Bruha, Radan

Ferenci, P.

Hofer, H.

Houwen, RHJ

Stauber, Rudolf

Steindl-Munda, Petra

Stremmel, Wolfgang

Stättermayer, Albert Friedrich

Szalay, Ferenc

Weiss, Karl Heinz

Zoller, Heinz

Utrecht University Repository

428A AASLD ABSTRACTS HEPATOLOGY, October, 2014compensated and 36% decompensated). At end of FU, liver disease severity was improved, stable or deteriorated in 20%, 46% and 24% of all cases, respectively. Twenty-eight patients received a liver transplant. Five patients died due to complica-tions of their liver disease and two deaths were related to liver transplantation. In patients who were treated for at least one year (n=111), zinc, penicillamine or trientine (alone, sequen-tially or combined) were prescribed in 92%, 69% and 14% of patients, respectively. At the end of FU, efficacy of decop-pering, based on values of serum non-ceruloplasmin-bound copper concentration (aim: <10 μg/dL) and 24-hour-urinary copper excretion (aim: <100 μg/24 hours), was excellent in 34% of patients, moderate in 42%, poor in 13% and unknown in 11%. Two patients developed HCC. The first patient was a 39-year-old male and presented with decompensated cirrhosis in combination with HCC. The second patient was a 63-year-old female with unequivocal WD diagnosed 50 years earlier. Despite excellent decoppering at the end of FU, she progressed to decompensated cirrhosis in which an HCC developed. No additional risk factors for liver disease were present in both patients. Estimated annual HCC risk for all patients was 0.09% (95% confidence interval: 0.01-0.28). Subgroup analysis in cirrhotic patients revealed an annual HCC risk of 0.14% (95% confidence interval: 0.02-0.45). Conclusion: Even in case of cirrhosis, HCC risk is low in Wilson’s disease and appears not related to efficiency of decoppering. Our data do not support regular HCC surveillance in WD.Disclosures:Robert A. de Man - Advisory Committees or Review Panels: Norgine; Grant/Research Support: Gilead, BiotestKarel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers Squibb, AbbvieThe following people have nothing to disclose: Suzanne van Meer, Aad P. van den Berg, Roderick Houwen, Francisca Linn, Peter D. Siersema464Patients with Wilson disease without detectable ATP7B mutationsAlbert Stättermayer1, Heinz M. Zoller2, Karl Heinz Weiss3, Ferenc Szalay4, Radan Bruha5, Roderick Houwen6, Rudolf E. Stauber7, Petra E. Steindl-Munda1, Harald Hofer1, Wolfgang Stremmel3, Peter Ferenci1; 1Gastroenterology & Hepatology, Medical Univer-sity of Vienna, Vienna, Austria; 2Medicine II, Medical University of Innsbruck, Innsbruck, Austria; 3Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany; 4Medicine I, Semmelweis University, Budapest, Hungary; 5Internal Medicine IV, Charles University, Prague, Czech Republic; 6Pediatric Gastro-enterology, Wilhelmina Children’s Hospital, Utrecht, Netherlands; 7Gastroenterology & Hepatology, Medical University of Graz, Graz, AustriaBackground/aim: Wilson disease (WD) is an inherited autoso-mal-recessive disorder of hepatic copper excretion resulting in copper accumulation in the liver. The responsible gene muta-tion is located within the ATP7B gene encoding for a P-type copper transporting ATPase. More than 500 mutations in the ATP7B gene have been described so far. Nevertheless, in up to seven percent of patients with WD, no mutation can be found. Aim of our study was to identify diagnostic characteristics of patients with WD without detectable mutations in ATP7B. Meth-ods: Clinical data and DNA for genetic analysis were obtained from WD patients as part of an international cooperation proj-ect. The diagnosis of WD was established if the WD diagnostic score recommended by the EASL Clinical Practice Guidelines on WD was ≥ 4. Mutation analysis was carried out by direct sequencing on an ABI Prism 310 Genetic Analyzer (Perkin Elmer, Norwalk, USA). Next-generation sequencing is ongo-ing and was performed in ten patients so far. Results: Out of 1294 WD patients collected since 1985 in 65 (5.0%) patients no mutation in the ATP7B gene could be detected. Thirty-nine (60.0%) of them were male. Thirty-one patients (47.7%) pre-sented with neurologic symptoms and 29 (44.6%) with hepatic symptoms (of whom one had fulminant hepatic failure). Five (7.7%) patients were asymptomatic siblings of patients with WD. Mean age at onset of WD was 19.5±10.9 years and 21.4±10.5 years at diagnosis. Kayser-Fleischer corneal rings were present in 38 (58.5%) patients. Hepatic copper content was available in 33 patients (784±586 μg/g dry weight; SD) and coeruloplasmin was decreased in 50 (76.9%) patients (mean: 8.9±7.6 mg/dL). Conclusions: Our data suggest that yet unidentified mutations of genes other than ATP7B might lead to a disease identical to WD. Further research is needed to get more insights into the causes of copper overload in patients without mutations in ATP7B.Disclosures:Rudolf E. Stauber - Advisory Committees or Review Panels: Gilead, Janssen-Cilag, AbbVie, BMS; Grant/Research Support: MSD; Speaking and Teaching: RocheHarald Hofer - Speaking and Teaching: Janssen, Roche, MSD, Gilead, AbbviePeter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, MSD, Jans-sen, AbbVie, BMS, Tibotec, B√∂hringer Ingelheim; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, SalixThe following people have nothing to disclose: Albert Stättermayer, Heinz M. Zoller, Karl Heinz Weiss, Ferenc Szalay, Radan Bruha, Roderick Houwen, Petra E. Steindl-Munda, Wolfgang Stremmel465Sex differences in liver SAM:SAH ratios and gene tran-script levels after pre-and post-natal choline supple-mentation and copper chelation treatment in an animal model of Wilson diseaseValentina Medici1, Noreene Shibata1, Kusum K. Kharbanda2, Charles H. Halsted1; 1Division of Gastroenterology and Hepa-tology, UC Davis Medical Center, Sacramento, CA; 2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NEBackground. Methionine metabolism, central to DNA methyl-ation reactions, may provide epigenetic regulation of genes involved in liver damage in Wilson disease (WD). We hypoth-esized that peri-natal maternal treatment with choline could modify the sex specific response to penicillamine in offspring in the tx-j model of WD. Methods. Control (choline 8 mmol/Kg) or choline supplemented (36 mmol/Kg) diets were fed to wildtype and tx-j female mice starting at 2 weeks before mating and continuing in offspring up to 24 weeks of age. A subgroup of tx-j of both sexes received oral penicillamine with or without choline supplemented diet from 12 to 24 weeks of age. Results. Decreased S-adenosylmethionine (SAM) to S-adenosylhomo-cysteine (SAH) ratio, an index of DNA methylation capacity, was decreased in each sex of offspring tx-j mice, compatible with the known down-regulation of SAH hydrolase levels in this mouse model of WD (Table 1). The SAM:SAH ratio was higher in untreated female versus male tx-j mice (p<0.05). Separate choline or penicillamine treatments were associated with simi-lar increases of SAM:SAH ratio in male tx-j vs wildtype levels. Whereas the ratio was increased by each separate treatment in tx-j males, it was reduced by each separate treatment in tx-j females, but was unchanged in either sex by the combina-tion of choline and penicillamine. Transcript levels of Dnmt3b, a regulator of DNA methylation in tx-j mice, were increased in untreated tx-j of either sex, and were down-regulated by separate or combined penicillamine and choline treatment in male tx-j, but were unchanged by any treatment in female tx-j mice. Grp78 transcript levels were increased in tx-j mice of 

Patients with Wilson disease without detectable ATP7B mutations

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Patients with Wilson disease without detectable ATP7B mutations

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