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The University of Warwick, Coventry, UK
Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)2D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)2D3 and 24,25(OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)2D3 levels were low at baseline (normal range: 60–120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)2D3. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0–47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5–143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)2D3 and 24,25(OH)2D3 increased from 48.3 pmol/L (IQR: 35.9–57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3–6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1–130.6 pmol/L) and 12.3 nmol/L (IQR: 9–16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)2D3 in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)2D3 deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.
Department of Clinical Chemistry, Hematology and Immunology, Noordwest Ziekenhuis, Alkmaar, The Netherlands
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Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam, The Netherlands
Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands
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The measurement of vitamin D metabolites aids in assessing vitamin D status and in diagnosing disorders of calcium homeostasis. Most laboratories measure total 25-hydroxyvitamin D (25(OH)D), while others have taken the extra effort to measure 25(OH)D2 and 25(OH)D3 separately and additional metabolites such as 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. The aim of this review is to provide an updated overview of the main markers of vitamin D metabolism, define the intended measurands, and discuss the advantages and disadvantages of the two most widely used assays, automated assays and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Whether using the easy and fast automated assays or the more complex LC-MS/MS, one should know the pitfalls of the used technique in order to interpret the measurements. In conclusion, automated assays are unable to accurately measure 25(OH)D in all patient groups, including persons using D2. In these cases, an LC-MS/MS method, when appropriately developed and standardized, produces a more reliable measurement.
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Department of Health & Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Department of Health & Life Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Skeletal muscle wasting is a serious disorder associated with health conditions such as aging, chronic kidney disease and AIDS. Vitamin D is most widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance. Recently, vitamin D supplementation has been shown to improve muscle performance and reduce the risk of falls in vitamin D deficient older adults. However, little is known of the underlying molecular mechanism(s) or the role it plays in myogenic differentiation. We examined the effect of 1,25-D3 on myogenic cell differentiation in skeletal muscle derived stem cells. Primary cultures of skeletal muscle satellite cells were isolated from the tibialis anterior, soleus and gastrocnemius muscles of 8-week-old C57/BL6 male mice and then treated with 1,25-D3. The efficiency of satellite cells isolation determined by PAX7+ cells was 81%, and they expressed VDR. Incubation of satellite cells with 1,25-D3 induces increased expression of: (i) MYOD, (ii) MYOG, (iii) MYC2, (iv) skeletal muscle fast troponin I and T, (v) MYH1, (vi) IGF1 and 2, (vii) FGF1 and 2, (viii) BMP4, (ix) MMP9 and (x) FST. It also promotes myotube formation and decreases the expression of MSTN. In conclusion, 1,25-D3 promoted a robust myogenic effect on satellite cells responsible for the regeneration of muscle after injury or muscle waste. This study provides a mechanistic justification for vitamin D supplementation in conditions characterized by loss of muscle mass and also in vitamin D deficient older adults with reduced muscle mass and strength, and increased risk of falls.
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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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.
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
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Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland
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Lambe Institute for Translational Research, School of Medicine, NUIG, Galway, Ireland
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Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
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Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
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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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Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Ruperto-Carola University of Heidelberg, Heidelberg, Germany
Synlab Medical Center of Human Genetics Mannheim, Mannheim, Germany
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Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Objective
The aim was to explore the effects of preoperative calcium and activated vitamin D3 supplementation on post-thyroidectomy hypocalcemia and hypo-parathyroid hormone-emia (hypo-PTHemia).
Methods
A total of 209 patients were randomly divided into control group (CG) and experimental group (EG). Oral calcium and activated vitamin D3 supplementation were preoperatively administered to EG, whereas a placebo was administered to CG. Data on serum calcium, phosphorus, and PTH concentrations before operation, on postoperative day 1 (POPD1), at postoperative week 3 (POPW3), and on the length of postoperative hospitalization were collected.
Results
The serum calcium, phosphorus, and PTH concentrations, as well as the incidence of postoperative hypocalcemia and hypo-PTHemia, did not significantly differ between EG and CG. Subgroup analysis revealed that the serum calcium concentrations of the experimental bilateral thyroidectomy subgroup (eBTS) on POPD1 and POPW3 were higher than that of the control bilateral thyroidectomy subgroup (cBTS) (P < 0.05); the reduction of serum calcium in eBTS on POPD1 and POPW3 was less than those in cBTS (P < 0.05). However, significant differences were not observed between the unilateral thyroidectomy subgroups (UTS) (P > 0.05). Moreover, the incidence of postoperative hypocalcemia in cBTS on POPD1 was significantly higher than that in eBTS (65.9% vs 41.7%) (P < 0.05). The length of hospitalization in cBTS (3.55 ± 1.89 days) was significantly longer than that (2.79 ± 1.15 days) in eBTS (P < 0.05).
Conclusion
Short-term preoperative prophylactic oral calcium and activated vitamin D3 supplementation could effectively reduce the incidence of postoperative hypocalcemia and decrease the length of postoperative hospitalization in patients who have undergone bilateral thyroidectomy.
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Background
Hypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism.
Methods
We describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements.
Results
Three infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation.
Conclusion
Intercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.
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Department of Health Sciences, Department of Epidemiology and Biostatistics, Department of Public Health, Department of General Practice, Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Department of Internal Medicine, Faculty of Earth and Life Sciences, EMGO Institute for Health and Care Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
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Objective
A disturbed vitamin D–parathyroid hormone (PTH)–calcium axis may play a role in the pathogenesis of heart failure. Therefore, we investigated whether lower 25-hydroxyvitamin D (25(OH)D) and higher PTH are cross sectionally and after 8 years of follow-up associated with higher B-type natriuretic peptide (BNP) levels in older men and women.
Design and methods
We measured baseline 25(OH)D, PTH, and BNP in 502 subjects in 2000–2001 in the Hoorn Study, a population-based cohort. Follow-up BNP was available in 2007–2009 in 278 subjects. Subjects were categorized according to season- and sex-specific quartiles of 25(OH)D and PTH at baseline. We studied the association of 25(OH)D and PTH quartiles with BNP using linear regression analyses adjusting for confounders. Analyses were stratified by kidney function estimated glomerular filtration rate (eGFR; ≤60 ml/min per 1.73 m2) because of significant interaction.
Results
At baseline, subjects had a mean age of 69.9±6.6 years, mean 25(OH)D level was 52.2±19.5 nmol/l and mean PTH 6.1±2.4 pmol/l. Cross sectionally, 25(OH)D was associated with BNP in subjects with impaired kidney function (eGFR ≤60 ml/min) only. The association attenuated after adjustment for PTH. PTH was cross sectionally associated with BNP, also in subjects with impaired kidney function only: regression coefficient of highest quartile 9.9 pmol/l (95% confidence interval 2.5, 17.4) with a significant trend across quartiles. Neither 25(OH)D nor PTH was associated with BNP in longitudinal analyses.
Conclusion
This study showed overall no strong association between 25(OH)D and BNP. However, PTH was associated with BNP in subjects with impaired kidney function and may point to a potential role in myocardial function.
Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
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Department of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
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Intrauterine growth restriction (IUGR) reflects inadequate growth in-utero and is prevalent in low resource settings. This study aimed to assess the association of maternal delivery parathyroid hormone (PTH) – a regulator of bone turnover and calcium homeostasis – with newborn anthropometry, to identify regulators of PTH, and to delineate pathways by which maternal PTH regulates birth size using path analysis. This was a cross-sectional analysis of data from participants (n = 537) enrolled in the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh. Primary exposures were maternal delivery intact PTH (iPTH) or whole PTH (wPTH) and outcomes were gestational age- and sex-standardized z-scores for birth length (LAZ), weight (WAZ), and head circumference (HCAZ). Hypothesized regulators of PTH included calcium and protein intake, vitamin D, magnesium, fibroblast-like growth factor-23 (FGF23), and C-reactive protein. Maternal iPTH was not associated with birth size in linear regression analyses; however, in path analysis models, every SD increase in log(iPTH) was associated with 0.08SD (95% CI: 0.002, 0.162) higher LAZ. In linear regression and path analysis models, wPTH was positively associated with WAZ. Vitamin D suppressed PTH, while FGF23 was positively associated with PTH. In path analysis models, higher magnesium was negatively associated with LAZ; FGF23 was positively associated and protein intake was negatively associated with LAZ, WAZ, and HCAZ. Higher maternal PTH in late pregnancy is unlikely to contribute to IUGR. Future studies should investigate maternal FGF23, magnesium and protein intake as regulators of fetal growth, particularly in settings where food insecurity and IUGR are public health problems.
