1. Wilson Disease By Geo Cherian Roll no.1487

2. OUTLINE What is Wilsons Disease Genetics Normal Copper Physiology/metabolism Pathogenesis Morphology Manifestation in the brain Clinical Features Diagnosis Treatment

3. What is Wilsons Disease? Wilsons Disease is an autosomal recessive disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye. -Discovered by Samuel Alexander kinnier Wilson (1878-1937)

4. Genetics of the disease 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 Incidence of the disease is approximately 1 per 30,000 population (less than hemochromatosis)

5. Normal Copper Physiology/metabolism Normal copper physiology involves the following sequence: 1. Absorption of ingested copper (2 to 5 mg/day) 2. Plasma transport in complex with albumin 3. Hepatocellular uptake, followed by binding to an α2- globulin (apoceruloplasmin) to form ceruloplasmin 4. Secretion of ceruloplasmin- bound copper into plasma, where it accounts for 90% to 95% of plasma copper 5. Hepatic uptake of desialylated, senescent ceruloplasmin from the plasma, followed by lysosomal degradation and secretion of free copper into bile

6. In 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 lead to red cell hemolysis. It also is deposited in many other tissues, such as the brain, cornea, kidneys, bones, joints, and parathyroid glands, where it also produces damage through the same mechanisms that injure hepatocytes. Concomitantly, urinary excretion of copper increases markedly. PATHOGENISIS

7. Morphology The liver often bears the brunt of injury in Wilson disease, with protean hepatic changes ranging from relatively minor to massive damage and mimicking many other diseases. 1. Wilson disease may mimic fatty liver disease, with mild to moderate steatosis, steatohepatitis, and even similar patterns of scarring. 2. Patterns of A) acute hepatitis: in its most severe form, may manifest as fulminant hepatic failure. AND B)chronic hepatitis : coexist with features of fatty liver disease, including the mononuclear infiltrates and lobular- interface hepatitis of the former(Acute), with the steatosis, hepatocyte ballooning, and Mallory- Denk bodies of the latter(chronic).  CIRROHSIS Both simulate those of viral hepatitis.

8. Manifestation in the Brain In the brain, toxic injury primarily affects the basal ganglia, particularly the putamen, which demonstrates atrophy and even cavitation. Nearly all patients with neurologic involvement develop eye lesions called Kayser-Fleischer rings (green to brown deposits of copper in Descemet membrane in the limbus of the cornea)  AKA hepatolenticular degeneration

9. CLINICAL FEATURES disorder rarely manifests before the age of 6 years or in elderly persons. most common presentation is acute or chronic liver disease. Abnormal posture of limbs, mobility issues, confusion and delirium, emotional or behavioral changes, abdomen enlargement, speech impairment, jaundice Neuropsychiatric manifestations, including mild behavioral changes, frank psychosis, or a Parkinson disease–like syndrome Unlike nearly all other forms of cirrhosis, hepatocellular carcinoma is quite uncommon in Wilson disease.

10. DIAGNOSIS Excess copper deposition can often be demonstrated by special stains 1. rhodanine stain for copper, 2. orcein stain for copper- associated protein). Because copper also accumulates in chronic obstructive cholestasis, and because histologic analysis cannot reliably distinguish Wilson disease from other causes of liver disease, demonstration of hepatic copper content in excess of 250 μg/g dry weight is most helpful for making a diagnosis. Demonstration of Kayser- Fleischer rings or of markedly elevated hepatic copper levels in a person with low serum ceruloplasmin strongly favors the diagnosis.  SLIT EYE LAMP EXAMINATION

11. TREATMENT Early recognition and long- term therapy with copper chelators (such as D- penicillamine) and zinc salts (which lower copper uptake from the gut) have dramatically altered the usual progressive downhill course. PENNY’s=COPPER  PENNYcilamine Other Chelators: TRIENTINE, ZINC ACETATE

12. Thank You!