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WILSON`S DISEASE
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- 2. • Progressive lenticular degeneration,a familial nervous disase associated with cirrhosis of the liver. SAMUEL ALEXANDER KINNIER WILSON Thesis, Univ. of Edinburgh, 1912.
- 3. HISTORY • 1902-KAYSER&FLEISCHER • 1912-SAKWILSON • 1921-HALL • 1948-CUMMINGS • 1951-BAL IS INTRODUCED • 1952-SCHEINBERG&GITLIN-LOW CERULOPLASMIN. • 1953-PATTERN OF INHERITANCE
- 4. • 1956-WALSHE –D-PENCILLAMINE •1961-SCHOUWINK-EFFECTIVENESS OF ZINC • 1969-TRIENTINE • 1985-WILSONS CHROMOSOME • 1986-AMMONIUM TETRA THIO MOLYBDATE • 1993-MENKES GENE AND WILSONS GENE IDENTIFIED
- 5. Epidemology • Occurs worldwide •Incidence of one in 30,000 • Prevalence • Europe: 30/100,000 • Asia : 33-68/100,000 Incidence 1/30000 • El Salvador 1 in 186. • Carrier: 1/100 (El Salvador 1/4) • The age at onset of symptoms ranges from 6 to about 40 years.
- 6. • India • Hepatic19.7% Metabolic liver diseasein children commonest WD • NIMHANS: 15-20 New casesper year • Ageof onset: 10-20 (<5 never, >50 rare) • Hepatic :10-15 • Neurologic 15-20 • Sex: M>F .
- 7. THE COPPER PATHWAY •Copper is a micro nutrient and an essential cofactor for many enzymes cytochrome c oxidase and superoxide dismutase. • Daily copper intake is 1-4 mg • Of this 50%is unabsorbed and passed in stool,30%lost through the skin,20%is absorbed in enterocyte by metallothionein. • Copper is then exported from enterocyte to the portal blood with the help of menkes protein.
- 8. • In theportal blood copper is carried loosely bound to albumin,aminoacids esp,histidineand transcuprein. • Copper is transported to the hepatocyte at the basolateral membrane,from the portal blood. • The hepatocyte protects itself against copper toxicity by following mechanisms • 1)controlling uptake of copper • 2)chaperoning copper to various locations • 3)binding free cytoplasmic copper • 4)actively transporting copper (by wisons disease protein.)
- 9. Copper chaperone proteins •1)Hah 1 • 2)Lys 7 • 3)Cox 17.
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- 11. Foods rich incopper • Liver,kidney,choclate,nuts,dried beans,green chillies ,mushroom,legumes,unprocessed meat,milk products,dried fishand shell fish.
- 12. WD – GeneticLink • Autosomal recessive disorder • The WD gene, ATP7B is located on the long arm of chrom. 13q14.21 • The WD gene encodes a copper-transporting P-Type ATPase) which is expressed predominantly in the liver
- 13. Mutations in WDgene (ATP7B) ATP7B gene • Deletions 60 • Insertions 21 • Nonsense 19 • Missense 166 • Splice 23 total 289 • India • Chandigarh: T3305C, C2975A, 29977insA • Kolkata: C813A 19% • Vellore: G3182A 16%, C813A 12% • 51 Mutation of ATP7B, 34 novel • C813A mutation commonest • World • European PH1069Q 60% • Chinese pR778L 45%
- 14. Molecular Mechanism • TheWilson Disease Protein (WNDP) has two functions: 1. Export of copper from the cell and 2. Incorporation into copper-dependent enzymes
- 15. Copper Metabolism -Normal
- 16. Copper Metabolism –WD Mutations
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- 18. WD - Pathophysiology •Mutations in the ATP7B gene result in 1. Retention of copper in the liver 2. Impaired incorporation of copper into ceruloplasmin • This accumulation is then followed by hepatic and/or neurological symptoms due to copper toxicity
- 19. Pathology • The earliestchanges include the glycogen deposition in nuclei of periportal hepatocytes and microvesicular fatty infiltration. • Then comes the infiltration of lymphocytes and plasma cells. • If untreated it progresses to macronodular cirrhosis and fulminant hepatitis.
- 20. Histopathology • Histologic abnormalitiesprecede clinical appearance • Helpful diagnostic clues: • Steatosis • Ballooned hepatocytes • Glycogenated nuclei • Moderate to marked copper deposition • Lymphocytic portal and interface hepatitis • Untreated, progresses to cirrhosis
- 21. WD- cirrhotic stage(Rhodanine stain) This reveals accumulation of copper , most in a nodular cluster of hepatocytes
- 22. DEISS’S STAGING OFWD • Stage 1 : Begins at Birth , pts are Asymptomatic • Stage 2: liver is saturated , Copper is released into serum • 2.a : It can debut with Hemolytic Anemia or • 2b. Liver failure • Stage 3 : Copper accumulates in extra hepatic tissues like brain and Eyes (KF rings) • Stage 4 : Neurological Symptoms Develop • Stage 5 : therapy is initiated and Symptoms to fade away
- 23. HEPATIC PRESENTATION • Ahepatic presentation of Wilson disease is more common in children than in adults. • Symptoms may be vague and nonspecific, • Pts may present with a self-limited clinical illness – acute hepatitis, • Pts may present with severe, established chronic liver disease — portal HTN. • Wilson disease may manifest as clinical liver disease indistinguishable from autoimmune hepatitis.
- 24. • Wilson diseasemay also manifest as fulminant hepatic failure, with severe coagulopathy and encephalopathy . • Recurrent bouts of hemolysis may predispose to the development of gallstones . • Wilson disease is rarely complicated by hepatocellular carcinoma. • Asymptomatic hepatomegaly.
- 25. NEUROLOGIC PRESENTATION • Tendsto occur in the 2nd and 3rd decades or later • Two main patterns, 1. MOVEMENT DISORDER 2. RIGID DYSTONIA
- 26. PSYCHIATRIC PRESENTATION • 20%of patients may present with purely psychiatric symptoms . • Phobias , compulsive behaviors, aggressive and antisocial behaviors have been reported.
- 27. OCULAR SIGNS • Theclassic Kayser-Fleischer ring is caused by copper deposition in Descemet's membrane of the cornea. • A careful slit-lamp examination is mandatory. • Copper deposition in the lens (sunflower cataract), which does not interfere with vision
- 29. • Pts withexclusively hepatic involvement have KF rings in 30 to 50 % • Pts with a neurologic or psychiatric presentation of WD have KF rings in almost 95% . • KF rings are not specific for WD. • They may be found in other chronic liver disease, PBC, PSC, AIH, and familial cholestatic syndromes.
- 30. Extrahepatic disorders • Hypoparathyroidism •Pancreatitis • Amenorrhea • Hyperpigmentation. • Testicular problems • Infertility • Hemolytic anemia • Arthritis, • Fanconi's syndrome • Rhabdomyolysis. • Nephrolithiasis • Cardiomyopathy
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- 32. • High indexof suspicion. • Classic triad include • Hepatic disease • Neurologic disease and KF ring. • No single test is diagnostic of WD,but the presence of any two of the following is sufficient for the diagnosis. • Low sr ceruloplasmin,KF ring,hepatic cu>250micrgm/gm dry wt.
- 34. 1)serum ceruloplasmin 2)KF ring 3)serumcopper 4)serum free copper 5)urine copper 6)liver biopsy and liver copper 7)features of hemolysis 8)scanning of brain 9)molecular genetic testing 10)radio copper loading test.
- 35. Diagnosis of fulminantWD • H/O consanguinity • Absence of other factors • h/o sibling death due to undiagnosed liver disease • h/o neuropsychiatric illness in family • High bilirubin with low transaminases • Bermans ratio <2 • Evidence of hemolysis in peripheral smear • Siblings or parents with low ceruloplasmin levels • High urine copper.
- 36. MRI in WD a.‘Face of giant panda’ sign; b. MRSS: decreased NAA and therefore a decreased ratio with other products c. Bright lateral putamen or claustral sign; d. Pallidal hyperintensity
- 37. Modified calicut score score Consanguinity2 Sibling death due to liver disease 2 Low ceruloplasmin 3 Low ceruloplasmin and high SGPT in siblings and parents 3 KF ring 3 High urine copper 3 Sun flower cataract 4
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- 39. TREATMENT 1954 Peters BAL 1956Walshe Penicillamine 1969 Walshe Trientine 1984 Walshe Tetrathiomolybdate 1983 Brewer zinc acetate
- 40. D-Penicillamine • Mode :General chelator , induces urinary Cu excretion. • Dose Initial: 1-1.5 g/day adults or 20 mg/kg/day children , Maintenance: 0.75-1 g/day
- 41. • Side effects: • Fever, rash Proteinuria Lupus like reaction • Aplastic anemia • Leukopenia • Thrombocytopenia • Nephrotic syndrome • Degenerative changes in skin • Hepatotoxicity • ND occurs in 10%-20% during initial phase .
- 42. Trientine (triethylene tetramine dihydrochloride) •Mode :General chelator , induces urinary Cu excretion. • Initial: 1-1.2 g/day ; Main : same • Side effects : • Gastritis • Aplastic anemia rare • ND 10%-15% during initial phase .
- 43. Zinc • Mode :Metallothionein inducer, blocks intestinal absorption of copper . • Dose : Initial: 50 mg T.I.D (adults) • Side effects • Gastritis • Zinc accumulation • Possible changes in immune • ND can occur during initial phase .
- 44. Tetrathiomolybdate • Mode :Chelator and also blocks copper absorption • Side effects : • BM suppresion • Hepatotoxicity • Rare reports of ND during initial phase of treatment
- 45.
- 46. Prognostic Index ofNazer Score points
- 47. • Pts withscores 6 - medical therapy. • Pts with scores 10 - OLT, • Pts with scores between 7 and 9 require clinical judgment . • Treatment is life long.
- 48. At present: Livertransplantation in liver failure At present: Zinc acetate ,Trientine authorised in the US and EU Tetrathiomolybdate used experimentally in the US and EU In the future: Gene therapy, cell therapy… based on current molecular knowledge
- 49.
Editor's Notes
- #14 Wilson&apos;s disease is an autosomal recessive disorder of hepatocyte copper trafficking caused by impaired function of P-type adenosine triphosphatase (ATPase), encoded by ATP7B gene located on chromosome 13q14 and consists of 21 exons. This important genetic breakthrough came in 1993 from three independent groups. [15],[16],[17] Until now more than 400 mutations in the gene have been documented from various countries. [18] Genetic analyses from India have reported mainly from three centers: Chandigarh, Kolkata and Vellore. [19],[20],[21] The commonest mutations in these studies are variable and include: (a) Chandigarh group: T3305C, C2975A, 2977insA and 3031insC-6% each; (B) Kolkata group: C813A-19% and (c) Vellore group: G3182A-16% and C813A-12%. Till date all together, a total of 51 mutations of ATP7B have been documented in India including 34 novel mutations (Chandigarh-18, Kolkata-5, and Vellore-11). Of the mutations documented in India, C813A is the common mutation. There is no single predominant mutation noted in the Indian population unlike the studies in other countries: PH1069Q in 60% of central European population and pR778L in 45% of Chinese population, thus suggesting genetic heterogeneity in India. [18] Molecular Genetic Testing Mutation analysis for diagnosis is cumbersome because of the occurrence of many mutations, each of which is rare. Furthermore, most patients are compound heterozygotes (i.e. carry two different mutations). Direct mutation analysis for diagnosis is only helpful if a mutation occurs with a reasonable frequency in the population. In northern, central and eastern Europe,[12,14,15] the most common mutations are: H1069Q mutation (allele frequency, 43.5%), mutations of exon 8 (6.8%), 3400delC (3%) and P969Q (1.6%).[32] In other parts of the world, the pattern of mutations is different (Turkey, A1003T and P969Q;[33] Sardinia, UTR -441/-427del, 2463delC;[34] Far East, R778L[35,36]). Eventually, a multiplex polymerase chain reaction for the most frequent Wilson&apos;s disease mutations in the region should make direct mutation analysis for diagnosis feasible and obtainable within a week.
- #37 Figure 4 :(a) MRI in a patient with Wilson’s disease showing the classical ‘Face of giant panda’ sign; (b) Proton MR spectroscopy showing decreased NAA and therefore a decreased ratio with other products in a patient with WD; (c) bright lateral putamen or claustral sign; (d) A 26-year-old woman with hepatic form of WD showing pallidal hyperintensity in axial T1WI