Perspective | Published:


Past, present and future perspectives in nonalcoholic fatty liver disease


Nonalcoholic fatty liver disease (NAFLD) was first described as a distinct clinical entity four decades ago. However, the condition has become the centre of attention within hepatology owing to its high prevalence and growing contribution to the burden of end-stage liver disease in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD with a focus on landmark findings that have influenced current paradigms and key knowledge gaps that need to be filled to make progress. Specifically, a timeline of scientific discovery of both basic disease mechanisms (with a focus on human data) and the evolution of knowledge about the clinical course of the disease is provided and related to current approaches to treat and eventually prevent NAFLD.

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  1. 1.

    Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

  2. 2.

    Estes, C., Razavi, H., Loomba, R., Younossi, Z. & Sanyal, A. J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018).

  3. 3.

    Younossi, Z. M. et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64, 1577–1586 (2016).

  4. 4.

    Farrell, G. C., Wong, V. W. & Chitturi, S. NAFLD in Asia—as common and important as in the West. Nat. Rev. Gastroenterol. Hepatol. 10, 307–318 (2013).

  5. 5.

    Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol. 69, 896–904 (2018).

  6. 6.

    Thaler, H. The fatty liver and its pathogenetic relation to liver cirrhosis [German]. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 335, 180–210 (1962).

  7. 7.

    Thaler, H. Editorial: fatty liver-steatonecrosis-cirrhosis. Acta Hepatogastroenterol. (Stuttg.) 22, 271–273 (1975).

  8. 8.

    Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980).

  9. 9.

    Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).

  10. 10.

    Powell, E. E. et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 11, 74–80 (1990).

  11. 11.

    Crawford, D. H., Powell, E. E., Searle, J. & Powell, L. W. Steatohepatitis: comparison of alcoholic and non-alcoholic subjects with particular reference to portal hypertension and hepatic complications. J. Gastroenterol. Hepatol. 4 (Suppl. 1), 36–38 (1989).

  12. 12.

    Powell, E. E., Searle, J. & Mortimer, R. Steatohepatitis associated with limb lipodystrophy. Gastroenterology 97, 1022–1024 (1989).

  13. 13.

    Maheshwari, A. & Thuluvath, P. J. Cryptogenic cirrhosis and NAFLD: are they related? Am. J. Gastroenterol. 101, 664–668 (2006).

  14. 14.

    Chitturi, S. et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36, 403–409 (2002).

  15. 15.

    Yang, S. Q., Lin, H. Z., Lane, M. D., Clemens, M. & Diehl, A. M. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc. Natl Acad. Sci. USA 94, 2557–2562 (1997).

  16. 16.

    Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).

  17. 17.

    McPherson, S. et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol. 62, 1148–1155 (2015).

  18. 18.

    Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

  19. 19.

    Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).

  20. 20.

    Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–455 (1999).

  21. 21.

    Pagano, G. et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 35, 367–372 (2002).

  22. 22.

    Caldwell, S. H. et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J. Hepatol. 31, 430–434 (1999).

  23. 23.

    Leclercq, I. A. et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J. Clin. Invest. 105, 1067–1075 (2000).

  24. 24.

    Valenti, L. et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 138, 905–912 (2010).

  25. 25.

    Feldstein, A. E. et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437–443 (2003).

  26. 26.

    Puri, P. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134, 568–576 (2008).

  27. 27.

    Henkel, A. & Green, R. M. The unfolded protein response in fatty liver disease. Semin. Liver Dis. 33, 321–329 (2013).

  28. 28.

    Hirsova, P., Ibrahim, S. H., Gores, G. J. & Malhi, H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J. Lipid Res. 57, 1758–1770 (2016).

  29. 29.

    Puri, P. et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46, 1081–1090 (2007).

  30. 30.

    Araya, J. et al. Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring) 18, 1460–1463 (2009).

  31. 31.

    Min, H. K. et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 15, 665–674 (2012).

  32. 32.

    Lima-Cabello, E. et al. Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin. Sci. 120, 239–250 (2011).

  33. 33.

    Puri, P. et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology 67, 534–548 (2017).

  34. 34.

    Brenner, D. A. et al. Non-alcoholic steatohepatitis-induced fibrosis: Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. Hepatol. Res. 41, 683–686 (2011).

  35. 35.

    Roh, Y. S. & Seki, E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J. Gastroenterol. Hepatol. 28 (Suppl. 1), 38–42 (2013).

  36. 36.

    Miura, K. et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577–589 (2013).

  37. 37.

    Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

  38. 38.

    Miura, K., Seki, E., Ohnishi, H. & Brenner, D. A. Role of toll-like receptors and their downstream molecules in the development of nonalcoholic fatty liver disease. Gastroenterol. Res. Pract. 2010, 362847 (2010).

  39. 39.

    Mridha, A. R. et al. TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival. Clin. Sci. 131, 2145–2159 (2017).

  40. 40.

    Kisseleva, T. et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J. Hepatol. 45, 429–438 (2006).

  41. 41.

    Miura, K., Yang, L., van Rooijen, N., Ohnishi, H. & Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310–G1321 (2012).

  42. 42.

    Itoh, M. et al. CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis. JCI Insight 2, 92902 (2017).

  43. 43.

    Brunt, E. M. et al. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 49, 809–820 (2009).

  44. 44.

    Cazanave, S. et al. The transcriptomic signature of disease development and progression of nonalcoholic fatty liver disease. Sci. Rep. 7, 17193 (2017).

  45. 45.

    Feaver, R. E. et al. Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight 1, e90954 (2016).

  46. 46.

    Syn, W. K. et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 137, 1478–1488 (2009).

  47. 47.

    Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).

  48. 48.

    Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

  49. 49.

    Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLOS Genet. 7, e1001324 (2011).

  50. 50.

    Puri, P. et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 50, 1827–1838 (2009).

  51. 51.

    Cheung, O. et al. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 48, 1810–1820 (2008).

  52. 52.

    Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

  53. 53.

    He, S. et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 285, 6706–6715 (2010).

  54. 54.

    BasuRay, S., Smagris, E., Cohen, J. C. & Hobbs, H. H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111–1124 (2017).

  55. 55.

    Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).

  56. 56.

    Smagris, E., Gilyard, S., BasuRay, S., Cohen, J. C. & Hobbs, H. H. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J. Biol. Chem. 291, 10659–10676 (2016).

  57. 57.

    Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).

  58. 58.

    Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007).

  59. 59.

    Loomba, R. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–1062 (2017).

  60. 60.

    Puri, P. & Sanyal, A. J. The intestinal microbiome in nonalcoholic fatty liver disease. Clin. Liver Dis. 22, 121–132 (2018).

  61. 61.

    Santhekadur, P. K., Kumar, D. P. & Sanyal, A. J. Preclinical models of nonalcoholic fatty liver disease. J. Hepatol. 68, 230–237 (2017).

  62. 62.

    Horie, Y., Ohshima, S., Sato, W., Suzuki, A. & Watanabe, S. Hepatocyte-specific Pten deficient mice [Japanese]. Nippon Rinsho 64, 1033–1042 (2006).

  63. 63.

    Rinella, M. E. & Green, R. M. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J. Hepatol. 40, 47–51 (2004).

  64. 64.

    Saito, K. et al. Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis. Sci. Rep. 5, 12466 (2015).

  65. 65.

    Hill-Baskin, A. E. et al. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum. Mol. Genet. 18, 2975–2988 (2009).

  66. 66.

    Tsuchida, T. et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J. Hepatol. 69, 385–395 (2018).

  67. 67.

    Asgharpour, A. et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J. Hepatol. 65, 579–588 (2016).

  68. 68.

    Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).

  69. 69.

    Welsh, J. A., Karpen, S. & Vos, M. B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 162, 496–500 (2013).

  70. 70.

    India State-Level Disease Burden Initiative Diabetes Collaborators. The increasing burden of diabetes and variations among the states of India: the Global Burden of Disease Study 1990–2016. Lancet Glob. Health 6, e1352–e1362 (2018).

  71. 71.

    Williams, C. D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124–131 (2011).

  72. 72.

    Noureddin, M. et al. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology 58, 1644–1654 (2013).

  73. 73.

    Schwimmer, J. B. et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42, 641–649 (2005).

  74. 74.

    Carter-Kent, C. et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 50, 1113–1120 (2009).

  75. 75.

    Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A. & Bacon, B. R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 94, 2467–2474 (1999).

  76. 76.

    Everhart, J. E. et al. Prognostic value of Ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 51, 585–594 (2010).

  77. 77.

    Goodman, Z. D. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J. Hepatol. 47, 598–607 (2007).

  78. 78.

    Bedossa, P. & the FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 60, 565–575 (2014).

  79. 79.

    Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).

  80. 80.

    Ekstedt, M., Franzen, L. E., Mathiesen, U. L. & Kechagias, S. Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression. Scand. J. Gastroenterol. 47, 108–115 (2012).

  81. 81.

    Hagstrom, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).

  82. 82.

    Dongiovanni, P. et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J. Intern. Med. 283, 356–370 (2018).

  83. 83.

    Brunt, E. M. et al. Improvements in histologic features and diagnosis associated with improvement in fibrosis in NASH: results from the NASH Clinical Research Network Treatment Trials. Hepatology (2018).

  84. 84.

    Sanyal, A. J. et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 61, 1392–1405 (2015).

  85. 85.

    Argo, C. K., Northup, P. G., Al-Osaimi, A. M. & Caldwell, S. H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J. Hepatol. 51, 371–379 (2009).

  86. 86.

    Ratziu, V. Back to Byzance: Querelles byzantines over NASH and fibrosis. J. Hepatol. 67, 1134–1136 (2017).

  87. 87.

    Harrison, S. A. et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 155, 1140–1153 (2018).

  88. 88.

    Matteoni, C. A. et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413–1419 (1999).

  89. 89.

    Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865–873 (2006).

  90. 90.

    Singh, S. et al. Fibrosis progression in nonalcoholic fatty liver versus nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin. Gastroenterol. Hepatol. 13, 643–654 (2015).

  91. 91.

    Yano, M. et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 23, 1334–1340 (1996).

  92. 92.

    Sanyal, A., Poklepovic, A., Moyneur, E. & Barghout, V. Population-based risk factors and resource utilization for HCC: US perspective. Curr. Med. Res. Opin. 26, 2183–2191 (2010).

  93. 93.

    White, D. L., Kanwal, F. & El-Serag, H. B. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin. Gastroenterol. Hepatol. 10, 1342–1359 (2012).

  94. 94.

    Wong, R. J., Cheung, R. & Ahmed, A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 59, 2188–2195 (2014).

  95. 95.

    Steele, C. B. et al. Vital signs: trends in incidence of cancers associated with overweight and obesity - United States, 2005–2014. MMWR Morb. Mortal. Wkly Rep. 66, 1052–1058 (2017).

  96. 96.

    Sanyal, A. J. et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 43, 682–689 (2006).

  97. 97.

    Sanyal, A. J. A. et al. Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J. Hepatol. 66, S54 (2017).

  98. 98.

    Nagula, S., Jain, D., Groszmann, R. J. & Garcia-Tsao, G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J. Hepatol. 44, 111–117 (2006).

  99. 99.

    Idilman, I. S. et al. Hepatic steatosis: quantification by proton density fat fraction with MR imaging versus liver biopsy. Radiology 267, 767–775 (2013).

  100. 100.

    Siddiqui, M. S. et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 17, 156–163 (2018).

  101. 101.

    Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2017).

  102. 102.

    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. 64, 1388–1402 (2016).

  103. 103.

    Rinella, M. E. & Sanyal, A. J. Management of NAFLD: a stage-based approach. Nat. Rev. Gastroenterol. Hepatol. 13, 196–205 (2016).

  104. 104.

    Rockey, D. C. et al. Liver biopsy. Hepatology 49, 1017–1044 (2009).

  105. 105.

    Yatsuji, S. et al. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J. Gastroenterol. Hepatol. 24, 248–254 (2009).

  106. 106.

    Castera, L., Vilgrain, V. & Angulo, P. Noninvasive evaluation of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 666–675 (2013).

  107. 107.

    Shah, A. G. et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7, 1104–1112 (2009).

  108. 108.

    Angulo, P. et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 145, 782–789 (2013).

  109. 109.

    Dulai, P. S. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65, 1557–1565 (2017).

  110. 110.

    Vuppalanchi, R. et al. Performance characteristics of vibration-controlled transient elastography for evaluation of non-alcoholic fatty liver disease. Hepatology 67, 134–144 (2017).

  111. 111.

    Park, C. C. et al. Magnetic resonance elastography versus transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology 152, 598–607 (2017).

  112. 112.

    Sanyal, A. J. et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 2, 1107–1115 (2004).

  113. 113.

    Lavine, J. E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J. Pediatr. 136, 734–738 (2000).

  114. 114.

    Ratziu, V. et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51, 445–453 (2010).

  115. 115.

    Lavine, J. E. et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305, 1659–1668 (2011).

  116. 116.

    Cusi, K. Pioglitazone for the treatment of NASH in patients with prediabetes or type 2 diabetes mellitus. Gut 67, 1371 (2017).

  117. 117.

    Sanyal, A. J. et al. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 147, 377–384 (2014).

  118. 118.

    Argo, C. K. et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J. Hepatol. 62, 190–197 (2015).

  119. 119.

    Dasarathy, S. et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 49, 137–144 (2015).

  120. 120.

    Wei, J., Qiu de, K. & Ma, X. Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease. J. Dig. Dis. 10, 85–90 (2009).

  121. 121.

    Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582 (2013).

  122. 122.

    Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

  123. 123.

    US National Library of Medicine. (2019).

  124. 124.

    Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).

  125. 125.

    US National Library of Medicine. (2019).

  126. 126.

    Mathurin, P. et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 137, 532–540 (2009).

  127. 127.

    Friedman, S. et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR phase 2b study design. Contemp. Clin. Trials 47, 356–365 (2016).

  128. 128.

    Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

  129. 129.

    Africa, J. A. et al. In children with nonalcoholic fatty liver disease, zone 1 steatosis is associated with advanced fibrosis. Clin. Gastroenterol. Hepatol. 16, 438–446 (2018).

  130. 130.

    Patel, Y. A. et al. Baseline parameters in clinical trials for nonalcoholic steatohepatitis: recommendations from the Liver Forum. Gastroenterology 153, 621–625 (2017).

  131. 131.

    Siddiqui, M. S. et al. Case definitions for inclusion and analysis of endpoints in clinical trials for NASH through the lens of regulatory science. Hepatology 67, 2001–2012 (2017).

  132. 132.

    Woodcock, J. & LaVange, L. M. Master protocols to study multiple therapies, multiple diseases, or both. N. Engl. J. Med. 377, 62–70 (2017).

  133. 133.

    Vilar-Gomez, E. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 367–378 (2015).

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The author acknowledges funding from NIH project RO1 DK 105961.

Competing interests

A.J.S. is President of Sanyal Biotechnology and has stock options in Akarna, Durect, Exhalenz, Genfit, Haemoshear, Indalo and Tiziana. He has served as a consultant to AbbVie, Amarin, Ardelyx, Astra Zeneca, Boehringer, Conatus, Fibrogen, Genfit, Gilead, Jannsen, Lilly, Nimbus, Nitto Denko, Novartis, Pfizer, Salix, Takeda, Tobira and Zafgen. He has been an unpaid consultant to Affimune, Bristol Myers Squibb, Chemomab, Echosens, Fractyl, Galectin, Immuron, Intercept, Nordic Bioscience, Novartis, Novo Nordisk and Syntlogic. His institution has received grant support from Astra Zeneca, Bristol Myers Squibb, Cumberland, Gilead, Intercept, Malinckrodt, Merck, Salix, Shire and Tobira. He receives royalties from Elsevier and UptoDate. Virginia Commonwealth University also has ownership interests in Sanyal Biotechnology.

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Correspondence to Arun J. Sanyal.

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Fig. 1: A timeline of key developments in nonalcoholic steatohepatitis.
Fig. 2: A model of disease development for nonalcoholic steatohepatitis.
Fig. 3: Current therapeutic targets for nonalcoholic steatohepatitis.