Wilson Disease

Diagnostic Algorithm

  Wilson Disease Testing Algorithm

Clinical Background

Wilson disease (also called hepatolenticular degeneration, Westphal-Struempell disease, and Westphal pseudosclerosis) is an autosomal recessive inherited disorder of copper metabolism.

Epidemiology

• Incidence – 1/30,000
• Age – onset of symptoms <40 years
• Sex – M:F, equal

Inheritance

• Caused by mutation in the ATP7B gene (located on chromosome 13)
• Autosomal recessive transmission
  • ~1% of population are carriers

Pathophysiology

• Ceruloplasmin, a late acute phase reactant, is the principal copper-containing protein of plasma and is transported into the trans-Golgi network of all cells by copper-transporting ATPases
• Disease results from the absence or dysfunction of copper-transporting ATPases
• Variant P-type ATPase prevents incorporation of copper into ceruloplasmin resulting in elevated concentrations of circulating free copper
• Excess copper is deposited in the kidneys, liver (causes cirrhosis), eyes (manifests Kaiser-Fleischer rings) and brain (damages the basal ganglia)
• Other conditions that prevent the elimination of copper (eg, biliary obstruction) may also lead to elevated free copper concentrations

Clinical Presentation

• Ophthalmic manifestations
  • Kayser-Fleischer rings (copper deposit on corneal Descemet membrane)
    • Seen in 50-60% of patients
    • Not specific for Wilson disease – can also be seen in chronic cholestasis
    • Presence does not correlate with severity
• Hepatic manifestations – hepatomegaly, fatty liver, hepatitis, cirrhosis
• Neurologic manifestations – movement disorders
  • Typically develop in the 20s and affect 40-50% of patients
  • Dystonia, tremor, incoordination
  • Bulbar and pseudobulbar palsies with hypokinetic speech and dysphagia
• Psychiatric manifestations
  • Behavioral disturbances, depression, hallucinations, paranoia
  • Frequently occur prior to hepatic and neurologic symptoms
• Complications
  • Hematologic – hemolytic anemia
  • Musculoskeletal – arthritis, osteoporosis
  • Renal – nephrolithiasis, aminoaciduria
  • Cardiac – cardiomyopathy, arrhythmias
  • Endocrine – hypoparathyroidism, infertility

Treatment

• Goal of therapy is to reduce copper accumulation; prompt diagnosis is crucial as treatment requires 3-6 months for the desired effect
• Untreated Wilson disease can be fatal – result of fulminant liver failure and/or brain damage

Diagnosis

Indications for Testing

• Unexplained liver disease in patients <40 years of age
• Unexplained neurological disease, especially in concert with liver disease
• Kayser-Fleischer rings on ophthalmic exam
• Family history of the disease in first-degree relative

Laboratory Testing

• Pattern of results consistent with Wilson disease is most useful for diagnosis
  • Ceruloplasmin – decreased (<200 mg/L is highly suggestive of disease)
  • Serum free copper – increased (>10 μg/dL is suggestive)
  • Urine (24 hour) copper – increased (>100 μg/24-hours is considered diagnostic)
  • Hepatic function – transaminases may be elevated; however, not useful in diagnosis
  • Molecular testing – ATP7B mutation

Histology

• Liver biopsy – increased copper concentrations (>250mg/g dry weight is diagnostic)
  • Copper content may be less in cirrhotic liver because of uneven distribution of copper in parenchyma

Imaging Studies

• MRI is most useful – increased signal intensity in the basal ganglia on T2 weighted images

Differential Diagnosis

• Hepatic manifestations
  • Viral hepatitis – hepatitis A, B, C or D
  • Chronic hepatitis – hepatitis B or C, autoimmune hepatitis
  • Chronic cholestasis – primary sclerosing cholangitis, primary biliary cirrhosis
• Neurologic manifestations
  • Degenerative cerebellar or metabolic diseases
  • Demyelinating disease – amyotrophic lateral sclerosis (ALS)
  • Metabolic storage disease – Gaucher disease
  • Vasculitis – microscopic polyangiitis, Churg-Strauss syndrome, polyarteritis nodosa
  • Central nervous system infections – viral, bacterial, parasitic, fungal
  • Seizure disorder
  • Parkinson’s disease
  • Transverse myelitis
  • Familial chorea
  • Early onset Huntington disease
• Psychiatric
  • Psychoses
  • Depression
  • Schizophrenia
  • Drug abuse

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Copper, Serum 0020096 Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry	Test available alone or as part of Wilson disease serum screening panel that also includes serum ceruloplasmin and serum free copper False positives from infection, inflammation, stress, copper supplementation, oral contraceptives, pregnancy  Pregnancy – concentrations are 2-3 times normal in third trimester Copper may be lowered by corticosteroids, zinc, malnutrition, malabsorption