Liver histological changes in untreated chronic hepatitis B patients in indeterminate phase

BACKGROUND Studies with large size samples on the liver histological changes of indeterminate phase chronic hepatitis B(CHB)patients were not previously conducted.AIM To assess the liver histological changes in the indeterminate phase CHB patients using liver biopsy.METHODS The clinical and laboratory data of 1532 untreated CHB patients were collected,and all patients had least once liver biopsy from January 2015 to December 2021.The significant differences among different phases of CHB infection were compared with t-test,and the risk factors of significant liver histological changes were analyzed by the multivariate logistic regression analysis.RESULTS Among 1532 untreated CHB patients,814(53.13%)patients were in the indeterminate phase.Significant liver histological changes(defined as biopsy score≥G2 and/or≥S2)were found in 488/814(59.95%)CHB patients in the indete-rminate phase.Significant liver histological changes were significant differences among different age,platelets(PLTs),and alanine aminotransferase(ALT)subgroup in indeterminate patient.Multivariate logistic regression analysis indicated that age≥40 years old[adjust odd risk(aOR),1.44;95%confidence interval(CI):1.06-1.97;P=0.02],PLTs≤150×10^(9)/L(aOR,2.99;95%CI:1.85-4.83;P<0.0001),and ALT≥upper limits of normal(aOR,1.48;95%CI:1.08,2.05,P=0.0163)were independent risk factors for significant liver histological changes in CHB patients in the indeterminate phase.CONCLUSION Our results suggested that significant liver histological changes were not rare among the untreated CHB patients in indeterminate phase,and additional strategies are urgently required for the management of these patients.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients

BACKGROUND The clinical and histological features of chronic hepatitis B(CHB)patients who fall into the"grey zone(GZ)"and do not fit into conventional natural phases are unclear.AIM To explore the impact of varying the threshold of alanine aminotransferase(ALT)levels in identifying significant liver injury among GZ patients.METHODS This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy.The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines.GZ CHB patients were classified into four groups:GZ-A(HBeAg positive,normal ALT levels,and HBV DNA≤10^(7) IU/mL),GZ-B(HBeAg positive,elevated ALT levels,and HBV DNA<10^(4) or>10^(7) IU/mL),GZC(HBeAg negative,normal ALT levels,and HBV DNA≥2000 IU/mL),and GZ-D(HBeAg negative,elevated ALT levels,and HBV DNA≤2000 IU/mL).Significant hepatic injury(SHI)was defined as the presence of notable liver inflammation(≥G2)and/or significant fibrosis(≥S2).RESULTS The results showed that 50.22%of patients were classified as GZ,and 63.7%of GZ patients developed SHI.The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria(35 U/L for men and 25 U/L for women)can more accurately identify patients with significant liver damage in the GZ phases.In total,the proportion of patients with ALT≤40 U/L who required antiviral therapy was 64.86%[(221+294)/794].When we lowered the ALT treatment threshold to the new criteria(30 U/L for men and 19 U/L for women),the same outcome was revealed,and the proportion of patients with ALT≤40 U/L who required antiviral therapy was 75.44%[(401+198)/794].Additionally,the proportion of SHI was 49.1%in patients under 30 years old and increased to 55.3%in patients over 30 years old(P=0.136).CONCLUSION These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Significant histological changes are not rare in indeterminate‐phase chronic hepatitis B patients with hepatitis B e antigen‐negative and normal alanine aminotransferase levels

Background&Objectives:The degree of liver injury in indeterminate chronic hepatitis B(CHB)infection patients with Hepatitis B e antigen(HBeAg)‐negative and persistently normal alanine aminotransferase(PNALT)levels is yet unclear.Therefore,we aimed to assess liver histological changes in such patients by liver biopsy and explore possible predictors.Methods:Overall,711 HBeAg‐negative CHB patients with PNALT levels who underwent liver biopsy from January 2017 to June 2022 were included in this retrospective study.The relationships between histological changes and predictors were assessed by smooth curve fitting and multivariate logistic regression analysis models.Data were also analyzed using American Association for the Study of Liver Disease(AASLD)modified alanine aminotransferase(ALT)criteria.Results:The proportion of significant histological changes in the indeterminate phase was higher than that in the inactive phase(53.97%vs.41.33%).The adjusted odds ratios(aORs)of significant necroinflammation and histological changes for the indeterminate phase were 2.05 and 1.43,respectively,when compared with the inactive phase by multivariate logistic regression analyses.Significant histological changes in the‐phase were positively associated with age,ALT,Aspartate aminotransferase(AST),Hepatitis B surface antigen(HBsAg),and Hepatitis B virus(HBV)DNA levels but negatively correlated with platelet(PLT)levels.HBV DNA≥5 log10 U/L and PLT<200�109/L were independent predictive factors for assessing histological changes in indeterminate‐phase patients.Similar analysis findings were obtained using the two sets of modified ALT criteria.Conclusions:Significant histological changes are not rare in indeterminatephase CHB patients and are higher than in the inactive phase,regardless of the ALT criteria.Histological investigation is strongly suggested for intermediate stage patients with HBV DNA>5 log10 U/L or PLT<200�109/L and antiviral therapy should be considered for such patients.

Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA

With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression,there is a hot discussion on whether HBeAg-negative chronic hepatitis B(CHB)patients with normal alanine aminotransferase(ALT)and positive HBV DNA should be treated.According to the international guidelines on the stages of the natural history of HBV infection,HBeAgnegative CHB patients with normal ALT and positive HBV DNA can be divided into two groups:one is the well-known“inactive carrier phase”,which is defined as serum HBV DNA<2000 IU/ml and no significant liver inflammation;and the other is the“indeterminate phase”,which is defined as serum HBV DNA≥2000 IU/mL regardless of the pathological changes in liver tissue,or HBV DNA<2000 IU/mL but accompanied by significant pathological changes in the liver.In this minireview,we will expound the disease characteristics,disease progression,and clinical management status of these two groups.Based on the analysis,we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated,regardless of their age,family history of hepatocellular carcinoma(HCC)or the severity of liver necroinflammation.Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression,and consequently reduce the risk of HCC development.