Wilson’s disease academic

academic base Harrisons 19th edition

1. Wilson’s disease Dr kirankumar Bikkad

2. INTRODUCTION Autosomal recessive ( AR ) Mutations in the ATP7B gene E ncodes a membrane-bound, copper transporting ATPase . Clinical manifestations caused by copper toxicity involveing liver and brain.

3. Frequency :- 1 in 30,000–40,000 Carriers of ATP7B mutations is ∼1%. Siblings have a 1 in 4 risk of Wilson’s disease Children have 1 in 200 risk. DNA haplotype analysis used to genotype siblings

4. MEDNIK syndrome A rare multisystem disorder of copper metabolism mutations in AP1S1 gene Mental retardation Enteropathy Deafness Neuropathy Ichthyosis Keratodermia ATP7A ( Menkes disease) and ATP7B (Wilson’s disease).

5. PATHOGENESIS ATP7B protein deficiency impairs biliary copper excretion Positive copper balance Hepatic copper accumulation Copper toxicity from oxidant damage Excess hepatic copper is bound to metallothionein Liver damage begins as this storage capacity is exceeded

6. Defective copper incorporation into apoceruloplasmin  excess catabolism of ceruloplasmin L/T low ceruloplasmin . Serum copper levels are low bcoz low blood ceruloplasmin , which binds >90% of Sr copper. Non- ceruloplasmin serum copper “free” copper increase  copper build up in other body parts ( e.g.brain  neurologic and psychiatric disease)

7. CLINICAL PRESENTATION Hepatic Features Hepatitis Cirrhosis Hepatic decompensation Elevated serum aminotransferase levels, with or without jaundice Hepatic decompensation :- elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites , peripheral edema , and hepatic encephalopathy.

8. In severe hepatic failure  hemolytic anemia Copper derived from hepatocellular necrosis  released into the bloodstream. The association of hemolysis and liver disease makes Diagnosis of Wilsons Likely Patients age group:- teenage years and extends till fifth decade.

9. Neurologic Features Early twenties & can be seen till sixth decade of life. MRI and CT scans:- basal ganglia occasionally : pons, medulla , thalamus, cerebellum, and subcortical areas. Main movement disorders Dystonia Incoordination Tremor . Dysarthria and dysphagia.

10. In some patients, the clinical picture closely resembles Parkinson’s disease. Autonomic disturbances :  Orthostatic hypotension Sweating abnormalities Bowel , bladder dysfunction Sexual dysfunction.

11. Memory loss Migraine -type headaches Seizures may occur. Patients have difficulty focusing on tasks, but cognition usually is not grossly impaired. There is no Sensory abnormalities and muscular weakness .

12. Psychiatric Features Seen in Half of patients with neurologic disease Onset - 5 years before diagnosis . loss of emotional control (temper tantrums, crying bouts) Depression Hyperactivity Loss of sexual inhibition .

13. Other Manifestations Female :- Repeated spontaneous abortions, become amenorrheic Cholelithiasis and nephrolithiasis Osteoarthritis (particularly of knee) Microscopic hematuria Sunflower cataracts Kayser -Fleischer rings (copper deposits in the outer rim of the cornea )

14. Increased Levels of urinary excretion of Phosphates Amino acids Glucose Urates (Features S/O Fanconi syndrome )

15. DIAGNOSIS Serum ceruloplasmin normal in up to 10% of affected patients & reduced in 20% of carriers. Kayser -Fleischer rings using a slit lamp . present in >99% of patients with neurologic/psychiatric 30–50 % of patients diagnosed in the hepatic state 24hr Urine copper measurement Patients : >1.6 μmol (>100 μg ) per 24 h Heterozygotes : <1.3 μ mol (<80 μ g) per 24 h. Liver biopsy : definitive diagnosis G old standard Quantitative copper assays. Affected patients have Cu >3.1 μmol /g (> 200μg/g) [dry weight] of liver

16. TREATMENT Penicillamine : previously primary anticopper treatment but now have minor role because of its toxicity and worsens neurologic disease. Always given with pyridoxine(25 mg/d ). Trientine : a less toxic chelator .

17. For patients with hepatitis or cirrhosis without evidence of hepatic decompensation or neurologic/psychiatric symptoms zinc therapy of choice Nontoxic Produces a negative copper balance by blocking intestinal absorption of copper Induces hepatic metallothionein synthesis (sequester additional toxic Copper) All presymptomatic patients should be treated prophylactically

18. For initial medical treatment of patients with hepatic decompensation :- chelator ( trientine ) + zinc . Zinc should not be ingested simultaneously with trientine , which chelates zinc Administer 2 drugs at least 1 h apart. For initial neurologic therapy:- tetrathiomolybdate (DOC) because of its rapid control of free copper, preservation of neurologic function, and low toxicity. Avoid :- Penicillamine and trientine ( because both have risk of worsening neurologic condition)

19. Tetrathiomolybdate & Hepatic transplantation:- alleviate neurologic symptoms Pregnant patients treated with zinc or trientine throughout pregnancy without tight copper control because copper deficiency can be teratogenic . Anticopper therapy must be lifelong. Neurologic and psychiatric symptoms improve after 6–24 months of treatment

20. Dosage Zinc acetate ( Galzin ) 50 mg TDS of elemental zinc, with each dose separated by at least 1 h from consumption of food and beverages other than water as well as from trientine or penicillamine doses. Trientine ( Syprine ) and penicillamine ( Cuprimine ) adult dosage for both drugs is 500 mg BD , with each dose at least 0.5 h before or 2 h after meals and separated by at least 1 h from zinc administration .

21. Nazer prognostic index To establish disease severity Sr Bilirubin, AST, PT. Scores <7  managed with medical therapy. Scores >9  considered for liver transplantation. For patients with scores between 7 and 9  clinical judgment Combination of trientine and zinc  to treat patients with Nazer scores as high as 9, but (Look for indications of hepatic deterioration)

22. MONITORING ANTICOPPER THERAPY Trientine / penicillamine bone marrow suppression and proteinuria CBC & urinalys weekly intervals for 1 month Once in 2 week intervals for 2 or 3 months Monthly intervals for 3 or 4 months 4 to 6-month intervals thereafter. The anticopper effects of trientine and penicillamine can be monitored by following “free” serum copper levels.

23. Zinc Treatment does not require monitoring of blood or urine for toxicity. Side effect is gastric burning or nausea in ∼10% patients, with first morning dose. First dose taken an hour after breakfast or taken with a small amount of protein .

24. Free serum copper = total serum copper - ceruloplasmin copper . Each 1 mg/ dL ceruloplasmin contributes 3 μg / dL serum copper. The normal serum free copper value is 10–15 μg / dL Level is often as high as 50 μg / dL in untreated Wilson’s disease. With treatment , the serum free copper should be <25 μg / dL .

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