Interactions of vitamin A with the effects of vitamin D and their potential for confounding investigations on the effects of vitamin D on human health
Boucher BJ; Centre for Diabetes, Queen Mary University of London, London El 2AT, UK.
Background: Ligand-bound vitamin D:retinol-X receptor heterodimers are important vitamin D effectors. Retinol-X receptors heterodimerize with retinol-A receptors and the availability of RXR falls in the presence of excessive vitamin A. Westernized populations often ingest more vitamin A than is advisable and up to 30% have circulating concentrations above the recommended maximum level (e.g. in NHANES111). Populations in developing countries are often deficient in vitamin A. U or J shaped curves for benefits of increases in vitamin D supplementation in are a growing concern, as reported in the Western world. Retinoid formation from carotinoids is self-regulated and avoids vitamin A toxicity. High retinoid intakes have been associated with increases in mortality. 2 large Randomized Controlled Trials (RCTs) of vitamin A have had to be stopped due to an increased incidence of lung cancer and in cardiac deaths.
Methods: Review of the literature (using original literature identified and accessed through PubMed etc.), and the examination of mechanistic, experimental and epidemiological data.
Results: Retinol does not affect vitamin D metabolism directly. Vitamin D does not affect serum retinoids directly. High dose retinol prevents toxic effects, including death, in vitamin D poisoning, experimentally High-intakes of retinol induces rickets in normal animals and are associated with increased osteoporotic risks in older women and maybe associated with increased fracture risks in some population groups. High intakes (above recommended daily amounts) of vitamin A have been reported to counteract the effects of vitamin D (including effects in RCTs). For Example:- Vitamin D-induced calcium absorption by the gut is reduced by vitamin A in fish, animals and humans. GWAS data shows raised retinol levels in those with specific retinol binding protein gene polymorphisms. Overall reductions in lung cancer risks in never-smokers in the Women's Health Initiative (1771 cases in 128,779 women) were seen with vitamin D intakes > 400 lU/day (OR=0.37, 95% CI:0.18-0.77); however, RCT data for the 12% of women given vitamin D supplements showed lower lung cancer risk only in those with low intakes of retinol (OR=0.69, 95%CI, 0.5-0.96). RCTs of retinyl palmitate increased lung cancer risk in the large CARET trial. Lower death rates from malignant melanoma are seen with higher vitamin D intakes (OR = 0.77, 95% CI, 0.64-0.93) but this benefit is smaller in those with high retinol intakes (OR=0.99, 95% CI, 0.72-1.36).
- 1. Since the use of supplements containing vitamin A as well as vitamin D is common, whether in cod liver oil or multi-vitamins, especially in developed countries, vitamin A status is likely to confound RCTs of vitamin D in Westernized populations.
- 2. In particular, high vitamin A intakes could account for J or inverse U shaped curves for outcomes in RCTs, as could gene polymorphisms increasing circulating retinol/retinoids.
- 3. Conversely, poor vitamin D status may be expected to confound RCTs of vitamin A in developing countries.
- 4. As well as vitamin A intakes, other lifestyle factors that are potential confounders of the effects of vitamin D should be considered in the planning of future RCTs of supplemental vitamin D, including intakes of other nutrients, tobacco usage, and also betel-chewing which may increase catabolism of vitamin D and is a habit used by 10% of the world population.
Poster presentation at Vitamin D conference in England - April 23-25 2014
The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements
European Journal of Nutrition, February 2015, Date: 21 Feb 2015
Einat Avital Schmutz, Michael Bruce Zimmermann, Sabine Rohrmann
Low serum 25-hydroxyvitamin D 25(OH)D levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements.
We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95 % confidence intervals (CI) were estimated by proportional hazards regression.
Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95 % CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 μg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant.
25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.
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