Metabolic Liver Disease - Etzion

Question 1

Wilson Disease and Copper Metabolism

Etiology, diagnosis, presentation

Answer 1

Copper enters cell complexed to albumin and attaches to chaperones. ATP7B copper transporter in the golgi at low copper levels, moves copper from sinusoid to bile canniculi. To be excreted converts into apoceruloplasmin and cruloplasmin (6 atoms) into blood. Metallothionein stores Cu as nontoxic form.

ATP7B protein deficiency–>accumulation in liver (homozygous-250ug instead of 55). Defective copper incorporation into apocerulloplasmin leads to its excess catabolism and low blood levels.

High rate of carriers (1%, especially in Caucasians)

Presentation:
Asymptomatic; hepatitis; cirrhosis; ALF
Mid-late teenage, neurologic sequelae in early 20s
In ALF hemolytic anemia may occur secondary to copper toxicity
CT/MRI shows damage in basal ganglia.
Dystonia, tremor, dysarthria and dysphagia.
Difficulty focusing but preserved cognition.
Keiser Fleischer Rings later on
Copper in urine
Kayser-Fleischer rings
Jaundice
Abdominal swelling
Behavioural changes
Pseudo-Parkinsonisms
Dystonia in limbs
Rigidity
Ataxia
Premature arthritis
Cirrhosis
Hepatitis
Low transaminases and ALP

Screen patients under 55 with unexplained liver disease, especially if family history or neurologic/psychiatric symptoms. Screening by low ceruloplasmin

Diagnosis:
Ophthalmic slit lamp test
Serum ceruloplasmin test
24-hour urine copper test
Liver biopsy

Low ceruloplasmin with KF rings
Low ceruloplasmin and elevated liver copper (>250 ug/g dry wt)
Histology/histochemistry/ultrastructure and elevated liver copper >250 ug/g dry wt
evidence for homozygosity or compound heterozygosity for known ATP7B mutation
Rule out autoimmune

Question 2

Treatment of Wilson’s Disease

Answer 2

Must be taken for life

Low copper diet (avoid mushrooms, chocolate, nuts, shellfish, legumes)

Chelators:
Penicillamine (can cause nephrotoxicity and worsen neurological symptoms)
Trientine (weaker, less toxic, new first choice)

Metallothionein inducers:
 Zinc Therapy (Acetate/Sulfate used in pregnant women, works well together with trientine if taken separately)

Ammonium tetrathiomolybdenate (prevents copper absorption and induces bile excretion)

Depends on the severity of the neurological or hepatic features
Assess any sign of hepatic decompensation
24-h urinary Cu excretion (denotes adequate treatment)
Monitor penicillamine side effects

Can still have neurological symptoms and cirrhosis with treatment