REFERENCES
1. Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol. 2022;77:219-36.
2. Huang CF, Huang JF, Yu ML, Chuang WL. Metabolic Dysfunction-Associated Steatotic Liver Disease After Hepatitis C Virus Cure. Kaohsiung J Med Sci. 2026;42:e70155.
3. Cacoub P, Saadoun D. Extrahepatic manifestations of chronic HCV infection. N Engl J Med. 2021;384:1038-52.
4. Leumi S, El Kassas M, Zhong J. Hepatitis C virus genotype 4: a poorly characterized endemic genotype. J Med Virol. 2021;93:6079-88.
5. Gaggini M, Carli F, Rosso C, et al. Altered metabolic profile and adipocyte insulin resistance mark severe liver fibrosis in patients with chronic liver disease. Int J Mol Sci. 2019;20:6333.
6. Pais R, Rusu E, Zilisteanu D, et al. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease. Eur J Intern Med. 2015;26:30-6.
7. 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.
8. Kim MN, Han K, Yoo J, Hwang SG, Ahn SH. Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver. Aliment Pharmacol Ther. 2022;55:97-107.
9. Shengir M, Elgretli W, Cinque F, et al. Metabolic factors drive early increase in hepatic steatosis despite improvement in non-invasive fibrosis markers after hepatitis C eradication with direct-acting antivirals. Clin Res Hepatol Gastroenterol. 2025;49:102639.
11. Soliman H, Ziada D, Hamisa M, et al. The effect of HCV eradication after direct-acting antiviral agents on hepatic steatosis: a prospective observational study. Endocr Metab Immune Disord Drug Targets. 2022;22:100-7.
12. 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.
13. Yamaguchi A, Tazuma S, Nishioka T, et al. Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci. 2005;50:1361-71.
14. Lin W, Tsai WL, Shao RX, et al. Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner. Gastroenterology. 2010;138:2509-18.
15. Sato C, Saito T, Misawa K, et al. Impaired mitochondrial β-oxidation in patients with chronic hepatitis C: relation with viral load and insulin resistance. BMC Gastroenterol. 2013;13:112.
16. 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;118:683-94.
17. Yang W, Hood BL, Chadwick SL, et al. Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production. Hepatology. 2008;48:1396-403.
18. Tsutsumi T, Suzuki T, Shimoike T, et al. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002;35:937-46.
19. 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.
20. Levy G, Habib N, Guzzardi MA, et al. Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection. Nat Chem Biol. 2016;12:1037-45.
21. 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.
22. Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari FV. Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol. 2008;82:2120-9.
23. Perlemuter 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.
24. Kim SJ, Syed GH, Khan M, et al. Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proc Natl Acad Sci U S A. 2014;111:6413-8.
25. Moriya K, Miyoshi H, Shinzawa S, et al. Hepatitis C virus core protein compromises iron-induced activation of antioxidants in mice and HepG2 cells. J Med Virol. 2010;82:776-92.
26. Ripoli M, D'Aprile A, Quarato G, et al. Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation. J Virol. 2010;84:647-60.
27. Kim SJ, Syed GH, Siddiqui A. Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog. 2013;9:e1003285.
28. Dustin LB. Innate and adaptive immune responses in chronic HCV infection. Curr Drug Targets. 2017;18:826-43.
29. Hengst J, Falk CS, Schlaphoff V, et al. Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered cytokine and chemokine milieu in patients with chronic hepatitis C. J Infect Dis. 2016;214:1965-74.
30. Osuch S, Metzner KJ, Caraballo Cortés K. Reversal of T cell exhaustion in chronic HCV infection. Viruses. 2020;12:799.
31. Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. HCV-specific T cell responses during and after chronic HCV infection. Viruses. 2018;10:645.
32. Wherry E, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486-99.
33. Gerlach JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4+ T-cell response in acute hepatitis C. Gastroenterology. 1999;117:933-41.
34. Golden-Mason L, McMahan RH, Kriss MS, et al. Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment. Hepatol Commun. 2018;2:364-75.
35. Sekoguchi S, Nakajima T, Moriguchi M, et al. Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2007;22:182-90.
36. Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. 2017;18:175-86.
37. Kang TW, Yevsa T, Woller N, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479:547-51.
38. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232-6.
39. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15:978-90.
40. Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017;12:153-86.
41. Baglieri J, Brenner DA, Kisseleva T. The role of fibrosis and liver-associated fibroblasts in the pathogenesis of hepatocellular carcinoma. Int J Mol Sci. 2019;20:1723.
42. Bates J, Vijayakumar A, Ghoshal S, et al. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020;73:896-905.
43. Manolakopoulos S, Bethanis S, Liapi C, et al. An assessment of serum leptin levels in patients with chronic viral hepatitis: a prospective study. BMC Gastroenterol. 2007;7:17.
44. Myers MG Jr, Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 2010;21:643-51.
45. Do A, Esserman DA, Krishnan S, et al. Excess weight gain after cure of hepatitis C infection with direct-acting antivirals. J Gen Intern Med. 2020;35:2025-34.
47. Battineni G, Sagaro GG, Chintalapudi N, Amenta F, Tomassoni D, Tayebati SK. Impact of obesity-induced inflammation on cardiovascular diseases (CVD). Int J Mol Sci. 2021;22:4798.
48. Siphepho PY, Liu YT, Shabangu CS, et al. The impact of steatosis on chronic hepatitis C progression and response to antiviral treatments. Biomedicines. 2021;9:1491.
49. Sheridan DA, Shawa IT, Thomas EL, et al. Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis. Sci Rep. 2022;12:5562.
50. Hourioux C, Patient R, Morin A, et al. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut. 2007;56:1302-8.
51. Patra T, Sasaki R, Meyer K, Ray RB, Ray R. Transforming growth factor β acts as a regulatory molecule for lipogenic pathways among hepatitis C virus genotype-specific infections. J Virol. 2019;93:e00811-19.
52. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130:1661-9.
53. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991-8.
54. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450-6.
56. 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.
57. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499-508.
58. Miyamoto H, Moriishi K, Moriya K, et al. Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol. 2007;81:1727-35.
59. Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384-92.
60. Rahadini AAD, Rahadina A. Association between metabolic associated fatty liver disease and HCC risk after SVR in HCV patients: a systematic review and meta-analysis. Clin Exp Hepatol. 2025;11:129-36.
61. Hamed AE, Elwan N, Naguib M, et al. Diabetes association with liver diseases: an overview for clinicians. Endocr Metab Immune Disord Drug Targets. 2019;19:274-80.
62. Huang CF, Dai CY, Lin YH, et al. Dynamic change of metabolic dysfunction-associated steatotic liver disease in chronic hepatitis C patients after viral eradication: a nationwide registry study in Taiwan. Clin Mol Hepatol. 2024;30:883-94.
63. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182-236.
64. Jelic S; ESMO Guidelines Working Group. Hepatocellular carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20:41-5.
65. Ghany MG, Morgan TR; AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C Guidance 2019 update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology. 2020;71:686-721.
66. Elsharkawy A, Samir R, El-Kassas M. Fibrosis regression following hepatitis C antiviral therapy. World J Hepatol. 2022;14:1120-30.
67. Peleg N, Issachar A, Sneh Arbib O, et al. Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response. J Viral Hepat. 2019;26:1257-65.
68. Benhammou JN, Moon AM, Pisegna JR, et al. Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C. Dig Dis Sci. 2021;66:2394-406.
69. Degasperi E, D’Ambrosio R, Iavarone M, et al. Factors associated with increased risk of de novo or recurrent hepatocellular carcinoma in patients with cirrhosis treated with direct-acting antivirals for HCV infection. Clin Gastroenterol Hepatol. 2019;17:1183-91.e7.
70. van der Meer AJ, Feld JJ, Hofer H, et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. J Hepatol. 2017;66:485-93.
71. Wiese M, Fischer J, Löbermann M, et al.; East German HCV Study Group. Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology. 2014;59:49-57.
72. Di Nardo F, Dallio M, Romeo M, et al. A head-to-head comparison of MAFLD and MASLD diagnostic criteria in estimating the risk of hepatocellular carcinoma (HCC) in HCV patients achieving sustained virological response. Dig Liver Dis. 2026;58:S26-7.
74. Masuzaki R, Kanda T, Sasaki R, et al. Noninvasive assessment of liver fibrosis: current and future clinical and molecular perspectives. Int J Mol Sci. 2020;21:4906.
75. Sporea I, Gilja OH, Bota S, Şirli R, Popescu A. Liver elastography - an update. Med Ultrason. 2013;15:304-14.
76. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology. 2015;61:292-302.
77. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-26.
78. Sterling RK, Lissen E, Clumeck N, et al.; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317-25.
79. Ishiba H, Sumida Y, Tanaka S, et al. ; Japan Study Group of Non-Alcoholic Fatty Liver Disease (JSG-NAFLD). The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study. J Gastroenterol. 2018;53:1216-24.
80. Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517-24.
81. Minola E, Prati D, Suter F, et al. Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C. Blood. 2002;99:4588-91.
82. Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol. 2007;7:40.
83. Archer AJ, Belfield KJ, Orr JG, Gordon FH, Abeysekera KW. EASL clinical practice guidelines: non-invasive liver tests for evaluation of liver disease severity and prognosis. Frontline Gastroenterol. 2022;13:436-9.
84. Feld JJ, Jacobson IM, Hézode C, et al. ; ASTRAL-1 Investigators. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373:2599-607.
85. Butt AA, Yan P, Shuaib A, Abou-Samra AB, Shaikh OS, Freiberg MS. Direct-acting antiviral therapy for HCV infection is associated with a reduced risk of cardiovascular disease events. Gastroenterology. 2019;156:987-96.e8.
86. Di Marco L, La Mantia C, Di Marco V. Hepatitis C: standard of treatment and what to do for global elimination. Viruses. 2022;14:505.
87. Sano T, Amano K, Ide T, et al. ; SAKS Study Group. Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: a multicenter study. Hepatol Res. 2024;54:326-35.
88. Roman S, Ojeda-Granados C, Ramos-Lopez O, Panduro A. Genome-based nutrition: an intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21:3449-61.
89. Raza S, Rajak S, Upadhyay A, Tewari A, Anthony Sinha R. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front Biosci. 2021;26:206-37.
90. Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62:606-15.
91. Ma S, Zheng Y, Xiao Y, Zhou P, Tan H. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients. Medicine 2017;96:e6888.
92. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382:1018-28.
93. Simon TG, Duberg AS, Aleman S, et al. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Intern Med. 2019;171:318-27.
94. Simon TG, King LY, Zheng H, Chung RT. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J Hepatol. 2015;62:18-23.
95. Tsai WL, Chang TH, Sun WC, et al. Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase. Oncotarget. 2017;8:91928-37.
96. Tsai PC, Kuo HT, Hung CH, et al. ; T-COACH Study Group. Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan. J Hepatol. 2023;78:281-92.
97. Tsai PC, Huang CF, Yeh ML, et al. ; T-COACH Study Group. Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy. Clin Mol Hepatol. 2024;30:468-86.
98. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797-835.
99. Sanyal AJ, Chalasani N, Kowdley KV, et al.; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-85.
100. Bunchorntavakul C, Wootthananont T, Atsawarungruangkit A. Effects of vitamin E on chronic hepatitis C genotype 3: a randomized, double-blind, placebo-controlled study. J Med Assoc Thai. 2014;97:S31-40.
101. US. Food and Drug Administration. Novel drug approvals for 2024. Available from https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024. [accessed 10 September 2026].
102. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81:492-542.
103. Chen VL, Morgan TR, Rotman Y, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025;81:312-20.
104. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol. 2021;75:659-89.
105. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and kinetics of decrease in liver stiffness after antiviral therapy in patients with chronic hepatitis C: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16:27-38.e4.
106. Pietsch V, Deterding K, Attia D, et al. Long-term changes in liver elasticity in hepatitis C virus-infected patients with sustained virologic response after treatment with direct-acting antivirals. United European Gastroenterol J. 2018;6:1188-98.
107. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - renewing consensus in portal hypertension. J Hepatol. 2022;76:959-74.
108. Sanyal AJ, Newsome PN, Kliers I, et al. ; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392:2089-99.
109. Loomba R, Hartman ML, Lawitz EJ, et al. ; SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299-310.
110. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. ; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221-32.
111. Anker SD, Butler J, Filippatos G, et al. ; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451-61.
112. Herrington WG, Staplin N, Wanner C, et al. ; The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with Chronic Kidney Disease. N Engl J Med. 2023;388:117-27.
113. Eisenberg D, Shikora SA, Aarts E, et al. 2022 American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): indications for metabolic and bariatric surgery. Surg Obes Relat Dis. 2022;18:1345-56.
114. Verrastro O, Panunzi S, Castagneto-Gissey L, et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet. 2023;401:1786-97.
