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Cognitive impairment in stable Wilson disease across phenotype


In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients with neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes. In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by the PortoSystemic Encephalopathy (PSE) and the Continuous Reaction Time (CRT) tests. Half of the patients were female, and their median age was 35.5 years (IQR 24.5). Their phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 (14%). The duration of treatment was > 2 year in all patients, and their condition was stable as judged by urinary copper excretion, liver enzymes, and clinical assessment. The hepatic patients did not show signs of liver failure. In total, 16 (57%) patients performed worse than normal in the PSE and/or the CRT tests. The two tests were correlated (rho = 0.60, p = 0.0007), but neither correlated with phenotype, MELD-, Child–Pugh score, 24 h-U-Cu, or treatment type. Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.

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Fig. 1

Data availability

The datasets used in the current study are available from the corresponding author on reasonable request.



Wilson disease


Portosystemic Encephalopathy test


Continuous reaction time


Model for End-stage Liver Disease


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This study was supported with a grant from “The memorial foundation of manufacturer Vilhelm Pedersen and wife—and the Aarhus Wilson consortium”. Design of the study and collection, analysis and interpretation of data as well as writing of the manuscript was independently performed by the research group. Research grants were obtained and accounted for in the Competing interest’s section.

Author information




FK wrote the manuscript, analyzed the data and acquired parts of the data. DM, TL, MML, TS assisted in writing the manuscript. TL acquired data and assisted in data analysis. DM and TS also assisted in data analysis. HV, PO and HG helped form the project and gave inputs to the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Frederik Teicher Kirk.

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Ethics approval and consent to participate

The study was approved by The Central Denmark Region Committees on Health Research Ethics (50611) and approved by the Danish Data Protection Agency (1–16-02–614-15). The study was conducted in accordance with the Helsinki II declaration.

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Not applicable.

Competing interests

H.G.: research grants from Intercept, Abbvie, NOVO Nordisk Foundation, Arla, ADS AIPHIA Development Services AG, and “Savværksejer Jeppe Juhl og hustru Ovita Juhls mindelegat”. Advisory board at Ipsen. Speaker Norgine.

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Kirk, F.T., Munk, D.E., Laursen, T.L. et al. Cognitive impairment in stable Wilson disease across phenotype. Metab Brain Dis 36, 2173–2177 (2021).

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  • Wilson disease
  • Neurological phenotype
  • Hepatic phenotype
  • Portosystemic encephalopathy test
  • Continuous reaction test
  • Cognitive function