Liver transplantation has become an extraordinarily valuable and useful operation, but one that is not perfect and that has not been exploited to anything like its full potential. Better immunosuppression may become available soon as exemplified by developments with the Japanese drug, FK506. Improved preservation with the UW solution is already here. With these advantages, liver transplantation is certain to become far more widely used than at any time in the past. Examples were cited of innovative approaches using liver transplantation for the treatment of hepatic malignancies

Concepcion, W

Gordon, RD

Iwatsuki, S

Makowka, L

Podesta, L

Starzl, TE

Stieber, A

Todo, S

Tzakis, AG

Yanaga, K

English

PubMed

Name not available

Liver transplantation: An unfinished product

D-Scholarship@Pitt

Liver Transplantation: An Unfinished Product Thomas E. Starzl, Saturo Todo, Andreas G. Tzakis, Robert D. Gordon, Leonard Makowka, A. Stieber, Luis Podesta, Katsuhiko Yanaga, Waldo Concepcion, and Shunzaburo Iwatsuki AFTER THE introduction of cyclosporine for immuno-suppression l and its combination with steroids/ liver transplantation transformed the practice of hepatology worldwide.3 In our own program (University of Colorado until 1980 and University of Pittsburgh thereafter), the yearly number of liver replacements rose to a new high of 30 in 1981, the second year of the so-called cyclosporine era. By 1987, the number was 396 and over the first six months of 1988, the number was 250, projecting to a total in 1988 alone of about 500 (Figure 1). SURVIVAL The improved survival in the cyclosporine era explains the avalanche of clinical activity. Whereas only one in three patients in the precyclosporine era lived for as long as a year postoperatively, survival has more than doubled since then (Figure 2). The one- and five-year actuarial survival of our 1,179 patients treated with cyclosporine before the end of 1987 with a minimum follow-up of at least seven months is 73 and 64%, respectively. There has been considerable stability of this patient popu-lation after one year (Figure 2). However, a gradual mortal-ity has continued after one year and a disproportionate contribution to this late fall-off has been from two diseases that have a high rate of recurrence, namely cancer and B virus hepatitis (Figure 3).4 PREVENTION OF RECURRENT 8-VIRUS HEPATITIS Prevention of the recurrent B-virus carrier state is one of the improvements that can be envisioned. A human monoclonal antibody directed against HBsAg has been produced (San-GRAFTS ~ r---------------------------------**~ 450 400 350 300 250 200 150 100 50 o Cyclosporine era Azathioprine era 63 65 67 69 71 73 75 77 79 81 83 85 87 YEAR Fig 1. Liver transplantation by year at the University of Colorado (through 1980) and the University of Pittsburgh (1981,onward)_ doz Corporation, East Hanover, NJ) by fusing peripheral blood lymphocytes from an immune adult human male to a mouse x human myeloma cell.s The resulting human mono-clonal HBIgG is 50,000 times more potent than commer-cially available HBlgG prepared from the blood of immune donors. Two patients have been treated with this monoclonal HBIgG beginning preoperatively or at the anhepatic phase of liver transplantation. Using only a few milligrams of the super HIBgG one recipient had reduction of the surface antigen titer from 1 :30,000 to equivocally detectable (titers 0 to 1:8), and the other (Figure 4) has had clearing of the surface antigen. The half-life of the human monoclonal IgG has been more than three weeks, allowing maintenance of an antibody excess with widely spaced injections (Figure 4). Although past efforts to treat the carrier state before and after transplantation with commercial HBIgG or interferon have failed, the monoclonal preparation looks more promis-ing. % SURVIVAL 100% 80 CYCLOSPORINE (n = 1179) • - - ~ - - - - - - - -I. ___________ • __________ • 60 40 AZATHIOPRINE (n = 170) 20 f-o 6 12 18 24 30 36 42 48 54 60 MONTHS AFTER LIVER TRANSPLANTATION Fig 2_ Actuarial survival of orthotopic liver recipients in the precyclosporine era (1963-1979) and after the introduction of cyclosporlne-steroid therapy In early 1980 (1980-1987). From the Department of Surgery, University of Pittsburgh Health Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Address reprint requests to Thomas E. Starzl, MD, Department of Surgery, 3601 Fifth Avenue, Falk Clinic, Pittsburgh, PA 15213, USA. Supported by Research Grants from the Veterans Administra-tion; Project Grant No. AM29961 from the National Institutes of Health, Bethesda, Maryland, USA. © 1989 by Appleton Lange, Inc. 0041-1345/89/$03.00/ +0 Transplantation Proceedings, Vol 21, No 1 (February), 1989: pp 2197·2200 2197 2198 % SURVIVAL l00·!. 80 ~ ..... K~ OTHER (n = 1088) ."""" .. ~I .. "".= .. ""K~""K --I~:=-=~ 601-40- 8-VIRUS (n = 47) 20 - p.O.Ol LIVER CANCER (n = 44) o 6 12 18 24 30 36 42 48 54 60 MONTHS Fig 3. Survival curves of patients who were B-vlrus carriers, or whose reasons for transplantation was hepatic malignan-cy. TRANSPLANTATION AND CANCER: ORGAN CLUSTERS New strategies may also improve the outlook after hepatic replacement for the indication of liver malignancies, using the liver as part of an organ cluster. The most extreme example has been a multivisceral transplantation of the liver, pancreas, stomach, small bowel, and colon. This operation was performed in dogs in 19606 and again 27 years later in a 31/2-year-old child with a short-gut syndrome and hepatic failure.' The recipient lived for more than six months, and achieved meaningful nutritional function of the hollow vis-cera. For long periods, the child was liberated nearly com-pletely from parenteral hyperalimentation. She died from complications of Epstein-Barr virus associated lymphoprolif-erative tumors (B-celllymphomas) in the liver that eventu-ally caused biliary obstruction and lethal bacterial sepsis. There was no rejection in the graft. In addition, there was no evidence of graft-versus-host disease (GvHD), possibly because the multivisceral donor had been treated with a large Patient #2 J.R. Date of Transplant: 5/23/88 28,664 :i. 175 e 150 Q. 125 ~ OIl 100 00( 75 ;, :I: 50 25 Pre-op ~ 1 15 30 45 60 t' ~ HB Monoclonal k t Antibody Dose i'l Days Fig 4. Results of treatment of a B-virus carrier with human monoclonal HBlgG before and after orthotopic liver transplan-tation. The surface antigen titers were measured with a sandwich technique, using a gamma counter. HepatitiS B antigen was eliminated from the blood after administration of monoclonal antibody. STARZL. TODO. TZAKIS ET AL dose of OKT3, with intense localization in donor lymphoid tissue of the mouse immunoglobulin.7 Shaffer and Monaco, et al,8 have shown in rat Fl hybrid studies how donor. pretreatment with antilymphocyte serum (ALS) can prevent GvHD and this objective may have been achieved in our human case. Multivisceral transplantation is not an all-or-none proce-dure. Recently, we have provided two patients with pancreas-liver grafts which in one case included the duodenum and a segment of jejunum. The first patient had sclerosing cholan-gitis with cholangiocarcinoma of the distal common duct. The second had a spindle cell sarcoma of the duodenum which had metastasized to the liver, but not elsewhere (Figure 5). In these patients, most of the colon and all of the organs in the upper abdomen (liver, pancreas, stomach, duodenum, spleen, and proximal jejunum) were removed. Under veno-venous bypass from the superior mesenteric vein and from the vena caval bed, the hepatico-pancreatic grafts were placed and GI continuity was restored as shown in Figure 6. These recipients are well but still with a postopera-tive follow-up of only a few weeks. The use of organ clusters that inciude the liver-pancreas axis will undoubtedly be used more frequently. A number of tumors which cannot be treated now will become susceptible to excisional therapy including those already mentioned as well as bile duct cell carcinomas and neuroendocrine tumors of the pancreas which metastasize to the liver. IMPROVEMENTS OF IMMUNOSUPPRESSION Although cyclosporine has been central to the revolution of the last decade in transplantation, its principal side effect of nephrotoxicity puts a cap on the permissible dosage, and this has meant that not enough of the drug can be given to control all rejections. As an alternative, polypharmaceutical regi-mens have been developed based on cyclosporine and ste-roids2 to which azathioprine or monoclonal ALGs can be added in what have been called double, triple, and quadruple regimens. By using smaller doses of individual drugs, their toxicity usually can be minimized. The other approach is to continue to add new and safer agents to our armamentar-ium. A prime contender as a new agent is the immunosuppres-sive drug, FK506, which was first reported by Ochai, et ai, at this meeting two years ago,9 and described most optimisti-cally by Todo, et ai, of the University of Pittsburgh. IO Much of Todo's work has been published, but we will mention some unpublished observations as well as follow-ups of seven previously reported dogs given orthotopic livers and then treated with FK506 on postoperative days four, five, and six. 1o In these dogs, no other therapy was given. A remark-able prolongation of survival was obtained with three of the animals living beyond a half year. Two beagle recipients are still alive in their eighth month with well tolerated livers from mongrel donors (Table 1). It has been difficult in the past to achieve this kind of tolerance induction (or quasi-tolerance) in outbred large animals with short course treatment or AN UNFINISHED PRODUCT Fig 5. CAT scan In a patient with a spindle cell sarcoma of the duodenum whose liver, pancreas, spleen, total stomach, ascending colon and transverse colon were removed en bloc. The re-placement organs are shown In Figure 6. Note the Involve-ment by tumor metastases 0 " all segments of the liver and cavitation of a dominant mass In the right lobe. single dose therapy, antilymphocyte serum (ALS) being the only previous agent that has made this possi ble." The most significant new (and unpublished) studies with FK506 have been with baboons, using the kidney (rather than the liver) model for testing. At first, Todo's results with baboons were disappointing, using doses per kg that were taken from rat and dog experiments (Groups I·III, Table 2). When the doses were increased by 5 to 10 times (G roups IV and V, T able 2), nearly universal success was achieved . The lack of effect of FK in doses that were extrapola ted fro m ra ts and dogs was perplexing but eventually expla inable by experiments of Dr Adriana Zeevi (of Pittsburgh) in which the allo-reactivity of baboon lymphocytes was quantitated in tissue culture after exposure to donor antigens. It required Fig 6. Reconstruction after removal of upper abdominal organs en bloc Including the liver, total pancreas, spleen, colon and all or part of the stomach. The homograft organ clusters are shaded. Left-The patient had sclerosing cholan-gitis and cholanglocarcinoma of the distal duct. Right-The patient had spindle cell sarcoma of duodenum with massive liver metastases (see Fig 5). 2199 almost 10 times more FK506 in the tissue culture medium to switch off the mixed lymphocyte reactions than was neces-sary to suppress rat and dog lymphocyte reactions. Thus, there is a major species variability in sensitivity to FK506. This can be quantitated with Zeevi's clever in vitro technique instead of the trial and error approach of times past. FK506 will undoubtedly be tried clinically within a short time. The drug is not toxic to baboons as was feared in some of the preliminary observations reported at an FK sympo-sium in Gothenberg a little more than a year ago.' 2 ORGAN PRESERVATION Another reason to project an increased acceptance and wider application of liver transplantation is improved preservation. Until last autumn, human livers were transplanted with a sense of urgency, the outside margin of safety being pretty much set at 8 or 10 hours using Collin's solution ll or plasma-like infusates.'4 This was drastical.Jy changed by Jamieson, Kalayoglu, Belzer, and their associates,'S with the so-called University of Wisconsin (UW) solution. Using the UW solution for slush preservation, we have reported a lack of correlation between the time of preservation out to one day , and liver injury as reflected by the longest prothrombin time in the first postoperative week. highest SGOT, graft survival. or patient surviva1.'6 When the UW solution was tried more widely , there were word-of-mouth reports by others of a syndrome of late hepatic failure three or four days after seemingly good primary function . This delayed syndrome has been said to be characterized by a secondary rise of bilirubin, or a failure of the bilirubin to fall to normal in the first place, To examine this question . we have now looked at an even larger total of 266 liver preservations of livers given to 2200 STARZL. TODO. TZAKIS ET AL Table 1. "Tolerance" Induction by Acute High Dose Treatment with FK506 Treatment Post Op No Treatment One mg I kg FK i.m. on days 4. 5. 6 6 (BIB) 24 (M/B) (B/B)-Beagle donor to beagle recipient (M I B)-Mongrel donor to beagle recipient 6 (M/B) 28 (M/B) 7 (BIB) 58 (BIB) patients undergoing primary transplantation. The preserva-tion time was for an average of 12.1 ± 6.6 (SD) hours (range 4 to 35) in the UW groups versus 6.0 ± 1.6 (SD) hours (range 4 to 9) in 142 comparable restrospective controls in which Euro-Collins solution was used. These studies have merely confirmed the revolutionary value of the UW solu-tion. Clearly, preservation for a day, or possibly even longer, is safe. There was no evidence of a late injury pattern that made the recovery profile of the recipients differ from that in the past with Euro-Collins solution. SUMMARY Liver transplantation has become an extraordinarily valu-able and useful operation, but one that is not perfect and that has not been exploited to anything like its full potential. Better immunosuppression may become available soon as exemplified by developments with the Japanese drug, FK506. Improved preservation with the UW solution is Table 2. FK506 for Renal Transplantation in Unrelated Baboons Dose (mg I kg I day) Groups I.M.· P.O·' 0 0 II 0.5 2 III 1.0 6 IV 2.0 12 V 2.0 18 *I.M.: on days 1.2.3 **P.O.: from day 4, onward ***Rejected. Survival Days 5,7. 11. 14 14.18 7.23,76 >22.>22,>25.>25,>27 23***.>78.>76,>77.>77 Canine OL TX Survival in Days 7 (M/B) 72 (BIB) 7 (M/B) 193 (BIB) 19 (BIB) >232 (M/B) 35 (BIB) >233 (M/B) already here. With these advantages, liver transplantation is certain to become far more widely used than at any time in the past. Examples were cited of innovat.ive approaches using liver transplantation for the treatment of hepatic malignan-cies. REFERENCES I. Caine RY, Rolles K, White DJG. ei a1: Lancet 2:1033, 1979 2. Starzl TE, Klintmalm GBG, Porter KA, et al: N Engl J Med 303:266, 1981 3. Starzl TE, lwatsuki S, Van Thiel DH. et al: Hepatology 2:614, 1982 4. Iwatsuki S, Starzl TE, Todo S, et al: Transplant Proc 20:498, 1988 5. Ostbert L, Pursch E: Hybridoma 2:361, 1983 6. Starzl TE, Kaupp HA Jr, Brock DR, et al: Am J Surg 103:219, 1962 7. Starzl TE, Rowe M, Todo S, et al: JAMA 1988 (In press) 8. Shaffer D, Maki T, DeMichele SJ, et al: Transplantation 45:262, 1988 9. Ochiai T, Nakajima K, Nagata M, et al: Transplant Proc 19:1284.1987 10. Todo S. Ueda Y, Demetris JA, et al: Surgery, 1988 104:239, 1988 11. Starzl TE, Marchioro TL, Porter KA, et al: Surg Gynecol Obstet 124:301, 1967 12. Starzl TE, Makowka L, Todo S (eds): 19 (suppI6):4, 1987 13. Benichou J, Halgrimson CG, Weil R III, et al: Transplanta-tion 24:407, 1977 14. Wall WJ, CaIne RY, Herbertson BM, et al: Transplantation 23:210,1977 15. Jamieson NV, Sundberg R, Lindell S, et al: Transplant Proc 20:945, 1988 16. Todo S, Tzakis A, Nery J, et al: JAMA, 1988 (In press) 

Liver transplantation: an unfinished product.

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Liver transplantation: an unfinished product.

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