Tuesday, September 24, 2013

Association between vitamin D and hepatitis C virus infection: A meta-analysis

Published online 2013 September 21. doi: 10.3748/wjg.v19.i35.5917.
Association between vitamin D and hepatitis C virus infection: A meta-analysis
Livia Melo Villar, José Antonio Del Campo, Isidora Ranchal, Elisabeth Lampe and Manuel Romero-Gomez.

Abstract & Discussion Only
Full Text Available @ World J Gastroenterol

AIM: To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and sustained virological response (SVR) in hepatitis C virus (HCV) infected individuals.

METHODS: Relevant studies were identified by systematically searching MEDLINE databases up to March 2012 and abstracts of the European and American Congress of Hepatology conducted in 2011. Studies must provide information on SVR and the levels of 25(OH)D3 and/or 25(OH)D2 [henceforth referred to as 25(OH)D] in sera samples from HCV infected individuals. The inclusion criteria were: clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group; provided information on SVR rates; and were reported in the English language as full papers. Due to the heterogeneity of studies in categorizing serum vitamin D levels, a cut-off value of 30 ng/mL of serum 25(OH)D was used. Heterogeneity was assessed using I2 statistics. The summary odds ratios with their corresponding 95%CI were calculated based on a random-effects model.

RESULTS: Overall, 11 studies (8 observational and 3 interventional) involving 1575 individuals were included and 1117 HCV infected individuals (71%) showed low vitamin D levels. Most of the studies included mono-infected HCV individuals with the mean age ranging from 38 to 56 years. Four studies were conducted in human immunodeficiency virus/HCV infected individuals. Regarding vitamin D measurement, most of the studies employed radioimmunoassays (n = 5) followed by chemiluminescence (n = 4) and just one study employed high performance/pressure liquid chromatography (HPLC). Basal vitamin D levels varied from 17 to 43 ng/mL in the studies selected, and most of the HCV infected individuals had genotype 1 (1068/1575) with mean viral load varying from log 4.5-5.9 UI/mL. With regard to HCV treatment, most of the studies (n = 8) included HCV individuals without previous treatment, where the pooled SVR rate was 46.4%. High rates of SVR were observed in HCV individuals with vitamin D levels above 30 ng/mL (OR = 1.57; 95%CI: 1.12-2.2) and those supplemented with vitamin D (OR = 4.59; 95%CI: 1.67-12.63) regardless of genotype.

CONCLUSION: Our results demonstrated high prevalence of vitamin D deficiency and high SVR in individuals with higher serum vitamin D levels or receiving vitamin D supplementation.

Received December 14, 2012; Revised January 31, 2013; Accepted February 9, 2013;
Published online 2013 September 21. doi: 10.3748/wjg.v19.i35.5917.

Discussion Only

Our review and meta-analysis summarize the results of eleven studies, which included a total of 1575 cases with hepatitis C, where basal 25(OH)D levels and 25(OH)D supplementation were associated with SVR in HCV patients. This updated review confirms and extends earlier results of a systematic review conducted by Cholangitis[6], who reported that vitamin D deficiency is very frequent before liver transplantation and ranges between 51% and 92%, whereas, in the liver transplantation setting, the prevalence of vitamin D deficiency is also high.

Vitamin D is metabolized by the liver and converted to 1,25-dihydroxyvitamin D3, which is the active form of the vitamin[29,30]. Individuals with chronic liver disease may have poor conversion from vitamin D3 or any of its other biologically active metabolites[31]. Severe liver disease may increase the risk of vitamin D deficiency and/or there might be a relationship between vitamin D deficiency and fibrosis. Putz-Bankuti et al[32] and Baur et al[33] also showed that low levels of 25(OH)D are associated with fibrosis and suggested that low 25(OH)D levels may predict hepatic decompensation and mortality in patients with chronic liver failure. More recently, Gal-Tanamy et al[34] showed that vitamin D3 increased the expression of the VDR and inhibited viral replication in cell culture.

Due to the observation of vitamin D deficiency in chronic liver disease patients, some studies have been conducted to evaluate vitamin D supplementation in these patients[20,26,27]. In some of these studies, it is reported that higher sunlight exposure or vitamin D supplementation should be recommended in patients with CHC[20,26,27]. In the present meta-analysis, vitamin D supplementation was related to higher SVR rates in HCV infected individuals, where the highest level was observed among genotype 1 HCV infected individuals. Although only a few studies regarding vitamin D supplementation fulfilled the eligibility criteria, different patterns were observed. The first study included only genotypes 2 and 3, the second included only genotype 1 and the third study involved genotypes 1, 2 and 3. Moreover, two of these studies were prospective and one was retrospective. Some limitations of these studies included the small number of patients, lack of vitamin D level assessment during therapy in the treatment and control groups, the design of prospective and randomized studies which were not placebo-controlled in one study[27], and the retrospective design of the study where immunocompromised HCV patients were supplemented with low-dose vitamin D (800 IU/d) after liver transplantation and most of the HCV patients (75%) had low vitamin D levels despite treatment[20].

In this meta-analysis, the levels of vitamin D were also associated with SVR, although different methods of vitamin D determination were used. Lai et al[8] demonstrated bias and variability in 25(OH)D measurements between laboratories and between different assays [quimioluminescence and liquid chromatography-tandem mass spectrometry (LC-MS/MS)] which can significantly affect clinical decision-making. In this situation, the adoption of common standards to allow assay calibration is urgently required.

Our study is the first meta-analysis of serum 25(OH)D levels and HCV infection in observational and interventional studies. Given the very small numbers of studies available to date, additional studies, ideally from different countries and populations are needed to assess potential differences in the associations between 25(OH)D and SVR for HCV. Large differences can be observed in different populations, depending on exposure to sunlight or vitamin D supplementation, and genetic differences[23]. Moreover, patients of African and Hispanic descent are less likely to respond to standard therapy[23] probably due to polymorphisms of the interleukin (IL)-28B gene, polymorphism of the VDR or vitamin D deficiency[17,35,36]. In this meta-analysis, all the individuals were Caucasian and most lived in Europe, which could explain vitamin D deficiency in this population resulting from possible low exposure to sunlight.

Meta-analysis is an important tool for revealing trends that may not be apparent in a single study. Pooling of independent, but similar studies increases precision and therefore the confidence level of the findings. A particular strength of our study is the application of advanced statistical techniques which allowed a summary of adjusted associations across studies and over the entire range of serum 25(OH)D values, despite the very heterogeneous categorization of 25(OH)D levels in the individual studies. Our study also has important limitations. First, as data on serum 25(OH)D in individuals were not available in each study, median, midpoints and mean of the groups were used for pooling. As a result, estimates of risk may have been less accurate than if data points on each individual had been used. Second, our meta-analysis was limited by the data provided in the individual studies, and although the authors tried to obtain the raw data from the articles, not all were available. Finally, although our review searched the MEDLINE database, recent Congress of Hepatology and Gastroenterology articles, and extensive checks for completeness by cross-referencing were employed, we cannot exclude the possibility that relevant studies may have been missed.
Despite its limitations, our review and meta-analysis support previous suggestions and provide the most comprehensive empirical evidence to date that basal serum 25(OH)D levels and vitamin D supplementation improves SVR in HCV infected individuals. However, available data are still sparse and in-depth analyses of these associations, in the context of additional longitudinal and prospective studies, are highly desirable to enable more precise estimates and a better understanding of the role of vitamin D in HCV infection.

Full Text Available @ World J Gastroenterol

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