Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: A systematic review

Background & Aims: The adequacy of monitoring HBeAg-negative patients based on ALT activity is controversial and current guidelines favor liver biopsy in HBeAg-negative cases with normal ALT and HBV DNA >2000 IU/ml. We systematically reviewed all the available histological data on HBeAg-negative patients with persistently normal ALT (PNALT) to determine the prevalence of significant liver disease and its associating factors. Methods: Literature search to identify studies with adult HBeAg-negative patients who had PNALT as defined by the authors, a minimum follow-up of 1 year and histological data. Traditional cut-off values of normal ALT were used in all studies. The definitions of PNALT were considered as acceptable or good if there were ≥3 ALT determinations at unspecified intervals during 6-12 months or predefined intervals during ≥12-month periods, respectively. Results: Six studies including 335 patients met our inclusion criteria. Of these, four studies with 246 patients had good or acceptable definitions of PNALT. In the latter four studies, more than minimal (usually mild) necro-inflammatory activity was observed in 10% and more than mild fibrosis in 8% of all patients (moderate fibrosis: 7%, severe fibrosis: 1%, cirrhosis: 0%), and in 3% and 5% of patients with HBV DNA ≤20,000 IU/ml, respectively. Conclusions: Histologically significant liver disease is rare in HBeAg-negative patients with PNALT based on stringent criteria and serum HBV DNA ≤20,000 IU/ml. Such cases can be considered as true inactive HBV carriers, who require neither liver biopsy nor immediate therapy but continued follow-up.