute mean differences.

Results

The 48 participants had a mean age of 43.8 ± 13.8 years. After supplementation, 25-OHD levels increased from 17.9 ± 4.6 nmol/L to 62.5 ± 20.7 nmol/L 6.4 ± 3.0 weeks after inclusion. Endogenous thrombin potential and thrombin generation peak values both decreased significantly (−95.4 nM × min (95%CI −127.9 to −62.8), P < 0.001; −15.1 nM (−23.3 to −6.8), P < 0.001). The maximum absorbance by turbidimetry decreased significantly (P = 0.001) after supplementation. There was no change in clot lysis time, coagulation times or plasminogen activator inhibitor-1 and homocysteine levels.

Conclusions

In severe vitamin D deficiency, a high-dose cholecalciferol supplementation was associated with a reduction in thrombin generation and an average decreased number of fibrin protofibrils per fibers and fibrin fiber size measured by turbidimetry. This suggests that severe vitamin D deficiency may be associated with a potentially reversible prothrombotic profile.

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R Perchard Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

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L Magee Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

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A Whatmore Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

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F Ivison Department of Biochemistry, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

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P Murray Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK
Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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A Stevens Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK

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M Z Mughal Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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S Ehtisham Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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J Campbell Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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S Ainsworth Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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M Marshall Department of Biochemistry, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

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M Bone Department of General Paediatrics, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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I Doughty Department of General Paediatrics, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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P E Clayton Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK
Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester, UK

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Background

Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c.

Aims

(1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c.

Methods

Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2–10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded.

Results

Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = −0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = −1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level.

Conclusion

We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

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Sarah Bakhamis Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Faiqa Imtiaz Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Khushnooda Ramzan Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Edward De Vol Department of Biostatistics, Epidemiology & Scientific Computing, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Osamah Al-Sagheir Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Abdulrahman Al-Rajhi Department of Orthopedics, King Saud University Medical City, Riyadh, Saudi Arabia

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Abdullah Alashwal Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Bassam Bin Abbas Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Nadia Sakati Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Afaf Al-Sagheir Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cases with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.

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Maxime Duval Department of Medicine, Clinique Jules Verne, Nantes, France

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Kalyane Bach-Ngohou Department of Biology, Laboratory of Clinical Biochemistry, CHU Nantes, Nantes, France

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Damien Masson Department of Biology, Laboratory of Clinical Biochemistry, CHU Nantes, Nantes, France

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Camille Guimard Department of Emergency Medicine, CHU Nantes, Nantes, France

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Philippe Le Conte Department of Emergency Medicine, CHU Nantes, Nantes, France

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David Trewick Department of Medicine, Clinique Jules Verne, Nantes, France
Department of Emergency Medicine, CHU Nantes, Nantes, France

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Objective

Severe hypocalcemia (Ca <1.9 mmol/L) is often considered an emergency because of a potential risk of cardiac arrest or seizures. However, there is little evidence to support this. The aim of our study was to assess whether severe hypocalcemia was associated with immediately life-threatening cardiac arrhythmias or neurological complications.

Methods

A retrospective observational study was carried out over a 2-year period in the Adult Emergency Department (ED) of Nantes University Hospital. All patients who had a protein-corrected calcium concentration measure were eligible for inclusion. Patients with multiple myeloma were excluded. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED.

Results

A total of 41,823 patients had protein-corrected calcium (pcCa) concentrations measured, 155 had severe hypocalcemia, 22 were excluded because of myeloma leaving 133 for analysis. Median pcCa concentration was 1.73 mmol/L (1.57–1.84). Seventeen (12.8%) patients presented a life-threatening condition, 14 (10.5%) neurological and 3 (2.2%) cardiac during ED stay. However, these complications could be explained by the presence of underlying co-morbidities and or electrolyte disturbances other than hypocalcemia. Overall, 24 (18%) patients died in hospital. Vitamin D deficiency, chronic kidney disease and hypoparathyroidism were the most frequently found causes of hypocalcemia.

Conclusion

Thirteen percent of patients with severe hypocalcemia presented a life-threatening cardiac or neurological complication on the ED. However, a perfectly valid alternative cause could account for these complications. Further research is warranted to define the precise role of hypocalcemia.

Open access
Tomás P Griffin Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland

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Caroline M Joyce Department of Clinical Biochemistry, Cork University Hospital, Cork, Ireland

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Sumaya Alkanderi Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Liam M Blake Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Derek T O’Keeffe Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Delia Bogdanet Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Md Nahidul Islam Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Michael C Dennedy Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Lambe Institute for Translational Research, School of Medicine, NUIG, Galway, Ireland

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John E Gillan Department of Histopathology, SUHCG, GUH, Galway, Ireland

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John J Morrison Department of Obstetrics and Gynaecology, SUHCG, GUH, Galway, Ireland

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Timothy O’Brien Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland

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John A Sayer Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK

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Marcia Bell Centre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group (SUHCG), Galway University Hospitals (GUH), Galway, Ireland

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Paula M O’Shea Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland

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Introduction

Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.

Methods

The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.

Results

The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up.

Conclusions

W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

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Kristin Godang Section of Specialized Endocrinology, Oslo University Hospital, Oslo, Norway

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Karolina Lundstam Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Charlotte Mollerup Clinic of Breast and Endocrine Surgery, Center HOC, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Stine Lyngvi Fougner Department of Endocrinology, St. Olavs Hospital, Trondheim, Norway

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Ylva Pernow Departments of Molecular Medicine, Surgery and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Jörgen Nordenström Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Thord Rosén Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

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Svante Jansson Department of Endocrine Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

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Mikael Hellström Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Jens Bollerslev Section of Specialized Endocrinology, Oslo University Hospital, Oslo, Norway
Faculty of Medicine, University of Oslo, Oslo, Norway

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Ansgar Heck Section of Specialized Endocrinology, Oslo University Hospital, Oslo, Norway
Faculty of Medicine, University of Oslo, Oslo, Norway

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the SIPH Study Group
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Context

Mild primary hyperparathyroidism has been associated with increased body fat mass and unfavorable cardiovascular risk factors.

Objective

To assess the effect of parathyroidectomy on fat mass, glucose and lipid metabolism.

Design, patients, interventions, main outcome measures

119 patients previously randomized to observation (OBS; n = 58) or parathyroidectomy (PTX; n = 61) within the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, an open randomized multicenter study, were included. Main outcome measures for this study were the differences in fat mass, markers for lipid and glucose metabolism between OBS and PTX 5 years after randomization.

Results

In the OBS group, total cholesterol (Total-C) decreased from mean 5.9 (±1.1) to 5.6 (±1.0) mmol/L (P = 0.037) and LDL cholesterol (LDL-C) decreased from 3.7 (±1.0) to 3.3 (±0.9) mmol/L (P = 0.010). In the PTX group, the Total-C and LDL-C remained unchanged resulting in a significant between-group difference over time (P = 0.013 and P = 0.026, respectively). This difference was driven by patients who started with lipid-lowering medication during the study period (OBS: 5; PTX: 1). There was an increase in trunk fat mass in the OBS group, but no between-group differences over time. Mean 25(OH) vitamin D increased in the PTX group (P < 0.001), but did not change in the OBS group. No difference in parameters of glucose metabolism was detected.

Conclusion

In mild PHPT, the measured metabolic and cardiovascular risk factors were not modified by PTX. Observation seems safe and cardiovascular risk reduction should not be regarded as a separate indication for parathyroidectomy based on the results from this study.

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