Transcript Wilson`s disease

PHM142 Fall 2015
Instructor: Dr. Jeffrey Henderson
Wilson’s Disease
Ho Yin Calvin Chu, Sanghyuk (Simon) Oh,
Soojin Oh, Zi Teng (Steven) Shao
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
Symptoms
• Hepatic
• Neurological
• Ophthalmic
• Psychiatric
• Others
Diagnosis
• Number of methods in diagnosis
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Biochemical Findings
Genetic Screening
Kayser Fleischer Rings
Liver Biopsy
Imaging
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
Pathogenesis
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
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
Penicillamine
D-penicillamine
Pharmaceutical Drug
L-penicillamine
Toxic
Mechanism
+
Cu
copper-D-penicillamine complex
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
Oral Zinc Therapy
• Zinc Salts (zinc acetate, zinc phosphate)
• GalzinTM (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
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
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 nontoxic metallothionien-bound form
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
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
Management Therapy
Anti-copper Therapy
• Diet
• Vitamin E
Future Directions
• Liver transplant
• Restores liver function
• Normal copper excretion
• Gene therapy
Summary
• 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
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/10.1007/978-160761-835-5
• 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