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

• 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
  • Parkinsons disease
  • Transverse myelitis
  • Familial chorea
  • Early onset Huntington disease
• Psychiatric
  • Psychoses
  • Depression
  • Schizophrenia
  • Drug abuse

Screening

Monitoring

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
  • Hematologic – hemolytic anemia, thrombocytopenia
  • Musculoskeletal – arthritis, osteoporosis
  • Renal – nephrolithiasis, aminoaciduria, Fanconi syndrome
  • Cardiac – cardiomyopathy, arrhythmias
  • Endocrine – hypoparathyroidism, infertility
  • Other – gall stones, pancreatitis

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

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	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

Diagnostic Algorithm

  Wilson Disease Testing Algorithm