Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection
Jason M Hui
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorGeoffrey C Farrell
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorRita Lin
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorDev Samarasinghe
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorChristopher Liddle
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorKaren Byth
Medicine, Westmead Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Jacob George
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Dr J George, Storr Liver Unit, Department of Medicine, Westmead Hospital, Westmead, NSW 2145, Australia. Email: [email protected]Search for more papers by this authorJason M Hui
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorGeoffrey C Farrell
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorRita Lin
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorDev Samarasinghe
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorChristopher Liddle
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Search for more papers by this authorKaren Byth
Medicine, Westmead Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Jacob George
Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Departments of
Dr J George, Storr Liver Unit, Department of Medicine, Westmead Hospital, Westmead, NSW 2145, Australia. Email: [email protected]Search for more papers by this authorAbstract
Abstract Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non-alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection.
Methods: In 124 chronic hepatitis C patients, the association between liver histology and the following was investigated: demographic and anthropometric data, alcohol intake, alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein–cholesterol, high-density lipoprotein–cholesterol, triglyceride, transferrin saturation, ferritin, insulin, c-peptide, glucose and insulin resistance (homeostasis model).
Results: By multivariate analysis, genotype 3 was associated with increased steatosis grade (P = 0.02). There were significant pairwise interactions between genotype 3 status and total cholesterol (P = 0.01), current alcohol intake (P = 0.04) and serum ALT (P = 0.01). This showed that the etiology of steatosis was different in patients with genotype 3 and those with non-genotype 3 chronic hepatitis C infection. In genotype 3 patients, the degree of steatosis was inversely associated with serum cholesterol (P = 0.005) and positively associated with serum triglyceride (P = 0.02). There was no association between body mass index (BMI) and the extent of steatosis. Among patients with other genotypes, the steatosis grade was strongly influenced by BMI (P < 0.0001) and serum ALT (P < 0.01). Independent predictors of fibrosis were age (P = 0.001), past alcohol intake (P = 0.04), ALT (P = 0.002), serum insulin (P = 0.001) and portal inflammation (P < 0.001).
Conclusions: Hepatitis C genotype 3 may interfere with pathways of hepatic lipid metabolism, whereas increased BMI appears to be a more important pathogenic factor in other genotypes. Although steatosis and BMI were not associated with hepatic fibrosis, their relationship with serum insulin suggests that metabolic factors related to insulin action could influence fibrogenesis in hepatitis C.
References
- 1 Bach N, Thung SN, Schaffner F. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: A comparative analysis. Hepatology 1992; 15: 572–4.
- 2 Lefkowitch JH, Schiff ER, Davis GL et al.. Pathological diagnosis of chronic hepatitis C. A multicenter comparative study with chronic hepatitis B. Gastroenterology 1993; 104: 595–603.
- 3 Giannini E, Ceppa P, Botta F et al.. Steatosis and bile duct damage in chronic hepatitis C. Distribution and relationships in a group of northern Italian patients. Liver 1999; 19: 432–7.
- 4 Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J. Hepatol. 1998; 29: 198–206.
- 5 Hourigan LF, Macdonald GA, Purdie D et al.. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29: 1215–19.
- 6 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.
- 7 Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997; 25: 735–9.
- 8 Rubbia-Brandt L, Quadri R, Abid K et al.. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J. Hepatol. 2000; 33: 106–15.DOI: 10.1016/S0168-8278(00)80166-X
- 9 Adinolfi LE, Utili R, Andreana A et al. Relation-ship between HCV genotypes of hepatitis C virus and histopathological manifestations in chronic hepatitis C patients. Eur. J. Gastroenterol. Hepatol. 2000; 12: 299–304.
- 10
Fujie H,
Yotsuyanngi H,
Morija K et al..
Steatosis and intrahepatic hepatitis C virus in chronic hepatitis.
J. Med. Virol.
1999; 59: 141–5.DOI: 10.1002/(SICI)1096-9071(199910)59:2<141::AID-JMV3>3.3.CO;2-X
10.1002/(SICI)1096-9071(199910)59:2<141::AID-JMV3>3.0.CO;2-5 CAS PubMed Web of Science® Google Scholar
- 11 Khan MH, Thomas L, Byth K et al.. How much does alcohol contribute to the variability of hepatic fibrosis in chronic hepatitis C? J. Gastroenterol. Hepatol. 1998; 13: 419–26.
- 12 International Diabetes Institute. The Asia-Pacific Perspective: Redefining Obesity and its Treatment. Melbourne: Health Communications Australia, 2000.
- 13 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 1972; 18: 499–502.
- 14 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment. insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–19.
- 15 Bonora E, Targher G, Alberiche M et al.. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: Studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000; 23: 57–63.
- 16 Petrides AS, Vogt C, Schulze-Berge D, Matthews Strohmeyer G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994; 19: 616–27.
- 17 Merli M, Leonetti F, Riggio O et al.. Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation. Hepatology 1999; 30: 649–54.
- 18 Scheuer PJ. Classification of chronic viral hepatitis: A need for reassessment. J. Hepatol. 1991; 13: 372–4.
- 19 Khan MH, Farrell GC, Byth K et al.. Which patients with hepatitis C develop liver complications? Hepatology 2000; 31: 513–20.
- 20 Shev S, Widell A, Foberg A et al.. HCV genotypes in Swedish blood donors as correlated to epidemiology, liver disease and hepatitis C virus antibody profile. Infection 1995; 23: 253–7.
- 21 Fiore G, Fera G, Napoli N, Vella F, Schiraldi O. Liver steatosis and chronic hepatitis C. A spurious association? Eur. J. Gastroenterol. Hepatol. 1996; 8: 125–9.
- 22 Barba G, Harper F, Harada T et al.. Hepatitis C virus core protein shows a cytoplasmic localization and associated to cellular lipid storage droplets. Proc. Natl Acad. Sci. USA 1997; 94: 1200–5.
- 23 Sabile A, Perlemuter G, Bono F et al.. Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates. Hepatology 1999; 30: 1064–76.
- 24 Thomssen R, Bonk S, Thiele A. Density heterogeneities of hepatitis C virus in human sera due to the binding of β-lipoproteins and immunoglobulins. Med. Microbiol. Immunol. 1993; 182: 329–34.
- 25 Agnello V, Abel G, Elfahal M, Knight G, Zhang Q-X. Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proc. Natl Acad. Sci. USA 1999; 96: 12766–71.
- 26 Serfaty L, Andreani T, Giral P, Carbonell N, Chazouilleres O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: A possible mechanism for steatosis in chronic hepatitis C. J. Hepatol. 2001; 34: 428–34.
- 27 Marceau P, Biron S, Hould FS et al.. Liver pathology and the metabolic syndrome X in severe obesity. J. Clin. Endocrinol. Metab. 1999; 84: 1513–17.
- 28 Moberly JB, Cole TG, Alpers DH, Schonfeld G. Oleic acid stimulation of apolipoprotein B secretion from HepG2 and Caco-2 cells occurs post-transcriptionally. Biochim. Biophys. Acta 1990; 20: 70–80.
- 29 Pullinger CR, North JD, Teng BB et al.. The apolipoprotein B gene is constitutively expressed in HepG2 cells: Regulation of secretion by oleic acid, albumin, and insulin, and measurement of the mRNA half-life. J. Lipid Res. 1989; 30: 1065–77.
- 30 Dixon JL, Ginsberg H. Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: Information obtained from cultured liver cells. J. Lipid Res. 1993; 34: 167–79.
- 31 Lo SY, Masiarz F, Hwang SB, Lai MM, Ou JH. Differential subcellular localization of hepatitis C virus core gene products. Virology 1995; 213: 455–61.
- 32 Schonfeld G. The hypobetalipoproteinemias. Annu. Rev. Nutr. 1995; 15: 123–35.
- 33 Tarugi P, Lonardo A, Ballarini G et al.. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology 1996; 111: 1125–33.
- 34 Adinolfi LE, Gambardella M, Andreana A, Tripodi M-F, 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.DOI: 10.1053/jhep.2001.24432
- 35 Abdelmalek M, Ludwig J, Lindor KD. Two cases from the spectrum of nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 1995; 20: 127–30.
- 36 Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis. A follow-up study of forty-two paitents for up to 21 years. Hepatology 1990; 11: 74–80.
- 37 Ostapowicz G, Watson KJR, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998; 27: 1730–5.
- 38 Pianko S, Blatt LM, Behling C et al.. The degree of elevation of ALT levels in chronic hepatitis C virus infection do indicate the degree of histological liver injury. J. Gastroenterol. Hepatol. 2000; 15 (Suppl.): J93 (Abstract).
- 39 Wong VS, Wright DGD, Palmer CR, Alexander GJM. Fibrosis and other histological features in chronic hepatitis C virus infection: A statistical model. J. Clin. Pathol. 1996; 49: 465–9.
- 40 Vaquer P, Canet R, Llompart A, Riera J, Obrador A, Gaya J. Histological evolution of chronic hepatitis C. Factors related to progression. Liver 1994; 14: 265–9.
- 41 American Diabetes Association. Consensus development conference on insulin resistance. Diabetes. Care 1998; 21: 310–14.
- 42 Scharf JG, Knittel T, Dombrowski F et al.. Characterization of the IGF axis components in isolated rat hepatic stellate cells. Hepatology 1998; 27: 1275–84.
- 43 Svegliati-Baroni G, Ridolfi F, Di Sario A et al.. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways. Hepatology 1999; 29: 1743–51.
- 44 Augulo P, Keach J, Batts K, Lindor K. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356–62.
- 45 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.
Citing Literature
