REFERENCES
1. Association for the Study of the Liver; Electronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.
2. Liu Z, Jiang Y, Yuan H, et al. The trends in incidence of primary liver cancer caused by specific etiologies: results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention. J Hepatol 2019;70:674-83.
3. Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015;19:361-79.
6. 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 for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402.
7. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-8.
9. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46.
10. Eslam M, Sanyal AJ, George J. International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158:1999-2014.e1.
11. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020;73:202-9.
12. Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524-530.e1; quiz e60.
13. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.
14. Foschi FG, Bedogni G, Domenicali M, et al. Prevalence of and risk factors for fatty liver in the general population of Northern Italy: the Bagnacavallo Study. BMC Gastroenterol 2018;18:177.
15. Soresi M, Noto D, Cefalù AB, et al. Metabolic Syndrome Study Group. Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society. Acta Diabetol 2013;50:241-9.
16. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015;62:1723-30.
17. Cho EJ, Kwack MS, Jang ES, et al. Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area. Digestion 2011;84 Suppl 1:17-22.
18. Myers S, Neyroud-Caspar I, Spahr L, et al. NAFLD and MAFLD as emerging causes of HCC: a populational study. JHEP Rep 2021;3:100231.
19. Office fédéral de la statitique. Enquête Suisse Sur La Santé 2017. https://www.bfs.admin.ch/bfs/fr/home/statistiques/sante/determinants/exces-poids.html [Last accessed on 17 Jan 2021].
20. Younossi Z, Stepanova M, Ong JP, et al. Global Nonalcoholic Steatohepatitis Council. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol 2019;17:748-755.e3.
21. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389-97.e10.
22. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155:1828-37.e2.
23. Amarapurkar DN, Dharod M, Gautam S, Patel N. Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis. Trop Gastroenterol 2013;34:159-63.
24. Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009;24:248-54.
25. Hsiang JC, Bai WW, Raos Z, et al. Epidemiology, disease burden and outcomes of cirrhosis in a large secondary care hospital in South Auckland, New Zealand. Intern Med J 2015;45:160-9.
26. Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018;69:896-904.
27. Goossens N, Bellentani S, Cerny A, et al. Nonalcoholic fatty liver disease burden - Switzerland 2018-2030. Swiss Med Wkly 2019;149:w20152.
28. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328-57.
29. Kodama K, Kawaguchi T, Hyogo H, et al. Clinical features of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without advanced fibrosis. J Gastroenterol Hepatol 2019;34:1626-32.
30. Mittal S, El-Serag HB, Sada YH, et al. Hepatocellular carcinoma in the absence of cirrhosis in united states veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:124-31.e1.
31. Tokushige K, Hyogo H, Nakajima T, et al. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. J Gastroenterol 2016;51:586-96.
32. Yasui K, Hashimoto E, Komorizono Y, et al. Japan NASH Study Group. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:428-33; quiz e50.
33. Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 2016;63:827-38.
34. Koh YX, Tan HJ, Liew YX, et al. Liver resection for nonalcoholic fatty liver disease-associated hepatocellular carcinoma. J Am Coll Surg 2019;229:467-478.e1.
35. Paradis V, Zalinski S, Chelbi E, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009;49:851-9.
36. Bengtsson B, Stål P, Wahlin S, Björkström NK, Hagström H. Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis. Liver Int 2019;39:1098-108.
37. Tobari M, Hashimoto E, Taniai M, et al. The characteristics and risk factors of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis. J Gastroenterol Hepatol 2020;35:862-9.
38. Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med 2014;11:e1001624.
39. Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020;6:e204564.
40. Romeo S, Sanyal A, Valenti L. Leveraging Human genetics to identify potential new treatments for fatty liver disease. Cell Metab 2020;31:35-45.
41. Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol 2020;72:1196-209.
42. Bianco C, Jamialahmadi O, Pelusi S, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol 2021;74:775-82.
43. Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification. J Hepatol 2019;71:523-33.
44. Adler M, Larocca L, Trovato FM, Marcinkowski H, Pasha Y, Taylor-Robinson SD. Evaluating the risk of hepatocellular carcinoma in patients with prominently elevated liver stiffness measurements by FibroScan: a multicentre study. HPB (Oxford) 2016;18:678-83.
45. Kanwal F, Singal AG. Surveillance for hepatocellular carcinoma: current best practice and future direction. Gastroenterology 2019;157:54-64.
46. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68:526-49.
48. Marchesini G, Brizi M, Morselli-labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450-5.
50. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005;54:533-9.
51. Yang JD, Ahmed F, Mara KC, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 2020;71:907-16.
52. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003;348:1625-38.
53. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010;140:197-208.
54. Healy ME, Lahiri S, Hargett SR, et al. Dietary sugar intake increases liver tumor incidence in female mice. Sci Rep 2016;6:22292.
55. Piguet AC, Saran U, Simillion C, et al. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. J Hepatol 2015;62:1296-303.
56. Baumeister SE, Schlesinger S, Aleksandrova K, et al. Association between physical activity and risk of hepatobiliary cancers: a multinational cohort study. J Hepatol 2019;70:885-92.
57. Caussy C, Soni M, Cui J, et al. Familial NAFLD Cirrhosis Research Consortium. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest 2017;127:2697-704.
58. Long MT, Gurary EB, Massaro JM, et al. Parental non-alcoholic fatty liver disease increases risk of non-alcoholic fatty liver disease in offspring. Liver Int 2019;39:740-7.
59. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-5.
60. BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017;66:1111-24.
61. Mazo DF, Malta FM, Stefano JT, et al. Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population. Ann Hepatol 2019;18:466-71.
62. Liu YL, Patman GL, Leathart JB, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014;61:75-81.
63. Liu YL, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5:4309.
64. Pelusi S, Baselli G, Pietrelli A, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep 2019;9:3682.
65. Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019;16:411-28.
66. Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014;109:325-34.
67. Yang J, Trépo E, Nahon P, et al. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int J Cancer 2019;144:533-44.
68. Trépo E, Romeo S, Zucman-Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol 2016;65:399-412.
69. Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015;63:705-12.
70. Dongiovanni P, Donati B, Fares R, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013;19:6969-78.
71. Pirazzi C, Adiels M, Burza MA, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012;57:1276-82.
72. Scorletti E, West AL, Bhatia L, et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: results from the WELCOME trial. J Hepatol 2015;63:1476-83.
73. Liu Z, Que S, Zhou L, et al. The effect of the TM6SF2 E167K variant on liver steatosis and fibrosis in patients with chronic hepatitis C: a meta-analysis. Sci Rep 2017;7:9273.
74. Smagris E, Gilyard S, BasuRay S, Cohen JC, Hobbs HH. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J Biol Chem 2016;291:10659-76.
75. Mahdessian H, Taxiarchis A, Popov S, et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 2014;111:8913-8.
76. Prill S, Caddeo A, Baselli G, et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci Rep 2019;9:11585.
77. Kim DS, Jackson AU, Li YK, et al. Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns. J Lipid Res 2017;58:1471-81.
78. Dongiovanni P, Petta S, Maglio C, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506-14.
79. Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta-analysis. Hepatology 2015;62:1742-56.
80. Donati B, Dongiovanni P, Romeo S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017;7:4492.
81. Tang S, Zhang J, Mei TT, et al. Association of TM6SF2 rs58542926 T/C gene polymorphism with hepatocellular carcinoma: a meta-analysis. BMC Cancer 2019;19:1128.
82. Buch S, Stickel F, Trépo E, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015;47:1443-8.
83. Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent. Gastroenterology 2016;150:1219-1230.e6.
84. Gijón MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem 2008;283:30235-45.
85. Johansen A, Rosti RO, Musaev D, et al. Mutations in MBOAT7, encoding lysophosphatidylinositol acyltransferase I, lead to intellectual disability accompanied by epilepsy and autistic features. Am J Hum Genet 2016;99:912-6.
86. Teo K, Abeysekera KWM, Adams L, et al. EU-PNAFLD Investigators. , GOLD Consortium. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: a meta-analysis. J Hepatol 2021;74:20-30.
87. Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-9.
88. Beer NL, Tribble ND, McCulloch LJ, et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 2009;18:4081-8.
89. Barbara M, Scott A, Alkhouri N. New insights into genetic predisposition and novel therapeutic targets for nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr 2018;7:372-81.
90. Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol 2015;26:88-95.
91. Kawaguchi T, Shima T, Mizuno M, et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One 2018;13:e0185490.
92. Dewey FE, Murray MF, Overton JD, et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science 2016;354:aaf6814.
93. Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018;378:1096-106.
94. Yang J, Trépo E, Nahon P, et al. A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease. Hepatology 2019;70:231-40.
95. Wang P, Wu CX, Li Y, Shen N. HSD17B13 rs72613567 protects against liver diseases and histological progression of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2020;24:8997-9007.
96. Moeller G, Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 2009;301:7-19.
97. Tsachaki M, Odermatt A. Subcellular localization and membrane topology of 17β-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 2019;489:98-106.
98. Saloniemi T, Jokela H, Strauss L, Pakarinen P, Poutanen M. The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models. J Endocrinol 2012;212:27-40.
99. Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic inflammation in non-alcoholic steatohepatitis: molecular mechanisms and therapeutic strategies. Front Endocrinol (Lausanne) 2020;11:597648.
100. Gehrke N, Schattenberg JM. Metabolic inflammation-a role for hepatic inflammatory pathways as drivers of comorbidities in nonalcoholic fatty liver disease? Gastroenterology 2020;158:1929-1947.e6.
101. Cai J, Zhang XJ, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology 2019;70:1026-37.
103. Koo SY, Park EJ, Lee CW. Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma. Exp Mol Med 2020;52:1209-19.
104. Stiglund N, Strand K, Cornillet M, et al. Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease. Front Immunol 2019;10:1255.
105. Narayanan S, Surette FA, Hahn YS. The Immune landscape in nonalcoholic steatohepatitis. Immune Netw 2016;16:147-58.
106. Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008;129:428-37.
107. Hoechst B, Voigtlaender T, Ormandy L, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009;50:799-807.
109. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci 2016;61:1294-303.
110. Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol 2015;12:387-400.
111. Aron-Wisnewsky J, Prifti E, Belda E, et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut 2019;68:70-82.
112. Debédat J, Clément K, Aron-Wisnewsky J. Gut microbiota dysbiosis in human obesity: impact of bariatric surgery. Curr Obes Rep 2019;8:229-42.
113. Abenavoli L, Scarpellini E, Colica C, et al. Gut microbiota and obesity: a role for probiotics. Nutrients 2019;11:2690.
114. Aoun A, Darwish F, Hamod N. The influence of the gut microbiome on obesity in adults and the role of probiotics, prebiotics, and synbiotics for weight loss. Prev Nutr Food Sci 2020;25:113-23.
115. Gomes AC, Hoffmann C, Mota JF. The human gut microbiota: metabolism and perspective in obesity. Gut Microbes 2018;9:308-25.
116. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008;3:213-23.
117. Weiss GA, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci 2017;74:2959-77.
118. Chatelier E, Nielsen T, Qin J, et al; MetaHIT consortium. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541-6.
119. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022-3.
121. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 2016;13:412-25.
122. Brandi G, De Lorenzo S, Candela M, et al. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis 2017;38:231-40.
123. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97-101.
124. Wu L, Feng J, Li J, et al. The gut microbiome-bile acid axis in hepatocarcinogenesis. Biomed Pharmacother 2021;133:111036.
125. Ðanić M, Stanimirov B, Pavlović N, et al. Pharmacological applications of bile acids and their derivatives in the treatment of metabolic syndrome. Front Pharmacol 2018;9:1382.
127. Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015;36:44-50.
128. Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014;509:183-8.
129. Su H, Ma C, Liu J, et al. Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 2012;303:G1245-53.
130. Wolfe A, Thomas A, Edwards G, Jaseja R, Guo GL, Apte U. Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther 2011;338:12-21.
131. Takahashi S, Tanaka N, Fukami T, et al. Role of farnesoid X receptor and bile acids in hepatic tumor development. Hepatol Commun 2018;2:1567-82.
132. Bosman FT, Carneiro F, Hruban RH, Theise ND. . WHO classification of tumours of the digestive system. 4th ed. Geneva: World Health Organization; 2010.
133. Lokuhetty D. Organisation mondiale de la santé, Centre international de recherche sur le cancer. WHO classification of tumours. https://whobluebooks.iarc.fr/ [Last accessed on 17 Jan 2021].
134. Salomao M, Yu WM, Brown RS Jr, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am J Surg Pathol 2010;34:1630-6.
135. Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum Pathol 2012;43:737-46.
136. Shibahara J, Ando S, Sakamoto Y, Kokudo N, Fukayama M. Hepatocellular carcinoma with steatohepatitic features: a clinicopathological study of Japanese patients. Histopathology 2014;64:951-62.
137. Qin J, Higashi T, Nakagawa S, et al. Steatohepatitic variant of hepatocellular carcinoma is associated with both alcoholic steatohepatitis and nonalcoholic steatohepatitis: a study of 2 cohorts with molecular insights. Am J Surg Pathol 2020;44:1406-12.
138. Lee JS, Yoo JE, Kim H, et al. Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma. PLoS One 2017;12:e0171922.
139. Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol 2017;67:727-38.
140. Ziol M, Poté N, Amaddeo G, et al. Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance. Hepatology 2018;68:103-12.
141. Reddy SK, Steel JL, Chen HW, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012;55:1809-19.
142. Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 2010;26:2183-91.
143. Pelusi S, Cespiati A, Rametta R, et al. Prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis. Clin Gastroenterol Hepatol 2019;17:2310-9.e6.
144. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603-8.
145. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-9.
146. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367-78.e5; quiz e14.
147. Turati F, Trichopoulos D, Polesel J, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol 2014;60:606-11.
148. Gepner Y, Shelef I, Komy O, et al. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J Hepatol 2019;71:379-88.
149. EPIC - European Prospective Investigation into Cancer and Nutrition. https://epic.iarc.fr/ [Last accessed on 17 Jan 2021].
150. Lee Y, Doumouras AG, Yu J, et al. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2019;17:1040-60.e11.
151. Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg 2005;242:610-7; discussion 618.
152. Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-88; quiz e15.
153. Lassailly G, Caiazzo R, Ntandja-Wandji LC, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 2020;159:1290-301.e5.
154. Kwak M, Mehaffey JH, Hawkins RB, Hsu A, Schirmer B, Hallowell PT. Bariatric surgery is associated with reduction in non-alcoholic steatohepatitis and hepatocellular carcinoma: a propensity matched analysis. Am J Surg 2020;219:504-7.
155. Malehmir M, Pfister D, Gallage S, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 2019;25:641-55.
156. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 2016;5:e189.
157. Foderà D, D'Alessandro N, Cusimano A, et al. Induction of apoptosis and inhibition of cell growth in human hepatocellular carcinoma cells by COX-2 inhibitors. Ann N Y Acad Sci 2004;1028:440-9.
158. Kern MA, Schubert D, Sahi D, et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 2002;36:885-94.
159. Chen H, Cai W, Chu ESH, et al. Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene 2017;36:4415-26.
160. 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.
161. Huang MY, Chung CH, Chang WK, et al. The role of thiazolidinediones in hepatocellular carcinoma risk reduction: a population-based cohort study in Taiwan. Am J Cancer Res 2017;7:1606-16.
162. Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int 2010;30:750-8.
163. Hassan M, Li D, Kaseb A, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010;116:1938-46.
164. Bosetti C, Franchi M, Nicotra F, et al. Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases. Pharmacoepidemiol Drug Saf 2015;24:771-8.
165. Kasmari AJ, Welch A, Liu G, Leslie D, McGarrity T, Riley T. Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome. Am J Med 2017;130:746.e1-7.
166. Miele L, Bosetti C, Turati F, et al. Diabetes and insulin therapy, but not metformin, are related to hepatocellular cancer risk. Gastroenterol Res Pract 2015;2015:570356.
167. Zheng L, Yang W, Wu F, et al. Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res 2013;19:5372-80.
168. Cunha V, Cotrim HP, Rocha R, Carvalho K, Lins-Kusterer L. Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review. Ann Hepatol 2020;19:232-7.
169. Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-43.
171. Cauchy F, Zalinski S, Dokmak S, et al. Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome. Br J Surg 2013;100:113-21.
172. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.
173. Howell J, Samani A, Mannan B, Hajiev S, sharma R. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study. JCO 2021;39:289.
174. Jian C, Fu J, Cheng X, et al. Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab 2020;31:892-908.e11.
175. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
176. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-73.
177. Zhu AX, Kang Y, Yen C, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282-96.
178. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
179. Finn RS, Qin S, Ikeda M, et al. IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-905.
180. Galle PR, Finn RS, Qin S, et al. Patient-reported outcomes (PROs) from the Phase III IMbrave150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). JCO 2020;38:476.
181. Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 2020;38:4317-45.
182. Rakhra K, Bachireddy P, Zabuawala T, et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 2010;18:485-98.
183. Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016;531:253-7.
184. Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 2021;70:204-14.
185. Yau T, Park J, Finn R, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019;30:v874-5.
186. Heinrich B, Brown Z, Vormehr M, et al. Abstract 1728: Nonalcoholic steatohepatitis (NASH) impairs treatment of intrahepatic metastases with CD4 + T cell dependent RNA vaccine. Cancer Res 2018;78:1728.
187. Artaç M, Korkmaz L, Coşkun HŞ, et al. Bevacuzimab may be less effective in obese metastatic colorectal cancer patients. J Gastrointest Cancer 2019;50:214-20.
188. Guiu B, Petit JM, Bonnetain F, et al. Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer. Gut 2010;59:341-7.
