Evidence supporting a beneficial role of vitamin D in chronic hepatitis C
Authors: Qing Pang, Kai Qu, Jing-Yao Zhang, Chang Liu
Journal: Journal of Hepatology (2015)

Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: A systematic review and meta-analysisJournal of HepatologyVol. 61Issue 6PreviewThe baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. Full-Text PDF Reply to: “Evidence supporting a beneficial role of vitamin D in chronic hepatitis C”Journal of HepatologyVol. 63Issue 2PreviewWe thank Pang et al. for their interest in our recently published systematic review and meta-analysis involving 2605 patients which found no association between baseline 25-hydroxyvitamin D level and sustained virologic response (SVR) to interferon-based antiviral therapy in chronic hepatitis C infection [1]. They are correct to highlight the influence of ethnicity on both vitamin D status and genetic polymorphisms in key proteins involved in vitamin D synthesis. The studies included in our meta-analysis contained only a small number of participants of Asian [2] or African-American [3] ethnicity, leading us to highlight the study’s inability to adjust for ethnicity as one of its limitations. Full-Text PDF Open Access We read with interest the recent meta-analysis by Kitson et al. [[1]Kitson M.T. Sarrazin C. Toniutto P. Eslick G.D. Roberts S.K. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.J Hepatol. 2014; 61: 1247-1252Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. The authors show that baseline vitamin D level is not associated with sustained virologic response (SVR) to pegylated interferon (PegIFN) plus ribavirin therapy in patients with chronic hepatitis C (CHC). Based on this finding, they question [[1]Kitson M.T. Sarrazin C. Toniutto P. Eslick G.D. Roberts S.K. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.J Hepatol. 2014; 61: 1247-1252Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] the non-skeletal benefits of vitamin D supplements, an essential determinant in regulating bone metabolism in chronic liver disease [[2]Yurci A. Kalkan A.O. Ozbakir O. Karaman A. Torun E. Kula M. et al.Efficacy of different therapeutic regimens on hepatic osteodystrophy in chronic viral liver disease.Eur J Gastroenterol Hepatol. 2011; 23: 1206-1212Crossref PubMed Scopus (16) Google Scholar], on CHC. However, as vitamin D deficiency has been identified as a main risk factor for CHC development, we believe that the non-skeletal benefits of this kind of vitamin on patients with CHC cannot be negligible and the conclusions of this meta-analysis [[1]Kitson M.T. Sarrazin C. Toniutto P. Eslick G.D. Roberts S.K. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.J Hepatol. 2014; 61: 1247-1252Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] needs to be further discussed and researched. First, the studies included in the meta-analysis by Kitson et al. [[1]Kitson M.T. Sarrazin C. Toniutto P. Eslick G.D. Roberts S.K. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.J Hepatol. 2014; 61: 1247-1252Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar] were performed in patients from America, Europe, Australia, or Israel, all of whom were predominantly white in skin color. Interestingly, a community-based cross-sectional study showed that, compared with white people, blacks had lower levels of vitamin D and vitamin D-binding protein [[3]Powe C.E. Evans M.K. Wenger J. Zonderman A.B. Berg A.H. Nalls M. et al.Vitamin D-binding protein and vitamin D status of black Americans and white Americans.N Engl J Med. 2013; 369: 1991-2000Crossref PubMed Scopus (816) Google Scholar]. In addition, potential differences were also observed between whites and blacks in relation to the influence of vitamin D status in the degree of hepatic fibrosis in CHC patients [[4]White D.L. Tavakoli-Tabasi S. Kanwal F. Ramsey D.J. Hashmi A. Kuzniarek J. et al.The association between serological and dietary vitamin D levels and hepatitis C-related liver disease risk differs in African American and white males.Aliment Pharmacol Ther. 2013; 38: 28-37Crossref PubMed Scopus (8) Google Scholar]. As a consequence, levels of vitamin D and its benefits may vary in individuals with different ethnicity, therefore the irrelevance between vitamin D and SVR, and the ineffectiveness of vitamin D in CHC shown in this study, needs to be also confirmed in other races. Second, this meta-analysis only summarized eleven studies, seven of which, with 1951 patients, were published articles and the other four were conference abstracts with less convincing evidence. Among the eleven studies, the sole outlier, identified by funnel and forest plots, belonged to a conference abstract. Another coexisting meta-analysis with eleven full-text studies demonstrated that a lower level of vitamin D was significantly associated with a lower probability of SVR in CHC patients receiving Peg-IFNα/ribavirin therapy, especially when a cut-off value of 20 ng/ml for vitamin D deficiency was adopted [[5]Garcia-Alvarez M. Pineda-Tenor D. Jimenez-Sousa M.A. Fernandez-Rodriguez A. Guzman-Fulgencio M. Resino S. Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis.Hepatology. 2014; 60: 1541-1550Crossref PubMed Scopus (67) Google Scholar]. Furthermore, a low vitamin D status was also found to be associated with a higher risk of advanced liver fibrosis in these patients [[5]Garcia-Alvarez M. Pineda-Tenor D. Jimenez-Sousa M.A. Fernandez-Rodriguez A. Guzman-Fulgencio M. Resino S. Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis.Hepatology. 2014; 60: 1541-1550Crossref PubMed Scopus (67) Google Scholar]. Numerous clinical evidence also suggested that vitamin D supplementation might protect against disease progression and elevate the SVR rate following treatment for CHC [6Villar L.M. Del Campo J.A. Ranchal I. Lampe E. Romero-Gomez M. Association between vitamin D and hepatitis C virus infection: a meta-analysis.World J Gastroenterol. 2013; 19: 5917-5924Crossref PubMed Scopus (73) Google Scholar, 7Rahman A.H. Branch A.D. Vitamin D for your patients with chronic hepatitis C?.J Hepatol. 2013; 58: 184-189Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Recurrence of hepatitis C after liver transplantation is universal worldwide [[8]Bitetto D. Fabris C. Fornasiere E. Pipan C. Fumolo E. Cussigh A. et al.Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.Transpl Int. 2011; 24: 43-50Crossref PubMed Scopus (124) Google Scholar]. In addition to its association with primary CHC, vitamin D insufficiency could also result in a low SVR in patients with recurrent hepatitis C following antiviral therapy while vitamin D supplementation significantly improves the probability of achieving a SVR [[8]Bitetto D. Fabris C. Fornasiere E. Pipan C. Fumolo E. Cussigh A. et al.Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.Transpl Int. 2011; 24: 43-50Crossref PubMed Scopus (124) Google Scholar]. Potential mechanisms that link vitamin D and CHC are complex and varied. Treatment with vitamin D reduces the extra- and intracellular levels of hepatitis C virus (HCV) core antigen in a dose-dependent manner [[9]Matsumura T. Kato T. Sugiyama N. Tasaka-Fujita M. Murayama A. Masaki T. et al.25-Hydroxyvitamin D3 suppresses hepatitis C virus production.Hepatology. 2012; 56: 1231-1239Crossref PubMed Scopus (62) Google Scholar] and produces calcitriol which could markably inhibit HCV productions [[10]Gal-Tanamy M. Bachmetov L. Ravid A. Koren R. Erman A. Tur-Kaspa R. et al.Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes.Hepatology. 2011; 54: 1570-1579Crossref PubMed Scopus (147) Google Scholar], suggesting that vitamin D plays a natural antiviral role. In addition, the anti-inflammatory effects by reducing several pro-inflammatory factors like TNF-α, IFN-γ, and IL-17, as well as the anti-fibrotic role of vitamin D [[7]Rahman A.H. Branch A.D. Vitamin D for your patients with chronic hepatitis C?.J Hepatol. 2013; 58: 184-189Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar], might also partly explain the benefits of this vitamin supplementation in CHC. As there is a global high prevalence of hypovitaminosis D among CHC patients, it is crucial to determine the association between vitamin D status/vitamin D supplementation and outcomes of CHC. Larger, random clinical trials are still required to confirm the important non-skeletal effects of vitamin D in patients with CHC. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.