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Wilson Disease

Synonym: Hepatolenticular Degeneration
, MD
Wilson Disease Clinic
Internal Medicine IV
University of Heidelberg
Heidelberg, Germany

Initial Posting: ; Last Update: May 16, 2013.


Clinical characteristics.

Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to over 50 years; symptoms vary among and within families.

  • Liver disease includes recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease.
  • Neurologic presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement).
  • Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration.

Kayser-Fleischer rings, frequently present, result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body.


Wilson disease is suspected in individuals with low serum copper and ceruloplasmin concentrations, increased urinary copper excretion, Kayser-Fleisher rings in the cornea, and/or increased hepatic copper concentration. The diagnosis is confirmed by the detection of biallelic ATP7B mutations.


Treatment of manifestations: Treatment with copper chelating agents or zinc – initiated as soon as possible – can reduce hepatic, neurologic, and psychiatric findings in many symptomatic individuals. Treatment is life-long. Copper chelating agents (penicillamine or trientine) increase urinary excretion of copper. High-dose oral zinc interferes with absorption of copper from the gastrointestinal tract and is most effective after initial decoppering with a chelating agent. Antioxidants, such as vitamin E, may be used with a chelator or zinc to prevent tissue damage, particularly to the liver. Orthotopic liver transplantation is used for individuals who fail to respond to medical therapy or cannot tolerate it.

Prevention of primary manifestations: Treatment with copper chelating agents or zinc can prevent the development of hepatic, neurologic, and psychiatric findings in asymptomatic affected individuals.

Surveillance: At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio (INR), complete blood count (CBC), urinalysis, and physical examination. At least once annually: 24-hour urinary excretion of copper

Agents/circumstances to avoid: Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts), especially at the beginning of treatment

Evaluation of relatives at risk: If the disease-causing mutations in an affected family member are known, molecular genetic testing of sibs of a proband allows early diagnosis and initiation of therapy before symptoms occur. If the disease-causing mutations in an affected family member are not known, biochemical assessment of parameters of copper metabolism (serum copper, urinary copper, ceruloplasmin) and liver function tests as well as ultrasound imaging of the liver and slit lamp examination for the presence of Kayser-Fleischer rings can be conducted.

Pregnancy management: Treatment must be continued during pregnancy because of the risk of fulminant hepatic failure.

Genetic counseling.

Wilson disease is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in an affected family member.


Diagnosis of Wilson disease cannot be made by a single test alone and a combination of tests is always needed as outlined in detail in the AASLD guidelines [Roberts & Schilsky 2008].

The diagnostic algorithm of the more recent EASL Clinical Practice Guidelines [European Association for Study of Liver 2012] is based on a diagnostic index (“Leipzig” score) proposed by an expert panel [Ferenci et al 2003]. This score includes clinical, biochemical, and molecular features, but has not been validated in large patient series.

The diagnosis of Wilson disease is suspected in individuals from age three to 60 years (commonly 6-45 years) [Ferenci et al 2007], with varying combinations of hepatic, neurologic, and psychiatric disturbances.

The diagnosis of Wilson disease is established by the presence of typical biochemical findings in combination with Kayser-Fleisher rings in the cornea. These copper deposits in the periphery of the cornea are observed in approximately 50%-60% of individuals with liver disease and about 90% of individuals with either neurologic findings or psychiatric disturbance. They are observed most reliably by slit lamp examination.

The biochemical diagnosis of Wilson disease in a symptomatic individual relies on a combination of the following findings:

  • Low serum ceruloplasmin concentration
    • In children, interpretation of test results requires age correction or age-specific reference ranges.

      Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and by two to three years of age peak at a concentration that may exceed the healthy adult reference range.
    • In adults with Wilson disease, serum ceruloplasmin concentration is often below the normal range and typically very low.

      Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic symptoms and up to 40% of individuals with hepatic symptoms [Steindl et al 1997]. Serum ceruloplasmin concentration is, therefore, not a reliable screening test for Wilson disease.
  • Serum concentration of copper and of non-ceruloplasmin-bound copper

    Most individuals with Wilson disease have a subnormal serum copper concentration that is proportional to the serum ceruloplasmin concentration.

    NOTE: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and by age two to three years peak at a concentration that may exceed the healthy adult reference range.

    The combination of low ceruloplasmin serum concentration and a normal or high serum copper concentration may suggest excess non-ceruloplasmin-bound copper in the serum. Such high non-ceruloplasmin-bound serum copper concentrations often present as a result of copper overload; however, it is not reliable for diagnosis because of its high dependency on the accuracy of both the serum ceruloplasmin concentration and the serum copper concentration.

    The serum concentration of non-ceruloplasmin-bound copper (in µg/L) is most reliably estimated by subtracting the amount of copper associated with ceruloplasmin, determined by the enzymatic assay (ceruloplasmin in mg/L x 3.15) from the total serum copper concentration. Normal serum concentration of non-ceruloplasmin-bound copper is approximately 50-100 µ/L. In individuals with Wilson disease, the serum concentration of non-ceruloplasmin-bound copper is usually higher than 200 µ/L.

    Note: Enzymatic methods for quantification of ceruloplasmin measure holoceruloplasmin (i.e., with copper incorporated) and are therefore preferred, particularly for calculation of the free copper concentration [Walshe 2003a, Macintyre et al 2004].
  • High urinary copper. Measurement of copper in three 24-hour urine collections, free from contamination by external sources of copper, is advised. The testing laboratory should be consulted regarding its trace-element urine collection protocol prior to initiating urine specimen collection.
    • Basal urinary copper excretion (without the use of chelating agent) is almost invariably elevated above 0.6 µmol/24 hours in the symptomatic individual.
    • A provocative test of urinary copper excretion following oral administration of penicillamine has been validated only in pediatric cohorts, but has proven useful in many cases [Martins da Costa et al 1992], although levels in affected individuals can overlap with those of heterozygotes.
  • Increased hepatic copper concentration. Hepatic copper concentration in Wilson disease is usually greater than 250 µg/g dry weight (normal: <55 µg/g dry weight [Nuttall et al 2003]); however, such levels may be seen in other chronic liver disorders and in cholestatic conditions as well.

    Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration — 100 to 250 µg/g dry weight, which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease.

Molecular Genetic Testing

ATP7B, encoding a copper-transporting P-type ATPase, is the only gene in which mutations are known to cause Wilson disease (Table 1). Identification of two disease-causing mutations establishes the diagnosis of Wilson disease.

Table 1.

Summary of Molecular Genetic Testing Used in Wilson Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ATP7BTargeted mutation analysisVariable 4, 5100% for the targeted mutations
Sequence analysis of select exons 6, 7Sequence variantsSee footnote 8
Sequence analysisSequence variants98%
Deletion/duplication analysis 9Exonic or whole-gene deletionsRare 10

See Table A. Genes and Databases for chromosome locus and protein.


See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a mutation that is present in the indicated gene


Panels to detect a limited number of mutations appear to be feasible in selected populations, such as those in Sardinia [Lovicu et al 2003] and eastern Germany [Huster et al 2004]. Mutations vary by laboratory and ethnicity of population.


p.His1069Gln [Tanzi et al 1993] is the only mutation found relatively frequently in populations of European origin. It accounts for 35%-45% of Wilson disease alleles in a mixed European population and a greater percent in eastern Europe [Caca et al 2001]. The frequency of this mutation may be somewhat lower in probands with childhood onset and in probands presenting with liver disease. p.Arg778Leu [Thomas et al 1995] is the only relatively common mutation in Asian populations, accounting for approximately 57% of Wilson disease alleles in the Asian population younger than age 18 years. A single mutation, 15-bp deletion, has been identified in the 1-kb promoter, non-coding region and is common in Sardinia [Loudianos et al 1999]. Promoter mutations have not been described in other populations and are presumed to be rare [Cullen et al 2003].


Exons vary by laboratory.


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


The mutation detection rate varies depending on the regions analyzed and the ethnicity of the individual. Mutations in exons 8, 14, and 18 account for approximately 60% of alleles in the British population [Curtis et al 1999]. Mutations in exons 8 and 12 account for approximately 57% of alleles in the Chinese population [Wu et al 2001].


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Large deletions and duplications, encompassing one or more exons, are rare. Exonic and multi-exonic deletions have been reported [e.g., Moller et al 2005, Tatsumi et al 2011].

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight), which make these tests unreliable in clarifying carrier status.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family. As index patients may present with compound heterozygous ATP7B mutations the predictive testing is most reliable in sibs only.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Characteristics

Clinical Description

Wilson disease can manifest as hepatic, neurologic, hematologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 60 years. Phenotypic expression varies even within families. The phenotypic spectrum has further expanded through molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings [Dening & Berrios 1989, Walshe 1989, Steindl et al 1997, Cox & Roberts 2006, Ala et al 2007].

Table 2 outlines the typical clinical findings of Wilson disease. Of note, the "classic triad" of liver disease, movement disorder, and Kayser-Fleischer ring is uncommon.

Table 2.

Clinical Findings in Individuals with Wilson Disease by Presenting Finding

Presenting Finding % of IndividualsTypical Age of Presentation (Range) Liver DiseaseNeurologic DiseasePsychiatric DisturbanceKayser-Fleischer Rings
Liver disease~40% 6-45 (3-70) + +/– +/– ~50%
Neurologic disease ~40% Mid-teen - mid-adult (6-50) –/mild + +/–~90%
Psychiatric disturbance~20% Adolescent - young adult –/mild +/– + ~90%
Hemolitic anemiaFew %Adolescent - young adult+ +

Liver disease. Wilson disease manifests as liver disease more commonly in children and younger adults, typically between the ages of six and 45 years; however, severe liver disease can be the initial finding in preschool-aged children [Wilson et al 2000] and in older adults. The clinical manifestations vary and can include the following findings:

  • Recurrent jaundice, possibly caused by hemolysis
  • Simple, acute, self-limited hepatitis-like illness with fatigue, anorexia, abdominal pain
  • Autoimmune hepatitis, often manifest acutely with fatigue, malaise, arthropathy, and rashes. This form of liver disease responds well to chelation therapy even if cirrhosis is present (see Management).
  • Fulminant hepatic failure with severe coagulopathy, encephalopathy, acute Coombs-negative intravascular hemolysis, and often rapidly progressive renal failure. Serum activity of aminotransferases is only moderately increased, and serum concentration of alkaline phosphatase is normal or extremely low. These individuals do not respond to chelation treatment and require urgent liver transplantation (see Management).
  • Chronic liver disease with portal hypertension, hepatosplenomegaly, ascites, low serum albumin concentration, and coagulopathy
  • Fatty liver of mild to moderate degree with abnormal liver function
  • Hemolytic anemia, with either acute or chronic hemolysis, a reflection of a high serum concentration of non-ceruloplasmin-bound copper, which leads to destruction of erythrocytes. Liver disease is likely to be present in such individuals, as are Kayser-Fleischer rings. Recurrent hemolysis predisposes to cholelithiasis, even in children.

Neurologic disease. Neurologic involvement follows two general patterns: movement disorders or rigid dystonia.

  • Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine-motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis.
  • Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [Svetel et al 2001].

Pseudobulbar involvement such as dysarthria, drooling, and difficulty swallowing is more common in older individuals, but also occurs in children and adolescents.

In contrast to the neurologic findings in individuals with a frank neurologic presentation, the neurologic findings in individuals with a hepatic presentation may be subtle. Mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills (especially handwriting) or gross motor skills may be observed.

Psychiatric manifestations. The psychiatric manifestations are variable. Depression is common. Neurotic behavior includes phobias, compulsive behaviors, aggression, or antisocial behavior. Older individuals may have subtle psychopathology such as progressive disorganization of personality with anxiety and affective changes such as labile mood and disinhibition. Intellectual deterioration may also occur with poor memory, difficulty in abstract thinking, and shortened attention span. Pure psychotic disorders are uncommon.

Kayser-Fleischer rings. These result from copper deposition in Descemet's membrane of the cornea, and reflect a high degree of copper storage in the body. They are reduced or disappear with effective decoppering treatment.

Other findings

  • Renal involvement. Low-molecular weight proteinuria, microscopic hematuria, and Fanconi syndrome
  • Arthritis. Involvement of large joints from synovial copper accumulation
  • Reduced bone mineral density with a prevalence of osteoporosis in ~10% of affected individuals
  • Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders
  • Sunflower cataracts. Observed occasionally on slit lamp examination
  • Hepatocellular carcinoma rarely develops in Wilson disease: the estimated incidence is below 1% [Devarbhavi et al 2012]. However, abdominal malignancies have been reported in treated individuals [Walshe et al 2003].

Fertility and pregnancy. Most individuals with Wilson disease are fertile. Successful pregnancies of women with Wilson disease who received treatment have been reported [Brewer et al 2000, Tarnacka et al 2000, Furman et al 2001]. Prior to diagnosis and treatment, affected women may experience infertility or recurrent miscarriage.

Genotype-Phenotype Correlations

Mutations that completely prevent function of the gene may tend to produce a more severe phenotype than certain types of missense mutation [Cox 1996, Deguti et al 2004, Liu et al 2004, Panagiotakaki et al 2004].

Several studies have found a mean age of onset of 20 to 22 years in individuals homozygous for the common p.His1069Gln mutation [Stapelbroek et al 2004], although earlier onset also occurs.

However, disease severity and clinical features are also influenced by other modifying factors, as suggested by marked differences between sibs in some families. Thus, it has been proposed that the clinical phenotype of Wilson disease is modified by mutations in other genes including MTHFR (encoding methylenetrahydrofolate reductase) [Gromadzka et al 2011], COMMD1 [Weiss et al 2006], ATOX1 [Simon et al 2008], XIAP [Weiss et al 2010]. Although some minor associations have been reported, to date none of these genes is clinically relevant or has a significant diagnostic or predictive value.


The neurologic form of Wilson disease has also been known as Westphal-Strumpell pseudosclerosis.


The prevalence of Wilson disease is estimated at one in 30,000 in most populations, with a corresponding carrier frequency in the general population of one in 90 [Bachmann et al 1991, Reilly et al 1993, Olivarez et al 2001].

Recent studies suggest a prevalence as high as one in 10,000 [Coffey et al 2013], especially in isolated populations like Sardinia [Gialluisi et al 2013].

Differential Diagnosis

Other liver diseases presenting with abnormal liver biochemistries with or without hepatomegaly that need to be considered include the following:

*Note: Wilson disease must be specifically excluded in individuals thought to have NASH or the opportunity for life-saving treatment will be missed.

Other liver diseases presenting as fulminant hepatic failure that need to be considered are acute viral hepatitis of any etiology and severe drug toxicity.

Kayser-Fleischer rings are not specific for Wilson disease and may in extremely rare cases be seen in copper accumulation associated with cholestatic liver diseases or autoimmune hepatitis.

Subnormal serum concentration of ceruloplasmin is not per se specific for Wilson disease, as ceruloplasmin synthesis can be reduced with acute liver failure or decompensated cirrhosis of any etiology. Decreased serum concentrations of ceruloplasmin are observed in protein-losing enteropathy, nephrotic syndrome, and malnutrition, but also in some heterozygotes for Wilson disease.

Serum concentration of ceruloplasmin is physiologically low in neonates.

Almost complete absence of ceruloplasmin is found in hereditary aceruloplasminemia, which results in iron storage [Miyajima et al 1987, Yoshida et al 1995].

Elevated liver copper content greater than 250 µg/g dry weight may be seen in other chronic liver disorders as well. As copper is secreted exclusively via the bile, hepatic copper concentration is not reliable in conditions associated with chronic cholestasis or impaired biliary excretion.

Familial/environmental copper storage diseases not related to Wilson disease have been identified but are rare; the most common of these is Indian childhood cirrhosis.

Other neurologic disorders that need to be considered:


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Wilson disease, the following evaluations are recommended:

  • Evaluation of severity of the liver disease by biochemical testing and imaging of the liver
  • Upper GI endoscopy to exclude or confirm esophageal varices
  • Detailed clinical neurologic assessment. A validated neurologic rating scale is available [Czlonkowska et al 2007].
  • Brain MRI to assess for structural alteration
  • Assessment of kidney function
  • Medical genetics consultation

Treatment of Manifestations

The goal of therapy is to institute treatment with chelating agents as soon as possible in individuals with symptomatic Wilson disease. See extensive review by the American Association for the Study of Liver Diseases [Roberts & Schilsky 2008 (full text)] and EASL Clinical Practice Guidelines: Wilson's disease [European Association for Study of Liver 2012 (full text)].

  • Treatment is life-long, including during pregnancy.
  • If one treatment modality is discontinued, an alternative modality must be substituted.
  • Discontinuation of all treatment leads to hepatic and neurologic decompensation, which is usually refractory to further medical intervention.

Copper chelating agents that increase urinary excretion of copper are the first-line treatment for persons with symptomatic Wilson disease. Note: Routine institution of chelation therapy before age three years has not been adequately assessed and may have adverse effects on growth.

  • Penicillamine (chelator). Used since the 1950s as first-line therapy for Wilson disease [Durand et al 2001, Walshe 2003b], penicillamine is given as D-penicillamine tablets by mouth two or three times daily. Pyridoxine must be given along with penicillamine. Twenty-four-hour urine copper excretion is used to confirm chelation and increased excretion of copper. Urinary copper values should be five to ten times normal; if the values are lower, non-compliance may be an issue, or body copper stores may have been adequately depleted.
    • Complete blood count and urinalysis must be monitored regularly during penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include: severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D- penicillamine induced adverse events might be manageable by co-administration of steroids.
    • Penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and possibly other trace metals.
    • Penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy.
  • Trientine (chelator), also known as triethylene tetramine dihydrochloride (2,2,2-tetramine) or trien, is the usual second-line treatment for individuals who cannot tolerate penicillamine. It is gaining acceptance as a first-line drug because of good efficiency and better tolerance compared to D- penicillamine, however, it is still not generally available in all countries.
    • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine.
    • Rare side effects are gastritis with nausea and in cases of overtreatment iron deficiency anemia has been reported.
    • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered 5-6 hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [Santos Silva et al 1996, Askari et al 2003].

Zinc (metallothionein inducer). High-dose oral zinc interferes with absorption of copper from the gastrointestinal tract presumably by inducing enterocyte metallothionein, which preferentially binds copper from the intestinal contents and is lost in the feces as enterocytes are shed in normal turnover. Zinc therapy is most effective after initial decoppering with a chelating agent [Brewer 2001, Brewer et al 2001]. In selected cases, it can be used as an initial treatment [Milanino et al 1992, Linn et al 2009]. Zinc is taken as tablets by mouth at least twice (usually 3 times) daily, before meals. The dose is based on the elemental zinc in the tablet. Twenty-four-hour urine copper excretion is used to monitor total body copper stores, which should decrease. Increase of urinary copper excretion under zinc therapy might indicate insufficient treatment efficacy [Weiss et al 2011]. The computed estimate of non-ceruloplasmin-bound copper may be used to titrate the zinc dose. Serum or urinary zinc concentration can be measured to monitor compliance in individuals taking zinc.

Note: (1) Gastritis, a common side effect, can be reduced with the use of zinc acetate or zinc gluconate; (2) zinc should NOT be used simultaneously with any chelator, pending further clinical investigation.

Antioxidants. Serum and hepatic vitamin E concentrations are reported to be low in individuals with Wilson disease [Sokol et al 1994, Ogihara et al 1995], likely because of excessive consumption to counteract free radicals produced by excess copper. Antioxidants, such as vitamin E, may be used along with a chelator or zinc in protecting tissues from damage.

Restriction of foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) seems prudent, especially at the beginning of treatment. It is recommended that individuals with special dietary needs (e.g., vegetarians) consult with a trained dietitian.

Orthotopic liver transplantation (OLT) is reserved for individuals who fail to respond to medical therapy or cannot tolerate it because of serious adverse side effects [Schilsky et al 1994, Emre et al 2001, Sutcliffe et al 2003]. It remains controversial whether orthotopic liver transplantation should be a primary treatment for individuals with Wilson disease who have severe neurologic disease [Medici et al 2005].

Prevention of Primary Manifestations

Medical therapy is recommended for asymptomatic patients to prevent development of symptoms (see Treatment of Manifestations).

Prevention of Secondary Complications

Monitoring of patients under therapy should include routine assessments of treatment efficacy by biochemical testing and clinical evaluation:

  • Insufficient therapy, underdosage or malcompliance could lead to reaccumulation of copper and development of new symptoms
  • Adverse events related to medical treatment (especially under D- penicillamine treatment) should be evaluated.
  • Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron, as observed in aceruloplasminemia, and to neurologic symptoms of copper deficiency [Horvath et al 2010, da Silva-Júnior et al 2011].


According to current guidelines (AASLD [Roberts & Schilsky 2008] and EASL Clinical Practice Guidelines [European Association for Study of Liver 2012]), routine monitoring should include the following examinations

  • At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio (INR), complete blood count (CBC), urinalysis, and physical examination

    Note: Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment
  • At least once annually: 24-hour urinary excretion of copper

    Note: Measurements are recommended more frequently if there are questions on compliance or if dosage of medications is adjusted.

Agents/Circumstances to Avoid

Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) should be avoided, especially at the beginning of treatment.

Evaluation of Relatives at Risk

The goal is to identify those sibs of a proband who have Wilson disease preferably before symptoms occur so that the therapies described under Treatment of Manifestations can be initiated as soon as possible. Affected sibs can be by molecular genetic testing if both disease-causing mutations in the proband are known). If the disease-causing mutations in an affected family member are not known, biochemical assessment of parameters of copper metabolism (serum copper, urinary copper, ceruloplasmin) and liver function tests as well as ultrasound imaging of the liver and slit lamp examination for the presence of Kayser-Fleischer rings can be conducted.

Note: Because presymptomatic individuals generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion, biochemical testing can be used; however, sometimes asymptomatic affected individuals cannot be distinguished from heterozygotes.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Treatment must be continued during pregnancy because of the risk of fulminant hepatic failure.

  • Penicillamine has been used in many pregnancies with no adverse outcomes, but embryopathy may occur, possibly in about 5% of births. Such adverse outcomes may depend on dose, which should be kept as low as possible. The dose of penicillamine should be maintained at the lowest effective dose with the plan to reduce by approximately 30% in the third trimester if the mother has been well chelated prior to pregnancy. A possible over-chelated (copper deficiency) status prior to pregnancy or genetic characteristics of the mother can contribute to fetal abnormalities [Pinter et al 2004].
  • Trientine has been used successfully during pregnancy, but the total number of reported cases is small.
  • Zinc has been used effectively during pregnancy.

Therapies Under Investigation

Ammonium tetrathiomolybdate (chelator) interferes with copper absorption from the intestine and binds plasma copper with high affinity. It may be useful for treatment of severe neurologic Wilson disease because, unlike penicillamine, it appears not to be associated with early neurologic deterioration [Brewer et al 2003]. The safety and efficacy of this drug for treatment of Wilson disease are not established; serious side effects such as bone marrow depression (leukopenia) and hepatitis are problematic. Treatment duration with ammonium tetrathiomolybdate should be limited to only a few months, as copper depletion can occur.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Curcumin. Experimental in vitro studies suggest partially restored protein expression of some ATP7B mutants by curcumin [van den Berghe et al 2009]. This could enable novel treatment strategies in Wilson disease by directly enhancing the protein expression of mutant ATP7B with residual copper export activity. Furthermore, curcumin is an ideal antioxidant and an effective scavenger of reactive oxygen species and can act as a copper-chelating agent. However, clinical data in patients with Wilson disease are not yet available.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Wilson disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an individual with Wilson disease are obligate heterozygotes as they carry one mutant allele.
  • Clinical disease is not known to occur in carriers although the possibility has not been adequately excluded at older ages.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) with clinical symptoms have not been reported.

Offspring of a proband

  • Offspring of an affected individual are obligate carriers.
  • Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual would have an affected child is one in 180.
  • Because the risk for an affected individual of having an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in young children with a parent with Wilson disease, except in populations with a high incidence of Wilson disease or a high incidence of consanguinity, in which molecular testing may be useful. Repeat biochemical testing (including cerulosplasmin and urinary copper excretion) of offspring is strongly encouraged if initial biochemical testing was performed before age three years.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible if the ATP7B disease-causing mutation(s) have been identified in an affected family member.

Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight), which make these tests unreliable in clarifying carrier status.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Predictive testing of adults and children. Because Wilson disease is a treatable condition, it is appropriate to offer predictive testing to asymptomatic at-risk adults and children (see Management, Evaluation of Relatives at Risk).

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation, or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like Wilson disease) have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. In Wilson disease, diagnosis before early childhood is not necessary for treatment purposes. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Wilson's Disease Association (WDA)
    5572 North Diversey Boulevard
    Milwaukee WI 53217
    Phone: 866-961-0533 (toll-free); 414-961-0533
  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
  • Canadian Liver Foundation (CLF)
    2235 Sheppard Avenue East
    Suite 1500
    Toronto Ontario M2J 5B5
    Phone: 800-563-5483 (toll-free); 416-491-3353
    Fax: 416-491-4952
  • EuroWilson Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Wilson Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Wilson Disease (View All in OMIM)


Normal allelic variants. More than 40 normal allelic variants have been reported in several ethnic groups. In some studies, normal variants may have been inaccurately reported as disease-causing mutations.

Pathologic allelic variants. More than 500 mutations have been identified (see Wilson Disease Mutation Database [Kenney & Cox 2007].

ATP7B mutations in have been identified in different racial groups.

Table 3.

Pathologic ATP7B Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The product of ATP7B is copper-transporting ATPase 2, an intracellular transmembrane copper transporter that is key in incorporating copper into ceruloplasmin and in moving copper out of the hepatocyte into bile. The protein is a P-type ATPase, characterized by cation channel and phosphorylation domains containing a highly conserved Asp-Lys-Thr-Gly-Thr (DKTGT) motif, in which the aspartate residue forms a phosphorylated intermediate during the transport cycle. The six copper-binding domains are similar to those found in yeast and bacteria. Eight hydrophobic regions span the cell membrane. Protein structure has been modeled based on a similar calcium transporting ATPase, SERVA1 [Fatemi & Sarkar 2002, Morgan et al 2004].

The gene is expressed mainly in liver and kidney.

ATP7B has 57% identity to ATP7A, the gene defective in Menkes disease [Bull et al 1993, Tanzi et al 1993].

Abnormal gene product. Tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver. Even when no transporter function is present, accumulation of copper occurs over several years.


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Suggested Reading

  1. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Lancet. 2007;369:397–408. [PubMed: 17276780]
  2. Burkhead JL, Gray LW, Lutsenko S. Biometals. Systems biology approach to Wilson's disease.2011; 24:455-66. [PMC free article: PMC3106420] [PubMed: 21380607]
  3. Cox DW, Roberts EA. Wilson Disease. In: Feldman M, Scharschmidt B,Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 7 ed. Philadelphia, PA: WB Saunders; 2002:1269-77.
  4. Roberts EA, Cox DW. Wilson disease. In: Boyer T, Manns M, Wright T, eds. Zakim and Boyer's Hepatology. 5 ed. Philadelphia, PA: Elsevier; 2006:1221-38.
  5. Rosencrantz R, Schilsky M. Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Semin Liver Dis. 2011;31:245–59. [PubMed: 21901655]
  6. Wiggelinkhuizen M, Tilanus ME, Bollen CW, Houwen RH. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther. 2009;29:947–58. [PubMed: 19210288]

Chapter Notes

Author History

Diane Cox, PhD, FCCMG, University of Alberta (1999-2013)
Eve Roberts, MD, FRCP(C), University of Toronto (1999-2013)
Karl Heinz Weiss, MD (2013-present)

Revision History

  • 16 May 2013 (me) Comprehensive update posted live
  • 24 January 2006 (me) Comprehensive update posted to live Web site
  • 24 April 2003 (me) Comprehensive update posted to live Web site
  • 22 October 1999 (me) Review posted to live Web site
  • 12 May 1999 (dc) Original submission
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