Wilson disease (hepatolenticular degeneration) is an autosomal recessive defect of cellular copper export. Reduced biliary excretion leads to accumulation of copper, initially in the liver and then in other tissues, particularly the brain. Tissue copper deposition causes a multitude of signs and symptoms that reflect hepatic, neurologic, hematologic, and renal impairment. The incorporation of copper into ceruloplasmin is also impaired.
Patients most often present with liver disease (which can range from an asymptomatic elevations in the serum aminotransferase or bilirubin concentrations to fulminant hepatic failure to chronic hepatitis) or with neuropsychiatric disease.
AASLD Recommendations for Diagnosis & Screening for Wilson Disease (WD)
Clinical features:
- WD should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD.
- WD must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder.
- In a patient in whom WD is suspected, Kayser-Fleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of Kayser-Fleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurological disease.
Diagnostic testing:
- An extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of WD. Modestly subnormal levels suggest further evaluation is necessary. Serum ceruloplasmin within the normal range does not exclude the diagnosis. Basal 24-hour urinary excretion of copper should be obtained in all patients in whom the diagnosis of WD is being considered. The amount of copper excreted in the 24-hour period is typically >100 mcg (1.6 micromol) in symptomatic patients, but finding >40 mcg (>0.6 micromol or >600 nmol) may indicate WD and requires further investigation.
- Penicillamine challenge studies may be performed for the purpose of obtaining further evidence for the diagnosis of WD in symptomatic children if basal urinary copper excretion is <100 mcg/24 hours (1.6 micromol/24 hours). Values for the penicillamine challenge test of >1600 mcg copper/24 hours (>25 micromol/24 hours) following the administration of 500 mg of D-penicillamine at the beginning and again 12 hours later during the 24-hour urine collection are found in patients with Wilson disease. The predictive value of this test in adults is unknown.
- Hepatic parenchymal copper content >250 mcg/g dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients. In untreated patients, normal hepatic copper content (<40-50 mcg/g dry weight) almost always excludes a diagnosis of WD. Further diagnostic testing is indicated for patients with intermediate copper concentrations (70-250 mcg/g dry weight) especially if there is active liver disease or other symptoms of WD.
- Neurologic evaluation and radiologic imaging of the brain, preferably by MR imaging, should be considered prior to treatment in all patients with neurologic WD and should be part of the evaluation of any patient presenting with neurological symptoms consistent with WD.
- Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical and biochemical testing. Haplotype analysis or specific testing for known mutations can be used for family screening of first-degree relatives of patients with WD. A clinical geneticist may be required to interpret the results.
Diagnostic considerations in specific target populations:
- Patients in the pediatric age bracket who present a clinical picture of autoimmune hepatitis should be investigated for WD.
- Adult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapy should also be investigated for WD.
- WD should be considered in the differential diagnosis of patients presenting with nonalcoholic fatty liver disease or have pathologic findings of nonalcoholic steatohepatitis.
- WD should be suspected in any patient presenting with acute hepatic failure with Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, or low serum alkaline phosphatase and ratio of alkaline phosphatase to bilirubin of <2.
- First-degree relatives of any patient newly diagnosed with WD must be screened for WD.