EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease

Obesity Facts

Volumn 9, Issue 2, 2016, Pages 65-90

  Marchesini, Giulio ^a   Day, Christopher P ^a   Dufour, Jean François ^a   Canbay, Ali ^a   Nobili, Valerio ^a   Ratziu, Vlad ^a   Tilg, Herbert ^a   Roden, Michael ^a   Gastaldelli, Amalia ^a   Yki Järvinen, Hannele ^a   Schick, Fritz ^a   Vettor, Roberto ^a   Frühbeck, Gema ^a   Mathus Vliegen, Lisbeth ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; EZETIMIBE; LIRAGLUTIDE; METFORMIN; OBETICHOLIC ACID; PIOGLITAZONE; ROSIGLITAZONE; TETRAHYDROLIPSTATIN; URSODEOXYCHOLIC ACID;

ALCOHOL CONSUMPTION; BARIATRIC SURGERY; CARDIOVASCULAR DISEASE; CHRONIC KIDNEY DISEASE; CHRONIC LIVER DISEASE; CLINICAL DECISION MAKING; COLORECTAL CANCER; DIET THERAPY; DISEASE COURSE; ETHNIC DIFFERENCE; EVIDENCE BASED MEDICINE; FOLLOW UP; GENETIC ASSOCIATION; GLYCOGEN STORAGE DISEASE; GROUPS BY AGE; HUMAN; INCIDENCE; INSULIN RESISTANCE; INSULIN SENSITIVITY; IRON DEPLETION; LIFESTYLE; LIFESTYLE MODIFICATION; LIPODYSTROPHY; LIVER BIOPSY; LIVER CELL CARCINOMA; LIVER FIBROSIS; LIVER TRANSPLANTATION; METABOLIC DISORDER; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NON INVASIVE PROCEDURE; NONALCOHOLIC FATTY LIVER; OBESITY; OSTEOPOROSIS; PATHOGENESIS; PATIENT CARE; PHASE 2 CLINICAL TRIAL (TOPIC); PRACTICE GUIDELINE; PREVALENCE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SEX DIFFERENCE; STEATOSIS; VITAMIN D DEFICIENCY;

EID: 84964038722     PISSN: 16624025     EISSN: 16624033     Source Type: Journal    
DOI: 10.1159/000443344     Document Type: Review

References (148)

1. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G: A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53: 372-384.
2. 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.
3. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-117.
4. 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.
5. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, et al: Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine 2012; 91: 319-327.
6. Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni E, et al: Risk of severe liver disease in NAFLD with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 2008; 48: 792-798.
7. Marchesini G, Mazzotti A: NAFLD incidence and remission: only a matter of weight gain and weight loss? J Hepatol 2015; 62: 15-17.
8. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al: The diagnosis and management of nonalcoholic 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.
9. Barrera F, George J: The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis 2014; 18: 91-112.
10. Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, et al: Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 2014; 68: 416-423.
11. Gerber L, Otgonsuren M, Mishra A, Escheik C, Birerdinc A, Stepanova M, et al: Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical activity: a population-based study. Aliment Pharmacol Ther 2012; 36: 772-781.
12. Anstee QM, Targher G, Day CP: Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10: 330-344.
13. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, 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: 1209-1217.
14. Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al: Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014; 61: 75-81.
15. 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.
16. 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.
17. Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, et al: I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52: 1274-1280.
18. Nobili V, Donati B, Panera N, Vongsakulyanon A, Alisi A, Dallapiccola B, et al: A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2014; 58: 632-636.
19. 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.
20. Kleiner DE, Brunt EM: Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012; 32: 3-13.
21. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al: Design and validation of a histo-logical scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-1321.
22. Bedossa PFLIP 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.
23. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, Network NCR: Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011; 53: 810-820.
24. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al: Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61: 1547-1554.
25. Brunt EM, Kleiner DE, Wilson LA, Unalp A, Behling CE, Lavine JE, et al: Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009; 49: 809-820.
26. Alkhouri N, De Vito R, Alisi A, Yerian L, Lopez R, Feldstein AE, et al: Development and validation of a new histo-logical score for pediatric nonalcoholic fatty liver disease. J Hepatol 2012; 57: 1312-1318.
27. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al: The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-750.
28. Fishbein M, Castro F, Cheruku S, Jain S, Webb B, Gleason T, et al: Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol 2005; 39: 619-625.
29. Ryan CK, Johnson LA, Germin BI, Marcos A: One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002;8:1114-1122.
30. Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V, et al: Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2014; 40: 1209-1222.
31. Machado MV, Cortez-Pinto H: Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol 2013; 58: 1007-1019.
32. European Association for the Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado: EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63: 237-264.
33. 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.
34. Kwok R, Tse YK, Wong GL, Ha Y, Lee AU, Ngu MC, et al: Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease-the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther 2014; 39: 254-269.
35. 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:e2121-e2122.
36. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al: Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008; 47:455-460.
37. McPherson S, Anstee QM, Henderson E, Day CP, Burt AD: Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels? Eur J Gastroenterol Hepatol 2013; 25: 652-658.
38. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al: Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51: 454-462.
39. Castera L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al: Pitfalls of liver stiffness measurement: a 5-year prospective study of 13, 369 examinations. Hepatology 2010; 51: 828-835.
40. Wong VW, Vergniol J, Wong GL, Foucher J, Chan AW, Chermak F, et al: Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012; 107: 1862-1871.
41. Petta S, Vanni E, Bugianesi E, Di Marco V, Camma C, Cabibi D, et al: The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 2015; 35: 1566-1573.
42. Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, et al: Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastro-enterol Nutr 2012; 54: 700-713.
43. Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P: A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58: 1218-1229.
44. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A: Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 2013; 5: 1544-1560.
45. Alberti A, Vario A, Ferrari A, Pistis R: Review article: chronic hepatitis C- natural history and cofactors. Aliment Pharmacol Ther 2005; 22: 74-78.
46. Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, et al: Adaptation of hepatic mitochondrial function in humans with nonalcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015; 21: 739-746.
47. Yki-Järvinen H: Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2: 901-910.
48. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
49. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM: Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62: 1148-1155.
50. Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, et al: A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59: 550-556.
51. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S: Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005; 42: 44-52.
52. Frith J, Day CP, Robinson L, Elliott C, Jones DE, Newton JL: Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease. J Hepatol 2010; 52: 112-116.
53. Caldwell SH, Crespo DM: The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol 2004; 40: 578-584.
54. Aron-Wisnewsky J, Minville C, Tordjman J, Levy P, Bouillot JL, Basdevant A, et al: Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 2012; 56: 225-233.
55. Gomez-Ambrosi J, Silva C, Galofre JC, Escalada J, Santos S, Millan D, et al: Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. Int J Obes (Lond) 2012; 36: 286-294.
56. Chang Y, Ryu S, Suh BS, Yun KE, Kim CW, Cho SI: Impact of BMI on the incidence of metabolic abnormalities in metabolically healthy men. Int J Obes (Lond) 2012; 36: 1187-1194.
57. Gomez-Ambrosi J, Catalan V, Rodriguez A, Andrada P, Ramirez B, Ibanez P, et al: Increased cardiometabolic risk factors and inflammation in adipose tissue in obese subjects classified as metabolically healthy. Diabetes Care 2014; 37: 2813-2821.
58. 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: 1156-1161.
59. Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al: Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 2007; 133: 496-506.
60. Kotronen A, Juurinen L, Hakkarainen A, Westerbacka J, Corner A, Bergholm R, et al: Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care 2008; 31: 165-169.
61. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al: Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56: 943-951.
62. Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014; 59: 1174-1197.
63. American Diabetes Association: Standards of medical care in diabetes- 2014. Diabetes Care 2014; 37:S14-S80.
64. Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, et al: Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care 2012; 35: 873-878.
65. Juurinen L, Tiikkainen M, Häkkinen AM, Hakkarainen A, Yki-Järvinen H: Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 2007; 292:E829-E835.
66. Llaurado G, Sevastianova K, Sadevirta S, Hakkarainen A, Lundbom N, Orho-Melander M, et al: Liver fat content and hepatic insulin sensitivity in overweight patients with type 1 diabetes. J Clin Endocrinol Metab 2015; 100: 607-616.
67. Anderwald C, Bernroider E, Krssak M, Stingl H, Brehm A, Bischof MG, et al: Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle. Diabetes 2002; 51: 3025-3032.
68. 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 Gastro-enterol Hepatol 2015; 13: 643-654, e641-e649; quiz e639-e640.
69. Haflidadottir S, Jonasson JG, Norland H, Einarsdottir SO, Kleiner DE, Lund SH, et al: Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease. BMC Gastroen-terol 2014; 14: 166.
70. 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: 1357-1365.
71. 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.
72. 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.
73. Targher G, Day CP, Bonora E: Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363: 1341-1350.
74. Bhatia LS, Curzen NP, Calder PC, Byrne CD: Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J 2012; 33:1190-1200.
75. Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, et al: Fatty liver index and mortality: the Cremona study in the 15th year of follow-up. Hepatology 2011; 54: 145-152.
76. Pacifico L, Chiesa C, Anania C, De Merulis A, Osborn JF, Romaggioli S, et al: Nonalcoholic fatty liver disease and the heart in children and adolescents. World J Gastroenterol 2014; 20: 9055-9071.
77. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al: Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60: 110-117.
78. Wong RJ, Cheung R, Ahmed A: Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.. Hepatology 2014; 59: 2188-2195.
79. Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, et al: Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014; 11:e1001680.
80. Targher G, Bertolini L, Chonchol M, Rodella S, Zoppini G, Lippi G, et al: Nonalcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 2010; 53: 1341-1348.
81. Kim NH, Park J, Kim SH, Kim YH, Kim DH, Cho GY, et al: Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population. Heart 2014; 100: 938-943.
82. Hazlehurst JM, Tomlinson JW: Non-alcoholic fatty liver disease in common endocrine disorders. Eur J Endo-crinol 2013; 169:R27-R37.
83. 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.
84. 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.
85. 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.
86. Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, et al: A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006; 4: 639-644.
87. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al: Randomized placebo-controlled trial of urso-deoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006; 4: 1537-1543.
88. 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.
89. 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.
90. Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, et al: Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44: 853-860.
91. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA: Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009; 49: 80-86.
92. 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 steatohepa-titis (NASH): a pilot trial. Therap Adv Gastroenterol 2009; 2: 157-163.
93. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al: Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010; 51: 121-129.
94. 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.
95. 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.
96. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle 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.
97. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et al: Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54: 1610-1619.
98. 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.
99. 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 multi-centre, randomised, placebo-controlled trial. Lancet 2015; 385: 956-965.
100. Valenti L, Fracanzani AL, Dongiovanni P, Rovida S, Rametta R, Fatta E, et al: A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia. World J Gastroenterol 2014; 20: 3002-3010.
101. Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, Kato K, et al: The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 2014; 57: 878-890.
102. 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. Gastroen-terology 2014; 147:e377-384.e1.
103. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, et al: Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61: 1239-1250.
104. Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, et al: Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol 2015; 62: 190-197.
105. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al: Liraglutide safety and effi cacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2015;doi: 10.1016/S0140-6736(15)00803-X.
106. Zelber-Sagi S, Ratziu V, Oren R: Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol 2011; 17: 3377-3389.
107. Boden G: High- or low-carbohydrate diets: which is better for weight loss, insulin resistance, and fatty livers? Gastroenterology 2009; 136: 1490-1492.
108. Lazo M, Solga SF, Horska A, Bonekamp S, Diehl AM, Brancati FL, et al: Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care 2010; 33: 2156-2163.
109. Perreault L, Pan Q, Mather KJ, Watson KE, Hamman RF, Kahn SE: Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. Lancet 2012; 379: 2243-2251.
110. Thoma C, Day CP, Trenell MI: Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012; 56: 255-266.
111. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al: The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013; 59: 138-143.
112. Liangpunsakul S, Chalasani N: What should we recommend to our patients with NAFLD regarding alcohol use? Am J Gastroenterol 2012; 107: 976-978.
113. Kwon HK, Greenson JK, Conjeevaram HS: Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease. Liver Int 2014; 34: 129-135.
114. 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.
115. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN: The incidence and risk factors of hepato-cellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51: 1972-1978.
116. Saab S, Mallam D, Cox 2nd GA, Tong MJ: Impact of coffee on liver diseases: a systematic review. Liver Int 2014; 34: 495-504.
117. Keating SE, Hackett DA, George J, Johnson NA: Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012; 57: 157-166.
118. Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, et al: Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 2013; 58: 1287-1295.
119. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI: Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005; 54: 603-608.
120. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al: Weight loss via lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastro-enterology 2015; 149: 367-378.e5; quiz e14-e15.
121. Rodriguez B, Torres DM, Harrison SA: Physical activity: an essential component of lifestyle modification in NAFLD. Nat Rev Gastroenterol Hepatol 2012; 9: 726-731.
122. 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: 132-138.
123. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L; American Association for the Study of Liver Diseases, United States Food and Drug Administration: Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015; 61: 1392-1405.
124. Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L: Systematic review with meta-analysis: non-alcoholic steatohepatitis - a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther 2014; 39: 3-14.
125. Mazzella N, Ricciardi LM, Mazzotti A, Marchesini G: The role of medications for the management of patients with NAFLD. Clin Liver Dis 2014; 18: 73-89.
126. Ratziu V, Goodman Z, Sanyal A: Current efforts and trends in the treatment of NASH. J Hepatol 2015; 62:S65-S75.
127. Tiikkainen M, Häkkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Järvinen H: Effects of rosigli-tazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004;53: 2169-2176.
128. Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, et al: Metformin prevents liver tumori-genesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila) 2012; 5: 544-552.
129. Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE: Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and metaanalysis. J Clin Endocrinol Metab 2012; 97: 2347-2353.
130. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL: Effects of glucagonlike peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012; 344:d7771.
131. Hoofnagle JH, Van Natta ML, Kleiner DE, Clark JM, Kowdley KV, Loomba R, et al: Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2013; 38: 134-143.
132. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C: Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007; 297: 842-857.
133. Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T: Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010; 341:c5702.
134. Klein EA, Thompson Jr 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.
135. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al: Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastro-enterology 2013; 145:e571.
136. Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J: Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012; 56: 944-951.
137. Dongiovanni P, Petta S, Mannisto V, Margherita Mancina R, Pipitone R, Karja V, et al: Statin use and nonalcoholic steatohepatitis in at risk individuals. J Hepatol 2015;doi: 10.1016/j.jhep.2015.05.006.
138. Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, et al: Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 2007; 102: 1251-1258.
139. Nobili V, Alisi A, Raponi M: Pediatric non-alcoholic fatty liver disease: preventive and therapeutic value of lifestyle intervention. World J Gastroenterol 2009; 15: 6017-6022.
140. Mitchel EB, Lavine JE: Review article: the management of paediatric nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2014; 40: 1155-1170.
141. 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.
142. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al: Bariatric surgery versus intensive medical therapy for diabetes-3-year outcomes. N Engl J Med 2014; 370: 2002-2013.
143. Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H, Raverdy V, et al: Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg 2014; 260: 893-898, Discussion 898-899.
144. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al: Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015; 149: 377-388.
145. 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.
146. Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 12:e391.
147. Heuer M, Kaiser GM, Kahraman A, Banysch M, Saner FH, Mathe Z, et al: Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience. Digestion 2012; 86: 107-113.
148. Sebagh M, Samuel D, Antonini TM, Coilly A, Degli Esposti D, Roche B, et al: Twenty-year protocol liver biopsies: invasive but useful for the management of liver recipients. J Hepatol 2012; 56: 840-847.