Table of Contents Author Guidelines Submit a Manuscript
Current Gerontology and Geriatrics Research
Volume 2011 (2011), Article ID 831536, 12 pages
http://dx.doi.org/10.1155/2011/831536
Review Article

Mechanisms and Implications of Age-Related Changes in the Liver: Nonalcoholic Fatty Liver Disease in the Elderly

Liver Research Group, Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University Medical School, Yamba Drive, Garran, ACT 2605, Australia

Received 30 May 2011; Accepted 9 July 2011

Academic Editor: Victoria Cogger

Copyright © 2011 Lay Gan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. Ludwig, T. R. Viggiano, D. B. McGill, and B. J. Ott, “Nonalcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease,” Mayo Clinic Proceedings, vol. 55, no. 7, pp. 434–438, 1980. View at Google Scholar · View at Scopus
  2. J. Jou, S. S. Choi, and A. M. Diehl, “Mechanisms of disease progression in nonalcoholic fatty liver disease,” Seminars in Liver Disease, vol. 28, no. 4, pp. 370–379, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. S. S. Choi and A. M. Diehl, “Hepatic triglyceride synthesis and nonalcoholic fatty liver disease,” Current Opinion in Lipidology, vol. 19, no. 3, pp. 295–300, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. C. K. Argo and S. H. Caldwell, “Epidemiology and natural history of non-alcoholic steatohepatitis,” Clinics in Liver Disease, vol. 13, no. 4, pp. 511–531, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. E. Hashimoto and K. Tokushige, “Prevalence, gender, ethnic variations, and prognosis of NASH,” Journal of Gastroenterology, vol. 46, supplement 1, pp. 63–69, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. H. M. Patton, J. E. Lavine, M. L. van Natta, J. B. Schwimmer, D. Kleiner, and J. Molleston, “Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis,” Gastroenterology, vol. 135, no. 6, pp. 1961–1971, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. J. Frith and J. L. Newton, “Liver disease in older women,” Maturitas, vol. 65, no. 3, pp. 210–214, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. J. I. Cleeman, “Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III),” Journal of the American Medical Association, vol. 285, no. 19, pp. 2486–2497, 2001. View at Google Scholar · View at Scopus
  9. IDF, “The IDF consensus worldwide definition of the metabolic syndrome,” Metabolic Syndrome, pp. 1–16, 2007. View at Google Scholar
  10. N. Méndez-Sánchez, M. Arrese, D. Zamora-Valdés, and M. Uribe, “Current concepts in the pathogenesis of nonalcoholic fatty liver disease,” Liver International, vol. 27, no. 4, pp. 423–433, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. G. Musso, R. Gambino, and M. Cassader, “Non-alcoholic fatty liver disease from pathogenesis to management: an update,” Obesity Reviews, vol. 11, no. 6, pp. 430–445, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. C. Z. Larter, S. Chitturi, D. Heydet, and G. C. Farrell, “A fresh look at NASH pathogenesis. Part 1: the metabolic movers,” Journal of Gastroenterology and Hepatology, vol. 25, no. 4, pp. 672–690, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. J. G. Fan, J. Zhu, X. J. Li et al., “Fatty liver and the metabolic syndrome among Shanghai adults,” Journal of Gastroenterology and Hepatology, vol. 20, no. 12, pp. 1825–1832, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. P. J. Hsiao, K. K. Kuo, S. J. Shin et al., “Significant correlations between severe fatty liver and risk factors for metabolic syndrome,” Journal of Gastroenterology and Hepatology, vol. 22, no. 12, pp. 2118–2123, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. T. Wasada, T. Kasahara, J. Wada et al., “Hepatic steatosis rather than visceral adiposity is more closely associated with insulin resistance in the early stage of obesity,” Metabolism, vol. 57, no. 7, pp. 980–985, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. S. Chitturi and G. C. Farrell, “Etiopathogenesis of nonalcoholic steatohepatitis,” Seminars in Liver Disease, vol. 21, no. 1, pp. 27–41, 2001. View at Google Scholar · View at Scopus
  17. G. C. Farrell, “The liver and the waistline: fifty years of growth,” Journal of Gastroenterology and Hepatology, vol. 24, pp. S105–S118, 2009. View at Google Scholar · View at Scopus
  18. M. Tobari, E. Hashimoto, S. Yatsuji, N. Torii, and K. Shiratori, “Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography,” Internal Medicine, vol. 48, no. 10, pp. 739–746, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. P. Mofrad, M. J. Contos, M. Haque et al., “Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values,” Hepatology, vol. 37, no. 6, pp. 1286–1292, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. M. Yoneda, Y. Nozaki, H. Endo et al., “Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis (NASH) independent of HFE gene mutation,” Digestive Diseases and Sciences, vol. 55, no. 3, pp. 808–814, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. J. Choudhury and A. J. Sanyal, “Clinical aspects of fatty liver disease,” Seminars in Liver Disease, vol. 24, no. 4, pp. 349–362, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. V. W. Wong and H. L. Y. Chan, “Transient elastography,” Journal of Gastroenterology and Hepatology, vol. 25, no. 11, pp. 1726–1731, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. V. W. S. Wong, J. Vergniol, G. L. H. Wong et al., “Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease,” Hepatology, vol. 51, no. 2, pp. 454–462, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. V. de Lédinghen, J. Vergniol, J. Foucher, F. El-Hajbi, W. Merrouche, and V. Rigalleau, “Feasibility of liver transient elastography with FibroScan® using a new probe for obese patients,” Liver International, vol. 30, no. 7, pp. 1043–1048, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. M. Lazo and J. M. Clark, “The epidemiology of nonalcoholic fatty liver disease: a global perspective,” Seminars in Liver Disease, vol. 28, no. 4, pp. 339–350, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. L. A. Adams, P. Angulo, and K. D. Lindor, “Nonalcoholic fatty liver disease,” Canadian Medical Association Journal, vol. 172, no. 7, pp. 899–905, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. C. D. Williams, J. Stengel, M. I. Asike et al., “Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study,” Gastroenterology, vol. 140, no. 1, pp. 124–131, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. J. D. Browning, L. S. Szczepaniak, R. Dobbins et al., “Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity,” Hepatology, vol. 40, no. 6, pp. 1387–1395, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. D. N. Amarapurkar, E. Hashimoto, L. A. Lesmana, J. D. Sollano, P. J. Chen, and K. L. Goh, “How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences?” Journal of Gastroenterology and Hepatology, vol. 22, no. 6, pp. 788–793, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. T. Okanoue, A. Umemura, K. Yasui, and Y. Itoh, “Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in Japan,” Journal of Gastroenterology and Hepatology, vol. 26, no. 1, pp. 153–162, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. Z. Younossi, M. Stepanova, M. Afendy et al., “The changing face of chronic liver disease (CLD) in the United States: the rising epidemic of non-alcoholic fatty liver disease (NAFLD),” Journal of Hepatology, vol. 54, no. S1, p. S8, 2011. View at Google Scholar
  32. K. Tominaga, E. Fujimoto, K. Suzuki, M. Hayashi, M. Ichikawa, and Y. Inaba, “Prevalence of non-alcoholic fatty liver disease in children and relationship to metabolic syndrome, insulin resistance, and waist circumference,” Environmental Health and Preventive Medicine, vol. 14, no. 2, pp. 142–149, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. G. Tsuruta, N. Tanaka, M. Hongo et al., “Nonalcoholic fatty liver disease in Japanese junior high school students: its prevalence and relationship to lifestyle habits,” Journal of Gastroenterology, vol. 45, no. 6, pp. 666–672, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. N. Kagansky, S. Levy, D. Keter et al., “Non-alcoholic fatty liver disease—a common and benign finding in octogenarian patients,” Liver International, vol. 24, no. 6, pp. 588–594, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. A. Dahshan, L. J. Chalmers, and V. Tolia, “Nonalcoholic fatty liver disease in children,” Therapy, vol. 6, no. 1, pp. 83–91, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. J. G. Fan and G. C. Farrell, “Epidemiology of non-alcoholic fatty liver disease in China,” Journal of Hepatology, vol. 50, no. 1, pp. 204–210, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. J. Frith, C. P. Day, E. Henderson, A. D. Burt, and J. L. Newton, “Non-alcoholic fatty liver disease in older people,” Gerontology, vol. 55, no. 6, pp. 607–613, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. G. de Bruyn and E. A. Graviss, “A systematic review of the diagnostic accuracy of physical examination for the detection of cirrhosis,” BMC Medical Informatics and Decision Making, vol. 1, pp. e1–e11, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Bellentani, G. Bedogni, L. Miglioli, and C. Tiribelli, “The epidemiology of fatty liver,” European Journal of Gastroenterology and Hepatology, vol. 16, no. 11, pp. 1087–1093, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. C. H. Chen, M. H. Huang, J. C. Yang 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,” Journal of Clinical Gastroenterology, vol. 40, no. 8, pp. 745–752, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. J. G. Fan, F. Li, X. B. Cai, Y. D. Peng, Q. H. Ao, and Y. Gao, “The importance of metabolic factors for the increasing prevalence of fatty liver in Shanghai factory workers,” Journal of Gastroenterology and Hepatology, vol. 22, no. 5, pp. 663–668, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. T. Yamada, M. Fukatsu, S. Suzuki, T. Wada, T. Yoshida, and T. Joh, “Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup,” Journal of Gastroenterology and Hepatology, vol. 25, no. 2, pp. 352–356, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. J. Frith, D. Jones, and J. L. Newton, “Chronic liver disease in an ageing population,” Age and Ageing, vol. 38, no. 1, pp. 11–18, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. D. L. Schmucker, “Aging and the liver: an update,” The Journals of Gerontology Series A, vol. 53, no. 5, pp. B315–B320, 1998. View at Google Scholar · View at Scopus
  45. G. Mentha, O. Huber, J. Robert, C. Klopfenstein, R. Egeli, and A. Rohner, “Elective hepatic resection in the elderly,” British Journal of Surgery, vol. 79, no. 6, pp. 557–559, 1992. View at Publisher · View at Google Scholar · View at Scopus
  46. J. L. Kuk, T. J. Saunders, L. E. Davidson, and R. Ross, “Age-related changes in total and regional fat distribution,” Ageing Research Reviews, vol. 8, no. 4, pp. 339–348, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. T. T. Tran, Y. Yamamoto, S. Gesta, and C. R. Kahn, “Beneficial effects of subcutaneous fat transplantation on metabolism,” Cell Metabolism, vol. 7, no. 5, pp. 410–420, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. S. Petta, M. Amato, D. Cabibi et al., “Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1,” Hepatology, vol. 52, no. 5, pp. 1543–1552, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. J. R. Churilla, E. C. Fitzhugh, and D. L. Thompson, “The metabolic syndrome: how definition impacts the prevalence and risk in U.S. adults: 1999–2004 NHANES,” Metabolic Syndrome and Related Disorders, vol. 5, no. 4, pp. 331–341, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. K. Reynolds and R. P. Wildman, “Update on the metabolic syndrome: hypertension,” Current Hypertension Reports, vol. 11, no. 2, pp. 150–155, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. C. C. Liu, C. L. Hung, S. C. Shih et al., “Age-related differences in the clinical presentation, associated metabolic abnormality, and estimated cardiovascular risks from nonalcoholic fatty liver disease: a cross-sectional study from health evaluation center in Taiwan,” International Journal of Gerontology, vol. 4, no. 4, pp. 184–191, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. H. Nomura, S. Kashiwagi, J. Hayashi, W. Kajiyama, S. Tani, and M. Goto, “Prevalence of fatty liver in a general population of Okinawa, Japan,” Japanese Journal of Medicine, vol. 27, no. 2, pp. 142–149, 1988. View at Google Scholar · View at Scopus
  53. E. E. Powell, W. G. E. Cooksley, R. Hanson, J. Searle, J. W. Halliday, and L. W. Powell, “The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years,” Hepatology, vol. 11, no. 1, pp. 74–80, 1990. View at Google Scholar
  54. S. A. Harrison, S. Torgerson, and P. H. Hayashi, “The natural history of nonalcoholic fatty liver disease: a clinical histopathological study,” American Journal of Gastroenterology, vol. 98, no. 9, pp. 2042–2047, 2003. View at Publisher · View at Google Scholar · View at PubMed
  55. E. Fassio, E. Álvarez, N. Domínguez, G. Landeira, and C. Longo, “Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies,” Hepatology, vol. 40, no. 4, pp. 820–826, 2004. View at Publisher · View at Google Scholar · View at PubMed
  56. L. A. Adams, S. Sanderson, K. D. Lindor, and P. Angulo, “The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies,” Journal of Hepatology, vol. 42, no. 1, pp. 132–138, 2005. View at Publisher · View at Google Scholar · View at PubMed
  57. L. A. Adams, J. F. Lymp, J. S. Sauver et al., “The natural history of nonalcoholic fatty liver disease: a population-based cohort study,” Gastroenterology, vol. 129, no. 1, pp. 113–121, 2005. View at Publisher · View at Google Scholar
  58. C. P. Day and O. F. W. James, “Steatohepatitis: a tale of two “Hits”?” Gastroenterology, vol. 114, no. 4, pp. 842–845, 1998. View at Publisher · View at Google Scholar
  59. A. Berson, V. De Beco, P. Lettéron et al., “Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes,” Gastroenterology, vol. 114, no. 4, pp. 764–774, 1998. View at Publisher · View at Google Scholar
  60. D. J. Chiang, M. T. Pritchard, and L. E. Nagy, “Obesity, diabetes mellitus, and liver fibrosis,” American Journal of Physiology, vol. 300, no. 5, pp. G697–G702, 2011. View at Publisher · View at Google Scholar · View at PubMed
  61. W. K. Syn, S. S. Choi, and A. M. Diehl, “Apoptosis and cytokines in non-alcoholic steatohepatitis,” Clinics in Liver Disease, vol. 13, no. 4, pp. 565–580, 2009. View at Publisher · View at Google Scholar · View at PubMed
  62. H. Malhi and G. J. Gores, “Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease,” Seminars in Liver Disease, vol. 28, no. 4, pp. 360–369, 2008. View at Publisher · View at Google Scholar · View at PubMed
  63. M. Shimabukuro, Y. T. Zhou, M. Levi, and R. H. Unger, “Fatty acid-induced β cell apoptosis: a link between obesity and diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 5, pp. 2498–2502, 1998. View at Publisher · View at Google Scholar
  64. K. H. Hellemans, J. C. Hannaert, B. Denys et al., “Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARα-dependent stearoyl-coenzyme a desaturase,” PLoS One, vol. 4, no. 9, Article ID e7266, 2009. View at Publisher · View at Google Scholar · View at PubMed
  65. N. G. Morgan, “Fatty acids and β-cell toxicity,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 12, no. 2, pp. 117–122, 2009. View at Publisher · View at Google Scholar · View at PubMed
  66. B. A. Neuschwander-Tetri, “Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites,” Hepatology, vol. 52, no. 2, pp. 774–788, 2010. View at Publisher · View at Google Scholar · View at PubMed
  67. G. C. Farrell and C. Z. Larter, “Nonalcoholic fatty liver disease: from steatosis to cirrhosis,” Hepatology, vol. 43, no. 2, pp. S99–S112, 2006. View at Publisher · View at Google Scholar · View at PubMed
  68. K. L. Donnelly, C. I. Smith, S. J. Schwarzenberg, J. Jessurun, M. D. Boldt, and E. J. Parks, “Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease,” Journal of Clinical Investigation, vol. 115, no. 5, pp. 1343–1351, 2005. View at Publisher · View at Google Scholar
  69. G. Shiota, “Adiponectin as a therapeutic target of non-alcoholic steatohepatitis,” Hepatology Research, vol. 39, no. 10, pp. 951–953, 2009. View at Publisher · View at Google Scholar · View at PubMed
  70. B. J. Park, Y. J. Kim, D. H. Kim et al., “Visceral adipose tissue area is an independent risk factor for hepatic steatosis,” Journal of Gastroenterology and Hepatology, vol. 23, no. 6, pp. 900–907, 2008. View at Publisher · View at Google Scholar · View at PubMed
  71. O. Cheung, A. Kapoor, P. Puri et al., “The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome,” Hepatology, vol. 46, no. 4, pp. 1091–1100, 2007. View at Publisher · View at Google Scholar · View at PubMed
  72. T. Yamauchi, J. Kamon, H. Waki et al., “Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis,” Journal of Biological Chemistry, vol. 278, no. 4, pp. 2461–2468, 2003. View at Publisher · View at Google Scholar · View at PubMed
  73. C. N. Lumeng, J. B. Delproposto, D. J. Westcott, and A. R. Saltiel, “Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes,” Diabetes, vol. 57, no. 12, pp. 3239–3246, 2008. View at Publisher · View at Google Scholar · View at PubMed
  74. Y. Kamada, T. Takehara, and N. Hayashi, “Adipocytokines and liver disease,” Journal of Gastroenterology, vol. 43, no. 11, pp. 811–822, 2008. View at Publisher · View at Google Scholar · View at PubMed
  75. M. Ekstedt, L. E. Franzén, U. L. Mathiesen et al., “Long-term follow-up of patients with NAFLD and elevated liver enzymes,” Hepatology, vol. 44, no. 4, pp. 865–873, 2006. View at Publisher · View at Google Scholar · View at PubMed
  76. J. P. Ong, A. Pitts, and Z. M. Younossi, “Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease,” Journal of Hepatology, vol. 49, no. 4, pp. 608–612, 2008. View at Publisher · View at Google Scholar · View at PubMed
  77. N. Rafiq, C. Bai, Y. Fang et al., “Long-term follow-up of patients with nonalcoholic fatty liver,” Clinical Gastroenterology and Hepatology, vol. 7, no. 2, pp. 234–238, 2009. View at Publisher · View at Google Scholar · View at PubMed
  78. K. Cusi, “Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis,” Clinics in Liver Disease, vol. 13, no. 4, pp. 545–563, 2009. View at Publisher · View at Google Scholar · View at PubMed
  79. A. R. Saltiel and C. R. Kahn, “Insulin signalling and the regulation of glucose and lipid metabolism,” Nature, vol. 414, no. 6865, pp. 799–806, 2001. View at Publisher · View at Google Scholar · View at PubMed
  80. Y. Yilmaz, “Systematic review: caspase-cleaved fragments of cytokeratin 18—the promises and challenges of a biomarker for chronic liver disease,” Alimentary Pharmacology and Therapeutics, vol. 30, no. 11-12, pp. 1103–1109, 2009. View at Publisher · View at Google Scholar · View at PubMed
  81. G. C. Farrell, N. C. Teoh, and R. S. McCuskey, “Hepatic microcirculation in fatty liver disease,” Anatomical Record, vol. 291, no. 6, pp. 684–692, 2008. View at Publisher · View at Google Scholar · View at PubMed
  82. Y. Nakamura, A. Sekikawa, T. Kadowaki et al., “Visceral and subcutaneous adiposity and adiponectin in middle-aged Japanese men: the ERA JUMP study,” Obesity, vol. 17, no. 6, pp. 1269–1273, 2009. View at Publisher · View at Google Scholar · View at PubMed
  83. S. Chitturi, V. W. S. Wong, and G. Farrell, “Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground,” Journal of Gastroenterology and Hepatology, vol. 26, no. 1, pp. 163–172, 2011. View at Publisher · View at Google Scholar · View at PubMed
  84. J. M. Hui, J. G. Kench, S. Chitturi et al., “Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C,” Hepatology, vol. 38, no. 2, pp. 420–427, 2003. View at Publisher · View at Google Scholar · View at PubMed
  85. P. Angulo, J. C. Keach, K. P. Batts, and K. D. Lindor, “Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis,” Hepatology, vol. 30, no. 6, pp. 1356–1362, 1999. View at Google Scholar
  86. G. Marchesini, E. Bugianesi, G. Forlani et al., “Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome,” Hepatology, vol. 37, no. 4, pp. 917–923, 2003. View at Publisher · View at Google Scholar · View at PubMed
  87. J. B. Dixon, P. S. Bhathal, and P. E. O'Brien, “Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese,” Gastroenterology, vol. 121, no. 1, pp. 91–100, 2001. View at Google Scholar
  88. C. García-Monzón, E. Martín-Pérez, O. L. Iacono et al., “Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated obesity,” Journal of Hepatology, vol. 33, no. 5, pp. 716–724, 2000. View at Publisher · View at Google Scholar
  89. V. Ratziu, P. Giral, F. Charlotte et al., “Liver fibrosis in overweight patients,” Gastroenterology, vol. 118, no. 6, pp. 1117–1123, 2000. View at Google Scholar
  90. T. Gramlich, D. E. Kleiner, A. J. McCullough, C. A. Matteoni, N. Boparai, and Z. M. Younossi, “Pathologic features associated with fibrosis in nonalcoholic fatty liver disease,” Human Pathology, vol. 35, no. 2, pp. 196–199, 2004. View at Publisher · View at Google Scholar
  91. H. Miyaaki, T. Ichikawa, K. Nakao et al., “Clinicopathological study of nonalcoholic fatty liver disease in Japan: the risk factors for fibrosis,” Liver International, vol. 28, no. 4, pp. 519–524, 2008. View at Publisher · View at Google Scholar · View at PubMed
  92. I. Bouneva and D. F. Kirby, “Management of nonalcoholic fatty liver disease: weight control,” Clinics in Liver Disease, vol. 8, no. 3, pp. 693–713, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. G. Targher, A. Bellis, P. Fornengo et al., “Prevention and treatment of nonalcoholic fatty liver disease,” Digestive and Liver Disease, vol. 42, no. 5, pp. 331–340, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. D. T. Villareal, S. Chode, N. Parimi et al., “Weight loss, exercise, or both and physical function in obese older adults,” The New England Journal of Medicine, vol. 364, no. 13, pp. 1218–1229, 2011. View at Publisher · View at Google Scholar · View at PubMed
  95. D. E. Larson-Meyer, L. K. Heilbronn, L. M. Redman et al., “Effect of calorie restriction with or without exercise on insulin sensitivity, β-cell function, fat cell size, and ectopic lipid in overweight subjects,” Diabetes Care, vol. 29, no. 6, pp. 1337–1344, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. K. J. Stewart, A. C. Bacher, K. Turner et al., “Exercise and risk factors associated with metabolic syndrome in older adults,” American Journal of Preventive Medicine, vol. 28, no. 1, pp. 9–18, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. N. Rafiq and Z. M. Younossi, “Effects of weight loss on nonalcoholic fatty liver disease,” Seminars in Liver Disease, vol. 28, no. 4, pp. 427–433, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. T. Ueno, H. Sugawara, K. Sujaku et al., “Therapeutic effects of restricted diet and exercise in obese patients with fatty liver,” Journal of Hepatology, vol. 27, no. 1, pp. 103–107, 1997. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Shah, A. Stufflebam, T. N. Hilton, D. R. Sinacore, S. Klein, and D. T. Villareal, “Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults,” Obesity, vol. 17, no. 12, pp. 2162–2168, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. S. Chitturi, “Review: treatment options for nonalcoholic fatty liver disease,” Therapeutic Advances in Gastroenterology, vol. 1, no. 3, pp. 173–189, 2008. View at Google Scholar
  101. G. Marchesini, M. Brizi, G. Bianchi, S. Tomassetti, M. Zoli, and N. Melchionda, “Metformin in non-alcoholic steatohepatitis,” The Lancet, vol. 358, no. 9285, pp. 893–894, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Uygun, A. Kadayifci, A. T. Isik et al., “Metformin in the treatment of patients with non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 19, no. 5, pp. 537–544, 2004. View at Publisher · View at Google Scholar
  103. S. Nair, A. M. Diehl, M. Wiseman, G. H. Farr Jr., and R. P. Perrillo, “Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 1, pp. 23–28, 2004. View at Publisher · View at Google Scholar · View at PubMed
  104. J. C. Nisbet, J. M. Sturtevant, and J. B. Prins, “Metformin and serious adverse effects,” Medical Journal of Australia, vol. 180, no. 2, pp. 53–54, 2004. View at Google Scholar · View at Scopus
  105. F. Angelico, M. Burattin, C. Alessandri, M. Del Ben, and F. Lirussi, “Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis.,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD005166, 26 pages, 2007. View at Google Scholar
  106. S. H. Caldwell, E. E. Hespenheide, J. A. Redick, J. C. Iezzoni, E. H. Battle, and B. L. Sheppard, “A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis,” American Journal of Gastroenterology, vol. 96, no. 2, pp. 519–525, 2001. View at Publisher · View at Google Scholar · View at Scopus
  107. B. A. Neuschwander-Tetri, E. M. Brunt, K. R. Wehmeier, D. Oliver, and B. R. Bacon, “Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-γ ligand rosiglitazone,” Hepatology, vol. 38, no. 4, pp. 1008–1017, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. K. Promrat, G. Lutchman, G. I. Uwaifo et al., “A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis,” Hepatology, vol. 39, no. 1, pp. 188–196, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. A. J. Sanyal, P. S. Mofrad, M. J. Contos et al., “A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis,” Clinical Gastroenterology and Hepatology, vol. 2, no. 12, pp. 1107–1115, 2004. View at Publisher · View at Google Scholar
  110. V. Ratziu, F. Charlotte, C. Bernhardt et al., “Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial,” Hepatology, vol. 51, no. 2, pp. 445–453, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. H. Reynaert, A. Geerts, and J. Henrion, “Review article: the treatment of non-alcoholic steatohepatitis with thiazolidinediones,” Alimentary Pharmacology and Therapeutics, vol. 22, no. 10, pp. 897–905, 2005. View at Publisher · View at Google Scholar · View at PubMed
  112. S. E. Nissen and K. Wolski, “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes,” The New England Journal of Medicine, vol. 356, no. 24, pp. 2457–2471, 2007. View at Google Scholar · View at Scopus
  113. I. Hopper, “Cardiac effects of non-cardiac drugs,” Australian Prescriber, vol. 34, no. 2, pp. 52–54, 2011. View at Google Scholar
  114. E. J. DeMaria, “Bariatric surgery for morbid obesity,” The New England Journal of Medicine, vol. 356, no. 21, pp. 2176–2183, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  115. C. G. Solomon and R. G. Dluhy, “Bariatric surgery—quick fix or long-term solution?” The New England Journal of Medicine, vol. 351, no. 26, pp. 2751–2753, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. L. Sjöström, A.-K. Lindroos, M. Peltonen et al., “Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery,” The New England Journal of Medicine, vol. 351, no. 26, pp. 2683–2693, 2004. View at Publisher · View at Google Scholar · View at PubMed
  117. P. E. O'Brien, J. B. Dixon, W. Brown et al., “The laparoscopic adjustable gastric band (Lap-Band®): a prospective study of medium-term effects on weight, health and quality of life,” Obesity Surgery, vol. 12, no. 5, pp. 652–660, 2002. View at Publisher · View at Google Scholar · View at Scopus
  118. P. E. O'Brien, “Bariatric surgery: mechanisms, indications and outcomes,” Journal of Gastroenterology and Hepatology, vol. 25, no. 8, pp. 1358–1365, 2010. View at Publisher · View at Google Scholar · View at PubMed
  119. J. G. Kral, S. N. Thung, S. Biron et al., “Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis,” Surgery, vol. 135, no. 1, pp. 48–58, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  120. J. B. Dixon, P. S. Bhathal, N. R. Hughes, and P. E. O'Brien, “Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss,” Hepatology, vol. 39, no. 6, pp. 1647–1654, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. J. E. Varela, S. E. Wilson, and N. T. Nguyen, “Outcomes of bariatric surgery in the elderly,” American Surgeon, vol. 72, no. 10, pp. 865–869, 2006. View at Google Scholar · View at Scopus
  122. E. Koehler, K. Watt, and M. Charlton, “Fatty liver and liver transplantation,” Clinics in Liver Disease, vol. 13, no. 4, pp. 621–630, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  123. P. N. Bromley, I. Hilmi, K. C. Tan, R. Williams, and D. Potter, “Orthotopic liver transplantation in patients over 60 years old,” Transplantation, vol. 58, no. 7, pp. 800–803, 1994. View at Google Scholar · View at Scopus
  124. C. E. Garcia, R. F. L. Garcia, A. D. Mayer, and J. Neuberger, “Liver transplantation in patients over sixty years of age,” Transplantation, vol. 72, no. 4, pp. 679–684, 2001. View at Google Scholar · View at Scopus