Perspective:TheHigh-Folate–Low-VitaminB-12 InteractionIsaNovelCauseofVitaminB-12 DepletionwithaSpecificEtiology—AHypothesis

Abstract

Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involvedinvitaminB-12traffickingandfunctions.AnotherputativecauseofvitaminB-12deficiencyisthehigh-folate–lowvitaminB-12interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribedhighoraldosesoffolicacid.WeproposethatthisinteractionisrealandrepresentsanovelcauseofvitaminB-12depletionwithspecific etiology.Wehypothesizethatexcessiveintakeoffolicaciddepletesserumholotranscobalamin(holoTC),therebydecreasingactivevitaminB-12in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12coenzymestotheirrespectiveenzymes,andconsequentlyamorepronouncedstateofbiochemicaldeficiency.Thishypothesisisdrawnfrom evidence of observational and intervention studies of vitamin B-12–deficient patients and epidemiological cohorts. The evidence also suggests that,inadepletedstate,vitaminB-12isdivertedtothehematopoieticsystemorthekidney.Thismostlikelyreflectsaselectiveresponseoftissues expressingfolatereceptorswithhighaffinityforunmetabolizedfolicacid(UMFA;e.g.,hematopoieticprogenitorsandrenaltubules)comparedwith thosetissues(e.g.,liver)thatonlyexpressthereducedfolatecarrier,whichisuniversallyexpressedbuthaspooraffinityforUMFA.Thebiochemical andphysiologicalmechanismsunderlyingthisinteractionrequireelucidationtoclarifyitspotentialpublichealthsignificance