- Email: [email protected]
65 CLINICAL, BIOCHEMICAL AND GENETIC FEATURES IN TRANSALDOLASE DEFICIENCY, A NEW DISORDER IN PEDIATRIC HEPATOLOGY
ORAL PRESENTATIONS 63 GENDER EFFECTS IN A NOVEL INDUCIBLE MOUSE MODEL OF PRIMARY BILIARY CIRRHOSIS (PBC) D. Schwinge1 , A. Carambia1 , A. Quaas2 , T. Trautmann1 , J. Herkel1 , A.W. Lohse1 , C. Schramm1 . 1 Department of Medicine I, 2 Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany E-mail: [email protected] Primary Biliary Cirrhosis is an autoimmune liver disease that predominantly affects middle-aged women, characterized by lymphocytic infiltration in portal tracts and destruction of intrahepatic small bile ducts, causing liver fibrosis and eventually liver failure. The histopathology is presumably mediated by CD8 T cells. Here, we describe a novel mouse model which shows gender differences similar to the female predominance observed in PBC patients. Adoptive cell transfer experiments of OVA-specific CD8+ T cells into K14-Ovap transgenic mice were performed. K14-Ovap mice express the antigenic SINFEKL peptide (residues 257–264 of OVA) under the control of human keratinocyte-specific promoter which directs expression in biliary epithelial cells. OT1 CD8+ T cells were injected intraperitoneally in male and female mice and survival rate, serum transaminases and histologic sections of the liver were analysed. Serum transaminase levels were significantly increased in female recipient mice in comparison to PBS control animals after adoptive transfer of 4×106 OT1 CD8+ T cells (**p < 0.009). In contrast transaminase levels of male mice recipient did not increase even after transfer of 10×106 OT1 CD8+ T cells. After adoptive transfer of 4×106 OT1 CD8+ T cells, histopathologic examinations of female mice showed peribiliary lymphocytic infiltrates and granuloma like lesions, whereas in male mice no histological lesions were seen. On day 6 after adoptive transfer of 20×106 and 10×106 OT1 CD8+ T cells 100% of female recipient mice died. Survival rate increased with transfer of lower cells numbers (4×106 survival rate of 80%). Male mice which received the corresponding cell numbers survived. In previously described models of PBC the immunopathology develops equally in male and female mice, in contrast to the female predominance in humans. In our model female mice showed a higher susceptibility against OT1 CD8+ T cell mediated hepatobiliary injury. We here describe an inducible, gender affected, immune-mediated model of PBC which could serve as an important tool to study gender effects on early autoimmune liver injury. 64 ANTIGEN-SPECIFIC REGULATORY T-CELLS IN AUTOIMMUNE HEPATITIS TYPE 2: CYTOKINE PROFILE AND EFFECT OF SEMI-MATURE DENDRITIC CELLS ON SUPPRESSOR FUNCTION M.S. Longhi, G. Mieli-Vergani, Y. Ma, D. Vergani. Institute of Liver Studies, King‘s College London School of Medicine at King‘s College Hospital, London, UK E-mail: [email protected] Background: CD4pos CD25pos regulatory T-cells (T-regs), a cell subset central to immune-tolerance, are defective in autoimmune hepatitis type 2 (AIH-2), a severe hepatopathy often leading to endstage liver disease despite immunosuppression. T-regs specific for cytochrome P450IID6 (CYP2D6), the main autoantigen in AIH-2, can be generated from CD4pos CD25high after co-culture with semimature dendritic cells (smDCs) and are currently investigated for their potential at reconstituting immune-tolerance in this condition. Aim: To investigate the relationship between the cytokine profile of antigen-specific T-regs and their inhibitory function in AIH-2. S30
Patients and Methods: 13 AIH-2 patients positive for HLA-DRB1*07 and/or DRB1*03, the HLA-DR alleles predisposing to this condition, were studied. CYP2D6-T-regs were obtained from CD4pos CD25high cells cultured in the presence of CYP2D6 peptide, high-dose interleukin 2 (IL-2) and anti-CD3/anti-CD28 T-cell expander. CYP2D6-T-reg cytokine production and suppressor function were tested before and after culture with CYP2D6-peptide-pulsed smDCs. CYP2D6-T-reg IFNg, IL-2, IL-4, IL-10, TGF-b and IL-17 production was determined by intracellular staining; suppressor function by proliferation assay following T-reg addition to CD25neg T-cells. Results: Proliferation of CD25neg cells (77,893±8,298 cpm) was reduced by 25.8% (P = 0.02) after addition of CYP2D6-T-regs and by 54.9% (P < 0.001) after addition of smDCs-CYP2D6-T-regs. The frequency of IFNg, IL-2, IL-4, IL-10, and IL-17 producing cells within T-reg subsets with or without smDCs was lower than in CD25neg cells (P < 0.001). In contrast, the frequency of TGF-b-producing cells was higher in both T-reg subsets compared to CD25neg cells (P < 0.001). While no difference in the frequency of IL-2, IL-4, IL-10, TGF-b and IL-17 producing cells was observed between CYP2D6T-regs and smDCs-CYP2D6-T-regs, IFNg-producing cells were more frequent in the absence of smDCs (1.19±0. 3 vs 0.3±0.03, P = 0.022). Treatment with anti-IFNg neutralizing antibodies enhanced the suppressor function of CYP2D6-T-regs from 25.8% to 50.5% (P = 0.005), but did not enhance further smDC-CYP2D6-T-regs suppression. Summary and Conclusion: smDCs co-cultured with CYP2D6-Tregs enhance their ability to suppress. The increase in CYP2D6T-reg suppression after IFNg neutralization suggests the presence of IFNg-producing cells among CYP2D6-T-regs. The combined use of smDCs and anti-IFNg should be considered for generation of ‘clinical-grade’ antigen-specific T-regs. 65 CLINICAL, BIOCHEMICAL AND GENETIC FEATURES IN TRANSALDOLASE DEFICIENCY, A NEW DISORDER IN PEDIATRIC HEPATOLOGY M.M.C. Wamelink1 , V. Valayannopoulos2 , E.A. Struys1 , G.S. Salomons1 , C. Jakobs1 . 1 Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; 2 Metabolic Unit and Reference Center of Metabolic Diseases, Hˆ opital Necker-Enfants Malades, Universit´e Paris Descartes, Paris, France E-mail: [email protected] Background and Aims: Transaldolase (TALDO) deficiency is a rare and only recently described inborn error of metabolism of the reversible part of the pentose phosphate pathway (PPP) presenting with mostly liver pathology [1–3]. So far only fourteen patients from eight families have been diagnosed. Methods: All patients were investigated clinical, biochemical and molecular. Results: All fourteen (or thirteen when an affected fetus was excluded) patients presented in the antenatal, neonatal or early childhood with (hepato)splenomegaly (14/14), abnormal liver function tests (14/14) and hepatic fibrosis (14/14). Most showed haemolytic anemia (10/13), dysmorphic features (9/14) (e.g. antimongoloid slant, low set ears and cutis laxa), congenital heart defects (9/14), renal problems (6/13) (tubulopathy, renal failure, nephrocalcinosis), neonatal edema (4/14) and/or intermittent hypoglycaemia (4/13). All TALDO deficient patients have elevated urinary excretion of erythritol, arabitol, ribitol, sedoheptitol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose7P [1–4]. Elevations are striking in the neonatal period, and more subtle in older patients. In plasma and CSF, only minor accumulation of these compounds occur. In the patients with TALDO deficiency thus far, four homozygous mutations have been detected and one patient was found compound heterozygous. Currently, for two additional patients with biochemical profiles and
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ORAL PRESENTATIONS clinical presentation of transaldolase deficiency, the DNA mutation analysis is pending. Conclusions: We advice to screen all patients with unexplained hepatosplenomegaly, liver function problems, hepatic fibrosis/cirrhosis and haemolytic anemia presenting in the neonatal or antenatal period for TALDO deficiency by measuring urinary polyols and/or seven-carbon sugars. Reference(s) [1] Verhoeven et al. (2001) Am J Hum Genet; 68;1086–1092. [2] Valayannopoulos et al (2006) J Pediatr; 149; 713–717. [3] Wamelink et al (2008) J Inher Metab Dis; 31; 703–713. [4] Wamelink et al (2007) J Inher Metab Dis;30; 735–742.
66 GROWTH OF LIVER VOLUME STOPS AFTER ONE YEAR OF LANREOTIDE IN PATIENTS WITH POLYCYSTIC LIVERS M. Chrispijn1 , L. van Keimpema1 , F. Nevens2 , R. Vanslembrouck3 , M.G.H. van Oijen1 , A.L. Hoffmann4 , H.M. Dekker5 , R.A. de Man6 , J.P.H. Drenth1 . 1 Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 2 Department of Hepatology, 3 Department of Radiology, University Hospital Leuven, Leuven, Belgium; 4 Department of Radiation Oncology, 5 Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, 6 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands E-mail: [email protected] Background and Aims: Polycystic livers are characterized by multiple cysts scattered throughout the liver parenchyma and are present in autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). Symptoms are due to mass effect of the liver. We performed the LOCKCYST trial which showed that lanreotide effectively reduces liver volume in patients with polycystic liver given for six months, while without treatment, polycystic livers keep growing. The aim of this study was to assess the effect of prolonged lanreotide treatment up to one year. Methods: This is an extension of the LOCKCYST trial, a multicentre, randomized, placebo-controlled trial which studied the effect of lanreotide 120 mg, administered every 28 days during 24 weeks in patients with a polycystic liver due to ADPKD or PCLD. All 54 patients who participated in the LOCKCYST trial during 24 weeks were asked to continue or start with lanreotide 120 mg every 28 days during 24 or 48 weeks, depending on whether they were randomized to either lanreotide or placebo, respectively. Primary endpoint was change in total liver volume, as determined by CTvolumetry, after six and twelve months in the group of patients that was treated with lanreotide for one year. Statistical analysis was performed using the Wilcoxon Signed Ranks test. Results: There were 41 patients who were treated with lanreotide for one year. Baseline median liver volume in this group was 4974 mL (range 1775–10,427). After six months of lanreotide, median liver volume decreased to 4785 mL (range 1852–9832) (−2.5%, p < 0.01), while after one year, it decreased to 4767 mL (range 1963–10,273), a decrease of 1.8% from baseline (p = 0.01). There was no significant difference in median liver volume between six and twelve months (p = 0.19). Conclusions: Lanreotide reduces liver volume after six months of treatment, while liver volume stabilizes when lanreotide is given for another six months.
67 CLUES FOR MINIMAL HEPATIC ENCEPHALOPATHY IN CHILDREN WITH PRE-HEPATIC PORTAL HYPERTENSION L. D’Antiga1 , P. Dacchille2 , C. Boniver2 , S. Poledri2 , S. Schiff3 , L. Zancan2 , P. Amodio3 . 1 Unit of Paediatrics Liver, GI and Transplantation, Ospedali Riuniti di Bergamo, Bergamo, 2 Dpt. of Paediatrics, 3 Clinical and Experimental Medicine, University of Padova, Padova, Italy E-mail: [email protected] Background: Scanty information exists on whether minimal hepatic encephalopathy (MHE) occurs in children with pre-hepatic portal hypertension (PHPH) due to portal vein thrombosis; this matter is relevant, since these condition might impair their intellectual development. We aimed to investigate children with PHPH to seek proofs of subclinical features consistent with MHE. Material and Methods: A consecutive sample of 13 children (age range 4–18 years, males 46%) with PHPH due to perinatal portal thrombosis without liver disease who had been referred to the Paediatric Clinic of Padua underwent an extensive psychometric battery comprising of 26 psychometric tests exploring the learning ability, abstract reasoning, phonemic and semantic fluency, selective attention, executive functions, short-term verbal and visual memory, long-term verbal memory, visuo-practic ability. Psychometric performance was evaluated by age and education stratified according to norms for Italian population. The same day the patients underwent fasting ammonia measurement on cooled blood samples immediately delivered to laboratory and digitalized EEG. Spectral analysis was performed on eye-closed EEG. Mean dominant frequency (MDF) and frequency bands were considered. The EEG of 14 age matched normal controls was considered for comparison. Results: Ten subjects had at least one altered psychometric test and two subjects had more than 5 abnormal tests. No subject had alteration concerning abstract reasoning, phonemic and semantic fluency. In contrast, selective attention, executive function and short-term visual memory were the domains more frequently altered (up to 50% of individuals). The EEG measures were predicted by age, whereas PHPH did not enter as a predictor (ANCOVA). Ammonia plasma level was higher than the reference values of our laboratory (35 mmol/L) in 5 subjects. Age (b=0.68±0.19 p < 0.01) and ammonia (b=-0.44±0.19 p < 0.05) were found to be independent predictors of the EEG MDF on multivariate regression. No relationship was found between ammonia and psychometric performance or EEG. Conclusions: Cognitive impairment with a profile typical of MHE and hyperammonaemia were found to be common in children with PHPH, without underlying liver disease. Hyperammonaemia was found to be related to EEG slowing. These findings are in keeping with the existence of MHE in children with PHPH. 68 IMPACT OF GENDER ON THE CLINICAL PRESENTATION OF WILSON DISEASE P. Ferenci1 , U. Merle2 , A. Czlonkowska3 , R. Bruha4 , R. Houwen5 , F. Szalay6 , W. Vogel7 , W. Stremmel2 . 1 Internal Medicine 3, Medical University of Vienna, Wien, Austria; 2 Internal Medicine 4, University of Heidelberg, Heidelberg, Germany; 3 Second Department of Neurology, Institute of Psychiatry and Neurology, Warszawa, Poland; 4 Internal Medicine, Charles University, Prague, Czech Republic; 5 Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands; 6 Internal Medicine 2, Semmelweis University, Budapest, Hungary; 7 Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria E-mail: [email protected] Wilson disease (WD) is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in liver disease and/or
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Patients and Methods: 13 AIH-2 patients positive for HLA-DRB1*07 and/or DRB1*03, the HLA-DR alleles predisposing to this condition, were studied. CYP2D6-T-regs were obtained from CD4pos CD25high cells cultured in the presence of CYP2D6 peptide, high-dose interleukin 2 (IL-2) and anti-CD3/anti-CD28 T-cell expander. CYP2D6-T-reg cytokine production and suppressor function were tested before and after culture with CYP2D6-peptide-pulsed smDCs. CYP2D6-T-reg IFNg, IL-2, IL-4, IL-10, TGF-b and IL-17 production was determined by intracellular staining; suppressor function by proliferation assay following T-reg addition to CD25neg T-cells. Results: Proliferation of CD25neg cells (77,893±8,298 cpm) was reduced by 25.8% (P = 0.02) after addition of CYP2D6-T-regs and by 54.9% (P < 0.001) after addition of smDCs-CYP2D6-T-regs. The frequency of IFNg, IL-2, IL-4, IL-10, and IL-17 producing cells within T-reg subsets with or without smDCs was lower than in CD25neg cells (P < 0.001). In contrast, the frequency of TGF-b-producing cells was higher in both T-reg subsets compared to CD25neg cells (P < 0.001). While no difference in the frequency of IL-2, IL-4, IL-10, TGF-b and IL-17 producing cells was observed between CYP2D6T-regs and smDCs-CYP2D6-T-regs, IFNg-producing cells were more frequent in the absence of smDCs (1.19±0. 3 vs 0.3±0.03, P = 0.022). Treatment with anti-IFNg neutralizing antibodies enhanced the suppressor function of CYP2D6-T-regs from 25.8% to 50.5% (P = 0.005), but did not enhance further smDC-CYP2D6-T-regs suppression. Summary and Conclusion: smDCs co-cultured with CYP2D6-Tregs enhance their ability to suppress. The increase in CYP2D6T-reg suppression after IFNg neutralization suggests the presence of IFNg-producing cells among CYP2D6-T-regs. The combined use of smDCs and anti-IFNg should be considered for generation of ‘clinical-grade’ antigen-specific T-regs. 65 CLINICAL, BIOCHEMICAL AND GENETIC FEATURES IN TRANSALDOLASE DEFICIENCY, A NEW DISORDER IN PEDIATRIC HEPATOLOGY M.M.C. Wamelink1 , V. Valayannopoulos2 , E.A. Struys1 , G.S. Salomons1 , C. Jakobs1 . 1 Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; 2 Metabolic Unit and Reference Center of Metabolic Diseases, Hˆ opital Necker-Enfants Malades, Universit´e Paris Descartes, Paris, France E-mail: [email protected] Background and Aims: Transaldolase (TALDO) deficiency is a rare and only recently described inborn error of metabolism of the reversible part of the pentose phosphate pathway (PPP) presenting with mostly liver pathology [1–3]. So far only fourteen patients from eight families have been diagnosed. Methods: All patients were investigated clinical, biochemical and molecular. Results: All fourteen (or thirteen when an affected fetus was excluded) patients presented in the antenatal, neonatal or early childhood with (hepato)splenomegaly (14/14), abnormal liver function tests (14/14) and hepatic fibrosis (14/14). Most showed haemolytic anemia (10/13), dysmorphic features (9/14) (e.g. antimongoloid slant, low set ears and cutis laxa), congenital heart defects (9/14), renal problems (6/13) (tubulopathy, renal failure, nephrocalcinosis), neonatal edema (4/14) and/or intermittent hypoglycaemia (4/13). All TALDO deficient patients have elevated urinary excretion of erythritol, arabitol, ribitol, sedoheptitol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose7P [1–4]. Elevations are striking in the neonatal period, and more subtle in older patients. In plasma and CSF, only minor accumulation of these compounds occur. In the patients with TALDO deficiency thus far, four homozygous mutations have been detected and one patient was found compound heterozygous. Currently, for two additional patients with biochemical profiles and
Journal of Hepatology 2010 vol. 52 | S23–S41
ORAL PRESENTATIONS clinical presentation of transaldolase deficiency, the DNA mutation analysis is pending. Conclusions: We advice to screen all patients with unexplained hepatosplenomegaly, liver function problems, hepatic fibrosis/cirrhosis and haemolytic anemia presenting in the neonatal or antenatal period for TALDO deficiency by measuring urinary polyols and/or seven-carbon sugars. Reference(s) [1] Verhoeven et al. (2001) Am J Hum Genet; 68;1086–1092. [2] Valayannopoulos et al (2006) J Pediatr; 149; 713–717. [3] Wamelink et al (2008) J Inher Metab Dis; 31; 703–713. [4] Wamelink et al (2007) J Inher Metab Dis;30; 735–742.
66 GROWTH OF LIVER VOLUME STOPS AFTER ONE YEAR OF LANREOTIDE IN PATIENTS WITH POLYCYSTIC LIVERS M. Chrispijn1 , L. van Keimpema1 , F. Nevens2 , R. Vanslembrouck3 , M.G.H. van Oijen1 , A.L. Hoffmann4 , H.M. Dekker5 , R.A. de Man6 , J.P.H. Drenth1 . 1 Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 2 Department of Hepatology, 3 Department of Radiology, University Hospital Leuven, Leuven, Belgium; 4 Department of Radiation Oncology, 5 Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, 6 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands E-mail: [email protected] Background and Aims: Polycystic livers are characterized by multiple cysts scattered throughout the liver parenchyma and are present in autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). Symptoms are due to mass effect of the liver. We performed the LOCKCYST trial which showed that lanreotide effectively reduces liver volume in patients with polycystic liver given for six months, while without treatment, polycystic livers keep growing. The aim of this study was to assess the effect of prolonged lanreotide treatment up to one year. Methods: This is an extension of the LOCKCYST trial, a multicentre, randomized, placebo-controlled trial which studied the effect of lanreotide 120 mg, administered every 28 days during 24 weeks in patients with a polycystic liver due to ADPKD or PCLD. All 54 patients who participated in the LOCKCYST trial during 24 weeks were asked to continue or start with lanreotide 120 mg every 28 days during 24 or 48 weeks, depending on whether they were randomized to either lanreotide or placebo, respectively. Primary endpoint was change in total liver volume, as determined by CTvolumetry, after six and twelve months in the group of patients that was treated with lanreotide for one year. Statistical analysis was performed using the Wilcoxon Signed Ranks test. Results: There were 41 patients who were treated with lanreotide for one year. Baseline median liver volume in this group was 4974 mL (range 1775–10,427). After six months of lanreotide, median liver volume decreased to 4785 mL (range 1852–9832) (−2.5%, p < 0.01), while after one year, it decreased to 4767 mL (range 1963–10,273), a decrease of 1.8% from baseline (p = 0.01). There was no significant difference in median liver volume between six and twelve months (p = 0.19). Conclusions: Lanreotide reduces liver volume after six months of treatment, while liver volume stabilizes when lanreotide is given for another six months.
67 CLUES FOR MINIMAL HEPATIC ENCEPHALOPATHY IN CHILDREN WITH PRE-HEPATIC PORTAL HYPERTENSION L. D’Antiga1 , P. Dacchille2 , C. Boniver2 , S. Poledri2 , S. Schiff3 , L. Zancan2 , P. Amodio3 . 1 Unit of Paediatrics Liver, GI and Transplantation, Ospedali Riuniti di Bergamo, Bergamo, 2 Dpt. of Paediatrics, 3 Clinical and Experimental Medicine, University of Padova, Padova, Italy E-mail: [email protected] Background: Scanty information exists on whether minimal hepatic encephalopathy (MHE) occurs in children with pre-hepatic portal hypertension (PHPH) due to portal vein thrombosis; this matter is relevant, since these condition might impair their intellectual development. We aimed to investigate children with PHPH to seek proofs of subclinical features consistent with MHE. Material and Methods: A consecutive sample of 13 children (age range 4–18 years, males 46%) with PHPH due to perinatal portal thrombosis without liver disease who had been referred to the Paediatric Clinic of Padua underwent an extensive psychometric battery comprising of 26 psychometric tests exploring the learning ability, abstract reasoning, phonemic and semantic fluency, selective attention, executive functions, short-term verbal and visual memory, long-term verbal memory, visuo-practic ability. Psychometric performance was evaluated by age and education stratified according to norms for Italian population. The same day the patients underwent fasting ammonia measurement on cooled blood samples immediately delivered to laboratory and digitalized EEG. Spectral analysis was performed on eye-closed EEG. Mean dominant frequency (MDF) and frequency bands were considered. The EEG of 14 age matched normal controls was considered for comparison. Results: Ten subjects had at least one altered psychometric test and two subjects had more than 5 abnormal tests. No subject had alteration concerning abstract reasoning, phonemic and semantic fluency. In contrast, selective attention, executive function and short-term visual memory were the domains more frequently altered (up to 50% of individuals). The EEG measures were predicted by age, whereas PHPH did not enter as a predictor (ANCOVA). Ammonia plasma level was higher than the reference values of our laboratory (35 mmol/L) in 5 subjects. Age (b=0.68±0.19 p < 0.01) and ammonia (b=-0.44±0.19 p < 0.05) were found to be independent predictors of the EEG MDF on multivariate regression. No relationship was found between ammonia and psychometric performance or EEG. Conclusions: Cognitive impairment with a profile typical of MHE and hyperammonaemia were found to be common in children with PHPH, without underlying liver disease. Hyperammonaemia was found to be related to EEG slowing. These findings are in keeping with the existence of MHE in children with PHPH. 68 IMPACT OF GENDER ON THE CLINICAL PRESENTATION OF WILSON DISEASE P. Ferenci1 , U. Merle2 , A. Czlonkowska3 , R. Bruha4 , R. Houwen5 , F. Szalay6 , W. Vogel7 , W. Stremmel2 . 1 Internal Medicine 3, Medical University of Vienna, Wien, Austria; 2 Internal Medicine 4, University of Heidelberg, Heidelberg, Germany; 3 Second Department of Neurology, Institute of Psychiatry and Neurology, Warszawa, Poland; 4 Internal Medicine, Charles University, Prague, Czech Republic; 5 Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands; 6 Internal Medicine 2, Semmelweis University, Budapest, Hungary; 7 Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria E-mail: [email protected] Wilson disease (WD) is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in liver disease and/or
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