Elevated Levels of 1,25-Dihydroxyvitamin D in Plasma as a Missing Risk Factor for Celiac Disease

The prevalence of celiac disease (CD) has increased significantly in some developed countries in recent decades. Potential risk factors that have been considered in the literature do not appear to provide a convincing explanation for this increase. This has led some researchers to hypothesize that there is a "missing environmental factor" that increases the risk of CD. Based on evidence from the literature, the author proposes that elevation in plasma levels of 1,25-dihydroxyvitamin D [1,25(OH)₂D] is a missing risk factor for CD, and relatedly that significant oral vitamin D exposure is a "missing environmental factor" for CD. First, elevated plasma levels of 1,25(OH)₂D are common in CD, especially in the newly diagnosed. Second, nine distinct conditions that increase plasma levels of 1,25(OH)₂D are either associated with CD or have indications of such an association in the literature. Third, a retrospective study shows that sustained oral vitamin D supplementation in infancy is associated with increased CD risk, and other studies on comorbid conditions support this association. Fourth, large doses of oral vitamin D upregulate many of the same cytokines, chemokines, and toll-like receptors that are upregulated in CD. Fifth, epidemiological evidence, such as the timing of the inception of a CD "epidemic" in Sweden, the increased prevalence of CD in Finland and the United States in recent decades, the unusually low prevalence of CD in Germany, and the differential in prevalence between Finnish Karelians and Russian Karelians, may all be explained by oral vitamin D exposure increasing CD risk. The same is true of some seemingly contradictory results in the literature on the effects of breastfeeding on CD risk. If future research validates this hypothesis, adjustments to oral vitamin D consumption among those who have genetic susceptibility may decrease the risk of CD in these individuals.