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Hepatitis C Viremia Increases the Association With Type 2 Diabetes Mellitus in a Hepatitis B and C Endemic Area: An Epidemiological Link With Virological Implication
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Am J of Gastroenterology, June 2007
Jee-Fu Huang, M.D et al. 1Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
ABSTRACT
OBJECTIVES: There is growing evidence with regard to the association between hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM). However, the mutual link and related virological implication have not been fully clarified. The impact of hepatitis B virus (HBV) infection on the epidemiological link remains unclear. This study aimed to elucidate the link between T2DM and viral hepatitis infections, especially HCV infection. It also aimed to analyze the associated virological characteristics and implication.
METHODS: Cross-sectional analysis of a computer-sampling survey among 10,975 participants (aged 40-65 yr) was performed in an area endemic for HBV and HCV infections in Taiwan. Outcome measures included prevalence of T2DM among different groups of viral hepatitis infection, and comparison of related biochemical and virological profiles.
RESULTS: Of 10,975 participants studied, 9,932 eligible participants were analyzed. The prevalence of T2DM, seropositivity for HBV surface antigen (HBsAg) and HCV antibodies (anti-HCV), and HCV viremia was 12.5%, 13.1%, 6.5%, and 4.8%, respectively. Prevalence of HCV viremia showed significant difference between T2DM and non-T2DM subjects (6.9% vs 4.5%, P < 0.001), whereas anti-HCV seropositivity showed borderline significance (7.8% vs 6.3%, P = 0.047).
There was no HCV genotype-specific difference between HCV genotype 1 and 2 in the association with T2DM. On the other side, the prevalence of HBsAg (+) did not differ between T2DM and non-T2DM subjects (12.5% vs 13.9%, P = 0.19). The prevalence of T2DM among HCV viremic subjects (18.0%, 86/478) was significantly higher than HBsAg (+) subjects (11.4%, 155/1,363, P = 0.001) and those negative for both viral hepatitis markers (12.5%, 997/8,004, P = 0.001). Multivariate logistic regression analyses showed that HCV viremia was the leading significant factor associated with T2DM, followed by male gender, hypertension, body mass index, and age.
CONCLUSIONS: HBV infection did not increase the association with T2DM. A significant mutual link between T2DM and HCV viremia existed in this HBV/HCV endemic area. There was no HCV genotype-specific difference between HCV genotype 1 and 2 in the association with T2DM.
INTRODUCTION
Hepatitis C virus (HCV) infection is one of the most important causes of cirrhosis and hepatocellular carcinoma worldwide. It has been shown to be a lymphotropic as well as a hepatotropic virus (1). Replication of HCV in diseased extrahepatic organs and tissues may have cytopathic effects. It, therefore, may either trigger latent autoimmunity or induce de novo an autoimmune disease (2). In addition to established liver injury, there are multiple examples of extrahepatic disease attributed to HCV infection, such as thyroiditis, thrombocytopenia, lichen planus, arthritis, glomerulonephritis, mixed cryoglobulinemia, and other immunological disorders (3-6). Diabetes mellitus (DM), mostly type 2 diabetes mellitus (T2DM), is a less recognized extrahepatic manifestation of HCV infection. A high prevalence of T2DM among patients with HCV infection has been consistently reported, and there is growing evidence to support the concept that HCV infection is a risk factor for developing T2DM (7-10). However, negative results regarding the association between T2DM and HCV infection have also been postulated (11, 12).
HCV infection and T2DM are two common disorders with a high impact on health worldwide. Present evidence linking HCV infection and T2DM has mainly been obtained from retrospective case-control studies and/or studies performed in hospital-based settings of western countries. Data addressing this debated issue are relatively uncommon in Asia Pacific-an endemic region of viral hepatitis infections (13-16). Virological analysis such as HCV RNA measurement and genotype testing was rarely investigated in most previous studies. In addition, the impact of hepatitis B virus (HBV) on the association between T2DM and HCV infection also deserves elucidation.
Consequently, we conducted a large-scale community survey in an area endemic for HBV and HCV infections aiming to investigate the association between T2DM and viral hepatitis infections. We also aimed to elucidate the related clinical and virological features between them in this community-based study.
RESULTS
There were 10,975 participants enrolled into the current study from June 2002 through May 2004. After excluding alcoholism (>40 g/day), type 1 DM subjects, or those who did not complete or refused the study, 9,932 eligible subjects (4,290 men and 5,642 women) constituted the study pool. The mean age and number of men among those nonresponding or excluded were 56.7 ± 6.23 yr and 18,030, respectively. There was no significant difference regarding sex and age among responders and nonresponders. The demographic and clinical characteristics of 9,932 responders are shown in Table 1. Their mean age was 55.2 ± 5.95 yr. The prevalence of DM and hypertension was 12.5% (N = 1,237) and 33.4% (N = 3,317), respectively. The prevalence of HBsAg (+), anti-HCV (+), and HCVRNA (+) was 13.1% (N = 1,304), 6.5% (N = 642), and 4.8% (N = 478), respectively. HCV genotypes were determined among 421 of 478 HCV viremic subjects. It revealed 181 subjects (43.0%) of 1b, 135 (32.1%) of 2a, 36 (8.6%) of 2b, 48 (11.4%) of mixed, and 21 (5.0%) unclassified. The HCV genotype distribution among T2DM subjects was similar to that of non-T2DM subjects (Table 1).
Among the related variables, age, male sex, hypertension, HCV viremia, BMI, ALT, and TG levels were significantly associated with T2DM. The prevalence of anti-HCV (+) among T2DM and non-T2DM subjects were 7.8% and 6.3%, respectively (P = 0.047, borderline significance). For HCV viremic subjects, it showed significant difference among T2DM and non-T2DM subjects (6.9% vs 4.5%, P = 0.001). On the other side, the prevalence of HBsAg seropositivity did not differ between T2DM and non-T2DM subjects (12.5% vs 13.9%, P = 0.19).
The prevalence of T2DM among subjects for HBsAg (+), anti-HCV (+), HCV RNA (+), and those negative for viral hepatitis markers were 11.4% (155/1,363), 15.0% (96/642), 18.0% (86/478), and 12.5% (997/8,004), respectively (Fig. 1). The prevalence of T2DM among HCV viremic subjects was significantly higher than the HBsAg (+) (18.0% vs 11.4%, P < 0.001) subjects and the HBsAg (-) and anti-HCV (-) subjects (18.0% vs 12.5%, P < 0.001). By contrast, the prevalence of T2DM did not differ between HBsAg (+) subjects and the HBsAg (-) and anti-HCV (-) subjects (11.4% vs 12.5%, P = 0.26). There were 74 subjects (31 men and 43 women) with HBV and HCV dual infection. Ten subjects (13.5%) had T2DM. The prevalence between HCV infection and HBV and HCV dual infection did not show significant difference.
Multivariate logistic regression analyses were conducted among 9,932 pooled subjects to clarify the independent factors associated with DM (Table 2). Variables included into analyses were age, sex, BMI, ALT, TC, TG, hypertension, HBsAg, and anti-HCV. The risk ratio attributable to anti-HCV seropositivity was also calculated using dummy variables (viremic anti-HCV (+) vs anti-HCV (-), nonviremic anti-HCV (+) vs anti-HCV (-)). It showed that HCV viremia (OR 1.53) was the most significant independent factor associated with T2DM, followed by male gender (OR 1.39), hypertension (OR 1.27), BMI (OR 1.10), and age (OR 1.05).
DISCUSSION
This large-scale epidemiological study supported the mutual link between HCV infection and T2DM. Subjects with T2DM carried a higher prevalence of HCV infection, whereas subjects with HCV viremia had a higher risk of T2DM than those with HBV infection and controls. Intriguingly, our study demonstrated that anti-HCV seropositivity alone did not increase the association with T2DM. HCV viremia was the leading significant independent factor associated with T2DM, followed by established factors such as male gender, hypertension, BMI, and age in multivariate logistic regression analyses. In addition, there was no HCV genotype-specific difference between HCV genotype 1 and 2 in the association with T2DM.
There have been several case-control studies depicting the correlation between viral hepatitis, mostly HCV infection, and T2DM (7-10, 12, 19-23). Most of the previous studies addressing this association were based on retrospective analysis. Mason et al. demonstrated 52% of both HCV infection and T2DM patients had risk factors for HCV infection before the onset of T2DM (7). The diagnosis of HCV infection preceding the diagnosis of T2DM in 73% of anti-HCV(+) diabetics was shown by Knobler et al. (8). Recently, a well-designed prospective cross-sectional study containing risk factors for T2DM and controlling for previous exposure to interferon and for histological stage by Zein et al. demonstrated that chronic hepatitis C (CHC) patients had a higher prevalence of T2DM compared with the general population (23). T2DM represented one more disease to be included in the list of established extrahepatic manifestations of HCV infection. Taken together, the prevalence of anti-HCV seropositivity in the T2DM population ranged from 1.8 to 12.1%, whereas T2DM developed in 14.5-33.0% of CHC patients (7, 9, 10, 19-23). However, negative results in terms of this association have also been postulated (11, 12). Some inherent limitations, e.g., bias of patient selection, limited numbers of cases and/or controls, more frequent parenteral exposures and/or hospitalizations of T2DM patients, and inadequate control of other related metabolic factors remained in these studies. Different background in terms of ethnicity, age, prevalence of T2DM, and viral hepatitis might also partly contribute to the divergent results of previous observations. The unique geographic background of the current study, i.e., an area endemic for both HBV and HCV infections, provided a better scope of view concerning the influence of viral hepatitis infections in the association with T2DM in a community-based setting. Our data demonstrated that the prevalence of T2DM among HCV viremia subjects (18.0%) was significantly higher than HBsAg-positive (11.4%) and normal (12.5%) subjects. By contrast, there was no difference in prevalence of T2DM between HBsAg-positive and normal subjects. Most of the asymptomatic HBV carriers among adults in Taiwan were of vertical transmission during their infancy and carried an inactive status during their adulthood (24). Almost all of the subjects with HBV infection in our study were in the postseroconversion stage because of the age factor (mean age 54.5 yr), and the presence of HBeAg rarely existed among this age group (24, 25). It, therefore, reflects the concordant background of HBV infection among the adult population in this area. Our data further suggested the increased prevalence of T2DM associated with viral hepatitis infections is unique to HCV, but not HBV infection.
T2DM is a common endocrine disorder encompassing multifactorial pathogenetic mechanisms. These mechanisms include resistance to the action of insulin, increased hepatic glucose production, and a defect in insulin secretion, all of which contribute to the development of overt hyperglycemia (26). Although the precise mechanisms whereby these factors interact to produce glucose abnormalities are uncertain, it has been suggested that the final common pathway responsible for the development of T2DM is the failure of the pancreatic beta-cells to compensate for the insulin resistance. The biological mechanism underlying insulin resistance or T2DM in HCV infection remains unclear. Shintani et al. demonstrated that the ability of insulin to lower the plasma glucose level was impaired without a gain in body weight at a young age in an HCV core gene transgenic mice study. A high level of tumor necrosis factor-alpha was considered to be one of the bases of insulin resistance, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate (IRS)-1, a central molecule of the insulin-signaling cascade. These findings provided direct experimental evidence for the contribution of HCV in the development of insulin resistance and in the pathogenesis of T2DM (27). In addition, a human study by Kawaguchi et al. indicated that an increase in fasting insulin levels was associated with the presence of serum HCV core protein, the severity of hepatic fibrosis, and a decrease in expression of IRS-1 and IRS-2 in patients with HCV infection. More severe insulin resistance was present in noncirrhotic patients with HCV infection than in patients with other liver diseases (28). HCV core-induced suppressor of cytokine signaling 3 may promote proteosomal degradation of IRS-1 and IRS-2 through ubiquitination, which may be a unique mechanism of HCV-associated insulin resistance. In patients with undetectable levels of HCV core fasting insulin levels were within the normal range. In contrast, in patients with detectable levels of HCV core, fasting insulin levels were increased. Thus, HCV core seemed to play a crucial role in HCV-associated insulin resistance. Reduced insulin resistance and subsequent improved glucose control after interferon therapy had been shown among patients with chronic hepatitis B and C infections by Tai et al. (29). Our data, which compnised serological and virological features of HCV infection, showed that HCV viremia, but not anti-HCV seropositivity alone, increased the association with T2DM. It was a result echoing previous studies from another aspect of view in an epidemiological setting. The link between T2DM and HCV infection might be limited to those viremic patients. It may imply that a persistent and/or active phase of HCV infection is associated with T2DM.
Generally, T2DM to some extent is associated with immuno-compromised state, leading to derangements of immune function. Aggravation of chronicity of HCV infection might thus occur. Meanwhile, both insulin resistance and T2DM might play some role in the alteration of the nature course of HCV infection, thus leading to enhanced steatosis, steatohepatitis, and liver fibrosis (30, 31). However, the actual or present activity of HCV infection could not be precisely reflected by anti-HCV seropositivity alone without virological assessment. From the viewpoint of clinical management, it is important to perform an HCV RNA assay on every anti-HCV-positive subject. Further study, showing a better control of T2DM decreases HCV viral load, will provide a different means of approaching the possible etiopathogenic mechanism between them and the management of the common endocrine disease.
The relationship between T2DM and HCV genotypes remains controversial (7, 8, 22, 32). Zignego et al. demonstrated that HCV genotype 2a was specifically linked with extrahepatic manifestations such as cryoglobulinemia (33). An association between genotype 2a and T2DM was also reported by Mason et al. (7). However, no association was found between fasting insulin levels and HCV genotypes in Kawaguchi's study (28). Our results showed that neither HCV genotype 1 nor genotype 2 was significantly associated with T2DM. The cross-sectional nature of the current study and incomplete coverage of all genotypes may prevent making a definite conclusion in this issue. A large collaborative study covering and comparing patients with different genotypes is needed to further clarify whether there is any specific HCV genotype that predisposes to or protects from insulin resistance and glucose abnormalities.
Because glucose abnormalities are more frequent in patients with advanced liver disease, the extent of liver injury should be taken into consideration when evaluating the prevalence of T2DM in patients with HCV infection (23). The lack of liver biopsy is an inherent limitation of community-based studies. It is therefore insufficient to evaluate the role of T2DM related to the extent of disease activity and the histological progression of HCV infection in this cross-sectional study. Previous studies regarding liver transplantation among CHC patients demonstrated that there was a high prevalence of T2DM among liver transplant recipients infected with HCV both before and after transplantation (34, 35). A prospective cross-sectional study by Zein et al. also demonstrated the association between CHC and T2DM (23). They concluded that the presence of advanced histological disease in genetically predisposed CHC patients was associated with a higher prevalence of T2DM. Another limitation of the current study is that the low participation rate might overestimate disease prevalence and thus undermine the results and/or conclusion. Although the overall participation rate (22%) of the current study was not high, the prevalence of T2DM, hypertension, and HBV/HCV infections were comparable to those of previous epidemiological studies in Taiwan (15, 16, 24, 25, 36). Meanwhile, no significant difference of sex and age between enrolled and nonenrolled subjects and its multipurpose health checkup in intent much lessened the limitations of our study. Despite these limitations, the unique HBV- and HCV-endemic area of the current study provided the comparison between HCV infection and other established risk factors in the association with T2DM in a community-based setting. Multivariate logistic regression analyses in our study showed that HCV viremia was the leading significant factor associated with T2DM, followed by gender, hypertension, body mass index, and age. It further supported the mutual link, either epidemiologically or virologically, between T2DM and HCV infection. Further investigation regarding the association with different stages of glucose abnormalities and other metabolic factors related to glucose homeostasis is warranted to clarify this intriguing and important issue.
In conclusion, the present large-scale, community-based study demonstrated the mutual link between T2DM and HCV viremia in the HBV- and HCV-endemic area among adults. Subjects with T2DM carried a higher prevalence of HCV infection, whereas subjects with HCV viremia had a higher risk of T2DM than those with HBV infection and controls. There was no HCV genotype-specific difference between HCV genotype 1 and 2 in the risk of T2DM. It might suggest that persistent and/or active phase of HCV infection may play a role in the association with T2DM.
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