WILSON DISEASE

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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 Insertions 21 Nonsense 19 Missense 166 Splice 23 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 gallstones . 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. Nephrolithiasis Cardiomyopathy Hypoparathyroidism Pancreatitis Amenorrhea and Testicular problems Infertility .

Histopathology : 

Histopathology Histologic 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

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 Sr. ceruloplasmin Sr. copper 24 Hrs Urinary copper Liver 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 Proteinuria Lupus like reaction • Aplastic anemia • Leukopenia • Thrombocytopenia • Nephrotic syndrome • Degenerative changes in skin • Hepatotoxicity ND occurs in 10%-20% during 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 copper absorption Side effects : • BM suppresion • Hepatotoxicity 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