Significant Histologic Changes Are Not Rare in Treatment-naive Hepatitis B Patients with Normal Alanine Aminotransferase Level: A Meta-analysis

Abstract

Background and Aims Chronic hepatitis B is the main cause of liver cancer. However, the most neglected group has been treatment-naive chronic hepatitis B patients with normal alanine aminotransferase (ALT). People have tended to subjectively assume that the liver lesions of these patients are not serious and do not need antiviral treatment. However, the truth is not as optimistic as we thought. We aimed in this study to analyze the proportion of significant inflammation or fibrosis in aforementioned patients. Methods Medline, Embase, and Cochrane Library were searched up to January 10 th 2020, to identify studies of these patients with liver biopsy. The double arcsine method was used with a random-effect model to combine the proportion of significant inflammation or fibrosis. Potential heterogeneity was explored by subgroup analysis and meta-regression. Outcome of interests included the proportion of significant inflammation or fibrosis and cirrhosis. The secondary outcome was to find the risk factors of significant histological changes. Results Nineteen eligible studies, with 2,771 participants, were included. The pooled proportion of significant inflammation or fibrosis was 35% [95% confidence interval (CI): 27 to 43] and 30% (95% CI: 25 to 36), respectively. The pooled proportion of cirrhosis was 3% [95% CI: 1 to 5, (12 studies; 1,755 participants)]. In subgroup analysis, old age [vs. young (<40 years-old), 44% vs. 26%, p =0.012] was significantly associated with higher fibrosis stage as well as cirrhosis [vs. young (<40 years-old), 4.8% vs. 1.8%, p <0.001]. Conclusions About 1/3 of the treatment-naive chronic hepatitis B patients with normal ALT show significant histological changes, and some even have cirrhosis.

Precision medicine in the era of potent antiviral therapy for chronic hepatitis B

“…13 Furthermore, significant proportion of those with persistently normal serum ALT shared significant inflammation (35%), significant fibrosis (30%), and cirrhosis (3%) in a recent meta-analysis. 14 Especially, the rates of significant inflammation, significant fibrosis, and cirrhosis were not different between the HBeAg positive and HBeAg negative patients. Older age over 40 years was significantly associated with fibrosis and liver cirrhosis.…”

“…reported that those who are clinically considered to be in the immune‐tolerant phase (HBeAg positive, HBV DNA > 20 000 IU/mL, serum ALT < 19 U/L for female and < 30 U/L for male) had significantly higher risks of HCC (hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.54–4.18) and death/transplantation (HR 3.38, 95% CI 1.85–6.16) than those of NA‐treated immune‐active phase patients 13 . Furthermore, significant proportion of those with persistently normal serum ALT shared significant inflammation (35%), significant fibrosis (30%), and cirrhosis (3%) in a recent meta‐analysis 14 . Especially, the rates of significant inflammation, significant fibrosis, and cirrhosis were not different between the HBeAg positive and HBeAg negative patients.…”

“…Especially, the rates of significant inflammation, significant fibrosis, and cirrhosis were not different between the HBeAg positive and HBeAg negative patients. Older age over 40 years was significantly associated with fibrosis and liver cirrhosis 14 . The main issue is that HBV DNA and serum ALT levels are poor surrogate markers in the prediction of inflammation and fibrosis without liver biopsy.…”

“…Older age over 40 years was significantly associated with fibrosis and liver cirrhosis. 14 The main issue is that HBV DNA and serum ALT levels are poor surrogate markers in the prediction of inflammation and fibrosis without liver biopsy. And it is difficult to discriminate the patients in the genuine immune-tolerant phase from the patients in the transition of immune-tolerant to immune-active phase.…”

Dose–response relationship between qAnti‐HBc and liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase based on liver biopsy

“…However, the proportion of moderate to severe inflammation in CHB patients with normal ALT was inconsistent in different studies, and most of them are small sample studies. Subsequently, we performed a meta‐analysis that included 2771 individuals (19 studies) 7 . Our results showed a high rate of moderate to severe inflammation and significant fibrosis confirmed by liver biopsy in up to 35% (95% confidence interval [CI] 27%–43%) and 30% (95% CI 25%–36%).…”