Nonalcoholic fatty liver disease and diabetes mellitus: Pathogenesis and treatment

Nature Reviews Endocrinology

Volumn 7, Issue 8, 2011, Pages 456-465

  Smith, Briohny W ^a   Adams, Leon A ^a  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; ASCORBIC ACID; BETAINE; CARNITINE; METFORMIN; PENTOXIFYLLINE; PIOGLITAZONE; ROSIGLITAZONE; TELMISARTAN; URSODEOXYCHOLIC ACID;

ANTIOXIDANT ACTIVITY; BRAIN HEMORRHAGE; CARDIOTOXICITY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DEATH; DISEASE ASSOCIATION; DNA POLYMORPHISM; EXERCISE; FATTY LIVER; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIFESTYLE MODIFICATION; LIPOTOXICITY; LIVER BIOPSY; LIVER CELL DAMAGE; LIVER CIRRHOSIS; LIVER TRANSPLANTATION; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; WEIGHT REDUCTION;

DIABETES MELLITUS, TYPE 2; FATTY LIVER; HUMANS; INSULIN RESISTANCE; RISK FACTORS; THIAZOLIDINEDIONES; TREATMENT OUTCOME; VITAMIN E; WEIGHT LOSS;

EID: 79960847840     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2011.72     Document Type: Review

References (139)

1. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221-1231 (2002).
2. Neuschwander-Tetri, B. A. & Caldwell, S. H. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37, 1202-1219 (2003). (Pubitemid 36538699)
3. Rafiq, N. et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin. Gastroenterol. Hepatol. 7, 234-238 (2009).
4. de Marco, R. et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 22, 756-761 (1999). (Pubitemid 29220775)
5. Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 87, 4-14 (2010).
6. Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434-438 (1980). (Pubitemid 10057164)
7. Schaffner, F. & Thaler, H. Nonalcoholic fatty liver disease. Prog. Liver Dis. 8, 283-298 (1986).
8. Clark, J. M., Brancati, F. L. & Diehl, A. M. The prevalence and etiology of elevated aminotransferase levels in the United States. Am. J. Gastroenterol. 98, 960-967 (2003). (Pubitemid 36733754)
9. 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). (Pubitemid 39657013)
10. Fan, J. G. et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J. Hepatol. 43, 508-514 (2005).
11. 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). (Pubitemid 41224170)
12. Nomura, H., Hayashi, J., Kajiyama, W. & Kashiwagi, S. Prevalence of liver abnormalities in the general population of Okinawa, Japan. Fukuoka Igaku Zasshi 88, 345-351 (1997).
13. Bedogni, G. et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 42, 44-52 (2005). (Pubitemid 40911310)
14. Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388-1393 (2006). (Pubitemid 46393782)
15. Marchesini, G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917-923 (2003). (Pubitemid 36397405)
16. 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). (Pubitemid 20075105)
17. Bacon, B. R., Farahvash, M. J., Janney, C. G. & Neuschwander-Tetri, B. A. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107, 1103-1109 (1994). (Pubitemid 24294573)
18. Baldridge, A. D., Perez-Atayde, A. R., Graeme-Cook, F., Higgins, L. & Lavine, J. E. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J. Pediatr. 127, 700-704 (1995).
19. Angulo, P., Keach, J. C., Batts, K. P. & Lindor, K. D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30, 1356-1362 (1999).
20. Knobler, H. et al. Fatty liver-an additional and treatable feature of the insulin resistance syndrome. QJM 92, 73-79 (1999). (Pubitemid 29097631)
21. Rashid, M. & Roberts, E. A. Nonalcoholic steatohepatitis in children. J. Pediatr. Gastroenterol. Nutr. 30, 48-53 (2000). (Pubitemid 30349945)
22. Beymer, C. et al. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. Arch. Surg. 138, 1240-1244 (2003). (Pubitemid 37392401)
23. Gholam, P. M., Flancbaum, L., Machan, J. T., Charney, D. A. & Kotler, D. P. Nonalcoholic fatty liver disease in severely obese subjects. Am. J. Gastroenterol. 102, 399-408 (2007). (Pubitemid 46160554)
24. Machado, M., Marques-Vidal, P. & Cortez-Pinto, H. Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 45, 600-606 (2006). (Pubitemid 44307393)
25. Gupte, P. et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J. Gastroenterol. Hepatol. 19, 854-858 (2004). (Pubitemid 39093200)
26. Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183-1192 (2001). (Pubitemid 32246672)
27. Jacqueminet, S. et al. Screening for liver fibrosis by using a noninvasive biomarker in patients with diabetes. Clin. Gastroenterol. Hepatol. 6, 828-831 (2008).
28. 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, E526-E531 (2010).
29. Toledo, F. G., Sniderman, A. D. & Kelley, D. E. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care 29, 1845-1850 (2006). (Pubitemid 44156640)
30. Kelley, D. E., McKolanis, T. M., Hegazi, R. A., Kuller, L. H. & Kalhan, S. C. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 285, E906-E916 (2003). (Pubitemid 37176440)
31. Banerji, M. A. et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int. J. Obes. Relat. Metab. Disord. 19, 846-850 (1995). (Pubitemid 26003019)
32. 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).
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).
34. Younossi, Z. M., Gramlich, T., Matteoni, C. A., Boparai, N. & McCullough, A. J. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 2, 262-265 (2004). (Pubitemid 38293314)
35. Ratziu, V. et al. Liver fibrosis in overweight patients. Gastroenterology 118, 1117-1123 (2000). (Pubitemid 30346988)
36. 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). (Pubitemid 40038911)
37. Matteoni, C. A. et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413-1419 (1999). (Pubitemid 29258890)
38. Dam-Larsen, S. et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53, 750-755 (2004). (Pubitemid 38561456)
39. 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).
40. Targher, G. et al. Increased prevalence of cardiovascular disease in type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet. Med. 23, 403-409 (2006).
41. Targher, G. et al. Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled type 2 diabetic patients. J. Endocrinol. Invest. 29, 55-60 (2006). (Pubitemid 43355836)
42. Targher, G. et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54, 3541-3546 (2005). (Pubitemid 43334347)
43. Targher, G. et al. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet. Med. 22, 1354-1358 (2005). (Pubitemid 41391311)
44. Lautamäki, 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). (Pubitemid 44035287)
45. Kilpatrick, E. S., Rigby, A. S. & Atkin, S. L. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: "double diabetes" in the Diabetes Control and Complications Trial. Diabetes Care 30, 707-712 (2007). (Pubitemid 46354357)
46. Manton, N. D. et al. Non-alcoholic steatohepatitis in children and adolescents. Med. J. Aust. 173, 476-479 (2000).
47. Leeds, J. S. et al. Abnormal liver function tests in patients with type 1 diabetes mellitus: prevalence, clinical correlations and underlying pathologies. Diabet. Med. 26, 1235-1241 (2009).
48. 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).
49. Torbenson, M. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am. J. Surg. Pathol. 30, 508-513 (2006). (Pubitemid 43740153)
50. Struben, V. M., Hespenheide, E. E. & Caldwell, S. H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am. J. Med. 108, 9-13 (2000). (Pubitemid 30058272)
51. Guerrero, R., Vega, G. L., Grundy, S. M. & Browning, J. D. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49, 791-801 (2009).
52. Weston, S. R. et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 41, 372-379 (2005). (Pubitemid 40165382)
53. Riquelme, A. et al. Non-alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C reactive protein in Hispanics. Liver Int. 29, 82-88 (2009).
54. Mohanty, S. R. et al. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 50, 797-804 (2009).
55. Speliotes, E. K. Genetics of common obesity and nonalcoholic fatty liver disease. Gastroenterology 136, 1492-1495 (2009).
56. Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585-1592 (2009).
57. Wagenknecht, L. E. et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 17, 1240-1246 (2009).
58. 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).
59. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008).
60. 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).
61. Day, C. P. Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig. Dis. 28, 255-260 (2010).
62. Petersen, K. F. et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N. Engl. J. Med. 362, 1082-1089 (2010).
63. Adams, L. A., Angulo, P. & Lindor, K. D. Nonalcoholic fatty liver disease. CMAJ 172, 899-905 (2005). (Pubitemid 40543601)
64. Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147-152 (2004). (Pubitemid 39071617)
65. Charlton, M., Sreekumar, R., Rasmussen, D., Lindor, K. & Nair, K. S. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35, 898-904 (2002). (Pubitemid 34258385)
66. Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774-788 (2010).
67. Alkhouri, N., Dixon, L. J. & Feldstein, A. E. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev. Gastroenterol. Hepatol. 3, 445-451 (2009).
68. Monetti, M. et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell. Metab. 6, 69-78 (2007). (Pubitemid 46995777)
69. Li, Z. Z., Berk, M., McIntyre, T. M. & Feldstein, A. E. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284, 5637-5644 (2009).
70. Jaeschke, A. & Davis, R. J. Metabolic stress signaling mediated by mixed-lineage kinases. Mol. Cell 27, 498-508 (2007). (Pubitemid 47126942)
71. Feti Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860-867 (2006).
72. Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. F. The c Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate 1 and phosphorylation of Ser(307). J. Biol. Chem. 275, 9047-9054 (2000). (Pubitemid 30180265)
73. Weston, C. R. & Davis, R. J. The JNK signal transduction pathway. Curr. Opin. Cell Biol. 19, 142-149 (2007). (Pubitemid 46386399)
74. Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539-1543 (2008).
75. Solinas, G. et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell. Metab. 6, 386-397 (2007). (Pubitemid 350012000)
76. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333-336 (2002). (Pubitemid 35398190)
77. Schattenberg, J. M., Wang, Y., Singh, R., Rigoli, R. M. & Czaja, M. J. Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. J. Biol. Chem. 280, 9887-9894 (2005). (Pubitemid 40395836)
78. Wieckowska, A. et al. Increased hepatic and circulating interleukin 6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372-1379 (2008). (Pubitemid 351813900)
79. Senn, J. J. et al. Suppressor of cytokine signaling 3 (SOCS 3), a potential mediator of interleukin 6 dependent insulin resistance in hepatocytes. J. Biol. Chem. 278, 13740-13746 (2003). (Pubitemid 36799910)
80. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF kappaB. Nat. Med. 11, 183-190 (2005). (Pubitemid 40321354)
81. van der Poorten, D. et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48, 449-457 (2008).
82. Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11-18 (2010).
83. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808 (2003). (Pubitemid 38063703)
84. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793-1801 (2006). (Pubitemid 44033299)
85. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111-1119 (2005). (Pubitemid 40629025)
86. Hui, J. M. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40, 46-54 (2004). (Pubitemid 38868922)
87. Leclercq, I. A., Farrell, G. C., Schriemer, R. & Robertson, G. R. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J. Hepatol. 37, 206-213 (2002). (Pubitemid 34833082)
88. Anania, F. A. Leptin, liver, and obese mice-fibrosis in the fat lane. Hepatology 36, 246-248 (2002). (Pubitemid 34700783)
89. Feldstein, A. E. et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40, 185-194 (2004). (Pubitemid 38868937)
90. Haque, M. & Sanyal, A. J. The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Pract. Res. Clin. Gastroenterol. 16, 709-731 (2002).
91. Paradis, V. et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34, 738-744 (2001). (Pubitemid 32927998)
92. Sugimoto, R. et al. High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase. Liver Int. 25, 1018-1026 (2005). (Pubitemid 41404025)
93. Saadeh, S. et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123, 745-750 (2002). (Pubitemid 34977081)
94. Van Ness, M. M. & Diehl, A. M. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes? Ann. Intern. Med. 111, 473-478 (1989). (Pubitemid 19231304)
95. Torres, D. M. & Harrison, S. A. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 134, 1682-1698 (2008). (Pubitemid 351615413)
96. Fracanzani, A. L. et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 48, 792-798 (2008).
97. Harrison, S. A. & Neuschwander-Tetri, B. A. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin. Liver Dis. 8, 861-879 (2004). (Pubitemid 39311147)
98. Yun, J. W. et al. Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease. Liver Int. 29, 525-529 (2009).
99. Palmentieri, B. et al. The role of bright liver echo pattern on ultrasound B mode examination in the diagnosis of liver steatosis. Dig. Liver Dis. 38, 485-489 (2006). (Pubitemid 44356237)
100. Hamaguchi, M. et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am. J. Gastroenterol. 102, 2708-2715 (2007). (Pubitemid 350179336)
101. Mottin, C. C. et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes. Surg. 14, 635-637 (2004). (Pubitemid 38716583)
102. Mazhar, S. M., Shiehmorteza, M. & Sirlin, C. B. Noninvasive assessment of hepatic steatosis. Clin. Gastroenterol. Hepatol. 7, 135-140 (2009).
103. Fishbein, M. H., Gardner, K. G., Potter, C. J., Schmalbrock, P. & Smith, M. A. Introduction of fast MR imaging in the assessment of hepatic steatosis. Magn. Reson. Imaging 15, 287-293 (1997). (Pubitemid 27280484)
104. Charatcharoenwitthaya, P. & Lindor, K. D. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin. Liver Dis. 11, 37-54 (2007). (Pubitemid 46829975)
105. 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). (Pubitemid 40110657)
106. Roldan-Valadez, E. et al. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry. J. Hepatol. 53, 732-737 (2010).
107. Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A. & Bacon, B. R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 94, 2467-2474 (1999). (Pubitemid 29420675)
108. Adams, L. A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113-121 (2005). (Pubitemid 41002048)
109. Harrison, S. A., Brunt, E. M., Goodman, Z. D. & Di Bisceglie, A. M. Diabetic hepatosclerosis: diabetic microangiopathy of the liver. Arch. Pathol. Lab. Med. 130, 27-32 (2006). (Pubitemid 43077231)
110. McPherson, S., Stewart, S. F., Henderson, E., Burt, A. D. & Day, C. P. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 59, 1265-1269 (2010).
111. Guha, I. N. et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 47, 455-460 (2008). (Pubitemid 351280713)
112. Wong, V. W. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51, 454-462 (2010).
113. 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).
114. Juurinen, L., Tiikkainen, M., Häkkinen, A. M., Hakkarainen, A. & Yki-Järvinen, H. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292, E829-E835 (2007). (Pubitemid 46411061)
115. Johnson, N. A. & George, J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 52, 370-381 (2010).
116. Larson-Meyer, D. E. et al. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29, 1337-1344 (2006). (Pubitemid 44125932)
117. Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603-608 (2005). (Pubitemid 40322060)
118. Tamura, Y. 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, 3191-3196 (2005). (Pubitemid 41014274)
119. Huang, M. A. et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am. J. Gastroenterol. 100, 1072-1081 (2005). (Pubitemid 40769044)
120. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121-129 (2010).
121. Harrison, S A., Fecht, W., Brunt, E. M. & Neuschwander-Tetri, B. A. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology 49, 80-86 (2009).
122. St George, A. et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 50, 68-76 (2009).
123. Sjöström, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741-752 (2007). (Pubitemid 47295641)
124. Chavez-Tapia, N. C. et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD007340. doi:10.1002/14651858.CD007340.pub2 (2010).
125. Selvin, E. et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch. Intern. Med. 168, 2070-2080 (2008).
126. Musso, G., Gambino, R., Cassader, M. & Pagano, G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52, 79-104 (2010).
127. Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176-1184 (2008).
128. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297-2307 (2006). (Pubitemid 44837778)
129. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675-1685 (2010).
130. Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135, 100-110 (2008). (Pubitemid 351916703)
131. Omer, Z. et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 22, 18-23 (2010).
132. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457-2471 (2007). (Pubitemid 46919772)
133. Adams, L. A. & Angulo, P. Treatment of non-alcoholic fatty liver disease. Postgrad. Med. J. 82, 315-322 (2006). (Pubitemid 43780662)
134. Guallar, E., Hanley, D. F. & Miller E. R. 3rd. An editorial update: Annus horribilis for vitamin E. Ann. Intern. Med. 143, 143-145 (2005). (Pubitemid 40994306)
135. Lindor, K D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39, 770-778 (2004). (Pubitemid 38337657)
136. Leuschner, U F. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52, 472-479 (2010).
137. Abdelmalek, M. F. et al. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50, 1818-1826 (2009).
138. Malaguarnera, M. et al. L carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis - a randomized and controlled clinical trial. Am. J. Gastroenterol. 105, 1338-1345 (2010).
139. Georgescu, E. F., Ionescu, R., Niculescu, M., Mogoanta, L. & Vancica, L. Angiotensin-receptor blockers as therapy for mild to moderate hypertension-associated non-alcoholic steatohepatitis. World J. Gastroenterol. 15, 942-954 (2009).