Wilson Disease

Indications for Testing

Testing for WD is appropriate in patients with:

• Unexplained liver disease, especially in young patients (<40 years)
• Unexplained neurologic disease, especially in concert with liver disease
• Kayser-Fleischer (KF) rings visualized by ophthalmic exam
• Family history of WD in a first-degree relative

Laboratory Testing

Two main clinical practice guidelines provide recommendations for the diagnosis of WD: the American Association for the Study of Liver Diseases (AASLD) guideline  and the European Association for the Study of the Liver (EASL) guideline.  In addition, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guideline specifically addresses WD diagnosis in children.  The AASLD guideline adopts an algorithmic approach, whereas the EASL guideline is based on the Leipzig score (refer to the Quick Answers for Clinicians for more information on the Leipzig score). Despite the differences in diagnostic strategy, these guidelines generally agree on laboratory testing methods.

Diagnosis

The diagnosis of WD is based on a combination of biochemical and genetic findings. Initial testing for suspected WD should include serum ceruloplasmin and a 24-hour urinary copper test. ^,  Genetic testing is used to confirm the diagnosis. ^,  In addition to the laboratory tests detailed in the following sections, a physical examination to determine the presence or absence of KF rings is important, given that KF rings are strongly suggestive of WD. The Wilson Disease Testing Algorithm provides more information on the WD diagnostic strategy.

Serum Ceruloplasmin

Low serum ceruloplasmin levels are suggestive of WD in most patients, but serum ceruloplasmin testing alone is insufficient to diagnose WD. A normal serum ceruloplasmin concentration does not exclude a diagnosis of WD, and other disorders with neurologic and hepatic symptoms are also associated with low serum ceruloplasmin concentrations.  Additional testing is required to confirm WD. ^,  For children, age-specific reference ranges are required because of a natural variation in ceruloplasmin in children younger than 3 years. 

Urinary Copper

The measurement of total copper excreted in urine over a 24-hour period reflects the amount of nonceruloplasmin-bound copper (also referred to as exchangeable or “free” copper) in circulation. The urine copper test can be a useful diagnostic test in many cases, although results are not applicable in the case of renal failure. Interpretation of 24-hour urinary copper excretion may be difficult due to the fact that abnormal findings are not specific for WD and may also be observed in other types of liver disease. ^,  In symptomatic pediatric patients, a 24-hour urinary copper excretion D-penicillamine challenge test can be used as an adjunctive test to differentiate between WD and other liver disorders. 

Serum Copper Concentration

Exchangeable serum copper (which does not include ceruloplasmin-bound copper) is generally elevated in patients with untreated WD and is considered by the EASL to be a better indicator of WD than total serum copper.  Total serum copper values include both exchangeable and ceruloplasmin-bound copper and are usually decreased in WD, proportionate with ceruloplasmin levels. ^,  In patients with WD and severe liver injury or acute liver failure, total serum copper may be normal or elevated independent of decreased serum ceruloplasmin levels. 

Hepatic Parenchymal Copper

A high hepatic parenchymal copper concentration is very suggestive of WD, although it may also be observed in other chronic liver disorders or cholestatic conditions. This testing, performed on biopsy tissue, is particularly useful for patients in whom the diagnosis is not straightforward and for pediatric patients. Liver copper distribution is often uneven, so hepatic parenchymal copper results will vary based on biopsy location. A normal copper concentration usually excludes a diagnosis of WD. ^, 

Genetic Testing

Generally, genetic testing is performed after biochemical testing to confirm a diagnosis of WD. However, nucleic acid-based testing is gaining popularity as a primary diagnostic tool as variants are identified and the technology advances. Diagnosis of WD relies on detection and identification of biallelic pathogenic (or likely pathogenic) variants in ATP7B. This testing may be performed as a single-gene test, a part of multigene panel testing, or a component of more comprehensive genomic testing. 

Screening

The AASLD and EASL recommend that all first-degree relatives of a patient with confirmed WD be screened for WD. The preferred screening method is mutational analysis, if available. Biochemical screening should include serum copper, ceruloplasmin, and basal 24-hour urinary copper testing; screening should also include a brief patient history for information related to liver disease and subtle features that would suggest neurologic involvement, along with physical examination for KF rings. ^,