Wilson Disease

Key Points

Wilson disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Patients typically present with progressive neurologic dysfunction in association with liver disease due to excess copper storage. Early diagnosis of the disease allows for treatment and prevention of permanent end organ damage. Two recent society guidelines are available that 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 to diagnose 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 to diagnose 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 not necessary
      • Decreased in proportion to the decreased ceruloplasmin
    • Usually not necessary
      • Decreased in proportion to the 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 measures 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 measures 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

    • Not necessary if copper excretion and ceruloplasmin are abnormal and in diagnostic range
    • >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
    • Not necessary if copper excretion and ceruloplasmin are abnormal and in diagnostic range
    • >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 testing is time intensive
    • 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 levels likely more accurate assessment if serum copper testing 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 patients <40 years
  • 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

  • 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, rings should break up and disappear with therapy
  • Measuring serum free copper – useful in monitoring therapy effectiveness
    • Aim is to reduce to normal concentrations

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 as 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, rigidity, hypomimia
    • 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

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

Diagnose conditions of copper overload in symptomatic patients or patients with a family history of Wilson disease

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

See individual component tests

Ceruloplasmin false positives may reflect malabsorption, aceruloplasminemia, Menkes disease

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

Supportive test in diagnosis of Wilson disease

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

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

Supportive test in diagnosis of Wilson disease

Not necessary if copper excretion and ceruloplasmin are abnormal and in diagnostic range

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

Supportive test in diagnosis of Wilson disease

Monitoring therapy in patient with Wilson disease

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

Performed with serum ultrafiltrates   

Elevated in Wilson disease or other conditions of copper overload

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

 
Ceruloplasmin 0050160
Method: Quantitative Immunoturbidimetry

Supportive test in diagnosis of Wilson disease

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

Positive result may not necessarily indicate Wilson disease because decreased ceruloplasmin levels may also be found in inflammatory conditions

Pregnancy and oral contraceptives increase ceruloplasmin levels

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

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Copper, Serum or Plasma 0020096
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Usually not necessary

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