NAFLD in Asia -As common and important as in the West

Nature Reviews Gastroenterology and Hepatology

Volumn 10, Issue 5, 2013, Pages 307-318

  Farrell, Geoffrey C ^a   Wong, Vincent Wai Sun ^b   Chitturi, Shiv ^a  

^a AUSTRALIAN NATIONAL UNIVERSITY   (Australia)

^b CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIRETROVIRUS AGENT; APOLIPOPROTEIN C3; ATORVASTATIN; CORTICOSTEROID; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; METFORMIN; PENTOXIFYLLINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; PNPLA3 PROTEIN; SITAGLIPTIN; TAMOXIFEN; TRIACYLGLYCEROL LIPASE; UNCLASSIFIED DRUG;

ABDOMINAL OBESITY; AGE; ASIAN; BODY COMPOSITION; BODY MASS; CARDIOVASCULAR DISEASE; DIETARY INTAKE; DISEASE ASSOCIATION; DISEASE COURSE; DISEASE PREDISPOSITION; DISEASE SEVERITY; DRUG EFFICACY; DRUG SAFETY; EATING HABIT; END STAGE LIVER DISEASE; EUROPE; FATTY LIVER; GENDER; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; HEPATITIS C; HEPATOCYTE BALLOONING; HUMAN; INSULIN RESISTANCE; LIFESTYLE MODIFICATION; LIPID METABOLISM; LIVER CARCINOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER PROTECTION; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NUTRITION; OBESITY; PANDEMIC; PATHOGENESIS; PHYSICAL ACTIVITY; PREVALENCE; PRIORITY JOURNAL; PUBLIC HEALTH; REVIEW; RISK FACTOR; TOXIC HEPATITIS; UNITED STATES;

ASIA; FATTY LIVER; GENETIC PREDISPOSITION TO DISEASE; GENOTYPE; HUMANS; PREVALENCE; RISK FACTORS;

EID: 84877585029     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2013.34     Document Type: Review

References (166)

1. Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis; Mayo experience with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434-438 (1980).
2. Yoshitoshi, Y. Clinical aspects of fatty liver [Japanese]. Chiryo 46, 1-12 (1964).
3. Maruhama, Y. et al. Interactions of obesity and glucose-stimulated insulin secretion in familial hypertriglyceridemia. Diabetes 27, 682-693 (1978).
4. Farrell, G. C. NASH: What is it, and why is it important in the Asia-Pacific region? J. Gastroenterol. Hepatol. 18, 124-138 (2003).
5. Chitturi, S., Farrell, G. C. & George, J. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock? J. Gastroenterol. Hepatol. 19, S242-S250 (2004).
6. Okanoue, T., Umemura, A., Yasui, K. & Itoh, Y. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan. J. Gastroenterol. Hepatol. 26 (Suppl. 1), S153-S163 (2011).
7. Chitturi, S., Wong V. W.-S. & Farrell, G. C. Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground. J. Gastroenterol. Hepatol. 26 (Suppl. 1), S163-S172 (2011).
8. Wong, V. W. Non-alcoholic fatty liver disease in Asia-A story of growth. J. Gastroenterol. Hepatol. 28, 18-23 (2013).
9. Chitturi, S. et al. Non-alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J. Gastroenterol. Hepatol. 22, 778-787 (2007).
10. Farrell, G. C. 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, 775-777 (2007).
11. Amarapurkar, D. N. et al. How common is non-alcoholic fatty liver disease in the Asia-Pacific region, and are there local differences? J. Gastroenterol. Hepatol. 22, 788-793 (2007).
12. Fan J.-G. et al. What are the risk factors for non-alcoholic fatty liver disease in Asia-Pacific? J. Gastroenterol. Hepatol. 22, 794-800 (2007).
13. Chan H. L, et al. How should we manage patients with non-alcoholic fatty liver disease in 2007? J. Gastroenterol. Hepatol. 22, 801-808 (2007).
14. Ratzui, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position paper on NAFLD/NASH based on the EASL special conference. J. Hepatol. 53, 372-384 (2010).
15. 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).
16. Larter, C. Z., Chitturi, S., Heydet, D. & Farrell, G. C. A fresh look at NASH pathogenesis. Part 1: The metabolic movers. J. Gastroenterol. Hepatol. 25, 672-690 (2010).
17. Angulo, P. Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts. Hepatology 53, 1792-1794 (2011).
18. Dunn, W., Xu, R. & Schwimmer, J. B. Modest wine drinking and decreased prevalence of suspected non-alcoholic fatty liver disease. Hepatology 47, 1947-1954 (2008).
19. Dunn, W., et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J. Hepatol. 57, 384-391 (2012).
20. Dixon, J. B., Bhathal, P. S. & O'Brien, P. E. Nonalcoholic fatty liver disease: predictors of non-alcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121, 91-100 (2001).
21. Davies, M. J. et al. Effects of moderate alcohol intake on fasting serum insulin and glucose concentrations and insulin sensitivity in postmenopausal women. JAMA 287, 2559-2562 (2002).
22. Di Castelnuovo, A. et al. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch. Int. Med. 166, 2437-2445 (2006).
23. Hamaguchi, M. et al. Protective effect of alcohol consumption for fatty liver but not metabolic syndrome. World J. Gastroenterol. 18, 156-167 (2012).
24. Wong, V. W. et al. Hepatitis B virus infection and fatty liver in the general population. J. Hepatol. 56, 533-540 (2012).
25. Shi, J. P. et al. Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection. J. Gastroenterol. Hepatol. 23, 1419-1425 (2008).
26. Wong, G. L. et al. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 58, 111-117 (2009).
27. Yakoo, T., Tang, A. & Sirlin, C. in Non-alcoholic fatty liver disease. A practical guide (eds Farrell, G. C., Day, C. P., McCullough, A. J.) Wiley Blackwell 352 pages (in press).
28. Saadeh, S. et al. The utility of radiological imaging in non-alcoholic fatty liver disease. Gastroenterology 123, 745-750 (2002).
29. Wong, V. W. et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut 61, 409-415 (2012).
30. Brunt, E. M. & Tiniakos, D. G. Histopathology of non-alcoholic fatty liver disease. World J. Gastroenterol. 16, 5286-5296 (2010).
31. Neuschwander-Tetri, B. A. et al. Clinical, laboratory and histological associations in adults with non-alcoholic fatty liver disease. Hepatology 52, 913-924 (2010).
32. Younossi, Z. M. et al. Pathologic criteria for non-alcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 53, 1874-1882 (2011).
33. Wong, V. W. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51, 454-462 (2010).
34. Wong, G. L. et al. Factors associated with unreliable liver stiffness measurement and its failure with transient elastography in the Chinese population. J. Gastroenterol. Hepatol. 26, 300-305 (2011).
35. Hashimoto, E., Tokushige, K. & Farrell, G. C. Histological features of non-alcoholic fatty liver disease: what is important? J. Gastroenterol. Hepatol. 27, 5-7 (2012).
36. Chalasani, N. et al. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. J. Hepatol. 48, 829-834 (2008).
37. Guy, C. D. et al. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum. Pathol. 43, 790-800 (2012).
38. Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865-873 (2006).
39. Argo, C. K., Northup, P. G., Al-Osaimi, A. M. & Caldwell, S. H. Systematic review of risk factors for fibrotic progression in non-alcoholic steatohepatitis. J. Hepatol. 51, 371-379 (2009).
40. 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).
41. Wong, V. W. et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59, 969-974 (2010).
42. Ratziu, V. et al. Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability. Aliment. Pharmacol. Ther. 26, 821-830 (2007).
43. Bugianesi, E. et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123, 134-140 (2002).
44. Caldwell, S. H. et al. NASH and cryptogenic cirrhosis: a histological analysis. Ann. Hepatol. 8, 346-352 (2009).
45. Lee, K. Relationship between uric acid and hepatic steatosis among Koreans. Diabetes Metab. 35, 447-451 (2009).
46. Park, S. H. et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J. Gastroenterol. Hepatol. 21, 138-143 (2006).
47. 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).
48. Fan, J. G. & Farrell, G. C. Epidemiology of non-alcoholic fatty liver disease in China. J. Hepatol. 50, 204-210 (2009).
49. Chen, C. H. et al. Prevalence and etiology of elevated serum alanine aminotransferase in an adult population of Taiwan. J. Gastroenterol. Hepatol. 22, 1482-1489 (2007).
50. Tsai, C. H., Li, T. C. & Lin, C. C. Metabolic syndrome as a risk factor for non-alcoholic fatty liver disease. South Med. J. 101, 900-905 (2008).
51. Lin, Y. C., Chang, P. F., Yeh, S. J., Liu, K. & Chen, H. C. Risk factors for liver steatosis in obese children and adolescents. Pediatr. Neonatol. 51, 149-154 (2010).
52. Lee, Y. S., Kek, B. L., Poh, L. K., Saw, S. M. & Loke, K. Y. Association of raised liver transaminases with physical inactivity, increased waist-hip ratio, and other metabolic morbidities in severely obese children. J. Pediatr. Gastroenterol. Nutr. 47, 172-178 (2008).
53. Fan, J. G. et al. Fatty liver and the metabolic syndrome among Shanghai adults. J. Gastroenterol. Hepatol. 20, 1825-1832 (2005).
54. Mohan, V., Farooq, S., Deepa, M., Ravikumar, R. & Pitchumoni, C. S. Prevalence of non-alcoholic fatty liver disease in urban south Indians in relation to different grades of glucose intolerance and metabolic syndrome. Diabetes Res. Clin. Pract. 84, 84-91 (2009).
55. Das, K. et al. Nonobese population in a developing country has a high prevalence of non-alcoholic fatty liver and significant liver disease. Hepatology 51, 1593-1602 (2010).
56. Dassanayake, A. 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, 1284-1288 (2009).
57. Pinidiyapathirage, M. J. et al. Non-alcoholic fatty liver disease in a rural, physically active, low income population in Sri Lanka. BMC Res. Note 4, 513 (2011).
58. Magosso, E. et al. Prevalence of non-alcoholic fatty liver in a hypercholesterolemic population of northwestern peninsula Malaysia. Southeast Asian J. Trop. Med. Public Health 41, 936-942 (2010).
59. Malik, A., Cheah, P. L., Hilmi, I. N., Chap, S. P. & Goh, K. L. Non-alcoholic fatty liver disease in Malaysia a demographic, anthropometric, metabolic and histologic study. J. Dig Dis. 8, 58-64 (2007).
60. Chow, W. C. et al. Significant non-alcoholic fatty liver disease is found in non-diabetic, pre-obese Chinese in Singapore. Singapore Med. J. 48, 752-757 (2007).
61. Liu, C. J. Prevalence and risk factors for NAFLD in Asian people who are not obese. J. Gastroenterol. Hepatol. 27, 1555-1560 (2012).
62. Yoon K.-H. et al. Epidemic obesity and type diabetes in Asia. Lancet 368, 1681-1688 (2006).
63. Chang, Y. et al. Weight gain within the normal weight range predicts ultrasonographically detected fatty liver in health Korean men. Gut 58, 1419-1425 (2009).
64. Park, S. H. et al. Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men. J. Gastroenterol. Hepatol. 19, 694-698 (2004).
65. Weston, S. R. et al. Racial and ethnic distribution of non-alcoholic fatty liver in persons with newly diagnosed liver disease. Hepatology 41, 372-379 (2005).
66. Bambha, K. et al. Ethnicity and non-alcoholic fatty liver disease. Hepatology 55, 769-780 (2012).
67. Urakami, T. et al. Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus. Pediatr. Int. 54, 516-519 (2012).
68. Williams, C. D. et al. Prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124-131 (2011).
69. Cusi, K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis (NASH): clinical implications. Gastroenterology 142, 711-725 (2012).
70. Hamaguchi, M. et al. The metabolic syndrome as a predictor of non-alcoholic fatty liver disease. Ann. Int. Med. 143, 722-728 (2005).
71. Wong, V. W. et al. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 24, 1215-1222 (2006).
72. Kimura, Y. et al. Postprandial insulin secretion pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior known diabetes mellitus. J. Gastroenterol. Hepatol. 26, 517-522 (2011).
73. Manchanayake, J., Chitturi, S., Nolan, C. & Farrell, G. C. Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 26, 510-516 (2011).
74. Chitturi, S. et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 35, 373-379 (2002).
75. Anjana, R. M. et al. Parental history of type 2 diabetes mellitus, metabolic syndrome and cardiometabolic risk factors in Asian Indian adolescents. Metabolism 58, 344-350 (2009).
76. Loomba, R. et al. Association between diabetes, family history of diabetes and risk of non-alcoholic steatohepatitis and fibrosis. Hepatology 56, 943-951 (2012).
77. Kasturiratne, A. et al. Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus. J. Gastroenterol. Hepatol. http://dx.doi.org/10.111/j.1440-17462012.07264.x.
78. 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).
79. Fan, J. G. & Farrell, G. C. Does non-alcoholic fatty liver disease predispose patients to type 2 diabetes in the absence of obesity? J. Gastroenterol. 25, 223-225 (2010).
80. 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).
81. Fan, J. G. et al. Effects of non-alcoholic fatty liver disease on the development of metabolic disorders. J. Gastroenterol. Hepatol. 22, 1086-1091 (2007).
82. Sung, K. C., Jeong, W. S., Wild, S. H. & Byrne, C. D. Combined influence of insulin resistance/obesity and fatty liver as risk factors for type 2 diabetes. Diabetes Care 35, 717-722 (2012).
83. Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846-854 (2007).
84. Tsang, S. W. et al. Predictors of fibrosis in Asian patients with non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 21, 116-121 (2006).
85. Noto, H., Osame, K., Sasazuki, T. & Noda, M. Substantially increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis of epidemiological evidence in Japan. J. Diabetes Complications 24, 345-353 (2010).
86. Lai, S. W. et al. Risk of hepatocellular carcinoma in diabetic patients and risk reduction with anti-diabetic therapy: a population-based cohort study. Am. J. Gastroenterol. 107, 46-52 (2012).
87. Marchesini, G. & Forlani, G. Diabetes and hepatocellular carcinoma: not only a matter of hyperglycemia. Hepatology 55, 1298-1300 (2012).
88. Musso, G., Cassader, M., Rosino, F. & Gambino, R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55, 885-904 (2012).
89. Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J. M. & Lustig, R. H. The role of fructose in pathogenesis of NAFLD and the metabolic syndrome. Nat. Rev. Gastroenterol. Hepatol. 7, 251-264 (2010).
90. Abdelmalek, M. F. et al. Increased fructose consumption is associated with fibrosis severity in patients with non-alcoholic fatty liver disease. Hepatology 51, 1961-1971 (2010).
91. Toshimitsu, K. et al. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition 23, 46-52 (2007).
92. Enjoji, M. & Nakamuta, M. Is the control of dietary cholesterol intake sufficiently effective to ameliorate non-alcoholic fatty liver disease? World J. Gastroenterol. 16, 800-803 (2010).
93. Ioannou, G. N., Morrow, O. B., Connole, M. L. & Lee, S. P. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population. Hepatology 50, 175-184 (2009).
94. Farrell G. C. & van Rooyen, D. Liver cholesterol: is it playing possum in NASH? Am. J. Physiol. Gastrointest Liver Physiol. 303, G9-G11 (2012).
95. Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic fatty liver disease. Prog. Lipid Res. 52, 175-191 (2013).
96. Musso, G., Gambino, R., Cassader, M. & Pagano, G. A meta-analysis of randomized trials for the treatment of non-alcoholic fatty liver disease. Hepatology 52, 79-104 (2010).
97. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675-1685 (2010).
98. Kistler, K. D. et al. Physical activity recommendations, exercise intensity, and histological severity of non-alcoholic fatty liver disease. Am. J. Gastroenterol. 106, 460-468 (2011).
99. Thoma, C. & Day, C. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J. Hepatol. 56, 255-266 (2012).
100. Jin, J. Y. 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, 1341-1347 (2012).
101. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008).
102. Speliotes, E. C. et al. Genome-wide association analysis identifies variants associated with non-alcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324. (2011).
103. Romeo, S. et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J. Hepatol. 53, 335-338 (2010).
104. Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of non-alcoholic fatty liver disease. Gastroenterology 139, 1567-1576 (2010).
105. Chen, S., Li, Y., Li, S. & Yu, C. A Val227Ala substitution in the peroxisome proliferator activated receptor α (PPARα) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-hip-ratio. J. Gastroenterol. Hepatol. 23, 1415-1418 (2008).
106. Yamakawa-Kobayashi, K., Ishiguro, H., Arinami, T., Miyakzaki, R. & Hamaguchi, H. A Val227Ala polymorphism in the peroxisome proliferator activated receptor α (PPARα) gene is associated with variations in serum lipid levels. J. Med. Genet. 39, 189-191 (2002).
107. Adams, L. A. et al. Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity. J. Gastroenterol. Hepatol. 27, 1520-1527 (2012).
108. Hui, Y. et al. Effect of peroxisome proliferator-activated receptors-gamma and co-activator-1α genetic polymorphisms on plasma adiponectin levels and susceptibility of non-alcoholic fatty liver disease in Chinese people. Liver Int. 28, 385-392 (2008).
109. Chen, H. H., Lee, W. J., Fann, C. S., Bouchard, C. & Pan, W. H. Severe obesity is associated with novel single nucleotide polymorphisms of the ESR1 and PPARgamma locus in Han Chinese. Am. J. Clin. Nutr. 90, 255-262 (2009).
110. Wang, C. W. et al. The PNPLA3 I148M polymorphism is associated with insulin resistance and non-alcoholic fatty liver disease in a normoglycaemic population. Liver Int. 31, 1326-1331 (2011).
111. Zain, S. M. et al. A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Hum. Genet. 131, 1145-1152 (2012).
112. 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).
113. Duseja, A. & Aggarwal, R. ApoC3 and PNPLA3 in non-alcoholic fatty liver disease: need to clear the air. J. Gastroenterol. Hepatol. 27, 848-851 (2012).
114. 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).
115. Petersen K. F. et al. Apolipoprotein C3 gene variants in non-alcoholic fatty liver disease. N. Engl. J. Med. 362, 1082-1089 (2010).
116. Valenti, L. et al. The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls. BMC Gastroenterol. 12, 111 (2012).
117. Wong, V. W. et al. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 4, 1154-1161 (2006).
118. Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520-528 (2008).
119. Stickel, F. & Hampe, J. Genetic determinants of alcoholic liver disease. Gut 61, 150-159 (2012).
120. Tian, C., Stokowski, R. P., Kershenobich, D., Ballinger, D. G. & Hinds, D. A. Variant in PNPLA3 is associated with alcoholic liver disease. Nat. Genet. 42, 21-23 (2010).
121. Xin, Y. N. et al. Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity. Proteins 81, 406-414 (2012).
122. Li, J. Z. et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130-4144 (2012).
123. Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276-1282 (2012).
124. Wong, V. W. et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59, 969-974 (2010).
125. Jain, D., Nayak, N. C. & Saigal, S. Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients. Eur. J. Gastroenterol. Hepatol. 24, 840-848 (2012).
126. Hashimoto, E. & Tokushige, K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: growing evidence of an epidemic? Hepatol. Res. 42, 1-14 (2012).
127. Ascha, M. S. et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51, 1972-1978 (2010).
128. Bhala, N. et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 54, 1208-1216 (2011).
129. Cho, E. J. et al. Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area. Digestion 84 (Suppl 1.), 17-22 (2011).
130. Kawamura, Y. et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am. J. Gastroenterol. 107, 253-261 (2012).
131. Adams, L. A. et al. The natural history of non-alcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113-121 (2005).
132. Chitturi, S. & Farrell, G. C. Clues from the carotids: An appraisal of cardiovascular disease risk in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 24, 1311-1319 (2009).
133. Stepanova, M. & Younossi, Z. M. Independent association between non-alcoholic fatty liver disease and cardiovascular disease in the US population. Clin. Gastroenterol. Hepatol. 10, 646-650 (2012).
134. Hsaio, P. J. et al. Significant correlations between severe fatty liver and risk factors for metabolic syndrome. J. Gastroenterol. Hepatol. 22, 2118-2123 (2009).
135. Wang, C. C. et al. Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 24, 1411-1416 (2009).
136. Kim, D. et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology 56, 605-613 (2012).
137. Kim, B. J., Kim, N. H., Kim, B. S. & Kang, J. H. The association between non-alcoholic fatty liver disease, metabolic syndrome and arterial stiffness in nondiabetic, nonhypertensive individuals. Cardiology 123, 54-61 (2012).
138. Wong, V. W. et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 60, 1721-1727 (2011).
139. 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).
140. Hwang, S. T. et al. Relationship of non-alcoholic fatty liver disease to colorectal adenomatous polyps. J. Gastroenterol. Hepatol. 27, 91-95 (2010).
141. Lee, Y. I., Lim, Y. S. & Park, H. S. Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: a retrospective study. J. Gastroenterol. Hepatol. 25, 562-567 (2012).
142. Wong, V. W. et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut 60, 829-836 (2011).
143. Starley, B. Q., Calcagno, C. J. & Harrison, S. A. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51, 1820-1832 (2010).
144. Larsson, S. C. & Wolk, A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br. J. Cancer 97, 1005-1008 (2007).
145. Chen, C. L. et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 135, 111-121 (2008).
146. Welzel, T. M. et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54, 463-471 (2011).
147. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121-129 (2010).
148. Lindström, J. et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 368, 1673-1679 (2006).
149. Dixon, J. B., Bhathal, P. S. & O'Brien, P. E. Weight loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histological improvement. Obes. Surg. 16, 1278-1286 (2008).
150. 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).
151. Ratzui, V. et al. A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France. J. Hepatol. 57, 376-383 (2012).
152. Athyros, V. G. et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 376, 1916-1922 (2010).
153. Lonardo, A. & Loria, P. Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J. Gastroenterol. Hepatol. 27, 1654-1664 (2012).
154. Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 367, 1792-1802 (2012).
155. Park, H. et al. Efficacy of long-term ezetimibe therapy in patients with non-alcoholic fatty liver disease. J. Gastroenterol. 46, 101-107 (2011).
156. Tanaka, N. et al. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 42, 413-418 (2008).
157. Satapathy, S. K., Sakhuja, P., Malhotra, V., Sharma, B. C. & Sarin, S. K. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 22, 634-638 (2007).
158. Chitturi, S. & Farrell, G. C. TNF-α as therapeutic target in NASH: tried, but not yet proven. J. Gastroenterol. Hepatol. 22, 613-614 (2007).
159. Madan, K. et al. Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease. Indian J. Gastroenterol. 24, 251-255 (2005).
160. Hasegawa, T., Yoneda, M., Nakamura, K., Makino, I. & Terano, A. Plasma transforming growth factor-β1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment. Pharmacol. Ther. 15, 1667-1672 (2001).
161. Wang, C. L. et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J. Gastroenterol. 14, 1598-1602 (2008).
162. Ono, M. et al. Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones. Metabolism 54, 529-532 (2005).
163. Hyogo, H. et al. Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property. Dig. Liver Dis. 44, 492-496 (2012).
164. Iwasaki, T. et al. Sitagliptin as a novel treatment agent for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 58, 2103-2105 (2011).
165. Enjoji, M. et al. Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. Int. J. Mol. Med. 22, 521-527 (2008).
166. Zein, C. O. et al. Pentoxifylline improves non-alcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54, 1610-1619 (2011).