Wilson's disease

wilson's disease in brief

1. WILSON’S DISEASE

2. Copper (Cu) Total body copper is about 100mg Sources :liver, fish, meat, lentils milk is a poor source RDA: 1-3mg

3. Functions Mobilization of iron Fe 2+ Ceruloplasmin Fe 3+ Formation of enzymes dopamine oxidase, serum ferroxidase , ALA synthase, monoamine oxidase, tyrosinase etc.

4. Functions of ATP7B Binds Cu to Apoceruloplasmin Packages Cu into vesicles for exocytosis in bile Cu 2+ Absorption : from duodenum Metallothionein – facilitates absorption Phytates , zinc and molybdenum decrease Cu uptake Excretion of copper 90% Bile fecal Cu 10% urine

5. Excess of Cu Initially bound to metallothionein , but as this storage capacity is exceeded , liver damage begins Cu 2+ Cu 2+ + *OH + - OH H 2 O 2 Free radical Tissue damage

6. DEFINITION Wilson’s disease occurs due to a defect of copper transport by the hepatic lysosomes. Genetic defect in excretion of Cu resulting in excess deposition of Cu in body tissues. It is autosomal recessive disorder.

7. Frequency of carriers ~1% Siblings of diagnosed patient have a 1 in 4 risk Whereas children of affected individual have 1 in 200 risk.

8. ETIOLOGY Mutations in the ATP7B gene, A membrane bound, copper transporting ATPase.

9. WD-PATHOPHYSIOLOGY

10. LIVER Slice of enlarged liver shows micro and macronodular cirrhosis. Inset demonstrates copper deposits within hepatocytes on rubeanic acid stain. Inset: Rubeanic acid

11. CLINICAL FEATURES Broad age of presentation Early twenties, extends to sixth decade .

12. APPROACH FOR EVALUATION OF WD Clinical suspicion Classical Acute hepatitis Unexplained jaundice Hepatic features with extrapyramidal manifestations Family history High degree of suspicion Early/young onset extrapyramidal Symptoms Progressive behavioural symptoms Multi-axial psychiatric involvement psychiatric symptoms poor scholastic performance seizures Recurrent pathological fractures Unexplained haematological abnormalities

13. Confirmatory work-up Biochemical Raised 24 hr urinary Copper (>100mg/24hr) Low serum cerruloplasmin copper Ophthalmic Slip lamp confirmed Kayser -Fleisher ring Radiological USG Abdomen cirrhotic liver portal hypertension MRI Brain bilateral basal ganglia changes tectal plate changes CPM like features and combination of basal ganglia Brainstem signal changes Genetics Genetic analysis For mutations

14. INVESTIGATIONS 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

15. 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; Pallidal hyperintensity

16. Treatment Options Reduced Copper intake Low copper diet Reduce copper absorption Zinc Increase copper excretion Penicillamine Trentine Tetrathiomolybdate Liver Transplantation Gene Therapy

17. Management Symptomatic Medical Surgical Symptomatic medical treatment Of disabling symptoms Surgical therapy for medically Refractory symptoms thalamotomy splenectomy Disease modifying Medical Surgical Penicillamine Zinc Trientine Ammonium tetrathiomolybdate Liver transplantation For fulminant hepatic failure

18. Chelating agents : Penicillamine and Trientine intestine Copper Ceruloplasmin Penicillamine / Trientine urine

19. D- Penicillamine Dose Initial : 1-1.5 g/day adults or 20 mg/kg/day children Maintenance : 0.75-1 g/day Adverse effects Fever, rash Proteinuria Lupus like reaction Aplastic anemia Neurological Deterioration occurs in 10%-20% during initial phase Leukopenia Thrombocytopenia Nephrotic syndrome Degenerative changes in skin Hepatotoxicity

20. Trientine ( triethylene tetramine dihydrochloride ) Dose: 1-1.2 g/day Adverse effects : Gastritis Aplastic anemia rare Neurological Deterioration 10%-15% during initial phase .

21. intestine Copper Albumin Ceruloplasmin Zinc metallothionein Zinc Acetate/Sulfate

22. Zinc Indication: Following penicillamine Penicillamine intolerance Prophylactic to aymptomatic sibs New cases (cannot afford Penicillamine ) Dose : Initial : 50 mg T.I.D (adults) Adverse effects Gastritis Zinc accumulation Possible changes in immune ND can occur during initial phase

23. Monitoring Family Care giver education Screening of siblings Education regarding Mode of transportation Patient Education Clinical course Copper restricted diet 24 hour urinary copper Radiological improvement

24. C omplications Hepatosplenomegaly Renal disease Hemolytic anemia

25. Prognosis Life long treatment is needed to control Wilson’s disease. If not treated early, Wilson’s disease is fatal.

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