Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis

International Journal of Cancer

Volumn 128, Issue 10, 2011, Pages 2436-2443

  Ertle, Judith ^a   Dechêne, Alexander ^a   Sowa, Jan Peter ^a   Penndorf, Volker ^a   Herzer, Kerstin ^a   Kaiser, Gernot ^a   Schlaak, Jörg F ^a   Gerken, Guido ^a   Syn, Wing Kin ^b   Canbay, Ali ^a  

^a UNIVERSITY HOSPITAL ESSEN   (Germany)

^b University Hospitals Birmingham NHS Foundation Trust   (United Kingdom)

Author keywords

BMI; hepatocellular carcinoma; metabolic syndrome; NAFLD; NASH

Indexed keywords

ALBUMIN; ALPHA FETOPROTEIN; BILIRUBIN; CREATININE;

AGED; ARTICLE; ASCITES; BODY MASS; CONTROLLED STUDY; CORONARY ARTERY DISEASE; DISEASE COURSE; DYSLIPIDEMIA; FEMALE; HEMOCHROMATOSIS; HEPATITIS B; HEPATITIS C; HISTOPATHOLOGY; HUMAN; HYPERTENSION; INCIDENCE; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; MAJOR CLINICAL STUDY; MALE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OBESITY; PORTAL VEIN THROMBOSIS; PREVALENCE; PRIMARY SCLEROSING CHOLANGITIS; PRIORITY JOURNAL; RISK FACTOR; SPLENOMEGALY; THROMBOCYTOPENIA;

AGED; CARCINOMA, HEPATOCELLULAR; FATTY LIVER; FEMALE; HUMANS; INCIDENCE; LIVER CIRRHOSIS; LIVER NEOPLASMS; MALE;

EID: 79953185045     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.25797     Document Type: Article

References (50)

1. Angulo P,. Nonalcoholic fatty liver disease. Rev Gastroenterol Mex 2005; 70 (Suppl 3): 52-56.
2. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR,. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J. Gastroenterol 1999; 94: 2467-74. (Pubitemid 29420675)
3. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P,. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-21. (Pubitemid 41002048)
4. Starley BQ, Calcagno CJ, Harrison SA,. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820-32.
5. Bruix J, Sherman M,. Sortable Practice Guidelines-Hepatocellular Carcinoma. Available at:. Accessed on March 18th 2010.
6. Fabbrini E, Sullivan S, Klein S,. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010; 51: 679-89.
7. Kotronen A, Yki-Järvinen H, Männistö S, Saarikoski L, Korpi-Hyövälti E, Oksa H, Saltevo J, Saaristo T, Sundvall J, Tuomilehto J, Peltonen M,. Non-alcoholic and alcoholic fatty liver disease-two diseases of affluence associated with the metabolic syndrome and type 2 diabetes: the FIN-D2D survey. BMC Public Health 2010; 10: 237.
8. Prashanth M, Ganesh HK, Vima MV, John M, Bandgar T, Joshi SR, Shah SR, Rathi PM, Joshi AS, Thakkar H, Menon PS, Shah NS,. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2009; 57: 205-10.
9. Edmison JM, Kalhan SC, McCullough AJ,. Obesity, hepatic metabolism and disease. Nestle Nutr Workshop Ser Pediatr Program 2009; 63: 163-72; discussion 172-176, 259-268.
10. Siegel AB, Zhu AX,. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 2009; 115: 5651-5661.
11. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S,. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005; 42: 44-52. (Pubitemid 40911310)
12. Bellentani S, Scaglioni F, Marino M, Bedogni G,. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010; 28: 155-61.
13. Chen J, Zhu J, Parkin DM, Zhang Y, Lu J, Zhu Y, Chen T,. Trends in the incidence of cancer in Qidong, China, 1978-2002. Int J Cancer 2006; 119: 1447-54. (Pubitemid 44258824)
14. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH,. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-95. (Pubitemid 39657013)
15. Simonetti RG, Cammà C, Fiorello F, Politi F, D'Amico G, Pagliaro L,. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 1991; 36: 962-72.
16. Anzola M,. Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis. J Viral Hepat 2004; 11: 383-93. (Pubitemid 39336219)
17. Morgan TR, Mandayam S, Jamal MM,. Alcohol and hepatocellular carcinoma. Gastroenterology 2004; 127 (5 Suppl 1): S87-96. (Pubitemid 39423374)
18. Calle EE, Kaaks R,. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 579-91. (Pubitemid 39025053)
19. Bzowej N, Han S, Degertekin B, Keeffe EB, Emre S, Brown R, Reddy R, Lok AS,. Liver transplantation outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B. Liver Transpl 2009; 15: 1010-20.
20. Yau T, Chan P, Epstein R, Poon R,. Evolution of systemic therapy of advanced hepatocellular carcinoma. World J Gastroenterol 2008; 14: 6437-41.
21. El-Serag HB,. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127 (5 Suppl 1): S27-34. (Pubitemid 39423367)
22. Bruix J, Sherman M,. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208-36. (Pubitemid 43112690)
23. 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.
24. Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DSJ, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J,. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003; 108: 414-19. (Pubitemid 36935533)
25. Metwally MA, Zein CO, Zein NN,. Predictors and noninvasive identification of severe liver fibrosis in patients with chronic hepatitis C. Dig Dis Sci 2007; 52: 582-88. (Pubitemid 46202844)
26. Negro F, Sanyal AJ,. Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data. Liver Int 2009; 29 (Suppl 2): 26-37.
27. Wisniewska-Ligier M, Wozniakowska-Gesicka T, Kups J, Sulat-Syncerek D,. Lipid metabolism in children with chronic hepatitis C, A preliminary report. Hepatogastroenterology 2006; 53: 887-91. (Pubitemid 44851222)
28. Wedemeyer I, Bechmann LP, Odenthal M, Jochum C, Marquitan G, Drebber U, Gerken G, Gieseler RK, Dienes HP, Canbay A,. Adiponectin inhibits steatotic CD95/Fas up-regulation by hepatocytes: therapeutic implications for hepatitis C. J Hepatol 2009; 50: 140-9.
29. Doll R, Peto R, Boreham J, Sutherland I,. Mortality in relation to alcohol consumption: a prospective study among male British doctors. Int J Epidemiol 2005; 34: 199-204. (Pubitemid 40347395)
30. Elkind MSV, Sciacca R, Boden-Albala B, Rundek T, Paik MC, Sacco RL,. Moderate alcohol consumption reduces risk of ischemic stroke: the Northern Manhattan Study. Stroke 2006; 37: 13-9. (Pubitemid 43732041)
31. 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.
32. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G, Arcaro G,. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29: 1325-30. (Pubitemid 44125930)
33. Tellez-Avila FI, Sanchez-Avila F, García-Saenz-de-Sicilia M, Chavez-Tapia NC, Franco-Guzman AM, Lopez-Arce G, Cerda-Contreras E, Uribe M,. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World J Gastroenterol 2008; 14: 4771-5.
34. Chagas AL, Kikuchi LOO, Oliveira CPMS, Vezozzo DCP, Mello ES, Oliveira AC, Cella LC, Herman P, Bachella T, Caldwell SH, Alves VAF, Carrilho FJ,. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? Braz J Med Biol Res 2009; 42: 958-62.
35. Kawada N, Imanaka K, Kawaguchi T, Tamai C, Ishihara R, Matsunaga T, Gotoh K, Yamada T, Tomita Y,. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 2009; 44: 1190-4.
36. Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K, Shiratori K,. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (Suppl 19): 89-95.
37. Park EJ, Lee JH, Yu G, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M,. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208.
38. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, Belghiti J,. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49: 851-9.
39. Herzer K, Hofmann TG, Teufel A, Schimanski CC, Moehler M, Kanzler S, Schulze-Bergkamen H, Galle PR,. IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res 2009; 69: 855-62.
40. Cazanave SC, Mott JL, Elmi NA, Bronk SF, Werneburg NW, Akazawa Y, Kahraman A, Garrison SP, Zambetti GP, Charlton MR, Gores GJ,. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem 2009; 284: 26591-602.
41. Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F, Weber A, Weiskirchen R, Liedtke C, Gassler N, Müller M, de Vos R, et al,. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 2010; 17: 481-96.
42. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M,. Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007; 11: 119-32. (Pubitemid 46209851)
43. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ,. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 2006; 43: 163-172. (Pubitemid 43733603)
44. Zhang YH, Wang SQ, Sun CR, Wang M, Wang B, Tang JW,. Inhibition of JNK1 expression decreases migration and invasion of mouse hepatocellular carcinoma cell line in vitro. Med Oncol. 2010 May 20. Available at
45. Fleig SV, Choi SS, Yang L, Jung Y, Omenetti A, VanDongen HM, Huang J, Sicklick JK, Diehl AM,. Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab Invest 2007; 87: 1227-39. (Pubitemid 350126712)
46. Bechmann LP, Zahn D, Gieseler RK, Fingas CD, Marquitan G, Jochum C, Gerken G, Friedman SL, Canbay A,. Resveratrol amplifies profibrogenic effects of free fatty acids on human hepatic stellate cells. Hepatol Res 2009; 39: 601-8.
47. Caldwell SH, Lee VD, Kleiner DE, Al-Osaimi AMS, Argo CK, Northup PG, Berg CL,. NASH and cryptogenic cirrhosis: a histological analysisdagger. Ann Hepatol 2009; 8: 346-52.
48. Ghosh A, Liu T, Khoury MJ, Valdez R,. Family History of Diabetes and Prevalence of the Metabolic Syndrome in U.S. Adults without Diabetes: 6-Year Results from the National Health and Nutrition Examination Survey (1999-2004). Public Health Genomics 2010; 13: 353-9.
49. Arun J, Jhala N, Lazenby AJ, Clements R, Abrams GA,. Influence of liver biopsy heterogeneity and diagnosis of nonalcoholic steatohepatitis in subjects undergoing gastric bypass. Obes Surg 2007; 17: 155-61. (Pubitemid 47091575)
50. Forner A, Reig ME, de Lope CR, Bruix J,. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010; 30: 61-74.