Vitamin D binding protein is a key determinant of 25‐hydroxyvitamin D levels in infants and toddlers

Circulating 25‐hydroxyvitamin D (25‐OHD) levels vary among human populations. Only limited information regarding determinants of these measures is available for infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25‐OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25‐OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self‐reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25‐OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self‐reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25‐OHD. GC SNPs were associated with both circulating DBP and 25‐OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25‐OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25‐OHD. Moreover, the effect of GC SNPs on 25‐OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25‐OHD. However, the GC genotype also affects circulating 25‐OHD independently of its effect on circulating DBP. These findings provide data that may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds. © 2013 American Society for Bone and Mineral Research     

Vitamin D deficiency is associated with increased fecal incontinence symptoms

Introduction and hypothesis

Vitamin D is an important micronutrient in muscle function. We hypothesize that vitamin D deficiency may contribute to fecal incontinence (FI) symptoms by affecting the anal continence mechanism. Our goal was to characterize the association of vitamin D deficiency as a variable affecting FI symptoms and its impact on health-related quality of life (HR-QoL).

Methods

This case–control study assessed women seen at a tertiary-care referral center. Participants were identified as having had a serum vitamin D level obtained within a year of their visit: cases were women presenting for care for FI symptoms; controls were women without any pelvic floor symptoms presenting to the same clinical site for general gynecologic care. Cases completed the Modified Manchester Health Questionnaire (MMHQ) and the Fecal Incontinence Severity Index to measure symptom severity and burden on QoL.

Results

Among the 31 cases and 81 controls, no demographic or medical differences existed. Women with FI had lower vitamin D levels (mean 29.2?±?12.3 cases vs. 35?±?14.1 ng/ml controls p?=?0.04). The odds of vitamin D deficiency were higher in women with FI compared with controls [odds ratio (OR) 2.77, 95 % confidence interval (CI) 1.08–7.09]. Among cases, women with vitamin D deficiency (35 %) had higher MMHQ scores, indicating greater FI symptom burden [51.3?±?29.3 (vitamin D deficient) vs. 30?±?19.5 (vitamin D sufficiency), p?=?0.02]. No differences were noted for FI severity, p?=?0.07.

Conclusions

Vitamin D deficiency is prevalent in women with fecal incontinence and may contribute to patient symptom burden.     

Treatment of renal osteodystrophy in children with 1αOHD3 and 24, 25(OH)2D3

Three pediatric patients with renal osteodystrophy were treated with 1αOHD₃ and 24, 25(OH)₂D₃. While serum calcium level significantly decreased, no significant effects were found on serum phosphorus, alkaline phosphatase, parathyroid hormone and urinary excretion of calcium. These results suggest that 24, 25(OH)₂D₃ may play some roles in bone and mineral metabolism.     

Vitamin D metabolites and their binding protein in adult diabetic patients

Vitamin D metabolites and vitamin D-binding protein were measured in the serum of nonketotic Bantu and Caucasian insulin-requiring diabetic subjects from Zaire and Belgium, respectively. In Caucasian diabetics, whether untreated (N = 18) or insulin treated (N = 26), no abnormalities were found. The Bantu diabetics (N = 20) were more insulin-deficient and had a poorer glucose control than the Caucasians. They presented, compared with Bantu controls, a significant decrease in the serum concentrations of 25-hydroxyvitamin D3 (26 +/- 10 vs. 35 +/- 14 micrograms/L, P less than .01), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (38 +/- 15 vs. 58 +/- 17 ng/L, P less than .001), and vitamin D-binding protein (303 +/- 55 vs. 356 +/- 41 mg/L, P less than .001). The decreased concentrations of vitamin D metabolites in the adult Bantu diabetic patients may be partly explained by a concomitant decrease in the concentration of vitamin D-binding protein, possibly due to insulin deficiency. The ratio between the molar concentrations of 1,25-(OH)2D3 and vitamin D-binding protein, used as an index of the free hormonal level, was also decreased, in association with a decreased serum calcium level. In conclusion, no abnormalities in vitamin D metabolism were found in Caucasian insulin-dependent diabetics, whereas low serum 1,25(OH)2D3 concentrations and hypocalcemia were found in poorly controlled Bantu diabetic subjects.     

Vitamin D deficiency is common in children and adolescents with chronic kidney disease

Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.     

Reduced plasma concentration of 1,25-dihydroxyvitamin D in children with moderate renal insufficiency

We measured the plasma concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) in 39 children comprising three groups; eight with moderate renal insufficiency (GFR of 25 to 50 ml/min/1.73 M2, seven of whom had tubulointerstitial disease), eight with severe renal insufficiency (on chronic hemodialysis), and 23 healthy control subjects. The mean plasma concentration of 1,25-(OH)2D was reduced by some 40% (P less than 0.002) in the children with moderate renal insufficiency, and by some 80% (P less than 0.001) in the children with severe renal insufficiency. In the children with moderate renal insufficiency, the reduced concentration of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of calcium and phosphorus. When analyzed over the range of renal function from normal through severely impaired, values of iPTH correlate inversely and significantly with those of 1,25-(OH)2D. Growth was impaired in four of the eight children with moderate renal insufficiency. The results of the current study suggest that in children with moderate renal insufficiency, a reduction in the renal synthesis and in the plasma concentration of 1,25-(OH)2D may be important pathogenetic events in disordered metabolism of calcium and phosphorus, including secondary hyperparathyroidism.     

Vitamin D insufficiency is prevalent and vitamin D is inversely associated with parathyroid hormone and calcitriol in pregnant adolescents

Few large studies have assessed changes in calcitropic hormones and maternal 25‐hydroxyvitamin D (25(OH)D) status across pregnancy, and how this may impact maternal bone turnover and neonatal hormone status. We aimed to identify determinants of 25(OH)D, parathyroid hormone (PTH), and calcitriol across pregnancy in a longitudinal study of 168 pregnant adolescents (≤18 years of age). Maternal 25(OH)D, PTH, and calcitriol were assessed at mid‐gestation (～26 weeks), delivery, and in cord blood. Data were related to measures of maternal anthropometrics, dietary intake, physical activity, and bone turnover markers. Approximately 50% of teens and their infants had serum 25(OH)D ≤ 20 ng/mL; 25(OH)D was lower in African Americans versus whites (p < 0.001). PTH increased across gestation (p < 0.001). Elevated PTH (≥60 pg/mL) was detected in 25% of adolescents at delivery, and was associated with increased concentrations of serum N‐telopeptide (NTX) (p = 0.028). PTH and calcitriol did not significantly differ across the range of Ca intake consumed (257–3220 mg/d). In the group as a whole, PTH was inversely associated with 25(OH)D in maternal circulation at mid‐gestation (p = 0.023) and at delivery (p = 0.019). However, when the cohort was partitioned by 25(OH)D status, this relationship was only present in those with 25(OH)D ≤ 20 ng/mL, suggestive of a threshold below which 25(OH)D impacts PTH during pregnancy. Mid‐gestation 25(OH)D was inversely associated with calcitriol at delivery (p = 0.023), irrespective of Ca intake. Neonatal PTH and calcitriol were significantly lower than (p < 0.001), but unrelated to maternal concentrations. These findings indicate that maternal 25(OH)D status plays a role in calcitropic hormone regulation in pregnant adolescents. © 2012 American Society for Bone and Mineral Research     

Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25)

IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S(i)] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K(ITT)] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S(i) and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S(i), sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.     

Vitamin D deficiency is common in kidney transplant recipients,but is not associated with infections after transplantation

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25-OH vitamin D (25-OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri-transplant and 6 months post-transplant. Logistic regression was used to address the associations of 25-OHD and overall infections and bacterial infections, respectively. For the first 6 months post-transplant, 25-OHD peri-transplant, and for the second period (after 6 to 30 months post-transplant), 25-OHD at 6 months post-transplant was considered. Vitamin D deficiency was common peri-transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25-OHD levels increased from 12.0 ng/mL (IQR 5.3-19.5) peri-transplant to 16.5 ng/mL (IQR 10.6-22.6) 6 months post-transplant (P = .005). We did not detect a significant association between 25-OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44-2.51; aOR 0.67, 95%CI 0.31-1.43) or bacterial infections (aOR 0.79, 95%CI 0.32-1.96; aOR 0.79, 95%CI 0.35-1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25-OHD in the longitudinal course was observed. No significant association between 25-OHD and infections was detected.     

Vitamin D status in children with chronic kidney disease

Background

The role of vitamin D status in patients with renal insufficiency and its relation to dietary intake and parathyroid hormone (PTH) secretion is of utmost interest given the morbidity and mortality associated with the disordered mineral metabolism seen in chronic kidney disease (CKD).

Methods

We conducted a cross-sectional study of 100 pediatric patients with a diagnosis of CKD stage 1–5 at Children's Hospital Boston, measuring blood levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)₂D], and parathyroid hormone and obtaining data on nutrient intake and other variables related to vitamin D status.

Results

Subjects ranged in age from 6 months to 18?years, and 60 were male, 40 female. Of the 100 patients, 16 % were deficient in 25(OH)D (≤20?ng/mL) and another 24 % were insufficient (≤30?ng/mL), with 40 % in the suboptimal range. Serum 25(OH)D and dietary vitamin D intake were not correlated.

Conclusions

We found a high prevalence of hyperparathyroidism in early-stage CKD and a significant relationship between 25(OH)D and PTH regardless of calcitriol level. Our study results support the suggestion that optimization of vitamin D levels may provide additional benefit in preventing or improving hyperparathyroidism in patients with early CKD and likely remains important as an adjunctive therapy in children with advanced CKD.     

Decreased protein binding of alfentanil in plasma from children with kidney or liver failure

Disease states, including end-stage kidney or liver failure, can alter the protein binding of various drugs in children. The plasma protein binding of alfentanil was evaluated in blood samples from 15 children about to undergo kidney transplantation, 21 children undergoing liver transplantation, and 28 otherwise healthy children undergoing elective surgery. Compared with the healthy children, patients with kidney disease had a significant decrease in protein binding (89.2%± 5.4 v. 93.1%± 3.2), an increase in α₁-acid glycoprotein concentration (108.8 mg·dl^?1± 44.3 v. 71.8 mg·dl^?1± 30.7), and no change in albumin concentration (3910 mg·dl^?1± 754 v. 4555 mg·dl^?1± 524); whereas patients with liver disease had a significant decrease in protein binding (85.9%± 6.2 v. 93.1%± 3.2), no change in α₁-acid glycoprotein concentration (65.8 mg·dl^?1± 31.8 v. 71.8 mg·dl ± 30.7), and a decrease in albumin concentration (3045 mg·dl^?1± 1255 v. 4555 mg·dl^?1± 524). Because alfentanil is highly protein bound, even small changes in the drug's free fraction could have marked pharmacodynamic effects in patients with kidney or liver failure.     

Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women

It has been reported that vitamin K supplementation effectively prevents fractures and sustains bone mineral density in osteoporosis. However, there are only limited reported data concerning the association between vitamin K nutritional status and bone mineral density (BMD) or fractures in Japan. The objectives were to evaluate the association between plasma phylloquinone (K1) or menaquinone (MK-4 and MK-7) concentration and BMD or fracture in Japanese women prospectively. A total of 379 healthy women aged 30-88 years (mean age, 63.0 years) were consecutively enrolled. Plasma K1, MK-4, MK-7, and serum undercarboxylated osteocalcin (ucOC) concentrations, BMD, and incidence of vertebral fractures were evaluated. In stepwise multiple linear regression analyses, L2-4 BMD and a bone turnover marker, log K1, concentrations were independently correlated with vertebral fracture incidence. When subjects were divided into low and high K1 groups by plasma K1 concentration, the incidence of vertebral fracture in the low K1 group (14.4%) was significantly higher than that in the high K1 group (4.2%), and its age-adjusted RR was 3.58 (95% CI, 3.26-3.93). L2-4 BMD was not different between the two groups. These results suggest that subjects with vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD.     

Vitamin D binding protein, bone status and body composition in community-dwelling elderly men

The vitamin D binding protein (DBP) is the major carrier protein for vitamin D metabolites in plasma. Polymorphisms in DBP have been described to be associated with an increased bone fracture risk and diabetes. The present study investigates the influence of both phenotypic and (TAAA)(n)-Alu repeat DBP-polymorphism and DBP-concentration on bone mineral density, body composition, bone turnover- and metabolic markers in a cohort of ambulatory elderly men. We included 211 men (>70 years) in this study. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum osteocalcin, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline, together with 25(OH)-vitamin D and 1,25(OH)(2)-vitamin D concentrations. DBP-phenotypes were determined electrophoretically and the (TAAA)(n)-Alu repeat polymorphism was determined by polymerase chain reaction. Body composition was estimated using bioelectrical impedance analysis, together with handgrip and arm strength, fasting serum glucose and leptin concentrations. No differences in BMD or bone turnover markers among DBP-phenotypes or (TAAA)(n)-genotypes were observed in this study. Serum 25(OH)-vitamin D was comparable among DBP-variants and did not relate to DBP-concentrations, whereas 1,25(OH)(2)-vitamin D was different among DBP-phenotypes and was correlated positively with DBP-concentrations. DBP-concentrations related positively to body mass index, fat mass, leptin and glucose concentration. The correlation with leptin remained significant after correction for fat mass. Fasting glucose concentrations were different among DBP-phenotypes, whereas no difference was observed between (TAAA)(n)-genotypes. In conclusion, serum 1,25(OH)(2)-vitamin D concentrations are codetermined by DBP-phenotypes and DBP-concentrations. No major effect of DBP-polymorphism was demonstrated on BMD, bone turnover markers or body composition.     

Vitamin D status is associated with physical performance: the results of three independent cohorts

Summary

This study, on the association between vitamin D status and physical performance and its decline, shows that vitamin D status is associated with physical performance in several older age groups. However, vitamin D status does not predict a decline in physical performance in individuals aged 55–65 years.

Introduction

Previous research in the Longitudinal Aging Study Amsterdam (LASA) showed an association of vitamin D status with physical performance and its decline in persons aged 65 years and older. The current study aims to determine these associations in younger individuals and to replicate previous research of LASA.

Methods

Data from three independent cohorts were used: two cohorts of LASA (LASA-II with measurements in 2002 (n?=?707) and 2009 (n?=?491), LASA-I-2009 (n?=?355)) and the baseline measurement of the B-Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) study (n?=?2,813). Participants performed three tests (walking test, chair stands, and tandem stand; range total score 0–12), except in LASA-II-2002 (only walking and chair stands tests; range total score 0–8). Multiple linear and logistic regression were used to assess whether vitamin D status was associated with total physical performance and its decline, respectively.

Results

The mean age of the participants was 60.0 (SD 3.0), 65.9 (2.9), 78.4 (5.3), and 74.4 (6.8) years for LASA-II-2002, LASA-II-2009, LASA-I-2009, and B-PROOF, respectively. Vitamin D status was not predictive of a clinical decline in total physical performance score in the LASA-II-2002 cohort (aged 55–65 years). After adjustment for confounding, participants with serum 25(OH)D?<?50 nmol/L scored 0.8 (95 % confidence interval 0.4–1.2), 0.9 (0.3–1.5), 1.5 (0.8–2.3), and 0.6 (0.3–0.9) points lower on total physical performance than participants with serum 25(OH)D?≥?75 nmol/L.

Conclusion

Our study confirmed that serum 25(OH)D is associated with physical performance. However, vitamin D status did not predict a clinical decline in physical performance in individuals aged 55–65 years.