Should Liver Biopsies Be Performed on All Hepatitis B Carriers?

We read with great interest the article “Virologic and Histologic Features of Chronic Hepatitis B Virus-Infected Asymptomatic Patients With Persistently Normal ALT” by Kumar et al. in the May 2008 issue of Gastroenterology.1Kumar M. Sarin S.K. Hissar S. et al.Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT.Gastroenterology. 2008; 134: 1376-1384Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar In this article, the authors studied alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA. and liver histology of >1,000 asymptomatic HBV carriers. They found that 60% of hepatitis B e antigen (HBeAg)-positive and 35% of HBeAg-negative patients with persistently normal ALT (PNALT) had an HBV DNA level >5-log copies/ml. They also reported that approximately 21% of HBeAg-negative patients with PNALT and HBV DNA <5-log copies/ml had histologically active liver disease (histologic activity index [HAI] ≥3 and/or fibrosis stage ≥2). The authors concluded that in light of their findings, the definitions and recommendations as regards to HBeAg-negative chronic hepatitis B patients with normal ALT might need revision because a significant proportion of HBeAg-negative patients with PNALT would be deprived of the possible benefits of antiviral therapy if the criteria of HBV DNA >5-log are to be followed. However, the results of this and other studies on this topic need to be interpreted carefully. In most studies, the number of patients with PNALT seen during the same period that were not biopsied was not reported.2Tsang P.S. Trinh H. Garcia R.T. et al.Significant prevalence of histologic disease in patients with chronic hepatitis B and mildly elevated serum alanine aminotransferase levels.Clin Gastroenterol Hepatol. 2008; 6: 569-574Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 3Lai M. Hyatt B.J. Nasser I. et al.The clinical significance of persistently normal ALT in chronic hepatitis B infection.J Hepatol. 2007; 47: 760-767Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar In Kumar et al's study, only 58 of 116 (50%) HBeAg-negative patients with PNALT were biopsied. This raises the concern of selection bias. It is possible that the patients who were biopsied had clinical or laboratory features suggesting more active or advanced liver disease prompting the biopsies. Another problem is that, although the initial cohort included >1,000 patients, the statement that 21% of HBeAg-negative patients with PNALT and HBV DNA <5-log copies/ml had histologically active liver disease was based on histologic findings of 6 patients who had a maximum fibrosis score of 1 and a maximum HAI of 5. A third issue is that although blood samples were collected at each visit, only baseline HBV DNA was analyzed. Given the fluctuating nature of chronic HBV infection, it is likely that some patients whose HBV DNA was <5-log at presentation may have higher HBV DNA levels during follow-up. We agree with the authors that patients with normal ALT including those with normal ALT on 3 occasions within a 1-year period (the definition of PNALT in Kumar et al's paper) may have significant liver disease and current guidelines need to be constantly appraised. We would like to point out that the American Association for the Study of Liver Diseases (AASLD) guidelines (see page 513 of Lok and McMahon)4Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2182) Google Scholar recommended that liver biopsy and treatment be considered in HBeAg-positive patients with high HBV DNA and persistently borderline normal or slightly elevated ALT levels, particularly if the patient is above the age of 40, and HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml (<4 log copies/ml) should be monitored with ALT determination every 3 months during the first year to verify that they are truly in the “inactive carrier state.” We feel that the Kumar et al's findings support the AASLD guideline recommendations. We would also like to point out that the headings in Table 5 may have been transposed because there were more HBeAg-negative patients with PNALT that had HBV DNA <3 − log copies/mL than HBV DNA <4 log copies/mL (65 vs 52). ReplyGastroenterologyVol. 135Issue 5PreviewWe thank Dr Degertekin and Dr Lok for their interest in our paper. Only 58 of 116 (50%) HBeAg-negative patients with persistently normal alanine aminotransferase (PNALT) were biopsied.1 Their concern about the potential selection bias is well formed. Although patients who agreed to undergo liver biopsy were of similar age (33.5 ± 15.2 vs 36.2 ± 14.4 years; P = .291), gender (M:F = 40:18 vs 41:17; P = .96], body mass index (22.5 ± 2.5 vs 22.8 ± 1.6 kg/m2; P = .499), and baseline ALT levels (27 IU/l [range, 11–40] vs 25 [14–40]; P = .255], they had higher baseline HBV DNA levels (4.97 [range, 2.78–8.41] vs 3.38 [2.78–9.20]; P < .001] as compared with patients who did not agree to undergo a liver biopsy. Full-Text PDF