Learn About Wilson Disease

What is Wilson disease?

Wilson disease is a genetic disease that prevents the body from removing extra copper. Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver, brain, and other tissues. Wilson disease is often fatal if not recognized and treated when symptomatic.

The body needs a small amount of copper from food to stay healthy; however, too much copper is poisonous. Normally, the liver filters extra copper and releases it into bile. Bile is a fluid made by the liver that carries toxins and wastes out of the body through the gastrointestinal tract. In Wilson disease, the liver does not filter copper correctly and copper builds up in the liver, brain, eyes, and other organs. Over time, high copper levels can cause life-threatening organ damage.

What causes Wilson disease?

Wilson disease is caused by an inherited autosomal recessive mutation, or change, in the ATP7B gene. In an autosomal recessive disease, the child has to inherit the gene mutation from both parents to have an increased likelihood for the disease.

The chance of a child inheriting autosomal recessive mutations from both parents with a gene mutation is 25 percent, or one in four. If only one parent carries the mutated gene, the child will not get the disease, although the child may inherit one copy of the gene mutation. The child is called a “carrier” of the disease and can pass the gene mutation to the next generation. Genetic testing is a procedure that identifies changes in a patient’s genes and can show whether a parent or child is a carrier of a mutated gene. Autosomal recessive diseases are typically not seen in every generation of an affected family.

The following chart shows the chance of inheriting an autosomal recessive mutation from parents who both carry the mutated gene.

Who is more likely to develop Wilson disease?

Men and women develop Wilson disease at equal rates. About one in 30,000 people have Wilson disease. Symptoms usually appear between ages 5 and 35; however, new cases have been reported in people ages 3 to 72.

A person’s risk of being a carrier or having Wilson disease increases when his or her family has a known history of Wilson disease. Some people may not know about a family history of the condition because the mutation is often passed to a child by a parent who is a carrier. A person’s chances of having Wilson disease increase if a health care provider has diagnosed one or both parents with the condition.

Signs and symptoms

Hepatic dysfunction is the presenting feature in more than half of patients. Although the condition may manifest as acute hepatitis, the 3 major patterns of hepatic involvement are as follows:

• Chronic active hepatitis
• Cirrhosis (the most common initial presentation)
• Fulminant hepatic failure

Signs of fulminant hepatic failure include the following:

• Ascites and prominent abdominal veins
• Spider nevi
• Palmar erythema
• Digital clubbing
• Hematemesis
• Jaundice

Neuropsychiatric features

Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, which is variable in character and may be predominantly resting, postural, or kinetic.

Frequent early symptoms include the following:

• Difficulty speaking
• Excessive salivation
• Ataxia
• Masklike facies
• Clumsiness with the hands
• Personality changes

Late manifestations (now rare because of earlier diagnosis and treatment) include the following:

• Dystonia
• Spasticity
• Grand mal seizures
• Rigidity
• Flexion contractures

Psychiatric features (10-20% of patients) include the following:

• Emotional liability
• Impulsiveness
• Disinhibition
• Self-injurious behavior

Psychiatric abnormalities associated with Wilson disease has been divided into the following 4 basic categories:

• Behavioral
• Affective
• Schizophrenic-like
• Cognitive

Musculoskeletal manifestations

• The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis
• Symptomatic joint disease usually arises late in the course of the disease, frequently after age 20 years
• The arthropathy generally involves the spine and large appendicular joints (eg, knees, wrists, hips)
• Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described

Hematologic and renal manifestations

• Coombs-negative acute intravascular hemolysis (10-15%)
• Urolithiasis
• Hematuria

Kayser-Fleischer rings

• Formed by the deposition of copper in the Descemet membrane in the limbus of the cornea
• The color may range from greenish gold to brown
• Well-developed rings may be readily visible to the naked eye or with an ophthalmoscope set at +40
• When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy
• Observed in up to 90% of individuals with symptomatic Wilson disease and almost invariably present in those with neurologic manifestations
• No longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations, as they may also be observed in patients with chronic cholestatic disorders

Additional manifestations

• Skeletal abnormalities (eg, osteoporosis, osteomalacia, rickets, spontaneous fractures, polyarthritis)
• Cardiac manifestations (eg, rhythm abnormalities, increased autonomic tone)
• Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae)

Diagnosis

Considerations in the workup of Wilson disease are as follows:

• Serum ceruloplasmin levels are less than 20 mg/dL (reference range, 20-40 mg/dL) in approximately 90% of all patients with Wilson disease
• The urinary copper excretion rate is greater than 100 mcg/day (reference range, < 40 mcg/day) in most patients with symptomatic Wilson disease, but it may also be elevated in other cholestatic liver diseases
• In a patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 0 mg/dL and 24-hoyr urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease
• Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250 mcg/g of dry weight even in asymptomatic patients; a normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease, but elevation may be found in other chronic hepatic disorders
• Radiolabeled copper testing directly assays hepatic copper metabolism
• Genetic testing is limited to screening of family members for an identified mutation detected in the index patient
• Brain imaging shows characteristic findings; MRI appears to be more sensitive than CT in detecting early lesions
• Abdominal imaging findings are neither sensitive nor specific
• Resting ECG abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias

Electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry

Management

Features of treatment of Wilson disease are as follows:

• The mainstay of therapy is lifelong use of chelating agents (eg, penicillamine, trientine)
• Symptoms, particularly neurologic ones, may worsen with initiation of chelation
• Surgical decompression or transjugular intrahepatic shunting (TIPS) is reserved for recurrent or uncontrolled variceal bleeding unresponsive to standard conservative measures
• Orthotopic liver transplantation is curative

Other treatments for Wilson disease include the following:

• Anticholinergics, baclofen, GABA antagonists, and levodopa to treat parkinsonism and dystonia
• Antiepileptics to treat seizures
• Neuroleptics to treat psychiatric symptoms
• Protein restriction, lactulose, or both to treat hepatic encephalopathy