I,if. Pathology of Hepatic Transplantation. A Review of 62 Adult Allograft Recipients Immunosuppressed With a CyclosporinelSteroid Regimen

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1 "~ Pathology of Hepatic Tansplantation A Review of 62 Adult Allogaft Recipients mmunosuppessed With a CyclospoinelSteoid Regimen ; ~.,if 1,1 H A. JAKE DEMETRS, MD, STEVEN LASKY, MD. DAVD H. VAN THEL, MD, THOMAS E. STARZL, MD, PhD, and ANDREW DEKKER, MD Fom the Depatments of Pathology, Medicine, and Sugey, Univesity Health Cente of Pittsbugh, Pesbyteian Univesity Hospital, Pittsbugh, Pennsylvania The pathologic spedmens (n = 118) and hospital couse petinent to each of 62 adult live allogaft ecipients wee eviewed. Biopsies and etansplanted ogans wee obtained at the discetion of the sugical team on the basis of the postopeative clinical couse «1 day to >12 yeas afte tansplantation), and final intepetation of the pathologi.:: mateial was based on a coelation of all available data. Most of the specimens (n = 8?) wee obtained within the fist 2 months, and diagnoses in this time peiod included ejection, biliay obstuction/cholangitis, vascula injuy, hepesvius and cytomegalovius hepatitis, gaft necosis, and functional cholestasis. Theeafte, ejection and ecuent o pimay vial hepatitis wee the majo causes of gaft dysfunction. Histologically, hepatic ejection is manifested by a cellula mediated injuy of hepatocytes and bile ductules and a spectum of vascula lesions in medium-sized hila ateies. Mophologic changes of biliay duct obstuction and vial live disease wee at times difficult to diffeentiate fom ejection. Two petansplant disodes, type B vial hepatitis and the Budd-Chiai syndome, ecued in gafted ogans. Although intepetation of pathologic mateial may be difficult at times, it fequently is helpful in planning an appoach to management of live allogaft ecipients. (Am J Pathol 1985, 118: ) RECOGNTON of ej~ction and othe hepatic complications by needle biopsy can playa significant ole in the management of live allogaft ecipients. 1-3 Clinically. the diagnosis of ejection is difficult and is often made by the exclusion of othe causes of gaft dysfunction. Discepancies exist, howeve, in the histologic desciption of ejection, paticulaly in efeence to the appeaance of acute and chonic foms and the extent of involvement of small intelobula bile ductules.-5.9.o Moeove, desciption of othe hepatic complications 6 - lo and ecuent disease 8 11 is limited. The following is a eview of hepatic pathology in 62' adult live allogaft ecipients maintained on cyclospoine/steoid immunosuppession. The epot is based upon a eview of all the needle biopsies, failed allogafts, and autopsy specimens fom these patients. The histologic ecognition of ejection and its sepaation fom othe hepatic complications and ecuent disease is discussed and coelated with the clinical data. Case Selection Mateials and Methods Patients wee selected on the basis that at least one posttansplant live specimen wee available fo pathologic eview. The population consisted of 30 males and 32 females with an aveage age of 33 yeas (ange, yeas) who undewent tansplants fom 1972 to 1981 at Denve (4 patients) and fom 1981 to the pesent at the Univesity of Pittsbugh (58 patients). Accepted fo publication August 23, Addess epint equests to Andew Dekke, MD, Depatment of Pathology. Pesbyteian Univesity Hospital, DeSoto at O'Haa Steet, Pittsbugh, PA

2 152 DEMETRS ET AL Table 1 -Summay of Histologic Findings in Specimens With Rejection Total specimens Potal inflammation Disuption of limiting plate Bile ductula injuy t Centilobula necosis Centilobula intlammation:j: Cholestasis <2 Months post-tx' (%) 21 (100) Modeate-sevee (100) 5 (24) 9 (43) 18 (86) 19 (90) Modeate (100) >2 Months post-tx' (%) 15 (100) Mild-Modeate (100) 11 (73) 12 (80) 7 (47) 7 (47) Mild-Modeate (73) Afte tansplantation. t Paanuclea vacuolization, cytoplasmic eosinophilia, nuclea pyknosis, inflammatoy-cell infiltation, o 1055 of bile ductules. 1= Lage lymphocytes in the cente of the lobule and/o infiltating the subendothelial space of teminal hepatic (cental) veins. The emaining specimens had minimal o no cholestasis. Pathologic Mateial and Review A total of 118 specimens wee eviewed, which included 71 needle biopsies, 26 sugically emoved allogafts, and 21 autopsies. Sugical specimens anging fom less than 30 minutes to geate than 12 yeas afte tansplantation wee obtained at the discetion of the sugical team. All slides wee outinely stained with hematoxylin and eosin (H&E), eticulin, and tichome. Special stains wee utilized when appopiate and included ocein, hodamine, ion, elastin, and the immunopeoxidase technique 12 fo hepatitis B suface and coe antigen and hepes simplex. The slides wee eviewed once blindly and a second time with clinical infomation available. Clinical Review and Final Diagnosis Hospital chats wee eviewed; and the hospital couse petinent to each specimen, including adiogaphic, endoscopic, and sugical pocedues, along with laboatoy data, medications, and clinical impessions, was ecoded. A final diagnosis fo each specimen was made afte a coelative eview of both the pathologic and clinical mateial. Opeative Pocedue and mmunosuppession All opeative pocedues wee othotopic allogaft tansplantations with end-to-end vascula anastomosis of all pe- and post-hepatic vessels. The majoity of the biliay anastomoses wee choledochocholedochostomies o Roux-en-Y choledochojejunostomies, both with dono cholecystectomy. The immunosuppession potocol in 58 of the 62 patients studied consisted of a loading dose of cyclospoine (17.5 mg/kg/day) given just pio to sugey, fol-. AJP Januay 1985 lowed by a maintenance dose of 10 mg/kg/day. This was combined with steoids at an initial dose of 200 mg/day pednisone, which was tapeed apidly to 40 mg/day and then gadually to a maintenance dose of mg/day. Suspected ejection was teated with supplemental steoids geneally given as a log bolus of Solucotef (U pjohn) on altenate days. Histopathology Rejection Results Rejection was the pimay pocess in 36 of the 118 specimens examined. This diagnosis was neve made befoe 6-7 days afte tansplantation, occued commonly within the fist 2 months, but could be seen any time theeafte. n ealy (less than 2 months) episodes of ejection (see Table ), a modeate to sevee inflammatoy infiltate expanded the potal tacts (Figue la). t consisted of lage and plasmacytoid lymphocytes with occasional mitotic figues, macophages, and smalllymphocytes with fewe polymophonuclea leukocytes and eosinophils. These cells occasionally spilled into the peiphey of the lobule and wee associated with peipotal hepatocyte necosis (5 of 21 specimens). nflammatoy cells wee also seen in and aound the cental veins (19 of 21 specimens) and to a much lesse degee pemeating though the sinusoids and space of Disse. Banches of the potal veins within the potal tacts contained subendothelial inflammatoy cells and fequently had a hypeplastic and focally disupted endothelium (Figue b). Fibin in the potal tacts was fequently deposited in a concentic fashion aound the veins. Small bile ductules geneally showed hypeplastic changes; howeve, ductula cell damage as evidenced by inflammatoy-cell infiltation, paanuclea vacuolization, nuclea pyknosis, cytoplasmic eosinophilia, mitoses, dysplasia, o luminal disuption was pesent in 9 of 21 specimens (Figue d). Changes in the small ateioles included intimal scleosis and hypeplasia, thickening, and eosinophilia, evaluation of which was quite subjective. Alteations in the teminal hepatic (cental) veins (Figue e) wee identical to those descibed fo potal veins except fo the degee of inflammation, which was geneally less. A modeate degee of canalicula and hepatocellula bile stasis was pesent in Zone 3 and occasionally also in Zone 2 (of Rappapot) in all specimens with ejection (less than 2 months). These changes wee accompanied by vaying degees of centilobula necosis (18 of 21), eticulin collapse with cental-to-cental linkage (2 of 21) (Figue e), centilobula inflammation (19 of 21 specimens) simila in natue to that ptsent in potal tacts, and hemohage. n moe sevee examples (2 specimens) the

3 Vol. 118 No. 1 ',!_)ATC TRANSPLANTATON 153 '' '.10 "t1(." ' Figue 1- Rejection. a - Retansplant specimen fom OLT 310, 58 days afte tansplantation. Note the pominent inflammatoy infiltate n the potal tact (PT) and centilobula egion (CL). (H&E, x 100) b- High-powe photogaph of the potal tact fom a. Note the infiltation of the potal vein (Pf) by inflammatoy (aow) cells and diffuse potal infiltate obscuing bile ductules. (H&E, x 250) c - High-powe photogaph of centilobula egion fom a. Note the subendothelial inflammatoy cells (aow) in the cental vein (Cf) and hemohage (Hem). (H&E, x 250) d-retansplant specimen fom OLT days afte tansplantation. Note the inflammatoy-cell infiltation and disuption of the bile ductuia lumen and changes indicative of biliay epithelial cell damage (aows). (H&E, x 250) e-retansplant specimen fom OLT days afte tansplantation Note the centilobula eticulin collapse with cental-to-cental bidging. (Reticulin stain. x 100) f - Needle biopsy. Specimen fom OLT 181,1 yea afte tansplantation showing diffuse potal tact inflammation with spillove into lobule (small aow) and lack of ecognizable bile ductule. The potal vein contains subendothelial inflammatoy cells (lage aow). (H&E, x 250)

4 l ' " 154 DEMETRlS ET AL inflammatoy infiltate inceased in intensity and in the elative numbe of polymophonuclea leukocytes. n addition, in these 2 cases of sevee ejection, bile ductula cell polifeation was moe pominent, as well as centilobula necosis, hemohage, and eticulin collapse. As the ejection episode abated, as a consequence. of bolsteed immunosuppession, the inflammatoy infiltate subsided, leaving a mild esidual thickening of the potal and teminal hepatic (cental) veins and a mild to modeate degee of centilobula cholestasis and potal fibosis. Ealy ejection episodes (within the fist 2 months) appeaed to have the most intense inflammatoy infiltate, wheeas subsequent episodes (geate than 2 months afte tansplant) wee geneally less sevee but on occasion could also be quite sevee. Although simila in composition, the inflammatoy infiltate in cases of ejection geate than 2 months appeaed less intense in potal tacts and fequently was absent fom the centilobula aeas. Specimens obtained late than 2 months afte tansplantation (Figue f) wee also chaacteized by the pesence of moe pevalent disuption of the limiting plate (11 of 15 specimens), bile ductula injuy (12 of 15), and centilobula hepatocellula atophy. Cholestasis and centilobula necosis (7 of 15 specimens) wee much less pevalent. This histologic appeaance was simila to that seen in chonic pesistent o active live disease. n these paticula specimens immunopeoxidase studies fo hepatitis B-elated antigens wee pefomed and found to be negative, which uled out pimay o ecuent B vial infection. Bile ductula damage. and venous subendothelial infiltation wee pominent in these specimens. Moeove, seveal of the patients with this change had a pompt biopsy-poven-histopathologic esponse to bolsteed immunosuppession. A summay of these histologic findings is shown in Table 1. n patients expeiencing seveal episodes of ejection, ove a peiod of time thee was a decease in the numbe of small intelobula bile ductules (5 patients). Although this finding was focal and nonquantitative, it was commonly associated with a emakably high seum level of gammaglutamyl tanspeptidase (GGTP) in the absence of clinically documented lage-duct obstuction. Ateial Alteations in Rejection The ateial lesions of ejection (Figue 2a-d) wee most ecognizable in medium-sized hila ateies and theefoe bette appeciated in etansplant and autopsy specimens than in biopsy specimens. Acute ateial lesions wee seen within the fist 2 months afte tansplantation and included inflammatoy-cell infiltation AJP J,nuay 1985 (vasculitis) consisting oflymphocytes and macophages with disuption of the elastic lamina and fibinoid necosis. Chonic ateial lesions wee seen usually late than 4 months afte tansplantation and included deposition of subintimal foam cells, intimal scleosis, and myointimal hypeplasia. These alteations often led to significant naowing o complete occlusion of these ateies. A summay of the vascula lesions is pesented in Table 2. Two of the 36 specimens with ejection (11 and 144 months afte tansplantation) had significant chonic ateial lesions and only a mild to modeate paenchymal inflammatoy infiltate. Usually, howeve, both ateial and paenchymal lesions wee pesent simultaneously. One live emoved 12 yeas afte tansplantation had significant naowing of the hepatic ateies seconday to subintimal foam cells and niyointimal hypeplasia (Figue 2d). Thee was only a scant inflammatoy infiltate in the potal tacts. Teminal hepatic (cental) and potal veins wee mildly thickened, and in addition thee was sub sinusoidal and modeate potal fibosis indicative of ealie ejection episodes. Pota-topotal and potal-to-cental linkage by thin fibous bands associated with an intalobula egeneative nodulaity was also pesent. Many potal tacts wee entiely devoid of small bile ductules, and cuiously some of these same potal tacts wee fee of inflammation. Centilobula hepatocytes wee atophic, which esulted in an appaent widening of the sinusoids. Foam cells simila to those seen in the hila ateies wee pesent (occasionally in small clustes) within the sinusoids. As indicated above, the changes noted in the small intelobula potal ateioles wee athe subjective and consisted of intimal scleosis and medial thickening with eosinophilia, findings which may not be eliable fo the diagnosis of chonic vascula lesions of ejection in the absence of clinical data uling out othe causes fo gaft injuy o failue. Vial Live Disease Thee wee 2 cases of ecuent type B vial hepatitis, with one leading to cihosis. The histologic appeaance of vial hepatitis in this setting (Figue 3a) was not dissimila to that seen in nonallogaft lives and was chaacteized by a geate degee of lobula disaay, hepatocyte ballooning, and individual hepatocyte necosis thoughout the lobule when compaed with those in which ejection was the pimay pocess. n addition, the inflammatoy infiltate in these cases of ecuent vial disease appeaed to extend a geate distance fom potal tacts into the lobule and to suound individual o clustes of hepatocytes (i.e., piecemeal..

5 Vol. 118 No. 1 HL;'\ j,;, TRANSPLANTATON 155 Figue 2 - Vascula alteations of ejection, a - Retansplant specimen fom OLT 31,58 days afte tansplantation showing fibinoid necosis of medium sized hila atey. (H&E, x 250) b - Retansplant specimen fom OL T 212, 8 months afte tansplantation, showing a thickened banch of hepatic atey (HA) with deposition of foam cells in media, (H&E, x 100) c - Same specimen as in b showing subintimal foam cells naowing a hila atey, (H&E, x 100) d-retansplant specimen fom OLT 56,12 yeas afte tansplantation, showing myointimal hypeplasia of the hila atey. necosis) and contained fewe lage lymphocytes. Convesely, inflammatoy cell infiltation and disuption of the venous subendothelium and bile ductula destuction was much less conspicuous. All diagnoses of ecuent vial disease wee confimed by the immunopeoxidase technique fo coe (HBcAg) and/o suface. (HGsAg) antigens. Thee was one case of hepes simplex Type hepatitis chaacteized by well-demacated aeas of confluent necosis which was not confined to the limits of the lobula achitectue. These aeas contained nuclea Cowdy type A inclusions, multinucleated giant cells and an inflammatoy cell infiltate with abundant polymophonuclea leukocytes. Fou cases of cytomegalovius (CMV) hepatitis wee seen, and two pattens of hepatic involvement wee noted. n the fist, small collections (micoabscesses o micoganuloma) of inflammatoy cells (pedominantly polymophonuclea leukocytes o a mixed infiltate) wee pesent andomly thoughout the lobule, some of which suounded hepatocytes containing nuclea andlo cytoplasmic inclusions typical of CMV (Figue 3b). The potal aeas of these same lives wee elatively fee of inflammatoy cells, theefoe poviding little evidence fo the pesence of coexistent ejection. The second patten of CMV involvement was much moe extensive, with numeous inclusion-beaing cells, which wee noted pedominantly in the potal vein en-

6 156 DEMETRS ET AL AJP Jaau,'Y 1985 Table 2 - Summay of Vascula Alteations in Rejection * Time afte tansplant (weeks) >52 No. % No. % No. % No. % No. % Total numbe etansplanted lives with ejection Subintimal foam cells 4 67t 4 67t Fibinoid necosis a '0 Vasculitis a 0 Myointimal hypeplasia a a a 0 50* Based on etansplant specimens with ejection (n = 18) as the pimay pocess. t Accumulations wee much less than those found in late specimens. t Fom OL T yeas afte tansplantation. dothelium, small bile ductules, and peipotal hepatocytes. Although inclusion-beaing cells wee distibuted andomly thoughout the lobule and wee often suounded by inflammatoy cells as descibed above, thee also was a pominent lymphocytic infiltate in the potal tacts and centilobula egions identical to that seen in ejection (Figue 3c). This latte patten followed the fome in two cases, 3 and 4 days afte a decease of immunosuppessive theapy. Gaft Necosis Massive subtotal o total gaft necosis was pesent in 5 specimens (4 autopsies, 1 sugical etansplant). n only one instance could this finding be attibuted to postmotem autolysis. n two of the fou othes vascula compomise appeaed to be the esponsible facto. Changes of sevee ejection wee pesent in emaining viable live in the two othe cases. Blood and live cultues fom these late two patients wee positive fo gam-negative oganisms. A simila elationship between gaft ejection, gaft necosis, and gam-negative infection was epoted by Stazp3 in the pe-cya ea and has been temed "septic hepatic gangene." Functional Cholestasis Thee wee 8 specimens in which the only histologic finding was modeate to sevee centilobula hepatocellula and canalicula cholestasis. The potal tacts of these lives wee elatively fee of an inflammatoy infiltate, which suggests cell-mediated injuy as an unlikely cause of gaft dysfunction. Clinically, all of these patients had a significant elevations of seum biliubin ( indiect faction), coagulopathy, and no evidence of lage duct obstuction. Medication egimens in these patients wee not significantly diffeent fom the othes, and esponse to bolsteed immunosuppession was disappointing. Biliay'Obstuction, Cholangitis, and Vascula njuy Hepatic pathology seconday to bilay obstuction,14-16 cholangitis,17.18 and hepatic vascula inj uy l9.10 occued most commonly in the fist 1-2 months and wee histologically identical to that epoted to OCCu in nonallogafts. Septic cholangitis, howeve, was moe fequent in those patients with biliay tact infection pio to tansplantation. Nonspecific Changes Mild histologic alteations wee pesent in many of the tissue specimens examined to which no specific etiology could be ascibed. These changes included mild potal tact edema, lymphatic and potal vein dilation, Kuppfe-cell activation, two-cell-thick hepatic plates, and mild centilobula cholestasis. Clinical Pathologic' Coelative Review Causes of gaft dysfunction wee often difficult to detemine fom clinical paametes alone, and the diagnosis of ejection was often made by exclusion. Likewise, intepetation based on biopsy histology alone, although somewhat moe eliable, was also limited. Howeve, when all available infomation was consideed, etiologic factos could be identified in a lage majoity of cases. Duing the ealy postopeative peiod (the fist 2-3 months) most causes of gaft dysfunction wee attibutable to biliay tact obstuction, cholangitis, vascula insults, and ejection (see Table 3). Pathologically, in this time peiod biliay tact disodes wee at times difficult to diffeentiate fom ejection; theefoe fo substantiation of the diagnosis, esults of studies of biliay tact patency (cholangiogaphy, abdominal ultasonogaphy, etc.) and bile cultues (when available) wee examined. The diffeential diagnosis of specimens obtained in late (>2 months) instances of gaft dysfunction both clinically and pathologically included ecuent o pimay vial live disease, ecuent oiginal disease, and ejection. Diffeentiation was paticulaly difficult when the biopsy showed a chonic active o pesistent live disease histology. n addition to biliay tact studies (above), ~m ateiogam showing diffuse naowing of i l... ( f l,

7 \ No.1 HEPATC TkA.i\iSPLANTATON 157 the hepatic ateial tee, negative hepatitis seologic tests negative immunopeoxidase tissue staining (vial antigens), significant elevations of GGTP in the. absence of lage-duct obstuction, caeful histologic examination (see histopathology), and pompt esponse to bolsteed immunosuppession wee helpful but not absolute distinguishing featues of ejection in such cases. Cause of Gaft Failue Only lives emoved at etansplantation wee consideed as failed gafts. Autopsy specimens wee excluded fom this analysis because of fequent complicating clinical cicumstances suounding the patient's demise which made detemination of gaft viability difficult. The causes of gaft failue as a function of time afte tansplantation ae shown in Table 4. Most gaft failues (20 of 26 specimens) occued ealy within the fist 2 months following tansplantation, and those which wee due to technical complications (8 of 26 specimens) occued within the fist 4 weeks. Theeafte, ejection accounted fo 11 of the 12 gaft failues necessitating etansplantation '. -.~...~~.<~ : : " '.. "," ~>."....., ",... ::.~ Figue 3-Vial hepatitis. a- Needle biopsy specimen fom OLT 195,10 months atte tansplantation, with ecuent hepatitis B. Note the ballooning of hepatocytes, lobula "disaay," and extension of infiltate into the lobule. (H&E, x100; inset, x250) b-needle biopsy specimen fom OL T 336, 27 days afte tansplantation, with CMV hepatitis. Note the few necotic hepatocytes with inclusions (aow) suounded by polymophonuclea leukocytes. The potal tacts wee fee of an inflammatoy infiltate. (H&E, x 250) c- ncidence of Rejection No pecise statement as to the incidence of ejection can be made fom this study because pathologic mateial available fo evaluation came fom only 62 of the 95 adult patients undegoing tansplantation at Pittsbugh, and suspected ejection was teated without live biopsy in many cases. Nevetheless, in the Pittsbugh expeience, in 35 patients sampled, ejection was pesent to at least some degee in one specimen. Theefoe, the lowest estimate fo incidence of ejection, if one assumes that ejection did not occu in those patients without specimens available fo examination, is 35/95, o 370/0; the actual incidence is pobably much geate. Recuence of Pimay Disease and Relationship to Rejection The possibility of ecuent disease following tansplantation is an impotant consideation in evaluating patients fo the pocedue. As mentioned, this study is limited to patients with pathology specimens, and Retansplant specimen fom OL T 334, 48 days afte tansplantation afte immunosuppessive theapy had been deceased seconday to CMV hepatitis similaly to that in b. Note the numeous CMV inclu sions (aows) and nfiltate of the potal tacts involving potal vein (PV). The teminal hepatic (cental) veins showed simila changes identical to those seen in ejection. (H&E, x 100; inset, x 450)

8 158 DEMETRS ET AL AJP Januay 1985 Table 3-Specimen Diagnosis as a Function of Time Afte Tansplantation Time afte tansplantation (weeks) Specimen diagnosis < >52 Total Rejection CMV /ejection Obstuction/Cholangitis Vascula insult Vial hepatitis (8) Hepes/CMV hepatitis Necosis Functional cholestasis Nonspecific changes Total the follow-up peiod is elatively shot. Theefoe, no definitive conclusions can be dawn. The numbe of ecuences confimed pathologically in patients with specific petansplant disease is shown in Table 5. Only vial hepatitis B (2 cases at 4 and 10 months) both HBsAg and HBeAg positive at the time of tansplantation and the Budd-Chiai syndome (1 case at 15 months afte tansplantation) wee noted to ecu. No instances of ecuent pimay biliay cihosis (PBC) wee documented eithe clinically o histologically. The aveage peiod of follow-up in this unique goup of patients was 10 months, the maximum being 18 months. Recuence of PBC following othotopic live tansplantation has been peviously epoted ll in thee patients whose featues pesented afte 3 -yeas. Although the histologic appeaance of ejection has been compaed with that of PBC,4.5 no ganulomas, lymphoid follicles, o inceased deposition of coppeassociated poteins was seen in the cases of ejection obseved in ou patients whose oiginal disease was PBC. Seveal of these patients had histologic evidence of bile ductula injuy, but the histopathologic featues wee thought to be moe epesentative of ejection than of ecuent PBC. Likewise, no definite conclusions on the elationship of ejection to petansplant disease could be made (see Table 5). Howeve, fom the data available, it appeas that no goup (common petansplant disease) is moe likely to expeience ejection than anothe. Discussion Rejection in the tansplanted live was not ecognized histologically befoe 6-7 days. t is fequently seen within the fist 2 months and is a common ealy cause of gaft failue. Although this is makedly diffeent fom that epoted ealie by Fennell, 6.10 many factos have evolved in hepatic tansplantation 13 since that ealie epot. These ealie epots 6 10 wee based lagely on autopsy studies in whi<.:h the majoity of patients epoted suffeed fom infections and technical complications. Since then, sugical techniques have impoved, deceasing the fequency of technical complications; and cyclospoine has eplaced moe conventional immunosuppessants, loweing the incidence of infective complications. 13 Fequently autopsy specimens also have othe complicating lesions and may not show ejection which was pesent days peviously and teated with supplemental steoids. n ealy episodes (within the fist two months) of ejection, the histologic appeaance is vey simila to that epoted in excellent studies by Pote 9 and may esult in esidual potal and cental venous thickening. Late episodes of ejection may be sevee and can occu at any time but ae geneally associated with a somewhat milde potal and/o lobula inflammatoy infiltate. Disuption of the limiting plate and bile ductula cell injuy is moe pevalent in these latte specimens. Repeated o ongoing ejection may lead to a decease of intelobula bile ducts and potal fibosis but aely cihosis (one case). Ealy episodes of ejection may be confused with biliay obstuction and/o cholangitis,21-23 while those episodes occuing late ae difficult to distinguish fom Table 4-Cause of Gaft Failue (Retansplantation) as a Function of Time Afte Tansplantation Time afte tansplantation (weeks) Diagnosis >52 Total Rejection 6 4 3' t 2t 16 CMV /ejection Obstuction/cholangitis Vascula insult Total , Two-thids of these patients had histologic changes identical to those descibed below.t t These cases epesent those failues attibuted to chonic vascula lesions and a paucity of intelobula bile ducts with a mild to modeate potal inflammatoy infiltate.

9 Vol. 118 No.1 HEPATC TRANSPLANTATTON 159!, Table 5 - Petansplant Disease: Recuence and Relationship to Rejection Petan sp lantat i on Numbe of Numbe expeienc- Recuence of Maximum follow-up djagnosls cases ing ejection pimay disease- (months) Pimay biliay cihosis Scleosing cholangitis Nonalcoholic cihosis Alpha-1-antitypsin deficiency Hepatitis B Budd-Chiai syndome Hepatocellula cacinoma Cholangiola cacinoma Caoli's disease Hepatic necosis (toxin) Congenital biliay hypoplasia Seconday biliay cihosis Tyosinemia/hepatoma Hemangiosacoma Wilson's disease Total ot 18 6 o=!: Histologically documented. t See text. =!: Fou patients with peopeative biliay sepsis developed septic cholangitis postopeatively. Seconday to 2-nitopopane exposue." vial live disease without knowledge of the clinical data. Howeve, infiltation and disuption of the potal and cental venous endothelium, pominent bile ductula cell injuy, imnunopeoxidase studies, and vaious clinical paametes ae helpful distinguishing featues of ejection in such cases. The ateial lesions of ejection may be an impotant facto in gaft failue and ae simila to those descibed in heat and kidney gafts_ 2.4,.15 These lesions ae most evident in medium-sized ateies, which ae not well epesented in biopsies. Pevious studies 2,9,10 based on human mateial have equated the vascula lesions with the pesence of subendothelial foam cells, which was the most common finding in this study in such cases. Howeve, as illustated above, a spectum of ateial changes may be seen simila to those epoted by Pote 9 in expeimental animals. Moeove, because the evaluation of the ateioles is subjective in needle biopsy specimens, such biopsies, may not be a paticulaly good method fo the evaluation of these vascula lesions. Sepaation of hepatic ejection into acute and chonic foms may be by convention and somewhat atificial, because any of the lesions attibuted to ejection may occu at any time afte tansplantation. Nevetheless, the moe acute lesions ae usually seen within the fist 2 months, although, as mentioned they may be seen anytime theeafte. The chonic ateial lesions and loss of small intelobula bile ductules associated with a mild to modeate potal infiltate appeas to be a gadual and moe indolent o chonic pocess, somewhat esistant to maintenance immunosuppessive theapy. n many specimens, howeve, both wee pesent simultaneously. The lowest estimate fo the incidence of hepatic ejection afte tansplantation was detemined to be 37070_ Although the actual incidence is pobably significantly highe, these findings ae appeciably diffeent fom those epoted by Fennel and Roddy6 and Roddy et al. 10 As shown in this study, hepatitis B may occu in tansplanted lives eithe as acute o chonic disease. Although no make(s) fo non-a, non-b (NANB) hepatitis exists, some of the cases in the pesent study and othe epots' with "chonic active live disease" following tansplantation may be attibutable to this agent(s), athe than ejection_ Although a pompt clinical esponse to supplemental steoids may be indicative of ejection in such cases, we cannot be cetain that NANB hepatitis may not do likewise. Hepes simplex and CMV hepatitis can also be a cause of gaft dysfunction. The histologic appeaance of hepes simplex and the less sevee fom of CMV hepatitis is simila to that epoted in non-liveallogaft patients Howeve, the deteioation of gaft function with a tansition fom the less to moe sevee CMV hepatitis afte a decease in immunosuppessive theapy is an inteesting initial obsevation. Whethe the deteioation is due to 1) CMV alone because of delayed effects of immunosuppession and/o 2) enhanced vial eplication 29 3o seconday to a simultaneous acute ejection episode is uncetain. Howeve, both clinically and histologically, coexistent ejection appeas to have been a significant facto in these two cases. The suggestion of a elationship between an exacebation of CMV infection and allogaft ejection episodes has been aised fo othe ogan ecipients. 31 Pathologically documented ecuent pimay disodes obseved in this study included type B vial hep-

10 ------~ 160 DEMETRS ET AL atitis and the Budd-Chiai syndome. No cases of ecuent pimay biliay cihosis wee seen on the basis of ou clinicopathologic analysis. t should be noted, howeve, that the length of ou follow-up is much less than that epoted by Neubege. 11 One study based on needle biopsies 1 showed that bile ductula injuy was not a component of ejectioi, as opposed to othe ealie studies. 3-5 Small bile ductula injuy was obseved in ou specimens and, although not pominent in ealy episodes, was moe pevalent in late specimens (see Table 1). The pocess is focal, howeve, and is theefoe bette appeciated in tansplant and autopsy specimens than it is in needle biopsies. This fact may account fo some of the epoted discepancies. Diffeences in sugical technique, teatment potocol, and immunosuppessive agents may also be impotant factos. Although ductula damage appeas to be a pat of the ejection pocess, and its ecognition may be helpful in diffeentiating it fom othe complications, ductula injuy should not be the sole citeia used to establish the diagnosis of ejection. Othe disodes affecting the gaft may also injue intelobula bile ducts" 23,32,33 and need to be consideed as well. n this egad, the histologic appeaance of ejection in the live, paticulaly late than 2 months afte tansplantation, has been compaed with idiopathic autoimmune chonic active hepatitis,1.34 pimay biliay cihosis,4,5,35 and chonic gaft-vesus-host-disease (GVHD).45,36 t is not supising that many of the featues descibed fo chonic GVHD36 ae identical to those seen in ejection. We also noted, as epoted in GVHD,37 that bile ductula cell injuy, although pesent in ealie specimens (less than 2 months), is moe pevalent in late specimens (geate than 2 months). The cellula injuy mediated by T-ymphocytes in GVHD appeas to be selective fo ductal epithelium,38 which may,be elated to expession of a antigens on taget cells that nomally do not expess the antigen. 39 A simila phenonemen may occu in hepatic ejection40 and may be also elated to the pefeential expession of Class and HLA antigens on endothelial, eticuloendothelial, and bile ductule cells. 41 Although much has yet to be leaned concening the identification and pathogenesis of the histologic lesions that occu in these patients, the live biopsy fequently is of significant value in foming teatment plans. Howeve, in some cases, the histopathologic findings can only povide a diffeential diagnosis, which may only be fully esoluble with the availability of complete clinical data. When no definitive conclusions can be dawn based on histologic study alone, communication between the clinician and the pathologist, pefeably with AJP Januay 1985 a select inteest in live pathology, is necessay fo povision of optimal cae to the tansplant patient. Refeences. 1. Eggink HF, Hofstee N, Gips CR, Kom RAF, Houthoff. HJ: Histopathology of seial gaft biopsies fom live tansplant ecipients. Am J J::>athol 1984, 114: Wight DGD: Pathology of ejection, Live Tansplantation: The Cambidge/King's College Hospital Expeience. Edited by RY Caine. New Yok, Gune and Statton, 1983, pp Snove DC, Sibley RK, Feese D, Bloome J, Shap H, Asche N: Othotopic live tansplant ejection: A sequentiallive biopsy study (Abst). Lab nvest 1984, 50:55A 4. Potmann B, Neubege JM, Williams R: ntahepatic bile duct lesions,2 pp , 5. Fennell RH: Ductula damage in live tansplant ejection. Pathol Annu 1981, 16: Fennell RH, Roddy HJ: Live tansplantation: The pathologist's pespective. Pathol Annu 1979, 2: Stazl TE: Expeience in hepatic tanplantation. Philadelphia, W.B. Saundes Co., 1969, Wight DGD: Pathology of live tanplantation (othe than ejection),' pp Pote KA: Pathology of live tanplantation. Tansplant Rev 1969, 2: Roddy H, Putnam CW, Fennell RH: Pathology of live tanplantation. Tansplantation 1976, 22: Neubege J, Potmann B, MacDougall BRD, Caine RY, Williams R: Recuence of pimay biliay cihosis afte live tanplantation. N Engl J Med 1982, 306: Hsu SM, Raine L, Fange H: Use of avidin-biotinpeoxidase complex (ABC) in immunopeoxidase techniques: A compaison between ABC and unlabeled antibody (PAP) pocedues. J Histochem Cytochem 1981, 29: Staz! TE, watsuki S, Van Thiel, Gatne JC, Zitelli BJ, Malatack J J, Schade RR, Shaw BW, Hakala TR, Rosenthal JT, Pote KA: Evolution of live tansplantation. Hepatology, 1982, 2: Shote RG, Baggenstoss AH: Extahepatic cholestasis -. Am J Clin Pathol 1959, 32: Gall EA, Dobogoski 0: Hepatic alteations in obstuctive jaundice. Am J Clin Pathol 1964, 41: Mois JS, Gallo GA, Scheue PJ, Shelock S: Pecutaneous live biopsy in patients with lage duct obstuction. Gastoenteology 1975, 68: Scott AJ: Pogess epot bacteia and disease of the biliay tact. Gut 1971, 12: Tan EGC, Waen KW: Diseases of the gallbladde and bile ducts, n Diseases of the Live. Edited by L. Schiff, E Schiff) 5th edition. Philadelphia, J.B. Lippincott Co. 1982, pp Seeley TT, Blumenfeld CM, keda R, Knapp W, Ruebne BH: Hepatic nfaction. Human Pathol 1972, 3: Caoll R: nfaction of the human live. J Clin Path 1%3, 16: Koetz RL, Sutfin SC, Gitnick GL: Post-tansfusion chonic live disease. Gastoenteology 1976, 71 : Baggenstoss AH, Solway RD, Summeskill WHJ, Elveback LR, Schoenfield LJ: Chonic active live disease: The ange of histologic lesions, thei esponse to teatment and evolution. Hum Pathol 1972, 3: Poulson H, Chistoffesen P: Abnomal bile duct epithelium in chonic aggessive hepatitis and cihosis: A eview of mophology and clinical, biochemical and im-. munologic featues. Hum Pathol 1972, 3: ,- / i t., l, l \ l

11 Vol. 118 No. 1 litis, chonic active hapatitis B and pimay biliay cihosis. Clin Exp mmunol 1982, 50: Biebe CP, Stinson EB, Shumway NE, Payne R, Kosek J: Cadiac tansplantation in man: V. Cadiac allogaft pathology. Ciculation 1970, 41: Anuas S, Summes R: Fulminant hepes simplex hepatitis in an adult: Repot of a case in a enal tansplant ecipient. Gastoenteology 1976, 70: Eon L, Kosinski K, Hisch MS: Hepatitis in an adult caused by hepes simplex vius type 1. Gastoenteology 1976, 71: Henson DE, Gimley PM, Stano AJ. Postnatal cytomegalovius hepatitis: An autopsy and live biopsy study. Hum Pathol 1974, 5: Lang DJ: Cytomegalovius infection in ogan tansplantation and posttansplantation: An hypothesis. Achiv fu die Gesamte Viusfoschung 1972, 37: Jodan MC, Takagi JL, Stevens JG: Activation of latent muine cytomegalovius in vivo and vito: A pathogenic ole fo acute infection. J nfect Dis 1982, 145: Myeowitz RL: Cytomegalovius infection, The Pathology of 0ppotunistic nfections With Pathogenetic, Diagnostic and Clinical Coelations. New Yok, Raven Pess, 1983, pp Chistoffesen P, Poulsen H, Scheue PJ: Abnomal bile duct epithelium in chonic aggessive hepatitis and pimay biliay cihosis. Hum Pat ho 1972, 3: Scheue PJ, Teixeia MR, Welle VD, Muay A, Bambe M, Thomas HC, Shelock S: Pathology of acute hepatitis A, B, and non-a, non~b (Abst). Gastoenteology 1980, 79: Eggiiik HF, HoathoffHJ, Haitema S, Gips CH, Popema S: Cellula and humoal immune eactions in chonic active live disease: Lymphocyte subsets in live biopsies of patients with unteated idiopathic autoimmune hepa- HEPATC TRANSPLANTATON Heptinstall RH: Pathology of the Kidney. 3d edition. Boston Little, Bown, 1983, pp Scheue PJ: Pimay biliay cihosis: Diagnosis, pathology and pathogenesis. Postgad Med J 1983, 59: Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Stike GE, Sale GE, Hackman R, Tsoi M, Stob R, Thomas ED: chonic gaft-vesus-host syndome in man: A long-tem clinicopathologic study of 20 Seattle patients. Am J Med 1980, 69: Snove DC: Acute and chonic gaft vesus host disease: Histopathologic evidence fo two distinct pathogenetic mechanisms. Hum Pathol 1984, 15: Seemaye TA, Gatne JG, Lapp WS: The gaft-vesushost eaction. Hum Pathol 1983, 14: Lampet la, Suittes AJ, Chisholm PM: Expession of la antigen on epidemal keatinocytes in gaft-vesus-host disease. Natue 1981, 293: Takacs L, Szende B, Monostoi E, Rot A, Lapis K, Szecsey A, Ando : Expession of HLA-DR antigens on bile duct cells of ejected live tansplant (Coes). Lancet 1983, 2: Lautenschlage, Hayy P: Expession of the majo histocompatability complex antigens on diffeent live cellula components in at and man. Scand J mmunol1981, 14: Hine CH, Pasi A, Stephens BG: Fatalities following exposue to 2-nitopopane. J Occup Med 1978,20: Acknowledgments The ecognition of the histopathologic changes associated with hepatic ejection was guided by the fundamental detailed obsevations of K. A. Pote" in animals and humans