Wilson Disease

Epidemiology and Etiology:

• Autosomal recessive
• Accumulation of copper in multiple organs
• In liver, free copper is normally incorporated into an alpha-2-globulin to form ceruloplasmin, which is secreted into the blood
• Ceruloplasmin is then desialated in the blood over time
• Liver degrades the desialated ceruloplasmin and excretes the copper into the bile
• In Wilson disease:
• Build up of copper in the liver
• Toxic liver injury through copper-catalyzed formation of reactive oxygen species
• Non-cerruloplasmin bound copper spills out in the blood (usually by 5y)
• Causes hemolysis
• Causes pathologic changes in other organs
• Urinary excretion of copper markedly increased

Common sites:

• Liver mostly
• Brain
• Basal ganglia, particularly putamen
• Cornea
• Kidney
• Bone
• Joints
• parathyroid

Gross features:

• basal ganglia atrophy or cavitation
• Kayser-Fleischer rings
• Green to brown copper deposits in Descemet’s membrane and limbus of cornea

Histologic features:

• Macrovesicular steatosis
• Vacuolated hepatocyte nuclei (glycogen or water)
• Focal hepatocyte necrosis occasionally
• Acute hepatitis mimicking viral hepatitis maybe
• Mallory bodies
• Massive liver necrosis rarely
• Brain:

Immunophenotype and Special Stains:

Marker:	Sensitivity:	Specificity:
Rhodanine stain for copper		Also seen in chronic obstructive cholestasis
Orcein stain for copper-associated protein		Also seen in chronic obstructive cholestasis

Molecular features:

• ATP7B gene (13q)
• Over 30 mutations have been identified
• Overwhelming majority of patients are compound heterozygotes with a different mutation on each allele

Other features:

• Urinary excretion of copper markedly increased
• Hepatic copper content > 250 ug / g dry weight is most useful for diagnosis

References:

• Robbins & Cotran Pathologic Basis of Disease (2005)