Wilson’s disease (WD) is a rare inherited disorder causing excessive copper accumulation, primarily in the liver and brain. This buildup results from a defect in the ATP7B gene, which normally helps the body excrete copper. Since its symptoms—including liver disease, tremors, and psychiatric issues—mimic many other conditions, diagnosing WD is challenging. Confirmation requires a combination of laboratory, clinical, and genetic tests, as no single test is sufficient. The diagnostic process moves from initial non-invasive screening to specialized organ assessments and definitive procedures like tissue analysis or genetic sequencing.
Initial Biochemical Indicators
The diagnostic process begins with blood and urine tests to measure copper levels and copper-managing proteins. The primary screening test measures serum ceruloplasmin concentration, the protein carrying most copper in the bloodstream. A low ceruloplasmin level (typically below 20 mg/dL) is a strong indicator, as the defective gene prevents copper incorporation into this carrier protein. However, this finding is not conclusive; levels can be low due to other conditions like severe liver failure, or confusingly normal in up to 36% of children with WD.
Total serum copper levels are also measured, but they can be misleading depending on the disease stage. A more reliable non-invasive test is the 24-hour urinary copper excretion, which measures the copper eliminated in the urine over a full day. In untreated WD patients, the excretion level is usually significantly elevated, often exceeding 100 µg per 24 hours in adults. Accurate collection instructions must be followed, as errors can compromise the result. These initial biochemical results establish suspicion before moving to specific clinical evaluations.
Specialized Organ Assessments
Beyond biochemical tests, specialized examinations of the eyes and a thorough neurological assessment look for physical signs of copper accumulation. An ophthalmologist performs a slit-lamp examination to check for Kayser-Fleischer (K-F) rings. These characteristic golden-brown deposits of copper appear in the cornea’s Descemet membrane. While K-F rings are a classic sign present in nearly all patients with neurological symptoms, they may be absent in up to 50% of those with only liver disease, meaning their absence does not exclude the diagnosis.
A neurologist or psychiatrist evaluates the patient for symptoms resulting from copper buildup in the brain. These symptoms include movement disorders like tremors, dystonia, or difficulty with speech (dysarthria). Psychiatric manifestations are also common, ranging from subtle personality changes to depression or psychosis. Imaging studies, specifically Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans, provide visual evidence of copper deposition. MRI typically reveals characteristic symmetrical bright spots in the basal ganglia, thalami, and brainstem, correlating with neurological symptoms.
Definitive Confirmation Procedures
When initial assessments are inconclusive, definitive procedures are required to confirm the diagnosis. The most established method, especially for cases presenting with only liver symptoms, is a liver biopsy to measure hepatic copper concentration. A small sample of liver tissue is analyzed; a concentration greater than 250 µg of copper per gram of dry tissue is highly diagnostic. This test directly measures the excess copper stored in the organ, providing the most direct evidence of the defect.
Genetic testing offers a highly specific alternative by sequencing the ATP7B gene. Identifying two disease-causing mutations confirms the diagnosis, regardless of other biochemical results. This method is particularly useful for screening asymptomatic siblings, as it avoids an invasive biopsy. Clinicians often integrate all findings using a validated diagnostic scoring system, such as the Leipzig score. A score of four or more points, derived from parameters like ceruloplasmin levels, K-F rings, and genetic results, definitively establishes the diagnosis.