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Vitamin D-vitamin a interaction.

What if worries about overdosing on fat-soluble vitamins D, A, K, and E have less to do with the intake amount of the individual vitamins and more to do with the ratio between them? While the body eliminates excess water-soluble vitamins, it stores excess fat-soluble vitamins. Anyone who takes a nutrition class is taught that taking too much of a fat-soluble vitamin can lead to toxic reactions. Still, the fact that vitamin A levels in the liver decrease with the addition of vitamin D from ultraviolet light or diet indicates that these two vitamins have a largely unrecognized relationship.

Christopher Masterjohn, in articles for the Weston A. Price Foundation publication Wise Traditions, suggests that vitamin A protects against vitamin D toxicity. He expanded his hypothesis in the journal Medical Hypotheses (December 2007) with the idea that too much vitamin D depletes vitamin K. In his view, vitamins D, A, and K are interrelated. According to Masterjohn's hypothesis, vitamin D increases the level of vitamin K-dependent proteins; their activation leads to vitamin K depletion. Among other effects, vitamin K protects against bone loss and calcification of peripheral soft tissues. Calcification of the soft tissues of the heart, blood vessels, renal tubules, and lungs is a defining characteristic of vitamin D toxicity (hypervitaminosis D). Vitamin A mitigates vitamin K depletion without affecting vitamin D's benefits. A 2007 animal study by Drs. Xiang-Dong Wang and Heather Memitz at Tufts University showed that "an activated vitamin A derivative [protected] against kidney stones caused by activated vitamin D without antagonizing its ability to protect against lung cancer." This study did not examine the role of vitamin K.

In December 2010, Tufts University researchers, with whom Masterjohn had been communicating, published a study that supports Masterjohn's hypothesis that vitamin D affects vitamin K activity. This Tufts study showed that vitamin D supplementation alone causes a large increase in the production of vitamin-K-dependent matrix gamma-carboxyglutamic acid protein (MGP) in the kidneys of mice. Mice receiving vitamin A in combination with vitamin D showed a 2.2-fold increase of gamma-carboxylated MGP (showing the presence of vitamin K activity) compared with the control. Mice receiving just A or just D did not exhibit the same level of gamma-carboxylated MGP. All mice in the study had the same amount of phylloquinone (vitamin K) in their diet. Nonetheless, the kidney concentration of menaquinone-4 (a vitamin K conversion product) was higher in the D-only group and lower in the A-only group compared with the A + D group or control data. Clearly, vitamins D, A, and K have a symbiotic relationship.

The interaction between vitamin D and vitamin A has been hotly debated. In November 2008, Dr. John Cannell of the Vitamin D Council along with 16 other scientists published a commentary in the journal Annals of Otology, Rhinology & Laryngology. In the commentary, they expressed concern about supplementation with cod liver oil because of its high vitamin A content and the possibility that A will counteract D's beneficial effects. Unlike vitamin D, many foods contain vitamin A and its precursor beta-carotene, making the possibility of an A overdose more likely. Cannell refers to a rat study conducted by C. M. Rohde et al. that reported "all-trans retinoic acid [an activated form of vitamin A] antagonizes the action of calciferol [activated vitamin D] and its active metabolite, 1, 25-dihydroxycholecalciferol, in rats." In a January 2010 rebuttal to the commentary, Linda Linday, MD, and colleagues point out that Rohde's research used very high vitamin A:D ratios. According to Rohde's research, vitamin A produces toxicity at vitamin A:D ratios of 54,702:1 and interferes with vitamin D at ratios of 11,353 and 5676 (based on international units). Agricultural research concerning bone growth and calcium metabolism in poultry indicates that a much lower ratio has beneficial effects. "The most recent recommendations for growing turkeys," write Linday and colleagues, "are 5,000 IU of vitamin A and 1,100 IU of vitamin D3 per kilogram per day, yielding a vitamin A/D ratio of 4.4. For immature Leghorn-type chickens laying white eggs, the recommendations are 1,500 IU of vitamin A and 200 to 300 IU of vitamin D3 per kilogram per day, yielding ratios of 5 to 7.5." (my emphasis) We do not yet know the optimal A:D ratio for human children or adults.

Even though cod liver oil has a long history as a traditional food, both commentaries point out that modern cod liver widely varies in its vitamin content because company manufacturing practices differ. At this time, cod liver oil is not standardized in the US. Cannell's commentary recommends avoiding cod liver oil altogether because of the active retinol (vitamin A) content and the possibility of overdose and/or negation of vitamin D's effect. Linday's commentary recommends that consumers read the label, keeping the A:D ratio of about 5 in mind. Cod liver oil should not be used as a source for high doses of omega-3 or D. The Linday commentary states; "It is not appropriate to use a combination product, whether a pharmaceutical product or cod liver oil, to provide high doses of a single constituent." As more research about the interaction between A, D, and K becomes known, we may need to consider all three when supplementing.

Cannell J. Vitamin A toxicity [Wed article]. Vitamin D Newsletter. December 2008. Accessed November 16, 2010.

FuZ, Wang XD, Memitz H, Wallin R, et al. 9-Cis retinoio acid reduces 1 alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice [abstract].J Nutr. December 2008;138(12):2337-2341. Available at: Accessed December 28, 2010.

Linday LA, Umhau JC, Shindledecker RD, Dolitsky JN, Holick MF. Cod liver oil, the ratio of vitamins A and D, frequent respiratory tract infections, and vitamin D deficiency in young children in the United States. Ann Otol Rhinol Laryngol. 2010;119(1):64-70.

Masterjohn C. Drs. Linday and Holick and colleagues defend cod liver oil, citing the Weston A. Price Foundation [blog entry]. WAPF blog. May 27, 2010. Accessed November 22, 2010.

Masterjohn C. Tufts University confirms that vitamin A protects against vitamin D toxicity by curbing excess production of vitamin K-dependent proteins [blog entry]. Daily Lipid. April 7, 2009. Accessed November 16, 2010.

Masterjohn C. Vitamin D toxicity redefined: Vitamin. K and the molecular mechanism [summary]. Med Hypotheses. 2007;68(5); 1025-1034. Available at: Accessed November 22, 2010.
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Title Annotation:Shorts
Author:Klotter, Jule
Publication:Townsend Letter
Geographic Code:1USA
Date:Feb 1, 2011
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