Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Mayo Clinic Proceedings

Volumn 90, Issue 9, 2015, Pages 1233-1246

  Spengler, Erin K ^a   Loomba, Rohit ^b  

^a UNIVERSITY OF IOWA HOSPITALS AND CLINICS   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA TOCOPHEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; METFORMIN; OBETICHOLIC ACID; PENTOXIFYLLINE; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; BIOLOGICAL MARKER;

BONE ATROPHY; BRAIN HEMORRHAGE; CHRONIC LIVER DISEASE; CORONARY ARTERY DISEASE; DIARRHEA; DISEASE COURSE; DRUG WITHDRAWAL; FATIGUE; GASTROINTESTINAL SYMPTOM; HEART FAILURE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; HYPERTRANSAMINASEMIA; INFORMATION RETRIEVAL; LACTIC ACIDOSIS; LEG EDEMA; LIVER BIOPSY; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER INJURY; MEDLINE; MYALGIA; MYOPATHY; NAUSEA; NONALCOHOLIC FATTY LIVER; NONHUMAN; OUTCOME ASSESSMENT; PATIENT REFERRAL; PRACTICE GUIDELINE; PREVALENCE; PRURITUS; REVIEW; RISK ASSESSMENT; SCREENING; UNITED STATES; VOMITING; BIOPSY; BLOOD; DECISION SUPPORT SYSTEM; FEMALE; LIVER; LIVER FUNCTION TEST; MALE; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; RISK FACTOR; STATISTICS AND NUMERICAL DATA; UTILIZATION;

BIOMARKERS; BIOPSY; DECISION SUPPORT TECHNIQUES; FEMALE; HUMANS; LIVER; LIVER FUNCTION TESTS; MALE; NON-ALCOHOLIC FATTY LIVER DISEASE; REFERRAL AND CONSULTATION; RISK FACTORS; UNITED STATES;

EID: 84940573777     PISSN: 00256196     EISSN: 19425546     Source Type: Journal    
DOI: 10.1016/j.mayocp.2015.06.013     Document Type: Review

References (114)

1. N. Chalasani, Z. Younossi, J.E. Lavine, and 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 55 6 2012 2005 2023
2. R. Loomba, and A.J. Sanyal The global NAFLD epidemic Nat Rev Gastroenterol Hepatol 10 11 2013 686 690
3. G. Vernon, A. Baranova, and Z.M. Younossi Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults Aliment Pharmacol Ther 34 3 2011 274 285
4. A. Fraser, M.P. Longnecker, and D.A. Lawlor Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004 Gastroenterology 133 6 2007 1814 1820
5. C.D. Williams, J. Stengel, M.I. Asike, and 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 140 1 2011 124 131
6. V.W. Wong, G.L. Wong, P.C. Choi, and et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years Gut 59 7 2010 969 974
7. L.A. Adams, J.F. Lymp, J. St Sauver, and et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study Gastroenterology 129 1 2005 113 121
8. N. Bhala, P. Angulo, D. van der Poorten, and et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study Hepatology 54 4 2011 1208 1216
9. M.R. Teli, O.F. James, A.D. Burt, M.K. Bennett, and C.P. Day The natural history of nonalcoholic fatty liver: a follow-up study Hepatology 22 6 1995 1714 1719
10. L.A. Adams, S. Sanderson, K.D. Lindor, and P. Angulo The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies J Hepatol 42 1 2005 132 138
11. C.A. Matteoni, Z.M. Younossi, T. Gramlich, N. Boparai, Y.C. Liu, and A.J. McCullough Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity Gastroenterology 116 6 1999 1413 1419
12. S. McPherson, T. Hardy, E. Henderson, A.D. Burt, C.P. Day, and Q.M. Anstee Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management J Hepatol 62 5 2015 1148 1155
13. S. Singh, A.M. Allen, Z. Wang, L.J. Prokop, M.H. Murad, and R. Loomba Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies Clin Gastroenterol Hepatol 13 4 2015 643-654.e641-e649; quiz e639-e640
14. R. Pais, F. Charlotte, L. Fedchuk, et al. LIDO Study Group A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver J Hepatol 59 3 2013 550 556
15. Arulanandan A, Ang B, Bettencourt R, et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis [published online ahead of print February 3, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.01.027.
16. M.M. Yeh, and E.M. Brunt Pathological features of fatty liver disease Gastroenterology 147 4 2014 754 764
17. D.E. Kleiner, and E.M. Brunt Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research Semin Liver Dis 32 1 2012 3 13
18. N. Chalasani, L. Wilson, D.E. Kleiner, O.W. Cummings, E.M. Brunt, and A. Unalp NASH Clinical Research Network. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease J Hepatol 48 5 2008 829 834
19. R. Loomba, M. Abraham, A. Unalp, et al. Nonalcoholic Steatohepatitis Clinical Research Network Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis Hepatology 56 3 2012 943 951
20. C. Pirazzi, M. Adiels, M.A. Burza, and et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro J Hepatol 57 6 2012 1276 1282
21. S.M. Grundy, J.I. Cleeman, S.R. Daniels, et al. American Heart Association; National Heart, Lung, and Blood Institute Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement [published corrections appear in Circulation. 2005;112(17):e298 and Circulation. 2005;112(17):e297] Circulation 112 17 2005 2735 2752
22. M. Noureddin, K.P. Yates, I.A. Vaughn, et al. NASH CRN Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients Hepatology 58 5 2013 1644 1654
23. E. Fassio, E. Alvarez, N. Domínguez, G. Landeira, and C. Longo Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies Hepatology 40 4 2004 820 826
24. C.K. Argo, P.G. Northup, A.M. Al-Osaimi, and S.H. Caldwell Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis J Hepatol 51 2 2009 371 379
25. M.S. Ascha, I.A. Hanouneh, R. Lopez, T.A. Tamimi, A.F. Feldstein, and N.N. Zein The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis Hepatology 51 6 2010 1972 1978
26. Y. Takuma, and K. Nouso Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review World J Gastroenterol 16 12 2010 1436 1441
27. J.A. Marrero, R.J. Fontana, G.L. Su, H.S. Conjeevaram, D.M. Emick, and A.S. Lok NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States Hepatology 36 6 2002 1349 1354
28. E. Hamaguchi, T. Takamura, M. Sakurai, and et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis Diabetes Care 33 2 2010 284 286
29. B.A. Neuschwander-Tetri, and S.H. Caldwell Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference [published correction appears in Hepatology. 2003;38(2):536] Hepatology 37 5 2003 1202 1219
30. R.J. Wong, R. Cheung, and A. Ahmed Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S Hepatology 59 6 2014 2188 2195
31. R.J. Wong, M. Aguilar, R. Cheung, and et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States Gastroenterology 148 3 2015 547 555
32. E. Hashimoto, S. Yatsuji, M. Tobari, and et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis J Gastroenterol 44 suppl 19 2009 89 95
33. C.P. Day, and O.F. James Steatohepatitis: a tale of two "hits"? Gastroenterology 114 4 1998 842 845
34. J.K. Dowman, J.W. Tomlinson, and P.N. Newsome Pathogenesis of non-alcoholic fatty liver disease QJM 103 2 2010 71 83
35. Z. Tariq, C.J. Green, and L. Hodson Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)? Liver Int 34 7 2014 e180 e190
36. B.A. Neuschwander-Tetri Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites Hepatology 52 2 2010 774 788
37. A.E. Feldstein Novel insights into the pathophysiology of nonalcoholic fatty liver disease Semin Liver Dis 30 4 2010 391 401
38. R. Loomba, O. Quehenberger, A. Armando, and E.A. Dennis Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis J Lipid Res 56 1 2015 185 192
39. D. Schuppan, and J.M. Schattenberg Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches J Gastroenterol Hepatol 28 suppl 1 2013 68 76
40. M. Trauner, T. Claudel, P. Fickert, T. Moustafa, and M. Wagner Bile acids as regulators of hepatic lipid and glucose metabolism Dig Dis 28 1 2010 220 224
41. B.A. Neuschwander-Tetri, R. Loomba, A.J. Sanyal, et al. NASH Clinical Research Network Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial [published correction appears in Lancet. 2015;385(9972):946] Lancet 385 9972 2015 956 965
42. M. Mouzaki, E.M. Comelli, B.M. Arendt, and et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease Hepatology 58 1 2013 120 127
43. M. Raman, I. Ahmed, P.M. Gillevet, and et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease Clin Gastroenterol Hepatol 11 7 2013 868-875.e861-e863
44. A.J. Wigg, I.C. Roberts-Thomson, R.B. Dymock, P.J. McCarthy, R.H. Grose, and A.G. Cummins The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis Gut 48 2 2001 206 211
45. G. Musso, R. Gambino, F. De Michieli, M. Durazzo, G. Pagano, and M. Cassader Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH Hepatology 47 4 2008 1167 1177
46. G. Musso, R. Gambino, M. Durazzo, and et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease Hepatology 42 5 2005 1175 1183
47. Z. Li, M.J. Soloski, and A.M. Diehl Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease Hepatology 42 4 2005 880 885
48. J.J. Maher, P. Leon, and J.C. Ryan Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis Hepatology 48 2 2008 670 678
49. K. Cusi Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications Gastroenterology 142 4 2012 711 725.e716
50. J.K. Dowman, J.W. Tomlinson, and P.N. Newsome Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis Aliment Pharmacol Ther 33 5 2011 525 540
51. D.S. Pratt, and M.M. Kaplan Evaluation of abnormal liver-enzyme results in asymptomatic patients N Engl J Med 342 17 2000 1266 1271
52. D. Sorbi, J. Boynton, and K.D. Lindor The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease Am J Gastroenterol 94 4 1999 1018 1022
53. E. Yan, F. Durazo, M. Tong, and K. Hong Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management Nutr Rev 65 8, Pt 1 2007 376 384
54. P. Angulo, E. Bugianesi, E.S. Bjornsson, and et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease Gastroenterology 145 14 2013 782 789.e784
55. P. Angulo, J.M. Hui, G. Marchesini, and et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD Hepatology 45 4 2007 846 854
56. E.M. Koehler, J.N. Schouten, B.E. Hansen, A. Hofman, B.H. Stricker, and H.L. Janssen External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study Clin Gastroenterol Hepatol 11 9 2013 1201 1204
57. K. Cusi, Z. Chang, S. Harrison, and et al. Limited value of plasma cytokeratin-18 as a biomarker for nash and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) J Hepatol 60 1 2014 167 174
58. J. Bazick, M. Donithan, B.A. Neuschwander-Tetri, and et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD Diabetes Care 38 7 2015 1347 1355
59. N. Chalasani, Z. Younossi, J.E. Lavine, et al. American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology Gastroenterology 142 7 2012 1592 1609
60. D.L. White, F. Kanwal, and H.B. El-Serag Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review Clin Gastroenterol Hepatol 10 12 2012 1342 1359.e1342
61. D. Festi, R. Schiumerini, L. Marzi, and et al. Review article: the diagnosis of non-alcoholic fatty liver disease - availability and accuracy of non-invasive methods Aliment Pharmacol Ther 37 4 2013 392 400
62. R. Hernaez, M. Lazo, S. Bonekamp, and et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis Hepatology 54 3 2011 1082 1090
63. A.E. Bohte, J.R. van Werven, S. Bipat, and J. Stoker The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis Eur Radiol 21 1 2011 87 97
64. Idilman IS, Keskin O, Celik A, 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 [published online ahead of print April 8, 2015]. Acta Radiol. doi: 10.1177/0284185115580488.
65. A. Tang, A. Desai, G. Hamilton, and et al. Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease Radiology 274 2 2015 416 425
66. A. Tang, J. Tan, M. Sun, and et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis Radiology 267 2 2013 422 431
67. Z. Permutt, T.A. Le, M.R. Peterson, and et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD Aliment Pharmacol Ther 36 1 2012 22 29
68. V.W. Wong, J. Vergniol, G.L. Wong, and et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease Hepatology 51 2 2010 454 462
69. S. Naveau, K. Lamouri, G. Pourcher, and et al. The diagnostic accuracy of transient elastography for the diagnosis of liver fibrosis in bariatric surgery candidates with suspected NAFLD Obes Surg 24 10 2014 1693 1701
70. R. Loomba, T. Wolfson, B. Ang, and et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study Hepatology 60 6 2014 1920 1928
71. J. Cui, B. Ang, W. Haufe, and et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study Aliment Pharmacol Ther 41 12 2015 1271 1280
72. S. Singh, S.K. Venkatesh, Z. Wang, and et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data Clin Gastroenterol Hepatol 13 3 2015 440 451.e446
73. S.C. Lin, E. Heba, T. Wolfson, and et al. Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique Clin Gastroenterol Hepatol 13 7 2015 1337 1345.e1336
74. N.C. Chavez-Tapia, F.I. Tellez-Avila, T. Barrientos-Gutierrez, N. Mendez-Sanchez, J. Lizardi-Cervera, and M. Uribe Bariatric surgery for non-alcoholic steatohepatitis in obese patients Cochrane Database Syst Rev 1 2010 CD007340
75. V. Ratziu, S. Bellentani, H. Cortez-Pinto, C. Day, and G. Marchesini A position statement on NAFLD/NASH based on the EASL 2009 special conference J Hepatol 53 2 2010 372 384
76. V. Ratziu, F. Charlotte, A. Heurtier, et al. LIDO Study Group Sampling variability of liver biopsy in nonalcoholic fatty liver disease Gastroenterology 128 7 2005 1898 1906
77. K. Promrat, D.E. Kleiner, H.M. Niemeier, and et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis Hepatology 51 1 2010 121 129
78. S. Sullivan, E.P. Kirk, B. Mittendorfer, B.W. Patterson, and S. Klein Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease Hepatology 55 6 2012 1738 1745
79. E. Bacchi, C. Negri, M.E. Zanolin, and et al. Metabolic effects of aerobic training and resistance training in type 2 diabetic subjects: a randomized controlled trial (the RAED2 study) Diabetes Care 35 4 2012 676 682
80. M. Lazo, S.F. Solga, A. Horska, et al. Fatty Liver Subgroup of the Look AHEAD Research Group Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes Diabetes Care 33 10 2010 2156 2163
81. Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients [published online ahead of print April 25, 2015]. Gastroenterology. doi: 10.1053/j.gastro.2015.04.014.
82. T. Ribeireiro, J. Swain, M. Sarr, and et al. NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery-a prospective analysis Obes Surg 21 3 2011 310 315
83. T.N. Weingarten, J.M. Swain, M.L. Kendrick, and et al. Nonalcoholic steatohepatitis (NASH) does not increase complications after laparoscopic bariatric surgery Obes Surg 21 11 2011 1714 1720
84. L. Pestana, J. Swain, R. Dierkhising, M.L. Kendrick, P.S. Kamath, and K.D. Watt Bariatric surgery in patients with cirrhosis with and without portal hypertension: a single-center experience [published corrections appear in Mayo Clin Proc. 2015;90(4):558-559] Mayo Clin Proc 90 2 2015 209 215
85. J.I. Mechanick, A. Youdim, D.B. Jones, et al. American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient - 2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery Endocr Pract 19 2 2013 337 372
86. E. Boettcher, G. Csako, F. Pucino, R. Wesley, and R. Loomba Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis Aliment Pharmacol Ther 35 1 2012 66 75
87. L.N. Bell, J. Wang, S. Muralidharan, et al. Nonalcoholic Steatohepatitis Clinical Research Network Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study Hepatology 56 4 2012 1311 1318
88. A.J. Sanyal, N. Chalasani, K.V. Kowdley, et al. NASH CRN Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis N Engl J Med 362 18 2010 1675 1685
89. A.J. Sanyal, E.M. Brunt, D.E. Kleiner, and et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis Hepatology 54 1 2011 344 353
90. A.M. Lincoff, K. Wolski, S.J. Nicholls, and S.E. Nissen Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials JAMA 298 8 2007 1180 1188
91. J.E. Lavine, J.B. Schwimmer, M.L. Van Natta, et al. Nonalcoholic Steatohepatitis Clinical Research Network Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial JAMA 305 16 2011 1659 1668
92. G. Bjelakovic, D. Nikolova, and C. Gluud Meta-regression analyses, meta-analyses, and trial sequential analyses of the effects of supplementation with beta-carotene, vitamin A, and vitamin E singly or in different combinations on all-cause mortality: do we have evidence for lack of harm? PLoS One 8 9 2013 e74558
93. G. Bjelakovic, D. Nikolova, L.L. Gluud, R.G. Simonetti, and C. Gluud Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis [published correction appears in JAMA. 2008;299(7):765-766] JAMA 297 8 2007 842 857
94. E.A. Klein, I.M. Thompson Jr., C.M. Tangen, and et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) JAMA 306 14 2011 1549 1556
95. M. Schürks, R.J. Glynn, P.M. Rist, C. Tzourio, and T. Kurth Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials BMJ 341 2010 c5702
96. B. Cariou The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis Diabetes Metab 34 6, Pt 2 2008 685 691
97. B. Cariou, K. van Harmelen, D. Duran-Sandoval, and et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice J Biol Chem 281 16 2006 11039 11049
98. V. Ratziu, V. de Ledinghen, F. Oberti, et al. FRESGUN A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis J Hepatol 54 5 2011 1011 1019
99. K.D. Lindor, K.V. Kowdley, E.J. Heathcote, and et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial Hepatology 39 3 2004 770 778
100. A. Ward, and S.P. Clissold Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy Drugs 34 1 1987 50 97
101. C.O. Zein, R. Lopez, X. Fu, and et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism Hepatology 56 4 2012 1291 1299
102. L.B. Van Wagner, S.W. Koppe, E.M. Brunt, and et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial Ann Hepatol 10 3 2011 277 286
103. C.O. Zein, L.M. Yerian, P. Gogate, and et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial Hepatology 54 5 2011 1610 1619
104. Diabetes Prevention Program (DPP) Research Group The Diabetes Prevention Program (DPP): description of lifestyle intervention Diabetes Care 25 12 2002 2165 2171
105. S. Nair, A.M. Diehl, M. Wiseman, G.H. Farr, and R.P. Perrillo Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial Aliment Pharmacol Ther 20 1 2004 23 28
106. R. Loomba, G. Lutchman, D.E. Kleiner, and et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis Aliment Pharmacol Ther 29 2 2009 172 182
107. G.A. Garinis, B. Fruci, A. Mazza, and et al. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study Int J Obes (Lond) 34 8 2010 1255 1264
108. W.W. Shields, K.E. Thompson, G.A. Grice, S.A. Harrison, and W.J. Coyle The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial Therap Adv Gastroenterol 2 3 2009 157 163
109. X. Zhang, W.S. Harmsen, T.A. Mettler, and et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes Hepatology 60 6 2014 2008 2016
110. M. Pearlman, and R. Loomba State of the art: treatment of nonalcoholic steatohepatitis Curr Opin Gastroenterol 30 3 2014 223 237
111. R.J. Wong, C. Chou, C.A. Bonham, W. Concepcion, C.O. Esquivel, and A. Ahmed Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data Clin Transplant 28 6 2014 713 721
112. X. Wang, J. Li, D.R. Riaz, G. Shi, C. Liu, and Y. Dai Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis Clin Gastroenterol Hepatol 12 3 2014 394 402.e391
113. L.A. Fussner, M.R. Charlton, J.K. Heimbach, and et al. The impact of gender and NASH on chronic kidney disease before and after liver transplantation Liver Int 34 8 2014 1259 1266
114. K.F. Murray, R.L. Carithers Jr. AASLD AASLD practice guidelines: evaluation of the patient for liver transplantation Hepatology 41 6 2005 1407 1432