The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

Hepatology

Volumn 67, Issue 1, 2018, Pages 328-357

  Chalasani, Naga ^a   Younossi, Zobair ^b   Lavine, Joel E ^c   Charlton, Michael ^d   Cusi, Kenneth ^e   Rinella, Mary ^f   Harrison, Stephen A ^g   Brunt, Elizabeth M ^h   Sanyal, Arun J ⁱ  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b INOVA FAIRFAX HOSPITAL   (United States)

^c Och Spine at New York Presbyterian Hospitals   (United States)

^d UNIVERSITY OF CHICAGO   (United States)

^e UNIVERSITY OF FLORIDA   (United States)

^f NORTHWESTERN UNIVERSITY   (United States)

^g Pinnacle Clinical Research   (United States)

^h WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁱ VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA TOCOPHEROL; GLUCAGON LIKE PEPTIDE 1 DERIVATIVE; ICOSAPENTAENOIC ACID; INSULIN SENSITIZING AGENT; METFORMIN; OMEGA 3 FATTY ACID; URSODEOXYCHOLIC ACID;

ALCOHOL CONSUMPTION; ARTICLE; BARIATRIC SURGERY; CARDIOVASCULAR DISEASE; DIABETES MELLITUS; DYSLIPIDEMIA; FATTY LIVER; HIGH RISK POPULATION; HISTOPATHOLOGY; HUMAN; INCIDENCE; LIFESTYLE MODIFICATION; LIVER BIOPSY; LIVER TRANSPLANTATION; NONALCOHOLIC FATTY LIVER; OBESITY; OUTCOME ASSESSMENT; PRACTICE GUIDELINE; PREVALENCE; PRIMARY MEDICAL CARE; PRIORITY JOURNAL; RISK FACTOR; ADOLESCENT; ADULT; CHILD; COMPLICATION; DISEASE MANAGEMENT; MASS SCREENING;

ADOLESCENT; ADULT; CHILD; DISEASE MANAGEMENT; HUMANS; INCIDENCE; LIVER TRANSPLANTATION; MASS SCREENING; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY; PREVALENCE;

EID: 85030176004     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.29367     Document Type: Article

References (287)

1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023.
2. Eddy DM. A Manual for Assessing Health Practices and Designing Practice Policies: The Explicit Approach. Philadelphia, PA: American College of Physicians; 1992.
3. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-926.
4. Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 2016;13:196-205.
5. Hannah WN, Jr., Harrison SA. Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2016;64:2234-2243.
6. Gawrieh S, Chalasani N. Pharmacotherapy for nonalcoholic fatty liver disease. Semin Liver Dis 2015;35:338-348.
7. Khan RS, Newsome PN. Non-alcoholic fatty liver disease and liver transplantation. Metabolism 2016;65:1208-1223.
8. Bedossa P, Patel K. Biopsy and noninvasive methods to assess progression of nonalcoholic fatty liver disease. Gastroenterology 2016;150:1811-1822.e4.
9. Ahmed A, Wong RJ, Harrison SA. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol 2015;13:2062-2070.
10. Sung K-C, Wild SH, Byrne CD. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension. J Hepatol 2014;60:1040-1045.
11. Tsuneto A, Hida A, Sera N, Imaizumi M, Ichimaru S, Nakashima E, et al. Fatty liver incidence and predictive variables. Hypertens Res 2010;33:638-643.
12. Wong VW, Wong GL, Yeung DK, Lau TK, Chan CK, Chim AM, et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol 2015;62:182-189.
13. Chang Y, Jung HS, Cho J, Zhang Y, Yun KE, Lazo M, et al. Metabolically healthy obesity and the development of nonalcoholic fatty liver disease. Am J Gastroenterol 2016;111:1133-1140.
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;7:119-124.
15. Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56:1145-1151.
16. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.
17. Golabi P, Sayiner M, Fazel Y, Koenig A, Henry L, Younossi ZM. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis. Expert Rev Gastroenterol Hepatol 2016;10:63-71.
18. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015;62(1 Suppl):S47-S64.
19. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009;13:511-531.
20. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524-530.e1; quiz, e60.
21. Fujioka K. Current and emerging medications for overweight or obesity in people with comorbidities. Diabetes Obes Metab 2015;17:1021-1032.
22. VanWagner LB, Rinella ME. Extrahepatic manifestations of nonalcoholic fatty liver disease. Curr Hepatol Rep 2016;15:75-85.
23. Sasaki A, Nitta H, Otsuka K, Umemura A, Baba S, Obuchi T, et al. Bariatric surgery and non-alcoholic fatty liver disease: current and potential future treatments. Front Endocrinol. 2014;5:164.
24. Subichin M, Clanton J, Makuszewski M, Bohon A, Zografakis JG, Dan A. Liver disease in the morbidly obese: a review of 1000 consecutive patients undergoing weight loss surgery. Surg Obes Relat Dis 2015;11:137-141.
25. Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int 2009;29:113-119.
26. Prashanth M, Ganesh HK, Vima MV, John M, Bandgar T, Joshi SR, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2009;57:205-210.
27. Fan N, Zhang L, Xia Z, Peng L, Wang Y, Peng Y. Sex-specific association between serum uric acid and nonalcoholic fatty liver disease in type 2 diabetic patients. J Diabetes Res 2016;2016:3805372.
28. Fruci B, Giuliano S, Mazza A, Malaguarnera R, Belfiore A. Nonalcoholic fatty liver: a possible new target for type 2 diabetes prevention and treatment. Int J Mol Sci 2013;14:22933-22966.
29. Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 2000;45:1929-1934.
30. Wu KT, Kuo PL, Su SB, Chen YY, Yeh ML, Huang CI, et al. Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol. J Clin Lipidol 2016;10:420-425.e1.
31. Fischer GE, Bialek SP, Homan CE, Livingston SE, McMahon BJ. Chronic liver disease among Alaska-Native people, 2003-2004. Am J Gastroenterol 2009;104:363-370.
32. Bialek SR, Redd JT, Lynch A, Vogt T, Lewis S, Wilson C, et al. Chronic liver disease among two American Indian patient populations in the southwestern United States, 2000-2003. J Clin Gastroenterol 2008;42:949-954.
33. Fattahi MR, Niknam R, Safarpour A, Sepehrimanesh M, Lotfi M. The prevalence of metabolic syndrome in non-alcoholic fatty liver disease; a population-based study. Middle East J Dig Dis 2016;8:131-137.
34. Park KS, Lee YS, Park HW, Seo SH, Jang BG, Hwang JY, et al. Factors associated or related to with pathological severity of nonalcoholic fatty liver disease. Korean J Intern Med 2004;19:19-26.
35. Koehler EM, Schouten JN, Hansen BE, van Rooij FJ, Hofman A, Stricker BH, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol 2012;57:1305-1311.
36. Kagansky N, Levy S, Keter D, Rimon E, Taiba Z, Fridman Z, et al. Non-alcoholic fatty liver disease—a common and benign finding in octogenarian patients. Liver Int 2004;24:588-594.
37. Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology 2009;55:607-613.
38. Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, Oren R. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int 2006;26:856-863.
39. Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci 2013;1281:106-122.
40. Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2013;19:5219-5238.
41. Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis 2010;28:162-168.
42. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-1362.
43. Noureddin M, Yates KP, Vaughn IA, Neuschwander-Tetri BA, Sanyal AJ, McCullough A, et al. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology 2013;58:1644-1654.
44. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389-397.e10.
45. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141:1249-1253.
46. Bedogni G, Miglioli L, Masutti F, Castiglione A, Crocè LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology 2007;46:1387-1391.
47. 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;43:617-649.
48. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-285.
49. Zezos P, Renner EL. Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol 2014;20:15532-15538.
50. Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51:595-602.
51. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sørensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004;53:750-755.
52. Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009;7:234-238.
53. Sayiner M, Otgonsuren M, Cable R, Younossi I, Afendy M, Golabi P, et al. Variables associated with inpatient and outpatient resource utilization among Medicare beneficiaries with nonalcoholic fatty liver disease with or without cirrhosis. J Clin Gastroenterol 2017;51:254-260.
54. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-121.
55. Younossi Z, Henry L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality. Gastroenterology 2016;150:1778-1785.
56. Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis 2016;20:205-214.
57. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1459-1544.
58. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874-1882.
59. Hossain N, Stepanova M, Afendy A, Nader F, Younossi Y, Rafiq N, et al. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand J Gastroenterol 2011;46:479-484.
60. Mohamad B, Shah V, Onyshchenko M, Elshamy M, Aucejo F, Lopez R, et al. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. Hepatol Int 2016;10:632-639.
61. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015;62:1723-1730.
62. Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:124-131.e1.
63. Caldwell SH, Lee VD, Kleiner DE, Al-Osaimi AM, Argo CK, Northup PG, et al. NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol 2009;8:346-352.
64. Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism 2016;65:1080-1086.
65. Haga Y, Kanda T, Sasaki R, Nakamura M, Nakamoto S, Yokosuka O. Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis. World J Gastroenterol 2015;21:12989-12995.
66. Young K, Aguilar M, Gish R, Younossi Z, Saab S, Bhuket T, et al. Lower rates of receiving model for end-stage liver disease exception and longer time to transplant among non-alcoholic steatohepatitis hepatocellular carcinoma. Liver Transpl 2016;22:1356-1366.
67. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-555.
68. Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011;54:344-353.
69. National Institute on Alcohol Abuse and Alcoholism. What is a standard drink? [Internet]. Available at: https://pubs.niaaa.nih.gov/publications/practitioner/pocketguide/pocket_guide2.htm. Accessed on: December 12, 2016.
70. Liangpunsakul S, Chalasani N. What should we recommend to our patients with NAFLD regarding alcohol use? Am J Gastroenterol 2012;107:976-978.
71. Wright AP, Desai AP, Bajpai S, King LY, Sahani DV, Corey KE. Gaps in recognition and evaluation of incidentally identified hepatic steatosis. Dig Dis Sci 2015;60:333-338.
72. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015;100:2231-2238.
73. Koehler EM, Plompen EP, Schouten JN, Hansen BE, Darwish Murad S, Taimr P, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology 2016;63:138-147.
74. Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016;65:1359-1368.
75. Corey KE, Klebanoff MJ, Tramontano AC, Chung RT, Hur C. Screening for nonalcoholic steatohepatitis in individuals with type 2 diabetes: a cost-effectiveness analysis. Dig Dis Sci 2016;61:2108-2117.
76. Wong VW, Chalasani N. Not routine screening, but vigilance for chronic liver disease in patients with type 2 diabetes. J Hepatol 2016;64:1211-1213.
77. Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJ, Norris JM, Chen YD, et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 2009;17:1240-1246.
78. 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;4:1162-1169.
79. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000;108:9-13.
80. Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001;96:2957-2961.
81. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009;136:1585-1592.
82. Tarnoki AD, Tarnoki DL, Bata P, Littvay L, Osztovits J, Jermendy G, et al. Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: a twin study. Liver Int 2012;32:1287-1293.
83. Makkonen J, Pietiläinen KH, Rissanen A, Kaprio J, Yki-Järvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 2009;50:1035-1042.
84. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 2015;149:1784-1793.
85. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55:77-85.
86. Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010;138:905-912.
87. Vuppalanchi R, Gould RJ, Wilson LA, Unalp-Arida A, Cummings OW, Chalasani N, et al. Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. Hepatol Int 2012;6:379-385.
88. Chalasani N, Wilson L, Kleiner DE, Cummings OW, Brunt EM, Unalp A, et al. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. J Hepatol 2008;48:829-834.
89. Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: causal association or epiphenomenon? Diabetes Metab 2016;42:142-156.
90. Li X, Xia M, Ma H, Hu Y, Yan H, He W, et al. Liver fat content, evaluated through semi-quantitative ultrasound measurement, is associated with impaired glucose profiles: a community-based study in Chinese. PLoS One 2013;8:e65210.
91. Shah RV, Allison MA, Lima JA, Bluemke DA, Abbasi SA, Ouyang P, et al. Liver fat, statin use, and incident diabetes: the multi-ethnic study of atherosclerosis. Atherosclerosis 2015;242:211-217.
92. 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:spcone.
93. Idilman IS, Keskin O, Celik A, Savas B, Halil Elhan A, Idilman R, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol 2016;57:271-278.
94. Heba ER, Desai A, Zand KA, Hamilton G, Wolfson T, Schlein AN, et al. Accuracy and the effect of possible subject-based confounders of magnitude-based MRI for estimating hepatic proton density fat fraction in adults, using MR spectroscopy as reference. J Magn Reson Imaging 2016;43:398-406.
95. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le TA, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013;58:1930-1940.
96. De Lédinghen V, Wong GL, Vergniol J, Chan HL, Hiriart JB, Chan AW, et al. Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2016;31:848-855.
97. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2009;49:306-317.
98. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917-923.
99. Kang H, Greenson JK, Omo JT, Chao C, Peterman D, Anderson L, et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol 2006;101:2247-2253.
100. Ryan MC, Wilson AM, Slavin J, Best JD, Jenkins AJ, Desmond PV. Associations between liver histology and severity of the metabolic syndrome in subjects with nonalcoholic fatty liver disease. Diabetes Care 2005;28:1222-1224.
101. 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;62:352-360.
102. Cusi K, Chang Z, Harrison S, Lomonaco R, Bril F, Orsak B, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014;60:167-174.
103. Chen J, Zhu Y, Zheng Q, Jiang J. Serum cytokeratin-18 in the diagnosis of non-alcoholic steatohepatitis: a meta-analysis. Hepatol Res 2014;44:854-862.
104. Kaswala DH, Lai M, Afdhal NH. Fibrosis assessment in nonalcoholic fatty liver disease (NAFLD) in 2016. Dig Dis Sci 2016;61:1356-1364.
105. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2016;150:626-637.e7.
106. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846-854.
107. Tapper EB, Challies T, Nasser I, Afdhal NH, Lai M. The performance of vibration controlled transient elastography in a US cohort of patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2016;111:677-684.
108. Nozaki Y, Fujita K, Wada K, Yoneda M, Shinohara Y, Imajo K, et al. Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution. BMC Gastroenterol 2015;15:177.
109. Vuppalanchi R, Siddiqui MS, Hallinan EK, Abdelmalek MF, Neuschwander-Tetri B, Loomba R, et al. Transient elastography is feasible with high success rate for evaluation of non-alcoholic fatty liver disease (NAFLD) in a multicenter setting. Hepatology 2015;62:1290A.
110. Kim D, Kim WR, Talwalkar JA, Kim HJ, Ehman RL. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology 2013;268:411-419.
111. Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 2014;60:1920-1928.
112. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One 2012;7:e38322.
113. 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;53:1883-1894.
114. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ; NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010;52:894-903.
115. Speliotes EK, Butler JL, Palmer CD, Voight BF, GIANT Consortium, MIGen Consortium, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010;52:904-912.
116. Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5:4309.
117. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46:352-356.
118. Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506-514.
119. Donati B, Motta BM, Pingitore P, Meroni M, Pietrelli A, Alisi A, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology 2016;63:787-798.
120. Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent. Gastroenterology 2016;150:1219-1230.e6.
121. Franzen R, Rashidisangsary B, Ozturan S, Vanweersch L, Gutknecht N. Intrapulpal temperature changes during root surface irradiation with dual-wavelength laser (2780 and 940 nm): in vitro study. J Biomed Opt 2015;20:018002.
122. Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146:1231-1239.e1-6.
123. Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J, et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 2008;135:1961-1971.e2.
124. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005;42:641-649.
125. Suzuki A, Abdelmalek MF, Schwimmer JB, Lavine JE, Scheimann AO, Unalp-Arida A, et al. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:786-794.
126. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012;32:3-13.
127. Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147:754-764.
128. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-1321.
129. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012;56:1751-1759.
130. Bedossa P; 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;60:565-575.
131. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898-1906.
132. 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;5:1329-1332.
133. Vuppalanchi R, Unalp A, Van Natta ML, Cummings OW, Sandrasegaran KE, Hameed T, et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:481-486.
134. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology 2009;49:1017-1044.
135. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012;55:885-904.
136. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367-378.
137. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A 2004;101:6659-6663.
138. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Mayurranjan MS, Patterson BW, et al. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009;136:1552-1560.
139. Haufe S, Engeli S, Kast P, Böhnke J, Utz W, Haas V, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology 2011;53:1504-1514.
140. Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB, et al. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 2011;106:460-468.
141. Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Biltoff E, et al. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 2006;130:2023-2030.
142. St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 2009;50:68-76.
143. Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol 2016;65:791-797.
144. Wu T, Gao X, Chen M, van Dam RM. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes Rev 2009;10:313-323.
145. Kurklinsky AK, McEachen JC, Friese JL. Bilateral traumatic chylothorax treated by thoracic duct embolization: a rare treatment for an uncommon problem. Vasc Med 2011;16:284-287.
146. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893-894.
147. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537-544.
148. Nair S, Diehl AM, Wiseman M, Farr GH, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004;20:23-28.
149. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082-1090.
150. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2009;29:172-182.
151. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Ther Adv Gastroenterol 2009;2:157-163.
152. Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44:853-860.
153. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2008;28:200-208.
154. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, et al. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann. Hepatol 2007;6:222-226.
155. Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 2009;46:113-118.
156. Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yilmaz C, et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2010;22:18-23.
157. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep 2013;1:57-64.
158. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010;52:79-104.
159. Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 2014;20:573-591.
160. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-725.e6.
161. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology 2008;135:100-110.
162. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010;51:445-453.
163. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N Engl J Med 2013;369:1285-1287.
164. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-2307.
165. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016;165:305-315.
166. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:1176-1184.
167. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685.
168. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, 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;140:124-131.
169. Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep 2013;13:329-341.
170. Levin D, Bell S, Sund R, Hartikainen SA, Tuomilehto J, Pukkala E, et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493-504.
171. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.
172. Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015;314:265-277.
173. Eguchi Y, Kitajima Y, Hyogo H, Takahashi H, Kojima M, Ono M, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res 2015;45:269-278.
174. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-690.
175. Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrønd B, Gough SC, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther 2013;37:234-242.
176. Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 2010;105:2707-2709.
177. Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther 2007;29:139-153.
178. Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001;15:1667-1672.
179. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485-2490.
180. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:1537-1543.
181. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004;2:1107-1115.
182. Yakaryilmaz F, Guliter S, Savas B, Erdem O, Ersoy R, Erden E, et al. Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study. Intern Med J 2007;37:229-235.
183. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-1668.
184. Sato K, Gosho M, Yamamoto T, Kobayashi Y, Ishii N, Ohashi T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition 2015;31:923-930.
185. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int J Clin Exp Med 2015;8:3924-3934.
186. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
187. Gerss J, Köpcke W. The questionable association of vitamin E supplementation and mortality—inconsistent results of different meta-analytic approaches. Cell Mol Biol 2009;55(Suppl):OL1111-OL1120.
188. Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: a meta-analysis. Curr Aging Sci 2011;4:158-170.
189. Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556.
190. Kristal AR, Darke AK, Morris JS, Tangen CM, Goodman PJ, Thompson IM, et al. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 2014;106:djt456.
191. Chan JM, Darke AK, Penney KL, Tangen CM, Goodman PJ, Lee GS, et al. Selenium- or vitamin E-related gene variants, interaction with supplementation, and risk of high-grade prostate cancer in SELECT. Cancer Epidemiol Biomark Prev 2016;25:1050-1058.
192. Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56-65.
193. Pontiroli AE, Morabito A. Long-term prevention of mortality in morbid obesity through bariatric surgery. A systematic review and meta-analysis of trials performed with gastric banding and gastric bypass. Ann Surg 2011;253:484-487.
194. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357:753-761.
195. Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741-752.
196. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532-540.
197. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-388.
198. Bower G, Toma T, Harling L, Jiao LR, Efthimiou E, Darzi A, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg 2015;25:2280-2289.
199. Mosko JD, Nguyen GC. Increased perioperative mortality following bariatric surgery among patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:897-901.
200. Jan A, Narwaria M, Mahawar KK. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg 2015;25:1518-1526.
201. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464-1467.
202. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rössle M, Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472-479.
203. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770-778.
204. Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011-1019.
205. Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, 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;23:1143-1151.
206. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids—a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010;31:679-692.
207. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology 2014;60:1211-1221.
208. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M; EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 2014;147:377-384.e1.
209. What's at-risk or heavy drinking?—rethinking drinking—NIAAA [Internet]. Available at: http://rethinkingdrinking.niaaa.nih.gov/How-much-is-too-much/Is-your-drinking-pattern-risky/whats-At-Risk-Or-Heavy-drinking.aspx. Accessed on: September 6, 2016.
210. Dunn W, Xu R, Schwimmer JB. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology 2008;47:1947-1954.
211. Gunji T, Matsuhashi N, Sato H, Fujibayashi K, Okumura M, Sasabe N, et al. Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the Japanese male population. Am J Gastroenterol 2009;104:2189-2195.
212. 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;102:1912-1919.
213. Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, et al. Alcohol consumption appears to protect against non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011;33:378-388.
214. Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121:91-100.
215. 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;21:969-972.
216. Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol 2012;57:384-391.
217. Sookoian S, Pirola CJ. How safe is moderate alcohol consumption in overweight and obese individuals? Gastroenterology 2016;150:1698-1703.e2.
218. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-873.
219. Pais R, Giral P, Khan JF, Rosenbaum D, Housset C, Poynard T, et al. Fatty liver is an independent predictor of early carotid atherosclerosis. J Hepatol 2016;65:95-102.
220. Francque SM, van der Graaff D, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol 2016;65:425-443.
221. Corey KE, Misdraji J, Gelrud L, Zheng H, Chung RT, Krauss RM. Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile. Lipids Health Dis 2014;13:100.
222. Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol 2015;13:1000-1008.e3.
223. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, et al. Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin Endocrinol Metab 2016;101:644-652.
224. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010;376:1916-1922.
225. Tikkanen MJ, Fayyad R, Faergeman O, Olsson AG, Wun CC, Laskey R, et al. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 2013;168:3846-3852.
226. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2015;129(25 Suppl 2):S1-45.
227. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287-1292.
228. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007;46:1453-1463.
229. Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011;106:71-77.
230. Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, Nabeshima Y, et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010;45:750-757.
231. Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 2007;47:135-141.
232. Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008;57:1711-1718.
233. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990-994.
234. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-965.
235. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150:1147-1159.e5.
236. Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Morillas R, et al. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology 2011;54:555-561.
237. O'Leary JG, Landaverde C, Jennings L, Goldstein RM, Davis GL. Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants. Clin Gastroenterol Hepatol 2011;9:700-704.e1.
238. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105-109.
239. Hakeem AR, Cockbain AJ, Raza SS, Pollard SG, Toogood GJ, Attia MA, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013;19:551-562.
240. Leonard J, Heimbach JK, Malinchoc M, Watt K, Charlton M. The impact of obesity on long-term outcomes in liver transplant recipients—results of the NIDDK liver transplant database. Am J Transplant 2008;8:667-672.
241. Heimbach JK, Watt KD, Poterucha JJ, Ziller NF, Cecco SD, Charlton MR, et al. Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant 2013;13:363-368.
242. Kim TN, Park MS, Lim KI, Choi HY, Yang SJ, Yoo HJ, et al. Relationships between sarcopenic obesity and insulin resistance, inflammation, and vitamin D status: the Korean Sarcopenic Obesity Study. Clin Endocrinol (Oxf) 2013;78:525-532.
243. Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value. Liver Transpl 2012;18:1209-1216.
244. Hong HC, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, et al. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study. Hepatology 2014;59:1772-1778.
245. Abellan van Kan G, Houles M, Vellas B. Identifying sarcopenia. Curr Opin Clin Nutr Metab Care 2012;15:436-441.
246. Montano-Loza AJ, Meza-Junco J, Baracos VE, Prado CM, Ma M, Meeberg G, et al. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl 2014;20:640-648.
247. Durand F, Buyse S, Francoz C, Laouénan C, Bruno O, Belghiti J, et al. Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography. J Hepatol 2014;60:1151-1157.
248. Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients. Nutrition 2005;21:113-117.
249. Figueiredo FA, Dickson ER, Pasha TM, Porayko MK, Therneau TM, Malinchoc M, et al. Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease. Liver Transpl 2000;6:575-581.
250. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Pichiri I, et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J Hepatol 2010;53:713-718.
251. Oni ET, Agatston AS, Blaha MJ, Fialkow J, Cury R, Sposito A, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013;230:258-267.
252. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2012;60:434-480.
253. Singal AK, Hasanin M, Kaif M, Wiesner R, Kuo YF. Nonalcoholic steatohepatitis is the most rapidly growing indication for simultaneous liver kidney transplantation in the United States. Transplantation 2016;100:607-612.
254. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20-29.
255. Maor-Kendler Y, Batts KP, Burgart LJ, Wiesner RH, Krom RA, Rosen CB, et al. Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases. Transplantation 2000;70:292-297.
256. Dumortier J, Giostra E, Belbouab S, Morard I, Guillaud O, Spahr L, et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil.” Am J Gastroenterol 2010;105:613-620.
257. Bhati C, Idowu MO, Sanyal AJ, Rivera M, Driscoll C, Stravitz RT, et al. Long term outcomes in patients undergoing liver transplantation for nonalcoholic steatohepatitis related cirrhosis. Transplantation 2017;101:1867-1874.
258. Everhart JE, Lombardero M, Lake JR, Wiesner RH, Zetterman RK, Hoofnagle JH. Weight change and obesity after liver transplantation: incidence and risk factors. Liver Transpl Surg 1998;4:285-296.
259. Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl 2011;17:15-22.
260. Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002;96:23-43.
261. Øzbay LA, Smidt K, Mortensen DM, Carstens J, Jørgensen KA, Rungby J. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol 2011;162:136-146.
262. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65:310-335.
263. Heimbach J, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology [Internet]. 2017 Available at: http://onlinelibrary.wiley.com/doi/10.1002/hep.29086/abstract. Accessed on: April 5, 2017.
264. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388-1393.
265. Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One 2015;10:e0140908.
266. Sundaram SS, Sokol RJ, Capocelli KE, Pan Z, Sullivan JS, Robbins K, et al. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr 2014;164:699-706.e1.
267. Molleston JP, Schwimmer JB, Yates KP, Murray KF, Cummings OW, Lavine JE, et al. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 2014;164:707-713.e3.
268. Schwimmer JB, Newton KP, Awai HI, Choi LJ, Garcia MA, Ellis LL, et al. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013;38:1267-1277.
269. 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;58:1538-1544.
270. Lavine JE, Yates KP, Brunt EM, Kleiner DE, Schwimmer D, Murray KF, et al. The natural history of nonalcoholic fatty liver disease in children and adolescents assessed in placebo recipients in the TONIC trial. Hepatology 2012;56:905A.
271. Riley MR, Bass NM, Rosenthal P, Merriman RB. Underdiagnosis of pediatric obesity and underscreening for fatty liver disease and metabolic syndrome by pediatricians and pediatric subspecialists. J Pediatr 2005;147:839-842.
272. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 2007;120(Suppl 4):S164-S192.
273. Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 2009;50:1282-1293.
274. Mansoor S, Collyer E, Alkhouri N. A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic fatty liver disease. Curr Gastroenterol Rep 2015;17:23.
275. Alkhouri N, Carter-Kent C, Lopez R, Rosenberg WM, Pinzani M, Bedogni G, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol 2011;9:150-155.
276. Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 2009;136:160-167.
277. Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC, et al. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014;12:2121-2130.e1-2.
278. Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 2009;50:1113-1120.
279. Africa JA, Behling CA, Brunt EM, Zhang N, Luo Y, Wells A, et al. In children with nonalcoholic fatty liver disease, zone 1 steatosis is associated with advanced fibrosis. Clin Gastroenterol Hepatol 2017 Mar 7. pii: S1542-3565(17)30261-6. doi: 10.1016/j.cgh.2017.02.030. [Epub ahead of print]
280. Nobili V, Manco M, Devito R, Ciampalini P, Piemonte F, Marcellini M. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2006;24:1553-1561.
281. Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008;48:119-128.
282. Koot BG, van der Baan-Slootweg OH, Vinke S, Bohte AE, Tamminga-Smeulders CL, Jansen PL, et al. Intensive lifestyle treatment for non-alcoholic fatty liver disease in children with severe obesity: inpatient versus ambulatory treatment. Int J Obes (Lond) 2016;40:51-57.
283. Barlow SE, Dietz WH. Management of child and adolescent obesity: summary and recommendations based on reports from pediatricians, pediatric nurse practitioners, and registered dietitians. Pediatrics 2002;110:236-238.
284. Schwimmer JB, Lavine JE, Wilson LA, Neuschwander-Tetri BA, Xanthakos SA, Kohli R, et al. In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores. Gastroenterology 2016;151:1141-1154.
285. Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A, Mazur A, Neuhoff-Murawska J, Matusik P, et al. Omega-3 Fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr 2015;166:1358-1363.e1-3.
286. Pacifico L, Bonci E, Di Martino M, Versacci P, Andreoli G, Silvestri LM, Chiesa C. A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2015;25:734-741.
287. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735-2752.