CLINICAL REYIEW DIGESTLIUER MS 2000;32:822-6 Occult Hepatitis B virus infection G. Raimondo C. Balsano I A. Craxi * F. Farinati 3 M. Levrero 4 M. Mondelli 5 T. Pollicino G. Squadrito C. Tiribelli 6 Depmment of Imefv7e~Medicine, University of Messina; ’ Department of lnternel Medicine, Universky of L ‘Aquik B Institute of 08stmn~1~gy. University of Palermo; 3 Department of Surgical and Gestroantaroio@ai Sciances, Ukwsity of Padove; 4 Lalmwmy of &we Exprasebn, FIX&B&~ A, Caaafpino, U-&w&y of Rwna ‘La Sapisma*; 5 Depertment of Infectijous Diseeses, University of Pevia; @ Dapartment of BibchemWy, Bi@ysri; and Chgmisbrv of Macromolecules, Univereky of Trieste, k&lJC .it Submitted Dctaber I?, 2iX7D Revised Mwem&er 22.2iWD. Accepted &vambar 252iXZ Many studies have shown that hepatitis B virus infection may also occur in hepatitis B surface antigen-negative patients. This occult infection has been identified both in patients with cryptogenic liver disease and in patients with hepatitis C virus-related chronic he- patitis, and much evidence suggests that it may be a risk factor of hepatocellular carcinoma development. However: several aspects of this occult infection remain unclear such as its prevalence and the factor[s] involved in the lack of circulating hepatitis B surface antigen. Moreover it is uncertain whether the occult hepatitis B virus infection may contribute to chronic liver damage, considering that it is usually associated with a suppressed viral replication. Ev- idence and hypotheses concerning this fascinating field of bio-med- ical research are reviewed. Digest Liver Dis 2000;32:822-6 Key words: HEW genome; HElsAg-negative; liver DNA; liver disease The amazing development of Molecular Biology that has occurred over the last two decades of the past Century has led to very important progress in the medical sciences. In particular, new frontiers have been opened in the field of Virology. Molecular Biology has, in fact, allowed the identification and evaluation both of viruses responsible for severe and widespread dis- eases, such as the hepatitis C virus (HCV) and the human immunodeficien- cy virus (HIV), and of viruses, like the so-called hepatitis G virus and TTV, that infect, to a large extent, the general population but are of uncertain clin- ical relevance lm4. In this context, the demonstration that viruses, strongly suspected to be responsible for human illness, are carried in a latent form by a very large number of healthy individuals, as, for instance, Kaposi’s sar- coma-associated herpes virus, is of some relevance 5. This observation would appear to suggest that the persistence of virus infections at very low levels of replication might be a more frequent event than previously be- lieved. Hepatitis B virus (HBV) is a virus, spread worldwide, that infects about 3.50,000,000 individuals and that may show a large spectrum of clinical forms ranging from the healthy carrier state to cirrhosis and hepatocellular carcinoma (HCC) 6. HBV infection is usually diagnosed when the circulat- ing HB surface antigen (HBsAg) is identified. However, many studies have clearly shown that HBV infection may occur in HBsAg negative individu- als with or without serologic markers of previous infection [antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc)] ‘-‘?. This persistence of virus genomes under unexpected conditions, called “oc- cult” HBV infection, is characterized by a strong suppression of virus repli- cation and gene expression and is usually identified by highly sensitive molecular biology techniques. Such an intriguing type of infection has sev- eral undefined aspects that mainly concern: a) the factor(s) involved in the lack of circulating HBsAg, b) the mechanism(s) responsible for the sup-