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Published in: Tumor Biology 7/2016

01-07-2016 | Original Article

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

Authors: Xing Lv, Fan Yang, Xin Guo, Tao Yang, Ti Zhou, Xiaoping Dong, Yong Long, Dan Xiao, Yong Chen

Published in: Tumor Biology | Issue 7/2016

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Abstract

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.
Literature
1.
go back to reference Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.CrossRefPubMed Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.CrossRefPubMed
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol. 2014;20:2555–63.CrossRefPubMedPubMedCentral Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol. 2014;20:2555–63.CrossRefPubMedPubMedCentral
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
17.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
18.
go back to reference Ikegami T, Shimada M, Imura S. Recent role of splenectomy in chronic hepatic disorders. Hepatol Res. 2008;38:1159–71.PubMed Ikegami T, Shimada M, Imura S. Recent role of splenectomy in chronic hepatic disorders. Hepatol Res. 2008;38:1159–71.PubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference Laffi G, Tarquini R, Marra F. Thrombocytopenia in chronic liver disease: lessons from transplanted patients. J Hepatol. 2007;47:625–9.CrossRefPubMed Laffi G, Tarquini R, Marra F. Thrombocytopenia in chronic liver disease: lessons from transplanted patients. J Hepatol. 2007;47:625–9.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
27.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
30.
go back to reference 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.PubMed 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.PubMed
31.
go back to reference 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.PubMed 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.PubMed
32.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
34.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.PubMed 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.PubMed
36.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
38.
go back to reference 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.PubMed 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.PubMed
Metadata
Title
Hypersplenism is correlated with increased risk of hepatocellular carcinoma in patients with post-hepatitis cirrhosis
Authors
Xing Lv
Fan Yang
Xin Guo
Tao Yang
Ti Zhou
Xiaoping Dong
Yong Long
Dan Xiao
Yong Chen
Publication date
01-07-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 7/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4764-5

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