1. Wilson’s Disease Ho Yin Calvin Chu, Sanghyuk (Simon) Oh, Soojin Oh, Zi Teng (Steven) Shao PHM142 Fall 2015 Instructor: Dr. Jeffrey Henderson

2. What is Wilson’s Disease? Autosomal recessive disorder of hepatic copper disposition Prevalence of about 30 per million in population Early onset and late onset well documented

3. Symptoms Hepatic Neurological Ophthalmic Psychiatric Others

4. Diagnosis Number of methods in diagnosis Biochemical Findings Genetic Screening Kayser Fleischer Rings Liver Biopsy Imaging

5. Pathogenesis Chromosome 13 is responsible for Wilson’s Disease Mutations in the ATP7B ATP7B is a gene responsible for producing P type ATPase Participates in incorporation of copper into budding ceruloplasmin Speeds up biliary excretion of copper Mutation in P type ATPase leads to copper accumulation

6. Pathogenesis

7. Brief History In 1956 John Walshe found that penicillamine can be used for Wilson's disease Found penicillamine in urine of patient who took penicillin Discovered penicillamine stimulates copper excretion by chelation

8. Chelation A particular way that ions and molecules bind metal ions Porphyrin rings in Hemoglobin is a chelating agent where it’s chelating to iron with 4 bonds Peniciillamine chelates excess copper from tissue and secrete it through urine

9. Penicillamine D-penicillamineL-penicillamine Pharmaceutical Drug Toxic

10. Mechanism + Cu

11. copper-D-penicillamine complex

12. Excretion of penicillamine copper-D-penicillamine complex is very stable, excreted readily through urine Amount of copper excreted can be measured in urine Based on result, dosage of penicillamine can be adjusted

13. Oral Zinc Therapy Zinc Salts (zinc acetate, zinc phosphate) Galzin TM (zinc acetate) Used in: Presymptomatic phase Maintenance phase Following initial phase of aggressive decoppering using copper chelating agents During initial therapy: zinc therapy is less effective than chelating agents Toxicity is rare, preferred treatment in pregnancy Over treatment leads to copper deficiency

14. Paradigm Shift Copper Chelating agents = “Decoppering” Zinc Salts = “Copper Intoxication” Copper bind to ceruloplasmin (copper carrying protein) is non-toxic Free bound copper in blood is toxic

15. Mechanism of Action Metallothionein Metal-binding protein higher affinity for dietary copper than zinc Zinc induces metallothionein in hepatocytes in the liver and enterocytes in the gut Liver: Promote sequestration of free serum copper in a non- toxic metallothionien-bound form

16. Mechanism of Action Intestine: Oral zinc binds and traps metallothionein within the mucosa Metallothionein sequesters copper within the enterocyte Sequestered copper is excreted in the intestinal lumen as the enterocytes are sloughed Excretion via the stools

17. Drug Interactions Penicillamine Chelating agent that targets both copper and zinc Decreased effect with zinc therapy Solution Avoid using penicillamine and zinc together Penicillamine as initial treatment Zinc as maintenance treatment

18. Management Therapy Anti-copper Therapy Diet Vitamin E

19. Future Directions Liver transplant Restores liver function Normal copper excretion Gene therapy

20. Wilson’s disease is mutation in the gene ATP7B which affects production of P-type ATPase. P-type ATPase is responsible for copper excretion and incorporation of copper into ceruloplasmin Peniciillamine chelates excess copper from tissue and secrete it through urine Copper-D-penicillamine complex is stable and therefore it can be secreted readily, amount of copper excreted can be measured in urine Oral zinc therapy is used in presymptomatic and maintenance phase There is a paradigm shift from decoppering to copper intoxication as bound copper is intoxic Zinc salts induces metallothionein, a metal-binding protein, in enterocytes and hepatocytes, which renders copper intoxic Method of therapy management has to be carefully monitored in order to avoid a potential drug interaction Even after initial treatment, maintenance therapy is needed for symptomatic treatment and to keep copper levels low Summary

21. References Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., & Schilsky, M. L. (2007). Wilson’s disease. The Lancet, 369(9559), 397–408. http://doi.org/10.1016/S0140-6736(07)60196-2 Bandmann, O., Weiss, K. H., & Kaler, S. G. (2015). Wilson’s disease and other neurological copper disorders. Lancet Neurol, 14(1), 103–113. http://doi.org/10.1016/S1474-4422(14)70190-5 Brewer, G. J. (2013). Movement Disorder Emergencies, 305–318. http://doi.org/10.1007/978-1- 60761-835-5 Brewer, G. J., & Askari, F. K. (2005). Wilson’s disease: clinical management and therapy. Journal of Hepatology, 42(1), S13–S21. http://doi.org/10.1016/j.jhep.2004.11.013 Dalvi, A., & Padmanaban, M. (2014). Wilson’s disease: Etiology, diagnosis, and treatment. Disease-a-Month, 60(9), 450–459. http://doi.org/10.1016/j.disamonth.2014.07.002 European Association for Study of, L. (2012). EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol, 56(3), 671–685. http://doi.org/10.1016/j.jhep.2011.11.007 Hoogenraad, T. U. (2006). Paradigm shift in treatment of Wilson’s disease: Zinc therapy now treatment of choice. Brain and Development, 28(3), 141–146. http://doi.org/10.1016/j.braindev.2005.08.008 Roberts, E. A. (2011). Wilson’s disease. Medicine, 39(10), 602–604. http://doi.org/10.1016/j.mpmed.2011.08.006 Schilsky, M. L. (2014). Liver transplantation for Wilson’s disease. Annals of the New York Academy of Sciences, 1315(1), 45–49. http://doi.org/10.1111/nyas.12454