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Nonalcoholic fatty liver disease

Nature Reviews Disease Primers volume 1, Article number: 15080 (2015) Cite this article

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10–40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.

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Figure 1: Histological features of NAFLD.
Figure 2: Factors associated with NAFLD development and progression.
Figure 3: Mechanisms of steatosis and liver injury in NASH.
Figure 4: Overview of factors involved in the modulation of cellular epigenome.
Figure 5: Diagnosis of liver fibrosis and NASH.
Figure 6: The lipotoxicity model of NASH and targets for therapy.

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References

  1. Yki-Järvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2, 901–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Brunt, E. M. Non-alcoholic fatty liver disease: what's new under the microscope? Gut 60, 1152–1158 (2011). This article provides a detailed description of the histological lesions of NAFLD and NASH and their correlations with pathophysiology and the clinical features of disease.

    Article  PubMed  Google Scholar 

  3. Torres, D. M. & Harrison, S. A. Nonalcoholic fatty liver disease: fibrosis portends a worse prognosis. Hepatology 61, 1462–1464 (2015).

    Article  PubMed  Google Scholar 

  4. Adams, L. A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113–121 (2005).

    Article  PubMed  Google Scholar 

  5. Ekstedt, M. et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61, 1547–1554 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Baffy, G., Brunt, E. M. & Caldwell, S. H. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J. Hepatol. 56, 1384–1391 (2012).

    Article  PubMed  Google Scholar 

  7. 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).

    Article  PubMed  Google Scholar 

  8. Harmon, R. C., Tiniakos, D. G. & Argo, C. K. Inflammation in nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 5, 189–200 (2011).

    Article  PubMed  Google Scholar 

  9. Rinella, M. E. Nonalcoholic fatty liver disease. JAMA 313, 2263–2273 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Araújo, L. M., De Oliveira, D. A. & Nunes, D. S. Liver and biliary ultrasonography in diabetic and non-diabetic obese women. Diabetes Metab. 24, 458–462 (1998).

    PubMed  Google Scholar 

  11. Bedogni, G. et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 42, 44–52 (2005).

    Article  PubMed  Google Scholar 

  12. 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).

    Article  PubMed  Google Scholar 

  13. Zelber-Sagi, S., Nitzan-Kaluski, D., Halpern, Z. & Oren, R. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int. 26, 856–863 (2006).

    Article  PubMed  Google Scholar 

  14. 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).

    Article  PubMed  Google Scholar 

  15. Targher, G. et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30, 1212–1218 (2007).

    Article  PubMed  Google Scholar 

  16. Wanless, I. R. & Lentz, J. S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12, 1106–1110 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Silverman, J. F. et al. Liver pathology in morbidly obese patients with and without diabetes. Am. J. Gastroenterol. 85, 1349–1355 (1990).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Dixon, J. B., Bhathal, P. S. & O'Brien, P. E. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121, 91–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Hyysalo, J. et al. A population-based study on the prevalence of NASH using scores validated against liver histology. J. Hepatol. 60, 839–846 (2014).

    Article  PubMed  Google Scholar 

  21. Ascha, M. S. et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51, 1972–1978 (2010).

    Article  PubMed  Google Scholar 

  22. Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015). Data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry indicate that NASH is the most rapidly growing indication for liver transplantation in the United States in the past 10 years.

    Article  PubMed  Google Scholar 

  23. Fan, J.-G. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J. Gastroenterol. Hepatol. 28 (Suppl. 1), 11–17 (2013).

    Article  PubMed  Google Scholar 

  24. Kojima, S.-I., Watanabe, N., Numata, M., Ogawa, T. & Matsuzaki, S. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J. Gastroenterol. 38, 954–961 (2003).

    Article  PubMed  Google Scholar 

  25. Wong, V. W.-S. et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J. Hepatol. 62, 182–189 (2015).

    Article  PubMed  Google Scholar 

  26. Wong, V. W.-S. et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut 61, 409–415 (2012).

    Article  PubMed  Google Scholar 

  27. 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).

    Article  PubMed  Google Scholar 

  28. Mangge, H. et al. Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages. Aliment. Pharmacol. Ther. 42, 99–105 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Nobili, V. et al. Nonalcoholic fatty liver disease. JAMA Pediatr. 169, 170–176 (2015).

    Article  PubMed  Google Scholar 

  30. Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006). This was the first study to accurately assess fatty liver in the paediatric population. The study was based on autopsies of individuals with no known liver disease; careful racial and ethnic and gender assessments were made.

    Article  PubMed  Google Scholar 

  31. Dunn, W. & Schwimmer, J. B. The obesity epidemic and nonalcoholic fatty liver disease in children. Curr. Gastroenterol. Rep. 10, 67–72 (2008).

    Article  PubMed  Google Scholar 

  32. Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585–1592 (2009).

    Article  PubMed  Google Scholar 

  33. Yang, H. R., Yi, D. Y. & Choi, H. S. Comparison between a pediatric health promotion center and a pediatric obesity clinic in detecting metabolic syndrome and non-alcoholic fatty liver disease in children. J. Korean Med. Sci. 29, 1672–1677 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Loomba, R. & Sanyal, A. J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 10, 686–690 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Chan, D. F. Y. et al. Hepatic steatosis in obese Chinese children. Int. J. Obes. Relat. Metab. Disord. 28, 1257–1263 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Booth, M. L. et al. The population prevalence of adverse concentrations and associations with adiposity of liver tests among Australian adolescents. J. Paediatr. Child Health 44, 686–691 (2008).

    Article  PubMed  Google Scholar 

  37. Maher, J. J., Leon, P. & Ryan, J. C. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 48, 670–678 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. He, J., Lee, J. H., Febbraio, M. & Xie, W. The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Exp. Biol. Med. (Maywood) 236, 1116–1121 (2011).

    Article  CAS  Google Scholar 

  39. Mitsuyoshi, H. et al. Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol. Res. 39, 366–373 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Samuel, V. T. et al. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117, 739–745 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Postic, C. & Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829–838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lambert, J. E., Ramos-Roman, M. A., Browning, J. D. & Parks, E. J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146, 726–735 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005). This paper documents the relative contribution of dietary fat, DNL and adipose tissue lipolysis to hepatic lipid accumulation in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 3441–3446 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kammoun, H. L. et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119, 1201–1215 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 (2014). This review documents the role of gut dysbiosis in the pathogenesis of NAFLD.

    Article  CAS  PubMed  Google Scholar 

  48. Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015). This paper documents that hepatic steatosis is marked by a compensatory increase in mitochondrial activity, but this compensation is lost as NASH develops.

    Article  CAS  PubMed  Google Scholar 

  49. Begriche, K., Massart, J., Robin, M.-A., Bonnet, F. & Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58, 1497–1507 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Luedde, T., Kaplowitz, N. & Schwabe, R. F. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765–783 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Upton, J.-P. et al. Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress. Mol. Cell. Biol. 28, 3943–3951 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Johnson, E. S. et al. Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis. J. Biol. Chem. 288, 14463–14475 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Machado, M. V. et al. Reduced lipoapoptosis, Hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 64, 1148–1157 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  55. Cazanave, S. C. et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J. Biol. Chem. 286, 39336–39348 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Inokuchi-Shimizu, S. et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J. Clin. Invest. 124, 3566–3578 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gautheron, J. et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 6, 1062–1074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wehr, A. et al. Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. PLoS ONE 9, e112327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Syn, W.-K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Syn, W.-K. et al. NKT-associated Hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Harley, I. T. W. et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59, 1830–1839 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Sutti, S. et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59, 886–897 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mehal, W. Z. The inflammasome in liver injury and non-alcoholic fatty liver disease. Dig. Dis. 32, 507–515 (2014). This review describes the role of inflammasome activation in the pathogenesis of NAFLD.

    Article  PubMed  Google Scholar 

  66. Tosello-Trampont, A.-C., Landes, S. G., Nguyen, V., Novobrantseva, T. I. & Hahn, Y. S. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J. Biol. Chem. 287, 40161–40172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Leroux, A. et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57, 141–149 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Wallace, M. C., Friedman, S. L. & Mann, D. A. Emerging and disease-specific mechanisms of hepatic stellate cell activation. Semin. Liver Dis. 35, 107–118 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Tomita, K. et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154–169 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Jiang, J. X. et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-α-converting enzyme activity in mice. Hepatology 58, 1339–1348 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Rangwala, F. et al. Increased production of Sonic Hedgehog by ballooned hepatocytes. J. Pathol. 224, 401–410 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Choi, S. S., Omenetti, A., Syn, W.-K. & Diehl, A. M. The role of Hedgehog signaling in fibrogenic liver repair. Int. J. Biochem. Cell Biol. 43, 238–244 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Hirsova, P., Ibrahim, S. H., Bronk, S. F., Yagita, H. & Gores, G. J. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS ONE 8, e70599 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330–344 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Al-Serri, A. et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case–control and intra-familial allele association studies. J. Hepatol. 56, 448–454 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Dong, H. et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J. Hepatol. 46, 915–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, L. et al. Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition. Hepatology 61, 119–128 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Miele, L. et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 135, 282–291 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008). This is the first genome-wide association study in NAFLD and convincingly identified PNPLA3 as a risk factor for NAFLD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 139, 1567–1576 (2010).

    Article  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Anstee, Q. et al. Genome-wide association analysis confirms importance of PNPLA3 and identifies novel variants associated with histologically progressive steatohepatitis in NAFLD. Hepatology 56, 265A–266A(2012).

    Google Scholar 

  84. Kawaguchi, T. et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS ONE 7, e38322 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Feitosa, M. F. et al. The ERLIN1–CHUK–CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart study. Atherosclerosis 228, 175–180 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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). This exome-wide association study identified TM6SF2 as the second gene that confers susceptibility to NAFLD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. DiStefano, J. K. et al. Genome-wide analysis of hepatic lipid content in extreme obesity. Acta Diabetol. 52, 373–382 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Liu, Y.-L. et al. Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61, 75–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Smagris, E. et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108–118 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu, Y.-L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Holmen, O. L. et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 46, 345–351 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kahali, B. et al. TM6SF2: catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease? Gastroenterology 148, 679–684 (2015).

    Article  PubMed  Google Scholar 

  95. Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Sookoian, S. & Pirola, C. J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53, 1883–1894 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Murphy, S. K. et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 145, 1076–1087 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Mann, J. et al. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 14, 275–285 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Kitamoto, T. et al. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease. J. Hepatol. 63, 494–502 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Zeybel, M. et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin. Epigenetics 7, 25 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sookoian, S. et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 52, 1992–2000 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Pirola, C. J. et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62, 1356–1363 (2013). This study provides first evidence of the role of mitochondrial epigenetics in human NAFLD.

    Article  CAS  PubMed  Google Scholar 

  103. Horvath, S. et al. Obesity accelerates epigenetic aging of human liver. Proc. Natl Acad. Sci. USA 111, 15538–15543 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pirola, C. J. et al. Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore) 94, e1480 (2015).

    Article  CAS  Google Scholar 

  105. Zeybel, M. et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat. Med. 18, 1369–1377 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sookoian, S., Gianotti, T. F., Burgueño, A. L. & Pirola, C. J. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr. Res. 73, 531–542 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Carr, S. K. et al. Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver. FASEB J. 28, 2191–2201 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Suter, M. A. et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J. 26, 5106–5114 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shen, J. et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J. Hepatol. 56, 1363–1370 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pirola, C. J. et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 64, 800–812 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hsu, S.-H. et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Invest. 122, 2871–2883 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Li, J. et al. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J. Hepatol. 58, 522–528 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Csak, T. et al. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int. 35, 532–541 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Takaki, Y. et al. Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. Cancer Sci. 105, 1254–1260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wu, Q. et al. Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery. Int. J. Obes. (Lond.) 39, 1126–1134 (2015).

    Article  CAS  Google Scholar 

  118. Ahrens, M. et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 18, 296–302 (2013). This study shows the plasticity of the liver epigenome, which can be modulated by therapeutic intervention.

    Article  CAS  PubMed  Google Scholar 

  119. Li, P. et al. A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab. 21, 455–467 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Vassilatou, E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J. Gastroenterol. 20, 8351–8363 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Hossain, N. et al. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand. J. Gastroenterol. 46, 479–484 (2011).

    Article  PubMed  Google Scholar 

  122. Armstrong, M. J., Adams, L. A., Canbay, A. & Syn, W.-K. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 59, 1174–1197 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Reiner, Ž . et al. Lysosomal acid lipase deficiency — an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 235, 21–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Bernstein, D. L., Hülkova, H., Bialer, M. G. & Desnick, R. J. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J. Hepatol. 58, 1230–1243 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J. Hepatol. 53, 372–384 (2010).

    Article  PubMed  Google Scholar 

  126. Bugianesi, E., McCullough, A. J. & Marchesini, G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 42, 987–1000 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Alberti, K. G., Zimmet, P., Shaw, J. & IDF Epidemiology Task Force Consensus Group. The metabolic syndrome — a new worldwide definition. Lancet 366, 1059–1062 (2005).

    Article  PubMed  Google Scholar 

  128. Browning, J. D. Statins and hepatic steatosis: perspectives from the Dallas Heart study. Hepatology 44, 466–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Fraser, A. et al. γ-Glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women's Heart and Health study and meta-analysis. Arterioscler. Thromb. Vasc. Biol. 27, 2729–2735 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Bugianesi, E. et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 39, 179–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Neuschwander-Tetri, B. A. et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 52, 913–924 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).

    Article  CAS  PubMed  Google Scholar 

  133. American Diabetes Association. Standards of medical care in diabetes — 2014. Diabetes Care 37, S14–S80 (2014).

    Article  Google Scholar 

  134. Sasso, M. et al. Controlled attenuation parameter (CAP): a novel VCTETM guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med. Biol. 36, 1825–1835 (2010).

    Article  PubMed  Google Scholar 

  135. Chan, W.-K., Nik Mustapha, N. R. & Mahadeva, S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 29, 1470–1476 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Myers, R. P. et al. Controlled attenuation parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography. Liver Int. 32, 902–910 (2012).

    Article  PubMed  Google Scholar 

  137. Karlas, T. et al. Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy. PLoS ONE 9, e91987 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Reeder, S. B., Hu, H. H. & Sirlin, C. B. Proton density fat-fraction: a standardized MR-based biomarker of tissue fat concentration. J. Magn. Reson. Imaging 36, 1011–1014 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Tang, A. et al. Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease. Radiology 274, 416–425 (2015).

    Article  PubMed  Google Scholar 

  140. Tang, A. et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. Radiology 267, 422–431 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Schwimmer, J. B. et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology 61, 1887–1895 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Permutt, Z. et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease — MRI accurately quantifies hepatic steatosis in NAFLD. Aliment. Pharmacol. Ther. 36, 22–29 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Artz, N. S. et al. Reproducibility of MR-based liver fat quantification across field strength: same-day comparison between 1.5T and 3T in obese subjects. J. Magn. Reson. Imaging 42, 811–817 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Hines, C. D. G. et al. T1 independent, T2* corrected chemical shift based fat-water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis. J. Magn. Reson. Imaging 33, 873–881 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Hansen, K. H., Schroeder, M. E., Hamilton, G., Sirlin, C. B. & Bydder, M. Robustness of fat quantification using chemical shift imaging. Magn. Reson. Imaging 30, 151–157 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Kleiner, D. E. & Brunt, E. M. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin. Liver Dis. 32, 3–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Marchesini, G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917–923 (2003).

    Article  PubMed  Google Scholar 

  148. European Association for the Study of the Liver. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J. Hepatol. 63, 237–264 (2015). These are the most recent guidelines for the non-invasive detection of liver fibrosis in liver disease of different aetiology, including NAFLD and NASH.

    Article  Google Scholar 

  149. Fedchuk, L. et al. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment. Pharmacol. Ther. 40, 1209–1222 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  151. Kwok, R. et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease — the role of transient elastography and plasma cytokeratin-18 fragments. Aliment. Pharmacol. Ther. 39, 254–269 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Machado, M. V. & Cortez-Pinto, H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J. Hepatol. 58, 1007–1019 (2013).

    Article  PubMed  Google Scholar 

  153. Awai, H. I., Newton, K. P., Sirlin, C. B., Behling, C. & Schwimmer, J. B. Evidence and recommendations for imaging liver fat in children, based on systematic review. Clin. Gastroenterol. Hepatol. 12, 765–773 (2014).

    Article  PubMed  Google Scholar 

  154. Tang, A., Cloutier, G., Szeverenyi, N. M. & Sirlin, C. B. Ultrasound elastography and MR elastography for assessing liver fibrosis: part 1, principles and techniques. AJR Am. J. Roentgenol. 205, 22–32 (2015).

    Article  PubMed  Google Scholar 

  155. Sandrin, L. et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med. Biol. 29, 1705–1713 (2003).

    Article  PubMed  Google Scholar 

  156. Bamber, J. et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: basic principles and technology. Ultraschall Med. 34, 169–184 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Ferraioli, G. et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: part 3: liver. Ultrasound Med. Biol. 41, 1161–1179 (2015).

    Article  PubMed  Google Scholar 

  158. Myers, R. P. et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 55, 199–208 (2012).

    Article  PubMed  Google Scholar 

  159. Bota, S. et al. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int. 33, 1138–1147 (2013).

    Article  PubMed  Google Scholar 

  160. Friedrich-Rust, M. et al. Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur. J. Radiol. 81, e325–e331 (2012).

    Article  PubMed  Google Scholar 

  161. Muthupillai, R. et al. Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 269, 1854–1857 (1995).

    Article  CAS  PubMed  Google Scholar 

  162. Venkatesh, S. K., Yin, M. & Ehman, R. L. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J. Magn. Reson. Imaging 37, 544–555 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Serai, S. D., Yin, M., Wang, H., Ehman, R. L. & Podberesky, D. J. Cross-vendor validation of liver magnetic resonance elastography. Abdom. Imaging 40, 789–794 (2014).

    Article  Google Scholar 

  164. Kim, D., Kim, W. R., Talwalkar, J. A., Kim, H. J. & Ehman, R. L. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology 268, 411–419 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Loomba, R. et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 60, 1920–1928 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Arulanandan, A. et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 13, 1513–1520 (2015).

    Article  PubMed  Google Scholar 

  167. Ichikawa, S. et al. Comparison of the diagnostic accuracies of magnetic resonance elastography and transient elastography for hepatic fibrosis. Magn. Reson. Imaging 33, 26–30 (2015).

    Article  PubMed  Google Scholar 

  168. Neuschwander-Tetri, B. A. Lifestyle modification as the primary treatment of NASH. Clin. Liver Dis. 13, 649–665 (2009).

    Article  PubMed  Google Scholar 

  169. Johnson, N. A. & George, J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 52, 370–381 (2010).

    Article  CAS  PubMed  Google Scholar 

  170. Vilar-Gomez, E. et al. Weight loss via lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 367–378 (2015). This is the largest trial of lifestyle intervention to date that demonstrated resolution of NASH and improvement or stabilization of fibrosis in those that lost >7% body weight.

    Article  PubMed  Google Scholar 

  171. Bellentani, S., Dalle Grave, R., Suppini, A. & Marchesini, G. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 47, 746–754 (2008).

    Article  PubMed  Google Scholar 

  172. Centis, E., Marzocchi, R., Di Domizio, S., Ciaravella, M. F. & Marchesini, G. The effect of lifestyle changes in non-alcoholic fatty liver disease. Dig. Dis. 28, 267–273 (2010).

    Article  PubMed  Google Scholar 

  173. Pillai, A. A. & Rinella, M. E. Non-alcoholic fatty liver disease: is bariatric surgery the answer? Clin. Liver Dis. 13, 689–710 (2009).

    Article  PubMed  Google Scholar 

  174. Lassailly, G. et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149, 379–388 (2015).

    Article  PubMed  Google Scholar 

  175. Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774–788 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Cusi, K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142, 711–725 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. Fuchs, M. & Sanyal, A. J. Lipotoxicity in NASH. J. Hepatol. 56, 291–293 (2012).

    Article  PubMed  Google Scholar 

  178. Bouret, S., Levin, B. E. & Ozanne, S. E. Gene–environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol. Rev. 95, 47–82 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Wisløff, U. et al. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307, 418–420 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Cypess, A. M. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Crane, J. D. et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat. Med. 21, 166–172 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Neuschwander-Tetri, B. A. Food energy efficiency, cannabinoids, and a slow death of the weight loss dogma. Hepatology 46, 12–15 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Kalaany, N. Y. & Mangelsdorf, D. J. LXRS and FXR: the Yin and Yang of cholesterol and fat metabolism. Annu. Rev. Physiol. 68, 159–191 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. 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).

    Article  CAS  PubMed  Google Scholar 

  185. Lomonaco, R. et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55, 1389–1397 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Gastaldelli, A. et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50, 1087–1093 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Doycheva, I. & Loomba, R. Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD). Adv. Ther. 31, 30–43 (2014).

    Article  CAS  PubMed  Google Scholar 

  190. Cariou, B., Zaïr, Y., Staels, B. & Bruckert, E. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34, 2008–2014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  192. Musso, G. et al. Nitrosative stress predicts the presence and severity of nonalcoholic fatty liver at different stages of the development of insulin resistance and metabolic syndrome: possible role of vitamin A intake. Am. J. Clin. Nutr. 86, 661–671 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Hoofnagle, J. H. et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 38, 134–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  194. Sanyal, A. J., Abdelmalek, M. F., Suzuki, A., Cummings, O. W. & Chojkier, M. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a Phase 2 trial. Gastroenterology 147, 377–384 (2014).

    Article  CAS  PubMed  Google Scholar 

  195. Cao, S. S. & Kaufman, R. J. Targeting endoplasmic reticulum stress in metabolic disease. Expert Opin. Ther. Targets 17, 437–448 (2013).

    Article  CAS  PubMed  Google Scholar 

  196. Ioannou, G. N., Haigh, W. G., Thorning, D. & Savard, C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J. Lipid Res. 54, 1326–1334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Bays, H., Cohen, D. E., Chalasani, N., Harrison, S. A. & The National Lipid Association's Statin Safety Task Force. An assessment by the Statin Liver Safety Task Force: 2014 update. J. Clin. Lipidol. 8, S47–S57 (2014).

    Article  PubMed  Google Scholar 

  198. Eslami, L., Merat, S., Malekzadeh, R., Nasseri-Moghaddam, S. & Aramin, H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst. Rev. 12, CD008623 (2013).

    Google Scholar 

  199. Dongiovanni, P. et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J. Hepatol. 63, 705–712 (2015).

    Article  CAS  PubMed  Google Scholar 

  200. Ratziu, V. et al. Lack of efficacy of an inhibitor of PDE4 in Phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 12, 1724–1730 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Ratziu, V. et al. A Phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 55, 419–428 (2012).

    Article  CAS  PubMed  Google Scholar 

  202. Dan, A. A. et al. Health-related quality of life in patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 26, 815–820 (2007).

    Article  CAS  PubMed  Google Scholar 

  203. Afendy, A. et al. Predictors of health-related quality of life in patients with chronic liver disease. Aliment. Pharmacol. Ther. 30, 469–476 (2009).

    Article  CAS  PubMed  Google Scholar 

  204. Hickman, I. J. et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 53, 413–419 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. David, K. et al. Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatology 49, 1904–1912 (2009).

    Article  PubMed  Google Scholar 

  206. Bray, G. A. The missing link — lose weight, live longer. N. Engl. J. Med. 357, 818–820 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Sjöström, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).

    Article  PubMed  Google Scholar 

  208. Adams, T. D. et al. Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357, 753–761 (2007).

    Article  CAS  PubMed  Google Scholar 

  209. Sjöström, L. et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N. Engl. J. Med. 351, 2683–2693 (2004).

    Article  PubMed  Google Scholar 

  210. Meek, C. L., Lewis, H. B., Reimann, F., Gribble, F. M. & Park, A. J. The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptideshttp://dx.doi.org/10.1016/j.peptides.2015.08.013 (2015).

  211. Ryan, K. K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Kuipers, F. & Groen, A. K. FXR: the key to benefits in bariatric surgery? Nat. Med. 20, 337–338 (2014).

    Article  CAS  PubMed  Google Scholar 

  213. Birkmeyer, N. J. O. et al. Hospital complication rates with bariatric surgery in Michigan. JAMA 304, 435–442 (2010).

    Article  CAS  PubMed  Google Scholar 

  214. Jan, A., Narwaria, M. & Mahawar, K. K. A. Systematic review of bariatric surgery in patients with liver cirrhosis. Obes. Surg. 25, 1518–1526 (2015).

    Article  PubMed  Google Scholar 

  215. Yang, J. D. et al. Hepatocellular carcinoma in olmsted county, Minnesota, 1976–2008. Mayo Clin. Proc. 87, 9–16 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Malik, S. M., Gupte, P. A., de Vera, M. E. & Ahmad, J. Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 7, 800–806 (2009).

    Article  PubMed  Google Scholar 

  217. Younossi, Z. M. et al. Association of non-alcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004–2009. Hepatologyhttp://dx.doi.org/10.1002/hep.28123 (2015).

  218. Welzel, T. M. et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am. J. Gastroenterol. 108, 1314–1321 (2013). This paper includes important data from the SEER database demonstrating that, although the risk of HCC in patients with NASH may be lower than other diseases (for example, in hepatitis C virus infection), its high prevalence makes the population attributable risk of HCC in NASH nearly 40%.

    Article  PubMed  PubMed Central  Google Scholar 

  219. 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).

    Article  PubMed  Google Scholar 

  220. Wideroff, L. et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J. Natl Cancer Inst. 89, 1360–1365 (1997).

    Article  CAS  PubMed  Google Scholar 

  221. Yasui, K. et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 9, 428–433 (2011).

    Article  PubMed  Google Scholar 

  222. Mittal, S. & El-Serag, H. B. Epidemiology of hepatocellular carcinoma: consider the population. J. Clin. Gastroenterol. 47, S2–S6 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Jiang, W. et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci. Rep. 5, 8096 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Mehal, W. Z. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 637–644 (2013).

    Article  PubMed  Google Scholar 

  225. Shen, J., Obin, M. S. & Zhao, L. The gut microbiota, obesity and insulin resistance. Mol. Aspects Med. 34, 39–58 (2013).

    Article  CAS  PubMed  Google Scholar 

  226. Boursier, J. & Diehl, A. M. Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog. 11, e1004559 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  228. Bedossa, P. et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 56, 1751–1759 (2012).

    Article  PubMed  Google Scholar 

  229. Nobili, V. et al. Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7, 575–579 (2009).

    Article  CAS  PubMed  Google Scholar 

  230. Younossi, Z. M. et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes. Surg. 18, 1430–1437 (2008).

    Article  PubMed  Google Scholar 

  231. Palekar, N. A., Naus, R., Larson, S. P., Ward, J. & Harrison, S. A. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 26, 151–156 (2006).

    Article  PubMed  Google Scholar 

  232. Harrison, S. A., Oliver, D., Arnold, H. L., Gogia, S. & Neuschwander-Tetri, B. A. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 57, 1441–1447 (2008).

    Article  CAS  PubMed  Google Scholar 

  233. Ratziu, V. et al. Liver fibrosis in overweight patients. Gastroenterology 118, 1117–1123 (2000).

    Article  CAS  PubMed  Google Scholar 

  234. Speliotes, E. K. et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart study. Hepatology 51, 1979–1987 (2010).

    Article  CAS  PubMed  Google Scholar 

  235. Hwang, S. et al. The effect of donor weight reduction on hepatic steatosis for living donor liver transplantation. Liver Transpl. 10, 721–725 (2004).

    Article  PubMed  Google Scholar 

  236. Malik, A., Cheah, P.-L., Hilmi, I. N., Chan, S. P. & Goh, K.-L. Non-alcoholic fatty liver disease in Malaysia: a demographic, anthropometric, metabolic and histological study. J. Dig. Dis. 8, 58–64 (2007).

    Article  CAS  PubMed  Google Scholar 

  237. Hamaguchi, M. et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann. Intern. Med. 143, 722–728 (2005).

    Article  CAS  PubMed  Google Scholar 

  238. Fan, J.-G. et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J. Hepatol. 43, 508–514 (2005).

    Article  PubMed  Google Scholar 

  239. Das, K. et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51, 1593–1602 (2010).

    Article  CAS  PubMed  Google Scholar 

  240. Kwon, Y.-M. et al. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. Am. J. Gastroenterol. 107, 1852–1858 (2012).

    Article  CAS  PubMed  Google Scholar 

  241. el-Hassan, A. Y., Ibrahim, E. M., al-Mulhim, F. A., Nabhan, A. A. & Chammas, M. Y. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management. Br. J. Radiol. 65, 774–778 (1992).

    Article  CAS  PubMed  Google Scholar 

  242. Aboueisha, H. et al. A retrospective evaluation of causes of exempting living liver donors in an Egyptian centre. Arab J. Gastroenterol. 14, 10–13 (2013).

    Article  PubMed  Google Scholar 

  243. Strauss, R. S., Barlow, S. E. & Dietz, W. H. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J. Pediatr. 136, 727–733 (2000).

    CAS  PubMed  Google Scholar 

  244. Zou, C. C., Liang, L., Hong, F., Fu, J. F. & Zhao, Z. Y. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr. J. 52, 519–524 (2005).

    Article  CAS  PubMed  Google Scholar 

  245. Guzzaloni, G., Grugni, G., Minocci, A., Moro, D. & Morabito, F. Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test. Int. J. Obes. Relat. Metab. Disord. 24, 772–776 (2000).

    Article  CAS  PubMed  Google Scholar 

  246. Fu, J. et al. Nonalcoholic steatohepatitis in obese children: the prevalence and possible mechanism. Zhejiang Da Xue Xue Bao Yi Xue Ban 35, 64–68 (in Chinese) (2006).

    CAS  PubMed  Google Scholar 

  247. Schwimmer, J. B. et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J. Pediatr. 143, 500–505 (2003).

    Article  PubMed  Google Scholar 

  248. Nobili, V. et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44, 458–465 (2006).

    Article  PubMed  Google Scholar 

  249. Feldstein, A. E. et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58, 1538–1544 (2009).

    Article  CAS  PubMed  Google Scholar 

  250. Bedogni, G. et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 6, 33 (2006). The Fatty Liver Index is the first and most widely used index for the non-ultrasound detection of NAFLD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Kotronen, A. et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 137, 865–872 (2009).

    Article  CAS  PubMed  Google Scholar 

  252. Poynard, T. et al. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS ONE 7, e30325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Angulo, P. et al. The NAFLD Fibrosis Score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007). The NAFLD Fibrosis Score is the only non-invasive index for the identification of NASH that has been validated both cross-sectionally and longitudinally.

    Article  CAS  PubMed  Google Scholar 

  254. Ratziu, V. et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 6, 6 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Adams, L. A. et al. Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 26, 1536–1543 (2011).

    Article  CAS  PubMed  Google Scholar 

  257. Guha, I. N. et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 47, 455–460 (2008).

    Article  PubMed  Google Scholar 

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Acknowledgements

E.B. is a member of the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Programme of the European Union under Grant Agreement 634413.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 Euclid Avenue, Campus Box 8118, Saint Louis, 63110, Missouri, USA

    Elizabeth M. Brunt

  2. Department of Medicine and Therapeutics and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong

    Vincent W.-S. Wong

  3. Hepatometabolic Unit, Bambino Gesu Children Hospital, Rome, Italy

    Valerio Nobili

  4. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

    Christopher P. Day

  5. Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires, National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

    Silvia Sookoian

  6. Department of Medicine, University of California at San Francisco, San Francisco, 94110, California, USA

    Jacquelyn J. Maher

  7. Department of Medical Sciences, University of Torino, Città della Salute e della Scienza, Torino, Italy

    Elisabetta Bugianesi

  8. Department of Radiology, Liver Imaging Group, University of California at San Diego, San Diego, 92103, California, USA

    Claude B. Sirlin

  9. Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Missouri, Saint Louis, 63110, USA

    Brent A. Neuschwander-Tetri

  10. Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Mary E. Rinella

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  1. Elizabeth M. Brunt
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  2. Vincent W.-S. Wong
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Contributions

Introduction (E.M.B.); Epidemiology (V.W.-S.W., V.N. and E.M.B.); Mechanisms/pathophysiology (C.P.D., S.S. and J.J.M.); Diagnosis, screening and prevention (E.B. and C.B.S.); Management (B.A.N.-T.); Quality of life (M.E.R.); Outlook (M.E.R.); Overview of Primer (E.M.B.).

Corresponding author

Correspondence to Elizabeth M. Brunt.

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Competing interests

E.M.B. has received consulting fees from Eli Lilly and acted as a paid study pathologist for Rottapharm. C.B.S. has received research grants from GE Healthcare and Siemens. V.W.-S.W. is or has been an advisory board member for Gilead and Janssen, a consultant for AbbVie, Merck and NovoMedica, and has received lecture fees from AbbVie, Echosens and Gilead. B.A.N.-T. has received consulting fees from Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Conatus, Scholar Rock, Novartis, Galmed, Zafgen and Pfizer. All other authors declare no competing interests.

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Brunt, E., Wong, VS., Nobili, V. et al. Nonalcoholic fatty liver disease. Nat Rev Dis Primers 1, 15080 (2015). https://doi.org/10.1038/nrdp.2015.80

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