Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis.

BACKGROUND: Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms. METHODS: We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort. RESULTS: Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm. CONCLUSIONS: Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.

Youngest Living Donor Liver Transplant for End-Stage Liver Disease in a 6-Month-Old With a Novel Aggressive Mutation in KIF12 Gene.

BACKGROUND: Kinesin family member 12 (KIF12) mutation-related cholestatic disorder represents a rare subtype of progressive familial intrahepatic cholestasis (PFIC), referred to as PFIC Type 8, with only 21 reported cases globally to date. METHODS: Here, we present a unique case of a 6-month-old boy diagnosed with homozygous KIF12 gene mutation, who successfully underwent a living donor liver transplant at our center for end-stage liver disease. RESULTS: This case marks the youngest patient of KIF12-related cholestatic disorder necessitating a liver transplant to date. The child initially presented with neonatal cholestasis and then developed infantile hepatic decompensation. Our report discusses the diagnostic process and management strategies employed. It underscores the importance of prompt diagnosis through clinical suspicion, biochemical parameters, and genetic testing, as well as the adoption of suitable management strategies, including the early contemplation of liver transplant in such exceptional and rare cases of genetic intrahepatic cholestasis. CONCLUSION: KIF12-related genetic disease should be considered in neonatal cholestasis cases with high gamma glutamyl transpeptidase to differentiate from conditions like biliary atresia. Favorable outcomes post liver transplant stress the importance of early genetic testing and referral to liver transplant centers for unresponsive patients, potentially saving lives.

Hepatitis A Liver Failure in Children: Native Liver Survival Despite Poor Prognosis.

Background: Hepatitis A virus (HAV) infection is the commonest cause of pediatric acute liver failure (PALF) in developing countries. Literature has shown good outcomes of HAV-induced PALF as compared to other etiologies. The advanced critical care and use of extracorporeal liver assist devices (ELAD) have improved the survival with native liver in PALF and overall outcomes. Various liver transplant listing criteria have been proposed in PALF, however none of them is specific enough to predict the outcome. The timing of liver transplant in living donor setting has never been straightforward. Dynamic clinical and biochemical monitoring of the ALF child is the key to decide for LT. Cases: Here we report three children with HAV-induced PALF presented with advanced hepatic encephalopathy (HE) and high international normalized ratio (INR > 10). These children survived with native liver despite fulfilling the liver transplant criteria. The first child is a 14-year-old male who had peak INR of more than 10.2 and grade 3-4 HE with cerebral edema and acute kidney injury. He responded to medical management and CRRT as liver assist device. The second one is a 7-year-old male child who also recovered well with native liver despite advanced HE and INR of more than 10. Third child is a 16-year-old male who had peak INR of 12.6 and grade 2 HE. He received ELAD (Therapeutic plasma exchange and CRRT) and survived with native liver. Conclusion: Children with HAV-induced PALF can recover with their native liver despite extremely poor prognostic markers like very high INR, ammonia and advanced HE.

ABO Incompatible Living Donor Liver Transplantation in Children: A Single Centre Experience from India.

Background: In recent years, paediatric ABO incompatible (ABOi) living donor liver transplant (LT) has shown promising outcomes and can potentially eliminate organ shortage. This study aims to report paediatric ABOi LT experience, including short- and long-term outcomes. Methods: It is a single-centre retrospective study. Out of 108 LTs, 20 were done in children. We compared the outcomes between ABOi (n = 20) and non-ABOi (n = 220) paediatric living donor liver transplantation (LDLT) performed during the study period. All the children received pre-LT desensitization therapy comprising rituximab and plasmapheresis targeting pre-LT isohemagglutinin (IHA) titres of ≤1:16. Results: Out of 239 paediatric LDLTs from 2017 to 2022, 19 children (11 females) underwent 20 ABOi LTs (including one retransplant with an ABOi domino allograft) at a median age of 12 (12, 51) months, with the majority being biliary atresia (60%). The median change in CD19 cell%, CD20 cell%, and IHA titres after rituximab from day -14 to day -1 (before LT) was satisfactory. In the first 3 months following LT, acute cellular rejection, culture-proven sepsis, and biliary and vascular complications were seen in 10%, 20%, 20%, and 15%, respectively. None of the ABOi LT recipients developed antibody-mediated rejection. ABOi LT recipients, as compared to non-ABOi LT recipients, had a higher incidence of bile leaks and prolonged hospital stay, with the rest of the complications, including biliary strictures and long-term outcomes, being comparable. At a median follow-up of 21 (14, 33) months, 4 children expired (21%). Conclusion: ABOi LT in children shows excellent outcomes and can be performed safely with prior desensitization when a compatible liver is unavailable.

Delayed diagnosis of bronchobiliary fistula complicating a pediatric living donor liver transplantation: a case report.

Bronchobiliary fistula (BBF) is a very rare condition in children. Only a few pediatric BBF cases have been reported, in the context of a ruptured hydatid cyst or liver abscess. BBF after living donor liver transplantation (LDLT) has not been reported in the pediatric literature. We report a 7-year-old female child with Wilson disease, who developed BBF post-LDLT. She had a clinically uneventful course in the immediate post-transplant period. She was readmitted on postoperative day (POD) 75 with a productive cough and respiratory difficulty, which was diagnosed as bilioptysis secondary to BBF. Endoscopic retrograde cholangiopancreaticography was attempted but failed. Exploratory laparotomy showed a fistula from the strictured biliary anastomotic site to the right thoracic cavity; it was excised, and a Roux-en-Y hepaticojejunostomy was performed. She tolerated the procedure well and remained clinically well on follow-up through POD 185. BBF is extremely rare in children. This is the first case report of BBF in a child following LDLT. BBF requires a high index of suspicion for a timely intervention to prevent subsequent complications.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

BACKGROUND: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. METHODS: It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. RESULTS: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Percutaneous Cholecystocholangiography-A Tool to Conclusively Exclude Biliary Atresia.

The objective of this study was to evaluate the feasibility, safety, and diagnostic accuracy of percutaneous cholecystocholangiography (PCC) in cases of conjugated hyperbilirubinemia in which biliary atresia (BA) could not be diagnosed or ruled out based on clinical, radiological, and histopathological findings. This was a retrospective, chart review of all cholestatic infants who underwent PCC within the last 5 y. PCC was performed via the transhepatic route using 23-g needle. The patency of both the proximal and distal biliary trees was assessed. PCC was technically feasible in 12/13 (92.3%) of infants without any procedure-related complications. PCC demonstrated proximal and distal biliary patencyin 7/12 (58.3%) infants, thereby avoiding unnecessary laparotomy in them. PCC failed to demonstrate biliary patency in 5 infants; of which, 4 were confirmed as cases of BA on laparotomy. PCC can correctly differentiate BA from non-BA cases of conjugated hyperbilirubinemia preoperatively, reducing the negative laparotomy rates.