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