Nonobese Fatty Liver Disease

Clinical Gastroenterology and Hepatology

Volumn 15, Issue 4, 2017, Pages 474-485

  Kim, Donghee ^a   Kim, W Ray ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Body Mass Index; Hepatic Steatosis; Lean; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; Nonobese; Nonoverweight

Indexed keywords

ALANINE AMINOTRANSFERASE; CHOLESTEROL ESTER TRANSFER PROTEIN; FERRITIN; FRUCTOSE; GLUCOSE; GLYCOSYLATED HEMOGLOBIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; TRIACYLGLYCEROL; URIC ACID;

AGE; ALANINE AMINOTRANSFERASE BLOOD LEVEL; BODY FAT; BODY MASS; CARBOHYDRATE INTAKE; CETP GENE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL INTAKE; DIABETES MELLITUS; FERRITIN BLOOD LEVEL; GENDER; GENE; GENETIC POLYMORPHISM; GLUCOSE BLOOD LEVEL; HEMOGLOBIN BLOOD LEVEL; HISTOLOGY; HOMEOSTASIS MODEL ASSESSMENT; HUMAN; INSULIN RESISTANCE; INTRAPERITONEAL FAT; LIFESTYLE MODIFICATION; MAGNETIC RESONANCE ELASTOGRAPHY; METABOLIC SYNDROME X; NONALCOHOLIC FATTY LIVER; OBESITY; PHYSICAL ACTIVITY; PNPLA3 GENE; PREVALENCE; PROGNOSIS; REVIEW; SAGITTAL ABDOMINAL DIAMETER; SKINFOLD THICKNESS; SREBF GENE; TM6SF2 GENE; TRANSIENT ELASTOGRAPHY; TRIACYLGLYCEROL BLOOD LEVEL; URIC ACID BLOOD LEVEL; WAIST CIRCUMFERENCE; WEIGHT REDUCTION; ETHNIC GROUP; EXERCISE; FEEDING BEHAVIOR; GENETIC PREDISPOSITION; LIFESTYLE; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; SURVIVAL ANALYSIS;

ETHNIC GROUPS; EXERCISE; FEEDING BEHAVIOR; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LIFE STYLE; NON-ALCOHOLIC FATTY LIVER DISEASE; PREVALENCE; SURVIVAL ANALYSIS;

EID: 85007591985     PISSN: 15423565     EISSN: 15427714     Source Type: Journal    
DOI: 10.1016/j.cgh.2016.08.028     Document Type: Review

References (131)

1. 1 Clark, J.M., The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40:Suppl 1 (2006), S5–S10.
2. 2 Erickson, S.K., Nonalcoholic fatty liver disease. J Lipid Res 50:Suppl (2009), S412–S416.
3. 3 Khashab, M.A., Liangpunsakul, S., Chalasani, N., Nonalcoholic fatty liver disease as a component of the metabolic syndrome. Curr Gastroenterol Rep 10 (2008), 73–80.
4. 4 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 (2011), 274–285.
5. 5 Adams, L.A., Lymp, J.F., St Sauver, J., et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129 (2005), 113–121.
6. 6 Ekstedt, M., Franzen, L.E., Mathiesen, U.L., et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44 (2006), 865–873.
7. 7 Machado, M., Marques-Vidal, P., Cortez-Pinto, H., Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 45 (2006), 600–606.
8. 8 Das, K., Das, K., Mukherjee, P.S., et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51 (2010), 1593–1602.
9. 9 Alberti, K.G., Zimmet, P., Shaw, J., et al. The metabolic syndrome–a new worldwide definition. Lancet 366 (2005), 1059–1062.
10. 10 Browning, J.D., Szczepaniak, L.S., Dobbins, R., et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40 (2004), 1387–1395.
11. 11 Foster, T., Anania, F.A., Li, D., et al. The prevalence and clinical correlates of nonalcoholic fatty liver disease (NAFLD) in African Americans: the Multiethnic Study of Atherosclerosis (MESA). Dig Dis Sci 58 (2013), 2392–2398.
12. 12 Younossi, Z.M., Stepanova, M., Negro, F., et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 91 (2012), 319–327.
13. 13 Kim, D., Kim, W., Non-overweight fatty liver disease (NOFLD): a distinct entity?. Hepatology 56 (2012), A886–A887.
14. 14 Bellentani, S., Saccoccio, G., Masutti, F., et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 132 (2000), 112–117.
15. 15 Kwon, Y.M., Oh, S.W., Hwang, S.S., 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 (2012), 1852–1858.
16. 16 Sinn, D.H., Gwak, G.Y., Park, H.N., et al. Ultrasonographically detected non-alcoholic fatty liver disease is an independent predictor for identifying patients with insulin resistance in non-obese, non-diabetic middle-aged Asian adults. Am J Gastroenterol 107 (2012), 561–567.
17. 17 Wood, N.J., Liver: nonobese individuals in the developing world are at risk of nonalcoholic fatty liver and liver disease. Nat Rev Gastroenterol Hepatol, 7, 2010, 357.
18. 18 Xu, C., Yu, C., Ma, H., et al. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol 108 (2013), 1299–1304.
19. 19 Wei, J.L., Leung, J.C., Loong, T.C., et al. Prevalence and severity of nonalcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Am J Gastroenterol 110 (2015), 1306–1314 quiz 15.
20. 20 Omagari, K., Kadokawa, Y., Masuda, J., et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 17 (2002), 1098–1105.
21. 21 Kim, H.J., Kim, H.J., Lee, K.E., et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 164 (2004), 2169–2175.
22. 22 Fan, J.G., Zhu, J., Li, X.J., et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 43 (2005), 508–514.
23. 23 Chen, C.H., Huang, M.H., Yang, J.C., et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol 40 (2006), 745–752.
24. 24 Park, S.H., Jeon, W.K., Kim, S.H., et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 21 (2006), 138–143.
25. 25 Dassanayake, A.S., Kasturiratne, A., Rajindrajith, S., et al. Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population. J Gastroenterol Hepatol 24 (2009), 1284–1288.
26. 26 Fu, C.C., Chen, M.C., Li, Y.M., et al. The risk factors for ultrasound-diagnosed non-alcoholic fatty liver disease among adolescents. Ann Acad Med Singapore 38 (2009), 15–17.
27. 27 Lankarani, K.B., Ghaffarpasand, F., Mahmoodi, M., et al. Non alcoholic fatty liver disease in southern Iran: a population based study. Hepat Mon, 13, 2013, e9248.
28. 28 Nishioji, K., Sumida, Y., Kamaguchi, M., et al. Prevalence of and risk factors for non-alcoholic fatty liver disease in a non-obese Japanese population, 2011-2012. J Gastroenterol 50 (2015), 95–108.
29. 29 Marchesini, G., Bugianesi, E., Forlani, G., et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37 (2003), 917–923.
30. 30 Manco, M., Alisi, A., Real, J.M., et al. Early interplay of intra-hepatic iron and insulin resistance in children with non-alcoholic fatty liver disease. J Hepatol 55 (2011), 647–653.
31. 31 Vos, B., Moreno, C., Nagy, N., et al. Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. Acta Gastroenterol Belg 74 (2011), 389–394.
32. 32 Margariti, A., Deutsch, M., Manolakopoulos, S., et al. The severity of histologic liver lesions is independent of body mass index in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol 47 (2013), 280–286.
33. 33 Akyuz, U., Yesil, A., Yilmaz, Y., Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. Scand J Gastroenterol, 2014, 1–6.
34. 34 Alam, S., Gupta, U.D., Alam, M., et al. Clinical, anthropometric, biochemical, and histological characteristics of nonobese nonalcoholic fatty liver disease patients of Bangladesh. Indian J Gastroenterol 33 (2014), 452–457.
35. 35 Leung, J.C., Loong, T.C., Wei, J.L., et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in non-obese patients. Hepatology, 2016 Jun 23 http://dx.doi.org/10.1002/hep.28697 Epub ahead of print.
36. 36 Dela Cruz, A., Bugianesi, E., George, J., et al. Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology, 146, 2014, S-909.
37. 37 Bluher, M., The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 21 (2010), 38–43.
38. 38 Karelis, A.D., St-Pierre, D.H., Conus, F., et al. Metabolic and body composition factors in subgroups of obesity: what do we know?. J Clin Endocrinol Metab 89 (2004), 2569–2575.
39. 39 Stefan, N., Kantartzis, K., Machann, J., et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 168 (2008), 1609–1616.
40. 40 Messier, V., Karelis, A.D., Robillard, M.E., et al. Metabolically healthy but obese individuals: relationship with hepatic enzymes. Metabolism 59 (2010), 20–24.
41. 41 Wildman, R.P., Muntner, P., Reynolds, K., et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med 168 (2008), 1617–1624.
42. 42 Ruderman, N., Chisholm, D., Pi-Sunyer, X., et al. The metabolically obese, normal-weight individual revisited. Diabetes 47 (1998), 699–713.
43. 43 Kennedy, A.P., Shea, J.L., Sun, G., Comparison of the classification of obesity by BMI vs. dual-energy X-ray absorptiometry in the Newfoundland population. Obesity (Silver Spring) 17 (2009), 2094–2099.
44. 44 Shea, J.L., Randell, E.W., Sun, G., The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry. Obesity (Silver Spring) 19 (2011), 624–630.
45. 45 Stommel, M., Schoenborn, C.A., Variations in BMI and prevalence of health risks in diverse racial and ethnic populations. Obesity (Silver Spring) 18 (2010), 1821–1826.
46. 46 Cusi, K., Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142 (2012), 711–725 e6.
47. 47 Lomonaco, R., Ortiz-Lopez, C., Orsak, B., et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55 (2012), 1389–1397.
48. 48 Farrell, G.C., Larter, C.Z., Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43:Suppl 1 (2006), S99–S112.
49. 49 Farrell, G.C., Chitturi, S., Lau, G.K., et al. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J Gastroenterol Hepatol 22 (2007), 775–777.
50. 50 Finelli, C., Tarantino, G., Is visceral fat reduction necessary to favour metabolic changes in the liver?. J Gastrointest Liver Dis 21 (2012), 205–208.
51. 51 Yim, J.Y., Kim, D., Lim, S.H., et al. Sagittal abdominal diameter is a strong anthropometric measure of visceral adipose tissue in the Asian general population. Diabetes Care 33 (2010), 2665–2670.
52. 52 Kuk, J.L., Lee, S., Heymsfield, S.B., et al. Waist circumference and abdominal adipose tissue distribution: influence of age and sex. Am J Clin Nutr 81 (2005), 1330–1334.
53. 53 McLaughlin, T., Lamendola, C., Liu, A., et al. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol Metab 96 (2011), E1756–E1760.
54. 54 Freedland, E.S., Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutr Metab, 1, 2004, 12.
55. 55 Ayonrinde, O.T., Olynyk, J.K., Beilin, L.J., et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology 53 (2011), 800–809.
56. 56 Conus, F., Allison, D.B., Rabasa-Lhoret, R., et al. Metabolic and behavioral characteristics of metabolically obese but normal-weight women. J Clin Endocrinol Metab 89 (2004), 5013–5020.
57. 57 Katsuki, A., Sumida, Y., Urakawa, H., et al. Increased visceral fat and serum levels of triglyceride are associated with insulin resistance in Japanese metabolically obese, normal weight subjects with normal glucose tolerance. Diabetes Care 26 (2003), 2341–2344.
58. 58 Park, B.J., Kim, Y.J., Kim, D.H., et al. Visceral adipose tissue area is an independent risk factor for hepatic steatosis. J Gastroenterol Hepatol 23 (2008), 900–907.
59. 59 Hamaguchi, M., Kojima, T., Itoh, Y., et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 102 (2007), 2708–2715.
60. 60 Kim, D., Park, B.J., Kim, W., et al. Visceral fat as a strong and independent risk factor of nonalcoholic fatty liver disease. Gastroenterology 134 (2008), A782–A783.
61. 61 Eguchi, Y., Eguchi, T., Mizuta, T., et al. Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 41 (2006), 462–469.
62. 62 Kim, D., Chung, G.E., Kwak, M.S., et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 14 (2016), 132–138 e4.
63. 63 Meng, K., Lee, C.H., Saremi, F., Metabolic syndrome and ectopic fat deposition: what can CT and MR provide?. Acad Radiol 17 (2010), 1302–1312.
64. 64 Larter, C.Z., Chitturi, S., Heydet, D., et al. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol 25 (2010), 672–690.
65. 65 Nazare, J.A., Smith, J.D., Borel, A.L., et al. Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile: the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity. Am J Clin Nutr 96 (2012), 714–726.
66. 66 Zelber-Sagi, S., Lotan, R., Shlomai, A., et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 56 (2012), 1145–1151.
67. 67 Chang, Y., Ryu, S., Sung, E., et al. Weight gain within the normal weight range predicts ultrasonographically detected fatty liver in healthy Korean men. Gut 58 (2009), 1419–1425.
68. 68 Kim, H.K., Park, J.Y., Lee, K.U., et al. Effect of body weight and lifestyle changes on long-term course of nonalcoholic fatty liver disease in Koreans. Am J Med Sci 337 (2009), 98–102.
69. 69 Wong, V.W., Wong, G.L., Yeung, D.K., et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol 62 (2015), 182–189.
70. 70 Musso, G., Gambino, R., De Michieli, F., et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37 (2003), 909–916.
71. 71 Yasutake, K., Nakamuta, M., Shima, Y., et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand J Gastroenterol 44 (2009), 471–477.
72. 72 Enjoji, M., Yasutake, K., Kohjima, M., et al. Nutrition and nonalcoholic fatty liver disease: the significance of cholesterol. Int J Hepatol, 2012, 2012, 925807.
73. 73 Kainuma, M., Fujimoto, M., Sekiya, N., et al. Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis. J Gastroenterol 41 (2006), 971–980.
74. 74 Matsuzawa, N., Takamura, T., Kurita, S., et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46 (2007), 1392–1403.
75. 75 Wouters, K., van Gorp, P.J., Bieghs, V., et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 48 (2008), 474–486.
76. 76 Nakamuta, M., Kohjima, M., Higuchi, N., et al. The significance of differences in fatty acid metabolism between obese and non-obese patients with non-alcoholic fatty liver disease. Int J Mol Med 22 (2008), 663–667.
77. 77 McCarthy, E.M., Rinella, M.E., The role of diet and nutrient composition in nonalcoholic fatty liver disease. J Acad Nutr Diet 112 (2012), 401–409.
78. 78 Pagadala, M.R., McCullough, A.J., Non-alcoholic fatty liver disease and obesity: not all about body mass index. Am J Gastroenterol 107 (2012), 1859–1861.
79. 79 Enjoji, M., Machida, K., Kohjima, M., et al. NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease. Lipids Health Dis, 9, 2010, 29.
80. 80 Loomba, R., Sirlin, C.B., Ang, B., et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 61 (2015), 1239–1250.
81. 81 Zelber-Sagi, S., Nitzan-Kaluski, D., Goldsmith, R., et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 47 (2007), 711–717.
82. 82 Assy, N., Nasser, G., Kamayse, I., et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 22 (2008), 811–816.
83. 83 Abid, A., Taha, O., Nseir, W., et al. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 51 (2009), 918–924.
84. 84 Schwimmer, J.B., Celedon, M.A., Lavine, J.E., et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136 (2009), 1585–1592.
85. 85 Romeo, S., Kozlitina, J., Xing, C., et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40 (2008), 1461–1465.
86. 86 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 (2011), 1883–1894.
87. 87 Liu, Y.L., Patman, G.L., Leathart, J.B., 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 (2014), 75–81.
88. 88 Singal, A.G., Manjunath, H., Yopp, A.C., et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 109 (2014), 325–334.
89. 89 Rotman, Y., Koh, C., Zmuda, J.M., et al. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52 (2010), 894–903.
90. 90 Speliotes, E.K., Butler, J.L., Palmer, C.D., et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52 (2010), 904–912.
91. 91 Valenti, L., Al-Serri, A., Daly, A.K., et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51 (2010), 1209–1217.
92. 92 Lallukka, S., Sevastianova, K., Perttila, J., et al. Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3. Diabetologia 56 (2013), 886–892.
93. 93 Shen, J., Wong, G.L., Chan, H.L., et al. PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome. Aliment Pharmacol Ther 39 (2014), 532–539.
94. 94 Ioannou, G.N., Beyond obesity: is cholesterol-induced liver injury the cause of non-alcoholic steatohepatitis?. J Gastroenterol Hepatol 27 (2012), 1412–1414.
95. 95 Adams, L.A., Marsh, J.A., Ayonrinde, O.T., et al. Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity. J Gastroenterol Hepatol 27 (2012), 1520–1527.
96. 96 Musso, G., Gambino, R., Cassader, M., Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res 52 (2013), 175–191.
97. 97 Caballero, F., Fernandez, A., De Lacy, A.M., et al. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol 50 (2009), 789–796.
98. 98 Musso, G., Cassader, M., Bo, S., et al. Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism. Diabetes 62 (2013), 1109–1120.
99. 99 Kozlitina, J., Smagris, E., Stender, S., et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 46 (2014), 352–356.
100. 100 Liu, Y.L., Reeves, H.L., Burt, A.D., et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun, 5, 2014, 4309.
101. 101 Dongiovanni, P., Petta, S., Maglio, C., et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61 (2015), 506–514.
102. 102 Mahdessian, H., Taxiarchis, A., Popov, S., et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 111 (2014), 8913–8918.
103. 103 Stepanova, M., Rafiq, N., Younossi, Z.M., Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut 59 (2010), 1410–1415.
104. 104 European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO), EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64 (2016), 1388–1402.
105. 105 Kim, D., Kim, W.R., Kim, H.J., et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 57 (2013), 1357–1365.
106. 106 Angulo, P., Kleiner, D.E., Dam-Larsen, S., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149 (2015), 389–397 e10.
107. 107 Younossi, Z.M., Stepanova, M., Rafiq, N., et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 53 (2011), 1874–1882.
108. 108 McPherson, S., Stewart, S.F., Henderson, E., et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 59 (2010), 1265–1269.
109. 109 Musso, G., Gambino, R., Cassader, M., et al. 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 (2011), 617–649.
110. 110 Shah, A.G., Lydecker, A., Murray, K., et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 7 (2009), 1104–1112.
111. 111 Wong, V.W., Wong, G.L., Chim, A.M., et al. Validation of the NAFLD fibrosis score in a Chinese population with low prevalence of advanced fibrosis. Am J Gastroenterol 103 (2008), 1682–1688.
112. 112 Fujii, H., Enomoto, M., Fukushima, W., et al. Applicability of BARD score to Japanese patients with NAFLD. Gut 58 (2009), 1566–1567 author reply 7.
113. 113 Yu, S.J., Kim, D.H., Lee, J.H., et al. Validation of P2/MS and other noninvasive fibrosis scoring systems in the Korean population with nonalcoholic fatty liver disease. Korean J Gastroenterol 57 (2011), 19–27.
114. 114 Nobili, V., Vizzutti, F., Arena, U., et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 48 (2008), 442–448.
115. 115 Wong, V.W., Vergniol, J., Wong, G.L., et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51 (2010), 454–462.
116. 116 Chen, J., Talwalkar, J.A., Yin, M., et al. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 259 (2011), 749–756.
117. 117 Kim, D., Kim, W.R., Talwalkar, J.A., et al. Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology 268 (2013), 411–419.
118. 118 Castera, L., Foucher, J., Bernard, P.H., et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 51 (2010), 828–835.
119. 119 Chalasani, N., Younossi, Z., Lavine, J.E., 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 (2012), 1592–1609.
120. 120 Wong, V.W., Chan, R.S., Wong, G.L., et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol 59 (2013), 536–542.
121. 121 Jin, Y.J., Kim, K.M., Hwang, S., et al. Exercise and diet modification in non-obese non-alcoholic fatty liver disease: analysis of biopsies of living liver donors. J Gastroenterol Hepatol 27 (2012), 1341–1347.
122. 122 Shen, J., Wong, G.L., Chan, H.L., et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 30 (2015), 139–146.
123. 123 Sevastianova, K., Kotronen, A., Gastaldelli, A., et al. Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. Am J Clin Nutr 94 (2011), 104–111.
124. 124 Marzuillo, P., Grandone, A., Perrone, L., et al. Weight loss allows the dissection of the interaction between abdominal fat and PNPLA3 (adiponutrin) in the liver damage of obese children. J Hepatol 59 (2013), 1143–1144.
125. 125 van der Poorten, D., Milner, K.L., Hui, J., et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48 (2008), 449–457.
126. 126 Zelber-Sagi, S., Nitzan-Kaluski, D., Goldsmith, R., et al. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology 48 (2008), 1791–1798.
127. 127 Magkos, F., Exercise and fat accumulation in the human liver. Curr Opin Lipidol 21 (2010), 507–517.
128. 128 Hallsworth, K., Fattakhova, G., Hollingsworth, K.G., et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 60 (2011), 1278–1283.
129. 129 Bae, J.C., Suh, S., Park, S.E., 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, 2012, e46819.
130. 130 Tamura, Y., Tanaka, Y., Sato, F., et al. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 90 (2005), 3191–3196.
131. 131 Kwak, M.S., Kim, D., Chung, G.E., et al. Role of physical activity in nonalcoholic fatty liver disease in terms of visceral obesity and insulin resistance. Liver Int 35 (2015), 944–952.