WILSON’S DISEASE (Hepatolenticular Degeneration)

1. Definition

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism due to mutation in the ATP7B gene, leading to:

  • ↓ hepatic copper excretion into bile
  • ↓ incorporation into ceruloplasmin
  • → toxic copper accumulation in:
    • Liver
    • Brain (basal ganglia)
    • Cornea
    • Kidneys

2. Epidemiology

  • Age of presentation:
    • Hepatic: childhood (5–15 yrs)
    • Neurological: adolescence/young adults (15–35 yrs)

3. Pathophysiology

Normal copper metabolism

  • Absorbed in intestine → transported to liver
  • Incorporated into ceruloplasmin via ATP7B
  • Excess excreted in bile

In Wilson’s disease

  • Defective ATP7B →
    • ↓ biliary excretion
    • ↓ ceruloplasmin binding
  • Free copper accumulates → oxidative damage

Target organ injury

  • Liver → hepatitis, cirrhosis
  • Brain → basal ganglia degeneration
  • RBC → hemolysis
  • Kidney → tubular dysfunction

4. Clinical Features

A. Hepatic manifestations

  • Asymptomatic transaminitis
  • Acute hepatitis (mimics viral)
  • Chronic hepatitis → cirrhosis
  • Acute liver failure (ALF)
    • Coombs-negative hemolysis
    • Low ALP (important clue)
    • ALP:bilirubin ratio < 4

B. Neurological manifestations

  • Tremor (classically wing-beating tremor)
  • Dysarthria
  • Dystonia
  • Parkinsonism
  • Ataxia

C. Psychiatric features

  • Personality changes
  • Depression
  • Psychosis
  • Cognitive decline

D. Ophthalmic signs

  • Kayser–Fleischer (KF) rings
    • Copper in Descemet membrane
    • Seen best on slit lamp
    • Almost universal in neuro WD
  • Sunflower cataract (rare)

E. Other systemic features

  • Hemolytic anemia (Coombs negative)
  • Renal tubular dysfunction (Fanconi syndrome)
  • Osteopenia
  • Cardiomyopathy (rare)

5. Diagnosis 

Leipzig scoring system (gold standard)

  • KF rings
  • Neurological features
  • Ceruloplasmin
  • Urinary copper
  • Liver copper
  • Genetic testing

 Score ≥ 4 = diagnostic

 

Key investigations

1. Serum ceruloplasmin

  • ↓ (< 0.2 g/L)
  • BUT:
    • Normal in inflammation/pregnancy
    • Low in malnutrition → false positive

2. 24-hour urinary copper

  • 100 µg/day (diagnostic)
  • 40 µg/day (suggestive)

3. Hepatic copper concentration

  • 250 µg/g dry weight → diagnostic

4. Slit lamp examination

  • KF rings

5. Genetic testing

  • ATP7B mutation (confirmatory)

6. Blood tests clues (exam pearls)

  • Coombs-negative hemolysis
  • Low ALP in ALF
  • AST > ALT

 

6. Differential Diagnosis

  • Autoimmune hepatitis
  • Hemochromatosis
  • NAFLD
  • Drug-induced liver injury
  • Young patient with cirrhosis → always rule out WD

7. Management 

A. General principles

  • Lifelong treatment
  • Avoid copper-rich foods:
    • Shellfish, nuts, chocolate, mushrooms

B. First-line therapy

1. Chelation therapy

  • D-penicillamine
    • First-line (traditional)
    • Increases urinary copper excretion
    • Give with pyridoxine

 Side effects:

  • Bone marrow suppression
  • Nephrotic syndrome
  • Worsening neurological symptoms
  • Trientine
    • Better tolerated
    • Preferred if penicillamine intolerant

2. Zinc therapy

  • Zinc acetate
    • Blocks intestinal copper absorption
    • Used for:
      • Maintenance
      • Asymptomatic patients

 

C. Acute liver failure

  • Urgent evaluation for transplant

D. Liver transplantation

  • Indications:
    • Acute liver failure
    • Decompensated cirrhosis
    • Treatment failure

 Curative (corrects metabolic defect)

 

8. Monitoring

  • Urinary copper
  • LFTs
  • CBC (for drug toxicity)
  • Neurological status

9. Prognosis

  • Excellent with early treatment
  • Untreated → fatal