- Email: [email protected]
Study of reactivation of chronic hepatitis delta infection
Journalo~Hepalology. 1989;9: 204-208 %%,ier
204
Study of reactivation
of chronic hepatitis delta infection
Antonina Smedile, Kevin M. De Cock, Boontar Valinluck, Allan G. Redeker and John L. Gerin “,li”ersilyofsourlwm carifomia,Liver ““i,, Dwvney,Gl and George*own ““i”,i,, .schoo,ofMedicine “,,dDmrbrry.u,c~“r,le,MU ,U.S.A., (Rcccivcd15November1988) (Accepted21March1989)
Sugantha
Govindarajan,
Five patients with chronic hepatitis delta virus (HDV) infection suffered spontaneous episodes of liver enzyme elevation on a background of otherwise biochemically stable liver disease. In all five patients these episodes were ~conlpanied by a rise in strwn levels of anti-HDV IgM. HDV antigen and HDV RNA. These episodes of increased HDV replication acco:!l@ed by biochemical evidence of live: injury are reminiscent of reactivation in chronic heparitis B. Surges of i?crezscd HDV replication may be important in the pmgression of liver disease in chronic HDV infection.
Introduction Chronic hepatitis B virus (HBV) infection, usually a stable or slowly progressive condition, is sometimes complicated by episodes of virus replication that can mimic acute hepatitis B [l]. Reactivation of this nawe is characterized by abrupt elevation of aminotxwsferase levrls, in addition to an increase in serum levels of HBV DNA and the presence of other markers of HBV replication [2,3]. Although such episodes of reactivation are most often spontaneous, a similar clinical picture may complicate the sudden with-
drawal of immunosuppressive drugs in persons chronically infected with HBV 14-61. Hepatitis delta virus (HDV) is a defective RNA virus which requires the presence of HBV to allow infection [7]. Three clinical categories of disease are recognized, acute I-IBV and HDV coinfection, acute HDV superinfection in an HBV carrier, and established, chronic infection with both agents [S]. We have recently observed episodes of marked spontaneous elevation of aminotransferase leve!s in persons chronic delta hepatitis, reminiscent of HBV reactivation in the chronic HPV carrier state. This
with
Correspondtnce:Supntha Govindarsjan,M.D., Departmeatof Pathology,USC Livx Unit, RanchoLosAmigosMedicalCenter, ii05 GoiondrindsSlrec~.ILL aldg.. Down~y.CA 90242.U.S.A 016%8?781891303.50~ 1989ElswierSciencePublishersB.V.(BvxwdicalDivirion)
REACTIVATION OF HDV
study examines markers of HDV and HBV replication in this previously unreported clinical event. The resuits suggest that chronic HDV infection can undergo episodes of reactivation leading to increased circulating viral markers and accompanying biochemical
evidence
of accte liver injury.
?esients, materials and methuds
Patients were drawn from the weekly Hepatitis Clinic which is held free of charge at the Los Angeles County-University of Sonthem California Medical Center. Patients enrolled had chronic HDV infection, either front first observation in the clinic or as a consequence of HDV superinfection of the HBV carrier state. The serologic profile of HDV superinfection and chronic de!ta hepatitis have been previously described [Sl. Patients selected for further study were those who suffered a marked elevation of alanine aminotransferase (ALT) levels occurring abruptly in the course of an otherwise stable illness. None of the patients were taking immunopressive or anti-viral therapy. Pafient A: (Fig. IA). This patient was a 29.yearold Asian man, who denied risk factors for viral hepatitis, although homosexuality was suepected. ‘While in hospital in March i985 for a pyogenic liver abscess he was noted to be HBsAg pr%ive with a normal ALT value. Anti-delta was not done. In July 1985, during follow-up, the ALT had rised to 1070 IU without jaundice or symptoms. Anti-delta I& was positive; but anti-delta IgM was not detected. The ALT slowly declined and in February 1986 was again normal. HBsAg and anti-delta IgG were still demonstrable. One month later ALT rose to 1255 IU, then decreased to 66 IU in April 1986. With the increase in ALT, anti-delta IgM was detectable, although there was no jaundice or symptoms. HBsAg remained positive throughout the course. Pafiml Z?: (Fi: ZB). This 29-year-old male homosexual was first seen in March 1985. He was not ill hut was found iv be HasAG positive, anti-delta neg ative. He was the sexual partner of a man who had re-
205 cently died with fulminanr hepatitis B. There was no past history of hepatitis. ALT was normal. Three months later he developed mild jaundice and ALT rose to 930 IU. Anti-delta IgG was detectable. Ten months later the ALT rose to I295 IU dnd both antidelta IgM and ‘gCr were present. He remained HBsAg positive throughout the coume. Patient C: (Fig. IC). This Zl-year-old Lebanese man bad lrcently immigrated to Los Angeles to marry his cousin. Four months later in January 1986, he deve1ope.l severe ac!Xe hepatiris. He was HBsAg postive, anti-HBc IgM negative, anti-delta IgM positive and HBV-DNA negative. Prothrombin activity was 10%. His wife was found to be HBsAg and antidelta IgG positive and was presumed to he the source of his delta virus superinfection. On 13 Rbruary 1986, his ALT was 273 IU. but 3 months later was 40 IU. However, in May 1986, the ALT rose again to 1385 IU, falling to 1161U in January 1987. P&w D: (Fig. ID). This patient, a 24-year-old homosexual man, was being followed as an HRsAg carrier after being rejected as a blood donor in September 198I. Anti-delta was negative. In September 1984, he developed a severe acute hepatiiis tith jaundice and ALT of 2868 IU. Ann-delta IgM was now present. A liver biopsy showed positive staining for delta antigen. ALT remained greater than 500 IU for the next 5 months, but in May 1985, was only 66 IU. This then fluctuated over the next ?!h yezs demonstrating two further peak values of 740 and 525 IU. On one of these occasions, the serum bilirubin rose to 7.2 mg/dl (122.4ymohl). HBsAg and anti-de!ta were persistently positive. Patient E: (Fig. 1E). This 2%year-old male hotnosexual developed severe acute hepatitis in November 1981. He wus HBsAg positive, anticore IgM neg. ative. and anti-delta IgM positive then. Two months later he had become anicteric and the ALT was 37 IU. In May I982, the ALT rose to 1155 IU and the serum bilirubin to 3.4 mg/dl. Sii weeks later the ALT was abruptly increased to 975 IU and in 1 month had fallen to 90 III. Again in October 1982, the ALT rose to 710 IU. Subsequently, over the next 2 years, the ALT remained elevated between 150 and 350 IU. HBsAg and anti-delta remained positive.
206
S. GOVllWARAJAN et at.
Serdogic em
Anti-NDV IgM and IgG antibodies were detected by capture radioimmunoassay as previously dcscribed [9]. The strength of the antibody response is expressed as the ratio of the counts per minute of the test serum to those of a negative control (pin ratio), a
positive bring grearer than 2.1. Hepatitis B surface antigen was detected bg commercially available radioimmunoassay (Abbott Laboratories, IL). IgM antibody to hepatitis B core antigen (anti-HBc IgM) was detected by testing column-separated IgM by a commercially available radioimmunoassay for anti-
Fig. I.(Forlegendand lE,seeeappcsirepage.)
KEACIlVAnON
OF
207
HDV
HBc (Abbott Laboratories, IL) as previously described [lo]. Serum HBV DNA levels were measured by dot-blot byhridization using a “P&belted HBV cDNA probe with a sensitivity dw~ t? 0.05 pg of DNA. All serum samples in all five patients were tested for HBV DNA, anti-HBc IgM, anti-HDV IgM and IgG antibodies. Serum HDAg Serum HDAg was detected by a western blot method as previously descriheti [ll]. Serial samples from an individual case were assayed together and scored as l+ to 4+ based on the relative intensity of the autoradiograph; every sample that was scored 3s 1+ or greater contained both the 24 and 27 kDa structural HDVproteins. Serum HDV RNA
Serum HDV RNA was tested using “P-labelled sin$-stranded RN.4 probes specific for the HDV genome. The probes were transcribed as follows: A 950 bp EcoRI fragment representing 57% of the HDV genome, was excised from the plasmid pD4 [Ej and inserted in the unique EcoRTl site of pGEM-1 (Promega). Recombinants were selected so
that, after linearization with BarnHI, transcription with I7 RNA noiymerase yielded probes recogrtixing HDV sequencre of genomic polarity. Tits assay is ihat &scribed previously [13] modified as foilows: filters were prehybridiied for 4-6 h at 60 “C in a mixture containing 40% formamide, SXS?C, 8x Denhardt’s soWion, SO mM NaPOG (pH 6.5), 0.1% SDS, 25O&ml salmon sperm DNA, 5Opg/ml yeast tRNA. The hybridization mixture wasprepared adding SO% dextran sulpha?c tothe above mixture to a final concentration of i(s*lc;RNA probes ware ad&d to a final concentration of 1 x 106 cpm/ml and the whole mixture was denatured for S min in boiling wat; nd quickly cooled on ice. Hybridization was carrb outovernight at 60 “C. Filters were then WashCd at room tempratsre 3x25 nin in Z~SSC,O.l% SSC, 0.1% SDS. After drying, filters were exposed for time periods of 16 h to 3 days. Serial samples from an individual case were assayed to8cther and scored as I+ !o 4t based on the relative k:cnsities of the iuttoradiwgraphic bands. &I samples that scored l+ or greater contained both the 1.7 and 2.0 kb forms of HDV RNA.
Fig. 1 shows the course of the serologic and virologic markers measured ia live patients. A temporti association was observed between ammotransferase elevations in all five patients and fluctuations in antiHDV IgM, HDV antigen and HDV RNA. HBV DNA was absent from at1 serum samples in four of the five eases studied. In the fifth patient, HBV DNA and HDV RNA both appeared at the time of aminotransferase elevation and remained present in high quantity for8 months until the Pxti‘;c;t was lost to follow-up. Serum anti-HBc IgM was absent in all serum samples of all five patients.
,981
148
1981
pagelffij and E: the wurse ofserologic viral markersand aminoiransferases in five patients reponed (0. A: AST,ALT; X. 0: I& I& anti-HDV:0, A! HDV
Discussion
Fig. I, A, B. C, D (see
RNA and HDV Ag).
This study shows that patients with chronic HDY infection can suffer episodes of liver injury thet are
S. GOVINDARAJAN
208
associated with serologic evidence of increased HDV replication. Spontaneous elevations of liver enzymes were temporally related to increases in circulating levels of anti-HDV IgM, HDV antigen and HDV RNA. Such episodes were observed as early as 3 months after HDV superinfection, or, less frequently, later in the course of chronic delta hepatitis. They may be multiple. occurring as often as three times over 10 months in one of our patients, and may las? from a few weeks to several months. We believe that such episodes may represent a phenomenon analogous to what is referred to as reactivation in chronic hepati!is B. The possibility of hepatocellular necrosis occurring during these episodes as a result of other superimposed agents such as non-A, non-8 virus infection cannot be absolutely IttIed out. Although none of our patients experienced symptoms of acute hepatitis related to these episodes, these may be relevant to the progressive nature of the liver disease that characterizes chronic HDV infection. We have shown previously that necroinflam-
1 Davis Gt. Hoolnaglc JH. \aggoner JO. Spontaneous reacfiwfion of chronichepatitisB virus infection. Gastrae”terolo8p1984:86: 230-235. 2 Perillo RF, Campbell CR, SanderGE, et al. Sp~nfaneous clearanceand reactivation of hepatitis B virus infection among mate hernesexual~with chronic typz B hepanlis. Ann lntrr,, Med 1984:tw: 43-46. 3 Tong MJ. SamptinerRE, Govindarajan S. et at. Spontaneousreacdvauonof hepntirisB in Chinesepalicmr with HBs.48 positivschronicactivehepariris.tiepatotogy 1987; 7: 713-7ul. 4 Haofnagk JH. DuseheikoGM, Schalar DF, et al. Reactivationuf chronichepatitisB virus infec;ionby can;er chemallcrapy. A”” tntcm MEd 1982;96: ,47-449. 5 R&Eta J. Redckcr P.G. wctity B. Eff\?Ecl of short ‘erm prednisonctherapy on aminotransieraselevels and hep alitis B v.rus markersin chronictype B hepatitis. Gastroenterology15x33; 84: 9x-960. 6 Davis GL. Haofnagle JH. Reaaivadon of cbnric type B hepatitis presentingas acute vrral hepatitis. Ann Intern Med 1985:102:762-765. 7 Rivetto M. The delta agent.Hepatology 1983;3: 729-731. 8 De Cock KM. Govindarajan S. Chin KP. Redeksr AG. Delta hepatitis in the Los Angeles urea. A report of 126
et at.
matory activity on liver biopsy is greatest early on in the course of chronic delta hepatitis. patients with longstanding HDV infection typica!ly having advanced but quiescent disease [14]. Smedile and colleagues have found an association between the presence of HDV RNA in serum and histologic activity on liver biopsy [13]. Patients with quiescent, HDV-
had demonstrable circulating HDV RNA. The serologic findings in the current cases of HDV reacti-ation resemble those of HBV reactivation. Hence, the pathogen&s jf i_‘DV-r-lated liver disease might be similar to that of HBV, namely immune-mediated liver damage [15]. Whether the hepatic damage ir related to the direct cyto-
related cirrhosis rarely
pathic effect of the virus or to the host immune reac-
However, it is clear that in HDV replication described here may play an inrponant role in causing progression of liver disease in chronic HDV infection. tion to the virus is debatable. the spontaneous increases
cases.Ann Intern Mrd 1986:105:108-I 14. 9 Gorindaraian S. Chin KP. Redeker AG. PetersRL. Fulminant B vi& hepatitis. Rote of delta agent. Gastroenterotcgy ,984; 86: t‘lt,-,420. i0 De Cock KM, AshcavaiM. GavindarajanS. Redeker AG. Evaluation of anti-H& !gM estimation on column separatedIgM. Ann Clin !.:b Sci 1987;17: 27-X. Bagmann KF, Gxin JL. Antigensof hepatitisdelta uilus in liver nod serumfrom infectedhanms and animals.3 tnfeet D,s 1986;14: 702-796. 12 Wang K-S. Chow O-L, Weiner Al, it al. Structure, sz. quenceand expressionof the hepatitis delta (d) viral genome.Nature 1986;323: 508-514. 13 Smedik A, Baraudy EM, Bergman”KF, Riuetto M, Pwcell RH, Gerin JL. Clinical significanceof HDV RNA in HDY disease.In: Rizzetto M, Gcrin Jl., Purccl: RH, cd.. The t-lepaais D&s Virus and tts rnfection. New York: Alan R. Liss, 1987:US-242. 14 Gavindsrajan S. De Cock KM, Redeker AG. Natural courseof delta supcrinfenion in chronichepatitis B virus infected patients - histopatholcgicstudieswith multiple liver biopsies.Hepatology 1986:6: MO-M4. 15 New F, Baldi M. Bonino F, et al. ChronicHDV (hepatitis delta virus) hepatitis.Intrahepatlcexpressionof delta antigen, histologicactiwy and ouwome of liver disease.J Hepatot ?988:6: S-14.
II
204
Study of reactivation
of chronic hepatitis delta infection
Antonina Smedile, Kevin M. De Cock, Boontar Valinluck, Allan G. Redeker and John L. Gerin “,li”ersilyofsourlwm carifomia,Liver ““i,, Dwvney,Gl and George*own ““i”,i,, .schoo,ofMedicine “,,dDmrbrry.u,c~“r,le,MU ,U.S.A., (Rcccivcd15November1988) (Accepted21March1989)
Sugantha
Govindarajan,
Five patients with chronic hepatitis delta virus (HDV) infection suffered spontaneous episodes of liver enzyme elevation on a background of otherwise biochemically stable liver disease. In all five patients these episodes were ~conlpanied by a rise in strwn levels of anti-HDV IgM. HDV antigen and HDV RNA. These episodes of increased HDV replication acco:!l@ed by biochemical evidence of live: injury are reminiscent of reactivation in chronic heparitis B. Surges of i?crezscd HDV replication may be important in the pmgression of liver disease in chronic HDV infection.
Introduction Chronic hepatitis B virus (HBV) infection, usually a stable or slowly progressive condition, is sometimes complicated by episodes of virus replication that can mimic acute hepatitis B [l]. Reactivation of this nawe is characterized by abrupt elevation of aminotxwsferase levrls, in addition to an increase in serum levels of HBV DNA and the presence of other markers of HBV replication [2,3]. Although such episodes of reactivation are most often spontaneous, a similar clinical picture may complicate the sudden with-
drawal of immunosuppressive drugs in persons chronically infected with HBV 14-61. Hepatitis delta virus (HDV) is a defective RNA virus which requires the presence of HBV to allow infection [7]. Three clinical categories of disease are recognized, acute I-IBV and HDV coinfection, acute HDV superinfection in an HBV carrier, and established, chronic infection with both agents [S]. We have recently observed episodes of marked spontaneous elevation of aminotransferase leve!s in persons chronic delta hepatitis, reminiscent of HBV reactivation in the chronic HPV carrier state. This
with
Correspondtnce:Supntha Govindarsjan,M.D., Departmeatof Pathology,USC Livx Unit, RanchoLosAmigosMedicalCenter, ii05 GoiondrindsSlrec~.ILL aldg.. Down~y.CA 90242.U.S.A 016%8?781891303.50~ 1989ElswierSciencePublishersB.V.(BvxwdicalDivirion)
REACTIVATION OF HDV
study examines markers of HDV and HBV replication in this previously unreported clinical event. The resuits suggest that chronic HDV infection can undergo episodes of reactivation leading to increased circulating viral markers and accompanying biochemical
evidence
of accte liver injury.
?esients, materials and methuds
Patients were drawn from the weekly Hepatitis Clinic which is held free of charge at the Los Angeles County-University of Sonthem California Medical Center. Patients enrolled had chronic HDV infection, either front first observation in the clinic or as a consequence of HDV superinfection of the HBV carrier state. The serologic profile of HDV superinfection and chronic de!ta hepatitis have been previously described [Sl. Patients selected for further study were those who suffered a marked elevation of alanine aminotransferase (ALT) levels occurring abruptly in the course of an otherwise stable illness. None of the patients were taking immunopressive or anti-viral therapy. Pafient A: (Fig. IA). This patient was a 29.yearold Asian man, who denied risk factors for viral hepatitis, although homosexuality was suepected. ‘While in hospital in March i985 for a pyogenic liver abscess he was noted to be HBsAg pr%ive with a normal ALT value. Anti-delta was not done. In July 1985, during follow-up, the ALT had rised to 1070 IU without jaundice or symptoms. Anti-delta I& was positive; but anti-delta IgM was not detected. The ALT slowly declined and in February 1986 was again normal. HBsAg and anti-delta IgG were still demonstrable. One month later ALT rose to 1255 IU, then decreased to 66 IU in April 1986. With the increase in ALT, anti-delta IgM was detectable, although there was no jaundice or symptoms. HBsAg remained positive throughout the course. Pafiml Z?: (Fi: ZB). This 29-year-old male homosexual was first seen in March 1985. He was not ill hut was found iv be HasAG positive, anti-delta neg ative. He was the sexual partner of a man who had re-
205 cently died with fulminanr hepatitis B. There was no past history of hepatitis. ALT was normal. Three months later he developed mild jaundice and ALT rose to 930 IU. Anti-delta IgG was detectable. Ten months later the ALT rose to I295 IU dnd both antidelta IgM and ‘gCr were present. He remained HBsAg positive throughout the coume. Patient C: (Fig. IC). This Zl-year-old Lebanese man bad lrcently immigrated to Los Angeles to marry his cousin. Four months later in January 1986, he deve1ope.l severe ac!Xe hepatiris. He was HBsAg postive, anti-HBc IgM negative, anti-delta IgM positive and HBV-DNA negative. Prothrombin activity was 10%. His wife was found to be HBsAg and antidelta IgG positive and was presumed to he the source of his delta virus superinfection. On 13 Rbruary 1986, his ALT was 273 IU. but 3 months later was 40 IU. However, in May 1986, the ALT rose again to 1385 IU, falling to 1161U in January 1987. P&w D: (Fig. ID). This patient, a 24-year-old homosexual man, was being followed as an HRsAg carrier after being rejected as a blood donor in September 198I. Anti-delta was negative. In September 1984, he developed a severe acute hepatiiis tith jaundice and ALT of 2868 IU. Ann-delta IgM was now present. A liver biopsy showed positive staining for delta antigen. ALT remained greater than 500 IU for the next 5 months, but in May 1985, was only 66 IU. This then fluctuated over the next ?!h yezs demonstrating two further peak values of 740 and 525 IU. On one of these occasions, the serum bilirubin rose to 7.2 mg/dl (122.4ymohl). HBsAg and anti-de!ta were persistently positive. Patient E: (Fig. 1E). This 2%year-old male hotnosexual developed severe acute hepatitis in November 1981. He wus HBsAg positive, anticore IgM neg. ative. and anti-delta IgM positive then. Two months later he had become anicteric and the ALT was 37 IU. In May I982, the ALT rose to 1155 IU and the serum bilirubin to 3.4 mg/dl. Sii weeks later the ALT was abruptly increased to 975 IU and in 1 month had fallen to 90 III. Again in October 1982, the ALT rose to 710 IU. Subsequently, over the next 2 years, the ALT remained elevated between 150 and 350 IU. HBsAg and anti-delta remained positive.
206
S. GOVllWARAJAN et at.
Serdogic em
Anti-NDV IgM and IgG antibodies were detected by capture radioimmunoassay as previously dcscribed [9]. The strength of the antibody response is expressed as the ratio of the counts per minute of the test serum to those of a negative control (pin ratio), a
positive bring grearer than 2.1. Hepatitis B surface antigen was detected bg commercially available radioimmunoassay (Abbott Laboratories, IL). IgM antibody to hepatitis B core antigen (anti-HBc IgM) was detected by testing column-separated IgM by a commercially available radioimmunoassay for anti-
Fig. I.(Forlegendand lE,seeeappcsirepage.)
KEACIlVAnON
OF
207
HDV
HBc (Abbott Laboratories, IL) as previously described [lo]. Serum HBV DNA levels were measured by dot-blot byhridization using a “P&belted HBV cDNA probe with a sensitivity dw~ t? 0.05 pg of DNA. All serum samples in all five patients were tested for HBV DNA, anti-HBc IgM, anti-HDV IgM and IgG antibodies. Serum HDAg Serum HDAg was detected by a western blot method as previously descriheti [ll]. Serial samples from an individual case were assayed together and scored as l+ to 4+ based on the relative intensity of the autoradiograph; every sample that was scored 3s 1+ or greater contained both the 24 and 27 kDa structural HDVproteins. Serum HDV RNA
Serum HDV RNA was tested using “P-labelled sin$-stranded RN.4 probes specific for the HDV genome. The probes were transcribed as follows: A 950 bp EcoRI fragment representing 57% of the HDV genome, was excised from the plasmid pD4 [Ej and inserted in the unique EcoRTl site of pGEM-1 (Promega). Recombinants were selected so
that, after linearization with BarnHI, transcription with I7 RNA noiymerase yielded probes recogrtixing HDV sequencre of genomic polarity. Tits assay is ihat &scribed previously [13] modified as foilows: filters were prehybridiied for 4-6 h at 60 “C in a mixture containing 40% formamide, SXS?C, 8x Denhardt’s soWion, SO mM NaPOG (pH 6.5), 0.1% SDS, 25O&ml salmon sperm DNA, 5Opg/ml yeast tRNA. The hybridization mixture wasprepared adding SO% dextran sulpha?c tothe above mixture to a final concentration of i(s*lc;RNA probes ware ad&d to a final concentration of 1 x 106 cpm/ml and the whole mixture was denatured for S min in boiling wat; nd quickly cooled on ice. Hybridization was carrb outovernight at 60 “C. Filters were then WashCd at room tempratsre 3x25 nin in Z~SSC,O.l% SSC, 0.1% SDS. After drying, filters were exposed for time periods of 16 h to 3 days. Serial samples from an individual case were assayed to8cther and scored as I+ !o 4t based on the relative k:cnsities of the iuttoradiwgraphic bands. &I samples that scored l+ or greater contained both the 1.7 and 2.0 kb forms of HDV RNA.
Fig. 1 shows the course of the serologic and virologic markers measured ia live patients. A temporti association was observed between ammotransferase elevations in all five patients and fluctuations in antiHDV IgM, HDV antigen and HDV RNA. HBV DNA was absent from at1 serum samples in four of the five eases studied. In the fifth patient, HBV DNA and HDV RNA both appeared at the time of aminotransferase elevation and remained present in high quantity for8 months until the Pxti‘;c;t was lost to follow-up. Serum anti-HBc IgM was absent in all serum samples of all five patients.
,981
148
1981
pagelffij and E: the wurse ofserologic viral markersand aminoiransferases in five patients reponed (0. A: AST,ALT; X. 0: I& I& anti-HDV:0, A! HDV
Discussion
Fig. I, A, B. C, D (see
RNA and HDV Ag).
This study shows that patients with chronic HDY infection can suffer episodes of liver injury thet are
S. GOVINDARAJAN
208
associated with serologic evidence of increased HDV replication. Spontaneous elevations of liver enzymes were temporally related to increases in circulating levels of anti-HDV IgM, HDV antigen and HDV RNA. Such episodes were observed as early as 3 months after HDV superinfection, or, less frequently, later in the course of chronic delta hepatitis. They may be multiple. occurring as often as three times over 10 months in one of our patients, and may las? from a few weeks to several months. We believe that such episodes may represent a phenomenon analogous to what is referred to as reactivation in chronic hepati!is B. The possibility of hepatocellular necrosis occurring during these episodes as a result of other superimposed agents such as non-A, non-8 virus infection cannot be absolutely IttIed out. Although none of our patients experienced symptoms of acute hepatitis related to these episodes, these may be relevant to the progressive nature of the liver disease that characterizes chronic HDV infection. We have shown previously that necroinflam-
1 Davis Gt. Hoolnaglc JH. \aggoner JO. Spontaneous reacfiwfion of chronichepatitisB virus infection. Gastrae”terolo8p1984:86: 230-235. 2 Perillo RF, Campbell CR, SanderGE, et al. Sp~nfaneous clearanceand reactivation of hepatitis B virus infection among mate hernesexual~with chronic typz B hepanlis. Ann lntrr,, Med 1984:tw: 43-46. 3 Tong MJ. SamptinerRE, Govindarajan S. et at. Spontaneousreacdvauonof hepntirisB in Chinesepalicmr with HBs.48 positivschronicactivehepariris.tiepatotogy 1987; 7: 713-7ul. 4 Haofnagk JH. DuseheikoGM, Schalar DF, et al. Reactivationuf chronichepatitisB virus infec;ionby can;er chemallcrapy. A”” tntcm MEd 1982;96: ,47-449. 5 R&Eta J. Redckcr P.G. wctity B. Eff\?Ecl of short ‘erm prednisonctherapy on aminotransieraselevels and hep alitis B v.rus markersin chronictype B hepatitis. Gastroenterology15x33; 84: 9x-960. 6 Davis GL. Haofnagle JH. Reaaivadon of cbnric type B hepatitis presentingas acute vrral hepatitis. Ann Intern Med 1985:102:762-765. 7 Rivetto M. The delta agent.Hepatology 1983;3: 729-731. 8 De Cock KM. Govindarajan S. Chin KP. Redeksr AG. Delta hepatitis in the Los Angeles urea. A report of 126
et at.
matory activity on liver biopsy is greatest early on in the course of chronic delta hepatitis. patients with longstanding HDV infection typica!ly having advanced but quiescent disease [14]. Smedile and colleagues have found an association between the presence of HDV RNA in serum and histologic activity on liver biopsy [13]. Patients with quiescent, HDV-
had demonstrable circulating HDV RNA. The serologic findings in the current cases of HDV reacti-ation resemble those of HBV reactivation. Hence, the pathogen&s jf i_‘DV-r-lated liver disease might be similar to that of HBV, namely immune-mediated liver damage [15]. Whether the hepatic damage ir related to the direct cyto-
related cirrhosis rarely
pathic effect of the virus or to the host immune reac-
However, it is clear that in HDV replication described here may play an inrponant role in causing progression of liver disease in chronic HDV infection. tion to the virus is debatable. the spontaneous increases
cases.Ann Intern Mrd 1986:105:108-I 14. 9 Gorindaraian S. Chin KP. Redeker AG. PetersRL. Fulminant B vi& hepatitis. Rote of delta agent. Gastroenterotcgy ,984; 86: t‘lt,-,420. i0 De Cock KM, AshcavaiM. GavindarajanS. Redeker AG. Evaluation of anti-H& !gM estimation on column separatedIgM. Ann Clin !.:b Sci 1987;17: 27-X. Bagmann KF, Gxin JL. Antigensof hepatitisdelta uilus in liver nod serumfrom infectedhanms and animals.3 tnfeet D,s 1986;14: 702-796. 12 Wang K-S. Chow O-L, Weiner Al, it al. Structure, sz. quenceand expressionof the hepatitis delta (d) viral genome.Nature 1986;323: 508-514. 13 Smedik A, Baraudy EM, Bergman”KF, Riuetto M, Pwcell RH, Gerin JL. Clinical significanceof HDV RNA in HDY disease.In: Rizzetto M, Gcrin Jl., Purccl: RH, cd.. The t-lepaais D&s Virus and tts rnfection. New York: Alan R. Liss, 1987:US-242. 14 Gavindsrajan S. De Cock KM, Redeker AG. Natural courseof delta supcrinfenion in chronichepatitis B virus infected patients - histopatholcgicstudieswith multiple liver biopsies.Hepatology 1986:6: MO-M4. 15 New F, Baldi M. Bonino F, et al. ChronicHDV (hepatitis delta virus) hepatitis.Intrahepatlcexpressionof delta antigen, histologicactiwy and ouwome of liver disease.J Hepatot ?988:6: S-14.
II