Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection
Authors: Steven J. Weintraub
Journal: Journal of Hepatology (2013)

Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infectionJournal of HepatologyVol. 58Issue 3PreviewThe relationship between vitamin D status and response to antiviral therapy and liver histology in hepatitis C virus genotype 1 (HCV-1) infection remains unclear, with studies to date yielding inconsistent results and failing to use reference assay methodology. We therefore analyzed pre-treatment 25-hydroxyvitamin D [25(OH)D] level, using reference liquid chromatography–tandem mass spectrometry methodology, in a cohort of treatment-naïve patients with HCV-1 to evaluate the association between vitamin D status, virologic response, and liver histology. Full-Text PDF Reply to: “Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection”Journal of HepatologyVol. 59Issue 1PreviewWe thank Dr. Weintraub for his in-depth analysis of our paper and the insightful questions he has raised. Our study of 274 patients showing no independent association between baseline 25-hydroxyvitamin D [25(OH)D] status and sustained virologic response (SVR) in chronic hepatitis C genotype 1 (HCV-1) infection [1] was similar to 3 other published studies [2–4] involving 765 patients with HCV-1. Notably, published studies with the contrary finding of an association between baseline 25(OH)D level and SVR in HCV-1 have involved only 448 patients in total, with the largest including 171 patients. Full-Text PDF Open Access In their recent study published in the Journal of Hepatology, Kitson et al. report that vitamin D status does not predict sustained virologic response (SVR) in genotype 1 chronic hepatitis C patients [[1]Kitson M.T. Dore G.J. George J. Button P. McCaughan G.W. Crawford D.H. et al.Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection.J Hepatol. 2013; 58: 467-472Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Their findings are consistent with those of another group [[2]Lange C.M. Bibert S. Kutalik Z. Burgisser P. Cerny A. Dufour J.F. et al.A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C.PloS One. 2012; 7: e40159Crossref PubMed Scopus (49) Google Scholar], but in contrast to the findings of several other studies, in which a correlation between the serum 25-hydroxyvitamin D [25(OH)D] level and rate of attaining an SVR was identified [3Petta 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.Hepatology. 2010; 51: 1158-1167Crossref PubMed Scopus (361) Google Scholar, 4Bitetto 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, 5Bitetto D. Fattovich G. Fabris C. Ceriani E. Falleti E. Fornasiere E. et al.Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/Tpolymorphism in predicting antiviral response in chronic hepatitis C.Hepatology. 2011; 53: 1118-1126Crossref PubMed Scopus (122) Google Scholar, 6Falleti E. Bitetto D. Fabris C. Fattovich G. Cussigh A. Cmet S. et al.Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C.Hepatology. 2012; 56: 1641-1650Crossref PubMed Scopus (60) Google Scholar, 7Weintraub S.J. Fleckenstein J.F. Marion T.N. Madey M.A. Mahmoudi T.M. Schechtman K.B. Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response.Am J Clin Nutr. 2012; 96: 1025-1031Crossref PubMed Scopus (21) Google Scholar]. Kitson et al. argue for the strength of their conclusion and suggest that the correlation between 25(OH)D level and SVR identified in the other studies was secondary to confounding effects. They thereby imply that the 25(OH)D level is not a determinant of treatment outcome. However, they do not address the significant evidence, from clinical, genetic, animal, and cell culture studies, that supports a role for endogenous vitamin D in the treatment response [[8]Gutierrez J.A. Parikh N. Branch A.D. Classical and emerging roles of vitamin D in hepatitis C virus infection.Semin Liver Dis. 2011; 31: 387-398Crossref PubMed Scopus (56) Google Scholar]. In light of this evidence, it would have been prudent for Kitson et al. to have explored the possibility that certain aspects of their study may have obscured evidence of a functional relationship between 25(OH)D level and response to treatment. For example, whereas all of the study populations, in which a correlation between 25(OH)D level and the rate of SVR was identified, were racially homogeneous, the patients in the Kitson et al. study were racially diverse. This is of potential consequence in that there is increasing evidence that there are clinically significant racial differences in vitamin D physiology and some of these may affect genotype 1 chronic hepatitis C treatment outcome (discussed in [[7]Weintraub S.J. Fleckenstein J.F. Marion T.N. Madey M.A. Mahmoudi T.M. Schechtman K.B. Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response.Am J Clin Nutr. 2012; 96: 1025-1031Crossref PubMed Scopus (21) Google Scholar]). In this regard, it is notable that the Asian patients in the Kitson et al. study had lower levels of 25(OH)D, but a higher rate of SVR than the study group as a whole – it is possible that the level of 25(OH)D necessary for an optimal treatment response is lower in Asians when compared to levels required for an optimal treatment response in other groups. This would have attenuated a correlation between 25(OH)D levels and rate of SVR when their entire group of patients was analyzed together. Indeed, there is tangible evidence that there are quantitative differences in the relationship between 25(OH)D and the response to genotype 1 chronic hepatitis C treatment outcome between individual patients. There are alleles of single nucleotide polymorphisms (SNPs) in two different genes in the vitamin D metabolic pathway that increase the physiologic effects of 25(OH)D and these same alleles are also associated with an improved rate of SVR [2Lange C.M. Bibert S. Kutalik Z. Burgisser P. Cerny A. Dufour J.F. et al.A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C.PloS One. 2012; 7: e40159Crossref PubMed Scopus (49) Google Scholar, 6Falleti E. Bitetto D. Fabris C. Fattovich G. Cussigh A. Cmet S. et al.Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C.Hepatology. 2012; 56: 1641-1650Crossref PubMed Scopus (60) Google Scholar, 9Chun R.F. New perspectives on the vitamin D binding protein.Cell Biochem Funct. 2012; 30: 445-456Crossref PubMed Scopus (188) Google Scholar]. This suggests that there is a functional relationship between 25(OH)D level and treatment response in genotype 1 chronic hepatitis C patients. However, because the alleles of these SNPs vary between individual patients, this relationship would be quantitatively different from patient to patient, such that a correlation may not be evident when the relationship between 25(OH)D level and SVR is evaluated among a group of patients. Another characteristic of their study that could have weakened a correlation between 25(OH)D level and treatment response is the liquid chromatography–tandem mass spectrometry methodology that they used to measure 25(OH)D. This assay does not distinguish between 25(OH)D and an epimer of 25(OH)D that is present in variable amounts in most adults, with levels of the epimer exceeding 7.5 nmol/L in 8% of the adults in one large study [[10]Bailey D. Veljkovic K. Yazdanpanah M. Adeli K. Analytical measurement and clinical relevance of vitamin D(3) C3-epimer.Clin Biochem. 2013; 46: 190-196Crossref PubMed Scopus (161) Google Scholar]. The epimer binds to the vitamin D receptor, but it lacks many of the activities of vitamin D [[10]Bailey D. Veljkovic K. Yazdanpanah M. Adeli K. Analytical measurement and clinical relevance of vitamin D(3) C3-epimer.Clin Biochem. 2013; 46: 190-196Crossref PubMed Scopus (161) Google Scholar], so it is likely that the epimer acts as a competitive inhibitor for some of the activities of vitamin D. Therefore, the differences in the relationship between the measured 25(OH)D level [i.e., 25(OH)D plus epimer] and the actual 25(OH)D level could have compromised the conclusions of their study. In contrast, most of the studies, in which a correlation between 25(OH)D level and the rate of SVR was identified, used a 25(OH)D assay that is unaffected by the epimer [4Bitetto 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, 5Bitetto D. Fattovich G. Fabris C. Ceriani E. Falleti E. Fornasiere E. et al.Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/Tpolymorphism in predicting antiviral response in chronic hepatitis C.Hepatology. 2011; 53: 1118-1126Crossref PubMed Scopus (122) Google Scholar, 6Falleti E. Bitetto D. Fabris C. Fattovich G. Cussigh A. Cmet S. et al.Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C.Hepatology. 2012; 56: 1641-1650Crossref PubMed Scopus (60) Google Scholar, 7Weintraub S.J. Fleckenstein J.F. Marion T.N. Madey M.A. Mahmoudi T.M. Schechtman K.B. Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response.Am J Clin Nutr. 2012; 96: 1025-1031Crossref PubMed Scopus (21) Google Scholar, 10Bailey D. Veljkovic K. Yazdanpanah M. Adeli K. Analytical measurement and clinical relevance of vitamin D(3) C3-epimer.Clin Biochem. 2013; 46: 190-196Crossref PubMed Scopus (161) Google Scholar]. Considering the variation in vitamin D physiology between patients and the complexity of measuring vitamin D levels, a lack of a correlation between 25(OH)D level and the rate of SVR among a group of patients should not be interpreted as a lack of importance of vitamin D status in genotype 1 chronic hepatitis C treatment outcome. In the context of the evidence that vitamin D has a functional role as a determinant treatment response [[8]Gutierrez J.A. Parikh N. Branch A.D. Classical and emerging roles of vitamin D in hepatitis C virus infection.Semin Liver Dis. 2011; 31: 387-398Crossref PubMed Scopus (56) Google Scholar], it is important to consider the possibility that the level of 25(OH)D may be important in the response to treatment of an individual genotype 1 chronic hepatitis C patient, but that this may not be apparent when the relationship between 25(OH)D level and the rate of attaining an SVR is analyzed among a group of patients. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this letter.