2. SAK Wilson MD Thesis: 1911 10 cases of ”Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver” 6cases from past publication 4 cases of his own, 3 diagnosed at post mortom one antemortom
3.
4.
5. Ormerod - 1890 A case of cirrhosis of liver with obscure fatal nervous symptom Mild bilateral atrophy of putamen
6. Homen - 1892 A peculiar disease in two brother and sister in the form of progressive dementia probably LuesHeriditariaTarda Fixed smile, open mouth, contracture and emaciation Symmetrical softening of putamen
12. Clinical conclusion - Wilson In pure cases the affection constitutes an extrapyramidal motor disease occurring in young people and very often familial. It is progressive and fatal within a varying period months to years. It is characterized by : generalized tremor, dysarthria and dysphagia, muscular rigidity and hypertonicity, emaciation, spasmodic contractions, contractures, emotionalism. In some ways the disease bears a resemblance to paralysis agitans, and throws light on the problem of that affection. 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.
13. Wilson on – Pathophysiology (IM) Jackson: “Positive symptom cannot be caused by negative lesion” IM - not caused by pyramidal system irritation IM needs intact pyramidal system hence IM Extrapyramidal system must be injured ChroeaAthetosis caused by lesion of Affrent Tremor rigidity by efferent Dysarthriadysphagia is due to hypertonia
14. Wilson on Treatment “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”
15. Further development 1948 : Cumings – Cu increased in liver and brain, BAL (1951) 1952: Scheinberg – Ceruloplasmin 1956: J Walsh – Penicillamine, Trientine (82) 1980: Genetic basis Inida : 1963 first Case report Dr NH Wadia and Dasture 1970 WD Clinic at NIMHANS
16. Epidemiology 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) India Neurological ? Hepatic 19.7% Metabolic liver disease in children commonest WD NIMHANS : 15-20 New cases per year Age of onset: 10-20 (<5 never, >50 rare) Hepatic :10-15 (40%) Neurologic 15-20 (40%) Sex: M>F .
17. WD – Genetic Link Autosomal recessive disorder The WD gene, ATP7B is located on the long arm of chrom. 13q14.1 The WD gene encodes a copper-transporting P-Type ATPase) which is expressed predominantly in the liver
18. Mutations in WD gene (ATP7B) ATP7B gene Deletions 60 Insertions 21 Nonsense 19 Missense166 Splice 23 total 289 India Chandigarh: T3305C, C2975A, 29977ins A Kolkata: C813A 19% Vellore: G3182A 16%, C813A 12% 51 Mutation of ATP7B, 34 novel C813A mutation commonest World European PH1069Q 60% Chinese pR778L 45%
20. Pathology: Brain bilaterally symmetrical putaminal (P) softening (arrows) extending laterally up to the external capsule Whole mount preparation stained with Luxol Fast Blue shows relative preservation of internal capsule and pale and softened neuropil in the putamen (P, arrow). 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 Large opalski cell characteristic of Wilson’s disease has irregular eosinophilic cytoplasm and small peripherally placed pyknotic nucleus. H and E
21. Liver histology Histological abnormalities precede clinical appearance Helpful diagnostic clues: steatosis ballooned hepatocytes glycogenated nuclei moderate to marked copper deposition lymphocytic portal and interface hepatitis Untreated, progresses to cirrhosis
22. Liver Pathology Slice of enlarged liver shows microandmacronodular cirrhosis. Inset demonstrates copper deposits within hepatocytes on rubeanic acid stain. Inset: Rubeanic acid
23. Pathological Stages Stage I - The initial period of accumulation of copper by hepatic binding sites Stage II - The acute redistribution of copper within the liver and its release into the circulation Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease Stage IV - The achievement of copper balance with chronic chelation therapy
27. North west study (21 cases) Wilson's disease: A study of 21 cases from north-west India. Annals of Indian Academy of Neurology, December 2007
28. North East India (49 cases) J Assoc Physicians India. 2001 Sep;49:881-4. Wilson's disease in Eastern India.
29. KF Ring Neuropsychiatric: 95% . Hepatic : 30 to 50 % KF rings are not specific for WD. They may be found in other chronic liver disease, PBC, PSC, AIH, and familial cholestatic syndromes.
30. PSYCHIATRIC PRESENTATION 15-20% of patients may present with purely psychiatric symptoms . Phobias , compulsive behaviors, aggressive and antisocial behaviors Schizophrenia Psychosis Cognitive decline
31. HEPATIC PRESENTATION Acute hepatitis, Chronic liver disease— portal HTN. Autoimmune hepatitis. Fulminant hepatic failure, with sev. coagulopathy and encephalopathy . Recurrent bouts of hemolysismay predispose to the development of gallstones . Wilson disease is rarely complicated by hepatocellular carcinoma.
33. Clinical Pointers Classical Unexplained jaundice Hepatic + Extrapyramidal syndrome Family History Most likely Extrapyramidal syndrome in young Progressive behavioral syndrome Multi axial neurological Psychiatric Poor school performance Seizure Recurrent pathological # Unexpalined hematological abnormality
39. MRI brain Atrophy of the cerebrum, 70% Brainstem, 66% Cerebellum 52% Signal abnormality in putamen, 72% Caudate, 61% Thalami, 58% Midbrain, 49% Pons , 20% Cerebral white matter 25% Cortex 9% Medulla 12% Cerebellum 10% Face of giant panda' sign 12% CPM like feature 7% Bright claustral sign 4%
40. MRI in WD ‘Face of giant panda’ sign; MRSS: decreased NAA and therefore a decreased ratio with other products Bright lateral putamen or claustral sign; Pallidalhyperintensity
41. Brain Stem changes: CPM like Classical: Hyperintensity of whole of the central pons sparing a peripheral rim; Bisected pontine signal change by a horizontal line and; Trisected: Pontine hyperintensity trisected by a hypointense line like ‘Mercedes Benz’ sign
42. MRI other changes Bilateral basal ganglionic and thalamic hyperintensity in addition to mild-to-moderate degree diffuse atrophy Extensive diffuse white matter changes Bilateral lentiform, thalamic, midbrain and white matter hyperintensity Midbrain hyperintensity in the tectal region
43. Family Screening Biochemical Testing Children of patient: Begin at age 2 if asymptomatic, repeat once in 5 years unless reason to pursue further. Siblings of patient: Physical examination and brief history of any liver or neurological symptoms. Liver Function Tests: ALT, AST, Albumin, Bilirubin. Ceruloplasmin and Serum Copper. 24 hour urine copper Slit-lamp exam of the eyes for Kayser-Fleischer ring If no K-F rings, abnormal liver functions tests, and low ceruloplasmin: liver bio
44. Molecular Genetic Testing Linkage analysis (Haplotype analysis) Identify a set of closely linked segments of DNA, patient with family members Gene sequencing (mutation screening of the entire ATP7B gene) Analysis of a specific location in the ATP7B gene for a known particular mutation
50. Tetrathiomolybdate Mode : Chelator and also blocks copper absorption Side effects : BM suppresion Hepatotoxicity Rare reports of ND during initial phase of treatment
63. Follow up Depends on the severity of the neurological or hepatic features Assess any sign of hepatic decompensation 24-h urinary Cu excretion (denotes adequate treatment) Monitor penicillamine side effects