Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Wilson disease is a rare, autosomal recessive, inherited condition affecting copper metabolism that is characterized by the excessive accumulation of copper in the body’s tissues, especially the liver, brain, and eyes. Without treatment, this disorder can become fatal, necessitating early and accurate diagnosis for optimal patient outcomes.1
Diagnostic workup for Wilson disease consists of a thorough physical examination, patient and family histories, biochemical laboratory testing, molecular and genetic testing, imaging, and histopathological assessment.1
Biochemical laboratory assessments include serum ceruloplasmin levels, 24-hour urinary copper excretion, total serum copper (TSC) levels, blood liver tests, a test for Coombs-negative hemolytic anemia, and ATP7B protein quantification.1
Normal serum ceruloplasmin levels range from 0.2 to 0.5 g/L. Individuals with Wilson disease have low levels of ceruloplasmin in the blood, typically below 0.2 g/L. It is important to note that ceruloplasmin levels may rise to normal values during acute phases of concurrent inflammatory diseases, in pregnancy, or in women using estrogen replacement therapy. Low ceruloplasmin levels may also indicate other liver diseases as well as protein deficiencies caused by protein-losing enteropathy, malabsorption/malnutrition, and nephrotic syndrome, so they are not exclusive to diagnosing Wilson disease.1,2
24-Hour Urinary Copper Excretion
Normal 24-hour urinary copper excretion ranges from 0 to 50 µg/day. Elevated 24-hour urinary copper excretion levels exceeding 40 µg/day in children and 100 µg/day in adults confirm a diagnosis of Wilson disease. Patients with the neuropsychiatric form of Wilson disease often exceed a urinary copper excretion of 100 µg/day.1
Urinary copper excretion may also be elevated in other cholestatic liver diseases. While it is unreliable as a screening tool, this laboratory assessment may confirm the diagnosis of Wilson disease and measure patient response to treatment with chelating agents.3
Total Serum Copper
Total serum copper measures the amount of copper in the blood that is incorporated in ceruloplasmin (approximately 90%) as well as free copper that is not bound to ceruloplasmin. However, TSC levels do not measure the amount of copper within the tissues, making TSC an unreliable measurement for the diagnosis of Wilson disease. Newer measurements, including exchangeable copper fraction (CuEXC) and relative exchangeable copper (REC; REC=CuEXC/total % of copper), are more sensitive and specific biomarker tests to diagnose Wilson disease.1
Blood Liver Tests
In many patients, the initial manifestation of Wilson disease involves hepatic dysfunction. Elevated serum levels of the liver enzymes, alanine transaminase (ALT) and aspartate transaminase (AST), and increased bilirubin levels point toward early hepatocellular injury, while lower albumin levels and thrombocytopenia occur during end-stage liver disease.1
Increased AST:ALT ratio and decreased serum alkaline phosphatase (ALP) levels have been found to correlate with the fulminant form of Wilson disease.1 When combined, an AST:ALT ratio above 2.2 and an ALP to total bilirubin ratio below 4 diagnostically predict acute hepatic failure secondary to Wilson disease.1,4
Coombs-Negative Hemolytic Anemia
Up to 15% of patients with Wilson disease may also develop Coombs-negative hemolytic anemia. Copper accumulation within erythrocytes causes increased oxidative stress, leading to early hemolysis.1,5
ATP7B Protein Quantification
Adjunctive testing for Wilson disease may include the quantification of ATP7B protein taken from dried blood using immunoaffinity enrichment mass spectrometry.1
The diagnosis of Wilson disease using genetic and molecular testing is difficult because of the plethora of possible causative mutations in the ATP7B gene.1 It may be a more useful approach for diagnosis within specific, well-defined populations expressing a limited spectrum of ATP7B variants.6
Genetic testing may confirm a suspected diagnosis of Wilson disease, and it may be used to screen first- and second-degree relatives of a person already diagnosed with Wilson disease.1
Neuroimaging to rule out copper accumulation within the central nervous system is required for all patients with Wilson disease regardless of the presence of neurological symptoms.1
Magnetic Resonance Imaging vs Computed Tomography
Magnetic resonance imaging (MRI) of the brain demonstrates greater sensitivity for the early detection of brain lesions than cranial computed tomography scans. Brain MRIs can locate small focal lesions in the white matter, pons, and deep cerebellar nuclei as well as decreased signal intensity within the putamen and other regions within the basal ganglia.7
Positron Emission Tomography
Positron emission tomography (PET) scans detect a reduction in the rate of glucose consumption in the cerebellum, striatum, thalamus, and cortex. Repeat PET scans can detect improvements in these abnormalities, monitoring patient response to chelation therapy.8
Liver biopsy to measure hepatic copper concentrations remains the gold-standard test for the diagnosis of Wilson disease. Normal hepatic copper concentrations range from 15 to 55 μg/g of dry weight, while levels above 250 μg/g of dry weight indicate Wilson disease, even in patients without symptoms.3
Biopsy samples are stained either with rhodamine or orcein to reveal focal hepatic copper concentrations in lysosomes, which are detected using electron microscopy.1,9 Atomic absorption spectrophotometry is used to quantify the amount of hepatic copper.9
Leipzig Diagnostic Criteria
The Leipzig scoring system standardizes the diagnosis and management of Wilson disease.1 Nagral and colleagues published an updated, modified version of the Leipzig scoring system in 2019.10 Leipzig scores of 4 or higher confirm the diagnosis of Wilson disease.1,10
The Modified Leipzig Scoring System for the Diagnosis of Wilson Disease10
|Serum ceruloplasmin levels|
|Normal (>20 mg/dL)||0|
|24-hour urinary copper excretion (in the absence of acute hepatitis)|
|Coombs-negative hemolytic anemia with liver disease|
|Detected on both chromosomes||4|
|Detected on 1 chromosome||1|
|No mutation detected/test not performed||0|
|Typical features on brain magnetic resonance imaging|
|Liver biopsy for histology suggestive of Wilson disease|
|Orcein- or rhodamine-positive granules||1|
|Family history of Wilson disease|
|Sibling death from liver/neurological disease suggestive of Wilson disease||1|
|≥ 4||Wilson disease diagnosis confirmed|
|3||Wilson disease diagnosis possible; more tests needed|
|≤2||Wilson disease diagnosis very unlikely|
- Kasztelan-Szczerbinska B, Cichoz-Lach H. Wilson’s disease: an update on the diagnostic workup and management. J Clin Med. 2021;10(21):5097. doi:10.3390/jcm10215097
- Gilroy RK. Wilson disease workup: serum ceruloplasmin. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Gilroy RK. Wilson disease workup: urinary copper excretion and hepatic copper concentration. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Korman JD, Volenberg I, Balko J, et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174. doi:10.1002/hep.22446
- Grudeva-Popova JG, Spasova MI, Chepileva KG, Zaprianov ZH. Acute hemolytic anemia as an initial clinical manifestation of Wilson’s disease. Folia Med (Plovdiv). 2000;42(2):42-46.
- Gilroy RK. Wilson disease workup: genetic testing. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Gilroy RK. Wilson disease workup: brain MRI. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Gilroy RK. Wilson disease workup: PET scanning. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Gilroy RK. Wilson disease workup: electron microscopy. Medscape. Updated February 14, 2019. Accessed September 12, 2022.
- Nagral A, Sarma MS, Matthai J, et al. Wilson’s disease: clinical practice guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol. 2019;9(1):74-98. doi:10.1016/j.jceh.2018.08.009
Reviewed by Kyle Habet, MD, on 9/25/2022.