Diagnostic delay

Diagnosis of Wilson disease is often delayed or it is mistaken for other disorders, which can result in serious consequences for patients, including avoidable disease progression and death.2,3

A study of 163 patients with Wilson disease revealed:1

  • A mean delay of ~25 months from symptom onset to diagnosis
  • A roughly three-fold greater delay in patients with neurologic presentation versus hepatic presentation
    • Hepatic presentation: ~14-month delay
    • Neurologic presentation: ~44-month delay

If you see a patient presenting with liver abnormalities, unexplained neurologic movement disorders, or unexplained liver disease in combination with neurologic or neuropsychiatric disorders, a potential diagnosis of Wilson should be considered.2 Wilson disease should also be suspected in patients presenting with:3

  • Non-alcoholic fatty liver disease or pathologic findings of non-alcoholic steatohepatitis
  • Acute hepatic failure with Coombs-negative intravascular hemolysis
  • Elevations in serum aminotransferases
  • Low serum alkaline phosphate and ratio of alkaline phosphatase to bilirubin of <2

Wilson disease should be suspected in children older than 1 year presenting with liver disease, including symptoms ranging from increased liver enzymes to cirrhosis with hepatosplenomegaly and ascites or acute liver failure.4

Wilson disease can manifest at any age and diagnosis of Wilson disease should not be ruled out based on age alone.2



Wilson’s disease diagnosis
Wilson’s disease diagnosis
Urinary copper and serum ceruloplasmin laboratory testing to diagnose Wilson’s disease

Diagnosis of Wilson disease

Diagnostic recommendations and algorithms for Wilson disease are available from AASLD, EASL, and ESPGHAN, providing approaches to diagnosis for adult and pediatric patients presenting with a variety of symptoms.2-4 The key components of diagnosis are laboratory testing and a physical exam.

A single diagnostic test may not provide definitive confirmation so multiple laboratory tests may be required to confirm a diagnosis of Wilson disease, including:2-4,7-9

Serum ceruloplasmin2,3,8

Measures the concentration of the copper-bound ceruloplasmin protein in the blood and is usually decreased in patients with Wilson disease

24-hour urinary copper excretion2-4

Reflects the amount of non-ceruloplasmin-bound copper in circulation and is usually elevated in patients with Wilson disease

Serum non-ceruloplasmin-bound copper2,4

Calculated by subtracting ceruloplasmin-bound copper from total serum copper and is usually elevated in patients with Wilson disease

  • Measurement of non-ceruloplasmin-bound copper depends on the adequacy of measurements of both serum copper and ceruloplasmin, which may lead to inaccuracies; guidance documents do not recommend the use of this assay to diagnose Wilson diseasea,2,3

Hepatic copper2,3,9

Measured by analyzing ≥1 cm biopsy samples and is often elevated in patients with Wilson disease

Biochemical liver testing3

Serum aminotransferase activity is generally elevated in people with Wilson disease except at a very early age (infancy); the degree of elevation may be mild and not proportional to the severity of the liver disease

Neurologic findings and radiologic imaging of the brain2,3

Neurologic evaluation should be performed in individuals with Wilson disease, including pre-symptomatic and hepatic Wilson disease

Physical examination is an important aspect of diagnosis and it can detect a variety of manifestations, including hepatomegaly, portal hypertension (detected by the presence of hepatic encephalopathy, ascites, varices, and splenomegaly), and chronic liver disease, as well as altered sleep patterns and tremor.2,3,14

Ophthalmologic examination is another common tool used in the diagnosis of Wilson disease. Kayser–Fleischer rings result from copper deposition in the cornea and can be detected as a golden-brownish ring using slit-lamp eye examination; however Kayser–Fleischer rings are not present in all patients and their absence should not rule out a diagnosis of Wilson disease.3,5,15-17 A slit-lamp examination may sometimes be aided by gonioscopy by an experienced observer.3

Other, new technologies for imaging Kayser–Fleischer rings include:3,18,19

  • Anterior segment optical coherence tomography, which can be used for quantitative and qualitative assessment, determining the specific size and location of Kayser–Fleischer rings in the cornea3
  • Non-invasive Scheimpflug imaging to evaluate the anterior and posterior parts of the cornea and the anterior chamber angle3,18
  • Non-invasive in vivo confocal microscopy to evaluate changes at different regions of the cornea3,19

aMethods are being developed to directly measure non-ceruloplasmin-bound copper in order to improve accuracy in research.12,13

Images adapted from information and shown for illustrative purposes only.

In cases where a final diagnosis cannot be reached based on clinical signs and symptoms and non-invasive tests, or if additional liver pathologies are suspected, liver biopsy may be required to quantify hepatic copper concentration and assess liver histology.2-4 Liver histology alone is not sufficient for Wilson disease diagnosis as the main features are non-specific and can overlap with other disorders, resulting in misdiagnosis.4 Copper staining methods often used on liver biopsies, such as rhodanine, produce highly variable results and can fail to identify increased liver copper content.4,24 Copper is heterogeneously deposited in the liver in Wilson disease, varying between lobules and, in cases of cirrhosis, varying between nodules. This heterogenous deposition may lead to negative staining results, especially in small samples.3

Current diagnostic guidelines also recommend the use of brain imaging, including MRI, as over 90% of patients with Wilson disease with neurologic symptoms have brain pathologies detectable by MRI.2,3,25,26 A validated method for quantifying pathologies on brain MRI in Wilson disease was lacking until a novel, semi-quantitative, MRI visual rating scale was developed and validated for the assessment and classification of radiologic severity in Wilson disease.27 This semi-quantitative MRI rating scale may be useful for patient monitoring during therapy.27 However, repeated MRIs are not useful for determining prognosis or monitoring neurologic progression.3

Establishing a diagnosis of Wilson disease can require consideration of the results of multiple diagnostic investigations, and the Leipzig diagnostic scoring system (also known as the Ferenci scoring system) was developed to aid this process.2-4,6 This system uses the results of common diagnostic tests and symptoms to provide a score indicating the likelihood of a patient having Wilson disease and whether further tests are required to confirm the diagnosis.6

Between 18% and 23% of patients with Wilson disease remain pre-symptomatic with only mild elevations in liver tests.14 It is, therefore, important that a thorough examination of patients is carried out so that subtle or mild manifestations are detected at an early stage.2,3,14


aBased on a retrospective study of 163 patients with Wilson disease at a center in Germany between 2000 and 2005.1

bBased on a retrospective study of 229 patients diagnosed with Wilson disease in Austrian tertiary referral centers between 1961 and 2013.20

cBased on a multicenter observational cohort study of 715 patients with Wilson disease in China between 2004 and 2019.21

dBased on an Austrian registry study of 1357 patients from 1985 onwards, from different departments, including internal medicine, hepatology/gastroenterology, pediatrics, and neurology.22

eBased on a retrospective review of clinical and laboratory findings from 26 children diagnosed with Wilson disease in Spain from 1982 to 1996.16

fBased on a retrospective study of 57 children diagnosed with Wilson disease in Greece from 1983 to 2004. Kayser–Fleisher rings were present in 19/39 (48.7%) of patients who were symptomatic and had abnormal liver test results and/or hepatomegaly.23

Images adapted from information and shown for illustrative purposes only.

Think diagnosis


Practicalities of diagnosing a patient with Wilson disease and potential limitations of current diagnostic methods.

Assessment to establish a diagnosis of Wilson’s disease

Differential diagnosis

Wilson disease symptoms often mimic those of common hepatic disorders, leading to misdiagnosis and diagnostic delay.2,3 In a self-reported survey of 97 patients with Wilson disease:a,28

  • One-third reported receiving a misdiagnosis
  • Approximately one-third reported a delay of more than 1 year from symptom onset to diagnosis
  • 10% reported experiencing a delay of more than 5 years from symptom onset to diagnosis

aBased on a qualitative survey sent to 887 patients with Wilson disease in the Wilson Disease Association based in the USA in 2016. 97/887 responded to the self-reported survey; patients had an average age of 46 years (range 6–75) and 93% of patients were from the USA.28

Hepatic disorders resembling Wilson disease include those that mimic Wilson disease clinically and mechanistically.3 It is important to consider Wilson disease in patients appearing to present with other disorders; differential diagnoses commonly observed include:2,3,29-33


  • Acute hepatitis or autoimmune hepatitis in young patients2,3
  • Cirrhosis29
  • Fatty liver disease2,3
  • Congenital disorders of glycosylation in young patients3,31
  • Lysosomal acid lipase deficiency in young patients32


  • Parkinson’s disease33
  • Essential tremor33
  • Aceruloplasminemiaa,3


  • Psychosis29,30
  • Schizophrenia29,30
  • Depression3,29


aAceruloplasminemia may present with a range of neurologic disturbances, including movement disorders.3

Family screening

Family screening should be performed for all patients diagnosed with Wilson disease to enable early detection and prevent disease progression among family members.2,3 The likelihood of a sibling of a patient being homozygous and developing the disease is 25%34; for children of a patient, the likelihood is 0.5%.2,34

Assessment should include clinical (physical, neurologic, psychiatric, ophthalmologic) and biochemical assessment, as well as genetic testing:2,3,34

  • Brief history relating to jaundice, liver disease, and subtle features of neurologic or psychiatric involvement
  • Biochemical assessment, including serum copper, ceruloplasmin, biochemical liver tests, and basal 24-hour urinary copper excretion
  • Slit-lamp examination of the eyes for Kayser–Fleischer rings
  • Genetic testing for ATP7B mutations or haplotype, if available


  1. AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; ESPGHAN, European Society for Paediatric Gastroenterology, Hepatology and Nutrition; MRI, magnetic resonance imaging.


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