Randomized trial of two doses of vitamin D3 in preterm infants \u3c32 weeks: Dose impact on achieving desired serum 25(OH)D3 in a NICU population.

BACKGROUND: Recommendations for vitamin D supplementation for preterm infants span a wide range of doses. Response to vitamin D supplementation and impact on outcomes in preterm infants is not well understood. OBJECTIVE: Evaluate serum 25(OH)D3 concentration changes after 4 weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants and quantify the impact on NICU outcomes. DESIGN: 32 infants born at 24-32 weeks gestation were prospectively randomized to receive 400 or 800 IU/day vitamin D3 supplementation. Serum 25(OH)D3 levels were measured every 4 weeks. The Wilcoxon signed rank test was used to compare serum levels of 25(OH)D3 at 4 weeks and each subsequent time point. A p-value of RESULTS: Serum 25(OH)D3 levels at birth were 41.9 and 42.9 nmol/l for infants in the 400 IU group and 800 IU group, respectively (p = 0.86). Cord 25(OH)D3 concentrations significantly correlated with gestational age (r = 0.40, p = 0.04). After 4 weeks of D3 supplementation, median 25(OH)D3 levels increased in both groups (84.6vs. 105.3 nmol/l for 400 vs. 800 IU/day respectively, with significantly more improvement in the higher dose (p = 0.048). Infants in the 400 IU group were significantly more likely to have dual energy x-ray absorptiometry (DEXA) bone density measurements(56% vs 16%, p = 0.04). CONCLUSIONS: Improvement in 25(OH)D3 levels at 4 weeks, bone density, and trends towards improvement in linear growth support consideration of a daily dose of 800 IU of vitamin D for infantsNICU

Vitamin D Toxicity–A Clinical Perspective

Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite – 1,25(OH)2D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)2D in congenital disorders, such as Williams–Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D–related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase

Vitamin D status in mothers with pre-eclampsia and their infants: a case-control study from Serbia, a country without a vitamin D fortification policy

Objective: The objective of the present study was to determine if vitamin D intake and status are associated with pre-eclampsia in a country without a vitamin D fortification policy. Design: A case-control study of pregnancies with (case) and without (control) pre-eclampsia was conducted from January to April when UVB is minimal. Maternal and cord blood obtained at delivery were measured for plasma 25-hydroxycholecalciferol (25-OH-D-3), 3-epimer of 25-OH-D-3 (3-epi-25-OH-D-3) and 24,25-dihydroxycholecalciferol (24,25-(OH)(2)D-3) by LC-MS/MS and maternal 1,25-dihydroxyvitamin D (1,25-(OH) 2D). Differences between groups were tested with ANOVA and Bonferroni post hoc tests (P lt 0.05). Setting: Clinical Center of Serbia. Subjects: Pregnant women with and without pre-eclampsia (n 60) and their infants. Results: Exogenous vitamin D intake (0.95-16.25 mu g/d (38-650 IU/d)) was not significantly different between groups. Women with pre-eclampsia delivered infants at an earlier gestational age and had significantly lower mean total plasma 25-hydroxyvitamin D (25-OH-D; case: 11.2 (SD 5.1); control: 16.1 (SD 5.7) ng/ml; P=0.0006), 25-OH-D-3 (case: 10.0 (SD 4.9); control: 14.2 (SD 5.8) ng/ml; P=0.002), 3-epi-25-OH-D-3 (case: 0.5 (SD 0.2); control: 0.7 (SD 0.2) ng/ml; P=0.0007) and 1,25-(OH)(2)D (case: 56.5 (SD 26.6); control: 81.0 (SD 25.7) pg/ml; P=0.018), while 24,25-(OH)(2)D-3 was not different between groups. Infants did not differ in total plasma 25-OH-D, 25-OH-D-3, 3-epi-25-OH-D-3 and 24,25-(OH)(2)D-3, but the mean proportion of 3-epi-25-OH-D-3 was higher in the infant case group (case: 7.9 (SD 1.1); control: 7.0 (SD 1.4) % of total 25-OH-D-3; P=0.005). Conclusions: A high prevalence of vitamin D deficiency, as defined by plasma 25-OH-D lt 12 ng/ml, was observed in 47 % of all mothers and 77 % of all infants. These data underscore the need for prenatal vitamin D supplementation and a food fortification policy in Serbia

Supplementary material for the article: Djekic-Ivankovic, M.; Weiler, H.; Jones, G.; Kaufmann, M.; Kaludjerovic, J.; Aleksic-Velickovic, V.; Mandić, L. M.; Glibetic, M. Vitamin D Status in Mothers with Pre-Eclampsia and Their Infants: A Case-Control Study from Serbia, a Country without a Vitamin D Fortification Policy. Public Health Nutrition 2017, 20 (10), 1825–1835. https://doi.org/10.1017/S1368980016000409

Supplementary material for: [https://doi.org/10.1017/S1368980016000409]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2161

Genetic Diseases of Vitamin D Metabolizing Enzymes

International audienc

Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1

Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D3 to 24,25(OH)2D3 ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396w/w mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors

Calcium pyrophosphate deposition disease revealing a hypersensitivity to vitamin D

International audienceOBJECTIVE:Hypersensitivity to vitamin D (HVD) due to a loss of function mutation of the CYP24A1 gene, which encodes vitamin D catabolizing enzyme was initially described as a cause of acute hypercalcemia in children and chronic renal diseases in adults.METHODS:We describe the first case of a patient presenting a calcium pyrophosphate deposition disease (CPDD) revealing a HVD.RESULTS:An abnormality of phospho-calcic metabolism was discovered during the course of an etiological workup for CPDD in a 52-year-old patient. Laboratory tests revealed a blood calcium level at the upper limit of normal range, a markedly low parathormone level, a 25-hydroxyvitamin D level within the upper level of normal, an elevated 1,25-dihydroxyvitamin D level and an elevated urine calcium level. CYP24A1 gene sequencing analysis revealed two mutations in a heterozygous state. The study of the 25-hydroxyvitamin D3: 24,25-dihydroxyvitamin D3 ratio, two metabolites of vitamin D confirmed the enzyme deficiency in vivo. Our observation suggests that this disease could correspond to a rare cause of CPDD.CONCLUSION:In cases of CPDD associated with calcium values within the upper limit of normal range (or hypercalcemia) with an abnormally low PTH, one could suggest searching for HVD