Diagnosis and Management of Wilson Disease

Publication Date: September 23, 2022
Last Updated: January 31, 2023

Clinical Spectrum of Disease

  • WD should be considered in any individual 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 associated with neurological or psychiatric disorder. Assessment by a neurologist specializing in movement disorders may be advantageous. Psychiatric evaluation is essential for any patient with WD presenting with psychiatric or neuropsychiatric features of WD.
  • WD should be suspected in any patient presenting with ALF with nonimmune hemolytic anemia including acute intravascular hemolysis. These patients require urgent evaluation for liver transplantation.
  • Evaluation for WD is critical in patients exhibiting recurrent self-limited nonimmune hemolysis.
  • At clinical presentation, WD may involve organ systems besides the liver and nervous system (such as renal, musculoskeletal, cardiac, or endocrine).

Diagnosis and Screening

  • Once WD is considered, a detailed personal and family medical history should be conducted and a physical examination focused on evidence of liver, neurological, and psychiatric disease performed. Assessment should include the following:
    • liver biochemistries;
    • complete blood count and international normalized ratio (INR);
    • serum ceruloplasmin and, in some patients, serum copper;
    • basal 24-h urinary copper excretion;
    • slit-lamp or optical tomography examination for KF rings;
    • neurological evaluation; and
    • molecular genetic investigation of ATP7B (depending on logistics).
  • An extremely low serum ceruloplasmin level (<5 mg/dl) more strongly suggests a diagnosis of WD than modestly subnormal levels. Serum ceruloplasmin by itself is insufficient for making a diagnosis of WD. Serum ceruloplasmin within the normal range does not exclude the diagnosis of WD.
  • Basal 24-h urinary excretion of copper in WD is typically >100 μg/24 h (>1.6 μmol/24 h) in symptomatic patients, but a lower reference value of >40 μg/24 h (>0.6 μmol/24 h) may indicate WD in asymptomatic individuals or children and therefore requires clinical correlation and further investigation.
  • Liver biopsy for histology can aid in the diagnosis of WD by identifying findings consistent with WD and permitting disease staging/grading. It may also suggest an alternative or concurrent diagnosis of liver disease. It allows quantification of liver tissue copper. Hepatic parenchymal copper content more than >250 μg/g dry weight occurs in most patients; a lower content still above normal occurs less frequently but should prompt other confirmatory testing. In untreated patients, normal hepatic copper content (<50 μg/g dry weight) almost always excludes a diagnosis of WD. Electron microscopic evaluation of liver tissue may aid diagnosis of WD, notably in pediatric patients.
  • If neurological evaluation reveals abnormalities, radiologic imaging of the brain, preferably by MRI, should be considered to establish baseline status and exclude other potential causes.
  • Diagnostic scoring systems may aid clinicians in establishing or refuting a diagnosis of WD in patients not meeting classic descriptions of the disease and are also useful for purposes of research studies on WD.
  • Prognostic scoring systems may help in determining the potential for successful medical therapy for WD. Applying such a score serially over time may be critical to improve accuracy.
  • First-degree relatives of patients newly diagnosed with WD must be screened for WD. Within a pedigree where there is one or more individuals with WD, any person with signs or symptoms consistent with WD, irrespective of closeness of relationship, should be evaluated for WD. Available strategies are genotype assessment of ATP7B and comprehensive clinical evaluation (summarized in Figure 4).



Diagnosis and Management of Wilson Disease

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