Publications by authors named "Antal Dezsofi"

43 Publications

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

Hepatology 2021 Mar 5. Epub 2021 Mar 5.

Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs <194 µmol/L: 49% versus sBAs ≥194 µmol/L: 15%; P=0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P=0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P=0.06) and post-SBD sBA concentrations <65μmol/L (P=0.05) tended to be associated with improved NLS. Conclusion: Less than half of FIC1 deficiency patients reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
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http://dx.doi.org/10.1002/hep.31787DOI Listing
March 2021

Genotype correlates with the natural history of severe bile salt export pump deficiency.

J Hepatol 2020 07 20;73(1):84-93. Epub 2020 Feb 20.

Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Electronic address:

Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date.

Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category.

Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001).

Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS.

Lay Summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.
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http://dx.doi.org/10.1016/j.jhep.2020.02.007DOI Listing
July 2020

Liver Biopsy in High-risk Children: Which Way to Go?

J Pediatr Gastroenterol Nutr 2020 04;70(4):411-412

Institut für Pathologie, Medizinische Universität Graz, Graz, Austria.

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http://dx.doi.org/10.1097/MPG.0000000000002620DOI Listing
April 2020

Similarities and Differences in Allocation Policies for Pediatric Liver Transplantation Across the World.

J Pediatr Gastroenterol Nutr 2019 05;68(5):700-705

Department of Pediatrics, Recanati/Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Objectives: We aimed to investigate national allocation policies for pediatric liver transplantation (LT).

Method: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries.

Results: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality.

Conclusions: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.
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http://dx.doi.org/10.1097/MPG.0000000000002283DOI Listing
May 2019

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

J Pediatr Gastroenterol Nutr 2019 03;68(3):377-383

First Department of Pediatrics, Semmelweis University, Budapest, Hungary.

Objectives: Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children.

Methods: A total of 42 LT recipients (21 men, age 9.93 ± 3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed.

Results: Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%.

Conclusions: Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.
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http://dx.doi.org/10.1097/MPG.0000000000002196DOI Listing
March 2019

[Solid organ transplantation in childhood].

Orv Hetil 2018 11;159(46):1948-1956

I. Gyermekgyógyászati Klinika, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Bókay J. u. 53., 1083.

Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948-1956.
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http://dx.doi.org/10.1556/650.2018.31284DOI Listing
November 2018

The Health Care Transition of Youth With Liver Disease Into the Adult Health System: Position Paper From ESPGHAN and EASL.

J Pediatr Gastroenterol Nutr 2018 Jun;66(6):976-990

Department of Paediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center, Groningen, The Netherlands.

Background: Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system.

Aim: The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services.

Methods: Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique.

Results: We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients.

Conclusions: Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.
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http://dx.doi.org/10.1097/MPG.0000000000001965DOI Listing
June 2018

Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.

J Pediatr Gastroenterol Nutr 2018 02;66(2):345-360

MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK.

Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
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http://dx.doi.org/10.1097/MPG.0000000000001801DOI Listing
February 2018

Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

J Pediatr Gastroenterol Nutr 2018 02;66(2):334-344

Pediatric Hepatology Unit, Centre National de Référence de la Maladie de Wilson, Hôpital Necker-APHP, Paris, France.

Background: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children.

Methods: Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.
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http://dx.doi.org/10.1097/MPG.0000000000001787DOI Listing
February 2018

Treatment of Chronic Hepatitis C Virus Infection in Children: A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

J Pediatr Gastroenterol Nutr 2018 03;66(3):505-515

Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children.

Methods: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique.

Results: The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin.

Conclusions: This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection.
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http://dx.doi.org/10.1097/MPG.0000000000001872DOI Listing
March 2018

Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis.

World J Gastroenterol 2017 Aug;23(29):5412-5421

Tamas Tornai, Zsuzsanna Vitalis, Istvan Tornai, Eszter Palyu, Maria Papp, Institute of Internal Medicine, Department of Gastroenterology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, H-4032 Debrecen, Hungary.

Aim: To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients.

Methods: Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls.

Results: A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG ( < 0.001, for both) and AGA IgG ( = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies ( < 0.001 for EndoCab IgA and = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABP: 365 166 pg/mL, = 0.011), but not with serum LBP level.

Conclusion: Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.
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http://dx.doi.org/10.3748/wjg.v23.i29.5412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550791PMC
August 2017

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference.

J Pediatr Gastroenterol Nutr 2017 09;65(3):e53-e59

*Swiss Center for Liver Disease in Children, University Hospitals Geneva, Geneva, Switzerland †Division of Infectious Diseases and the Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, Canada ‡Pediatric Nephrology, Imagine Institute, Necker-Enfants Malades Hospital, APHP, Paris Descartes University-Sorbonne Paris Cité, Paris, France §Pediatric Liver Care Center, Cincinnati Children's Hospital, Cincinnati, OH ||Department of Surgery, Ospedale Papa Giovanni XXIII, Bergamo, Italy ¶Faculté de Médecine, University de Nantes, Nantes, France #Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy **Pediatric Hepatology Unit, Necker Enfants Malades Hospital, Paris, France ††First Department of Pediatrics, Semmelweis University, Budapest, Hungary ‡‡University Tor Vergata, Rome, Italy §§Pediatric Liver GI and Nutrition Centre, King's College Hospital, London, UK ||||Faculty of Medicine, Istanbul University, Istanbul, Turkey ¶¶Institute of Transplant Immunology, FIB-Tx, Hannover Medical School, Germany ##Abdominal Transplant Surgery, University of California San Francisco, San Francisco, CA ***Department of Pediatrics, Karolinska University Hospital, CLINTEC Karolinska Institutet, Stockholm, Sweden †††Pediatric Radiology Department, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud- Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France ‡‡‡Pediatric Hepatology and Liver Transplantation, Hospital Universitario Infantil La Paz, Madrid, Spain §§§Department of Pediatrics, University Children's Hospital Bonn, Bonn, Germany ||||||Center for Cell and Gene Therapy and Texas Children's Cancer Center, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX ¶¶¶Pediatric Liver GI and Nutrition Centre, King's College, London, UK ###Seattle Children's Hospital and University of Washington, Seattle, WA ****School of Cancer Sciences ††††Department of Cellular Pathology, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK ‡‡‡‡The European Transplant Registry, APHP Paul Brousse Hospital, Villejuif, France §§§§Liver Unit, Birmingham Children's Hospital, Birmingham, UK ||||||||Department of Pediatric Hematology/Oncology and Integrated Research and Treatment Center for Transplantation, Hannover Medical School, Germany ¶¶¶¶Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, PA ####Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Section of Pediatrics, University of Salerno, Baronissi, Italy *****Bambino Gesu Children's Hospital, Rome, Italy †††††Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Ege University, Izmir, Turkey ‡‡‡‡‡Pediatric Surgery and Transplantation Unit, Cliniques Universitaires de Saint-Luc, Université Catholique de Louvain, Brussels, Belgium §§§§§ISMETT, University of Pittsburgh Medical Center, Palermo, Italy ||||||||||The Children's Memorial Health Institute, Warsaw, Poland ¶¶¶¶¶Divisions of Abdominal and Transplant Surgery, Faculty of Medicine and University Hospitals Geneva, Geneva, Switzerland #####University of Salerno, Baronissi, Italy ******King's College Hospital, Institute of Liver Studies, London, UK ††††††Department for Pediatric Kidney, Liver and Metabolic Disease, Division of Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.
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http://dx.doi.org/10.1097/MPG.0000000000001564DOI Listing
September 2017

Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis: Results of a European Survey.

J Pediatr Gastroenterol Nutr 2017 06;64(6):864-868

*Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria †Department of Paediatrics, CLINTEC, Karolinska University Hospital, Stockholm, Sweden ‡Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy §Pediatric Hepatology Unit, Hôpital Necker-Enfants-Malades, Paris, France ||First Department of Paediatrics, Semmelweis University, Budapest, Hungary ¶Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany #Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK **Pediatric Hepatology and Liver Transplantation Unit, Hôpital Bicêtre, Reference Centre for Pediatric Liver Diseases-DHU Hepatinov, Assistance Publique-Hôpitaux de Paris and INSERM UMR-S 1174, Université Paris-Sud 11, Le Kremlin-Bicêtre ††Pediatric Hepatology and Gastroenterology Unit, University Children's Hospital, Bordeaux, France ‡‡Department of Medical Sciences, Paediatric Section, University Hospital Arcispedale Sant'Anna, University of Ferrara, Ferrara, Italy §§Division of Gastroenterology/Hepatology/Nutrition, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA ||||Department of Pediatrics, Pediatric Gastroenterology Unit, Azienda Ospedaliera-Universitaria Citta[Combining Grave Accent] della Salute e della Scienza di Torino, University of Torino, Torino, Italy ¶¶Department of Paediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands ##Paediatric Hepatology Service, Hospital Infantil Universitario "La Paz," Madrid, Spain ***Paediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals Geneva, Geneva, Switzerland †††Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Objective: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to determine the prevalence of 2 common disorders, 3β-hydroxy-Δ-C27-steroid dehydrogenase (3β-HSD) and Δ-3-oxosteroid-5β-reductase (Δ-3-oxoR) deficiencies and to describe current diagnostic and treatment strategies among different European paediatric hepatology centres.

Methods: A total of 52 clinical paediatric centres were approached and 39 centres in 21 countries agreed to participate in the Web-based survey. The survey comprised questions regarding general information, number of cases, diagnostic, and therapeutic management.

Results: Seventeen centres located in 11 countries reported patients with inborn errors in primary BA synthesis, 22 centres never had cases diagnosed. In total, we could identify 63 patients; 55 with 3β-HSD and 8 with Δ-3-oxoR deficiency in 21 countries. The minimum estimated combined prevalence of these diseases was 1.13 cases per 10 million (0.99 and 0.14 for 3β-HSD and Δ-3-oxoR deficiencies, respectively). The surveyed colleagues indicated their main challenges to be the rarity of diseases and the lack of convenient laboratory facilities nearby.

Conclusion: We have identified the largest cohort of patients with 3β-HSD or Δ-3-oxoR deficiency described so far. These diseases are likely underdiagnosed mainly due to unawareness of their existence and the lack of laboratory facilities.
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http://dx.doi.org/10.1097/MPG.0000000000001546DOI Listing
June 2017

Hepatitis E in Children: A Position Paper by the ESPGHAN Hepatology Committee.

J Pediatr Gastroenterol Nutr 2016 08;63(2):288-94

*Department of Paediatrics, CLINTEC, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden †Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany ‡First Department of Paediatrics, Semmelweis University, Budapest, Hungary §Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK ||Paediatric Hepatology Service, Hospital Infantil Universitario "La Paz," Madrid, Spain ¶Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Austria #Paediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals Geneva, Switzerland **Hepatometabolic Unit, Bambino Gesu Children's Hospital, Rome, Italy ††Pediatric Gastroenterology and Hepatology Unit, IREC, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium ‡‡Department of Paediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands §§Pediatric Hepatology Unit, Hôpital NECKER-APHP, Paris, France.

Background: Hepatitis E virus (HEV) is endemic in large parts of the developing world. Waterborne transmission of genotypes 1 or 2 commonly causes acute hepatitis, which is usually self-limited in healthy individuals. In addition, acute HEV infections also occur outside endemic areas, mostly related to foodborne transmission of HEV genotype 3. A growing number of publications in the last decade have reported chronic infection progressing to cirrhosis in immunosuppressed patients. It has also been suggested that HEV transmission may occur via contaminated blood products. This publication aims to provide recommendations for diagnosis, prevention, and treatment of HEV infection, particularly in children after solid organ transplantation.

Methods: A systematic PubMed literature search on HEV infection from 1990 to January 2016 was performed focusing on pediatric studies. The existing body of evidence was reviewed and recommendations were agreed upon following discussion and unanimous agreement by all members of the ESPGHAN Hepatology Committee during a consensus meeting in January 2016. In the absence of randomized controlled studies these recommendations were considered to be expert opinions.

Key Recommendations: Immunocompetent children with increased transaminases and/or extrahepatic manifestations should be considered for testing for evidence of HEV infection. Immunocompromised children with increased aminotransferases should be repeatedly tested for HEV and may require therapeutic intervention.
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http://dx.doi.org/10.1097/MPG.0000000000001231DOI Listing
August 2016

Seasonal variability of vitamin D and bone metabolism in infliximab-treated paediatric Crohn's disease.

Dig Liver Dis 2015 Aug 19;47(8):652-7. Epub 2015 May 19.

1st Department of Pediatrics, Semmelweis University, Budapest, Hungary. Electronic address:

Background: Paediatric Crohn's disease patients suffer from several complications, including low bone mineral density and inadequate serum levels of 25-hydroxy vitamin D.

Aims: The aim of this prospective study was to address the effect of infliximab therapy on bone metabolism, bone mineral density and vitamin D homeostasis. The seasonal variability of serum vitamin D levels in relation to infliximab treatment was also analysed.

Methods: Serum osteocalcin and beta-crosslaps (markers of bone metabolism), seasonal variability of vitamin D, and bone mineral density were assessed and followed throughout the yearlong treatment regimen of infliximab in 50 consecutive paediatric patients with moderate to severe Crohn's disease.

Results: Bone forming osteocalcin levels were significantly (p<0.001) increased during infliximab therapy. In contrast, no significant changes in beta-crosslaps and vitamin D levels were observed. Vitamin D levels were significantly different when the summer and winter periods were compared at week 0 (p=0.039); however, this difference was not detected after one year of infliximab therapy. Despite the beneficial clinical effect of infliximab, there was no significant change in bone mineral density Z-scores after one year of treatment.

Conclusion: Infliximab may beneficially affect bone homeostasis. Moreover, seasonal variability in vitamin D levels observed prior to initiation of infliximab treatment was diminished after one year of treatment.
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http://dx.doi.org/10.1016/j.dld.2015.05.006DOI Listing
August 2015

Indications and limitations of bariatric intervention in severely obese children and adolescents with and without nonalcoholic steatohepatitis: ESPGHAN Hepatology Committee Position Statement.

J Pediatr Gastroenterol Nutr 2015 Apr;60(4):550-61

*Unit of Hepato-Metabolic Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome †Department of Medicine and Surgery, Pediatric Section, University of Salerno, Baronissi (Salerno), Italy ‡First Department of Pediatrics, Semmelweis University, Semmelweis, Hungary §Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden ||Paediatric Gastrointestinal, Liver and Nutrition Centre Variety Children's Hospital King's College Hospital NHS Foundation Trust Denmark Hill Camberwell, London, UK ¶Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria #Pediatric Gastroenterology Unit, Children's Hospital, Place Amelie Raba, Bordeaux, France **Liver Unit, Birmingham Children's Hospital, Birmingham, UK ††Swiss Center for Liver Disease in Children, Pediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals, Geneva, Switzerland ‡‡Department of Gastroenterology, Hepatology and Eating Disorders, Children's Memorial Health Institute, Warsaw, Poland §§Paediatric Viral Hepatitis, Paediatric Gastrointestinal, Liver and Nutrition Centre Variety Children's Hospital King's College Hospital NHS Foundation Trust Denmark Hill Camberwell, London, UK ||||Hannover Medical School, Children's Hospital, Division of Paediatric Gastroenterology and Hepatology, Hannover, Germany.

Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD), which is one of the most common causes of chronic liver disease worldwide. The present best treatment for NAFLD and nonalcoholic steatohepatitis (NASH) is weight reduction through lifestyle modification. Because of frustrating inefficiency of such a therapeutic approach, bariatric surgery is increasingly performed in adolescents as an alternative option for weight reduction. Standards of care and consensus for indications are, however, scarce. We explore the indications and limitations of bariatric surgery in children with severe obesity with and without NASH and aim to provide guidance for the exceptional indications for adolescents with extreme obesity with major comorbidity that may benefit from these controversial interventions. Present evidence suggests that bariatric surgery can decrease the grade of steatosis, hepatic inflammation, and fibrosis in NASH. Uncomplicated NAFLD is not an indication for bariatric surgery. Roux-en-Y gastric bypass is considered a safe and effective option for adolescents with extreme obesity, as long as an appropriate long-term follow-up is provided. Laparoscopic adjustable gastric banding has not been approved by the Food and Drug Administration for use in adolescents and therefore should be considered investigational. Finally, sleeve gastrectomy and other types of weight loss surgery that have grown increasingly common in adults, still need to be considered investigational. Temporary devices may be increasingly being used in pediatrics; however, future studies, including a long-term risk analysis of patients who undergo surgery, are much needed to clarify the exact indications for bariatric surgery in adolescents.
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http://dx.doi.org/10.1097/MPG.0000000000000715DOI Listing
April 2015

Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee.

J Pediatr Gastroenterol Nutr 2015 Mar;60(3):408-20

*First Department of Pediatrics, Semmelweis University, Budapest, Hungary †Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany ‡Kings College London School of Medicine at Kings College Hospital, London, UK §Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey ||Department of Pediatrics, CLINTEC, Karolinska University Hospital, Stockholm, Sweden ¶Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK #Pediatric Hepatology Service, Hospital Infantil Universitario "La Paz," Madrid,Spain **Necker-Enfants Malades Hospital, Paris, France ††Pediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals Geneva, Switzerland ‡‡Hepatometabolic Unit, Bambino Gesu Children's Hospital, Rome, Italy §§Department of Gastroenterology, Hepatology and Nutritional Disturbances, Children's Memorial Health Institute, Warsaw, Poland ||||Department of Medicine and Surgery, University of Salerno, Salerno, Italy ¶¶Institute of Liver Studies/King's College Hospital, London, UK.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.
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http://dx.doi.org/10.1097/MPG.0000000000000632DOI Listing
March 2015

Hepatic neoplasms in children: a focus on differential diagnosis.

Clin Res Hepatol Gastroenterol 2014 Sep 16;38(4):399-402. Epub 2014 Jun 16.

Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK.

Paediatric hepatic neoplasias are rare, accounting for 1-4% of all solid childhood tumors. Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation. Two-thirds of liver tumors in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, and hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a paediatric liver tumour guides the treatment and prognosis. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ.
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http://dx.doi.org/10.1016/j.clinre.2014.05.001DOI Listing
September 2014

Liver biopsy in children 2014: who, whom, what, when, where, why?

Clin Res Hepatol Gastroenterol 2014 Sep 9;38(4):395-8. Epub 2014 Jun 9.

Institute of Liver Studies, King's College Hospital, London, UK.

Liver biopsy is the standard procedure for obtaining hepatic tissue for histopathological examination. The three major techniques are percutaneous, transvenous, and laparoscopic/open biopsy, with either cutting or suction needles. The indications for liver biopsy are shifting as knowledge of etiologies, non-invasive biomarker alternatives, and treatment options in paediatric liver disease expand. This mini-review presents specific indications, alternative approaches, methods, complications, and contraindications for paediatric liver biopsy.
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http://dx.doi.org/10.1016/j.clinre.2014.05.002DOI Listing
September 2014

[Post-transplantation lymphoproliferative disorder in childhood].

Orv Hetil 2014 Feb;155(8):313-8

Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay J. u. 53. 1083.

Introduction: Among possible complications of transplantation the post-transplant lymphoproliferative disease due to immunosuppressive therapy is of paramount importance. In most cases the direct modulating effect of Epstein-Barr virus on immune cells can be documented.

Aim: The aim of the authors was to evaluate the incidence os post-transplant lymphoproliferative diseases in pediatric transplant patients in Hungary.

Method: The study group included kidney, liver and lung transplant children followed up at the 1st Department of Pediatrics, Semmelweis University, Budapest and stem cell transplant children at Szent László Hospital, Budapest. Data were collected from 78 kidney, 109 liver and 17 lung transplant children as well as from 243 children who underwent allogenic stem cell transplantation.

Results: Between 1998 and 2012, 13 children developed post-transplant lymphoproliferative disorder (8 solid organ transplanted and 5 stem cell transplanted children). The diagnosis was based on histological findings in all cases. Mortality was 3 out of the 8 solid organ transplant children and 4 out of the 5 stem cell transplant children. The highest incidence was observed among lung transplant children (17.6%).

Conclusions: These data indicate that post-transplant lymphoproliferative disease is a rare but devastating complication of transplantation in children. The most important therapeutic approaches are reduction of immunosuppressive therapy, chemotherapy and rituximab. Early diagnosis may improve clinical outcome and, therefore, routine polymerase chain reaction screening for Epstein-Barr virus of high risk patients is recommended.
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http://dx.doi.org/10.1556/OH.2014.29796DOI Listing
February 2014

Autoregressive cross-lagged models of IMPACT-III and Pediatric Crohn's Disease Activity Indexes during one year infliximab therapy in pediatric patients with Crohn's disease.

J Crohns Colitis 2014 Aug 14;8(8):747-55. Epub 2014 Jan 14.

1st Department of Pediatrics, Semmelweis University, Budapest, Hungary. Electronic address:

Background: Quality of life (QoL) is an important outcome measure in the evaluation of therapies for inflammatory bowel disease. The primary aim of this study was to determine the effect of one year infliximab treatment on QoL and clinical parameters in pediatric patients with Crohn's diseases (CD).

Methods: Our prospective study involved 51 children with conventional therapy resistant, severe CD (mean age: 15.25years, range: 11-18years). Infliximab was given according to the protocol (5mg/kg, at weeks 0, 2, 6 and every 8weeks). During the infliximab courses QoL of patients was evaluated by IMPACT-III questionnaire at weeks 0, 6, 30 and 53. At the same time, the Pediatric Crohn's Disease Activity Index (PCDAI) score was calculated. Moreover, serum C-reactive protein (CRP), serum platelets and serum albumin were followed up. Auto-regressive, cross-lagged models were used to assess relation between QoL and the clinical parameters.

Results: The initial IMPACT-III scores [median, percentile 25-75 (pc 25-75) at week 0: 115, 102.5-130.25] increased significantly (p<0.001) following infliximab therapy at week 54 (median: 141.5, 124.5-153.75). Clinical and laboratory parameters also improved significantly (p<0.001). Auto-regressive regression coefficients (β value) were significant between each variable over time. The strongest cross-lagged relations were observed between IMPACT-III and serum albumin, IMPACT-III and platelets. Reliability test of IMPACT-III revealed an excellent level of internal consistency (Cronbach's alpha=0.931).

Conclusion: Infliximab treatment has beneficial clinical effect which is confirmed by decrease of PCDAI and increase of IMPACT-III. Autoregressive regression analysis showed regression relation between IMPACT-III and PCDAI and laboratory parameters.
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http://dx.doi.org/10.1016/j.crohns.2013.12.020DOI Listing
August 2014

Incidence, Paris classification, and follow-up in a nationwide incident cohort of pediatric patients with inflammatory bowel disease.

J Pediatr Gastroenterol Nutr 2013 Nov;57(5):576-82

1st Department of Pediatrics, Semmelweis University, Budapest, Hungary

Objectives: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed.

Methods: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification.

Results: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/10⁵ (95% confidence interval [CI] 6.34/10⁵-8.83/10⁵). The incidence for Crohn disease (CD) was 4.72/10⁵ (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/10⁵ (95% CI 1.71-3.09), and for IBD-unclassified 0.45/10⁵ (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%.

Conclusions: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.
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http://dx.doi.org/10.1097/MPG.0b013e31829f7d8cDOI Listing
November 2013

[The role of intestinal alkaline phosphatase in pediatric inflammatory bowel and celiac diseases].

Orv Hetil 2012 Sep;153(35):1389-95

Semmelweis Egyetem, Általános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay J.

Intestinal alkaline phosphatase enzyme plays a pivotal role in the maintenance of intestinal mucosal barrier integrity with the detoxification capacity of lipopolysaccharide, the ligand of Toll-like receptor 4. The inappropriate immune responses and the damage of the mucosal barrier may contribute to the initiation of inflammatory bowel and celiac diseases. In the inflamed colonic mucosa of children with inflammatory bowel disease and in the duodenal mucosa of newly diagnosed children with celiac disease, the decreased intestinal alkaline phosphatase and increased Toll-like receptor 4 protein expression may generate enhanced lipopolysaccharide activity, which may strengthen tissue damaging processes. The enhancement of intestinal alkaline phosphatase activity in an animal model of colitis and in therapy resistant, adult patients with ulcerative colitis reduced the symptoms of intestinal inflammation. In accordance with these results, the targeted intestinal administration of the enzyme in the two examined disorders may be a supplemental therapeutic option in the future.
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http://dx.doi.org/10.1556/OH.2012.29441DOI Listing
September 2012

Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening.

Mol Genet Metab 2012 Aug 20;106(4):439-41. Epub 2012 Apr 20.

Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Introduction: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.

Method: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis.

Results: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common.

Discussion: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.
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http://dx.doi.org/10.1016/j.ymgme.2012.04.006DOI Listing
August 2012

Low mannose-binding lectin (MBL) is associated with paediatric inflammatory bowel diseases and ileal involvement in patients with Crohn disease.

J Crohns Colitis 2013 Mar 13;7(2):134-41. Epub 2012 Apr 13.

Department of Paediatrics, Petz Aladár County and Teaching Hospital, Győr, Hungary.

Background: Mannose-binding lectin (MBL) is a pattern-recognition molecule of the innate immune system and may be involved in the pathogenesis of inflammatory bowel disease (IBD). Our aim was to assess the prevalence of MBL deficiency in a cohort of patients with paediatric-onset IBD and study whether it is associated with the clinical manifestations, serum antibody formation, or genetic factors.

Methods: This prospective study included 159 paediatric patients (mean age: 14.0 years) with IBD [107 patients with Crohn disease (CD) and 52 patients with ulcerative colitis (UC)]. Furthermore, 95 controls were investigated. Serum samples were determined for MBL by enzyme-linked immunosorbent assay (ELISA) and for serologic markers [autoantibodies against Saccharomyces cerevisiae (ASCA) and perinuclear components of neutrophils (pANCA)] by indirect immunofluorescent assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism.

Results: The MBL serum concentration was significantly lower in IBD patients(both with CD and UC) compared to controls (IBD, p=0.007, CD, p=0.04, UC p=0.004). Prevalence of low MBL level (<500 ng/mL) was significantly higher in both CD and UC groups compared to controls (p=0.002 and p=0.006). Furthermore, low MBL level was associated with isolated ileal involvement (p=0.01) and MBL deficiency (<100 ng/mL) with male gender (p=0.004) in patients with CD. We failed to confirm any correlation between MBL deficiency and serum autoantibodies or NOD2/CARD15 variants.

Conclusions: Our results suggest that low MBL associated with paediatric-onset IBD and ileal CD may be considered an additional marker of the IBD pathogenesis.
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http://dx.doi.org/10.1016/j.crohns.2012.03.008DOI Listing
March 2013

Pancreatic autoantibodies and autoantibodies against goblet cells in pediatric patients with inflammatory bowel disease.

J Pediatr Gastroenterol Nutr 2012 Oct;55(4):429-35

Department of Pediatrics, Petz Aladár County and Teaching Hospital, Győr, Hungary.

Background: Significance of pancreatic autoantibodies determined by using exocrine pancreas (PAB) and antibodies against recombinant pancreas antigen (rPAB), as well as the importance of autoantibodies against goblet cells (GAB), is not known in pediatric patients with inflammatory bowel disease (IBD). Our aim was to determine the complex analysis of PAB, rPAB, GAB, antibodies against Saccharomyces cerevisiae, and perinuclear components of neutrophils in pediatric patients with IBD. Moreover, association with NOD2/CARD15 and disease phenotype was determined.

Methods: A total of 152 pediatric patients (median age 13.9 years) with IBD (103 patients with Crohn disease [CD] and 49 patients with ulcerative colitis [UC]) and 104 controls were included. Serum autoantibodies were determined by indirect immunofluorescence assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism.

Results: The presence of PAB and rPAB was significantly higher in CD (34% and 35.9%) and in UC (20.4% and 24.5%) compared with pediatric control cohort (0% and 0%, P<0.0001). In addition, GAB positivity was significantly increased in patients with UC in comparison with CD and controls, respectively (UC, 12.2%; CD, 1.9%; controls, 1.9%; P=0.02). Specificity of PAB and rPAB was 100%; however, sensitivity was low. The combination of PAB and/or antibodies against Saccharomyces cerevisiae/perinuclear components of neutrophils improved the sensitivity of serological markers in CD (87.4%) and in UC (79.6%); specificities were 89.3% and 93.2%, respectively. Pancreatic autoantibodies (PAB, rPAB) and GAB were not related to clinical presentation, medical therapy, or need for surgery in CD or in UC.

Conclusions: Pancreatic autoantibodies and GAB were specific for IBD, but the sensitivity was limited as well because there was lack of correlation with clinical phenotype. Combinations of these antibodies have shown increased sensitivity; therefore, it may be recommended in the diagnostic procedure of IBD.
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http://dx.doi.org/10.1097/MPG.0b013e318256b516DOI Listing
October 2012

Decreased mucosal expression of intestinal alkaline phosphatase in children with coeliac disease.

Virchows Arch 2012 Feb 20;460(2):157-61. Epub 2012 Jan 20.

1st Department of Paediatrics, Semmelweis University, Bókay u. 53, H-1083 Budapest, Hungary.

A major function of the enzyme intestinal alkaline phosphatase (iAP) is the detoxification of lipopolysaccharide (LPS), the ligand of Toll-like receptor 4 (TLR4). Hence, iAP has a role in the defence of maintaining intestinal barrier integrity. As intestinal barrier integrity is impaired in coeliac disease (CD), we tested the expression and localization of iAP in duodenal mucosa specimens from children with newly diagnosed CD (n = 10), with CD on gluten-free diet (GFD) (n = 5) and compared to those from ten healthy children. The mRNA and protein expression was determined by RT-PCR and Western blot analysis, respectively. Tissue localization of iAP and TLR4 was determined by immunofluorescence staining. iAP protein expression level was significantly lower than normal in newly diagnosed CD, while it was normalised in children on GFD. iAP and TLR4 colocalized at the epithelial surface of duodenal mucosa in each group of subjects enrolled. The finding of decreased iAP protein levels in newly diagnosed CD is consistent with its role in decreased intestinal barrier integrity. The latter may be the result of decreased LPS-detoxifying ability.
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http://dx.doi.org/10.1007/s00428-011-1188-5DOI Listing
February 2012

Diagnostic yield of upper endoscopy in paediatric patients with Crohn's disease and ulcerative colitis. Subanalysis of the HUPIR registry.

J Crohns Colitis 2012 Feb 23;6(1):86-94. Epub 2011 Aug 23.

Petz Aladár County Teaching Hosp., Győr, Hungary.

Background, Aims: According to Porto Criteria upper gastrointestinal (UGI) endoscopy is recommended in patients with suspected inflammatory bowel disease (IBD). Nevertheless, previous studies revealed frequent involvement of UGI tract even in patients with ulcerative colitis (UC). The aim of the present study was to determine the diagnostic role of esophagogastroduodenoscopy (EGD) and assess the prevalence and different aspects of UGI involvement in children registered in the Hungarian Pediatric IBD Registry (HUPIR) from 1st of January 2007 to 31th of December 2009.

Methods: Twenty seven institutes provided prospective follow-up data about newly diagnosed IBD patients to HUPIR. The registry was based on detailed questionnaire (76 parameters) involving anamnestic data, laboratory findings, activity indexes, diagnostic procedures, endoscopic examinations (EGD and ileocolonoscopy), and histological data. Localization and phenotype of disease were based on the Montreal classification criteria.

Results: During the 3-year period 420 children were diagnosed with IBD, 265 (63%) of them had Crohn's disease (CD), 130 (31%) UC, and 25 (6%) IBD-unclassified (IBD-U). The mean age at diagnosis was 13.2 years (range: 1.2-18 years). EGD was performed in 237 patients (56%), in most cases in patients suffering from CD. Macroscopic lesions on EGD were noted in 64% of patients with CD and 40% of children with UC. Characteristic lesions for CD (ulcer, erosion, aphthous lesion, and granuloma) were noted in 31% of CD patients, however, EGD helped to establish the final diagnosis in 9% of CD patients (diagnostic yield, 9%).

Conclusions: There was a high frequency of UGI involvement in children with CD and UC. One third of CD patients showed significant lesions at upper endoscopy and one patient out of ten had real diagnostic help from EGD.
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http://dx.doi.org/10.1016/j.crohns.2011.07.008DOI Listing
February 2012

Duodenal ulceration in a patient with celiac disease and plasminogen I deficiency: coincidence or cofactors?

Pediatrics 2011 Nov 3;128(5):e1302-6. Epub 2011 Oct 3.

First Department of Pediatrics, Semmelweis University, Budapest, Hungary.

Celiac disease (CD) is a gluten-dependent inflammatory disease of the small bowel that affects up to 1% of the worldwide population. Despite severe mucosal abnormalities including total villous atrophy and autoantibody deposition, duodenal ulcer is not a feature of CD. However, a recent study found an elevated rate of peptic ulcer disease in patients with CD. Plasminogen deficiency (PLD) is an autosomal recessive disease that causes pseudomembranous lesions in different organs, but gastrointestinal involvement is rare. Here we report the case of a 6-year-old girl who had a sudden onset of hematemesis caused by duodenal ulcer. On the basis of mucosal atrophy, elevated celiac antibody levels, decreased plasminogen serum activity, and homozygous missense mutation R216H in the plasminogen gene, CD and PLD were diagnosed. This report is, to our knowledge, the first description of the 2 entities, and results of our double-immunofluorescent studies also suggest that both diseases may have a role in the ulceration process. Excessive amounts of fibrin deposition due to PLD caused the distortion of the vessels and was responsible for the unusual celiac immunoglobulin A and tissue transglutaminase 2 in vivo binding pattern. On the basis of this result, patients with CD and unknown cause of gastrointestinal ulcer may require investigation for PLD.
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http://dx.doi.org/10.1542/peds.2010-2251DOI Listing
November 2011

Immune phenotype in children with therapy-naïve remitted and relapsed Crohn's disease.

World J Gastroenterol 2010 Dec;16(47):6001-9

Research Group for Pediatrics and Nephrology, Semmelweis University and Hungarian Academy of Sciences, H-1083, Budapest, Hungary.

Aim: To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy-naïve childhood Crohn's disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease.

Methods: We enrolled 26 pediatric patients with CD. 14 therapy-naïve CD children; of those, 10 children remitted on conventional therapy and formed the remission group. We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab; and 15 healthy children who served as controls. The prevalence of Th1 and Th2, naïve and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK-T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll-like receptor (TLR)-2 and TLR-4 expression were determined in peripheral blood samples.

Results: Children with therapy-naïve CD and those in relapse showed a decrease in Th1 cell prevalence. Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed. In addition, the ratio of myeloid /plasmocytoid DCs and the prevalence of TLR-2 or TLR-4 positive DCs and monocytes were also higher in therapy-naïve CD than in controls. The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy.

Conclusion: The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD. Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007111PMC
http://dx.doi.org/10.3748/wjg.v16.i47.6001DOI Listing
December 2010