J Hepatol 2011;54:887-893

The prevalence of hepatitis C virus (HCV) infection in adults over age 40 is 1.29%, and the common HCV genotypes are Ib (40-59%) and 2a (33-52%) in Korea.1,2 The best predictor of long-term response for chronic hepatitis C (CHC) to treatment is sustained virological response (SVR), defined as undetectable serum HCV RNA by PCR assay at 24 weeks after cessation of therapy.3 The standard of choice for HCV treatment is the combination of a pegylated interferon alpha and ribavirin (Peg/RBV). According to Korean data, the response rates to the recommended strategies have been observed to be high compared to Western data, but 20-40% of patients did not achieve an SVR.4-6 Two major predictors of SVR are genotypes and viral load.3 Other baseline predictors include the doses of Peg/RBV, gender, age, race, body weight, and fibrosis stage.3

Recently, two emerged predictors of response to antiviral treatment are interleukin-28B (IL-28B) rs12979860 C/T polymorphism and serum vitamin D concentration. IL-28B polymorphism is associated with SVR, and SVR rates are doubled in patients with the C/C homozygotes compared with the carrier of the T/T or T/C alleles.7,8 However, this polymorphism represents a nonmodifiable factor that predicts SVR, and plays a smaller role in Korean patients due to high frequency of favorable allele.9 Pre-treatment serum vitamin D concentrations affect SVR, and vitamin D deficiency shows low SVR in Peg/RBV treatment.10,11 Clinicians have increasing interest in vitamin D because it is easily modifiable and its supplementation may improve response to antiviral treatment.12 Patients with CHC have higher incidence of severe vitamin D deficiency (25-hydroxyvitamin D, 25(OH)D <10 ng/mL) compared to the normal control (25% versus 12%, P<0.0001).13 The prevalence of vitamin D deficiency (25(OH)D <20 ng/mL) was 47.3% of males and 64.5% of females,14 but there was no report on that in patients with CHC in Korea.

Vitamin D, as a regulatory factor of phosphorus and calcium absorption in intestine and renal reabsorption of calcium, plays a role in calcium metabolism. Through hydroxylation process of liver and kidney, vitamin D from the skin and diet is converted into the major circulating form, 25(OH)D, and then into the active form, 1,25-dihydroxyvitamin D (1,25(OH)D), respectively.15 In relation to vitamin D synthesis in the liver, mild to moderate liver dysfunction causes malabsorption of vitamin D and dysfunction of 90% or more results in inability to make sufficient 25(OH)D.15 Therefore, low vitamin D serum level in patients with CHC is correlated to severity of fibrosis.11 In addition to CHC, 25(OH)D serum level is an independent predictor of risk for cancer, autoimmune disease, cardiovascular disease, and metabolic disease.15

1,25(OH)D is activated by binding with the vitamin D receptors (VDRs), which are found in almost immune cells such as CD4⁺ and CD8⁺ T cells, B cells, neutrophils, and antigen presenting cells, and is an important mediator of innate immune and adaptive immune systems.16 1,25(OH)D enhances chemotactic and phagocytic responses of macrophage as well as induces antimicrobial actions with the upregulation cathelicidin via VDRs.17 At the level of antigen presenting cells (like dendritic cells), 1,25(OH)D decreases antigen recognition by inhibited expression of MHC II molecules and co-stimulatory molecules (CD40, CD80, CD86). Furthermore, by suppressing production of IL-12 and IL-23, which are important Th1 and Th17 development, 1,25(OH)D inhibits the production of Th1 cytokines (IL-2 and IFN-γ) and Th17 cytokines (IL-17 and IL-23). A shift from Th1 to Th2 development stimulates Th2 cytokine production (IL-4). In addition, it induces regulatory T cells via modulation of dendritic cells and regulatory T cells and produce IL-10, which has the ability to interfere the development of the other Th subclasses. Finally, the action of 1,25(OH)D on B cells blocks proliferation, maturation to plasma cells, and immunoglobulin production.16

Petta et al11, by analyzing retrospectively a cohort of 197 patients, detected an association between lower vitamin D serum levels and failure to achieve SVR. Of different isoforms of cytochrome P450 (CYP) involved in vitamin D metabolism, CYP2R1 and CYP27A1 exist in liver and CYP27B1 exists in kidney. Levels of CYP27A1, but not CYP2R1, were directly related to vitamin serum D levels and inversely correlated with necro-inflammation.11 Bitetto et al10 suggested that correction of vitamin D serum levels may play a complementary role to improve SVR in patients with difficult-to-treat HCV genotype and with IL-28B polymorphism. Based on the relationship between follow-up viral response rates and baseline 25(OH)D serum level, Bitetto et al10 suggested that vitamin D plays an important role in early HCV decline after antiviral treatment. In two reports about additional effect of vitamin D on SVR in patients with CHC, Abu Mouth et al18 showed vitamin D supplementation to Peg/RBV treatment significantly improved SVR in naïve genotype 1 patients (86% versus 43%, P<0.001), and Bitetto et al12 showed the increase of SVR to antiviral treatment for recurrent hepatitis C (5/18 versus 5/27, P<0.02). The latter two studies have limited value due to small number of patients.

Together with these studies, Lange et al13 retrospectively analyzed serum vitamin D levels and genetic polymorphisms in 468 naïve patients with CHC. As above mentioned, 25(OH)D is converted to the 1,25(OH)D by 1-α-hydroxylase (CYP27B1) in the kidney and the biological activities of vitamin D are mainly mediated via the VDRs. Unlike other studies,10,11 subjects were investigated about correlation between polymorphisms within genes of vitamin D cascade (VDR and CYP27B-1260 promoter) and serum vitamin D levels.13 Three main findings are as follows. First, in similar to recent reports, the occurrence of vitamin D deficiency was more frequently observed in the patients (66%) than in the controls (41%). In addition, severe vitamin D deficiency was more observed in the patients (25%) than in the controls (12%). Second, pretreatment serum vitamin D level was related to high responsiveness of Peg/RBV treatment in patients with HCV genotype 2/3, but not in patients with HCV genotype 1. This point is different from recent reports. Interestingly, in HCV genotype 1 patients, authors reported a positive association between SVR and 1-α-hydroxylase promoter polymorphism (CYP27B1-1260) and they suggested that 25(OH)D serum levels might not be an optimal predictor of SVR. Therefore, further researches are needed to investigate the effect of vitamin D according to race, polymorphism, and genotypes. Third, SVR rates were significantly higher in patients with CYP27B1-1260 genotype AA or AC compared to CYP27B1-1260 genotype CC (77% and 65% versus 42%, respectively; P=0.02), but VDR polymorphism is not associated with SVR. This study has some limitations due to retrospective data, absence of on-treatment vitamin D serum levels, and absence of potential confounders.

In conclusion, this study showed that the incidence of vitamin D deficiency is high in patients with CHC, vitamin D serum levels is linked to SVR, and a CYP27B-1260 promoter polymorphism is related with poor response to Peg/RBV treatment. To date, there are a few published reports on the role of vitamin D supplementation in patients with CHC and no domestic data on the relationship between vitamin D and CHC. Adding vitamin D to standard interferon therapy may increase SVR rates without serious adverse events. However, to prove these findings, well designed and large prospective studies are needed.