Principal Historical Milestones and Breakthroughs
The basic technique of orthotopic liver transplantation was developed in dogs by Thomas E. Starzl in the early 1960s; the dog I watched myself when I was a research fellow with him in 1965 to 1966 lived for over 13 years under steroids and Imuran and served as the proof of concept. This original technique was successfully transposed to human beings with minor changes.
The Piggyback Technique
To avoid caval occlusion and veno-venous bypass, Tzakis described the piggyback technique : the native liver is excised with preservation of the retrohepatic vena cava (VC); the suprahepatic VC of the donor graft is implanted on the enlarged orifices of the recipient suprahepatic veins. Lateral clamping of the VC avoids the need for decompression of the lower part of the body. Decompression of the splanchnic bed during the anhepatic phase is not needed in cirrhotic children with portal hypertension because of spontaneous portosystemic collaterals. When the liver to be removed has a normal vascular resistance, like in metabolic diseases and hepatoblastoma, a swift vascular reconstruction is required.
This technique has become standard also for implantation of a segmental graft, both from cadaveric and from living donors.
Portal Vein Reconstruction
In children with biliary atresia, which is the most frequent pediatric liver transplantation (LT) indication, the very frequent hypoplasia of the portal vein must be appropriately corrected by portoplasty to avoid post-operative thrombosis. My first trainee in liver transplantation, Jean de Ville de Goyet, described the meso-Rex shunt for bypassing the thrombosed portal vein ; this has become the standard in most centers. This technique could also be used after LT.
Except in larger children where end-to-end biliary reconstruction is possible, the most reliable technique is an end-to-side anastomosis on a Roux-en-Y intestinal loop of sufficient length (50 cm) to prevent reflux.
Initiation of Clinical Experience
Thomas E. Starzl ( Fig. 1.1 ) performed in Denver, USA, the first attempts in children in the 1960s, with the first long-term survival obtained in a child transplanted in 1970 for biliary atresia with an incidental hepatocellular arcinoma who survived over 40 years, off medications for more than10 years.
In Europe, the first attempts were performed by Roy Calne in Cambridge in a child with biliary atresia in 1968 (death from cardiac arrest 90 minutes after the surgery). We also tried LT in Brussels for the same indication in 1971 (death after 7 weeks from biopsy-related bleeding).
The National Institutes of Health Statement
The increasing number of successful adult and pediatric liver transplants in the United States and Europe led the National Institutes of Health (NIH) in 1984 to state that liver transplantation had become a clinical service. This statement triggered the development of several LT programs in the United States and Europe. In 1986, a symposium I organized in Brussels convened four US and three European centers that had started LT in the early 1980s and performed at least 20 cases (Starzl’s team, initially in Denver and later in Pittsburgh, had already performed over 300 cases). The 1-year survival rates were between 30% and 83% ( Table 1.1 ).
|Centre||Period||Number||% Biliary Atresia||Patient survival|
|Cambridge||12/1983–8/1986||35||31||Overall: 60% at 14 months|
|Boston||1/1984–6/1986||23||55||Actuarial: 59% at 30 months|
|Brussels||3/1984–10/1986||34||73||Actuarial: 83%at 2 years|
|Dallas||9/1984–9/1986||44||41||Actuarial: 74% at 1 year|
|Hannover||6/1978–6/1986||35||48||Actuarial: 57% at 5 years|
|Minneapolis||4/1984–6/1986||35||60||Actuarial: 65% at 1 year|
|Pre-CyA, 1967–1979 |
CyA era, 1980–1986
|30% at 2 years |
70% at 2 years
Holistic Pediatric Approach
Success in LT is not limited to the mastering the technique and adequate immunosuppression. All needs of children requiring an LT should be covered by a pediatric multidisciplinary approach, something which is exemplified in this book.
Technical Variants Addressing Shortage of Full-Size Grafts From Pediatric Donors
To fill the gap between the number of pediatric candidates of young age and small size and the scarcity of size-matched pediatric donors, various techniques have been developed to reduce the graft volume to a certain anatomical part of an adult donor liver. Reducing the volume of an adult donor liver to fit into the abdomen of a small-size pediatric recipient was the first step allowing the real launch of LT. Conceptually, this approach did not intend to increase the total number of available liver grafts and was initially considered to be detrimental for adult recipients. This obstacle was overcome by the development of the “split” liver concept by R. Pichlmayer, H. Bismuth, C. Broelsch, and J.B. Otte (one liver for two recipients) and living liver donation. The technique of liver splitting is based on the dual anatomy of the biliary and vascular tree of the liver, allowing sharing between the left lobe adapted to a small child’s abdominal capacity, whereas an extended right lobe would fit an adult recipient; or between the right and the left hemilivers that would fit two small-size adolescent or adult recipients. The surgical splitting can be performed in situ as the first step of a multivisceral organ procurement or ex situ on the isolated cooled-down liver. This technique has been validated for the two options but is surgically more complex and time consuming. It is still underused except in countries with an intent-to-split policy like the United Kingdom, Switzerland, and Italy.
The persisting shortage of cadaveric donors provided the impetus to develop living-related liver transplantation (LRLT). After the failed attempts in two children by Raia in Brazil and the first success obtained by Russel Strong in Australia, Broelsch in Chicago in 1989, and Tanaka in Kyoto 1990 standardized the technique, which was implemented worldwide later on. My own group has acquired vast expertise with pediatric LRLT, currently exceeding 400 cases since 1993. Long-term patient survival rates show a significant advantage in favor of living donation: the 15-year patient survival rate was 93% in 254 consecutive LRLT compared with 83% in 236 post mortem grafts ( P = .002). Other potential advantages of living liver donation include the optimal quality of the graft; the shortening of the waiting time—reducing nearly to nil the risk of dying on the waiting list—the possibility to optimize the timing of transplantation, for example, for hepatoblastoma; and the possibility of a better immunologic tolerance when the mother is the donor. One-year acute rejection-free survival was 55.2% for maternal grafts compared with 39.8% ( P = .041) for paternal grafts but only in children with biliary atresia.
My comments will be limited to biliary atresia. We are coming a long way in this area. The first progress in the treatment of this condition, which when not operated, is always lethal within the first 2 years of life, was achieved by Morio Kasai (Sendai, Japan), who described the portoenterostomy in the late 1970s to reconnect the vestigial bile ducts to the gut.
Although about one-third of the children having undergone this type of innovative surgery will reach adult life with their native liver, another third will derive no benefits, and the remaining third will develop, sooner or later, biliary cirrhosis. For these two latter thirds, LT is the only therapeutic option.
In 1963, Starzl performed the first LT for biliary atresia in a 3-year-old child. He said: “Nothing we had done in the past could have prepared us for the enormity of the task. Several hours were required just to make the incision end enter the abdomen. … Bennie’s liver was encased in scar tissue leftover from operations performed shortly after birth. To make things worse, Bennie’s blood would not clot. The operation could not be completed…”
We encountered this inextricable situation at the beginning of our practice. The pediatric surgeons, failing to restore any biliary flow, used to operate again and sometimes again, often with the result described by Starzl. The validation of liver replacement has changed the picture with the description of a standardized sequential treatment, including a single attempt at hepatoportoenterostomy below the age of 3 months, adequate placement of the abdominal incision in regard of the liver, and prevention of adhesions between the liver and gastrointestinal tract. The overall management of a baby with an unsuccessful Kasai operation also made significant progress with medical measures, including artificial nutrition, when needed. Fig. 1.2 illustrates the example history of one of my own patients: unsuccessful portoenterostomy in 1983, desperate appeal of the mother in 1985 when informed about our initial experience with LT, and a desperate clinical condition with severe malnutrition and several long bones fractures. We referred the child to Claude Ricour, who had developed in Paris a remarkable program of parenteral nutrition. After that, the child was successfully transplanted; he is alive 33 years later, fully grown up, without any sequelae, and off immunosuppression for several years now.