Wilson's disease

Question 1

Wilson’s disease is the autosomal recessive disorder of excessive copper accumulation.

Mutation of ATP7B gene on chromosome 13.

Prevalence: 1 in 30,000-40,000

Question 2

Pathophysiology of Wilson’s disease

Answer 2

Normal: ATP7B in copper homeostasis
- Incorporates copper + apocaeruloplasmin to form caeruloplasmin and secreted into blood
- Mediates excretion of excess copper into bile

Wilson’s disease:
1. Reduced incorporation of copper into apocaeruloplasmin
- Low levels of caeruloplasmin
2. Impaired biliary excretion of copper

Question 3

Sequence of copper accumulation

Answer 3

1. Liver - oxidative stress, mitochondrial dysfunction, apoptosis
   - Steatosis, hepatitis, cirrhosis, failure
2. Brain - preferentially in basal ganglia, thalamus, brainstem, cerebellum
   - Neurological and psychiatric manifestations
3. Eyes - Kayser-Fleischer rings, sunflower cataracts
4. Renal tubular dysfunction
5. Coombs negative haemolytic anaemia
6. Cardiomyopathy
7. Arthritis
8. Hypoparathyroidism

Question 4

Clinical presentation of patients with Wilson’s disease

Answer 4

1. Liver disease
   - Asymptomatic elevated liver enzymes
   - Hepatic steatosis, hepatitis
   - Cirrhosis and complications
   - Acute liver failure
2. Neurological disease
   - Movement disorders: tremors, dystonia, Parkinsonism, ataxia, choreoathetosis
   - Dysarthria, dysphagia, drooling
   - Fine motor and coordination impairment
   - Seizures
3. Psychiatric disease
   - Depression, anxiety
   - Personality and behaviour change
   - Psychosis
   - Cognitive impairment, declining performance
4. Kayser-Fleischer rings and sunflower cataracts
   - Golden-brown/green-yellow discolouration of cornea
5. Renal disease
   - Renal tubular acidosis
   - Fanconi syndrome (aminoaciduria, glycosuria, phosphaturia, uricosuria)
   - Nephrolithiasis
6. Endocrine disturbance
   - Hypoparathyroidism
   - Amenorrhoea
   - Infertility
7. Haemolytic anaemia (Coombs negative)
8. Cardiomyopathy and arrhythmias
9. Arthropathy and osteomalacia

Question 5

Investigations for Wilson’s disease

Answer 5

1. Serum caeruloplasmin - low < 0.2g/L
2. 24-hour urinary copper excretion - high
3. Serum free copper - high
4. Liver biopsy with high copper content
5. Genetic testing - ATP7B gene
6. Slit-lamp examination - KF rings
7. MRI brain - T2 hyperintensity over basal ganglia, thalamus, brainstem, cerebellum

Question 6

Considerations for caeruloplasmin levels

Answer 6

Falsely normal / elevated
1. Acute liver failure
2. Hepatitis
3. Infections and sepsis (acute phase reactant)

Falsely low
1. Malabsorption
2. Nephrotic syndrome
3. Protein-losing enteropathy
4. Acaeruloplasminaemia

Question 7

Treatment of Wilson’s disease

Answer 7

1. Chelating agent
   - D-penicillamine
   - Trientine
2. Maintenance agent
   - Zinc salts (sulfate or acetate): blocks intestinal absorption of copper
   - Low dose chelators
3. Avoid copper rich food
   - Liver, shellfish, chocolate, nuts, mushroom
4. Liver transplant