Pathogenesis and significance of hepatitis C virus steatosis: An update on survival strategy of a successful pathogen

World Journal of Gastroenterology

Volumn 20, Issue 23, 2014, Pages 7089-7103

  Lonardo, Amedeo ^a   Adinolfi, Luigi Elio ^b   Restivo, Luciano ^b   Ballestri, Stefano ^a   Romagnoli, Dante ^a   Baldelli, Enrica ^a   Nascimbeni, Fabio ^a   Loria, Paola ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^b SECOND UNIVERSITY OF NAPLES   (Italy)

Author keywords

Atherosclerosis; Fibrosis; Hepatitis C virus; Hepatitis C associated dysmetabolic syndrome; Hepatocellular carcinoma; Steatohepatitis; Sustained virological response

Indexed keywords

ALPHA2B INTERFERON; APOLIPOPROTEIN B100; FATTY ACID; GLUCOSE; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE 3 PHOSPHATASE; RIBAVIRIN; STEROL REGULATORY ELEMENT BINDING PROTEIN; UNCLASSIFIED DRUG; ANTIVIRUS AGENT;

ARTICLE; ATHEROSCLEROSIS; BODY FAT DISTRIBUTION; CANCER GROWTH; DISEASE ASSOCIATION; FATTY LIVER; FIBROGENESIS; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HYPERTENSION; HYPERURICEMIA; HYPOCHOLESTEROLEMIA; INSULIN RESISTANCE; LIPOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; META ANALYSIS (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATION; PATHOGENESIS; RISK FACTOR; TREATMENT FAILURE; TREATMENT RESPONSE; VIRUS SURVIVAL; ANIMAL; COMPLICATION; DRUG EFFECTS; GROWTH, DEVELOPMENT AND AGING; HEPACIVIRUS; HOST PATHOGEN INTERACTION; LIPID METABOLISM; LIVER; LIVER CIRRHOSIS; LIVER TUMOR; METABOLISM; OXIDATIVE STRESS; PATHOGENICITY; PATHOLOGY; PROGNOSIS; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; ATHEROSCLEROSIS; CARCINOMA, HEPATOCELLULAR; FATTY LIVER; HEPACIVIRUS; HEPATITIS C; HOST-PATHOGEN INTERACTIONS; HUMANS; LIPID METABOLISM; LIVER; LIVER CIRRHOSIS; LIVER NEOPLASMS; OXIDATIVE STRESS; PROGNOSIS; RISK FACTORS;

EID: 84902675173     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i23.7089     Document Type: Article

References (134)

1. Kryger P, Christoffersen P. Light microscopic morphology of acute hepatitis non-A, non-B. A comparison with hepatitis type A and B. Liver 1982; 2: 200-206 [PMID: 6817013 DOI: 10.1111/j.1600-0676.1982.tb00197.x]
2. Wiese M, Haupt R. [Histomorphologic picture of chronic non-A, non-B hepatitis]. Dtsch Z Verdau Stoffwechselkr 1985; 45: 101-110 [PMID: 3930205]
3. Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; Epub ahead of print [PMID: 24731669 DOI: 10.1016/S2213-8587(14)70032-4]
4. Lonardo A, Caldwell SH, Loria P. Clinical physiology of NAFLD: a critical overview of pathogenesis and treatment. Expert Rev Endocrinol Metab 2010; 5: 403-423 [DOI: 10.1586/ eem.10.5]
5. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004; 126: 586-597 [PMID: 14762795 DOI: 10.1053/ j.gastro.2003.11.020]
6. Lonardo A, Loria P. The hepatitis C virus-associated dysmetabolic syndrome. Hepatology 2008; 48: 1018-1019; author reply 1019 [PMID: 18756483 DOI: 10.1002/hep.22425]
7. Lonardo A, Loria P, Carulli N. Dysmetabolic changes associated with HCV: a distinct syndrome? Intern Emerg Med 2008; 3: 99-108 [PMID: 18274709 DOI: 10.1007/s11739-008-0127-1]
8. Lonardo A, Ballestri S, Adinolfi LE, Violi E, Carulli L, Lombardini S, Scaglioni F, Ricchi M, Ruggiero G, Loria P. Hepatitis C virus-infected patients are 'spared' from the metabolic syndrome but not from insulin resistance. A comparative study of nonalcoholic fatty liver disease and hepatitis C virus-related steatosis. Can J Gastroenterol 2009; 23: 273-278 [PMID: 19373421]
9. Lonardo A, Adinolfi LE, Loria P. Mechanisms of hepatitis C virus-induced fatty liver disease. Hot Topics Viral Hep 2009; 5: 23-28
10. Adinolfi LE, Restivo L, Zampino R, Lonardo A, Loria P. Metabolic alterations and chronic hepatitis C: treatment strategies. Expert Opin Pharmacother 2011; 12: 2215-2234 [PMID: 21883025 DOI: 10.1517/14656566.2011.597742]
11. Lonardo A, Loria P, Adinolfi LE, Carulli N, Ruggiero G. Hepatitis C and steatosis: a reappraisal. J Viral Hepat 2006; 13: 73-80 [PMID: 16436124 DOI: 10.1111/j.1365-2893.2005.00669. x]
12. Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004; 126: 840-848 [PMID: 14988838 DOI: 10.1053/j.gastro.2003.11.056]
13. Serfaty L, Capeau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int 2009; 29 Suppl 2: 13-25 [PMID: 19187069 DOI: 10.1111/j.1478-3231.2008.01952. x]
14. Lonardo A, Adinolfi LE, Petta S, Craxì A, Loria P. Hepatitis C and diabetes: the inevitable coincidence? Expert Rev Anti Infect Ther 2009; 7: 293-308 [PMID: 19344243 DOI: 10.1586/ eri.09.3]
15. Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012; 56 Suppl 1: S56-S65 [PMID: 22300466 DOI: 10.1016/ S0168-8278(12)60007-5]
16. Lonardo A, Carulli N, Loria P. HCV and diabetes. A twoquestion-based reappraisal. Dig Liver Dis 2007; 39: 753-761 [PMID: 17611176 DOI: 10.1016/j.dld.2007.05.005]
17. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol 2008; 49: 831-844 [PMID: 18814931 DOI: 10.1016/ j.jhep.2008.08.006]
18. Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol 2011; 26: 1361-1367 [PMID: 21649726]
19. Balasubramanyam A, Sekhar RV, Jahoor F, Jones PH, Pownall HJ. Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of 'systemic steatosis'. Curr Opin Lipidol 2004; 15: 59-67 [PMID: 15166810 DOI: 10.1097/00041433-200402000-00011]
20. Guaraldi G, Lonardo A, Ballestri S, Zona S, Stentarelli C, Orlando G, Carli F, Carulli L, Roverato A, Loria P. Human immunodeficiency virus is the major determinant of steatosis and hepatitis C virus of insulin resistance in virus-associated fatty liver disease. Arch Med Res 2011; 42: 690-697 [PMID: 22227046 DOI: 10.1016/j.arcmed.2011.12.009]
21. Aghemo A, Prati GM, Rumi MG, Soffredini R, D'Ambrosio R, Orsi E, De Nicola S, Degasperi E, Grancini V, Colombo M. Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology 2012; 56: 1681-1687 [PMID: 22619107 DOI: 10.1002/ hep.25867]
22. Kuo YH, Chuang TW, Hung CH, Chen CH, Wang JH, Hu TH, Lu SN, Lee CM. Reversal of hypolipidemia in chronic hepatitis C patients after successful antiviral therapy. J Formos Med Assoc 2011; 110: 363-371 [PMID: 21741004 DOI: 10.1016/S0929-6646(11)60054-5]
23. Blaising J, Pécheur EI. Lipids: a key for hepatitis C virus entry and a potential target for antiviral strategies. Biochimie 2013; 95: 96-102 [PMID: 22884392 DOI: 10.1016/ j.biochi.2012.07.016]
24. Peyrou M, Bourgoin L, Foti M. PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis 2010; 28: 236-246 [PMID: 20460918 DOI: 10.1159/000282095]
25. Domitrovich AM, Felmlee DJ, Siddiqui A. Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion. J Biol Chem 2005; 280: 39802-39808 [PMID: 16203724 DOI: 10.1074/jbc.M510391200]
26. Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, McHutchison JG, Subramanian M, Millington DM, Kelley RI, Patel K. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology 2012; 56: 49-56 [PMID: 22318926 DOI: 10.1002/hep.25631]
27. Revie D, Salahuddin SZ. Human cell types important for hepatitis C virus replication in vivo and in vitro: old assertions and current evidence. Virol J 2011; 8: 346 [PMID: 21745397 DOI: 10.1186/1743-422X-8-346]
28. Mostafa A, Mohamed MK, Saeed M, Hasan A, Fontanet A, Godsland I, Coady E, Esmat G, El-Hoseiny M, Abdul-Hamid M, Hughes A, Chaturvedi N. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut 2010; 59: 1135-1140 [PMID: 20584782 DOI: 10.1136/ gut.2009.202317]
29. Zampino R, Coppola N, Cirillo G, Boemio A, Pisaturo M, Marrone A, Macera M, Sagnelli E, Perrone L, Adinolfi LE, Miraglia del Giudice E. Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. J Viral Hepat 2013; 20: 517-523 [PMID: 23808989 DOI: 10.1111/ jvh.12053]
30. Petta S, Macaluso FS, Cammà C, Marco VD, Cabibi D, Craxì A. Hyperuricaemia: another metabolic feature affecting the severity of chronic hepatitis because of HCV infection. Liver Int 2012; 32: 1443-1450 [PMID: 22764879 DOI: 10.1111/ j.1478-3231.2012.02842.x]
31. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther 2013; 37: 647-652 [PMID: 23384408 DOI: 10.1111/apt.12234]
32. Lonardo A, Loria P, Leonardi F, Borsatti A, Neri P, Pulvirenti M, Verrone AM, Bagni A, Bertolotti M, Ganazzi D, Carulli N; POLI. ST.E.N.A. Study Group. Policentrica Steatosi Epatica Non Alcolica. Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of nonalcoholic fatty liver disease. A case-control study. Dig Liver Dis 2002; 34: 204-211 [DOI: 10.1016/S1590-8658(02)80194-3]
33. Petta S, Cammà C, Cabibi D, Di Marco V, Craxì A. Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 34: 757-766 [PMID: 21790685 DOI: 10.1111/ j.1365-2036.2011.04788.x]
34. Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 2013; 62: 392-399 [PMID: 23036645 DOI: 10.1016/j.metabol.2012.08.013]
35. Bugianesi E. Mechanisms of insulin resistance associated with hepatitis C virus infection. Hot Topics Viral Hep 2012; 8: 13-17
36. Lambert JE, Bain VG, Ryan EA, Thomson AB, Clandinin MT. Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans. Hepatology 2013; 57: 1697-1704 [PMID: 23417775 DOI: 10.1002/hep.25990]
37. Wu JM, Skill NJ, Maluccio MA. Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma. HPB (Oxford) 2010; 12: 625-636 [PMID: 20961371 DOI: 10.1111/j.1477-2574.2010.00207.x]
38. Ye J, Wang C, Sumpter R, Brown MS, Goldstein JL, Gale M. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci USA 2003; 100: 15865-15870 [PMID: 14668447 DOI: 10.1073/pnas.2237238100]
39. Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 2005; 102: 2561-2566 [PMID: 15699349 DOI: 10.1073/pnas.0409834102]
40. Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002; 122: 366-375 [PMID: 11832451 DOI: 10.1053/gast.2002.30983]
41. Roe B, Kensicki E, Mohney R, Hall WW. Metabolomic profile of hepatitis C virus-infected hepatocytes. PLoS One 2011; 6: e23641 [PMID: 21853158 DOI: 10.1371/journal.pone.0023641]
42. Sato C, Saito T, Misawa K, Katsumi T, Tomita K, Ishii R, Haga H, Okumoto K, Nishise Y, Watanabe H, Ueno Y, Kawata S. Impaired mitochondrial β-oxidation in patients with chronic hepatitis C: relation with viral load and insulin resistance. BMC Gastroenterol 2013; 13: 112 [PMID: 23841691 DOI: 10.1186/1471-230X-13-112]
43. Lonardo A, Loria P, Argo C, Caldwell S. Perspectives on cellular dysfunction in nonalcoholic steatohepatitis: a case of 'multiorganelle failure'? Proceedings of a virtual workshop on nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011; 5: 135-139 [PMID: 21476906 DOI: 10.1586/ egh.11.24]
44. Roingeard P. Hepatitis C virus diversity and hepatic steatosis. J Viral Hepat 2013; 20: 77-84 [PMID: 23301542 DOI: 10.1111/jvh.12035]
45. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012; 56: 952-964 [PMID: 22173168 DOI: 10.1016/j.jhep.2011.08.025]
46. Hourioux C, Patient R, Morin A, Blanchard E, Moreau A, Trassard S, Giraudeau B, Roingeard P. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007; 56: 1302-1308 [PMID: 17213339 DOI: 10.1136/gut.2006.108647]
47. Pawlotsky JM, Tsakiris L, Roudot-Thoraval F, Pellet C, Stuyver L, Duval J, Dhumeaux D. Relationship between hepatitis C virus genotypes and sources of infection in patients with chronic hepatitis C. J Infect Dis 1995; 171: 1607-1610 [PMID: 7769300 DOI: 10.1093/infdis/171.6.1607]
48. Nalpas B, Thiers V, Pol S, Driss F, Thepot V, Berthelot P, Brechot C. Hepatitis C viremia and anti-HCV antibodies in alcoholics. J Hepatol 1992; 14: 381-384 [PMID: 1380027 DOI: 10.1016/0168-8278(92)90187-T]
49. Verbaan H, Andersson K, Eriksson S. Intravenous drug abuse--the major route of hepatitis C virus transmission among alcohol-dependent individuals? Scand J Gastroenterol 1993; 28: 714-718 [PMID: 7692588 DOI: 10.3109/00365529309 098279]
50. Pereira IV, Stefano JT, Oliveira CP. Microsomal triglyceride transfer protein and nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2011; 5: 245-251 [PMID: 21476919 DOI: 10.1586/egh.11.22]
51. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chrétien Y, Koike K, Pessayre D, Chapman J, Barba G, Bréchot C. 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: 185-194 [PMID: 11818366 DOI: 10.1096/fj.01-0396com]
52. Mirandola S, Realdon S, Iqbal J, Gerotto M, Dal Pero F, Bortoletto G, Marcolongo M, Vario A, Datz C, Hussain MM, Alberti A. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology 2006; 130: 1661-1669 [PMID: 16697730 DOI: 10.1053/j.gastro.2006.02.035]
53. Ferré P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53 Suppl 1: S43-S50 [PMID: 14749265 DOI: 10.2337/diabetes.53.2007.S43]
54. de Gottardi A, Pazienza V, Pugnale P, Bruttin F, Rubbia-Brandt L, Juge-Aubry CE, Meier CA, Hadengue A, Negro F. 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: 107-114 [PMID: 16393287 DOI: 10.1111/ j.1365-2036.2006.02729.x]
55. Fujita N, Kaito M, Kai M, Sugimoto R, Tanaka H, Horiike S, Konishi M, Iwasa M, Watanabe S, Adachi Y. Effects of bezafibrate in patients with chronic hepatitis C virus infection: combination with interferon and ribavirin. J Viral Hepat 2006; 13: 441-448 [PMID: 16792537 DOI: 10.1111/ j.1365-2893.2005.00718.x]
56. Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 2008; 118: 683-694 [PMID: 18188449]
57. Vluggens A, Reddy JK. Nuclear receptors and transcription factors in the development of fatty liver disease. Curr Drug Metab 2012; 13: 1422-1435 [PMID: 22978397 DOI: 10.2174/138 920012803762710]
58. Joven J, Espinel E, Rull A, Beltrán-Debón R, Aragonès G, Rodríguez-Gallego E, Camps J, Pedro-Botet J, Sans T, Menéndez JA, Alonso-Villaverde C. Serum fatty acid synthase concentration is increased in patients with hepatitis viral infection and may assist in the prediction of liver steatosis. J Clin Virol 2011; 51: 199-201 [PMID: 21555238 DOI: 10.1016/ j.jcv.2011.04.003]
59. Jackel-Cram C, Babiuk LA, Liu Q. Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core. J Hepatol 2007; 46: 999-1008 [PMID: 17188392 DOI: 10.1016/ j.jhep.2006.10.019]
60. Ryan MC, Desmond PV, Slavin JL, Congiu M. Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver. J Viral Hepat 2011; 18: 53-60 [PMID: 20196803 DOI: 10.1111/j.1365-2893.2010.01283. x]
61. Oem JK, Jackel-Cram C, Li YP, Zhou Y, Zhong J, Shimano H, Babiuk LA, Liu Q. Activation of sterol regulatory elementbinding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol 2008; 89: 1225-1230 [PMID: 18420801 DOI: 10.1099/vir.0.83491-0]
62. Clément S, Peyrou M, Sanchez-Pareja A, Bourgoin L, Ramadori P, Suter D, Vinciguerra M, Guilloux K, Pascarella S, Rubbia-Brandt L, Negro F, Foti M. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology 2011; 54: 38-49 [PMID: 21465511 DOI: 10.1002/ hep.24340]
63. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29: 1215-1219 [PMID: 10094967 DOI: 10.1002/hep.510290401]
64. 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: 1358-1364 [PMID: 11391523]
65. Clouston AD, Jonsson JR, Purdie DM, Macdonald GA, Pandeya N, Shorthouse C, Powell EE. Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation. J Hepatol 2001; 34: 314-320 [PMID: 11281562]
66. Hwang SJ, Luo JC, Chu CW, Lai CR, Lu CL, Tsay SH, Wu JC, Chang FY, Lee SD. Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation. J Gastroenterol Hepatol 2001; 16: 190-195 [PMID: 11207900 DOI: 10.1046/j.1440-1746.2001.02407.x]
67. Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M, Giordano M, Ruggiero G. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci 2001; 46: 1677-1683 [PMID: 11508667]
68. Westin J, Nordlinder H, Lagging M, Norkrans G, Wejstål R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 2002; 37: 837-842 [PMID: 12445426 DOI: 10.1016/ S0168-8278(02)00299-4]
69. Hui JM, Kench J, Farrell GC, Lin R, Samarasinghe D, Liddle C, Byth K, George J. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol 2002; 17: 873-881 [PMID: 12164963 DOI: 10.1046/ j.1440-1746.2002.02813.x]
70. 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: 729-736 [PMID: 12198667 DOI: 10.1053/jhep.2002.35064]
71. Castéra L, Pawlotsky JM, Dhumeaux D. Worsening of steatosis and fibrosis progression in hepatitis C. Gut 2003; 52: 1531 [PMID: 12970153 DOI: 10.1136/gut.52.10.1531]
72. Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S, Younossi Z, Albrecht J. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003; 38: 75-85 [PMID: 12829989 DOI: 10.1053/jhep.2003.50267]
73. Romero-Gómez M, Castellano-Megias VM, Grande L, Irles JA, Cruz M, Nogales MC, Alcón JC, Robles A. Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol 2003; 98: 1135-1141 [PMID: 12809839 DOI: 10.1111/j.1572-0241.2003.07450.x]
74. Hickman IJ, Powell EE, Prins JB, Clouston AD, Ash S, Purdie DM, Jonsson JR. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. J Hepatol 2003; 39: 1042-1048 [PMID: 14642624 DOI: 10.1016/S0168-8278(03)00463-X]
75. Wyatt J, Baker H, Prasad P, Gong YY, Millson C. Steatosis and fibrosis in patients with chronic hepatitis C. J Clin Pathol 2004; 5: 402-406 [DOI: 10.1136/jcp.2003.009357]
76. Hu KQ, Kyulo NL, Esrailian E, Thompson K, Chase R, Hillebrand DJ, Runyon BA. Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States. J Hepatol 2004; 40: 147-154 [PMID: 14672626 DOI: 10.1016/ S0168-8278(03)00479-3]
77. Fartoux L, Chazouillères O, Wendum D, Poupon R, Serfaty L. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology 2005; 41: 82-87 [PMID: 15690484 DOI: 10.1002/hep.20519]
78. Adinolfi LE, Ingrosso D, Cesaro G, Cimmino A, D'Antò M, Capasso R, Zappia V, Ruggiero G. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology 2005; 41: 995-1003 [PMID: 15834927 DOI: 10.1002/hep.20664]
79. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A, Terrault N, Pazienza V, Giordani MT, Giostra E, Sonzogni A, Ruggiero G, Marcellin P, Powell EE, George J, Negro F. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006; 130: 1636-1642 [PMID: 16697727 DOI: 10.1053/j.gastro.2006.03.014]
80. Masarone M, La Mura V, Bruno S, Gaeta GB, Vecchione R, Carrino F, Moschella F, Torella R, Persico M. Steatohepatitis is associated with diabetes and fibrosis in genotype 1b HCVrelated chronic liver disease. J Viral Hepat 2007; 14: 714-720 [PMID: 17875006]
81. Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH, Paradis V, Vidaud M, Valla D, Bedossa P, Marcellin P. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416-423 [PMID: 18164296 DOI: 10.1053/j.gastro.2007.11.010]
82. Hora C, Negro F, Leandro G, Oneta CM, Rubbia-Brandt L, Muellhaupt B, Helbling B, Malinverni R, Gonvers JJ, Dufour JF. Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C. Liver Int 2008; 28: 370-376 [PMID: 17976159 DOI: 10.1111/j.1478-3231.2007.01608.x]
83. Vidali M, Tripodi MF, Ivaldi A, Zampino R, Occhino G, Restivo L, Sutti S, Marrone A, Ruggiero G, Albano E, Adinolfi LE. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. J Hepatol 2008; 48: 399-406 [PMID: 18164507 DOI: 10.1016/j.jhep.2007.10.011]
84. Terrault NA, Im K, Boylan R, Bacchetti P, Kleiner DE, Fontana RJ, Hoofnagle JH, Belle SH. Fibrosis progression in African Americans and Caucasian Americans with chronic hepatitis C. Clin Gastroenterol Hepatol 2008; 6: 1403-1411 [PMID: 19081528 DOI: 10.1016/j.cgh.2008.08.006]
85. Hanouneh IA, Feldstein AE, Lopez R, Yerian L, Pillai A, Zein CO, Zein NN. Clinical significance of metabolic syndrome in the setting of chronic hepatitis C virus infection. Clin Gastroenterol Hepatol 2008; 6: 584-589 [PMID: 18455698 DOI: 10.1016/j.cgh.2008.02.034]
86. Cua IH, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology 2008; 48: 723-731 [PMID: 18688878 DOI: 10.1002/hep.22392]
87. Hu SX, Kyulo NL, Xia VW, Hillebrand DJ, Hu KQ. Factors associated with hepatic fibrosis in patients with chronic hepatitis C: a retrospective study of a large cohort of U.S. patients. J Clin Gastroenterol 2009; 43: 758-764 [PMID: 19238091 DOI: 10.1097/MCG.0b013e31818be17c]
88. Cross TJ, Quaglia A, Hughes S, Joshi D, Harrison PM. The impact of hepatic steatosis on the natural history of chronic hepatitis C infection. J Viral Hepat 2009; 16: 492-499 [PMID: 19200134 DOI: 10.1111/j.1365-2893.2009.01098.x]
89. Livingston SE, Deubner H, Bruden DL, McMahon BJ, Homan CE, Townshend-Bulson LJ, Bruce MG, Hennessy TW, Williams JL, Gretch DR. Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C. Can J Gastroenterol 2010; 24: 445-451 [PMID: 20652161]
90. Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: a meta-analysis of the risk factors. Hepatology 2010; 52: 71-78 [PMID: 20578130 DOI: 10.1002/ hep.23619]
91. Sterling RK, Wegelin JA, Smith PG, Stravitz RT, Luketic VA, Fuchs M, Puri P, Shiffman ML, Contos MA, Mills AS, Sanyal AJ. Similar progression of fibrosis between HIV/HCVinfected and HCV-infected patients: Analysis of paired liver biopsy samples. Clin Gastroenterol Hepatol 2010; 8: 1070-1076 [PMID: 20728569 DOI: 10.1016/j.cgh.2010.08.004]
92. Petta S, Cammà C, Di Marco V, Macaluso FS, Maida M, Pizzolanti G, Belmonte B, Cabibi D, Di Stefano R, Ferraro D, Guarnotta C, Venezia G, Craxì A. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int 2011; 31: 507-515 [PMID: 21382161 DOI: 10.1111/ j.1478-3231.2011.02453.x]
93. Ahmed AM, Hassan MS, Abd-Elsayed A, Hassan H, Hasanain AF, Helmy A. Insulin resistance, steatosis, and fibrosis in Egyptian patients with chronic Hepatitis C virus infection. Saudi J Gastroenterol 2011; 17: 245-251 [PMID: 21727730 DOI: 10.4103/1319-3767.82578]
94. Brandman D, Pingitore A, Lai JC, Roberts JP, Ferrell L, Bass NM, Terrault NA. Hepatic steatosis at 1 year is an additional predictor of subsequent fibrosis severity in liver transplant recipients with recurrent hepatitis C virus. Liver Transpl 2011; 17: 1380-1386 [PMID: 21770018 DOI: 10.1002/lt.22389]
95. Rubbia-Brandt L, Fabris P, Paganin S, Leandro G, Male PJ, Giostra E, Carlotto A, Bozzola L, Smedile A, Negro F. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004; 53: 406-412 [PMID: 14960525 DOI: 10.1136/gut.2003.018770]
96. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallée M, Heaton S, Conrad A, Pockros PJ, McHutchison JG. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 2004; 40: 484-490 [PMID: 15123364 DOI: 10.1016/ j.jhep.2003.11.004]
97. Nieminen U, Arkkila PE, Kärkkäinen P, Färkkilä MA. Effect of steatosis and inflammation on liver fibrosis in chronic hepatitis C. Liver Int 2009; 29: 153-158 [PMID: 18482270 DOI: 10.1111/j.1478-3231.2008.01779.x]
98. 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 [PMID: 9722200 DOI: 10.1016/ S0168-8278(98)80004-4]
99. Asselah T, Boyer N, Guimont MC, Cazals-Hatem D, Tubach F, Nahon K, Daïkha H, Vidaud D, Martinot M, Vidaud M, Degott C, Valla D, Marcellin P. Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Gut 2003; 52: 1638-1643 [PMID: 14570735 DOI: 10.1136/gut.52.11.1638]
100. Matos CA, Perez RM, Pacheco MS, Figueiredo-Mendes CG, Lopes-Neto E, Oliveira EB, Lanzoni VP, Silva AE, Ferraz ML. Steatosis in chronic hepatitis C: relationship to the virus and host risk factors. J Gastroenterol Hepatol 2006; 21: 1236-1239 [PMID: 16872303 DOI: 10.1111/j.1440-1746.2006.04308.x]
101. Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, López-Cortés LF, Moreno A, González-Serrano M, Iribarren JA, Ortega E, Miralles P, Mira JA, Pineda JA. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology 2009; 50: 1056-1063 [PMID: 19670415]
102. Restivo L, Zampino R, Guerrera B, Ruggiero L, Adinolfi LE. Steatosis is the predictor of relapse in HCV genotype 3-but not 2-infected patients treated with 12 weeks of pegylated interferon-α-2a plus ribavirin and RVR. J Viral Hepat 2012; 19: 346-352 [PMID: 22497814 DOI: 10.1111/ j.1365-2893.2011.01555.x]
103. Rafi H, Kabbaj N, Salihoun M, Amrani L, Acharki M, Guedira M, Nya M, Amrani N. Influence of steatosis on progression of fibrosis and virological response in chronic hepatitis C cases. Arab J Gastroenterol 2011; 12: 136-138 [PMID: 22055591 DOI: 10.1016/j.ajg.2011.07.003]
104. Shah SR, Patel K, Marcellin P, Foster GR, Manns M, Kottilil S, Healey L, Pulkstenis E, Subramanian GM, McHutchison JG, Sulkowski MS, Zeuzem S, Nelson DR. Steatosis is an independent predictor of relapse following rapid virologic response in patients with HCV genotype 3. Clin Gastroenterol Hepatol 2011; 9: 688-693 [PMID: 21640198 DOI: 10.1016/ j.cgh.2011.04.029]
105. AlQaraawi AM, Sanai FM, Al-Husseini H, Albenmousa A, AlSheikh A, Ahmed LR, Hersi A, Al-Otaibi MM, Syed M, Ali SM, Al-hamoudi W, Alswat KA, Abdo AA. Prevalence and impact of hepatic steatosis on the response to antiviral therapy in Saudi patients with genotypes 1 and 4 chronic hepatitis C. Dig Dis Sci 2011; 56: 1222-1228 [PMID: 20931285 DOI: 10.1007/s10620-010-1417-9]
106. Rodriguez-Torres M, Govindarajan S, Diago M, Morgan T, Anand B, Barange K, Suter F, Lin A, Hooper G, Shiffman M. Hepatic steatosis in patients with chronic hepatitis C virus genotype 2 or 3 does not affect viral response in patients treated with peginterferon alpha-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) for 16 or 24 weeks. Liver Int 2009; 29: 237-241 [PMID: 18710427 DOI: 10.1111/ j.1478-3231.2008.01859.x]
107. Gad RR, Males S, El Makhzangy H, Shouman S, Hasan A, Attala M, El Hoseiny M, Zalata K, Abdel-Hamid M, Fontanet A, Mohamed MK, Esmat G. Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C. Liver Int 2008; 28: 1112-1119 [PMID: 18397226 DOI: 10.1111/j.1478-3231.2008.01750.x]
108. Reddy KR, Govindarajan S, Marcellin P, Bernstein D, Dienstag JL, Bodenheimer H, Rakela J, Messinger D, Schmidt G, Ackrill A, Hadziyannis SJ. Hepatic steatosis in chronic hepatitis C: baseline host and viral characteristics and influence on response to therapy with peginterferon alpha-2a plus ribavirin. J Viral Hepat 2008; 15: 129-136 [PMID: 18184196]
109. Hu KQ, Currie SL, Shen H, Cheung RC, Ho SB, Bini EJ, McCracken JD, Morgan T, Bräu N, Schmidt WN, Jeffers L, Wright TL. Clinical implications of hepatic steatosis in patients with chronic hepatitis C: a multicenter study of U.S. veterans. Dig Dis Sci 2007; 52: 570-578 [PMID: 17226072 DOI: 10.1007/s10620-006-9418-4]
110. Yaginuma R, Ikejima K, Okumura K, Kon K, Suzuki S, Takei Y, Sato N. Hepatic steatosis is a predictor of poor response to interferon alpha-2b and ribavirin combination therapy in Japanese patients with chronic hepatitis C. Hepatol Res 2006; 35: 19-25 [PMID: 16531110 DOI: 10.1016/j.hepres.2006.02.001]
111. Harrison SA, Brunt EM, Qazi RA, Oliver DA, Neuschwander-Tetri BA, Di Bisceglie AM, Bacon BR. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2005; 3: 604-609 [PMID: 15952103 DOI: 10.1016/ S1542-3565(05)00246-6]
112. Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M, Izumi N. α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology 2013; 58: 1253-1262 [PMID: 23564522 DOI: 10.1002/hep.26442]
113. Nkontchou G, Ziol M, Aout M, Lhabadie M, Baazia Y, Mahmoudi A, Roulot D, Ganne-Carrie N, Grando-Lemaire V, Trinchet JC, Gordien E, Vicaut E, Baghad I, Beaugrand M. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J Viral Hepat 2011; 18: e516-e522 [PMID: 21914071 DOI: 10.1111/j.1365-2893.2011.01441.x]
114. Salomao M, Yu WM, Brown RS, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virusrelated cirrhosis with associated NAFLD/NASH. Am J Surg Pathol 2010; 34: 1630-1636 [PMID: 20975341]
115. Nojiri K, Sugimoto K, Shiraki K, Kusagawa S, Tanaka J, Beppu T, Yamamoto N, Takei Y, Hashimoto A, Shimizu A, Omori S, Tameda M, Takase K. Development of hepatocellular carcinoma in patients with chronic hepatitis C more than 10 years after sustained virological response to interferon therapy. Oncol Lett 2010; 1: 427-430 [PMID: 22966320]
116. Tanaka A, Uegaki S, Kurihara H, Aida K, Mikami M, Nagashima I, Shiga J, Takikawa H. 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: 5180-5187 [PMID: 17876888]
117. Takuma Y, Nouso K, Makino Y, Saito S, Takayama H, Takahara M, Takahashi H, Murakami I, Takeuchi H. Hepatic steatosis correlates with the postoperative recurrence of hepatitis C virus-associated hepatocellular carcinoma. Liver Int 2007; 27: 620-626 [PMID: 17498246 DOI: 10.1111/ j.1478-3231.2007.01462.x]
118. Pekow JR, Bhan AK, Zheng H, Chung RT. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer 2007; 109: 2490-2496 [PMID: 17487861 DOI: 10.1002/ cncr.22701]
119. 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: 1395-1400 [PMID: 16105127 DOI: 10.1111/j.1440-1746.2005.04007.x]
120. Ohata K, Hamasaki K, Toriyama K, Matsumoto K, Saeki A, Yanagi K, Abiru S, Nakagawa Y, Shigeno M, Miyazoe S, Ichikawa T, Ishikawa H, Nakao K, Eguchi K. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003; 97: 3036-3043 [PMID: 12784339 DOI: 10.1002/cncr.11427]
121. Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007; 22 Suppl 1: S108-S111 [PMID: 17567457 DOI: 10.1111/j.1440-1746.2006.04669.x]
122. Lonardo A, Loria P. Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J Gastroenterol Hepatol 2012; 27: 1654-1664 [PMID: 22849701 DOI: 10.1111/j.1440-1746.2012.07232.x]
123. Lonardo A, Bagni A, Tarugi P, Loria P. The wide spectrum of steatohepatitis: a report of four cases and a review of the literature. Eur J Gastroenterol Hepatol 2004; 16: 1043-1050 [PMID: 15371930 DOI: 10.1097/00042737-200410000-00015]
124. Ong JP, Younossi ZM, Speer C, Olano A, Gramlich T, Boparai N. Chronic hepatitis C and superimposed nonalcoholic fatty liver disease. Liver 2001; 21: 266-271 [PMID: 11454190 DOI: 10.1034/j.1600-0676.2001.021004266.x]
125. Brunt EM, Ramrakhiani S, Cordes BG, Neuschwander-Tetri BA, Janney CG, Bacon BR, Di Bisceglie AM. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol 2003; 16: 49-56 [PMID: 12527713 DOI: 10.1097/01.MP.0000042420.21088.C7]
126. Liu CJ, Jeng YM, Chen PJ, Lai MY, Yang HC, Huang WL, Kao JH, Chen DS. Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C. Antivir Ther 2005; 10: 405-415 [PMID: 15918331]
127. Bedossa P, Moucari R, Chelbi E, Asselah T, Paradis V, Vidaud M, Cazals-Hatem D, Boyer N, Valla D, Marcellin P. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46: 380-387 [PMID: 17659580 DOI: 10.1002/hep.21711]
128. Solis-Herruzo JA, Pérez-Carreras M, Rivas E, Fernández-Vázquez I, Garfia C, Bernardos E, Castellano G, Colina F. Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C. Am J Gastroenterol 2005; 100: 1091-1098 [PMID: 15842583 DOI: 10.1111/ j.1572-0241.2005.41059.x]
129. Lonardo A, Ballestri S, Restivo L, Adinolfi LE, Loria P. Hepatitis C and cardiovascular risk: facts and controversies. Hot Topics Viral Hep 2012; 8: 27-35
130. Stassen FR, Vainas T, Bruggeman CA. Infection and atherosclerosis. An alternative view on an outdated hypothesis. Pharmacol Rep 2008; 60: 85-92 [PMID: 18276989]
131. Petta S, Torres D, Fazio G, Cammà C, Cabibi D, Di Marco V, Licata A, Marchesini G, Mazzola A, Parrinello G, Novo S, Licata G, Craxì A. Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations. Hepatology 2012; 55: 1317-1323 [PMID: 22135089 DOI: 10.1002/hep.25508]
132. Adinolfi LE, Restivo L, Zampino R, Guerrera B, Lonardo A, Ruggiero L, Riello F, Loria P, Florio A. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCVrelated steatosis. Atherosclerosis 2012; 221: 496-502 [PMID: 22385985 DOI: 10.1016/j.atherosclerosis.2012.01.051]
133. Adinolfi LE, Restivo L, Guerrera B, Sellitto A, Ciervo A, Iuliano N, Rinaldi L, Santoro A, Li Vigni G, Marrone A. Chronic HCV infection is a risk factor of ischemic stroke. Atherosclerosis 2013; 231: 22-26 [PMID: 24125405 DOI: 10.1016/j.atherosclerosis.2013.08.003]
134. Loria P, Marchesini G, Nascimbeni F, Ballestri S, Maurantonio M, Carubbi F, Ratziu V, Lonardo A. Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. Atherosclerosis 2014; 232: 99-109 [PMID: 24401223 DOI: 10.1016/j.atherosclerosis.2013.10.030]