Journal of Hepatology
Volume 34, Issue 3 , Pages 471-473, March 2001

Occult hepatitis B virus infection and liver disease: fact or fiction?

Unit of Clinical and Biomolecular Hepatology, Department of Internal Medicine, University of Messina, 98124 Messina, Italy

See Article, pages 447–454

Article Outline

 

Hepatitis B virus (HBV) is a world-wide diffuse virus that infects about 350 000 000 individuals and may induce a large spectrum of clinical forms ranging from the healthy carrier state to cirrhosis and hepatocellular carcinoma (HCC) [1]. HBV infection is usually diagnosed when the circulating hepatitis B surface antigen (HBsAg) is detected. However, the availability of highly sensitive molecular biology techniques has allowed the identification of HBV infection also in HBsAg-negative individuals with or without circulating antibodies to HBsAg (anti-HBs) and/or hepatitis B core antigen (anti-HBc) [2], [3], [4], [5], [6], [7].

The lack of HBsAg detection despite the persistence of virus genomes is due in most cases to the strong suppression of viral replication and gene expression that characterize this ‘occult’ HBV infection [6], [8], [9], [10], [11], although the mechanism(s) responsible for the suppression of HBV is mostly not understood.

The essential question in the occult HBV infection issue is whether or not it has any clinical impact. In other words, is it involved in the etiopathogenesis of a liver disease or is looking for HBV genomes in HBsAg-negative subjects just an exercise for laboratory workers?

Undoubtedly, carriers of occult infection may transmit HBV in the case of blood transfusion or organ transplantation and the recipients may develop a type B hepatitis that may have all the possible outcomes of the typical HBV infection, including the fulminant course and the development of chronic hepatitis [12], [13], [14], [15], [16], [17]. Another aspect in favour of the clinical relevance of occult HBV infection is its potential oncogenic role. In fact, many epidemiological and molecular studies performed since the 1980s indicate that a persisting HBV infection might play a critical role in the development of HCC also in HBsAg-negative patients [18], [19], [20], [21], [22]. This evidence is confirmed by data in animal models showing that both woodchucks and ground squirrels, once infected by the corresponding hepadnaviruses (WHV, GSHV), are at high risk of developing HCC also after the apparent clearance of the virus [23], [24]. Occult HBV should contribute to hepatocellular transformation through the same mechanisms traditionally considered to be the basis of the tumorigenic properties of the HBV, mainly the potential pro-oncogenic activity of the X protein and the capacity of the virus to integrate into the host genome, as recently reviewed by Brechot et al. [25]. In this context, it has to be considered that much evidence suggests that free episomal HBV-DNA commonly persists in the liver cells during an occult infection [3], [5], [17], [26], [27], [28].

Therefore, occult HBV infection appears to have relevance in terms of infectivity and contribution to HCC development; however, can it induce liver injury?

Several reports have shown that HBV genomes may persist for decades after recovery from self-limited acute hepatitis [29], [30], [31], [32]. These data would suggest that the occult infection is inoffensive in itself and it might become injurious only in the case of viral reactivation occurring under immunosuppressive circumstances [33], [34], [35]. Nevertheless, HBV genomes have often been found also in patients with idiopathic liver disease [8], [36], [37]. Moreover, a recent study on woodchucks convalescent from acute WHV hepatitis demonstrated the lifelong persistence of small amounts of replicating virus that induce a very mild liver necroinflammation continuing for life [38].

Analyzing a large series of liver biopsy specimens from patients with HCV-related chronic liver disease, we found a high prevalence of occult HBV infection both in anti-HBc-positive and -negative individuals [37]. Among HCV patients, those carrying the occult HBV had more severe and precocious liver disease and seemed to have a poor response to interferon-α therapy. Finally, in a control group of subjects with non-HCV-related chronic hepatitis occult HBV infection was significantly associated with cases of cryptogenic liver disease [37].

The aim of the study by Chemin et al. [39] published in this issue of the Journal of Hepatology was to investigate the possible role of known hepatotropic (and some hypothetically hepatotropic) viruses in the etiology of cryptogenic chronic hepatitis. Through the use of properly sensitive biomolecular methods, they analyzed serum and liver samples from 50 patients with idiopathic liver disease who had been followed-up for a long time. Among the several viruses tested, they found that only HBV was highly prevalent (15 (30%) cases positive), providing an important confirmation that occult HBV infection is significantly associated with liver diseases of unknown etiology. As underlined by the authors, the histopathological findings were the most important and original aspect of their study. In fact, 53% of the patients with occult HBV infection had high grade fibrosis or cirrhosis, whereas only 16% of the HBV-DNA-negative subjects showed a severe histological pattern. Moreover, when sequential liver biopsy specimens were available, patients with occult hepatitis B seem to suffer from a progressive aggravation of the liver pathology. Finally, examination of serial samples collected during the follow-up confirmed the persistence of HBV genomes over time. All these data provide further support to the hypothesis that occult HBV infection might be responsible for liver injury, although we are still far from clear proof that a strongly suppressed HBV infection can be directly involved in the development of chronic hepatitis. As Chemin et al. admit, it can not be excluded that other not yet identified factors (unknown viruses?) may be the main cause of the liver damage in cases of cryptogenic hepatitis. However, their report adds more evidence to the observation that occult HBV often associates with the most severe forms of liver disease, and such association needs an explanation in any case.

Considering all the data of the literature available so far, one might speculate that a silent HBV infection is usually not able in itself to provoke a clinically relevant liver injury. However, if other causes of liver damage co-exist (HCV infection, alcohol abuse, iron overload, etc.), it might be a factor that negatively influences the outcome of the disease. The mechanisms utilized by the occult HBV infection for playing such a hypothetical deleterious role are at present unknown, but to define them is the true challenge for people working in this fascinating field of biomedical research.

Back to Article Outline

References 

  1. Lee MY. Hepatitis B virus infection. N Engl J Med. 1997;24:1733–1745
  2. Brechot C, Hadchouel M, Scotto J, Degos F, Charnay P, Trepo C, et al.  State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen positive and negative liver disease. Proc Natl Acad Sci USA. 1981;78:3906–3910
  3. Thiers V, Nakajima E, Kremsdorf D, Mack D, Schellekens H, Driss F, et al.  A transmission of hepatitis B from hepatitis B seronegative subjects. Lancet. 1988;2:1273–1276
  4. Kaneko S, Miller RH, Feinstone SM, Unoura M, Kobayashi K, Hattori N, et al.  Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Natl Acad Sci USA. 1989;86:312–316
  5. Wang JT, Wang TH, Sheu JC, Shih LN, Lin JT, Chen DS. Detection of hepatitis B virus DNA by polymerase chain reaction in plasma of volunteer blood donors negative for hepatitis B surface antigen. J Infect Dis. 1991;163:397–399
  6. Loriot MA, Marcellin P, Bismuth E, Martinot-Peignouxet M, Boyer N, Degott C, et al.  Demonstration of hepatitis B virus DNA by polymerase chain reaction in the serum and the liver after spontaneous or therapeutically induced HBeAg to anti-HBe or HBsAg to anti-HBs seroconversion in patients with chronic hepatitis B. Hepatology. 1992;15:32–36
  7. Zhang Y-Y, Hansson BG, Kuo LS, Widell A, Nordenfelt E. Hepatitis B virus DNA in serum and liver is commonly found in Chinese patients with chronic liver disease despite the presence of antibodies to HBsAg. Hepatology. 1993;17:538–544
  8. Liang TJ, Baruch Y, Ben-Porath E, Enat R, Bassan L, Brown NV, et al.  Hepatitis B virus infection in patients with idiopathic liver disease. Hepatology. 1991;13:1044–1051
  9. Sardo MA, Rodinò G, Brancatelli S, Pernice M, Campo S, Squadrito G, et al.  Inapparent wild-type and e-minus variant HBV infection in patients with HCV-related chronic hepatitis. Liver. 1994;14:241–244
  10. Villa E, Grottola A, Buttafoco P, Trande P, Merighi A, Fratti N, et al.  Evidence for hepatitis B virus infection in patients with chronic hepatitis C with and without serological markers of hepatitis B. Dig Dis Sci. 1995;40:8–13
  11. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Villari D, deFranchis R, et al.  Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with chronic HBV infection. Hepatology. 2000;31:507–512
  12. Hoofnagle JH, Seeff LD, Bales ZB, Zimmerman HJ. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen. N Engl J Med. 1978;298:1379–1383
  13. Chazouilleres O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, et al.  Occult hepatitis B virus as a source of infection in liver transplant recipients. Lancet. 1994;343:142–146
  14. Degos F, Lugassy C, Degot C, Debure A, Carnot F, Thiers V, et al.  Hepatitis B virus and hepatitis B related viral infection in renal transplant recipients. Gastroenterology. 1988;94:151–156
  15. Japanese Red Cross nonA-nonB Hepatitis Research Group . Effect of screening for hepatitis C virus antibody and hepatitis B virus core antibody on incidence of post-transfusion hepatitis. Lancet. 1991;338:1040–1041
  16. Wachs ME, Amed WJ, Ascher NL, Bretan PN, Emond J, Lake JR, et al.  The risk of transmission of hepatitis B from HBsAg (−), HBcAb (+), HBV IgM (−) organ donors. Transplantation. 1995;59:230–234
  17. Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg EC, Wiesner RH, et al.  Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology. 1997;113:1668–1674
  18. Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. N Engl J Med. 1981;305:1067–1073
  19. Paterlini P, Gerken G, Nakajima E, Terre S, D'Errico A, Grigioni W, et al.  Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl J Med. 1990;323:80–85
  20. Sheu JC, Huang GT, Shih LN, Lee WC, Chou HC, Wang JT, et al.  Hepatitis C and B viruses in hepatitis B surface antigen-negative hepatocellular carcinoma. Gastroenterology. 1992;103:1322–1327
  21. Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 1995;21:313–321
  22. Huo TI, Wu JC, Lee PC, Chau GY, Lui WY, Tsay SH, et al.  Seroclearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology. 1998;28:231–236
  23. Korba BE, Wells FV, Baldwin B, Cote PJ, Tennant BC, Popper H, et al.  Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections. Hepatology. 1989;9:461–470
  24. Marion PL. Ground squirrel hepatitis virus. In:  McLachlan A editors. Molecular biology of hepatitis B virus. London: CRC Press; 1991;p. 39–51
  25. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular basis for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol. 2000;10:211–231
  26. Nalpas D, Berthelot P, Thiers V, Duhamel G, Courouce AM, Tiollais P, et al.  Hepatitis B virus multiplication in the absence of usual serological markers. J Hepatol. 1985;1:89–97
  27. Blum HE, Offensperger WB, Walter E, Offensperger S, Gerok W. Latent hepatitis B virus infection with full-length viral genome in a patient serologically immune to hepatitis B virus infection. Liver. 1988;8:307–316
  28. Marusawa H, Uemoto S, Hijikata M, Ueda Y, Tamaka K, Shimotomho K, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology. 2000;31:488–495
  29. Penna A, Artini M, Cavalli A, Levrero M, Bertoletti A, Pilli M, et al.  Long-lasting memory T-cell responses following self-limited acute hepatitis B. J Clin Invest. 1996;98:1185–1194
  30. Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest. 1994;93:230–239
  31. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2(10):1104–1108
  32. Yotsuyanagi H, Yasuda K, Iino S, Moriya K, Shintani Y, Fujie H, et al.  Persistent viremia after recovery from self-limited acute hepatitis B. Hepatology. 1998;27:1377–1382
  33. Waite J, Gilson RJC, Weller IVD, Lacey CJ, Hambling MH, Hawkins A, et al.  Hepatitis B virus reactivation or reinfection associated with HIV-1 infection. AIDS. 1988;2:443–448
  34. Grumayer ER, Panzer S, Ferenci P, Gadner H. Recurrence of hepatitis B in children with serologic evidence of past hepatitis B virus infection undergoing antileukemic chemotherapy. J Hepatol. 1989;8:232–235
  35. Lok ASF, Liang RHS, Chiu EKW, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology. 1991;100:182–188
  36. Preisler-Adams S, Schlayr HJ, Peters T, Hettler F, Gerok W, Rasenach J. Sequence analysis of hepatitis B virus DNA in immunologically negative infection. Arch Virol. 1993;133:385–396
  37. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med. 1999;341:22–26
  38. Michalak TI, Pardoe IU, Coffin CS, Churchill ND, Freake DS, Smith P, et al.  Occult lifelong persistence of infectious hepadna virus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology. 1999;29:928–938
  39. Chemin I, Zoulim F, Merle P, Arkhis A, Chevallier M, Kay A, et al.  High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol. 2001;34:447–454

PII: S0168-8278(01)00016-2

doi:10.1016/S0168-8278(01)00016-2

Journal of Hepatology
Volume 34, Issue 3 , Pages 471-473, March 2001

Article Tools