Systematic review and meta-analysis: Significant histological changes among treatment-naïve chronic hepatitis B patients with normal alanine aminotransferase levels by different criteria

The upper limits of normal (ULNs) of ALT are not consistent across the major international guidelines which may affect the eligibility for antiviral therapy for chronic hepatitis B (CHB). To estimate the proportions of histological changes among treatment-naïve patients with CHB within differently defined ALT ULNs. We searched PubMed and Embase up to May 15th, 2023, to identify studies of treatment-naïve CHB patients with liver biopsies. We pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis in those patients within different ALT ULNs by using random-effect models. We included 23 studies with 4010 participants. Within ALT ULN at 40 IU/L, the pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis were 33% (95% CI: 26%-42%), 32% (95% CI: 27%-38%), and 3% (95% CI: 1%-5%), respectively. Within ALT ULN at 30 IU/L for men and 19 IU/L for women, the pooled proportion of significant fibrosis remained at 30% (95% CI: 25%-34%; 432 participants). However, it was 21% (95% CI: 11%-37%; 361 participants) even in those within ALT ULN at 20 IU/L. Subgroup analyses suggested a significantly higher proportion of significant fibrosis among studies with prospective design or enrolled patients' mean age >35 or >40 years. Significant histological changes occurred in approximately 1/3 of treatment-naïve CHB patients within ALT ULN at 40 IU/L, whereas the proportion of significant fibrosis was approximately 1/5 even in those within ALT ULN at 20 IU/L.