• Wilson’s disease (WD) is an autosomal recessive defect in cellular copper transport characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic, neurologic, and other systemic abnormalities.
• Also called: Copper storage disease, hepatolenticular degeneration
• Manifests as liver disease in children, peaking at ages 10–13 years
• Manifests as neuropsychiatric illness in young adults aged 19–20 years
• Males and females affected equally in all ethnic groups.
The gene frequency is 0.56% with a carrier frequency of 1 in 90 (see Genetics section).
Approximately 1 case in 30,000 in most populations
• Inherited as an autosomal recessive trait
• Genetic defect localized to chromosome 13, which codes for the ATP7B protein (1).
– Can be affected by mutations at many different sites
– Mediates copper transport by sequestering copper into vesicles, which undergo exocytosis across the plasma membrane.
• Normal variations in the PRNP gene modify the course of WD.
– PRNP gene codes for prion protein, which is involved in copper transport.
– Normal variation in the PRNP gene may delay the age of onset of WD or affect clinical manifestations.
• Impaired transport of copper from the liver into bile leads to excess copper accumulation in the liver.
• Excess copper may act as a prooxidant.
– Promotes free radical formation
– Progressive hepatic damage manifests as asymptomatic liver function test (LFT) abnormality, chronic hepatitis, portal hypertension, acute liver failure, and eventual cirrhosis.
• Once cirrhosis occurs, free copper leaks into the bloodstream.
– Accumulates in and damages other tissues
– Neuropsychiatric, hematologic, renal, and other organ system disease manifestations
• Incorporation of copper into apoceruloplasmin to form ceruloplasmin is also impaired, accounting for the decreased serum ceruloplasmin.
See Genetics section.
• Difficulty speaking
• Involuntary shaking
• Personality changes
• Easy bruising
• Joint pain
• Night blindness
• Family history of WD
• Signs of acute or chronic liver failure and portal hypertension
– Yellowing of the skin and eyes (jaundice)
– Swelling of arms and legs
• Neurologic symptoms
– Cerebellar and pyramidal signs
– Impairment of vertical eye movements, in particular vertical pursuits, more often than vertical optokinetic nystagmus and vertical saccades (2)
• Kayser–Fleischer ring
– Brownish or gray–green rings that represent fine pigmented granular deposits of copper in Descemet’s membrane in the cornea close to the limbus
– Formation begins first at superior pole, then the inferior pole, and ultimately circumferentially
• Renal dysfunction
– Kidney stones
– Fanconi syndrome (proximal tubular dysfunction) causes abnormal number of amino acids excreted in the urine (aminoaciduria).
DIAGNOSTIC TESTS & INTERPRETATION
• Liver enzymes: mildly to moderately elevated, often with aspartate aminotransferase (AST) > alanine aminotransferase (ALT)
• Blood ceruloplasmin
– An extremely low serum ceruloplasmin level (<5 mg/dL) is strong evidence for the diagnosis.
– A serum ceruloplasmin concentration<20 mg/dL in a patient who also has Kayser–Fleischer rings is diagnostic (1).
– Serum ceruloplasmin alone has a low positive predictive value, only 6% in one study (3)
– Low serum ceruloplasmin levels also found in asymptomatic WD heterozygotes, marked renal or enteric protein loss, end-stage liver disease of any cause, and other rare disease of copper deficiency
– Normal ceruloplasmin does not rule out WD
Can be elevated in the presence of acute liver inflammation, pregnancy, and estrogen supplementation
• Basal 24-h urinary excretion of copper
– 24-h urinary copper excretion of >100 μg is typical in symptomatic patients (normal <40 μg/day).
– Penicillamine challenge useful in symptomatic children if urinary copper excretion is <100 μg/24 h
– Values of >1,600 μg copper/24 h following the administration of 500 mg of d-penicillamine are found in WD (4).
• Serum copper concentration
– Nonceruloplasmin-bound copper levels are greater than 25 μg/dL in the majority of untreated patients with WD (normal<15 μg/dL).
– Values may be influenced by a variety of conditions; therefore, the sensitivity, specificity, and positive predictive value have not been well-established.
• Slit lamp exam
– Kayser–Fleischer rings, dependent upon type of presentation (1)
– Present in 50–60% of patients who present with isolated hepatic involvement
– Present in 98% of patients who present with neurologic involvement
– Absence of Kayser–Fleischer rings does not exclude the diagnosis.
– Not absolutely specific for WD; reported in other chronic cholestatic diseases.
– Sunflower cataracts, representing copper deposits in the lens
– Rarely, optic neuritis or pallor of the optic disc
• Brain CT
– Slit-like, low-attenuation foci involving the basal ganglia, particularly the putamen
– Larger regions of low attenuation in the basal ganglia, thalamus, or dentate nucleus
– Widening of the frontal horns of the lateral ventricles and diffuse cerebral and cerebellar atrophy
• Brain MRI
– More sensitive than CT in detecting early lesions
– Focal abnormalities in the white matter, pons, and deep cerebellar nuclei are typically bilateral with low signal intensity on T1-weighted images, representing cell loss and gliosis.
– Decreased signal intensity in the putamen and other parts of the basal ganglia may represent either copper or iron ferritin deposition.
• Liver biopsy
– Essential for diagnosis in absence of Kayser–Fleischer rings or neurologic abnormalities
– Quantitative copper determination (1)
Levels of more than 250 μg/g of dry weight found even in asymptomatic patients.
Normal hepatic copper concentration (15–55 μg/g) excludes the diagnosis.
• Genetic testing currently limited to screening of family members for an identified mutation detected in the index patient.
• Liver biopsy
– Ranges from fatty infiltration to cirrhosis
– May appear similar to chronic active hepatitis
– Histochemical staining of liver specimens for copper is of little diagnostic value.
– Acute or chronic hepatitis of any etiology, commonly mimicking autoimmune hepatitis
• Neuropsychiatric disorders
• Chelating agents: Remove excess copper from body.
– Penicillamine (Cuprimine, Depen) (5)
– Adult: Initial 1.5–2 g PO qday; Maintenance: 750 mg to 1 g/day PO q.i.d.
– Pediatric: 25 mg/kg PO qday
– Extensive side effects including skin problems, bone marrow suppression, worsening of neurological symptoms, and birth defects.
– Must be administered with pyridoxine 25 mg PO qday
– Trientine (Syprine) 250–500 mg PO t.i.d. (6)
If unable to tolerate penicillamine
Risk of bone marrow suppression and worsening neurologic symptoms
Should be administered with zinc
• Zinc acetate (150–300 mg PO qday) prevents your body from absorbing copper from the food.
– Approved for maintenance after initial chelation therapy
– Drug of choice in presymptomatic, pregnant, and pediatric populations
See Diet section
Issues for Referral
Consultation with a hepatologist recommended
• Liver transplantation
– Primarily reserved for treatment of patients with fulminant liver failure or end-stage liver cirrhosis despite chelation therapy
• Weekly for the first 4–6 weeks following initiation of chelation therapy
– Physical examination, 24-h urinary copper excretion assay, CBC, urinalysis, serum-free copper measurement, and renal and LFTs
• Bimonthly evaluations through the first year, followed by yearly examinations thereafter
• Yearly slit lamp examination to document fading of Kayser–Fleischer rings
• Limit dietary copper intake
– Avoid liver, shellfish (especially lobster), mushrooms, nuts, legumes, and chocolate
– Avoid copper pots, pans, or containers
– Replace well water with purified water if the copper content is greater than 0.2 ppm.
• Avoid alcohol and hepatotoxic drug therapy
• Wilson’s Disease Association
• Fatal if not treated in a timely manner
• If treated early, symptomatic recovery is often complete with a normal life expectancy.
• Residual dysarthria and mild dystonia are relatively common in neurological WD.
• Lifelong chelation therapy is necessary.
• Chronic liver failure and cirrhosis can lead to bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation abnormalities.
• Fulminant liver failure may occur, especially due to medication noncompliance.
1. El-Youssef M. Wilson disease. Mayo Clin Proc 2003;78(9):1126–1136.
2. Ingster-Moati I, Bui Quoc E, Pless M, et al. Ocular motility and Wilson’s disease: A study on 34 patients. J Neurol Neurosurg Psychiatry 2007;78:1199–1201.
3. Cauza E, Maier-Dobersberger T, Polii C, et al. Screening for Wilson’s disease in patients with liver diseases by serum ceruloplasmin. J Hepatol 1997;27:358.
4. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: An update. Hepatology 2008;47:2089.
5. Durand F, Bernuau J, Giostra E, et al. Wilson’s disease with severe hepatic insufficiency: Beneficial effects of early administration of D-penicillamine. Gut 2001;48:849–852.
6. Dahlman T, Hartvig P, Lofholm M, et al. Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). QJM 1995;88:609–616.