{fql. Table 1 Indications for Orthotopic Liver Transplantation. Number of Transplantations

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1 {fql Experience in Orthtpic Liver Transplantatin Indicatins, results and future Prspects I. Penn, J. Crman, A. Gustafssn, C. G. Halgrimsn, C. W. Putnam, G. Schrter, C. G. Grth, T. E. Starzl Since the first liver transplantatin in man was perfrmed in Denver in March 1963, 162 such peratins have been perfrmed thrughut the wrld. Apprximately ne third f the patients have been treated at the University f Clrad Medical Center and the Denver Veterans Administratin Hspital. This reprt will discuss ur experience with the indicatins fr hepatic replacement, the results btained and the prspects fr future imprvement. Indicatins Replacement f the liver is indicated in patients with serius liver disease whse life expectancy can be measured in days r weeks r perhaps a few mnths. The reasns fr peratin in ur center are listed in Table 1. Frm the Departments f Surgery and Pediatrics, University f Clrad Schl f Medicine and the Veterans Administratin Hspital, Denver, Clrad. This wrk was supprted by research grants frm the Veterans Administratin, by grants RR-OOSl and RR frm the general clinical research centers prgram f the Divisin f Research Resuces, Natinal Institutes f Health, and by grants A/! , AI-AM-08898, AM , and HE f the United States Public Health Service. We have nt transplanted the liver fr metastatic malignancy, as has been attempted in ther centers, because f the strng pssibility f ther extrahepatic metastases. With the exceptin f ne case where the tumr was adherent t the pylrus which als required resectin, we have nt perfrmed transplants fr primary hepatic malignancies which have extended beynd the cnfines f the liver. Table 1 Indicatins fr Orthtpic Liver Transplantatin Disease Number f Transplantatins Biliary Atresia 26 Primary Hepatic Tumrs 13 Cirrhsis 9 Chrnic Agressive Hepatitis 5 Wilsn's Disease 2 lupid Hepatitis 1 Retransplantatin fr severe rejectin 4 Ttal 60 "One patient had an incidental hepatma. As ur experience has grwn we have becme prgressively mre disappinted with the results f transplantatin fr primary malignant disease f the liver as we shall indicate later. We nw rarely recmmend transplantatin fr this indicatin.

2 Experience in Orthtpic Liver Transplantatin Fig. 1 a The extremely rapid develpment f pulmnary metastases in a patient wh underwent liver replacement fr hepatma. A. The chest is clear six days after transplantatin. B. Twenty-nine days pst-perative. Tw metastases are visible in the lwer left lung field (arrws). C. Five days later the tumr depsits previusly seen have grwn in size (hrizntal arrws) and a third fcus is nw present in the right lbe (vertical arrw). D. Frty-fur days. Metastatic grwths are scattered thrughut the lungs (arrws). E. Seventy-fur days pstperative. F. Fur mnths after transplantatin. Transient dyspnea was first nticed a few days later. The patient died f pulmnary and hepatic insufficiency 143 days after peratin. R L p A B c D Fig. 1 b Destructin f the hepatic hmgraft by tumr recurrence, as demnstrated by serial technetium liver scans. A. 68 days - The scan appears nrmal. B. 94 days - The patient had becme jaundiced. Hepatmegaly is evident. C. 101 days - Multiple areas f pr istpe cncentratin are nw visible. D. 111 days - The prcess has cntinued its rapid prgressin. By the time f death the hmgraft was almst cmpletely replaced by tumr.

3 c Experience in Orthtpic Liver Transplantatin Results Lng term survival can be achieved after liver transplantatin. In experiments in dgs and pigs we have had many survive mere than a. year. One dg is still alive mre than 8 years after transplantatin. In ur first 42 patients, in whm a minimum fllwup f 12 mnths was available, 11 survived at least ne year (Table 2). Three f these recipients lived mre than 2 years. One patient, wh was the lngest survivr in the wrld, died 31,'2 years after transplantatin. Table 2 11 One-y ar Survivrs after Orthtpic Liver Transplantatin An example is the patient in Fig. 1a. He was a 15 year ld by frm whm a large hepatma was remved. N secndary depsits were apparent at the time f transplantatin. Twenty-nine days later pulmnary metastases appeared and subsequently became larger and mre numerus. Serial scans f the hmgraft als shwed prgressive replacement with tumr, Fig. lb. The patient died f pulmnary and hepatic insufficiency 143 days after transplantatin. At autpsy the lungs and the hmgraft shwed extensive invasin by tumr (Figs. Ic and 1d). 29 Alive 3, II - Ili6 t 25 /8 years Died ~ II - 1 t 3 1/2 years 12 Mnths Cancer' 12 Mnths - Serum hepatitis, liver failure ]4 Mnths - Cancer 15 Mnths - Cancer 15 Mnths - Rejectin, liver failure 20 Mnths - Disseminated ncardia infectin" 30 Mnths - Rejectin, liver failure 42 Mnths -? Rejectin, liver failure 'This patient actually died a few days shrt f ne year. "The hmgraft shwed severe chrnic aggressive hepatitis, just as in her previusly remved native liver. Fig. 1 c Lungs shwing multiple large metastases. At the present time 8 patients are alive at 1~, ,31 2,10,14,28, and 34 mnths pst-transplantatin respectively, Primary malignant tumrs f the liver. In ur early experience it was hped that hepatic replacement might be useful therapy fr primarv malignant tumrs f the liver. Hwever, as lng term survival was achieved it became bvius that metastases were a majr prblem. In 6 f 7 patients treated fr hepatma and fllwed frm 2 t 14 mnths after transplantatin metastases appeared in the lungs, brain and even in the hmgrafts. Fig, 1 d Invasin and nearly cmplete destructin f the liver hmgraft by recurrent hepatma. At autpsy almst all the transplanted hepatic tissue was replaced by tumr. (By permissin f W. B, Saunders C., 1969.)

4 30 This disheartening experience has been repeatedly seen in ther cases. The sle exceptin was in a child aged almst 4 years wh was perated upn fr severe cngenital biliary atresia. An incidental finding in the liver specimen was a hepatma abut 2 em in diameter. The patient has nw been fllwed fr clse t 21/2 years with n clinical, radilgic r serlgic (ufetprtein estimatins) evidence f recurrent tumr. Experience in Orthtpic liver Transplantatin It is pssible that slwer grwing tumrs, such as chlangicarcinmas may have a ;'etter prgnsis, but thus far we have nt treated any such cases. Hwever, we have had the pprtunity t treat ne patient with an unusual tumr which des nt cmmnly metastasize utside the liver, primarily because it usually kills thrugh extensive replacement f the hepatic parenchyma leading t liver failure, r by causing fatal hemrrhage. The tumr was a hemangiend- Rejectin Cnsls weight 8~5 kg Rejectin 52 year ld c! Cnsls Platelets (mm3) wac rmm~ Cycl Phsphamide [mg/day) Prednisne (mg/day) ALG Bilirubin (mg%) Prthrmbin time 60 (%normal) SGOT 300 ( I.u.) Trarlsplant Time in days Fig. 2 The early curse f a 52 year ld male wh had liver replacement as treatment fr a hemangiendthelisarcma. After transplantatin, there was a severe rejectin crisis. The prtracted thrmbcytpenia pstperatively is ften nted after liver transplantatin and is prbably due t thrmbcyte sequestratin in the hmgraft. A LG - hrse antilymphcyte glbulin; SGOT - serum glutamic xalacetic transaminase in internatinal units; and ARROW milligrams f methyl prednislne intravenusly. (By permissin f Surg. Gynec. Obstet. 133:981, 1971).

5 Experience in Orthtpic Liver Transplantatin thelisarcma. The patient's curse is illustrated in Fig. 2. At the time f transplantatin he was gravely ill with severe hepatic dysfunctin and a serum bilirubin f '*0 mgm Uill. Fllwing peratin there was initial gd functin f the hepatic hmgraft. The patient then successfully wea~hered a but f severe rejectin after which liver functin remained satisfactry fr apprximately 3 mnths when his cnditin deterirated and he died. At autpsy examinatin, there were numerus metastases in the lungs and the hmgraft itself was the seat f large tumr depsits. These varius experiences with hepatic malignancies have made us adpt a plicy f restricting liver transplantatin almst exclusively t patients with benign hepatic disease. Cngenital biliary atresia. Encuraging results have been btained in this grup f patients. Tw patients lived at least ne year after transplantatin, tw mre survived mre than tw years and a further patient fr 3'/2 years. His curse is illustrated in Fig. 3. Despite a very pr tissue match the patient had nly tw minr rejectin episdes in the early pstperative perid. Thereafter, he enjyed gd health and excellent liver functin till shrtly befre his death. A bipsy f the hmgraft at 914 days shwed almst nrmal liver architecture. Terminally the patient develped a febrile illness which led t massive hepatic necrsis and death. It is nt knwn fr certain whether this was caused by a virus infectin r was a manifestatin f late rejectin. 31 SGOT (I.u. ) Alkaline Phsphatase (I.U.) Serum Prtein ig/100ml) ttal- Albumin rglbulin.. Bilirubin (mg/100ml) ttal- cnjugated- --- Azathiprine (mg) Prednisne (mg) ALG OT19 4 y. (j 14.3~18. kg O~~==~~~~~~~~~~==~========== ~~~~~~--~------~~~==--~~~=== ~ ~... ~-,, :.. ~.. ~.~ , ~.~ ~.--:.. :.::::.. ~.~.: ~.~:::.~.-:.:.~".. ~-~... """"" Rejectin 0~~~8-~~~-L~~~--~~~==~--~==----~ dall ever" a twice a week PRE-QP I OrthtpiC Transplantatin Time in days, Time in mnths Fig.3 The early curse f a 4 year ld child wh survived fr 3 1 /t years after liver transplantatin perfrmed as treatment f cngenital biliary atresia. Nte the rejectin episdes at 1 mnth and 21!~ mnths, which were easily cntrlled. (By permissin f W. B. Saunders C ) /"

6 32 Experience in Orthtpic Liver T ransplanta tin Orthtpic Transplantatin OT ~ 30.0kg II Y.. d Alkalln', PhOSPhiltase (I.U.I Serum Prtein (g/lqoml) ttal- Albumin rglhljl1n Bilirllblrl ijnql Hi)ml, ttalcnjllqated ---_ AzathiPrine (mg) Prednisne (mgl PredniSOlne IVlg) ALG (3mll Time in days Time in weeks mnths Fig. 40J Pstperative curse f an 11 year ld recipient f a liver hmgraft fr cirrhsis secnjary t Wilsn's disease. A severe reject:n crisis beginning abut 3 weeks pst-transplantatin eventually reversed and hepatic functin has been essentially nrmal since the sixth pstperative mnth. The patient remains in gd health almst 3 years after peratin. Wi/SOIl'S disease. Our experience with liver tr.lnspiantatin has given us a better uncll'r.,t.lncling f this metablic disrder. The wnditin is believed t be caused by an en7.yme deficiency which causes disturbed cpper metablism leading t its extensive depsitin in the liver, basal ganglia, the l'iirneas (Kayser-Fleischer rings) and ther tissues. The main clinical manifestatins.lre severe cirrhsis, r neurlgic disturb.lnces r bth. Experience with liver transpljntatin suggests that the enzyme defkil'nry may be cmpensated fr by rer l ln I11, nt f the diseased liver with a Ill'.lli h v 'lne and that cpper metablism m.ly ll!' restred t nrmal. The results in ne slilh patient are illustrated in Fig. 4a. Th(' ".Itient was seriusly ill with advanced -tcxx)1 T := 400i ~~l I ~~j H' BIOPsy," ~= 0~1--~~~,-~~--~--~~~~~ Time In days pst-transplantatin Fig. 4 b There was massive urinary excretin f cpper fllowing transplantatin. This lasted 6 mnths. A secndary peak f cpper excretin ccurred in respnse t a 3-day test curse f penicillamine. (By permissin f Lancet 1:505,1971).

7 Experience in Orthtpic Liver Transplantatin cirrhsis. After transplantatin the hmgraft underwent the wrst rejectin crisis that we have ever bserved in any f ur liver transplant recipients. The bilirubin rse t almst 50 mgm % with assciated rises in the alkaline phsphatase. Frtunately, it was pssible t reverse the immunlgic reactin and the patient has enjyed ~irtually nrmal liver functin ever since. He is nearly 3 years pst-transplantatin and is attending schl. Large amunts f cpper were passed in the urine fr 6 mnths after peratin (Fig. 4b) and bipsies f the hmgraft at 6, 18 and 30 mnths shwed a nrmal cpper cncentratin within the rgan. Similar results were btained in the case f anther by aged 15 years, wh in additin t advanced cirrhsis had severe neurlgic symptms. He is nw mre than a year pst-transplantatin. One and a half mnths after the peratin he develped jaundice, and elevatins f the SCOT (Fig. 5) and the alkaline phsphatase. Simultan- 33 Australia Antigen (CF Titer) Bilirubin (mg%) Cycl Phsphamide (mg/day) Prednisne (mg/day) ALG ,000 10,000 5, Transplant weight 50~ 47 kg year ldd' Time in days Fig.5 Triple drug therapy with cyclphsphamide, prednisne and hrse antilymphcyte glbulin (ALG) in a patient wh underwent liver transplantatin fr Wilsn's disease. Rejectin has never been diagnsed pstperatively. The temprary deteriratin in hepatic functin in the secnd pstperative mnth was accmpanied by Australia antigenemia detected by the cmplement fixatin (CF) technique and cnsequently was thught t be a manifestatin f serum hepatitis. (By permissin f 5urg. Gynec. Obstet. 133: 981, 1971).

8 34 eusly his serum became psitive fr the Australia antigen. He was diagnsed as having serum hepatitis and immunsuppressive therapy was nt increased as wuld have been the case had rejectin been suspected. The abnrmal liver chemistries gradually returned t nrmal and the patient has remained in gd health. This case illustrates a vitally imprtant pint - that pst-perative elevatin f the bilirubin and alkaline phsphatase is nt synnymus with rejectin. In fact, they may als be caused by serum hepatitis as in this case, but b- Experience in Orthtpic liver Transplantatin structin f the extrahepatic bile ducts r hepattxicity f the immunsuppressive drugs may be respnsible as will be discussed later. It is imperative t establish the crrect diagnsis as each cnditin requires a different frm f treatment. Hepatitis. Hepatitis ccurs pst-transplantatin in mre than 20 % f ur renal hmgraft recipients. As illustrated by the last case it may als ccur in hepatic hmgraft patients wh are expsed t many risks including thse impsed by the much larger bld transfusins required in liver 1 j l ~ AG.. IEOP,. Titer :... HI CF '.. Titer,. ACA Titer..J SGOT --,.,.. (I.U),- I ~ li '000 f " Alcaline Phsphatase (B-L units), 0 " Bilirubin (mg%) " Tfal /... COnjUgdted---J ='=== L -=:::::~="""' Serum Prtein 4 - Ttal_, Albumin- - -,t----===::.::::=--p'=========::::::=======::::=======::::::===:. -~ _._ J'Glbulin i ~ Azathiprine i8 Prednisne (mg)..: "t i_... (mg) z......, f=predn islne ~=-:,,,!,:"" ~~amll ui:i;~~~w~ic~e~a~w~e~e~_:=~::::t:~3jn~c~eja!::w~e~e~kt:::::;~~:;= (lg.i.v.) 1'I... 1/7'1'0 ""'70 "~"04N7Qunft s ' t c 110 llo ALG OrthtpiC Transplantatin (8/9/70) Time In days t ~, II. Fig. 6 Orthtpic hepatic transplantatin fr liver failure caused by chrnic aggressive hepatitis. The Australia antigen which had been de tectable in multiple serum samples fr ne year befre peratin, disappeared within hurs after remval f the patient's wn liver. Hwever, the Australia antigen reappeared in her bld stream abut 2 mnths pst-transplantatin at a time when she develped a clinical episde f hepatitis.

9 Experience in Orthtpic Liver Transplantatin replacement. In view f these findings is there any hpe f treating lethal serum hepatitis with liver transplantatin? In the present state f ur knwledge it is nt pssible t give a definite answer t t!tis questin. We have n experience with hepatic replacement in the treatment f acute fulminating hepatitis, althugh it has been unsuccessfully attempted elsewhere. Hwever, we have perfrmed liver replacement in cases f hepatic failure caused by chrnic aggressive hepatitis, Australia antigen psitive. Fig. 6 shws the curse f a 28 year ld wman with this disrder. Her serum had been persistently psitive fr the Australia antigen fr 2 years. At the time f admissin t the hspital she was gravely ill with severe ascites, large pleural effusins, a serum albumin f less than 2 gm/ioo rnl and a prthrmbin time f less than 20 %. Fllwing transplantatin her serum prmptly became negative fr the Australia antigen and remained s fr apprximately 2 mnths when it again became psitive. Sn afterwards her liver chemistries became abnrmal and it was apparent that she again had hepatitis. Despite slwly deterirating liver functin she was restred t a useful life amng her family and friends fr 20 mnths, when she died f a disseminated ncardia infectin. At autpsy, there was recurrence f chrnic aggressive hepatitis. T ecjmical prblems affecting results. Orthtpic liver transplantatin is a difficult prcedure as mst f the patients have severe prtal hypertensin. Remval f the recipients wn liver is cmplicated by the presence f extensive venus cllaterals and by cagulatin defects. In previus publicatins we have mentined prblems with anatmic abnrmalities, cltting f vascular anastmses, phrenic nerve palsy and ther hazards. In this reprt we wish t cncentrate n a cmplicatin f biliary drainage which we have encuntered in 4 recently treated patients. Our usual technique f biliary recnstructin is by means f a chlecystdudenstmy after having ligated the cmmn bile duct distal t its junctin with the cystic duct (Fig. 7). This area is ptentially 3S ) // Fig. 7 Orthtpic liver transplantatin- ch~ lecystdudenstmy has been perfrmed fr biliary drainage. G. B. = gall bladder; H. A. = hepatic artery; 1. V. C. = inferir vena cava; P. V. = prtal vein. (By permissin f Ann. Surg. 168:392, 1968). vulnerable and may becme bstructed with inspissated bile r pssibly with cellular debris cast ff int the lumen in the curse f rejectin. In the 4 recent cases mentined abve biliary bstructin develped after an initial perid f nrmal bile drainage. Tw f the patients were perated upn in an attempt t relieve the bstructin which was cnfirmed by perative chlangigraphy (Fig. 8). Hwever, surgery was undertaken t late and the patients died f hepatic damage caused by the bstructin, cmplicated by ascending chlangitis. In the ther 2 patients the lesin was fund at autpsy examinatin. In each case the epithelial cells

10 30 Experience in Orthtpic Liver Transplantatin Chlecystdudenstmy B Fig. 8 Chlangigraphy f a hepatic hmgraft in which biliary recnstructin was with chlecystdudenstmy. LEFT - Technique f dye injectin thrugh a dudentmy and the anastmsis. RIGHT - Obstructed duct system. Despite re-explratin and cnversin t chledchdudenstmy, the recipient died f uncntrlled sepsis 46 days after transplantatin. f the bile ducts were swllen and cntained large numbers f cytmegalvirus inclusins, which were als present in the large accumulatins f intraluminal debris. It appears pssible that these bstructins were caused r at least cntributed t by cytmegalvirus infectin. In an attempt t avid this cmplicatin chledchdudenstmy was attempted in 4 subsequent cases using a new methd illustrated in Figs. 9a and 9b. Hwever in ne case the implanted bile duct retracted ut f the dudenum causing a fatal biliary peritnitis. We have since reverted t using chlecystdudenstmy. Future Prspects As experience has accumulated we have learned t avid many tedmical pitfalls which we encuntered in ur early cases. The biliary drainage prblems mentined abve have made us adpt a plicy f early explratin in any cases f prlnged pstperative jaundice, with chlangiography and, if necessary, biliary recnstructin. If warranted, antiviral therapy with cytsine arabinside will als be instituted. It is 'hped that these measures will imprve ur lng term results. Anther reasn fr hpe that we may imprve n ur 26 % ne year survival fig-

11 Experience in Orthtpic Liver Transplantatin ft' " k' A 5 ' ',~~('~ ~ --1.~~~-_ '.-... ;>::. ",C,''U,2de, nstmy." ~ I 37 \/W' ~) " 0 " i:.,' \ \ I; E'~ Fur sutures in place Fig. 9 a Technique f chledchdudenstmy. After pening the dudenum (A), a submucsal tunnel is created (8, C) thrugh which the hmgraft cmmn bile duct is passed (E). Fig. 9 b Chledchdudenstmy (cntinued). The hmgraft bile duct is secured in place with fur fine sutures (G, H, I) in such a way as t create an everting nipple (J). ure hinges n new develpments in immunsuppressin. Studies in renal hmgraft recipients during the past 15 mnths have shwn that Imuran can be effectively replaced as an immunsuppressive agent by small dses f cyclphsphamide, which d nt appear t be as hepattxic. Furthermre, a prly functining liver may fail t metablize Imuran prperly. Cyclphsphamide, n the ther hand, is given in its metablically active frm and shuld be effective n matter what the state f hepatic functin. In ur mst recent experience using cyclphsphamide in cmbinatin with prednisne and ALG, 4 f 5 liver re- cipients have dne well frm 1 t 4 mnths after peratin. If these preliminary encuraging findings are cnfirmed by further experience we may be n the threshld f a majr new advance in liver transplantatin. Summary The prime indicatin fr liver replacement is advanced benign hepatic disease. A ne-year survival rate is currently being achieved. A vidance f technical pitfalls and imprvements in immunsuppressive therapy may result in better lng term survival figures.

12 38 References: 1. Martineau, G., K. A. Prter, 7. Crman, B. Launis, G. T. Schrter, W. Palmer, C. W. Putnam, C. G. Grth, C. G. H algrimsn, I. Penn and T. E. Starz!: Delayed biliary duct bstructin after rthtpic liver transplantatin. Surgery 72, , Penn, 1. and T. E. Starzl: The clinical aspects f rthtpic liver transplantatin. In: Bilgy and Surgery f Tissue Transplantatin, ed. Andersn, J. M. Oxfrd, Blackwell Scientific Publicatins, 1970, p. 245 Experience in Orthtpic Liver Transplantatin 3. Penn, J., C. G. Halgrimsn and T. E. Starz!: Liver transplantatin in man. Ann. N. Y. Acad. Sci. 170; 251, Starzl, T. E. and C. W. Putnam: Experience in Hepatic Transplantatin. Philadelphia, Saunders, 1969 S. Starzl, T. E., C. W. Putnam, C. G. Halgrimsn, G. T. Schrter, G. Martzneau, B. Launis, 7. L. Crman, I. Penn, A. S. Bth 7r., C. G. Grth and K. A. Prter: Cyclphsphamide and whle rgan transplantatin in human beings. Surg. Gynec. Obstet. 133; 981, 191