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  • Review Article
  • Published:

Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis

Nature Reviews Gastroenterology & Hepatology volume 10, pages 330–344 (2013)Cite this article

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Abstract

NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).

Key Points

  • NAFLD is a spectrum of progressive liver disease that includes steatosis, NASH, fibrosis, cirrhosis and hepatocellular carcinoma

  • NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus

  • NAFLD, and especially NASH, are associated with an increased risk of morbidity and mortality related to the liver and cardiovascular system

  • NAFLD is also associated with an increased risk of developing type 2 diabetes mellitus

  • Considerable interindividual variation exists in the severity of NAFLD and the risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors

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Figure 1: Patients with NAFLD have a myriad of traditional and nontraditional risk factors for CVD.
Figure 2: The putative mechanisms underlying the contribution of NAFLD to the increased risk of developing CVD and T2DM.

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References

  1. Anstee, Q. M., McPherson, S. & Day, C. P. How big a problem is non-alcoholic fatty liver disease? BMJ 343, d3897 (2011).

    PubMed  Google Scholar 

  2. de Alwis, N. M. & Day, C. P. Non-alcoholic fatty liver disease: the mist gradually clears. J. Hepatol. 48 (Suppl. 1), S104–S112 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Sanyal, A. J. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 123, 1705–1725 (2002).

    Article  PubMed  Google Scholar 

  4. 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).

    PubMed  Google Scholar 

  5. 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).

    CAS  PubMed  Google Scholar 

  6. Baumeister, S. E. et al. Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. Gastroenterology 134, 85–94 (2008).

    Article  PubMed  Google Scholar 

  7. Charlton, M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin. Gastroenterol. Hepatol. 2, 1048–1058 (2004).

    Article  PubMed  Google Scholar 

  8. Cobbold, J. F., Anstee, Q. M. & Taylor-Robinson, S. D. The importance of fatty liver disease in clinical practice. Proc. Nutr. Soc. 69, 518–527 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Ratziu, V. et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128, 1898–1906 (2005).

    Article  PubMed  Google Scholar 

  11. Argo, C. K. & Caldwell, S. H. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 511–531 (2009).

    Article  PubMed  Google Scholar 

  12. Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55, 2005–2023 (2012).

    Article  PubMed  Google Scholar 

  13. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 123, 1364–1366 (2002).

  14. Saadeh, S. et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123, 745–750 (2002).

    Article  PubMed  Google Scholar 

  15. Schwenzer, N. F. et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J. Hepatol. 51, 433–445 (2009).

    Article  PubMed  Google Scholar 

  16. Dasarathy, S. et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J. Hepatol. 51, 1061–1067 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Thomas, E. L. et al. Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. Gut 54, 122–127 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cobbold, J. F. et al. Phenotyping murine models of non-alcoholic fatty liver disease through metabolic profiling of intact liver tissue. Clin. Sci. (Lond.) 116, 403–413 (2009).

    Article  CAS  Google Scholar 

  19. Armstrong, M. J. et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J. Hepatol. 56, 234–240 (2012).

    Article  PubMed  Google Scholar 

  20. 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 

  21. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274–285 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Minervini, M. I. et al. Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests. J. Hepatol. 50, 501–510 (2009).

    Article  PubMed  Google Scholar 

  23. Nadalin, S. et al. Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits. Liver Transpl. 11, 980–986 (2005).

    Article  PubMed  Google Scholar 

  24. Tran, T. T. et al. Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors. J. Gastroenterol. Hepatol. 21, 381–383 (2006).

    Article  PubMed  Google Scholar 

  25. Ryan, C. K., Johnson, L. A., Germin, B. I. & Marcos, A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 8, 1114–1122 (2002).

    Article  PubMed  Google Scholar 

  26. 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 

  27. Szczepaniak, L. S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462–E468 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. 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 

  29. Jimba, S. et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med. 22, 1141–1145 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Williamson, R. M. et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34, 1139–1144 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bellentani, S., Bedogni, G., Miglioli, L. & Tiribelli, C. The epidemiology of fatty liver. Eur. J. Gastroenterol. Hepatol. 16, 1087–1093 (2004).

    Article  PubMed  Google Scholar 

  33. 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 

  34. Silverman, J. F., Pories, W. J. & Caro, J. F. Liver pathology in diabetes mellitus and morbid obesity. Clinical, pathological, and biochemical considerations. Pathol. Annu. 24, 275–302 (1989).

    PubMed  Google Scholar 

  35. Smith, B. W. & Adams, L. A. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat. Rev. Endocrinol. 7, 456–465 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  37. Kotronen, A. & Yki-Jarvinen, H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 27–38 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Vanni, E. et al. From the metabolic syndrome to NAFLD or vice versa? Dig. Liver Dis. 42, 320–330 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Kotronen, A., Westerbacka, J., Bergholm, R., Pietilainen, K. H. & Yki-Jarvinen, H. Liver fat in the metabolic syndrome. J. Clin. Endocrinol. Metab. 92, 3490–3497 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Kotronen, A. et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care 31, 165–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Ryysy, L. et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49, 749–758 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Adams, L. A. et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am. J. Gastroenterol. 105, 1567–1573 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. de Marco, R. et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 22, 756–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Targher, G. et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 51, 444–450 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Targher, G. et al. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin. J. Am. Soc. Nephrol. 5, 2166–2171 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Targher, G. et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 53, 1341–1348 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Targher, G. Elevated serum γ-glutamyltransferase activity is associated with increased risk of mortality, incident type 2 diabetes, cardiovascular events, chronic kidney disease and cancer - a narrative review. Clin. Chem. Lab. Med. 48, 147–157 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, D. H. et al. Gamma-glutamyltransferase and diabetes--a 4 year follow-up study. Diabetologia 46, 359–364 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Hanley, A. J. G. et al. Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 54, 3140–3147 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Monami, M. et al. Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism 57, 387–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Goessling, W. et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 135, 1935–1944 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Ford, E. S. et al. Liver enzymes and incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes Care 31, 1138–1143 (2008).

    Article  PubMed  Google Scholar 

  54. Adams, L. A., Waters, O. R., Knuiman, M. W., Elliott, R. R. & Olynyk, J. K. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am. J. Gastroenterol. 104, 861–867 (2009).

    Article  PubMed  Google Scholar 

  55. Fraser, A. et al. Alanine aminotransferase, γ-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis. Diabetes Care 32, 741–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Okamoto, M. et al. The association of fatty liver and diabetes risk. J. Epidemiol. 13, 15–21 (2003).

    Article  PubMed  Google Scholar 

  57. Fan, J. G. et al. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J. Gastroenterol. Hepatol. 22, 1086–1091 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Shibata, M., Kihara, Y., Taguchi, M., Tashiro, M. & Otsuki, M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 30, 2940–2944 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Kim, C. H., Park, J. Y., Lee, K. U., Kim, J. H. & Kim, H. K. Fatty liver is an independent risk factor for the development of Type 2 diabetes in Korean adults. Diabet. Med. 25, 476–481 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Yamada, T. et al. Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup. J. Gastroenterol. Hepatol. 25, 352–356 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Sung, K. C. & Kim, S. H. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J. Clin. Endocrinol. Metab. 96, 1093–1097 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bae, J. C. et al. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care 34, 727–729 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sung, K. C., Jeong, W. S., Wild, S. H. & Byrne, C. D. Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes. Diabetes Care 35, 717–722 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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 

  65. Targher, G., Day, C. P. & Bonora, E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341–1350 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Bhatia, L. S., Curzen, N. P., Calder, P. C. & Byrne, C. D. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur. Heart J. 33, 1190–1200 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Targher, G., Chonchol, M., Zoppini, G., Abaterusso, C. & Bonora, E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J. Hepatol. 54, 1020–1029 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Li, Y., Xu, C., Yu, C., Xu, L. & Miao, M. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J. Hepatol. 50, 1029–1034 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Sirota, J. C. et al. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 62, 392–399 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Petta, S., Camma, C., Cabibi, D., Di Marco, V. & Craxi, A. Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 34, 757–766 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Targher, G. et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr. Metab. Cardiovasc. Dis. 17, 517–524 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Hui, J. M., Farrell, G. C., Kench, J. G. & George, J. High sensitivity C-reactive protein values do not reliably predict the severity of histological changes in NAFLD. Hepatology 39, 1458–1459 (2004).

    Article  PubMed  Google Scholar 

  73. Targher, G. et al. Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 64, 679–683 (2006).

    Article  CAS  Google Scholar 

  74. Bugianesi, E. et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J. Clin. Endocrinol. Metab. 90, 3498–3504 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Targher, G. et al. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin. Thromb. Hemost. 35, 277–287 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Northup, P. G., Argo, C. K., Shah, N. & Caldwell, S. H. Hypercoagulation and thrombophilia in nonalcoholic fatty liver disease: mechanisms, human evidence, therapeutic implications, and preventive implications. Semin. Liver Dis. 32, 39–48 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Sookoian, S. et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 209, 585–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Wieckowska, A. et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372–1379 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Sookoian, S. et al. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 218, 378–385 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Greco, D. et al. Gene expression in human NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1281–G1287 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Westerbacka, J. et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 56, 2759–2765 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Villanova, N. et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 42, 473–480 (2005).

    Article  PubMed  Google Scholar 

  83. Pacifico, L. et al. Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease. Hepatology 52, 1643–1651 (2010).

    Article  PubMed  Google Scholar 

  84. Salvi, P. et al. Increased arterial stiffness in nonalcoholic fatty liver disease: the Cardio-GOOSE study. J. Hypertens. 28, 1699–1707 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Lee, Y.-J. et al. The relationship between arterial stiffness and nonalcoholic fatty liver disease. Dig. Dis. Sci. 57, 196–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Targher, G. et al. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care 27, 2498–2500 (2004).

    Article  PubMed  Google Scholar 

  87. Brea, A. et al. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler. Thromb. Vasc. Biol. 25, 1045–1050 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Volzke, H. et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J. Gastroenterol. 11, 1848–1853 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Fracanzani, A. L. et al. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am. J. Med. 121, 72–78 (2008).

    Article  PubMed  Google Scholar 

  90. Kozakova, M. et al. Fatty liver index, γ-glutamyltransferase, and early carotid plaques. Hepatology 55, 1406–1415 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Sookoian, S. & Pirola, C. J. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 49, 600–607 (2008).

    Article  PubMed  Google Scholar 

  92. Targher, G. et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 29, 1325–1330 (2006).

    Article  PubMed  Google Scholar 

  93. Colak, Y. et al. Assessment of endothelial function in patients with nonalcoholic fatty liver disease. Endocrine 43, 100–107 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Sung, K. C., Wild, S. H., Kwag, H. J. & Byrne, C. D. Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people. Diabetes Care 35, 2359–2364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Goland, S. et al. Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment. J. Clin. Gastroenterol. 40, 949–955 (2006).

    Article  PubMed  Google Scholar 

  96. Fallo, F. et al. Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension. Nutr. Metab. Cardiovasc. Dis. 19, 646–653 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Bonapace, S. et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35, 389–395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hallsworth, K. et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2012.11.015.

  99. Perseghin, G. et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47, 51–58 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Rijzewijk, L. J. et al. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J. Am. Coll. Cardiol. 56, 225–233 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Lautamaki, R. et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 291, E282–E290 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Stepanova, M. & Younossi, Z. M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin. Gastroenterol. Hepatol. 10, 646–650 (2012).

    Article  PubMed  Google Scholar 

  103. Lazo, M. et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 343, d6891 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lin, Y. C., Lo, H. M. & Chen, J. D. Sonographic fatty liver, overweight and ischemic heart disease. World J. Gastroenterol. 11, 4838–4842 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Targher, G. et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J. Hepatol. 53, 713–718 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Mirbagheri, S. A., Rashidi, A., Abdi, S., Saedi, D. & Abouzari, M. Liver: an alarm for the heart? Liver Int. 27, 891–894 (2007).

    Article  PubMed  Google Scholar 

  107. Assy, N., Djibre, A., Farah, R., Grosovski, M. & Marmor, A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology 254, 393–400 (2010).

    Article  PubMed  Google Scholar 

  108. Wong, V. W. et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 60, 1721–1727 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. 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 

  110. Dam-Larsen, S. et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53, 750–755 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rafiq, N. et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin. Gastroenterol. Hepatol. 7, 234–238 (2009).

    Article  PubMed  Google Scholar 

  112. 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 

  113. Soderberg, C. et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51, 595–602 (2010).

    Article  PubMed  Google Scholar 

  114. Jepsen, P., Vilstrup, H., Moller, J. K. & Sorensen, H. T. Prognosis of patients with liver cirrhosis and spontaneous bacterial peritonitis. Hepatogastroenterology 50, 2133–2136 (2003).

    PubMed  Google Scholar 

  115. Hamaguchi, M. et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J. Gastroenterol. 13, 1579–1584 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Targher, G. et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 30, 2119–2121 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Haring, R. et al. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum γ-glutamyl transpeptidase levels. Hepatology 50, 1403–1411 (2009).

    Article  PubMed  Google Scholar 

  118. Zhou, Y. J., Li, Y. Y., Nie, Y. Q., Huang, C. M. & Cao, C. Y. Natural course of nonalcoholic fatty liver disease in southern China: a prospective cohort study. J. Dig. Dis. 13, 153–160 (2012).

    Article  PubMed  Google Scholar 

  119. Fraser, A. et al. Gamma-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 

  120. Treeprasertsuk, S. et al. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int. 32, 945–950 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  123. Harrison, S. A., Torgerson, S. & Hayashi, P. H. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am. J. Gastroenterol. 98, 2042–2047 (2003).

    Article  PubMed  Google Scholar 

  124. Evans, C. D., Oien, K. A., MacSween, R. N. & Mills, P. R. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J. Clin. Pathol. 55, 689–692 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Adams, L. A., Sanderson, S., Lindor, K. D. & Angulo, P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 42, 132–138 (2005).

    Article  PubMed  Google Scholar 

  126. Lee, R. G. Nonalcoholic steatohepatitis: a study of 49 patients. Hum. Pathol. 20, 594–598 (1989).

    Article  CAS  PubMed  Google Scholar 

  127. Bacon, B. R., Farahvash, M. J., Janney, C. G. & Neuschwander-Tetri, B. A. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107, 1103–1109 (1994).

    Article  CAS  PubMed  Google Scholar 

  128. Fassio, E., Alvarez, E., Dominguez, N., Landeira, G. & Longo, C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 40, 820–826 (2004).

    PubMed  Google Scholar 

  129. Caldwell, S. H. et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29, 664–669 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Poonawala, A., Nair, S. P. & Thuluvath, P. J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 32, 689–692 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Porepa, L., Ray, J. G., Sanchez-Romeu, P. & Booth, G. L. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ 182, 526–531 (2010).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  133. Parkin, D. M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Starley, B. Q., Calcagno, C. J. & Harrison, S. A. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51, 1820–1832 (2010).

    Article  PubMed  Google Scholar 

  135. Hashimoto, E. et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J. Gastroenterol. 44 (Suppl. 19), 89–95 (2009).

    Article  PubMed  Google Scholar 

  136. 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 

  137. El-Serag, H. B. & Rudolph, K. L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557–2576 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).

    PubMed  Google Scholar 

  139. Moller, H., Mellemgaard, A., Lindvig, K. & Olsen, J. H. Obesity and cancer risk: a Danish record-linkage study. Eur. J. Cancer 30A, 344–350 (1994).

    Article  CAS  PubMed  Google Scholar 

  140. Oh, S. W., Yoon, Y. S. & Shin, S. A. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J. Clin. Oncol. 23, 4742–4754 (2005).

    Article  PubMed  Google Scholar 

  141. El-Serag, H. B., Tran, T. & Everhart, J. E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126, 460–468 (2004).

    Article  PubMed  Google Scholar 

  142. Guzman, G. et al. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch. Pathol. Lab. Med. 132, 1761–1766 (2008).

    PubMed  Google Scholar 

  143. Bonora, E. & Targher, G. Increased risk of cardiovascular disease and chronic kidney disease in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 9, 372–381 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Ix, J. H. & Sharma, K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J. Am. Soc. Nephrol. 21, 406–412 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yki-Jarvinen, H. Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Dig. Dis. 28, 203–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Badman, M. K. & Flier, J. S. The adipocyte as an active participant in energy balance and metabolism. Gastroenterology 132, 2103–2115 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Shoelson, S. E., Herrero, L. & Naaz, A. Obesity, inflammation, and insulin resistance. Gastroenterology 132, 2169–2180 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Stefan, N., Kantartzis, K. & Haring, H.-U. Causes and metabolic consequences of fatty liver. Endocr. Rev. 29, 939–960 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Tilg, H. & Moschen, A. R. Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol. Metab. 19, 371–379 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Yamaguchi, K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366–1374 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Malhi, H., Gores, G. J. & Lemasters, J. J. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31–S44 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Anstee, Q. M. et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53, 542–550 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Farrell, G. C. et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J. Gastroenterol. Hepatol. 24, 443–452 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Iredale, J. P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 117, 539–548 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Anstee, Q. M., Daly, A. K. & Day, C. P. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin. Liver Dis. 31, 128–146 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Anstee, Q. M. & Goldin, R. D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int. J. Exp. Pathol. 87, 1–16 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. McCarthy, M. I. & Zeggini, E. Genome-wide association studies in type 2 diabetes. Curr. Diab. Rep. 9, 164–171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Anstee, Q. M., Daly, A. K. & Day, C. P. Genetic modifiers of non-alcoholic fatty liver disease progression. Biochim. Biophysica Acta 1812, 1557–1566 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 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 

  163. 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 

  164. Anstee, Q. M. et al. Genome-wide association analysis confirms importance of PNPLA3 and identifies novel variants associated with histologically progressive fibrosing steatohepatitis in NAFLD [abstract 146]. Hepatology 56 (Suppl.), 265A–266A (2012).

    Google Scholar 

  165. 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 

  166. 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 

  167. Kotronen, A. et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 52, 1056–1060 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Sookoian, S. et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 50, 2111–2116 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kantartzis, K. et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 58, 2616–2623 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Rotman, Y., Koh, C., Zmuda, J. M., Kleiner, D. E. & Liang, T. J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52, 894–903 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Namikawa, C. et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J. Hepatol. 40, 781–786 (2004).

    Article  CAS  PubMed  Google Scholar 

  172. 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 

  173. 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 

  174. Song, J. et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). Faseb J. 19, 1266–1271 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Narla, G. et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res. 65, 1213–1222 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. 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 

  177. Romeo, S., Huang-Doran, I., Baroni, M. G. & Kotronen, A. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein. Curr. Opin. Lipidol. 21, 247–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  178. Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383–1386 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Kollerits, B. et al. A common variant in the adiponutrin gene influences liver enzyme values. J. Med. Genet. 47, 116–119 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Li, J. Z. et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130–4144 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Thoma, C., Day, C. P. & Trenell, M. I. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J. Hepatol. 56, 255–266 (2012).

    Article  PubMed  Google Scholar 

  182. Hallsworth, K. et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 60, 1278–1283 (2011).

    Article  PubMed  Google Scholar 

  183. Kerr, T. A. & Davidson, N. O. Cholesterol and nonalcoholic fatty liver disease: Renewed focus on an old villain. Hepatology 56, 1995–1998 (2012).

    Article  PubMed  Google Scholar 

  184. Ouyang, X. et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol. 48, 993–999 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J. M. & Lustig, R. H. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat. Rev. Gastroenterol. Hepatol. 7, 251–264 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Abdelmalek, M. F. et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51, 1961–1971 (2010).

    Article  CAS  PubMed  Google Scholar 

  187. Bergheim, I. et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J. Hepatol. 48, 983–992 (2008).

    Article  CAS  PubMed  Google Scholar 

  188. Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Spruss, A. et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 1094–1104 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Payne, J. H., Dewind, L. T. & Commons, R. R. Metabolic observations in patients with jejunocolic shunts. Am. J. Surg. 106, 273–289 (1963).

    Article  CAS  PubMed  Google Scholar 

  191. Catlin, R. Liver dysfunction after intestinal bypass. JAMA 236, 1693–1694 (1976).

    Article  CAS  PubMed  Google Scholar 

  192. Wigg, A. J. et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48, 206–211 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877–1887 (2009).

    Article  CAS  PubMed  Google Scholar 

  194. Harte, A. L. et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J. Inflamm. (Lond.) 7, 15 (2010).

    Article  CAS  Google Scholar 

  195. Weinstock, G. M. Genomic approaches to studying the human microbiota. Nature 489, 250–256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Abu-Shanab, A. & Quigley, E. M. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 7, 691–701 (2010).

    Article  PubMed  Google Scholar 

  197. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Musso, G. et al. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology 47, 1167–1177 (2008).

    Article  CAS  PubMed  Google Scholar 

  200. Kotronen, A. et al. Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts. Eur. J. Endocrinol. 160, 593–602 (2009).

    Article  CAS  PubMed  Google Scholar 

  201. Yoneda, M. et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int. 29, 1078–1085 (2009).

    Article  CAS  PubMed  Google Scholar 

  202. Dixon, J. B. et al. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J. Hepatol. 39, 967–971 (2003).

    Article  CAS  PubMed  Google Scholar 

  203. Petersen, K. F. et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N. Engl. J. Med. 362, 1082–1089 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Valenti, L. et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage in patients with nonalcoholic fatty liver. J. Hepatol. 55, 1409–1414 (2012).

    Article  CAS  Google Scholar 

  205. Sazci, A. et al. Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis. Dig. Dis. Sci. 53, 3218–3224 (2008).

    Article  CAS  PubMed  Google Scholar 

  206. Demirag, M. D. et al. Apolipoprotein E gene polymorphism in nonalcoholic fatty liver disease. Dig. Dis. Sci. 52, 3399–3403 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Sookoian, S., Castano, G., Gianotti, T. F., Gemma, C. & Pirola, C. J. Polymorphisms of MRP2 (ABCC2) are associated with susceptibility to nonalcoholic fatty liver disease. J. Nutr. Biochem. 20, 765–770 (2009).

    Article  CAS  PubMed  Google Scholar 

  208. Day, C. P., Leathart, J., McTernan, P., Mathew, C. & Daly, A. Genetic evidence for a role of gut flora in the pathogenesis of NASH in humans. Hepatology 44 (Suppl. 1), 261A (2006).

    Google Scholar 

  209. Dongiovanni, P. et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 59, 267–273 (2010).

    Article  CAS  PubMed  Google Scholar 

  210. Carulli, L. et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig. Liver Dis. 41, 823–828 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Oliveira, C. P. et al. Association of polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 25, 357–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  212. George, D. K. et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114, 311–318 (1998).

    Article  CAS  PubMed  Google Scholar 

  213. Nelson, J. E. et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology 46, 723–729 (2007).

    Article  CAS  PubMed  Google Scholar 

  214. 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 

  215. Nobili, V., Daly, A. K., Al-Serri, A., Leathart, J. B. & Day, C. P. The mitochondrial superoxide dismutase 2 (SOD2) targeting sequence polymorphism is associated with fibrotic NAFLD: consistent evidence from case-control and intra-familial allelic association studies. Hepatology 46, 760A (2007).

    Google Scholar 

  216. Sazci, A. et al. Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH). Cell Biochem. Funct. 26, 291–296 (2008).

    Article  CAS  PubMed  Google Scholar 

  217. Sookoian, S. et al. The nuclear receptor PXR gene variants are associated with liver injury in nonalcoholic fatty liver disease. Pharmacogenet. Genomics 20, 1–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  218. Musso, G. et al. Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH. Hepatology 49, 426–435 (2009).

    Article  CAS  PubMed  Google Scholar 

  219. Valenti, L. et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 122, 274–280 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Q. M. Anstee would like to acknowledge the support of a Clinical Senior Lectureship Award from the Higher Education Funding Council for England (HEFCE). Q. M. Anstee and C. P. Day are members of the European Union FP7-funded Fatty Liver Inhibition of Progression (FLIP) Consortium.

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  1. Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK

    Quentin M. Anstee & Christopher P. Day

  2. Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Ospedale Civile Maggiore, Piazzale Stefani 1, Verona, 37126, Italy

    Giovanni Targher

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Anstee, Q., Targher, G. & Day, C. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10, 330–344 (2013). https://doi.org/10.1038/nrgastro.2013.41

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