A patient suffering from chronic active hepatitis with macronodular cirrhosis, positive for hepatitis B surface antigen (HBsAg), was treated with an orthotopic liver allograft. The HBs antigenemia, as measured with several precipitation tests and by complement fixation, became negative after transplantation and remained so for about 2½ months. During the interval, very low titers of the antigen were detectable by radioimmunoassay. At about three months after transplantation, she had an attack of acute hepatitis, at which time HBsAg became detectable by all tests. She recovered, but progressive liver disease developed during the remaining 1½ years of her life. She died of disseminated nocardiosis and candidiasis with deteriorating hepatic function. The homograft at autopsy showed no evidence of rejection, but was the site of chronic active liver disease, although of a different pathologic pattern than that affecting her native liver. The differences in histology may reflect the influence of chronic immunosuppression on the features of chronic active hepatitis. © 1979, American Medical Association. All rights reserved

Corman, JL

Iwatsuki, S

Peters, RL

Porter, KA

Putnam, CW

Redeker, AG

Schröter, G

Starzl, TE

English

PubMed

D-Scholarship@Pitt

""3t1 \ ~iver Allograft .:. .,- ..... Its Use in chronic Active Hepatitis With Macronodular Cirrhosis, Hepatitis B Surface Antigen ,arq'* L Corman, 110; Charles W. Putnam, 'MD; Shunzaburo l,..atsulti. MD; AJIan G. Redeker, ND; K. A. PONr, MD; Robert L. Peters. MO; ~rbaq4 Scbr6w, NO; Thomas E. Starzl, MD, PhD • A palient .uflerlng Irom chronic active hepalltla with ""CJonodular cirrhosis, positive lor hepatitis 8 surface anllien (HB"A;), was treated with an orthotopic nve, allograft. The HB. -"rlSlenemla, as measured with several predpltalion lests and by complement nutlon, became negative aHer transplantation and remained ao lor about 2% months. During the Inlerval, very low IterS of the anllgen were'delectable b, radlolmmunoa~uIK AI abOut Ihree months aner transplantalion, ahe had an anack 01 .calle hepatHls, at which time H8"Ag became detectable b, all tests. She recoyered, but progressive Jlver disease de"eloped during the remaining 1% years 01 her life. She died ~f disseml-naled noclrTdiOSls and candidiasis wllh delerloraling hepatic ~nctionK The homograft at autops, showed no e"idence 01 .ejection, but was the site of chronic active liver disease, although of a different palhologlc panern Ihan Ihal aHecting her naUve Jiver. The dlNerences In histology may reneel the Innuence cI chronic Immunosuppression on the features of chronic acllve hepatitis. (Aleh SUIg 114:75·78,1979) In K~u~st 1970, a patient with end-stage chronic aggres-sh'e hepatitis and cirrhosis, hepatitis B surface antigen IHB.Ag)' positive, was treated at the University· of Colorado Medical Center, Demer, by total replacement of the lh·er. Her dinical course is reported and discussed in this report, with particular reference to the inf~ction of the new liver by the hepatitis B \"irus. . REPORT OF A CASE 1n 1964, a 22·year-01d v.·oman, a cbronic intra"enous drug user, -'U admitted to a Los Angeles hospital with acute "hepatitis. She ,\n· .. ptcd for publication 1Iiay 16.1978-Trom \M fepanm~ny of purg~ry (Dn Corman. Putnam. h ... t.suki, Schreter. anel SUrzl). Un;"rnity of Colorado Mrdical unLtr. aen~rr; the ffK-g~"m~nD of Medicine, Uni\enit)" of &!uth.,m Californi •• Rancho. Lm "",;,01 HospiLal, Do,,·n.,y (Dr gf~d~hrF; thr a~partm~ny of Patholor:r. St '!ary·. HospiLaI Medical School. London (prof PorlA!r); Ind a~partmtnt of hth01ocr, John "D·e~lry HospiLaI. Los ADlrlrs (Dr Peten). Dr Corman ia :.o.r with L 1Jnh'ersite d~ )Iontrral. HopiLaI Notre·Dame; Dr Polllam the ~"ment of Surlery. Tocson (AnI) Veterans Administration Hospital; K~ Dr h .. atsuki the atparlm~nt of Surlery, io~Dola Uni-·tlS;t}" )hdical (" cr.' .. r. )fay ... ·ood. Ill. . '-li.lint nqutSts t.o a~pan m~nt of Surl.ry (BoJ: C305). t!ni\"trsity of C';'J"'.c1o !lltc1ical UnLtr. 4200 E Ninlll An, a~gfy"tDrK CO 80262 (Dr b •. ,]}. 'Jch Surg-Vol ,,.., Jan 1979 appeared to recover fully, but five yean later,jaundiee and ascites developed and she W.IS admitted to the Universit)' of Southeru California Liver Unit, John Wesley Hospital, Los Angeles. Tbe HB.Ag was positive by cOunt.ere1ec:trophoresis (CEP). .A liver biopsy spedmen '·as taken in 1969. At that time, the lobular architecture was comp1etel)' distorted by large discrete regenerative nodules.. There were scattered foci of hepa\.ocytolysis SWTOUndec1 br lymphocytes. )5any of the hepa\.ocyt.es .. ·ere banooned. The biopsy specimen was considered to represent a coarsely nodular cirrhotic liver in a relatively quiescent stage of chronic active hepatitiL (h;er the next year, there "'as progressi\le deterioration of liver function, necessitating several admissions to the hospital for the treatment of ascites, hepatic encepha10path)·, and gastrointestinaJ bleeding. In early August 1970, the patient ""as transferred to the Unh-ersity of Colorado Medical Center, Den\'er, for lh'er trans-plantation. She had massive ascites, bnateral pleural effusions, and jaundIce. The laboratory findings (Fig 1) were typical of adunced cirrhosis, sho .. ;ng the foDov.·ing le,·els: serum total bilirubin. 6." mg/dl (direct. 4.6 mg/d!); SGOT. 240 JU; and alkaline phosphatase,330 IU. TIle prothrombin acth;ty was less than 2O'i. 'The serum albumin level "'as 1.9 i/dl. and the f>erum globulin level was 4 g/d!. On Aug 9. 1970, she unde,..",'ent total hepatectomy, orthotopic lh·u transplantation.' and splenectomy. The procedure was made difficult by the portal hypertension and numerous "enous collaw-alL During the operation, she required 18 units of blood. aD of .,,·hich "'ere negati"e for HB.Ag antibody by CEP. Aliquots of the transfusion blood were not '-ept for subsequent radioimmunoas.-say. The t'"dst'd lher weighed 688 g (Fig 2). Jts lobular pattern " .. as entirely distorted by bulging ..... ell·defined. 0.5 lo 0.6 cm-regener-ath'e nodules separaLed by loose connective tissue septa. }di~ s<:opicaJly, the discrete nodules were made up of markedly hychop-it hepa\.ocl1.es v."ith "esicular nuclei. There .·ere only occ:asionaJ foci of hepat.oc:ytolysis, and most of the lymphocytic and plasma-cytic infiltrates were confined to the loosel)' arranged fibrous septa. Kuptru uns "'ere only moderately prominent. Postoperath'ely, she '''IS treated .;th a triple "rug immunosup-pressiv~ program consisting of aZathioprine or cyclophosphamide, prednisone. and horse antilymphocyte globulin'" (Fig i). Despite . her poor condition prior to transp1anlation. the early conules-cence ""as une\"l:ntful and the patient was di~harged from the hospital 32 "ays afler the operation. Postoperath-ely, HB .... ' "'as Liver Homo1ransplilnla\ion-Cormiln et al 75 1 not detectable by CEP or agarose gel immunodiffusion (AG). Eighty days after transplantation, she was readmitted to the hospital with malaise, fever, arthralgia, and anorexia. There was a marked increase in the levels of the serum albumin, SGOT, and alkaline phosphatase (Fig 1); prothrombin activity was 50% of normal. Because of the reappearance of AG- and CEP-detectable HB.Ag, this illness was thought to be acute viral hepatitis. rather than a rejection episode. and her program of immunosuppression was therefore not altered. During the ensuing few weeks. there was further deterioration of hepatic function, and ascites was transiently present. Her condition then gradually improved, with return of the liver function test values to essentially normal levels (Fig 1). A needle biopsy of the liver was taken in September 1971. approximately 13 months after transplantation and ten months after the episode of acute hepatitis. Microscopically. this specimen showed a decidedly atypical pattern. with regularly arranged but more closely approximated portal structures from which irtsidious arachnoid collagen fibers extended varying distances into the lobules. The cord pattern was completely effaced by the hydropic parenchymal cells that formed irregularly distributed clusters of cells that bulged against adjacent areas of less swollen hepatC}o cytes. The central veins were difficult to find. but were normal when found. There was only a modest increase of cells in the portal areas. consisting mostly of duct epithelial cells. fibroblasts. endC}o thelial cells. and a few lymphocytes and plasma cells (Fig 3). The bloated hepatocytes had vesicular nuclei with prominent AG SGOT (I. U.) ALKALINE PHOSPHATASE (I.U·) BILIRUBIN (mg%) TOTAL-CONJUGATED •.•• + + + + • III(GATlII( 5000 4000 3000 2000 1000 0 400 300 200 100 0 15 10 nucleoli. Inflammatory infiltration into the lobule was meager, but there were occasional relatively inconspicuous clusters of Kupffet cells and a rare eosinophilic body, but no other frank necrosis (Fir 4). Vascular structures in portal areas were not sclerotic. It wa. thought that the pattern probably represented an early stage of chronic active hepatitis. modified by immunosuppressive the", py. Soon after this. the patient was readmitted to the hospital with fever and headaches. A complete neurological evaluation wa. normal. A month later. Nocardia cuteroides was isolated frol1la skin nodule, and she was treated with sulfonamides.' She Wa. subsequently readmitted to the hospital on several more occasiolll with headaches and fever. By January 1972. seventeen montba after transplantation. her liver function had deteriorated (Fill) with recurrence of jaundice and ascites. In late Marcil 1972, foeaj neurologic signs developed. Craniotomy was performed. reveali'l multiple intracerebral NOt:ardia abscesses. Liver function conti .. ued to worsen. and she died of hepatic failure and neuroloric dysfunction on April 21. 1972, twenty months after transplanta. tion. At postmortem examination, multiple Nocardia asteroidt, and Candida albicans abscesses were found in the brain. heart, lungs. liver, and kidneys. The allografted liver at autopsy weighed 1.120 g. Since the liver was obtained from a male donor who weighed more than 70 kg, it. weight at the time of transplantation was estimated to have heeD 1,800 g, based on.a liver weight/total body weight ratio of 2.5'l. The surface of the allograft had a fine. sandpaper appearance (Fir + + + + + + + SERUM ~+-___ ~ ____ -L __ ~~=-____ am~~~~~~~~~~~ OR PROTEIN 41 TOTAl- 4 ALBUMIN ._--- 2 -" __ _ ----------------~ ------ ....... _- .. - - .", .... J" ... r GLOBULIN - - - zog +----r---------------------;KKKK-=-"-~-;KK;;-=-;K::-=::K::-=D-----------D-----D-=-AZATHIOPRINE _ 100 CYCLOPHOSPHAMIDE E::::l 0 (mg) 100 PREDNISONE (mg) f • PREDNI SOlONE (lg. i. y.) AlG 100 300 400 TRANSPLANTATION (8/9110) TIME IN DAYS Fig 1.-Clinical course of patient before and after liver replacement. AG indicates agarose gel immunodiffusion test for hepatitis B surface antigen; ALG. antilym-phocyte globulin. 500 600 18 Arch Surg-VOI114. Jan 1979 Uver Homotransplantation-Ccuman Fig 5.-that Ih structL • !±&L -Cormall ll All 2.-Cut surface of shrunken nodular liver removed at time of pnsplantation on Aug 9. 1970 (x 2.4). Fig 3.-Uver biopsy specimen taken of allografted liver ten months after appearance of elevated transaminase activity and hepatitis in B surface antigen serum. Note widened portal tracts and bloated hepatocytes with very little lobular Inflammatory infiltrate (hematoxylin-eosin. x 120). Fig 4.-High-power photomicrographs of liver biopsy specimen shown in Fig 3. Hepatocytes are hydropic and nuclei are enlarged. with finely divided chromatin. Left. Eosinophilic body (arrows) is shown. Right. Focus of hepatocytolysis (arrows) filled with swollen Kupffer cells. macro phages. and a few lymphocytes (hematoxylin-eosin. x 600). FIg S.-Cut surface of allografted liver removed at autopsy. Note that liver. although toughened. is not CirrhotiC. and that portal Itructures are regularly distributed ( x 2.4). Arch Surg-Vol 114. Jan 1979 Fig S.-Photomicrograph of allografted liver at autopsy. There are no fibrous septa incorporating portal areas (P). CentrHobular areas (C) are obliterated by fibrosis and there is diffuse interstitial fibrosis with collagen enveloping hepatocytes. (hematoxylin-eosin. x 240). liver Homotransplantation-Corman et al 77 I! , I I , I I ! Ji). The parenchyma was toughened. but the lobular architecture was intact (Fig 5) and the liver was not truly cirrhotic. Microscop-ically, there were no regenerative nodules. The portal and central areas had a proper relationship to one another. However. there were fine collagen fibers that extended throughout the sinusoids. enveloping segments of hepatic cords that were arranged in restricted, acinar-like structures (Fig 6). The short hepatic cord structures were not arranged in a radial fashion. but were in disarray, The centrilobular areas had many finely foamy hepato-cytes, with the vesicles ranging from about 1 to 3 It. Canaliculi were dilated with bile plugs. Kupffer cells were numerous and had unusually abundant cytoplasm. There was no exudate into the lobules, nor was there inflammatory hyperplasia in portal ~onsK Serologic Studle. During the patient's hospital course. mUltiple serum s~imens were tested for the hepatitis B antigen in laboratories at the Universities of Southern California and Colorado by a variety of techniques, incIudingmicro-Ouchterlony agarose gel immunodif-fusion, counterelectrophoresis, and complement fixation (CF) and radioimmunoassay (RIA).' Serum specimens tested in California at intervals during the year prior to transplantation were all positive (Fig 1) for HB,Ag by AG and CEP. These findings were confirmed in the same samples at the Colorado laboratories using all the methods but RIA. Serum samples were obtained for analysis in Colorado immedi-ately before transplantation. after hepatectomy but before place-ment of the homograft, and at 3D-minute intervals after revascu-larization of the graft. The preoperative sample was positive in all test systems, while the specimen taken during the anhepatic phase was positive only with the more sensitive complement fixation test.· The five subsequent intraoperative serum samples were al1 negative by the AG. CEP. and CF tests. The patient remained HB,Ag negative by the above techniques for 43 days after transplantation. At that time, although hepatic function tests were essentially normal, HB.Ag was again detect-able, first by CF and later by CEP, Henceforth, until her death 18 months later, all serum specimens tested were positive by all techniques. After the patient's death, serum samples that had been obtained during the early postoperative period (days 5, 9, 17, and 31) were retested ~y radioimmunoassay. Although these four samples had initially been found to be HB.Ag negative by AG, CEP, and CF. a11 were positive by RIA (positively confirmed by blocking with anti-HB,AG antibody).' Hepatitis B surface antigen subtype determinations were done in the California laboratory. Both the pretransplant antigen and the antigen detected during the post-transplant acute hepatitis were subtype ay. COMMENT The outcome aCter orthotopic hepatic transplantation in this patient was not readily predictable. It could be theo-rized that the new and genetically different lh'er might be affected differently by the hepatitis virus than the nati\'e organ. Furthermore. the response of the new liver, iC infected. would be conditioned by an iatrogenically altered host immune response. Removal of the host liver resulted in an immediate. marked reduction in HB,Ag titer, suggesting that the liver was the major source of circulating H B.Ag. Apparently, the amount oC infectious material retained extrahepatical-71 Arch Surg-Vol 1141, Jan 1979 ly, as reflected by the positive RIA test, was sufficient to infect the new organ. The only alternative, and an unlikely one since the HB.Ag screening tests oC the blood baths with CEP were negative, was that the inCection came from one of the blood transfusions. Whatever its origin, viral replication then occurred, presumably mainly in the freshly infected hepatic homograft, leading eventually to the release of large amounts of HB.Ag into the blood circula-tion. The situation was thus somewhat comparable to post transfusion type B hepatitis. The development of clinical symptoms and biochemical abnormalities about 80 days after transplantation terminated the "incubation period," after which the less sensitive serologic tests readily detected HB.Ag in the serum. The bout of acute hepatitis at that time was not obviously different than would have been expected in a patient with a normal immune system. Although it was hoped that provision of new liver tissue of a different genetic constitution than the native organ or the use of an immunosuppressive program would protect against redevelopment of chronic active hepatitis, such was not the case in our patient. A chronic and progressive liver disorder developed, but one that was histologically dissim-ilar to chronic active viral hepatitis in that collagen devel-oped in fine intrasinusoidal strands not forming septa, hepatocyte regeneration was minimal, and inflammatory cell infiltration was meager. The histological features that developed in the liver homograft were also unlike the changes that can be induced by either rejection or immu-nosuppression. It seems most likely that the posttransplan-tation hepatic disorder in our patient was chronic active viral hepatitis modified by immunosuppression. In future cases, treatment should be considered at the time of operation to neutralize the residual virus with human anti-HB.Ag antibody. Successful therapy of this kind would make similar patients attractive candidates for liver replacement. One patient recently treated by us with hyperimmune serum has had complete clearing of HB.Ag for the entire 4th months of postoperative follow-up. It is not known to what extent this approach has been used at other centers. NonproprIetary Name and Trademark of Drug Azathioprine-1m uran. Reference. 1. Blumberg BS, Sutnick AI, London WT. et al: Current concepts, Australia antigen and hepatitis. N Engl J .Ytd 283:349-354, 1970. 2. St.&rU TE. Putnam CW: Erptritnct in Htparir Tranopla,,'a,ioll. Philadelphia. WB Saunden Co, 1969. 3. St.&nl TE. Putnam CWo Halgrim!lOn CG, et al: Cyclophosphamide and whole organ transplantation in humans. Su rg Gynuol Ob8l11 133:981·991, 1971. -4. Goodman JS, Koenie MD: Nocardia infections in a general hospital. Artn .'II}' Acad Sci 174:552·567.1970. 5. Walsh JH, YalOIII' RS, Benan SA: Detection of Australia antigen and antibody by means of radioimmunoasaa)' techniques. J In/ec, Di, 121:550-554, 1970. 6. Torisu M. Yokoyama T, Amemiya H. et al: Immunosuppression, liver injury. and hepatitis in renal. hepatic, and cardiac homograft recipients: With particular reference to the Australia antigen. Alln Surg 174:62().639, 1971. Liver Homotransplantation-Corman et al l e £ 9 c c It a Ii It 9 d; nl o In N' ch gl. cy tic Arc 

Liver Allograft: Its Use in Chronic Active Hepatitis with Macronodular Cirrhosis, Hepatitis B Surface Antigen

Schroter, G

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Liver allograft. Its use in chronic active hepatitis with macronodular cirrhosis, hepatitis B surface antigen

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Liver Allograft: Its Use in Chronic Active Hepatitis with Macronodular Cirrhosis, Hepatitis B Surface Antigen

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