INTRODUCTION — Wilson disease (hepatolenticular degeneration) is an autosomal recessive defect in cellular copper transport. It is found worldwide, with a prevalence of approximately 1 case in 30,000 live births in most populations. Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic and fails. In addition, patients may develop neurologic complications, which can be severe and progressive, or psychiatric symptoms. Establishing a diagnosis of Wilson disease is crucial since early detection and treatment may prevent disease progression and even reverse damage in some patients.
Wilson disease should be considered in any patient with unexplained liver, neurologic, or psychiatric abnormalities. In addition, first-degree relatives of patients with Wilson disease should be screened for Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'When to consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Screening family members'.)
This topic will review the diagnostic tests used in the evaluation of patients with suspected Wilson disease and the scoring system developed to assist clinicians in diagnosing this disorder. The epidemiology, pathogenesis, clinical manifestations, approach to diagnosis, and treatment of Wilson disease are discussed separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Clinical manifestations, diagnosis, and natural history" and "Wilson disease: Treatment and prognosis".)
DIAGNOSTIC APPROACH — In patients with clinical features suggestive of Wilson disease (eg, abnormal liver tests combined with neurologic symptoms), we start by obtaining liver biochemical tests, a complete blood count, serum ceruloplasmin and copper levels, an ocular slit-lamp examination (or optical tomography), and a 24-hour urinary copper excretion. The results of these tests may be sufficient to make a diagnosis of Wilson disease (see scoring system below), but patients with indeterminate results will require additional testing, such as a liver biopsy with copper quantitation and histologic evaluation or molecular testing for ATP7B mutations.
The general approach to diagnosing Wilson disease, including when to obtain additional testing, is discussed separately. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis'.)
Scoring system — Diagnostic criteria to establish a diagnosis of Wilson disease were developed at an international meeting in Leipzig, Germany [1]. This scoring system gives weighted numeric values for specific tests described below (table 1). These include specific biochemical testing (ceruloplasmin, urine copper, and hepatic copper), clinical manifestations of Wilson disease (presence of Kayser-Fleischer rings and neurologic manifestations), and molecular testing for ATP7B mutations. A score of only 1 or 2 after all the testing is done excludes Wilson disease, while a score of 3 (prior to completing testing) suggests further evaluation is needed, and a score of 4 or more at any point in the evaluation is diagnostic for Wilson disease. This scoring system has been validated in adults and children and also has been incorporated into society guidelines for the diagnosis and treatment of Wilson disease (table 1) [2]. Some rare disorders may mimic Wilson disease, and in such disorders, there may be values for the Leipzig score that can reach 4 (eg, progressive familial intrahepatic cholestasis 3 [PFIC3] or glycosylation disorders). These alternative diagnoses require careful consideration and exclusion. In patients with rare disorders, testing usually reveals no disease specific mutations of ATP7B, and other features including the histologic and clinical findings often suggest an alternative diagnoses. (See "Causes of cholestasis in neonates and young infants".)
SERUM CERULOPLASMIN CONCENTRATION — Approximately 85 to 90 percent of patients with Wilson disease have low serum ceruloplasmin levels (<20 mg/dL or 200 mg/L). A serum ceruloplasmin concentration less than the laboratory lower limit for normal, most often near 20 mg/dL (200 mg/L), in a patient who also has Kayser-Fleischer rings is considered to be diagnostic of Wilson disease [3-5]. A very low serum ceruloplasmin concentration (<5 mg/dL or <50 mg/L) has a higher predictive value than levels near the lower limit of normal for the laboratory and provides strong evidence for the diagnosis of Wilson disease. However, low ceruloplasmin levels can be seen in patients without Wilson disease, and normal or elevated ceruloplasmin levels may be seen in patients with Wilson disease. (See 'Limitations of serum ceruloplasmin' below.)
Ceruloplasmin is a 132-kd protein synthesized by hepatocytes and secreted into the circulation. It is the major carrier of copper in the blood, with each molecule of ceruloplasmin carrying up to six copper atoms. Ceruloplasmin with bound copper is referred to as holoceruloplasmin (representing most of circulating ceruloplasmin), whereas ceruloplasmin that does not contain bound copper is referred to as apoceruloplasmin. The genetic mutations causing Wilson disease impair the hepatic incorporation of copper into apoceruloplasmin, leading to a reduction in the total serum ceruloplasmin concentration due to the instability of the apoceruloplasmin relative to the holoprotein with its full complement of copper in the circulation. (See "Wilson disease: Epidemiology and pathogenesis".)
Normal values for serum ceruloplasmin vary by age. They are very low during early infancy through approximately six months, then peak in early childhood (approximately 30 to 50 mg/dL or 300 to 500 mg/L), and then decline to the adult range (20 to 35 mg/dL or 200 to 350 mg/L). Ceruloplasmin is estrogen-sensitive, and levels are elevated in pregnancy and in patients on hormonal supplementation. It is also an acute phase reactant and may be increased above basal levels with inflammatory states.
Limitations of serum ceruloplasmin — Serum ceruloplasmin may be low in patients without Wilson disease and may be normal or elevated in patients with Wilson disease [6-11]. As a result, a low ceruloplasmin level is not sufficient to make a diagnosis of Wilson disease, and a normal level does not exclude a diagnosis of Wilson disease.
Serum ceruloplasmin alone has a low positive predictive value in patients undergoing evaluation for liver disease. One of the largest prospective studies to assess the value of serum ceruloplasmin in patients with liver disease focused on 2867 patients, of whom 17 had a low serum ceruloplasmin (<20 mg/dL or 200 mg/L). Only one of these patients was ultimately diagnosed with Wilson disease (positive predictive value of 6 percent) [8]. The other patients with low serum ceruloplasmin concentrations had a variety of conditions:
●Heterozygous carriers for Wilson disease (three patients)
●Acute viral hepatitis (three patients)
●Chronic hepatitis (two patients)
●Drug-induced liver disease (three patients)
●Alcohol-induced liver disease (two patients)
●Malabsorption (three patients)
Approximately 10 to 20 percent of asymptomatic heterozygous carriers have serum ceruloplasmin concentrations less than 20 mg/dL (200 mg/L), but values are typically above 10 mg/dL. Other causes of low serum ceruloplasmin concentrations include [2]:
●Disorders that cause marked renal or enteric protein loss, such as nephrotic syndrome or protein-losing gastroenteropathy.
●End-stage liver disease of any cause with associated poor synthetic function for production of all hepatic proteins.
●Rare diseases such as Menkes disease (an X-linked disorder of copper transport leading to decreased intestinal copper absorption) and aceruloplasminemia (a rare disorder leading to the absence of ceruloplasmin and problems in iron metabolism).
●Copper deficiency (eg, due to inadequate copper inclusion in parenteral nutrition [11-13], malabsorptive conditions (eg, following gastric bypass surgery [14,15]), excessive zinc administration [16], or idiopathic deficiency [17]).
On the other hand, serum ceruloplasmin concentrations may be normal or elevated in patients with Wilson disease. One cause of normal serum ceruloplasmin in patients with Wilson disease is the presence of acute hepatitis, which can increase serum ceruloplasmin values to the normal range. Other causes include pregnancy, estrogen supplementation, and use of oral contraceptives since the mRNA for ceruloplasmin has an estrogen responsive upstream region for its transcription [3]. In addition, ceruloplasmin is an acute phase reactant, so levels may be elevated in the setting of inflammation and tissue injury.
The method used for measuring ceruloplasmin may influence the results. Serum ceruloplasmin can be measured enzymatically, by antibody-dependent assays, by radial immunodiffusion, and by nephelometry. The results are generally similar, except for the antibody-dependent and the immunodiffusion assays, which may overestimate the ceruloplasmin levels. The overestimation may occur because the two testing methods do not discriminate between apoceruloplasmin and holoceruloplasmin [18]. Determination of ceruloplasmin activity using a method based on oxidation of 0-dianisidine dihydrochloride had sensitivity and specificity of 94 and 100 percent in one report, but more studies are needed [19]. Other methods of chromatographic isolation of ceruloplasmin and accurate determination of its copper content using inductively coupled plasma spectroscopy is advancing the accurate determination of ceruloplasmin concentration and its copper content [20]. This has direct implications for determining non-ceruloplasmin bound copper.
SERUM COPPER CONCENTRATION — In Wilson disease, the serum copper concentration is decreased in proportion to the reduction in serum ceruloplasmin, despite the presence of copper overload, and a low level of copper therefore indicates further evaluation for Wilson disease or alternative conditions is appropriate. One exception to this is the marked elevation of serum copper that occurs in the setting of acute liver failure due to Wilson disease where values may exceed 200 mcg/dL. Measurement of serum copper levels includes both ceruloplasmin-bound and nonceruloplasmin-bound copper. Determination of the serum nonceruloplasmin-bound copper concentration has been proposed as a diagnostic test for Wilson disease, but its utility is likely better for therapeutic monitoring of treatment [21].
Another method for determining nonceruloplasmin copper focuses on copper that can be "exchanged" or mobilized from proteins and peptides other than ceruloplasmin using the chelating agent ethylenediaminetetraacetic acid (EDTA, known as exchangeable copper) [22,23]. This exchangeable copper itself has low predictive value for disease diagnosis, but can be analyzed further and normalized by the total serum copper, giving rise to the term "relatively exchangeable copper" which may have some utility for disease diagnosis. This methodology still needs larger validation studies. This method is not yet available commercially, and data on its use outside of the laboratories where the methods were developed are not yet available.
OCULAR SLIT-LAMP EXAMINATION — Patients in whom Wilson disease is suspected should have a slit-lamp examination for detection of Kayser-Fleischer rings and other ocular manifestations related to Wilson disease. As an alternative to a slit lamp examination or complementary to its use is optical coherence tomography where the copper present in the cornea can be detected and the size of the ring quantified [24-26].
Kayser-Fleischer rings — Kayser-Fleischer rings are seen in 50 to 60 percent of patients with isolated hepatic Wilson disease and in over 90 percent of patients with clinical neurologic involvement [4,6,7,27-29]. Among patients presenting with acute liver failure, Kayser-Fleischer rings are present in approximately half. While highly suggestive of Wilson disease, Kayser-Fleischer rings are not specific for Wilson disease. They have rarely been reported in other chronic cholestatic diseases, such as primary biliary cholangitis, and in children with neonatal cholestasis [30].
Kayser-Fleischer rings are brownish or gray-green rings that result from fine pigmented granular deposits of copper in Descemet's membrane in the cornea close to the endothelial surface. Copper is primarily deposited in a granular complex with sulfur, which gives the ring its color. They are usually most pronounced at the inferior and superior poles of the cornea (picture 1). Some healthy patients have a dark ring that appears to be in the cornea when examined under moderate magnification in ambient light. However, such rings are not Kayser-Fleischer rings, which are best identified with a slit-lamp examination or by optical tomography.
Kayser-Fleischer rings gradually disappear with effective medical treatment for Wilson disease or following liver transplantation. Their reappearance suggests noncompliance with therapy.
Sunflower cataracts — Sunflower cataracts (which represent copper deposits in the lens) may also be seen by slit-lamp examination in patients with Wilson disease [31,32]. Their prevalence in Wilson disease is not well-established, and they do not appear to interfere with vision. Like Kayser-Fleischer rings, the cataracts gradually disappear with treatment.
URINARY COPPER EXCRETION — Urinary copper excretion is useful for the diagnosis of Wilson disease and for monitoring therapy. Wilson disease is typically associated with 24-hour urinary copper excretion of >100 mcg (>1.6 micromol), although lower values have been described in up to 25 percent of asymptomatic patients with confirmed disease [9,33]. Values >40 mcg/24-hours (0.64 micromol/24-hours) are suggestive of Wilson disease, and individuals with this finding should undergo further evaluation. Elevated urinary copper excretion may also be seen in patients with other forms of chronic active liver disease and in heterozygotes for Wilson disease, but most often levels are below 100 mcg per 24 hours [10,34].
The 24-hour collection is begun at the usual time the patient awakens. At that time, the first void is discarded and the exact time noted. Subsequently, all urine voids are collected, with the last void timed to finish the collection at exactly the same time the next morning. The time of the final urine specimen should vary by no more than 5 or 10 minutes from the time of starting the collection the previous morning. An inexpensive basin urinal that fits into the toilet bowl facilitates collection for children and for women.
In order to assess the completeness of the collection, the urinary creatinine excretion may be measured. The 24-hour urine creatinine excretion should be between 15 and 20 mg/kg body weight. Values substantially above or below this estimate suggest over- and under-collection, respectively, and should call into question the accuracy of the 24-hour urinary copper excretion result.
The test should not be used in patients with renal failure. In addition, spot urine collections are highly variable and are not reliable for making a diagnosis of Wilson disease. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
Normal values for urinary copper excretion vary among laboratories but are in the range of ≤30 to 40 mcg/day (0.48 to 0.64 micromol/day) [7]. A value >40 mcg/day (0.64 micromol/day) warrants further investigation [35]. Care should be taken to avoid copper contamination of the urine collection containers. The container should be rinsed with distilled (not tap) water, or a new, disposable container should be used. Prior to analysis, some laboratories add a small amount of hydrochloric acid (30 mL of 6N solution) to the urine to prevent precipitation of copper hydroxide, which occurs when the urine is alkaline and may result in falsely low urinary copper concentrations. In most patients with neutral pH or acidic urine, this is not necessary.
Penicillamine challenge — Because urinary copper excretion can be increased in a variety of liver diseases, penicillamine challenge (administration of d-penicillamine during the course of the 24-hour urine collection, see below) has been proposed as a means to increase sensitivity and specificity of the 24-hour urine study for diagnosing Wilson disease. Penicillamine greatly increases urinary copper excretion in patients with Wilson disease, and to a lesser extent, in patients with other forms of liver disease. The penicillamine challenge is rarely used because it is unreliable for excluding Wilson disease in asymptomatic siblings, has not been evaluated for differentiating heterozygous carriers from affected homozygotes, and has not been well-standardized in adults [6,34,36]. However, the penicillamine challenge has been standardized in children, where it has been proposed as an adjunctive test [2,11,37].
The penicillamine challenge is performed by giving a 500 mg dose of penicillamine (regardless of the patient's weight) at the beginning of the 24-hour urine collection and then again at 12 hours. Urinary copper excretion greater than 1600 mcg per 24 hours (>25 micromol) is much more likely in Wilson disease compared with other types of liver disease.
In the largest study, the penicillamine challenge was performed in 75 consecutive children with a variety of liver problems, of whom 17 were ultimately diagnosed with Wilson disease [11]. Urinary copper excretion greater than 1600 mcg per 24 hours (>25 micromol) was found in 15 of 17 patients with Wilson disease compared with only 1 of 58 with other disorders (sensitivity and specificity of 88 and 98 percent, respectively). However, when examined closely, the results for the penicillamine challenge added little when the threshold for normal urine copper excretion was lowered to 40 mcg (0.64 micromol/day) [38].
ADDITIONAL TESTING — While a diagnosis of Wilson disease is established in patients with low serum ceruloplasmin levels, Kayser-Fleischer rings, and elevated urinary copper excretion, additional testing is required in patients with indeterminate results (ie, a Leipzig score of three or less). (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Interpretation of test results'.)
Typically, the next step is a liver biopsy to determine the hepatic copper concentration and to look for histologic changes suggestive of Wilson disease, especially in patients with abnormal liver tests. Genetic testing is gaining an increasing role in the diagnosis of Wilson disease given its wider availability and our increasing knowledge of disease specific mutations. However, when availability of genetic testing is limited, it may be reserved for those in whom a diagnosis cannot be established in other ways, or to identify mutations within a given family to assist with screening asymptomatic family members. (See 'Genetic testing' below and "Wilson disease: Epidemiology and pathogenesis", section on 'Genetic defect in Wilson disease'.)
Liver biopsy — A liver biopsy permits the quantification of the hepatic copper concentration and the examination of liver histology, including staining for copper. Liver biopsies in patients suspected of having Wilson disease should include one biopsy specimen for histology and one for copper quantitation that is at least 1 cm in length. The specimen for copper quantitation should be placed in a dry, copper-free container [2]. Additional precautions for the specimen to be used for copper quantitation, such as freezing or vacuum drying the specimen, are required to prevent destruction of the tissue since an accurate weight determination is required for the quantitation. In addition, copper content can be determined from liver tissue extracted from paraffin-embedded specimens, which may be helpful when the diagnosis is considered retrospectively, provided enough material is available. (See "Approach to liver biopsy".)
Hepatic copper concentration — Quantitative hepatic copper determination in patients with Wilson disease usually reveals more than 250 mcg (4 micromol) of copper per gram of dry weight (normal <50 mcg [0.8 micromol] per gram of dry weight) [39-41]. This is generally considered to be the gold standard for diagnosis; however, a lower threshold for copper content increases sensitivity but reduces specificity.
One study that evaluated test characteristics of hepatic copper determination compared hepatic copper content from 114 liver biopsies from patients with Wilson disease with 219 patients with noncholestatic liver disease, and 26 patients without liver disease (a liver biopsy had been performed for various reasons, but no liver disease was found) [40]. The following observations were made:
●Liver copper content was >250 mcg/g dry weight in 95 patients with Wilson disease (sensitivity 83 percent), but was between 50 and 250 mcg/g in 15 patients, and below 50 mcg/g in 4 patients. Liver copper content did not correlate with age, the grade of fibrosis, or the presence of stainable copper.
●Among patients with noncholestatic liver disease, liver copper content was >250 mcg/g in 3 patients (1.4 percent) and between 50 and 250 mcg/g in 20 patients (9.1 percent).
●Among patients without liver disease, the average hepatic copper content was 35 mcg/g (0.6 micromol/g; 95% confidence interval [CI] 12.5-80.8 mcg/g [0.2-1.3 micromol/g]). Only two patients with Wilson disease fell within the 95% CI for hepatic copper content of the control subjects.
●Using a cutoff of 250 mcg/g, the sensitivity and specificity for diagnosis of Wilson disease were 83 percent (95% CI 75-90%) and 99 percent (95% CI 96-100%), respectively. Lowering the cutoff value to 75 mcg/g (1.2 micromol/g) increased sensitivity, with a small decline in specificity (97 and 95 percent, respectively).
However, as seen in these studies, normal hepatic copper concentrations have been described in rare patients with Wilson disease [6]. There are several possible explanations for this:
●Reports describing such patients may have been limited by use of older laboratory equipment and use of insufficiently sized specimens.
●There can be variability in copper distribution within the liver, contributing to sampling error (particularly among patients with cirrhosis) [42,43]. As an example, in a report of two patients with acute liver failure undergoing transplantation, the explanted livers showed up to a 630-fold variation in copper distribution in different areas of the liver that were biopsied [43].
●In patients with acute liver failure, massive release of copper from necrotic hepatocytes and parenchymal collapse can lead to normal tissue concentration in biopsy material. However, most patients with Wilson disease with acute liver failure have an elevated copper content (above 250 mcg/g dry weight liver) [44].
Because of potential errors in evaluation of hepatic copper concentration, the hepatic copper concentration should always be evaluated in the context of other diagnostic criteria. Wilson disease is not excluded based solely on a hepatic copper concentration less than 250 mcg/g (4 micromol/g) since approximately 15 percent of Wilson disease patients fall below this cutoff. On the other hand, a copper concentration greater than 250 mcg/g is virtually diagnostic unless the patient has chronic cholestatic liver disease, which is usually clinically distinct from Wilson disease. (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)
Liver histology — Histologic findings in patients with Wilson disease who are early in the course of their illness include fatty infiltration within hepatocytes, glycogen inclusions within nuclei, and portal fibrosis (picture 2). Findings on biopsy in this disorder may also be similar to those of autoimmune hepatitis and nonalcoholic steatohepatitis. At the time of diagnosis, cirrhosis is seen in 35 to 45 percent of patients. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Chronic hepatitis and cirrhosis' and "Wilson disease: Epidemiology and pathogenesis", section on 'Pathologic findings'.)
A histologic stain for copper deposition can be suggestive of Wilson disease. However, copper stains have limited sensitivity, and the absence of copper staining does not exclude the diagnosis.
Genetic testing — Genetic testing for Wilson disease is being used increasingly as a diagnostic test and is more widely available. It is particularly useful when the diagnosis remains unclear despite extensive testing, when liver biopsy is not possible, and for screening family members when the mutations in the proband are known. In addition, genetic testing is particularly useful as the initial test for screening siblings of patients with Wilson disease. Genetic testing is not used as first order testing for other extended family members. Patients considering genetic testing should discuss the testing with a genetic counselor or a clinician with expertise in Wilson disease. (See "Genetic testing" and "Wilson disease: Epidemiology and pathogenesis", section on 'Genetic defect in Wilson disease'.)
In populations with a higher frequency of a predominant mutation, diagnosis of Wilson disease using allele-specific probes for specific mutations in ATP7B may be an option. Since most patients are compound heterozygotes, the identification of one mutation supports the diagnosis, and the identification of two mutations confirms the diagnosis [45]. Predominant mutations have been described in several discrete geographic areas, such as Sardinia, Iceland, Korea, Japan, the Canary Islands, and in some Eastern European populations [36,46-50]. A database of mutations in ATP7B (the gene mutated in Wilson disease) is available online [51].
Haplotype analysis can be used to establish the diagnosis of Wilson disease in full siblings; however, similar to the use of allele specific probes, this testing is mostly supplanted by direct mutation analysis given advances in DNA sequencing. When haplotype analysis is performed, the pattern of genetic markers around ATP7B is determined for both copies of chromosome 13 in the affected proband. Siblings with two matches are affected, those with one are carriers, and those with none are homozygous normal. A positive linkage analysis predicts Wilson disease with 99 percent accuracy in the full sibling.
Mutation analysis by whole-gene sequencing is another option to identify mutations in ATP7B and is available commercially [52].
Brain imaging — Brain magnetic resonance imaging (MRI) often shows abnormalities in patients with neuropsychiatric involvement but may be normal when the presentation is solely with hepatic involvement. MRI findings for Wilson disease include abnormal T-2 signals in the basal ganglia, brainstem, and white matter.
Other tests — Measurement of ATP7B peptide concentration from blood spots has shown promise for identifying patients with Wilson disease [53,54]. In a study involving samples of blood spots from 216 patients with genetically or clinically confirmed Wilson disease, 48 carriers, and 150 healthy individuals, two surrogate peptides were measured by immunoaffinity enrichment mass spectrometry [53]. Among 216 patients with confirmed Wilson disease, 199 patients (92 percent) had at least one ATP7B peptide below the established minimum threshold. In this cohort, ATP7B analysis proved sensitive and specific for the diagnosis of Wilson disease. Quantifying ATP7B peptides in blood may be useful as a neonatal screening test for Wilson disease, and may be helpful for disease diagnosis in older patients. Further validation is needed to determine the role of peptide measurement in routine clinical practice.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited liver disease".)
SUMMARY AND RECOMMENDATIONS
●When to suspect Wilson disease – Wilson disease should be considered in any patient with unexplained liver, neurologic, or psychiatric abnormalities. First-degree relatives of patients with Wilson disease should be screened for Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'When to consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Screening family members'.)
●Diagnostic testing – In patients with clinical features suggestive of Wilson disease, we start by obtaining liver biochemical tests, a complete blood count, a serum ceruloplasmin level, a slit-lamp examination for Kayser-Fleischer rings, and a 24-hour urinary copper excretion. Results of these tests determine the need for additional testing. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis'.)
•Serum ceruloplasmin – Approximately 85 to 90 percent of patients with Wilson disease have serum ceruloplasmin concentrations below the laboratory limit for normal, typically 20 mg/dL (200 mg/L). Among patients with less specific clinical manifestations, a serum ceruloplasmin level below 5 mg/dL (50 mg/L) is highly suspicious for Wilson disease. However, low ceruloplasmin levels can be seen in patients without Wilson disease, and normal or elevated ceruloplasmin levels may be seen in patients with Wilson disease. (See 'Serum ceruloplasmin concentration' above.)
•Ocular slit-lamp examination – Corneal Kayser-Fleischer rings are seen in 50 to 60 percent of patients with isolated hepatic Wilson disease and in >90 percent of patients with neurologic involvement. (See 'Ocular slit-lamp examination' above.)
•Urinary copper excretion – Wilson disease is typically associated with 24-hour urinary copper excretion of >100 mcg (>1.6 micromol) in symptomatic patients, although lower values have been described in up to 25 percent of asymptomatic patients with confirmed disease. Values >40 mcg/24-hours (0.64 micromol/24-hours) are suggestive of Wilson disease. (See 'Urinary copper excretion' above.)
•Additional testing – While a diagnosis of Wilson disease is established in patients with low serum ceruloplasmin levels, Kayser-Fleischer rings, and elevated urinary copper excretion, additional testing is required in patients with indeterminate results. Typically, this involves a liver biopsy to determine the hepatic copper concentration and to look for histologic changes suggestive of Wilson disease. Results of these tests may be tabulated using a scoring system (table 1). (See 'Liver biopsy' above and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis'.)
Genetic testing also has a role in the diagnosis of Wilson disease. There are a large number of disease specific mutations seen in Wilson disease, and most patients have two different mutations (compound heterozygotes). Genetic testing is used to screen siblings of patients with Wilson disease when the mutation in ATP7B in the proband is known, and may help establish a diagnosis in indeterminate cases. (See 'Genetic testing' above and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Screening family members'.)
