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Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid

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Abstract

We report a case of hepatocellular carcinoma (HCC) arising in nonalcoholic steatohepatitis (NASH). The patient, a 64-year-old man, was incidentally found to have multiple tumors in the liver when admitted for pneumonia. He had been obese, had been receiving a standard dose of valproic acid since clipping surgery for subarachnoid hemorrhage 17 years previously, and had not consumed any alcohol since the surgery. Laboratory data revealed moderate hyperlipidemia and no evidence of diabetes mellitus, hepatitis B or C infection. The patient died of hepatic insufficiency, and an autopsy was performed. A tumor, a maximum of 13 cm in diameter, grossly occupied the entire left lobe and one third of the right lobe of the liver. Histologically, moderately differentiated HCC was found with foci of poorly differentiated HCC. The non-tumorous area showed NASH with moderate bridging fibrosis, without interface hepatitis, hemochromatosis, or copper accumulation. In this patient, obesity, hyperlipidemia, and long-term treatment with valproic acid could have all been associated with induction of NASH. The present case suggests that HCC could develop in non-cirrhotic NASH liver, and that chronic inflammation in itself could be an important risk factor in the development of HCC.

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References

  1. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231

    Article  PubMed  CAS  Google Scholar 

  2. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS (2001) Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology 56:172–177

    Article  PubMed  CAS  Google Scholar 

  3. Brunt EM (2004) Nonalcoholic steatohepatitis. Semin Liver Dis 24:3–20

    PubMed  Google Scholar 

  4. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M (2002) Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123:134–140

    Article  PubMed  Google Scholar 

  5. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM (2004) Obesity and hepatocellular carcinoma. Gastroenterology 127:S97–S103

    Article  PubMed  CAS  Google Scholar 

  6. Cotrim HP, Parana R, Braga E, Lyra L (2000) Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history? Am J Gastroenterol 95:3018–3019

    Article  PubMed  CAS  Google Scholar 

  7. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  8. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ (2001) Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 21:17–26

    Article  PubMed  CAS  Google Scholar 

  9. Farrell GC (2002) Drugs and steatohepatitis. Semin Liver Dis 22:185–194

    Article  PubMed  CAS  Google Scholar 

  10. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978

    Article  PubMed  Google Scholar 

  11. Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370

    Article  PubMed  CAS  Google Scholar 

  12. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36:1349–1354

    Article  PubMed  Google Scholar 

  13. Mori S, Yamasaki T, Sakaida I, Takami T, Sakaguchi E, Kimura T, Kurokawa F, Maeyama S, Okita K (2004) Hepatocellular carcinoma with nonalcoholic steatohepatitis. J Gastroenterol 39:391–396

    Article  PubMed  Google Scholar 

  14. Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 37:1202–1219 (Erratum in: Hepatology 2003;38:536)

    Article  PubMed  Google Scholar 

  15. Ong J, Younossi ZM, Reddy V, Price LL, Gramlich T, Mayes J, Boparai N (2001) Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 7:797–801

    Article  PubMed  CAS  Google Scholar 

  16. Orikasa H, Ohyama R, Tsuka N, Eyden BP, Yamazaki K (2001) Lipid-rich clear-cell hepatocellular carcinoma arising in non-alcoholic steatohepatitis in a patient with diabetes mellitus. J Submicrosc Cytol Pathol 33:195–200

    PubMed  CAS  Google Scholar 

  17. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW (1990) The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 11:74–80

    Article  PubMed  Google Scholar 

  18. Schafer DF, Sorrell MF (1999) Hepatocellular carcinoma. Lancet 353:1253–1257

    Article  PubMed  CAS  Google Scholar 

  19. Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, Takasaki K, Ludwig J (2002) Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 37:154–160

    Article  PubMed  Google Scholar 

  20. Singh G, Driever PH, Sander JW (2005) Cancer risk in people with epilepsy: the role of antiepileptic drugs. Brain 128:7–17

    Article  PubMed  Google Scholar 

  21. Soga M, Kishimoto Y, Kawamura Y, Inagaki S, Makino S, Saibara T (2003) Spontaneous development of hepatocellular carcinomas in the FLS mice with hereditary fatty liver. Cancer Lett 196:43–48

    Article  PubMed  CAS  Google Scholar 

  22. Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY (2005) Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A 102:4120–4125

    Article  PubMed  CAS  Google Scholar 

  23. Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I, Nakanuma Y (2001) Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathol Int 51:127–131

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Katsuaki Sato.

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Sato, K., Ueda, Y., Ueno, K. et al. Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid. Virchows Arch 447, 996–999 (2005). https://doi.org/10.1007/s00428-005-0042-z

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  • DOI: https://doi.org/10.1007/s00428-005-0042-z

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