Wilson Disease

Primary Author: Strathmann, Frederick G., PhD, MS.

  • Key Points
  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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.

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 of brain is most useful – increased signal intensity in the basal ganglia on T2 weighted images

Differential Diagnosis

  • Refer to Key Points section
  • Measuring serum free copper – useful in monitoring therapy effectiveness
    • Goal is to reduce copper to normal concentration

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 (EASL, 2012)
  • 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 due to mutation in ATP7B gene
  • 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, eyes, and brain (basal ganglia)

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
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.

Wilson Disease (ATP7B) Sequencing 2010716
Method: Polymerase Chain Reaction/Sequencing

Limitations 

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

Copper, Serum Free (Direct) 0020596
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Limitations 

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

Copper, Liver 0020694
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Limitations 

False-positive test results from cholestatic syndromes, active liver disease 

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

Limitations 

False-positive test results from hepatocellular necrosis, cholestasis, contamination

Wilson Disease Screening Panel, Serum (Temporary Referral as of 08/16/16) 0020598
Method: Quantitative Immunoturbidimetry/Quantitative Inductively Coupled Plasma-Mass Spectrometry

Limitations 

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

Guidelines

European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012; 56(3): 671-85. PubMed

Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47(6): 2089-111. PubMed

General References

Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson's disease. Lancet. 2007; 369(9559): 397-408. PubMed

Bennett J, Hahn SH. Clinical molecular diagnosis of Wilson disease. Semin Liver Dis. 2011; 31(3): 233-8. PubMed

Gouider-Khouja N. Wilson's disease. Parkinsonism Relat Disord. 2009; 15 Suppl 3: S126-9. PubMed

Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010; 24(5): 531-9. PubMed

Kanwar P, Kowdley KV. Metal storage disorders: Wilson disease and hemochromatosis. Med Clin North Am. 2014; 98(1): 87-102. PubMed

Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci. 2010; 1184: 173-87. PubMed

Mak CM, Lam C. Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci. 2008; 45(3): 263-90. PubMed

McMillin GA, Travis JJ, Hunt JW. Direct measurement of free copper in serum or plasma ultrafiltrate. Am J Clin Pathol. 2009; 131(2): 160-5. PubMed

Walshe JM. Monitoring copper in Wilson's disease. Adv Clin Chem. 2010; 50: 151-63. PubMed

Zarrilli F, Elce A, Scorza M, Giordano S, Amato F, Castaldo G. An update on laboratory diagnosis of liver inherited diseases. Biomed Res Int. 2013; 2013: 697940. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

McMillin GA, Travis JJ, Hunt JW. Direct measurement of free copper in serum or plasma ultrafiltrate. Am J Clin Pathol. 2009; 131(2): 160-5. PubMed

Medical Reviewers

Last Update: August 2016