Wilson Disease

Key Points

Wilson disease (WD) is a rare, autosomal recessively inherited disorder of copper metabolism. Patients typically present with progressive neurological dysfunction in association with liver disease due to excess copper storage. Early diagnosis of the disease allows for treatment and prevention of permanent organ damage. Guidelines from two medical societies delineate diagnosis strategies.

  • Society Guidelines (AASLD, EASL)
     

    American Association for the Study of Liver Diseases

    (AASLD 2008)

    European Association for the Study of the Liver

    (EASL 2012)

    General Statements

     
    • No single test can usually diagnose WD
    • No single test can usually diagnose WD
    • Use of WD scoring system has good diagnostic accuracy
      • See tables below for scoring system and interpretation

    Laboratory Testing

    Ceruloplasmin*

    ARUP Test

    Ceruloplasmin 0050160

    False negatives – pregnancy, estrogens, inflammation, end-stage liver disease

    False positives – malabsorption, aceruloplasminemia, heterozygotes, Menkes disease

    • Initial recommended test
      • May be used in conjunction with serum free copper (copper tends to parallel ceruloplasmin changes)
    • Insufficient alone for diagnosing WD
      • Low-normal levels occur in patients with liver-predominant WD
    • <200 mg/L plus Kayser-Fleisher rings (KF) – diagnostic for WD
    • <50 mg/L – strong evidence of WD even in the absence of KF
    • Initial recommended test
      • May be used in conjunction with serum free copper (copper tends to parallel ceruloplasmin changes)
    • Insufficient alone for diagnosing WD
      • Low-normal levels occur in patients with liver-predominant WD
    • <100 mg/L plus KF – diagnostic for WD

    Serum copper*

    ARUP Test

    Copper, Serum 0020096

    False negatives – severe liver injury

    False positives – acute liver failure due to WD

    • Usually unnecessary
      • Decreased in proportion to decreased ceruloplasmin
    • Usually unnecessary
      • Decreased in proportion to decreased ceruloplasmin

    Serum free (calculated) copper

    False negatives – inaccurate serum copper or overestimation of holoceruloplasmin by serum ceruloplasmin measurement due to inadequate methodology of test

    False positives – acute liver failure of any etiology, chronic cholestasis, copper intoxication from ingestion or poisoning

    • Free (calculated) copper is typically >25 µg/dL in untreated patients
    • Free (calculated) copper measurements based on calculations may be inadequate for diagnostic purposes
    • See ARUP Alternative Testing section below regarding Serum Free (Direct) Copper assessment
    • Free (calculated) copper is typically >25 µg/dL in untreated patients
    • Free (calculated) copper measurements based on calculations may be inadequate for diagnostic purposes
    • See ARUP Alternative Testing section below regarding Serum Free (Direct) Copper assessment

    24 hour urinary copper excretion

    ARUP test: Copper, Urine 0020461

    False negatives – children with WD and no liver involvement, renal failure, incomplete collection

    False positives – hepatocellular necrosis, cholestasis, contamination

    • >100 µg (1.6 µmol)/24 h – diagnostic in symptomatic patients
    • >40 µg (0.6 µmol)/24 h – further evaluation recommended
    • <100 µg/24 h – in children, D-penicillamine challenge recommended
      • >1600 µg (25 µmol)/24 h – positive
      • Predictive value of test in adults – unknown
    • >100 µg (1.6 µmol)/24 h – diagnostic in symptomatic patients
    • >40 µg (0.64 µmol)/24 h – further evaluation recommended
    • <100 µg/24 h – in children, D-penicillamine challenge recommended
      • >1600 µg (25 µmol)/24 h – positive
      • D-penicillamine challenge only standardized in children
      • Recent studies suggest using threshold of >40 µg (0.64 µmol)/24 h to eliminate need for D-penicillamine challenge

    Hepatic copper concentration

    ARUP Test

    Copper, Liver 0020694

    False negatives –  sampling error

    False positives – cholestatic syndromes, active liver disease

    • Unnecessary if copper excretion and ceruloplasmin are in diagnostic range for WD
    • >250 µg/g dry weight – diagnostic for WD
    • <40-50 µg/g dry weight – excludes the diagnosis of WD
    • Hepatic parenchymal copper distribution may be uneven in cirrhotic liver
    • Unnecessary if copper excretion and ceruloplasmin are diagnostic range for WD
    • >4 µmol/g dry weight – diagnostic for WD

    Genetic testing for ATP7B

    • Proband
      • Mutation analysis by whole gene sequencing in the following situations
        • WD diagnosis is unequivocal
        • To identify gene for family screening
    • Family screening – first-degree relatives
      • Haplotype analysis or targeted gene screening based on known mutation
    • Proband
      • Mutation analysis by whole gene sequencing in the following situations
        • WD diagnosis is unequivocal
        • To identify gene for family screening
      • Problems with genetic testing
        • >500 mutations (most of which are rare)
        • Most patients are compound heterozygotes, making whole gene sequencing necessary, even though genetic testing is time-consuming and expensive
    • Family screening – first-degree relatives
      • Targeted gene screening based on known mutation is reasonable in children of proband
      • If mutation of index patient is not identified, then pedigree analysis using haplotypes based on polymorphisms is test of choice if genetic screening is considered

    *Wilson Disease Screening Panel, Serum 0020598 includes ceruloplasmin, serum copper, and free (direct) serum copper

    References: Diagnosis and treatment of Wilson disease: an update. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2003 June (Revised 2008 June). EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012; 56 (3) :671-685.

    Wilson disease scoring system (developed at the 8th International Meeting on Wilson disease, Leipzig 2001)

    Typical Clinical Symptoms and Signs

    Kayser-Fleisher (KF) rings

    Present

    2

    Absent

    0

    Neurologic symptoms* 

    Severe

    2

    Mild

    1

    Absent

    0

    Serum ceruloplasmin

    ARUP Test

    Ceruloplasmin 0050160

    Normal (>0.2 g/L)

    0

    0.1-0.2 g/L

    1

    <0.1 g/L

    2

    Coombs-negative hemolytic anemia

    ARUP Test

    Direct Coombs (Anti-Human Globulin) 0013008

    Present

    1

    Absent

    0

    Other Tests

    Liver copper (in the absence of cholestasis)

    ARUP Test

    Copper, Liver 0020694

    Normal (<0.8 µmol/g)

    -1

    >5x ULN (>4 µmol/g)

    2

    0.8-4 µmol/g

    1

    Rhodanine-positive granules**

    1

    Urinary copper (in the absence of acute hepatitis)

    ARUP Test

    Copper, Urine 0020461

    Normal

    0

    1-2x ULN

    1

    >2x ULN

    2

    Normal, but >5x ULN after D-penicillamine

    2

    Mutation analysis 

    On both chromosomes – detected

    4

    On 1 chromosome – detected

    1

    No mutations detected

    0

    Total Score and Evaluation

    ≥4 – diagnosis established

    3 – diagnosis possible; more tests needed

    ≤2 – diagnosis very unlikely

    *Or typical abnormalities at brain magnetic resonance imaging

    **If no quantitative liver copper available

    Diagnostic interpretation of WD scoring system

    Diagnostic Interpretation of WD Scoring System

    Typical clinical symptoms (extra pyramidal symptoms, Kayser-Fleisher rings, ceruloplasmin)

    Score 0-2

    • Initial test – urinary copper
      • 2x ULN (and original score 2) – score ≥4 (diagnosis established)
      • 1-2x ULN (and original score 2) – proceed with hepatic copper testing
    • Perform hepatic copper testing if urinary copper abnormal (>1.6 µmol/D*)
      • >4 µmol/g – score ≥4 (diagnosis established)
      • Normal or <4 µmol/g – score ≤3
        • Perform mutation analysis
          • 2 mutations – score ≥4 (diagnosis established)
          • 1 mutation – score ≥4 (diagnosis established)
            • If original score 0 – score ≤3
            • If original score 1 – score ≥4 (diagnosis established)
          • 0 mutations – score ≤3

    Score 3

    Urinary copper >1.6 µmol/D* – score ≥4 (diagnosis established)

    Score ≥4

    Diagnosis established

    *In children the cutoff can be lowered to 0.64 µmol/d

    Abbreviation: ULN = upper limit of normal

    Reference: EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012; 56 (3) :671-685.

    ARUP Alternative Testing

    Serum Free (Direct) Copper 0020596

    ARUP recommended alternative to free (calculated) serum copper

    • Free (direct) copper level testing likely more accurate assessment if serum copper testing is performed
    • Free (direct) copper is determined with serum ultrafiltrate

    >10 µg/dL may be indicative of Wilson disease or other conditions of copper overload.

Diagnosis

Indications for Testing

  • Unexplained liver disease in young patients (<40 years)
  • Unexplained neurologic disease, especially in concert with liver disease
  • Kayser-Fleischer rings visualized by ophthalmic exam
  • Family history of the disease in first-degree relative

Laboratory Testing

  • Refer to Key Points section

Histology

  • Refer to Key Points section

Imaging Studies

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

Differential Diagnosis

Screening

  • Refer to Key Points section

Monitoring

  • If Kayser-Fleischer rings are initially present, they should break up and disappear with therapy
  • Measuring serum free copper – useful in monitoring therapy effectiveness
    • Goal is to reduce copper to normal concentration

Clinical Background

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

Epidemiology

  • Incidence – 1/30,000-50,000
  • Age – onset of symptoms early childhood to late adulthood
  • 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 concentration of circulating free copper
  • Excess copper is deposited in the kidneys, liver (causes cirrhosis), eyes (manifests as Kayser-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 concentration

Clinical Presentation

  • Ophthalmic manifestations
    • Kayser-Fleischer rings (copper deposit on corneal Descemet membrane)
      • Occurs in 50-60% of patients
      • Not specific for Wilson disease –  also occurs in chronic cholestasis
      • Presence does not correlate with severity
  • Hepatic manifestations – hepatomegaly, fatty liver, hepatitis, cirrhosis, jaundice, end-stage liver disease
  • Neurologic manifestations – movement disorders
    • Typically develop in the 20s and affect 40-50% of patients
    • Dystonia, tremor, incoordination, rigidity, hypomimia
      • Difficulty with fine and gross motor tasks
    • Bulbar and pseudobulbar palsies with hypokinetic speech and dysphagia
  • Psychiatric manifestations
    • Mood disturbances (eg, depression, hallucinations, paranoia)
    • Frequently occur prior to hepatic and neurologic symptoms
    • Cognitive decline, memory problems
  • Complications

Treatment

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

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
Test Name and Number Recommended Use Limitations Follow Up
Wilson Disease Screening Panel, Serum 0020598
Method: Quantitative Immunoturbidimetry/Quantitative Inductively Coupled Plasma-Mass Spectrometry

Preferred panel to diagnose conditions of copper overload in symptomatic patients or individuals with a family history of Wilson disease (WD)

Panel includes serum ceruloplasmin, serum copper, and free (direct) serum copper

Positive test result may not necessarily indicate WD because decreased ceruloplasmin level may also be found in inflammatory conditions

Pregnancy and oral contraceptives increase ceruloplasmin level

Low ceruloplasmin level also found in malabsorption, aceruloplasminemia, heterozygotes, Menkes disease

Elevated level should be confirmed with a second specimen to exclude the possibility of external contamination

 
Copper, Urine 0020461
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Supportive test in diagnosis of WD

Preferred initial screening is panel with serum ceruloplasmin, serum copper, and free (direct) serum copper

False-positive test results from hepatocellular necrosis , cholestasis, contamination  
Copper, Liver 0020694
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Supportive test in diagnosis of WD

Unnecessary if copper excretion and ceruloplasmin are abnormal and in diagnostic range

False-positive test results from cholestatic syndromes, active liver disease  
Copper, Serum Free (Direct) 0020596
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Preferred initial screening for WD is panel that includes serum ceruloplasmin, serum copper, and free (direct) serum copper

Monitoring therapy in patient with WD

Performed with serum ultrafiltrates   

Elevated in patients with WD or other conditions of copper overload

Elevated level should be confirmed with a second specimen to exclude the possibility of external contamination

 
Wilson Disease (ATP7B) Sequencing 2010716
Method:

Confirm a diagnosis of WD

Carrier testing for individuals with a family history of WD or reproductive partners of WD carriers

Distinguish between affected and carrier status in individuals with equivocal biochemical findings

Clinical sensitivity – 98%

Analytical sensitivity/specificity – 99%

Diagnostic errors can occur due to rare sequence variations

Not detected:

  • Large deletions/duplications
  • Regulatory region and deep intronic mutations
  • Mutations in genes other than ATP7B
 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Ceruloplasmin 0050160
Method: Quantitative Immunoturbidimetry

Supportive test in diagnosis of WD

May be used as initial screening test; preferred initial testing is panel with serum ceruloplasmin, serum copper, and free (direct) serum copper

Positive test result may not necessarily indicate WD because decreased ceruloplasmin level may also be found in inflammatory conditions, malabsorption, aceruloplasminemia, heterozygotes, Menkes disease

Pregnancy and oral contraceptives increase ceruloplasmin level

Low ceruloplasmin level also found in malabsorption, aceruloplasminemia, heterozygotes, Menkes disease

Copper, Serum or Plasma 0020096
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Usually unnecessary in evaluation for WD

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Supportive test in diagnosis of hepatic dysfunction

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; bilirubin, total