Wilson disease

Wilson disease manifests with hepatic, neurologic, psychiatric, and ophthalmologic features. Age at onset ranges from early childhood to late adulthood, with most individuals presenting between 5 and 35 years. Children typically present with hepatic disease, ranging from asymptomatic elevations of liver enzymes to chronic hepatitis, cirrhosis, or acute liver failure. Adults commonly present with hepatic disease, with or without neurologic or psychiatric involvement. Neurologic features include tremor, dystonia, dysarthria, parkinsonism, and gait disturbance. Kayser–Fleischer rings, representing copper deposition at the corneal periphery, are present in most individuals with neurologic disease but may be absent in those with isolated hepatic involvement. Phenotypic expression varies widely, even within families.

The prevalence of Wilson disease is estimated to be approximately 1 in 30,000 individuals, although higher frequencies have been reported in certain populations.

Wilson disease is caused by biallelic germline pathogenic variants in ATP7B (13q14.3). ATP7B encodes copper-transporting ATPase 2, a transmembrane P-type ATPase that incorporates copper into ceruloplasmin and exports copper from hepatocytes into bile. Loss-of-function variants impair biliary copper excretion, leading to progressive copper accumulation predominantly in the liver, brain, cornea, and kidney.

Wilson disease is inherited in an autosomal recessive manner.

The diagnosis of Wilson disease is established using the . A clinical diagnosis is made when the score exceeds the defined threshold. Supportive findings include low serum ceruloplasmin (typically <0.1 g/L), increased 24-hour urinary copper excretion (>40 µg at baseline and >100 µg in symptomatic individuals), and elevated hepatic copper concentration (>250 µg/g dry weight) on liver biopsy, as well as Kayser–Fleischer rings on slit-lamp examination. In individuals with neurologic involvement, brain MRI may show characteristic signal abnormalities in the basal ganglia and brainstem.

Main differential diagnoses include:

• Chronic liver disease of other aetiologies: including viral, autoimmune, or metabolic liver diseases presenting with hepatic dysfunction without copper accumulation
• Autoimmune hepatitis: characterised by hepatic inflammation and autoantibodies, which may mimic hepatic presentations of Wilson disease.
• Menkes disease: X-linked copper deficiency in infancy with neurodegeneration and connective-tissue abnormalities; ATP7A
• type C: hepatosplenomegaly with vertical supranuclear gaze palsy and ataxia/dystonia, without copper overload; NPC1, NPC2
• Aceruloplasminemia: iron (not copper) accumulation in liver, pancreas, retina, and basal ganglia with low serum ceruloplasmin and copper; CP

• Establishing the diagnosis: identification of pathogenic variants in ATP7B supports diagnostic confirmation and clarifies the underlying genetic cause.
• Clinical management: genetic testing may assist in confirming the diagnosis, particularly in equivocal cases, support family screening strategies, and facilitate early diagnosis and timely initiation of copper-lowering therapy.
• Family member testing: identification of the familial pathogenic variant(s) enables targeted testing of at-risk relatives and supports genetic counselling.

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• Zimny S, Bourhis H, Weber S, Reiter FP, Hohenester S, Kraft E, et al. Medical care of patients with Wilson disease in Germany: a multidisciplinary survey among university centers. Orphanet J Rare Dis. 2023;18(1):122. doi:10.1186/s13023-023-02731-4. PMID: . PMCID: PMC10207775.
• Salman HM, Amin M, Syed J, Sarfraz Z, Sarfraz A, Sarfraz M, et al. Biochemical testing for the diagnosis of Wilson’s disease: a systematic review. J Clin Lab Anal. 2022;36(2):e24191. doi:10.1002/jcla.24191. PMID: . PMCID: PMC8842170.
• Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases. 2022;10(14):4334-4347. doi:10.12998/wjcc.v10.i14.4334. PMID: . PMCID: PMC9125272.