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Management of NAFLD: a stage-based approach

Key Points

  • NAFLD is the most common cause of liver disease, affecting 30% of the US population; however, the goals of treatment differ based on stage of disease

  • Lifestyle modification and excellent control of comorbid metabolic illness is important for all patients

  • Patients with NASH, the progressive subtype of NAFLD, should be targeted for treatment, especially if they have concomitant fibrosis because such patients are more likely to have adverse outcomes

  • Currently available pharmacological options include vitamin E, pioglitazone and pentoxifylline

  • Although bariatric surgery has not been studied prospectively specifically as a treatment for NASH, indirect evidence suggests it is effective at improving histological features of NASH, including fibrosis

  • Several promising drug therapies for NASH targeting a broad array of targets are in clinical trials and are anticipated to pave the way for new and more effective treatment options

Abstract

NAFLD is the most prevalent form of liver disease in the USA, affecting an estimated 30% of the population. The condition is associated with increased mortality related to cardiovascular disease, malignancy and liver disease. Identification of patients who might be at increased risk of adverse outcomes is critical as it is not feasible to screen all patients with suspected NAFLD. Patients with NASH, the progressive subtype of NAFLD, should be targeted for treatment, especially if they have concomitant fibrosis because such patients are more likely than those without fibrosis to have adverse outcomes. Treatment goals in patients with NAFLD vary depending on the disease stage owing to differential risk of progression and the particularities of an individual's comorbid disease. Lifestyle intervention is important for all patients irrespective of disease stage, but other therapies should be targeted to those most likely to benefit. In this Review, we highlight risk factors for disease progression and offer a stage-based treatment approach for patients with NAFLD.

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Figure 1: Proposed risk stratification for patients with NAFLD.
Figure 2: A stage-based approach to the treatment of NAFLD.

References

  1. 1

    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 

  2. 2

    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 

  3. 3

    Pais, R. et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J. Hepatol. 59, 550–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Pais, R. et al. Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease. Clin. Res. Hepatol. Gastroenterol. 35, 23–28 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    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).

    Article  PubMed  Google Scholar 

  6. 6

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

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Angulo, P., Keach, J. C., Batts, K. P. & Lindor, K. D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30, 1356–1362 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Nishizawa, H. et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur. J. Endocrinol. 167, 67–74 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Adams, L. A., Feldstein, A., Lindor, K. D. & Angulo, P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 39, 909–914 (2004).

    Article  PubMed  Google Scholar 

  10. 10

    Portillo Sanchez, P. et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J. Clin. Endocrinol. Metab. http://dx.doi.org/10.1210/jc.2014-2739 (2014).

  11. 11

    Mofrad, P. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286–1292 (2003).

    Article  PubMed  Google Scholar 

  12. 12

    Musso, G., Gambino, R., Cassader, M. & Pagano, G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann. Med. 43, 617–649 (2011).

    Article  PubMed  Google Scholar 

  13. 13

    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 

  14. 14

    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  PubMed Central  Google Scholar 

  15. 15

    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 

  16. 16

    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. e10 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    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 

  18. 18

    Ripoll, C. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133, 481–488 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Ripoll, C. et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J. Hepatol. 50, 923–928 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Kim, D., Kim, W. R., Kim, H. J. & Therneau, T. M. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 57, 1357–1365 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Myers, R. P., Elkashab, M., Ma, M., Crotty, P. & Pomier-Layrargues, G. Transient elastography for the noninvasive assessment of liver fibrosis: a multicentre Canadian study. Can. J. Gastroenterol. 24, 661–670 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    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  PubMed Central  Google Scholar 

  24. 24

    Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 142, 1592–1609 (2012).

    Article  PubMed  Google Scholar 

  25. 25

    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 

  26. 26

    Prinz, P. et al. Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients. Front. Neurosci. 9, 199 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    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 

  28. 28

    Sanyal, A. Longitudinal changes in FIB-4 and improvement in fibrosis stage with obeticholic acid: a secondary analysis of FLINT Trial. Presented at the American Academy for the Study of Liver Diseases 2015 Annual Meeting (2015).

  29. 29

    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; e1–e9; quiz e39–e40 (2015).

    Article  PubMed  Google Scholar 

  30. 30

    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 

  31. 31

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

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Wong, V. W. et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J. Hepatol. 59, 536–542 (2013).

    Article  PubMed  Google Scholar 

  33. 33

    Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121–129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Lassailly, G. et al. Bariatric surgery reduces features of non-alcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149, 379–388; quiz e15–e16 (2015).

    Article  PubMed  Google Scholar 

  35. 35

    Browning, J. D. et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am. J. Clin. Nutr. 93, 1048–1052 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Browning, J. D. et al. Alterations in hepatic glucose and energy metabolism as a result of calorie and carbohydrate restriction. Hepatology 48, 1487–1496 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Oarada, M. et al. Refeeding with glucose rather than fructose elicits greater hepatic inflammatory gene expression in mice. Nutrition 31, 757–765 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Nakamuta, M. et al. Impact of cholesterol metabolism and the LXRα–SREBP-1c pathway on nonalcoholic fatty liver disease. Int. J. Mol. Med. 23, 603–608 (2009).

    CAS  PubMed  Google Scholar 

  39. 39

    Yasutake, K. et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand. J. Gastroenterol. 44, 471–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Goff, D. C. Jr et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J. Am. Coll. Cardiol. 63, 2935–2959 (2014).

    Article  PubMed  Google Scholar 

  41. 41

    Ryan, M. C. et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J. Hepatol. 59, 138–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. 42

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

    Article  PubMed  Google Scholar 

  43. 43

    Freedman, N. D., Park, Y., Abnet, C. C., Hollenbeck, A. R. & Sinha, R. Association of coffee drinking with total and cause-specific mortality. N. Engl. J. Med. 366, 1891–1904 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Klatsky, A. L. & Armstrong, M. A. Alcohol, smoking, coffee, and cirrhosis. Am. J. Epidemiol. 136, 1248–1257 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Johnson, S. et al. Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study. Cancer Causes Control 22, 503–510 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ruhl, C. E. & Everhart, J. E. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology 128, 24–32 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Anty, R. et al. Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J. Hepatol. 57, 1090–1096 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Johnson, N. A. et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 50, 1105–1112 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Bae, J. C. et al. Regular exercise is associated with a reduction in the risk of NAFLD and decreased liver enzymes in individuals with NAFLD independent of obesity in Korean adults. PLoS ONE 7, e46819 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Slentz, C. A. et al. Effects of aerobic versus resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT. Am. J. Physiol. Endocrinol. Metab. 301, E1033–E1039 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Oh, S. et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 61, 1205–1215 (2014).

    Article  CAS  Google Scholar 

  52. 52

    Stewart, K. E. et al. Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int. 35, 936–943 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Cleator, J., Abbott, J., Judd, P., Sutton, C. & Wilding, J. P. Night eating syndrome: implications for severe obesity. Nutr. Diabetes 2, e44 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Briancon-Marjollet, A. et al. The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. Diabetol. Metab. Syndr. 7, 25 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Sjostrom, 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 

  56. 56

    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 

  57. 57

    Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am. J. Clin. Nutr. 55, 615S–619S (1992).

  58. 58

    Taitano, A. A. et al. Bariatric surgery improves histological features of nonalcoholic Fatty liver disease and liver fibrosis. J. Gastrointest. Surg. 19, 429–437 (2015).

    Article  PubMed  Google Scholar 

  59. 59

    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).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    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 

  61. 61

    Osto, E. et al. Rapid and body weight-independent improvement of endothelial and high-density lipoprotein function after Roux-en-Y gastric bypass: role of glucagon-like peptide-1. Circulation 131, 871–881 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Nergard, B. J. et al. Mucosal glucagon-like peptide-1 and gastric inhibitory polypeptide cell numbers in the super-obese human foregut after gastric bypass. Surg. Obes. Relat. Dis. 11, 1237–1246 (2015).

    Article  PubMed  Google Scholar 

  63. 63

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

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Sanyal, A. J., Sugerman, H. J., Kellum, J. M., Engle, K. M. & Wolfe, L. Stomal complications of gastric bypass: incidence and outcome of therapy. Am. J. Gastroenterol. 87, 1165–1169 (1992).

    CAS  PubMed  Google Scholar 

  65. 65

    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 

  66. 66

    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).

    Article  CAS  PubMed  Google Scholar 

  67. 67

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    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 

  69. 69

    Kowdley, K. V. et al. CRN trials. Hepatology 62, 1 (2015).

    Google Scholar 

  70. 70

    Miller, E. R. 3rd et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297, 842–857 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Gee, P. T. Unleashing the untold and misunderstood observations on vitamin E. Genes Nutr. 6, 5–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Curtis, A. J., Bullen, M., Piccenna, L. & McNeil, J. J. Vitamin E supplementation and mortality in healthy people: a meta-analysis of randomised controlled trials. Cardiovasc. Drugs Ther. 28, 563–573 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Jiang, S. et al. Meta-analysis: low-dose intake of vitamin E combined with other vitamins or minerals may decrease all-cause mortality. J. Nutr. Sci. Vitaminol. (Tokyo) 60, 194–205 (2014).

    Article  CAS  Google Scholar 

  75. 75

    Ye, Y., Li, J. & Yuan, Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS ONE 8, e56803 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Lippman, S. M. et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301, 39–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Gaziano, J. M. et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301, 52–62 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Schurks, M., Glynn, R. J., Rist, P. M., Tzourio, C. & Kurth, T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 341, c5702 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Choudhury, J. & Sanyal, A. J. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 575–594 (2004).

    Article  PubMed  Google Scholar 

  80. 80

    Mahady, S. E., Webster, A. C., Walker, S., Sanyal, A. & George, J. The role of thiazolidinediones in non-alcoholic steatohepatitis — a systematic review and meta analysis. J. Hepatol. 55, 1383–1390 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Neuschwander-Tetri, B. A., Brunt, E. M., Wehmeier, K. R., Oliver, D. & Bacon, B. R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-γ ligand rosiglitazone. Hepatology 38, 1008–1017 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Van Wagner, L. B. et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann. Hepatol. 10, 277–286 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Zein, C. O. et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54, 1610–1619 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Patterson, E., Wall, R., Fitzgerald, G. F., Ross, R. P. & Stanton, C. Health implications of high dietary omega-6 polyunsaturated fatty acids. J. Nutr. Metab. 2012, 539426 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Pettinelli, P. et al. Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim. Biophys. Acta 1792, 1080–1086 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. 86

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

    Article  CAS  PubMed  Google Scholar 

  87. 87

    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. e1 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    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).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Calder, P. C. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469–484 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Mullen, A., Loscher, C. E. & Roche, H. M. Anti-inflammatory effects of EPA and DHA are dependent upon time and dose-response elements associated with LPS stimulation in THP-1-derived macrophages. J. Nutr. Biochem. 21, 444–450 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Ferrebee, C. B. & Dawson, P. A. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm. Sin. B 5, 129–134 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Keitel, V. et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45, 695–704 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    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. e1 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Matsukuma, K. E. et al. Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase. J. Lipid Res. 47, 2754–2761 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Evans, M. J. et al. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G543–G552 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Sirvent, A. et al. Farnesoid X receptor represses hepatic lipase gene expression. J. Lipid Res. 45, 2110–2115 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Zhang, Y. et al. Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J. Biol. Chem. 285, 3035–3043 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Rohatgi, A. et al. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 371, 2383–2393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Urizar, N. L. et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296, 1703–1706 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Miyazaki-Anzai, S., Masuda, M., Levi, M., Keenan, A. L. & Miyazaki, M. Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis. PLoS ONE 9, e108270 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Giby, V. G. & Ajith, T. A. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J. Hepatol. 6, 570–579 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Bojic, L. A. & Huff, M. W. Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player. Curr. Opin. Lipidol. 24, 171–177 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Staels, B. et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Cariou, B., Zair, 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 

  107. 107

    Cariou, B. et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923–2930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Ratziu, V. et al. An international, phase 2 randomized controlled trial of the dual PPAR alpha-delta aginist GFT505 in adult patients with NASH. Hepatology 62, 1 (2015).

    Google Scholar 

  109. 109

    Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (2015).

  110. 110

    Armstrong, A. Liraglutide is effective in the histological clearance of non-alcoholic steatohepatitis in a multicentre, double-blinded, randomised, placebo-controlled phase II trial. J. Hepatol. 62 (Suppl. 2) S187 (2015).

    Article  Google Scholar 

  111. 111

    Vlachogiannakos, J. et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J. Gastroenterol. Hepatol. 28, 450–455 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Marcellin, P. & Asselah, T. Long-term therapy for chronic hepatitis B: hepatitis B virus DNA suppression leading to cirrhosis reversal. J. Gastroenterol. Hepatol. 28, 912–923 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Rockey, D. C., Bell, P. D. & Hill, J. A. Fibrosis — a common pathway to organ injury and failure. N. Engl. J. Med. 372, 1138–1149 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Wong, C. C. et al. Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology 60, 1645–1658 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Di Prospero, N. A. et al. CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Diabetes Obes. Metab. 16, 1055–1064 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Traber, P. G. et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 8, e75361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

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

    Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Bambha, K. et al. Coffee consumption in NAFLD patients with lower insulin resistance is associated with lower risk of severe fibrosis. Liver Int. 34, 1250–1258 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Molloy, J. W. et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 55, 429–436 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Safadi, R. et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2085–2091. e2 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Bi, Y. et al. Effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in drug-naive subjects with type 2 diabetes. Acta Diabetol. 51, 865–873 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Safar Zadeh, E. et al. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J. Hepatol. 59, 131–137 (2013).

    Article  CAS  PubMed  Google Scholar 

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All authors contributed equally to discussion of content, writing and reviewing/editing the manuscript before submission. M.E.R. researched data for the article.

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Correspondence to Arun J. Sanyal.

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M.E.R. has served as a consultant to AbbVie, FibroGen, Genentech, Intercept, NGM Biopharmaceuticals, NuSirt, Shire, Takeda and W.L Gore & Associates. A.J.S. has stock options in Genfit. He is the President of Sanyal Biotechnologies and has served as a consultant to AbbVie, Astra Zeneca, Boehringer Ingelhiem, Exalenz Bioscience, FibroGen, Genfit, Hemoshear, Immune Pharma, Immuron, Lilly, Nimbus Therapeutics, Nitto Denko, Salix Pharmaceuticals, Takeda and Tobira Therapeutics. He has been an unpaid consultant to Echosens and Intercept Pharmaceuticals. His institution has received grant support from Astra Zeneca, Bristol Myers, Gilead, Merck, Novartis, Salix Pharmaceuticals and Tobira Therapeutics.

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Rinella, M., Sanyal, A. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 13, 196–205 (2016). https://doi.org/10.1038/nrgastro.2016.3

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