| Abstract|| |
Pediatric liver transplantation has become a widely accepted therapy for children with end-stage liver disease. The objectives of this article are to review the development of liver transplantation in children, provide an overview of indications and complications, examine some of the exciting technical advances made over the last decade that have improved donor organ availability for children, look at some of the technical problems that still need to be solved, discuss current outcomes and outline new directions of research.
|How to cite this article:|
Ishitani MB. Pediatric liver transplantation. Saudi J Gastroenterol 1997;3:65-9
| History|| |
The first human liver transplant was performed by Starzl in 1963 on a three-year-old child with biliary atresia; however, the patient died shortly after the procedure. Similar efforts in Boston and Paris were also unsuccessful. In 1967, Starzl was successful in transplanting an 18-month-old child with hepatocellular carcinoma who lived 13 months before dying from metastatic disease  . Survival in these early patients was poor due to difficulties with immunosuppression and technical problems with the operation itself.
The introduction of cyclosporin A in the late 1970s coupled with advances in surgical technique led to major improvement in patient survival. By 1983, a National Institute of Health (NIH) consensus statement declared that liver transplanation was no longer experimental and was now an accepted form of therapy for end-stage liver disease  . Over the last decade, survival rates of children undergoing liver transplantation have improved with current one-year survival rates of 80% and three-year survival rates of 77%  .
One major problem in pediatric liver transplantation has been the difficulty in finding adequate size-matched donors in a timely fashion. Initial reports indicated mortality rates of 25-50% among children awaiting liver transplantation. To address this problem, Bismuth and Houssin in France and Broelsch in the United States developed the technique of reduced-size liver grafts, whereby an adult donor liver could be reduced in volume and used in a child with nearly equivalent results to a size-matched pediatric donor graft ,,, . In the 1990's, other advances in technique led to the successful use of split-liver grafts, in which a single liver is split between two recipients, and livingrelated liver transplants, in which a segment of liver from an adult living donor is retrieved and transplanted into a child.
| Indications|| |
The general indications for liver transplantation in children are:
- Primary end-stage progressive liver disease,
- Secondary progressive liver disease,
- Acute hepatic failure,
- Disorders of metabolism that can be corrected by liver transplantation for which there is no acceptable treatment, and
- Neoplastic conditions if a reasonable chance for cure is present.
The usual clinical indications for referral and evaluation of children with chronic liver failure include patients with: 1.Encephalopathy, 2.Failure to grow and develop (failure to thrive) 3.Complications of portal hypertension, such as ascites, gastrointestinal bleeding, and subacute bacterial peritonitis, 4.Decreased hepatic synthetic function, such as low albumin and impaired coagulation, 5.Intractable pruritus, 6.Recurrent episodes of cholangitis, 7.Bone complications of liver disease (hepatic osteodystrophy) or 8. Pulmonary complications of liver disease (hepatopulmonary syndrome).
Acute fulminant hepatic failure presents with the sudden onset of encephalopathy, coagulopathy, and jaundice in children with no previous history of liver disease. The most common causes are viral hepatitis (usually non-A, non-B or hepatitis B) or druginduced liver failure (acetaminophen, valproic acid). Mortality can be very high and early referral is mandatory to maximize the chance for survival.
Certain disorders of metabolism are also successfully treated by liver transplantation. These include common disorders where the liver is injured by the underlying disease process (Wilson's disease, alpha- l-antitrypsin deficiency) and uncommon disorders (omithine transcarbamylase deficiency, tyrosinemia) where the new liver provides a missing enzyme and allows phenotypic normal function.
Experience with liver transplantation in children with unresectable neoplasms is limited, although there does appear to be improved survival in children with unresectable hepatoblastoma who have undergone transplantation followed by adjuvant chemotherapy  .
Referral to a transplant center should be made as soon as the patient has been identified as having a progressive condition that will require transplantation. Early referral allows the greatest flexibility possible for the transplant center to assist in the management of the patient and provides the parents with the best choice of alternatives for treatment that could allow the transplant center time to find a suitable donor. Results of liver transplantation are also significantly better in patients who are transplanted electively versus those in a state of acute hepatic decompensation (a).
Primary liver disease
The major indication for liver transplantation in children is progressive hepatic failure brought on by complications of biliary atresia. Over 60 percent of children at most centers in the United States are transplanted for the progressive biliary cirrhosis brought on by this condition. Other common causes of liver failure in children include neonatal hepatitis, autoimmune hepatitis, viral hepatitis (A,B,C, nonA,non-B, non-C) and metabolic disorders, such as alpha-l-antitrypsin deficiency and Wilson's disease.
Secondary liver disease
Rare causes of secondary hepatic disease amenable to liver transplantation include cystic fibrosis with minimal pulmonary involvement and sclerosing cholangitis.
Acute hepatic failure
The majority of children with acute hepatic failure will present with the sudden onset of encephalopathy, jaundice, and coagulopathy. The most common etiologies are viral hepatitis (usually B, or C hepatitis) or drug-induced liver failure (acetaminophen, valproic acid). Mortality can be very high (>70%) and early referral is mandatory to maximize the chance for survival.
Diseases of metabolism
Certain disorders of metabolism can be treated successfully by liver transplantation. These include relatively common disorders, such as alpha-lantitrypsin disease and Wilson's disease and uncommon disorders, such as urea cycle defects (omithine transcarbamylase deficiency) and inborn errors of metabolism (tryosinemia, primary oxalosis). Many other rare disorders have also been successfully treated with transplantation, including glycogen storage disease type I, hypercholesterolemia Type I and IV, hemophilia A and B, galactosemia, Crigler-Najjar syndrome type I, and sea-blue histiocyte syndrome.
The most common malignant primary liver tumors in children are hepatocellular carcinoma and hepatoblastoma. Experience with liver transplantation in these children is limited, although there appears to be improved survival in children with hepatoblastoma who have undergone transplantation followed by adjuvant chemotherapy  .
| Contraindications|| |
There are a number of absolute and relative contraindications to liver transplantation in children. The current absolute contraindications are children with: 1. Untreated systemic infection, 2. HIV positivity 3. Acceptable alternative therapy or 4. Untreated malignancy outside the confines of the liver.
Relative contraindications include: 1. Poor neurologic or physical condition prior to transplantation with no expectation for improvement (example: cerebral palsy) 2. Impairment of other organ systems at the time of transplant that would preclude successful transplantation or 3. Disease that is expected to recur following transplantation (example: hepatocellular carcinoma).
| New technical advances in pediatric liver transplantation|| |
A major problem in pediatric liver transplantation in the early 1980s was the lack of suitable sizematched donors. Biliary atresia is the most common etiology for liver failure in children; these children often present during the first or second year following a failed Kasai portoenterostomy and are usually less than 10 kg in weight. Recent advances in reduced-size, split-liver, and living-related grafts have led to improved access to donor organs for children and have decreased the mortality among those children awaiting transplant to <5% , .
Reduced-size liver transplantation
The technique of reduced-size liver transplantation was initially suggested and performed by Bismuth and Houssin in 1984  . The technique was popularized in the United States by Broelsch and it is now a commonly used technique in pediatric liver transplantation. In most cases, an adult donor liver is obtained using standard techniques of multiorgan procurement. A decision is then made to perform the appropriate segmental anatomic dissection of the liver. Generally, a left lateral segment graft (segment 2,3) can be used in a recipient up to eight times smaller than the donor (example: 80 kg donor, 10 kg recipient). A left lobe graft (segment 2, 3, 4) can be used in recipients up to four times smaller than the donor. A large amount of leeway is present in the size differentials depending upon the anatomy of the donor liver (example: long, slender left lateral segment versus short wide lateral segment) and the size of the abdominal cavity in the recipient (example: a large abdominal cavity with a significant amount of ascites, large recipient liver).
After dissection of the donor liver, the recipient hepatectomy is done in standard fashion and the reduced size graft placed in orthotopic position. Care is taken to place the graft so as not to have it twist upon itself and cause kinking of any of the vascular or biliary structures.
Split liver grafts
A logical extension of this approach was to split the liver into two separate portions and to use the pieces in two different recipients. Initial results indicated a 20 percent increase in mortality with this technique  , but recent experience indicates this approach may be as successful as reduced-size graft techniques as further refinements in techniques are made.
Another approach towards increasing the donor organ pool has been to use living-related donor grafts from adults to provide a graft for a child. In most cases, a consenting parent volunteers to undergo a full medical and surgical evaluation, including an arteriogram. If he is deemed an appropriate candidate with suitable vascular anatomy, a donor left lateral hepatic segmentectomy is done and a standard orthotopic liver transplant is performed in the child. In many cases, the vascular structures are augmented by preserved cadaveric arterial or venous grafts to provide adequate length. Initial results of this technique indicate excellent recipient survival and low donor morbidity and mortality  . However, the overall acceptance of this approach is still unclear since the use of cadaveric reduced-size liver techniques has resulted in decreased pediatric waiting list mortality and it is controversial as to whether the small, but real risk of significant donor morbidity and mortality make living-related liver grafts a reasonable alternative. At least one donor has died of complications following the donor procedure  .
| Current surgical issues in pediatric liver transplantation|| |
Hepatic artery thrombosis
Hepatic artery thrombosis continues to be one of the major technical problems in pediatric liver transplantation, especially in recipients <10 kg. The small size of the common hepatic artery and comparatively low blood flow results in hepatic arterial thrombosis rates as high as 25%  . Several surgical techniques have been utilized to address this problem. These include: 1. Arterial anastomosis of the donor liver to the infrarenal recipient aorta using cadaveric saphenous vein or iliac artery grafts, 2. Use of low-level postoperative anticoagulation with dextran or antiplatelet agents, 3. Avoidance of hypotension and vasoconstrictive agents in the postoperative period. The results are improved with these different techniques, but hepatic artery thrombosis remains a formidable technical complication , .
Bile duct complications
Children usually undergo transplantation for complications of biliary atresia; therefore, they almost exclusively are treated with a Roux-en-Y Choledochojejunostomy for biliary drainage. Even if the recipient biliary anatomy is normal, the relatively small size of the recipient common bile duct makes a duct-to-duct common bile duct anastomosis impractical and Roux-en-Y biliary drainage is preferred. Complications generally occur because of ischemia to the bile duct or technical problems during the recipient operation. Ischemia is either due to interruption of the normal blood supply from the gastroduodenal artery during the donor hepatectomy or due to complications of hepatic arterial thrombosis.
Bile leaks can also develop from the cut edge of liver after a reduce size graft is performed. These can generally be managed with simple reexploration, suture ligation, and drainage  .
| Outcomes and the future|| |
The survival of children with end-stage liver disease has improved significantly as surgical techniques to widen access to donor organs has evolved. Survival after transplantation has also improved; in 1987 one-year survival rates were in the 60-70% range, while in 1993 one-year survival rates were in the 80-85% range. Results with new immunosuppressive agents, such as tacrolimus (FK506) and mycophenolate (RS-61443), may result in further improvements in graft survival and allow decrease in other agents with significant side effects in children. In particular, these new agents may allow a more rapid reduction in corticosteroid dosage which may allow more rapid catch-up growth in these children after transplantation.
| References|| |
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Michael B Ishitani
Assistant Professor of Surgery, Transplant Division, University of Virginia Health Sciences Center, P.O. Box 1005, Charlottesville, Virginia 22908
Source of Support: None, Conflict of Interest: None