Wilson Disease (Hepatolenticular Degeneration)

A 17-year-old male presents with progressive fatigue, behavioral changes, and difficulty with speech and coordination over several months. He has a history of mild jaundice and intermittent abdominal discomfort. On examination, he has dysarthria, a resting tremor, and mild hepatomegaly. Slit-lamp examination reveals brownish rings at the corneal margins. Laboratory studies show elevated AST and ALT, low serum ceruloplasmin, and increased 24-hour urinary copper excretion. Hemolytic anemia is noted with elevated LDH and low haptoglobin. MRI brain demonstrates hyperintensities in the basal ganglia. Diagnosis?

Diagnosis is Wilson Disease.

1. Definition

Wilson disease is an autosomal recessive disorder of copper metabolism characterized by impaired biliary copper excretion and accumulation of copper in the liver and extrahepatic tissues.

2. Etiology

1. Mutation in ATP7B gene (chromosome 13)
2. Defective copper transport in hepatocytes
3. Impaired incorporation into ceruloplasmin
4. Reduced biliary excretion of copper

3. Pathophysiology

1. Copper accumulates in hepatocytes → oxidative injury → hepatocyte death
2. Release of non–ceruloplasmin-bound (“free”) copper into circulation
3. Copper deposition in extrahepatic tissues:
• Brain (basal ganglia) → movement disorders
• Cornea → Kayser–Fleischer rings
• Kidney → aminoaciduria, nephrolithiasis
• Heart → cardiomyopathy
4. Progressive liver injury → hepatitis → cirrhosis → liver failure
5. Free copper toxicity → Coombs-negative hemolytic anemia

4. Clinical Features

4.1 Core Features

1. Hepatic disease
2. Neuropsychiatric manifestations
3. Kayser–Fleischer rings

Note: The classic triad may not be present in all patients

4.2 Hepatic Manifestations

1. Acute hepatitis
2. Chronic hepatitis → cirrhosis
3. Fulminant liver failure
4. Coombs-negative hemolytic anemia

4.3 Neurologic / Psychiatric Features

1. Tremor (wing-beating tremor)
2. Rigidity, bradykinesia (parkinsonism)
3. Dysarthria
4. Dystonia, chorea, incoordination
5. Psychiatric:
• Depression
• Personality changes
• Irritability, impulsivity
• Psychosis

4.4 Ocular Features

1. Kayser–Fleischer rings
• Copper deposition in Descemet membrane
• Seen on slit-lamp examination
• Vision unaffected

4.5 Other Features

1. Renal: aminoaciduria, nephrolithiasis
2. Cardiac: cardiomyopathy

High-Yield Clinical Clues

1. Young patient with unexplained liver disease ± neurologic symptoms
2. Coombs-negative hemolytic anemia
3. Low or inappropriately normal alkaline phosphatase relative to bilirubin (especially in acute liver failure)
4. Neuropsychiatric symptoms with abnormal LFTs

5. Diagnosis

Diagnosis is based on a combination of clinical, biochemical, and histologic findings (Leipzig scoring system may be used).

5.1 Laboratory Tests

1. ↓ Serum ceruloplasmin
• Present in most patients
• May be normal in some cases
• Can be low in other conditions (e.g., malnutrition, nephrotic syndrome)
2. ↑ 24-hour urinary copper excretion (>100 µg/day typical)
3. Liver function abnormalities:
• ↑ AST, ALT, bilirubin
• ↑ INR in advanced disease
4. Evidence of hemolysis:
• ↑ LDH, ↓ haptoglobin

5.2 Ophthalmologic Examination

1. Kayser–Fleischer rings on slit-lamp examination

5.3 Imaging (Supportive, NOT diagnostic)

1. MRI brain:
• T2 hyperintensities in basal ganglia (especially putamen)
• May show “face of the giant panda” sign

5.4 Liver Biopsy

1. Copper accumulation in hepatocytes
2. Special stains:
• Rhodanine
• Rubeanic acid

5.5 Quantitative Hepatic Copper (Confirmatory)

1. Hepatic copper >250 µg/g dry weight

Note: May be falsely low in advanced cirrhosis due to sampling error

5.6 Genetic Testing

1. ATP7B mutation confirmation
2. Useful for family screening

5.7 Family Screening

1. All first-degree relatives should be screened

6. Management

6.1 Initial Stabilization (if severe hepatic disease)

1. Supportive care
2. Manage complications (coagulopathy, encephalopathy)

6.2 Definitive Treatment (Lifelong)

1. Chelation therapy (copper removal):
• D-penicillamine + pyridoxine
• Effective
• May worsen neurologic symptoms initially
• Trientine
• Preferred in neurologic disease or intolerance

6.3 Copper Absorption Inhibition

1. Zinc therapy:
• Blocks intestinal copper absorption
• Used for:
• Maintenance therapy
• Presymptomatic patients
• Mild hepatic disease

6.4 Other Therapy

1. Ammonium tetrathiomolybdate
• May be used in neurologic disease
• Not standard first-line; limited availability

6.5 Dietary Modification

Avoid copper-rich foods:

• Shellfish
• Liver (organ meats)
• Nuts
• Chocolate
• Mushrooms

6.6 Liver Transplantation

Indications:

• Fulminant hepatic failure
• Decompensated cirrhosis / refractory disease

→ Curative (restores normal copper metabolism)

6.7 Monitoring

1. 24-hour urinary copper (treatment monitoring)
2. Non–ceruloplasmin-bound (“free”) copper (if available)
3. Liver function tests (AST, ALT, bilirubin, INR)
4. Neurologic and psychiatric status

Note: Ceruloplasmin is not reliable for monitoring

7. Complications

1. Liver cirrhosis and failure
2. Neurologic deterioration
3. Hemolytic anemia
4. Renal dysfunction

8. Key Clinical Insight

Young patient + liver disease + neuropsychiatric symptoms + Kayser–Fleischer rings + abnormal copper studies → Wilson disease → confirm with ↓ ceruloplasmin + ↑ 24-hour urinary copper ± hepatic copper >250 µg/g → start lifelong therapy (chelators: D-penicillamine or trientine ± zinc) → consider liver transplant if fulminant or decompensated disease

9. Exam Level Pearls

1. Kayser–Fleischer rings + neurologic symptoms + liver disease = classic triad
2. Coombs-negative hemolytic anemia is a key clue
3. Low ALP relative to bilirubin supports diagnosis (especially in acute liver failure)
4. MRI findings are supportive, not diagnostic
5. Diagnosis requires a combination of findings (no single definitive test in all cases)
6. Treatment is lifelong
7. Always screen first-degree relatives