Wilson disease (WD) is a rare inherited genetic disorder caused by variants in the ATP7B gene that result in copper accumulation in the body, particularly in the liver, brain, and eyes. WD can present with hepatic, neurologic, or psychiatric disturbances, alone or in combination. Most commonly, patients present with progressive neurologic dysfunction and liver disease. Early diagnosis of WD allows for treatment and prevention of permanent organ damage. Clinical practice guidelines agree that no single laboratory test is sufficient for the accurate diagnosis of WD, but rather multiple testing methods should be used in conjunction. These include gene sequencing and tests for ceruloplasmin and urinary or serum free copper.
Quick Answers for Clinicians
Signs and symptoms of Wilson disease (WD) may occur in individuals ranging in age from 3-74 years. Children are often more difficult to diagnose because they are rarely symptomatic before 5 years of age, and they often have different biochemical presentations than adults. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recently published a guideline that contains specific recommendations for WD in children. For more information, refer to Wilson’s Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.
Kayser-Fleisher (KF) rings are caused by copper deposition in Descemet’s membrane of the cornea and are generally considered to be a key feature of Wilson disease (WD). KF rings are present in approximately 95% of patients with neurologic presentation of Wilson disease. They are less common in patients with hepatic disease and are usually completely absent in children. The presence of KF rings is highly suggestive of WD, but additional testing is required for definitive diagnosis.
The European Association for the Study of the Liver (EASL) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) both incorporate the Leipzig score into their diagnostic recommendations. The American Association for the Study of Liver Diseases (AASLD) does not recommend use of the Leipzig score for diagnosis, but rather opts for an algorithmic approach. The Leipzig score was established by an international consensus of experts and combines clinical symptoms, biochemical testing results, and mutational analysis. Some components of the Leipzig score include the presence or absence of Kayser-Fleischer (KF) rings, liver copper concentration, and presence or absence of deleterious ATP7B variants. The EASL Clinical Practice Guidelines provide more information on the interpretation of the Leipzig score for diagnosis.
Indications for Testing
- 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 the disease in a first-degree relative
There are two main clinical practice guidelines with 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. More recently, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) released a guideline specifically for WD diagnosis in children. The AASLD guideline adopts an algorithmic approach, whereas the EASL guideline is based on the Leipzig score (refer to Quick Answers for Clinicians for more information). Despite the differences in diagnostic strategy, these guidelines generally agree on laboratory testing methods.
The diagnosis of WD is based on a combination of biochemical and genetic findings. In addition to the laboratory tests detailed below, 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 diagnostic strategy.
Low serum ceruloplasmin levels are suggestive of WD in most patients, especially those with neurologic symptoms, but are less commonly observed in patients with hepatic symptoms. For children, age-specific reference ranges are required because of a natural variation in ceruloplasmin in children younger than 3 years.
The measurement of total copper excreted in urine over a 24-hour period reflects the amount of nonceruloplasmin-bound 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.
Serum Copper Concentration
Free serum copper (which does not include ceruloplasmin-bound copper) is generally elevated in patients with untreated WD and is considered to be a better indication of WD than total serum copper. Total serum copper values include both free and ceruloplasmin-bound copper and generally change proportionately with ceruloplasmin levels. However, in some cases, total serum copper may be normal or low, even in patients with WD. For example, in patients with severe liver injury or acute liver failure, total serum copper may be elevated independent of decreased serum ceruloplasmin levels.
Hepatic Parenchymal Copper
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 is particularly useful in patients in whom the diagnosis is not straightforward and in pediatric patients. In late-stage WD, 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.
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 variants in ATP7B. This testing may be performed as a single-gene test, as part of multigene panel testing, or as a component of more comprehensive genomic testing.
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.
ARUP Laboratory Tests
European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012; 56 (3): 671-85.
Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47 (6): 2089-111.
Weiss KH. Wilson disease. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Jul 2016; Accessed: Jun 2020]
Socha P, Janczyk W, Dhawan A, et al. Wilson's disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-344.