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Write a short note on Wilson disease.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Wilson disease (hepatolenticular degeneration) = an autosomal recessive disorder of copper metabolism in which copper accumulates in the liver, brain, cornea and kidney.

Defect in the ATP7B gene on chromosome 13, encoding a copper-transporting ATPase
Incidence about 1 in 30,000

Biochemical Basis

ATP7B defective → Two consequences → 1.
Copper cannot be incorporated into caeruloplasmin → serum caeruloplasmin low → 2.
Copper cannot be excreted into bile — the only route of elimination → Copper accumulates in the liver → Hepatocytes are damaged and release free copper into blood → Deposited in brain, cornea, kidney
Free (non-caeruloplasmin-bound) copper is the toxic species — it generates free radicals by the Fenton reaction

Clinical Features

System	Features
Hepatic (younger patients)	Fatty liver, acute or chronic hepatitis, cirrhosis, fulminant hepatic failure with haemolysis
Neurological (older patients)	Tremor, dysarthria, dystonia, parkinsonism, chorea; ataxia
Psychiatric	Personality change, depression, psychosis, declining school performance
Ocular	KAYSER–fleischer rings — golden-brown copper deposits in Descemet membrane, seen on slit lamp; sunflower cataract
Renal	Fanconi syndrome, aminoaciduria, renal tubular acidosis, stones
Haematological	Coombs-negative haemolytic anaemia

Diagnosis

Test	Finding
Serum caeruloplasmin	Low (< 20 mg/dL) — the screening test
Serum total copper	Low (most is carried on caeruloplasmin)
Free serum copper	High
24-hour urinary copper	High (> 100 µg/day)
Liver copper on biopsy	> 250 µg/g dry weight — the gold standard
Slit lamp examination	Kayser–Fleischer rings
Genetic testing	ATP7B mutation; used for family screening

CLINICAL PEARL

Note the apparent paradox: serum total copper is low in a disease of copper overload. The explanation is that most circulating copper is normally bound to caeruloplasmin, which is deficient. The free copper and the urinary copper are both high.

Treatment

D-Penicillamine — chelates copper and promotes urinary excretion; give pyridoxine with it, since it antagonises B6
Trientine — an alternative chelator, better tolerated
Zinc — induces intestinal metallothionein, which traps copper in the enterocyte so it is lost when the cell is shed; used for maintenance
Avoid copper-rich foods — liver, shellfish, nuts, chocolate, mushrooms
Liver transplantation for fulminant failure or decompensated cirrhosis; it is curative, since the defect is hepatic
Treatment is lifelong

Applied Aspects

Wilson disease must be excluded in any young person with unexplained liver disease, a movement disorder, or new psychiatric illness — it is one of the few treatable causes, and untreated it is fatal
Siblings must be screened, since presymptomatic treatment prevents all organ damage
Contrast with Menkes disease — also a copper transport defect (ATP7A), but X-linked and causing deficiency, with kinky hair and neurodegeneration
Kayser–Fleischer rings are present in almost all patients with neurological disease, but may be absent in purely hepatic presentations

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