Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogenous group of inherited hepatocellular disorders and the clinical aspects, role of liver transplantation (LT), and its outcomes remain largely unelucidated. We present our data of LT for each type of PFIC and compare their early, and long-term outcomes, highlighting their individual differences and management strategies. METHODS: Prospectively collected data over a decade (2011-2022) of children with PFIC who underwent LT was analyzed. The groups (PFIC 1-4) were compared with regard to early and long-term outcomes including attainment of catch-up growth. RESULTS: Of 60 children with PFIC who underwent LT, 13, 11, 31 & 5 were of PFIC 1, 2, 3 & 4, respectively. There were no significant differences in gender, PELD scores, BMI, type of grafts, cold and warm ischemia times, intraoperative blood loss, and morbidity among the groups. Post-LT chronic diarrhea was observed in 6 (46.1%) children with PFIC-I, and of them, 3 (23%) developed graft steatohepatitis. Three of these children underwent total internal biliary diversion (TIBD) and on 1-year follow-up, their graft steatosis resolved and they attained catch-up growth. Catch-up growth was significantly poorer in the PFIC1 group (44.4% vs. 88%, 90%, 100% p < .001). Overall 1- and 5-year patient survival of the four PFIC groups (1-4) were 69.2%, 81.8%, 96.8%, 100% & 69.2%, 81.8%, 96.8%, 100%, respectively. CONCLUSION: Ours is the largest to-date series of LT for PFIC illustrating their short- and long-term outcomes. While the results for the whole cohort were excellent, those after LT for PFIC1 was relatively poorer as reflected by catch-up growth, graft steatosis, and post-LT diarrhea, which can be optimized by the addition of TIBD during LT.

Emergency ABO-incompatible living donor liver transplantation in Wilson disease-induced acute liver failure.

We report the clinical outcome of an emergency ABO incompatible-liver transplantation (LT) for an 8-year-old child with Wilson's disease-induced acute liver failure. The pretransplant anti-A antibody titer was 1:64, and hence he underwent three cycles of conventional plasma exchange as pretransplant liver supportive treatment for deranged coagulopathy and liver function followed by one cycle of immunoadsorption (IA) prior to LT. The posttransplant immunosuppression consisted of rituximab, tacrolimus, mycophenolate mofetil, and corticosteroid. The patient had anti-A isoagglutinin rebound with elevated aminotransferases levels from postoperative day 7 for which he was restarted on IA plasmapheresis, but antibody titers did not decrease. Hence, he was switched to conventional plasmapheresis (CP) with which anti-A antibody titers decreased. The total dose of rituximab (150 milligrams/square meter of body surface area) was given in two divided doses of 75 mg at D-1 and D + 8 which was much less than the dose conventionally advocated (375 milligrams/square meter of body surface area). He is clinically well with good graft function without rejection after 1 year of follow-up. This case illustrates that IA and CP in conjunction with adequate immunosuppression is a viable approach in emergency ABO-incompatible-LT in Wilson disease-induced acute liver failure.

Graft-Versus-Host Disease in Pediatric Living Donor Liver Transplant.

Acute graft-versus-host disease is an extremely rare complication after pediatric liver transplant. Despite a better prognosis in pediatric than in adult recipients, graft-versus-host disease is associated with high mortality. We report 2 cases of pediatric recipients with acute graft-versus-host disease; both had identical clinical presentation. Remission was achieved in both patients, but the first patient developed Epstein-Barr virus-induced posttransplant lymphoproliferative disease and recurrence of graft-versus-host disease after the immunosuppression regimen was altered. The treatment options and clinical considerations for care of such patients are discussed. It is important to maintain a high degree of suspicion for graft-versus-host disease in every posttransplant patient with persistent skin rash, with or without fever and diarrhea, and confirm the diagnosis.

Liver Transplantation: A Safe and Definitive Alternative to Lifelong Nitisinone for Tyrosinemia Type 1.

OBJECTIVES: To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). METHODS: Clinical data of children with TT-1 who underwent living donor LT between July 2009 and May 2020 were retrospectively analyzed. Data included pre-LT nitisinone therapy, graft type, post-LT complications, HCC incidence, and graft/patient survival. RESULTS: Nine children were diagnosed with TT-1 at a median age of 12 mo (6-54 mo). Nitisinone was started in 6 patients at a median age of 15 mo (6-42 mo), but all had frequent interruption of therapy due to logistics with drug procurement including its cost. Median age at transplantation was 5 y (2-11 y). Explant liver showed HCC in 5 patients (55% of total cohort). The graft and patient survival are 100% with median follow-up of 58 mo (24-84 mo). CONCLUSION: LT is curative for TT-1 and excellent results can be obtained in experienced centers. This is especially favorable in countries with limited resources where the cost of medical therapy is highly prohibitive, with lifelong diet restrictions and unclear long-term risk of HCC.

Cystic fibrosis associated liver disease in children.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene. CF liver disease develops in 5%-10% of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications. We review the pathogenesis, clinical presentations, complications, diagnostic evaluation, effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.

Improved survival in children with HPS: Experience from two high volume liver transplant centers across continents.

BACKGROUND: Severe HPS increases morbidity and mortality after LT in children. We reviewed the combined experience of LT for HPS in children from two LT centers in Europe and Asia. METHODS: All children with "proven" HPS as per ERS Task Force criteria (detailed in manuscript) who underwent LT were categorized into M (PaO2 ≥80 mmHg), Mo (PaO2  = 60-79 mmHg), S (50-59 mmHg), and VS (PaO2 <50 mmHg) HPS, based on room air PaO2 . RESULTS: Twenty-four children with HPS underwent 25 LT (one re-transplantation) at a median age of 8 years (IQR, 5-12), after a median duration of 8 (4-12) months following HPS diagnosis. Mechanical ventilation was required for a median of 3 (1.5-27) days after LT. Ten children had "S" post-operative hypoxemia, requiring iNO for a median of 5 (6-27) days. "VS" category patients had significantly prolonged invasive ventilation (median 35 vs. 3 and 1.5 days; p = .008), ICU stay (median 39 vs. 8 and 8 days; p = .007), and hospital stay (64 vs. 26.5 and 23 days; p < .001) when compared to "S" and "M/Mo" groups, respectively. The need for pre-transplant home oxygen therapy was the only factor predicting need for re-intubation. Patient and graft survival at 32 (17-98) months were 100% and 95.8%. All children ultimately had complete resolution of HPS. CONCLUSIONS: VS HPS is associated with longer duration of mechanical ventilation and hospital stay, which emphasizes the need for early LT in these children.

Recurrent Intestinal Perforation After Cessation of Immunosuppression in Posttransplant Lymphoproliferative Disease in Pediatric Liver Transplant Recipient.

Posttransplant lymphoproliferative disease (PTLD) is the most common malignant complication after solid organ transplantation. Gastrointestinal involvement as the presentation in early PTLD can occur in 25-30% of pediatric liver transplant recipients and can be the only system involved in 20%. Recurrent gastrointestinal perforation due to resolution of PTLD is an extremely rare complication. We report a 13-month-old male child diagnosed with PTLD, treatment of which lead to recurrent intestinal perforations. The child presented with gastrointestinal bleed 5 months after living donor liver transplantation for biliary atresia. Evaluation was suggestive of PTLD and biopsy confirmed diffuse large B-cell lymphoma. Positron emission tomography scan showed diffuse involvement of small intestine and ileum. Tacrolimus was withdrawn abruptly following diagnosis of PTLD as there was associated renal impairment. Child developed six episodes of small intestinal perforations over 3 weeks which required multiple laparotomies with closure of perforation and/or small bowel resection. Complete remission was achieved six months after diagnosis with cessation of immunosuppression alone and child is alive at 48 months follow-up without any recurrence. To avoid bowel perforation and complications related to tumor necrosis, immunosuppression reduction in PTLD should be gradual while carefully monitoring Epstein-Barr virus levels, tumor response, graft function, and general health status of the patient.

Wolcott-Rallison Syndrome- Endocrinopathy with Recurrent Acute Liver Failure.

A 2-yr-old child with early onset diabetes and hypothyroidism, and diagnosed as Wolcott-Rallison Syndrome, developed two episodes of acute liver failure and recovered, but he remains at high risk of developing another episode of acute liver failure. Autoimmune, metabolic or genetic disorders should be evaluated in children with recurrent acute liver failure and genetic tests needs to be considered.

Living donor liver transplantation in Alagille syndrome-Single center experience from south Asia.

To analyze the clinical characteristics and the outcomes of living donor liver transplantation in children with Alagille syndrome (AGS). Clinical data of children with AGS who underwent liver transplantation between July 2009 and May 2019 in our unit were retrospectively analyzed. Primary end-points were patient and graft survival. Ten children with AGS underwent living donor liver transplantation at a median age of 28 months (range, 12-84 months). Jaundice was the most common initial symptom and was noted after a median duration of 20 days after birth (range, 7-60 days). Two patients had undergone Kasai porto-enterostomy for misdiagnosis of biliary atresia. The most common indication for transplantation was severe pruritus with poor quality of life. Explant livers in three children showed cirrhosis with early well-differentiated hepatocellular carcinoma. We have 100% patient and graft survival at a mean follow-up of 32 months (range 3-72 months). The median z-score for weight and height at liver transplantation was -2.66 (range: -6.44 to -0.9) and -3.6 (range: -7.96 to -0.93) while at follow-up was -1.7 (range: -3.4 to -0.35) and -2.1 (range: -3.9 to -1.4), respectively. The estimated glomerular filtration rate was normal pretransplant and follow-up. This is the first series of LDLT for Alagille syndrome in the Indian sub-continent. We report excellent post-transplant outcomes in contrast to outcomes reported from Western literature.

Auxiliary Partial Orthotopic Liver Transplantation for Monogenic Metabolic Liver Diseases: Single-Centre Experience.

PURPOSE: Auxiliary partial orthotopic liver transplantation (APOLT) in metabolic liver disease (MLD) has the advantage of correcting the metabolic defect, preserving the native liver for gene therapy in the future with the possibility of withdrawal of immunosuppression. METHODS: Retrospective analysis of safety and efficacy of APOLT in correcting the underlying defect and its impact on neurological status of children with MLD. RESULTS: A total of 13 APOLT procedures were performed for MLD during the study period. The underlying aetiologies being propionic acidemia (PA)-5, citrullinemia type 1 (CIT1)-3 and Crigler-Najjar syndrome type 1 (CN1)-5 cases respectively. Children with PA and CIT1 had a median of 8 and 4 episodes of decompensation per year, respectively, before APOLT and had a mean social developmental quotient (DQ) of 49 (<3 standard deviations) as assessed by Vineland Social Maturity Scale prior to liver transplantation. No metabolic decompensation occurred in patients with PA and CIT1 intraoperatively or in the immediate post-transplant period on protein-unrestricted diet. Patients with CN1 were receiving an average 8-15 h of phototherapy per day before APOLT and had normal bilirubin levels without phototherapy on follow-up. We have 100% graft and patient survival at a median follow-up of 32 months. Progressive improvement in neurodevelopment was seen in children within 6 months of therapy with a median social DQ of 90. CONCLUSIONS: APOLT is a safe procedure, which provides good metabolic control and improves the neurodevelopment in children with selected MLD.

Clinical profile and etiology of diabetes mellitus with onset at less than 6 months of age.

The aim of this study was to determine the clinical profile and etiology of diabetes mellitus (DM) with onset at < 6 months of age. All children aged < 6 months diagnosed with DM at a tertiary referral center between 2005 and 2008 were included in the study. Three cases of DM with onset at < 6 months of age were identified. All patients were female and of the same ethnic origin, with nonconsanguineous parents. Intrauterine growth retardation was noted in all three patients, and diabetic ketoacidosis and hypertriglyceridemia in two of the three. Blood samples from all three patients and their parents were analyzed for mutations in the KCNJ11 gene (inwardly-rectifying potassium channel, subfamily J, member 11 gene; OMIM 600937). A heterozygous de novo mutation in the KCNJ11 gene was detected in one patient, which confirmed the diagnosis of permanent neonatal DM. Neither C-peptide secretion nor circulating islet cell antibodies were detected in any patient during diagnosis, but C-peptide elevation was detected in the patient with permanent neonatal DM after treatment with sulfonylurea. One infant had clinical and immunological evidence of congenital cytomegalovirus infection while the diabetes in another case was postulated to be syndromic. DM within the first 6 months of life is a rare condition with various etiologies. The high prevalence of Kir6.2 mutations in neonatal diabetes means that all children < 6 months of age diagnosed with diabetes should be tested for Kir6.2 mutations at diagnosis.

Clinical profile of Chikungunya in infants.

OBJECTIVE: To define the clinical manifestations of Chikungunya infection in infants. METHODS: The inclusion criteria was fever (defined as axillary temperature > 99.6 degrees F) with any one of the following features; seizure, loose stools, peripheral cyanosis, skin manifestations or pedal edema in children less than one year. Details of disease from onset of illness till admission were noted and a thorough clinical examination was done at the time of admission. Daily follow-up was performed and the serial order of appearance of clinical features was noted till complete recovery. The sera collected from patients after the 7th day of onset of fever was analyzed for specific chikungunya antibody by IgM antibody capture enzyme linked immunosorbent assay (ELISA). RESULTS: Fifty six (56) infants were laboratory confirmed for chikungunya, consisting of 34 (60.71%) males and 22 (39.29%) females. 4 (7.14%) infants were less than 1 month of age, 39 (69.64%) 2-6 months old and 13 (23.21%) 7-12 months old. Fever was invariably present, but associated constitutional symptoms in infants consisted of lethargy or irritability and excessive cry. The most characteristic feature of the infection in infants was acrocyanosis and symmetrical superficial vesicobullous lesions were noted in most infants. Erythematous asymmetrical macules and patches were observed which later progressed to morbiliform rashes. The face and oral cavity was spared in all observed patients. CONCLUSION: An entirely different spectrum of disease is seen in infants with chikungunya as compared to older children who need to be carefully observed for. The morbidity and mortality of the disease may be avoided by the rational use of drugs and close monitoring of all infants.

Permanent neonatal diabetes due to KCNJ11 gene mutation.

Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of diabetes within the first six months of life and insulin dependence life long. It has been recently discovered that mutation in KCNJ11 gene encoding Kir6.2, the pore forming subunit of ATP sensitive potassium channel (K ATP) is the most common cause and such patients may respond better to oral sulphonylurea drugs than insulin. Here is a rare case of permanent neonatal diabetes due to R20IC mutation in KCNJ11 gene.