Association between serum vitamin D and severity of liver fibrosis in chronic hepatitis C patients: a systematic meta-analysis

Association between serum vitamin D and severity of liver fibrosis in chronic hepatitis C patients: a systematic meta-analysis 慢性丙型肝炎患者的血清维生素D与严重肝纤维化相关性研究：系统性的荟萃分析 1 2 3 first-author 1 1 3 1 3 1 3 1 3 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:cxiang@zju.edu.cn †E-mail:cxiang@zju.edu.cn cxiang@zju.edu.cn State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China To conduct a systematic review of group studies assessing the association of serum vitamin D status with the severity of liver fibrosis in chronic hepatitis C patients using meta-analysis. The relevant research literatures were identified by searching PubMed and EMBASE databases prior to October 2013 with no restrictions. We included group studies that reported odds ratio (OR) estimates with 95% confidence intervals (CIs) or a mean with standard deviation (SD) for the association between serum vitamin D status and the severity of liver fibrosis in chronic hepatitis C patients. Approximately 8321 participants from several countries were included in this analysis. Six studies on serum vitamin D status and the severity of liver fibrosis were included in this meta-analysis. ORs with 95% CIs were extracted from four studies and the pooled ORs were 0.866 (95% CI, 0.649 to 1.157). The means with SDs were extracted from three studies and the pooled means were −0.487 (95% CI, −0.659 to −0.315). There was statistically significant heterogeneity among the mean data extracted studies ( P =0.029; I 2 =71.8%) but not among the OR data extracted studies ( P =0.061; I 2 =55.6%). Finally, results from the mean data extracted studies suggest that lower serum vitamin D is a risk factor for the severity of liver fibrosis in chronic hepatitis C patients. However, there is no conclusive evidence on this association because of inconsistencies between the OR data extracted studies and the mean data extracted studies. 研究目的 2 利用meta分析方法来探索慢性丙型肝炎患者低血清维生素D水平与严重肝纤维化相关性。 创新要点 2 丙型病毒性肝炎病人的低血清维生素D水平与严重肝纤维化并不一定有相关性。 研究方法 2 结合已发表的临床研究数据，采用荟萃分析方法，定量分析低血清维生素D水平与慢性丙型肝炎患者严重肝纤维化相关性（图2；表2）。 重要结论 2 此荟萃分析对于认识丙型肝炎病人低血清维生素D水平与肝纤维化严重程度的相关性有重要意义，对未来相关临床研究具有指导意义。 Vitamin D Fibrosis Hepatitis C virus Meta-analysis 维生素D 纤维化 丙型病毒性肝炎 荟萃分析 Introduction 1 It is reported that there are 120–180 million hepatitis C virus (HCV) carriers around the world, with the worldwide prevalence estimated at 3% (Shepard et al., 2005 2005 ; Tong et al., 2012 2012 ). Chronic hepatitis C is considered to be a major cause of liver disease, including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma (Hoofnagle, 2002 2002 ; Shepard et al., 2005 2005 ; Thomas and Seeff, 2005 2005 ; Micallef et al., 2006 2006 ; Zhu et al., 2014 2014 ). The risk factors like older age, consumption of alcohol, metabolic alterations, liver necroinflammation, duration of infection and viral co-infections (Poynard et al., 2003 2003 ), and insulin resistance (Romero-Gómez et al., 2005 2005 ) can influence the degree of liver fibrosis. More and more evidence also shows that vitamin D status is very important for the liver disease severity in patients who are infected with chronic hepatitis C (Terrier et al., 2012 2012 ; Kitson et al., 2013 2013 ; Ladero et al., 2013 2013 ; Lange et al., 2013 2013 ). 25-Hydroxyvitamin D or 25(OH) D is a metabolite of vitamin D in liver, and is exported to combine with vitamin D binding protein (VDBP). Because the half-life of serum 25(OH) D is long, the serum concentration of 25(OH) D is the most commonly used biomarker for vitamin D status (Wang et al., 2004 2004 ; Stokes et al., 2013 2013 ). Vitamin D plays an important role not only in maintenance of skeletal health, but also in the immune response, wound healing and many other important physiological functions (Cholongitas et al., 2012 2012 ). 1,25-Dihydroxyvitamin D also plays an important role for innate and adaptive immune pathways (von Essen et al., 2010 2010 ). Recently, studies have reported that the 25(OH) D level decreased in patients with various forms of chronic liver disease and advanced fibrosis (Arteh et al., 2010 2010 ; Geier, 2011 2011 ). A lower serum 25(OH) D level significantly correlates with an increasing risk of advanced fibrosis and a higher severity of necroinflammatory activity has been related to different populations with individuals infected with chronic hepatitis C (Lange et al., 2011 2011 ; 2013 2013 ; Kitson et al., 2013 2013 ; Petta et al., 2013 2013 ). However, the results are not consistent in different studies and by race (Kitson et al., 2013 2013 ; White et al., 2013 2013 ). Taking into account that a single study may have been insufficient to detect the overall effects that vitamin D can have on populations with different genetic backgrounds, the accumulated data from different studies and quantitative synthesis were thought to be very important in providing evidence of the association of serum vitamin D levels and the severity of liver fibrosis in the patients who are infected with HCV. So, we carried out this meta-analysis on all published studies to estimate the overall effects of serum vitamin D levels and the severity of liver fibrosis. The heterogeneity between the individual studies and the potential publication bias was also evaluated. This meta-analysis is different from that reported by Villar et al. ( 2013 2013 ), which focused on the association between 25(OH) D and sustained virological response (SVR) in HCV-infected individuals. Materials and methods 1 Literature search strategy 2 We conducted a literature search of available materials prior to October 2013 in the PubMed and EMBASE databases without restrictions. The search items were “vitamin D or 25(OH) D” and “HCV or chronic hepatitis C or chronic liver disease”. The search results also included articles reviewed ahead of publication. Moreover, the references cited by the selected articles and published reviews were scanned for additional relevant studies. We also contacted the authors for additional information if necessary. Eligibility criteria 2 Studies were included in the meta-analysis if they met the following standards: (1) the association between the severity of liver fibrosis and the blood (plasma or serum) vitamin D or 25(OH) D status was evaluated; (2) the results showed interest and relevance to the fibrosis stage of the patients infected with HCV; (3) the results provided the odds ratio (OR) with 95% confidence intervals (CIs) or a mean with standard deviation (SD) or adequate information to calculate them. Abstracts, conference proceedings, case reports, reviews, patients co-infected with HIV, and repeated literatures were excluded. The most complete studies were those selected in which there were several studies available from the same investigators. Data extraction 2 All data from the included studies were independently extracted by two authors. Any disagreements were resolved by discussions according to the selection criteria guidelines. Finally, the data for this meta-analysis were made available from six studies. The following data were extracted: name of the first author, publication year, ethnic background, participant sex and age, sample size (cases and controls or group size), fibrosis stage, measure of vitamin D, OR estimates with 95% CIs, or mean with SD (all of the data are shown in Table 1 1 ). Data are expressed as mean±SD or mean (range) Study quality was judged on the basis of the Newcastle-Ottawa scale (1–9 stars) n c : number of cases; n p : number of participants; M: male; F: female; CHARIOT: collaborative group hepatitis C study using high-dose Pegasys RBV induction dose in genotype one; HPLC: high performance liquid chromatography; LC: liquid chromatography; MS: mass spectrometry; G1, 2, 3, 4: hepatitis C genotype 1, 2, 3, or 4 infection; NA: not available Source Ethnic background Study Sex Age (year) 1 1 n c n p Study quality 2 2 Measure of vitamin D Petta et al., 2013 2013 Italy Consecutive M/F 52.8±11.9 74 260 7 Chromosystem reagent and HPLC Lange et al., 2011 2011 Germany Retrospective M/F 45 (22–72) 146 6567 6 Radioimmunoassay Arteh et al., 2010 2010 55% Caucasian, 45% African American Consecutive M/F 53±9 43 118 6 Automated chemiluminescence immunoassay 2 White et al., 2013 2013 African Cross-sectional M 57.4±4.2 63 289 6 Automated immunochemiluminometric assay American White (non-Hispanic) 55.7±5.5 54 6 Automated immunochemiluminometric assay Kitson et al., 2013 2013 Caucasian CHARIOT M/F 43.9±9.4 44 896 7 LC-MS/MS methodology Amanzada et al., 2013 2013 Germany (Caucasian) Cohort M/F 51±10 36 191 6 Chromatographic system and HPLC 9 9 Source OR/relative risk (95% CI) Mean (95% CI) HCV type 4 How fibrosis assessed and diagnosis criteria Severe fibrosis vs. zero or lesser degrees 9 Petta et al., 2013 2013 0.958 (0.919, 0.999) −0.44 (−0.71, −0.16) G1 4 Biopsy according to Scheuer numerical scoring system F3–F4 vs. F0–F1 Lange et al., 2011 2011 0.74 (0.548, 1.000) G1, 2, 3 4 Biopsy according to METAVIR model F2–F4 vs. F0–F1 Arteh et al., 2010 2010 0.681 (0.377, 1.229) NA 4 By liver biopsy or by clinical or biochemical evidence of hepatocellular failure and/or portal hypertension Cirrhosis vs. without cirrhosis 2 White et al., 2013 2013 12.91 (1.30, 128.16) G1, 2, 3, 4 4 By biochemical evidence according to FibroSURE-ActiTest model F3/F4–F4 vs. F0–F3 0.84 (0.20, 3.59) Kitson et al., 2013 2013 −0.21 (−0.53, 0.12) G1 4 Liver biopsy according to METAVIR model F3/F4 vs. F0–F2 Amanzada et al., 2013 2013 −0.80 (−1.10, −0.50) G1 4 Liver specimens, NA Severe fibrosis/cirrhosis vs. absent/mild/moderate Statistical analysis 2 We quantified the relationship between serum vitamin D status and severity of liver fibrosis in chronic hepatitis C patients by using a random-effects model, which considered variation both within and between the studies. Sensitivity analysis was performed by deleting each study which reflected the influence of the individual dataset on the pooled ORs. Subgroup analysis was performed by geographic region and ethnic background. An estimation of potential publication bias was assessed by using Egger’s linear regression test (Egger et al., 1997 1997 ). All statistical tests were performed with the STATA software 12.0. P < 0.05 was considered statistically significant. Results 1 Literature search 2 A flow diagram of our literature search is shown in Fig. 1 1 . Our total search yielded 775 entries. We identified six eligible publications (Arteh et al., 2010 2010 ; Lange et al., 2011 2011 ; Amanzada et al., 2013 2013 ; Kitson et al., 2013 2013 ; Petta et al., 2013 2013 ; White et al., 2013 2013 ) concerning the association between vitamin D and severity of liver fibrosis in patients infected with chronic hepatitis C. Among these studies, two (Arteh et al., 2010 2010 ; Petta et al., 2013 2013 ) were consecutive studies, one (Lange et al., 2011 2011 ) was a retrospective study, one (White et al., 2013 2013 ) was a cross-sectional study, one (Kitson et al., 2013 2013 ) was a CHARIOT study, and one was a cohort study (Amanzada et al., 2013 2013 ). Study characteristics 2 The six studies concerning the relationship between serum vitamin D and the severity of liver fibrosis were published between 2010 and 2013 (Table 1 1 ), which involved a total of 8321 patients. Of these six studies, three (Lange et al., 2011 2011 ; Amanzada et al., 2013 2013 ; Petta et al., 2013 2013 ) were conducted in Europe, two (Arteh et al., 2010 2010 ; White et al., 2013 2013 ) in the United States, and one (Kitson et al., 2013 2013 ) in Australia. The five (Arteh et al., 2010 2010 ; Amanzada et al., 2013 2013 ; Kitson et al., 2013 2013 ; Petta et al., 2013 2013 ; White et al., 2013 2013 ) studies assessed included a review of serum 25(OH) D status, and one (Lange et al., 2011 2011 ) on 25(OH)D 3 and 1,25(OH) 2 D 3 status. Three studies (Amanzada et al., 2013 2013 ; Kitson et al., 2013 2013 ; Petta et al., 2013 2013 ) included patients with chronic hepatitis C genotype 1 infection, one (Lange et al., 2011 2011 ) with chronic hepatitis C genotype 1, 2, or 3-infection, one (White et al., 2013 2013 ) with chronic hepatitis C genotype 1, 2, 3, or 4-infection, and one (Arteh et al., 2010 2010 ) did not specify the kind of HCV type. Four studies (Baur et al., 2012 2012 ; Corey et al., 2012 2012 ; Weintraub et al., 2012 2012 ; Ladero et al., 2013 2013 ) were excluded because they did not report usable data. One study (Petta et al., 2010 2010 ) was excluded because it reported on the same author. Serum vitamin D status and severity of liver fibrosis 2 The overall results for the serum vitamin D status associated with the severity of liver fibrosis are shown in Fig. 2 2 . Results from studies concerning the relationship between serum vitamin D status and severity of liver fibrosis were inconsistent with inverse or positive associations reported. The pooled OR was 0.866 (95% CI, 0.649 to 1.157) and mean was −0.487 (95% CI, −0.659 to −0.315). There was statistically significant heterogeneity among mean data extracted studies ( P =0.029; I 2 =71.8%) but not among OR data extracted studies ( P =0.061; I 2 =55.6%). (a) Pooled OR; (b) Pooled mean Stratifying analysis 2 Stratifying by geographic region, the pooled ORs of studies were 1.33 (95% CI, 0.35 to 5.08; P =0.052; I 2 =66.2%) for studies conducted in the United States, and 0.88 (95% CI, 0.694 to 1.116; P =0.096; I 2 =64.0%) for studies conducted in Europe. There was no statistically significant heterogeneity among the studies (United States, P =0.052 and P =0.096). Stratifying by ethnic background, the pooled ORs of studies were 0.902 (95% CI, 0.762 to 1.068; P =0.246; I 2 =28.8%) for those with a European ethnic origin (Table 2 2 ). We did not do subgroup analysis about the mean data extracted studies because only three studies were included in our research (Amanzada et al., 2013 2013 ; Kitson et al., 2013 2013 ; Petta et al., 2013 2013 ). RR: relative risk; CI: confidence interval 2 Factor 2 RR 2 95% CI 2 Heterogeneity P I 2 (%) Geographic region  United States 1.33 0.35–5.08 0.052 66.2  Europe 0.88 0.694–1.116 0.096 64.0 Ethnic background  European 0.902 0.762–1.068 0.246 28.8 Sensitivity analysis and publication bias 2 We performed sensitivity analysis by omitting one study at a time and calculating the pooled OR for the remainder of the studies. The result showed that the study of White et al. ( 2013 2013 ) influenced the pooled OR. After excluding this single study, the heterogeneity was significantly reduced ( P =0.246; I 2 =28.8%; 95% CI, 0.762 to 1.068). The Egger’s test showed no evidence of publication bias for OR ( P =0.902) or mean ( P =0.888) data extracted studies. Discussion 1 Vitamin D deficiency is a global problem. There are 20% to 100% of people suffering from this problem when referring to serum vitamin D concentrations < 20 ng/ml (Holick et al., 2011 2011 ). Low vitamin D status associated with advanced fibrosis in chronic hepatitis C patients (Arteh et al., 2010 2010 ; Geier, 2011 2011 ) has been reported. The reasons why vitamin D deficiency occurs in chronic hepatitis C patients are far from conclusive. A possible reason of this finding should consider the multiple interconnections among vitamin D, the immune response, and inflammatory status (Baeke et al., 2010 2010 ; Hewison, 2010 2010 ). The current meta-analysis summarizes the results of group studies, including six studies and a total of 8321 participants. The findings from the mean data extracted studies indicated that serum vitamin D status is inversely associated with the severity of liver fibrosis, but the results from the OR data extracted studies showed that there was no significant association between serum vitamin D status and the severity of liver fibrosis. When the analysis was stratified according to geographic region and ethnic background, the results were unchanged. However, after excluding the study of White et al. ( 2013 2013 ), the heterogeneity was significantly reduced. White et al. ( 2013 2013 ) found that serum levels of vitamin D ( > 50 ng/ml) have a higher risk of advanced fibrosis (F3/F4–F4) in African American males. Corey et al. ( 2012 2012 ) found that African Americans whose liver fibrosis clinically progressed over a 4-year period had higher baseline vitamin D levels compared with African Americans whose fibrosis had not progressed (32.7 ng/ml vs. 25.2 ng/ml; P =0.08). These different results may be due to the different vitamin D measurements, study design, or skin tone. It has been reported that very few foods naturally contain vitamin D and the major cause of vitamin D deficiency is due to the inadequate exposure to sunlight (Holick et al., 2007 2007 ; Holick and Chen, 2008 2008 ). People with a naturally dark skin tone have natural sun protection and require three to five times longer exposure to make the same amount of vitamin D as a person with a white skin tone (Clemens et al., 1982 1982 ; Hintzpeter et al., 2008 2008 ). The findings from this meta-analysis need to be confirmed in large randomized clinical trials. Some suggestions should be considered in further studies. First, most of the studies included were conducted in America and Europe. Even more studies should be conducted in other populations such as South-African and Asian, considering the underlying disease-effect unconformity across different geographical locations. Second, more accurate questionnaires or other accurate methods assessing serum vitamin D status could provide better results for estimating the association. Several limitations of this study should be addressed. First, meta-analyses are considered hypothesis-generating. The quality and usefulness of any meta-analysis are dependent on the quality and comparability of data from the component studies (Hennekens and Demets, 2009 2009 ). Inadequate or inaccurate data may bias the results. And unknown confounding cannot be excluded as a potential explanation for the observed findings. Second, the related data on serum vitamin D concentration were measured by different methods. This may possibly lead to less accurate estimates of risk. Meanwhile, only six studies were available for this study, some of the subgroup analyses were difficult to perform. Third, although there was a lack of any indication of major publication bias in the formal evaluation we used, potential publication bias is impossible to completely exclude because some studies with null results tend not to be published. Finally, There was significant heterogeneity for mean data extracted studies ( I 2 =71.8%) in the pooled analysis. This may be due to the different serum vitamin D concentration detection, different ethnic backgrounds included, different fibrosis assessing models, or other confounding factors which have not been considered. 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This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1400073 Project supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2012ZX10002006), the Key Technologies R&D Program of Zhejiang Province (No. 2012C03SA170003), and the Hangzhou Key Technologies R&D Program (No. 20122513A49), China 2014-03-11 2014-09-14 2014-07-20 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2014 2014 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 10 15