病理学与病理生理学 消化系统疾病 肝豆状核变性（双语学习）.pptxVIP

Wilson DiseaseSong Wen-gangDepartment of PathologyLuohe Medical CollegeDecember 25, 2014ContentVocabularycopperautosomal recessivechromosomehereditary hemochromatosisproteanfulminantIntroductionThis autosomal recessive disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye. The cause is loss-of-function mutations in the ATP7B gene, more than 300 of which have been identified. This gene, located on chromosome 13, encodes an ATPase metal ion transporter that localizes to the Golgi region of hepatocytes.About 1 in 100 people are asymptomatic carriers, and the incidence of the disease is approximately 1 per 30,000 population; thus, it is much less common than hereditary hemochromatosis.PATHOGENESISNormal copper physiology involves the following sequence:1. Absorption of ingested copper (2 to 5 mg/day)2. Plasma transport in complex with albumin3. Hepatocellular uptake, followed by binding to an α2-globulin (apoceruloplasmin) to form ceruloplasmin4. Secretion of ceruloplasmin-bound copper into plasma, where it accounts for 90% to 95% of plasma copper5. Hepatic uptake of desialylated, senescent ceruloplasmin from the plasma, followed by lysosomal degradation and secretion of free copper into bilePATHOGENESISIn Wilson disease, the initial steps of copper absorption and transport to the liver are normal. However, without ATP7B activity, copper cannot be passed on to apoceruloplasmin and therefore cannot be excreted into bile, the primary route for copper elimination from the body. Copper thus accumulates progressively in hepatocytes, apparently causing toxic injury by a three-step mechanism:(1) promoting the formation of free radicals,(2) binding to sulfhydryl groups of cellular proteins, and (3) displacing other metals in hepatic metalloenzymes.Usually by the age of 5 years, copper begins to escape from the overloaded, damaged hepatocytes into the circulation. Free copper generates oxidants that can