Pediatric liver transplantation : The Indian perspective

Liver transplantation is now the accepted treatment for end stage liver disease, hepaticbased inborn errors of metabolism and localised primary hepatic malignancies. In children the commonest indication is biliary atresia. Innovations in surgical techniques, particularly liver reductions/splits and living related transplants have not only shortened the waiting period but have improved the results of surgery as well. The long term survival for pediatric liver transplant recipients in most large series from the Western world is more than 85%. Treatment protocols for ITU care of donors and recipients, anaesthetic care during surgery and post-operative immunosuppression are available. A country like India has a crying need for the development of facilities for liver transplantation in children but a number of factors have hampered the progress. The cost of surgery and post-operative immunosuppression and attitudes on life and death issues have been the greatest impediment. A few organisational details have also to be addressed to in order to minimise interdepartmental clashes of interest. It is hoped that a viable programme would soon be available for the children in India.     

Development of a pediatric liver transplantation program in Argentina

This article describes the preliminary experimental steps and clinical implementation of a purely pediatric liver transplantation (LT) program in a large public children's hospital in Buenos Aires, Argentina, a city with well over 10 million inhabitants and a referral population of over 30 million. Between 1993 and 1997, 84 LTs were performed in 81 patients, of which one-fourth weighed below 10 kg. The main indications were biliary atresia (n= 25, 30%) and fulminant liver failure (n= 23, 27%), followed by autoimmune cirrhosis (n= 14, 16%) and other liver diseases. Shortage of organs due to local conditions led to the use of liver-reduction techniques in 48 cases (57%), split liver in 2, and living-related donor (LRD) in 2. Retransplantation was necessary in 3 instances. Seventy-eight percent of the recipients survived for more than 1 year and 71% were alive after 4 years. The authors comment on the need for adaptation to local conditioning factors when developing a pediatric LT program in any country in which demographics and economic, medical, and sociological environments have a decisive influence on organ procurement, the actual performance of the operation, and the lifelong postoperative medication. In Buenos Aires, where the hospital setting is well-developed, the indications are in part determined by the high incidence of hepatitis A. Organ shortages in our area led to liberal use of liver reduction, split-liver, and LRD techniques. The overall results of the first years of such a program were largely satisfactory.     

Acute liver failure

Acute liver failure in children is a rare but potentially fatal disease. Causes of ALF in neonatal period are different from those in early or late childhood. Despite the improvement in the paediatric intensive care, liver transplantation remains the only effective treatment. Use of newer treatment modalities (liver assist devices and hepatocyte transplantation) is still in experimental phase. Management requires early recognition, prompt diagnosis of treatable condition, supportive therapy and prevention of complications hence these children should ideally be treated in a specialist unit.     

Current status of small bowel transplantation in children

Small bowel transplantation is gradually changing from an experimental procedure to a very desirable and viable treatment option in children with irreversible intestinal failure due to either short bowel syndrome or functional impairment. Long term total parenteral nutrition and home parenteral nutrition would be necessary to manage these children in the absence of a small bowel transplant programme. Parenteral nutrition is also associated with complications which can result in chronic liver disease. In India, there is no infrastructure for this treatment option and even if it was there the cost of this method of treatment is likely to be more than the cost of post-operative immunosuppression. Small bowel can be transplanted as an isolated graft, in combination with the liver or as part of a multiviscera! transplant. The operative techniques have been standardised. Major post-operative complications result from sepsis and lymphoproliferative diseases. The best results have been obtained with a combined liver and small bowel transplant.     

Current status of oxidative stress in pediatric liver transplantation

Czubkowski P, Socha P, Pawlowska J. Current status of oxidative stress in paediatric liver transplantation.
Pediatr Transplantation 2010:14: 169–177. © 2010 John Wiley & Sons A/S. Abstract: Generation of free radicals in children after liver transplantation is multifactorial from ischemia‐reperfusion injury, immunosuppression and post‐transplant complications. Thus, this group is at higher risk of oxidative imbalance with molecular and clinical consequences. We discuss pathogenesis and ways of action against oxidative stress in liver transplant recipients.     

Current status and actual need for pediatric liver transplantation in Southern Vietnam

Liver transplantation (LT) has considerably improved the outcome of patients with end‐stage liver disease, especially in children. The first pediatric LT in Vietnam was performed in 2004. To assess the current need for pediatric LT in Southern Vietnam, a total of 280 patients with chronic liver disease followed at Children's Hospital 2 (Ho Chi Minh City), the only pediatric LT center in this region, were evaluated from January 2009 to June 2014. Sixty‐seven patients satisfied criteria for LT but only one transplant surgery occurred since 2009. Parental consent for LT was obtained only in 28.4% of patients. The main reasons for the small number of LTs were financial costs, far distance from home, lifelong follow‐up and treatment, and shortage of organ donors. We conclude that the current need for pediatric LT in Southern Vietnam is high. Efforts should be made to develop the liver transplant program in this developing country.     

Portal vein reconstruction using vein grafts in pediatric living donor liver transplantation: Current status

PV reconstruction is an important aspect of LDLT, with post‐transplant outcomes depending on PV reconstruction methods. However, it is unclear whether the preferential selection of these techniques is dependent on preoperative recipient characteristics. This retrospective study assessed whether preoperative recipient factors differed in pediatric patients who did and did not receive VGs for PV reconstruction. Of 113 pediatric patients who underwent LDLT from January 2010 to July 2015, 31 (27%) underwent PV reconstruction with VGs and the other 82 (73%) without VGs. The presence of collateral vessels (P<.0001) and ascites (P=.02); PV size (P<.001), thrombosis (P=.01) and the direction of flow (P=.01), Child‐Pugh class A vs B/C liver function (P=.01), Alb concentration (P=.02), primary diagnosis: BA vs non‐BA (P=.03), and previous abdominal surgery (P<.005) differed significantly in patients who did and did not receive VGs for PV reconstruction. PV complications, patient survival, and graft survival did not differ significantly in patients with and without VGs at 1‐year follow‐up. VGs should be harvested for recipients with pretransplant hypoplastic PV, intense collaterals, hepatofugal flow, poor liver status, or previous abdominal surgery.     

Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience

Heffron TG, Pillen T, Smallwood G, Rodriguez J, Sekar S, Henry S, Vos M, Casper K, Gupta NA, Fasola CG, Romero R. Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience.
Pediatr Transplantation 2010:14:228–232. © 2009 John Wiley & Sons A/S. Abstract: Children transplanted for ALF urgently require an optimal graft and have lower post‐transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One‐ and three‐yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow‐up was 1452 days. ABOI one‐ and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non‐acute disease.     

Anesthetic issues in pediatric liver transplantation

Pediatric liver transplantations are becoming increasingly more common. Recent advances in the surgical and anesthetic management of these cases have greatly improved the survival rate. In order to successfully manage the anesthesia in these patients, one needs to have a thorough understanding of the pathophysiology of end-stage liver disease and the subsequent anesthetic implications. It is also necessary to appreciate the stages of the surgical procedure, as each stage presents different dilemmas to the anesthesiologist. This article will review the pathophysiology of liver failure in pediatric patients and outline the particular issues related to each stage of liver transplantation, allowing for the anticipation and management of the derangements that occur during surgery.     

Mutations in NBAS and SCYL1, genetic causes of recurrent liver failure in children: Three case reports and a literature review

Acute liver failure (ALF) in childhood is a life-threatening emergency. ALF is often caused by drug toxicity, autoimmune hepatitis, inherited metabolic diseases, and infections. However, despite thorough investigations, a cause cannot be determined in approximately 50% of cases. Here, we report three cases with recurrent ALF caused by NBAS and SCYL1 pathogenic variants. These patients did not present with any other phenotypic sign usually associated with NBAS and SCYL1 pathogenic variants. Two of them underwent liver transplantation and are healthy without recurrence of ALF. We propose NBAS and SCYL1 genetic analysis in children with unexplained fever-triggered recurrent ALF even without a typical phenotype.     

Improved outcomes in pediatric liver transplantation for acute liver failure

Miloh T, Kerkar N, Parkar S, Emre S, Annunziato R, Mendez C, Arnon R, Suchy F, Rodriguez‐Laiz G, Del Rio Martin J, Sturdevant M, Iyer K. Improved outcomes in pediatric liver transplantation for acute liver failure.
Pediatr Transplantation 2010: 14:863–869. © 2010 John Wiley & Sons A/S. Abstract: OLT is a life‐saving option for ALF. Aim: To evaluate our outcomes in pediatric OLT for ALF. Methods: Retrospective review of our data between 1992 and 2007. Results: Of 142 children with ALF, 126 were listed, of which 40 spontaneously improved, nine died, and 77 underwent OLT (median waiting time four days). Fifty‐three children received deceased donor grafts (34 whole and 19 split grafts), and there were 24 living donor grafts. The one‐ and five‐yr patient survival was 87% and 80%, and graft survival 83% and 79%, respectively. Thirteen patients died after OLT, and there were nine retransplants in seven patients. Patient weight, length of stay, creatinine, and infection were significantly associated with death; increased weight and black ethnicity were associated with graft loss on univariate analysis, but not on multivariate analysis. There were no significant differences in patient survival (one and five yr), graft loss, or other complications between the groups. Conclusion: We report the largest single‐center study of OLT in pediatric ALF, demonstrating no difference in outcomes between different graft types. Our liberal use of segmental grafts may allow earlier OLT in this high‐risk cohort and contribute to our excellent outcomes.     

Lifesaving liver transplantation for multi‐organ failure caused by Bacillus cereus food poisoning

Bacillus cereus is a spore‐forming, gram‐positive bacterium that causes food poisoning presenting with either emesis or diarrhea. Diarrhea is caused by proteinaceous enterotoxin complexes, mainly hemolysin BL, non‐hemolytic enterotoxin (NHE), and cytotoxin K. In contrast, emesis is caused by the ingestion of the depsipeptide toxin cereulide, which is produced in B. cereus contaminated food, particularly in pasta or rice. In general, the illness is mild and self‐limiting. However, due to cereulide intoxication, nine severe cases with rhabdomyolysis and/or liver failure, five of them lethal, are reported in literature. Here we report the first case of life‐threatening liver failure and severe rhabdomyolysis in this context that could not be survived without emergency hepatectomy and consecutive liver transplantation.     

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 ± 1.1 years). Pre-transplantation serum GH levels (7.5 ± 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 ± 0.5 ng/ml). However, post-transplantation levels (1.8 ± 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 ± 9.4 vs 190 ± 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 ± 96 ng/ml). In comparison with pre-transplantation data (z− 2.70), there was an increase in height 4 years postoperatively (z− 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z−1.58 ± 1.63 vs 2.59 ± 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.     

Living-donor liver transplantation for propionic acidemia

Propionic acidemia is a rare autosomal recessive disorder affecting the catabolism of branched-chain amino acids because of a genetic defect in PCC. Despite the improvements in medical treatment with protein restriction, sufficient caloric intake, supplementation of l-carnitine, and metronidazole, patients with the severe form of propionic acidemia have life-threatening metabolic acidosis, hyperammonemia, and cardiomyopathy, which results in serious neurologic sequelae and sometimes death. This study retrospectively reviewed three children with neonatal-onset propionic acidemia who received LDLT. Between November 2005 and December 2010, 148 children underwent LDLT, with an overall patient survival of 90.5%, in our center. Three patients were indicated for transplantation because of propionic acidemia. All recipients achieved a resolution of metabolic derangement and better quality of life with protein restriction and medication, although urine methylcitrate and serum propionylcarnitine levels did not decrease markedly. LT can reduce the magnitude of progressive cardiac/neurologic disability as a result of poor metabolic control. Further evaluation is therefore required to determine the long-term suitability of this treatment modality.     

Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure

This report describes a teenager who developed aplastic anemia (AA) because of non-A-E acute liver failure (ALF) requiring orthotopic liver transplantation (OLT). His AA did not recover spontaneously and he required treatment with ATG 9 months post-OLT. Bone marrow recovery occurred 4 months after immunotherapy and coincided with further intensification of immunusuppression required to treat early chronic rejection of the liver graft. Three years post-OLT he remains well with good bone marrow and liver function. Intensification of immunosuppression can lead to successful resolution of AA associated with non-A-E ALF.     

High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure

OTCD can present with ALF at any age. Under adequate therapy symptoms resolve quickly. We report a three-yr-old girl with the manifestation of an OTCD as ALF. Despite adequate pharmacotherapy and protein restriction, the patient deteriorated and developed hepatic encephalopathy. A high urgency liver transplantation was performed and the patient recovered completely. We conclude that in patients with ALF urea cycle defects in general and OTCD in particular should be considered as differential diagnosis. Patients should be managed in a center that has the capacity for an emergency liver transplantation.     

Successful liver transplantation in a child with Caroli's disease

Abstract:  CD is a rare autosomal recessive disease, characterized by multifocal cystic dilatation of intrahepatic bile ducts. The course of the disease is characterized by intrahepatic cholelithiasis, recurrent episodes of cholangitis, because of cholelithiasis, hepatic abscesses often ending in death caused by uncontrolled infection. Other conditions such as choledochal cyst and renal cystic disease are frequently associated, and patients have a higher risk for the development of cholangiocarcinoma. Endoscopic drainage of the bile duct is palliative and ineffective. OLT appears to be the treatment of choice. In monolobar cases partial liver resection has been shown to be a curative therapeutic option. We report on the course of disease in a Turkish girl who was diagnosed with CD in the neonatal period. At the age of 8.2 yr, she received OLT and is in good health 57 months post-transplantation.     

Liver transplantation for acute liver failure due to toxic agent ingestion in children

Abstract: ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow‐up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post‐operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.