Wilson Disease

Clinical characteristics.

Wilson disease is a disorder of copper metabolism that, when untreated, can present with hepatic, neurologic, or psychiatric disturbances – or a combination of these – in individuals ages three years to older than 70 years. Manifestations in untreated individuals vary among and within families.

• Liver disease can include recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease.
• Neurologic presentations can include dysarthria, movement disorders (tremors, involuntary movements, chorea, choreoathetosis), dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement), dysautonomia, seizures, sleep disorders, or insomnia.
• Psychiatric disturbances can include depression, bipolar disorder / bipolar spectrum disorder, neurotic behaviors, personality changes, or psychosis.
• Other multisystem involvement can include the eye (Kayser-Fleischer rings), hemolytic anemia, the kidneys, the endocrine glands, and the heart.

Diagnosis/testing.

The diagnosis of Wilson disease is established in most instances by a combination of biochemical findings (low serum ceruloplasmin concentration, low serum concentration of total copper, and increased urinary copper excretion) and/or detection of biallelic pathogenic (or likely pathogenic) variants in ATP7B identified by molecular genetic testing, based on the diagnostic scoring system developed at the 8th International Meeting on Wilson Disease.

Management.

Treatment of manifestations: Lifelong medical interventions to prevent/treat copper accumulation need to be instituted as soon as possible in all individuals with Wilson disease whether they are asymptomatic (i.e., individuals with biallelic ATP7B pathogenic variants who have no clinical manifestations or tissue damage related to Wilson disease), clinically asymptomatic (i.e., individuals with biallelic ATP7B pathogenic variants who have no clinical manifestations of Wilson disease, but have Wilson disease-related tissue damage), or symptomatic (i.e., individuals with clinical manifestations of Wilson disease and Wilson disease-related tissue damage), regardless of age and including pregnant women. As Wilson disease treatment decisions might be complex, the consultation of disease experts (primarily hepatologists and neurologists) or Wilson disease centers of excellence is advised. The first-line therapy is copper chelating agents (D-penicillamine and trientine). Zinc salts (which interfere with absorption of copper from the gastrointestinal tract) cannot be used with a copper chelating agent and are most effective after initial decoppering with a chelating agent; however, in some individuals zinc salts can be used as an initial treatment. Orthotopic liver transplantation is used for individuals who fail to respond to medical therapy or present with fulminant acute liver failure.

The goals of supportive treatment for extrahepatic manifestations of individuals with symptomatic Wilson disease are individualized to maximize function and reduce complications. Depending on their clinical manifestations, symptomatic individuals may require specialists in neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech-language pathology, social work, and psychology/psychiatry.

Surveillance: To assess treatment effectiveness and adherence to medical interventions that prevent/treat copper accumulation, the following are recommended:

• At least twice annually: assessment of serum copper and ceruloplasmin levels, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment
• At least once annually: measurement of 24-hour urinary excretion of copper

Monitoring the individual's response to supportive treatment for extrahepatic manifestations and the emergence of new manifestations is per the recommendations of the treating clinical specialists.

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.

In case of biochemical abnormalities in liver function tests or transaminases, alcohol consumption is strongly discouraged.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of medical interventions to prevent/treat copper accumulation.

Pregnancy management: Treatment must be continued during pregnancy because of the risk for fulminant hepatic failure or irreversible neurologic deterioration. Because of possible adverse effects on the fetus from chelating agents, the dose should be kept as low as possible.

Genetic counseling.

Wilson disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATP7B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once both ATP7B pathogenic variants have been identified in an affected family member, carrier and predictive genetic testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for Wilson disease are possible.

Suggestive Findings

Wilson disease should be suspected in individuals ages three to 45 years, but age alone should not exclude consideration of the diagnosis, as affected individuals have been diagnosed in their early 70s. At diagnosis, individuals with Wilson disease may have varying combinations of the following clinical findings, brain MRI findings (in those with neurologic manifestations), biochemical findings, and family history [Schilsky et al 2022b].

Establishing the Diagnosis

The diagnosis of Wilson disease, using clinical, biochemical, and molecular genetic findings, is based on the diagnostic scoring system developed at the 8th International Meeting on Wilson Disease, Leipzig 2001 [Ferenci et al 2003, Członkowska et al 2018] (see Table 1).

Table 1.

Diagnostic Scoring System for Wilson disease

Per the diagnostic scoring system (see Table 1), the diagnosis of Wilson disease can be established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ATP7B identified by molecular genetic testing (see Table 2).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ATP7B variants of uncertain significance (or of one known ATP7B pathogenic variant and one ATP7B variant of uncertain significance) does not establish or rule out a diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) (see Option 1) and comprehensive genomic testing (exome sequencing, genome sequencing) (see Option 2). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Wilson Disease

Clinical Description

Untreated symptomatic Wilson disease can manifest in individuals ages three years to older than 70 years as hepatic, neurologic, psychiatric, or hematologic disturbances, or a combination of these. Phenotypic expression varies even within families. The understanding of the phenotypic spectrum has further expanded through the widespread use of molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings.

Table 3 outlines the typical presenting clinical findings of untreated Wilson disease. Of note, the "classic triad" of liver disease, movement disorder, and Kayser-Fleischer ring is uncommon.

Table 3.

Clinical Findings in Individuals with Untreated Symptomatic Wilson Disease by Presenting Finding

Genotype-Phenotype Correlations

No genotype-phenotype correlations for ATP7B have been identified [Członkowska et al 2018, Ferenci et al 2019].

Nomenclature

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

Prevalence

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 [Sandahl et al 2020].

In some population-based studies, the genetic prevalence was three to four times higher than clinically based estimates [Olivarez et al 2001, Coffey et al 2013], pointing to the complexity when classifying variants regarding its disease-causing potential and raising the question of whether penetrance is really 100%, as generally assumed.

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

Founder variants have been identified in persons of Ashkenazi Jewish and Druze heritage, as well as individuals from the Canary Islands and Sardinia (see Table 7).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual with symptomatic untreated Wilson disease, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Symptomatic Untreated Wilson Disease

Treatment of Manifestations

Surveillance

Supportive Care

To monitor the individual's response to supportive care and the emergence of new manifestations, the evaluations in Table 6 are recommended based on the supportive treatment required by the individual.

Table 6.

Recommended Surveillance of Extrahepatic Manifestations for Individuals with Symptomatic Wilson Disease

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.

In case of biochemical abnormalities in liver function tests or transaminases, alcohol consumption is strongly discouraged.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of medical interventions to prevent/treat copper accumulation (see Medical Interventions to Prevent/Treat Copper Accumulation). Asymptomatic and clinically asymptomatic individuals with Wilson disease should remain asymptomatic on treatment, even if they have biochemical abnormalities, histologic findings, or imaging evidence of organ damage. Evaluations can include:

• Molecular genetic testing if the ATP7B pathogenic variants in the family are known;
• If the ATP7B pathogenic variants 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 (the finding of a "fatty liver" is common, even in young or asymptomatic individuals) and slit lamp examination for the presence of Kayser-Fleischer rings.
  Note: Asymptomatic individuals with Wilson disease generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion; however, sometimes asymptomatic individuals with Wilson disease cannot be easily distinguished from heterozygotes.

Although Wilson disease is an autosomal recessive disorder and the risk to the parents and offspring of a proband is low, screening of all first-degree relatives is recommended in order to ascertain clinically asymptomatic family members in whom treatment may prevent liver disease and other manifestations of Wilson disease [Schilsky et al 2022b].

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

Pregnancy and Lactation Concerns

Pregnancy. Treatment must be continued during pregnancy because of the risk of fulminant hepatic failure and/or neurologic decline in the affected pregnant woman. Baseline biochemical and clinical assessment as soon as a pregnancy is recognized is important. This includes evaluation for portal hypertension in those who have cirrhosis because of the risk of peripartum variceal hemorrhage [Członkowska et al 2018].

• D-penicillamine has been used in many pregnancies with no adverse outcomes; however, congenital connective tissue disorders encompassing inguinal hernias and skin laxity have been reported in some exposed infants. Such adverse outcomes may depend on dose, which should be kept as low as possible while still preventing copper deficiency in the pregnant woman and accounting for the need for fetal copper during development [Członkowska et al 2018]. The dose of D-penicillamine should be maintained at the lowest effective dose during the first and second trimesters of pregnancy. Further reduction in dose may be considered in the third trimester – based on acceptable results of maternal biochemical liver function tests – to account for the increasing copper utilization by the growing fetus.
• Trientine has been used successfully during pregnancy, but the total number of reported individuals is small. Reduction of the dose to the lowest effective dose is recommended using a comparable approach to that for D-penicillamine.
• Zinc has been used effectively in pregnant women and typically does not require a decreased dose during pregnancy. However, changing medical therapy to zinc during pregnancy does not appear to decrease the risk of either miscarriage or adverse fetal outcomes [Członkowska et al 2018].

Lactation. All anti-copper medications appear to pass into breast milk, which can lead to copper deficiency in infants. Therefore, breastfeeding or using expressed maternal breast milk from a mother taking an anti-copper medication is not generally recommended [Członkowska et al 2018].

See MotherToBaby for further information on medication use during pregnancy and lactation.

Therapies Under Investigation

Tetrathiomolybdate (TTM) is an orally administered chelating agent proposed to work by multiple mechanisms [Plitz & Boyling 2019] including:

• Detoxifying non-ceruloplasmin-bound copper by creating a nonreactive tripartite complex with albumin and copper;
• Extracting copper from the endogenous cellular chelator metallothionein (based on its high affinity for copper); and
• Interfering with the intestinal uptake of copper when administered with food.

In a Phase II study [Weiss et al 2017], TTM effectively reduced non-ceruloplasmin-bound copper (corrected for copper-TTM-albumin complex) and improved clinical neurologic findings, without paradoxical neurologic worsening, as demonstrated by an overall improvement in Unified Wilson's Disease Rating Scale scores [Leinweber et al 2008]. Early elevation of serum aminotransferases in approximately 30% of individuals resolved with dose discontinuation or reduction; none developed evidence of drug-induced liver injury. Suitability for treating advanced hepatic Wilson disease requires further investigation. A Phase III trial of bis-choline TTM for Wilson disease is under way.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Wilson disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an ATP7B pathogenic variant.
• If a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ATP7B pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight).

Sibs of a proband

• If both parents are known to be heterozygous for an ATP7B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Clinical symptoms may vary between sibs (including monozygotic twins) with untreated Wilson disease. The range of clinical variability observed between sibs with the same biallelic ATP7B pathogenic variants and treated Wilson disease depends primarily on the age of diagnosis and treatment initiation, reflecting the period of exposure to copper overload conditions.
• Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight).

Offspring of a proband

• Unless an affected individual's reproductive partner also has Wilson disease or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ATP7B.
• Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual will have an affected child is one in 180. A higher carrier frequency is observed in some population groups due to founder variants (see Prevalence).
• Because the risk that an individual with Wilson disease will have an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in offspring of a proband, except in populations with a high incidence of Wilson disease and/or a high incidence of consanguinity. In these populations, molecular testing may be useful. If molecular testing is not performed, repeat biochemical testing (including ceruloplasmin 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 of an ATP7B pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the ATP7B pathogenic variants in the family.

Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-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

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).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
• Carrier testing for the reproductive partners of affected individuals and known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Founder variants have been identified in some populations (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ATP7B pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for Wilson disease are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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 gene is expressed mainly in the liver and kidneys.

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.

Mechanism of disease causation. Various pathogenic variants lead to different impairments in ATP7B function.

ATP7B-specific laboratory technical considerations. Comprehensive ATP7B testing should include promotor variants, as assessment of exonic sequences only does not rule out the diagnosis of Wilson disease when biochemical and/or clinical features are consistent with the diagnosis.

Table 7.

Notable ATP7B Pathogenic Variants

Author Notes

Dr Michael Schilsky's clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver, in particular Wilson disease and hemochromatosis. Dr Schilsky co-wrote the AASLD and EASL practice guidelines for Wilson disease and chaired the writing group for the newly released 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject. He is the Principal Investigator on clinical trials of pharmacotherapy and gene therapy for Wilson disease. Dr Schilsky is the organizer and Principal Investigator for the multicenter, multinational registry trial for Wilson disease sponsored by the Wilson Disease Association with data coordinating center at Yale University. He is a member of the NIH-sponsored Acute Liver Failure Study Group. He currently serves as Chair of the Medical Advisory Committee for the Wilson Disease Association.

Dr Karl Heinz Weiss's clinical and research interests include transplant hepatology, Wilson disease, and liver tumors. Dr Weiss co-wrote the 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject.

Drs Weiss and Schilsky are actively involved in clinical research regarding individuals with Wilson disease. They would be happy to communicate with persons who have any questions regarding diagnosis of Wilson disease or other considerations.

Contact Drs Weiss and Schilsky to inquire about review of ATP7B variants of uncertain significance. Both authors are also interested in hearing from clinicians treating families affected by Wilson disease in whom no causative variant has been identified.

Acknowledgments

MLS receives research support from the Wilson Disease Association (USA), Alexion, Orphalan, and Vivet Therapeutics. KHW receives research support from Morbus Wilson e.V., Alexion, Orphalan, Univar, and Vivet Therapeutics.

We would like to acknowledge the Wilson Disease Association for their support of patient care, research, and educational activities.

Author History

Diane Cox, PhD, FCCMG, University of Alberta (1999-2013)
Eve Roberts, MD, FRCP(C), University of Toronto (1999-2013)
Michael Schilsky, MD (2023-present)
Karl Heinz Weiss, MD (2013-present)

Revision History

• 12 January 2023 (bp) Comprehensive update posted live
• 29 July 2016 (bp) Comprehensive update posted live
• 16 May 2013 (me) Comprehensive update posted live
• 24 January 2006 (me) Comprehensive update posted live
• 24 April 2003 (me) Comprehensive update posted live
• 22 October 1999 (me) Review posted live
• 12 May 1999 (dc) Original submission

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