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Published in: Digestive Diseases and Sciences 3/2017

01-03-2017 | Original Article

Rapid Alanine Aminotransferase Normalization with Entecavir and Hepatocellular Carcinoma in Hepatitis B Virus-Associated Cirrhosis

Authors: Eui Joo Kim, Jong Eun Yeon, Oh Sang Kwon, Heon Nam Lee, Seung Kak Shin, Seong Hee Kang, Kwan Soo Byun, Jeong Han Kim, So Young Kwon, Sang Jun Suh, Hyung Joon Yim, Yun Soo Kim, Ju Hyun Kim

Published in: Digestive Diseases and Sciences | Issue 3/2017

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Abstract

Background

Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B.

Aim

This study is aimed to confirm the impact of rapid ALT normalization (≤30 IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement.

Methods

A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51 ± 9 years, male sex 63.3%) were treated with ETV for more than 1 year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12 months after ETV commencement) and subjected to risk factor analysis.

Results

Median follow-up after ETV commencement was 43 (12–98) months. Cumulative incidences of HCC at 1, 3, 5, and 7 years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6 months or 12 months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12 months were not risk factors. Multivariate analysis showed that older age (P < 0.001), abnormal ALT at 12 months (P = 0.006), and lower platelet count (P = 0.034) were the risk factors for HCC.

Conclusions

Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.
Literature
1.
go back to reference Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–S16.CrossRefPubMed Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–S16.CrossRefPubMed
2.
go back to reference The Korean Central Cancer Registry, National Cancer Center. Annual report of cancer statistics in Korea in 2011. Ministry of Health and Welfare. 2013. The Korean Central Cancer Registry, National Cancer Center. Annual report of cancer statistics in Korea in 2011. Ministry of Health and Welfare. 2013.
3.
go back to reference El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576.CrossRefPubMed El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576.CrossRefPubMed
4.
go back to reference Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.CrossRefPubMed Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.CrossRefPubMed
5.
go back to reference Yang HI, Yeh SH, Chen PJ, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:1134–1143.CrossRefPubMedPubMedCentral Yang HI, Yeh SH, Chen PJ, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:1134–1143.CrossRefPubMedPubMedCentral
6.
go back to reference Chen CF, Lee WC, Yang HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology. 2011;141:1240–1248. 1248 e1241–1242.CrossRefPubMed Chen CF, Lee WC, Yang HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology. 2011;141:1240–1248. 1248 e1241–1242.CrossRefPubMed
7.
go back to reference Matsumoto A, Tanaka E, Rokuhara A, et al. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: a multicenter retrospective study of 2795 patients. Hepatol Res. 2005;32:173–184.CrossRefPubMed Matsumoto A, Tanaka E, Rokuhara A, et al. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: a multicenter retrospective study of 2795 patients. Hepatol Res. 2005;32:173–184.CrossRefPubMed
8.
go back to reference Kurokawa M, Hiramatsu N, Oze T, et al. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection. J Gastroenterol. 2012;47:577–585.CrossRefPubMed Kurokawa M, Hiramatsu N, Oze T, et al. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection. J Gastroenterol. 2012;47:577–585.CrossRefPubMed
9.
go back to reference Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531.CrossRefPubMed Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531.CrossRefPubMed
10.
go back to reference Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105–117.CrossRefPubMed Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105–117.CrossRefPubMed
11.
go back to reference Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–430.CrossRefPubMed Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–430.CrossRefPubMed
12.
go back to reference Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107.CrossRefPubMed Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107.CrossRefPubMed
13.
go back to reference Lim YS, Han S, Heo NY, Shim JH, Lee HC, Suh DJ. Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 2014;147:152–161.CrossRefPubMed Lim YS, Han S, Heo NY, Shim JH, Lee HC, Suh DJ. Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 2014;147:152–161.CrossRefPubMed
15.
go back to reference Korean Liver Cancer Study G, National Cancer Center K. Practice guidelines for management of hepatocellular carcinoma. Korean J Hepatol. 2009;15:391–423.CrossRef Korean Liver Cancer Study G, National Cancer Center K. Practice guidelines for management of hepatocellular carcinoma. Korean J Hepatol. 2009;15:391–423.CrossRef
16.
go back to reference World Health Organization. The Asia-Pacific perspective: redefining obesity and its treatment. 2000. World Health Organization. The Asia-Pacific perspective: redefining obesity and its treatment. 2000.
17.
go back to reference Ministry of Health and Welfare; Korea Centers for Disease Control and Prevention. Korea health statistics. Korea National Health and Nutrition Examination Survey (KNHANES V-3). Seoul: Ministry of Health and Welfare; 2012:2013. Ministry of Health and Welfare; Korea Centers for Disease Control and Prevention. Korea health statistics. Korea National Health and Nutrition Examination Survey (KNHANES V-3). Seoul: Ministry of Health and Welfare; 2012:2013.
18.
go back to reference Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12:S294–S308.CrossRefPubMed Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12:S294–S308.CrossRefPubMed
19.
go back to reference Kato Y, Nakata K, Omagari K, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer. 1994;74:2234–2238.CrossRefPubMed Kato Y, Nakata K, Omagari K, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer. 1994;74:2234–2238.CrossRefPubMed
20.
go back to reference Lo KJ, Tong MJ, Chien MC, et al. The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan. J Infect Dis. 1982;146:205–210.CrossRefPubMed Lo KJ, Tong MJ, Chien MC, et al. The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan. J Infect Dis. 1982;146:205–210.CrossRefPubMed
21.
go back to reference Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–S50.CrossRefPubMed Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–S50.CrossRefPubMed
22.
go back to reference Siest G, Schiele F, Galteau MM, et al. Aspartate aminotransferase and alanine aminotransferase activities in plasma: statistical distributions, individual variations, and reference values. Clin Chem. 1975;21:1077–1087.PubMed Siest G, Schiele F, Galteau MM, et al. Aspartate aminotransferase and alanine aminotransferase activities in plasma: statistical distributions, individual variations, and reference values. Clin Chem. 1975;21:1077–1087.PubMed
23.
go back to reference Alberti A, Morsica G, Chemello L, et al. Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV. Lancet. 1992;340:697–698.CrossRefPubMed Alberti A, Morsica G, Chemello L, et al. Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV. Lancet. 1992;340:697–698.CrossRefPubMed
24.
go back to reference Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. 1999;94:3010–3014.CrossRefPubMed Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. 1999;94:3010–3014.CrossRefPubMed
25.
go back to reference Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10.CrossRefPubMed Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10.CrossRefPubMed
26.
go back to reference Lee JK, Shim JH, Lee HC, et al. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010;51:1577–1583.CrossRefPubMed Lee JK, Shim JH, Lee HC, et al. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010;51:1577–1583.CrossRefPubMed
27.
go back to reference Sohn W, Jun DW, Kwak MJ, et al. Upper limit of normal serum alanine and aspartate aminotransferase levels in Korea. J Gastroenterol Hepatol. 2013;28:522–529.CrossRefPubMed Sohn W, Jun DW, Kwak MJ, et al. Upper limit of normal serum alanine and aspartate aminotransferase levels in Korea. J Gastroenterol Hepatol. 2013;28:522–529.CrossRefPubMed
28.
go back to reference Kang HS, Um SH, Seo YS, et al. Healthy range for serum ALT and the clinical significance of “unhealthy” normal ALT levels in the Korean population. J Gastroenterol Hepatol. 2011;26:292–299.CrossRefPubMed Kang HS, Um SH, Seo YS, et al. Healthy range for serum ALT and the clinical significance of “unhealthy” normal ALT levels in the Korean population. J Gastroenterol Hepatol. 2011;26:292–299.CrossRefPubMed
29.
go back to reference Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.CrossRefPubMedPubMedCentral Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.CrossRefPubMedPubMedCentral
30.
go back to reference Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–1341. quiz 1286.CrossRefPubMed Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–1341. quiz 1286.CrossRefPubMed
31.
go back to reference Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010.CrossRefPubMed Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010.CrossRefPubMed
32.
go back to reference Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020.CrossRefPubMed Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020.CrossRefPubMed
33.
go back to reference Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther. 2013;38:98–106.CrossRefPubMed Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther. 2013;38:98–106.CrossRefPubMed
34.
go back to reference Sinn DH, Lee J, Goo J, et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology. 2015;62:694–701.CrossRefPubMed Sinn DH, Lee J, Goo J, et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology. 2015;62:694–701.CrossRefPubMed
35.
go back to reference Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21:77–82.PubMed Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21:77–82.PubMed
36.
go back to reference Stroffolini T, Esvan R, Biliotti E, Sagnelli E, Gaeta GB, Almasio PL. Gender differences in chronic HBsAg carriers in Italy: evidence for the independent role of male sex in severity of liver disease. J Med Virol. 2015;87:1899–1903.CrossRefPubMed Stroffolini T, Esvan R, Biliotti E, Sagnelli E, Gaeta GB, Almasio PL. Gender differences in chronic HBsAg carriers in Italy: evidence for the independent role of male sex in severity of liver disease. J Med Virol. 2015;87:1899–1903.CrossRefPubMed
37.
go back to reference Kao JH, Chen PJ, Lai MY, Chen DS. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol. 2002;40:1207–1209.CrossRefPubMedPubMedCentral Kao JH, Chen PJ, Lai MY, Chen DS. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol. 2002;40:1207–1209.CrossRefPubMedPubMedCentral
38.
go back to reference Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–272.CrossRefPubMed Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–272.CrossRefPubMed
39.
go back to reference Yuen MF, Sablon E, Yuan HJ, et al. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma. Hepatology. 2003;37:562–567.CrossRefPubMed Yuen MF, Sablon E, Yuan HJ, et al. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma. Hepatology. 2003;37:562–567.CrossRefPubMed
40.
go back to reference Sumi H, Yokosuka O, Seki N, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology. 2003;37:19–26.CrossRefPubMed Sumi H, Yokosuka O, Seki N, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology. 2003;37:19–26.CrossRefPubMed
41.
go back to reference Kim HC, Seo GS, Kim YS, Song WG, Moon HB, Cho JH. Hepatitis B virus (HBV) genotype in korean chronic HBV carriers: whole HBV genome and it;s nucleotide sequence by single polymerization chain reaction (PCR) Method. Korean J Med. 2001;61:479–488. Kim HC, Seo GS, Kim YS, Song WG, Moon HB, Cho JH. Hepatitis B virus (HBV) genotype in korean chronic HBV carriers: whole HBV genome and it;s nucleotide sequence by single polymerization chain reaction (PCR) Method. Korean J Med. 2001;61:479–488.
Metadata
Title
Rapid Alanine Aminotransferase Normalization with Entecavir and Hepatocellular Carcinoma in Hepatitis B Virus-Associated Cirrhosis
Authors
Eui Joo Kim
Jong Eun Yeon
Oh Sang Kwon
Heon Nam Lee
Seung Kak Shin
Seong Hee Kang
Kwan Soo Byun
Jeong Han Kim
So Young Kwon
Sang Jun Suh
Hyung Joon Yim
Yun Soo Kim
Ju Hyun Kim
Publication date
01-03-2017
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 3/2017
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-016-4431-8

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