Wilson’s disease


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Wilson disease overview for CME on Movement Disorder at GNRC Guwahati 2011 Feb 19th

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Wilson’s disease

  1. 1. Wilson’s Disease<br />Dr PS Deb MD, DM<br />GNRC Gawhati India<br />
  2. 2. SAK Wilson <br />MD Thesis: 1911<br />10 cases of ”Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver”<br />6cases from past publication<br />4 cases of his own, 3 diagnosed at post mortom one antemortom<br />
  3. 3. Gower’s 1888 - Tetanoid Chorea<br /><ul><li>10 years old boy, suffering with progressive extrapyramidal syndrome (dystonic) died in 7 months, but autopsy of brain was normal.
  4. 4. brother and three other relations also died of similar illness</li></li></ul><li>Gower’s case: 1888<br />
  5. 5. Ormerod - 1890<br />A case of cirrhosis of liver with obscure fatal nervous symptom<br />Mild bilateral atrophy of putamen<br />
  6. 6. Homen - 1892<br />A peculiar disease in two brother and sister in the form of progressive dementia probably LuesHeriditariaTarda<br />Fixed smile, open mouth, contracture and emaciation<br />Symmetrical softening of putamen<br />
  7. 7. Wilson’s Cases 1 S.T. <br />
  8. 8. Wilson’s case 3 E.P.<br />
  9. 9. Wilson’s Case 1- Pathology <br /><ul><li>Hepatic cirrhosis
  10. 10. Bilateral symmetrical degeneration of leniticularnucleus</li></li></ul><li>Wilson on - Etiology<br />Diseases is not congenital, most likely acquired<br />Familial, not hereditary<br />The morbid agent is probably of the nature of a toxin but not syphilitic<br />Acute or sudden onset <br />Variability of symptom<br />Toxin may be elaborated in the liver like Kernicterus<br />Toxin has a specific action on the lenticular nucleus<br />Nature of toxin is unknown but not microbial<br />
  11. 11. Wilson’s Summary of cases<br />
  12. 12. Clinical conclusion - Wilson<br />In pure cases the affection constitutes an extrapyramidal motor disease occurring in young people and very often familial. <br />It is progressive and fatal within a varying period months to years.<br />It is characterized by : generalized tremor, dysarthria and dysphagia, muscular rigidity and hypertonicity, emaciation, spasmodic contractions, contractures, emotionalism. <br />In some ways the disease bears a resemblance to paralysis agitans, and throws light on the problem of that affection.<br />Although cirrhosis of the liver is constantly found in this affection, and-is an essential feature of it, there are no signs of liver disease during life.<br />
  13. 13. Wilson on – Pathophysiology (IM)<br />Jackson: “Positive symptom cannot be caused by negative lesion”<br />IM - not caused by pyramidal system irritation <br />IM needs intact pyramidal system hence IM <br />Extrapyramidal system must be injured<br />ChroeaAthetosis caused by lesion of Affrent<br />Tremor rigidity by efferent<br />Dysarthriadysphagia is due to hypertonia<br />
  14. 14. Wilson on Treatment<br />“What can be said of the treatment of disease? Its nature must be discovered before treatment can be lifted from empirical to the rational level”<br />
  15. 15. Further development<br />1948 : Cumings – Cu increased in liver and brain, BAL (1951)<br />1952: Scheinberg – Ceruloplasmin<br />1956: J Walsh – Penicillamine, Trientine (82)<br />1980: Genetic basis<br />Inida : <br />1963 first Case report <br />Dr NH Wadia and Dasture <br />1970 WD Clinic at NIMHANS<br />
  16. 16. Epidemiology <br /> Prevalence<br />Europe: 30/100,000<br />Asia : 33-68/100,000<br />Incidence 1/30000<br />El Salvador 1 in 186. <br />Carrier: 1/100 (El Salvador 1/4)<br />India <br />Neurological ?<br />Hepatic 19.7% Metabolic liver disease in children commonest WD <br />NIMHANS : 15-20 New cases per year<br />Age of onset: 10-20 (<5 never, >50 rare)<br />Hepatic :10-15 (40%)<br />Neurologic 15-20 (40%)<br />Sex: M>F<br />. <br />
  17. 17. WD – Genetic Link<br />Autosomal recessive disorder<br />The WD gene, ATP7B is located on the long arm of chrom. 13q14.1<br />The WD gene encodes a copper-transporting P-Type ATPase) which is expressed predominantly in the liver<br />
  18. 18. Mutations in WD gene (ATP7B)<br />ATP7B gene <br />Deletions 60<br />Insertions 21<br />Nonsense 19<br />Missense166<br />Splice 23<br />total 289 <br />India<br />Chandigarh: T3305C, C2975A, 29977ins A<br />Kolkata: C813A 19%<br />Vellore: G3182A 16%, C813A 12%<br />51 Mutation of ATP7B, 34 novel<br />C813A mutation commonest<br />World<br />European PH1069Q 60%<br />Chinese pR778L 45%<br />
  19. 19. Wilson Disease Pathophysiology<br />
  20. 20. Pathology: Brain<br />bilaterally symmetrical putaminal (P) softening (arrows) extending laterally up to the external capsule<br />Whole mount preparation stained with Luxol Fast Blue shows relative preservation of internal capsule and pale and softened neuropil in the putamen (P, arrow).<br />Softened area in the putamen has bizarre astrocytes with vesicular lobulated nuclei (arrow) with inset showing Alzheimer type 2 astrocytes in the neuropil(arrow). H and E<br />Large opalski cell characteristic of Wilson’s disease has irregular eosinophilic cytoplasm and small peripherally placed pyknotic nucleus. H and E<br />
  21. 21. Liver histology<br />Histological abnormalities precede clinical appearance<br />Helpful diagnostic clues: <br />steatosis<br />ballooned hepatocytes<br />glycogenated nuclei<br />moderate to marked copper deposition<br />lymphocytic portal and interface hepatitis<br />Untreated, progresses to cirrhosis<br />
  22. 22. Liver Pathology <br />Slice of enlarged liver shows microandmacronodular cirrhosis. <br />Inset demonstrates copper deposits within hepatocytes on rubeanic acid stain. Inset: Rubeanic acid<br />
  23. 23. Pathological Stages<br />Stage I - The initial period of accumulation of copper by hepatic binding sites<br />Stage II - The acute redistribution of copper within the liver and its release into the circulation<br />Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease<br />Stage IV - The achievement of copper balance with chronic chelation therapy<br />
  24. 24. Clinical Manifestation<br />
  25. 25. WD: Clinical Features - Indian<br />
  26. 26. NEUROLOGIC PRESENTATION: NIMHANS (307 cases)<br />
  27. 27. North west study (21 cases)<br />Wilson's disease: A study of 21 cases from north-west India.<br />Annals of Indian Academy of Neurology, December 2007<br />
  28. 28. North East India (49 cases)<br />J Assoc Physicians India. 2001 Sep;49:881-4.<br />Wilson's disease in Eastern India.<br />
  29. 29. KF Ring<br />Neuropsychiatric: 95% . <br />Hepatic : 30 to 50 % <br />KF rings are not specific for WD.<br />They may be found in other chronic <br /> liver disease, PBC, PSC, AIH, and familial cholestatic syndromes. <br />
  30. 30. PSYCHIATRIC PRESENTATION<br />15-20% of patients may present with purely psychiatric symptoms .<br />Phobias , <br />compulsive behaviors, <br />aggressive and antisocial behaviors<br />Schizophrenia<br /> Psychosis<br />Cognitive decline<br />
  31. 31. HEPATIC PRESENTATION<br />Acute hepatitis,<br />Chronic liver disease— portal HTN.<br />Autoimmune hepatitis. <br />Fulminant hepatic failure, with sev. coagulopathy and encephalopathy .<br />Recurrent bouts of hemolysismay <br /> predispose to the development of gallstones .<br />Wilson disease is rarely complicated by hepatocellular carcinoma.<br />
  32. 32. Extrahepatic disorders<br />Hemolytic anemia <br />Fanconi's syndrome<br />Nephrolithiasis<br />Hypoparathyroidism<br />Amenorrhea and <br />Testicular problems <br />Infertility . <br />Arthritis, <br />Rhabdomyolysis.<br />Cardiomyopathy<br />Pancreatitis<br />
  33. 33. Clinical Pointers<br />Classical<br />Unexplained jaundice<br />Hepatic + Extrapyramidal syndrome<br />Family History<br />Most likely<br />Extrapyramidal syndrome in young<br />Progressive behavioral syndrome<br />Multi axial neurological<br />Psychiatric<br />Poor school performance<br />Seizure<br />Recurrent pathological #<br />Unexpalined hematological abnormality<br />
  34. 34. Investigation<br />Biochemical<br />Serum ceruloplasmin <20mg/dL<br />24hr Urinary Copper >100micg/d<br />Serum free copper >10micg/dL<br />Liver Copper >250micg/g <br />Ophthalmological<br />Slit lamp KF ring<br />Imaging<br />X-ray Osteoporosis<br />Ultrasound Cirrhosis<br />CT Scan<br />MRI<br />Genetics <br />
  35. 35. Pathway for Investigation<br />
  36. 36. Electrophysiology<br />EEG 41.1%<br />VEP 35%<br />BAER 42.1%<br />Dyautomaumia<br />ECG <br />
  37. 37. Imaging<br />Ultrasound Abdomen<br />Cirrhosis <br />Portal hypertension<br />X-ray: Osteoarthritis, arthirtis<br />CT brain : Low sensitivity, <br />MRI brain High sensitivity<br />Bilateral basal ganglionic changes<br />Brain stem changes<br />White matter changes<br />
  38. 38. CT brain<br />Cortical atrophy 44.8%<br />Ventricular dilatation 44% <br />Caudate atrophy 25%<br />Brain stem atrophy 31.9%<br />Cerebellar atrophy 19%<br />Hemispheric hypodensities 29.3%<br />Basal ganglionichypodensities. 19.8%<br />Thalamic hypodensities. 10.3%<br />
  39. 39. MRI brain<br />Atrophy of the cerebrum, 70%<br />Brainstem, 66%<br />Cerebellum 52%<br />Signal abnormality in putamen, 72%<br />Caudate, 61%<br />Thalami, 58%<br />Midbrain, 49%<br />Pons , 20%<br />Cerebral white matter 25%<br />Cortex 9%<br />Medulla 12%<br />Cerebellum 10%<br />Face of giant panda' sign 12% <br />CPM like feature 7% <br />Bright claustral sign 4% <br />
  40. 40. MRI in WD<br />‘Face of giant panda’ sign; <br />MRSS: decreased NAA and therefore a decreased ratio with other products<br />Bright lateral putamen or claustral sign; <br />Pallidalhyperintensity<br />
  41. 41. Brain Stem changes: CPM like<br />Classical: Hyperintensity of whole of the central pons sparing a peripheral rim; <br /> Bisected pontine signal change by a horizontal line and; <br />Trisected: Pontine hyperintensity trisected by a hypointense line like ‘Mercedes Benz’ sign<br />
  42. 42. MRI other changes<br />Bilateral basal ganglionic and thalamic hyperintensity in addition to mild-to-moderate degree diffuse atrophy <br />Extensive diffuse white matter changes <br />Bilateral lentiform, thalamic, midbrain and white matter hyperintensity<br />Midbrain hyperintensity in the tectal region <br />
  43. 43. Family Screening<br />Biochemical Testing<br />Children of patient: Begin at age 2 if asymptomatic, repeat once in 5 years unless reason to pursue further.  <br />Siblings of patient:<br />Physical examination and brief history of any liver or neurological symptoms.<br />Liver Function Tests:  ALT, AST, Albumin, Bilirubin.<br />Ceruloplasmin and Serum Copper.<br />24 hour urine copper<br />Slit-lamp exam of the eyes for Kayser-Fleischer ring<br />If no K-F rings, abnormal liver functions tests, and low ceruloplasmin:  liver bio<br />
  44. 44. Molecular Genetic Testing<br />Linkage analysis (Haplotype analysis)<br />Identify a set of closely linked segments of DNA, patient with family members<br />Gene sequencing (mutation screening of the entire ATP7B gene)<br />Analysis of a specific location in the ATP7B gene for a known particular mutation<br />
  45. 45. Treatment Options<br />
  46. 46. Diet<br />Avoid Copper rich diet<br />liver, shellfish (especially lobster), nuts, chocolate, soya products, gelatin, and mushrooms.<br />Water with copper >1ppm (well water)<br />
  47. 47. Chelating agents: Penicillamine and Trientine<br />Copper<br />intestine<br />Penicillamine/Trientine<br />Ceruloplasmin<br />urine<br />
  48. 48. D-Penicillamine<br />Dose <br />Initial: 1-1.5 g/day adults or 20 mg/kg/day children<br />Maintenance: 0.75-1 g/day<br />Side effect<br />Fever, rash<br />Proteinuria<br />Lupus like reaction<br />Aplastic anemia<br />Leukopenia<br />Thrombocytopenia<br />Nephrotic syndrome<br /> Degenerative changes in skin<br />Hepatotoxicity<br />Neurological Deterioration occurs in 10%-20% during initial phase<br />
  49. 49. Trientine (triethylene tetramine dihydrochloride)<br />Dose: 1-1.2 g/day <br />Side effects : <br />Gastritis<br />Aplasticanemia rare<br />Neurological Deterioration 10%-15% during initial phase .<br />
  50. 50. Tetrathiomolybdate<br />Mode : Chelator and also blocks copper absorption<br /> Side effects : <br />BM suppresion<br />Hepatotoxicity<br />Rare reports of ND during initial phase of treatment<br />
  51. 51. Zinc Acetate/Sulfate<br />Copper<br />Zinc<br />intestine<br />metallothionein<br />Albumin<br />Ceruloplasmin<br />
  52. 52. Zinc<br /><ul><li>Indication:
  53. 53. Following penicillamine
  54. 54. Penicillamine intolerance
  55. 55. Prophylactic to aymptomatic sibs
  56. 56. New cases (cannot afford Penicillamine)
  57. 57. Dose : Initial: 50 mg T.I.D (adults)
  58. 58. Side effects
  59. 59. Gastritis
  60. 60. Zincaccumulation
  61. 61. Possible changes in immune
  62. 62. ND can occur during initial phase </li></li></ul><li>Indications (AALD)<br />
  63. 63. Follow up<br />Depends on the severity of the neurological or hepatic features<br />Assess any sign of hepatic decompensation<br />24-h urinary Cu excretion (denotes adequate treatment)<br />Monitor penicillamine side effects<br />