Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection

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Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection

Insulin resistance is associated with hepatocellular carcinoma(Liver Cancer) in chronic hepatitis C infection

Chao-Hung Hung, Jing-Houng Wang, Tsung-Hui Hu, Chien-Hung Chen, Kuo-Chin Chang, Yi-Hao Yen, Yuan-Hung Kuo,Ming-Chao Tsai, Sheng-Nan Lu, Chuan-Mo Lee

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AIM: To elucidate the role of insulin resistance (IR) and serum adiponectin level in hepatocellular carcinoma (HCC) associated with chronic hepatitis C.

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Key Words:

Hepatitis C virus =(HCV)

Hepatitis B Virus = (HBV)

diabetes mellitus = (DM)

type 2 diabetics = type 2 (DM)

hepatocellular carcinoma (HCC)=Liver Cancer

hepatic steatosis = (Fatty Liver)

Body Mass Index = (BMI)

homeostasis model = (HOMA)

Insulin resistance = (IR)

IR assessed by the homeostasis model = (HOMA-IR)

Diabetes; Adiponectin

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..Higher HCC risk with increased insulin resistance in hepatitis C patients

..Recent studies have demonstrated that type 2 diabetes mellitus (DM) is associated with high risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C.

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Insulin resistance (IR), which correlates inversely with circulating adiponectin concentration, is a consistent finding in patients with type 2 DM. Chronic hepatitis C virus (HCV) infection has been reported to be associated with increased IR. Recent studies suggest that IR plays a crucial role in fibrosis progression, and has been demonstrated to have a negative impact on treatment responses to antiviral therapy in patients with chronic hepatitis C.A research article to be published on May 14, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Hung from Kaohsiung Chang Gung Memorial Hospital prospectively investigated the IR assessed by the homeostasis model

(HOMA-IR) and serum adiponectin level in two independent cohorts of consecutive newly diagnosed HCC patients and those with different clinical stages of chronic HCV infection. Among 165 HCC patients, type 2 DM was more prevalent in HCV subjects compared to hepatitis B virus (HBV) or non-HBV, non-HCV cases. HOMA-IR was higher in HCC patients with HCV than in those with HBV infection.

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In 188 patients with chronic hepatitis C, HCC subjects had higher blood sugar, insulin level and HOMA-IR than those with chronic hepatitis and advanced fibrosis.,Based on stepwise logistic regression analysis, HOMA-IR was one of the independent factors associated with HCC development. This result was similar even if the diabetic subjects were excluded for analysis.

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The research team concluded that increased IR, regardless of the presence of diabetes, is significantly associated with HCC development in patients with chronic HCV infection.,These findings may have important prognostic and therapeutic implications in the management of chronic HCV-infected patients. Since IR is a potentially modifiable factor, therapeutic intervention aimed at decreasing IR may be warranted in these patients.

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..Abstract

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DISCUSSION ,.There is increasing evidence linking chronic HCV infection and (type 2 diabetics)= type 2 DM. Large community-based studies have shown that the prevalence of (diabetes mellitus) = DM in HCV-infected patients is much higher than that observed in the general population, and in patients with other chronic liver diseases such as HBV and alcoholic liver disease[28,29]. In this study, we found that among (hepatocellular carcinoma) = HCC patients, type 2 DM was more prevalent in those infected with HCV compared to those with HBV or non-HBV, non-HCV infection. This observation in accordance with previous studies suggests a strong

synergistic effect of metabolic factors and viral hepatitis in HCC development among HCV-infected patients[12,13]. Although there was no significant difference in (body mass index) = BMI among HCC patients with different etiology, this could be explained by the low prevalence of obesity in our study population.Chronic HCV infection is associated with the development of hepatic steatosis and unique, virus-specific alterations in host metabolism leading to the development of Insulin resistance =IR[19,30,31]. In this present study, we provide the first evidence that IR could potentially increase the risk of developing HCC in patients with chronic HCV infection. In a cross-sectional, hospital-based setting, we prospectively assessed the HOMA-IR value in different clinical stages of chronic HCV infection. Our data showed that

patients with HCC had a higher ratio of HOMA-IR > 4 than those with chronic hepatitis and advanced fibrosis. Furthermore, after adjusting for age and sex, HOMA-IR was an independent factor associated with the development of HCC. A novel finding of our work, not specifically evaluated in other studies, was the association of IR, regardless of diabetes, with the development of HCC. An alternative explanation for the observed association between HOMA-IR and HCC is that advanced hepatic fibrosis and disease severity results in IR and impairs insulin clearance. This possibility could be excluded by the similar prevalence of DM and platelet count that has been considered as a fibrosis marker in chronic HCV infection between patients with HCC and those with advanced fibrosis. Also, HOMA-IR did not correlate with Child-Pugh classification, which suggests that disease severity was not associated with IR in patients with HCC or advanced

fibrosis.Although our work was not designed to clarify the pathogenic interaction between IR and the development of HCC, a few hypotheses can be put forward. IR is defined as an increased requirement for insulin to maintain normal metabolic function, which results in the compensatory development of hyperinsulinemia[32]. Recent evidence has suggested that hyperinsulinemia can promote the synthesis and biological activity of insulin-like growth factor 1 (IGF-1), which is a peptide hormone that regulates energy-dependent growth processes[33]. IGF-I stimulates cell proliferation and inhibits apoptosis and has been shown to have strong mitogenic effects on a wide variety of cancer cell lines. Changes in the expression pattern of IGF-system components have been observed in patients with HCC, in human HCC cell lines and in their conditioned culture medium, as well as in rodent models of hepatocarcinogenesis[34].To study the role of adiponectin

in HCC may be more complex because of its underlying chronic hepatitis infection[19,35,36]. Previous studies have demonstrated that circulating adiponectin levels are inversely associated with the risk of malignancies associated with IR, including endometrial, breast, colon and gastric cancer[37-40]. Moreover, serum adiponectin level has been reported to be significantly elevated in chronic liver disease, and correlated with stage of liver cirrhosis, liver cell injury, e.g. aminotransferase activity, and inflammatory markers[35,36]. Thus, serum adiponectin level is modified according to the two opposing factors, IR and underlying liver condition. In this study, we found no difference in serum adiponectin level among different clinical stages of chronic HCV infection. Although HOMA-IR score was inversely associated with serum adiponectin level by univariate analysis, multiple linear regression analysis did not support this correlation.There are

some limitations to our study. First, the analysis was carried out in a cross-sectional setting with a relatively small number of HCC patients, and it would be interesting to determine whether this association holds true in longitudinal follow-up studies of larger groups of patients. Second, the cohort of patients, at low prevalence of obesity, was enrolled in a tertiary referral center for liver disease, which limits the broader application of the results. A further methodological issue resides in the inability to dissect the temporal relation between IR and HCC. Another limitation lies in the fact that there is some concern on the use of HOMA-IR in the presence of long-standing DM. However, a diagnosis of DM is per se expression of IR, and HOMA-IR is a less invasive, inexpensive, and less labor-intensive method to measure IR as compared with the glucose clamp test.In conclusion, we demonstrated the independent association between IR and HCC

development in chronic HCV infection. These findings may have important prognostic and therapeutic implications in the management of chronic HCV-infected patients. Since IR is a potentially modifiable factor, therapeutic intervention aimed at decreasing IR may be warranted in these patients.COMMENTSBackgroundRecent studies have demonstrated that diabetes mellitus (DM) is associated with high risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. Insulin resistance (IR), which correlates inversely with circulating adiponectin concentration, is a consistent finding in patients with type 2 DM. Chronic hepatitis C virus (HCV) infection has been reported to be associated with increased IR. Recent studies have suggested that IR plays a crucial role in fibrosis progression, and has been demonstrated to have a negative impact on treatment responses to

antiviral therapy in patients with chronic hepatitis C.Research frontiersIR has emerged as a risk factor for a wide variety of cancers. In a cross-sectional, hospital-based setting, the authors assessed the role of IR assessed by the homeostasis model (HOMA-IR) and serum adiponectin level in the development of HCC associated with chronic HCV infection.Innovations and breakthroughsThe authors have provided the first evidence that IR can potentially increase the risk of developing HCC in patients with chronic HCV infection. A novel finding, not specifically evaluated in other studies, is the association of IR, regardless of diabetes, with the development of HCC.ApplicationsThese findings may have important prognostic and therapeutic implications in the

management of chronic HCV-infected patients. Since IR is a potentially modifiable factor, therapeutic intervention aimed at decreasing IR may be warranted in these patients.Peer reviewThe authors present a clinical investigation of the correlation between IR and HCC. The title accurately reflects the major contents of the article, and the abstract delineates briefly and concisely the research background, objectives, materials and methods, results and conclusions

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