Common Genetic Variants and Other Host-related Factors Greatly Increase Susceptibility to Vitamin A Deficiency

Women are at risk of vitamin A deficiency.

In his presentation at the 2nd Hohenheim Nutrition Conference in Stuttgart, Germany, November 2009, Dr. Georg Lietz of England's Newcastle University, the senior investigator in research published April 2009 in the FASEB Journal (and summarized in our June 2009 LMR review, “Vitamin A – Tolerance Extends Longevity”), reported that a high percentage of women in the UK are at risk of vitamin A deficiency. Two common genetic variants greatly lessen the body’s ability to convert beta-carotene into vitamin A.

As noted in LMR’s Vitamin A review, concerns regarding potential toxicity from hypervitaminosis A have led to the recommendation that much, if not all, of the vitamin A requirement be met by consuming pro-vitamin A carotenoids, which have been thought to be readily converted to retinoic acid as needed. In fact, due to concerns about the teratogenic potential of hypervitaminosis A, beta-carotene has been considered the preferred source of vitamin A for women of reproductive age, and due to their dietary restrictions, is the primary source of the nutrient for vegetarians and its only source for vegans. The ability to convert beta-carotene into vitamin A has, however, recently been found to vary significantly in up to 45% of healthy individuals.¹

When Lietz and colleagues examined the gene that encodes the enzyme beta-carotene 15,15'-monoxygenase (BCMO1) the enzyme responsible for conversion of beta-carotene to retinoic acid in 62 female volunteers in Great Britain, 47% of the women were found to have at least one of two SNPs that greatly reduce activity of BCMO1.

Furthermore, these two SNPs (R267S and A379V) are common in the UK population at large, with variant allele frequencies of 42 and 24%, respectively. In vitro analysis by Lietz et al. revealed that the 267S + 379V double mutant produced a 57% reduction in catalytic activity of BCMO1. Female volunteers carrying both variant alleles and given a pharmacological dose of β-carotene were shown to have seriously reduced ability to convert β-carotene, indicated by reduced retinyl palmitate: beta-carotene ratios in the triglyceride-rich lipoprotein fraction of -32% and -69% , respectively, and increased fasting beta-carotene concentrations of +160% and +240% , respectively.

Interviewed at the 2nd Hohenheim Nutrition Conference, Leitz emphasized, "Vitamin A is incredibly important—particularly at this time of year when we are all trying to fight off the winter colds and flu. It boosts our immune system and reduces the risk of inflammation such as that associated with chest infections. What our research shows is that many women are simply not getting enough of this vital nutrient because their bodies are not able to convert the beta-carotene."

"Worryingly, younger women are at particular risk," Dr Lietz added. "The older generations tend to eat more eggs, milk and liver which are naturally rich in vitamin A whereas the health-conscious youngsters on low-fat diets are relying heavily on the beta-carotene form of the nutrient." Many health conscious elders also strive to follow a low-fat diet and thus avoid vitamin A rich foods.

In addition to the significant number of individuals whose genetic inheritance renders them “low-responders,” unable to absorb and/or convert provitamin A carotenoids to vitamin A, a number of food and other host-related factors can significantly impact carotenoid bioavailability, absorption and conversion to retinol.²

The presence of virtually any of the following factors can inhibit the conversion or render the amount of carotenoids absorbed insufficient to produce or maintain adequate levels of vitamin A, even in individuals who are not carriers of the SNPs R267S and/or A379V and thus should be able to metabolize provitamin A to vitamin A:

Normal absorption of carotenoids is minimal: About 70-90% of ingested retinol is absorbed, but even under optimal circumstances, only 3% or less of carotenoids.³
Vitamin A stores are depleted by at least 5% each day: Despite its being a fat-soluble nutrient, under normal conditions, 5% of vitamin A stores are lost daily.
Large variations in the concentration of provitamin A carotenoids in foodstuffs are typical—even in the same type of food—due to varietal differences, stage of maturity, climatic conditions, processing and/or cooking.
Food matrix and preparation: Efficiency of carotenoid absorption is affected not only by the amount of carotenoid ingested, but by processing and/ or cooking of the food, other dietary ingredients that stimulate absorption (e.g., the type and amount of dietary fat [carotenoids must be incorporated into mixed micelles and then into chylomicrons for absorption] or inhibit it [fiber, especially pectins], food matrix effects, and interactions between carotenoids [lutein and β-carotene appear to inhibit one another’s absorption]).⁴
Availability of bile acids, iron, riboflavin, niacin, and zinc: The enzyme beta-carotene 15,15'-monoxygenase, which converts the provitamin A carotenoids to retinal mainly in the intestinal mucosa (and, to a lesser extent, in testes, liver and kidneys), requires bile acids and iron for its three-step activity (epoxidation at the 15,15'-double bond, hydration to the diol, and oxidative cleavage). Retinal resulting from carotenoid cleavage is metabolized, mainly to retinol, by several tissue specific enzymes that require riboflavin, niacin, and zinc as cofactors.
Bile flow is compromised by acute and chronic liver diseases, including non-alcoholic steatohepatitis (NASH) related to insulin resistance / metabolic syndrome, which is now estimated to affect ~30% of the US population⁵, and alcoholism.
Alcoholism promotes vitamin A deficiency via two mechanisms. Not only is bile flow compromised, but alcohol dehydrogenase—the enzyme that catalyzes conversion of retinol to retinaldehyde, which is then oxidixed to retinoic acid—has a stronger affinity for ethanol.⁶
Drug induced depletion: Antacids containing aluminum hydroxide can impair vitamin A absorption. Cholesterol-lowering agents, e.g., bile acid sequesterants such as cholestyramine, cholesipol, colestipol, reduce fat absorption and thus absorption of vitamin A and other fat-soluble nutrients. Colchine impairs vitamin A absorption by blocking the release of retinol-retinol binding protein. Neomycin, if high doses over extended period, may impair vitamin A absorption. Sucralfate decreases absorption of fat-soluble nutrients.⁷
Impaired digestion: Absorption of β-carotene and other carotenoids from vegetables is only 5-30% of that absorbed from synthetic supplements, due to the food matrix of fiber and/or protein that must first be broken down by mastication, gastric acid and bile acids.⁸
Imbalanced gut ecology: due, for example, to parasitic infestation, food allergies such as gluten intolerance, celiac disease (U.S. incidence 1 in 133)⁹, lipid malabsorption, hydrochloric acid insufficiency (30% of the US population >60 is estimated to have atrophic gastritis)⁸, infection with H.pylori, (prevalence of H.pylori infection is 50% worldwide, 40% in the US¹⁰) or Clostridium difficile (annual incidence of C.difficile infection increased from 49.2 to 101.6 per 100,000 population from 2001-2005¹¹)
Exposure to heptatoxicants. Numerous hepatotoxicants, e.g., carbon tetrachloride, reduce retinol storage and or alter retinoid metabolism. In 2008, a study of common cleaning products found the presence of carbon tetrachloride in "very high concentrations" (up to 101 mg m−3) as a result of manufacturers' mixing of surfactants or soap with sodium hypochlorite, i.e. chlorine bleach.¹²
Supplementation with increasingly high levels of vitamin D. A plethora of studies published within the last 5 years have ensured clinicians awareness of the pandemic of vitamin D deficiency with the result that many are testing patients’ vitamin D levels and prescribing supplementation with 1,000 to up to 10,000 IU vitamin D daily. Retinoic acid and 1,25(OH)2D3 compete for the same nuclear receptor partners; both the retinoic acid receptor (RAR) and the vitamin D receptor (VDR) must form heterodimers with retinoic X receptors (RXRs) to be able to bind to response elements and initiate transcription. For this reason, 1,25(OH)2D3 and retinoic acid naturally mitigate against each other’s uncontrolled effects. High doses of vitamin D may upset the balance between it and vitamin A, which, as discussed in “Vitamin A -- Tolerance Extends Longevity,” is a key regulator of self and oral tolerance.¹³

Taken together, the genetic, food and host-related factors affecting carotenoid conversion to vitamin A clearly indicate that while the RDIs for vitamin A were intended to include a reasonable safety margin, they are based on overly optimistic assumptions regarding the amount of β-carotene the majority of individuals actually absorb and convert to retinol.

The spotlight Leitz has focused on the SNPs likely to induce vitamin A insufficiency is timely, especially given current concerns re the potential for an epidemic of H1N1 Swine Flu¹⁴, a public health threat that should underscore the importance of vitamin A sufficiency for immune function. Above and beyond this current challenge, vitamin A will remain critical for overall health and longevity because retinoic acid affects the expression of at least 532 genes, and the study by Leitz et al. both explains and confirms research conducted in a number of other geographical areas (including Indonesia¹⁵, France¹⁶, Germany¹⁷¹⁸and the U.S. (specifically University of California, Davis)¹⁹, suggesting widespread penetrance of the R267S and A379V SNPs in the human species.

For an in-depth discussion of vitamin A’s effects on immunity, relationship to vitamin D, and recommendations regarding assessment of patients’ vitamin A status, please see our review, “Vitamin A -- Tolerance Extends Longevity.”.Dr Lietz and his associates plan to assess whether body composition, i.e., BMI, also affects the ability to convert beta-carotene into vitamin A. Given the rapidly rising incidence of obesity in the western world, a negative impact of excessive adipose tissue on carotenoid conversion to retinoic acid would have serious implications. We will follow Lietz’s progress and keep you updated.