What is Wilson disease?

Wilson Disease: An Inherited Disorder of Copper Metabolism

Wilson disease is an autosomal recessive inherited disorder characterized by defective biliary excretion of copper leading to pathological copper accumulation primarily in the liver and brain, resulting in hepatic, neurological, and psychiatric manifestations that can be fatal if untreated. 1

Pathophysiology

Wilson disease results from mutations in the ATP7B gene on chromosome 13, which encodes a copper-transporting P-type ATPase (ATP7B) located in the trans-Golgi network of hepatocytes. This protein has two essential functions:

• Transport of copper into the secretory pathway for excretion into bile
• Incorporation of copper into apo-ceruloplasmin for synthesis of functional ceruloplasmin 1

When ATP7B function is impaired:

• Copper accumulates in hepatocytes
• When hepatic storage capacity is exceeded, copper is released into the bloodstream
• Free copper deposits in other organs, particularly the brain, kidneys, and cornea 1, 2

More than 500 distinct mutations have been identified in the ATP7B gene, with 380 having a confirmed role in disease pathogenesis 1.

Clinical Presentation

Wilson disease has a wide clinical spectrum with key manifestations including:

Hepatic Manifestations

• Asymptomatic hepatomegaly
• Isolated splenomegaly
• Persistently elevated liver enzymes
• Fatty liver
• Acute hepatitis
• Disease resembling autoimmune hepatitis
• Cirrhosis (compensated or decompensated)
• Fulminant hepatic failure 1

Neurological Manifestations

• Movement disorders (tremor, involuntary movements)
• Dysarthria and dyspraxia
• Rigid dystonia
• Pseudobulbar palsy
• Ataxia
• Parkinsonian-like symptoms
• Seizures
• Migraine headaches
• Insomnia 1, 3

Psychiatric Manifestations

• Depression
• Neuroses
• Personality changes
• Psychosis 1

Other Manifestations

• Kayser-Fleischer rings in the cornea (golden-brown rings)
• Coombs-negative hemolytic anemia
• Renal abnormalities (aminoaciduria, nephrolithiasis)
• Skeletal abnormalities (premature osteoporosis, arthritis)
• Cardiomyopathy and dysrhythmias
• Pancreatitis
• Hypoparathyroidism
• Menstrual irregularities, infertility, repeated miscarriages 1, 4

Age of Onset

Wilson disease may present at any age, although most patients present between ages 5 and 35. The youngest reported patient with cirrhosis due to Wilson disease was 3 years old, and patients have been diagnosed as late as in their eighth decade 1.

Diagnosis

Diagnosis of Wilson disease relies on a combination of clinical features and laboratory tests. The European Association for the Study of the Liver (EASL) recommends the following approach:

Key Diagnostic Tests

• Serum ceruloplasmin (typically <20 mg/dL in Wilson disease)
• 24-hour urinary copper excretion
• Hepatic copper content (>250 μg/g dry weight is diagnostic)
• Presence of Kayser-Fleischer rings on slit-lamp examination
• Genetic testing for ATP7B mutations 1

Brain Imaging

• MRI of the brain is preferred over CT for detecting structural abnormalities in the basal ganglia
• Typical findings include hyperintensity on T2-weighted images in the basal ganglia
• Significant abnormalities may be present even before onset of symptoms 1

Treatment

Treatment of Wilson disease has two main objectives:

1. Minimize dietary intake of copper
2. Promote excretion and detoxification of excess tissue copper 5

Dietary Management

• Limit copper intake to 1-2 mg/day
• Avoid foods high in copper: chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals
• Use distilled or demineralized water if drinking water contains >0.1 mg/L copper 5

Pharmacological Treatment

1. Chelating Agents:

   • D-penicillamine: First-line chelator that binds copper and promotes urinary excretion 5
   • Trientine hydrochloride: Alternative for patients intolerant to D-penicillamine with fewer side effects 6

2. Zinc Salts:

   • Block intestinal absorption of copper
   • May be used as maintenance therapy after initial decoppering with chelators 7

Monitoring Treatment

• Regular assessment of liver function
• Copper levels in urine and blood
• Neurological evaluation
• Complete blood counts to detect potential copper deficiency 3

Treatment Challenges

• Neurological deterioration may occur during initial treatment, particularly with D-penicillamine
• Up to 30% of patients experience adverse events with D-penicillamine
• Nearly 50% of neurologically affected patients have persistent deficits despite treatment 7

Prognosis

With proper treatment, Wilson disease has a good prognosis:

• Symptomatic patients typically show marked neurologic improvement
• Kayser-Fleischer rings fade
• Hepatic dysfunction gradually improves
• Asymptomatic patients who receive treatment can prevent disease manifestations indefinitely 1, 5

Without treatment, Wilson disease is progressive and fatal, typically due to liver failure or severe neurological deterioration 6.

Future Treatment Directions

Research is focusing on:

• New agents with better safety profiles
• CNS-penetrable chelators for more effective brain copper removal
• Non-chelating drugs for cellular copper removal
• Cell and gene therapy approaches 7, 4

Wilson disease represents a model of a treatable genetic disorder where early diagnosis and lifelong treatment can dramatically alter the natural history of the disease.