Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Wilson disease is a genetic disease caused by a defective ATP7B gene, which results in impaired copper metabolism. It has a range of clinical effects, from asymptomatic states to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological symptoms, and psychiatric manifestations. It is required that first- and second-degree relatives of index cases are screened, and treatment must start as soon as a diagnosis is made.1 Early diagnosis is essential to prevent severe liver damage and permanent neurological dysfunction.2
Serum ceruloplasmin levels should be measured if there is a strong suspicion of Wilson disease. Values under 20 mg/dL (reference range, 20–40 mg/dL) are indicative of the disease. Urinary copper levels are increased in patients with Wilson disease, who exhibit values greater than 100 μg/dL. These findings, along with the ophthalmologic detection of Kayser-Fleischer rings, are typically sufficient for diagnosis. However, the most accurate test for Wilson disease is the measurement of hepatic copper levels, which is recommended if there is a chance of an alternative diagnosis. It should be noted that any protein deficiency disorder may result in low amounts of ceruloplasmin.3
Presently, diagnosis is based on laboratory and patient factors, but genetic testing is beginning to play a more significant part in patient and sibling diagnosis. Comprehensive molecular genetic tests use DNA from blood cells to determine whether a patient’s full sibling is a carrier of the Wilson disease genetic mutation.2
Serum Ceruloplasmin Level
Serum ceruloplasmin level is reduced by about 50% of the lower normal value in Wilson disease. However, the disease can also show an increase in this value and therefore can produce false negative results in inflammatory states, as ceruloplasmin is an acute phase reactant.1 When there is a suspicion of Wilson disease, the serum ceruloplasmin test is frequently ordered in addition to measuring copper levels in the urine. Ceruloplasmin levels in the urine and serum may be affected by several variables, such as diet, hormone levels, and other hereditary diseases.4
Urinary Copper Excretion
The diagnosis and management of Wilson disease may benefit from a 24-hour urinary copper excretion test. It depends on the volume of urine and the total amount of creatinine excreted in a 24-hour period to accurately determine the amount of free copper in the circulation in untreated cases.This test provides erroneous values in patients with renal failure, so it cannot be used in such cases. Symptomatic patients are diagnosed with Wilson disease if their 24-hour urinary copper excretion is greater than 100 μg/dL.5
Liver biopsy is only recommended in cases where clinical manifestations and noninvasive diagnostics do not establish a diagnosis of Wilson disease.2 Liver biopsy can be a helpful addition in the diagnosis of indeterminate cases and in disease staging for the presence and degree of fibrosis, as fibrosis is identified in 90% of asymptomatic cases. Early stages of the disease show histopathological findings in the liver such as mild steatosis, glycogenated hepatocyte nuclei, and focal hepatocellular necrosis; nevertheless, when parenchymal damage progresses, fibrosis develops and can then progress to cirrhosis.
Wilson disease is a good representation of acute-on-chronic liver failure because substantial hepatocellular degeneration due to apoptosis and parenchymal collapse are observed against a background of cirrhotic changes. Ultrastructural examination findings show defects in the mitochondria, including increased intracristal space and dilated cristae tips, leading to a cystic appearance, which is considered a characteristic feature of Wilson disease. These findings can show regression over time with prolonged therapy.5
Hepatic Copper Concentration
The diagnostic gold standard for Wilson disease is the determination of hepatic copper concentration on liver biopsy samples. Even in patients who are asymptomatic, a sufficient liver biopsy sample shows copper levels of more than 250 μg/g of dry weight. To help prevent contamination, there are special collection jars available. The diagnosis of untreated Wilson disease is ruled out by a normal hepatic copper concentration (reference range, 15–55 μg/g). Other chronic hepatic diseases may also have an increased hepatic copper concentration, especially cholestatic disease.6
Serum Free Copper Level
Serum free copper level is characteristically more than 200 μg/L (normal reference, <150 μg/L) in patients with Wilson disease.1 Despite the fact that Wilson disease causes copper overload, total serum copper levels are often decreased in proportion to the fall in serum ceruloplasmin levels. In acute liver failure, however, they could be increased due to the abrupt release of copper from damaged liver tissue. A higher concentration of copper that is not bound to ceruloplasmin (“free copper”) is indicated by elevated or normal serum copper levels despite a reduction in ceruloplasmin levels.5
All first-degree relatives must be assessed for Wilson disease using biochemical markers such as liver function tests, serum copper and ceruloplasmin concentrations, urinary copper tests, and slit-lamp examinations for Kayser-Fleischer ring detection. Siblings have a 25% chance of being a homozygote. Liver biopsy to measure hepatic copper concentration can be helpful in indeterminate cases. When mutations are present in the index patient in a family, molecular genetic analysis can be beneficial; however, in cases where mutations are not identified, haplotype analysis can be useful.5 Molecular genetic testing methods include single-gene testing, multigene panel use, and more comprehensive genomic tests.7
Computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, and nuclear medicine liver studies are not helpful in diagnosis as they do not yield any specific or sensitive findings of Wilson disease.6
Patients with neuropsychiatric signs should undergo a neurologic examination, and presymptomatic and hepatic Wilson disease patients may also benefit from one. When differentiating the causes of early-onset extrapyramidal disorders, it is especially helpful to perform CT or MRI of the brain to look for structural abnormalities, such as increased density on CT or hyperintensity on T2 MRI in the basal ganglia, tectal plate, and central pons. Few patients exhibit the face of the giant panda sign, a distinguishing feature of Wilson disease. Early disease findings of brain damage can be detected by other neuroimaging methods such as magnetic resonance spectroscopy, single-photon emission CT, transcranial brain parenchyma sonography, and auditory-evoked brainstem potentials.5
- Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: a review of what we have learned. World J Hepatol. 2015;7(29):2859-2870. doi:10.4254/wjh.v7.i29.2859
- Vadday K. Wilson’s disease: diagnosis and management. Pharm J. 2022;308:7961. doi:10.1211/PJ.2022.1.141683
- Chaudhry HS, Anilkumar AC. Wilson disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 8, 2022. Accessed September 6, 2022.
- Lopez MJ, Royer A, Shah NJ. Biochemistry, ceruloplasmin. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated December 13, 2021. Accessed September 6, 2022.
- Patil M, Sheth KA, Krishnamurthy AC, Devarbhavi H. A review and current perspective on Wilson disease. J Clin Exp Hepatol. 2013;3(4):321-336. doi:10.1016/j.jceh.2013.06.002
- Gilroy RK. Wilson disease workup. Medscape. Updated February 14, 2019. Accessed September 6, 2022.
- Weiss KH. Wilson disease. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2022. October 22, 1999. Updated July 29, 2016. Accessed September 6, 2022.
Reviewed by Hasan Avcu, MD, on 9/19/2022.