Hepatocellular carcinoma in non-alcoholic steatohepatitis: Growing evidence of an epidemic?

Hepatology Research

Volumn 42, Issue 1, 2012, Pages 1-14

  Hashimoto, Etsuko ^a   Tokushige, Katsutoshi ^a  

^a TOKYO WOMEN'S MEDICAL UNIVERSITY   (Japan)

Author keywords

Cirrhosis; Cryptogenic cirrhosis; Hepatocellular carcinoma; Non alcoholic fatty liver disease; Nonalcoholic steatohepatitis

Indexed keywords

CANCER INCIDENCE; CANCER RECURRENCE; CHRONIC LIVER DISEASE; CLINICAL FEATURE; DISEASE ASSOCIATION; EPIDEMIC; HISTOPATHOLOGY; HUMAN; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OBESITY; PATHOGENESIS; PREVALENCE; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; RISK FACTOR; SEX DIFFERENCE; VIRUS HEPATITIS;

EID: 84055193440     PISSN: 13866346     EISSN: 1872034X     Source Type: Journal    
DOI: 10.1111/j.1872-034X.2011.00872.x     Document Type: Review

References (143)

1. World Health Organization. Mortality database. [Cited Feb 2010] Available from URL:
2. Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127 (5 Suppl 1): S5-16.
3. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors and screening. Semin Liver Dis 2005; 25: 143-54.
4. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-76.
5. Yuen MF, Hou JL, Chutaputti A. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 2009; 24: 346-53.
6. Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K. Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol 2009; 44 (Suppl 19): 102-7.
7. Younossi ZM, Stepanova M. Hepatitis C virus infection, age, and Hispanic ethnicity increase mortality from liver cancer in the United States. Clin Gastroenterol Hepatol 2010; 8: 718-23.
8. Yang JD, Harmsen WS, Slettedahl SW etal. Factors that affect risk for hepatocellular carcinoma and effects of surveillance. Clin Gastroenterol Hepatol 2011; 9: 617-23.
9. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820-32.
10. Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 2009; 115: 5651-61.
11. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960-7.
12. Browning JD, Szczepaniak LS, Dobbins R etal. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-95.
13. Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007; 11: 1-16 vii.
14. Bell BP, Manos MM, Zaman A etal. The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance. Am J Gastroenterol 2008; 103: 2727-36.
15. Shen L, Fan JG, Shao Y etal. Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol 2003; 9: 1106-10.
16. Tominaga K, Kurata JH, Chen YK etal. Prevalence of fatty liver in Japanese children and relationship to obesity; An epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: 2002-9.
17. Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12years: analysis of clinical background. J Gastroenterol 2003; 38: 954-61.
18. Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences? J Gastroenterol Hepatol 2007; 22: 788-93.
19. Okanoue T, Umemura A, Yasui K, Itoh Y. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in Japan. J Gastroenterol Hepatol 2011; 26 (Suppl 1): 153-62.
20. Malik SM, Gupte PA, de Vera ME, Ahmad J. Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2009; 7: 800-6.
21. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002; 36: 1349-54.
22. Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 2008; 132: 1761-6.
23. Journal of Health and Welfare Statistics. Health and Welfare Statistics Association. 2010 Japan.
24. Ikai I, Arii S, Okazaki M etal. Report of the 17th nationwide follow-up survey of primary liver cancer in Japan. Hepatol Res 2010; 40: 1043-59.
25. Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y, Onji M. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol 2010; 45: 86-94.
26. Tokushige K, Hashimoto E, Horie Y, Taniai M, Higuchi S. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease and chronic liver disease of unknown etiology: report of the Nationwide Survey. J Gastroenterol (Epub ahead of print).
27. Kawada N, Imanaka K, Kawaguchi T etal. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 2009; 44: 1190-4.
28. Naugler WE, Sakurai T, Kim S etal. Gender disparity in liver cancer due to sex differences in MyD88-Dependent IL-6 production. Science 2007; 317: 121-4.
29. Nakagawa H, Maeda S, Yoshida H etal. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 2009; 125: 2264-9.
30. Yatsuji S, Hashimoto E, Tobari M, Tokushige K, Shiratori K. Influence of age and gender in Japanese patients with non-alcoholic steatohepatitis. Hepatol Res 2007; 37: 1034-43.
31. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol 2011; 46: 63-9.
32. Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009; 24: 248-54.
33. Hashimoto E, Yatsuji S, Tobari M etal. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Gastroenterol 2009; 44: 89-95.
34. Ayonrinde OT, Olynyk JK, Beilin LJ etal. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology 2011; 53: 800-9.
35. Day CP, James OF. Steatohepatitis: a tale of two "hits". Gastroenterology 1998; 114: 842-5.
36. Starkel P, Sempoux C, Leclercq I etal. Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 2003; 39: 538-46.
37. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Heptaology 2010; 52: 1836-46.
38. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 2011; 53: 1752-63.
39. Amir M, Craja MJ. Autophagy in nonalcoholic stetohepatitis. Expert Rev Gastroenterol Hepatol 2011; 5: 159-66.
40. Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006; 40: 68-76.
41. Andrisani OM, Barnabas S. The transcriptional function of the hepatitis B virus X protein and its role in Hepatocarcinogenesis. Int J Oncol 1999; 15: 373-9.
42. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 2007; 11: 191-207 x-xi.
43. Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 2007; 46: 1104-10.
44. Wang Y, Ausman L, Greenberg AS, Russell RM, Wang XD. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 2009; 124: 540-6.
45. Park EJ, Lee JH, Yu GY etal. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208.
46. Roderburg C, Trautwein C. Obesity and liver cancer: a key role for interleukin-6 and signal transducer and activator of transcription 3? Hepatology 2010; 51: 1850-2.
47. Brakenhielm E, Veitonmaki N, Cao R etal. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 2004; 101: 2476-81.
48. Kamada Y, Matsumoto H, Tamura S etal. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 2007; 47: 556-64.
49. Hu W, Feng Z, Eveleigh J etal. The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 2002; 23: 1781-9.
50. Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci USA 2005; 102: 4120-5.
51. Maki A, Kono H, Gupta M etal. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 2007; 14: 1182-90.
52. Page JM, Harrison SA. NASH and HCC. Clin Liver Dis 2009; 13: 631-47.
53. Calle EE, Kaaks S. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 79-91.
54. Ish-Shalom D, Christoffersen CT, Vorwerk P etal. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 1997; 40: S25-S31.
55. Tanaka S, Wands J. Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res 1996; 56: 3391-4.
56. Horie Y, Suzuki A, Kataoka E etal. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004; 113: 1774-83.
57. Shiota G. Loss of function of retinoic acid in liver leads to steatohepatitis and liver tumor: A NASH animal model. Hepatol Res 2005; 33: 155-60.
58. Hirosumi J, Tuncman G, Change L etal. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333-6.
59. Puri P, Mirshahi F, Cheung O etal. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134: 568-76.
60. Chen F, Beezhold K, Castranova V. JNK1, a potential therapeutic target for hepatocellular carcinoma. Biochim Biophys Acta 2009; 1796: 242-51.
61. Chang Q, Zhang Y, Beezhold KJ etal. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol 2009; 50: 323-33.
62. Hui L, Zatloukal H, Scheuch H, Stepniak E, Wagner EF. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 2008; 118: 3943-53.
63. Chen F, Castanova V. Beyond apoptosis of JNK1 in liver cancer. Cell Cycle 2009; 8: 1145-7.
64. Fujishita T, Aoki M, Taketo MM. JNK signaling promotes intestinal tumorigenesis through activation of mTOR complex 1 in Apc(Δ716) Mice. Gastroenterology 2011; 140: 1556-63.
65. March HN, Winton DJ. mTOR regulation by JNK: rescuing the starving intestinal cancer cell? Gastroenterology 2011; 140: 1387-91.
66. Zhou L, Huang Y, Li J, Wang Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol 2010; 27: 255-61.
67. Chen JS, Wang Q, Fu XH etal. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 2009; 39: 177-86.
68. Cadwell S, Park SH. The epidemiology of hepatocellular cancer: from the perspectives of heath problem to tumor biology. J Gastroenterol 2009; 44: 96-101.
69. Kumar V, Kato N, Urabe Y etal. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43: 455-8.
70. Kato N, Ji G, Wang Y etal. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatology 2005; 42: 846-53.
71. Romeo S, Kozlitina J, Xing C etal. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-5.
72. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010; 52: 894-903.
73. Valenti L, Rumi M, Galmozzi E etal. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53: 791-9.
74. Nahon P, Sutton A, Rufat P etal. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134: 102-10.
75. Pietrangelo A. Iron in NASH, chronic liver diseases and HCC: how much iron is too much? J Hepatol 2009; 50: 249-51.
76. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625-38.
77. Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A: 344-50.
78. Wolk A, Gridley G, Svensson M etal. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 2001; 12: 13-21.
79. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 2005; 23: 4742-54.
80. N'Kontchou G, Paries J, Htar MTT etal. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol 2006; 4: 1062-8.
81. Muto Y, Sato S, Watanabe A etal. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res 2006; 35: 204-14.
82. Nair S, Mason A, Eason J, Loss G, Perrillo RP. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 2002; 36: 774.
83. Utsunomiya T, Okamoto M, Kameyama T etal. Impact of obesity on the surgical outcome following repeat hepatic resection in Japanese patients with recurrent hepatocellular carcinoma. World J Gastroenterol 2008; 14: 1553-8.
84. Ohki T, Tateishi R, Shiina S etal. Visceral fat accumulation is an independent risk factor of hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH. Gut 2009; 58: 839-44.
85. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.
86. Adami HO, Chow WH, Nyren O etal. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996; 88: 1472-7.
87. Wideroff L, Gridley G, Mellemkjaer L etal. Cancer incidence in a population based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89: 1360-5.
88. Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000; 92: 1096-9.
89. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005; 54: 533-9.
90. Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 2006; 166: 1871-7.
91. Donadon V, Balbi M, Ghersetti M etal. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 2009; 15: 2506-11.
92. Hassan MM, Curley SA, Li D etal. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010; 116: 1938-46.
93. Chen CL, Yang HI, Yang WS etal. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008; 135: 111-21.
94. Polesel J, Zucchetto A, Montella M etal. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol 2009; 20: 353-8.
95. Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology 1997; 112: 882-8.
96. Fujita N, Miyachi H, Tanaka H etal. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 2009; 18: 424-32.
97. George DK, Goldwurm S, MacDonald GA etal. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114: 311-18.
98. Sumida Y, Yoshikawa T, Okanoue T. Role of hepatic iron in non-alcoholic steatohepatitis. Hepatol Res 2009; 39: 213-22.
99. Valenti L, Fracanzani AL, Bugianesi E etal. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138: 905-12.
100. Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009; 50: 351-7.
101. Adams LA, Lymp JF, Sauver JST etal. The natural history of nonalcoholic fatty liver disease: a population based cohort study. Gastroenterology 2005; 129: 113-21.
102. Ekstedt M, Franz LE, Mathiesen UL etal. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.
103. Rafiq N, Bai C, Fang Y etal. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7: 234-8.
104. Söderberg C, Stål P, Askling J etal. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51: 595-602.
105. Sørensen HT, Mellemkjaer L, Jepsen P etal. Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study. J Clin Gastroenterol 2003; 36: 356-9.
106. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-19.
107. D-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol 2009; 44: 1236-43.
108. Evans CD, Oien KA, MacSween RN, Mills PR. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol 2002; 55: 689-92.
109. Hui J, Kench JG, Chitturi S etal. Long term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003; 38: 420-7.
110. Sanyal AJ, Banas C, Sargeant C etal. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatoloty 2006; 43: 682-9.
111. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51: 1972-8.
112. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21years. Hepatology 1990; 11: 74-80.
113. Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I, Nakanuma Y. Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathol Int 2001; 51: 127-31.
114. Orikasa H, Ohyama R, Tsuka N, Eyden BP, Yamazaki K. Lipid-rich clear-cell hepatocellular carcinoma arising in non-alcoholic steatohepatitis in a patient with diabetes mellitus. J Submicrosc Cytol Pathol 2001; 33: 195-200.
115. Cotrim HP, Paraná R, Braga E, Lyra L. Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history. Am J Gastroenterol 2000; 95: 3018-19.
116. Bencheqroun R, Duvoux C, Luciani A, Zafrani ES, Dhumeaux D. [Hepatocellular carcinoma without cirrhosis in a patient with nonalcoholic steatohepatitis]. Gastroenterol Clin Biol 2004; 28: 497-9.
117. Mori S, Yamasaki T, Sakaida I etal. Hepatocellular carcinoma with nonalcoholic steatohepatitis. J Gastroenterol 2004; 39: 391-6.
118. Bullock RE, Zaitoun AM, Aithal GP, Ryder SD, Beckingham IJ, Lobo DN. Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma. J Hepatol 2004; 41: 685-6.
119. Cuadrado A, Orive A, García-Suárez C etal. Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. Obes Surg 2005; 15: 442-6.
120. Sato K, Ueda Y, Ueno K, Okamoto K, Iizuka H, Katsuda S. Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid. Virchows Arch 2005; 447: 996-9.
121. Ichikawa T, Yanagi K, Motoyoshi Y etal. Two cases of non-alcoholic steatohepatitis with development of hepatocellular carcinoma without cirrhosis. J Gastroenterol Hepatol 2006; 21: 1865-6.
122. Ikeda H, Suzuki M, Takahashi H etal. Hepatocellular carcinoma with silent and cirrhotic non-alcoholic steatohepatitis, accompanying ectopic liver tissue attached to gallbladder. Pathol Int 2006; 56: 40-5.
123. Tsutsumi K, Nakayama H, Sakai Y etal. [Two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease after clinical courses of 26years]. Nippon Shokakibyo Gakkai Zasshi 2007; 104: 690-7.
124. Hashizume H, Sato K, Takagi H etal. Primary liver cancers with nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2007; 19: 827-34.
125. Hai S, Kubo S, Shuto T etal. Hepatocellular carcinoma arising from nonalcoholic steatohepatitis: report of two cases. Surg Today 2006; 36: 390-4.
126. Maeda T, Hashimoto K, Kihara Y etal. Surgically resected hepatocellular carcinomas in patients with non-alcoholic steatohepatitis. Hepatogastroenterology 2008; 55: 1404-6.
127. Chagas AL, Kikuchi LO, Oliveira CP etal. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? Braz J Med Biol Res 2009; 42: 958-62.
128. Takuma Y, Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol 2010; 16: 1436-41.
129. Abe H, Yoshizawa K, Kitahara T, Aizawa R, Matsuoka M, Aizawa Y. Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo. J Gastroenterol 2008; 43: 967-74.
130. Yasui K, Hashimoto E, Komorizono Y etal. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9 (5): 428-33.
131. Ertle J, Dechêne A, Sowa JP etal. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128: 2436-43.
132. Wakai T, Shirai Y, Sakata J, Korita PV, Ajioka Y, Hatakeyama K. Surgical outcomes for hepatocellular carcinoma in nonalcoholic fatty liver disease. J Gastrointest Surg 2011; 5: 140-8.
133. Kawai H, Nomoto M, Suda T, Kamimura K etal. Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis. World J Hepatol 2011; 3 (1): 15-23.
134. Tokushige K, Hashimoto E, Yatsuji S etal. Prospective study of hepatocellular carcinoma in nonalcoholic steatohepatitis in comparison with hepatocellular carcinoma cause by chronichepatitis C. J Gastroenterol 2010; 45: 960-7.
135. Yoshioka Y, Hashimoto E, Yatsuji S etal. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol 2004; 39: 1215-18.
136. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999; 29: 664-9.
137. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 2000; 32 (4 Pt 1): 689-92.
138. Yalamanchili K, Saadeh S, Klintmalm GB, Jennings LW, Davis GL. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transpl 2010; 16 (4): 431-9.
139. Ratziu V, Bonyhay L, Di Martino V etal. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002; 35: 1485-93.
140. Bugianesi E, Leone N, Vanni E etal. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134-40.
141. Regimbeau JM, Colombat M, Mognol P etal. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 2004; 10 (2 Suppl 1): S69-73.
142. Giannini EG, Marabotto E, Savarino V etal. Hepatocellular carcinoma in patients with cryptogenic cirrhosis. Clin Gastroenterol Hepatol 2009; 7: 580-5.
143. Paradis V, Zalinski S, Chelbi E etal. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49: 851-9.