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High-normal alanine aminotransferase is an indicator for liver histopathology in HBeAg-negative chronic hepatitis B

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Abstract

Objective

We aimed to assess liver histological changes of HBeAg-negative chronic hepatitis B (CHB) patients with normal ALT, and determined the association between significant liver injury and age, ALT, and HBV DNA levels.

Methods

We retrospectively examined 327 patients who underwent liver biopsy from 2009 to 2018. Significant liver histological change is defined as liver necroinflammation ≥ G2 and/or liver fibrosis ≥ F2.

Results

The proportion of patients with significant liver necroinflammation or fibrosis in the high-normal ALT group (ALT > 20 U/L) was higher than that in the low-normal ALT group (ALT ≤ 20 U/L) (44.6% vs 26.5%, 61.0% vs 41.7%, p < 0.01); also the proportion in the group with HBV DNA ≥ 2000 IU/mL was significantly higher than that in the group with HBV DNA < 2000 IU/mL (58.5% vs 27.1%, 67.9% vs 46.2%, p < 0.01). There was no significant difference in hepatic histopathology between < 40 and ≥ 40 years groups. Among 221 patients with normal ALT and low HBV DNA levels (< 2000 IU/mL), 27.1% of them had significant liver necroinflammation and 46.2% had significant liver fibrosis. The multiple logistic regression analysis showed that ALT > 20 U/L and HBV DNA ≥ 2000 IU/mL were independently associated with significant liver histopathology (p < 0.01).

Conclusion

HBeAg-negative CHB patients with normal ALT and low HBV DNA level (< 2000 IU/mL) were suggested to perform liver biopsy or noninvasive methods for histopathology assessment, then to be determined for antiviral therapy. ALT > 20 U/L and HBV DNA ≥ 2000 IU/mL are good independently predictive factors for evaluating significant liver histopathology for HBeAg-negative CHB patients with normal ALT.

Clinical Trials Registration

Chinese Clinical Trial Registry (ChiCTR-IOR-14005474).

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References

  1. World Health Organization. Global Hepatitis Report 2017. 2017; http://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/.

  2. Jing W, Liu J, Liu M. Eliminating mother-to-child transmission of HBV: progress and challenges in China. Front Med. 2020;14(1):21–9.

    Article  Google Scholar 

  3. Liu J, Liang W, Jing W, Liu M. Countdown to 2030: eliminating hepatitis B disease. China Bull World Health Organ. 2019;97(3):230–8.

    Article  Google Scholar 

  4. World Health Organization. (2016) Global health sector strategy on viral hepatitis 2016–2021. http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.

  5. Liaw YF. Natural history of chronic hepatitis B virus infection and long-term outcome under treatment. Liver Int. 2009;29(Suppl 1):100–7.

    Article  Google Scholar 

  6. Toy M, Salomon JA, Jiang H, Gui H, Wang H, Wang J, Richardus JH, Xie Q. Population health impact and cost-effectiveness of monitoring inactive chronic hepatitis B and treating eligible patients in Shanghai, China. Hepatology 2014;60(1):46–55.

    Article  Google Scholar 

  7. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.

    Article  Google Scholar 

  8. EASL. Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.

    Article  Google Scholar 

  9. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98.

    Article  CAS  Google Scholar 

  10. Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. The guidelines of prevention and treatment for chronic hepatitis B (2019 version). Zhonghua Gan Zang Bing Za Zhi. 2019;27(12):938–61.

    Google Scholar 

  11. Chu CM, Liaw YF. Incidence and risk factors of progression to cirrhosis in inactive carriers of hepatitis B virus. Am J Gastroenterol. 2009;104(7):1693–9.

    Article  Google Scholar 

  12. Park H, Lee JM, Seo JH, Kim HS, Ahn SH, Kim DY, Han KH, Chon CY, Park JY. Predictive value of HBsAg quantification for determining the clinical course of genotype C HBeAg-negative carriers. Liver Int. 2012;32(5):796–802.

    Article  CAS  Google Scholar 

  13. Zeng DW, Dong J, Zhang JM, Zhu YY, Jiang JJ, Liu YR. HBeAg-negative chronic hepatitis patients should be monitored more strictly: a cross-sectional retrospective study on antiviral treatment-naïve patients. J Med Virol. 2015;87(10):1682–8.

    Article  Google Scholar 

  14. Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol. 2012;57(1):196–202.

    Article  Google Scholar 

  15. Wang H, Ru GQ, Yan R, Zhou Y, Wang MS, Cheng MJ. Histologic disease in Chinese chronic hepatitis B patients with low viral loads and persistently normal alanine aminotransferase levels. J Clin Gastroenterol. 2016;50(9):790–6.

    Article  CAS  Google Scholar 

  16. Liao B, Wang Z, Lin S, Xu Y, Yi J, Xu M, Huang Z, Zhou Y, Zhang F, Hou J. Significant fibrosis is not rare in Chinese chronic hepatitis B patients with persistent normal ALT. PLoS ONE. 2013;8(10):e78672.

    Article  CAS  Google Scholar 

  17. Oliveira VOBD, Oliveira JPR, França EVCD, Brito HLDF, Nascimento TV, França A. Advanced liver injury in patients with chronic hepatitis B and viral load below 2,000 IU/mL. Rev Inst Med Trop Sao Paulo. 2016;58:65–65.

    PubMed  PubMed Central  Google Scholar 

  18. Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol. 2009;50(1):1–3.

    Article  Google Scholar 

  19. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344(7):495–500.

    Article  CAS  Google Scholar 

  20. Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, Conte D, Colombo M, Sirchia G. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–10.

    Article  CAS  Google Scholar 

  21. Lee JK, Shim JH, Lee HC, Lee SH, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010;51(5):1577–83.

    Article  CAS  Google Scholar 

  22. Assy N, Beniashvili Z, Djibre A, Nasser G, Grosovski M, Nseir W. Lower baseline ALT cut-off values and HBV DNA levels better differentiate HBeAg- chronic hepatitis B patients from inactive chronic carriers. World J Gastroenterol. 2009;15(24):3025–31.

    Article  CAS  Google Scholar 

  23. Gui HL, Wang H, Yang YH, Wu YW, Zhou HJ, Guo SM, Lin LY, Wang L, Cai W, Chen R, Guo Q, Zhou XQ, Bao SS, Xie Q. Significant histopathology in Chinese chronic hepatitis B patients with persistently high-normal alanine aminotransferase. J Viral Hepat. 2010;17(Suppl 1):44–50.

    Article  Google Scholar 

  24. Koc ÖM, Robaeys G, Topal H, Bielen R, Busschots D, Fevery J, Koek GH, Nevens F. Outcome in Caucasian patients with hepatitis B e antigen negative chronic infection: a long-term observational cohort study. J Med Virol. 2020;92(12):3373–80.

    Article  CAS  Google Scholar 

  25. Choi GH, Kim G-A, Choi J, Han S, Lim Y-S. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation. Aliment Pharmacol Ther. 2019;50(2):215–26.

    Article  CAS  Google Scholar 

  26. Diktas H, Karacaer Z, Özturk II, Cicek H. Comparison of relationship between histopathological, serological and biochemical parameters in patients with chronic hepatitis B infection. Postgra Med J. 2016;92(1094):693–6.

    Article  CAS  Google Scholar 

  27. Chen JD, Yang HI, Iloeje UH, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology. 2010;138(5):1747–54.

    Article  Google Scholar 

  28. Wu JF, Song SH, Lee CS, Chen HL, Ni YH, Hsu HY, Wu TC, Chang MH. Clinical predictors of liver fibrosis in patients with chronic hepatitis B virus infection from children to adults. J Infect Dis. 2018;217(9):1408–16.

    Article  CAS  Google Scholar 

  29. Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, Chen DS, Kao JH. Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology. 2007;45(5):1193–8.

    Article  CAS  Google Scholar 

  30. Kao JH, Hu TH, Jia J, Kurosaki M, Lim YS, Lin HC, Sinn DH, Tanaka Y, Wai-Sun Wong V, Yuen MF. East Asia expert opinion on treatment initiation for chronic hepatitis B. Aliment Pharmacol Ther. 2020;52(10):1540–50.

    CAS  PubMed  Google Scholar 

  31. Tsang PS, Trinh H, Garcia RT, Phan JT, Ha NB, Nguyen H, Nguyen K, Keeffe EB, Nguyen MH. Significant prevalence of histologic disease in patients with chronic hepatitis B and mildly elevated serum alanine aminotransferase levels. Clin Gastroenterol Hepatol. 2008;6(5):569–74.

    Article  Google Scholar 

  32. Sonneveld MJ, Brouwer WP, Xie Q, Hansen BE, Tabak F, Idilman R, de Knegt RJ, Janssen HL. High incidence of significant liver fibrosis among HBeAg-positive patients with low levels of ALT. Hepatology. 2016;64:874A-875A.

    Google Scholar 

  33. Nguyen MH, Garcia RT, Trinh HN, Lam KD, Weiss G, Nguyen HA, Nguyen KK, Keeffe EB. Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels. Am J Gastroenterol. 2009;104(9):2206–13.

    Article  CAS  Google Scholar 

  34. Tan Y, Ye Y, Zhou X, Chen L, Wen D. Age as a predictor of significant fibrosis features in HBeAg-negative chronic hepatitis B virus infection with persistently normal alanine aminotransferase. PLoS ONE. 2015;10(4):e0123452.

    Article  Google Scholar 

  35. Jeng WJ, Lok AS. Should Treatment Indications for Chronic Hepatitis B Be Expanded? Clin Gastroenterol and Hepatol. 2020;S1542–3565(20)30677–7

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Acknowledgements

We would like to acknowledge other members for performing biochemical test and liver biopsy, as well as members who have contributed to our study.

Funding

This study was supported by the Major Science and Technology Special Project of China. Thirteenth Five-Year Plan, No. 2018ZX10732401-003–015 and No.2013ZX10005002-002.

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Author notes

  1. Menghui Duan and Xiaoling Chi have contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Menghui Duan, Xueen Liu & Hui Zhuang

  2. Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, 510120, China

    Xiaoling Chi & Huanming Xiao

Authors
  1. Menghui Duan
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  2. Xiaoling Chi
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  3. Huanming Xiao
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  4. Xueen Liu
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  5. Hui Zhuang
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Contributions

Statistical analysis and drafting manuscript: MD. Writing guidance: XL. Critical revision of the manuscript: XL and HZ. Collection of clinical data: HX and XC.

Corresponding authors

Correspondence to Xueen Liu or Hui Zhuang.

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Duan, M., Chi, X., Xiao, H. et al. High-normal alanine aminotransferase is an indicator for liver histopathology in HBeAg-negative chronic hepatitis B. Hepatol Int 15, 318–327 (2021). https://doi.org/10.1007/s12072-021-10153-2

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  • DOI: https://doi.org/10.1007/s12072-021-10153-2

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