Hepatic steatosis and hepatitis C: Still unhappy bedfellows?
Shinn-Jang Hwang1,2,
Shou-Dong Lee2,*
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1440-1746.2010.06542.x
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Abstract
Hepatic steatosis is commonly seen in patients with chronic hepatitis C virus (HCV) infection, and the prevalence is much higher prevalence than in the general population or in patients with chronic hepatitis B. Hepatic steatosis in patients with chronic hepatitis C can be due to alcohol consumption and host metabolic factors such as high body mass index (BMI), obesity, hyperlipidemia, metabolic syndrome and diabetes mellitus in which insulin resistance plays an important role. However, in genotype 3 HCV infection, hepatic steatosis can result from direct viral cytopathic effect. Demographic and clinical characteristics associated with hepatic steatosis in patients with chronic hepatitis C including older age, higher BMI, more genotype 3 infection, and higher mean serum levels of triglyceride, alanine aminotransferase and -glutamyl transpeptidase. The clinical relevance of hepatic steatosis in patients with chronic hepatitis C includes a close correlation with hepatic fibrosis, and a poor response to combination peginterferon and ribavirin treatment. In addition, hepatic steatosis has been reported to associate with increased frequency of hepatocellular carcinoma in patients with chronic HCV infection. Whether life style modification such as weight reduction or adding an insulin resistance reducing agent such as metformin or thiazolidinediones combined with current standard peginterferon plus ribavirin treatment will benefit to the chronic hepatitis C patients with hepatic steatosis deserves further evaluation.
Introduction
Hepatitis C virus (HCV), discovered in 1989, is estimated to affect approximately 200 million people worldwide, and has a global prevalence of 3% with geographical variability.1 More than 80% of patients with HCV infection progress to chronicity, 20–30% of patients with chronic HCV infection progress to cirrhosis in 10 to 20 years, and some develop hepatocellular carcinoma (HCC).2 Thus, chronic HCV infection has become the most important cause of chronic liver disease worldwide after hepatitis B virus (HBV) infection, and in the future may be more so since the successful control of childhood acquisition of HBV by vaccination in most developed countries. Common histological characteristics seen in the liver of patients with chronic hepatitis C include steatosis, bile duct damage and portal lymphoid aggregation/follicles.3 In addition, chronic hepatitis C has been intriguingly associated with extrahepatic manifestations such as cryoglobinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, low-grade B cell lymphoma, and recently type 2 diabetes mellitus (DM).4,5
Hepatic steatosis, or fatty liver, is defined by the accumulation of lipid droplets in hepatocytes. It can be characterized by microvesicular and/or macrovesicular steatosis.6,7 Microvesicular steatosis is related to defective metabolism of free fatty acidse such as occurs with acute fatty liver of pregnancy and Reye's syndrome, whereas macrovesicular steatosis is related to complex alterations of lipid turnover that include increased delivery, enhanced synthesis (lipogenesis), inadequate fatty acid oxidation and/or reduced secretion of various forms of lipids in the liver. Macrovesicular steatosis is found in various clinical conditions including excessive alcohol intake, obesity, hyperlipidemia and DM. Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis in the absence of excessive alcohol intake, viral infections or toxin exposure. It encompasses a spectrum of disease ranging from simple steatosis to steatoheaptitis (NASH), with or without the development of fibrosis and cirrhosis.8 NAFLD/NASH is one of the most common causes of elevated liver enzymes and chronic liver disease in Westerns counties and Asia (see review by Wong and Chitturi in this supplement).9–11 The community prevalence of NAFLD and NASH among most Asian and Western populations has been estimated to be 20–30% and 2–3%, respectively.12
The prevalence of hepatic steatosis in patients with chronic hepatitis C is much higher than that in the general population.13–21 The pathogenic association between HCV infection and hepatic steatosis is multifactorial. Two forms of hepatic steatosis are found in patients with chronic hepatitis C. Metabolic steatosis is related to risk factors such as obesity, hyperlipidemia, metabolic syndrome and DM; this accounts for the majority of steatotic patients infected by non-genotype 3 HCV. In contrast, in HCV genotype-3-infected patients, steatosis is mainly induced by the direct cytopathic effects of HCV. This review discusses current knowledge of HCV-related steatosis including prevalence, pathogenesis, clinical characteristics, relevance and managements.
Prevalence of hepatic steatosis in patients with chronic hepatitis C
Despite the fact that hepatic steatosis and HCV infection are both relatively common in the general population, the prevalence of hepatic steatosis in patients with chronic hepatitis C ranges from 42 to 73% (mean, 50%),13–22 which is much higher than the general population (Table 1). Thus, the association of chronic HCV infection with hepatic steatosis is greater than could be explained by chance alone. In addition, hepatic steatosis is present in only about 18%–27% of patients with chronic HBV infection.23,24 In 1996, researchers showed that HCV core protein expressed in either cell culture system or transgenic mice directly led to the development of hepatic steatosis.25,26 Since then, numerous basic and clinical studies have been published with the aim of understanding the underlying pathogenesis of hepatic steatosis in patients with chronic hepatitis C and its clinical relevance.
Metabolic steatosis in patients with chronic hepatitis C
Several factors have been linked to hepatic steatosis in patients with chronic hepatitis C including alcohol consumption and risk factors for NAFLD/NASH; the latter include older age, high body mass index (BMI), obesity and the presence of hyperlipidemia or DM. Steatosis related to these metabolic factors in patients with chronic hepatitis C is usually independent of HCV genotype. Recently, insulin resistance (IR) and DM have been linked to hepatic steatosis in patient with chronic HCV infection, particularly non-3 genotype.
Type 2 DM is an important risk factor in patients with NAFLD/NASH.10,27 In chronic hepatitis C, the prevalence of type 2 DM is higher than in healthy controls or in patients with chronic hepatitis B.28–33 A meta-analyses of 34 studies revealed an adjusted odds ratio of 1.67 (95% confidence interval: 1.28–2.06) for chronic hepatitis C patients to have DM when compared with HCV non-infected subjects.34 A prospective study of middle-aged subjects showed that patients chronically infected with HCV have a two-fold risk of developing DM compared with those without HCV infection, and the risk increased to 11-fold in high risk patients after adjusting for the known effects of family history, age and BMI.31 In addition, patients with DM have a higher risk of contracting HCV infection than the general population.35,36
Despite the close association of chronic HCV infection and the development of DM, the pathogenic basis of this interaction remains to be elucidated. The presence of HCV RNA in pancreatic tissue could imply a direct cytopathic effect of HCV on pancreatic β-cells leading to the development of DM, but this would be more likely to explain insulinopenic (type 1) DM than the T2DM that occurs with chronic HCV infection.37,38 Further, induction of insulin resistance (IR) by HCV infection leading to the development of DM has been recently recognized, thereby providing a more plausible explanation of the high prevalence of DM in patients with chronic hepatitis C.
Patients with chronic hepatitis C have an increased risk of IR and impaired glucose metabolism.39,40 Likewise, higher levels of fasting serum insulin, C-peptide, and homeostatic model assessment (HOMA-IR) (a static measure of insulin resistance) are higher among patients with chronic HCV infection than in age-matched controls.30,40 In patients with chronic hepatitis C, there association has been reported between the severity of IR or actual DM and high HCV viral load, while improvement of IR after a sustained response to anti-viral treatment suggests a causal relation between HCV infection and IR/DM.41–45 In HCV core-gene transgenic mice, intraperitoneal insulin injection failed to lower plasma glucose concentration, displaying IR. This study also demonstrated that transgenic mice had a higher serum tumour necrosis factor-alpha (TNF-) than control mice, and the administration of anti-TNF- antibody restored insulin sensitivity.46 TNF- induces IR through the inhibition of insulin receptor substrate (IRS-1) tyrosine phosphorylation, hypophosphorylation of IRS-2 and impairing the translocation of glucose transporter GLUT4 to the cell membrane, thus diminishing the cellular glucose uptake.47–49
IR results in important changes in development of hyperinsulinemia, which itself can mediate important changes in lipid metabolism. It can induce hepatic steatosis by increasing influx of free fatty acids to the liver, owing to increased peripheral lipolysis, and it can increase hepatic lipogenesis via activation of the lipogenic transcription factor, sterol-regulatory element binding protein-1 (SREBP1).50 In addition, reduced fatty acid oxidation and decreased export of triglycerides from liver tissue in the form of very low density lipoprotein (VLDL) are other consequences of IR that would further accentuate hepatic steatosis. Furthermore, hyperinsulinemia increased glycogenolysis and lead to increase fatty acid synthesis in hepatocytes.,51 It can also directly activate SREBP1, leading to lipogenesis.52
Viral steatosis in patients with chronic hepatitis C
Genotype 3
HCV genotype 3 infection is independently associated with hepatic steatosis in patients with chronic hepatitis C.17,18,20,53 Thus, the severity of steatosis is directly related to the HCV viral load.15,18,21,53 Hepatic steatosis was found to disappear in patients infected by HCV genotype 3 who had a sustained viral response to a standard peginterferon plus ribavirin treatment, and to recur when HCV relapsed.18,21,53,54 Such a phenomenon was not observed in other HCV genotypes. The aforementioned clinical observations all point to the ability of HCV genotype 3 virus to directly induce hepatic steatosis.
HCV genotype 3 was three times more potent for inducing steatosis than other genotypes in in vitro studies.55 In animal studies, HCV core protein can induce the appearance of lipid droplets in transgenic mice.25 There was a topological relation with the HCV core protein being localized in the membrane of lipid vesicles.56 Several mechanisms have been proposed in the pathogenesis of HCV-induced steatosis. For instance, inhibition of microsomal triglyceride transfers protein activity by HCV core protein, an enzyme transfers lipids to endoplamic reticulum, allowing its integration to B apolipoprotein and triglyceride-rich VLDL assembly, was observed in one animal study.57 Hepatic steatosis could then develop in response to decreased hepatocyte lipid export as a consequence of a decreased assembly of triglycerides in VLDL particles and in VLDL secretion.
Secondly, reduced transcriptional activity of peroxisome proliferator activating receptor (PPAR) enhancs fatty acid uptake and reduces mitochondrial long chain fatty acid β-oxidation, similarly leading to hepatic steatosis.58 Dharancy et al. showed that PPAR levels and target gene expression were significantly decreased in chronic hepatitis C patients when compared with controls.59 De Gottardi et al. showed that PPAR mRNA was further reduced in the liver of HCV genotype 3 patients when compared with genotype 1.60 On the other hand, promotion of de novo fatty acid synthesis by increased SREBP1 and 2 activities (caused by nuclear expression of these proteins), transcription factors which induce genes involving in lipogenesis and cholesterologenesis, respectively, and SREBP mRNA was found to increased in cells transfected with HCV core protein, leading to increased fatty acid synthesis in hepatocytes.61
Clinical relevance of hepatic steatosis in chronic HCV infection: disease severity
Our retrospective literature review on the large clinical studies (case series more than 100 subjects) concerning hepatic steatosis in chronic hepatitis C patients found that the clinical characteristics associated with hepatic steatosis in patients with chronic hepatitis C include older age, higher BMI, genotype 3 infection, higher mean serum triglyceride level, alanine aminotransferase and gamma-glutamyl transpeptidase (-GT) activities (Table 1). An interesting finding is that chronic hepatitis C patients with steatosis have a higher mean serum -GT than those without steatosis.14,15,62,63-GT participates in the transfer of amino acids across cell membrane, and also in glutathione (an anti-oxidant) metabolism. The induction of -GT is an adaptive response against oxidative stress elicited by lipid peroxidation in the presence of hepatic steatosis.63 In addition, serum -GT levels are significantly correlated with IR in Pima Indian children.64 Elevated serum -GT in patients with chronic hepatitis C patients is associated with higher liver fibrotic score and may be a critical pointer to progression of the disease.65,66
Clinicians are also interested to know whether hepatic steatosis in patients with chronic hepatitis C, either metabolic or virus-induced, contributes to progression of liver fibrosis or is just simply an “innocent bystander.” Most retrospective studies have shown positive correlations between severity of steatosis and stage of hepatic fibrosis.14–16,18–21 Multivariate analyses identified steatosis as a significant predictor of liver fibrosis in most of these studies.13,14,18,21,53 Our previous study revealed that mean HOMA-IR progressively increase according to the severity of hepatic fibrosis in 192 Chinese patients with chronic hepatitis C; there was a significant correlation between HOMA-IR and METAVIR fibrotic score in these patients.67 A multinational, multicentre meta-analysis further confirmed that steatosis was independently associated with fibrosis severity in patients with chronic hepatitis C.22 Besides cross-sectional studies with single biopsy specimens, a longitudinal study conducted by French researchers showed that worsening of steatosis was the only independent predicting factor of progression of liver fibrosis in untreated patients with chronic hepatitis C for whom paired liver biopsies were obtained at an average interval of four years.68
There are also good pathological associations among hepatic steatosis, IR and oxidative stress-induced fibrosis. IR may lead to increased production of reactive oxygen species and secondary up-regulation of antioxidant genes, glycosylation of low density lipoprotein and the formation of advanced glycation end-products, finally to activate hepatic stellate cells and facilitate transition to the myofibroblast phenotype.69,70In vitro, hepatocyte culture medium undergoing oxidative stress increased proliferation activities and collagen production of hepatic stellate cells.71 Overall, hepatic steatosis, whether metabolic or virus-induced, may lead to the progression of fibrosis, and this needs to be addressed when managing chronic hepatitis C patients with hepatic steatosis.
Clinical relevance: treatment response
Another interesting question is whether hepatic steatosis will affect the results of treatment in patients with chronic hepatitis C. Most studies showed that hepatic steatosis in patients with chronic hepatitis C was correlated negatively with sustained virological response (SVR) to peginterferon and ribavirin treatment.18,21,54,68 IR appears to have a mechanistically important role in this phenomenon. Thus, raised HOMA-IR was associated with reduced treatment responses, irrespective of HCV genotype (1, 2 and 3).72–74
Role in hepatocarcinogenesis
Finally, HCC is an important long-term complication in patients with chronic HCV infection.75,76 Recently, HCC has also been recognized as a complication of NAFLD or NASH.77,78 Previous in vitro and in vivo studies have shown that HCV core protein expression either in cell cultures or in transgenic mice led to the development of hepatic steatosis, and also contributes to carcinogenesis.25,79–82 Tanaka et al. showed that persistent activation of PPAR is required for the development of HCV core protein-induced hepatic steatosis and HCC in their transgenic mice model.83 Several clinical studies have now confirmed that hepatic steatosis is an independent risk factor of HCC in patients with chronic hepatitis C.84,85 It is correlated with the risk of postoperative recurrence of HCV-related HCC.86 The one contradictory report may have been under-powered and too short in duration to observe this effect.87 Whether chronic hepatitis C patients with hepatic steatosis run a higher risk of developing HCC than those without steatosis deserves greater attention in future studies.
Management of hepatic steatosis in patients with chronic hepatitis C
Currently, the state of the art treatment for chronic hepatitis C is the combination of peginterferon and ribavirin, which confers an SVR rate in 50–80% of cases.88 However, both hepatic steatosis and obesity are negatively correlated with SVR after combination treatment. Weight loss in chronic hepatitis C patients could reduce serum transaminase, fasting insulin level, steatosis and fibrosis.89,90 Life-style modifications such as weight reduction, exercise, and specific diets that are commonly recommended for patients with NAFLD/NASH should be applied in chronic hepatitis C patients with hepatic steatosis if metabolic risk factors exist.
IR has a major negative impact on SVR in patients with chronic hepatitis C receiving peginterferon and ribavirin treatment, especially in genotype 1 patients. A large, multicentre, double-blind, randomized control trial showed that addition of oral metformin with peginterferon and ribavirin could decrease IR and increase SVR rate as compared with the control group.91 Whether combining an IR reducing agent such as metformin or thiazolidinediones will have additional benefit over peginterferon plus ribavirin treatment in patients with chronic hepatitis C deserves further clinical evaluation.
Conclusions
Hepatic steatosis is commonly seen in patients with chronic hepatitis C due to host metabolic factors such as obesity, hyperlipidemia, metabolic syndrome and type 2 diabetes mellitus in which insulin resistance plays an important role. However, in HCV genotype 3 infection, hepatic steatosis can be due to direct viral cytopathic effects. Hepatic steatosis in patients with chronic hepatitis C correlates with hepatic fibrosis and affected patients are substantially less likely to experience treatment response to the combination of peginterferon and ribavirin. In addition, hepatic steatosis has been reported to associate with increased frequency of HCC in patients with chronic hepatitis C. Whether lifestyle modification, such as weight reduction, or adding an insulin sensitizing agent such as metformin or thiazolidinediones, in combination with the current standard of care (peginterferon plus ribavirin) treatment, will benefit those chronic hepatitis C patients with hepatic steatosis deserves further evaluation.
World Health Organization. Hepatitis C- global surveillance update. Wkly. Epidemiol. Rec. 2000; 75: 17–28.
PubMed
2
Hwang SJ. Hepatitis C virus infection: an overview. J. Clin. Microbiol. Immunol. Infect. 2001; 34: 227–34.
PubMed,
ChemPort
3
Scheuer PJ, Afshrafzadeh P, Sherlock S, Brown D, Dusheiko GM. The pathology of hepatitis C. Hepatology 1992; 15: 567–71.
Direct Link:
Abstract
PDF(622K)
References
4
Palekar NA, Harrison SA. Extrahepatic manifestations of hepatitis C. South. Med. J. 2005; 98: 1019–23.
CrossRef,
PubMed,
Web of Science® Times Cited: 9
5
Hwang SJ, Chen LK. Chronic hepatitis C and diabetes Mellitus. J. Chin. Med. Assoc. 2006; 69: 143–5.
CrossRef,
PubMed
6
Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin. Liver Dis. 2001; 21: 3–16.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 292
7
Burt AD, Mutton A, Day CP. Diagnosis and interpretation of steatosis and steatohepatitis. Semin. Diagn. Pathol. 1998; 15: 246–58.
PubMed,
ChemPort,
Web of Science® Times Cited: 120
8
Angulo P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 2002; 346: 1221–31.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 1118
9
Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gatroenterology 2002; 122: 1649–57.
CrossRef,
PubMed,
Web of Science® Times Cited: 297
10
Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated amniotransferase among US adolescents and associated factors: NHANES 1999–2004. Gastroenterology 2007; 133: 1814–20.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 40
11
Tories DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gatroenterology 2008; 134: 1682–98.
CrossRef,
ChemPort,
Web of Science® Times Cited: 64
12
Neuschwander TBA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003; 37: 1202–19.
Direct Link:
Abstract
PDF(268K)
References
13
Hourigan LF, Macdonald GA, Purdie D et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29: 1215–9.
Direct Link:
Abstract
PDF(82K)
14
Hwang SJ, Luo JC, Chu CW et al. Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation. J. Gastroenterol. Hepatol. 2001; 16: 190–5.
Direct Link:
Abstract
Full Article (HTML)
PDF(68K)
References
15
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 1358–64.
Direct Link:
Abstract
PDF(117K)
References
16
Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002; 36: 729–36.
Direct Link:
Abstract
PDF(113K)
References
17
Hui JM, Kench J, Farrell GC et al. Genotype-specific mechanisms for hepatitis steatosis in chronic hepatitis C infection. J. Gatroenterol. Hepatol. 2002; 17: 873–81.
Direct Link:
Abstract
Full Article (HTML)
PDF(115K)
References
18
Poynard T, Ratziu V, McHutchison J et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003; 38: 75–85.
Direct Link:
Abstract
PDF(199K)
References
19
Asselah T, Boyer N, Guimont MC et al. Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Gut 2003; 52: 1638–43.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 69
20
Rubbia-Brandt L, Fabris P, Paganin S et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004; 53: 406–12.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 132
21
Patton HM, Patel K, Behling C et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J. Hepatol. 2004; 40: 484–90.
CrossRef,
PubMed,
Web of Science® Times Cited: 156
22
Leandro G, Mangia A, Hui J et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006; 130: 1636–42.
CrossRef,
PubMed,
Web of Science® Times Cited: 129
23
Thomopoulos KC, Arvaniti V, Tsmantas AC et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of association factors and of relationship with fibrosis. Eur. J. Gastroenterol. Hepatol. 2006; 18: 233–7.
CrossRef,
PubMed,
Web of Science® Times Cited: 37
24
Peng D, Han Y, Ding H, Wei L. Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral marker. J. Gatroenterol. Hepatol. 2008; 23: 1082–8.
Direct Link:
Abstract
Full Article (HTML)
PDF(89K)
References
25
Moriya K, Yotsuyanagi H, Shintani Y et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol 1997; 78: 1527–31.
PubMed,
ChemPort
26
Barba G, Harper F, Harada T et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 1200–5.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 327
27
Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin. Gastroenterol. Hepatol. 2004; 2: 1048–58.
CrossRef,
PubMed
28
Caronia S, Taylor K, Pagliaro L et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999; 30: 1059–63.
Direct Link:
Abstract
PDF(83K)
References
29
Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann. Intern. Med. 2000; 133: 592–9.
PubMed,
ChemPort,
Web of Science® Times Cited: 261
30
Chen LK, Hwang SJ, Tsai ST, Luo JC, Lee SD, Chang FY. Glucose intolerance in Chinese patients with chronic hepatitis C. World J. Gastroenterol. 2003; 9: 505–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 8
31
Mehta SH, Brancati FL, Strathdee SA et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology 2003; 38: 50–6.
Direct Link:
Abstract
PDF(139K)
References
32
Antonelli A, Ferri C, Fallahi P et al. Hepatitis C virus infection, evidence for an association with type 2 diabetes. Diabetes Care 2005; 28: 2548–50.
CrossRef,
PubMed,
Web of Science® Times Cited: 35
33
Zein CO, Levy C, Basu A, Zein NN. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am. J. Gatroenterol. 2005; 100: 48–55.
Direct Link:
34
White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J. Hepatol. 2008; 49: 831–44.
CrossRef,
PubMed,
Web of Science® Times Cited: 21
35
Simo R, Jardi R, Hernandez C, Mesa J, Genesca J. High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care 1996; 19: 998–1000.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 137
36
Chen HF, Li CY, Chen P, See TT, Lee HY. Seroprevalence of hepatitis B and C in type 2 diabetes patients. J. Chin. Med. Assoc. 2006; 69: 146–52.
CrossRef,
PubMed
37
Laskus T, Radkowski M, Wang LF, Vargas H, Rakela J. Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative-strain viral RNA in various tissue. Hepatology 1998; 28: 1398–401.
Direct Link:
Abstract
PDF(88K)
References
38
Gowans EJ. Distribution of markers of hepatitis C virus infection throughout the body. Semin. Liver Dis. 2000; 20: 85–102.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 48
39
Sougleri M, Labropoulou-Karatza C, Paraskevopoulou P, Fragopanagou H, Alexandrides T. Chronic hepatitis C virus infection without cirrhosis induces insulin resistance in patients with alpha-thalasemia major. Eur. J. Gastroenterol. Hepatol. 2001; 13: 1195–9.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 11
40
Hui JM, Sud A, Farrell GC et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology 2003; 125: 1695–704.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 257
41
Tai TY, Lu JY, Chen CL et al. interferon alpha reduces insulin resistance and beta cell secretion in responders among patients with chronic hepatitis B and C. J. Endocrinol. 2003; 178: 457–65.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 20
42
Simo R, Lecube A, Genesca J, Esteban JI, Hernandez C. Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care 2006; 29: 2462–6.
CrossRef,
PubMed,
Web of Science® Times Cited: 29
43
Kawaguchi T, Ide T, Taniguchi E et al. Clearance of HCV improves insulin resistance, beta cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am. J. Gastroenterol. 2007; 102: 570–6.
Direct Link:
44
Hsu CS, Liu CJ, Liu CH et al. High hepatitis viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int. 2008; 28: 271–7.
Direct Link:
Abstract
Full Article (HTML)
PDF(98K)
References
45
Moucari R, Asselah T, Cazals-Hatem D et al. Insulin resistance in chronic hepatitis C: association with genotype 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416–23.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 98
46
Shintani Y, Fujie H, Miyoshi H et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004; 126: 840–8.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 290
47
Hotamisligil GS. The role of TNF alpha and TNF receptor in obesity and insulin resistance. J. Intern. Med. 1999; 245: 621–5.
Direct Link:
Abstract
Full Article (HTML)
PDF(97K)
References
48
Knobler H, Zhornicky T, Sandler A, Haran N, Ashur Y, Schattner A. Tumor necrosis factor--induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am. J. Gastroenterol. 2003; 98: 2751–6.
PubMed,
ChemPort,
Web of Science® Times Cited: 48
49
Fernandez-Veledo S, Hernandez R, Teruel T, Mas JA, Ros M, Lorenzo M. Ceramide mediates TNF-alpha-induced insulin resistance on GLUT4 gene expression in brown adipocytes. Arch. Physiol. Biochen. 2006; 112: 13–32.
CrossRef,
ChemPort
50
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 2005; 115: 1343–51.
PubMed,
ChemPort,
Web of Science® Times Cited: 305
51
Sanyal AJ, Campbell-Sargent C, Mirshari F et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183–92.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 573
52
Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J. Virol. 2007; 81: 8122–30.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 48
53
Rubbia-Brandt L, Q uadri R, Abid K et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J. Hepatol. 2000; 33: 106–15.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 241
54
Kumar D, Farrell GC, Fung C et al. Hepatitis C virus genotype 3 is cytopathic to hepatocyte: reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002; 36: 1266–72.
Direct Link:
Abstract
PDF(252K)
References
55
Abid K, Pazienza V, de Gottardi A et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J. Hepatol. 2005; 42: 744–51.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 69
56
Chang ML, Chen JC, Yeh CT et al. Topological and evolutional relationships between HCV core protein and hepatic lipid vesicles: studies in vitro and in conditionally transgenic mice. World J. Gastroenterol. 2007; 13: 3472–7.
PubMed,
ChemPort,
Web of Science® Times Cited: 5
57
Perlemute G, Sabile A, Letteron P et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002; 16: 185–94.
CrossRef,
PubMed,
Web of Science® Times Cited: 228
58
Ferre P. The biology of perosisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53 (Suppl. 1): S43–50.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 187
59
Dharancy S, Malapel M, Perlemuter G et al. Impaired expression of the peroxisome proliferator-activated receptor-alpha during hepatitis C virus infection. Gastroenterology 2005; 128: 334–42.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 62
60
De Gottardi A, Pazienza V, Pugnale P et al. Peroxisome proliferator-activated receptor alpha and –gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment. Pharmacol. Ther. 2006; 23: 107–14.
Direct Link:
Abstract
Full Article (HTML)
PDF(194K)
References
61
Kim KH, Hong SP, Kim K, Park MJ, Kim KJ, Cheong J. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochem. Biophys. Res. Commun. 2007; 355: 883–8.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 30
62
Benini F, Pigozzi MG, aisini O et al. Increased serum gamma-glutamyl-transpeptidase concentration is associated with nonalcoholic steatosis and not with cholestasis in patients with chronic hepatitis C. J. Gastroenterol. Hepatol. 2007; 22: 1621–6.
Direct Link:
Abstract
Full Article (HTML)
PDF(131K)
References
63
Fierbinteanu-braticevici C, Mohora M, Cretoiu D et al. Role of oxidative stress in the pathogenesis of chronic hepatitis C (CHC). Roman. J. Morphol. Embryol. 2009; 50: 407–12.
64
Ortega E, Koska J, Salbe AD, Tataranni PA, Bunt JC. Serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in Pima Indian children. J. Clin. Endocrinol. Metab. 2006; 91: 1419–22.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 13
65
Hwang SJ, Luo JC, Lai CR et al. Clinical, virologic and pathologic significance of elevated serum -glutamyl transpeptidase in patients with chronic hepatitis C. Chin. Med. J. (Taipei) 2000; 63: 527–35.
PubMed,
ChemPort
66
Silva ISS, Ferraz MLCG, Perez RM, Lanzoni VP, Figueiredo VM, Silva AEB. Role of -glutamyl transferase activity in patients with chronic hepatitis C virus infection. J. Gastroenterol. Hepatol. 2004; 19: 314–8.
Direct Link:
Abstract
Full Article (HTML)
PDF(78K)
References
67
Chu CJ, Hung TH, Hwang SJ et al. Association of insulin resistance with hepatic steatosis and progression of fibrosis in Chinese patients with chronic hepatitis C. Hepatogastroenterology 2008; 55: 2157–61.
PubMed,
Web of Science®
68
Castéra L, Hézode C, Roudot-Thoraval F et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsy. Gut 2003; 52: 288–92.
CrossRef,
PubMed,
Web of Science® Times Cited: 142
69
Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and aging. Free Radic. Biol. Med. 1991; 10: 339–52.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 500
70
Fehrenbach H, Weiskirchen R, Kasper M et al. Up-regulated expression of the receptor for advanced glycation end products in culture rat hepatic stellate cell during transdifferentiation to myofibroblasts. Hepatology 2001; 34: 943–52.
Direct Link:
Abstract
PDF(396K)
References
71
Svegliati Baroni D, D'Ambrosio L, Ferretti G et al. Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology 1998; 27: 720–6.
Direct Link:
Abstract
PDF(151K)
References
72
Chu CJ, Lee SD, Huang TH et al. Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis C patients receving peginterferon -2b plus ribavirin. Aliment. Pharmacol. Ther. 2008; 29: 46–54.
Direct Link:
Abstract
Full Article (HTML)
PDF(153K)
References
73
Poustchi H, Negro F, Hui J et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotype 2 and 3. J. Hepatol. 2008; 48: 28–34.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 46
74
Dai CY, Huang JF, Hsieh MY et al. Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients. J. Hepatol. 2009; 50: 712–8.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 18
75
Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet 1998; 351: 214–5.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 195
76
El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N. Engl. J. Med. 1999; 340: 745–50.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 1365
77
Marreto JA, Fontana RJ, Su GL et al. NAFLD may be a common underlying liver disease in patients with HCC in the United States. Hepatology 2002; 36: 1349–54.
PubMed,
Web of Science® Times Cited: 164
78
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820–32.
Direct Link:
Abstract
Full Article (HTML)
PDF(308K)
References
79
Moradpour D, Englert C, Wakira T, Wands JR. Characterization of cell lines allowing tightly regulated expression of hepatitis C virus core protein. Virology 1996; 222: 51–63.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 123
80
Moriya K, Fujie H, Shintani Y et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mouse. Nat. Med. 1998; 4: 1065–7.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 576
81
Moriya K, Nakagawa K, Santa T et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 2001; 61: 4365–70.
PubMed,
ChemPort,
Web of Science® Times Cited: 199
82
Lerat H, Honda M, Beard MR et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002; 122: 352–65.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 217
83
Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzale FJ, Aoyama T. PPAR activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J. Clin. Invest. 2008; 118: 683–94.
PubMed,
Web of Science® Times Cited: 50
84
Ohata K, Hamasaki K, Kan T et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003; 97: 3063–43.
Direct Link:
Abstract
Full Article (HTML)
PDF(102K)
References
85
Tanaka A, Uegaki S, Kurihara H et al. Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C. World J. Gastroenterol. 2007; 13: 5180–7.
PubMed,
ChemPort,
Web of Science® Times Cited: 11
86
Takuma Y, Nouso K, Makino Y et al. Hepatic steatosis correlates with the postoperative recurrence of hepatic C virus-associated hepatocellular carcinoma. Liver Int. 2007; 27: 620–6.
Direct Link:
Abstract
Full Article (HTML)
PDF(120K)
References
87
Kumar D, Farrell GC, Kench J, George J. Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C. J. Gastroenterol. Hepatol. 2005; 20: 1395–400.
Direct Link:
Abstract
Full Article (HTML)
PDF(99K)
References
88
Lee SD, Yu ML, Cheng PN et al. Comparison of a 6-month Course Peginterferon -2b plus ribavirin and interferon-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan. J. Viral Hepat. 2005; 12: 283–91.
Direct Link:
Abstract
Full Article (HTML)
PDF(121K)
References
89
Clouston AD, Jonsson JR, Purdie DM et al. Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation. J. Hepatol. 2001; 34: 314–20.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 76
90
Hickman IJ, Clouston AD, Macdonald GA et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002; 51: 89–94.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 131
91
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