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Paleo woman developed vA toxicity with supposed liver consumption
I think the changes to agriculture have made agricultural foods higher in VA than they ever were before.
My guess is that everyone starts with a different load, and everyone also starts with different base levels of things like B vitamins and minerals too. Then on top of that we are all different in our tolerances. Some can put on fat in which to sock away VA, others don't. Some have higher intakes of other poisons than others.
That being said, I think that much of what we call "old age" is really "high VA". And when it happens in the young, it looks very strange to people and they call it disease. But when it happens to the old, they just call it natural.
This can be an interesting line of reasoning! All the things that help old people also will help young people with high VA. Does anyone remember how George Kastanza on Seinfeld always said his parent's place smelled of Kashi? Old people benefit from fiber. And B12. And getting moving. And good sleep. And flossing. And sunshine.
I’m a geneticist (degree, PhD) and I think that the vitamin A toxicity problem is environmentally induced. I would love to think everything is genetics as that is my area of expertise...but I don’t. Genetics always has a background influence (if you pull a chain it breaks at the weak link and some people are more vulnerable). I believe the level of toxicity we are now exposed to has damaged our liver’s ability to get rid of toxicity efficiently. This leaves us much more open to accumulation of vA which in turn damages our liver’s ability to get rid of toxicity. A negative cycle. Here we are trying to get out of this negative cycle and get rid of our toxicity more efficiently. Reducing vA is a major (but for many not the only) factor imo.
Genetic variance plays a large role in differences in nutrient status and nutrient metabolism. Is it the main decider for the development of Hypervitaminosis A once vitamin A intake is adjusted for? It's not known. However, there is no doubt that it plays a major role. If you have Hypervitaminosis A, you aren't necessarily more burdened with toxicity than others without Hypervitaminosis A and there may not be anything wrong with you other than that you consumed too much vitamin A.
Genetic Variations Associated with Vitamin A Status and Vitamin A Bioavailability
Abstract
Blood concentration of vitamin A (VA), which is present as different molecules, i.e., mainly retinol and provitamin A carotenoids, plus retinyl esters in the postprandial period after a VA-containing meal, is affected by numerous factors: dietary VA intake, VA absorption efficiency, efficiency of provitamin A carotenoid conversion to VA, VA tissue uptake, etc. Most of these factors are in turn modulated by genetic variations in genes encoding proteins involved in VA metabolism. Genome-wide association studies (GWAS) and candidate gene association studies have identified single nucleotide polymorphisms (SNPs) associated with blood concentrations of retinol and β-carotene, as well as with β-carotene bioavailability. These genetic variations likely explain, at least in part, interindividual variability in VA status and in VA bioavailability. However, much work remains to be done to identify all of the SNPs involved in VA status and bioavailability and to assess the possible involvement of other kinds of genetic variations, e.g., copy number variants and insertions/deletions, in these phenotypes. Yet, the potential usefulness of this area of research is exciting regarding the proposition of more personalized dietary recommendations in VA, particularly in populations at risk of VA deficiency.
ABSTRACT
Background: Although numerous environmental factors are documented to influence serum retinol and α-tocopherol concentrations, little is known about the genetic versus the environmental contributions to variations in these traits.
Objective: The aim of this study was to estimate additive genetic heritability and household effects for serum retinol and α-tocopherol concentrations in a variance component analysis.
Design: In a sample of 387 French families, information on serum retinol and α-tocopherol concentrations, usual dietary intake, lifestyle, and serum lipid profiles and related polymorphisms (apolipoprotein E, apolipoprotein C-III, apolipoprotein B, cholesteryl ester transfer protein, and lipoprotein lipase) was obtained.
Results: For serum retinol—after adjustment for sex, age, body mass index, alcohol consumption, oral contraceptive use, and serum albumin, triacylglycerol, and apolipoprotein A-I concentrations—additive genetic effects and shared common environment contributed 30.5% and 14.2% of the total variance, respectively. For serum α-tocopherol, ≈22.1% of the total variance was due to the additive effects of genes and 18.7% to those of household environment, after adjustment for the covariates sex, age, vitamin E intake, oral contraceptive use, and cholesterol, triacylglycerol, and apolipoprotein A-I concentrations. For both vitamins, the influence of measured polymorphisms was not significant. Moreover, heritability and household effect estimates were not significantly different between the 4 classes of relatives and did not vary significantly when families shared more meals at home.
Conclusions: The results show that serum retinol and α-tocopherol concentrations are under genetic control in healthy families.
It's worth looking at other vitamins as well:
Abstract
Vitamin D metabolism in individuals is affected not only by their exposure to the sun or dietary intake of vitamin D, their liver and kidney function and other tissue production, but also by genetic variations in genes associated with vitamin D metabolism. These genes include not only the vitamin D receptor (VDR) genes, but also Group–Specific Component (GC), 7-dehydrocholesterol reductase (DHCR7), cytochrome P450 2R1(CYP2R1), cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), and cytochrome p450 27B1 (CYP27B1). Particular single nucleotide polymorphisms (SNPs) from a number of these genes are being associated with lower or higher circulating vitamin D concentrations. Vitamin D metabolism is also affected by interactions with the individual’s microbiome. Other environmental changes in addition to vitamin D intake, particularly those associated with variations in nutrient intake and exposure to pathogens, can impact on these gene variations associated with vitamin D metabolism. Certain combinations of these, in addition to a lowering of circulating vitamin D, influence immune and metabolic pathways and contribute to immune dysregulation. The current enhancement and interplay of these permutations augurs the rise of chronic conditions in the Western world. To ameliorate this, vitamin D supplementation needs to be tailored to an individual’s genotype in the context of their environment.
Introduction
Vitamin D is a major regulator of gene expression and signaling in most tissues, and insufficiency affects many adults [1,2]. Genetic factors are thought to play a large part in this. Indeed, the genetic contribution to vitamin D status has been estimated to be from 28- 80% [3-5]. A number of particular single nucleotide polymorphisms (SNPs) for vitamin D associated genes or particular combinations of SNPs from genes relating to vitamin D metabolism can be involved in multiple signaling pathways. These pathways can be associated with lower or higher concentrations of circulating vitamin D. These particular SNPs from genes associated with vitamin D are also becoming increasingly relevant in their association with immune disorders.
Vitamin D deficiency is becoming well recognised as having a role in cell proliferation, differentiation, apoptosis and the immune response [6-13]. Vitamin D has been reported to be a significant factor in seventeen varieties of cancer [14-24], through its interactions with signaling pathways [8,21,25-31]. Vitamin D concentrations are also becoming particularly relevant in inflammatory disorders such as Crohn’s disease (CD), one of the common Inflammatory Bowel Diseases (IBD). Vitamin D plays a significant role in anomalous gene interactions, a critical factor in IBD [32-35]. Wang et al. showed that the active form, 1, 25 (OH) 2D3 affects the nucleotide-binding oligomerization domain containing 2 (NOD2) defense beta2 innate immune pathway, often found to be defective in people with CD [36]. Other immune disorders that have been associated with vitamin D are diabetes, coronary heart disease, blood pressure and outcomes of chronic kidney disease [37-49]. Particular variants of genes, the influence of microbiome, vitamin D metabolic pathways associated with them, and how our changing environment impinges on these and exacerbates immune dysfunction are the basis of the following discussion.
Genetic polymorphisms and folate status
Introduction
The classical symptom of folate deficiency in humans is megaloblastic anemia. Inadequate folate intake constitutes a leading cause of folate deficiency, which involves decreased serum or plasma folate concentrations followed by increased serum or plasma total homocysteine (tHcy) concentrations and reduced red blood cell (RBC) folate levels. Elevated tHcy represents a major risk factor of cardiovascular and cerebrovascular diseases (Homocysteine Studies Collaboration 2002). Moreover, lower serum folate and higher plasma tHcy may also be causes of neural tube defects (NTDs) (Smithells et al. 1976; Daly et al. 1995), cognitive dysfunction (Seshadri et al. 2002), and depression (Bottiglieri 2005).
Folate is an essential cofactor in the folate‐mediated one‐carbon metabolism pathway and is essential in many biochemical processes, such as amino acid metabolism, purine and thymidylate synthesis, and DNA methylation (Brody and Shane 2001). The folate pathway is also closely associated with Hcy metabolism. Hcy itself is located at a branch‐point of metabolic pathways: remethylation and the trans‐sulfuration pathway, in which B‐vitamins, i.e. folate, vitamin B12, vitamin B6, and vitamin B2, are required as cofactors. Therefore, inadequate levels of these vitamins can raise plasma tHcy levels.
Several studies have identified associations between genetic polymorphisms related to the folate pathway and Hcy metabolism. The common C677T variant in the gene encoding the folate‐metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) is the most well‐known genetic factor influencing folate status. MTHFR catalyzes the conversion of 5,10‐methylenetetrahydorfolate to 5‐methyltetrahydrofolate in an irreversible reaction. This enzyme is critical for the regulation of available folate in the remethylation of Hcy. Carriers of the T allele have lower enzyme activity (Frosst et al. 1995), leading to elevated Hcy concentrations (Tsang et al. 2015). The frequency of this polymorphism is known to vary among different ethnic groups and geographical regions (Binia et al. 2014); for example, the allele frequency in the Japanese population is 0.391 (Iida et al. 2009) and the frequency of the homozygous mutant TT genotype is approximately 15% in Japanese individuals (Sadewa et al. 2002; Hiraoka 2004), but about 10% in individuals worldwide (Wilcken et al. 2003). Thus, for prevention of various diseases associated with elevated tHcy, it is important to consider nutrient‐gene interactions.
In this review, we will explore the evidence linking polymorphism‐related folate‐Hcy metabolism with folate status and describe examples of health promotion programs with personalized nutritional intervention based on MTHFR C677T polymorphisms.
Conclusion
MTHFR C677T polymorphisms are major factors influencing folate status. Individuals with the TT genotype have lower serum folate concentrations and higher serum tHcy concentrations than those with the CC genotype; hence, folate intake of 400 μg/day above the Japanese current RDA (240 μg/day) is recommended to maintain serum folate and Hcy levels similar to those found in individuals with the 677CC/CT genotypes. Intervention of folate status based on personalized nutrition by notifying individuals of their genotype could be effective in motivating individuals to change their lifestyle and improve their nutrition status, particularly in individuals with the TT genotype. Folic acid‐fortified foods may allow individuals to more easily consume adequate folate to prevent diseases.
An update on vitamin B12-related gene polymorphisms and B12 status
Conclusion
In summary, our review has identified significant associations of vitamin B12 status with 59 B12-related SNPs from 19 genes. Among these genes, five were co-factors or regulators for the transport of vitamin B12 (FUT2, FUT6, MMACHC, TCN1 and TCN2); three were membrane transporters actively facilitating the membrane crossing of vitamin B12 (ABCD4, CUBN and CD320); three were involved in the catalysis of enzymatic reactions in the one-carbon cycle (CBS, MTHFR and MTRR); one was involved in cell cycle regulation (MS4A3); three were mitochondrial proteins (CLYBL, MMAA and MUT) and lastly four genes had an unknown function (ACTL9, CPS1, DNMT2/TRDMT1 and PON1). Our review highlights the complex nature of the B12 genetics where several genes/SNPs from various parts of B12 metabolic pathway contribute to the susceptibility to vitamin B12 deficiency. Identification of gene variants involved in this metabolic pathway using large-scale genetic association studies in diverse ethnic populations would contribute to our understanding of the pathophysiology of B12 deficiency and help in discovering biomarkers of vitamin B12-related chronic diseases.