Special articleHepatitis C infection and risk of diabetes: A systematic review and meta-analysis☆
Introduction
An estimated 3% of the world’s population (170+ million persons) are infected with the hepatitis C virus (HCV), 55–80% with chronic infection [1]. HCV is a significant cause of global morbidity and mortality, responsible for approximately 25% of both chronic liver disease (CLD) and hepatocellular carcinoma (HCC).
HCV infection has also been convincingly linked to several extra-hepatic manifestations including essential mixed cryoglobulinemia, glomeronephritis, and porphyria cutanea tarda [2]. Based on early clinical observation, type II diabetes mellitus (DM) was suggested to be another potential extrahepatic manifestation of HCV infection, with excess risk postulated to be due to either direct viral involvement or secondary to HCV-induced liver damage. However, even a small increase in DM risk in HCV-infected patients may be clinically important, as available pharamcotherapies for HCV are less effective with concomitant DM [3] and progression of liver disease has been shown to be worsened [4].
A number of epidemiologic studies have demonstrated significant excess DM risk with HCV infection [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. However, others found no significant excess risk [19], [20], [21], [22], [23], [24], [25], [26] or excess risk limited to specific segments of the population [27], [28], [29], [30], [31]. Differences in source of controls, case definition, sample size and underlying target population may explain much of this observed variability among studies. Several general narrative reviews have examined the association between HCV infection and DM. However, they have typically been limited in scope or non-systematic [32], [33]. The only published meta-analysis examined the association between HCV and DM in a highly limited sub-population of kidney transplant recipients [34].
Our primary goal was, therefore, to conduct meta-analyses to assess whether HCV infection conveys excess DM risk compared to that observed in the general population. We aimed to quantify and appropriately qualify any observed excess risk, to identify any high-risk sub-groups, and to explore potential sources of between-study heterogeneity. A secondary goal was examining DM risk with HCV infection in comparison to that observed in other sub-groups at risk of CLD, including those mono-infected with HBV or HIV. In addition to providing a greater understanding about the association between HCV and DM risk, the findings of these meta-analyses may also help inform clinical practice guidelines and suggest gaps in current understanding that may be important to address in future research.
Section snippets
Eligibility criteria
We followed published guidelines for the conduct and reporting of meta-analyses [35]. All published epidemiologic studies providing, or with data to calculate, an estimate of risk of type II or adult-onset diabetes mellitus (DM) among adults infected with hepatitis C (HCV+) compared to adults without infection (HCV−) or an estimate of risk of HCV among adults with DM compared to adults without DM were considered for possible inclusion in the current meta-analysis. To be eligible, both case and
Searches
We identified 223 potentially eligible reports. Review of abstracts and manuscripts resulted in exclusion of 190 reports (85%). The most frequent reasons for exclusion were: publication in an ineligible format including letters/abstracts or the results provided were not from original research including reviews/editorials (n = 66); there was no comparator group or else an ineligible case or comparator group (n = 45); it contained data on post-transplant patients (n = 37); it had a total sample size of
Discussion
This is the first meta-analysis to specifically examine the association between HCV infection and risk of diabetes (DM) in the general population as well as in sub-groups at particularly increased risk of chronic liver disease (CLD) including those with hepatitis B (HBV) or HIV infection, or with other causes of liver disease (OLD) like alcohol-related liver disease. Among 34 eligible studies identified for this review, eighteen (15 retrospective and 3 prospective) evaluated DM risk in
Acknowledgments
This research was supported in part by the Houston Center for Quality of Care & Utilization Studies, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs and a Department of Veterans Affairs Merit Review Award.
References (59)
- et al.
Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach
Dig Liver Dis
(2007) - et al.
Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients
Gastroenterology
(2005) - et al.
Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]
Gastroenterology
(2003) - et al.
Seroprevalence of hepatitis B and C in type 2 diabetic patients
J Chin Med Assoc
(2006) - et al.
Association between chronic hepatitis B virus infection and diabetes among Asian Americans and Pacific Islanders
Dig Liver Dis
(2007) - et al.
Increased frequency of HCV and HBV infection in type 2 diabetic patients
Diabetes Res Clin Pract
(2000) - et al.
Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation
Hepatology
(2000) - et al.
Hepatitis C virus infection and incident type 2 diabetes
Hepatology
(2003) - et al.
Extrahepatic manifestations of hepatitis C among United States male veterans
Hepatology
(2002) - et al.
Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis
J Hepatol
(2006)
Hepatitis C infection and diabetes
J Diabetes Complicat
Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies
Am J Transpl
Meta-analysis in clinical trials
Control Clin Trials
A simulation study of the number of events per variable in logistic regression analysis
J Clin Epidemiol
Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance
Gastroenterology
Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C
J Hepatol
Epidemiology of viral hepatitis and HIV co-infection
J Hepatol
Hepatitis C virus infection: evidence for an association with type 2 diabetes
Diabetes Care
Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients
Rheumatology (Oxford)
Association of hepatitis C infection and antiretroviral use with diabetes mellitus in drug users
Clin Infect Dis
Association of diabetes mellitus and chronic hepatitis C virus infection
Hepatology
Increased frequency of HCV but not HBV infection in type 2 diabetic patients in Turkey
Int J Clin Pract
High prevalence of hepatitis C virus infection in diabetic patients
Diabetes Care
Association of chronic hepatitis C infection and diabetes mellitus
Trop Gastroenterol
Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients
Liver Int
Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans
J Viral Hepatitis
Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study
Clin Infect Dis
Prevalence of Type-2 diabetes in patients with hepatitis C and B virus infection in Jeddah, Saudi Arabia
Med Prin Pract
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The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. H.B. El-Serag received funding from NIH NIDDK K-24-04-107.