Liver transplantation, which once was an experimental procedure of no practical interest, has become the preferred treatment for infants and children dying of almost all non-neoplastic end-stage liver diseases. Liver replacement is being provided by many well-trained teams on all of the continents, as is evident from the program today - the first international symposium on pediatric liver transplantation. I have been honored in giving the first paper in the process of introducing the remarkable work of a gifted younger generation of physicians and surgeons

Esquivel, C

Gordon, R

Starzl, TE

Todo, S

English

PubMed

Name not available

Pediatric liver transplantation

D-Scholarship@Pitt

Pediatric Liver Transplantation T.E. Starzl. C. Esquivel, R. Gordon. and S. Todo M y ASSIGNED TASK today is to pro-vide a history of liver transplantation in pediatric patients. The history is a rela-tively brief one, not much more than 25 years in duration. The seeds for the liver trials were planted in the laboratory in 1958 and 1959, with resulting descriptions of the operation and of the pathological changes caused by rejection. These quite extensive studies were completed before chemical immunosuppres-sion was a reality.I.3 IMMUNOSUPPRESSION AND KIDNEY TRANSPLANTATION Such immunosuppression was first tested in patients after the far more simple operation of renal transplantation. The drugs that were used throughout the years included azathio-prine alone,4 azathioprine plus prednisones to which antilymphocyte globulin (ALG) could be added as an adjunct,6 and more recently, cyclosporine (CsA) alone7 or with steroids8 and/or monoclonal ALG.9 The most impor-tant immunosuppressive programs of the last 25 years are summarized in Table 1. In the early 1960s when renal transplanta-tion was first tried in any numbers, few chil-dren were included except at our own center at the University of Colorado. One of the pedia-tricians there who had sent us an 8-year-old From the Department of Surgery. University Health Center of Pittsburgh. University of Pittsburgh. and the Veterans Administration Medical Center. Supported by Research Project Grant AM-29961 from the National Institutes of Health. Bethesda. MD. Address reprint requests to Thomas E. Starzl. MD. PhD. Department of Surgery. 3601 Fifth Ave. Falk Clinic 4 West. Pittsburgh. PA 15213. Presented by Dr Starzl at the European Symposium on Liver Transplantation in Children. Universite Catho-/ique de Louvain. Faculte de Medecine. October 11 and 12. 1986. © 1987 by Grune & Stratton. Inc. 0041-1345/87/1904-001 A$3.00/0 girl for renal transplantation witnessed so much morbidity in his own patient that he wrote a thoughtful editorial in the Journal of Pediatrics in 1964 that questioned deeply whether such endeavors should be allowed to go forward. lo One of his principal concerns was that with the necessity for long-term high-dose steroid therapy (combined with azathioprine), normal growth could not be expected. As it turned out, Dr Riley's little patient is today a practicing physician, and many other renal recipients of that era are still alive and well. It was not until 5 or 6 years later that it was realized that catch-up growth in many such children could be expected, especially if living related donors had been used with the consequent ability to greatly reduce steroid therapy for long-term mainte-nance. ll In 1966, the first systematic application of renal transplantation in children was de-scribed in Pediatric Clinics of North Ameri-ca. 12 In that article, it was noted in a general sense that the greatest application of whole organ transplanta-tion may prove to be in the field of pediatric medi-cine, in which the progression of disease is often due to failure of a single organ system. Under these circumstances the provision of good renal or hepatic or cardiac function might be expected to restore normal health. In adult patients comparable prob-lems are frequently and sometimes unexpectedly complicated by disorders other than those to which treatment was originally directed. The results with renal transplantation were so striking that many other centers began similar efforts, most notably at the Medical College of Virginia where Hume worked. 13 In the same Pediatric Clinics article, a brief notation was made about the possibility of liver transplantation as follows: It has been natural to think of extending comparable replacement therapy to diseases which result in 3230 Transplantation Proceedings. Vol XIX. No 4 (August), 1987: pp 3230-3235 PEDIATRIC LIVER TRANSPLANTATION Table 1. The Principal Developments in Immunosuppression. Developed With Kidney Transplantation and Applied to the Liver Agent(s) Year Reference Place Azathioprine 1962-1963 4 Boston Azathioprine-steroids 1962-1963 5 Denver ALG as adjunct 1966 6 Denver CsA 1978-1979 7 Cambridge. England CsA-steroids 1979-1980 8 Denver Monoclonal ALG 1980 21 Boston functional failure of other organs. At present, liver transplantation appears to offer the most immediate possibility of clinical utility. Such hope derives prin-cipally from studies in dogs. THE FIRST LIVER TRIALS Such optimism might have seemed exces-sive at that time since seven known clinical attempts at liver transplantation had already been made, five in Denverl4 and one each subsequently in Boston and in Paris, all unsuc-cessful. However, the basis for hope was demonstrable in a large series of dogs given nonrelated mongrel livers in 1963 and 1964 who had survived for more than 4 postopera-tive months and whose therapy with azathio-3231 prine was then stopped. ls A number of these dogs lived for long subsequent periods,16 and one died of old age more than a decade later. On July 23, 1967, a 19-month-old child with a large hepatoma was treated with liver replacement. Although she died 13 months later of metastases from the original malig-nancy, she provided the first prolonged sur-vival after orthotopic liver transplantation. 17 During the next 13 years, many additional examples of prolonged survival came from the Colorado program l8 and from other centers, most notably the Cambridge University and Kings College (London) consortium. 19 One of our patients from that era is the longest survi-vor in the world today, more than 17 years postoperative. However, during any time period between 1967 and 1980, between three fourths and half of all recipients of livers died during the first postoperative year. 18 These discouraging results were not appreciably improved with the acquisition of more experience. The most encouraging results were in children who throughout the years had a slight survival advantage both early and long after trans-plantation (Fig lA). X PATIENT SURVIVAL 100X AZATHIOPRINE TREATED PEDIA TRIC (86) -- ADULT (84) Fig 1. Total experience with orthotopic liver transplan-tation of 170 patients from 1t"63 to 1979 (A) and of 720 patients from 1980 to 1986 (B). Note the slight survival advan-tage of the pediatric recipients in both eras. Case accrual in the CsA era was until August 31. 1986. and follow-ups were to October 31. 1986. BOX 60X 40% --·-l~ ___ .. :_~IiD ________________ . 20% 22 A X PATIENT SURVIVAL 100% BOX J34 267 60" 190 40" 20" B ° : 24 '-- -------- --- --. -K--K_~ ~ __________ ..... -A!!. ______ •• __ . __ __ {J 18 16 16 14 CYCLOSPORINE TREATED 9J 47 23 7 K~-~----------... ----------------~~~-KII----------------... -92 42 2 YEARS 3 23 PEDIATRIC (265) AOUL T (455) 4 10 5 3232 There were a number of reasons for the poor results from 1967 through 1979 includ-ing uncertainty about the best method of biliary tract reconstruction, the commission of numerous technical errors, the use of livers before 1968 and 1969 from donors under other than brain death conditions, and the tendency to assume without ruling out other causes that rejection was always responsible for hepatic dysfunction in the posttransplan-tation period. However, the principal problem was that the immunosuppressive regimens used up to 1980 had little or no margin of safety in the context of liver transplantation. THE INFLUENCE OF CsA In 1976, Borel and his associates described the remarkable new immunosuppressive agent CsA.2o The subsequent clinical trials with this drug and its eventual marriage with steroids in a modern-day, double-drug program had a revolutionary effect on liver transplantation. 18 The one year survival more than doubled almost overnight, an advantage which has continued for at least the first 5 postoperative years (Figure IB). Since the introduction of CsA, a further refinement in immunosuppression has been the clinical use of monoclonal anti-T lympho-cyte antibodies9,21 manufactured with the hybridoma technique of Kohler and Mil-stein,22 The monoclonal ALGs produced with this method are many times more powerful than the older polyclonal preparations, and they are being used most commonly to reverse established rejection.9,21 TECHNICAL REFINEMENTS For children, the most important change in technique through the years was the standard-ization of bile duct reconstruction. In more than three fourths of pediatric cases, the recipient common duct is absent (biliary atre-sia) or too small to permit duct-to-duct recon-struction. Consequently, the most common procedure is duct-to-jejunal anastomosis after construction of a Roux limb.18 It is astonishing STARZl ET AL how this simple conclusion required so much time for final delineation, but until then one of the principal causes of failure was biliary tract obstruction or bile fistula formation postoper-atively. During the removal of the diseased native liver and the sewing-in of the new organ, occlusion of the systemic and splanchnic venous circulations can lead to such severe venous hypertension that all aspects of the operation are in a crisis atmosphere. Decom-pression of these pools with venovenous bypass techniques has made the operation of liver transplantation a more easily taught conven-tional procedure in adults. 18,23,24 Increasingly, the venovenous bypass tech-niques have made their way into the pediatric hospital. Initially, it was thought that a mini-mum bypass flow of 1,000 mLjmin would be necessary before the heparin-free venovenous bypasses would be safe, However, lower-flow bypasses have been complication free, and it is our present policy to use bypasses for all children over 15 kg. Today, the most common technical compli-cations in small recipients are of the vascular anastomoses, especially of the artery. Hepatic artery thrombosis is second only to rejection as a cause for retransplantation in infants. THE ORGAN PROCUREMENT PROBLEM The multiple-organ procurement tech-niques developed in the early 1980s have become standard worldwide.25 With the origi-nal technique, meticulous dissection of the hepatic hilum was carried out before infusions were begun in situ with cold solutions. In a more recent modification, the hilar dissection has been omitted, and all of the hiIar prepara-tion is done on the back table.26 Removal of the heart, kidneys, and liver can be completed in 30 to 60 minutes. Pediatric recipients, particularly very small ones, still die because of the lack of small donors. The possibility of reducing livers from larger donors by a partial hepatic resection has been extensively examined in the Catholic PEDIATRIC LIVER TRANSPLANTATION University of Louvain program by Dr Jean Otte. The most common procedure has been to remove the lateral segment of the left lobe for transplantation and discard the full right lobe or more. Although such procedures of transplanting partial hepatic remnants have been described before, the Belgium team has acquired the most extensive and encouraging experience. It is possible that the criteria for acceptance of pediatric donors are too inflexible, with consequent wastage of organs. In a recent retrospective study of our Pittsburgh cases in which donors were thought to be good, bad, or poor on the basis of liver function test results, blood gas determinations, and cardiocircula-tory status, there was no correlation between the outcome of the recipient and the quality classification of the donor.27 Our conclusion has been that there is almost no such thing as a poor pediatric donor. FACTORS IN SURVIVAL Throughout the history ofliver transplanta-tion, a slight (and frequently statistically insignificant) advantage has been enjoyed by the pediatric recipient (Fig 1). Since 1980, the 5-year actuarial survival rate of children has 3233 been just below 70%, marginally better than in adults. Most of the difference was accounted for by inclusion in the adult series of two diseases, chronic active hepatitis caused by B virus and malignant tumors, which have a high rate of recurrence after transplantation28 (Fig 2). In children, there have been no "bad dis-eases" (Fig 3), and so far, there have been no recurrences of original diseases. However, the poorest results have been with biliary atresia. With biliary atresia, the 5-year survival rate is projected at 64%, compared with almost t~n percentage points higher than this for the other common pediatric diseases (Fig 3). The reason is the great difficulty of treating patients with biliary atresia after extensive prior operations for the performance of por-toenterostomy or revisions of such proce-dures. The age of the recipient has proved to be the single most important prognostic factor in pediatric liver transplantation. Our own expe-rience with recipients of tiny size has been somewhat discouraging. Through June 1986 we have performed transplants on 20 patients weighing 5.2 to 9.7 kg.29 The ages of these recipients were 3 to 11 months, and all were INDICATIONS FOR 720 LIVER TRANSPLANTS Fig 2. Diseases in 720 pa-tients that led to liver replace-ment during 1980 to 1986. Note that malignant tumors and chronic active hepatitis were not heavily represented in the children. These latter diagnoses have carried a bad posttransplant prognosis in adults because of a high rate of recurrence of the original dis-ease. CIRRHOSIS BILIARY ATRESIA PRIMARY BILIARY CIRRHOSIS INBORN ERRORS SCLEROSING CHOLANGITIS PRIMARY TUMORS ACUTE HEPATIC FAILURE FAMILIAL CHOLESTASIS SECONDARY BILIARY CIRRHOSIS BUDD-CHIARI CONGENITAL FIBROSIS NEONATAL HEPATITIS TOXIC HEPATITIS 2 TRAUMA 2 ADENOMA 2 POL YCYSTIC 2 79 137 123 197 • PEDIATRIC Ill! ADULT ~~~ __ ~~~ __ ~~-i __ ~ o 50 100 150 200 250 NUMBER OF CASES 3234 STARZL ET Al 100X BOX 60X NEONATAL HEPATITIS (7) 40X INBORN ERRORS OF METABOLISM (54) -----------------20X o CIRRHOSIS (29) ............................ .. FAMILIAL CHOLESTASIS (15) BILIARY ATRESIA (136) _. __ .-1 2 3 YEARS profoundly ill. Otherwise, they would have been permitted to grow to a more advan-tageous size. Eight of the 20 recipients have died, including seven deaths in the early post-operative period and one late death from aspiration. Technical problems were frequent. Hepatic artery thrombosis occurred in five patients, but only one death was related to this complication. Three of these patients have received retransplants. One patient is stable and being allowed to grow before retransplan-tation will be done. Other technical problems included defects of biliary tract reconstruction and multiple intestinal perforations from ear-lier futile portoenterostomies. Encouraging as the overall results have been, the outlook would be less optimistic by about 20% without the frequent application of 4 5 Fig 3. Five-year actuarial survival rates of pediatric re-cipients with the most frequent diagnoses who were treated in the CsAera. retransplantation. 18,3o Thus, retransplantation has become one of the most common indica-tions for hepatic replacement. SUMMARY Liver transplantation, which once was an experimental procedure of no practical 'inter-est, has become the preferred treatment for infants and children dying of almost all non-neoplastic end-stage liver diseases. Liver replacement is being provided by many well-trained teams on all of the continents, as is evident from the program today-the first international symposium on pediatric liver transplantation. I have been honored in giving the first paper in the process of introducing the remarkable work of a gifted younger gen-eration of physicians and surgeons. REFERENCES 1. Starzl TE, Kaupp HA, Brock DR, et al: Surg GynecolObstet III :733, 1960 2. Moore FD, Wheeler HB, Demissianos HV, et al: Ann Surg 152:374, 1960 3. Starzl TE, Kaupp HA, Brock DR, et al: Surg Gynecol Obstet 112: 135, 1961 4. Murray JE, Merrill JP, Harrison JH, et al: N Engl J Med 268:1315,1963 5. Starzl TE, Marchioro TL, Waddell WR: Surg GynecolObstet 117:385, 1963 6. Starzl TE, Marchioro TL, Porter KA, et al: Surg GynecolObstet 124:301, 1967 7. Caine RY, RoUes K, White DJG, et al: Lancet 2: 1033, 1979 8. Starzl TE, Wei I RIll, Iwatsuki S, et al: Surg Gynecol Obstet 151: I 7, 1980 PEDIATRIC LIVER TRANSPLANTATION 9. Fung J1, Demetris AJ, Porter KA, et al: Nephron 1987 (in press) 10. Riky CM: J Pediatrics 65:797, 1964 II. Lilly JR, Giles G, Hurwitz R, et al: Pediatrics 47:548,1971 12. Starzl TE, Marchioro TL, Porter KA, et al: Pedi-atr Clin North Am 13:381, 1966 13. Williams OM, Lee HM, Hume DM: Transplant Proc 1 :262, 1969 14. Starzl TE, Marchioro TL, Von Kaulla KN, et al: Surg Gynecol Obstet 117:659, 1963 15. Starzl TE, Marchioro TL, Porter KA, et al: Sur-gery 58: 131, 1965 16. Starzl TE (with the assistance of Putnam CW): Experience in Hepatic Transplantation. Philadelphia, Saunders, 1969 17. Starzl TE, Groth CT, Brettschneider L, et al: Ann Surg 168:.392, 1968 18. Starzl TE, Iwatsuki S, Van Thiel DH, et al: Hepatology 2:614, 1982 19. CaIne RY, Williams R: Curr Probl Surg 16:3, 1979 3235 20. Borel JF, Feurer C, Gubler HU, et al: Agents Actions 6:468, 1976 21. Cosmi AB, Colvin RB, Burton RC, et al: N Engl 1 Med 305:308, 1981 22. Kohler G, Milstein C: Nature 256:495, 1975 23. Shaw BW Jr, Martin DJ, Marquez JM, et al: Ann Surg 200:524, 1984 24. Starzl TE, Iwatsuki S, Esquivel CO, et al: Semin Liver Dis 5:349, 1985 25. Starzl TE, Hakala TR, Shaw BW Jr, et al: Surg GynecolObstet 158:223, 1984 26. Starzl TE, Miller C, Broznick B. et al: Surg GynecolObstet 1987 (in press) 27. Makowka L, Gordon RD, Todo S, et al: Trans-plant Proc 19:2378-2382, 1987 28. Starzl TE, Iwatsuki S, Shaw BW Jr, et al: Semin Liver Dis 5:334, 1985 29. Esquivel CO, Koneru B, Karrer F, et al: 1 Pediat-rics 110:545-548, 1987 30. Shaw BW Jr, Gordon RD, Iwatsuki S, et al: Semin Liver Dis 5:394, 1985 

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Pediatric liver transplantation

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