Tumor Biology

, Volume 37, Issue 7, pp 8889–8900 | Cite as

Hypersplenism is correlated with increased risk of hepatocellular carcinoma in patients with post-hepatitis cirrhosis

  • Xing Lv
  • Fan Yang
  • Xin Guo
  • Tao Yang
  • Ti Zhou
  • Xiaoping Dong
  • Yong Long
  • Dan Xiao
  • Yong Chen
Original Article


Several risk factors exist for hepatocellular carcinoma in patients with post-hepatitis cirrhosis (PHC), including hypersplenism. Splenectomy is a common but controversial procedure in the management of hypersplenism, but its impact on hepatocellular carcinoma (HCC) remains uncertain. We conducted a hospital-based study of PHC patients to identify potential risk factors, including a history of splenectomy, which has been associated with progression from PHC to HCC. From 2002 to 2012, 2678 patients developed hypersplenism secondary to PHC. Of these patients, 828 developed HCC and 1850 did not. Potential risk factors of HCC were determined by univariate and multivariate analyses to exclude confounding variables. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined for each factor. Many factors, such as liver function, platelet (PLT) counts, Child-Pugh class, and history of hepatitis, were associated with progression to HCC. PHC patients with hypersplenism who displayed elevated levels of alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), ALK, phosphatase, and prolonged prothrombin time (PT) had a significantly increased risk of HCC. However, the patients who had splenectomy showed better liver function test results and less progression to HCC. In patients with PHC and hypersplenism, abnormal levels of ALT, AST, ALP, and GGT and prolonged PT are risk factors of HCC. Splenectomy, as the intervention method of hypersplenism, is performed less frequently in patients who developed HCC than in patients who did not develop HCC. Therefore, splenectomy may act as an independent factor that is significantly associated with HCC development.


Hypersplenism Splenectomy Hepatocellular carcinoma Liver function 



We gratefully acknowledge the valuable cooperation of Mell Williams (Medicine College of University of Johns Hopkins) in preparing this application note.

Compliance with ethical standard


Supported by the Natural Science Foundation of China No. 81372607

Conflicts of interest



  1. 1.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Fattovich G, Llovet JM. Risk factors for hepatocellular carcinoma in HCV-cirrhosis: what we know and what is missing. J Hepatol. 2006;44:1013–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Velazquez RF, Rodriguez M, Navascues CA, Linares A, Perez R, Sotorrios NG, et al. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology. 2003;37:520–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Lu SN, Wang JH, Liu SL, Hung CH, Chen CH, Tung HD, et al. Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma. Cancer. 2006;107:2212–22.CrossRefPubMedGoogle Scholar
  5. 5.
    Lu SN, Wang JH, Chen PF, Tung HD, Tseng PL, Hung CH, et al. Community-based mass ultrasonographic screening of hepatocellular carcinoma among thrombocytopenic adults. Cancer Epidemiol Biomarkers Prev. 2008;17:1813–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Lu SN. Cross-stage and combination treatment for Barcelona Clinic of Liver Cancer stage B (intermediate stage) hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27:991–3.CrossRefPubMedGoogle Scholar
  7. 7.
    Chang KC, Lu SN, Chen PF, Hung CH, Kee KM, Yen YH, et al. Incidence and associated risk factors of hepatocellular carcinoma in a dural hepatitis B and C virus endemic area: a surveillance study. Kaohsiung J Med Sci. 2011;27:85–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Tomikawa M, Hashizume M, Akahoshi T, Shimabukuro R, Gotoh N, Ohta M, et al. Effects of splenectomy on liver volume and prognosis of cirrhosis in patients with esophageal varices. J Gastroenterol Hepatol. 2002;17:77–80.CrossRefPubMedGoogle Scholar
  9. 9.
    Tomikawa M, Akahoshi T, Sugimachi K, Ikeda Y, Korenaga D, Takenaka K, et al. An assessment of surgery for portal hypertensive patients performed at a single community hospital. Surg Today. 2010;40:620–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu HQ, An JZ, Liu J, Yang YF, Zhang HX, Zhao BY, et al. Leukocyte telomere length predicts overall survival in hepatocellular carcinoma treated with transarterial chemoembolization. Carcinogenesis. 2012;33:1040–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Kodama T, Takehara T, Hikita H, Shimizu S, Li W, Miyagi T, et al. Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. Gastroenterology. 2010;138:2487–98. 2498.e1-7.CrossRefPubMedGoogle Scholar
  12. 12.
    Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol. 2014;20:2555–63.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Akahoshi T, Uehara H, Tomikawa M, Kawanaka H, Hashizume M, Maehara Y. Comparison of open, laparoscopic, and hand-assisted laparoscopic devascularization of the upper stomach and splenectomy for treatment of esophageal and gastric varices: a single-center experience. Asian J Endosc Surg. 2014;7:138–44.CrossRefPubMedGoogle Scholar
  14. 14.
    Akahoshi T, Hashizume M, Tanoue K, Shimabukuro R, Gotoh N, Tomikawa M, et al. Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1. J Gastroenterol Hepatol. 2002;17:59–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Banares R, Nunez O, Escudero M, Fernandez C, Vaquero J, Beceiro I, et al. Patients with cirrhosis and bare-stent TIPS may have increased risk of hepatocellular carcinoma. Hepatology. 2005;41:566–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Santambrogio R, Opocher E, Costa M, Bruno S, Ceretti AP, Spina GP. Natural history of a randomized trial comparing distal spleno-renal shunt with endoscopic sclerotherapy in the prevention of variceal rebleeding: a lesson from the past. World J Gastroenterol. 2006;12:6331–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yin L, Liu H, Zhang Y, Rong W. The surgical treatment for portal hypertension: a systematic review and meta-analysis. ISRN Gastroenterol. 2013;2013:464053.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ikegami T, Shimada M, Imura S. Recent role of splenectomy in chronic hepatic disorders. Hepatol Res. 2008;38:1159–71.PubMedGoogle Scholar
  19. 19.
    Ikegami T, Honda A, Miyazaki T, Kohjima M, Nakamuta M, Matsuzaki Y. Increased serum oxysterol concentrations in patients with chronic hepatitis C virus infection. Biochem Biophys Res Commun. 2014;446:736–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Chang KC, Wu YY, Hung CH, Lu SN, Lee CM, Chiu KW, et al. Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy. Br J Cancer. 2013;109:2481–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20:2072–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang JH, Chang KC, Kee KM, Chen PF, Yen YH, Tseng PL, et al. Hepatocellular carcinoma surveillance at 4- vs. 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am J Gastroenterol. 2013;108:416–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Laffi G, Tarquini R, Marra F. Thrombocytopenia in chronic liver disease: lessons from transplanted patients. J Hepatol. 2007;47:625–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Laffi G, Marra F, Tarquini R, Abbate R. Coagulation defects in cirrhosis—old dogmas not yet ready for burial. J Thromb Haemost. 2006;4:2068–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol. 2008;48 Suppl 1:S68–92.CrossRefPubMedGoogle Scholar
  26. 26.
    Liu H, Lee SS. The spleen is a player in portal hypertension. Exp Physiol. 2012;97:999–1000.CrossRefPubMedGoogle Scholar
  27. 27.
    Kim JM, Kwon CH, Joh JW, Park JB, Ko JS, Lee JH, et al. The effect of alkaline phosphatase and intrahepatic metastases in large hepatocellular carcinoma. World J Surg Oncol. 2013;11:40.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tarao K, Miyakawa K, Miyagi Y, Ohkawa S, Morinaga S, Oshige K, et al. Severe inflammation in the background liver cirrhosis correlates with the development of poorly differentiated HCC in HCV-associated liver cirrhosis. Intern Med. 2012;51:2495–501.CrossRefPubMedGoogle Scholar
  29. 29.
    Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54:1082–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yeh HC, Lin SM, Chen MF, Pan TL, Wang PW, Yeh CT. Evaluation of serum matrix metalloproteinase MMP-9 to MMP-2 ratio as a biomarker in hepatocellular carcinoma. Hepatogastroenterology. 2010;57:98–102.PubMedGoogle Scholar
  31. 31.
    Ma YG, Li XS, Zhao J, Chen H, Wu MC. Modified Sugiura procedure for the management of 160 cirrhotic patients with portal hypertension. Hepatobiliary Pancreat Dis Int. 2004;3:399–401.PubMedGoogle Scholar
  32. 32.
    Pettersen I, Andersen JH, Bjornland K, Mathisen O, Bremnes R, Wellman M, et al. Heterogeneity in gamma-glutamyltransferase mRNA expression and glycan structures. Search for tumor-specific variants in human liver metastases and colon carcinoma cells. Biochim Biophys Acta. 2003;1648:210–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Takayashiki T, Yoshidome H, Kimura F, Ohtsuka M, Shimizu Y, Kato A, et al. Increased expression of toll-like receptor 4 enhances endotoxin-induced hepatic failure in partially hepatectomized mice. J Hepatol. 2004;41:621–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Miyakawa K, Tarao K, Ohshige K, Morinaga S, Ohkawa S, Okamoto N, et al. High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis. Scand J Gastroenterol. 2009;44:1340–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Rino Y, Tarao K, Morinaga S, Ohkawa S, Miyakawa K, Hirokawa S, et al. Reduction therapy of alanine aminotransferase levels prevent HCC development in patients with HCV-associated cirrhosis. Anticancer Res. 2006;26:2221–6.PubMedGoogle Scholar
  36. 36.
    Elsebae MM, Abu-Zekri NB. A study of the effect of splenectomy on hepatic functional reserve and structural damage in patients with chronic hepatitis C virus infection by non-invasive serum markers. A prospective study. Int J Surg. 2008;6:362–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Moeini A, Cornellà H, Villanueva A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer. 2012;1:83–93.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lu Y, Lin N, Chen Z, Xu R. Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A. Mol Med Rep. 2015;11:691–7.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Xing Lv
    • 1
  • Fan Yang
    • 2
  • Xin Guo
    • 1
  • Tao Yang
    • 3
  • Ti Zhou
    • 1
  • Xiaoping Dong
    • 4
  • Yong Long
    • 5
  • Dan Xiao
    • 5
  • Yong Chen
    • 1
  1. 1.Department of Hepatobiliary Surgery, Xijing HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of C Area of General SurgeryThe First Affiliated Hospital of Inner Mongolia Medical CollegeInner MongoliaPeople’s Republic of China
  3. 3.Department of General Surgery, Tangdu HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  4. 4.Department of Cerebral Surgery, Tangdu HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  5. 5.Department of EpidemiologyFourth Military Medical UniversityXi’anPeople’s Republic of China

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