Wilson Disease

Overview

Wilson disease, also known as hepatolenticular degeneration, is a rare inherited disorder that prevents the body from properly eliminating excess copper. As a result, copper accumulates to dangerous levels in the liver, brain, eyes, and other organs. This buildup begins at birth but symptoms typically appear between ages 5 and 35, though they can emerge at any age from 2 to 72 years.

The condition is caused by mutations in the ATP7B gene, which provides instructions for making a protein that plays a key role in transporting copper from the liver to other parts of the body for elimination. When this protein doesn't function properly, copper cannot be excreted normally through bile, leading to toxic accumulation. Without treatment, Wilson disease is fatal, but with proper therapy, people with the condition can live normal, healthy lives.

Wilson disease affects approximately 1 in 30,000 people worldwide, though the prevalence may be higher in certain populations due to consanguinity. The disease is inherited in an autosomal recessive pattern, meaning both parents must carry the defective gene for a child to develop the condition. Carriers (those with one defective gene) do not develop symptoms but can pass the gene to their children.

Symptoms

Wilson disease symptoms vary widely depending on which organs are affected by copper accumulation. The disease typically presents in one of three ways: hepatic (liver), neurologic, or psychiatric manifestations. Some patients may have a combination of symptoms.

Common Symptoms

Hepatic (Liver) Symptoms

• Fatigue and weakness
• Jaundice (yellowing of skin and eyes)
• Abdominal swelling (ascites)
• Easy bruising
• Spider angiomas (spider-like blood vessels on skin)
• Hepatomegaly (enlarged liver)
• Acute liver failure (in severe cases)

Neurological Symptoms

• Tremors (often "wing-beating" tremor)
• Difficulty with speech and swallowing
• Uncontrolled movements (dystonia)
• Muscle stiffness and rigidity
• Problems with coordination and walking
• Drooling
• Facial grimacing

Psychiatric Symptoms

• Depression
• Anxiety
• Mood swings
• Personality changes
• Psychosis (rare)
• Behavioral problems

Other Signs

• Kayser-Fleischer Rings: Golden-brown or greenish rings around the cornea
• Sunflower Cataracts: Copper deposits in the lens
• Kidney problems (kidney stones, renal tubular dysfunction)
• Osteoporosis and arthritis
• Menstrual irregularities
• Hemolytic anemia

Causes

Wilson disease is caused by mutations in the ATP7B gene located on chromosome 13. This gene provides instructions for making a copper-transporting protein primarily found in liver cells.

Genetic Mechanism

• ATP7B Gene Mutation: Over 500 different mutations have been identified
• Protein Dysfunction: The defective protein cannot properly transport copper
• Copper Accumulation: Excess copper builds up in liver cells and eventually spills into the bloodstream
• Organ Damage: Accumulated copper causes oxidative damage to tissues

Inheritance Pattern

• Autosomal Recessive: Both parents must be carriers
• 25% Risk: Each child of carrier parents has a 1 in 4 chance of having Wilson disease
• 50% Carrier Risk: Each child has a 1 in 2 chance of being a carrier
• No Gender Preference: Affects males and females equally

Copper Metabolism Disruption

Normal copper metabolism involves:

• Absorption of dietary copper in the small intestine
• Transport to the liver via the portal blood
• Incorporation into ceruloplasmin or excretion in bile
• In Wilson disease, biliary excretion is impaired, leading to accumulation

Risk Factors

Since Wilson disease is genetic, risk factors are primarily related to family history and ethnicity:

Diagnosis

Diagnosing Wilson disease requires a combination of clinical, laboratory, and imaging findings. No single test is diagnostic, and the diagnosis often requires multiple investigations.

Laboratory Tests

• Ceruloplasmin: Usually low (<20 mg/dL), but can be normal in some cases
• 24-hour Urine Copper: Elevated (>100 μg/24h)
• Serum Copper: Usually low or normal despite tissue overload
• Liver Function Tests: May show elevated enzymes
• Complete Blood Count: May reveal hemolytic anemia

Specialized Tests

• Slit-Lamp Examination: To detect Kayser-Fleischer rings
• Liver Biopsy: Gold standard showing elevated hepatic copper (>250 μg/g dry weight)
• Genetic Testing: Can identify ATP7B mutations
• Radiocopper Test: Measures copper incorporation into ceruloplasmin

Imaging Studies

• Brain MRI: May show characteristic changes in basal ganglia
• Abdominal Ultrasound: Assesses liver size and texture
• CT Scan: Can detect liver cirrhosis or brain changes

Diagnostic Scoring System

The Leipzig scoring system combines various findings to establish diagnosis:

• Score ≥4: Diagnosis established
• Score 3: Diagnosis probable, more tests needed
• Score ≤2: Diagnosis unlikely

Treatment Options

Wilson disease requires lifelong treatment to remove excess copper and prevent re-accumulation. Early diagnosis and treatment can prevent or reverse many symptoms.

Chelation Therapy

• Penicillamine: First-line chelator that binds copper for urinary excretion
• Trientine: Alternative chelator with fewer side effects
• Tetrathiomolybdate: Newer agent for neurologic presentations
• Requires careful monitoring for side effects and effectiveness

Zinc Therapy

• Blocks intestinal copper absorption
• Used for maintenance therapy or initial treatment in asymptomatic patients
• Generally well-tolerated with minimal side effects
• Zinc acetate, zinc sulfate, or zinc gluconate

Dietary Management

• Avoid high-copper foods during initial treatment:
• Shellfish, liver, mushrooms, nuts, chocolate
• Use copper-free water if tap water is high in copper
• Avoid copper-containing supplements

Liver Transplantation

• Reserved for acute liver failure or decompensated cirrhosis
• Cures the underlying metabolic defect
• May improve neurological symptoms in some cases
• Requires lifelong immunosuppression

Symptomatic Treatment

• Physical therapy for movement disorders
• Speech therapy for dysarthria
• Psychiatric medications for mood symptoms
• Treatment of complications (portal hypertension, etc.)

Monitoring

• Regular liver function tests
• 24-hour urine copper levels
• Neurological assessments
• Eye examinations
• Adherence to medication

Prevention

While Wilson disease cannot be prevented as it's genetic, early detection and treatment can prevent symptoms and complications:

• Family Screening: Test siblings of affected individuals
• Genetic Counseling: For families with Wilson disease history
• Prenatal Testing: Available for at-risk pregnancies
• Early Treatment: Begin therapy before symptoms appear in diagnosed individuals
• Regular Monitoring: Of at-risk family members
• Awareness: Educate family members about the condition

When to See a Doctor

Seek medical attention if you experience symptoms suggestive of Wilson disease, especially with a family history:

Schedule an appointment for:

• Unexplained liver enzyme elevation
• Family history of Wilson disease
• Unexplained neurological symptoms in young adults
• Behavioral changes in children or young adults
• Chronic fatigue with liver abnormalities
• Tremors or movement disorders

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Frequently Asked Questions