Valentina Medici

Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders

A retrospective data analysis on liver transplantation for Wilsons 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. (Liver Transpl 2005;11:1056–1063.)

Diagnosis and management of Wilson's disease: results of a single center experience.

Aims To report on the diagnostic features, management, and clinical outcome after different treatments of Wilsons disease patients followed over a mean period of 15 years. Patients Thirty-five patients with Wilsons disease referred to the University of Padovas Department of Gastroenterology for diagnosis or treatment were observed for a mean 15 years. The diagnosis was based on clinical symptoms, laboratory tests (ceruloplasmin, urinary, and hepatic copper concentrations), and uptake of the radiostable isotope 65Cu into the plasma protein pool. Hepatic Cu content was measured by regular follow-up biopsies. Neurologic outcome after therapy was assessed using a newly developed scoring system. Results Twenty-three (65.7%) patients presented with liver disease; 12 (34.3%) had mixed neurologic and hepatic involvement. All patients had been initially treated with either penicillamine (23) or zinc sulfate (12). The neurologic symptoms became worse or remained stationary in 75% of those treated with penicillamine, whereas zinc treatment improved these symptoms in 90% of treated cases. Both treatments were effective in improving the hepatic symptoms. No differences in hepatic Cu content emerged between follow-up biopsies in either treatment group. Six patients (26%) had to abandon the penicillamine treatment due to side effects. In all, 4 patients underwent liver transplantation, which was successful in 3, with a mean survival after transplantation of 4.6 years; the fourth, who had a severe neurologic impairment, died of central pontine myelinolysis. Conclusions Penicillamine and zinc can effectively treat Wilsons disease, though the side effects of penicillamine may be severe enough to prompt its suspension. Liver transplantation remains the treatment of choice for end-stage liver disease.

Interaction between rifaximin and dietary fibre in patients with diverticular disease

Cyclic administration of rifaximin in association with dietary fibre achieves symptomatic relief in uncomplicated diverticular disease (DD) by means of a still undefined mechanism.

Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.

The first gene associated with Crohn disease (CD) has been identified as CARD15 (16q12). Three variants, R702W, G908R and 1007fsinsC are strongly and independently associated with the disease. A second gene, conveying a smaller risk for inflammatory bowel disease (IBD), has been identified as DLG5 (10q23). We assess the frequency of the CARD15 SNPs and of the R30Q mutation in DLG5 and their contribution to the development of CD in a cohort of unrelated IBD patients (151 CD, 325 ulcerative colitis (UC)) and healthy controls (236) from South-east Norway (IBSEN cohort). Genotype-based tests of population differentiation using 23 SNPs across CARD15, together with estimates of FST, indicated that the German and Norwegian background populations could be differentiated at the CARD15 locus. The Norwegian and German CD samples exhibited particularly strong differentiation at the three predisposing loci and those marking their background haplotype. There were significantly lower frequencies of the CARD15 SNPs and no significant association with CD in the Norwegian samples. Only a marginal association was observed for the subphenotypes ileitis and ileocolitis vs colitis (P=0.048). The population attributable risk percentage (PAR%) for CARD15 variants in the Norwegian cohort is the lowest reported for a European population (1.88%), except Iceland. Similarly, the DLG5 variant showed no association with CD or IBD, however, there was a negative correlation with stricture (P=0.035). The present results are consistent with an emerging pattern of a low frequency of the CARD15 variants in Northern countries where the prevalence of IBD is greatest.

Effect and possible role of Zn treatment in LEC rats, an animal model of Wilson's disease

The effect of oral zinc (Zn) treatment was studied in the liver, kidneys and intestine of Long-Evans Cinnamon (LEC) rats in relation to metals interaction and concentration of metallothionein (MT) and glutathione (GSH). We also investigated the change in the activity of antioxidant enzymes and determined the biochemical profile in the blood and metal levels in urine. We showed that the Zn-treated group had higher levels of MT in the hepatic and intestinal cells compared to both untreated and basal groups. Tissue Zn concentrations were significantly higher in the Zn-treated group compared to those untreated and basal, whereas Cu and Fe concentrations decreased. The antioxidant enzyme activities in the Zn-treated group did not change significantly with respect to those in the basal group, except for hepatic glutathione peroxidase activity. Moreover, the biochemical data in the blood of Zn-treated group clearly ascertain no liver damage. These observations suggest an important role for Zn in relation not only to its ability to compete with other metals at the level of absorption in the gastrointestinal tract producing a decrease in the hepatic and renal Cu and Fe deposits, but also to MT induction as free radical scavenger.

Effect of penicillamine and zinc on iron metabolism in Wilson's disease

Objective. The physiology of iron metabolism in Wilsons disease is largely unknown, and there is a paucity of data on the real presence and progression of iron accumulation. The purpose of this study was to assess the iron metabolism parameters, including hepatic iron concentration, in follow-up liver biopsies and serum, and urinary pro-hepcidin. Material and methods. Twenty-three Wilsons disease patients undergoing long-term treatment were enrolled in the study. Results. Hepatic iron content was significantly increased in penicillamine-treated patients compared with zinc-treated patients. Serum and urinary pro-hepcidin concentrations were significantly higher in Wilsons disease patients than in healthy volunteers, despite a normal biochemical pattern of iron metabolism. Conclusions. Long-term penicillamine treatment seems to be responsible for a more marked iron accumulation in the liver. This observation may justify a revision of long-term Wilsons disease treatment modalities with penicillamine. The finding that serum and urinary pro-hepcidin is significantly increased in Wilsons disease patients compared with healthy volunteers suggests a role for hepcidin in iron metabolism in Wilsons disease, but this needs to be confirmed by a study of hepatic hepcidin expression in these patients.

Adverse reaction after tetrathiomolybdate treatment for Wilson's disease: A case report

of these patients, we injected more than 4 muscles, with a mean of 8.5 treated muscles (mean dosages per kg body weight: 17.9 U; range: 5.1–32.3 U; mean dosage per muscle: 35.6 U; mean total dosage per session: 303.0 U). The data are summarized in Table 1. We did not observe any cases of adverse events that would have required discontinuation of BoNT therapy. The total rate of adverse events seen here was 8.8%. This is well below the 28% reported by Jankovic and Schwartz5 for the treatment of cervical dystonia in adult patients (58 of 205 patients). Thus, over a 5-year observational period, BoNT (preparation Botox) proved safe and effective in our multimuscle treatment regimen.6 These clinical observations are supported by experiments in a mouse model showing that BoNT (preparation Botox) has a migration profile with a particularly broad safety margin.7 In conclusion, as far as pharmacotherapy with BoNT is concerned, some of the needs of children with CP can be met: we can safely treat more muscles and give more substance.