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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.

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.

Standardization of immunomodulation protocols has enabled ABO-incompatible liver transplants with outcomes similar to those of ABO-compatible liver transplants. Patients with the A2 blood group are unique because they have a diminished expression of the A antigen. Despite rare immune complications, this phenomenon of diminished expression has led to treatment of type A2 donors according to the regimen for type O blood group donors in ABO-incompatible liver transplants. Additionally, the requirement for pretransplant recipient immunomodulation is consi dered minimal when considering these donors. The transplant of a type A2 donor kidney to a type B recipient is well recognized; however, for liver donation the A2-to-B transplant is rare. Here, we present a case of 48-year-old male patient with blood group type B who underwent ABO-incompatible liver transplant of a right lobe liver graft from a type A2 donor. Postoperatively, despite adequate immunosuppression and initiation of thera - peutic plasma exchange, the patient developed severe and refractory antibody-mediated rejection that ultimately abated with a splenectomy. This report highlights the low but tangible risk of antibody-mediated rejection in ABO-incompatible liver transp lants from type A2 donors and emphasizes the importance of serial monitoring of anti-A isohemag glutinin titers and posttransplant splenectomy to ensure that liver grafts with antibody-mediated rejection can be rescued.

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.

To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). 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. 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). 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.

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.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.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.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.

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.

Morphological diversity and several new distinct pathologic subtypes of hepatocellular carcinoma (HCC) are now well-recognized. Recent advances in tumor genomics and transcriptomics have identified several recurrent somatic/genetic alterations that are closely related with histomorphological subtypes and have therefore, greatly improved our understanding of HCC pathogenesis. Pathologic subtyping allows for a diagnosis which is clinically helpful and can have important implication in patient prognostication as some of these subtypes are extremely aggressive with vascular invasion, early recurrence, and worst outcomes. Several targeted treatments are now being considered in HCC, and the reporting of subtypes may be quite useful for personalized therapeutic purpose. This manuscript reviews the recently identified histomorphological subtypes and molecular alterations in HCC.

The impact of incidentally detected hepatocellular carcinoma (iHCC) in explanted liver on the prognosis of the patients undergoing orthotopic liver transplantation remains controversial with several studies reporting survival worse than true non-hepatocellular carcinoma (non-HCC) recipients. Patients undergoing living donor liver transplantation (LDLT) have the benefit of a shorter waiting time to transplant which in principle should reduce the frequency of new tumors developing while waiting for transplant. We aimed to evaluate the incidence, histopathological features, and impact of iHCC on short- and long-term outcomes in adult LDLT recipients. The present study retrospectively analyzed the patients’ demographics, tumor characteristics, and outcomes of iHCC in adult patients undergoing LDLT for non-HCC indications at our center between August 2009 and March 2018. Five hundred and forty-five adults underwent LDLT in our center during the study period. iHCC was detected in the explanted livers in 28 patients (5.1%) out of 545 LDLTs. Only one patient had iHCC beyond Milan criteria. No tumor recurrence was observed in the iHCC cohort after a median follow-up of 28 months. Five-year overall and recurrence-free survival was 96.4%. Incidence of iHCC in explanted livers after LDLT is low and most patients have very early-stage tumors with excellent recurrence-free survival. Hence, no specific post-transplant surveillance or treatment is necessary.

Congenital bile acid synthesis defect type 3 is a rare metabolic liver disease with only eight patients reported in literature. We describe clinical, pathological and molecular features for a ninth patient. A 4-month-old infant presented to us with conjugated hyperbilirubinemia. His liver biopsy revealed giant cell change, steatosis, and activity with diffuse fibrosis. Immunostaining with bile salt export pump showed preserved canalicular pattern and γ-glutamyl transferase 1 staining showed unusual complete membranous pattern. Genetic workup revealed homozygous single base pair duplication in exon 3 of the CYP7B1 gene. He succumbed to liver disease at 7 months of age.

Objective : Spectrum of hepatic presentation in Langerhans cell histiocytosis (LCH) varies from asymptomatic hepatomegaly to secondary sclerosing cholangitis leading to cirrhosis with or without decompensation. Conventional chemotherapy may be counterproductive in a patient with LCH and hepatic decompensation. We analysed the outcomes of our patients with hepatic presentation of LCH, including their post liver transplant (LT) follow up. Methods: A retrospective analysis was performed on patients with hepatic presentation of LCH referred to our unit. Their clinical profile, chemotherapy protocol, details of LT and survival were analysed. A management algorithm based on the outcomes was proposed. Results: Five of 8 patients were male. Median age of diagnosis was 25(9-48) months. 8(100%) patients had portal hypertension with 4(50%) having decompensated cirrhosis. 6 (75%) patients underwent LT of which 2 had acute decompensation and 4 had sclerosing cholangitis with portal hypertension. Of the two remaining patients, 1 did not tolerate chemotherapy and succumbed, whereas 1 patient after first cycle of chemotherapy was lost to follow up. As their liver disease was worsening during chemotherapy (after 8 & 20 weeks of chemotherapy), two patients underwent urgent LT followed by continuation of chemotherapy. After median follow-up of 30.5 (10.5-50) months, all patients were alive with stable graft function and no disease recurrence. Conclusion: As shown in our series, an algorithmic approach to patient and treatment selection for LCH patients with liver involvement combined with newer chemotherapeutic agents and an optimized immunosuppression can result in excellent outcomes for a hitherto unfamiliar disease.

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA (“Nestin High”, >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 (

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.

Liver transplantation (LT) is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease. With improvements in organ preservation techniques, perioperative care, and immunosuppression, there is better patient and graft survival following LT, and assessment of the liver allograft in long-term survivors is becoming increasingly important. Recurrent or

Background: Primary immunodeficiency (PID) having defects related to lymphocyte cytotoxic pathway or T-cell dysfunction are well known for developing opportunistic infections and Epstein-Barr virus (EBV)-associated diseases. CARMIL2 deficiency is a recently described combined immunodeficiency (CID) disorder characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, susceptibility to various infections and Epstein Barr Virus smooth muscle tumor (EBV-SMT). Case report: We report a homozygous CARMIL2 pathogenic variant presenting with recurrent infections and EBV associated smooth muscle tumor (SMT) in a child. Conclusion: The present study reports that EBV SMT may occur in a child with CARMIL2 deficiency.

Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).