Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience.

Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato-cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06-189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1-312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5-132): all alive at 19, 18 and 3 years post-LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early-onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre.

BACKGROUND: Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition. OBJECTIVE: To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS). DESIGN: Retrospective cohort study. PATIENTS: Young people with glycogenic hepatopathy. SETTING: Tertiary paediatric hepatology unit. RESULTS: Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c. CONCLUSIONS: Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice.

PURPOSE: To determine the usefulness of contrast-enhanced ultrasound (CEUS) in characterizing grey-scale sonographic indeterminate focal liver lesions (FLL) in pediatric practice. MATERIALS AND METHODS: Local Ethics Board approval waiver was attained. Consent for CEUS examinations was acquired from parents. Forty-four children referred for CEUS assessment of grey-scale sonographic indeterminate FLL over a 5-year period underwent standard multiphase CEUS performed by experienced operators. A phospholipid microbubble agent was used and low mechanical index ultrasound imaging techniques employed. Interpretation by consensus of the CEUS examination was compared to consensus interpretation of other imaging and to histology. Follow-up imaging was used to confirm stability of benign abnormalities. Any contrast reactions were recorded. RESULTS: The CEUS examination interpretation agreed with reference imaging in 29/34 (85.3 %) of cases. In discordant cases, reference imaging showed no abnormality (n = 5), with fatty change (n = 4) and regenerating nodules (n = 1) on CEUS and follow-up sonography. Where reference imaging was not performed (n = 10), histology (n = 7) or follow-up sonography (n = 3) confirmed the diagnosis. In one discordant case, all imaging modalities showed concordance identifying a malignant lesion; however histology demonstrated a benign hepatocellular adenoma. The specificity was 98.0 % (95 % CI; 86 - 100 %) and the negative predictive value was 100 %. No adverse effects to the contrast material were noted. CONCLUSION: These findings demonstrate the usefulness of CEUS in characterizing indeterminate grey-scale sonography FLL in pediatric patients with the potential to reduce exposure to ionizing radiation.

Colitis-associated sclerosing cholangitis in children: a single centre experience.

OBJECTIVE: Sclerosing cholangitis (SC) is an important immune-mediated extra-intestinal manifestation of inflammatory bowel disease (IBD), primarily affecting patients with ulcerative colitis (UC). The reported prevalence of SC in adults and children with UC is low at between 2 and 7%. We present findings from a hepatological work-up in children with inflammatory colitis and elevated liver function tests (LFT) from a tertiary paediatric gastroenterology unit. DESIGN: This study is designed as a retrospective review of the medical records of 17 children and adolescents with inflammatory colitis and abnormal LFTs who presented to our IBD service between April 2004 and April 2012. RESULTS: Over the eight year period a total of 52 patients were diagnosed with inflammatory colitis (ulcerative colitis and unclassified colitis). Seventeen of the 52 patients had abnormal liver function tests and underwent liver biopsy and cholangiography. All 17 patients (32.6%) were diagnosed with hepato-biliary disease. CONCLUSION: This is one of the largest reported series of children with inflammatory colitis and associated hepato-biliary disease. The data from this patient group indicate that the prevalence of IBD-associated hepato-biliary disease in children with abnormal LFTs is much higher than previously reported. As the diagnosis of IBD-associated hepato-biliary disease affects patient management, we recommend liver biopsy and cholangiography in all children with inflammatory colitis and abnormal liver function tests.

Epidemiology of biliary atresia in England and Wales (1999-2006).

OBJECTIVE: To identify the epidemiological characteristics of infants with biliary atresia in England and Wales, since centralisation of its management in 1999. METHODS: The care of infants with biliary atresia (BA) in England and Wales is centralised to only three centres. All infants (treated from January 1999 to December 2006) were identified from a prospective national database; demographic details were ascertained from medical records and compared between two groups based on presumed aetiology (isolated biliary atresia (IBA) and developmental biliary atresia (DBA) (for example, syndromic infants, biliary atresia splenic malformation, cystic biliary atresia)). RESULTS: There were 302 (133 male (44%)) infants with BA that could be divided into IBA (n = 219, 73%) and DBA (n = 76, 25%). The overall incidence was 0.58/10 000 (1 in 17,049) live births with marked regional differences along a north-west/south-east axis varying from 0.38 (north-west England) to 0.78 (south-east England)/10,000 live births (OR 2.05 (95% CI 1.26-3.41); p = 0.002). The commonest month of birth was September with December being the least common, although there was no evidence for significant seasonal variation (p = 0.2). Infants with DBA were more likely to be female (p<0.001), of white background (p = 0.01), first-born (p = 0.04) and to be formula-fed (p = 0.07). Infants of south Asian origin came to surgery at an older age (59 (IQ 45-75) versus 52 (IQ 42-65) days; p = 0.03). CONCLUSIONS: There is a remarkable variation of incidence of biliary atresia within England and Wales, some of which may have been caused by factors related to a different aetiological and racial background.

Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma.

Hepatoblastoma is the most common primary liver tumor in childhood and occurs more commonly in families with familial adenomatous polyposis. Germline mutations of the gene responsible for familial adenomatous polyposis--adenomatous polyposis coli (APC)--are described in patients with hepatoblastoma even without a family history. We investigated children presenting with apparently sporadic hepatoblastoma between 1991 and 2004. Blood samples were available from 29 children (18 boys) whose conditions were diagnosed at a median age of 22 months (range 6-119 months). No germline APC mutations were found, which does not support the need for routine screening in sporadic hepatoblastoma in the absence of a suggestive family history of colorectal cancer or suspicion of familial adenomatous polyposis.

Variable degree of liver involvement in siblings with PiZZ alpha-1-antitrypsin deficiency-related liver disease.

PiZZ alpha-1-antitrypsin deficiency is the commonest genetic cause of chronic liver disease, but only 10-15% of PiZZ individuals develop liver disease in childhood. Studies have demonstrated varying patterns of disease progression within siblings with the PiZZ phenotype. We retrospectively analysed the case-notes of all patients diagnosed with PiZZ A1ATD between 1978-2002 and compared the pattern of liver disease between affected siblings. We identified 29 families with more than 1 child with the PiZZ phenotype. Twenty-one (72%) PiZZ siblings of the 29 probands had liver disease, which was concordant for severity in 6 (29%), while 8 (28%) had no liver involvement. Five of 7 children requiring liver transplantation had siblings with no persistent liver dysfunction. This study suggests that there is a variable degree of liver involvement in siblings with PiZZ A1ATD-related liver disease and environmental and/or other genetic factors must be involved in determining disease severity.

Liver abscesses in children: a single center experience in the developed world.

OBJECTIVES: The aim of this study was to investigate the clinical and radiologic features, predisposing risk factors, and complications of children with pyogenic liver abscess (PLA) referred to a tertiary pediatric hepatology center. METHODS: We analyzed our database of all children referred to our unit over a 10 year period and performed a case note review of all patients with a radiologically proven PLA. RESULTS: PLA was diagnosed in 15 children (7 boys), 0.5% of all referrals. They presented at a median age of 10 years (range 2 months-15 years). In three children (2 boys), PLA was the first manifestation of chronic granulomatous disease. Among the others, five had radiologic evidence of other intra-abdominal pathology (1 with subsequently proven appendicitis), and four developed portal vein thrombosis with portal hypertension. The commonest isolated pathogen was Staphylococcus aureus. Combined treatment with guided aspiration and prolonged intravenous antibiotics was successful in all patients. CONCLUSION: PLA is a rare diagnosis in children in the developed world. It may be caused by primary neutrophil disorders even in the absence of a previous history of infection. Co-existent appendicitis, intra-abdominal sepsis, and ascending pylephlebitis must be sought because these children are at risk of developing portal vein obstruction and portal hypertension. Prolonged intravenous antibiotic treatment guided by microbiologic sensitivities is highly effective.

The outcome of the older (> or =100 days) infant with biliary atresia.

BACKGROUND: There is a detrimental effect of increasing age on the results of the Kasai portoenterostomy for biliary atresia (BA), and some centers routinely advocate primary liver transplantation for the older infant, irrespective of other criteria. This perception that such infants are indeed irretrievable was tested by retrospective analysis. METHODS: All infants who had undergone surgery for BA during the period 1980 through 2000 aged > or =100 days were reviewed. Actuarial survival was calculated using 2 end-points (death and transplantation). A retrospective review of their ultrasonography (n = 12) and preoperative liver histology (n = 22) was also undertaken to ascertain possible predictive criteria. RESULTS: A total of 422 infants had BA diagnosed during this period, of which 35 (8.2%) were > or =100 days at surgery (median [interquartile range], 133 [range, 108 to 180] days). Surgery included portoenterostomy (n = 26), hepaticojejunostomy (n = 7), and a resection and end-to-end anastomosis (n = 1). A laparotomy only was performed in 1. Five- and 10-year actuarial survival rate with native liver was 45% and 40%, respectively. Currently, 12 (35%) patients are alive with their native liver (8 are anicteric), 9 (28%) have undergone transplantation, and 13 have died. Although there were some survival advantages for types 1 or 2 BA and "noncirrhosis" at time of surgery, neither reached statistical significance. Individual histologic features (eg, degrees of fibrosis, giant cell transformation, bile duct destruction) in the retrospective review of available material were not discriminatory. The finding of a "heterogeneous" parenchyma on ultrasonography was predictive of poor outcome but lacked sensitivity. CONCLUSIONS: The potential for reasonable medium-term survival is present in about one third of infants 100 days or older coming to primary corrective surgery. In the absence of accurate discrimination, the authors continue to favor this option rather than subject all to transplant simply on the basis of age.

Non-myeloablative stem cell transplantation for congenital immunodeficiencies.

Allogeneic haematopoietic stem cell transplantation (HSCT) can be a highly successful treatment option for individuals with congenital immunodeficiency states. The strategy for HSCT is varied but in cases where there is preservation of residual T cell function, conditioning regimes have been used and have been based around a combination of busulphan and cyclophosphamide with or without serotherapy. In patients with coexisting organ damage this has resulted in significant morbidity and mortality. We have therefore used a low-intensity conditioning regime for transplantation in this group of immunodeficiency patients. Twenty-one patients with a variety of different immunodeficiencies were treated using the following conditioning regimes: (1) fludarabine/melphalan/ATG or Campath 1H (n=16), (2) fludarabine/cyclophosphamide/Campath 1H (n=1), (3) TBI/CyA/MMF (n=1), (4) fludarabine/melphalan/busulphan/ATG (n=3). In 13 cases matched (n=9) and 1 Ag mismatched (n=4) unrelated donors were used and in eight cases transplants from matched siblings (n=4), 1 Ag mismatched sibling (n=1), matched parent (n=1) and haploidentical parents (n=3) were performed. At a median follow-up of 13 months, 19 of 21 (90%) patients were still alive following the transplant procedure. Despite a T cell replete graft and the use of unrelated donor grafts in the majority of patients studied there was no evidence of significant organ disease. Immune reconstitution in terms of CD3+ and CD4+ T cell recovery and function was equivalent in comparison with a historical cohort. We believe that this low-intensity approach has significant implications for transplantation of individuals with immunodeficiency states with established organ disease.

Hepatic hemangioendothelioma associated with production of humoral thyrotropin-like factor.

We report on 7 patients referred for treatment of hepatic hemangioendothelioma with increased thyrotropin levels. The serum thyroxine level was decreased in 4 and increased in 2. Immunohistochemistry showed positive staining of tumor, but not of normal liver tissue, for thyrotropin. We propose secretion by the tumor of a thyrotropin-like factor.

Response to varicella immunization in pediatric liver transplant recipients.

BACKGROUND: Individuals undergoing therapeutic immunosuppression are at risk of severe varicella-zoster virus (VZV) infection, particularly those without evidence of previous infection. METHODS: Eleven children, median age 10 months (range 5.5 months to 7 years and 9 months) received one dose of varicella vaccine (Varilrix, SmithKline Beecham plc, UK) before liver transplantation (median interval 95 days, range 40-289 days). The serological response to varicella vaccine was evaluated retrospectively and matched with the outcome and management of any subsequent exposures to VZV. RESULTS: Three children responded postimmunization, six children showed no response, and in two children the outcome was difficult to interpret having received blood products. Four children required varicella-zoster immunoglobulin prophylaxis posttransplantation, two of whom developed mild chickenpox. CONCLUSIONS: Only 3 of 11 children developed a clear antibody response to varicella vaccine. Administration of varicella vaccine did not affect the management of subsequent VZV exposures.

Recurrence of Langerhans cell histiocytosis in the graft after pediatric liver transplantation.

Two girls were diagnosed with Langerhans cell histiocytosis (LCH) at the age of 16 and 7 months and developed end stage chronic liver disease related to LCH-induced sclerosing cholangitis at 28 and 8 months, respectively. They received liver transplants at 34 and 14 months of age. Five months post-orthotopic liver transplantation (OLT) one of the patients developed posttransplant lymphoproliferative disease, successfully treated with a combination of surgery and reduction of immunosuppression. Fourteen months post-OLT she developed diabetes insipidus, bilateral ear discharge, and new osteolytic lesions. After transplantation both girls had mild skin reactivations of LCH, requiring minimal steroid increments. At 60 and 5 months post-OLT intrahepatic LCH recurrence was diagnosed on the basis of abnormal biliary enzymes and presence of Langerhans cells in the grafts. Initial cholangiography in both patients was unremarkable. LCH activity was controlled by maintenance chemotherapy with vinblastine, etoposide, and prednisolone. Ten months after reappearance of LCH in the liver graft a follow-up cholangiography in one of the girls demonstrated a low grade cholangiopathy. Residual elevation of liver enzymes probably represents an ongoing pathogenic process.

Mycobacterium tuberculosis infection in pediatric liver transplant recipients.

OBJECTIVES: To study the incidence, clinical presentation, management, complications and outcome of tuberculosis in pediatric liver transplant recipients. METHODS: A retrospective review of the medical records of children who underwent liver transplantation between 1991 and 1998. RESULTS: Mycobacterium tuberculosis infection occurred in 6 of 254 (2.4%) children undergoing liver transplantation between 1991 and 1998. Cough, pyrexia and poor appetite were common presentations; one-half had normal chest radiographs. The median time to confirmation of diagnosis was 8 months (range, 1 to 17 months). Tests contributing to diagnosis included: Ziehl-Neelsen (ZN) stain (2 patients), M. tuberculosis polymerase chain reaction (1 patient), Mantoux test (1 patient) and histopathology (4 patients). Family health screening was productive for 4 patients. Duration of treatment varied from 9 to 18 months. Isoniazid-induced hepatitis was observed in 2 patients but resolved with dose reduction. Two patients died while receiving treatment, one of Klebsiella spp. septicemia and the other of pulmonary hemorrhage. CONCLUSIONS: Tuberculosis after liver transplantation has a significant morbidity and mortality. Pretransplantation a personal and family history of tuberculosis must be sought, and screening of patients and their families should be considered. Standard regimens incorporating isoniazid and rifampin are effective, but regular monitoring of liver function is essential to detect drug-induced hepatotoxicity.

Nonmyeloablative stem cell transplantation for congenital immunodeficiencies.

The optimal approach for stem cell transplantation in children with immunodeficiency has yet to be determined. Conditioning therapy is necessary for reliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short- and long-term treatment-related toxicity. Whether bone marrow transplantation with a nonmyeloablative preparative regimen was sufficient for the establishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated. Eight patients with severe immunodeficiency states underwent T-cell replete bone marrow transplantation from a human leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine-melphalan-anti-lymphocyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. All patients were engrafted with predominantly donor hematopoiesis, and the duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed chimerism. At a median follow-up of 1 year, all patients have had good recovery of CD3(+) T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation indices. The rate of immune reconstitution is comparable with that of historical controls undergoing standard myeloablative protocols. Two patients with CD40 ligand deficiency now show significant expression, and a patient with adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative stem cell transplantation permits rapid engraftment from both sibling and unrelated donors with minimal toxicity even in the presence of severe organ dysfunction. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer significant advantages compared with standard protocols by combining adequate immune reconstitution with reduced short- and long-term toxicity. (Blood. 2000;96:1239-1246)

Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation.

BACKGROUND/AIM: Alpha-1-antitrypsin deficiency (alpha1ATD) is the commonest metabolic disease leading to liver transplantation (LT) in children. Approximately 10-15% of the PiZZ population develops liver disease. Five percent of them will require LT within the first 4 years of life. This study aimed to investigate the prognosis of the liver disease associated with PiZZ alpha1ATD in the era of liver transplantation and to determine predictors of outcome. METHODS: We reviewed retrospectively the clinical notes of 97 consecutive patients referred from January 1989, when LT became routinely available in our Unit, to July 1998. RESULTS: Of 26 (27%) patients who developed end-stage liver disease, 24 have been transplanted and two are waiting for LT. Twenty-one (81%) of these patients presented with neonatal hepatitis at a median age of 2.1 months. Of 71 (73%) children who have not required LT, 61 (86%) presented with neonatal hepatitis at a median age of 1.6 months. Among infants with neonatal hepatitis who required LT, 18 out of 21 (86%) had jaundice for more than 6 weeks compared with 34 of 61 (56%) who survived without LT (p<0.01). Children requiring LT had higher aspartate aminotransferase (AST) at presentation (p<0.0001) and both higher AST and gamma-glutamyl transferase (GGT) at 6 months (p<0.001), 1-year (p<0.0003) and 5-year (p<0.01) follow up when compared to those who are well without LT. Furthermore, children who developed end-stage liver disease more frequently had severe bile duct reduplication (p<0.01), severe fibrosis (p<0.03) with bridging septa (p<0.02) and established cirrhosis (p<0.04) in the initial liver biopsy. Ninety-five of the 97 children (98%) are currently alive; two died after LT. CONCLUSIONS: The advent of liver transplantation has significantly improved the prognosis of liver disease associated with PiZZ alpha1ATD. Duration of jaundice, severity of histological features and biochemical abnormalities predict outcome at an early stage of the disease.