Wilson Disease : Wilson Disease Dr. Rakesh Kumar. Adi
M.D.,(D.M.) Slide 2: Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver.
SAK WilsonThesis, Univ. of Edinburgh,
1911 Epidemology : Epidemology Occurs worldwide
Incidence of one in 30,000
The age at onset of symptoms
ranges from 6 to about 40 years. THE COPPER PATHWAY : THE COPPER PATHWAY Copper is a micro nutrient and an essential cofactor for many enzymes ,
Daily copper intake is 1-4 mg Slide 5: Cu Metabolism WD – Genetic Link : 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 Molecular Mechanism : Molecular Mechanism The Wilson Disease Protein (WNDP) has two functions:
Export of copper from the cell and
Incorporation into copper-dependent
enzymes Copper Metabolism - Normal : Copper Metabolism - Normal Copper Metabolism – WD Mutations : Copper Metabolism – WD Mutations WD protein (ATPase) : WD protein (ATPase) Mutations in WD gene (ATP7B) : Mutations in WD gene (ATP7B) Deletions 60
total 289 WD - Pathophysiology : 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 CLINICAL FEATURES : CLINICAL FEATURES The clinical presentation of Wilson
disease is extremely variable . HEPATIC PRESENTATION : HEPATIC PRESENTATION A hepatic 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. Slide 15: Wilson disease may also manifest as fulminant hepatic failure, with sev. coagulopathy and encephalopathy .
Recurrent bouts of hemolysis may
predispose to the development of
Wilson disease is rarely complicated by hepatocellular carcinoma. NEUROLOGIC PRESENTATION : NEUROLOGIC PRESENTATION Tends to occur in the 2nd and 3rd decades or later .
Two main patterns,
1. movement disorder
2. rigid dystonia PSYCHIATRIC PRESENTATION : PSYCHIATRIC PRESENTATION 20% of patients may present with purely psychiatric symptoms .
Phobias , compulsive behaviors, aggressive and antisocial behaviors have been reported. OCULAR SIGNS : OCULAR SIGNS The classic 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 Slide 20: Pts with exclusively 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. Extrahepatic disorders : Extrahepatic disorders Hemolytic anemia Arthritis,
Fanconi's syndrome Rhabdomyolysis.
Infertility . Histopathology : Histopathology Histologic abnormalities precede clinical appearance
Helpful diagnostic clues:
moderate to marked copper deposition
lymphocytic portal and interface hepatitis
Untreated, progresses to cirrhosis WD- cirrhotic stage (Rhodanine stain) : WD- cirrhotic stage (Rhodanine stain) This reveals accumulation of copper ,
most in a nodular cluster of hepatocytes Management : Management Investigations : Investigations LFT - ALT << AST
Slit lamp examination
24 Hrs Urinary copper
Molecular diagnosis Biochemical Parameters : Biochemical Parameters TREATMENT : TREATMENT 1954 Peters BAL
1956 Walshe Penicillamine
1969 Walshe Trientine
1984 Walshe Tetrathiomolybdate
1983 Brewer zinc acetate D-Penicillamine : 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 Slide 30: Side effects :
• Fever, rash
Lupus like reaction
• Aplastic anemia
• Thrombocytopenia • Nephrotic syndrome
• Degenerative changes
ND occurs in
initial phase . Trientine (triethylene tetramine dihydrochloride) : 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 . Zinc : 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 . Tetrathiomolybdate : Tetrathiomolybdate Mode : Chelator and also blocks
Side effects : • BM suppresion
Rare reports of ND during initial
phase of treatment Drug choice : Drug choice Prognostic Index of Nazer : Prognostic Index of Nazer Score points Slide 36: Pts with scores 6 - medical therapy.
Pts with scores 10 - OLT,
Pts with scores between 7 and 9 require clinical judgment .
Treatment is life long. Slide 37: At present: Liver transplantation 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 PRESYMPTOMATIC DIAGNOSIS OF SIBS : PRESYMPTOMATIC DIAGNOSIS OF SIBS PE, LFT, Sr. copper and ceruloplasmin levels , a 24-hour urinary copper levels.
Children 6 years old or younger who appear to be unaffected should be rechecked at yearly intervals over the next 5 to 10 years. Slide 39: Genetic screening by direct mutation
analysis, is the most reliable way to
identify affected siblings .
However, up to now, heterozygotes
have not been known to become
clinically affected or to require treatment OTHER COPPER DISEASE : OTHER COPPER DISEASE Indian chilhood cirrhosis
Tyrolian infantile cirrhosis
Idiopathic copper toxicosis
Bedlington terrier copper toxicosis (DOGS) - MURR Indian chilhood cirrhosis : Indian chilhood cirrhosis A common killer disease of the past, (ICC), became preventable and treatable in the early 1990s, is now rare.
Grossly increased hepatic, urinary, and
serum CU concentrations are characteristic of ICC.
Environmental ingestion of copper appears to be the cause for ICC .
An inherited defect in copper metabolism is strongly suspected. Slide 42: In ICC, ceruloplasmin is normal and clinical recovery is maintained despite withdrawal of therapy.
ICC probably represents a specific form of copper-associated childhood cirrhosis that requires high environmental copper ingestion for its full expression. Pandit A, Bhave S.Department of Pediatrics,
KEM Hospital, India Slide 43: THANK Q