Research Article
Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy

https://doi.org/10.1016/j.jhep.2010.08.036Get rights and content

Background & Aims

Vitamin 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.

Methods

Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2, and 3 infected patients who were treated with interferon-alfa based regimens.

Results

Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D3 <10 ng/ml in 25% versus 12%, p <0.00001). 25(OH)D3 deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p <0.0001). In addition, the CYP27B1-1260 promoter polymorphism rs10877012 had substantial impact on 1,25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p = 0.04) and on SVR rates in HCV genotype 1, 2, and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p = 0.02).

Conclusions

Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYP27B1-1260 promoter polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, and 3 infected patients.

Introduction

Infection with hepatitis C virus (HCV) is a major global health problem that affects approximately 3% of all individuals worldwide. Most of these patients develop a chronic infection that results in various levels of hepatic inflammation and fibrosis. Due to a high risk of disease progression, chronic hepatitis C is a leading cause of liver cirrhosis, hepatocellular carcinoma, and liver transplantation. HCV can be eradicated by treatment with pegylated interferon-alfa and ribavirin with varying success. Infection with different HCV genotypes is a main predictor of virologic treatment response. This is evidenced by sustained virologic response (SVR) rates achieved by standard treatment of only 40–50% in patients infected with genotypes 1 or 4 in contrast to SVR rates of approximately 80% in those infected with genotypes 2 or 3 [1], [2], [3], [4], [5], [6]. In addition to this and other viral parameters [7], there is increasing evidence on the importance of host factors contributing to the high rate of viral persistence as well as to the outcome of antiviral therapy [8], [9], [10], [11]. In particular, innate and adaptive immune mechanisms have been identified to be crucial for spontaneous HCV clearance as well as for the success of antiviral therapy [8], [9], [10], [11], [12], [13], [14], [15]. 1,25-dihydroxyvitamin D, the activated hormonal form of vitamin D, is an important immune modulator that has an impact on innate and adaptive immune pathways [16]. With respect to its immune regulatory function, vitamin D deficiency is associated, for example, with autoimmune diseases, lethality during septic shock, or cancer [17], [18], [19]. The relationship between vitamin D and liver disease is reciprocal. Liver and kidneys are required to activate vitamin D by 25- and 1-alpha-hydroxylation, respectively. Therefore, liver diseases including chronic hepatitis C may be responsible for low serum levels of 25-hydroxyvitamin D (25(OH)D3) [20], [21], [22], [23], [24], [25], [26], [27]. In addition, in a recent study, vitamin D deficiency was associated with poor response to pegylated interferon-alfa and ribavirin in HCV genotype 1 [25]. Furthermore, an in vitro analysis in the replicon model revealed an inhibitory effect of vitamin D on HCV replication [28]. Most of the biological activities of activated vitamin D are mediated via a nuclear vitamin D receptor (VDR), which serves as a ligand-activated transcription factor. Polymorphisms within the VDR gene may, therefore, result in defective gene activation and consecutive impaired effector functions of vitamin D, such as calcium homeostasis, cell differentiation, or immune regulation [29], [30], [31], [32], [33]. In addition, polymorphisms within the promoter region of the 1α-hydroxylase are associated with dysregulated immunity [32], [34], [35], [36].

In the present study, we aimed to determine the incidence of vitamin D deficiency in patients with chronic hepatitis C in Middle Europe. In addition, we evaluated associations of vitamin D serum levels as well as polymorphisms within genes encoding the vitamin D receptor and 1α-hydroxylase with the virologic response of interferon-alfa based treatment in patients chronically infected with HCV genotypes 1, 2, or 3.

Section snippets

Patients

In the present retrospective study, 468 adult treatment-naïve patients, with chronic hepatitis C genotype 1, 2, or 3-infection and without evidence for other liver diseases, were enrolled. All patients lived in Germany. All HCV genotype 1 patients were treated with pegylated interferon-alfa-2a (180 μg/week) plus ribavirin (1000–1200 mg/dl) plus amantadine (n = 154) or placebo (n = 163) for 48 weeks within a randomized controlled clinical trial [37]. A total of 136 HCV genotype 2/3 patients were

Patient characteristics

Epidemiological, clinical, virologic, biochemical, and histological characteristics of 468 patients with chronic hepatitis C are summarized in Table 1. All patients lived in Germany (about 50° north) and approximately 98% of all patients were Caucasian. A total of 317 (68%), 43 (9%), and 108 (23%) out of 468 patients were infected with HCV genotypes 1, 2 or 3, respectively. A total of 68% of all HCV genotype 1 patients and 93% of all HCV genotype 2/3 patients achieved an early virologic

Discussion

The major results of the present study were: (i) a high incidence of (severe) vitamin D deficiency in patients with chronic hepatitis C, (ii) an association of 25-hydroxyvitamin D serum levels with response to therapy with pegylated interferon-alfa plus ribavirin in patients infected with HCV genotypes 2 and 3, and, (iii) a significant correlation of the CYP27B1-1260 promoter polymorphism rs10877012 with 1,25-hydroxyvitamin D serum levels and SVR rates in HCV genotype 1, 2, and 3 infected

Financial support

This study was supported by a BMBF grant “Host and viral determinants for susceptibility and resistance to hepatitis C virus infection” to C.S., E.H., and S.Z., (TP B, TP F), and a DFG grant to C.S., E.H. and S.Z.(Klinische Forschergruppe, KFO 129, TP2, TP1), and by a grant of the European Union to K.B. (EU-FP7 NAIMIT, project No. 241447).

Conflicts of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Author contributions

The authors have contributed to the manuscript by planning the study (CML, CS, SZ, EH, JB, and KB), collecting the data (CML, AH, JV, JB, and ERL), analysis of data (CML, JB, KB, ERL, EH, CS, and SZ), and preparation and revision of the manuscript (all authors).

Acknowledgements

The authors thank Doris Kaerger and Ursula Karey for technical assistance.

References (46)

  • D.L. Thomas et al.

    Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

    Nature

    (2009)
  • V. Suppiah et al.

    IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy

    Nat Genet

    (2009)
  • D. Ge et al.

    Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

    Nature

    (2009)
  • Y. Tanaka et al.

    Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C

    Nat Genet

    (2009)
  • C. Neumann-Haefelin et al.

    Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection

    Hepatology

    (2008 Jun)
  • R. Thimme et al.

    Determinants of viral clearance and persistence during acute hepatitis C virus infection

    J Exp Med

    (2001)
  • R. Thimme et al.

    Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease

    Proc Natl Acad Sci USA

    (2002)
  • Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with...
  • von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor...
  • Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, et al. Association between...
  • P. Lee et al.

    Vitamin D deficiency in critically ill patients

    N Engl J Med

    (2009)
  • J.R. Moro et al.

    Vitamin effects on the immune system: vitamins A and D take centre stage

    Nat Rev Immunol

    (2008)
  • Arteh J, Narra S, Nair S. Prevalence of Vitamin D Deficiency in Chronic Liver Disease. Dig Dis Sci 2009,...
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