Simultaneous total internal biliary diversion during liver transplantation for progressive familial intrahepatic cholestasis type 1: Standard of care?

Patients post liver transplant (LT) with progressive familial intrahepatic cholestasis type 1 (PFIC-1) often develop progressive graft steatohepatitis, intractable diarrhea, and growth failure. A total internal biliary diversion (TIBD) during an LT may prevent or reverse these adverse events. Children with PFIC-1 who underwent an LT at our institute were divided into 2 groups, A and B based on the timeline where we started offering a TIBD in association with LT. Pre-LT parameters, intraoperative details, and posttransplant complications like graft steatosis and diarrhea were also analyzed between the 2 groups, and their growth velocity was measured in the follow-up period. Of 550 pediatric LT performed between 2011 and 2022, 13 children underwent LT for PFIC-1. Group A had 7 patients (A1-A7) and group B had 6 (B1-B6). Patients A1, A4, B4, and B5 had a failed partial internal biliary diversion before offering them an LT. Patients A1, A2, and A6 in group A died in the post-LT period (2 early allograft dysfunction and 1 posttransplant lymphoproliferative disorder) whereas A3, A4, and A5 had graft steatosis in the follow-up period. A4 was offered a TIBD 4 years after LT following which the graft steatosis fully resolved. In group B, B1, B2, B5, and B6 underwent TIBD during LT, and B3 and B4 had it 24 and 5 months subsequently for intractable diarrhea and graft steatosis. None of the patients in group B demonstrated graft steatosis or diarrhea and had good growth catch-up during follow-up. We demonstrate that simultaneous TIBD in patients undergoing LT should be a standard practice as it helps dramatically improve outcomes in PFIC-1 as it prevents graft steatosis and/or fibrosis, diarrhea, and improves growth catch-up.

Nutrition in Pediatric Liver Disease.

In liver disease, there is derangement of appetite, digestion, absorption, assimilation, storage and metabolism of both macro and micronutrients. These derangements have an impact on mortality and morbidity associated with liver diseases. In infants, breast feeds should not be stopped unless there are compelling reasons such as underlying metabolic problem. Parenteral nutrition should be considered only if, oral or nasogastric feeding is not possible. The effect of malnutrition on liver disease and impact of liver failure on nutrition is vicious and nutritional intervention has to be done at the earliest to break that vicious cycle. This chapter gives an overview of nutritional management in acute and chronic liver diseases in children and also its impact on specific clinical scenarios including liver transplantation.

Liver Transplantation for Zellweger Syndrome.

Zellweger syndrome or cerebrohepatorenal syndrome is a rare, multisystem disorder occurring due to defect in metabolic pathway within the peroxisomes. Cirrhosis with portal hypertension is an important presentation of these patients. Given its progressive, multisystem nature, the role of liver transplantation (LT) in Zellweger syndrome remains undefined and controversial. An 11-y-old boy diagnosed with Zellweger syndrome presented to the authors with decompensated cirrhosis along with bilateral proptosis. After a meticulous evaluation, he was offered an ABO incompatible liver transplantation with his mother being the donor. He had an uneventful post operative period. After a follow up of 24 mo, he has normal graft function, normal cognition along with resolution of proptosis. Therefore, in a group of carefully selected patients with Zellweger syndrome, a liver transplantation can be offered successfully with an excellent prognosis.

Update on the Pathology of Pediatric Liver Tumors: A Pictorial Review.

Liver tumors in children are uncommon and show remarkable morphologic heterogeneity. Pediatric tumors may arise from either the epithelial or mesenchymal component of the liver and rarely may also show both lines of differentiation. Both benign and malignant liver tumors have been reported in children. The most common pediatric liver tumors by age are benign hepatic infantile hemangiomas in neonates and infants, malignant hepatoblastoma in infants and toddlers, and malignant hepatocellular carcinoma in teenagers. Here, we provide an up-to-date review of pediatric liver tumors. We discuss the clinical presentation, imaging findings, pathology, and relevant molecular features that can help in the correct identification of these tumors, which is important in managing these children.

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.

Pathologic and Immunophenotypic Characterization of Syncytial Giant Cell Variant of Pediatric Hepatocellular Carcinoma. A Distinct Subtype.

INTRODUCTION: Hepatocellular carcinoma (HCC) in pediatrics has a uniformly poor prognosis. Complete surgical resection or liver transplantation remain the only curative options. In contrast to adult HCC, literature on pediatric HCC is sparse and a majority of the distinct subtypes are undefined with regards to their histology, immunohistochemistry and prognosis. CASE REPORT: Two infants, one with biliary atresia and another with transaldolase deficiency, underwent living donor liver transplants. Explant-liver histopathology revealed tumor with diffuse neoplastic syncytial giant cell pattern. Immunophenotypic characterization highlighted expression of epithelial cell adhesion molecule, alpha fetoprotein and metallothionein. CONCLUSION: HCC with syncytial giant cells variant can occur in infants with underlying liver disease, specifically in our experience, with biliary atresia and another with transaldolase deficiency.

Outcomes of liver transplantation in children with Langerhans cell histiocytosis: Experience from a quaternary care center.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare but important cause of end-stage liver disease in children. Conventional chemotherapeutic agents that are otherwise the standard-of-care in LCH may be counterproductive in patients with hepatic decompensation. Furthermore, the precise role of liver transplantation (LT) in the management of LCH remains unclear. METHODS: Review of a prospectively collected database (January 2014 to December 2020) of children with liver disease was performed. All clinical details of patients with LCH managed at our center were collected and data analyzed. Based on the outcomes, a management algorithm was proposed. RESULTS: Of the eight (five male) patients referred to our unit, six (75%) underwent LT (four and two for compensated and decompensated cirrhosis, respectively). Median age at diagnosis of LCH was 25 (range: 9-48) months. Two patients, who had previously completed LCH-specific chemotherapy, underwent upfront LT for compensated cirrhosis. Other two patients with compensated cirrhosis showed evidence of active disease. They underwent LT following completion of chemotherapy. Two children with decompensated cirrhosis also had evidence of active disease and were started on modified chemotherapy Both of them had progression of liver disease while on chemotherapy. Hence, an urgent LT was performed which was followed by completion of chemotherapy in these patients. On a median follow-up of 30.5 (10.5-50) months, all post-LT patients were alive with stable graft function and showed no disease recurrence. CONCLUSION: We demonstrate that an algorithmic approach, along with newer chemotherapeutic agents, results in excellent outcomes in LCH patients with liver involvement. Larger multicentric studies on this rare disease are, however, needed to validate our findings.

Efficacy of Oral Psyllium in Pediatric Irritable Bowel Syndrome: A Double-Blind Randomized Control Trial.

OBJECTIVE: Pediatric irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with variable response to various therapeutic agents. Psyllium has been proven to be effective in adults; however, there is no study in children. The objective of this study is to evaluate the efficacy of psyllium husk as compared to placebo in pediatric IBS patients. METHODS: In this double-blind randomized controlled trial, 43 children were assigned to psyllium arm (Group A) and 38 into placebo arm (Group B). Severity is assessed at baseline and after 4 weeks of treatment using IBS severity scoring scale (IBS-SSS) and classified into mild, moderate, and severe categories. Categorical data was compared with chi-square test and paired categorical variable was compared with McNemer test. RESULTS: Mean ages (±SD; in years) of Groups A and B were 9.87 (2.7) and 9.82 (3.17), respectively, with median duration of illness of 12 months. At baseline, type, severity, and parameters (IBS-SSS) of IBS were equally distributed in 2 groups. There was a significant reduction in median interquartile range (IQR) of total IBS-SSS in psyllium versus placebo [75 (42.5-140) vs 225 (185-270); P < 0.001] at 4 weeks. Similarly 43.9% in Group A versus 9.7% in Group B attained remission [IBS-SSS < 75 ( P < 0.0001)]. The mean difference in IBS-SSS between Group A and Group B was -122.85 with risk ratio of 0.64 (95% CI; 0.42-0.83; P = 0.001) and absolute risk reduction of 32% (NNT = 3). CONCLUSIONS: Psyllium husk is effective for the therapy of pediatric IBS when compared with placebo in short term.

Current perspectives on the role of liver transplantation for Langerhans cell histiocytosis: A narrative review.

Langerhans cell histiocytosis (LCH) is a malignant disease of the histiocytes involving various organ systems. The spectrum of liver involvement in LCH ranges from mild transaminitis to end-stage liver disease. The hallmark of hepatic LCH is secondary sclerosing cholangitis, which manifests due to a progressive destruction of the biliary tree by malignant histiocytes. Chemotherapy remains the mainstay of treatment for active LCH. Early recognition, diagnosis and a systematic approach to the management of LCH can ameliorate the disease process. Nonetheless, the liver involvement in these patients may progress despite the LCH being in remission. Liver transplantation (LT) remains central in the management of such patients. Various facets of the management of LCH, especially those with liver involvement remain unclear. Furthermore, aspects of LT in LCH with regards to the indication, timing and post-LT management, including immunosuppression and adjuvant therapy, remain undefined. This review summarises the current evidence and discusses the practical aspects of the role of LT in the management of LCH.

Neurological complications in pediatric liver transplant recipients.

INTRODUCTION: There is paucity of data on neurological complications (NCs) and its predisposing factors, in pediatric liver transplant (PLT) recipients. METHODS: Records of seventy-one children who underwent LT between October 2018 and November 2019 were reviewed. Patients were categorized into group A: with NC and group B: without NC in the post-LT period. Various risk factors contributing to NC were studied. RESULTS: In total, 15 (21.1%) had NC (group A) and 56 (78.9%) had no NC in the post-LT period. NC included cerebrovascular accident (n = 1), seizures (n = 5; 4 generalized, 1 focal), central pontine myelolysis (CPM) (n = 1), diaphragmatic palsy (n = 2), peripheral neuropathy (n = 1), extrapyramidal movements (n = 3), and encephalopathy beyond 96 h (n = 2). The median onset of NC was at 8.5 days post-LT (1-58 days). Ten (66.7%) patients in group A had grades 2-4 hepatic encephalopathy (HE) prior to LT. Eight (14.3%) patients in group B also had pre-LT neurological issues including HE in six, epilepsy and spastic diplegia in one each. On univariate analysis, pre-existing HE, high PELD/MELD score, pre-LT ventilation, pre-LT infection, higher day 1 post-operative bilirubin (all p < .05), and higher tacrolimus were found to predict post-operative NC whereas on multivariate analysis, pre-LT HE was the only predictive factor. Median follow-up was 15.5 months. Four patients died in each group (survival log-rank p = .369). All the surviving patients in group A (n = 11) fully recovered from the NC. CONCLUSION: Pre-transplant HE was the single most significant predisposing factor for post-LT neurological complications.

Wolman's Disease: A Rare Cause of Infantile Cholestasis and Cirrhosis.

Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

Hilar Fibropolycystic Liver Disease of Unknown Etiology: A Revelation from the Explant Liver.

Fibropolycystic diseases of the liver comprise a spectrum of disorders affecting bile ducts of various sizes and arise due to an underlying ductal plate malformation (DPM). We encountered a previously unreported variant of DPM, the hilar fibropolycystic disease which we diagnosed in the explant liver. A 2-year-old boy was referred for liver transplantation with a diagnosis of biliary atresia (BA) and failed Kasai portoenterostomy (KPE). He had cirrhosis with portal hypertension along with synthetic failure indicated by coagulopathy and hypoalbuminemia. The child underwent liver transplant successfully. The explant liver had fibropolycystic disease confined to the perihilar liver and hilum. No pathogenic mutation was detected by whole exome sequencing. Fibropolycystic liver disease may represent a peculiar anatomical variant, which can be diagnosed by careful pathological examination of the explant liver. The neonatal presentation of hilar fibropolycystic liver disease can be misdiagnosed as BA.

Tacrolimus-induced Central Pontine Myelinolysis in a Pediatric Liver Transplant Recipient.

Central pontine myelinolysis (CPM) is a rare neurological complication reported in liver transplant recipients. A 16-year-old boy with Wilson disease underwent a living donor liver transplant for acute-on-chronic liver failure. On postoperative day 7, he was noted to have diplopia, dysphagia, and bilateral lower limb weakness with wide base gait with gradual progression to akinetic mutism. Magnetic resonance imaging (MRI) brain was performed which was suggestive of CPM, and it was attributed to tacrolimus. We stopped tacrolimus, and he was started on ciclosporin. His neurological symptoms started improving after 72 hours and he had a complete clinical recovery by 6 weeks. Repeat MRI brain at 16 weeks after liver transplantation showed complete radiological resolution of the pontine lesion.

Multidisciplinary Management of Alagille Syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.