Acute Liver Failure due to Wilson Disease: Eight Years of the National Liver Transplant Program in Uruguay.

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.

Liver Expression of a MiniATP7B Gene Results in Long-Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice.

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.

Therapeutic potential of hepatocyte-like-cells converted from stem cells from human exfoliated deciduous teeth in fulminant Wilson's disease.

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.

Long-term outcomes of patients with Wilson disease in a large Austrian cohort.

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.

The acute haemolytic syndrome in Wilson's disease--a review of 22 patients.

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.

Liver transplantation for fulminant Wilson's disease in children.

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.

Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.

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.

Dietary polyunsaturated fatty acids suppress acute hepatitis, alter gene expression and prolong survival of female Long-Evans Cinnamon rats, a model of Wilson disease.

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.

Management of chronic liver disease.

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.

Chelation treatment of neurological Wilson's disease.

The results of chelation treatment of 137 patients presenting with neurological Wilson's disease are described, together with the more commonly observed toxic reactions to the various drugs employed. Fifty-seven patients made an excellent response to treatment and became symptom free. Thirty-six patients made a good recovery, but were left with some minor neurological deficit. Twenty-four patients had a poor response: although the disease process was arrested they were left more or less disabled. Twenty patients died: nine had little or no treatment, but 11 died despite apparently adequate chelation therapy. There was no obvious reason for this failure. The liver copper level was estimated in six of these patients: it was still significantly elevated in only one, but in all four in whom it was possible to make the determination, the concentration of copper in the basal ganglia was in excess of 45 micrograms/g wet weight. It was not apparent why adequate therapy failed to remove copper from the brains of these patients. There was no obvious clinical, histological or biochemical indicator of failure to respond to treatment. Initial deterioration before improvement was seen in 30 patients: the prognosis for a useful recovery was not necessarily worse than that in patients who did not show this phenomenon.