Wilson's disease (hepatolenticular degeneration)

Dietary copper is normally absorbed from the stomach and upper small intestine. It is transported to the liver loosely bound to albumin. Here it is incorporated into apocaeruloplasmin, a glycoprotein synthesized in the liver, to produce caeruloplasmin which is secreted into the blood. Copper is normally excreted in the bile.

Wilson's disease is a very rare inborn error of copper metabolism that results in copper deposition in various organs, including the liver, the basal ganglia of the brain and the cornea. Autosomal recessive, incidance 1in 30000. It is potentially treatable and all young patients with liver disease must be screened for this condition.

Aetiology

Autosomal recessive disorder with a molecular defect within a copper-transporting ATPase encoded by a gene (designated ATP7B) located on chromosome 13. It occurs world-wide, particularly in countries where consanguinity is common. There is a failure of both incorporation and biliary excretion of copper. In the liver, copper is incorporated into caeruloplasmin and then excreted with bile. There is a low serum caeruloplasmin in over 80% of patients owing to poor synthesis, but the precise mechanism for the failure of copper excretion is not known.

The liver histology is not diagnostic and varies from that of chronic hepatitis to macronodular cirrhosis. Stains for copper show a periportal distribution but this can be unreliable. The basal ganglia are damaged and show cavitation, the kidneys show tubular degeneration, and erosions are seen in bones.

Pathology

Clinical features

Children usually present with hepatic problems, whereas young adults have more neurological problems, such as tremor, dysarthria, involuntary movements and eventually dementia. The liver disease varies from episodes of acute hepatitis, especially in children, which can go on to fulminant hepatic failure to chronic hepatitis or cirrhosis.

Typical signs are of chronic liver disease with neurological signs of basal ganglia involvement. The presence of neurological fidings is almost synonymous with cirrhosis. A specific sign is the Kayser-Fleischer ring, which is due to copper deposition in Descemet's membrane in the cornea. It appears as a greenish brown pigment at the corneoscleral junction just within the cornea. Identification of this ring frequently requires slit-lamp examination. It may be absent in young children. 95% of patients with neurologic or psychiatric presentation have Kayser-Fleischer ring. Copper deposition in the lens leads to sunflower cataract, which does not interfer with vision. Proximal renal tubular acidosis, nephrocalcinosis, aminoacidurea and hypouricaemia. Chondrocalcinosis, OA, oesteomalcia, oesteoprosis. Blue nails

Investigations

Serum copper and caeruloplasmin Extremely low level of caeruloplasmin should be taken as strong evidance for the diagnosis of WD, but normal level does not exclude the diagnosis. Decrease total serum copper but increase in free non-caeruloplasim bound copper. Urinary copper is usually increased (100-1000 mg in 24 hours; normal levels < 40 mg in 24 hours). Liver biopsy. The diagnosis depends on measurement of the amount of copper in the liver, although high levels of copper are also found in the liver in chronic cholestasis. Measurement of 64Cu incorporation into the liver may be helpful. Haemolysis and anaemia Coomb negagtive may be present (gall stones). Genetic analysis is limited as already over 200 mutations have been identified at the ATP7B locus. low ALP/low serum uric acid may occur in asymptomatic disease or neurological disease (due to Fanconi syndrome).

Treatment

Lifetime treatment with penicillamine, 1-1.5 g daily, is effective in chelating copper. If treatment is started early, clinical and biochemical improvement can occur. Urine copper levels should be monitored and the drug dose adjusted downwards after 2-3 years. Serious side-effects of the drug occur in 10% and include skin rashes, leucopenia and renal damage. Need to supplement pyridoxine Trientine is the second line treatment for patients intolerant to penicillamine. Oral Zinc is the third line. It compete eith copper for intestinal absorption. Tetrathiomolybdate suitable for severe neurologic WD Avoid chocolate, shellfish, liver, nuts, mushrooms. All siblings and children of patients should be screened and treatment given even in the asymptomatic if there is evidence of copper accumulation.

Prognosis

Early diagnosis and effective treatment have improved the outlook. Neurological damage is, however, permanent. Fulminant hepatic failure or decompensated cirrhosis should be treated by liver transplantation. Copper metabolism, my gastro room blog