Zdenek Marecek

Long-term follow-up of Wilson Disease: natural history, treatment, mutations analysis and phenotypic correlation

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.

Sleep disorders in Wilson's disease.

Background:  Wilson’s disease (WD) is an autosomal recessive inherited disease with copper accumulation; neurodegeneration is associated with dopaminergic deficit. The aim of the study is to verify sleep co‐morbidity by questionnaire and objective sleep examinations (polysomnography, multiple sleep latency test).

Effect of carvedilol on portal hypertension depends on the degree of endothelial activation and inflammatory changes.

Objective. Bleeding from esophageal varices is a major complication of liver cirrhosis. Non-selective beta-blockers exert an influence on the functional part of portal hypertension, thereby reducing the risk of bleeding. Direct measurement of this functional part is not possible; nevertheless, pro-inflammatory markers as well as parameters of endothelial dysfunction might serve as surrogate markers. The aim of study was to assess the correlation between the therapeutic efficacy of carvedilol and markers of endothelial dysfunction and systemic inflammation in patients with liver cirrhosis and portal hypertension. Material and methods. Thirty-six patients with cirrhosis and portal hypertension were given carvedilol, 25 mg q.i.d. for 30 days. Hepatic venous pressure gradient (HVPG) and biochemical determinations were performed prior to and after the treatment. Eight healthy individuals served as controls for comparison of biochemical markers. Results. In the whole group of cirrhotic patients, HVPG decreased from 17.7±3.8 to 14.9±4.8 mmHg (p<0.001). Complete response was seen in 15 patients (42%). Baseline serum levels of E-selectin were significantly higher in responders than in non-responders (119.8±70.6 versus 52.6±25.7 ng/ml; p=0.023) and in controls (28.8±22.2 ng/ml; p=0.004). Furthermore, baseline TNF-α levels were significantly higher in responders than in non-responders (22.8±15.7 versus 7±8.9; p=0.047) and in controls (5.5±5.9 pg/ml; p=0.005). Serum levels of ICAM-1 showed the same trend (4360±2870 versus 2861±1577 versus 651±196 ng/ml), although differences did not reach statistical significance. Conclusions. Markers of systemic inflammation and endothelial dysfunction seem to predict the hypotensive effect of carvedilol on portal hypertension in patients with liver cirrhosis and may be useful in the assessment of the efficacy of the therapy.

Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms

Background & AimsWilson disease (WD) is an inherited disorder of copper disposition caused by an ATP7B transporter gene mutation, leading to copper accumulation in predisposed tissues. In addition to a genetic predisposition, other factors are likely to contribute to its clinical manifestation. The aim of the study was to assess whether oxidative stress affects the phenotypic manifestation of WD.MethodsIn 56 patients with WD (29 men; 26 with the hepatic form, 22 with the neurologic form, and eight asymptomatic; mean age 38.5 ± 12 years), total serum antioxidant capacity (TAC) and inflammatory parameters (hs-CRP, IL-1β, IL-2, IL-6, IL-10, and TNF-α) were analyzed and related to the clinical manifestation, and mutations of the ATP7B gene. The control group for the TAC and inflammatory parameters consisted of 50 age- and gender-matched healthy individuals.ResultsWD patients had a significantly lower TAC (p < 0.00001), lower IL-10 levels (p = 0.039), as well as both higher IL-1β (p = 0.019) and IL-6 (p = 0.005) levels compared to the control subjects. TNF-α, hs-CRP, and IL-2 did not differ from the controls. Patients with the neurological form of WD had a significantly lower TAC than those with the hepatic form (p < 0.001). In addition, the lower TAC was associated with the severity of the neurological symptoms (p = 0.02). No relationship between the inflammatory parameters and clinical symptoms was found.ConclusionsData from our study suggest that the increased oxidative stress contributes significantly to the clinical manifestation of WD; as a lower TAC is associated with the neurological symptoms in WD patients.

Biochemical and clinical changes in Wilson's disease heterozygotes

This paper reports on a study of the heterozygous children of patients with Wilsons disease. A total of 16 children of 10 patients with the disease were followed up. Detailed biochemical, clinical and EEG tests were done. Nearly all the children were found to have reduced serum copper and caeruloplasmin levels and high rates of urine copper excretion following exposure to penicillamine. These findings were different from the results obtained in adult heterozygous carriers. Thirty per cent of the children had pathological neurological findings, and EEG abnormalities were found in 75%.

Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels

Background: Oxidation processes play an important role in atherogenesis. Bilirubin IX is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). Methods: The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n= 50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n=2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n=38) and control subjects (n=38). Results: The prevalence of IHD in GS subjects (aged 49.7 9.0 years) was 2% (0.05–10.7%, 95% confidence interval), compared to 12.1% in a general population (P 0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. Conclusions: In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity.