Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B
Tse-Ling Fong
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorAdrian M. Di Bisceglie
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorMichael A. Gerber
Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana 70112
Search for more papers by this authorJeanne G. Waggoner
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorCorresponding Author
Jay H. Hoofnagle M. D.
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Bldg. 31, Room 9A23, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892===Search for more papers by this authorTse-Ling Fong
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorAdrian M. Di Bisceglie
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorMichael A. Gerber
Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana 70112
Search for more papers by this authorJeanne G. Waggoner
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Search for more papers by this authorCorresponding Author
Jay H. Hoofnagle M. D.
The Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Bldg. 31, Room 9A23, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892===Search for more papers by this authorAbstract
To determine whether patients with chronic hepatitis B who lose hepatitis B virus DNA and HBsAg from the serum completely resolve the hepatitis and virus infection, we evaluated serum and liver tissue from 11 patients who had lost HBsAg. These patients were evaluated for clinical, histological and serological features and for hepatitis B virus DNA by use of hybridization and polymerase chain reaction techniques. Liver biochemical test results were normal in all except two patients who had mild aminotransferase elevations. All sera were negative for hepatitis B virus DNA by direct hybridization, and only one was positive transiently by polymerase chain reaction. Liver histology was abnormal in all patients, but the changes were mild and markedly improved compared with biopsy specimens taken before loss of HBsAg. Liver tissue from 10 patients was positive for hepatitis B virus DNA by polymerase chain reaction but not by direct hybridization. These findings indicate that loss of HBsAg is associated with marked improvements in clinical and serum biochemical features of chronic hepatitis B, yet mild degrees of hepatitis and low levels of viral DNA may persist in the liver (HEPATOLOGY 1993;18:1313–1318.
References
- 1 Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the “Healthy” HBsAg carrier state. HEPATOLOGY 1987; 7: 758–763.
- 2 Realdi G, Alberti A, Rugge M, Bortolotti F, Rigoli AM, Tremolada F, Ruol A. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980; 79: 195–199.
- 3 Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981; 94: 744–748.
- 4 Alexander GJM, Brahm J, Fagan EA, Smith HM, Daniels HM, Eddleston ALWF, Williams R. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987; 1: 66–68.
- 5 Hoofnagle JH, Peters MG, Mullen KD, Jones DB, Rustgi V, Di Bisceglie AM, Hallahan C, et al. Randomized controlled trial of a four-month course of recombinant human alpha interferon in chronic type B hepatitis. Gastroenterology 1988; 95: 1318–1325.
- 6 Perrillo RP, Schiff E, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, et al. A randomized controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990; 323: 295–301.
- 7 Lindsay KL, Redeker AG, Ashcavai M. Delayed HBsAg clearance in chronic hepatitis B viral infection. HEPATOLOGY 1981; 1: 586–589.
- 8 Perrillo RP, Brunt EM. Hepatic histologic and immunohistochemical changes in chronic hepatitis B after prolonged clearance of hepatitis B e antigen and hepatitis B surface antigen. Ann Intern Med 1991; 115: 113–115.
- 9 Moestrup T, Hanssen BG, Widell A, Nordenfelt E, Hagerstrand I. Long term follow up of chronic hepatitis B virus infection in intravenous drug abusers and homosexual men. BMJ [Clin Res] 1986; 292: 854–857.
- 10 Korenman J, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM, Hoofnagle JH. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med 1991; 114: 629–633.
- 11 Shindo M, Di Bisceglie AM, Cheung L, Shih JW-K, Cristiano K, Feinstone SM, Hoofnagle JH. Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatits C. Ann Intern Med 1991; 115: 700–704.
- 12 Purcell RH, Hoofnagle JH, Ticehurst J, Gerin JL. Hepatitis viruses. In: NJ Schmidt, RW Emmons, eds. Diagnostic procedures for viral, rickettsial and chlamydial infections. 6th edition. Washington, DC: American Public Health Association, 1989; 957–1065.
- 13 Kaneko S, Feinstone S, Miller RH. Rapid and sensitive method for the detection of serum hepatitis B virus DNA using the polymerase chain reaction technique. J Clin Microbiol 1989; 17: 1930–1933.
- 14 Baginski I, Ferrie A, Watson R, Mack D. Detection of hepatitis B virus. In: M Innis, J Gelfand, J Sninsky, T White, eds. Polymerase chain reaction: a guide to methods and applications. San Diego: Academic Press Inc., 1990; 21–27.
- 15 Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. HEPATOLOGY 1981; 1: 431–435.
- 16 Gerber MA, Vernace S. Chronic septal hepatitis. Virchows Arch A Pathol Anat Histopathol 1974; 363: 303–309.
- 17 Kuhns M, Mason A, McNamara A, Campbell C, Perillo R. Polymerase chain reaction in the detection of HBV DNA after HBsAg clearance in chronic hepatitis B. Gastroenterology 1992; 103: 1649–1656.
- 18 Loriot M-A, Marcellin P, Bismuth E, Martinot-Peignoux M, Boyer N, Degott C, Erlinger S, 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.
- 19 Adachi H, Kaneko S, Matsushita E, Inagaki Y, Unoura M, Kobayashi K. Clearance of HBsAg in seven patients with chronic hepatitis B. HEPATOLOGY 1992; 16: 1333–1337.
- 20 Carman WF, Dourakis S, Karayiannis P, Crossey M, Drobner R, Thomas HC. Incidence of hepatitis B viremia, detected using the polymerase chain reaction after successful therapy of hepatitis B virus carriers with interferon alpha. J Med Virol 1991; 34: 11–118.
- 21 Molina J, Bartolome J, Moraleda G, Ruiz-Moreno M, Rua MJ, Moreno A, Carreno V. Persistence of hepatitis B virus DNA after reduction of viral replication in serum and liver. J Med Virol 1992; 38: 11–15.
- 22 Brechot C, Degos F, Lugassy C, Thiers V, Zafrani S, Franco D, Bismuth H, et al. Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen. N Engl J Med 1985; 312: 270–276.
- 23 Blum HE, Liang TJ, Galun E, Wands JR. Persistence of hepatitis B viral DNA after serological recovery from hepatitis B virus infection. HEPATOLOGY 1991; 14: 56–63.
- 24 Bhat RA, Ulrich PP, Vyas GN. Molecular characterization of a new variant of hepatitis B virus in a persistently infected homosexual man. HEPATOLOGY 1990; 11: 271–276.
- 25 Lai M-Y, Chen P-J, Yang P-M, Sheu J-C, Sung J-L, Chen D-S. Identification and characterization of intrahepatic hepatitis B virus DNA in HBsAg-seronegative patients with chronic liver disease and hepatocellular carcinoma in Taiwan. HEPATOLOGY 1990; 12: 575–581.
- 26 Mason AL, Campbell C, Perrillo RP. Continued transcription of hepatitis B virus in the liver after clearance of serum HBsAg [Abstract]. HEPATOLOGY 1992; 16: 127.
- 27 Paterlini P, Gerber G, Nakajima E, Terre S, D'Errico A, Grigioni W, Nalpas B, 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.
- 28 Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of the liver cells in chronic liver disease and hepatocellular carcinoma. N Engl J Med 1981; 305: 1067–1073.
- 29 Di Bisceglie AM, Waggoner JG, Hoofnagle JH. Hepatitis B virus deoxyribonucleic acid in liver of chronic carriers. Gastroenterology 1987; 93: 1236–1241.
- 30 Yokosuka O, Omata M, Imazeki F, Ito Y, Okuda K. Hepatitis B virus RNA transcripts and DNA in chronic liver disease. N Engl J Med 1986; 315: 1187–1192.
- 31 Hoofnagle JH, Seeff LB, 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.
- 32 Katchaki JN, Siem TIY, Brouwer R, Brandt KH, van der Waart M. Detection and significance of anti-HBc in the blood bank: preliminary results of a controlled prospective study. J Virol Methods 1980; 2: 119–125.
- 33 Galbraith RM, Eddleston ALWF, Williams R, Zuckerman AJ, Bagshawe KD. Fulminant hepatic failure in leukaemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 1975; 2: 528–530.
- 34 Lok ASF, Liang RHS, Chiu EKW, Wong K-L, Chan T-K, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology 1991; 100: 182–188.
- 35 Wright TL, Mamish D, Combs C, Kim M, Donegan E, Ferrell L, Lake J, et al. Hepatitis B virus and apparent fulminant non-A, non-B hepatitis. Lancet 1992; 339: 952–955.
