Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment (original) (raw)

• Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002).
  Article CAS PubMed Google Scholar
• Neuschwander-Tetri, B. A. & Caldwell, S. H. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37, 1202–1219 (2003).
  Article PubMed Google Scholar
• 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
• 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
• 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).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Schaffner, F. & Thaler, H. Nonalcoholic fatty liver disease. Prog. Liver Dis. 8, 283–298 (1986).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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
• 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).
  Article PubMed Google Scholar
• 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
• 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).
  CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006).
  Article PubMed Google Scholar
• Marchesini, G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917–923 (2003).
  Article PubMed Google Scholar
• 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
• 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
• 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).
  Article CAS PubMed Google Scholar
• Angulo, P., Keach, J. C., Batts, K. P. & Lindor, K. D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30, 1356–1362 (1999).
  Article CAS PubMed Google Scholar
• Knobler, H. et al. Fatty liver—an additional and treatable feature of the insulin resistance syndrome. QJM 92, 73–79 (1999).
  Article CAS PubMed Google Scholar
• Rashid, M. & Roberts, E. A. Nonalcoholic steatohepatitis in children. J. Pediatr. Gastroenterol. Nutr. 30, 48–53 (2000).
  Article CAS PubMed Google Scholar
• Beymer, C. et al. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. Arch. Surg. 138, 1240–1244 (2003).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Machado, M., Marques-Vidal, P. & Cortez-Pinto, H. Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 45, 600–606 (2006).
  Article PubMed Google Scholar
• Gupte, P. et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J. Gastroenterol. Hepatol. 19, 854–858 (2004).
  Article PubMed Google Scholar
• Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).
  Article CAS PubMed Google Scholar
• Jacqueminet, S. et al. Screening for liver fibrosis by using a noninvasive biomarker in patients with diabetes. Clin. Gastroenterol. Hepatol. 6, 828–831 (2008).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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
• 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
• 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).
  Article PubMed Google Scholar
• Ratziu, V. et al. Liver fibrosis in overweight patients. Gastroenterology 118, 1117–1123 (2000).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Targher, G. et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54, 3541–3546 (2005).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Manton, N. D. et al. Non-alcoholic steatohepatitis in children and adolescents. Med. J. Aust. 173, 476–479 (2000).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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
• Torbenson, M. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am. J. Surg. Pathol. 30, 508–513 (2006).
  Article PubMed Google Scholar
• Struben, V. M., Hespenheide, E. E. & Caldwell, S. H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am. J. Med. 108, 9–13 (2000).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Mohanty, S. R. et al. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 50, 797–804 (2009).
  Article PubMed Google Scholar
• Speliotes, E. K. Genetics of common obesity and nonalcoholic fatty liver disease. Gastroenterology 136, 1492–1495 (2009).
  Article PubMed Google Scholar
• Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585–1592 (2009).
  Article PubMed Google Scholar
• Wagenknecht, L. E. et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 17, 1240–1246 (2009).
  CAS Google Scholar
• 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
• 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
• 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
• Day, C. P. Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig. Dis. 28, 255–260 (2010).
  Article CAS PubMed Google Scholar
• 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
• Adams, L. A., Angulo, P. & Lindor, K. D. Nonalcoholic fatty liver disease. CMAJ 172, 899–905 (2005).
  Article PubMed PubMed Central Google Scholar
• Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Charlton, M., Sreekumar, R., Rasmussen, D., Lindor, K. & Nair, K. S. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35, 898–904 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Monetti, M. et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell. Metab. 6, 69–78 (2007).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Jaeschke, A. & Davis, R. J. Metabolic stress signaling mediated by mixed-lineage kinases. Mol. Cell 27, 498–508 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Weston, C. R. & Davis, R. J. The JNK signal transduction pathway. Curr. Opin. Cell Biol. 19, 142–149 (2007).
  Article CAS PubMed Google Scholar
• Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• van der Poorten, D. et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48, 449–457 (2008).
  Article PubMed Google Scholar
• Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11–18 (2010).
  Article PubMed Google Scholar
• Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Hui, J. M. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40, 46–54 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Anania, F. A. Leptin, liver, and obese mice—fibrosis in the fat lane. Hepatology 36, 246–248 (2002).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Haque, M. & Sanyal, A. J. The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Pract. Res. Clin. Gastroenterol. 16, 709–731 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Saadeh, S. et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123, 745–750 (2002).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Torres, D. M. & Harrison, S. A. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 134, 1682–1698 (2008).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Harrison, S. A. & Neuschwander-Tetri, B. A. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin. Liver Dis. 8, 861–879 (2004).
  Article PubMed Google Scholar
• Yun, J. W. et al. Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease. Liver Int. 29, 525–529 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Mazhar, S. M., Shiehmorteza, M. & Sirlin, C. B. Noninvasive assessment of hepatic steatosis. Clin. Gastroenterol. Hepatol. 7, 135–140 (2009).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Charatcharoenwitthaya, P. & Lindor, K. D. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin. Liver Dis. 11, 37–54 (2007).
  Article PubMed Google Scholar
• 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
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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
• 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).
  PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Wong, V. W. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 51, 454–462 (2010).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Johnson, N. A. & George, J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 52, 370–381 (2010).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed Google Scholar
• Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121–129 (2010).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• St George, A. et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 50, 68–76 (2009).
  Article CAS PubMed Google Scholar
• Sjöström, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).
  Article PubMed Google Scholar
• 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).
• Selvin, E. et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch. Intern. Med. 168, 2070–2080 (2008).
  Article PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176–1184 (2008).
  Article CAS PubMed Google Scholar
• Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).
  Article CAS PubMed Google Scholar
• Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Omer, Z. et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 22, 18–23 (2010).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Adams, L. A. & Angulo, P. Treatment of non-alcoholic fatty liver disease. Postgrad. Med. J. 82, 315–322 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Guallar, E., Hanley, D. F. & Miller E. R. 3rd. An editorial update: Annus horribilis for vitamin E. Ann. Intern. Med. 143, 143–145 (2005).
  Article CAS PubMed Google Scholar
• Lindor, K. D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39, 770–778 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Abdelmalek, M. F. et al. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50, 1818–1826 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar