| Background and ObjectionHepatitis C virus (HCV) is one of the major causes of chronic liver disease and the patients frequently progress to cirrhosis and hepatocellular carcinoma (HCC). It has estimated that approximately1.3-1.7billion people, representing2%-3%of the world’s population are infected with HCV? Once infected,50%-85%patients will progress to chronic hepatitis C, Some published reports suggest that about15%of chronic hepatitis C developing cirrhosis at20years after infection. Whereas HCC occurs in this population at an estimated incidence of1-5%per year. Patients diagnosed with HCC have a3.3%probability of death during the first year.The goal of therapy is to prevent the complications of HCV-related liver disease, including fibrosis, cirrhosis, HCC, and death. A number of items appear to have a significant impact on the likelihood of progression of chronic liver disease. These include antiviral therapy, age, sex, alcohol consumption, viral factors, Hepatic steatosis, and coinfections and so on.The combination therapy of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current standard of care for patients with chronic hepatitis C. Unfortunately, approximately35%of patients infected with hepatitis C virus are resistant to this treatment regimen. Achieving SVR can not only reduce the incidence of liver cirrhosis and liver cancer, some patients can even cured. Therefore, all treatment-naive patients with compensated chronic liver disease related to HCV who are willing to be treated and have no contraindication to pegylated IFN or ribavirin should be considered for therapy. Two protease inhibitors, telaprevir and boceprevir have recently been be approved by the FDA and the EMA. However, due to the time difference of drug approval, the expensive of funds and Chinese patients treated with pegylated interferon plus ribavirin have high efficacy, therefore the treatment of chronic hepatitis C with SOC program will still last a long time in China.Several factors seem to influence the curative effect of standard treatment for CHC patients. Among them, HCV genotype results are the most important baseline factor. SVR rates after SOC are about40%-50%in patients with genotype1or4and80%in patients with genotype2or3. IL-28(interferon lambda3) gene polymorphism is also an important virological factor. Many studies demonstrate that IL-28B rs12979860CC genotype and rs8099917TT genotype are associated with sustained virological response to treatment with pegylated interferon alpha in combination with ribavirin in patients infected with HCV genotype lor4.Age is one of the most important risk factor for fibrosis progression in chronic HCV infection. The development of HCV related liver cirrhosis seems to be a dynamic process, which accelerates exponentially with increasing age. A higher rate of spontaneous viral clearance in patients younger than40years or female patients has been described in chronic hepatitis C. Patients over the age of40and men are easily to develop cirrhosis and liver cancer.Transfusion infected with hepatitis C virus generally develop faster, sexually transmitted infections were better prognosis. This may be a post-transfusion hepatitis C virus enters the amount of virus in the body more relevant.Excessive alcohol consumption is clearly an independent, major cause for liver cirrhosis. Alcohol can promote the proliferation of hepatitis C virus in human liver cells, exacerbate viremia and interfere with the anti-viral activity of IFN-a. On the other hand, coffee consumption may have beneficial effects on the overall mortality in population-based studies. Freedman, et al. were also able to show that a higher coffee consumption correlates with a lower grade of liver fibrosis as well as steatosis, insulin resistance and lower ALT levels with the best outcome in individuals drinking three or more cups per day.Hepatic steatosis is a histological hallmark of chronic hepatitis C. Several studies showed that steatosis is linked to the stage of liver fibrosis in patients with chronic HCV infection. Yet, there are some results show that HCV infection itself can trigger hepatic steatosis as well as nonalcoholic steatohepatitis (NASH). HCV infection may cause insulin resistance, which is an important risk factor for NASH. However, there are also some hints for a direct association between HCV and hepatic steatosis. The most obvious link exists between HCV genotype3infection and steatosis. HCV genotype3infection was identified as a remarkable risk factor for steatosis. In contrast, in chronic infection with HCV genotype3the link between liver fibrosis and hepatic steatosis is less clear.Viral factors have also been discussed to be associated with disease progression in hepatitis C. Indeed, differences in the natural history of hepatitis C were reported for different HCV genotypes. Several recent studies described an accelerated disease progression in patients infected with genotype3, which would be in line with higher mortality rates in patients with this HCV genotype. Flares of hepatitis seem to occur more frequently in HCV genotype2infection, which could also translate more severe courses of liver disease. In contrast, viral load is not related to the degree of liver fibrosis or liver damage.ALT elevated liver transaminases are widely used as a surrogate for ongoing intrahepatic inflammation. Therefore it is not surprising that elevated serum levels of ALT during chronic hepatitis C are associated with an increased risk of liver fibroses progression. Lower progression rates of fibrosis were reported in patients with normal ALT levels. However, normal liver enzymes do not exclude the possibility of fibrosis progression.Co-infection with other hepatitis virus, AIDS, schistosomiasis and fatty liver will accelerate the process of liver disease. Using hepatotoxic drugs or exposure to toxic substances also exhibits higher rates of progression to cirrhosis. In addition to the factors mentioned above, recent studies have shown that vitamin D may also have a significant impact on the likelihood of progression of chronic liver disease; vitamin D deficiency may lead to the treatment of chronic hepatitis C non-responders, and are also associated with progressive fibrosis and severe inflammation of the liver.Vitamin D deficiency is very common (92%) among patients with chronic liver disease, and at least one-third suffer from severe vitamin D deficiency (<12ng/mL). Two small prospective study in Israel showed that HCV genotype1or2/3patients treated with Peg-IFN/RVB, supplementing the vitamin level D to>32ng/mL increased the response to antiviral therapy to the same extent in patients with vitamin D deficiency as well as those with vitamin D insufficiency. Researching Forty-two consecutive patients treated for recurrent hepatitis C (RHC) with combination therapy with INF and ribavirin for48weeks, Bitetto D, et al. found that patients who received oral vitamin D3supplementation (cholecalciferol800IU/day) have higher SVR rate compared with those who did not supplement with cholecalciferol. In vitro studies showed that25-dihydroxyvitamin D could directly suppress hepatitis C virus assembly, and improve antiviral therapy effect. These all suggest that vitamin D may play an important role in chronic hepatitis C antiviral treatment.Consecutively evaluated179patients with biopsy-proven genotype1(G1) CHC and49healthy subjects matched by age and sex, Petta, et al. observed a significant trend in25(OH)D levels reduction with increasing stage of fibrosis, offered the first evidence that low25(OH)D serum levels, together with known risk factors for fibrosis severity, such as older age, low cholesterol levels, and high necroinflammatory activity, are independently associated with the presence of severe fibrosis. Analyzed25(OH) D statuses in712Caucasian patients with chronic liver diseases of mixed etiology and fibrosis stages. Grunhage, et al. demonstrated that serum25(OH)-vitamin D levels were inversely correlated with liver stiffness and histology, and speculated that the observed stiffness differences indicating a stronger influence of25(OH)-vitamin D on initiation rather than progression of hepatic fibrosis. However, a study in2013found that baseline25(OH)D level is not independently associated with SVR or fibrosis stage in HCV-1. Ladero, et al. also found that Vitamin D deficiency is related neither to biochemical and virological variables nor with the fibrosis stage. Vitamin D therapy has no immediate effect on HCV-RNA serum levels.Vitamin D is either synthesized in the skin following exposure to ultraviolet B radiation or ingested with the diet; in the organism it is then stored in fat cells. Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcidiol. Circulating calcidiol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys. Following the final converting step in the kidney, calcitriol (the physiologically active form of vitamin D) is released into the circulation. By binding to vitamin D-binding protein (VDBP), a carrier protein in the plasma, calcitriol is transported to various target organs. In addition to the kidneys, calcitriol is also synthesized by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders by stimulating the innate immune system.Vitamin D has long been recognized as essential to the skeletal system. It has been documented that Vitamin D plays a series of non-classical actions such as anti-proliferative, pro-differentiation, pro-apoptotic, anti-inflammatory, and immunoregu-lator activity.The nuclear of antigen presenting cells (APC) expressing VDR, mediated by VDR,1,25(OH)2D3can significantly decrease histocompatibility complex (MHC-Ⅱ) costimulatory molecules and molecules expression in monocyte.1,25(OH)2D3affect dendritic cells (dendritic cells, DCs) in all of the major life-cycle stages, including obstruct the differentiation of monocytes into DCs, prevent differentiation of immature DCs to mature DCs, down regulation of major MHC-Ⅱ molecules and costimulatory molecules CD40, and reduce DCs secrete IL-12and IL-10production.Resting T-cells express almost undetectable levels of VDR, but levels of the receptor increase as T-cells proliferate following antigenic activation. T cell-mediated immunity regulated by1,25(OH)2D3, vitamin D deficiency or excess will inhibit T cell-mediated immunity. Lemire and colleagues reported that1,25(OH)2D3preferentially inhibited T-helper1(Thl) cells, Thl-type cytokines IL-2and IFN-y have been shown to be the directly target of1,25(OH)2D3.1,25(OH)2D3can inhibit the secretion of IL-2by preventing the IL-2transcription factor Activity and the form of nuclear factor of activated T cells complex. At the same time,1,25(OH)2D3can increase the activity Th2cells and regulatory T cell, promoting Th2bias when the CD4+T cell differentiation, namely1,25(OH)2D3can regulate Thl/Th2immune deviation.The anti-inflammation effect of vitamin D is related with its anti-immune effect. It can inhibit Thl response, reduce the product of pro-inflammatory cytokines such as IL-2and IFN-y; meanwhile it can also enhance the function of Th2, and promote the secretion of anti-inflammatory cytokines such as IL-6, IL-4, IL-5, and IL-10.Clinical and experimental studies have suggested that25(OH) D and1,25(OH) D could potentially interfere with fibrogenesis. Hepatic stellate cell (HSCs) activation is the key to liver fibrosis, Vitamin D was shown to reduce the expression and the proliferation of Hepatic stellate cells. Under TGFβ1stimulation,1,25(OH) D inhibits the pro-fibrotic phenotype of lung fibroblasts and epithelial cells. Vitamin D insufficiency was found to be associated with increased circulating MMP2and MMP9, and enhance of collagenolytic.Recently, Targher, et al. observed lower25(OH)D serum levels in patients with biopsy-proven nonalcoholic fatty liver disease, identifying an independent association between the histological characteristics of nonalcoholic fatty liver disease and low25(OH)D levels. Experimental evidence also suggested the potential ability of vitamin D, through interaction with its nuclear receptor (vitamin D receptor), to interfere with inflammatory response and fibrogenesis.To further address these questions, we conducted an updated systematic review and meta-analysis to comprehensively assess serum level of vitamin D to verify whether baseline vitamin D have any independent role in predicting the rates of HCV virologic response after antiviral therapy, and whether circulating vitamin D has any association with the degree of fibrosis in CHC patients.Part1:The relationship between baseline Vitamin D levels and sustained virological response in patients with chronic hepatitis CMethodsRelevant studies were identified by systematically searching PubMed, Web of Science, EMBASE, The Cochrane Library and the Chinese Medical databases (CBM, CNKI and VP). Studies mentioned chronic hepatitis C patients treated with Pegylated interferon and Ribavirin and tested for levels of baseline vitamin D were included. We evaluated the differences of baseline vitamin D levels between the SVR groups and the non SVR groups.ResultsAfter the first phase,210references were found out. After the second round of screening, only5references were included in the primary analysis. Meta-analysis was performed with software Stata12using the random effects model. The results shows that the WMD of baseline vitamin D levels of the SVR group and the non SVR group is6.759(95%CI:1.786,11.733). The baseline vitamin D in the SVR group were significantly higher than that in the non SVR group (Z=2.66, P=0.008).ConclusionThe baseline vitamin D levels were related to SVR in chronic hepatitis C patients with genotypes1or4. Therefore, for HCV genotypes1or4patients, supplement of vitamin D before treatment may achieve better therapeutic effect.Part2:The relationship between Vitamin D levels and liver fibrosis in patients with chronic hepatitis CMethodsRelevant studies were selected and identified by systematically searching PubMed, Web of Science, EMBASE, and The Cochrane Library. The inclusion criteria were:clinical studies that included HCV infected patients aged older than18years regardless of HCV genotype or ethnic group; provided information on fibrosis diagnosis of liver; and were reported in the English language as full papers. Meta-analysis was performed to assess associations between25(OH) D and liver fibrosis.Results707potentially eligible citations records were identified and six articles were included. All six articles reported the relationship between fibrosis stage and vitamin D, and four different methods were employed for confirmation of the histological diagnosis of liver fibrosis. We converted all other measurements into METAVIR System and classified study participants as mild fibrosis if the METAVIR System was F0-F2, or advanced fibrosis if the METAVIR score was F3/F4. The meta analysis shown that the vitamin D level in mild fibrosis subjects was significantly higher (WMD:3.627,95%CI:2.476-4.778) than that in advanced fibrosis subjects (Z=6.18, P=0.000).ConclusionOur results demonstrated that there was a significant correlation between low serum25(OH)D levels and severe liver fibrosis in CHC patients, and suggested vitamin D might play a role in hepatic fibrogenesis in CHC patients. As there is no specific treatment available for liver fibrosis to date, because of no serious side effects and easily administered, vitamin D supplement may provide a new direction for the anti-fibrotic therapy. |
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