Wednesday, November 13, 2013

Hepatitis C Virus Infection and Risk of Stroke: A Systematic Review and Meta-Analysis

Hepatitis C Virus Infection and Risk of Stroke: A Systematic Review and Meta-Analysis

He Huang equal contributor, Rongyan Kang equal contributor, Zhendong Zhao mail                   

Published: Nov 12, 2013
DOI: 10.1371/journal.pone.0081305


Several studies analyzed the association between hepatitis C virus (HCV) infection and the risk of stroke or cerebrovascular death, but their findings were inconsistent. Up to date, no systematic review about the association between HCV infection and stroke was performed. We conducted a meta-analysis to examine whether HCV infection dose increase stroke risk in comparison to the population without HCV infection.


We followed standard guidelines for performance of meta-analysis. Two independent investigators identified eligible studies through structured keyword searches in several databases. Random-effects and fixed-effects models were used to synthesize the data. Heterogeneity between studies and publication bias were also accessed.


Combining the data from the eligible studies, we calculated the pooled multi-factor adjusted Odds Ratio (OR) with 95% confidence interval (CI). Upon the heterogeneity found between studies, the result was 1.58 (0.86, 2.30) by random-effects model. However, after omitting the study which induced heterogeneity, the pooled OR with 95% CI was 1.97 (1.64, 2.30).


This meta-analysis suggested that HCV infection increased the risk of stroke. More prospective cohort studies will be needed to confirm this association with underlying biological mechanisms in the future.

Discussion Only
Full Text Available @ PLOS ONE

As we know that the result of a single research may be affected by many factors, in order to reduce the bias and increase the efficiency of the small sample study of statistics, meta-analysis was performed to further explore the relationship between stroke and HCV infection. Six studies estimated the risk of stroke in HCV infected population were identified [10,12-16]. The final analysis suggested that HCV infection increased the risk of stroke with statistical significance. To our knowledge, this was the first to attempt to synthesize the existing world literature to evaluate the effect of HCV infection on stroke.

The mechanism(s) by which HCV may favor stroke is not known. Increasing evidence has showed that chronic HCV infection increased the risk of ultrasonographically defined carotid intima-media thickness and or plaque [25-27], which are predictors of cerebrovascular disease [28]. It is well-known that chronic inflammation plays an important role in the instability of plaque [29]. It was also found that HCV replicated with carotid plaque [30]. Beyond, HCV infection also increased the risk of metabolism diseases, such as type II diabetes[4]. All of these events potentially increased the risk of stroke. Thus, it is believed that there is potential association between HCV infection and stroke. However, studies from several groups provided conflicting results. Our meta-analysis consisted of more than 22171 HCV infected individuals and more than 87418 controls and might allow a much greater possibility of reaching reasonably strong conclusions.

The results of combing the four eligible studies suggested that HCV infection was not associated with stroke (Figure 2). However, a substantial heterogeneity among the studies included was found, which can influence the validity and reliability of the results of meta-analysis. Thus, sensitivity analysis was performed to identify the potential sources of between-study heterogeneity and to reduce heterogeneity [31]. Our analyses found that the study by Younossi et al. [16] was a major contributor to the heterogeneity. Inadequate adjusting variables used might induce bias and could be an important source of heterogeneity. We noted that several cofounders, such as race, gender, and hypertension, were significantly different between HCV+ and control in this study [16]. However, these factors were not involved in the adjustment. The differences in HCV positive criteria used might be another source of heterogeneity. After omitting this study, heterogeneity was reduced and the results suggested that HCV infection significantly increased the risk of stroke (Figure 4).

Some limitation in this meta-analysis should be demonstrated in the discussion of the results. Firstly, our search was limited to studies published in English. However, we found no evidence of publication bias, although the statistical tests for detecting this had limited power[32], especially for relatively small numbers of studies. Secondly, we should noted that the number of included studies in this analysis was relatively low (4 studies). Two of the studies were published only in abstract form on conferences[10,14] and the study by Adinolfi et al.[13] was the only one published article in the final analysis (Figure 4). This limitation might induce bias, although publication bias was not found in our analysis. Thirdly, HCV positive criteria and cofounder for adjusting ORs were different between the included studies, which might induce bias in our study. Fourthly, all the included studies were retrospective studies and the inherent limitations of such studies may influence our findings. More studies with prospective design will be needed. Fifthly, the studies were restricted to United States and Italy, so it was uncertain whether these results were generalizable to other populations. The other two studies excluded in the final analysis were performed in Taiwan [12,15]. However, they reported HRs which could not be combined with ORs. Never the less, the results form these two studies both supported our conclusion. Due to the limitations mentioned above, the results of this meta-analysis should be interpreted with care.

In conclusion, our meta-analysis revealed that  HCV infection significantly increased the risk of stroke. Due to the limitations mentioned above, more population-based well-designed cohort studies will be needed to confirm our results. Furthermore, future studies may evaluate the impacts of different genotypes of HCV infection on stroke. The updating of this meta-analysis will give us more information and may help inform clinical practice guidelines in the future.


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