JournalofHepatology, 1992; 14: 168-175

168

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HEPAT 00956

Course of hepatitis B and D virus infection in auxiliary liver grafts i hepatitis B-positive patients A light-microscopic and immunohistochemical

study

Fiebo J.W. ten Kate’, Solko W. Schalm2, Pierre J.A. Willemse2, Ary P.R. Blok’, Rudolf A. Heijtink3 and Onno T. Terpstra4 Departments of ‘Pathology, 21nternalMedicine H, 3Viroiogy and 4Surgery, UniversiryHospitaIDijkrigt, Erasmus University,Rotterdam and SDepartmentof Pathology, WesteindeHospital, The Hague, The Netherlands

(Received 26June 1990)

Four patients who received an auxiliary partial liver graft for decompensated liver cirrhosis due to hepatitis B (HBV), associated in two cases with hepatitis D virus (HDV) superinfection, were studied. The sequential appearance of hepatitis B and D antigens in the grafts was investigated in serial liver biopsies by immuno-histochemical methods and compared with the viral antigenic profiles of the host livers. The histological changes in the liver grafts were studied in relation to the viral expression patterns. One week after transp!antation, expression of HBsAg was already apparent in two grafts. HBcAg was found in the graft of the only patient with HBcAg in the host liver. HDAg was expressed in the grafts of both patients with HDV superinfection; in one of these cases HDAg was present without HBsAg. At 3 months, viral antigen expression was maximal. Expression of HBsAg and HBcAg in the grafts of the two HDV-positive patients was, however, less extensive than in the two HBV-positive patients. All patients developed a mild lobular hepatitis, histologically demonstrated between the 47th and 107th posttransplantation day. In the two HBV-positive, HDV-negative patients, cirrhotic tranformation of the graft occurred within 1 year. In the HDV-positive patients only a mild chronic active hepatitis with slight or moderate fibrosis was observed after 1 year. We conclude that recurrence of HBV and HDV infection in auxiliary liver grafts is demonstrable within l-3 weeks. HBV infection in liver grafts may be a rapidly progressive disease. Coinfection with HDV does not aggravate the acute hepatitis and may even suppress the progression of chronic HBV.

Liver transplantation has become an important therapeutic modality for patients with acute and chronic liver failure of various etiologies, including hepatitis B (l-2). A complication of liver transplantation for chronic hepatitis B is the frequent recurrence of hepatitis B or D in the transplanted liver despite passive immunization or antiviral therapy (3-8). The clinical implications of recurrence of the hepatitis B or D infection are not yet entirely clear since preliminary reports range frome excellent tolerance (3,5) to an aggressive disease in which histological cirrhosis develops within less than a year (7). A program for auxiliary partial

liver transplantation was begun in our hospital in October 1986 (9). Five chronic hepatitis B patients with decompensated cirrhosis have received a heterotopic liver graft, four of whom survived beyond 1 month. With this transplantation technique the host liver, and, thus, the source of the hepatitis B infection, remains in situ; therefore, serological viral parameters cannot be used to monitor viral events in the grafted liver. In this prospective study, we used serial liver biopsies to assess the evolution of hepatitis B infection in the auxiliary transplanted livers. Both the various antigens of hepatitis B and D infection and the accompanying histological

Correspondence: S.W. Schalm, Department of Internal Medicine II, University Hospital Dijkzigt, Dr. Molewaterplein 40,3015 GD Rotterdam,

The Netherlands.

HEPATITIS B IN AUXILIARY

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169

changes in the liver tissue were investigated. The possible mechanisms of liver damage due to the viral infection will be discussed.

portions and adjusted 100-200 rig/l..

viral markers in I. patient I exPatient II had Patients III and

Liver transplantation All four patients received an auxiliary partial liver transplant, as descrjbed previously (9). The liver grafts were reduced in size by segment resection of the left lobe. Transplantation was performed with both arterial and portal inflow and venous drainage through the suprahepatic inferior vena cava of the graft into the recipient inferior vena cava as crania1 as possi&e. Biliary drainage was by choledochojejunostomy with a Roux-and-Y loop. Immunosuppressive regimen Prednisolone (25 mg) was administered irr%ravenously prior to surgery and every 6 h during the first 24 h. It was then tapered off to a maintenance dose of 15 mg orally on the 14th postoperative day. Equine antilymphocyte globulin (Institut MCrieux, Lyon, France; 425 lymphocytotoxic units/kg per day) and azathioprine (1 mg/kg i.v.) were given until ihe 7th postoperative day. Cyclosporine A was started on the 6th postoperative day in a dosage of 3 mg/kg per 24 h via a continuous intravenous infusion and adjusted to plasma levels of 200 rig/l (conventional radioimmunoassay, Sandoz, Easel). After withdrawal of the biliary drainage catheter on the 10th postoperative day, cyclosporine A was adminstered orally in a dosage of four times the daily intravenous dose, divided into two daily TABLE

I II III IV

plasma

levels

of

Antibodies Commercially available polyclonal (Central Laboratory of The Netherlands Red Cross Blood Trans Jsion Services, Amsterdam, The Netherlands) and tionoclonal

1

Pretransplant

Patient

trough

Liver biopsies Needle (Tru-Cut R) biopsies of the transplanted livers were taken, according to protocol, 30 min after implantation of the graft and 1 week, 3 weeks, 3 months, 6 months and 1 year after transplantation. At the time of transplantation a needle biopsy of the recipient liver was also taken. Additiond biopsies were obtained in the event of clinical or biocbeKca1 signs of graft dysfunction. Follow-up biopsies of the recipient’s own liver were obtained only occasionally, partly in view of absence of a clinical indication partly in view of the observed atrophy. Part of each liver biopsy was fixed in 10% buffered formalin for routine histologicn! examination; the other part was quick-frozen in isopentane cooled by liquid nitrogen for immunohistochemical studies. For the light-microscopic studies the formalin-fixed tissue was embedded in paraffin, processed and routinely stained with hematoxylin and azophloxin (H and A), periodic acid-Schiff (PAS) with and without diastase digestion, Gomori’s reticulin, von Gieson’s elastin. Perl’s iron, orcein for hepatitis B surface antigen (10) a\d rubeanic acid for copper. For the immunohistochemical studies 4 pr+thick airdried sections of frozen liver tissue were fixed %r 10 min in acetone and tested with fluorochrome-labeled and unlabeled antibodies by the one and two-step immunofluorescence methods, respectively, as well as with peroxidase-labeled and unlabeled antibodies by the one and respectively methods, immunoperoxidase two-step (Table 2).

Patients and Metlm Patients Pretransplant data on liver disease and liver tissue and serum are given in Table hibited no signs of active viral replication. HBV with signs of active viral replication. IV had an HDV superinfection.

to

demographic

Age!sex

36/M 51lM 32/M 411M

data, liver disease and viral HBV and HDV Pretransplant

Viral markers liver

liver disease

cirrhosis (micro) + CAH moderate dysplasia cirrhosis (macro) + CAH cirrhosis (macro) + CAH moderate dysplasia cirrhosis (macro) + CAH severe dysplasia

markers

____-

HBsAg

HBcAg

+ -I-

+

+

-

+

serum HBsAg

HBeAg

DNAp

aHD

+ +

+

-I-

-

+

+

-

-

+

+

+

-

HDAg

+

F.J.W. TEN KATE et al.

170 TABLE 2 Methods for immunohistological study of liver biopsies Antigens tested

Method

Antibody

Source

HBsAg HBsAg HBcAg HBeAg HDV

dIF iIF/iIP iIF/iIP iINiIP dIF/dIP

Pab Mab Mab Mab Pab

C.L.B. Organon Organon Thomas Rixzetto

dIf, direct fluorescence method; dIP, immunoperoxidase method; iIF, indirect fluorescence method; iIP, indirect immunperoxidase method; Pab, polyclonal antibody; Mab, monoclonal antibody.

Thirty-minutebiopsies The biopsies taken from the liver graft 30 min after recirculation showed only minor light-microscopic changes. HBsAg, HBcAg, HBeAg and HDAg could no? be detected in any of these biopsies. One-week biopsies Light microscopically all biopsies showed an acute cholangiolitis with moderate centrilobular hepatocellular and

Delta negative patients Patient

(kindly provided by Organon, Oss, The Netherlands) antibodies against HBsAg were nA;edto detect hepatitis B surface antigens. For detection of HBcAg and HBeAg monoclonal antibodies were kindly provided by Organon (antiHBc) and H.C. Thomas (antiHBe); HDAg was assessed by a polyclonal human antibody kindly provided by M. Rixzetto (antiHD). The monoclonal antiHBe antit fody was negative for antiHBc in the standard radioimmunoassay (Corab, Abbott, U.S.A.). Similarly the monoclonal antiHBc antibody was negative in the radioimmunoassay for antiHBe (Abbott, U.S.A.). Nonimmune serum was substituted for the primary antibody to obtain a negative control for each staining procedure; no staining occurred. Liver tissues from seropositive patients with chronic hepatitis B and D were used as the positive controls,

I

Patient ii

Delta positive patil?nts Patient !!I

Patient IV

ONE WEEK GRAFT BDPSY

THREE WEEK GRAFT BIOPSY _

THREE MONTH GRAFT BIOPSY

SIX MONTH GRAFT BIOPSY

Results

Recipientliver biopsies Biopsies taken from the recipient’s liver during the auxiliary liver transplantation procedure showed a mixed micro/macronodular cirrhosis combined with chronic active hepatitis in all cases. In all four livers moderate to severe dysplastic changes were seen in the hepatocytes in some parenchymal nodules. Immunohistochemical studies revealed HBsAg expression along the membranes of almost all hepatocytes in all four biopsies; in three (patients I, II and IV) of the four biopsies intracytoplasmic HBsAg expression was observed in some nodules.

HDAg could be detected in about l-5% of the hepatocytic nuclei in two biopsies (patients III and IV). Neither HBcAg nor HBeAg could be demonstrated in either of these biopsies. One biopsy (patient 11)contained HBcAg and HBeAg. HBcAg, HBeAg and HDAg were not present in the biopsy from patient I.

AAA =HBsAg *** 0 0 0

=HBcAg = Delta-Ag

Fig. 1. Schematic drawing of HBV and HDV expression patterns in serial liver biopsies from livers transplanted into two HBV-positive (I and II) and two HDV-positive (III and IV) patients. The number of symbols in an area indicates the intensity of staining; the proportion of the nuclear or cytoplasm surface area with symbols reflects the percentage of hepatocytes in the liver biopsy positive for the HBV and HDV antigens.

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171

canalicular cholestasis in all cases. Only mild liver cell necrosis with scattered Councilman bodies was present; characteristic signs of acute rejection (11) were not found. Hepatitis B surface antigens could be detected in two of the four biopsies (Fig. 1). Only patient I, who exhibited no signs of active viral replication before tra~s~lantati~~, did not test positive for any of the In patients III and IV, who prior to transplantation, HDAg was pres respectively, of the hepatocytic nuclei, detected in either biopsy. In the biopsy from patient II, who exhibited active hepatitis B replication prior to transplantation, weak nuclear cAg fluorescence was detected in sporadic hepatocytes.

BsAg fluorescence. In the two I-l atients a large proportion of the h tocytes also exto moderate cytoplasmic sAg staining. In eAg were expressed in more tocytes, partly in tbe nucleus and partly in the cytoplasm. In t&e two DV-positive patients Ag was detected in about 50% of the hepatocytes, mamly in the nuclei. In addition, HBcAg was demonstrated in both the nucleus and the cytoplasm in patient IV.

The biopsies from the HBV-positive, HDV-negative patients showed an ongaing acute hepatitis, with focal hepatocyte necrosis. In patient II this acute (lobular) hepSitis was combined with periportal hepatitis. The HDVpositive patients sbowed mild chronic active hepxitis, accompanied by mild ch~~a~g~o~~t~s in patient III. Ali patients exhibited various degrees of fibrotic changes (Fable

Three-week biopsies In all cases a mild acute cholangiolitis, together with a mild lobular cholestasis, was still present. In one biopsy round cell invasion of the bile ductules was consistent witn the development of grade I graft rejection (patient IV). All biopsies contained viral antigens. IIBsAg was detected in a linear pattern along the ceil membranes of all hepatocytes. Only in the biopsy from patient IV was HBsAg found in the cytoplasm of a small proportion of the hepatocytes. WBsAg occurred in combination with HBcAg and HBeAg in the nucleus of a sporadic hepatocyte in patient I and in the cytoplasm of about 40% of the he patient II (see Fig. 1). In patients III and IV combined with nuclear accumulation of HDAg; IIBcAg could not be detected.

3). Viral autngen expression was similar to or less than that observed at 3 months. In the biopsies from patients 1 and II, liccar HEsAg deposits along the cell membranes were combined with intracytoplasmic sAg expression in marry hepatocjries. I-IBcAg and HBeAg were detected in 50-961% of the hepstocytes with varying amounts in the nucleus and the cytoplasm. The biopsies from the I-IDVpositive patients revealed I-IDAg together with I-IBcAg and I-IBeAg. I-lDAg was present in 50% of the hepatocytes but restricted to the nucleus in patient IV. In patient III cytoplasmic NDAg expression was marked, while I-IDAg was found in only a small percentage of the hepatocytic rmclei.

Three-mwnth biopsies Histologically three of the four biopsies were characterized by a lobular (acute) hepatitis with necrosis of many scattered, mainly centrolobular, hepatocytes. In one biopsy (patient I) only minimal changes were observed. Viral antigen expression was maximal at this time. All ffour biopsies showed a bright linear cell membrane-

One-year biopsies The biopsies from both I-IBV-positive, HDV-negative patients showed severe fibrosis with cirrhotic transformation of the hepatic parenchyma. The fibrous septa contained only an inconspicuous aspecific inflammatory infil-

TABLE 3 Evolution of liver graft liistology Patient

Type of infection One week F

I II III Iv

HBV HBV HBV HDV HBV HDV

H

Three weeks --H F

--Three months _._--_ H F + +

-

+

-

+

-Six months F

One year

H

F

H AH+CAH CAH moderate CAH slight CAH slight

AH AM

+ +++ f

AH AH+CAH CAH slight

++++ +++ + ++

AH

++

CAH slight

++

H, hepatitis; F, fibrosis; AH, acute hepatitis; CAH, chronic active hepatitis (periportal); +, slight fibrosis,. + + , moderate fibrosis; + + +, severe fibrosis; + + + + , cirrhosis.

F.J.W. TEN KATE et al.

172 trate. In the parenchymal nodules the hepatocytes were enlarged due to the abundant finely granular cytoplasm, that reacted positively to HBsAg antibodies. HBsAg-positive ‘ground-glass’ hepatocytes were present sporadically in patient I and in abundance in patient II. There was extensive HBcAg and HBeAg expression located in the nucleus as well as the cytoplasm of about 80% of the hepatocytes in patient I and mainly in the nucleus of about 40% of the hepatocytes in patient II. This nuclear localization of HBcAg and HBeAg in patient II is a reversal of the mainly cytoplasmic localization in the &month biopsy (Fig. 1). In contrast to the cirrhotic transformation found for both HBV-positive, HDV-negative patients, moderate fibrosis was the most severe change seen in the biopsies from the HDV-positive patients. Both HDV-positive patients exhibited signs of a mild chronic active hepatitis. Ground-glass hepatocytes could not be detected. HBsAg was found along the cell membranes of the hepatocytes; in patient II it was also visualized in the cytoplasm. For patient III, the numbers of HBcAg- and HDAg-positive cells and the antigen distribution patterns were essentially the same as in the sixmonth biopsy. In patient IV, the number of HDAg-positive hepatocytes had clearly diminished, whereas HBcAg and HBeAg expression remained constant (Fig. 1).

Incidentalbiopsies Due to a rise in the bilirubin and/or serum aminotransferase levels of unknown cause, four non-protocol biop sies were obtained from three of the four patients (I, II and III). A 65-day biopsy from HDV-positive patient IV showed histological signs of mild (grade 1) rejection based on a slight cholangitis combined with venous endothelialitis. In addition, the hepatic parenchyma contained several scat= tered Councilman bodies. This biopsy showed HBcAg in about 10% of the hepatocytes, mainly in the nucleus but sometimes also in the cytoplasm. HDV-positive patient IV underwent a biopsy on days 51 and 69. On day 51 the mild light-microscopic changes in the hepatic lobuli were considered with an early acute hepatitis, whereas on day 69 the picture had progressed to a lobular hepatitis with many scattered Councilman bodies. On day 51 nuclear HDV expression in about 70% of the hepatocytes was combined with nuclear and cytoplasmic localization of HBcAg and HBeAg in about 30% of the hepatocytes. On day 69, HBcAg had increased and was present in the cytoplasm of about 40% and in the nucleus of about 70% of the hepatocytes. HDV was present in about 50% of the hepatocytic nuclei. A 47-day biopsy from patient II showed cholangiolitis and also a mild lobular hepatitis component. HBsAg ap-

Fig. 2. One-year biopsy from a HBV-positive, HDV-negative patient (I). Note the completely disturbed liver architecture (PAS 60.X).

HEPATITIS

B IN AUXILIARY

LIVER GRAFTS

I73

Fig. 3. One-year biopsy from a HBV-positive, HDV-positive patient (III). Note the only slightly enlarged portal tracts (PAS 60x).

peared as a bright fluorescence pattern along the cell membranes of the hepatocytes and occasionally in the cytoplasm. HBcAg and HBeAg were found in the cytoplasm of nearly all hepatocytes and in the nucleus of only a small proportion of the hepatocytes.

Discussion After auxiliary partial liver transplantation the liver grafts of all four patients showed recurrence of HBV infection together with HDV infection in the two HDV-positive patients. Recurrence of HBV infection in the HBeAg-negative patients and HBV and HDV infection in the HDV-positive patients is consistent with the findings after orthotopic liver transplantation. In these latter patients ‘dormant’ HBV is presumably reactivated. Recurrence of viral infection was already apparent in the one-week biopsy in three of the four patients. For the HBV-positive, HBeAg-negative patient, however, recurrence could not be demonstrated until the three-week biopsy. Apparently this difference in recurrence time has to be explained by the time necessary for reactivaticn of the HBV infection. What actually triggers reactivation is not clear.

The early signs of an HBV infection are localization of HBsAg along the cell membranes of hepatocytes combined with HBcAg and HBeAg expression in a sporadic hepatocyte. An explanation for the early appearance of the diffuse HBsAg expression is a nearly simultaneous HBsAg production in all hepatocytes following infection of the hepatocytes by the hepatitis B virus. In sue! a case the synthesis of HBsAg proteins proceeds more rapidly or more abundantly than the synthesis of HBcAg and HBeAg proteins. In support of this hypothesis is the fact that HBsAg can already be detected in serum on the third day after inoculation of experimentally infected ducklings (12). Moreover Krugman et al. (13), who studied the natural history of hepatitis B infection in children inoculated with the MS-2 strain of hepatitis virus, found an interval of only 6 days between exposure and the appearance of HBsAg in serum. The diffuse expression of HBsAg on the hepatocyte cell surfaces was obviously not accompanied by increased destruction of hepatocytes, as indicated by the absence of lobular hepatitis in these early biopsies. On the contrary the liver cells exhibited high regenerative activity, as indicated by the numerous mitotic figures in the hepatocytes (14). Although HBsAg was detected mainly along the cell membranes of the hepatocytes in the

F.J.W. TEN KATE et al.

174 early reinfection phase (l- and 3-week biopsies), later it also appeared together with HBcAg in a diffuse pattern in the cytoplasm of the hepatocytes of the HBV-positive, HDV-negative patients. Typical HBsAg-positive groundglass cells did not appear in biopsies from the two HBVpositive, HDV-negative patients until the 6-month biop-

sies. In the two HDV-positive patients, HDAg appeared before or simultaneously with HBsAg and long before HBcAg; HDAg was already present ownthe 7-9th posttransplantation day (Fig. 1). In one of the HDV-positive patients viral recurrence was demonstrated only by the presence of HD viral antigens in 40% of the hepatocytic nuclei without concomitant HBV markers. This observation, also reported by others (15), suggests infection and replication of HDV in liver cells without obvious help from the hepatitis B virus. In all livers an acute lobular hepatitis developed between the 47-107th day. This acute hepatitis coincided with marked expression of HBcAg in the liver tissue, located in three of the four biopsies mainly in the cytoplasm and less obviously in the nuclei. This distribution pattern differs from that seen in livers with chronic persistent or chronic active hepatitis, in which HBcAg occurs predominantly in the hepatocytic nuclei. Possibly of major interest is the observation that the active hepatitis was characterized by necrosis of scattered hepatocytes which was not accompanied by a distinct inflammatory infiltrate. The concomitant appearance of HBcAg and necrosis of hepatocytes in the virtual absence of an inflammatory infiltrate suggests that a direct toxic effect of cytoplasmic HBcAg rather than immunological events plays a role in the pathogsnesis of viral hepatitis B in these patients. Cellular immunological mechanisms are also less likely because rejection phenomena were not prominent in any of the biopsies, indicating adequate suppression of the cellular immune system. In all patients the acute hepatitis ultimately changed into a mild chronic active hepatitis. Similar to the finding of a progressive hepatitis B infection in immunosuppressed renal (16,17) and orthotopic liver (6) transplant recipients, the two HBV-positive, HDV-negative pa-

l Corman JL, PutmanCW, IwatsukiS, et al. Liver allograft: its use in chronic active hepatitis with macronodular cirrhosis. Arch Surg 1970; 114: 75-8. 2 Maddrey WC, van ThieI DH. Liver transplantation: an overview. Hepatology 1988; 8: 948-59. 3 Demetris AJ, Jaffe R, Sheahan DG, et al. Recurrent hepatitis B in liver aIIograft recipients. Am J Path01 1986; 125: 161-72. 4 PortmannB, G’Grady J, ?Nilliams R. Disease recurrence following orthotopic liver transplantation. Transplant Proc 19%; 18:

tients in this study developed liver cirrhosis within 1 year. It seems likely that enhanced replication of the hepatitis B virus, especially in the event of expression of HBcAg and HBsAg in the cytoplasm of hepatocytes, is an important factor of hepatocyte necrosis which may be due to a direct toxic effect of the virus or viral components on the hepatocyte, The cytoplasmic localization of HBcAg in patients with aggressive disease was also stressed in the study of Hsu et al. (18). We suggest that hepatocyte necrosis in

hepatitis B might be attributable to two different mechanism; in the natural course of a hepatitis B infection, a Tcell-mediate J immune mechanism against membranebound HBV antigen plays the important role in hepatocyte destruction; in case of an immunosuppressed patient a direct cytotoxicity can occur when viral replication is high. The very early appearance of HDAg in the liver transplants, not associated with major morphological changes, and the mild course of the hepatitis D infection makes a direct toxic effect of HDV or HDAg unlikely. The two HDV-positive patients in this study (especially patient III who showed minimal HBcAg expression) exhibited little architectural liver damage after 1 year. This relatively favorable course can be explained by suppression of HBV by HDV (19). The course of the HBV/HDV coinfection in these immunosuppressed patients is in marked contrast to the relatively severe natural course of an HDV infection. Immunological mechanisms may, therefore, play a role during the HDV infection and imrrunosuppression may need to be reevaluated, despite the findings of Rizzetto et al. (20) who could not demonstrate a beneficial effect of standard immunosuppression in HDV-positive patients.

Acknowledgements

We would like to thank Professor V.D. Desmet for his critical comments. The authors are indebted to Johan van Lier for technical assistance, and Christien Tulling, who typed the manuscript.

136-41. 5 Lauchart W, MiiIIer R, PichImayr R. Immunoprophylaxis of hep-

atitis B virus reinfectionin recipients of human liver aUografts. TransplantProc 1987;19:2387-9. 6 Van Thiel DH. Liver transplantation for viral disease. In: Update on Hepatic Transplantation. American Association for the Study ofLiver Disease syllabus, Chicago; 1987. 7 Rizzetto M, Chiaberge E, Negro F, et aI. Liver transplantation in hepatitis Delta virus disease. Lancet 1987; ii: 469-71. 8 Samuel D, Z&ego L, Fabiani B, et a1. Medium terms results of liver transplantation in cirrhosis due to hepatitis Delta virus

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(HDV) infection. J Hepatoll988; 7(Suppl): 75. 9 Terpstra OT, Schalm SW, Reuvers CB, et al. Auxiliary partial liver transplantation for end-stage chronic liver disease. N Engl J Med 1988; 319: 1.507-11. 10 Shikata T, Uzawa T, Yashiwara N, Akatsuka T, Yamazaki S. Staining methods of Austealia antigen in paraffin sections. Detection of cytoplasmic inclusion bodies. J Exp Med 1974; 44: 25. 11 Snover DC. The pathology of acute rejection. Transplant Proc 1986; 18: 123-7. 1L Freiman JS, Allison JR, Dixon RJ, et al. Experimental duck hepatitis B virus infection: pathology and evolution of hepatic and extrahepatic infection. Hepatoiogy 1988; 8: 507-13. 13 Kmgman S, Overby LR, Mushahwar IK, Lmg CM, Frosner GG, Deinhardt F. Vial hepatitis type B. Studies on natural history and prevention. Re-examined. N Engl J Med 1979; 300: 101-6. 14 Wiiemse PJA. Ausema L, Terpstra OT, Krenning BP, ten Kate FJW, Schahu SW. Graft hypertrophy and host liver atrophy after auxiliary portal liver transplantation for chronic liver failure. Hepatology 1991; in press. 15 Rizxetto M, Canese MG, Purcell RH, London WT, Sly LD, Gerin JL. Experimental HBV and delta infections of chimpanzees: occurrence and significance of intrahepatic immune complexes of

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16

17 18

19

20

hepatitis B core antigen and delta antigen. Hepatology 1981; 1: 567-79. Parfrey PS, Forbes RDC, Hutchinson ‘IA, et al. The impact of renal transplantation on the course of hepatitis B liver disease. Transplantation 1985; 39: 610-S. Parfrey PS, Forbes RDC, Hutchinson TA. The climcal and pathological course of hepatitis B liver disease in renal transplant recipients. Transplantation 1984,37: 461-6. Hsu HC, Lin YH, Chang MI-I, Su IJ, Chen DS. Pathology of chronic hepatitis B virus infection in children: with special reference to the intrahepatic expression in hepatitis B virus antigen. Hepatology 1988; 8: 378-82. Chen P-J, Chen D-S, Chen C-R, Cnen Y-Y, Chen H-MI-I, Lai MY, Sung J-L. 6 Infection in asymptomatic carriers of hepatitis B surface antigen: low prevalence of delta activity and effective suppression of hepatitis B virus replication. Hepatology 1988; 8: 1121-4. Rizxetto M, Verne G, Reechia S. Chronic HBsAg hepatitis with intrahepatic expression of delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98: 437-41.

Course of hepatitis B and D virus infection in auxiliary liver grafts in hepatitis B-positive patients. A light-microscopic and immunohistochemical study.

Four patients who received an auxiliary partial liver graft for decompensated liver cirrhosis due to hepatitis B (HBV), associated in two cases with h...
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