This report reviews experience with 97 patients given liver transplants. We regard out survival statistics as unsatisfactory, but fell they should encourage further work since 22 patients have survived at least one year with a maximum survival of 5 13 YEARS. The Achilles' heel of liver transplantation os bile duct reconstruction. We presently rely upon Roux-en-Y reconstruction, or alternatively, duct-to-duct anastomosis with a T-tube stent. The prime indication for liver replacement is non-neoplastic liver disease, but a favourable malignancy for treatment may prove to be small intrahepatic duct cell carcinomas

Beart, RW

Bell, RH

Putnam, CW

Starzl, TE

PubMed

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~ '.' ~ !~ '. .. f' • 11' ; f~ ., f. ': " . . ~ .e> .. , . .,. ~ tt .. :. .t": ''''': .. ' IR !t !£ Postgraduate Medical Journal, 1976,52 (Suppl. 5), 104-108. Hepatic transplantation, 1975 CHARLES W. PUTNAM ROBERT W. BEART, JR RICHARD H. BELL, JR THOMAS E. STARZL From the Departments of Surgery. the University of Colorado Medical Center. and the Denver Veterans Administration Hospital. Denver. Colorado 80220, U.S.A. Summary This report reviews experience with 97 patients given liver transplants. We regard our survival statistics as unsatisfactory, but feel they should encourage further ", work since II patients have survived at least one year with a maximum survival of 5 2/ 3 years. The Achilles' heel of liver transplantation is bile duct reconstruction. We presently rely upon Roux-en-Y reconstruction, or alternatively, duct-tHud anastomosis with aT-tube stent. The prime indication for liver replacement is non-neoplastic liver disease, but a favourable malig-nancy for treatment may prove to be small intrahepatic duct cell carcinomas. DURING the last ten years over 200 patients have had liver replacement throughout the world. The Univer-sity of Colorado Group has contributed 97 cases to this total, at a rate of 10 to 20 per year, since 1967, when the first long term survival was achieved (Starzl and Putnam, 1969). On the basis of this experience, we would like to provide a progress re-port regarding survival statistics, indications for operation, our present views about bile duct recon-struction, and our current programme of immuno-suppression. Survival Table 1 depicts our 97 cases. Twenty-two patients have lived for-one year after operation, ten for two years and six have survived for three years. Two have passed the fi'(e years mark and both are alive now. Eighteen recipients are still alive, from three weeks to 51/, years postoperatively. An I8-year-old boy who is alive 52/ 3 years after transplantation represents the longest survival after liver transplan-tation in the world. There have been 11 late deaths, from 12 to 41 months postoperatively, for the reasons listed in The work was supported by research grants from the Veterans Administration; by grants Ar-AM-08898 and AM-01772 from the National Institute of Health; and by grants RR-OOOSI and RR-00069 from the General Clinical Research Centers Program of the Division of Research Resources. National Institutes of Health. TABLE 1. Cases of orthotopic liver transplantation treated . in Denver Lived 2 3 5 Alive Number year years years years now· 1963-1966 6 0 0 0 0 0 1967 6 I 0 0 0 0 1968 12 5 2 1 0 0 1969 6 2 1 1 1 1 1970 10 2 I 1 1 1 1971 11 2 2 2 0 2 1972 11 5 3 1 0 2 1973 13 3 1 0 0 3 1974 20 2 0 0 0 8 1975 2 0 0 0 0 I 97 22 10 6 2 18 • Longest survivors: 52/. years; 5 years. TABLE 2. Present status of 22 one-year survivors Alive 11/22-12 months to 68 months Dead 11/22-12 months to 31 years Recurrent cancer-3 Chronic rejection-2 Chronic hepatitis-2 Bile duct obstruction-2 Other infections-2 Table 2. Two late deaths were the direct consequence of failure of biliary drainage. The latest mortality was at three years, five months, and was related to an episode of haemophilus septicaemia. Recurrent cancer in patients treated for hepatoma caused three deaths after one year. This disease has also killed some of our patients earlier than this, and we therefore consider hepatoma to be a relatively poor indication for liver transplantation. However, it is not an abso-lute contraindication since one of our five year sur-vivors had a hepatoma in addition to biliary atresia. CaIne, and Daloze of Montreal, have also apparently cured hepatomas with liver transplantation. Biliary recon' With only the operatior important fa been a mult which com!=, tion lead the nical pro bIer we' have m choledochoc tube, cholec' graft comm, Because of c aforementioT we have rect cholecystoje.: None of I duct recons cholecystoen obstruction reated Alive now' o o o 1 1 2 2 3 8 1 18 tence ality ~d to rrent :hree ;ome ~fore ilion lbso-sur-esia. ~ntly Hepatic transplantation, 1975 105 Biliary reconstruction With only 22 one-year survivors, it is obvious that the operation is at present unsafe. The single most important factor in the high acute failure rate has been a multiplicity of technical misadventures, of which complications of biliary duct reconstruc-tion lead the list. Indeed, this is now the main tech-nical problem that we face. The different techniques we have used to restore bile drainage include choledochocholedochostomy with or without a T-tube, cholecystoduodenostomy after ligation of the graft common duct and choledochoduodenostomy. Because of continuing dissatisfaction with all of the aforementioned techniques of duct reconstruction, we have recently embarked on a trial of Roux-en-Y cholecystojejunostomy (Starzl et al., 1974). None of the commonly used methods of biliary duct reconstruction has been trouble-free. With cholecystoenterostomy, fistulae are uncommon, but obstruction occurs in 25% of the cases. These ob-structions at the cystic duct (Fig. 1) are sometimes due to cytomegalovirus (CMV) infection. Most commonly, however, no obvious aetiologic cause accounting.for the partial cystic duct obstruction is evident. Our main objection to choledochocholedochos-to my is the high incidence, about 50%, of bile fistula with subsequent subhepatic sepsis. We are sure that bile leak is always going to be a problem in the immunosuppressed recipient, so that if one does perform a duct-to-duct reconstruction, broad drain-age, such as by leaving part of the wound wide open, must be carried out. Under these conditiQ!)s, we have recently employed end-to-end duct reconstruction in two adult recipients. One patient is only three weeks post-transplantation, but the other is well six months after operation. With such well-defined technical complications, clinical evidence of cholangitis is easily understand-able and is often accompanied by histopathologic FIG. I. Partial cystic duct obstruction following orthotopic liver transplantation. Biliary drainage was provided by a Roux-en-Y cholecystojejunostomy. Two months after operation the patient suddenly became jaundiced. A transhepatic cholangiogram showed a partial obstruction of the cystic duct (small arrow). There was also a leak of the ligated common bile duct (large arrows). The patient died of sepsis before a secondary reconstruction could be accomplished. " 106 Charles W. Putnam et al. findings of cholangitis. In addition, a subtle and as yet hypothetical complication may occur in spite of an apparently satisfactory biliary duct reconstruc-tion. We have reported that systemic infection and even asymptomatic bacteraemia are common prob-lems in liver patients (Starzl and Putnam, 1969). In the liver recipients with bacteraemia, the failure to find any other focus of infection necessitates indict-ment of the homograft, as the site of entry, by the process of exclusion. The two possible routes of entry could be the portal vein or the duct system, but the latter seems the more likely to us. The exposed relation of the duct system of the orthotopic liver to gastrointestinal flora is probably the first step in bacterial 'leak' through the homograft which may well be bacteriologically porous without 0.,,,.,,.·· !if!JjJ Gall bladder removed ,--Common cIuc1 --Peristaltic - - - -direction the presence of histopathologically significant cholan-gitis. If bacteria enter the circulation through the duct system of hepatic homografts, the logical solution would be to carry out liver transplantation as far re-moved from the mainstream of the gastrointestinal tract as is possible (Fig. 2). The alternative would be to retain the sphincter of Oddi by using a choledo-chocholedochostomy with the important secondary defence provided by massive drainage. Obviously, we are recommending individualiza-tion of biliary duct reconstruction depending upon the circumstances of the case. But whatever the original technique, the development of either jaun-dice or systemic sepsis should cause intensification of diagnostic efforts to differentiate between duct obstruction and rejection. We always perform FIG. 2. Relative bacterial contamination with three kinds of biliary reconstruction. (A) Cholecystoduodenostomy. This procedure is the simplest, but probably carries the greatest risk of infection of the graft. (B) Roux-en-Y cholec:ystojcjunostomy. The liver is protected from bacterial contamination by creating an isoperistaltic limb of jejunum, 18 inches in length, isolating the biliary tree from the gastrointestinal tract. (C) Roux-en-Y choledochojejunostomy. A duct-to-bowel anastomosis is simple if the duct has become dilated. as would be the case if a conversion from B to C became necessary because of a cystic duct obstruction. (By permission of rrQnsplQntQlion Procudings, 6, 129. 1974.) intr ope de\ 1); per' exp nee< diaL Ind 11 incr hep antcholan-gh the duct al solution 'n as far re-'ointestinal e would be a choledo-secondary lividualiza-lding upon latever the ither jaun-:nsification 'ween duct s perform Hepatic transplantation, 1975 107 intravenous cholangiography in the early post-operative period. In almost all of our patients who develop jaundice, transhepatic cholangiography (Fig. I) and, frequently, percutaneous needle biopsy are performed. Cholangiography has been greatly expedited by the use of a thin-walled, small calibre needle which has great flexibility, permitting the diagnostic studies to be done with increased safety. Indications Indications for liver transplantation are becoming increasingly clear. Although we do not consider hepatomas to be a good indication, we have done three cases of small, unresectable duct cell carcinomas which were located at the bifurcation of the intrahepatic ducts (Fig. 3). Two of these patients are still alive, one at six months and the other one year after transplantation. Neither has evidence of recurrence. The best candidates for liver replacement are those with non-neoplastic liver disease. Biliary atresia, chronic aggressive hepatitis and Wilson's disease are disorders with which we have had mJ,!ltiple successes. Our worst results have been with alcoholics. Ten of 11 patients with end-stage Laennec's cirrhosis have died from three to 121 days post· transplantation. FIG. 3. Cholangioc:arcinoma. diagnosed by transhepatic cholangiography. and treated by orthotopic hepatic transplantation, The patient is well one year later. G B = gall bladder; CD = common duct. " , I 108 Charles W. Putnam et al. The only surviving recipient is in good condition ten months postoperative. If liver transplantation is to succeed in patients with alcoholic cirrhosis, potential recipients must be selected earlier, treated aggressively to prevent or correct infectious, pulmonary or other complications, and transplanted before their con-dition has markedly deteriorated. Immunosuppression Finally, a few words about immunosuppression, particularly antilymphocyte globulin. Our regimen of immunosuppression for liver transplantation has not changed appreciably in seven years. We use azathioprine and prednisone from the start. If we suspect hepatotoxicity from the azathioprine, we change to cyclophosphamide. Superimposed on these two drugs is a one-month course of anti-lymphocyte globulin. We are now using horse anti-lymphoblast globulin raised according to the schedules developed by Groth et al. (1972). In the average adult we give 4 ml per day for two weeks, then alternate days for another two weeks. We have not tried any kind of controlled study in our liver recipients-there are far too many variables and too few cases-but we are sure that our thinking about antilymphocyte globulin in these patients will be in-fluenced by the information shared at this conference and by what we see in controlled trials in renal recipients. References GROTH, C.G., KASHIWAOI, N., MOORE, G.E., HUSBERG, B .• BJORKEN, C., PUTNAM. C.W. &: STARZL, T.E. (1972) Pro. duction of a standardized antilymphocyte globulin. Behring Institute Mitteilungen. 51, 86. STARZL, T.E., ISHIKAWA, M., PUTNAM, CW., PORTER, K.A., PICACHE, R., HUSBERG, B.S., HALGRIMSON, CG. & SCHROTER, G. (1974) Progress in and deterrents to ortho. topic liver transplantation, with special reference to survival, resistance to hyperacute rejection, and biliary duct reconstruction. Transplantation Proceedings. 6, 129. STARZL, T.E. & PUTNAM, C.W. (1969) Experience in Hepatic Transplantation. Philadelphia, W. B. Saunders Co. Discussion HOBBS: As all your patients had ALG we cannot draw any conclusions about its role in liver transplantation, but I would like to know if any of your patients developed a cholestatic jaundice unrelated to technical surgical prob-lems. My reason for asking is that two other cases who had ALG for bone marrow transplantation, as well as~· the one I reported, developed a cholestatic jaundice. I think that this is almost certainly a form of chronic graft-versus-host reaction but it could be an unknown side effect of ALG. PUTNAM: We have had some cases of cholestatic jaundice but then this is a very prominent finding in rejection of liver grafts. It is difficult to separate drug related cholestasis from rejection. On biopsy using immunofluorescent techniques we have not found any evidence that ALG could be a causative factor. CALNE (Cambridge. United Kingdom): It is quite pos-sible to perform liver grafts without ALG. We have done 40 cases to date and our rejection rate would appear to be slightly less than yours. We have had many problems with bile drainage. The concept of maximum immunosuppression may well be wrong in all kinds of organ grafting, but especially in liver grafting. We have been able to have patients with liver transplants off steroids entirely which is something we have never been able to do in kidney graft patients. I feel the idea of the liver being less likely to reject is true for man as well as other species. I was also particularly pleased to hear that you had gone back to using azathioprine as a primary immuno-suppressant drug. Our early experimental work with cyclophosphamide suggested that it was a much less satisfactory immunosuppressant in kidney grafts in dogs, although it destroyed lymphocytes more efficiently than azathioprine. Naturally it is useful to have cyclophos-phamide as an alternative if the azathioprine causes hepatotoxicity but all in all I feel azathioprine is a better immunosuppressant. PUTNAM: I agree entirely with your comments regarding the liver graft and the need for immunosuppression. One thing we have come to realize is the tremendous flexi-bility required in the immunosuppressive regime if one is to achieve success in a liver graft. Some patients require absolute minimal suppression. Although we usually start with fairly large doses of prednisone, we attempt to reduce them rapidly. In some cases, with potential septic problems, we commence with a very small dose, and maintain this until obvious signs of rejection occur. In some of these latter cases this never happens. Thus alI in all the liver may well be less susceptible to rejection. postgraduc OF the c( deal, onl: blood dis immune ( The fi, which de: 1. It is bodl 2. The 3. The indh be s! 4. If a: the, adjl.: 

Hepatic transplantation, 1975.

Beart Jr, RW

Bell Jr, RH

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Hepatic transplantation, 1975

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Hepatic transplantation, 1975.

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