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Background and Aim: In this study, we used a national cohort of patients with Wilson's disease (WD) to investigate the admissions, mortality rates, and costs over the captured period to assess specific subpopulations at higher burden., Methods: Patients with WD were selected using 2016-2019 National Inpatient Sample (NIS). The weighted estimates and patient data were stratified using demographics and medical characteristics. Regression curves were graphed to derive goodness-of-fit for each trend from which R2 and P values were calculated., Results: Annual total admissions per 100 000 hospitalizations due to WD were 1075, 1180, 1140, and 1330 ( R2  = 0.75; P  = 0.13) from 2016 to 2019. Within the demographics, there was an increase in admissions among patients greater than 65 years of age ( R2  = 0.90; P  = 0.05) and White patients ( R2  = 0.97; P  = 0.02). Assessing WD-related mortality rates, there was an increase in the mortality rate among those in the first quartile of income ( R2  = 1.00; P  < 0.001). The total cost for WD-related hospitalizations was $20.90, $27.23, $24.20, and $27.25 million US dollars for the years 2016, 2017, 2018, and 2019, respectively ( R2  = 0.47; P  = 0.32). There was an increasing total cost trend for Asian or Pacific Islander patients ( R2  = 0.90; P  = 0.05). Interestingly, patients with cirrhosis demonstrated a decreased trend in the total costs ( R2  = 0.97; P  = 0.02)., Conclusion: Our study demonstrated that certain ethnicity groups, income classes and comorbidities had increased admissions or costs among patients admitted with WD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Wilson's disease may progress to cirrhosis and clinically significant portal hypertension (CSPH). We aimed to assess the prevalence and prognostic impact of CSPH-related features on hepatic decompensation and transplant-free survival in patients with Wilson's disease., Methods and Results: About 137 patients with Wilson's disease (Leipzig score ≥4), followed for a median observation period of 9.0 (3.9-17.7) years at the Vienna General Hospital, were included in this retrospective study. Overall, 49 (35.8%) developed features of CSPH: 14 (10.2%) varices, 40 (29.2%) splenomegaly, 20 (14.6%) ascites, 18 (13.1%) hepatic encephalopathy and 3 (2.2%) experienced acute variceal bleeding. Overall, 8 (5.8%) patients died, including three deaths caused by CSPH-related complications. Within 10 years, compensated patients with features of CSPH developed more decompensation events (8.3% vs. 1.5% in patients without CSPH, p = 0.3) and had worse transplant-free-survival (91.7% vs. 98.6%), which further declined in patients with hepatic decompensation (26.7%, log-rank: p < 0.0001). Patients with liver stiffness <15 kPa and normal platelets (≥150 G/L) were less likely to decompensate within 10 years (2.6% vs. 8.4%, p = 0.002) and had a better 10-year transplant-free-survival (97.7% vs. 83.9%, p = 0.006)., Conclusions: Patients with Wilson's disease developing features of CSPH are at an increased risk for hepatic decompensation and liver-related mortality, warranting for regular screening and timely initiation of effective CSPH-directed treatments., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The clinical profile varies in patients with Wilson's disease (WD). There is paucity of data regarding adult and pediatric patients with hepatic WD., Methods: As many as 140 consecutive patients diagnosed with hepatic WD between December 2006 and January 2021 were included in the study. Data was collected regarding the demographic parameters, clinical presentation, extrahepatic organ involvement, liver histology and laboratory investigations. Adult and children (0-14 years) with hepatic WD were compared regarding these features., Result: Eighty-eight adults and 52 children were included in the study. The median age of presentation was 17 years (range: 1.1-42 years). Male preponderance was seen (adult 68/88, 69%; children 40/52, 77%). Adults as compared to children presented more commonly as cirrhosis (52/88 vs. 15/52, p = 0.0005) and with hepatic decompensation (35/88 vs. 9/52, p = 0.005). Presentation with acute-on-chronic liver failure (ACLF) was more common in children (10/52 vs. 2/88, p = 0.0005). Twenty-eight-day mortality was 50% (5/10) in children and none in adults presenting with ACLF. Nazer's Prognostic Index (≥ 7) and New Wilson Index were more accurate in predicting mortality among children with ACLF with AUROC 1, while AARC (APASL ACLF Research Consortium) was less accurate with AUROC 0.45. Liver histology findings were similar in adults and children. Extrahepatic involvement was also similar. (8/88 in adults vs. 3/52 children, p value 0.48)., Conclusion: Most patients with WD present as cirrhosis in adulthood. ACLF is more common in children. Nazer's prognostic index and new Wilson Index score are accurate in predicting mortality in children with ACLF., (© 2024. Indian Society of Gastroenterology.)

Introduction and Objectives: Wilson's disease (WD) is a rare genetic disorder characterized by excessive copper disposition predominantly in the liver and brain. Hospitalization data on patients with WD are scarce. Hence, we sought to examine the inpatient characteristics and outcomes of patients with WD., Patients and Methods: We utilized the National Inpatient Database (2006-2011) and analyzed all adult patients with a diagnosis of WD., Results: There were 9046 hospitalizations during the study period. The leading etiologies for admissions were chronic liver disease (8.58%), WD (6.49%) and infections (septicemia 3.10% and pneumonia 2.50%). The overall inpatient mortality rate for WD patients was 2.58%. Independent predictors of mortality in WD patients were acute respiratory failure (OR: 4.53; 95% CI: 2.44-8.42), acute renal failure (OR: 4.09; 95% CI: 2.19-7.65), decompensated liver disease or liver failure (OR: 3.37; 95% CI: 1.72-6.59), and advanced age (every 10 year increase, OR: 1.48; 95% CI: 1.25-1.75). Propensity-score matched analysis revealed better inpatient survival in WD patients compared to matched non-WD patients (2.84% vs. 4.67%, p = 0.01)., Conclusions: Our study demonstrated the clinical characteristics and outcomes of hospitalized patients with WD. These findings add important knowledge to our understanding of the healthcare utilization and outcomes of this rare disease in the United States., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To study the efficacy and safety of high volume plasma exchange (HVPE) in Wilson disease presenting as acute liver failure (WD-ALF)., Methods: An analysis of prospectively collected data of consecutively admitted WD-ALF cases was done and patients were divided into two groups: (i) high volume plasma exchange (HVPE) group- who received HVPE + standard medical therapy (SMT), and (ii) SMT group- received only SMT. Outcome measure was transplant free survival (TFS) at 90 days post enrollment, change in biochemical, hemodynamic parameters & incidence of organ dysfunction in HVPE as compared to SMT group, and HVPE related complications., Results: Out of the total 43 cases of WD-ALF reported in the study period, 37 were enrolled (median age 9 years, 62.2% males). All biochemical parameters and prognostic indices except blood ammonia and serum creatinine improved significantly at 72 to 96 hours after enrollment in the HVPE group. Overall, TFS at 90 days was present in 9/19 (47.3%) in HVPE group vs 3/18 (16.6%) in the SMT group (OR 2.84, 95% CI 0.91-8.8, P = .049). Kaplan Meier survival analysis revealed that HVPE group had significantly higher cumulative survival as per the Log Rank test (P = .027); median days of survival was 38 days (IQR 12-63) in HVPE group vs 14 (IQR 5-22) days in SMT group., Conclusions: The present study indicates that in children with WD-ALF, HVPE not only acts as a bridging therapy to LT but may also improve proportion of the cases with TFS., (© 2020 Wiley Periodicals LLC.)

Introduction: Wilson's disease is a lethal-without-treatment inherited disorder of copper metabolism. Despite the increased focus on the diagnosis and treatment, liver transplantation is needed in a number of cases even nowadays. Aim: To collect and analyze the data of the Hungarian Wilson's disease patients who underwent liver transplantation. Method: Data of 24 Wilson's disease patients who underwent liver transplantation at the Semmelweis University have been analyzed retrospectively. The diagnosis of Wilson's disease was based on the international score system. The diagnosis of acute liver failure corresponded to the King's College criteria. All liver transplantations had been performed at the Department of Transplantation and Surgery of Semmelweis University, in 1996 for the first time. Results: The mean age was 26 years, F/M = 13/11. Twelve patients needed urgent liver transplantation for acute liver failure, and 12 underwent transplantation for decompensated liver cirrhosis. One patient had been retransplanted because of chronic rejection. Three patients with acute on chronic liver failure were transplanted via the Eurotransplant program. The mean time on the waiting list was 3 vs 320 days in acute liver failure and chronic liver disease groups, respectively. The overall 5-year survival was 66%, but it was 80% after 2002 indicating both the learning curve effect and the improvement of vigilance in Hungary. Despite difficulties of the diagnostic process, Wilson's disease was identified in 21/24 patients prior to the transplantation. Conclusion: Liver transplantation is needed in a number of cases of Wilson's disease. The ideal indication and timing of transplantation may improve the survival of the patients. Orv Hetil. 2019; 160(51): 2021-2025.

Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. Clinical features and mutational analysis of Chinese children with WD at early age were rarely described. Herein, we retrospectively examined 114 children with WD at the mean of 5.9 years old age at diagnosis. Eight patients developed acute liver failure at mean age of 9.7 years old, 4 of whom died. Among the 114 patients, 86.0% were presymptomatic with isolated elevation of transaminases at diagnosis, 99.1% had decreased ceruloplasmin, and 68.4% had urinary copper excretion over 100 μg/24 hr. Bi-allele pathogenic ATP7B mutations were identified in all patients. Among the 60 mutations detected, 10 were novel, including 7 missense mutations (p.I566N, p.T704I, p.C980F, p.G1030 V, p.A1096Q, p.L1327P, and p.L1373F), 1 nonsense mutation (p.K866X), 1 small insertion (p.Y44LfsX2), and 1 small deletion (p.R1118PfsX10). The most frequent mutations were p.R778L, p.P992L, and p.I1148T, which affected 27.2, 25.4, and 20.2% of the 114 WD children, respectively. The patients carrying p.R778L presented a higher rate of acute liver failure than the patients without p.R778L (9.7% vs. 4.8%). These results will be helpful in establishing early diagnosis of WD at the gene level, offering beneficial information for genetic counseling and providing clues to genotype/phenotype correlation of ATP7B mutations., (© 2019 Wiley Periodicals, Inc.)

Gene therapy with an adeno-associated vector (AAV) serotype 8 encoding the human ATPase copper-transporting beta polypeptide (ATP7B) complementary DNA (cDNA; AAV8-ATP7B) is able to provide long-term copper metabolism correction in 6-week-old male Wilson disease (WD) mice. However, the size of the genome (5.2 kilobases [kb]) surpasses the optimal packaging capacity of the vector, which resulted in low-yield production; in addition, further analyses in WD female mice and in animals with a more advanced disease revealed reduced therapeutic efficacy, as compared to younger males. To improve efficacy of the treatment, an optimized shorter AAV vector was generated, in which four out of six metal-binding domains (MBDs) were deleted from the ATP7B coding sequence, giving rise to the miniATP7B protein (Δ57-486-ATP7B). In contrast to AAV8-ATP7B, AAV8-miniATP7B could be produced at high titers and was able to restore copper homeostasis in 6- and 12-week-old male and female WD mice. In addition, a recently developed synthetic AAV vector, AAVAnc80, carrying the miniATP7B gene was similarly effective at preventing liver damage, restoring copper homeostasis, and improving survival 1 year after treatment. Transduction of approximately 20% of hepatocytes was sufficient to normalize copper homeostasis, suggesting that corrected hepatocytes are acting as a sink to eliminate excess of copper. Importantly, administration of AAVAnc80-miniATP7B was safe in healthy mice and did not result in copper deficiency. Conclusion: In summary, gene therapy using an optimized therapeutic cassette in different AAV systems provides long-term correction of copper metabolism regardless of sex or stage of disease in a clinically relevant WD mouse model. These results pave the way for the implementation of gene therapy in WD patients., (© 2019 by the American Association for the Study of Liver Diseases.)

Background and Aims: Doubts have been raised about efficacy of New Wilson's index (NWI) in predicting Liver Transplant (LT) or mortality in decompensated Wilson Disease (WD) patients. APASL ACLF Research Consortium (AARC) has introduced a new score (AARC-ACLF) which has not been studied in children., Methods: Data of all pediatric WD cases were prospectively collected and analyzed. Cox regression and Area Under Receiver Operative Curve (AUROC) analyses were used to identify best predictive score for mortality at 90 days., Results: Sixty-six confirmed cases of decompensated WD, 39 (59%) improved on medical management and 27 (41%) either died (20) or were transplanted (7). Among those with NWI ≥ 11 (42/66 cases) 19 survived versus those with NWI < 11 (24/66), 4 died. NWI (HR 1.23, 95% CI 1.07-1.42, p = 0.005), AARC-ACLF (HR 1.66, 95% CI 1.34-2.05, p = 0.000) and Chronic Liver Failure-Sequential Organ Failure Assessment score also known as CLIF-SOFA (HR 1.31, 95% CI 1.13-1.50, p = 0.000) were all significantly associated with death on univariate Cox regression analysis. On comparative evaluation of the predictive scores in the present cohort, the highest positive (6.02) and lowest negative (0.09) likelihood ratios as well as highest accuracy (87.88%) revealed AARC-ACLF as the best predictor of mortality. AARC-ACLF had the best predictability with AUROC of 0.939 and the minimum standard error of 0.027. For every unit increase in AARC-ACLF score, there is likelihood of 66% increase in 90 day mortality. The optimal cutoff for the AARC-ACLF score to predict mortality was 11 or more., Conclusion: AARC-ACLF is the best score for the prediction of mortality at 90 days in decompensated WD cases.

Wilson's disease (WD) is an inherited metabolic disease arising from ATPase copper transporting beta gene (ATP7B) mutation. Orthotoropic liver transplantation is the only radical treatment of fulminant WD, although appropriate donors are lacking at the onset of emergency. Given the hepatogenic capacity and tissue-integration/reconstruction ability in the liver of stem cells from human exfoliated deciduous teeth (SHED), SHED have been proposed as a source for curing liver diseases. We hypothesized the therapeutic potential of SHED and SHED-converted hepatocyte-like- cells (SHED-Heps) for fulminant WD. SHED and SHED-Heps were transplanted into WD model Atp7b-mutated Long-Evans Cinnamon (LEC) rats received copper overloading to induce a lethal fulminant liver failure. Due to the superior copper tolerance via ATP7B, SHED-Hep transplantation gave more prolonged life-span of fulminant LEC rats than SHED transplantation. The integrated ATP7B-expressing SHED-Heps showed more therapeutic effects on to restoring the hepatic dysfunction and tissue damages in the recipient liver than the integrated naïve SHED without ATP7B expression. Moreover, SHED-Heps could reduce copper-induced oxidative stress via ATP7B- independent stanniocalcin 1 secretion in the fulminant LEC rats, suggesting a possible role for paracrine effect of the integrated SHED-Heps. Taken together, SHED-Heps offer a potential of functional restoring, bridging, and preventive approaches for treating fulminant WD.

Introduction and Aim: Wilson's disease (WD) is an uncommon cause of acute liver failure (ALF). Our aim was to describe clinical features, diagnostic findings, treatments, and outcomes of patients with ALF due to WD., Material and Methods: Retrospective medical record reviews of all patients with ALF due to WD in eight years in Uruguay., Results: WD was the cause of six (15%) of thirty-nine ALF cases. All patients were females, with a mean age of 18 years. Four patients presented with hyperacute liver failure and two with acute failure. Jaundice was the main complaint of all patients. Mean total bilirubin (TB), alkaline phosphatase (AP), AST, and ALT were 27.5 mg/dL, 45.5 lU/l, 156 IU/L, and 51 IU/L, respectively. Ceruloplasmin levels were low in four patients, urinary cooper was high in four, and two had Kayser-Fleischer rings. All patients had Coombs-negative hemolytic anemia, acute kidney injury, histochemical identifiable copper, and advanced fibrosis on liver histology. The average MELD score was 36. All patients were treated with d-penicillamine and listed for urgent liver transplantation (LT). Prometheus® was performed in one patient. Three patients died: two without LT and one after LT. Three patients survived: one without LT (New Wilson Index<11) and two with LT. The referral time to the program and the total time (referral plus waiting list time) were longer for non-survivors than for survivors (14 vs. 3 days and 23 vs. 8 respectively)., Conclusion: All cases had typical clinical, analytical and histopathology characteristics. Early referral was determinant of prognosis., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Liver transplantation (LT) is a rescue therapy for life-threatening complications of Wilson's disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1-26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2-16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0-10.9 years) after LT. Overall patient survival rates were high with 87% (1-year survival), 84% (5-year survival), and 81% (10-year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end-stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found., (© 2018 by the American Association for the Study of Liver Diseases.)

To analyze the clinical features and prognosis of fulminant Wilson's disease (FWD) in patients with hepatitis B virus (HBV) infection. Twenty-seven patients were enrolled in Guangzhou Eighth People's Hospital from 2005 to 2015, including 13 FWD patients with HBV infection and 14 FWD patients without HBV infection. Clinical efficacy and survival rate were evaluated. Baseline biochemical data in two groups were comparable(P>0.05), including total bilirubin, prothrombin activity, serum albumin, alpha fetal protein, alanine transaminase, ceruloplasmin and 24 hours urine copper .Treatment in FWD group with HBV infection was ineffective, including 9(9/13) deaths and 4(4/13) patients receiveing liver transplants. However, 7(7/14)cases in the other group did not response to the treatment, including 6(6/14)deaths and 1(1/14)patient receiving liver transplant. The prognosis in the two groups is significantly different(P=0.006), which is much worse in FWD patients with HBV infection.

Background: Medical therapy is rarely effective in patients with fulminant Wilson's disease (FWD). Liver transplantation is limited by the lack of donor liver in most patients with FWD at the time of diagnosis. New Wilson's index, model for end-stage liver disease (MELD) and Child-Pugh score are useful tools for decision-making of liver transplantation; however, none of them is an independent decisive tool. It is worthwhile to explore a more effective and practical therapeutic strategy and reevaluate the prediction systems for patients with FWD., Methods: Nine patients with FWD associated with hemolytic crisis and fulminant hepatic failure (FHF) were investigated. The clinical presentation, prognostic score and medical therapies of the patients were analyzed., Results: In 7 of the 9 patients with FWD who received the comprehensive therapy of corticosteroid, copper-chelating agent (dimercaptopropansulfonate sodium) and therapeutic plasma exchange (TPE), 6 patients recovered from FHF. The remaining one had been improved through the comprehensive therapy but died of septicemia 51 days later. Two patients with spontaneous bacterial peritonitis (SBP) died from liver failure in three or five hospital days without plasma exchange or chelating therapy. All of the 9 patients with FWD presented with acute hepatic failure, severe jaundice and mild to severe hemolytic anemia. No marked difference in the incidence of severe hemolytic anemia was detected between the survival and deceased groups. However, the incidence and the degree of hepatic encephalopathy (HE) in the non-survival group were higher than those in the survival group. Unlike the deceased group, the survival group had no complications induced by bacterial infection. Compared to new Wilson's index, Child-Pugh score and MELD score, the variation of prothrombin activity (PTA) between the survival and deceased groups was more evident., Conclusion: For patients with FWD, the episode of severe hepatic encephalopathy or/and spontaneous bacterial peritonitis indicates worse prognosis, and PTA is a recommendable predictor. An emergent liver transplantation should be considered for patients whose PTA is below 20%, or for those with severe HE or/and SBP. The comprehensive therapy of corticosteroid, copper-chelating agent and TPE is effective for patients without SBP and whose PTA is higher than 20%.

Background & Aims: Wilson disease is an autosomal recessive disorder that affects copper metabolism, leading to copper accumulation in liver, central nervous system, and kidneys. There are few data on long-term outcomes and survival from large cohorts; we studied these features in a well-characterized Austrian cohort of patients with Wilson disease., Methods: We analyzed data from 229 patients diagnosed with Wilson disease from 1961 through 2013; 175 regularly attended a Wilson disease outpatient clinic and/or their physicians were contacted for information on disease and treatment status and outcomes. For 53 patients lost during the follow-up period, those that died and reasons for their death were identified from the Austrian death registry., Results: The mean observation period was 14.8 ± 11.4 years (range, 0.5-52.0 years), resulting in 3116 patient-years. Of the patients, 61% presented with hepatic disease, 27% with neurologic symptoms, and 10% were diagnosed by family screening at presymptomatic stages. Patients with a hepatic presentation were diagnosed younger (21.2 ± 12.0 years) than patients with neurologic disease (28.8 ± 12.0; P < .001). In 2% of patients, neither symptoms nor onset of symptoms could be determined with certainty. Most patients stabilized (35%) or improved on chelation therapy (26% fully recovered, 24% improved), but 15% deteriorated; 8% required a liver transplant, and 7.4% died within the observation period (71% of deaths were related to Wilson disease). A lower proportion of patients with Wilson disease survived for 20 years (92%) than healthy Austrians (97%), adjusted for age and sex (P = .03). Cirrhosis at diagnosis was the best predictor of death (odds ratio, 6.8; 95% confidence interval, 1.5-31.03; P = .013) and need for a liver transplant (odds ratio, 07; 95% confidence interval, 0.016-0.307; P < .001). Only 84% of patients with cirrhosis survived 20 years after diagnosis (compared with healthy Austrians, P =.008)., Conclusion: Overall, patients who receive adequate care for Wilson disease have a good long-term prognosis. However, cirrhosis increases the risk of death and liver disease. Early diagnosis, at a precirrhotic stage, might increase survival times and reduce the need for a liver transplant., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT., Methods: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5)., Results: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III., Conclusions: Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function., (Copyright © 2014. Published by Elsevier B.V.)

Background and Purpose: Wilson's disease (WD) is an inherited copper metabolism disorder that leads to dysfunction of affected tissues, mostly in the liver and brain. Anti-copper treatment should prevent clinically overt WD in pre-symptomatic patients but this has not been supported by strong evidence. Our aim was to evaluate the long-term effectiveness of treatment in clinically pre-symptomatic patients, with particular emphasis on patient compliance with treatment., Methods: Data were analyzed for 87 consecutive patients with no clinical symptoms of WD who were identified between 1957 and 2009 by family screening. All of them since diagnosis were treated with either zinc sulphate (Zn) (66.7%) or D-penicillamine (DPA) (33.3%)., Results: During a median follow-up of 12 years (range 3-52), 55 (63%) patients remained without clinical symptoms, 13 (15%) developed neuropsychiatric symptoms and 21 (24%) developed hepatic dysfunction, including five deaths from hepatic failure. Non-compliance for at least three consecutive months was observed in 39 patients, and in 29 cases this extended for more than 12 months. Multivariate analysis showed that the odds of developing symptomatic WD were independently increased by non-compliance (odds ratio 24.0, 95% confidence interval 6.0-99.0). According to Kaplan-Meier analysis patients who were compliant to treatment had a significantly higher likelihood of remaining symptom-free, and their overall survival was similar to the survival rate observed in the general population., Conclusion: The use of anti-copper agents in clinically pre-symptomatic patients diagnosed with WD allows clinically overt disease to be effectively prevented. However, compliance with therapy is extremely important., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background and Aims: Wilson disease (WD) associated acute liver failure (ALF) affects children more than adults. The predictors of mortality and outcome in patients without encephalopathy are not clear. We investigated the ability of prognostic factors and various models including model for end-stage liver disease (MELD) to predict mortality among children with WD and ALF., Methods: We analyzed the admission characteristics in 61 children <18 years with WD and ALF. Factors associated with mortality on univariate Cox regression analysis were analyzed by forward stepwise Cox hazards regression. The prognostic models such as Nazer's model, revised Kings College Model, and pediatric end-stage liver disease/model for end-stage liver disease (PELD/MELD) score were compared., Results: Of the 145 children < 18 years with WD, 61 experienced ALF of whom 33 (54%) died, including 22/27 (81.5%) with encephalopathy and 11/34 (32.4%) without encephalopathy. The mean age of children with ALF was 9.7 years, 38(62.3%) were boys. Prognostic factors significant for mortality included encephalopathy, international normalized ratio, total proteins, total and direct bilirubin, alkaline phosphatase, serum creatinine, and white blood cell count. Forward stepwise Cox proportional hazards regression identified encephalopathy (hazard ratio 2.88; CI 1.1-7.4) and total bilirubin (hazard ratio 1.05; CI: 1.02-1.09) as predictors of outcome. The area under the receiver operating curve (AUC) of the Nazer index, revised King's College Criteria, and PELD/MELD were 0.74, 0.76, and 0.75, respectively., Conclusions: Mortality in children with WD and ALF is 54% including 81.5% with encephalopathy and 32.4% without encephalopathy. The prognostic models, MELD/PELD score, Nazer index and Kings College Criteria are comparable with a AUC between 0.74-0.76., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

An analysis of 321 case notes of patients with Wilson's disease seen between 1955 and 2000 and one case seen in 1949 has revealed that 22 patients presented with a haemolytic crisis. This study was not a specific research project but a retrospective analysis of 321 patients with Wilson's disease seen between 1949 and 2000. All investigations were carried out in the best interests of diagnosis and management of patients referred to my clinic. The delay in diagnosis in 18 cases resulted in progression to severe hepatic disease in 14 cases and to neurological disease in 4 cases. One patient had no symptoms at the time her sister's illness was diagnosed as Wilson's disease. In a second patient, with liver disease, the diagnosis was also made when a sister was found to have Wilson's disease. There was a female to male ratio of 15:7. The average age of onset was 12.6 years and the incidence 6.9%. Delay in diagnosis resulted in nine deaths. Three patients, late in the series, were admitted in the acute phase, two female and one male; of these two responded to chelation therapy, the third required liver transplantation. Haemolysis appeared to be extravascular, and possible mechanisms of the haemolysis are discussed.

Background: Wilson disease (WD) is an autosomal recessive copper storage disease resulting in hepatic and neurologic dysfunction. Liver transplantation is an effective treatment for fulminant cases for patients with chronic liver disease. Reports on the outcome of neuropsychiatric symptoms after orthotopic liver transplantation (OLT) are limited., Aim: To assess the course of neuropsychiatric and hepatic symptoms after liver transplantation for Wilson disease, Methods: Nineteen patients with Wilson disease received liver transplantation and were followed prospectively from 2005 to 2010 for the development of hepatic, neurological and psychiatric symptoms., Results: Eight patients (all female) were transplanted for acute liver failure and eleven patients for chronic liver failure. Patient survival rates one and five yr after transplantation were 78% and 65%, respectively. Of the surviving patients, hepatic symptom scores improved in all patients and neurological symptom scores improved in all but one patient after OLT compared to the time of initial diagnosis and compared to pre-OLT status. Psychiatric symptoms showed moderate improvements., Conclusion: Survival after OLT for Wilson disease with end-stage liver disease is excellent. Overall, neuropsychiatric symptoms improved after transplantation, substantiating arguments for widening of the indication for liver transplantation in symptomatic neurologic Wilson disease patients with stable liver function., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The outcome of liver transplantation is usually reported in terms of graft and patient survival, medical and surgical complications, and quality of life, but when it comes to transplanted adolescents such conventional parameters are unable to give a full account of their life with a new liver, and their transition from adolescence to adulthood is a time when they are particularly vulnerable. Adolescents with liver transplants have excellent survival rates, over 80% of them surviving more than 10 years. Graft loss is most often associated with complications such as chronic rejection, hepatic artery thrombosis, and biliary complications. Calcineurin inhibitors may have various side effects, including hypertension and nephrotoxicity. Liver-transplanted adolescents are also exposed to viral infections, among which Epstein-Barr virus is very common and associated with the onset of post-transplant lymphoproliferative disorders. Growth retardation may also be an issue in some liver transplant recipients. Future studies will determine the best way to assess the functional immune status of adolescents with a transplanted liver with a view to ensuring the best treatment to induce tolerance without the complications of excessive immunosuppression. Schooling may be disrupted due to adolescent transplant recipients' poor adherence. Non-adherence is associated with a poor medical outcome. Both physical and psychosocial functioning is reportedly lower among young liver transplant recipients than in the general population., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: A subset of children with chronic liver disease (CLD) decompensate following an acute insult; however, data for children are not readily available. The present study aims to characterize the clinical presentation, etiology, outcome, and determinants of short-term mortality in children with an acute hepatic insult superimposed over CLD., Patients and Methods: Children of acute on chronic liver disease (ACLD) were grouped as acute on chronic liver failure (ACLF) and non-ACLF. ACLF was defined as per the definition proposed by Asian Pacific Association for the Study of Liver. The acute insult, etiology of CLD, and clinical and laboratory parameters at admission along with 3-month outcome were assessed. Receiver operating curve (ROC) was plotted to measure the performance of pediatric end-stage liver disease (PELD) score in predicting the 3-month mortality., Results: Of the 36 children with ACLD (median age 9.5; range 3-15 years), 17 fulfilled ACLF criteria and 19 non-ACLF. CLD was diagnosed for the first time in 86% children during their presentation with a superimposed acute insult. Wilson disease and autoimmune liver disease were the most common underlying etiology. Acute insult was caused by hepatitis E virus (HEV) in 27 (75%) children and hepatitis A virus (HAV) in 10 (28%). The 3-month mortality of ACLF group was significantly higher than that of non-ACLF group (59% vs 11%, P = 0.001). PELD score of >25.5 predicted death, with a sensitivity of 100% and specificity of 83.3%., Conclusions: Superinfection with hepatotropic viruses on CLD in children manifests as ACLD: ACLF and non-ACLF. Hepatitis E virus is the most common superinfection in the population studied. The mortality in ACLF is 5 times higher than that in the non-ACLF group. PELD score is useful in differentiating likely survivors and nonsurvivors.

Goals: To investigate variations in clinical epidemiology of Wilson disease in patients with concurrent liver disease and the effect of coexisting disease on current diagnostic algorithms., Background: Wilson disease is a rare disorder and few studies exist on diagnosis and natural history. Currently available tools have limited efficacy in complex patients, and the presence of coexisting diseases may further limit their use. More in-depth analyses of Wilson disease among complex patients with concurrent diseases will help improve algorithms for earlier diagnosis and treatment., Study: A retrospective cohort study using data from a large tertiary-care center to carry out a clinical assessment of Wilson disease among patients with coexisting liver disease., Results: Forty-two Wilson disease patients were identified; 9 had comorbid liver diseases. The average age of diagnosis was significantly older in patients with concurrent liver disease compared with those without underlying disease (49.1 y vs. 26.8 y, P<0.0001). Patients with concurrent liver disease had more evidence of cirrhosis at presentation (9/9, 100% vs. 15/33, 45.5%), and showed greater mortality (4/8, 50% vs. 4/29, 13.8%, P=0.0222). Without mutation analysis data, a definitive diagnosis of Wilson disease using Leipzig criteria was made in 44% of patients with concurrent liver diseases., Conclusions: Patients with concurrent liver diseases were diagnosed with Wilson disease at significantly older ages, presented with more liver cirrhosis, and showed greater mortality. Mutation analysis is crucial for definitive diagnosis among complex cohorts and those with intermediate Leipzig scores.

Background and Aims: Wilson disease (WD) is an inherited disorder of copper metabolism. When treated, the outcome can be excellent, although the long-term survival has yet to be well documented. The aim of this study was to describe the long-term outcome of a cohort of patients with WD and to assess those factors affecting the phenotypic manifestation of WD., Methods: The presence of mutations to the ATP7B gene, the clinical manifestations, treatments and the long-term outcomes were analysed retrospectively in 117 patients with WD (59 men and 58 women, aged at evaluation 38.5 ± 11, range 16-63 years)., Results: Fifty-five patients with a neurological presentation, 51 patients with a hepatic presentation and 11 asymptomatic patients were followed up for an average of 15.1 ± 10 years (median 12 years, range 1-41 years). The H1069Q ATP7B gene mutation was the most frequent genetic variant (54.3%); the frequency of this mutation did not differ between patients with either the hepatic or the neurological presentation (P = 0.099). d-penicillamine or zinc salts (81 and 17% respectively) were used for treatment, and three patients underwent liver transplantation. The majority of symptomatic patients became asymptomatic, or improved, during the follow-up (82% patients with hepatic presentation, 69% with neurological presentation). The long-term survival of patients with WD did not differ from that of the general Czech population (P = 0.95)., Conclusions: Long-term follow-up shows a satisfactory response in the great majority of adequately treated patients with WD and survival coincides with that of the general population., (© 2010 John Wiley & Sons A/S.)

Unlabelled: Liver transplantation (LT) is lifesaving for patients with Wilson disease (WD) presenting with fulminant hepatic failure (FHF) or chronic liver disease (CLD) unresponsive to treatment., Aim: To determine the outcome of LT in pediatric and adult patients with WD., Methods: United Network for Organ Sharing data on LT from 1987 to 2008 were analyzed. Outcomes were compared for patients requiring LT for FHF and CLD after 2002. Multivariate logistic regression was used to determine risk factors for death and graft loss., Results: Of 90,867 patients transplanted between 1987 and 2008, 170 children and 400 adults had WD. The one- and five-yr patient survival of children was 90.1% and 89% compared to 88.3% and 86% for adults, p = 0.53, 0.34. After 2002, 103 (41 children) were transplanted for FHF and 67 (10 children) for CLD. One- and five-yr patient survival was higher in children transplanted for CLD compared to FHF; 100%, 100% vs. 90%, 87.5% respectively, p = 0.30, 0.32. One- and five-yr patient survival was higher in adults transplanted for CLD compared to FHF; 94.7%, 90.1% vs. 90.3%, 89.7%, respectively, p = 0.36, 0.88. Encephalopathy, partial graft, and ventilator use were risk factors for death by logistic regression., Conclusion: LT is an excellent treatment option for patients with WD. Patients transplanted for CLD had higher patient survival rates than patients with FHF., (© 2010 John Wiley & Sons A/S.)

Long-Evans Cinnamon rats are a Wilson disease model highly susceptible to fulminant hepatitis around the age of 20 weeks, and hepatoma over the age of one year. Although prophylaxis has been established for the otherwise fatal hepatitis, effective treatment remains unknown. A blood exchange was tested to determine whether the prognosis of spontaneous hepatitis could be modified in icteric female rats. When bilirubinuria appeared, the rats immediately underwent surgery. Rats under anesthesia were first cannulated into the right atrium via the carotid vein, followed by 2.5 mL of blood exchange with heparinized fresh blood from Long-Evans agouti rats. Treated rats and controls were then observed for 2 months. Compared to the 50% mortality of untreated rats, all icteric rats that received a blood exchange survived the acute episode. We confirmed that Wilson disease animals are highly susceptible to acute hepatitis and show a poor prognosis. However, a single blood exchange improved spontaneous hepatitis in this animal model. This would serve as a first step for establishing a treatment for fatal hepatitis in animals. A blood exchange may improve fulminant hepatitis of Wilson disease model rats.

Background and Purpose: To investigate survival rates, prognostic factors, and causes of death in Wilson disease (WD)., Methods: In the years 1980-2007, a cohort of 142 patients with WD was prospectively registered (54 presented with neurologic symptoms, 49 with hepatic symptoms, 33 had mixed form, and data were missing for six patients). The duration of follow-up for patients alive was 11.1 +/- 8.8 years., Results: After initiation of treatment (d-penicillamine and zinc salts), 79% of patients had a stable or improved course of disease. Despite early diagnosis and appropriate therapy, 15 patients still had a relentlessly progressive course. Thirty patients died. The cumulative probability of survival in a 15-year period for the whole group was 76.7 +/- 4.9%. Better prognosis of WD was associated with male sex, younger age at onset, neurologic form of the disease, and treatment continuity. Causes of death were predominantly related to hepatic failure (16 patients), but also suicide (four patients) and cancer (three patients)., Conclusion: Despite the relatively early diagnosis and treatment of our patients with WD, mortality was still considerably high.

Background: Long-term outcomes after living donor liver transplantation (LDLT) in Wilson's disease (WD) with heterozygous donors for WD gene are unknown., Methods: LDLT was performed for 32 patients with WD (15 men, 17 women; mean age 16 years; range, 6-40 years) at Kyoto University Hospital from 1992 to 2006. The mean follow-up time from LDLT was 6.7+/-4.0 years (0.04-15.0 years). Donors were mainly parents (90.6%), who were obligatory carriers of the WD mutation. The present study examined retrospectively the copper metabolism, recurrence of WD, survival rate, and neurologic outcomes after LDLT., Results: Mean ceruloplasmin at the time of LDLT was 9.7+/-7.3 mg/dL and increased to 22.3+/-5.3 mg/dL (normal, 18-37 mg/dL). Urinary copper decreased from 2704+/-901 to 73.7+/-5.2 microg/day (normal, <50 microg/day). Serum copper improved from 72.9+/-33.9 to 81.0+/-14.9 mg/dL (normal, 78-131 mg/dL). Although six patients died and two received retransplantation, the remaining 24 remain alive without recurrence, with overall survival rates of 90.6%, 83.7%, and 79.9% at 1, 5, and 10 years, respectively. Patients with chronic liver failure had a poorer prognosis (P<0.05)., Conclusion: Use of liver grafts from heterozygous donors has been considered safe. Good improvements in copper metabolism were obtained without evidence of recurrence in long-term follow-up. Neuropsychologic presentations of WD improved or remained unchanged. Indications for liver transplantation in patients with WD with neurologic symptoms must be considered carefully based on the stage of neurologic damage and its irreversibility.

Background: Fulminant Wilson's disease (FWD) is rare and fatal condition in children unless liver transplantation is performed, however introduction of new technologies could change this poor prognosis. The aim of our study was retrospective analysis of clinical course, treatment and outcome of children with FWD treated in our institution., Material/methods: Between 1999-2007 we've treated in our hospital 13 patients with mean age of 15.5 yrs with FWD. We performed retrospective analysis of clinical course, biochemical parameters, MELD/PELD score, Wilson score and Kings'-College criteria for LTx in acute liver failure in all these patients. Type of treatment and final outcome were analyzed, as well as qualification for transplantation was reevaluated in each case in accordance to pathological examination of explanted during transplantation livers., Results: The initial symptoms of FWD were typically weakness, abdominal pain and developing later after 5-60 days (mean 20 days), jaundice. Eleven patients developed neurological symptoms with coma lasting for 2-11 days before transplantation or death. Maximal serum bilirubin concentration ranged between 4.5-71.6 mg% (mean 42.24 mg%), INR 2.9-10.0 (mean 5.4). MELD/PELD score was between 21-58 (mean 38), 10 patients fulfilled general King's-College criteria for transplantation in acute liver failure. Wilson's index ranged between 11 and 17 points (mean 13 points). In 11 children urgent liver transplantation (LTx) was performed, 1 child recovered on albumin dialysis and chelating treatment, 1 child died shortly after very late referral to our center. Actual follow-up of living patients is 0.36-7.43 years (mean 2.57 yrs), all are doing well with good liver function., Conclusions: FWD lead to death in almost all pediatric patients if LTx can not be performed, however early introduction of albumin dialysis (MARS) and chelating therapy allowed for survival without transplantation in single patient. It seems also that MARS therapy allows for at least prolongation of waiting time for LTx. Wilson's was slightly better predictor of need for LTx in our patients than classical King's-College criteria.

Before 1948, all patients with Wilson disease died shortly after diagnosis. In 1948, BAL (dimercaprol) was introduced as a possible effective treatment, to be followed by penicillamine (1955), zinc salts (1961), trientine (1969), liver transplantation (1982), and tetrathiomolybdate (1984). Despite this wide range of therapeutic options, patients still die. This article examines the cause of death in 67 patients (33 men, 34 women) out of a series of 300 seen between 1948 and 2000. Patients were classified according to their presentation as neurological, 32 patients, hepatic 11, mixed hepatic/neurological 10, hemolytic, 6, and "sibling biopsy " 8. Diagnostic failure was the principal cause of death but there were multiple other causes of which the principal was poor compliance and the development of malignant disease after 10 years of follow-up. The development of new symptoms should alert the physician to the possibility of a new pathology., ((c) 2007 Movement Disorder Society.)

A retrospective data analysis on liver transplantation for Wilson's disease (WD) was performed among Italian Liver Transplant Centers. Thirty-seven cases were identified. The main indication for liver transplantation was chronic advanced liver disease in 78% of patients. Mixed hepatic and neuropsychiatric symptoms were recorded in 32.3%. Eight patients presented with fulminant liver failure; 44.8% were on medical treatment. Patient and graft survival at 3 months, 12 months, 3 years, 5 years, and 10 years after transplantation were, respectively, 91.8%, 89.1%, 82.9%, 75.6%, and 58.8%, and 85.3%, 83.0%, 77.1%, 70.3%, and 47.2%. Neurological symptoms significantly improved after orthotopic liver transplantation (OLT), but the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than in patients with liver disease alone (P = 0.04). WD characterized by hepatic involvement alone is a rare but good indication for liver transplantation when specific medical therapy fails. Patients with neuropsychiatric signs have a significantly shorter survival even though liver transplantation has a positive impact on neurological symptoms. In conclusion, a combination of hepatic and neuropsychiatric conditions deserves careful neurological evaluation, which should contraindicate OLT in case of severe neurological impairment.

Orthotopic liver transplantation has been applied to the treatment of Wilson's disease (WD), living-related liver transplantation (LRLT) has also been indicated for WD with increasing frequency. Between January 2001 and November 2003, 22 LRLTs were performed on patients (19 pediatric, three adults) with WD in liver transplantation center. Two patients were transplanted because of a presentation coexistent with fulminant hepatic failure. Twenty presented with chronic advanced liver disease with (n = 9) or without (n = 11) associated neurologic manifestations. All the recipients had low serum ceruloplasmin levels with a mean value of 12.8 +/- 3.2 mg/dl before transplantation and increased to an average of 26.0 +/- 3.6 mg/dl after LRLT at the latest evaluation. The survival patients with neurologic manifestations such as tremor, dysarthia, dysphagia, dystonia and sialorrhea had improved after LRLT. This suggests that LRLT not only resolves the hepatic but also ameliorates the neurologic consequences of WD.

We studied the cause of death in a consecutive series of 164 patients with Wilson's disease (WD) diagnosed over an 11 year period. A total of 20 [12% (95% CI 10.3-16.0)] died during the observation period. The relative survival rate of all patients in our group was statistically smaller than in Polish population. The main cause of death was the diagnosis in advanced stage of disease, but in six patients presenting with mild signs, we observed the progression of the disease despite treatment. There was no difference in mortality rate in patients treated with d-penicillamine or zinc sulphate as initial therapy. The prognosis for survival in the majority of WD patients is favourable, provided that therapy is introduced early.

Wilson's disease (WD) is a rare liver-based disorder of copper metabolism. Prognostic criteria described by our group in 1986 to predict death without transplantation have not been universally validated. The clinical features of 88 children were reviewed, retrospectively in 74 and prospectively in 14. Data from the retrospectively recruited patients that died or survived on long-term chelation were used to evaluate the validity of our old scoring system and to devise a new prognostic index, then assessed in the 14 prospectively recruited patients. Using the old scoring system, 5 children scoring > or = 7, the cutoff value for death without transplantation, survived, whereas 4 scoring < or = 7 died (sensitivity 87% and specificity 90%). A new index based on serum bilirubin, international normalized ratio, aspartate aminotransferase (AST), and white cell count (WCC) at presentation identified a cutoff score of 11 for death and proved to be 93% sensitive and 98% specific, with a positive predictive value of 88%. When the new index was evaluated prospectively in 14 patients, it predicted the need for transplantation in only the 4 who required it, although 1 child with a score of 11 survived on medical treatment. In conclusion, the new Wilson Index is more sensitive and specific in predicting mortality without transplantation than the old scoring system, but needs to be validated in a larger number of patients.

Wilson disease is caused by disease-specific mutations of the copper transporting ATPase, ATP7B. The diagnosis is established by clinical and biochemical means, though advances in molecular diagnostics will someday permit de novo diagnosis. The patient may present with hepatic, neurologic, or psychiatric symptoms, or a combination of these. Both environmental and extragenic effects contribute to the varied phenotypic presentations of this disease. Patients can be treated effectively with chelating agents or zinc salts, or with liver transplantation. Liver cell transplant and gene therapy offer potential cures for this disorder, but at present only data from preclinical studies on animal models are available. Future advances in immunotolerization and gene therapy will likely enable human trials for treatment of this disorder and other genetic disorders of hepatic metabolism.

Background/aims: Wilson's disease has protean presentations. Most patients manifested as either hepatic or neurologic symptoms and signs initially. No study has investigated the predictor of presentation and differences in laboratory tests and survival between patients presented with hepatic or neurological disease so far., Methodology: Forty-one patients with Wilson's disease were diagnosed between 1981 and 2002 at our hospital. Their clinical features at presentation and laboratory findings were retrospectively collected. Survival was calculated using the Kaplan-Meier analysis., Results: Twelve patients initially presented with hepatic symptoms including chronic hepatitis, complications of cirrhosis, and fulminant hepatic failure. Twenty-nine patients presented with neurological symptoms including tremor, dysarthria, ataxia, and psychiatric diseases. No specific factor identified could predict the initial presentations. Compared to patients with neurological symptoms, patients with hepatic disease had significantly higher serum levels of aminotransferase, ceruloplasmin, copper, and 24-hour urine copper excretion. There was no significant difference in survival between these two groups. Among the patients who died, the most common causes of death were fulminant hepatic failure and complications of cirrhosis., Conclusions: Our results suggested that the overall survival did not differ significantly according to the initial presentations. There was no predictor found that could foretell the clinical course of Wilson's disease.

Wilson's disease is an autosomal recessive disease of copper metabolism, with an estimated prevalence of 1:30000. The most common presentations of WD are liver disease and neurological disturbance. For many years the diagnosis was based on the results of several clinical and biochemical tests, for which several limitations had been reported. In recent years the developments of new techniques in genetic and molecular biology have provided useful tools in the diagnosis of Wilson's disease. However, the presence of several mutations and the fact that most patients are compound heterozygote means that the problem is not completely resolved. Chelators and zinc salts have been largely used in the treatment of WD patients with a favorable outcome, but the debate continues as to the agents of first choice. Liver transplantation is a cure for patients with decompensated liver disease but its effect on the neurological outcome is still not clear.

In the Long-Evans Cinnamon rat, copper accumulates in the liver because of a mutation in the copper-transporting ATPase gene, and peroxidative stresses are supposed to be augmented. We examined the effects of dietary fatty acids on hepatitis, hepatic gene expression, and survival. Rats were fed a conventional, low-fat diet (CE2), a CE2 diet supplemented with 10 wt% of lard (Lar), high-linoleic soybean oil (Soy), or a mixture of docosahexaenoic acid (DHA)-rich fish oil and soybean oil (DHA/Soy). Among female rats, the mean survival times of the DHA/Soy and the Soy groups were longer by 17 approximately 20% than in the Lar and the CE2 groups. Among male rats, the survival times were much longer than in the females, but no significant difference in survival was observed among the dietary groups. Serum ceruloplasmin levels in female and male rats of all of the dietary groups were similar. Serum transaminase levels of the DHA/Soy group tended to be lower than in the CE2 group. Histological examinations revealed a marked degeneration in hepatic tissue integrity in the Lar and CE2 groups but not in the DHA/Soy group. Hepatic levels of metal-related genes, transferrin and ceruloplasmin, as well as those related to bile acid synthesis were up-regulated, and an inflammation-related gene (cyclooxygenase [COX]-2) was down-regulated in the DHA/Soy group. Some proliferation-related genes were also affected by the dietary fatty acids. These results indicate that polyunsaturated fatty acids suppress the development of acute hepatitis and prolong survival in females, regardless of whether they are of the n-6 or n-3 type, which are associated with altered gene expressions.

Objectives: To characterize fulminant Wilson's disease in children, outline clinical and biochemical differences to fulminant hepatic failure of other etiologies, and compare sensitivity and specificity in diagnosing fulminant Wilson's disease of alkaline phosphatase to total bilirubin ratio and aspartate aminotransferase to alanine aminotransferase ratio., Design: Retrospective case study., Setting: Twenty-two-bed multidisciplinary pediatric intensive care unit in a tertiary university hospital, national referral center for pediatric liver transplantation., Patients: Between March 1986 and December 1999, seven children, aged between nine and 16 yrs, were admitted in our unit for fulminant Wilson's disease. During the same period of time, aged-matched analysis identified 12 other children with fulminant hepatic failure of other etiologies., Interventions: None., Measurements and Main Results: On admission, pediatric risk of mortality score, coagulation variables, and hepatic encephalopathy grade were similar in both groups. Children with fulminant Wilson's disease (n = 7) were characterized by lowered hemoglobin and serum transaminases, elevated serum bilirubin, and the occurrence of Kayser-Fleischer rings. Although some admission variables were significantly different between both groups, the elevated variability did not allow us to define acceptable cutoff values. Receiver operating characteristics curve for alkaline phosphatase to total bilirubin ratio showed a good discriminative power (Az = 0.87) in differentiating fulminant Wilson's disease from fulminant hepatic failure of other causes, and a ratio <1 showed a 86% sensitivity and 50% specificity (odds ratio, 6; 95% confidence interval, 66-0.5; p =.173) for fulminant Wilson's disease diagnosis., Conclusions: Although requiring prospective study to confirm, Kayser-Fleischer rings and serum alkaline phosphatase to total bilirubin ratio may assist in the early diagnosis of fulminant Wilson's disease.

Thirty patients with Wilson's disease (WD) were observed at a movement disorder clinic between 1970 and 2000. Disease onset was at the mean age (SD) of 14.5 (+/-5.9) years. Presentation with hepatic disease occurred in 12 of 30 patients and with neurologic disease in 15. Three patients were asymptomatic at the time of diagnosis. The mean (SD) delay to diagnosis was 5.9 (+/-5.7) years. Five patients diagnosed in an advanced stage of disease died before initiating treatment. Eighteen patients were followed and treated with D-penicillamine alone or in combination with zinc sulphate. Treatment improved most of neurological symptoms. Dystonic postures, behavioural disturbances and dysarthria were the most resistant neurological signs. 'Pseudo-sclerotic' neurologic involvement predicted a good outcome, whereas hepatic onset and 'classic' neurologic involvement were associated with a poorer prognosis. Two of the 18 treated patients died of hepatic failure due to voluntary discontinuation of therapy. Both D-penicillamine and zinc sulphate were well tolerated. No teratogenic effect of D-penicillamine was observed throughout 5 pregnancies. Our results suggest that D-penicillamine or a combination of D-penicillamine and zinc sulphate is a safe and effective long-term treatment in patients with WD., (Copyright 2003 S. Karger AG, Basel)

Wilson's disease (WD) has moved on from being a recognized syndrome that was uniformly fatal to a curative disease for which the genetic basis has been discovered. Most pediatric patients present with hepatic manifestations, but some may have neurologic or psychiatric features. Clinical and biochemical screening, including liver biopsy for hepatic copper analysis, remain the standard for diagnosis, but haplotype analysis for siblings is now available and should be considered for family screening when possible. Lifelong medical therapy remains the mainstay of treatment, but treatment preferences are changing from penicillamine to alternative agents such as trientine and zinc. OLT remains lifesaving for those with fulminant WD and those in whom initial medical therapy fails. The future will probably see the application of rapid and accurate molecular diagnostic testing for this disorder and new therapeutic modalities such as hepatocyte transplantation, gene replacement therapy, and gene modification.

Background: Wilson's disease usually presents in childhood. Early recognition and treatment is crucial to retard the progression of this disease, which can be debilitating, if not fatal. We analysed the clinical manifestations and survival pattern of patients admitted at our centre from 1993 to 1996., Methods: Hospital records of patients were reviewed to obtain the clinical manifestations. The survival status of patients was determined by a prospective follow up. The Kaplan-Meier survival curve and univariate Cox proportional hazards model were used to determine the survival pattern and risk for death in Wilson's disease., Results: A total of 60 patients were studied. The median age at onset of symptoms was 12 years (range 5-52 years). The log rank test showed a significant difference in the mean (SD) survival between patients who presented with hepatic [87.36 (15.26) months] and neurological symptoms [114.33 (9.14) months]. Cox proportional hazards analysis showed a hazard ratio of 4.9 for patients with a hepatic presentation compared to those with neurological presentation., Conclusion: The presentation of Wilson's disease is not limited to the paediatric age group. Patients with a hepatic presentation had a five-fold higher risk of mortality when compared to those with a neurological presentation.

During the last 90 years, Wilson's hepatolenticular degeneration has evolved from a disease presenting insurmountable challenges to the clinician's diagnostic acumen to a metabolic disorder which is diagnosable woth certainty, treatable successfully, and even preventable. It may be long before the genetic defect becomes amenable to correction and a cure of the disease becomes possible.

Objective: To evaluate clinical, laboratory findings, treatment and long-term follow-up of children with Wilson's disease with hepatic presentation., Design: Retrospective study with a median follow-up period of 9 years., Setting: University medical center., Subjects: Thirty-four children with hepatic involvement, ranging in age from three to fifteen years, were diagnosed as Wilson's disease over an eighteen year period., Methods: The diagnosis was based on the presence of family history and Kayser-Fleischer rings, low serum ceruloplasmin levels and increased urinary and hepatic copper concentrations., Results: Four patients had also neurological manifestations. Eight patients were diagnosed as fulminating hepatic failure resulting in death in a few days. The most common symptoms were abdominal distension and abdominal pain. Hepatomegaly was the predominant physical finding and serum transaminases were elevated in most of the patients. Twenty patients had cirrhosis and six had chronic hepatitis histopathologically. All patients with fulminating hepatic failure had hyperbilirubinemia with normal alkaline phosphatase and higher aspartate aminotransferase than alanine aminotransferase. Patients were treated with D-penicillamine and zinc sulphate. Three patients underwent liver transplantation. Four more patients besides patients with fulminating hepatic failure died due to end stage liver disease. Twenty-two patients were followed for median 9 years. Four patients with poor compliance progressed to decompensated cirrhosis and the others were stable., Conclusions: Liver disease with unknown origin with positive family history and parental consanguinity should imply Wilson's disease strongly.

Wilson's disease is a hereditary defect in copper excretion leading to the accumulation of copper in the tissues, with subsequent tissue damage. The most serious sequela is that of progressive central nervous system involvement. The use of orthotopic liver transplantation (OLT) has been controversial for those patients with neurological symptoms attributed to Wilson's disease. The aim of this study is to determine the effectiveness of OLT for patients with Wilson's disease, including those with neurological involvement attributed to copper accumulation in the central nervous system. OLT was performed in 45 patients (19 men [42.2%], 26 women [57.8%]) with Wilson's disease between 1971 and 1993 who were followed up for at least 4 years. The age at diagnosis of Wilson's disease ranged from 3 to 41 years (mean, 17.7 +/- 7.4 years). The age at OLT ranged from 8 to 52 years (mean, 22.3 +/- 9.4 years). Nineteen patients (42.2%) were aged younger than 18 years at OLT. The indications for OLT included chronic hepatic failure in 15 patients (33.3%) and fulminant (FHF) or subfulminant hepatic failure in 30 patients (66. 6%). All but 1 of the 19 pediatric patients (94.7%) were in the latter group. Twenty-five patients (55.5%) were receiving D-penicillamine, 9 patients for more than 1 year; none of the patients treated long term presented as FHF. Thirty-three patients (73.3%) survived more than 5 years after OLT. Fourteen patients (31%) died during the posttransplantation period; 7 of the 14 patients (50%) were aged younger than 18 years. Twelve patients died during the first 3 months after OLT of complications of disease and surgery, 10 of whom underwent transplantation for FHF. The other 2 patients died 6 and 9 years after transplantation of infectious problems. Eleven patients (24.4%) required retransplantation because of a primary nonfunctioning graft (n = 6), chronic rejection (n = 4), and hepatic artery thrombosis (n = 1). Seventeen patients (37.7%) presented with neurological abnormalities; 14 patients with Wilsonian neurological manifestations and 3 patients with components of increased intracranial pressure. Ten of the 13 surviving patients with hepatic insufficiency and neurological abnormalities at OLT showed significant neurological improvement. Our experience shows OLT is a life-saving procedure in patients with end-stage Wilson's disease and is associated with excellent long-term survival. The neurological manifestation of the disease can improve significantly after OLT. Earlier transplantation in patients with an unsatisfactory response to medical treatment may prevent irreversible neurological deterioration and less satisfactory improvement after OLT.

Childhood liver disorders have, in general, mode of presentations which are distinct from that in adult population. It is due to varying etiology and natural history of the liver diseases in childhood. Chronic hepatitis B and C can be managed with alpha interferon. Remission rates in children have been reported to be between 20-58%. Recently available lamuvidine has also been used in combination with interferon therapy. Oral chelation therapy and liver transplantation have radically affected the outcome of patients with Wilson's disease. Corticosteroids and immunosuppressive therapy are effective in reducing both morbidity and mortality due to auto-immune hepatitis. Offending carbohydrates are eliminated from the diet of patients with galactosemia and hereditary fructose intolerance. The most important and often neglected component of management of chronic liver diseases in childhood are nutritional management and prompt interventions for ascites, spontaneous bacterial peritonitis, portal hypertension and hepatic encephalopathy. With definitive etiological and histological assessment and institution of specific as well as supportive therapy, children with chronic liver disease can have a prolonged survival with improved quality of life. Several of them can potentially receive the liver transplant as and when it becomes available.

Background/aims: As has been the case with other metabolic diseases of the liver in the last decade, orthotopic liver transplantation has been applied to the treatment of Wilson's disease with increasing frequency. The experience at the University of Pittsburg with orthotopic liver transplantation for Wilson's disease is reported., Methods: Between February 1981 and December 1991, 51 orthotopic liver transplants were performed on 39 patients (16 pediatric, 23 adults) with Wilson's disease. Twenty-two patients were transplanted because of a presentation co-existent with fulminant hepatic failure. Seventeen presented with chronic advanced liver disease with (n=9) or without (n=8) associated neurologic dysfunction., Results: The rate of primary graft survival (n-39) was 73% and patient survival was 79.4%. No patient mortality occurred beyond 3 weeks post-orthotopic liver transplantation. Survival was butter for those with a chronic advanced liver disease presentation (90%) than it was for those with a fulminant hepatic failure (73%) presentation, but the difference was not statistically significant., Conclusions: 1) Currently, orthotopic liver transplantation is the treatment of choice for Wilson's disease presenting as fulminant hepatic hepatic failure; 2) orthotopic liver transplantation should be considered for patients with Wilson's disease with advanced, chronic liver disease for whom no other therapy is possible; 3)orthotopic liver transplantation only partially corrects the underlying metabolic defect of patients with Wilson's disease and converts the copper kinetics from that characteristic of an individual affected with a homozygous disease to that of an individual who is an obligate heterozygote, thereby effecting a phenotypic cure.