Diabetes Metab J.  2020 Jun;44(3):382-401. 10.4093/dmj.2020.0010.

Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association

• Lee BW
• Lee Yh
• Park CY
• Rhee EJ
• Lee WY
• Kim NH
• Choi KM
• Park KG
• Choi YK
• Cha BS
• Lee DH
• Korean Diabetes Association (KDA) Fatty Liver Research Group

• KMID: 2512996
• DOI: http://doi.org/10.4093/dmj.2020.0010

Abstract

This clinical practice position statement, a product of the Fatty Liver Research Group of the Korean Diabetes Association, proposes recommendations for the diagnosis, progression and/or severity assessment, management, and follow-up of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NAFLD have an increased risk of non-alcoholic steatohepatitis (NASH) and fibrosis and a higher risk of cardiovascular diseases and diabetic complications compared to those without NAFLD. With regards to the evaluation of patients with T2DM and NAFLD, ultrasonography-based stepwise approaches using noninvasive biomarker models such as fibrosis-4 or the NAFLD fibrosis score as well as imaging studies such as vibration-controlled transient elastography with controlled attenuation parameter or magnetic resonance imaging-proton density fat fraction are recommended. After the diagnosis of NAFLD, the stage of fibrosis needs to be assessed appropriately. For management, weight reduction achieved by lifestyle modification has proven beneficial and is recommended in combination with antidiabetic agent(s). Evidence that some antidiabetic agents improve NAFLD/NASH with fibrosis in patients with T2DM is emerging. However, there are currently no definite pharmacologic treatments for NAFLD in patients with T2DM. For specific cases, bariatric surgery may be an option if indicated.

Keyword

Cardiovascular disease; Diabetes mellitus, type 2; Life style; Non-alcoholic fatty liver disease

Figure

• 

  Fig. 1 Algorithm for non-alcoholic fatty liver disease (NAFLD) evaluation. CV, cardiovascular; NFS, NAFLD fibrosis score; BMI, body mass index; IFG, impaired fasting glucose; DM, diabetes mellitus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; FIB-4, fibrosis-4; PLT, platelet; APRI, AST to platelet ratio index; ULN, upper limit of normal; VCTE, vibration-controlled transient elastography; ELF, enhanced liver fibrosis; MRE, magnetic resonance elastography. aHigher cutoffs for patients aged >65 years, bVariable cutoffs have been suggested. Measured values are affected by body factors, cFurther validation is required.

• 

  Fig. 2 Suggested algorithm for the management of patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).

Reference

1. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM. Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012; 56:943–951. PMID: 22505194.

2. Lee YH, Cho Y, Lee BW, Park CY, Lee DH, Cha BS, Rhee EJ. Nonalcoholic fatty liver disease in diabetes. Part I: epidemiology and diagnosis. Diabetes Metab J. 2019; 43:31–45. PMID: 30793550.

3. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care. 2017; 40:419–430. PMID: 28223446.

4. Han E, Lee YH. Non-alcoholic fatty liver disease: the emerging burden in cardiometabolic and renal diseases. Diabetes Metab J. 2017; 41:430–437. PMID: 29199410.

5. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67:328–357. PMID: 28714183.

6. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004; 40:1387–1395. PMID: 15565570.

7. 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. PMID: 21623852.

8. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64:73–84. PMID: 26707365.

9. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006; 21(1 Pt 1):138–143. PMID: 16706825.

10. Jeong EH, Jun DW, Cho YK, Choe YG, Ryu S, Lee SM, Jang EC. Regional prevalence of non-alcoholic fatty liver disease in Seoul and Gyeonggi-do, Korea. Clin Mol Hepatol. 2013; 19:266–272. PMID: 24133664.

11. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015; 100:2231–2238. PMID: 25885947.

12. Hyysalo J, Mannisto VT, Zhou Y, Arola J, Karja V, Leivonen M, Juuti A, Jaser N, Lallukka S, Kakela P, Venesmaa S, Simonen M, Saltevo J, Moilanen L, Korpi-Hyovalti E, Keinanen-Kiukaanniemi S, Oksa H, Orho-Melander M, Valenti L, Fargion S, Pihlajamaki J, Peltonen M, Yki-Jarvinen H. A population-based study on the prevalence of NASH using scores validated against liver histology. J Hepatol. 2014; 60:839–846. PMID: 24333862.

13. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011; 140:124–131. PMID: 20858492.

14. Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: implications for liver transplantation. Transplantation. 2019; 103:22–27. PMID: 30335697.

15. Kim BY, Jung CH, Mok JO, Kang SK, Kim CH. Prevalences of diabetic retinopathy and nephropathy are lower in Korean type 2 diabetic patients with non-alcoholic fatty liver disease. J Diabetes Investig. 2014; 5:170–175.

16. Mohan V, Farooq S, Deepa M, Ravikumar R, Pitchumoni CS. Prevalence of non-alcoholic fatty liver disease in urban south Indians in relation to different grades of glucose intolerance and metabolic syndrome. Diabetes Res Clin Pract. 2009; 84:84–91. PMID: 19168251.

17. Kim SK, Choi YJ, Huh BW, Park SW, Lee EJ, Cho YW, Huh KB. Nonalcoholic fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance. J Clin Endocrinol Metab. 2014; 99:1879–1884. PMID: 24512497.

18. Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, Arcaro G. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007; 30:2119–2121. PMID: 17519430.

19. Kim CH, Park JY, Lee KU, Kim JH, Kim HK. Fatty liver is an independent risk factor for the development of type 2 diabetes in Korean adults. Diabet Med. 2008; 25:476–481. PMID: 18346164.

20. Sung KC, Kim SH. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J Clin Endocrinol Metab. 2011; 96:1093–1097. PMID: 21252243.

21. Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab. 2013; 98:3637–3643. PMID: 23873989.

22. Yamazaki H, Tsuboya T, Tsuji K, Dohke M, Maguchi H. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes. Diabetes Care. 2015; 38:1673–1679. PMID: 26156527.

23. 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. PMID: 22408036.

24. 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; 13:643–654. PMID: 24768810.

25. 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. PMID: 25477264.

26. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346:1221–1231. PMID: 11961152.

27. Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, May SB, Kramer JR, Richardson PA, Davila JA. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol. 2015; 13:594–601. PMID: 25148760.

28. Pocha C, Kolly P, Dufour JF. Nonalcoholic fatty liver disease-related hepatocellular carcinoma: a problem of growing magnitude. Semin Liver Dis. 2015; 35:304–317. PMID: 26378646.

29. Lee SS, Jeong SH, Byoun YS, Chung SM, Seong MH, Sohn HR, Min BY, Jang ES, Kim JW, Park GJ, Lee YJ, Lee KH, Ahn S. Clinical features and outcome of cryptogenic hepatocellular carcinoma compared to those of viral and alcoholic hepatocellular carcinoma. BMC Cancer. 2013; 13:335. PMID: 23829392.

30. Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study. Hepatology. 2018; 67:1726–1736. PMID: 28941364.

31. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, Hultcrantz R. 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. PMID: 25125077.

32. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015; 149:389–397. PMID: 25935633.

33. Newsome PN, Cramb R, Davison SM, Dillon JF, Foulerton M, Godfrey EM, Hall R, Harrower U, Hudson M, Langford A, Mackie A, Mitchell-Thain R, Sennett K, Sheron NC, Verne J, Walmsley M, Yeoman A. Guidelines on the management of abnormal liver blood tests. Gut. 2018; 67:6–19. PMID: 29122851.

34. European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD). European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016; 59:1121–1140. PMID: 27053230.

35. Prati D, Colli A, Conte D, Colombo M. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005; 42:1460–1461. PMID: 16317678.

36. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017; 112:18–35. PMID: 27995906.

37. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560–1599. PMID: 29405329.

38. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011; 54:1082–1090. PMID: 21618575.

39. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019; 7:313–324. PMID: 30174213.

40. Bril F, Ortiz-Lopez C, Lomonaco R, Orsak B, Freckleton M, Chintapalli K, Hardies J, Lai S, Solano F, Tio F, Cusi K. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015; 35:2139–2146. PMID: 25847730.

41. Petta S, Ciminnisi S, Di Marco V, Cabibi D, Camma C, Licata A, Marchesini G, Craxi A. Sarcopenia is associated with severe liver fibrosis in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017; 45:510–518. PMID: 28028821.

42. Shen F, Zheng RD, Shi JP, Mi YQ, Chen GF, Hu X, Liu YG, Wang XY, Pan Q, Chen GY, Chen JN, Xu L, Zhang RN, Xu LM, Fan JG. Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease. Liver Int. 2015; 35:2392–2400. PMID: 25689614.

43. Vuppalanchi R, Siddiqui MS, Van Natta ML, Hallinan E, Brandman D, Kowdley K, Neuschwander-Tetri BA, Loomba R, Dasarathy S, Abdelmalek M, Doo E, Tonascia JA, Kleiner DE, Sanyal AJ, Chalasani N. NASH Clinical Research Network. Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology. 2018; 67:134–144. PMID: 28859228.

44. Kim KY, Song JS, Kannengiesser S, Han YM. Hepatic fat quantification using the proton density fat fraction (PDFF): utility of free-drawn-PDFF with a large coverage area. Radiol Med. 2015; 120:1083–1093. PMID: 25952293.

45. Capitan V, Petit JM, Aho S, Lefevre PH, Favelier S, Loffroy R, Hillon P, Krause D, Cercueil JP, Guiu B. Macroscopic heterogeneity of liver fat: an MR-based study in type-2 diabetic patients. Eur Radiol. 2012; 22:2161–2168. PMID: 22562090.

46. Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, Valasek M, Lin G, Brenner D, Gamst A, Ehman R, Sirlin C. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Version 2. Hepatology. 2014; 60:1920–1928. PMID: 25103310.

47. Kim D, Kim WR, Talwalkar JA, Kim HJ, Ehman RL. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology. 2013; 268:411–419. PMID: 23564711.

48. Caussy C, Alquiraish MH, Nguyen P, Hernandez C, Cepin S, Fortney LE, Ajmera V, Bettencourt R, Collier S, Hooker J, Sy E, Rizo E, Richards L, Sirlin CB, Loomba R. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018; 67:1348–1359. PMID: 29108123.

49. Nasr P, Forsgren MF, Ignatova S, Dahlstrom N, Cedersund G, Leinhard OD, Noren B, Ekstedt M, Lundberg P, Kechagias S. Using a 3% proton density fat fraction as a cut-off value increases sensitivity of detection of hepatic steatosis, based on results from histopathology analysis. Gastroenterology. 2017; 153:53–55. PMID: 28286210.

50. Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, Motosugi U, Sharma SD, Munoz del, Fernandez L, Reeder SB. Quantitative magnetic resonance imaging of hepatic steatosis: validation in ex vivo human livers. Hepatology. 2015; 62:1444–1455. PMID: 26224591.

51. Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A, Hernandez C, Nguyen P, Aryafar H, Valasek M, Haufe W, Hooker C, Richards L, Sirlin CB, Loomba R. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2016; 9:692–701.

52. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001; 344:495–500. PMID: 11172192.

53. Gunn NT, Shiffman ML. The use of liver biopsy in nonalcoholic fatty liver disease: when to biopsy and in whom. Clin Liver Dis. 2018; 22:109–119. PMID: 29128050.

54. Wong VW, Chalasani N. Not routine screening, but vigilance for chronic liver disease in patients with type 2 diabetes. J Hepatol. 2016; 64:1211–1213. PMID: 26921688.

55. Corey KE, Klebanoff MJ, Tramontano AC, Chung RT, Hur C. Screening for nonalcoholic steatohepatitis in individuals with type 2 diabetes: a cost-effectiveness analysis. Dig Dis Sci. 2016; 61:2108–2117. PMID: 26825843.

56. Bedossa P, Patel K. Biopsy and noninvasive methods to assess progression of nonalcoholic fatty liver disease. Gastroenterology. 2016; 150:1811–1822. PMID: 27003601.

57. Lichtinghagen R, Pietsch D, Bantel H, Manns MP, Brand K, Bahr MJ. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013; 59:236–242. PMID: 23523583.

58. Tada T, Kumada T, Toyoda H, Saibara T, Ono M, Kage M. New scoring system combining the FIB-4 index and cytokeratin-18 fragments for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease. Biomarkers. 2018; 23:328–334. PMID: 29308929.

59. Siddiqui MS, Vuppalanchi R, Van Natta ML, Hallinan E, Kowdley KV, Abdelmalek M, Neuschwander-Tetri BA, Loomba R, Dasarathy S, Brandman D, Doo E, Tonascia JA, Kleiner DE, Chalasani N, Sanyal AJ. NASH Clinical Research Network. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019; 17:156–163. PMID: 29705261.

60. Jayakumar S, Middleton MS, Lawitz EJ, Mantry PS, Caldwell SH, Arnold H, Mae Diehl A, Ghalib R, Elkhashab M, Abdelmalek MF, Kowdley KV, Stephen Djedjos C, Xu R, Han L, Mani Subramanian G, Myers RP, Goodman ZD, Afdhal NH, Charlton MR, Sirlin CB, Loomba R. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: analysis of data from a phase II trial of selonsertib. J Hepatol. 2019; 70:133–141. PMID: 30291868.

61. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D. Genetics of NAFLD in Twins Consortium. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015; 149:1784–1793. PMID: 26299412.

62. Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, Kluwe J, Boettler T, Lammert F, Geier A. NAFLD Clinical Study Group. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017; 58:247–255. PMID: 27836992.

63. Koo BK, Joo SK, Kim D, Bae JM, Park JH, Kim JH, Kim W. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2018; 33:1277–1285. PMID: 29193269.

64. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008; 40:1461–1465. PMID: 18820647.

65. Del Campo JA, Gallego-Duran R, Gallego P, Grande L. Genetic and epigenetic regulation in nonalcoholic fatty liver disease (NAFLD). Int J Mol Sci. 2018; 19:E911. PMID: 29562725.

66. Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, Amouyel P, Di Angelantonio E, Arveiler D, Assimes TL, Auer PL, Baber U, Ballantyne CM, Bang LE, Benn M, Bis JC, Boehnke M, Boerwinkle E, Bork-Jensen J, Bottinger EP, Brandslund I, Brown M, Busonero F, Caulfield MJ, Chambers JC, Chasman DI, Chen YE, Chen YI, Chowdhury R, Christensen C, Chu AY, Connell JM, Cucca F, Cupples LA, Damrauer SM, Davies G, Deary IJ, Dedoussis G, Denny JC, Dominiczak A, Dube MP, Ebeling T, Eiriksdottir G, Esko T, Farmaki AE, Feitosa MF, Ferrario M, Ferrieres J, Ford I, Fornage M, Franks PW, Frayling TM, Frikke-Schmidt R, Fritsche LG, Frossard P, Fuster V, Ganesh SK, Gao W, Garcia ME, Gieger C, Giulianini F, Goodarzi MO, Grallert H, Grarup N, Groop L, Grove ML, Gudnason V, Hansen T, Harris TB, Hayward C, Hirschhorn JN, Holmen OL, Huffman J, Huo Y, Hveem K, Jabeen S, Jackson AU, Jakobsdottir J, Jarvelin MR, Jensen GB, Jorgensen ME, Jukema JW, Justesen JM, Kamstrup PR, Kanoni S, Karpe F, Kee F, Khera AV, Klarin D, Koistinen HA, Kooner JS, Kooperberg C, Kuulasmaa K, Kuusisto J, Laakso M, Lakka T, Langenberg C, Langsted A, Launer LJ, Lauritzen T, Liewald DCM, Lin LA, Linneberg A, Loos RJF, Lu Y, Lu X, Magi R, Malarstig A, Manichaikul A, Manning AK, Mantyselka P, Marouli E, Masca NGD, Maschio A, Meigs JB, Melander O, Metspalu A, Morris AP, Morrison AC, Mulas A, Muller-Nurasyid M, Munroe PB, Neville MJ, Nielsen JB, Nielsen SF, Nordestgaard BG, Ordovas JM, Mehran R, O'Donnell CJ, Orho-Melander M, Molony CM, Muntendam P, Padmanabhan S, Palmer CNA, Pasko D, Patel AP, Pedersen O, Perola M, Peters A, Pisinger C, Pistis G, Polasek O, Poulter N, Psaty BM, Rader DJ, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Rich SS, Ridker PM, Rioux JD, Robertson NR, Roden DM, Rotter JI, Rudan I, Salomaa V, Samani NJ, Sanna S, Sattar N, Schmidt EM, Scott RA, Sever P, Sevilla RS, Shaffer CM, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith BH, Somayajula S, Southam L, Spector TD, Speliotes EK, Starr JM, Stirrups KE, Stitziel N, Strauch K, Stringham HM, Surendran P, Tada H, Tall AR, Tang H, Tardif JC, Taylor KD, Trompet S, Tsao PS, Tuomilehto J, Tybjaerg-Hansen A, van Zuydam NR, Varbo A, Varga TV, Virtamo J, Waldenberger M, Wang N, Wareham NJ, Warren HR, Weeke PE, Weinstock J, Wessel J, Wilson JG, Wilson PWF, Xu M, Yaghootkar H, Young R, Zeggini E, Zhang H, Zheng NS, Zhang W, Zhang Y, Zhou W, Zhou Y, Zoledziewska M, Howson JMM, Danesh J, McCarthy MI, Cowan CA, Abecasis G, Deloukas P, Musunuru K, Willer CJ, Kathiresan S. Charge Diabetes Working Group. EPIC-InterAct Consortium. EPIC-CVD Consortium. GOLD Consortium. VA Million Veteran Program. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet. 2017; 49:1758–1766. PMID: 29083408.

67. BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Version 2. Hepatology. 2017; 66:1111–1124. PMID: 28520213.

68. Kahali B, Liu YL, Daly AK, Day CP, Anstee QM, Speliotes EK. TM6SF2: catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease? Gastroenterology. 2015; 148:679–684. PMID: 25639710.

69. Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Boren J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxi A, Fargion S, Nobili V, Kakela P, Karja V, Mannisto V, Pihlajamaki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, Romeo S. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016; 150:1219–1230. PMID: 26850495.

70. Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, Petta S, Maier S, Rosso C, De Luca L, Vanni E, Grimaudo S, Romagnoli R, Colli F, Ferri F, Mancina RM, Iruzubieta P, Craxi A, Fracanzani AL, Grieco A, Corradini SG, Aghemo A, Colombo M, Soardo G, Bugianesi E, Reeves H, Anstee QM, Fargion S, Valenti L. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017; 7:4492. PMID: 28674415.

71. Yamashita A, Hayashi Y, Nemoto-Sasaki Y, Ito M, Oka S, Tanikawa T, Waku K, Sugiura T. Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms. Prog Lipid Res. 2014; 53:18–81. PMID: 24125941.

72. D'Souza K, Epand RM. Enrichment of phosphatidylinositols with specific acyl chains. Biochim Biophys Acta. 2014; 1838:1501–1508. PMID: 24120446.

73. Luukkonen PK, Zhou Y, Hyotylainen T, Leivonen M, Arola J, Orho-Melander M, Oresic M, Yki-Jarvinen H. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J Hepatol. 2016; 65:1263–1265. PMID: 27520876.

74. Zarini S, Hankin JA, Murphy RC, Gijon MA. Lysophospholipid acyltransferases and eicosanoid biosynthesis in zebrafish myeloid cells. Prostaglandins Other Lipid Mediat. 2014; 113-115:52–61. PMID: 25175316.

75. Perez-Chacon G, Astudillo AM, Balgoma D, Balboa MA, Balsinde J. Control of free arachidonic acid levels by phospholipases A2 and lysophospholipid acyltransferases. Biochim Biophys Acta. 2009; 1791:1103–1113. PMID: 19715771.

76. Danford CJ, Yao ZM, Jiang ZG. Non-alcoholic fatty liver disease: a narrative review of genetics. J Biomed Res. 2018; 32:389–400. PMID: 30355853.

77. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018; 378:1096–1106. PMID: 29562163.

78. Ma Y, Belyaeva OV, Brown PM, Fujita K, Valles K, Karki S, de Boer YS, Koh C, Chen Y, Du X, Handelman SK, Chen V, Speliotes EK, Nestlerode C, Thomas E, Kleiner DE, Zmuda JM, Sanyal AJ, Kedishvili NY, Liang TJ, Rotman Y. for the Nonalcoholic Steatohepatitis Clinical Research Network. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology. 2019; 69:1504–1519. PMID: 30415504.

79. Sliz E, Sebert S, Wurtz P, Kangas AJ, Soininen P, Lehtimaki T, Kahonen M, Viikari J, Mannikko M, Ala-Korpela M, Raitakari OT, Kettunen J. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum Mol Genet. 2018; 27:2214–2223. PMID: 29648650.

80. Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet. 2017; 49:842–847. PMID: 28436986.

81. Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Chalasani NP, Anstee QM, Kowdley KV, George J, Goodman ZD, Lindor K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2018; 68:361–371. PMID: 29222911.

82. Kim KS, Lee BW, Kim YJ, Lee DH, Cha BS, Park CY. Nonalcoholic fatty liver disease and diabetes: part II. Treatment. Diabetes Metab J. 2019; 43:127–143. PMID: 30993937.

83. Lazo M, Solga SF, Horska A, Bonekamp S, Diehl AM, Brancati FL, Wagenknecht LE, Pi-Sunyer FX, Kahn SE, Clark JM. 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. 2010; 33:2156–2163. PMID: 20664019.

84. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, Thomas AJ, Leslie DB, Chong K, Jeffery RW, Ahmed L, Vella A, Chuang LM, Bessler M, Sarr MG, Swain JM, Laqua P, Jensen MD, Bantle JP. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013; 309:2240–2249. PMID: 23736733.

85. 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. PMID: 15734833.

86. 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. PMID: 21723839.

87. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008; 6:1396–1402. PMID: 18986848.

88. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomized trials. Diabetologia. 2012; 55:885–904. PMID: 22278337.

89. Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017; 67:829–846. PMID: 28545937.

90. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015; 313:2263–2273. PMID: 26057287.

91. Kim MK, Ko SH, Kim BY, Kang ES, Noh J, Kim SK, Park SO, Hur KY, Chon S, Moon MK, Kim NH, Kim SY, Rhee SY, Lee KW, Kim JH, Rhee EJ, Chun S, Yu SH, Kim DJ, Kwon HS, Park KS. Committee of Clinical Practice Guidelines, Korean Diabetes Association. 2019 Clinical practice guidelines for type 2 diabetes mellitus in Korea. Diabetes Metab J. 2019; 43:398–406. PMID: 31441247.

92. Ko SH, Hur KY, Rhee SY, Kim NH, Moon MK, Park SO, Lee BW, Kim HJ, Choi KM, Kim JH. Committee of Clinical Practice Guideline of Korean Diabetes Association. Antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus 2017: a position statement of the Korean Diabetes Association. Diabetes Metab J. 2017; 41:337–348. PMID: 29086531.

93. Jang JE, Cho Y, Lee BW, Shin ES, Lee SH. Effectiveness of exercise intervention in reducing body weight and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus in Korea: a systematic review and meta-analysis. Diabetes Metab J. 2019; 43:302–318. PMID: 30604592.

94. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010; 51:121–129. PMID: 19827166.

95. Wong VW, Wong GL, Chan RS, Shu SS, Cheung BH, Li LS, Chim AM, Chan CK, Leung JK, Chu WC, Woo J, Chan HL. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol. 2018; 69:1349–1356. PMID: 30142427.

96. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015; 149:367–378. PMID: 25865049.

97. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009; 136:1552–1560. PMID: 19208352.

98. Haufe S, Engeli S, Kast P, Bohnke J, Utz W, Haas V, Hermsdorf M, Mahler A, Wiesner S, Birkenfeld AL, Sell H, Otto C, Mehling H, Luft FC, Eckel J, Schulz-Menger J, Boschmann M, Jordan J. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011; 53:1504–1514. PMID: 21400557.

99. Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, Kinoshita J, Ooka A, Kumashiro N, Igarashi Y, Kyogoku S, Maehara T, Kawasumi M, Hirose T, Kawamori R. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2005; 90:3191–3196. PMID: 15769987.

100. Keating SE, Hackett DA, Parker HM, O'Connor HT, Gerofi JA, Sainsbury A, Baker MK, Chuter VH, Caterson ID, George J, Johnson NA. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol. 2015; 63:174–182. PMID: 25863524.

101. Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, George J. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009; 50:1105–1112. PMID: 19637289.

102. 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. PMID: 22414768.

103. Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, Zanolin E, Schena F, Bonora E, Moghetti P. 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. PMID: 23504926.

104. Wu T, Gao X, Chen M, van Dam RM. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes Rev. 2009; 10:313–323. PMID: 19175510.

105. Maruthur NM, Wang NY, Appel LJ. Lifestyle interventions reduce coronary heart disease risk: results from the PREMIER trial. Circulation. 2009; 119:2026–2031. PMID: 19349322.

106. 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. PMID: 20578268.

107. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. 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; 305:1659–1668. PMID: 21521847.

108. Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Masaki T. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol. 2016; 22:6100–6113. PMID: 27468203.

109. Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018; 16:558–566. PMID: 29223443.

110. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017; 177:633–640. PMID: 28241279.

111. Lee YH, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM, Lee BW. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy and predictive factors related to responsiveness. J Korean Med Sci. 2017; 32:60–69. PMID: 27914133.

112. Ranjbar G, Mikhailidis DP, Sahebkar A. Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: think out of the box! Metabolism. 2019; 101:154001. PMID: 31672448.

113. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial). Diabetes Care. 2018; 41:1801–1808. PMID: 29895557.

114. Cusi K, Bril F, Barb D, Polidori D, Sha S, Ghosh A, Farrell K, Sunny NE, Kalavalapalli S, Pettus J, Ciaraldi TP, Mudaliar S, Henry RR. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019; 21:812–821. PMID: 30447037.

115. Itani T, Ishihara T. Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study. Obes Sci Pract. 2018; 4:477–482. PMID: 30338118.

116. Seko Y, Nishikawa T, Umemura A, Yamaguchi K, Moriguchi M, Yasui K, Kimura M, Iijima H, Hashimoto T, Sumida Y, Okanoue T, Itoh Y. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1-3 fibrosis. Diabetes Metab Syndr Obes. 2018; 11:835–843. PMID: 30568471.

117. Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, Iijima M, Takekawa H, Usui I, Hiraishi H, Aso Y. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019; 21:285–292. PMID: 30178600.

118. Akuta N, Kawamura Y, Watanabe C, Nishimura A, Okubo M, Mori Y, Fujiyama S, Sezaki H, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Ikeda K, Kumada H. Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus. Hepatol Res. 2019; 49:531–539. PMID: 30577089.

119. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes. 2020. Diabetes Care. 2020; 43(Suppl 1):S98–S110. PMID: 31862752.

120. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hubscher SG, Newsome PN. LEAN trial team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016; 387:679–690. PMID: 26608256.

121. Macauley M, Hollingsworth KG, Smith FE, Thelwall PE, Al-Mrabeh A, Schweizer A, Foley JE, Taylor R. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015; 100:1578–1585. PMID: 25664602.

122. Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C, Duman DG. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg. 2012; 75:240–244. PMID: 22870790.

123. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, Richards L, Salotti J, Bhatt A, Hooker J, Haufe W, Hooker C, Brenner DA, Sirlin CB, Loomba R. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016; 65:369–376. PMID: 27151177.

124. Kato H, Nagai Y, Ohta A, Tenjin A, Nakamura Y, Tsukiyama H, Sasaki Y, Fukuda H, Ohshige T, Terashima Y, Sada Y, Kondo A, Sasaoka T, Tanaka Y. Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes. Diabetes Res Clin Pract. 2015; 109:199–205. PMID: 25934525.

125. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362:1675–1685. PMID: 20427778.

126. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, Soaft L, Hooker J, Kono Y, Bhatt A, Hernandez L, Nguyen P, Noureddin M, Haufe W, Hooker C, Yin M, Ehman R, Lin GY, Valasek MA, Brenner DA, Richards L. San Diego Integrated NAFLD Research Consortium (SINC). 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. PMID: 25482832.

127. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996; 23:1464–1467. PMID: 8675165.

128. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A. Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006; 4:1537–1543. PMID: 17162245.

129. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004; 39:770–778. PMID: 14999696.

130. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, Zeuzem S, Hein J, Berg T. NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010; 52:472–479. PMID: 20683947.

131. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011; 54:1610–1619. PMID: 21748765.

132. Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011; 10:277–286. PMID: 21677329.

133. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E. 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; 385:956–965. PMID: 25468160.

134. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li Volti G, Galvano F. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis. A randomized and controlled clinical trial. Am J Gastroenterol. 2010; 105:1338–1345. PMID: 20068559.

135. Bae JC, Lee WY, Yoon KH, Park JY, Son HS, Han KA, Lee KW, Woo JT, Ju YC, Lee WJ, Cho YY, Lee MK. Improvement of nonalcoholic fatty liver disease with carnitine-orotate complex in type 2 diabetes (CORONA): a randomized controlled trial. Diabetes Care. 2015; 38:1245–1252. PMID: 25877813.

136. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A. GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016; 150:1147–1159. PMID: 26874076.

137. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, Francque S, Farrell G, Kowdley KV, Craxi A, Simon K, Fischer L, Melchor-Khan L, Vest J, Wiens BL, Vig P, Seyedkazemi S, Goodman Z, Wong VW, Loomba R, Tacke F, Sanyal A, Lefebvre E. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018; 67:1754–1767. PMID: 28833331.

138. Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006; 4:639–644. PMID: 16630771.

139. 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. PMID: 19053049.

140. Bower G, Toma T, Harling L, Jiao LR, Efthimiou E, Darzi A, Athanasiou T, Ashrafian H. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg. 2015; 25:2280–2289. PMID: 25917981.

141. Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, Anvari M, Hong D. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019; 17:1040–1060. PMID: 30326299.

142. Jan A, Narwaria M, Mahawar KK. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg. 2015; 25:1518–1526. PMID: 25982807.

143. Seo MH, Lee WY, Kim SS, Kang JH, Kang JH, Kim KK, Kim BY, Kim YH, Kim WJ, Kim EM, Kim HS, Shin YA, Shin HJ, Lee KR, Lee KY, Lee SY, Lee SK, Lee JH, Lee CB, Chung S, Cho YH, Choi KM, Han JS, Yoo SJ. Committee of Clinical Practice Guidelines, Korean Society for the Study of Obesity (KSSO). 2018 Korean Society for the Study of Obesity Guideline for the management of obesity in Korea. J Obes Metab Syndr. 2019; 28:40–45. PMID: 31089578.