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Hepatic Outcomes of Nonalcoholic Fatty Liver Disease Including Cirrhosis and Hepatocellular Carcinoma

  • Saleh A. Alqahtani
    Corresponding author. Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD.
    Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA

    Liver Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Wah-Kheong Chan
    Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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  • Ming-Lung Yu
    School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Hepatobiliary Section, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Published:March 09, 2023DOI:


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        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • et al.
        Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Li J.
        • Zou B.
        • Yeo Y.H.
        • et al.
        Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.
        Lancet Gastroenterol Hepatol. 2019; 4: 389-398
        • Wu K.T.
        • Kuo P.L.
        • Su S.B.
        • et al.
        Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol.
        J Clin Lipidol. 2016; 10: 420-425 e421
        • Hsiao P.J.
        • Kuo K.K.
        • Shin S.J.
        • et al.
        Significant correlations between severe fatty liver and risk factors for metabolic syndrome.
        J Gastroenterol Hepatol. 2007; 22: 2118-2123
        • Fan J.G.
        • Kim S.U.
        • Wong V.W.
        New trends on obesity and NAFLD in Asia.
        J Hepatol. 2017; 67: 862-873
        • Younossi Z.M.
        • Ong J.P.
        • Takahashi H.
        • et al.
        A global survey of physicians knowledge about nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2022; 20: e1456-e1468
        • Lazarus J.V.
        • Mark H.E.
        • Anstee Q.M.
        • et al.
        Advancing the global public health agenda for NAFLD: a consensus statement.
        Nat Rev Gastroenterol Hepatol. 2022; 19: 60-78
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • 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: 328-357
        • Anstee Q.M.
        • Reeves H.L.
        • Kotsiliti E.
        • et al.
        From NASH to HCC: current concepts and future challenges.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 411-428
        • Huang Y.H.
        • Chan C.
        • Lee H.W.
        • et al.
        Influence of nonalcoholic fatty liver disease with increased liver enzyme levels on the risk of cirrhosis and hepatocellular carcinoma.
        Clin Gastroenterol Hepatol. 2022; S1542-3565: 00105-00107
        • Sanyal A.J.
        • Van Natta M.L.
        • Clark J.
        • et al.
        Prospective study of outcomes in adults with nonalcoholic fatty liver disease.
        N Engl J Med. 2021; 385: 1559-1569
        • Sanyal A.J.
        • Anstee Q.M.
        • Trauner M.
        • et al.
        Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis.
        Hepatology. 2022; 75: 1235-1246
        • Younossi Z.M.
        Non-alcoholic fatty liver disease - a global public health perspective.
        J Hepatol. 2019; 70: 531-544
        • Lin T.Y.
        • Yeh M.L.
        • Huang C.F.
        • et al.
        Disease progression of nonalcoholic steatohepatitis in Taiwanese patients: a longitudinal study of paired liver biopsies.
        Eur J Gastroenterol Hepatol. 2019; 31: 224-229
        • Singh S.
        • Allen A.M.
        • Wang Z.
        • et al.
        Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
        Clin Gastroenterol Hepatol. 2015; 13 (e641-649;quiz e639-640): 643-654
        • Kleiner D.E.
        • Brunt E.M.
        • Wilson L.A.
        • et al.
        Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
        JAMA Netw Open. 2019; 2: e1912565
        • Xanthakos S.A.
        • Lavine J.E.
        • Yates K.P.
        • et al.
        Progression of fatty liver disease in children receiving standard of care lifestyle advice.
        Gastroenterology. 2020; 159: 1731-1751 e1710
        • Huang J.F.
        • Dai C.Y.
        • Huang C.F.
        • et al.
        First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.
        Hepatol Int. 2021; 15: 1136-1147
        • Ng C.H.
        • Xiao J.
        • Lim W.H.
        • et al.
        Placebo effect on progression and regression in NASH: evidence from a meta-analysis.
        Hepatology. 2022; 75: 1647-1661
        • Schattenberg J.M.
        • Straub B.K.
        On the value and limitations of liver histology in assessing non-alcoholic steatohepatitis.
        J Hepatol. 2020; 73: 1592-1593
        • Alqahtani S.A.
        • Schattenberg J.M.
        Nonalcoholic fatty liver disease: use of diagnostic biomarkers and modalities in clinical practice.
        Expert Rev Mol Diagn. 2021; 21: 1065-1078
        • Chang Y.
        • Jung H.S.
        • Cho J.
        • et al.
        Metabolically healthy obesity and the development of nonalcoholic fatty liver disease.
        Am J Gastroenterol. 2016; 111: 1133-1140
        • Whalley S.
        • Puvanachandra P.
        • Desai A.
        • et al.
        Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs.
        Clin Med. 2007; 7: 119-124
        • Dulai P.S.
        • Singh S.
        • Patel J.
        • et al.
        Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.
        Hepatology. 2017; 65: 1557-1565
        • Loomba R.
        • Adams L.A.
        The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH.
        Hepatology. 2019; 70: 1885-1888
        • Sanyal A.J.
        • Harrison S.A.
        • Ratziu V.
        • et al.
        The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
        Hepatology. 2019; 70: 1913-1927
        • Wong V.W.
        • Chu W.C.
        • Wong G.L.
        • et al.
        Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography.
        Gut. 2012; 61: 409-415
        • Hussain A.
        • Patel P.J.
        • Rhodes F.
        • et al.
        Decompensated cirrhosis is the commonest presentation for NAFLD patients undergoing liver transplant assessment.
        Clin Med. 2020; 20: 313-318
        • Chan W.K.
        • Tan S.S.
        • Chan S.P.
        • et al.
        Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction-associated fatty liver disease.
        J Gastroenterol Hepatol. 2022; 37: 795-811
        • de Franchis R.
        • Bosch J.
        • Garcia-Tsao G.
        • et al.
        Baveno VII - renewing consensus in portal hypertension.
        J Hepatol. 2022; 76: 959-974
        • Chan W.K.
        • Treeprasertsuk S.
        • Goh G.B.
        • et al.
        Optimizing use of nonalcoholic fatty liver disease fibrosis score, fibrosis-4 score, and liver stiffness measurement to identify patients with advanced fibrosis.
        Clin Gastroenterol Hepatol. 2019; 17: 2570-2580.e37
        • Wong V.W.
        • Irles M.
        • Wong G.L.
        • et al.
        Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease.
        Gut. 2019; 68: 2057-2064
        • Pons M.
        • Augustin S.
        • Scheiner B.
        • et al.
        Noninvasive diagnosis of portal hypertension in patients with compensated advanced chronic liver disease.
        Am J Gastroenterol. 2021; 116: 723-732
        • Szakacs Z.
        • Eross B.
        • Soos A.
        • et al.
        Baveno criteria safely identify patients with compensated advanced chronic liver disease who can avoid variceal screening endoscopy: a diagnostic test accuracy meta-analysis.
        Front Physiol. 2019; 10: 1028
        • Tantai X.
        • Liu Y.
        • Yeo Y.H.
        • et al.
        Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis.
        J Hepatol. 2022; 76: 588-599
        • Dasarathy S.
        • Merli M.
        Sarcopenia from mechanism to diagnosis and treatment in liver disease.
        J Hepatol. 2016; 65: 1232-1244
        • 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 (e365; quiz e314-365): 367-378
        • Newsome P.N.
        • Buchholtz K.
        • Cusi K.
        • et al.
        A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
        N Engl J Med. 2021; 384: 1113-1124
        • Wilding J.P.H.
        • Batterham R.L.
        • Calanna S.
        • et al.
        Once-weekly semaglutide in adults with overweight or obesity.
        N Engl J Med. 2021; 384: 989-1002
        • Burra P.
        • Becchetti C.
        • Germani G.
        NAFLD and liver transplantation: disease burden, current management and future challenges.
        JHEP Rep. 2020; 2: 100192
        • Saeed N.
        • Glass L.
        • Sharma P.
        • et al.
        Incidence and risks for nonalcoholic fatty liver disease and steatohepatitis post-liver transplant: systematic review and meta-analysis.
        Transplantation. 2019; 103: e345-e354
        • Akinyemiju T.
        • Abera S.
        • Ahmed M.
        • et al.
        The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
        JAMA Oncol. 2017; 3: 1683-1691
        • Younossi Z.M.
        • 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: 1723-1730
        • Geh D.
        • Anstee Q.M.
        • Reeves H.L.
        NAFLD-associated HCC: progress and opportunities.
        J Hepatocell Carcinoma. 2021; 8: 223-239
        • Desai A.
        • Sandhu S.
        • Lai J.P.
        • et al.
        Hepatocellular carcinoma in non-cirrhotic liver: a comprehensive review.
        World J Hepatol. 2019; 11: 1-18
      1. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2019; 30: 871-873
        • Geh D.
        • Rana F.A.
        • Reeves H.L.
        Weighing the benefits of hepatocellular carcinoma surveillance against potential harms.
        J Hepatocell Carcinoma. 2019; 6: 23-30
        • Perisetti A.
        • Goyal H.
        • Yendala R.
        • et al.
        Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: current insights and advancements.
        World J Gastroenterol. 2021; 27: 3466-3482
        • Rastogi A.
        Pathomolecular characterization of HCC in non-cirrhotic livers.
        Hepatoma Res. 2020; 6: 47
        • Yang J.D.
        • Addissie B.D.
        • Mara K.C.
        • et al.
        GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score.
        Cancer Epidemiol Biomarkers Prev. 2019; 28: 531-538
        • Best J.
        • Bechmann L.P.
        • Sowa J.P.
        • et al.
        GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis.
        Clin Gastroenterol Hepatol. 2020; 18: 728-735.e724
      2. Roche - doing now what patients need next, Available at: Accessed January 05, 2023.

        • Nakamura N.
        • Hatano E.
        • Iguchi K.
        • et al.
        Elevated levels of circulating ITIH4 are associated with hepatocellular carcinoma with nonalcoholic fatty liver disease: from pig model to human study.
        BMC Cancer. 2019; 19: 621
        • Heo M.J.
        • Yun J.
        • Kim S.G.
        Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma.
        Arch Pharm Res (Seoul). 2019; 42: 48-62
        • Li C.
        • Chen J.
        • Zhang K.
        • et al.
        Progress and prospects of long noncoding RNAs (lncRNAs) in hepatocellular carcinoma.
        Cell Physiol Biochem. 2015; 36: 423-434
        • Xu R.H.
        • Wei W.
        • Krawczyk M.
        • et al.
        Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma.
        Nat Mater. 2017; 16: 1155-1161
        • Baumeister S.E.
        • Schlesinger S.
        • Aleksandrova K.
        • et al.
        Association between physical activity and risk of hepatobiliary cancers: a multinational cohort study.
        J Hepatol. 2019; 70: 885-892
        • Turati F.
        • Trichopoulos D.
        • Polesel J.
        • et al.
        Mediterranean diet and hepatocellular carcinoma.
        J Hepatol. 2014; 60: 606-611