Nonalcoholic fatty liver disease - current status and future directions

Journal of Digestive Diseases

Volumn 16, Issue 10, 2015, Pages 541-557

  Demir, Münevver ^a   Lang, Sonja ^a   Steffen, Hans Michael ^a  

^a UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

Author keywords

Diagnosis; Epidemiology; Natural history; Non alcoholic fatty liver disease; Pathogenesis; Treatment

Indexed keywords

ALANINE AMINOTRANSFERASE; ALPHA TOCOPHEROL; ANGIOTENSIN 2 RECEPTOR ANTAGONIST; ASPARTATE AMINOTRANSFERASE; C REACTIVE PROTEIN; CENICRIVIROC; FARNESOID X RECEPTOR; GAMMA GLUTAMYLTRANSFERASE; GFT 9450; GLITAZONE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOSARTAN; METFORMIN; NIVOCASAN; NORURSODEOXYCHOLIC ACID; OBETICHOLIC ACID; PENTOXIFYLLINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA AGONIST; PIOGLITAZONE; PLACEBO; POLYUNSATURATED FATTY ACID; SIMVASTATIN; UNCLASSIFIED DRUG;

ACOUSTIC RADIATION FORCE IMPULSE IMAGING; ARTERIAL STIFFNESS; ARTICLE; BARIATRIC SURGERY; BODY MASS; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; CORONARY ARTERY CALCIFICATION; DIAGNOSTIC TEST ACCURACY STUDY; DISEASE ASSOCIATION; DRUG MEGADOSE; DYSBIOSIS; DYSLIPIDEMIA; ELASTOGRAPHY; ENDOTHELIAL DYSFUNCTION; GENETIC MARKER; GLUCONEOGENESIS; GLYCOLYSIS; HUMAN; HUMAN TISSUE; HYPERTENSION; INSULIN RESISTANCE; LIFESTYLE MODIFICATION; LIPOTOXICITY; LIVER BIOPSY; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER TRANSPLANTATION; MAJOR CLINICAL STUDY; METABOLIC SYNDROME X; MORBID OBESITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NUCLEAR MAGNETIC RESONANCE IMAGING; OBESITY; PREVALENCE; PRIORITY JOURNAL; RECEIVER OPERATING CHARACTERISTIC; SENSITIVITY AND SPECIFICITY; WEIGHT REDUCTION; FORECASTING; NON-ALCOHOLIC FATTY LIVER DISEASE;

FORECASTING; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE;

EID: 84955278132     PISSN: 17512972     EISSN: 17512980     Source Type: Journal    
DOI: 10.1111/1751-2980.12291     Document Type: Article

References (168)

1. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 2010; 5: 145-71.
2. Milić S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis 2012; 30: 158-62.
3. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52: 1836-46.
4. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356-62.
5. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013; 10: 627-36.
6. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013; 10: 656-65.
7. Söderberg C, Stål P, Askling J et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51: 595-602.
8. Adams LA, Lymp JF, St Sauver J et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-21.
9. Ekstedt M, Franzén LE, Mathiesen UL et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.
10. Loomba R, Wesley R, Pucino F, Liang TJ, Kleiner DE, Lavine JE. Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials. Clin Gastroenterol Hepatol 2008; 6: 1243-8.
11. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413-9.
12. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-9.
13. Pais R, Charlotte F, Fedchuk L et al. LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59: 550-6.
14. Tilg H, Moschen AR. Evolving therapies for non-alcoholic steatohepatitis. Expert Opin Drug Discov 2014; 9: 687-96.
15. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474: 327-36.
16. Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 2013; 24: 537-45.
17. Sanyal AJ, Chalasani N, Kowdley KV et al. NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675-85.
18. Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013; 10: 676-85.
19. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-8.
20. Younossi ZM, Stepanova M, Afendy M et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9: 524-30.e1.
21. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13: 511-31.
22. Szczepaniak LS, Nurenberg P, Leonard D et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-8.
23. Patton HM, Yates K, Unalp-Arida A et al. Association between metabolic syndrome and liver histology among children with nonalcoholic fatty liver disease. Am J Gastroenterol 2010; 105: 2093-102.
24. Bellentani S, Saccoccio G, Masutti F et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-7.
25. Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol 2003; 38: 954-61.
26. Amarapurkar D, Kamani P, Patel N et al. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol 2007; 6: 161-3.
27. Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol 2009; 50: 204-10.
28. Onyekwere CA, Ogbera AO, Balogun BO. Non-alcoholic fatty liver disease and the metabolic syndrome in an urban hospital serving an African community. Ann Hepatol 2011; 10: 119-24.
29. Al-hamoudi W, El-Sabbah M, Ali S et al. Epidemiological, clinical, and biochemical characteristics of Saudi patients with nonalcoholic fatty liver disease: a hospital-based study. Ann Saudi Med 2012; 32: 288-92.
30. 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: 274-85.
31. Chalasani N, Younossi Z, Lavine JE 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: 2005-23.
32. Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors in non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int 2009; 29: 113-9.
33. Wong RJ, Aguilar M, Cheung R et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148: 547-55.
34. Wong VW, Wong GL, Choi PC et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010; 59: 969-74.
35. Sanyal AJ, Banas C, Sargeant C et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006; 43: 682-9.
36. Ekstedt M, Hagström H, Nasr P et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61: 1547-54.
37. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51: 1972-8.
38. Dyson J, Jaques B, Chattopadyhay D et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60: 110-7.
39. White DL, Kanwal F, El-Serag H. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gantroenterol Hepatol 2012; 10: 1342-59.e2.
40. Mittal S, Sada YH, El-Serag HB et al. Temporal trends of non-alcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015; 13: 594-601.e1.
41. Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 2010; 26: 2183-91.
42. Yasui K, Hashimoto E, Komorizono Y et al. Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9: 428-33.
43. Rafiq N, Bai C, Fang Y et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7: 234-8.
44. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: A systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13: 643-54.e9.
45. Londoño MC, Abraldes JG, Altamirano J, Decaens T, Forns X. Clinical trial watch: Reports from the AASLD Liver Meeting®, Boston, November 2014. J Hepatol 2015; 62: 1196-203.
46. Angulo P, Kleiner D, Dam-Larsen S et al. The prognostic relevance of liver histology features in nonalcoholic fatty liver disease: the PRELHIN study. Hepatology 2014; 60 Suppl 1: 226-7A.
47. Bhala N, Angulo P, van der Poorten D et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 2011; 54: 1208-16.
48. Hamaguchi M, Kojima T, Takeda N et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13: 1579-84.
49. Targher G, Bertolini L, Padovani R et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30: 1212-8.
50. Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50: 1403-11.
51. 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: 617-49.
52. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49: 600-7.
53. Oni ET, Agatston AS, Blaha MJ et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver: should we care? Atherosclerosis 2013; 230: 258-67.
54. 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: 1357-65.
55. 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: 372-84.
56. Watanabe S, Hashimoto E, Ikejima K et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatol Res 2015; 45: 363-77.
57. Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 2014; 5: 211-8.
58. Browning JD, Szczepaniak LS, Dobbins R et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-95.
59. Mofrad P, Contos MJ, Haque M et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37: 1286-92.
60. Valenti L, Dongiovanni P, Fargion S. Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease. World J Gastroenterol 2012; 18: 3782-6.
61. Kowdley KV, Belt P, Wilson LA 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.
62. Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2004; 99: 1316-20.
63. Vuppalanchi R, Gould RJ, Wilson LA et al. Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. Hepatol Int 2012; 6: 379-85.
64. Kawada T, Otsuka T, Inagaki H, Wakayama Y, Katsumata M. Biological markers, lifestyles and metabolic syndrome in workers. Diabetes Metab Syndr 2015; 9: 71-3.
65. Eckel N, Mühlenbruch K, Meidtner K, Boeing H, Stefan N, Schulze MB. Characterization of metabolically unhealthy normal-weight individuals: Risk factors and their associations with type 2 diabetes. Metabolism 2015; 64: 862-71.
66. Oruc N, Ozutemiz O, Yuce G et al. Serum procalcitonin and CRP levels in non-alcoholic fatty liver disease: a case control study. BMC Gastroenterol 2009; 9: 16.
67. Hernaez R, Lazo M, Bonekamp S et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011; 54: 1082-90.
68. Saadeh S, Younossi ZM, Remer EM et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-50.
69. Mottin CC, Moretto M, Padoin AV et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg 2004; 14: 635-7.
70. Kwok R, Tse YK, Wong GL 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: 254-69.
71. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol 2013; 58: 1007-19.
72. Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol 2009; 51: 433-45.
73. McPherson S, Jonsson JR, Cowin GJ et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol 2009; 51: 389-97.
74. Sandrin L, Fourquet B, Hasquenoph JM et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29: 1705-13.
75. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007; 5: 1214-20.
76. Stebbing J, Farouk L, Panos G et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010; 44: 214-9.
77. Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011; 54: 650-9.
78. Castéra L, Foucher J, Bernard PH et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13, 369 examinations. Hepatology 2010; 51: 828-35.
79. Myers RP, Pomier-Layrargues G, Kirsch R et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012; 55: 199-208.
80. Myers RP, Pomier-Layrargues G, Kirsch R et al. Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe. J Hepatol 2012; 56: 564-70.
81. Shi KQ, Tang JZ, Zhu XL et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy. J Gastroenterol Hepatol 2014; 29: 1149-58.
82. Cassinotto C, Lapuyade B, Mouries A et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014; 61: 550-7.
83. Palmeri ML, Wang MH, Rouze NC et al. Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol 2011; 55: 666-72.
84. Friedrich-Rust M, Nierhoff J, Lupsor M et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012; 19: e212-9.
85. Nierhoff J, Chávez Ortiz AA, Herrmann E, Zeuzem S, Friedrich-Rust M. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis. Eur Radiol 2013; 23: 3040-53.
86. Friedrich-Rust M, Romen D, Vermehren J et al. Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol 2012; 81: e325-31.
87. Yoneda M, Suzuki K, Kato S et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010; 256: 640-7.
88. Fierbinteanu Braticevici C, Sporea I, Panaitescu E, Tribus L. Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease. Ultrasound Med Biol 2013; 39: 1942-50.
89. Kruger FC, Daniels CR, Kidd M et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J 2011; 101: 477-80.
90. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterol 1988; 95: 734-9.
91. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008; 57: 1441-7.
92. Demir M, Lang S, Schlattjan M et al. NIKEI: a new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD. PLoS One 2013; 8: e58360.
93. Sterling RK, Lissen E, Clumeck N et al. APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43: 1317-25.
94. Angulo P, Hui JM, Marchesini G et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45: 846-54.
95. Demir M, Lang S, Nierhoff D et al. Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic fatty liver disease. J Clin Gastroenterol 2013; 47: 719-26.
96. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ; NASH Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009; 7: 1104-12.
97. Angulo P, Bugianesi E, Bjornsson ES et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 782-9.e4.
98. Joka D, Wahl K, Moeller S et al. Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis. Hepatology 2012; 55: 455-64.
99. Tanwar S, Trembling PM, Guha IN et al. Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. Hepatology 2013; 57: 103-11.
100. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103: 1372-9.
101. Wong VW, Hui AY, Tsang SW et al. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006; 4: 1154-61.
102. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147: 577-94.e1.
103. Shen J, Chan HL, Wong GL et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol 2012; 56: 1363-70.
104. Cusi K, Chang Z, Harrison S 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: 167-74.
105. Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-5.
106. Zhang L, You W, Zhang H et al. PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis. J Gastroenterol Hepatol 2015; 30: 821-9.
107. Trépo E, Nahon P, Bontempi G et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology 2014; 59: 2170-7.
108. 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: 1883-94.
109. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10: 645-55.
110. Speliotes EK, Butler JL, Palmer CD, Voight BF; GIANT Consortium; MIGen Consortium; NASH CRN, Hirschhorn JN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010; 52: 904-12.
111. Kozlitina J, Smagris E, Stender S et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46: 352-6.
112. Liu YL, Reeves HL, Burt AD et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014; 5: 4309.
113. Sookoian S, Castaño GO, Scian R et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015; 61: 515-25.
114. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20: 9026-37.
115. Schneier AT, Citti CC, Dieterich DT. Management and diagnosis of fatty liver disease. Expert Rev Gastroenterol Hepatol 2015; 9: 671-83.
116. 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.
117. Nascimbeni F, Pais R, Bellentani S et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol 2013; 59: 859-71.
118. Treeprasertsuk S, Leverage S, Adams LA, Lindor KD, St Sauver J, Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int 2012; 32: 945-50.
119. Eichler K, Puhan MA, Steurer J, Bachmann LM. Prediction of first coronary events with the Framingham score: a systematic review. Am Heart J 2007; 153: 722-31.e8.
120. Conroy RM, Pyörälä K, Fitzgerald AP et al. SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: 987-1003.
121. Spruss A, Bergheim I. Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease. J Nutr Biochem 2009; 20: 657-62.
122. Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 2013; 57: 2525-31.
123. Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 2015; 77: 245-51.
124. Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10: 637-44.
125. Day C. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-78.
126. Sanyal AJ, Campbell-Sargent C, Mirshahi F et al. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183-92.
127. Eguchi Y, Eguchi T, Mizuta T et al. Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 2006; 41: 462-9.
128. Chitturi S, Abeygunasekera S, Farrell GC et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35: 373-9.
129. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010; 52: 774-88.
130. Han MS, Park SY, Shinzawa K et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 2008; 49: 84-97.
131. Schnabl B. Linking intestinal homeostasis and liver disease. Curr Opin Gastroenterol 2013; 29: 264-70.
132. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014; 15: 8591-638.
133. Ganz M, Szabo G. Immune and inflammatory pathways in NASH. Hepatol Int 2013; 7 Suppl 2: 771-81.
134. Promrat K, Kleiner DE, Niemeier HM et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010; 51: 121-9.
135. Liu X, Lazenby AJ, Clements RH, Jhala N, Abrams GA. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg 2007; 17: 486-92.
136. Barker KB, Palekar NA, Bowers SP, Goldberg JE, Pulcini JP, Harrison SA. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol 2006; 101: 368-73.
137. Taitano AA, Markow M, Finan JE, Wheeler DE, Gonzalvo JP, Murr MM. Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis. J Gastrointest Surg 2015; 19: 429-36.
138. Mathurin P, Hollebecque A, Arnalsteen L et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009; 37: 532-40.
139. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010; 1: CD007340.
140. Lassailly G, Caiazzo R, Buob D et al. Effects of bariatric surgery on severe liver injury in morbid obese patients with proven NASH: a prospective study. Hepatology 2014; 60 Suppl 1: 305-6A.
141. Lavine JE, Schwimmer JB, Van Natta ML 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 2011; 305: 1659-68.
142. Haukeland JW, Konopski Z, Eggesbø HB et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44: 853-60.
143. 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: 71-7.
144. 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: 990-4.
145. Yokohama S, Yoneda M, Haneda M et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004; 40: 1222-5.
146. 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: 377-84.
147. Orlando R, Azzalini L, Orando S, Lirussi F. Bile acids for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007; 1: CD005160.
148. Zein CO, Yerian LM, Gogate P et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54: 1610-9.
149. Belfort R, Harrison SA, Brown K et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297-307.
150. Frohnert BI, Hui TY, Bernlohr DA. Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. J Biol Chem 1999; 274: 3970-7.
151. Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 1996; 10: 1096-107.
152. Galli A, Crabb DW, Ceni E et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002; 122: 1924-40.
153. Yu JG, Javorschi S, Hevener AL et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968-74.
154. Morante M, Sandoval J, Gómez-Cabrera MC et al. Vitamin E deficiency induces liver nuclear factor-kappaB DNA-binding activity and changes in related genes. Free Radic Res 2005; 39: 1127-38.
155. Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia 2012; 55: 1953-62.
156. Nissen SE, Wolski K. Rosiglitazone revisited: An updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010; 170: 1191-201.
157. Argo CK, Iezzoni JC, Al-Osaimi AM, Caldwell SH. Thiazolidinediones for the treatment in NASH: sustained benefit after drug discontinuation? J Clin Gastroenterol 2009; 43: 565-8.
158. Miller ER 3rd, 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.
159. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7: 678-93.
160. Maneschi E, Vignozzi L, Morelli A et al. FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. J Endocrinol 2013; 218: 215-31.
161. Hollman DA, Milona A, van Erpecum KJ, van Mil SW. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta 2012; 1821: 1443-52.
162. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54: 1263-72.
163. Neuschwander-Tetri BA, Loomba R, Sanyal AJ 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. Lancet 2015; 385: 956-65.
164. Qin X, Xie X, Fan Y et al. Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 2008; 48: 432-41.
165. Cariou B, Hanf R, Lambert-Porcheron S et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013; 36: 2923-30.
166. Ratziu V, Sheikh MY, Sanyal AJ et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012; 55: 419-28.
167. Hardy T, Anstee QM, Day CP. Nonalcoholic fatty liver disease: new treatments. Curr Opin Gastroenterol 2015; 31: 175-83.
168. Dam-Larsen S, Franzmann M, Andersen IB et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004; 53: 750-5.