Long-term Outcomes of Patients With Wilson Disease in a Large Austrian Cohort

doi:10.1016/j.cgh.2013.09.025

Clinical Gastroenterology and Hepatology

Volume 12, Issue 4, April 2014, Pages 683-689

https://doi.org/10.1016/j.cgh.2013.09.025 Get rights and content

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.

Section snippets

Patients

This retrospective study included 229 Caucasian patients (male patients: 110 [48%]) diagnosed with WD in Austrian tertiary referral centers between 1961 and April 2013. The diagnosis of WD was established on typical symptoms and clinical, biochemical, histologic, and genetic findings; phenotypic diagnosis was based on the Leipzig score.¹⁰ In 165 (72%) patients, a liver biopsy was performed; genetic mutation analysis could be completed in 217 (95%) patients. One hundred seventy-six (77%)

Clinical Presentation of Wilson Disease

One hundred forty patients (61%; male 69, female 71) presented with predominantly hepatic symptoms, 61 patients (27%; male 31, female 30) showed neurologic presentation and 23 (10%; male 8, female 15) were diagnosed by family screening at a presymptomatic stage. In 5 (2%) patients, neither symptoms nor onset of symptoms could be determined with certainty. The mean age at onset of the first symptoms as well as at diagnosis was earlier in patients with a hepatic than with a neurologic

Discussion

The long-term outcome of this large cohort of Caucasian patients, representing almost all cases expected to occur in Austria (based on an incidence of 30 per million within in a country with about 8 million inhabitants), underscores the favorable long-term prognosis of WD. Nevertheless, even treated patients still have impaired survival compared with the general healthy Austrian population. To the best of our knowledge, this is the first study assessing the impact of orthotopic LTX on survival

Acknowledgements

First and foremost, the authors want to thank their patients as well as their patients' families participating in and, hence, enabling this study. The authors also thank Kerstin Zinober, Claudia Willheim, and Elisabeth Eder for sample collection and performing genetic determinations.

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Cited by (131)

Research progress in stem cell therapy for Wilson disease
2024, Regenerative Therapy
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder characterized by disorganized copper metabolism caused by mutations in the ATP7B gene. Currently, the main treatment options for WD involve medications such as d-penicillamine, trientine hydrochloride, zinc acetate, and liver transplantation. However, there are challenges that encompass issues of poor compliance, adverse effects, and limited availability of liver sources that persist. Stem cell therapy for WD is currently a promising area of research. Due to the advancement in stem cell directed differentiation technology in vitro and the availability of sufficient stem cell donors, it is expected to be a potential treatment option for the permanent correction of abnormal copper metabolism. This article discusses the research progress of stem cell therapy for WD from various sources, as well as the challenges and future prospects of the clinical application of stem cell therapy for WD.
Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients
2023, Molecular Genetics and Metabolism Reports
Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATP7B gene. WD is characterized by heterogeneous clinical presentations expressed by hepatic and neuropsychiatric phenotypes. The disease is difficult to diagnose, and misdiagnosed cases are commonly seen.
In this study, the presented symptoms of WD, the biochemical parameters as well as its natural history are described based on cases collected in Mohammed VI Hospital University of Marrakech (Morocco). We screened and sequenced 21 exons of ATP7B gene from 12 WD patients that confirmed through biochemical diagnosis.
Mutational assessment of the ATP7B gene showed six homozygous mutations in 12 individuals however, 2 patients had no evidence of any mutation in promoter and exonic regions. All mutations are pathogenic and most were missense mutations. c.2507G > A (p.G836E), c.3694A > C (p.T1232P) and c.3310 T > C (p.C1104R) that were identified in 4 patients. The other mutations were a non-sense mutation (c.865C > T (p.C1104R)) detected in 2 patients, a splice mutation (c.51 + 4A > T) detected in 2 patients and a frameshift mutation (c.1746 dup (p.E583Rfs*25) detected in 2 patients.
Our study is the first molecular analysis in Moroccan patients with Wilson's disease, the ATP7B mutational spectrum in the Moroccan population is diverse and still unexplored.
Clinical spectrum and genotype-phenotype associations in Finnish patients with Wilson's disease
2023, Journal of the Neurological Sciences
Genotype-phenotype correlation data covering all ages of Wilson's disease onset in Caucasian patients are limited. We therefore analyzed genotype-phenotype correlations in a retrospective cohort of Finnish patients. Six homozygous (HoZ) and 11 compound heterozygous (CoHZ) patients were included. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis (p > 0.30 for all) between HoZ and CoHZ patients, but HoZ patients had an earlier age of diagnosis (median 6.7 versus 34.5; p = 0.003). Severe liver affliction was almost exclusively associated with the p.H1069Q variant. Patients with p.H1069Q had a later mean age of diagnosis (30.2 ± 11.6 vs. 8.7 ± 4.9 years; p < 0.001) compared to those without. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis between p.H1069Q-positive and p.H1069Q-negative patients (p > 0.54 for all). These results suggest that population-specific factors may partly explain the high clinical variability of Wilson's disease.
ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants
2023, Clinical Gastroenterology and Hepatology
Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants.
This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators.
Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7–17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7–18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03).
Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.
A novel nomogram based on routine clinical indicators for screening for Wilson's disease
2023, Liver Research
There is currently no single model for predicting Wilson's disease (WD). We aimed to create a nomogram using daily clinical parameters to improve the accuracy of WD diagnosis in patients with abnormal liver function.
Between July 2016 and December 2020, we identified 90 WD patients with abnormal liver function who had homozygous or compound heterozygous mutations in the ATP7B gene. The control group included 128 patients with similar liver function but no WD during the same time period. To create a nomogram, we screened potential predictive variables using the least absolute shrinkage and selection operator model and multivariate logistic regression.
We developed a nomogram for screening for WD based on six predictive factors: serum copper, direct bilirubin, uric acid, cholinesterase, prealbumin, and reticulocyte percentage. In the training cohort, the area under curve (AUC) of the nomogram reached 0.967 (95% confidence interval (CI) 0.946–0.988), while the area under the precision-recall curve was 0.961. Based on the optimal cutpoint of 213.55, our nomogram performed well, with a sensitivity of 96% and a specificity of 87%. In the validation cohort, the AUC of the nomogram was as high as 0.991 (95% CI 0.970–1.000).
We developed a nomogram that can predict the risk of WD prior to the detection of serum ceruloplasmin or urinary copper, greatly increasing screening efficiency for patients with abnormal liver function.
Epidemiology, treatment and burden of Wilson disease in France: A 10-year analysis of the national health insurance database
2022, Clinics and Research in Hepatology and Gastroenterology
Wilson disease (WD) is a rare hereditary, debilitating disease that is fatal if untreated. Given its low prevalence, collecting longitudinal information on large cohorts of patients is challenging. Analysis of health insurance databases offers an approach to meet this challenge. The aim of this study was to evaluate longitudinal trends in the presentation and management of patients with WD identified in the French national health insurance database (SNDS).
This retrospective, longitudinal, observational study identified people with WD in the SNDS database through hospitalisation diagnosis codes and long-term illness status between 2009 and 2019 inclusive. For each patient, data were extracted on hospitalisations, liver transplantation, mortality, WD-specific treatments (d-penicillamine, trientine and zinc), disability status and sick leave.
1,928 patients with WD were identified, of whom 1,520 (78.8%) were analysed. Prevalence of WD in 2019 was estimated as 2.2 cases per 100,000. Of the 670 patients first documented between 2010 and 2019, 76.1% were hospitalised at least once for a mean duration of 4.63±10.6 days. 152 patients (10.0%) underwent liver transplantation and 205 died (13.5%). The mean age at death was 57.9 ± 23.1 years. 665 patients (43.8%) received a WD-specific treatment at least once. 167 patients (17.1%) received a government disability pension and 624 (41.1%) benefited from long-term illness status due to WD.
Unexpectedly, less than half of patients with WD received treatment recommended in practice guidelines, which may contribute to a high disease burden in terms of hospitalisations, disability and reduced life expectancy. Improving treatment rates, building patient awareness of long-term disease impact or developing a new paradigm of treatment could make a significant contribution to reducing the disease burden.

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: Conflict of interest The authors disclose no conflicts.

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Original articlePancreas, biliary tract, and liverLong-term Outcomes of Patients With Wilson Disease in a Large Austrian Cohort

Background & Aims

Methods

Results

Conclusion

Section snippets

Patients

Clinical Presentation of Wilson Disease

Discussion

Acknowledgements

Biochem Biophys Res Commun

Am J Hum Genet

Clin Gastroenterol Hepatol

J Neurol Sci

Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver

Brain

The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene

Nature Genet

The Wilson disease gene is a putative copper transporting P-type ATPase similar to Menkes gene

Nature Genet

The Wilson disease gene: spectrum of mutations and their consequences

Nature Genet

Identification of a novel Wilson disease gene mutation frequent in Upper-Austria: a genetic and clinical study

J Hum Genet

EASL clinical practice guidelines: Wilson's disease

J Hepatol

Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study

Gut

Original article
Pancreas, biliary tract, and liver
Long-term Outcomes of Patients With Wilson Disease in a Large Austrian Cohort