EASL clinical practice guidelines on the management of chronic hepatitis B: The need for liver biopsy
Authors: George V. Papatheodoridis, Spilios Manolakopoulos
Journal: Journal of Hepatology (2009)

We read with great interest the recent guidelines from the European Association for the Study of Liver (EASL) for the management of chronic hepatitis B [[1]European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar], which were eagerly anticipated. We think that they definitely represent a step forward in the right direction for the management of chronic hepatitis B, which is a rapidly evolving field. However, we would like to draw your attention on the indications for liver biopsy, which remain a controversial unresolved issue, at least in our opinion. In the recent EASL guidelines, "a liver biopsy is recommended for determining the degree of necroinflammation and fibrosis in patients with either increased ALT or HBV DNA levels >2000 IU/ml (or both) since hepatic morphology can assist the decision to start treatment" and this recommendation is graded as A1 (strong recommendation based on high quality evidence) [[1]European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar]. Since almost all HBeAg-positive patients have HBV DNA >2000 IU/ml, this recommendation suggests that almost all HBeAg-positive cases should undergo a liver biopsy regardless of ALT levels. In the 2002 EASL Consensus Conference on hepatitis B and in all recent guidelines including EASL's [1European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar, 2Fattovich G. Natural history of hepatitis B.J Hepatol. 2003; 39: S50-S58Abstract Full Text Full Text PDF PubMed Google Scholar, 3Lok A.S.F. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2187) Google Scholar], HBeAg-positive patients with high HBV DNA and normal ALT activity are considered to be within the first immunotolerant phase of chronic HBV infection and to have no or minimal histological changes. To our knowledge, strong data to change this concept have not been recently reported and therefore the vast majority of such patients are not expected to benefit from a liver biopsy showing minimal changes. The decision to treat such patients with very high viremia may be generally a matter of debate for several reasons, but the histological findings are not going to reveal lesions that require therapeutic intervention [1European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar, 2Fattovich G. Natural history of hepatitis B.J Hepatol. 2003; 39: S50-S58Abstract Full Text Full Text PDF PubMed Google Scholar, 3Lok A.S.F. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2187) Google Scholar] [at least moderate necroinflammation and/or fibrosis [[1]European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar]]. The issue of liver biopsy in HBeAg-negative chronic HBV patients with persistently normal ALT activity has always been debatable. It is widely accepted that liver biopsy is not required in such patients with HBV DNA <2000 IU/ml [1European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar, 3Lok A.S.F. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2187) Google Scholar, 4Papatheodoridis G.V. Manolakopoulos S. Dusheiko G. Archimandritis A.J. Therapeutic strategies in the management of patients with chronic hepatitis B.Lancet Infect Dis. 2008; 8: 167-178Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar], while HBeAg-negative patients with HBV DNA >2000 IU/ml appear to represent a controversial group. According to studies from our group and from France, 18–25% of HBeAg-negative chronic HBV patients with persistently normal ALT have HBV DNA >2000 IU/ml (<20,000 IU/ml in the vast majority of them) [5Papatheodoridis G.V. Chrysanthos N. Hadziyannis E. Cholongitas E. Manesis E.K. Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection.J Viral Hepat. 2008; 15: 434-441Crossref PubMed Scopus (71) Google Scholar, 6Martinot-Peignoux M. Boyer N. Colombat M. Akremi R. Pham B.-N. Ollivier S. et al.Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-548Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar], but histological lesions justifying therapeutic intervention are rather rarely present in such cases [6Martinot-Peignoux M. Boyer N. Colombat M. Akremi R. Pham B.-N. Ollivier S. et al.Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-548Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 7Papatheodoridis G.V. Manesis E.K. Manolakopoulos S. Elefsiniotis I.S. Goulis J. Giannousis J. et al.Is there a meaningful serum HBV DNA cut-off level for therapeutic decisions in HBeAg-negative chronic hepatitis B virus infection?.Hepatology. 2008; 48: 1451-1459Crossref PubMed Scopus (116) Google Scholar]. In fact, even when a liver biopsy showed changes fulfilling the histological criteria for therapeutic intervention (⩾moderate necroinflammation and/or moderate fibrosis), this was almost always due to the presence of moderate fibrosis accompanied by minimal necroinflammation [6Martinot-Peignoux M. Boyer N. Colombat M. Akremi R. Pham B.-N. Ollivier S. et al.Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-548Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 7Papatheodoridis G.V. Manesis E.K. Manolakopoulos S. Elefsiniotis I.S. Goulis J. Giannousis J. et al.Is there a meaningful serum HBV DNA cut-off level for therapeutic decisions in HBeAg-negative chronic hepatitis B virus infection?.Hepatology. 2008; 48: 1451-1459Crossref PubMed Scopus (116) Google Scholar]. In our opinion, which is based on reasonable clinical judgment, treatment should be given to chronic HBV patients with some degree of both necroinflammation and fibrosis. By such an approach, we may avoid unnecessary treatment in chronic HBV patients who do not actually require therapy, such as inactive chronic HBV carriers without hepatitis activity but with some fibrosis accumulated during the HBeAg seroconversion phase in the past. All reports about significant histological lesions in a substantial proportion of HBeAg-negative patients with persistently normal ALT come from non-European (usually Asian) studies including patients with different viral and host genetic characteristics and under a less strict biochemical follow-up [[8]Papatheodoridis G.V. Manesis E.K. Manolakopoulos S. Elefsiniotis I.S. Goulis J. Archimandritis A.J. HBeg-negative patients with persistently normal alanine aminotransferase levels and HBV DNA >2000 IU/mL: some concerns – reply.Hepatology. 2009; 49: 705-706Crossref Scopus (1) Google Scholar]. According to the above data [6Martinot-Peignoux M. Boyer N. Colombat M. Akremi R. Pham B.-N. Ollivier S. et al.Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-548Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 7Papatheodoridis G.V. Manesis E.K. Manolakopoulos S. Elefsiniotis I.S. Goulis J. Giannousis J. et al.Is there a meaningful serum HBV DNA cut-off level for therapeutic decisions in HBeAg-negative chronic hepatitis B virus infection?.Hepatology. 2008; 48: 1451-1459Crossref PubMed Scopus (116) Google Scholar], the majority of European HBeAg-negative patients with persistently normal ALT and HBV DNA >2000 IU/ml will not benefit from a liver biopsy which will show no or minimal necroinflammatory changes (perhaps with some inactive fibrosis in a minority of them) that do not require therapeutic intervention [[1]European Association for the Study of the Liver EASL clinical practice guidelines: management of chronic hepatitis B.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1493) Google Scholar]. In conclusion, a strict adherence to the recommendation for liver biopsy in all chronic HBV patients with either abnormal ALT or HBV DNA >2000 IU/ml will substantially increase the numbers of biopsies in both HBeAg-positive and HBeAg-negative patients without increasing the numbers of patients requiring treatment. Of course, all chronic HBV patients who remain untreated, irrespective of having a liver biopsy or not, should be followed for life. The need for life-long close follow-up may be further stressed in the guidelines that should always include strong and specific recommendations on the most widely accepted optimal follow-up for the various groups of untreated chronic HBV patients.