Epidemiology and Natural History of Nonalcoholic Fatty Liver Disease

Abstract

The epidemic of obesity has resulted in a parallel incremental burden of nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic fatty liver disease includes a spectrum of liver disease that ranges from simple fat accumulation in the liver to necroinflammation, fibrosis, cirrhosis, and hepatocellular carcinoma, which in essence represent the stages of the natural history of NAFLD. The rising prevalence of NAFLD globally may be accounted for by changes in dietary habits and an increase in sedentary lifestyle. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, is currently the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. In the current review, the authors discuss the uncertainty around the progression from NAFL (steatosis) to NASH (steatohepatitis), the undisputed progression of NASH to cirrhosis, and the risk factors that predispose to such progression. The published literature on the long-term cardiovascular complications and liver-related mortality of NAFLD is also discussed.

Keywords

nonalcoholic fatty liver disease - nonalcoholic steatohepatitis - alanine aminotransferase - fibrosis - cardiovascular disease - obstructive sleep apnea - polycystic ovarian syndrome

• References

• 1 Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis 2010; 28 (1) 162-168
• 2 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) 1413-1419
• 3 Adams LA, Lymp JF, St Sauver J , et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129 (1) 113-121
• 4 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) 389-397
• 5 Targher G, Bertolini L, Poli F , et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005; 54 (12) 3541-3546
• 6 Fracanzani AL, Burdick L, Raselli S , et al. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am J Med 2008; 121 (1) 72-78
• 7 Targher G, Bertolini L, Padovani R , et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29 (6) 1325-1330
• 8 Volzke H, Robinson DM, Kleine V , et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol 2005; 11 (12) 1848-1853
• 9 Targher G, Bertolini L, Padovani R , et al. Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled type 2 diabetic patients. J Endocrinol Invest 2006; 29 (1) 55-60
• 10 Targher G, Bertolini L, Padovani R , et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30 (5) 1212-1218
• 11 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) 547-555
• 12 Hamaguchi M, Kojima T, Takeda N , et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143 (10) 722-728
• 13 Suzuki A, Angulo P, Lymp J , et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 2005; 41 (1) 64-71
• 14 Whalley S, Puvanachandra P, Desai A, Kennedy H. Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs. Clin Med 2007; 7 (2) 119-124
• 15 Bedogni G, Miglioli L, Masutti F , et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology 2007; 46 (5) 1387-1391
• 16 Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M. Non alcoholic fatty liver: epidemiology and natural history. Rev Recent Clin Trials 2014; 9 (3) 126-133
• 17 Zhu JZ, Dai YN, Wang YM, Zhou QY, Yu CH, Li YM. Prevalence of Nonalcoholic Fatty Liver Disease and Economy. Dig Dis Sci 2015; . E-pub ahead of print
• 18 Saab S, Manne V, Nieto J, Schwimmer JB, Chalasani NP. Nonalcoholic fatty liver disease in Latinos. Clin Gastroenterol Hepatol 2015; E-pub ahead of print
• 19 Mohanty SR, Troy TN, Huo D, O'Brien BL, Jensen DM, Hart J. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J Hepatol 2009; 50 (4) 797-804
• 20 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) 1387-1395
• 21 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 (6) 524-530.e1 , quiz e60
• 22 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) 124-131
• 23 Fischer GE, Bialek SP, Homan CE, Livingston SE, McMahon BJ. Chronic liver disease among Alaska-Native people, 2003-2004. Am J Gastroenterol 2009; 104 (2) 363-370
• 24 Marcos A, Fisher RA, Ham JM , et al. Selection and outcome of living donors for adult to adult right lobe transplantation. Transplantation 2000; 69 (11) 2410-2415
• 25 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
• 26 Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005; 42 (3) 650-656
• 27 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10 (6) 330-344
• 28 Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 645-655
• 29 Valenti L, Al-Serri A, Daly AK , et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51 (4) 1209-1217
• 30 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
• 31 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 , 9, quiz e39–e40
• 32 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
• 33 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) 820-826
• 34 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) 969-974
• 35 Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003; 98 (9) 2042-2047
• 36 Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (4) 511-531
• 37 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) 132-138
• 38 Teli MR, Day CP, Burt AD, Bennett MK, James OF. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 1995; 346 (8981) 987-990
• 39 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
• 40 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) 550-556
• 41 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) 1148-1155
• 42 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) 1714-1719
• 43 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) 407-413
• 44 Hamaguchi E, Takamura T, Sakurai M , et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care 2010; 33 (2) 284-286
• 45 Argo CK, Iezzoni JC, Al-Osaimi AM, Caldwell SH. Thiazolidinediones for the treatment in NASH: sustained benefit after drug discontinuation?. J Clin Gastroenterol 2009; 43 (6) 565-568
• 46 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) 689-692
• 47 Hytiroglou P, Snover DC, Alves V , et al. Beyond “cirrhosis”: a proposal from the International Liver Pathology Study Group. Am J Clin Pathol 2012; 137 (1) 5-9
• 48 Marcellin P, Gane E, Buti M , et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381 (9865) 468-475
• 49 Morgan TR, Ghany MG, Kim HY , et al; HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010; 52 (3) 833-844
• 50 D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (1) 217-231
• 51 Saunders JB, Walters JR, Davies AP, Paton A. A 20-year prospective study of cirrhosis. Br Med J (Clin Res Ed) 1981; 282 (6260) 263-266
• 52 Ginés P, Quintero E, Arroyo V , et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987; 7 (1) 122-128
• 53 D'Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986; 31 (5) 468-475
• 54 Sanyal AJ, Banas C, Sargeant C , et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006; 43 (4) 682-689
• 55 Hui JM, Kench JG, Chitturi S , et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003; 38 (2) 420-427
• 56 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 (2) 248-254
• 57 Jansen PL. Non-alcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2004; 16 (11) 1079-1085
• 58 Nagaoki Y, Hyogo H, Aikata H , et al. Recent trend of clinical features in patients with hepatocellular carcinoma. Hepatol Res 2012; 42 (4) 368-375
• 59 Hashimoto E, Yatsuji S, Tobari M , et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (Suppl. 19) 89-95
• 60 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
• 61 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) 1349-1354
• 62 Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?. Arch Pathol Lab Med 2008; 132 (11) 1761-1766
• 63 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 (6) 1809-1819
• 64 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51 (5) 1820-1832
• 65 Kawada N, Imanaka K, Kawaguchi T , et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (12) 1190-1194
• 66 Karagozian R, Derdák Z, Baffy G. Obesity-associated mechanisms of hepatocarcinogenesis. Metabolism 2014; 63 (5) 607-617
• 67 Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001; 48 (2) 206-211
• 68 Shanab AA, Scully P, Crosbie O , et al. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci 2011; 56 (5) 1524-1534
• 69 Mouzaki M, Comelli EM, Arendt BM , et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58 (1) 120-127
• 70 Zhu L, Baker SS, Gill C , et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (2) 601-609
• 71 Velayudham A, Dolganiuc A, Ellis M , et al. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009; 49 (3) 989-997
• 72 Mencarelli A, Cipriani S, Renga B , et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS ONE 2012; 7 (9) e45425
• 73 Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS ONE 2013; 8 (5) e63388
• 74 Wong VW, Won GL, Chim AM , et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 2013; 12 (2) 256-262
• 75 Malaguarnera M, Vacante M, Antic T , et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012; 57 (2) 545-553
• 76 Dapito DH, Mencin A, Gwak GY , et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012; 21 (4) 504-516
• 77 Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4 (5) 382-387
• 78 Yoshimoto S, Loo TM, Atarashi K , et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456) 97-101
• 79 Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30 (6) 1356-1362
• 80 Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology 2009; 55 (6) 607-613
• 81 Wang Z, Xu M, Peng J , et al. Prevalence and associated metabolic factors of fatty liver disease in the elderly. Exp Gerontol 2013; 48 (8) 705-709
• 82 Chen CH, Huang MH, Yang JC , et al. Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan. J Gastroenterol Hepatol 2007; 22 (9) 1482-1489
• 83 Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118 (4) 1388-1393
• 84 A-Kader HH, Henderson J, Vanhoesen K, Ghishan F, Bhattacharyya A. Nonalcoholic fatty liver disease in children: a single center experience. Clin Gastroenterol Hepatol 2008; 6 (7) 799-802
• 85 Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009; 58 (11) 1538-1544
• 86 Reid AE. Nonalcoholic steatohepatitis. Gastroenterology 2001; 121 (3) 710-723
• 87 Ryu S, Suh BS, Chang Y , et al. Menopausal stages and non-alcoholic fatty liver disease in middle-aged women. Eur J Obstet Gynecol Reprod Biol 2015; 190: 65-70
• 88 Ryu S, Chang Y, Choi Y , et al. Age at menarche and non-alcoholic fatty liver disease. J Hepatol 2015; 62 (5) 1164-1170
• 89 Liu Y, Lu J, Xu M , et al. Association between history of abortion and nonalcoholic fatty liver disease in middle-aged and elderly Chinese women. Ann Epidemiol 2013; 23 (3) 119-123
• 90 Sanyal AJ ; American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123 (5) 1705-1725
• 91 Kubik JF, Gill RS, Laffin M, Karmali S. The impact of bariatric surgery on psychological health. J Obes 2013; 2013: 837989
• 92 [Anonymous] . Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000; 894: i-xii , 1–253
• 93 Finucane MM, Stevens GA, Cowan MJ , et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377 (9765) 557-567
• 94 Bellentani S, Saccoccio G, Masutti F , et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132 (2) 112-117
• 95 Ha Y, Seo N, Shim JH , et al. Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: a case-control study. J Gastroenterol Hepatol 2015; . E-pub ahead of print
• 96 Praveenraj P, Gomes RM, Kumar S , et al. Prevalence and predictors of non-alcoholic fatty liver disease in morbidly obese South Indian patients undergoing bariatric surgery. Obes Surg 2015; E-pub ahead of print
• 97 Lassailly G, Caiazzo R, Buob D , et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015; 149 (2) 379-388
• 98 Loomba R, Abraham M, Unalp A , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56 (3) 943-951
• 99 Abdelmalek MF, Liu C, Shuster J, Nelson DR, Asal NR. Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006; 4 (9) 1162-1169
• 100 Wagenknecht LE, Scherzinger AL, Stamm ER , et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 2009; 17 (6) 1240-1246
• 101 Angulo P, Hui JM, Marchesini G , et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45 (4) 846-854
• 102 Neuschwander-Tetri BA, Clark JM, Bass NM , et al; NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010; 52 (3) 913-924
• 103 Marchesini G, Brizi M, Morselli-Labate AM , et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107 (5) 450-455
• 104 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126 (2) 460-468
• 105 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) 134-140
• 106 Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98 (5) 960-967
• 107 Campos GM, Bambha K, Vittinghoff E , et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 2008; 47 (6) 1916-1923
• 108 Ratziu V, Giral P, Charlotte F , et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118 (6) 1117-1123
• 109 Anty R, Iannelli A, Patouraux S , et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol Ther 2010; 32 (11-12) 1315-1322
• 110 Cao W, Zhao C, Shen C, Wang Y. Cytokeratin 18, alanine aminotransferase, platelets and triglycerides predict the presence of nonalcoholic steatohepatitis. PLoS ONE 2013; 8 (12) e82092
• 111 Eguchi Y, Mizuta T, Sumida Y , et al. The pathological role of visceral fat accumulation in steatosis, inflammation, and progression of nonalcoholic fatty liver disease. J Gastroenterol 2011; 46 (Suppl. 01) 70-78
• 112 Verma S, Jensen D, Hart J, Mohanty SR. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int 2013; 33 (9) 1398-1405
• 113 Prati D, Taioli E, Zanella A , et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137 (1) 1-10
• 114 Yoneda M, Imajo K, Eguchi Y , et al; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Noninvasive scoring systems in patients with nonalcoholic fatty liver disease with normal alanine aminotransferase levels. J Gastroenterol 2013; 48 (9) 1051-1060
• 115 Seko Y, Sumida Y, Tanaka S , et al. Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients. Hepatol Res 2014; . E-pub ahead of print
• 116 Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg 2002; 12 (1) 49-51
• 117 Hoofnagle JH, Van Natta ML, Kleiner DE , et al; Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN). Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2013; 38 (2) 134-143
• 118 Neuschwander-Tetri BA. Lifestyle modification as the primary treatment of NASH. Clin Liver Dis 2009; 13 (4) 649-665
• 119 Perseghin G, Lattuada G, De Cobelli F , et al. Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care 2007; 30 (3) 683-688
• 120 Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest 2004; 113 (11) 1582-1588
• 121 Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 2006; 130 (7) 2023-2030
• 122 Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R , et al. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology 2008; 48 (6) 1791-1798
• 123 Tiikkainen M, Bergholm R, Vehkavaara S , et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 2003; 52 (3) 701-707
• 124 Suzuki A, Lindor K, St Saver J , et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 2005; 43 (6) 1060-1066
• 125 Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009; 49 (1) 80-86
• 126 York LW, Puthalapattu S, Wu GY. Nonalcoholic fatty liver disease and low-carbohydrate diets. Annu Rev Nutr 2009; 29: 365-379
• 127 Vilar L, Oliveira CP, Faintuch J , et al. High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects. Nutrition 2008; 24 (11-12) 1097-1102
• 128 Assy N, Nassar F, Nasser G, Grosovski M. Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol 2009; 15 (15) 1809-1815
• 129 Capanni M, Calella F, Biagini MR , et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23 (8) 1143-1151
• 130 Andersen CJ, Fernandez ML. Dietary strategies to reduce metabolic syndrome. Rev Endocr Metab Disord 2013; 14 (3) 241-254
• 131 Martínez-González MA, Martín-Calvo N. The major European dietary patterns and metabolic syndrome. Rev Endocr Metab Disord 2013; 14 (3) 265-271
• 132 Esposito K, Kastorini CM, Panagiotakos DB, Giugliano D. Mediterranean diet and metabolic syndrome: an updated systematic review. Rev Endocr Metab Disord 2013; 14 (3) 255-263
• 133 Georgoulis M, Kontogianni MD, Margariti A , et al. Associations between dietary intake and the presence of the metabolic syndrome in patients with non-alcoholic fatty liver disease. J Hum Nutr Diet 2015; 28 (4) 409-415
• 134 Ryan MC, Itsiopoulos C, Thodis T , et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013; 59 (1) 138-143
• 135 Kontogianni MD, Tileli N, Margariti A , et al. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease. Clin Nutr 2014; 33 (4) 678-683
• 136 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) 371-379
• 137 Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM. Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Hum Pathol 2004; 35 (2) 196-199
• 138 Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 2008; 48 (2) 670-678
• 139 Choi S, Diehl AM. Role of inflammation in nonalcoholic steatohepatitis. Curr Opin Gastroenterol 2005; 21 (6) 702-707
• 140 Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006; 290 (5) G852-G858
• 141 Day CP. From fat to inflammation. Gastroenterology 2006; 130 (1) 207-210
• 142 Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2007; 13 (26) 3540-3553
• 143 Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132 (6) 2169-2180
• 144 Romeo S, Kozlitina J, Xing C , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
• 145 Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011; 53 (6) 1883-1894
• 146 Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Sci Rep 2015; 5: 9284
• 147 Verrijken A, Beckers S, Francque S , et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring) 2013; 21 (10) 2138-2145
• 148 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 (3) 325-334
• 149 He S, McPhaul C, Li JZ , et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285 (9) 6706-6715
• 150 Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem 2011; 286 (43) 37085-37093
• 151 Valenti L, Dongiovanni P, Ginanni Corradini S, Burza MA, Romeo S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Dig Liver Dis 2013; 45 (8) 619-624
• 152 Anstee Q, Day C. The genetics of nonalcoholic fatty liver disease: spotlight on PNPLA3 & TM6SF2. Semin Liver Dis 2015; 35 (3) 270-290
• 153 Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 2004; 99 (2) 292-298
• 154 Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans?. Am J Gastroenterol 2002; 97 (6) 1496-1500
• 155 Gambarin-Gelwan M, Kinkhabwala SV, Schiano TD, Bodian C, Yeh HC, Futterweit W. Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol 2007; 5 (4) 496-501
• 156 Carmina E, Napoli N, Longo RA, Rini GB, Lobo RA. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol 2006; 154 (1) 141-145
• 157 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333 (13) 853-861
• 158 Romanowski MD, Parolin MB, Freitas AC, Piazza MJ, Basso J, Urbanetz AA. Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. Arq Gastroenterol 2015; 52 (2) 117-123
• 159 Hossain N, Stepanova M, Afendy A , et al. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand J Gastroenterol 2011; 46 (4) 479-484
• 160 Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91 (5) 1741-1747
• 161 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328 (17) 1230-1235
• 162 Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med 1994; 154 (15) 1705-1711
• 163 Tanné F, Gagnadoux F, Chazouillères O , et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005; 41 (6) 1290-1296
• 164 Newton JL, Jones DE, Henderson E , et al. Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut 2008; 57 (6) 807-813
• 165 Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease. Dig Dis Sci 2005; 50 (12) 2338-2343
• 166 Paschetta E, Belci P, Alisi A , et al. OSAS-related inflammatory mechanisms of liver injury in nonalcoholic fatty liver disease. Mediators Inflamm 2015; 2015: 815721
• 167 Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004; 28 (2) 87-91
• 168 Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005; 112 (17) 2660-2667
• 169 Christou K, Markoulis N, Moulas AN, Pastaka C, Gourgoulianis KI. Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients. Sleep Breath 2003; 7 (3) 105-110
• 170 Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Semin Liver Dis 2012; 32 (1) 49-64
• 171 Piguet AC, Stroka D, Zimmermann A, Dufour JF. Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci (Lond) 2010; 118 (6) 401-410
• 172 Aron-Wisnewsky J, Minville C, Tordjman J , et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 2012; 56 (1) 225-233
• 173 Mishra P, Nugent C, Afendy A , et al. Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis. Liver Int 2008; 28 (8) 1080-1086
• 174 Daltro C, Cotrim HP, Alves E , et al. Nonalcoholic fatty liver disease associated with obstructive sleep apnea: just a coincidence?. Obes Surg 2010; 20 (11) 1536-1543
• 175 Kallwitz ER, Herdegen J, Madura J, Jakate S, Cotler SJ. Liver enzymes and histology in obese patients with obstructive sleep apnea. J Clin Gastroenterol 2007; 41 (10) 918-921
• 176 Polotsky VY, Patil SP, Savransky V , et al. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med 2009; 179 (3) 228-234
• 177 Corey KE, Misdraji J, Gelrud L , et al. Obstructive sleep apnea is associated with nonalcoholic steatohepatitis and advanced liver histology. Dig Dis Sci 2015; 60 (8) 2523-2528
• 178 Gaziano JM, Buring JE, Breslow JL , et al. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med 1993; 329 (25) 1829-1834
• 179 Conigrave KM, Hu BF, Camargo Jr CA, Stampfer MJ, Willett WC, Rimm EB. A prospective study of drinking patterns in relation to risk of type 2 diabetes among men. Diabetes 2001; 50 (10) 2390-2395
• 180 Mukamal KJ, Conigrave KM, Mittleman MA , et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med 2003; 348 (2) 109-118
• 181 Tolstrup J, Jensen MK, Tjønneland A, Overvad K, Mukamal KJ, Grønbaek M. Prospective study of alcohol drinking patterns and coronary heart disease in women and men. BMJ 2006; 332 (7552) 1244-1248
• 182 Gaziano JM, Gaziano TA, Glynn RJ , et al. Light-to-moderate alcohol consumption and mortality in the Physicians' Health Study enrollment cohort. J Am Coll Cardiol 2000; 35 (1) 96-105
• 183 Suzuki A, Angulo P, St Sauver J, Muto A, Okada T, Lindor K. Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia. Am J Gastroenterol 2007; 102 (9) 1912-1919
• 184 Dunn W, Xu R, Schwimmer JB. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology 2008; 47 (6) 1947-1954
• 185 Gunji T, Matsuhashi N, Sato H , et al. Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the Japanese male population. Am J Gastroenterol 2009; 104 (9) 2189-2195
• 186 Yamada T, Fukatsu M, Suzuki S, Yoshida T, Tokudome S, Joh T. Alcohol drinking may not be a major risk factor for fatty liver in Japanese undergoing a health checkup. Dig Dis Sci 2010; 55 (1) 176-182
• 187 Hiramine Y, Imamura Y, Uto H , et al. Alcohol drinking patterns and the risk of fatty liver in Japanese men. J Gastroenterol 2011; 46 (4) 519-528
• 188 Moriya A, Iwasaki Y, Ohguchi S , et al. Alcohol consumption appears to protect against non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 33 (3) 378-388
• 189 Hamaguchi M, Kojima T, Ohbora A, Takeda N, Fukui M, Kato T. Protective effect of alcohol consumption for fatty liver but not metabolic syndrome. World J Gastroenterol 2012; 18 (2) 156-167
• 190 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) 384-391
• 191 Bellentani S, Saccoccio G, Costa G , et al; The Dionysos Study Group. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut 1997; 41 (6) 845-850
• 192 You M, Crabb DW. Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver. Am J Physiol Gastrointest Liver Physiol 2004; 287 (1) G1-G6
• 193 Moriya A, Iwasaki Y, Ohguchi S , et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015; 62 (4) 921-927
• 194 Mendeloff AI. Effect of intravenous infusions of ethanol upon estimated hepatic blood flow in man. J Clin Invest 1954; 33 (10) 1298-1302
• 195 You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005; 42 (3) 568-577
• 196 Hamabe A, Uto H, Imamura Y , et al. Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. J Gastroenterol 2011; 46 (6) 769-778
• 197 Oniki K, Hori M, Saruwatari J , et al. Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease. Toxicol Lett 2013; 220 (2) 143-149
• 198 Targher G, Alberiche M, Zenere MB, Bonadonna RC, Muggeo M, Bonora E. Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82 (11) 3619-3624
• 199 Rönnemaa T, Rönnemaa EM, Puukka P, Pyörälä K, Laakso M. Smoking is independently associated with high plasma insulin levels in nondiabetic men. Diabetes Care 1996; 19 (11) 1229-1232
• 200 Carnethon MR, Fortmann SP, Palaniappan L, Duncan BB, Schmidt MI, Chambless LE. Risk factors for progression to incident hyperinsulinemia: the Atherosclerosis Risk in Communities Study, 1987-1998. Am J Epidemiol 2003; 158 (11) 1058-1067
• 201 Weitzman M, Cook S, Auinger P , et al. Tobacco smoke exposure is associated with the metabolic syndrome in adolescents. Circulation 2005; 112 (6) 862-869
• 202 Liu Y, Dai M, Bi Y , et al. Active smoking, passive smoking, and risk of nonalcoholic fatty liver disease (NAFLD): a population-based study in China. J Epidemiol 2013; 23 (2) 115-121
• 203 Haenle MM, Brockmann SO, Kron M , et al; EMIL-Study group. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 2006; 6: 233
• 204 Jee SH, Ohrr H, Sull JW, Samet JM. Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea. J Natl Cancer Inst 2004; 96 (24) 1851-1856
• 205 Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 2005; 42 (2) 218-224
• 206 Chen ZM, Liu BQ, Boreham J, Wu YP, Chen JS, Peto R. Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths. Int J Cancer 2003; 107 (1) 106-112
• 207 Fujita Y, Shibata A, Ogimoto I , et al. The effect of interaction between hepatitis C virus and cigarette smoking on the risk of hepatocellular carcinoma. Br J Cancer 2006; 94 (5) 737-739
• 208 Samuel VT, Liu ZX, Qu X , et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004; 279 (31) 32345-32353
• 209 Cai D, Yuan M, Frantz DF , et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11 (2) 183-190
• 210 Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 2008; 135 (1) 122-130
• 211 Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH. Hepatology 2008; 47 (4) 1167-1177
• 212 Pagano C, Soardo G, Esposito W , et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005; 152 (1) 113-118
• 213 Targher G, Bertolini L, Scala L, Poli F, Zenari L, Falezza G. Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals. Clin Endocrinol (Oxf) 2004; 61 (6) 700-703
• 214 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291 (14) 1730-1737
• 215 Dam-Larsen S, Franzmann M, Andersen IB , et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004; 53 (5) 750-755
• 216 Rafiq N, Bai C, Fang Y , et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7 (2) 234-238
• 217 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
• 218 Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women's Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2729-2735
• 219 Goessling W, Massaro JM, Vasan RS, D'Agostino Sr RB, Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008; 135 (6) 1935-1944 , 1944.e1
• 220 Dunn W, Xu R, Wingard DL , et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol 2008; 103 (9) 2263-2271
• 221 Yun KE, Shin CY, Yoon YS, Park HS. Elevated alanine aminotransferase levels predict mortality from cardiovascular disease and diabetes in Koreans. Atherosclerosis 2009; 205 (2) 533-537
• 222 Elinav E, Ackerman Z, Maaravi Y, Ben-Dov IZ, Ein-Mor E, Stessman J. Low alanine aminotransferase activity in older people is associated with greater long-term mortality. J Am Geriatr Soc 2006; 54 (11) 1719-1724
• 223 Elinav E, Ben-Dov IZ, Ackerman E , et al. Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern. Am J Gastroenterol 2005; 100 (10) 2201-2204
• 224 Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 2010; 52 (3) 1156-1161
• 225 Hamaguchi M, Kojima T, Takeda N , et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13 (10) 1579-1584
• 226 Targher G, Bertolini L, Rodella S , et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007; 30 (8) 2119-2121
• 227 Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50 (5) 1403-1411
• 228 Treeprasertsuk S, Leverage S, Adams LA, Lindor KD, St Sauver J, Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int 2012; 32 (6) 945-950
• 229 Chan WK, Tan AT, Vethakkan SR, Tah PC, Vijayananthan A, Goh KL. Ultrasonography-diagnosed non-alcoholic fatty liver disease is not associated with prevalent ischemic heart disease among diabetics in a multiracial Asian hospital clinic population. Clin Res Hepatol Gastroenterol 2014; 38 (3) 284-291
• 230 Lazo M, Hernaez R, Bonekamp S , et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343: d6891
• 231 Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012; 10 (6) 646-650
• 232 Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57 (4) 1357-1365
• 233 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) 1874-1882
• 234 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) 3017-3023
• 235 Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metabolism 2013; 62 (3) 352-360
• 236 Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004; 2 (3) 262-265
• 237 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) 617-649
• 238 Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007; 191 (2) 235-240
• 239 Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?. Diabetologia 2008; 51 (11) 1947-1953
• 240 Lam B, Younossi ZM. Treatment options for nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2010; 3 (2) 121-137
• 241 Younossi ZM, Venkatesan C. A 2012 clinical update for internists in adult nonalcoholic fatty liver disease. Panminerva Med 2012; 54 (1) 29-37
• 242 Venkatesan C, Younossi ZM. Potential mechanisms underlying the associations between liver enzymes and risk for type 2 diabetes. Hepatology 2012; 55 (3) 968-970