Wilson Disease

Excerpt

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.

1. Liver disease can include recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease.

2. 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.

3. Psychiatric disturbances can include depression, bipolar disorder / bipolar spectrum disorder, neurotic behaviors, personality changes, or psychosis.

4. 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:

1. 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

2. 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.