Publications by authors named "Ulrich Baumann"

271 Publications

Diagnostic Yield and Therapeutic Consequences of Targeted Next-Generation Sequencing in Sporadic Primary Immunodeficiency.

Int Arch Allergy Immunol 2021 Oct 7:1-13. Epub 2021 Oct 7.

Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.

Introduction: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the >430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency.

Method: We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent's HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment.

Results: tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making.

Conclusion: Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.
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http://dx.doi.org/10.1159/000519199DOI Listing
October 2021

Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations.

Front Immunol 2021 14;12:739675. Epub 2021 Sep 14.

Institute for Transfusion Medicine, University Ulm, Ulm, Germany.

DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56CD16 NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19CD20 B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.
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http://dx.doi.org/10.3389/fimmu.2021.739675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478158PMC
September 2021

Two Sides of a Coin: Parental Disease-Specific Training as Seen by Health Care Practitioners and Parents in Pediatric Liver Transplantation.

Children (Basel) 2021 Sep 21;8(9). Epub 2021 Sep 21.

Pediatric Gastroenterology, Hepatology and Liver Transplantation, Hannover Medical School, 30625 Hannover, Germany.

In the absence of widely accepted education standards for parents of children after liver transplantation (LTx), the content and structure of parental training are influenced by health care practitioners' (HCP) individual knowledge and assessment of the relevance of its contents. This study examines the hypothesis that expectations towards training differ between HCPs and parents, and that the quality of parental training affects the job-satisfaction of HCPs. Attitudes towards disease-specific education were assessed by tailor-made questionnaires in HCPs ( = 20) and parents of children with chronic liver disease or after LTx ( = 113). These were supplemented by focused interviews in = 7 HCPs and = 16 parents. Parents were more satisfied with current counseling than HCP. Language barriers and low parental educational background were perceived as obstacles by 43% of HCPs. The quality of parental knowledge was felt to have a strong influence on HCPs job satisfaction. The expectations towards the content of disease-specific education largely overlap but are not synonymous. HCP and parents agreed with regards to the importance of medication knowledge. Parents rated the importance about the meaning of laboratory values and diagnostic procedures significantly higher (3.50 vs. 2.85, < 0.001 and 3.42 vs. 2.80, < 0.001) than HCPs. Parents and HCPs would prefer a structured framework with sufficient staff resources for disease-specific counseling.
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http://dx.doi.org/10.3390/children8090827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469562PMC
September 2021

A Case Series on Genotype and Outcome of Liver Transplantation in Children with Niemann-Pick Disease Type C.

Children (Basel) 2021 Sep 17;8(9). Epub 2021 Sep 17.

Division of Pediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany.

Background: To report on clinical presentation and outcomes of children who underwent liver transplantation (LTx) and were subsequently diagnosed to have Niemann-Pick type C (NPC).

Methods: Retrospective, descriptive, multi-centre review of children diagnosed with NPC who underwent LTx (2003-2018). Diagnosis was made by filipin skin test or genetic testing.

Results: Nine children were identified (six centres). Neonatal acute liver failure was the most common indication for LTx (seven children). Median age at first presentation: 7 days (range: 0-37). The most prevalent presenting symptoms: jaundice (8/9), hepatosplenomegaly (8/9) and ascites (6/9). 8/9 children had a LTx before the diagnosis of NPC. Genetic testing revealed mutations in NPC1 correlating with a severe biochemical phenotype in 5 patients. All 9 children survived beyond early infancy. Seven children are still alive (median follow-up time of 9 (range: 6-13) years). Neurological symptoms developed in 4/7 (57%) patients at median 9 (range: 5-13) years following LTx.

Conclusion: Early diagnosis of NPC continues to be a challenge and a definitive diagnosis is often made only after LTx. Neurological disease is not prevented in the majority of patients. Genotype does not appear to predict neurological outcome after LTx. LTx still remains controversial in NPC.
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http://dx.doi.org/10.3390/children8090819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470073PMC
September 2021

ABO Incompatible Liver Transplantation in Children: A 20 Year Experience from Centres in the TransplantChild European Reference Network.

Children (Basel) 2021 Aug 31;8(9). Epub 2021 Aug 31.

Department of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.

An increasing number of AB0-incompatible (AB0i) liver transplantations (LT) are being undertaken internationally in recent years due to organ shortages and the need for urgent transplantation. The aim of our study was establish the value of ABOi LT from available retrospective results of AB0i pediatric liver transplantations performed in European reference centers now belonging to the TransplantChild, European Reference Network (ERN). Data from medical records were analyzed, including demographic data, diagnosis, urgency of transplantation, time on the waiting list, PELD/MELD score, desensitization procedures, immunosuppression, selected post-transplant complications, and patient and graft survival. A total of 142 patients (pts) with transplants between 1986 and 2018 in 8 European transplant centers were included in the study. The indications for liver transplantation were: cholestatic diseases in 62 pts, acute liver failure in 42 pts, and other conditions in the remaining 38 pts. Sixty-six patients received grafts from living donors, and seventy-six received grafts from deceased donors. Both patient and graft survival were significantly affected by deceased donor type, urgent transplantation, and the development of vascular complications. In the multivariate analysis, vascular complications had a negative impact on patient and graft survival, while a longer time from the first AB0i LT in the study showed better results, suggesting an international learning experience. In conclusion, we believe that AB0i LT in children is now a safe procedure that may be adopted more readily in children.
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http://dx.doi.org/10.3390/children8090760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468154PMC
August 2021

Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation.

Transplant Direct 2021 Oct 20;7(10):e765. Epub 2021 Sep 20.

Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom.

The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).

Methods: One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively.

Results: In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8).

Conclusions: This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.
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http://dx.doi.org/10.1097/TXD.0000000000001221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454910PMC
October 2021

Reply to: "Multiple investigations for a very common disorder: Finding the right balance in NAFLD".

J Hepatol 2021 Sep 11. Epub 2021 Sep 11.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.08.032DOI Listing
September 2021

Collagen's primary structure determines collagen:HSP47 complex stoichiometry.

J Biol Chem 2021 Sep 3:101169. Epub 2021 Sep 3.

Institute of Biochemistry, Faculty of Mathematics and Natural Sciences, University of Cologne, 50674 Cologne, Germany. Electronic address:

Collagens play important roles in development and homeostasis in most higher organisms. In order to function, collagens require the specific chaperone HSP47 for proper folding and secretion. HSP47 is known to bind to the collagen triple-helix but the exact positions and numbers of binding sites are not clear. Here, we employed a collagen II peptide library to characterize high-affinity binding sites for HSP47. We show that many previously predicted binding sites have very low affinities due to the presence of a negatively charged amino acid in the binding motif. In contrast, large hydrophobic amino acids like phenylalanine at certain positions in the collagen sequence increase binding strength. For further characterization, we determined two crystal structures of HSP47 bound to peptides containing phenylalanine or leucine. These structures deviate significantly from previously published ones in which different collagen sequences were used. They reveal local conformational rearrangements of HSP47 at the binding site to accommodate the large hydrophobic side chain from the middle strand of the collagen triple helix and, most surprisingly, possess an altered binding stoichiometry in form of a 1:1 complex. This altered stoichiometry is explained by steric collisions with the second HSP47 molecule present in all structures determined thus far caused by the newly introduced large hydrophobic residue placed on the trailing strand. This exemplifies the importance of considering all three sites of homotrimeric collagen as independent interaction surfaces and may provide insight into the formation of higher oligomeric complexes at promiscuous collagen binding sites.
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http://dx.doi.org/10.1016/j.jbc.2021.101169DOI Listing
September 2021

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

J Clin Immunol 2021 Sep 3. Epub 2021 Sep 3.

The Royal Hospitals & Queen's University, Belfast, UK.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).
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http://dx.doi.org/10.1007/s10875-021-01090-8DOI Listing
September 2021

A Sorrow Shared Is a Sorrow Halved? Patient and Parental Anxiety Associated with Venipuncture in Children before and after Liver Transplantation.

Children (Basel) 2021 Aug 11;8(8). Epub 2021 Aug 11.

Department of Paediatric Liver, Kidney and Metabolic Diseases, Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany.

Taking blood via venipuncture is part of the necessary surveillance before and after liver transplantation. The spectrum of response from children and their parents is variable, ranging from a short and limited aversion to paralyzing phobia. The aim of this retrospective, cross-sectional study was to determine the level of anxiety amongst children during venipuncture, to compare the anxiety reported by children and parents, and to identify the factors affecting the children's and parents' anxiety in order to develop therapeutic strategies. In total, 147 children (aged 0-17 years, 78 female) and their parents completed questionnaires. Statistical analysis was performed using qualitative and quantitative methods. Results showed that the majority of children reported anxiety and pain during venipuncture. Younger children had more anxiety (self-reported or assessed by parents). Children and parental reports of anxiety were highly correlated. However, the child's anxiety was often reported as higher by parents than by the children themselves. The child's general anxiety as well as the parents' perceived stress from surgical interventions (but not the number of surgical interventions) prompted parental report of child anxiety. For children, the main stressors that correlated with anxiety and pain were factors during the blood collection itself (e.g., feeling the puncture, seeing the syringe). Parental anxiety was mainly related to circumstances before the blood collection (e.g., approaching the clinic, sitting in the waiting room). The main stressors mentioned by parents were the child's discomfort and their inability to calm the child. Results indicate that the children's fear of factors during the blood collection, along with the parents' perceived stress and helplessness as well as their anticipatory anxiety are important starting points for facilitating the drawing of blood from children before and after liver transplantation, thereby supporting a better disease course in the future.
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http://dx.doi.org/10.3390/children8080691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394744PMC
August 2021

Under-Vaccination in Pediatric Liver Transplant Candidates with Acute and Chronic Liver Disease-A Retrospective Observational Study of the European Reference Network .

Children (Basel) 2021 Aug 3;8(8). Epub 2021 Aug 3.

Department of Paediatric Liver, Kidney and Metabolic Diseases, Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany.

Infection is a serious concern in the short and long term after pediatric liver transplantation. Vaccination represents an easy and cheap opportunity to reduce morbidity and mortality due to vaccine-preventable infection. This retrospective, observational, multi-center study examines the immunization status in pediatric liver transplant candidates at the time of transplantation and compares it to a control group of children with acute liver disease. Findings show only 80% were vaccinated age-appropriately, defined as having received the recommended number of vaccination doses for their age prior to transplantation; for DTP-PV-Hib, less than 75% for Hepatitis B and two-thirds for pneumococcal conjugate vaccine in children with chronic liver disease. Vaccination coverage for live vaccines is better compared to the acute control group with 81% versus 62% for measles, mumps and rubella ( = 0.003) and 65% versus 55% for varicella ( = 0.171). Nevertheless, a country-specific comparison with national reference data suggests a lower vaccination coverage in children with chronic liver disease. Our study reveals an under-vaccination in this high-risk group prior to transplantation and underlines the need to improve vaccination.
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http://dx.doi.org/10.3390/children8080675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394134PMC
August 2021

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

Children (Basel) 2021 Jul 29;8(8). Epub 2021 Jul 29.

Unidade de Nefrologia e Transplantação Renal, Serviço de Pediatria Médica, Departamento de Pediatria, Hospital de Santa Maria, Centro Académico de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers' approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012-2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.
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http://dx.doi.org/10.3390/children8080661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394841PMC
July 2021

Recipient-Specific Risk Factors Impairing Patient and Graft Outcome after Pediatric Liver Transplantation-Analysis of 858 Transplantations in 38 Years.

Children (Basel) 2021 Jul 27;8(8). Epub 2021 Jul 27.

Pediatric Gastroenterology, Hepatology and Liver Transplantation, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.

(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983-2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983-1992) to 97.5%/86.5% (OR = 12.5; < 0.0001/OR = 6.5; < 0.0001) (2014-2020). Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation (log7.378/9.657; < 0.0001) and indication of acute liver failure (log = 1.944/2.667; HR = 2.015/1.772; = 0.0114/0.002) impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation (log = 1.755; HR = 1.744; = 0.0176) and prolonged waiting times in high-urgency status (log = 2.588; HR = 1.073; = 0.0026), whereas the indication of biliary atresia improved outcome (log = 1.502; HR = 0.575; = 0.0315). Graft survival was additionally impaired by pre-existing portal vein thrombosis (log = 1.482; HR = 2.016; = 0.0330). (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.
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http://dx.doi.org/10.3390/children8080641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393592PMC
July 2021

Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement.

Lancet Gastroenterol Hepatol 2021 10 6;6(10):864-873. Epub 2021 Aug 6.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.

The term non-alcoholic fatty liver disease (NAFLD), and its definition, have limitations for both adults and children. The definition is most problematic for children, for whom alcohol consumption is usually not a concern. This problematic definition has prompted a consensus to rename and redefine adult NAFLD associated with metabolic dysregulation to metabolic (dysfunction)-associated fatty liver disease (MAFLD). Similarities, distinctions, and differences exist in the causes, natural history, and prognosis of fatty liver diseases in children compared with adults. In this Viewpoint we, an international panel, propose an overarching framework for paediatric fatty liver diseases and an age-appropriate MAFLD definition based on sex and age percentiles. The framework recognises the possibility of other coexisting systemic fatty liver diseases in children. The new MAFLD diagnostic criteria provide paediatricians with a conceptual scaffold for disease diagnosis, risk stratification, and improved clinical and multidisciplinary care, and they align with a definition that is valid across the lifespan.
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http://dx.doi.org/10.1016/S2468-1253(21)00183-7DOI Listing
October 2021

Identification of Impaired Executive Functioning after Pediatric Liver Transplantation Using Two Short and Easily Applicable Tests: Cognitive Functioning Module PedsQL and Children's Color Trail Test.

Children (Basel) 2021 Jul 2;8(7). Epub 2021 Jul 2.

Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.

We aimed to assess executive functioning in children after liver transplantation compared with healthy controls and in relation to real-life school performance using the PedsQL Cognitive Functioning Scale (CogPedsQL) and the Childrens' Color Trail Test (CCTT). One hundred and fifty five children (78f, median age 10.4 (1.2-18.3) years) underwent testing with CogPedsQL and/or CCTT 4.9 (0.1-17.0) years after transplantation. Results were compared to those of 296 healthy children (165f, median age 10.0 (2.0-18.0) years). Liver transplanted children displayed significantly reduced scores for cogPedsQL and CCTT1&2 compared to healthy controls. Overall, school performance was lower in patients compared to controls. In both patients and controls, results of CCTT2 and CogPedsQL correlated strongly with school performance. In contrast to controls, school performance in patients correlated with the level of maternal but not paternal primary education degree (r = -0.21, = 0.03). None of the patient CCTT or CogPedsQL test results correlated with parental school education. Conclusion: CogPedsQL and CCTT 1&2 were easily applicable in children after OLT and revealed reduced executive functioning compared to controls. Results reflect real life school performance. The association of parental education with school performance is reduced in transplanted children, which possibly indicates the overriding impact of transplant-associated morbidity on cognitive outcomes.
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http://dx.doi.org/10.3390/children8070571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303617PMC
July 2021

Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: Phase 2 study.

Clin Res Hepatol Gastroenterol 2021 Jun 26;45(5):101751. Epub 2021 Jun 26.

Albireo Pharma, Boston, MA, United States.

Purpose: Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated.

Patients And Methods: In this phase 2, open-label, multicenter study, children received 10‒200 μg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored.

Results: Twenty patients were enrolled (8 females; 1‒17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26‒564) and were reduced in the majority (-123.1 μmol/L; range, -394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 μg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0-10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0-10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient.

Conclusions: Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.
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http://dx.doi.org/10.1016/j.clinre.2021.101751DOI Listing
June 2021

Survival Benefits Following Liver Transplantation: A Matched-pair Analysis in Pediatric Patients With Cystic Fibrosis.

J Pediatr Gastroenterol Nutr 2021 09;73(3):385-390

Pediatric Gastrolenterology and Hepatology, Hannover Medical School, Hannover.

Objectives: Cystic fibrosis-related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients. The aim of this study was to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison.

Methods: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx, and details of surgical procedures.

Results: At our institution, 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of posttransplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. Five patients died after LTx, none because of primary hepatic dysfunction (1 because of posttransplant proliferative disorder, 4 because of infection). Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function, and life expectancy of CFLD patients with LTx are comparable with matched CF peers without CFLD.

Conclusions: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy, and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.
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http://dx.doi.org/10.1097/MPG.0000000000003194DOI Listing
September 2021

Current Evidence on the Clinical Relevance of Donor-specific Antibodies in Paediatric Liver Transplantation.

J Pediatr Gastroenterol Nutr 2021 06;72(6):788-793

Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases.

Abstract: The clinical impact of donor-specific antibodies (DSA) occurring before or after liver transplantation (LT) against donor-human leucocyte antigen (HLA) on graft outcome is still unclear. We aim to present the current consensus based on recent paediatric LT case series. Compared to kidney transplantation, the liver seems to be less susceptible to antibody-mediated graft damage, which is likely due to protective Kupffer cell activity. The incidence of DSA after liver transplantation is higher in children than in adults. DSA directed against HLA class II molecules, mainly DQ, occur more often. The presence of such anti-class II DSA (DQ/DR), especially of the complement-binding IgG3 subclass, may be associated with endothelial injury, T-cell-mediated rejection (TCMR), inflammation, and fibrosis. Regular DSA-posttransplant monitoring cannot as yet be recommended in routine practice but may be useful in selected cases.
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http://dx.doi.org/10.1097/MPG.0000000000003127DOI Listing
June 2021

Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.

J Allergy Clin Immunol 2021 08 17;148(2):381-393. Epub 2021 Apr 17.

Division of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Background: Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known.

Objective: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease.

Methods: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids.

Results: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes.

Conclusion: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.
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http://dx.doi.org/10.1016/j.jaci.2021.03.045DOI Listing
August 2021

Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1.

Nat Commun 2021 04 12;12(1):2176. Epub 2021 Apr 12.

Max Planck Institute for Biology of Ageing, Cologne, Germany.

The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for glycosylation processes in mammals. It modulates the ER stress response and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting HP enzyme. GFAT-1 activity is modulated by UDP-GlcNAc feedback inhibition and via phosphorylation by protein kinase A (PKA). Molecular consequences of GFAT-1 phosphorylation, however, remain poorly understood. Here, we identify the GFAT-1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans. In human GFAT-1, the R203H substitution interferes with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Our data indicate that phosphorylation affects the interactions of the two GFAT-1 domains to control catalytic activity. Notably, Ser205 phosphorylation has two discernible effects: it lowers baseline GFAT-1 activity and abolishes UDP-GlcNAc feedback inhibition. PKA controls the HP by uncoupling the metabolic feedback loop of GFAT-1.
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http://dx.doi.org/10.1038/s41467-021-22320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041777PMC
April 2021

Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review.

Eur J Med Genet 2021 Jun 1;64(6):104214. Epub 2021 Apr 1.

I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.

Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.
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http://dx.doi.org/10.1016/j.ejmg.2021.104214DOI Listing
June 2021

Low-dose steroids do make a difference: Independent risk factors for impaired linear growth after pediatric liver transplantation.

Pediatr Transplant 2021 Jun 10;25(4):e13989. Epub 2021 Mar 10.

Division of Pediatric Gastroenterology, Hepatology and Liver Transplantation, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Growth failure persists after pediatric liver transplantation and impairs pediatric development and quality of life. Steroid dose minimization attempts to prevent growth impairment, yet long-term assessment in pediatric liver recipients is lacking. We identified risk factors for impaired linear growth after pediatric liver transplantation, with a special focus on low-dose steroid therapy. This is a single-center retrospective analysis of height development in pediatric liver recipients up to 5 years after transplantation. Risk factors for impaired linear growth (height Z-scores≤-2) at transplantation, after two (n = 347) and five years (n = 210) were identified by univariate and multivariate logistic regression. At transplantation, growth retardation was found in 52.2%, predominantly younger children. Height Z-scores improved from -2.23 to -1.40 (SE 0.11; 95%CI 0.74-1.16; p < .001) two years and -1.19 (SE 0.07;0.08-0.34; p = .017) five years post-transplant. Multivariate analysis showed previous growth impairment (OR=1.484; 95%-CI=1.107-1.988; p = .004), graft loss (49.006;2.232-1076; p = .006), and prolonged cold ischemic time (1.034;1.007-1.061; p = .011) as main long-term risk factors; steroid use was a significant predictor of 2-year but not 5-year growth impairment. In univariate analysis, impaired growth after 2 and 5 years was associated with continuous low-dose (2.5 mg/m BSA) steroid therapy (OR=3.323;1.578-6.996; p < .001/OR=8.352;1.089-64.07; p = .006)and graft loss (OR=2.513;1.395-4.525; p = .003/OR=3.378;1.815-7.576; p < .001). Furthermore, indication and era of transplantation affected growth. Our results show significant catch-up growth after pediatric liver transplantation, yet growth failure strongly affects particularly young liver recipients. The main influenceable long-term risk factor is pre-existing growth failure, emphasizing the importance of early aggressive nutritional therapy. Moreover, low-dose steroid therapy might impair growth and should therefore be critically questioned in long-term immunosuppression.
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http://dx.doi.org/10.1111/petr.13989DOI Listing
June 2021

Centralization of Biliary Atresia: Has Germany Learned Its Lessons?

Eur J Pediatr Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.

Introduction:  The majority of pediatric surgeons and hepatologists recommend the centralization of biliary atresia (BA) treatment within experienced liver units. We aimed to investigate whether voluntary self-restriction and acceptance of the need for this change in practice changed the BA referral policy in Germany during the last decade.

Materials And Methods:  In cooperation with pediatric surgeons, gastroenterologists or hepatologists, and pediatric liver transplant units, the 2-year follow-up data of infants with BA born in Germany between 2010 and 2014 were collected using www.bard-online.com or pseudonymized data transfer. Results were compared with our previous analysis of the outcome data of infants with BA born between 2001 and 2005 in Germany.

Result:  Overall, 173 infants with BA were identified, of whom 160 underwent Kasai portoenterostomy (KPE; 92.5%) and 13 (7.5%) underwent primary liver transplantation at 21 German centers. At 2-year follow-up, overall survival was 87.7% (vs. 81.9% in 2001-2005 [ = 0.19]), survival with native liver post-KPE was 29.2% (vs. 22.8% in 2001-2005 [ = 0.24]), and jaundice-free survival with native liver post-KPE was 24.0% (vs. 20.1% in 2001-2005 [ = 0.5]). Compared with the 2001-2005 analysis, all criteria showed improvement but the differences are statistically not significant.

Conclusion:  Our observation shows that KPE management requires improvement in Germany. Centralization of BA patients to German reference liver units is not yet mandatory. However, European and national efforts with regard to the centralization of rare diseases support our common endeavor in this direction.
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http://dx.doi.org/10.1055/s-0041-1723994DOI Listing
March 2021

Diagnosis and management of secondary causes of steatohepatitis.

J Hepatol 2021 06 10;74(6):1455-1471. Epub 2021 Feb 10.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address:

The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2021.01.045DOI Listing
June 2021

Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis.

J Pediatr Gastroenterol Nutr 2021 05;72(5):e105-e111

Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases.

Objectives: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests.

Methods: We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants.

Results: Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P = 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin).

Conclusions: DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.
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http://dx.doi.org/10.1097/MPG.0000000000003061DOI Listing
May 2021

Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta.

PLoS Genet 2021 02 1;17(2):e1009339. Epub 2021 Feb 1.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Heat shock protein 47 (HSP47), encoded by the SERPINH1 gene, is a molecular chaperone essential for correct folding of collagens. We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise. p.R222 is a highly conserved residue located within the collagen interacting surface of HSP47. Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen. This altered interaction leads to posttranslational overmodification of type I procollagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry. Since we also observed a normal intracellular folding and secretion rate of type I procollagen, this overmodification cannot be explained by prolonged exposure of the procollagen molecules to the modifying hydroxyl- and glycosyltransferases, as is commonly observed in other types of OI. We found significant upregulation of several molecular chaperones and enzymes involved in procollagen modification and folding on Western blot and RT-qPCR. In addition, we showed that an imbalance in binding of HSP47-R222S to unfolded type I collagen chains in a gelatin sepharose pulldown assay results in increased binding of other chaperones and modifying enzymes. The elevated expression and binding of this molecular ensemble to type I procollagen suggests a compensatory mechanism for the aberrant binding of HSP47-R222S, eventually leading to overmodification of type I procollagen chains. Together, these results illustrate the importance of HSP47 for proper posttranslational modification and provide insights into the molecular pathomechanisms of the p.(R222S) alteration in HSP47, which leads to a severe OI phenotype.
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http://dx.doi.org/10.1371/journal.pgen.1009339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877763PMC
February 2021

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Front Immunol 2020 26;11:606333. Epub 2020 Nov 26.

UCL Respiratory, University College London, London, United Kingdom.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.

Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.

Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS.

Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.

Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.
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http://dx.doi.org/10.3389/fimmu.2020.606333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726128PMC
June 2021

Liver Tumours in Children: The Hepatologist's View.

J Pediatr Gastroenterol Nutr 2021 04;72(4):487-493

Paediatric Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.

Abstract: Diagnostic and therapeutic innovations have changed the way we now approach liver tumours in children and adolescents. Novel imaging tools, increasing awareness, and surveillance has led to early diagnosis of benign and malignant liver tumours. Multidisciplinary interventions have favourably altered the natural course in some liver tumours. The role of liver transplantation is expanding and has become fully integrated into today's therapeutic algorithms. Transarterial locoregional and ablation therapies have been successful in adults and are being explored in children to facilitate resectability and improve outcome. For the first time, North American, Japanese, and European experts have designed a global trial to optimize management of malignant liver tumours and aim to find signature molecular profiles that will translate to individualised treatment strategies.This article aims to offer an overview of recent advances in our understanding of liver tumours in children. It focuses on the paediatric hepatologist's view and their role in the multidisciplinary management of benign and malignant liver tumours.
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http://dx.doi.org/10.1097/MPG.0000000000003006DOI Listing
April 2021

Characteristics, Trends, and Outcomes of Liver Transplantation for Primary Sclerosing Cholangitis in Female Versus Male Patients: An Analysis From the European Liver Transplant Registry.

Transplantation 2021 Oct;105(10):2255-2262

Hepatology and Liver Transplant Unit, La Fe University Hospital and Ciberehd, IISLaFe, Valencia, Spain.

Background: The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex.

Methods: Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome.

Results: European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000).

Conclusions: An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size.
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http://dx.doi.org/10.1097/TP.0000000000003542DOI Listing
October 2021
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