Indian Pediatrics 2001; 38: 287-291
Indiaís First Successful Pediatric Liver Transplant
Liver transplantation is an accepted therapy for end stage liver failure in the developed world(1). Till recently the option of liver transplantation was not available to the developing world due to the prohibitive costs, lack of expertise and sophisticated infrastructure(2,3). We report the first successful pediatric liver transplant in India in a child with extrahepatic biliary atresia (EHBA).
An 18-month-old male child was referred for evaluation for a liver transplant. He was the second child, born of a non-consan-guineous marriage, at term, of average birth weight following an uncomplicated preg-nancy. His parents had noticed jaundice on day 3 of life which had been progressively increasing. He had also been passing pale colored stools since the first week. He was diagnosed as a case of EHBA for which he underwent a Kasaiís portoenterostomy at 62 days of age. During surgery the liver was found to be cirrhotic. Post Kasai the jaundice persisted. He also had repeated episodes of fever, probably due to cholangitis. He was referred in view of progression of jaundice and failure to thrive.
On examination he was malnourished, with a weight of 7 kg (<3rd percentile) and a height of 72 cm (<3rd percentile) as per Indian standards(4). He was deeply icteric and had stigmata of chronic liver disease in the form of grade II clubbing, palmar and plantar erythema. He had marked hepato-splenomegaly (the liver being palpable 7 cm below right costal margin and the spleen 4 cm below left costal margin). The abdominal veins were prominent and there was ascites. Examination of other systems was within nor-mal limits. Investigations revealed deranged liver function tests with serum bilirubin of 23.5 mg/dl (direct 15.8 mg/dl), AST 241 IU/L, ALT 107 IU/L, alkaline phsophatase 498 IU/L, GGT 322 IU/L, albumin 2.8 mg/dl, prolonged prothrombin time at 23.5/12 with an international normalized ratio (INR) of 1.9. On ultrasound liver had abnormal echotexture with normal portal flow. Grade II esophageal varices were seen on endoscopy. The biopsy showed evidence of well established cirrhosis.
The family was counseled for a liver transplant as the child fulfilled international laid down criteria for liver transplant(5). A living related orthotopic liver transplant was planned for him, as few organ donations take place in our center. The father was the obvious donor as he and the child had the same blood group (B +ve) and a suitable anatomy. The CMV IgM and IgG of both father and child was negative. The pre-operative work up of the donor and recipient included cultures from various sites, kidney function tests and a cardiac assessment. The hepatitis B, C, D markers were negative in both donor and recipient. CT volumetry of the donor showed a left lobe volume of 230 cc and angiography revealed a normal vascular anatomy. A psychiatric evaluation of the donor showed no psychiatric problems that would contraindicate a liver donation. The recipient received hepatitis A, hepatitis B and typhoid vaccines. He had received all other vaccines appropriate for age as per the standard immunization schedule. In view of poor nutritional status, he had intensive nutritional rehabilitation receiving 150 Kcal/kg/day (protein of 2.5 g/kg/day) for 6 weeks prior to surgery during which time his weight was built up by 2.5 kg.
He was operated on 15 November 1998, receiving a segment II and III graft from the left lobe of his fatherís liver. He was given 3 units of packed cell transfusion and 2 units of fresh frozen plasma during surgery.
Donor hepatectomy was performed after carefully delineating the lobar artery, left lobar bile duct and left hepatic vein by a combination of ultrasonic dissector, bipolar cautery and suture ligations of all blood vessels and bile ductules. He did not require any blood transfusions during surgery. Postoperative course was uneventful and he was discharged after one week. He was declared fit to return to work after one month.
Postoperatively the recipient was stable and required no pressors. He was given broad spectrum antibiotic coverage with amoxy-cillin, cefuroxime, metrogyl and standard three drug immunosuppression with cyclo-sporin (10 mg/kg/d), hydrocortisone (2 mg/kg/d) and azathioprine (2 mg/kg/d), prophy-lactic antifungals (nystatin 100,000 units orally qid) and Pneumocystis carinii prophy-laxis with co-trimoxazole (240 mg/d on alternate days).
He was extubated on day 4 and gradually built up on oral feeds. On day 12, his bilirubin and liver enzymes were found to be increasing (serum bilirubin 22.6 mg/dl, ALT 392 IU/L, AST 362 IU/L) and a liver biopsy was performed. The biopsy showed features of acute cellular rejection in the form of portal inflammation, some bile duct damage and endothelialitis for which he was given methyl-prednisolone (30 mg/kg/dose) for 3 days. There was a good response (serum bilirubin 10.1 mg/dl, ALT 97 IU/L, AST 68 IU/L). On day 18 he developed signs of peritonitis and was found to have ileal and colonic per-forations on laparotomy. He developed perforations again on day 21 and 25 for which he required further laparotomies. Thereafter, he underwent planned re-explorations on day 28 and day 31, which revealed no further perforations. As a result of 5 laparotomies he required further ventilation for a total of 30 days. He was on total parentral nutrition for 38 days receiving 100 Kcal/kg/day. He also received a course of ganciclovir (10 mg/kg/d) for CMV infection (CMV IgM and PCR positive).
He was discharged on day 68 with a weight of 9.7 kg. At discharge his serum bilirubin was 0.7 mg/dl with a direct of 0.2 mg/dl, AST 55 IU/L, ALT 35 IU/L, GGT 59 IU/L, INR 1.2, albumin 3.3 mg/dl and satisfactory cyclosporin trough levels on a dose of 45 mg twice daily. Steroids were discontinued after 3 months and azathioprine after 1 year. Co-trimoxazole was stopped at 6 months and antifungal prophylaxis will be continued for life.
Presently, at 18 months post transplant, he weights 14 kg and is thriving well. He has had no major illnesses and he is continuing on cyclosporin (last trough levels 100 ng/ml) the levels of which are monitored once a month and the dose adjusted accordingly. Recent investigations show a serum bilirubin of 0.6 mg/dl, AST 32 IU/L, ALT 38 IU/L, alkaline phosphatase 352 IU/L and INR 1.2.
The major indication worldwide for pediatric liver transplantation is extrahepatic biliary atresia with a failed Kasaiís operation accounting for more than half the children undergoing a transplant under the age of 2 years in the developed world(1). In a study performed at our center to assess the need for liver transplantation. 21.1% of children referred to us with hepatobiliary disease needed a liver transplant and EHBA consti-tuted the largest group (72.7%). Twenty-two children with EHBA had a failed Kasaiís procedure and 2 were too old (>6 mo) and so a Kasaiís portoenterostomy was not per-formed(6). Mehrotra et al. reported that 30% of all children with liver diseases and 79% of all children with EHBA required a liver transplant in their center(7).
The initial high morbidity and complica-tion rate post transplant has reduced world-wide following increased medical and surgi-cal experience. Our patient had one episode of mild graft rejection, which responded well to high dose methylprednisolone. Acute cellular rejection rates vary from 20% in infants to 70% in older chilren(1). Approximately, 70% of acute rejection episodes respond to pulse methylprednisolone therapy. Steroid resistant rejection may respond to tacrolimus. He also had CMV infection for which he was success-fully treated with ganciclovir. Episodes of repeated intestinal perforations were probably related to cautery burns during initial dis-section. The incidence of perforations is higher in liver transplant recipients who have undergone a Kasaiís procedure earlier. The incidence has been reported to be 6.7% with a reperforation rate of 53%(8). Facilities for prolonged ventilation and total parenteral nutrition enabled a suitable recovery.
At 18 months post transplant our patient is in excellent clinical condition with a normal functioning liver. He is growing and develop-ing normally. Long term studies in children and adolescents have demonstrated striking nutritional rehabilitation achieved following successful liver transplantation. Poor linear growth may be seen during the first 6 months after transplantation during which time children receive daily steroids but onset of catch up growth is observed between 6 and 24 months after transplantation and its magnitude does not differ in boys and girls(9). There is normal psychosocial development and puberty is usually normal but can be sometimes delayed(1). Successful pregnancy on immunosuppression has been reported(11). The long-term effect of immunosuppression on the development of post transplant lymphoproliferative diseases and other tumors remains unknown(12). There has been a dramatic increase in survival rates throughout the 1990s with most international centers reporting one year actuarial survival rates of between 85-90% and 5 to 8 years survival of 75 to 80%(13,14).
The challenges that liver transplant poses in India are manifold. Delay in referral (8/33 of the children we have assessed for liver transplant were too unwell to be transplanted-unpublished observation), lack of donor organs, cost of the transplant surgery, lifelong immunosuppression, risk of infection and logistic difficulties in follow up are some of the problems.
In our case although the child had been referred to us with fairly advanced liver failure and malnutrition, a 6-week nutritional rehabilitation program made him fit enough to withstand major surgery. Organ donations take place rather infrequently and as the adult waiting lists are long, it is unrealistic to expect a child to receive a cadaver graft at present. Worldwide the concept of living related liver transplantation is gaining more acceptance in view of donor organ shortage. The risk of donor mortality has been estimated as low as 0.5% which is low enough to allow a parent or a close relative the option to donate a segment of their liver(15). In our case the father was willing to donate a portion of his liver and he had no major complications thereafter.
Cost of liver transplantation is high but it is only a fraction of the cost of this procedure elsewhere in the developed world even though all consumables used remain the same.
Reservations have been made about the risk of infection but our patient has not suffered any major infection in the last 18 months. Follow up in his hometown is by his pediatrician who informs us of his clinical condition and blood reports regularly, to enable joint decisions. We had arrnanged for monthly cyclosporin assays, which have now become quarterly. In our case monitoring has not been a problem.
This case proves that liver transplantation is possible in India using indigenous skills and infrastructure. Until organ donation becomes established, living related liver transplantation would be the mainstay in India. If benefits of liver transplantation are to reach more children, early referral to a transplant center is imperative so that a transplant can be offered before complications set in that preclude transplantation.
Contributors: VP and DVR were the clinical registrars responsible for the care of the transplanted child. AS was the pediatric hepatologist in charge while MRR and ASS were the transplant surgeons. VP drafted the paper under AS supervision. He will act as guarantor for the paper.