Clinical and Molecular Hepatology



Chu and Liaw: Letter regarding “Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune-tolerant phase”

Letter regarding “Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune-tolerant phase”

Chia-Ming Chu, Yun-Fan Liaw
Received January 19, 2023       Revised January 20, 2023       Accepted January 20, 2023
Dear Editor,
In a recent issue of this journal, Yoo et al. [1] reported a high frequency of significant inflammation and fibrosis in immunotolerant (IT) chronic hepatitis B patients and highlighted the need of liver biopsy for these patients. There are a few points that merit clarification and further discussion.
First, the average age of IT patients was quite high (42.7±12.5 years). The median age of IT patients ranged from 29 to 31 years in 4 previous studies [2-5]. Our earliest study in 1985, when we coined the term of IT, showed that the average age of 64 hepatitis B e antigen (HBeAg)-positive patients with minimal histological changes was 25±5 years [6]. In a later study, the age of 240 HBeAg-positive patients with persistently normal alanine aminotransferase (ALT) was 28±6 years [7]. One possible explanation could be that genotype C hepatitis B virus (HBV) predominates in Korea and that HBeAg seroconversion is significantly delayed in genotype C than genotype B infection (mean age of HBeAg seroconversion: 36.4±8.6 vs. 31.8±7.0 years) [8]. In addition, there appears to be a high selection bias, as patient enrollment in this study was based on biopsy which is strongly recommended in elderly patients to exclude significant disease [9].
Second, there is discordance between ALT and histological activity. It remained unclear why ALT levels were not significantly different between histologic IT and non-IT patients. On the other hand, only 35% of the patients with normal ALT (≤35 U/L for men and ≤25 U/L for women according to American Association for the Study of Liver Diseases [AASLD] 2018 guidelines [9]) were proved to be histologic IT patients. Many of these patients appear to be in the immune active phase with normal ALT at remission rather than truly in the IT phase. Diagnosis of IT in this study requiring at least two ALT measurements >3 months apart appears to be insufficient.
Third, the majority of IT patients demonstrated significant inflammation or fibrosis. Notably, the patients in this study were relatively older, with relatively lower HBV DNA (≥106 IU/mL vs. ≥107 IU/mL) and higher ALT (≤60 U/L vs. ≤40 U/L). Two earlier histologic studies including 57 and 40 patients with median age of 29 and 31 years, respectively, HBV DNA >107 copy/mL and normal ALT revealed only mild disease in all and no patients had significant fibrosis [3,5]. In another study including 40 patients with normal ALT and HBV DNA of 8.14 (4.83–10.96) log10 IU/mL, significant inflammation and fibrosis was noted in 2 and 0 of 17 patients with ALT ≤0.5xupper limit of normal (ULN), and in 7 and 4 of 23 patients with ALT 0.5–1xULN [4]. A large series study from China recruited 202 stringently defined IT patients with HBV DNA ≥107 IU/mL and ALT ≤40 U/L, according to European Association for the Study of the Liver (EASL) 2017 guidelines [10], for at least 2 years. Significant inflammation and fibrosis were extremely rare (2% and 0%) in 97 patients with low-normal ALT (≤30 U/L for men and ≤19 U/L for women), regardless of patient age, but much frequent (39% and 10%) in 105 patients with high-normal ALT (31‒40 U/L for men and 20‒40 U/L for women). Among the latter, the severity of histological activity correlated with patient age [11]. These data from “genuine IT” suggest that it seems appropriate to use the EASL 2017 guidelines to define IT phase, but for patients over 40 years old, it is better to use low-normal ALT [12].
Fourth, there was a high incidence of liver-related events in IT patients; cumulative rates at 15-years follow-up were 15% and 45% for histologic IT and non-IT patients, respectively. However, chronic HBV infection is a dynamic process that undergoes transition through various phases of disease activity. Patients should be censored at the time of phase transition, otherwise their results will be misleading.
Finally, the authors suggested to treat IT patients with significant fibrosis. Sixty-seven percent of patients had significant fibrosis, implying the need for systematic histologic evaluation in all. However, liver biopsy is an invasive procedure with potential complication. Recently, antiviral therapy is recommended for IT patients over age of 30 [10] or 40 [2] without the need of histological assessment. Studies from Korea have shown an extremely low or negligible risk of hepatocellular carcinoma (HCC) in IT patients with HBV DNA ≥107 IU/mL,13 HBV DNA ≥106 IU/mL and age <40 [14], and FIB-4 index <1.45 [15]. Therefore, it is recommended to use strict clinical criteria to define IT phase, i.e., HBV DNA ≥107 IU/mL and ALT ≤40 IU/L every 3 months for at least 1 year. Antiviral treatment can be limited to those over 40 years old only if they have high-normal ALT, significant fibrosis as seen using noninvasive serum fibrosis markers or Fibroscan, or family history of HCC [12].
In summary, strict clinical criteria are needed to define IT phase of chronic hepatitis B infection to avoid clinical confusion and unnecessary liver biopsy or treatment.

Authors’ contributions

CM Chu: Conception and design of the letter; Drafting of the manuscript; Approval of the final version of the manuscript. YF Liaw: Design of the letter; Critical revision of the manuscript; Approval of the final version of the manuscript.

Conflicts of Interest

The authors have no conflicts to disclose.


American Association for the Study of Liver Diseases


alanine aminotransferase


European Association for the Study of the Liver


hepatitis B e antigen


hepatitis B virus


hepatocellular carcinoma


immune tolerance


upper limit of normal



1. Yoo JJ, Park SY, Moon JE, Lee YR, Lee HA, Lee J, et al. Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune-tolerant phase. Clin Mol Hepatol 2023;29:482-495.
[Article] [PubMed]
2. Feld JJ, King WC, Ghany MG, Chang KM, Terrault N, Perrillo RP, et al.; Hepatitis B Research Network (HBRN). Characteristics of older patients with immunotolerant chronic hepatitis B virus infection. Clin Gastroenterol Hepatol. 2022 Jul 16. doi: 10.1016/j.cgh.2022.06.015.
[Article] [PubMed]
3. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al.; Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395-401.
4. Seto WK, Lai CL, Ip PP, Fung J, Wong DK, Yuen JC, et al. A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B. PLoS One 2012;7:e32622.
[Article] [PubMed] [PMC]
5. Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouillères O, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol 2007;5:636-641.
[Article] [PubMed]
6. Chu CM, Liaw YF, Sheen IS, Chen TJ. Correlation of age with the status of hepatitis B virus replication and histological changes in chronic type B hepatitis. Liver 1985;5:117-122.
[Article] [PubMed]
7. Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004;116:829-834.
[Article] [PubMed]
8. Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol 2005;43:411-417.
[Article] [PubMed]
9. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-1599.
[Article] [PubMed] [PMC]
10. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-398.
[Article] [PubMed]
11. He D, Shang Q, Zhang Y. Liver histology according to differing alanine aminotransferase level in immune tolerance phase patients with chronic hepatitis B virus infection. J Liver Clin Res 2015;2:1007.

12. Chu CM, Liaw YF. Management of older Patients with Immunotolerant Chronic Hepatitis B Infection. Clin Gastroenterol Hepatol 2022 Sep 8. doi: 10.1016/j.cgh.2022.08.039.
[Article] [PubMed]
13. Lee HA, Lee HW, Kim IH, Park SY, Sinn DH, Yu JH, et al. Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase. Aliment Pharmacol Ther 2020;52:196-204.
[Article] [PubMed]
14. Lee HW, Chon YE, Kim BK, Yip TC, Tse YK, Wong GL, et al. Negligible HCC risk during stringently defined untreated immune-tolerant phase of chronic hepatitis B. Eur J Intern Med 2021;84:68-73.
[Article] [PubMed]
15. Jeon MY, Kim BK, Lee JS, Lee HW, Park JY, Kim DY, et al. Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B. Clin Mol Hepatol 2021;27:295-304.

Go to Top