Karl Heinz Weiss

Wilson's disease and other neurological copper disorders

The copper metabolism disorder Wilsons disease was first defined in 1912. Wilsons disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilsons disease, and results from biochemical and genetic prevalence studies suggest that Wilsons disease might be much more common than previously estimated. Early diagnosis of Wilsons disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilsons disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilsons disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimers disease and Parkinsons disease.

Zinc Monotherapy Is Not as Effective as Chelating Agents in Treatment of Wilson Disease

BACKGROUND & AIMS Wilson disease is a genetic disorder that affects copper storage, leading to liver failure and neurologic deterioration. Patients are treated with copper chelators and zinc salts, but it is not clear what approach is optimal because there have been few studies of large cohorts. We assessed long-term outcomes of different treatments. METHODS Patients in tertiary care centers were retrospectively analyzed (n = 288; median follow-up time, 17.1 years) for adherence to therapy, survival, treatment failure, and adverse events from different treatment regimens (chelators, zinc, or a combination). Hepatic treatment failure was defined as an increase in activity of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase) >2-fold the upper limit of normal or >100% of baseline with an increase in urinary copper excretion. RESULTS The median age at onset of Wilson disease was 17.5 years. Hepatic and neuropsychiatric symptoms occurred in 196 (68.1%) and 99 (34.4%) patients, respectively. Hepatic treatment failure occurred more often from zinc therapy (14/88 treatments) than from chelator therapy (4/313 treatments; P < .001). Actuarial survival, without transplantation, showed an advantage for chelating agents (P < .001 vs zinc). Changes in treatment resulted mostly from adverse events, but the frequency did not differ between groups. Patients who did not respond to zinc therapy showed hepatic improvement after reintroduction of a chelating agent. CONCLUSIONS Treatments with chelating agents or zinc salt are effective in most patients with Wilson disease; chelating agents are better at preventing hepatic deterioration. It is important to identify patients who do not respond to zinc therapy and have increased activities of liver enzymes, indicating that a chelating agent should be added to the therapeutic regimen.

A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults

Cholestatic liver disease (CLD) is a major cause of progressive liver damage and liver failure. Several forms of biliary cirrhosis are caused by mutations in specific genes. We sought to identify a genetic defect in a family with CLD impossible to assign to a distinct pathogenic entity. Clinical and histopathological characterization of the family members, microarray‐based single‐nucleotide polymorphism genotyping, and analysis of candidate genes were performed. Among six of 11 siblings severely affected by idiopathic CLD in a family from a population isolate in Transylvania, three died of cirrhosis (aged 5, 7, and 43 years) and three had adult‐onset disease with small duct cholangiopathy, including ductopenia. Others were mildly affected and experienced intrahepatic cholestasis of pregnancy, miscarriages, or stillbirth. Pedigree studies revealed distant parental consanguinity. Genome‐wide linkage analysis and autozygosity mapping yielded a single maximal lod‐score of 3.88 on chromosome 7q21.1‐7q22, excluding other genomic loci. Sequencing of ABCB4 at this locus revealed a novel missense mutation c.2362C>T (p.Arg788Trp) which cosegregated with severity of disease. Bile from a mutation homozygote showed a reduced phosphatidylcholine/bile acid ratio, consistent with reduced ABCB4 phosphatidylcholine transport activity. Conclusion: We show that a missense mutation in ABCB4 is a cause for ductopenic CLD in adulthood. Allelic status correlated with severity of liver disease ranging from intrahepatic cholestasis of pregnancy through fibrosis to cirrhosis and death in childhood and adulthood. Mutational analysis of ABCB4 should be generally considered in all patients with cholestatic liver disease of unknown etiology regardless of age and onset of disease. (HEPATOLOGY 2008.)

Efficacy and Safety of Oral Chelators in Treatment of Patients With Wilson Disease

BACKGROUND & AIMS Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.

Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation

BackgroundDecompensated cirrhosis is associated with a poor prognosis and liver transplantation provides the only curative treatment option with excellent long-term results. The relative shortage of organ donors renders the allocation algorithms of organs essential. The optimal strategy based on scoring systems and/or waiting time is still under debate.MethodsData sets of 268 consecutive patients listed for single-organ liver transplantation for nonfulminant liver disease between 2003 and 2005 were included into the study. The Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores of all patients at the time of listing were used for calculation. The predictive ability not only for mortality on the waiting list but also for the need for withdrawal from the waiting list was calculated for both scores. The Mann-Whitney-U Test was used for the univariate analysis and the AUC-Model for discrimination of the scores.ResultsIn the univariate analysis comparing patients who are still on the waiting list and patients who died or were removed from the waiting list due to poor conditions, the serum albumin, bilirubin INR, and CTP and MELD scores as well as the presence of ascites and encephalopathy were significantly different between the groups (p < 0.05), whereas serum creatinine and urea showed no difference.Comparing the predictive abilities of CTP and MELD scores, the best discrimination between patients still alive on the waiting list and patients who died on or were removed from the waiting list was achieved at a CTP score of ≥9 and a MELD score of ≥14.4. The sensitivity and specificity to identify mortality or severe deterioration for CTP was 69.0% and 70.5%, respectively; for MELD, it was 62.1% and 72.7%, respectively. This result was supported by the AUC analysis showing a strong trend for superiority of CTP over MELD scores (AUROC 0.73 and 0.68, resp.; p = 0.091).ConclusionThe long term prediction of mortality or removal from waiting list in patients awaiting liver transplantation might be better assessed by the CTP score than the MELD score. This might have implications for the development of new improved scoring systems.

Is stenting necessary after balloon dilation of post-transplantation biliary strictures? Results of a prospective comparative study

BACKGROUND AND STUDY AIMS Biliary strictures are a major cause of morbidity following liver transplantation. In the present prospective comparative trial, we evaluated balloon dilation vs. balloon dilation plus stenting with regard to technical and clinical efficacy as well as complications. PATIENTS AND METHODS A total of 32 patients with symptomatic biliary strictures after liver transplantation were assigned to balloon dilation (n = 17) or balloon dilation plus plastic stent placement (n = 15). The main outcome parameter was sustained clinical success defined as an interval of at least 3 months without further endoscopic intervention. Additional outcome parameters were assisted clinical success and treatment failure, as well as procedure-related complications. RESULTS The initial technical success and primary clinical success rates in the dilation group were both 100%; in the stent group, the corresponding rates were 100% and 93% (n. s.). The sustained clinical success was 71% vs. 73%, respectively (n. s.). The time interval to reach sustained clinical success was 6.1 and 5.1 months, respectively (n. s.). No significant differences were found in assisted clinical success or in treatment failure. Complications were observed in 4.3% in the dilation group and 13.6% in the stent group (P < 0.05). Independent of the treatment group, a sustained clinical success in anastomotic strictures was achieved in 100%, whereas the success rate of strictures of the donor hepatic duct was 50% and of strictures involving the hilum, only 14% (P < 0.05). CONCLUSIONS In patients with biliary strictures after liver transplantation, endoscopic balloon dilation alone was as effective as dilation plus stent placement. Stent placement was associated with a significantly higher complication rate. Endoscopic treatment of strictures of the biliary anastomosis is highly effective, whereas attempts to treat more complex strictures are less promising.

Temporary placement of fully covered self-expandable metal stents in biliary complications after liver transplantation.

In the present study we prospectively evaluated the safety and efficacy of temporary fully covered, self-expandable metal stents (fcSEMS) to treat biliary strictures (n = 9), leaks (n = 9), and combined lesions (n = 1) occurring after liver transplantation, when standard endoscopic attempts had failed. Placement of fcSEMS and their removal in scheduled patients were successful and without complications. Resolution of the biliary lesion was confirmed in 15 of 19 patients (79 %). Treatment was not successful in two patients and not evaluable in 2 other patients. Complications occurred in 9 /19 patients (47 %): stent migration in 6, stent occlusion in 1, and de novo stricture after successful treatment of a biliary leak in 2. After a median follow-up of 12 months, one recurrent anastomotic stricture was noted. Temporary placement of fcSEMS in biliary strictures and leaks after liver transplantation provides satisfactory results even in patients who have undergone multiple previous conventional endoscopic attempts, and offers an alternative approach to surgical intervention.

FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS Allelic variants of fucosyltransferases 2 and 3 (FUT2/3) influence serum levels of CA19-9, a screening parameter commonly used for detection of biliary malignancy in PSC. We aimed at improving diagnostic accuracy of CA19-9 by determining the impact of FUT2/3 genotypes. METHODS CA19-9 levels were measured in 433 PSC patients, 41 of whom had biliary malignancy. Genotypes for FUT3 and FUT2 were used to assign patients to one of three groups: A, no FUT3 activity regardless of FUT2 activity; B, both FUT2 and FUT3 activity and C, no FUT2 activity without loss of FUT3 activity. Group-specific cut-off values were determined by Youdens index. RESULTS The median CA19-9 values of cancer-free patients were significantly different (p<0.001) in Groups A (2.0U/ml), B (17.0U/ml), and C (37.0U/ml). Biliary malignancy patients in Groups B and C had significantly higher CA19-9 values than cancer-free patients (p<0.001). The optimal cut-off, as determined by ROC analysis, for all patients was 88.5U/ml. Optimal cut-off values in Groups A, B, and C were 4.0U/ml, 74.5U/ml, and 106.8U/ml, respectively. Use of these values improved sensitivity of CA19-9 in Groups B and C. Further, use of group-dependent cut-off values with 90% sensitivity resulted in a 42.9% reduction of false positive results. CONCLUSIONS Use of FUT2/3 genotype-dependent cut-off values for CA19-9 improved sensitivity and reduced the number of false positive results.

Evolving Perspectives in Wilson Disease: Diagnosis, Treatment and Monitoring

Wilson disease (WD), the autosomal recessively inherited copper overload disorder, remains a diagnostic and therapeutic challenge. In the last decade, direct sequencing of the affected gene ATP7B became commercially available, but interpretation of the results still requires careful attention. Thus, a combination of tests reflecting the disturbed copper metabolism is needed to make the final diagnosis. Because of the low disease frequency, the existing treatment concepts are not based on controlled trails. Here, recent outcome reports of larger cohort studies challenge the recommended therapies and call for individualized treatment strategies. The notion, that certain medical regimens may either be insufficient to upkeep copper homeostasis or may lead to a clinically relevant overtreatment, demand a continuous monitoring of patients even after decades of therapy. In this article, we review current diagnostic and therapeutic approaches in WD.

Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease

BACKGROUND/AIMS A low serum ceruloplasmin concentration is considered diagnostic for Wilsons disease. We aimed to evaluate an enzymatic test for ceruloplasmin oxidase activity and to compare it with the routinely used immunological ceruloplasmin measurement. METHODS Serum ceruloplasmin was measured enzymatically with o-dianisidine dihydrochloride as substrate and immunologically. 110 Wilsons disease patients, 52 healthy controls, and 51 patients with impaired liver function not due to Wilsons disease were analyzed. Assay performance was tested by receiver operating characteristic curve analysis, McNemar test, and Spearmans rank correlation. RESULTS The greatest sum of sensitivity and specificity was seen for the enzymatic ceruloplasmin assay at a cut-off point of 55 U/L (93.6% and 100%, respectively) and for the immunologic assay at a cut-off point of 0.19 g/L (93.6% and 78.8%, respectively). For healthy controls, the differences in specificity between both assays were statistically significant (McNemar, p=0.02). When additionally including patients with impaired liver function into the control group the specificity declined to 84.5% for the enzymatic assay and to 68.9% for the immunologic assay. The correlation between the enzymatic and immunologic assay was high in healthy controls (r=0.94), but weaker in Wilsons disease patients (r=0.70) and patients with impaired liver function not due to Wilsons disease (r=0.65). CONCLUSIONS For the enzymatic assay the best cut-off point for predicting Wilsons disease was estimated to be 55 U/L. Our data suggest that the enzymatic ceruloplasmin assay is superior to the immunologic assay in diagnosing Wilsons disease and should become the preferred method.