Commentary: vitamin D deficiency and liver cancer - cause, effect or myth?

Abstract

An ever-increasing list of publications in recent years has highlighted the negative correlation between vitamin D deficiency and myriad of chronic diseases including cardiovascular, metabolic, autoimmune diseases and cancers.1 Finkelmeier et al.2 reported a prospective study showing a positive association between severe 25(OH) vitamin D and advanced stages of hepatocellular cancer. 25(OH) vitamin D deficiency also significantly prognosticates overall mortality independent of MELD and AFP levels. The mechanism of action, suggested by the authors, is due to the increased systemic inflammatory response in severe vitamin D deficiency. The biggest danger of observational studies is the intrinsic potential bias in extrapolating association factors to causative agents. Three recently published large review studies highlighted the disconnect between observational association studies of vitamin D-deficient disease states and interventional studies when vitamin D is supplemented under randomised controlled fashion.3-5 This has led to the opinion that low 25(OH) vitamin D is a marker of ill health rather than a mechanistic mediator.6 Vitamin D measurement is fraught by complexities including variability in individuals, racial differences and a lack of consensus of what constitute functional deficiency.7 In liver diseases, vitamin D may be depressed due to dietary malnutrition (epiphenomenon), poor mobility and thus reduced sunlight exposure (reverse causality), as well as reduction in (25)-hydroxylation of vitamin D by the liver (confounding).8 To be fair, in the study by Finkelmeier et al. the authors did control for MELD score in the multivariate analysis on prognostication of HCC and cautioned the effect of epiphenomenon. Regardless of the mechanistic role, vitamin D does appear to prognosticate overall survival of HCC patients. However, until and unless there is good evidence for therapeutic intervention in vitamin D deficiency, we should avoid taking the leap to do routine testing of vitamin D levels and supplementation which results in costs and benefits that are yet unproven. Declaration of personal and funding interests: None.