Indian Pediatrics 1999; 36:356-361 

Need for Liver Transplantation in Indian Children

Over the last three decades liver trans- plantation (LT) has developed as a major advancement and therapy of choice for end stage liver disease in adults and children. Technical advancement and better immunosuppression has led to improved results of L T in children. L T has become a life saving procedure for children with acute liver failure, end stage liver disease and some of the metabolic defects(1). L T in children is being carried 'out in most of the developed countries with great success. In our country L T in children has neither been widely attempted nor has the need been assessed. It is therefore mandatory to assess the need for L T in Indian children and clearly identify subgroups of liver diseases where this procedure could be done. We therefore assessed the need for LT in Indian children with liver disease at a tertiary care hospital.

Subject and Methods

We retrospectively analyzed data of children admitted with liver disease to Pediatric GE services of our hospital from January 1992 to June 1997. All the children with liver diseases were evaluated as per the clinical and diagnostic criteria described previously(2). These children were divided into subgroups of acute liver disease (ALD), chronic liver disease (CLD), neonatal cholestasis syndrome (NCS) and miscellaneous disorders. Individual subgroups were further categorized for the need for L T on the basis of well established criteria at or during admission to our hospital. Various criteria used(3-5) were as follows:

1. Fulminant hepatic failure (FHF) non- paracetamol induced: persistent elevation of International Normalised Ratio (Prothrombin time of patient divided by control value: INR) > 4 with encephalopathy.

2. Cirrhosis with decompensation (ence- phalopathy andlor ascites, recurrent variceal bleeding, poor growth, loss of synthetic function such as deranged clotting and unacceptable quality of life).

3. Neonatal Cholestasis Syndrome (NCS): (a) Extrahepatic Biliary Atresia (EHBA) with decompensation or late referral > 4 months of age with biopsy proven cirrhosis; (b) Neonatal hepatitis with cirrhosis or decompensation; and (c) Choledochal cyst with cilThosis and decompensation.

4. Wilson's disease with hepatic prognostic index score> 6.0: Wilson's disease hepatic prognostic scoring index is based on serum bilirubin, AST level and elevation of INR(6).

5. Criglar Najjar syndrome type I.

Results

Of the 301 children admitted with liver diseases, 35% (n=106) had Chronic Liver Disease (CLD), 27% (n=82) had NCS, 26% (n=79) were Acute Liver Disease (ALD) and 11 % (n=34) were due to other causes (Table I). Of the subgroup with ALD, FHF was diagnosed in 19% (n=15).

Among FHF subgroup, 67% (10 out of 15) children qualified for LT as per the criteria de- scribed above (all cases had encephalopathy and median INR 5.02 (range 4.24-6.02). Of these 90% died during hospital stay, only one patient survived. Etiology of FHF was acute viral hepatitis (hepatitis B=3) and none had drugs or toxin as the etiological agent. Among the CLD, 13% (2 out of 15) cases of Wilson's diseases qualified for LT (Wilson's score 7 and 9, respectively) and both these cases died while 61 % (n=40) of cirrhotic children qualified for LT. Among children qualifying for LT, encephalopathy was present in all the cases; ascites in 70% cases; mean serum albu- min level was 3.05 gldl (SD 0.96); mean INR was 2.48 (SD 1.98); and none of our patients had poor quality of life or growth failure or recurrent variceal bleeding as an indication for transplantation. During hospital stay 45% died and others were discharged after having explained the bad prognosis.

In our study, 27% (n=82) children had NCS. LT was indicated in 79% (n=34) of 43 cases of EHBA. Of all the children (n=34) qualifying for LT, 28 cases presented after four months of age with biopsy proven cirrhosis; 6 other babies had decompensation (2 cases presented before 4 months of age and 4 after 4 months of age). During hospital stay 6 children with EHBA (n=34) died and the remaining 28 children were discharged after being explained the prognosis. Two patients of NCS due to choledochal cyst had decompensation (ascites) at presentation. One patient of Crigler Najjar syndrome Type I had kernicterus at presentation. This child would have qualified for L T before development of kernicterus.
 

TABLE I

 Distribution of Children with Liver Diseases (n-301)

Figures in parentheses indicate percentages.
@ Cirrhosis=non Wilsonian; $CAH = chronic active hepatitis; ** A]ATD'= alpha-1-antitrypsin deficiency; # EHBA = extrahepatic billiary atresia; ! = paucity of intralobular bile duct; !! Infants in whom scintigraphy and ultrasound was suggestive of EHBA but liver biopsy could not be done for definitive diagnosis(7).

Based on the above data, overall requirement of liver transplantation was computed as 30% (Table II); of these the major subgroups are cirrhosis, extrahepatic biliary atresia and fulminant hepatic failure (Table II).

Discussion

Our data shows that 30% of Indian children with liver diseases require LT. Eleven per cent (10 out of 89) of our children with liver diseases qualifying for L Thad FHF which is similar and comparable to the data from the west (Table III)(8). Of the ten cases of FHF who qualified for L T, 9 died as the L T could not be offered and one child survived without LT. The child who survived had elevated INR > 4 at the time of admission but supportive measures given during hospital stay resulted in improvement in INR and recovery of liver functions. Enough literature is available(9,10), to suggest that spontaneous recovery in FHF due to viral etiology can occur in approximately 20% of cases even after listing for LT. Hence this child was no exception. It also stresses the point that serial monitoring of INR and liver profile is a must in such patients during their hospital stay, till the time donor organ is available. Despite these measures it would still be a dilemma in patients with FHF, to identify patients who are likely to recover spontaneously and in whom L T may not be ultimately required(11, 12).
 

TABLE II

 Overall Requirement of Liver Transplantation in Indian Children.
 

* Seven cases: HBY in 6 and HCY in I; 33 cases were Cryptogenic (HBY tHCY t ANAl AMAlLKMtSMA negative)

TABLE III

Comparison of Indications for Liver Transplantation,
 

$ Listed for liver transplantation
* Failed portoenterostomy or decompensation on follow up
# Failed or unattempted portoenterostomy-
@ Crigler Najjar syndrome type I with kernicterl1s- 1 case, choledochal cyst-2 cases
 

Kasai's procedure done in EHBA children before 8 weeks of age is highly successful and has good long term results. However, 80% of these cases ukimately require LT(13). In developed countries, 50% of pediatric LT are performed in children with EHBA(14). These cases have either failed portoenterostomy or following successful portoenterostomy develop hepatic decompensation at later stages(l5). Indian children with EHBA are usually referred late to the extent that they are either cirrhotic or have established decompensated liver(7). Delayed referral results in missed opportunity for offering Kasai' s portoenterostomy. Success rates of Kasai's operation dramatically fall after 8 weeks of age. Therefore, LT is the only definitive therapy in most of the cases in the Indian set- ting. The possible reason for this late referral is lack of awareness among the doctors and patients. Emphasis has to be laid for early referral of EHBA cases so that portoenterostomy is done in pre-cirrhotic stage to obviate the need for LT as the first procedure - of choice. In our data 38% (n=34) children with liver disease who qualified for LT had EHBA. Thase results are comparable with the western data (Table III). It is mandatory to highlight the fact that this comparison is only in terms of number of cases. However, indication of L T in our children with EHBA is progressive liver disease resulting in cirrhosis and decompensation without offering Kasai' s procedure rather than failed or late decompensation following successful portoenterostomy.

Of all the children who qualified for LT, 45% (n=40) of our cases had liver cirrhosis. This number is higher in comparison to the western data (Table III). The higher frequency of cirrhosis in our series may be due to yet unidentified factors. Other factors may be lack of awareness and financial constraints which prevent our patients to be treated at chronic hepatitis stage.

Choledochal cyst is another cause of NCS in children. Definitive therapy of surgical biliary drainage with cyst excision has shown good long term results. In the absence of corrective surgery, these children develop cirrhosis and decompensation when LT becomes the only option. In our data there were two children with choledochal cyst, presenting with decompensation due to delayed referral. Both these cases qualified for LT.

One child with Crigler Najjar syndrome type I (enzyme defect causing failure of conjugation of bilirubin) with kernicterus (CNS toxicity following very high levels of unconjugated bilirubin) qualified for LT. However, LT has to be done prior to development of kernicterus(16). The number of children with Wilson's disease and hepatic prognostic index >6 (n=2) in whom LT was indicated was similar to the western data (Table III). We did not identify any child with non-Wilsonian metabolic liver disease who qualified for LT. This is due to lack of good referal practices and non availability of complete diagnostic facilities to identify rare metabolic defects. We compared our data with the series from Cincinnati Ohio which is a major referral center for metabolic liver diseases in children.

We thus conclude that a sizeable proportion (30%) of children with liver disease in India require LT. However, this figure may be an underestimate of the overall population. The requirement of L T can be further decreased in this country by adopting strategies of early referral or subjects with liver disease. To this effect early portoenterostomy of EHBA cases, early surgery for choledochal cyst, diagnosis of Wilson's disease much before development of cirrhosis and prevention of hepatitis B by adopting policy of universal immunisation will be beneficial. Adoption of such a strategy will ultimaterly mean LT for cryptogenic cirrhosis; EHBA for failed portoenterostomy or progressive liver disease after initial successful portoenterostomy; FHF (encephalopathy and persistent INR >4), and Crigler Najjar syndrome type I before development of kernicterus.

In our country, live related L T for children would be the most suitabie option(17, 18). Crigler Najjar syndrome type I would need auxiliary liver transplantation. Cadaveric donor graft transplantation may not be feasible immediately due to lack of legislation of brain death in individual states, fewer intensive care units, inadequate facilities for graft retreival and immediate transportation and social factors.

Thus our study provides a baseline data of indications of LT at a tertiary referal center. Based on this, pediatric L T programme can be prioritised, planned and developed in the nation.