Modifiers of Liver-Related Manifestation in the Course of NAFLD

Page: [1062 - 1078] Pages: 17

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population. There is a strong association between the severity of NAFLD and the components of the metabolic syndrome. NAFLD is also independently associated with cardiovascular disease and type 2 diabetes mellitus (T2DM). The progressive potential of non-alcoholic fatty liver disease (NAFLD) is indisputable today, and the histological spectrum of NAFLD ranges from isolated steatosis to nonalcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. There is a substantial inter-patient variation in disease progression, therefore, this review will focus on potential modifiers of fibrosis progression, development of liver cirrhosis, decompensation and liver-related mortality. The potential drivers of disease progression that is discussed are; T2DM and Insulin Resistance, body weight, alcohol consumption, genetics (including HFE and alfa-1-antitrypsin) as well as histological features predictive of disease progression.

Keywords: End-stage liver disease, HCC, fibrosis, alcohol, fibrosis progression, NAFLD.

[1]
Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148(3): 547-55.
[http://dx.doi.org/10.1053/j.gastro.2014.11.039] [PMID: 25461851]
[2]
Pais R, Barritt AS IV, Calmus Y, et al. NAFLD and liver transplantation: Current burden and expected challenges. J Hepatol 2016; 65(6): 1245-57.
[http://dx.doi.org/10.1016/j.jhep.2016.07.033] [PMID: 27486010]
[3]
Collaboration NCDRF. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet 2017; 390(10113): 2627-42.
[http://dx.doi.org/10.1016/S0140-6736(17)32129-3] [PMID: 29029897]
[4]
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(1): 73-84.
[http://dx.doi.org/10.1002/hep.28431] [PMID: 26707365]
[5]
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116(6): 1413-9.
[http://dx.doi.org/10.1016/S0016-5085(99)70506-8] [PMID: 10348825]
[6]
Sanyal AJ, Association AG. American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123(5): 1705-25.
[http://dx.doi.org/10.1053/gast.2002.36572] [PMID: 12404245]
[7]
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62(1)(Suppl.): S47-64.
[http://dx.doi.org/10.1016/j.jhep.2014.12.012] [PMID: 25920090]
[8]
Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH. Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci (Lond) 2009; 116(7): 539-64.
[http://dx.doi.org/10.1042/CS20080253] [PMID: 19243311]
[9]
Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2(11): 901-10.
[http://dx.doi.org/10.1016/S2213-8587(14)70032-4] [PMID: 24731669]
[10]
Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: A systematic review and meta-analysis. Sci Rep 2016; 6: 33386.
[http://dx.doi.org/10.1038/srep33386] [PMID: 27633274]
[11]
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363(14): 1341-50.
[http://dx.doi.org/10.1056/NEJMra0912063] [PMID: 20879883]
[12]
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016; 65(3): 589-600.
[http://dx.doi.org/10.1016/j.jhep.2016.05.013] [PMID: 27212244]
[13]
Fracanzani AL, Tiraboschi S, Pisano G, et al. Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up. Atherosclerosis 2016; 246: 208-13.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.01.016] [PMID: 26803429]
[14]
Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016; 64(5): 1577-86.
[http://dx.doi.org/10.1002/hep.28785] [PMID: 27543837]
[15]
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10(11): 686-90.
[http://dx.doi.org/10.1038/nrgastro.2013.171] [PMID: 24042449]
[16]
Ratziu V, Sanyal A, Francque S, et al. Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: Year 2 analysis of the Phase 2b CENTAUR study. J Hepatol 2018; 68: S1-2.
[http://dx.doi.org/10.1016/S0168-8278(18)30221-6]
[17]
Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018; 67(5): 1754-67.
[http://dx.doi.org/10.1002/hep.29477] [PMID: 28833331]
[18]
Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol 2018; 68(2): 238-50.
[http://dx.doi.org/10.1016/j.jhep.2017.11.012] [PMID: 29154966]
[19]
Ratziu V, Charlotte F, Heurtier A, et al. LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128(7): 1898-906.
[http://dx.doi.org/10.1053/j.gastro.2005.03.084] [PMID: 15940625]
[20]
Vuppalanchi R, Ünalp A, Van Natta ML, et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic Fatty liver disease. Clin Gastroenterol Hepatol 2009; 7(4): 481-6.
[http://dx.doi.org/10.1016/j.cgh.2008.12.015] [PMID: 19162235]
[21]
Arun J, Jhala N, Lazenby AJ, Clements R, Abrams GA. Influence of liver biopsy heterogeneity and diagnosis of nonalcoholic steatohepatitis in subjects undergoing gastric bypass. Obes Surg 2007; 17(2): 155-61.
[http://dx.doi.org/10.1007/s11695-007-9041-2] [PMID: 17476865]
[22]
Younossi ZM, Gramlich T, Liu YC, et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol 1998; 11(6): 560-5.
[PMID: 9647594]
[23]
Larson SP, Bowers SP, Palekar NA, Ward JA, Pulcini JP, Harrison SA. Histopathologic variability between the right and left lobes of the liver in morbidly obese patients undergoing Roux-en-Y bypass. Clin Gastroenterol Hepatol 2007; 5(11): 1329-32.
[http://dx.doi.org/10.1016/j.cgh.2007.06.005] [PMID: 17702661]
[24]
Merriman RB, Ferrell LD, Patti MG, et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006; 44(4): 874-80.
[http://dx.doi.org/10.1002/hep.21346] [PMID: 17006934]
[25]
Pournik O, Alavian SM, Ghalichi L, et al. Inter-observer and intra-observer agreement in pathological evaluation of non-alcoholic fatty liver disease suspected liver biopsies. Hepat Mon 2014; 14(1): e15167
[http://dx.doi.org/10.5812/hepatmon.15167] [PMID: 24497882]
[26]
Jung ES, Lee K, Yu E, et al. Interobserver agreement on pathologic features of liver biopsy tissue in patients with nonalcoholic fatty liver disease. J Pathol Transl Med 2016; 50(3): 190-6.
[http://dx.doi.org/10.4132/jptm.2016.03.01] [PMID: 27086596]
[27]
Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6): 1313-21.
[http://dx.doi.org/10.1002/hep.20701] [PMID: 15915461]
[28]
Bedossa P, Consortium FP. FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 2014; 60(2): 565-75.
[http://dx.doi.org/10.1002/hep.27173] [PMID: 24753132]
[29]
Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43(8): 617-49.
[http://dx.doi.org/10.3109/07853890.2010.518623] [PMID: 21039302]
[30]
Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10(6): 330-44.
[http://dx.doi.org/10.1038/nrgastro.2013.41] [PMID: 23507799]
[31]
Dulai PS, 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(5): 1557-65.
[http://dx.doi.org/10.1002/hep.29085] [PMID: 28130788]
[32]
Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 2017; 67(6): 1265-73.
[http://dx.doi.org/10.1016/j.jhep.2017.07.027] [PMID: 28803953]
[33]
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(2): 389-97.e10.
[http://dx.doi.org/10.1053/j.gastro.2015.04.043] [PMID: 25935633]
[34]
Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol 2015; 62(1)(Suppl.): S65-75.
[http://dx.doi.org/10.1016/j.jhep.2015.02.041] [PMID: 25920092]
[35]
Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012; 56(1): 255-66.
[http://dx.doi.org/10.1016/j.jhep.2011.06.010] [PMID: 21723839]
[36]
Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 2017; 67(4): 829-46.
[http://dx.doi.org/10.1016/j.jhep.2017.05.016] [PMID: 28545937]
[37]
Collaboration NCDRF. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016; 387(10027): 1513-30.
[http://dx.doi.org/10.1016/S0140-6736(16)00618-8] [PMID: 27061677]
[38]
Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140(1): 124-31.
[http://dx.doi.org/10.1053/j.gastro.2010.09.038] [PMID: 20858492]
[39]
Björkström K, Stål P, Hultcrantz R, Hagström H. Histologic scores for fat and fibrosis associate with development of type 2 diabetes in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2017; 15(9): 1461-8.
[http://dx.doi.org/10.1016/j.cgh.2017.04.040] [PMID: 28479500]
[40]
Park SK, Seo MH, Shin HC, Ryoo JH. Clinical availability of nonalcoholic fatty liver disease as an early predictor of type 2 diabetes mellitus in Korean men: 5-year prospective cohort study. Hepatology 2013; 57(4): 1378-83.
[http://dx.doi.org/10.1002/hep.26183] [PMID: 23213066]
[41]
Lonardo A, Bellentani S, Argo CK, et al. Non-alcoholic Fatty Liver Disease Study Group. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis 2015; 47(12): 997-1006.
[http://dx.doi.org/10.1016/j.dld.2015.08.004] [PMID: 26454786]
[42]
Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019; 71(4): 793-801.
[http://dx.doi.org/10.1016/j.jhep.2019.06.021] [PMID: 31279902]
[43]
Ma J, Hwang S-J, Pedley A, et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol 2017; 66(2): 390-7.
[http://dx.doi.org/10.1016/j.jhep.2016.09.022] [PMID: 27729222]
[44]
Li Y, Wang J, Tang Y, et al. Bidirectional association between nonalcoholic fatty liver disease and type 2 diabetes in Chinese population: Evidence from the Dongfeng-Tongji cohort study. PLoS One 2017; 12(3): e0174291
[http://dx.doi.org/10.1371/journal.pone.0174291] [PMID: 28350839]
[45]
Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 2016; 31(5): 936-44.
[http://dx.doi.org/10.1111/jgh.13264] [PMID: 26667191]
[46]
Chen SC-C, Tsai SP, Jhao J-Y, Jiang W-K, Tsao CK, Chang L-Y. Liver fat, hepatic enzymes, alkaline phosphatase and the risk of incident type 2 diabetes: a prospective study of 132,377 adults. Sci Rep 2017; 7(1): 4649.
[http://dx.doi.org/10.1038/s41598-017-04631-7] [PMID: 28680048]
[47]
Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44(4): 865-73.
[http://dx.doi.org/10.1002/hep.21327] [PMID: 17006923]
[48]
Nasr P, Ignatova S, Kechagias S, Ekstedt M. Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. Hepatol Commun 2017; 2(2): 199-210.
[http://dx.doi.org/10.1002/hep4.1134] [PMID: 29404527]
[49]
McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62(5): 1148-55.
[http://dx.doi.org/10.1016/j.jhep.2014.11.034] [PMID: 25477264]
[50]
Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989; 20(6): 594-8.
[http://dx.doi.org/10.1016/0046-8177(89)90249-9] [PMID: 2656500]
[51]
Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11(1): 74-80.
[http://dx.doi.org/10.1002/hep.1840110114] [PMID: 2295475]
[52]
Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22(6): 1714-9.
[http://dx.doi.org/10.1002/hep.1840220616] [PMID: 7489979]
[53]
Evans CD, Oien KA, MacSween RN, Mills PR. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol 2002; 55(9): 689-92.
[http://dx.doi.org/10.1136/jcp.55.9.689] [PMID: 12195000]
[54]
Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118(6): 1117-23.
[http://dx.doi.org/10.1016/S0016-5085(00)70364-7] [PMID: 10833486]
[55]
Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003; 98(9): 2042-7.
[http://dx.doi.org/10.1111/j.1572-0241.2003.07659.x] [PMID: 14499785]
[56]
Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004; 40(4): 820-6.
[http://dx.doi.org/10.1002/hep.20410] [PMID: 15382171]
[57]
Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005; 42(1): 132-8.
[http://dx.doi.org/10.1016/j.jhep.2004.09.012] [PMID: 15629518]
[58]
Hui AY, Wong VW, Chan HL, et al. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005; 21(4): 407-13.
[http://dx.doi.org/10.1111/j.1365-2036.2005.02334.x] [PMID: 15709991]
[59]
Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010; 59(7): 969-74.
[http://dx.doi.org/10.1136/gut.2009.205088] [PMID: 20581244]
[60]
Pais R, Charlotte F, Fedchuk L, et al. LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59(3): 550-6.
[http://dx.doi.org/10.1016/j.jhep.2013.04.027] [PMID: 23665288]
[61]
Sanyal AJ, Harrison SA, Ratziu V, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 2019; 70(6): 1913-27.
[http://dx.doi.org/10.1002/hep.30664] [PMID: 30993748]
[62]
Stepanova M, Rafiq N, Makhlouf H, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2013; 58(10): 3017-23.
[http://dx.doi.org/10.1007/s10620-013-2743-5] [PMID: 23775317]
[63]
Adams LA, Harmsen S, St Sauver JL, et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 2010; 105(7): 1567-73.
[http://dx.doi.org/10.1038/ajg.2010.18] [PMID: 20145609]
[64]
Sebastiani G, Alshaalan R, Wong P, et al. Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis. PLoS One 2015; 10(6): e0128774
[http://dx.doi.org/10.1371/journal.pone.0128774] [PMID: 26083565]
[65]
Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 2018; 155(2): 443-457.e17.
[http://dx.doi.org/10.1053/j.gastro.2018.04.034] [PMID: 29733831]
[66]
Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-81.
[http://dx.doi.org/10.1016/j.diabres.2018.02.023] [PMID: 29496507]
[67]
Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364(9): 829-41.
[http://dx.doi.org/10.1056/NEJMoa1008862] [PMID: 21366474]
[68]
Muggeo M, Verlato G, Bonora E, et al. The Verona diabetes study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality. Diabetologia 1995; 38(3): 318-25.
[http://dx.doi.org/10.1007/BF00400637] [PMID: 7758879]
[69]
Weiderpass E, Gridley G, Nyrén O, Pennello G, Landström AS, Ekbom A. Cause-specific mortality in a cohort of patients with diabetes mellitus: a population-based study in Sweden. J Clin Epidemiol 2001; 54(8): 802-9.
[http://dx.doi.org/10.1016/S0895-4356(01)00342-0] [PMID: 11470389]
[70]
Zoppini G, Fedeli U, Gennaro N, Saugo M, Targher G, Bonora E. Mortality from chronic liver diseases in diabetes. Am J Gastroenterol 2004; 109(7): 1024-5.
[http://dx.doi.org/10.1038/ajg.2014.132]
[71]
Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care 2012; 35(9): 1835-44.
[http://dx.doi.org/10.2337/dc12-0002] [PMID: 22699290]
[72]
Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89(18): 1360-5.
[http://dx.doi.org/10.1093/jnci/89.18.1360] [PMID: 9308706]
[73]
Yu MC, Tong MJ, Govindarajan S, Henderson BE. Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 1991; 83(24): 1820-6.
[http://dx.doi.org/10.1093/jnci/83.24.1820] [PMID: 1660542]
[74]
Kingston ME, Ali MA, Atiyeh M, Donnelly RJ. Diabetes mellitus in chronic active hepatitis and cirrhosis. Gastroenterology 1984; 87(3): 688-94.
[http://dx.doi.org/10.1016/0016-5085(84)90544-4] [PMID: 6086443]
[75]
Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60(1): 110-7.
[http://dx.doi.org/10.1016/j.jhep.2013.08.011] [PMID: 23978719]
[76]
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126(2): 460-8.
[http://dx.doi.org/10.1053/j.gastro.2003.10.065] [PMID: 14762783]
[77]
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(4): 533-9.
[http://dx.doi.org/10.1136/gut.2004.052167] [PMID: 15753540]
[78]
White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10(12): 1342-1359.e2.
[http://dx.doi.org/10.1016/j.cgh.2012.10.001] [PMID: 23041539]
[79]
Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012; 28(2): 109-22.
[http://dx.doi.org/10.1002/dmrr.1291] [PMID: 21898753]
[80]
Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123(1): 134-40.
[http://dx.doi.org/10.1053/gast.2002.34168] [PMID: 12105842]
[81]
Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002; 36(6): 1349-54.
[http://dx.doi.org/10.1002/hep.1840360609] [PMID: 12447858]
[82]
Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 2004; 10(2)(Suppl. 1): S69-73.
[http://dx.doi.org/10.1002/lt.20033] [PMID: 14762843]
[83]
Hughes V. The big fat truth. Nature 2013; 497(7450): 428-30.
[PMID: 23698426]
[84]
Whitlock G, Lewington S, Sherliker P, et al. Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373(9669): 1083-96.
[http://dx.doi.org/10.1016/S0140-6736(09)60318-4] [PMID: 19299006]
[85]
Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010; 363(23): 2211-9.
[http://dx.doi.org/10.1056/NEJMoa1000367] [PMID: 21121834]
[86]
Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013; 309(1): 71-82.
[http://dx.doi.org/10.1001/jama.2012.113905] [PMID: 23280227]
[87]
Li L, Liu DW, Yan HY, Wang ZY, Zhao SH, Wang B. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev 2016; 17(6): 510-9.
[http://dx.doi.org/10.1111/obr.12407] [PMID: 27020692]
[88]
Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol 2013; 178(1): 38-45.
[http://dx.doi.org/10.1093/aje/kws448] [PMID: 23703888]
[89]
Reeder SB, Sirlin CB. Quantification of liver fat with magnetic resonance imaging. Magn Reson Imaging Clin N Am 2010; 18: 337-57.
[90]
Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging 2011; 34(4): 729-49.
[http://dx.doi.org/10.1002/jmri.22580] [PMID: 22025886]
[91]
Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288(2): E462-8.
[http://dx.doi.org/10.1152/ajpendo.00064.2004] [PMID: 15339742]
[92]
Loomba R, Sirlin CB, Ang B, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel MRI and MRE in a randomized trial (MOZART Trial). Hepatology 2015; 61: 1239-50.
[http://dx.doi.org/10.1002/hep.27647] [PMID: 25482832]
[93]
Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40(6): 1387-95.
[http://dx.doi.org/10.1002/hep.20466] [PMID: 15565570]
[94]
Tang A, Tan J, Sun M, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. Radiology 2013; 267(2): 422-31.
[http://dx.doi.org/10.1148/radiol.12120896] [PMID: 23382291]
[95]
Tang A, Desai A, Hamilton G, et al. Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease. Radiology 2015; 274(2): 416-25.
[http://dx.doi.org/10.1148/radiol.14140754] [PMID: 25247408]
[96]
Hong CW, Hamilton G, Hooker C, et al. Measurement of spleen fat on MRI-proton density fat fraction arises from reconstruction of noise. Abdom Radiol (NY) 2019; 44(10): 3295-303.
[http://dx.doi.org/10.1007/s00261-019-02079-z] [PMID: 31172210]
[97]
Rehm JL, Wolfgram PM, Hernando D, Eickhoff JC, Allen DB, Reeder SB. Proton density fat-fraction is an accurate biomarker of hepatic steatosis in adolescent girls and young women. Eur Radiol 2015; 25(10): 2921-30.
[http://dx.doi.org/10.1007/s00330-015-3724-1] [PMID: 25916386]
[98]
Nasr P, Forsgren MF, Ignatova S, et al. Using a 3% proton density fat fraction as a cut-off value increases sensitivity of detection of hepatic steatosis, based on results from histopathology analysis. Gastroenterology 2017; 153(1): 53-55.e7.
[http://dx.doi.org/10.1053/j.gastro.2017.03.005] [PMID: 28286210]
[99]
Xu C, Yu C, Ma H, Xu L, Miao M, Li Y. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol 2013; 108(8): 1299-304.
[http://dx.doi.org/10.1038/ajg.2013.104] [PMID: 23567356]
[100]
Wu J, He S, Xu H, et al. Non-alcoholic fatty liver disease incidence, remission and risk factors among a general Chinese population with a 6-year follow-up. Sci Rep 2018; 8(1): 7557.
[http://dx.doi.org/10.1038/s41598-018-25641-z] [PMID: 29765064]
[101]
VanWagner LB, Khan SS, Ning H, et al. Body mass index trajectories in young adulthood predict non-alcoholic fatty liver disease in middle age: The CARDIA cohort study. Liver Int 2018; 38(4): 706-14.
[http://dx.doi.org/10.1111/liv.13603] [PMID: 28963767]
[102]
Centis E, Marzocchi R, Di Domizio S, Ciaravella MF, Marchesini G. The effect of lifestyle changes in non-alcoholic fatty liver disease. Dig Dis 2010; 28(1): 267-73.
[http://dx.doi.org/10.1159/000282101] [PMID: 20460922]
[103]
Zelber-Sagi S, Lotan R, Shlomai A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012; 56(5): 1145-51.
[http://dx.doi.org/10.1016/j.jhep.2011.12.011] [PMID: 22245895]
[104]
Mathurin P, Gonzalez F, Kerdraon O, et al. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology 2006; 130(6): 1617-24.
[http://dx.doi.org/10.1053/j.gastro.2006.02.024] [PMID: 16697725]
[105]
Mathurin P, Hollebecque A, Arnalsteen L, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009; 137(2): 532-40.
[http://dx.doi.org/10.1053/j.gastro.2009.04.052] [PMID: 19409898]
[106]
Rabl C, Campos GM. The impact of bariatric surgery on nonalcoholic steatohepatitis. Semin Liver Dis 2012; 32(1): 80-91.
[http://dx.doi.org/10.1055/s-0032-1306428] [PMID: 22418890]
[107]
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(2): 367-78.e5.
[http://dx.doi.org/10.1053/j.gastro.2015.04.005] [PMID: 25865049]
[108]
Hagström H, Stål P, Hultcrantz R, Hemmingsson T, Andreasson A. Overweight in late adolescence predicts development of severe liver disease later in life: A 39years follow-up study. J Hepatol 2016; 65(2): 363-8.
[http://dx.doi.org/10.1016/j.jhep.2016.03.019] [PMID: 27321729]
[109]
Liu B, Balkwill A, Reeves G, Beral V. Million Women Study Collaborators. Body mass index and risk of liver cirrhosis in middle aged UK women: prospective study. BMJ 2010; 340: c912.
[http://dx.doi.org/10.1136/bmj.c912] [PMID: 20223875]
[110]
Ioannou GN, Weiss NS, Kowdley KV, Dominitz JA. Is obesity a risk factor for cirrhosis-related death or hospitalization? A population-based cohort study. Gastroenterology 2003; 125(4): 1053-9.
[http://dx.doi.org/10.1016/S0016-5085(03)01200-9] [PMID: 14517789]
[111]
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348(17): 1625-38.
[http://dx.doi.org/10.1056/NEJMoa021423] [PMID: 12711737]
[112]
Hagström H, Tynelius P, Rasmussen F. High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men. Gut 2018; 67(8): 1536-42.
[http://dx.doi.org/10.1136/gutjnl-2016-313622] [PMID: 28320770]
[113]
Williams R, Aspinall R, Bellis M, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014; 384(9958): 1953-97.
[http://dx.doi.org/10.1016/S0140-6736(14)61838-9] [PMID: 25433429]
[114]
European Association for the Study of the L. European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-402.
[http://dx.doi.org/10.1016/j.jhep.2015.11.004]
[115]
Becker U, Deis A, Sørensen TI, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology 1996; 23(5): 1025-9.
[http://dx.doi.org/10.1002/hep.510230513] [PMID: 8621128]
[116]
Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017; 66(6): 1138-53.
[http://dx.doi.org/10.1136/gutjnl-2017-313884] [PMID: 28314735]
[117]
Schrieks IC, Heil AL, Hendriks HF, Mukamal KJ, Beulens JW. The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies. Diabetes Care 2015; 38(4): 723-32.
[PMID: 25805864]
[118]
Thursz M, Gual A, Lackner C, et al. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol 2018; 69(1): 154-81.
[http://dx.doi.org/10.1016/j.jhep.2018.03.018] [PMID: 29628280]
[119]
Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction 1993; 88(6): 791-804.
[http://dx.doi.org/10.1111/j.1360-0443.1993.tb02093.x] [PMID: 8329970]
[120]
Niemelä O. Biomarker-based approaches for assessing alcohol use disorders. Int J Environ Res Public Health 2016; 13: 166.
[121]
Kechagias S, Dernroth DN, Blomgren A, et al. Phosphatidylethanol compared with other blood tests as a biomarker of moderate alcohol consumption in healthy volunteers: a prospective randomized study. Alcohol Alcohol 2015; 50(4): 399-406.
[http://dx.doi.org/10.1093/alcalc/agv038] [PMID: 25882743]
[122]
Cao G, Yi T, Liu Q, Wang M, Tang S. Alcohol consumption and risk of fatty liver disease: a meta-analysis. PeerJ 2016; 4: e2633
[http://dx.doi.org/10.7717/peerj.2633] [PMID: 27812428]
[123]
Moriya A, Iwasaki Y, Ohguchi S, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015; 62(4): 921-7.
[http://dx.doi.org/10.1016/j.jhep.2014.11.025] [PMID: 25433160]
[124]
Kechagias S, Zanjani S, Gjellan S, et al. Effects of moderate red wine consumption on liver fat and blood lipids: a prospective randomized study. Ann Med 2011; 43(7): 545-54.
[http://dx.doi.org/10.3109/07853890.2011.588246] [PMID: 21599573]
[125]
Chang Y, Cho YK, Kim Y, et al. Nonheavy Drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study. Hepatology 2019; 69(1): 64-75.
[http://dx.doi.org/10.1002/hep.30170] [PMID: 30019340]
[126]
Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61(5): 1547-54.
[http://dx.doi.org/10.1002/hep.27368] [PMID: 25125077]
[127]
Dunn W, Sanyal AJ, Brunt EM, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol 2012; 57(2): 384-91.
[http://dx.doi.org/10.1016/j.jhep.2012.03.024] [PMID: 22521357]
[128]
Hagström H, Nasr P, Ekstedt M, et al. Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2017; 52(2): 159-65.
[http://dx.doi.org/10.1080/00365521.2016.1239759] [PMID: 27650916]
[129]
Ekstedt M, Franzén LE, Holmqvist M, et al. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2009; 44(3): 366-74.
[http://dx.doi.org/10.1080/00365520802555991] [PMID: 19016382]
[130]
Ajmera V, Belt P, Wilson LA, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol 2018; 16(9): 1511-1520.e5.
[http://dx.doi.org/10.1016/j.cgh.2018.01.026] [PMID: 29378307]
[131]
Mahli A, Hellerbrand C. Alcohol and obesity: a dangerous association for fatty liver disease. Dig Dis 2016; 34(Suppl. 1): 32-9.
[http://dx.doi.org/10.1159/000447279] [PMID: 27548267]
[132]
Kimura T, Tanaka N, Fujimori N, et al. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol 2018; 24(13): 1440-50.
[http://dx.doi.org/10.3748/wjg.v24.i13.1440] [PMID: 29632425]
[133]
Hajifathalian K, Torabi Sagvand B, McCullough AJ. Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study. Hepatology 2019; 70(2): 511-21.
[http://dx.doi.org/10.1002/hep.30226] [PMID: 30125379]
[134]
Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011; 342: d671.
[http://dx.doi.org/10.1136/bmj.d671] [PMID: 21343207]
[135]
Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40(12): 1461-5.
[http://dx.doi.org/10.1038/ng.257] [PMID: 18820647]
[136]
Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN. GIANT Consortium; MIGen Consortium; NASH CRN. . PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010; 52(3): 904-12.
[http://dx.doi.org/10.1002/hep.23768] [PMID: 20648472]
[137]
Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46(4): 352-6.
[http://dx.doi.org/10.1038/ng.2901] [PMID: 24531328]
[138]
Kawaguchi T, Sumida Y, Umemura A, et al. Japan Study Group of Nonalcoholic Fatty Liver Disease. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One 2012; 7(6)e38322
[http://dx.doi.org/10.1371/journal.pone.0038322] [PMID: 22719876]
[139]
Trepo E, Guyot E, Ganne-Carrie N, et al. PNPLA3 (rs738409 C>G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology 2012; 55(4): 1307-8.
[http://dx.doi.org/10.1002/hep.25518] [PMID: 22162034]
[140]
Trépo E, Nahon P, Bontempi G, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology 2014; 59(6): 2170-7.
[http://dx.doi.org/10.1002/hep.26767] [PMID: 24114809]
[141]
Liu Y-L, 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(1): 75-81.
[http://dx.doi.org/10.1016/j.jhep.2014.02.030] [PMID: 24607626]
[142]
Emdin CA, Haas M, Khera AV, et al. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease. bioRxiv 2019. 594523 (Pre-print)
[143]
Ma Y, Belyaeva OV, Brown PM, et al. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoloholic fatty liver disease. Hepatology 2019; 69(4): 1504-19.
[http://dx.doi.org/10.1002/hep.30350] [PMID: 30415504]
[144]
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(12): 1096-106.
[http://dx.doi.org/10.1056/NEJMoa1712191] [PMID: 29562163]
[145]
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(5): 1219-1230.e6.
[http://dx.doi.org/10.1053/j.gastro.2016.01.032] [PMID: 26850495]
[146]
Sookoian S, Flichman D, Garaycoechea ME, et al. Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease. Sci Rep 2018; 8(1): 5097.
[http://dx.doi.org/10.1038/s41598-018-23453-9] [PMID: 29572551]
[147]
Speliotes EK, Yerges-Armstrong LM, Wu J, et al. NASH CRN; GIANT Consortium; MAGIC Investigators; GOLD Consortium.. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011; 7(3): e1001324
[http://dx.doi.org/10.1371/journal.pgen.1001324] [PMID: 21423719]
[148]
Chambers JC, Zhang W, Sehmi J, et al. Alcohol Genome-wide Association (AlcGen) Consortium; Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study; Genetic Investigation of Anthropometric Traits (GIANT) Consortium; Global Lipids Genetics Consortium; Genetics of Liver Disease (GOLD) Consortium; International Consortium for Blood Pressure (ICBP-GWAS); Metaanalyses of Glucose and Insulin-Related Traits Consortium (MAGIC). . Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 2011; 43(11): 1131-8.
[http://dx.doi.org/10.1038/ng.970] [PMID: 22001757]
[149]
Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107(4): 1103-9.
[http://dx.doi.org/10.1016/0016-5085(94)90235-6] [PMID: 7523217]
[150]
Nelson JE, Wilson L, Brunt EM, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53(2): 448-57.
[http://dx.doi.org/10.1002/hep.24038] [PMID: 21274866]
[151]
Fargion S, Mattioli M, Fracanzani AL, et al. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96(8): 2448-55.
[http://dx.doi.org/10.1111/j.1572-0241.2001.04052.x] [PMID: 11513189]
[152]
Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 1999; 31(3): 421-9.
[http://dx.doi.org/10.1016/S0168-8278(99)80032-4] [PMID: 10488699]
[153]
George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114(2): 311-8.
[http://dx.doi.org/10.1016/S0016-5085(98)70482-2] [PMID: 9453491]
[154]
Bugianesi E, Manzini P, D’Antico S, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39(1): 179-87.
[http://dx.doi.org/10.1002/hep.20023] [PMID: 14752836]
[155]
Manousou P, Kalambokis G, Grillo F, et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int 2011; 31(5): 730-9.
[http://dx.doi.org/10.1111/j.1478-3231.2011.02488.x] [PMID: 21457446]
[156]
Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity. J Hepatol 2011; 54(6): 1244-9.
[http://dx.doi.org/10.1016/j.jhep.2010.09.037] [PMID: 21145841]
[157]
Kowdley KV, Belt P, Wilson LA, et al. NASH Clinical Research Network. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012; 55(1): 77-85.
[http://dx.doi.org/10.1002/hep.24706] [PMID: 21953442]
[158]
Hagström H, Nasr P, Bottai M, et al. Elevated serum ferritin is associated with increased mortality in non-alcoholic fatty liver disease after 16 years of follow-up. Liver Int 2016; 36(11): 1688-95.
[http://dx.doi.org/10.1111/liv.13144] [PMID: 27064133]
[159]
Angulo P, George J, Day CP, et al. Serum ferritin levels lack diagnostic accuracy for liver fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12(7): 1163-1169.e1.
[http://dx.doi.org/10.1016/j.cgh.2013.11.035] [PMID: 24342745]
[160]
Valenti L, Fracanzani AL, Dongiovanni P, et al. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 2007; 102(6): 1251-8.
[http://dx.doi.org/10.1111/j.1572-0241.2007.01192.x] [PMID: 17391316]
[161]
Valenti L, Fracanzani AL, Dongiovanni P, et al. A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia. World J Gastroenterol 2014; 20(11): 3002-10.
[http://dx.doi.org/10.3748/wjg.v20.i11.3002] [PMID: 24659891]
[162]
Sumida Y, Kanemasa K, Fukumoto K, et al. Effect of iron reduction by phlebotomy in Japanese patients with nonalcoholic steatohepatitis: A pilot study. Hepatol Res 2006; 36(4): 315-21.
[http://dx.doi.org/10.1016/j.hepres.2006.08.003] [PMID: 16971174]
[163]
Beaton MD, Chakrabarti S, Levstik M, Speechley M, Marotta P, Adams P. Phase II clinical trial of phlebotomy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013; 37(7): 720-9.
[http://dx.doi.org/10.1111/apt.12255] [PMID: 23441892]
[164]
Adams LA, Crawford DH, Stuart K, et al. The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial. Hepatology 2015; 61(5): 1555-64.
[http://dx.doi.org/10.1002/hep.27662] [PMID: 25524401]
[165]
Maliken BD, Nelson JE, Klintworth HM, Beauchamp M, Yeh MM, Kowdley KV. Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 2013; 57(5): 1806-13.
[http://dx.doi.org/10.1002/hep.26238] [PMID: 23325576]
[166]
Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138(3): 905-12.
[http://dx.doi.org/10.1053/j.gastro.2009.11.013] [PMID: 19931264]
[167]
Karlsson M, Ekstedt M, Dahlström N, et al. Liver R2* is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease. J Magn Reson Imaging 2019; 50(1): 325-33.
[http://dx.doi.org/10.1002/jmri.26601] [PMID: 30637926]
[168]
Greene CM, Marciniak SJ, Teckman J, et al. α1-Antitrypsin deficiency. Nat Rev Dis Primers 2016; 2: 16051.
[http://dx.doi.org/10.1038/nrdp.2016.51] [PMID: 27465791]
[169]
Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009; 360(26): 2749-57.
[http://dx.doi.org/10.1056/NEJMcp0900449] [PMID: 19553648]
[170]
Blanco I, Bueno P, Diego I, et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis 2017; 12: 561-9.
[http://dx.doi.org/10.2147/COPD.S125389] [PMID: 28243076]
[171]
de Serres FJ, Blanco I, Fernández-Bustillo E. PI S. PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis 2007; 67(4): 184-208.
[172]
Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294(24): 1316-21.
[http://dx.doi.org/10.1056/NEJM197606102942404] [PMID: 1083485]
[173]
Silverman EK, Miletich JP, Pierce JA, et al. Alpha-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening. Am Rev Respir Dis 1989; 140(4): 961-6.
[http://dx.doi.org/10.1164/ajrccm/140.4.961] [PMID: 2679271]
[174]
Valenti L, Dongiovanni P, Piperno A, et al. α 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage. Hepatology 2006; 44(4): 857-64.
[http://dx.doi.org/10.1002/hep.21329] [PMID: 17006922]
[175]
Goltz D, Hittetiya K, Vössing LM, Kirfel J, Spengler U, Fischer H-P. Α1-antitrypsin PiMZ heterozygosity has an independent aggravating effect on liver fibrosis in alcoholic liver disease. Virchows Arch 2014; 465(5): 539-46.
[http://dx.doi.org/10.1007/s00428-014-1633-3] [PMID: 25070245]
[176]
Schaefer B, Mandorfer M, Viveiros A, et al. Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease. Liver Transpl 2018; 24(6): 744-51.
[http://dx.doi.org/10.1002/lt.25057] [PMID: 29573137]
[177]
Fischer H-P, Ortiz-Pallardó ME, Ko Y, Esch C, Zhou H. Chronic liver disease in heterozygous α1-antitrypsin deficiency PiZ. J Hepatol 2000; 33(6): 883-92.
[http://dx.doi.org/10.1016/S0168-8278(00)80119-1] [PMID: 11131449]
[178]
Regev A, Guaqueta C, Molina EG, et al. Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study. J Pediatr Gastroenterol Nutr 2006; 43(Suppl. 1): S30-5.
[http://dx.doi.org/10.1097/01.mpg.0000226387.56612.1e] [PMID: 16819398]
[179]
El-Rayah EA, Twomey PJ, Wallace EM, McCormick PA. Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland. Eur J Gastroenterol Hepatol 2018; 30(4): 364-7.
[http://dx.doi.org/10.1097/MEG.0000000000001056] [PMID: 29324588]
[180]
Strnad P, Buch S, Hamesch K, et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut 2019; 68(6): 1099-107.
[http://dx.doi.org/10.1136/gutjnl-2018-316228] [PMID: 30068662]
[181]
Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13(4): 643-54.e1.
[http://dx.doi.org/10.1016/j.cgh.2014.04.014] [PMID: 24768810]
[182]
Buzzetti E, Hall A, Ekstedt M, et al. Collagen proportionate area is an independent predictor of long-term outcome in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2019; 49(9): 1214-22.
[http://dx.doi.org/10.1111/apt.15219] [PMID: 30882933]
[183]
Hagström H, Nasr P, Ekstedt M, Stål P, Hultcrantz R, Kechagias S. Accuracy of noninvasive scoring systems in assessing risk of death and liver-related endpoints in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2019; 17(6): 1148-1156.e4.
[http://dx.doi.org/10.1016/j.cgh.2018.11.030] [PMID: 30471458]
[184]
Angulo P, Bugianesi E, Bjornsson ES, et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145(4): 782-9.e4.
[http://dx.doi.org/10.1053/j.gastro.2013.06.057] [PMID: 23860502]
[185]
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94(9): 2467-74.
[http://dx.doi.org/10.1111/j.1572-0241.1999.01377.x] [PMID: 10484010]
[186]
Nonalcoholic steatohepatitis clinical research network. Hepatology 2003; 37(2): 244.
[http://dx.doi.org/10.1002/hep.510370203] [PMID: 12540771]
[187]
Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011; 53(6): 1874-82.
[http://dx.doi.org/10.1002/hep.24268] [PMID: 21360720]
[188]
Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54(1): 344-53.
[http://dx.doi.org/10.1002/hep.24376] [PMID: 21520200]
[189]
Hagström H, Nasr P, Ekstedt M, et al. SAF score and mortality in NAFLD after up to 41 years of follow-up. Scand J Gastroenterol 2017; 52(1): 87-91.
[http://dx.doi.org/10.1080/00365521.2016.1230779] [PMID: 27616339]
[190]
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65(8): 1038-48.
[http://dx.doi.org/10.1016/j.metabol.2015.12.012] [PMID: 26823198]
[191]
Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol 2013; 3(4): 1473-92.
[http://dx.doi.org/10.1002/cphy.c120035] [PMID: 24265236]
[192]
Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009; 51(2): 371-9.
[http://dx.doi.org/10.1016/j.jhep.2009.03.019] [PMID: 19501928]
[193]
McPherson S, Pais R, Valenti L, et al. Further delineation of fibrosis progression in NAFLD: evidence from a large cohort of patients with sequential biopsies. J Hepatology: 2017; 66(1): S593.
[http://dx.doi.org/10.1016/S0168-8278(17)31613-6]
[194]
Ajmera V, Park CC, Caussy C, et al. Magnetic resonance imaging proton density fat fraction associates with progression of fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2018; 155(2): 307-310.e2.
[http://dx.doi.org/10.1053/j.gastro.2018.04.014] [PMID: 29660324]
[195]
Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007; 45(6): 1366-74.
[http://dx.doi.org/10.1002/hep.21655] [PMID: 17476695]
[196]
Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 2018; 68(2): 280-95.
[http://dx.doi.org/10.1016/j.jhep.2017.11.014] [PMID: 29154964]
[197]
Lazarus JV, Ekstedt M, Marchesini G, et al. EASL International Liver Foundation NAFLD Policy Review Collaborators. A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe. J Hepatol 2020; 72(1): 14-24.
[http://dx.doi.org/10.1016/j.jhep.2019.08.027] [PMID: 31518646]
[198]
Tanajewski L, Harris R, Harman DJ, et al. Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study. BMJ Open 2017; 7(6): e015659
[http://dx.doi.org/10.1136/bmjopen-2016-015659] [PMID: 28679676]
[199]
Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001; 121(1): 91-100.
[http://dx.doi.org/10.1053/gast.2001.25540] [PMID: 11438497]
[200]
Cotrim HP, Freitas LA, Alves E, Almeida A, May DS, Caldwell S. Effects of light-to-moderate alcohol consumption on steatosis and steatohepatitis in severely obese patients. Eur J Gastroenterol Hepatol 2009; 21(9): 969-72.
[http://dx.doi.org/10.1097/MEG.0b013e328328f3ec] [PMID: 19194305]
[201]
Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51(6): 1972-8.
[http://dx.doi.org/10.1002/hep.23527] [PMID: 20209604]
[202]
Kwon HK, Greenson JK, Conjeevaram HS. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease. Liver Int 2014; 34(1): 129-35.
[http://dx.doi.org/10.1111/liv.12230] [PMID: 23809459]
[203]
Sookoian S, Flichman D, Castaño GO, Pirola CJ. Mendelian randomisation suggests no beneficial effect of moderate alcohol consumption on the severity of nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2016; 44(11-12): 1224-34.
[http://dx.doi.org/10.1111/apt.13828] [PMID: 27778410]
[204]
Yamada K, Mizukoshi E, Seike T, et al. Light alcohol consumption has the potential to suppress hepatocellular injury and liver fibrosis in non-alcoholic fatty liver disease. PLoS One 2018; 13(1): e0191026
[http://dx.doi.org/10.1371/journal.pone.0191026] [PMID: 29342182]
[205]
Mitchell T, Jeffrey GP, de Boer B, et al. Type and pattern of alcohol consumption is associated with liver fibrosis in patients with non-alcoholic fatty liver disease. Am J Gastroenterol 2018; 113(10): 1484-93.
[http://dx.doi.org/10.1038/s41395-018-0133-5] [PMID: 29899440]