Pediatric Liver Transplantation

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Information about Pediatric Liver Transplantation

Published on September 30, 2015

Author: Apollo_Hospitals


1. Pediatric Liver Transplantation

2. Review Article INTRODUCTION Pediatric liver transplantation (LT) is now an established therapeutic entity for end stage liver failure of diverse etiologies. The use of superior immunosuppressive regimens, innovative surgical techniques, sophisticated pre and post-operative intensive care have allowed the application of LTto pediatric patients with excellent results. Recently presented data on graft survival in 52 children who survived more than 20 years after liver transplantation was 87%, 80%, 77%, 73%, and 59% at 1, 5, 10, 15, and 20 years, respectively [1]. Children operated at an older age have no less survival rates to that of adult patients and therefore with this trend, an increasing number of general pediatricians are confronted with the long-term care of LT patients [2]. HISTORICAL PERSPECTIVE Historically, children have been instrumental in the initial development and subsequent innovation in liver transplantation. Both the first attempted liver transplant in 1963 and the first successful transplant in 1967 involved young children [3,4]. While the late 1960s and early 1970s demonstrated the technical feasibility of LT, longer survival remained uncommon until cyclosporine was introduced in 1980 [5]. The natural history of childhood liver disease translates into a preponderance of infants and toddlers as transplant candidates. The shortage of size-matched organs 263 Apollo Medicine, Vol. 7, No. 4, December 2010 PEDIATRIC LIVER TRANSPLANTATION Akshay Kapoor*, Vidyut Bhatia**, Shilpi Jain***, Deepa Sharma****, Nameet Jerath*****, Manav Wadhawan******, Subash Gupta******* and Anupam Sibal******** *Junior Consultant, ** Attending Physician, *** Research fellow, **** Associate Consultant, ***** Senior Consultant, Pediatric Intensive Care,******Consultant, Gastroenterology, ******* Senior Consultant, Transplant Surgery, ******** Senior Consultant & Group Medical Director, Pediatric Gastroenterology and Hepatology, Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Anupam Sibal, Senior Consultant & Group Medical Director, Pediatric Gastroenterology and Hepatology, Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Pediatric Liver Transplant (LT) is now an established procedure for End Stage Liver Disease (ESLD) with biliary atresia being the commonest indication. Intensive pre-transplant evaluation, nutritional buildup and immunization are the fundamental pre-requisites of a successful LT. With improvement in surgical micro- anastomotic techniques and superior immunosuppressive regimens the success rate of pediatric LT is in excess of 90%. Most of the transplants in our country however are Living related, due to which a fairly large number of children expire awaiting a donor liver. There should be a concerted effort to evolve the cadaveric donation program, so that majority of the children are benefitted. Key words: Living Donor Liver Transplant (LDLT), Cadaveric transplant, Biliary atresia, Fulminant hepatic failure, Immunosuppression, Tacrolimus, Cyclosporine. translated into disturbingly high mortality rates of 25-40% for pediatric patients awaiting LT [6]. Techniques for transplantation of a reduced size liver were developed and validated in the late 1980s. The next innovation-splitting one liver into two smaller, transplantable grafts was developed and validated in the 1990s. In the early 1990s, living related LT emerged as an extension of the deceased donor split-liver strategy [7-9]. In parallel, utilization of microsurgical anastomotic techniques for the hepatic artery substantially enhanced graft outcomes. INDICATIONS FOR PEDIATRIC LIVER TRANSPLANTATION ThecommonestindicationforpediatricLTintheworld andinIndiaisextrahepaticbiliaryatresiafollowedbyacute liverfailure[10]. TheindicationsaresummarizedinTable1. Fulminant hepatic failure The indications for LT in FHF are based on the King’s College criteria (Table 2). End stage chronic liver failure As the natural history of biliary atresia is well known, patients with failed Kasai procedures should be referred to a transplant center as soon as it is clear that the operation

3. Apollo Medicine, Vol. 7, No. 4, December 2010 264 Review Article has failed. Failure of jaundice to clear 3 months post Kasai’s procedure is an indication for referral to a pediatric transplant unit. In other forms of chronic liver failure, including progressive biliary cirrhosis (familial cholestatic syndromes, sclerosing cholangitis), chronic hepatitis (hepatitis B and C, autoimmune, idiopathic), alpha-1- antitrypsin deficiency and Wilson’s disease, precise prediction of need for liver replacement is difficult. The best guide is a fall in albumin, prolongation of prothrombin time, and persistent rise in bilirubin (Table 3). Children should be referred to a transplant center before significant hepatic complications (such as variceal bleeding and encephalopathy) and impairment of growth and development set in. The pediatric end stage liver (PELD) disease scoring system In the United States in view of the increasing number of deaths while on the waiting list, inability to accurately categorize liver patients according to severity of liver disease using the partially subjective Child-Turcotte-Pugh classification and evidence that waiting time correlated Table 1 Summarized indications for pediatric liver transplantation [11] Cholestatic Metabolic Hepatocellular Biliary atresia Alpha-1-antitrypsin deficiency Acute and subacute hepatic failure Biliary hypoplasia (Alagille) Tyrosinemia Autoimmune liver disease (Type I & II) Nonsyndromic biliary paucity Wilson’s disease Chronic hepatitis B or C Progressive familial Neonatal hemochromatosis Polycystic liver disease intrahepatic cholestasis Giant cell hepatitis/neonatal Glycogen storage disease type I hepatitis of unknown etiology Cystic fibrosis Inborn errors of metabolism (not resulting in liver failure) Crigler-Najjar-syndrome Type I, ornithine transcarbamylase (OTC) deficiency, maple syrup liver disease (MSUD), familial hypercholesterolemia Non-resectable hepatic tumors Hepatoblastoma Hepatocellular carcinoma Table 2 King’s College criteria for LT in fulminant hepatic failure Acetaminophen poisoning Other causes of FHF Arterial pH < 7. 3 INR>6.5, or the following three factors INR>6.5 Age < 10 years S. creatinine > 3.4 mg/dL Non-A, non-B hepatitis or drug induced disease Duration of jaundice >7 days before encephalopathy INR > 3.5 S. bilirubin > 17.6 mg/dL Table 3 Indications for LT in end stage chronic liver failure A) Clinical parameters B) Laboratory parameters Recurrent variceal bleeding INR > 1. 4 Refractory ascites Indirect bilirubin > 6 mg/dL Intractable pruritis Albumin <3.5 mg/dL Growth retardation Cholesterol <100 mg/d Unacceptable quality of life

4. Review Article 265 Apollo Medicine, Vol. 7, No. 4, December 2010 poorly with death while on waiting list led to the creation of a revised allocation system the PELD scoring system in 2002. The essential elements include total bilirubin, INR, albumin, age <1 year and evidence of failure to thrive. PELD was developed to predict death in children while waiting for transplant or the need for transfer to ICU, so as to prioritize donor liver allocation to children [12]. In addition, the PELD system conferred special status and protection to pediatric organs and recipients. Contraindications to liver transplantation The contraindications to a liver transplant are detailed in Table 4. PRETRANSPLANT EVALUATION The aims of assessment for LT are to confirm the diagnosis and severity of disease, to identify any co- morbidities, to define the patient’s general medical status, to determine eligibility and priority for transplant and to arrange interim supportive care (Table 5). ECG-Electrocardiogram, EDTA-ethylene diamine tetera acetic acid, EEG-electroencephalogram, HIV-Human immunodeficiency virus, MRI-Magnetic Resonance Imaging. Nutritional rehabilitation Majority (70% at our center) of the children coming for LT are malnourished [13]. Nutritional rehabilitation optimizes nutrition and improves post surgical outcomes. Lower height z-score has been associated with longer post transplant hospital stays and increased hospitalisation costs [14]. Modular feeds allowing protein, carbohydrate and fat contents to be individually prescribed for each child are recommended. It is usual to provide a high protein (3 g/kg) and high carbohydrate intake using glucose polymers. The fat content of the feed should be balanced to provide 50% medium chain triglyceride and 50% long chain triglyceride. Many children require a high-energy intake (150% of Table 4 Contraindications for pediatric liver transplantation Active uncontrollable and untreatable sepsis Severe cardiopulmonary disease Multi-organ failure Extra-hepatic malignancy Mitochondrial disease Active substance abuse Advanced Grade-IV encephalopathy with severe neurological impairment Table 5 Pretransplant assessment guidelines Nutritional status Height, weight, triceps skinfold, mid-arm muscle area Identification of hepatic complications Ascites, hepatosplenomegaly, varices on endoscopy Cardiac assessment ECG, echo, chest X-ray (cardiac catheterization if required) Respiratory function Oxygen saturation, ventilation perfusion scan*, lung function tests† Neurological and developmental assessment EEG, Bayley developmental scales, Stanford–Binet intelligence scales Renal function Urea, creatinine, electrolytes Urinary protein/creatinine ratio Cr EDTA(if available) Dental assessment Radiology Ultrasound of liver and spleen for vascular anatomy Wrist X-ray for bone age and rickets MRI/angiography‡ Serology Cytomegalovirus Epstein-Barr virus Varicella zoster Herpes simplex Hepatitis A, B, C HIV Measles Haematology Full blood count, platelets, blood group *If cyanosed. †In cystic fibrosis. ‡If portal vein anatomy equivocal. recommended daily allowance) and fat soluble vitamin supplements to maintain growth. It is unusual for such sick babies to tolerate intensive feeding orally and most need nocturnal enteral feeding. Immunization It is essential to make sure that routine immunizations are complete. Children undergoing LTshould be immunized against measles, mumps, rubella, varicella, diphtheria,

5. Apollo Medicine, Vol. 7, No. 4, December 2010 266 Review Article tetanus, Hemophilus influenza type-B, Pneumococcus, influenza, hepatitis A and B and polio. Vaccines should be given at least one month before LT to ensure seroconversion.After LT, vaccination should be avoided in the first three months as these children are under high degree of immunosuppression, which may allow development of disease in case of live vaccines and inadequate seroconversion in case of others. Parents and other siblings should be advised to have annual influenza vaccines and pneumococcal vaccines should be repeated every five to six years [10]. Pre-transplant medical management Pre-transplant management aims at preventing and treating complications associated with end stage liver disease. These may include management of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, esophageal varices, hepatic encephalopathy and intense pruritus. Ascites and fluid retention is managed by restricted sodium and fluid intake and the use of diuretic therapy (spironolactone, furosemide and hydrochlorothiazide). Bleeding esophageal varices is a major cause of morbidity and mortality in patients with end stage liver disease. Initial management includes hemodynamic stabilization with aggressive fluid management and blood products. Subsequent treatment options include intravenous somatostatin/octreotide or endoscopic variceal band ligation. Pruritus may be very severe in some patients with cholestaticliverdisease.Amajorityofpatientsrespondtooral antihistamines, ursodeoxycholic acid and cholestyramine. Intractable pruritus sometimes responds to rifampicin. Hepatic encephalopathy may range from subtle neurological dysfunction to frank coma. Potential precipitating factors should be identified and treated. Living related liver transplantation Living related liver transplantation (LRLT) was developed to overcome the shortage of cadaveric livers. The major advantages of LRLT over a cadaveric LT are (i) the procedure is elective and can be done before severe hepatic decompensation has occurred (ii) a healthy donor is assured (iii) a very short cold ischemia time facilitates better graft quality and may reduce primary non-function of grafts and (iv) there may be an immunological advantage to the recipient if an organ is received from a parent or a sibling. LRLT has resulted in improved intra- operative stability, improved survival rates, shorter recuperation times, reduced time for hospitalization and markedly reduced overall cost of care. The donor mortality has been estimated at 0.5%. In India, since very few cadaveric organ donations take place and the adult waiting lists are long, it is unrealistic for a cadaveric organ to be offered to a pediatric recipient. In this situation, the only option is LRLT. Efforts are being made to encourage organ donation, but till then live related transplantation will have to be used more frequently. The postoperative course Postoperative management is done in the intensive care unit. The patient is monitored for early bile production, acid-base balance and coagulation. If the new graft is functioning well the early postoperative recovery may be straightforward, however, early-impaired graft function may rapidly result in a hemodynamically unstable patient with severe metabolic disturbances and multi-organ failure. Immunosuppression An enormous contribution to successful LT is from the phenomenal development in immunosuppressive therapy. Optimal immunosuppression aims prevention of rejection with least side effects and therefore demands a perfect balance of treatment during the vulnerable state after transplantation (Table 6). The usual immunosuppressive regimen consists of: Tacrolimus (Tac) and prednisolone, with or without mycophenolate mofetil (MMF).Although Cyclosporin has been successfully used safely and effectively in children, Table 6 Immunosuppressant drug toxicities Cyclosporin A Tacrolimus MMF Sirolimus Nephrotoxicity Nephrotoxicity Cytopenias Hyperlipidemia Neurotoxicity Neurotoxicity Gastrotoxic Gastrotoxic Hypertension Hypertension Cytopenias Hyperlipidemia Hyperglycemia Hirsutism Gastrointestinal-toxicity

6. Review Article 267 Apollo Medicine, Vol. 7, No. 4, December 2010 Tac based immunosuppression is preferred because it has been associated with less acute rejection, less estimated corticosteroid-resistant acute rejection rates and fewer cosmetic side effects such as hirsutism. It also is associated with better long-term graft survival. There is no evidence for an increased risk of lymphoproliferative disease in children treated with Tac [15]. Long-term renal dysfunction may be reduced with the use of induction immunosuppressants, such as daclizumab, a humanized antibody and basiliximab, a chimeric antibody and with MMF or sirolimus in maintenance immunosuppression [16]. The current protocol at our center is Tac with prednisolone. Complications Liver transplantation is a high-risk procedure with a mortality of 8-10%. The commonest complications are rejection, sepsis, arterial and venous thrombosis and biliary complications and primary graft failure. They can be divided into early and late (Table 7). Life after the transplant The majority of children resume normal growth within a year after liver transplant, and there appears to be a dramatic increase in general energy and activity. In a review or psychological adjustment and quality of life over a 5-year period, all children achieved normal growth velocity and 80% had normal height and weight measurement [18]. Early transplant, before significant, growth or developmental retardation occurs, leads to normal psychosocial development. Liver recipients participate in most age-related activities and attend school regularly including physical education classes. Increased numbers or severity of infectious illness does not appear to reduce school attendance. Table 7 Complications of liver transplantation [17] Early complications Late complications Primary graft non function Infections Acute rejection Varicella Vascular thrombosis (5-8%) EBV Sepsis HCV Biliary leak, stricture (5-6.7%) Systemic fungal infections GI complications: diarrhea, Chronic rejection perforation Renal dysfunction Others: hypertension, denovo Autoimmune hepatitis Liver transplantation in India The success of pediatric LT in developed countries has increased the awareness and need for such procedures in the developing world. With the establishment of transplant facilities successful pediatric LT is now available in India [19,20]. Selection of patients for transplantation requires consideration of not only medical criteria, but also the socioeconomic and educational background of the family. This is of paramount importance, because in addition to the initial expenditure, receiving a transplant also involves a lifelong commitment on the part of the patient and family to spend on immunosuppression and to adhere strictly to the postoperative care protocol including anti-infection precautions and long-term medication. The first pediatric liver transplant in the country was carried out at our center in November 1998 [21]. About 180 pediatric liver transplants have since been carried out in India till date. The commonest indications are biliary atresia, followed by fulminant hepatic failure, cryptogenic cirrhosis and progressive familial intrahepatic cholestasis. The longest follow up is of 12 years and the first successful recipient is leading a normal life and attending regular school. Our center has also carried out the youngest successful pediatric liver transplant in a 6 month old child, in a child with Crigler-Najjar syndrome and the first transplant for fulminant hepatic failure [22-24]. With increasing experience, LT has been successful in small infants particularly those with weights below 7.5 kgs [25]. Till date 50 pediatric liver transplants have been done at our center. The future of pediatric transplantation In previous decades, pediatric liver transplantation has become a state-of-the-art operation with excellent success rates and limited mortality. Graft and patient survival have continued to improve as a result of improvements in medical, surgical and anesthetic management, organ availability, immunosuppression, and identification and treatment of postoperative complications. The utilization of split-liver grafts and living-related donors has provided more organs for pediatric patients. Newer immunosuppression regimens, including induction therapy, have had a significant impact on graft and patient survival. The future entails identification of risk factors associated with long-term immunosuppression; development of tolerance-inducing regimens and definition of biomarkers that reflect the level of clinical immunosuppression. The development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver

7. Apollo Medicine, Vol. 7, No. 4, December 2010 268 Review Article transplantation and identification of barriers and facilitators that impact non adherence and transition of care for adolescents are other aspects which will require attention in the future. REFERENCES 1. Duffy JP, Kao K, Ko CY, Farmer DG, McDiarmid SV, Hong JC, et al. Long-term patient outcome and quality of life after liver transplantation: analysis of 20-year survivors. Ann Surg. 2010; 252(4): 652-661. 2. Mazariegos GV, editor. Pediatric kidney and liver transplantation: Cause for Optimism. American Transplant Congress; Seattle, Washington, 2005. 3. Starzl TE, Machioro TL, Faris TD. Liver transplantation. Ann Intern Med 1966; 64: 473-477. 4. Starzl TE, Groth CG, Brettschneider L, Penn I, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968;168: 392-415. 5. Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schroter GP. Liver transplantation with the use of cyclosporine a and prednisone. N Eng J Med 1981: 305: 266-269. 6. de Ville de Goyet J, Hansleithner V, Reding R, Lerut J, Janssen M, Otte JB. Impact of innovative techniques on the waiting list and results in pediatric liver transplantation. Transplantation 1993; 56: 1130-1136. 7. Singer PA, Siegler M, Whitington PF, Lantos JD, et al. Ethics of liver transplantation with living donors. N Eng J Med 1989; 321: 620-622. 8. Otte JB, de Ville de Goyet J, Reding R, et al. Living related donor liver transplantation in children: the Brussels experience. Transplant Proc 1996; 28: 2378-2379. 9. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991; 214: 428-437. 10. Taylor RM, Franck LS, Gibson F, Dhawan A. Liver transplantation in children: part 1—peri-operative issues. J Child Health Care. 2005; 9(4): 256-273. 11. Vilca-Melendez H. Paediatric liver transplantation: the surgical view. Postgrad Med J. 2004; 80(948): 571-576. 12. McDiarmid SV, Anand R, Lindblad AS. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation. 2002; 74(2): 173-181. 13. Sibal A, Pao M, Sharma S, Rajakumari DV, Rajasekar MR. Liver Transplantation. Apollo Medicine. 2005; 2(4): 324-327. 14. Barshes NR, Chang IF, Karpen SJ, Carter BA, Goss JA. Impact of pretransplant growth retardation in pediatric liver transplantation. J Pediatr Gastroenterol Nutr. 2006; 43(1): 89-94. 15. Kelly D, Jara P, Rodeck B, Lykavieris P, Burdelski M, Becker M, et al. Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial. Lancet. 2004; 364(9439):1054-1061. 16. Nobili V, Comparcola D, Sartorelli MR, Diciommo V, Marcellini M. Mycophenolate mofetil in pediatric liver transplant patients with renal dysfunction: preliminary data. Pediatr Transplant. 2003; 7(6): 454-457. 17. Rela M, Dhawan A. Liver transplantation in children. Indian J Pediatr. 2002; 69(2): 175-183. 18. Stone RD, Beasley PJ, Treacy SJ, TwenteAW, Vacanti JP. Children and families can achieve normal psychological adjustment and a good quality of life following pediatric liver transplantation: a long-term study. Transplant Proc. 1997; 29(1-2): 1571-1572. 19. Kelly DA, Sibal A. Liver transplantation in children. Indian Pediatr. 1999; 36(4): 353-355. 20. Sibal A, Rajasekar MR, Soin AS. Liver transplantation in the developing world. Indian J Pediatr. 1999; 66 (Suppl): S120-123. 21. Poonacha P, Sibal A, Soin AS, Rajshekhar MR, Rajakumari DV. India’s first successful pediatric liver transplant. Indian Pediatr 2001: 38: 287-291. 22. Guru FR, Sibal A. Liver transplant for Crigler-Najjar syndrome. Indian Pediatr. 2010; 47(3): 285-286. 23. Sibal A, Shah UH. The youngest successful pediatric liver transplant in India. Indian Pediatr. 2009; 46(5): 446. 24. Mishra D, Singh R, Sibal A. Liver transplantation for fulminant hepatitis A infection. Indian Pediatr. 2002; 39(2):189-192. 25. Kaur S, Wadhwa N, Sibal A, Jerath N, Sasturkar S. outcome of live donor liver transplantation in Indian children with bodyweight <7.5 kg. Indian Pediatr Aug 2010 [e-print].

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