wilson’s disease
DESCRIPTION
Wilson disease overview for CME on Movement Disorder at GNRC Guwahati 2011 Feb 19thTRANSCRIPT
WILSON’S DISEASE
Dr PS Deb MD, DM
GNRC Gawhati India
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
GOWER’S 1888 - TETANOID CHOREA
10 years old boy, suffering with progressive extrapyramidal syndrome (dystonic) died in 7 months, but autopsy of brain was normal.
brother and three other relations also died of similar illness
GOWER’S CASE: 1888
ORMEROD - 1890
A case of cirrhosis of liver with obscure fatal nervous symptom
Mild bilateral atrophy of putamen
HOMEN - 1892
A peculiar disease in two brother and sister in the form of progressive dementia probably Lues Heriditaria Tarda
Fixed smile, open mouth, contracture and emaciation
Symmetrical softening of putamen
WILSON’S CASES 1 S.T.
WILSON’S CASE 3 E.P.
WILSON’S CASE 1- PATHOLOGY
•Hepatic cirrhosis•Bilateral symmetrical degeneration of leniticular nucleus
WILSON ON - ETIOLOGY
Diseases is not congenital, most likely acquired
Familial, not hereditary The morbid agent is probably of the nature of
a toxin but not syphilitic Acute or sudden onset Variability of symptom Toxin may be elaborated in the liver like
Kernicterus Toxin has a specific action on the lenticular
nucleus Nature of toxin is unknown but not microbial
WILSON’S SUMMARY OF CASES
CLINICAL CONCLUSION - WILSON
1. In pure cases the affection constitutes an extrapyramidal motor disease occurring in young people and very often familial.
2. It is progressive and fatal within a varying period months to years.
3. It is characterized by : generalized tremor, dysarthria and dysphagia, muscular rigidity and hypertonicity, emaciation, spasmodic contractions, contractures, emotionalism.
4. In some ways the disease bears a resemblance to paralysis agitans, and throws light on the problem of that affection.
5. 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.
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
Chroea Athetosis caused by lesion of Affrent
Tremor rigidity by efferent Dysarthria dysphagia is due
to hypertonia
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”
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
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
.
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
MUTATIONS IN WD GENE (ATP7B)
ATP7B gene Deletions 60 Insertions 21 Nonsense 19 Missense
166 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%
WILSON DISEASE PATHOPHYSIOLOGY
PATHOLOGY: BRAIN
a. bilaterally symmetrical putaminal (P) softening (arrows) extending laterally up to the external capsule
b. Whole mount preparation stained with Luxol Fast Blue shows relative preservation of internal capsule and pale and softened neuropil in the putamen (P, arrow).
c. 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
d. Large opalski cell characteristic of Wilson’s disease has irregular eosinophilic cytoplasm and small peripherally placed pyknotic nucleus. H and E
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
LIVER PATHOLOGY
Slice of enlarged liver shows microand macronodular cirrhosis.
Inset demonstrates copper deposits within hepatocytes on rubeanic acid stain. Inset: Rubeanic acid
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
CLINICAL MANIFESTATION
WD: CLINICAL FEATURES - INDIAN
NEUROLOGIC PRESENTATION: NIMHANS (307 CASES)
Symptoms Percentage
Tremor 31.6
Dysarthria 15.6
Abnormal Gait 8.8
Musculoskeletal 5.2
Seizure 4.2
Behavioural 4.6
Dystonia 3.6
Clumsiness 2.6
Drooling 2.6
Altered sensorium 1.3
Dysphagia 0.9
Chorea 0.3
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
Symptoms Percentage
Tremor 85.7
Dysarthria 76.2
Dystonia 57.1
Cognitive abnormality 57.5
Seizure 38
Cerebellar sign 31.7
NORTH EAST INDIA (49 CASES)
J Assoc Physicians India. 2001 Sep;49:881-4.
Wilson's disease in Eastern India.
Symptoms Percentage
Dystonia 96
Silly smile 92
Dysarthria 80
Cognitive abnormality 71
Tremor 47
Bradykinesia 45
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.
PSYCHIATRIC PRESENTATION
15-20% of patients may present with purely psychiatric symptoms . Phobias , compulsive behaviors, aggressive and antisocial behaviors Schizophrenia Psychosis Cognitive decline
HEPATIC PRESENTATION
Acute hepatitis, Chronic liver disease— portal HTN. Autoimmune hepatitis. Fulminant hepatic failure, with sev.
coagulopathy and encephalopathy . Recurrent bouts of hemolysis may predispose to the development of
gallstones . Wilson disease is rarely complicated by
hepatocellular carcinoma.
EXTRAHEPATIC DISORDERS
Hemolytic anemia
Fanconi's syndrome Nephrolithiasis Hypoparathyroidism Amenorrhea and Testicular problems Infertility .
Arthritis, Rhabdomyolysis. Cardiomyopathy Pancreatitis
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
INVESTIGATION
Biochemical Serum ceruloplasmin <20mg/dL 24hr Urinary Copper >100micg/d Serum free copper >10micg/dL Liver Copper >250micg/g
Ophthalmological Slit lamp KF ring
Imaging X-ray Osteoporosis Ultrasound Cirrhosis CT Scan MRI
Genetics
PATHWAY FOR INVESTIGATION
ELECTROPHYSIOLOGY
EEG 41.1% VEP 35% BAER 42.1% Dyautomaumia ECG
IMAGING
Ultrasound Abdomen Cirrhosis Portal hypertension
X-ray: Osteoarthritis, arthirtis CT brain : Low sensitivity, MRI brain High sensitivity
Bilateral basal ganglionic changes Brain stem changes White matter changes
CT BRAIN
Cortical atrophy 44.8% Ventricular dilatation 44% Caudate atrophy 25% Brain stem atrophy 31.9% Cerebellar atrophy 19% Hemispheric hypodensities 29.3% Basal ganglionic hypodensities.
19.8% Thalamic hypodensities. 10.3%
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%
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
BRAIN STEM CHANGES: CPM LIKE
a. Classical: Hyperintensity of whole of the central pons sparing a peripheral rim;
b. Bisected pontine signal change by a horizontal line and;
c. Trisected: Pontine hyperintensity trisected by a hypointense line like ‘Mercedes Benz’ sign
MRI OTHER CHANGES
a. Bilateral basal ganglionic and thalamic hyperintensity in addition to mild-to-moderate degree diffuse atrophy
b. Extensive diffuse white matter changes
c. Bilateral lentiform, thalamic, midbrain and white matter hyperintensity
d. Midbrain hyperintensity in the tectal region
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
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
TREATMENT OPTIONS• Low copper dietReduced Copper
intake• ZincReduce copper
absorption• Penicillamine• Trentine• Tetrathiomolybdat
Increase copper excretion
Liver Transplantation
Gene Therapy
DIET
Avoid Copper rich diet liver, shellfish (especially lobster), nuts,
chocolate, soya products, gelatin, and mushrooms.
Water with copper >1ppm (well water)
CHELATING AGENTS: PENICILLAMINE AND TRIENTINE
intestine
Copper
Ceruloplasmin Penicillamine/
Trientine
urine
D-PENICILLAMINE
Dose Initial: 1-1.5 g/day adults or 20 mg/kg/day children Maintenance: 0.75-1 g/day
Side effect Fever, rash Proteinuria Lupus like reaction Aplastic anemia Leukopenia Thrombocytopenia Nephrotic syndrome Degenerative changes in skin Hepatotoxicity Neurological Deterioration occurs in 10%-20% during
initial phase
TRIENTINE (TRIETHYLENE TETRAMINE DIHYDROCHLORIDE)
Dose: 1-1.2 g/day Side effects :
Gastritis Aplastic anemia rare Neurological Deterioration 10%-15% during initial
phase .
TETRATHIOMOLYBDATE
Mode : Chelator and also blocks copper
absorption Side effects :
BM suppresion Hepatotoxicity Rare reports of ND during initial phase of treatment
intestine
Copper
Albumin Ceruloplasmin
Zinc
metallothionein
Zinc Acetate/Sulfate
ZINC
Indication: Following penicillamine Penicillamine intolerance Prophylactic to aymptomatic sibs New cases (cannot afford Penicillamine)
Dose : Initial: 50 mg T.I.D (adults) Side effects
Gastritis Zinc accumulation Possible changes in immune ND can occur during initial phase
INDICATIONS (AALD)
Penicillamine Hepatic diseaseNeurological disease
Zinc Neurological diseasePeinicillamine intoleranceMaintenance treatmentPregnancy
Trientine Hepatic disease (or first choice?) Neurological diseasePenicillamine side effects
Tetrathiomolybdate? Neurological patients?
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