Vitamin D deficiency and HCV chronic infection: What comes first?
Authors: Davide Bitetto, Carlo Fabris, Edmondo Falleti, Pierluigi Toniutto
Journal: Journal of Hepatology (2011)

Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapyJournal of HepatologyVol. 54Issue 5PreviewVitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We, therefore, performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment. Full-Text PDF Reply to "Vitamin D deficiency and HCV chronic infection: What comes first?"Journal of HepatologyVol. 55Issue 4PreviewWe thank Dr. Bitetto et al. for their interest in our study recently published in the Journal of Hepatology [1]. In this study, we reported a high prevalence of severe vitamin D deficiency in patients with chronic hepatitis C, even in the absence of significant liver fibrosis. We found that vitamin D deficiency was associated with failure to achieve a sustained virologic response (SVR) to therapy of chronic hepatitis C with pegylated interferon-alfa and ribavirin. Bitetto et al. have now accentuated the important question, whether vitamin D deficiency is caused by hepatitis C virus (HCV) infection, or whether vitamin D deficiency may confer an enhanced susceptibility to chronic HCV infection. Full-Text PDF Open Access Dear Sir, we read with great interest the paper published by Lange et al. [[1]Lange C.M. Bojunga J. Ramos-Lopez E. Wagner M.V. Hassler A. Vermehren J. et al.Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.J Hepatol. 2011; 54: 887-893Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar] reporting that serum vitamin D deficiency and the CYP27B1-1260 promoter polymorphism are more prevalent in patients with chronic hepatitis C compared to controls, and that they are associated with a lower response rate to interferon-alfa based therapy. Comparing patients with chronic hepatitis C to a large control group, the authors found a strong association between the presence of chronic hepatitis C and severe vitamin D (25-OH D3) deficiency (serum levels <10 ng/ml in 25% of the patients vs. 12% of controls, p<0.00001). Furthermore, adding new observations to the recently published data [[2]Petta S. Camma C. Scazzone C. Tripodo C. Di Marco V. Bono A. et al.Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C.Hepatol. 2010; 51: 1158-1167Crossref PubMed Scopus (356) Google Scholar], the authors showed that serum vitamin D deficiency is associated with a lower probability to achieve sustained viral response (SVR) after antiviral therapy in easy to treat hepatitis C virus (HCV) genotypes. The association between vitamin D deficiency and HCV chronic infection has been previously reported by several authors [[3]Fisher L. Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease.Clin Gastroenterol Hepatol. 2007; 5: 513-520Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar] and different studies demonstrated that it seems to be preferentially related to the HCV etiology rather than to the severity of liver disease [[4]Arteh J. Narra S. Nair S. Prevalence of vitamin D deficiency in chronic liver disease.Dig Dis Sci. 2010; 55: 2624-2628Crossref PubMed Scopus (292) Google Scholar]. These observations raise the question about what comes first, vitamin deficiency or HCV infection? In other words, may vitamin D deficiency confer an enhanced susceptibility to HCV chronic infection, or can HCV chronic infection, through a still unknown mechanism, cause vitamin D deficiency? To try to answer this question Dr. Lange et al. [[1]Lange C.M. Bojunga J. Ramos-Lopez E. Wagner M.V. Hassler A. Vermehren J. et al.Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.J Hepatol. 2011; 54: 887-893Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar] examined whether the eradication of HCV infection determined a significant increase in the serum levels of vitamin D. They determined 25-OH D3 serum concentrations before and 24 weeks after the end of antiviral therapy, in 50 patients with HCV genotype 1 chronic hepatitis who achieved SVR. Although in these patients the median value of 25-OH D3 serum concentrations increased slightly 24 weeks after the end of antiviral treatment (16.2 vs. 18.2 ng/ml), the authors outlined that a trend for having a lower prevalence of severe vitamin D deficiency (25-OH D3 <10 ng/ml) after HCV eradication has been detected (33% vs. 26%, p= 0.092). Hence the authors speculate that HCV infection itself may affect vitamin D metabolism, providing preliminary evidence that a potential direct viral effect on vitamin D synthesis could be hypothesized. Although this assumption may be acceptable, we are not completely convinced that this can be supported by the data presented, not only for the lack of statistical significance they have. In the analysis of vitamin D serum concentrations, the authors did not consider the season in which the serum sample was taken that represents a very important variable able to influence vitamin D serum concentration [[5]Wang T.J. Zhang F. Richards J.B. Kestenbaum B. van Meurs J.B. Berry D. et al.Common genetic determinants of vitamin D insufficiency: a genome-wide association study.Lancet. 2010; 376: 180-188Abstract Full Text Full Text PDF PubMed Scopus (1245) Google Scholar]. Analyzing a cohort of 211 north-Italian patients with chronic HCV related hepatitis treated with pegylated interferon and ribavirin, we identified as independent predictors low vitamin D serum levels (⩽20 ng/ml), age >50 years (O.R. 2.37, 95% C.I. 1.34–4.21, p= 0.002) and having drawn the blood sample for vitamin D measurement during the winter or spring months (O.R. 2.06, 95% C.I. 1.15–3.67, p= 0.016). When the analysis was performed in the subgroup of the 144 patients who underwent a pre antiviral treatment liver biopsy, a higher histology grade (O.R. 3.42, 95% C.I. 1.37–8.54, p= 0.004) and having drawn the blood sample for vitamin D measurement during the winter or spring months (O.R. 2.79, 95% C.I. 1.35–5.74, p= 0.005) were the only independent predictors of low vitamin D serum levels [[6]Bitetto D. Fattovich G. Fabris C. Ceriani E. Falleti E. Fornasiere E. et al.Complementary role of vitamin D deficiency and IL-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.Hepatol. 2011; 53: 1118-1126Crossref PubMed Scopus (121) Google Scholar]. As the authors evaluated vitamin D serum levels 24 weeks after the end of antiviral therapy, it is inevitable that the season in which the second assessment of the vitamin D serum levels was made can not be the same as that of the first determination. Thus the change in vitamin D serum levels in patients who achieved SVR, observed by Lange et al. [[1]Lange C.M. Bojunga J. Ramos-Lopez E. Wagner M.V. Hassler A. Vermehren J. et al.Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.J Hepatol. 2011; 54: 887-893Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar], may be preferentially due to the season influence rather than to the eradication of HCV infection. Since the time in which antiviral therapy has been started is generally an easily recoverable data, the authors should take into account this important variable in order to confirm the association they found toward a lower prevalence of vitamin D deficiency in patients who achieved SVR. In conclusion, it seems evident that a close interplay between low vitamin D serum levels and HCV chronic infection exists, but, until now, we still do not know what comes first. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.