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      The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients

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          Abstract

          Background/Aims

          Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment.

          Methods

          In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of β cells (HOMA-β) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx).

          Results

          A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0±11.2 years, mean±SD; non-SVR, 56.6±9.9 years; P<0.01), there were no significant differences in the baseline characteristics between the SVR and non-SVR groups. In the SVR group, low density lipoprotein-cholesterol (LDL-C) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-β were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group.

          Conclusions

          LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).

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          Most cited references31

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          Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis.

          Several studies found hepatitis C (HCV) increases risk of Type II diabetes mellitus (DM). However, others found no or only sub-group specific excess risk. We performed meta-analyses to examine whether HCV infection does increase DM risk in comparison to the general population and in other sub-groups with increased liver disease rates including with hepatitis B (HBV). We followed standard guidelines for performance of meta-analyses. Two independent investigators identified eligible studies through structured keyword searches in relevant databases including PubMed. We identified 34 eligible studies. Pooled estimators indicated significant DM risk in HCV-infected cases in comparison to non-infected controls in both retrospective (OR(adjusted)=1.68, 95% CI 1.15-2.20) and prospective studies (HR(adjusted)=1.67, 95% CI 1.28-2.06). Excess risk was also observed in comparison to HBV-infected controls (OR(adjusted)=1.80, 95% CI 1.20-1.40) with suggestive excess observed in HCV+/HIV+ cases in comparison to HIV+ controls (OR(unadjusted)=1.82, 95% CI 1.27-2.38). Our finding of excess DM risk with HCV infection in comparison to non-infected controls is strengthened by consistency of results from both prospective and retrospective studies. The excess risk observed in comparison to HBV-infected controls suggests a potential direct viral role in promoting DM risk, but this needs to be further examined.
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            Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.

            We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin. Patients (n=159; 94 men; age, 41.7 +/- 11.1 years) with chronic hepatitis C (genotype 1, n=113; non-1 genotype, n=46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated. A sustained virological response was associated with lower age, insulin resistance index, body mass index, and gamma-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P=.0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49-8.3; P=.001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08-3.06; P=.012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01-1.84; P=.029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%-43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%-75.1%) genotype 1 patients without insulin resistance (P=.007; odds ratio, 3.12, 95% confidence interval, 1.42-6.89). Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.
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              Role of cytokines in inducing hyperlipidemia.

              Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Journal
                Clin Mol Hepatol
                Clin Mol Hepatol
                CMH
                Clinical and molecular hepatology
                The Korean Association for the Study of the Liver
                2287-2728
                2287-285X
                March 2014
                26 March 2014
                : 20
                : 1
                : 38-46
                Affiliations
                [1 ]Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea.
                [2 ]Institute for Digestive Research, Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Soonchunhyang University College of Medicine, Seoul, Korea.
                [3 ]Department of Internal Medicine, Soonchunhyang University Hospital Cheonan, Soonchunhyang University College of Medicine, Cheonan, Korea.
                Author notes
                Corresponding author: Young Seok Kim. Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, 170 Jomaru-ro, Wonmi-gu, Bucheon 420-767, Korea. Tel. +82-32-621-6546, Fax. +82-32-621-5080, liverkys@ 123456schmc.ac.kr
                Article
                10.3350/cmh.2014.20.1.38
                3992328
                24757657
                30c9b5f1-33f1-4d5a-ad19-5518c8c5a6aa
                Copyright © 2014 by The Korean Association for the Study of the Liver

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 October 2013
                : 06 February 2014
                : 11 February 2014
                Funding
                Funded by: the Soonchunhyang University Research Fund
                Categories
                Original Article

                Gastroenterology & Hepatology
                lipid metabolism,insulin resistance,chronic hepatitis c
                Gastroenterology & Hepatology
                lipid metabolism, insulin resistance, chronic hepatitis c

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