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.

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.

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.

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.

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.

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.

Total Internal Biliary Diversion for Post-Liver Transplant PFIC-1-Related Allograft Injury.

Steatohepatitis and diarrhea are well-known complications in children undergoing liver transplantation (LT) for progressive familial intrahepatic cholestasis (PFIC) type 1. Despite medical management with bile acid binders, the condition is progressive and can be associated with allograft loss. We report the case of a seven-year-old boy who underwent LT at the age of 2 years for PFIC type 1. Over the next five years, he developed refractory diarrhea, emaciation, worsening liver function, and steatohepatitis. Aiming to interrupt the enterohepatic circulation, at the age of 7 years, he underwent a total internal biliary diversion. The patient's postprocedure period was uneventful. His diarrhea settled and the transaminases normalized his follow-up liver biopsy after a year showed a complete resolution of steatohepatitis. At 18 months' follow-up, he has gained weight and remains asymptomatic. In this report, we show post-LT complications especially allograft injury related to the pathology of PFIC-1 can be safely and effectively managed by performing a total internal biliary diversion.

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.

Late-Onset Peripheral T-Cell Lymphoma Not Otherwise Specified in a Liver Transplant Recipient: A Rare Subtype of Posttransplant Lymphoproliferative Disorder.

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication seen in the period after liver transplant. The commonest subtype is B-cell PTLD which is usually associated with Epstein-Barr virus (EBV) infection. T-cell PTLD is rare and the association with EBV is again rarer. CASE: Our patient, a 21-year-old young adult, presented to us with generalized lymphadenopathy, 5 years after liver transplantation. The biopsy of the lymph node was suggestive of peripheral T-cell lymphoma not otherwise specified, which was associated with EBV infection. The Positron emission tomography and computerised tomography (PET-CT) scan showed stage 3 disease. He was treated with standard cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisolone chemotherapy and is currently in remission. CONCLUSION: Peripheral T-cell lymphoma not otherwise specified is a rare subtype of PTLD and its association with EBV is even more rare. A few patients can achieve complete remission with standard chemotherapy.

Pediatric metabolic liver diseases: Evolving role of liver transplantation.

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis', arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.

Primary tuberculosis of the graft masquerading pyogenic liver abscess in a pediatric liver recipient.

Primary tuberculosis (TB) of the graft presenting as multiple liver abscesses is previously unreported. A 14-month-old male child in the early post liver transplant (LT) period presented with high-grade fever spikes and on evaluation was found to have multiple pyogenic liver abscesses (PLA) in the CT abdomen. His fever was not responding to intravenous antibiotics and liver biopsy was done which showed numerous acid fast bacilli. Genetic analysis confirmed the bacilli as Mycobacterium tuberculosis (MTB). Timely diagnosis and prompt introduction of antituberculosis therapy were lifesaving.

An interesting cause of chronic abdominal pain in a child.

We encountered an eight-year-old boy who was subsequently diagnosed with a retroperitoneal ganglioneuroma. In view of the rarity of this tumour and its presentation, we are prompted to report this case.

Bertiella studeri Infection-A Rare Cause of Chronic Abdominal Pain in a Child from North India.

Bertiella is a common parasite seen in non-human primates. It is rarely seen in humans. We present the case of a 2-year-old child with bertiellosis. He had recurrent abdominal pain, and worm fragments were found in stool, which were refractory to albendazole therapy.