• hepatitis B

We read with great surprise the article by Kim et al 1  reporting high risks of hepatocellular carcinoma (HCC) and death in patients with untreated chronic hepatitis B who were classified by them as patients in ‘immune-tolerant’ (IT) phase. This conclusion contradicts to the general belief that there is little or no disease progression during the IT phase of chronic HBV infection, as best demonstrated in a 5-year histological follow-up study.2 Some issues of serious concern on this study, especially their IT phase patients, require clarification and further discussion to minimise misleading messages.

IT phase of perinatally acquired chronic HBV infection is typically seen in Asian children or young adults with high HBV DNA, normal alanine aminotransferase (ALT), hepatitis B e-antigen (HBeAg) seropositivity and normal or minimal liver histological changes. After age of 20–25 years, IT phase may gradually convert to immune clearance or immune active (IA) phase, which is characterised by intermittent ALT elevations and remissions with eventual HBeAg seroconversion at a mean age of 30–35 years with 90% before age 40.3 HBeAg seropositivity in patients over age 40 is therefore uncommon4 and can be considered as ‘delayed HBeAg seroconversion’, which is associated with significantly higher risk of cirrhosis.5 Unfortunately, young age as an crucial feature of IT phase was neglected in more recent immunological studies,6 as was in this study. The mean age of the IT group of this study was 38±11 years, conceivably many of them were over age 40. It was also clearly shown in table 1 of this study that the serum HBV DNA levels overlapped extensively and showed no significant difference between the IT and IA groups. The cut-off HBV DNA levels for IT patients have been set at 10⁶ IU/ml to 10⁸ IU/ml by major liver associations,7–9 while 10⁴ IU/ml was adopted in this study. It seems reasonable to speculate that the IT group in this study might have included IA patients who were in remission state after having experienced prior asymptomatic, unrecognised hepatitis events. Furthermore, the risk of HCC or death correlated positively with age but negatively with baseline HBV DNA levels. Perhaps, the authors can compare and prove that the outcomes of their ‘genuine IT patients’ with high HBV DNA (>10⁶ IU/mL) and age <30 years are much better than their older counterparts. If confirmed, the data may also support the speculation that the older patients with lower baseline HBV DNA in their IT group are more likely IA patients in remission of hepatitis activity at enrolment. The findings that HBV DNA levels, albumin and platelet count significantly decreased, ALT levels significantly increased and 70% had advanced fibrosis or cirrhosis at the time of HCC development in their IT patients also highly suggest that many of these patients had experienced repeated bouts of hepatitis event leading to disease progression.

In summary, all characteristics of the patients classified as IT in this study were more likely IA patients at remission. Based on an incorrect classification of the study patients, the conclusion of high risks of HCC and death in patients with IT phase chronic hepatitis B is therefore not valid or at least questionable. Instead, their data strongly support the notion that delayed HBeAg seroconversion over age 40 is associated with increased risk of disease progression5 10 This is why HBeAg-positive patients over age 40 with normal ALT were recommended to receive liver biopsy to decide indication of antiviral therapy.7 8