Pathophysiology Normally, dietary copper is absorbed from the stomach and proximal small intestine and is rapidly taken into the liver, where it is stored and incorporated into caeruloplasmin, which is secreted into the blood. The accumulation of excessive copper in the body is ultimately prevented by its excretion, the most impoant route being bile. In Wilson's disease, there is almost always a failure of synthesis of caeruloplasmin; however, some 5% of patients have a normal circulating caeruloplasmin concentration and this is not the primary pathogenic defect. The amount of copper in the body at bih is normal but thereafter it increases steadily; the organs most affected are the liver, basal ganglia of the brain, eyes, kidneys and skeleton. The ATP7B gene encodes a member of the copper-transpoing P-type adenosine triphosphatase family, which functions to expo copper from various cell types. At least 200 different mutations have been described. Most cases are compound heterozygotes with two different mutations in ATP7B. Attempts to correlate the genotype with the mode of presentation and clinical course have not shown any consistent patterns. The large number of culprit mutations means that, in contrast to haemochromatosis, genetic diagnosis is not routine in Wilson's disease, although it may have a role in screening families following identification of the genotype in an index patient. Clinical features Symptoms usually arise between the ages of 5 and 45 years. Hepatic disease occurs predominantly in childhood and early adolescence, although it can present in adults in their fifties. Neurological damage causes basal ganglion syndromes and dementia, which tends to present in later adolescence. These features can occur alone or simultaneously. Other manifestations include renal tubular damage and osteoporosis, but these are rarely presenting features. Liver disease Episodes of acute hepatitis, sometimes recurrent, can occur, especially in children, and may progress to fulminant liver failure. The latter is characterised by the liberation of free copper into the blood stream, causing massive haemolysis and renal tubulopathy. Chronic hepatitis can also develop insidiously and eventually present with established cirrhosis; liver failure and poal hypeension may supervene. The possibility of Wilson's disease should be considered in any patient under the age of 40 presenting with recurrent acute hepatitis or chronic liver disease of unknown cause, especially when this is accompanied by haemolysis. Neurological disease Clinical features include a variety of extrapyramidal features, paicularly tremor, choreoathetosis, dystonia, parkinsonism and dementia . Unusual clumsiness for age may be an early symptom. Neurological disease typically develops after the onset of liver disease and can be prevented by effective treatment staed following diagnosis in the liver disease phase. This increases the impoance of diagnosis in the liver phase beyond just allowing effective management of liver disease. Ref Davidson edition23rd pg896