Current and future pharmacological therapies for NAFLD/NASH

Journal of Gastroenterology

Volumn 53, Issue 3, 2018, Pages 362-376

  Sumida, Yoshio ^a   Yoneda, Masashi ^a  

^a AICHI MEDICAL UNIVERSITY   (Japan)

Author keywords

Diabetes; GLP 1 receptor agonist; Hepatic fibrosis; NASH; SGLT2 inhibitor

Indexed keywords

ANTIDIABETIC AGENT; ANTIFIBROTIC AGENT; ANTIHYPERTENSIVE AGENT; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; APOPTOSIS INHIBITOR; FARNESOID X RECEPTOR; LIVER PROTECTIVE AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST;

ALL CAUSE MORTALITY; APOPTOSIS; BODY WEIGHT LOSS; DIETARY INTAKE; DRUG MECHANISM; DRUG REPOSITIONING; DYSLIPIDEMIA; ENDOTOXEMIA; EUROPE; EVIDENCE BASED PRACTICE; HUMAN; INFLAMMATION; INTESTINE FLORA; JAPAN; LIFESTYLE MODIFICATION; LIPID STORAGE; LIPOGENESIS; LIVER FIBROSIS; MICROBIOME; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PHARMACEUTICAL CARE; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; UNITED STATES; DRUG DEVELOPMENT; GLOBAL HEALTH; HEALTH CARE PLANNING; MOLECULARLY TARGETED THERAPY; PREVALENCE; TREATMENT OUTCOME;

DRUG DEVELOPMENT; GLOBAL HEALTH; HEALTH PLANNING GUIDELINES; HUMANS; MOLECULAR TARGETED THERAPY; NON-ALCOHOLIC FATTY LIVER DISEASE; PRACTICE GUIDELINES AS TOPIC; PREVALENCE; TREATMENT OUTCOME;

EID: 85038094859     PISSN: 09441174     EISSN: 14355922     Source Type: Journal    
DOI: 10.1007/s00535-017-1415-1     Document Type: Review

References (107)

1. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
2. Eguchi Y, Hyogo H, Ono M, et al; JSG-NAFLD. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2009;2012(47):586–95.
3. Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152:1090–9.
4. Nakamura J, Kamiya H, Haneda M, et al. Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001–2010: report of the committee on causes of death in diabetes mellitus. J Diabetes Invest. 2017;8:397–410.
5. Chalasani N, Younossi Z, Lavine JE, 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. 2012;142:1592–609.
6. Watanabe S, Hashimoto E, Ikejima K, Japanese Society of Gastroenterology, Japan Society of Hepatology. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol. 2015;50:364–77.
7. 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. J Hepatol. 2016;64:1388–402.
8. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology (In press).
9. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–65.
10. Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res. 2013;47:869–80.
11. Sumida Y, Nakashima T, Yoh T, et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol. 2003;38:32–8.
12. Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15:1667–72.
13. Yoneda M, Hasegawa T, Sato K. Vitamin E therapy for NAFLD/NASH. Nutrition. 2015;31:898–9.
14. 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.
15. Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31:923–30.
16. Sumida Y, Naito Y, Tanaka S, et al. Long-term (≥ 2 year) efficacy of vitamin E for non-alcoholic steatohepatitis. Hepatogastroenterology. 2013;60:1445–50.
17. Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016;13:196–205.
18. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.
19. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the selenium and vitamin E cancer prevention trial (SELECT). JAMA. 2009;301:39–51.
20. Schürks M, Glynn RJ, Rist PM, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;4(341):c5702.
21. Honda Y, Kessoku T, Sumida Y, et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017;17:96
22. Mitsuyoshi H, Nakashima T, Sumida Y, et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun. 1999;263:537–42.
23. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–8.
24. 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.
25. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.
26. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165:305–15.
27. DePaoli AM, Higgins LS, Henry RR, et al; INT131-007 Study Group. Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care. 2014;37:1918–23.
28. Saibara T, Onishi S, Ogawa Y, et al. Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis. Lancet. 1999;353:1802.
29. Shetty SR, Kumar S, Mathur RP, et al. Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients. Indian Heart J. 2015;67:23–6.
30. Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58:1941–52.
31. Ratziu V, Harrison SA, Francque S, et al; 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;150:1147–59.
32. Ruzehaji N, Frantz C, Ponsoye M, et al. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. 2016;75:2175–83.
33. Avouac J, Konstantinova I, Guignabert C, et al. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann Rheum Dis. 2017;76:1931–40
34. Sumida Y, Seko Y, Yoneda M; Japan Study Group of NAFLD (JSG-NAFLD). Novel antidiabetic medications for nonalcoholic fatty liver disease with type 2 diabetes. Hepatol Res. 2017;47:266–80
35. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–90.
36. Eguchi Y, Kitajima Y, Hyogo H, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. 2015;45:269–78.
37. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
38. Katsiki N, Athyros VG, Karagiannis A, et al. Semaglutide, lipid-lowering drugs, and NAFLD. Lancet Diabetes Endocrinol. 2017;5:329–30.
39. Seko Y, Sumida Y, Sasaki K, et al. Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials. J Gastroenterol (In press).
40. Leiter LA, Forst T, Polidori D, et al. Effect of canagliflozin on liver function tests in patients with type 2 diabetes. Diabetes Metab. 2016;42(1):25–32.
41. Seino Y, Sasaki T, Fukatsu A, et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin. 2014;30:1245–55.
42. Shima T, Uto H, Ueki K, et al. Clinicopathological features of liver injury in patients with type 2 diabetes mellitus and comparative study of histologically proven nonalcoholic fatty liver diseases with or without type 2 diabetes mellitus. J Gastroenterol. 2013;48:515–25.
43. Seko Y, Sumida Y, Tanaka S, et al. Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017;47:1072–8.
44. Komiya C, Tsuchiya K, Shiba K, et al. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS ONE. 2016;11:e0151511.
45. Takase T, Nakamura A, Miyoshi H, Yamamoto C, Atsumi T. Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects. Endocr J. 2017;64:363–7
46. Takeda A, Irahara A, Nakano A, et al. The improvement of the hepatic histological findings in a patient with non-alcoholic steatohepatitis with type 2 diabetes after the administration of the sodium–glucose cotransporter 2 inhibitor ipragliflozin. Intern Med. 2017;56:2739–44
47. Akuta N, Watanabe C, Kawamura Y, et al. Effects of a sodium–glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: preliminary prospective study based on serial liver biopsies. Hepatol Commun. 2017;1:46–52.
48. Shibuya T, Fushimi N, Kawai M, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab (In press).
49. Ito D, Shimizu S, Inoue K, et al. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care. 2017;40:1364–72
50. Yoneda M, Fujita K, Nozaki Y, et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study. Hepatol Res. 2010;40:566–73.
51. Park H, Shima T, Yamaguchi K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:101–7.
52. Loomba R, Sirlin CB, Ang B, et al; 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;61:1239–50.
53. Nakade Y, Murotani K, Inoue T, et al. Ezetimibe for the treatment of non-alcoholic fatty liver disease: a meta-analysis. Hepatol Res (In press).
54. Sanyal AJ, Abdelmalek MF, Suzuki A, et al; 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.
55. Scorletti E, Bhatia L, McCormick KG, et al; WELCOME Study. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology. 2014;60:1211–21.
56. Singh S, Singh PP, Singh AG, et al. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144:323–32.
57. Ishibashi S, Yamashita S, Arai H, et al; K-877-04 Study Group. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36–43.
58. Honda Y, Kessoku T, Ogawa Y, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017;7:42477
59. Gilat T, Leikin-Frenkel A, Goldiner L, et al. Arachidyl amido cholanoic acid (Aramchol) is a cholesterol solubilizer and prevents the formation of cholesterol gallstones in inbred mice. Lipids. 2001;36:1135–40.
60. Safadi R, Konikoff FM, Mahamid M, et al; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085–91.
61. Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest. 2012;122:1958–9.
62. 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.
63. Georgescu EF, Ionescu R, Niculescu M, et al. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15:942–54.
64. McPherson S, Wilkinson N, Tiniakos D, et al. A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis. PLoS ONE. 2017;12(4):e0175717.
65. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al; NASH Clinical Research Network. Farnesoid × nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65.
66. McMahan RH, Wang XX, Cheng LL, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem. 2013;288:11761–70.
67. Vatner DF, Weismann D, Beddow SA, et al. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab. 2013;305:E89–100. Lipids. 2001;36:1135–40.
68. Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54:1610–9.
69. Du J, Ma YY, Yu CH, et al. Effects of pentoxifylline on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2014;20:569–77.
70. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–94.
71. Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology (In press).
72. Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of nonalcoholic steatohepatitis. Liver Int. 2015;35:953–66.
73. Weston CJ, Shepherd EL, Claridge LC, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest. 2015;125:501–20.
74. Mizrahi M, Shabat Y, Ben Ya’acov A, et al. Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH. J Inflamm Res. 2012;5:141–50.
75. Rivera CA, Adegboyega P, van Rooijen N, et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47:571–9.
76. Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265–73
77. Di Prospero NA, Artis E, Andrade-Gordon P, et al. CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Diabetes Obes Metab. 2014;16:1055–64.
78. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147(3):577–94.
79. Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology (In press).
80. Moon HJ, Finney J, Ronnebaum T, et al. Human lysyl oxidase-like 2. Bioorg Chem. 2014;57:231–41.
81. Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009;230:160–71.
82. Harrison SA, Marri SR, Chalasani N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. 2016;44:1183.
83. Itoh N, Nakayama Y, Konishi M. Roles of FGFs as paracrine or endocrine signals in liver development, health, and disease. Front Cell Dev Biol. 2016;4:30.
84. Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333–40.
85. Leeming D, et al. Estimation of serum “true collagen type III formation” (Pro-C3) levels as a marker of non-alcoholic steatohepatitis in a prospective cohort. J Hepatol. 2017;66(Suppl1):S154.
86. Reilly SM, Chiang SH, Decker SJ, et al. An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nat Med. 2013;19:313–21.
87. Costabel U, Albera C, Lancaster LH, Lin CY, Hormel P, Hulter HN, Noble PW. An open-label study of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis (RECAP). Respiration. 2017;94:408–15
88. Komiya C, Tanaka M, Tsuchiya K, et al. Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis. Sci Rep. 2017;7:44754.
89. Hoofnagle JH, Van Natta ML, Kleiner DE, et al; Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN). Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013;38:134–43.
90. Seko Y, Sumida Y, Tanaka S, et al. Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients. Hepatol Res. 2015;45:E53–61.
91. Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology. 2016;63:1875–87.
92. Hamaguchi E, Takamura T, Sakurai M, et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care. 2010;33:284–6.
93. Shah AG, Lydecker A, Murray K, et al; Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1104–12.
94. Sumida Y, Yoneda M, Hyogo H, et al; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.
95. Xiao G, Zhu S, Xiao X, et al. Comparison of laboratory tests, ultrasound, or MRE to detect fibrosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Hepatology. 2017;66:1486–501
96. Yoneda M, Yoneda M, Mawatari H, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis. 2008;40:371–8.
97. Seki K, Shima T, Oya H, et al. Assessment of transient elastography in Japanese patients with non-alcoholic fatty liver disease. Hepatol Res. 2017;47:882–9.
98. Okajima A, Sumida Y, Taketani H, et al. Liver stiffness measurement to platelet ratio index predicts the stage of liver fibrosis in non-alcoholic fatty liver disease. Hepatol Res. 2017;47:721–30.
99. Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150:626–37.
100. Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65:1359–68.
101. Roulot D, Roudot-Thoraval F, NKontchou G, Kouacou N, Costes JL, Elourimi G, Le Clesiau H, Ziol M, Beaugrand M. Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan. Liver Int. 2017;37:1897–906
102. Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology. 2016;63:138–47.
103. Doycheva I, Cui J, Nguyen P, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther. 2016;43:83–95.
104. Nakahara T, Hyogo H, Yoneda M, et al; Japan Study Group of Nonalcoholic Fatty Liver Disease. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49:1477–84.
105. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49:608–12.
106. Oza N, Eguchi Y, Mizuta T, et al. A pilot trial of body weight reduction for nonalcoholic fatty liver disease with a home-based lifestyle modification intervention delivered in collaboration with interdisciplinary medical staff. J Gastroenterol. 2009;44:1203–8.
107. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–86.