Wilsons Disease

1
Wilsons Disease
February 6th, 2008

• Alex Domijan alex.domijan_at_utoronto.ca
• Olivia LeBelle olivia.tomiczek_at_utoronto.ca
• Stephanie Williams steph.london_at_utoronto.ca

2
Copper

• Copper is a trace metal ion and an essential
  cofactor for many enzymes and proteins
• It plays a fundamental role in the biochemistry
  of the human nervous system
• Toxic in excess
• Daily copper intake is 1-2 mg
• 50 of that is absorbed by the small intestine

3
Wilsons Disease

• First described by Kinnear Wilson in 1912
• Occurs worldwide incidence of one in 30,000

4
Wilsons Disease Genetic Link

• Autosomal recessive disorder
• The Wilson disease (WD) gene, ATP7B is a mutation
  on the long arm of chromosome 13 (13q14.1)
• The WD gene encodes a copper-transporting P-type
  adenosine triphosphatase (P-Type ATPase) which is
  expressed predominantly in the liver

5
Wilsons Disease
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Wilsons Disease - Pathophysiology

• Disorder of hepatic copper transport
• Characterized by copper accumulation in the liver
  and then other organs (mainly brain and cornea)
• This accumulation is then followed by hepatic
  and/or neurological symptoms due to copper
  toxicity

7
Molecular Mechanism

• The exact molecular mechanism of copper toxicity
  in humans (especially the effect of accumulated
  copper on human behaviour) is poorly understood
• The Wilson Disease Protein (WNDP) has two
  functions facilitate export of copper from the
  cell and to deliver copper to the secretory
  pathway for incorporation into copper-dependent
  enzymes

8
Copper Metabolism and Effects of WD mutation
? Normal
WD mutation ?
9
Example
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Symptoms

• Hepatic ranging from acute hepatitis to liver
  failure
• Neurological movement disorders, drooling,
  seizures, migraines, insomnia
• Psychiatric depression, neuroses, personality
  changes, psychosis
• Other kidney, skeletal, thyroid, heart, pancreas
  and gynecological problems, recurrent and
  unexplained fever, jaundice, shortness of breath,
  excessive tiredness, stiff limbs, difficulty
  breathing, abdominal and bone pain and hemolytic
  anemia

11
Diagnostic Tests

• There is no single diagnostic test although the
  following can be used to help diagnose the
  disease
• Serum copper test
• Serum ceruloplasmin test
• 24 hour urine copper test
• Liver biopsies for histology and histochemistry
  and copper quantification
• DNA testing for mutation analysis
• Opthamalogic slit lamp examination of
  Kayser-Fleisher rings

12
Treatment

• Dietary Treatment
• Avoid eating certain foods such as liver, and
  shellfish
• Foods like mushrooms, nuts, chocolate, and dried
  fruit are also high in copper, but there is
  conflicting evidence regarding their restriction
• Intake of Vitamin B6
• Water purification is advisable

13
Treatment

• Drug Treatment
• Reduction of Copper Storage
• Penicillamine (no longer used)
• Trientine hydrochloride
• Tetrathiomolybdate
• Reduction of Intestinal Copper Reabsorption
• Zinc acetate or zinc sulphate

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Why Do We Care as Pharmacists?

• Pharmacological interventions are continually
  changing we need to stay knowledgeable in order
  to minimize adverse effects
• We need to be aware of drug interactions that may
  occur due to the high levels of copper the
  resulting liver and organ deficiencies and
  prevent them from occurring to our patients
• Overall, we need to provide optimal care by
  understanding the mechanism(s) through which any
  adverse events/interactions may occur for our
  future patients with Wilsons Disease

15
Summary

• Disorder of hepatic copper transport
  characterized by copper accumulation in the liver
  and then other organs (mainly brain and cornea).
  The accumulation is followed by hepatic and/or
  neurological symptoms due to copper toxicity
• Autosomal recessive disorder
• The Wilson disease (WD) gene, ATP7B is a mutation
  on the long arm of chromosome 13
• The WD gene encodes a copper-transporting P-type
  adenosine triphosphatase (P-Type ATPase) which is
  expressed predominantly in the liver
• The exact molecular mechanism of copper toxicity
  in humans (especially the effect of accumulated
  copper on human behaviour) is poorly understood
• The Wilson Disease Protein (WNDP) has two
  functions facilitate export of copper from the
  cell and to deliver copper to the secretory
  pathway for incorporation into copper-dependent
  enzymes
• Symptoms
• Hepatic ranging from acute hepatitis to liver
  failure
• Neurological movement disorders, drooling,
  seizures, migraines, insomnia
• Psychiatric depression, neuroses, personality
  changes, psychosis
• Other kidney, skeletal, thyroid, heart, pancreas
  and gynecological problems, recurrent and
  unexplained fever, jaundice, shortness of breath,
  excessive tiredness, stiff limbs, difficulty
  breathing, abdominal and bone pain and hemolytic
  anemia

16
Summary contd

• Diagnostic tests
• There is no single diagnostic test although the
  following can be used to help diagnose the
  disease
• Serum copper test
• Serum ceruloplasmin test
• 24 hour urine copper test
• Liver biopsies for histology and histochemistry
  and copper quantification
• DNA testing for mutation analysis
• Opthamalogic slit lamp examination of
  Kayser-Fleisher rings (rusty-brown coloured rings
  in cornea)
• Treatments
• Dietary Treatment
• Avoid eating certain foods such as liver, and
  shellfish
• Foods like mushrooms, nuts, chocolate, and dried
  fruit are also high in copper, but there is
  conflicting evidence regarding their restriction
• Intake of Vitamin B6
• Water purification is advisable
• Drug Treatment
• Reduction of Copper Storage
• Penicillamine (no longer used)
• Trientine hydrochloride
• Tetrathiomolybdate

17
References

• Cleveland Clinic Center for Continuing Education
  Wilsons Disease, http//www.clevelandclinicmed.
  com/medicalpus.diseasemanagement/gastro/wilsons/wi
  lsons.htm retrieved January 29, 2008
• Cox, D.W., and Moore, S.D.P. (2002) Copper
  Transporting P-Type ATPase and Human Disease.
  Journal of Bioenergetics and Biomembranes, 34(5)
  333-338
• Fatemi, N., and Sarkar, B. (2002) Structural and
  Functional Insights of Wilson Disease
  Copper-Transporting ATPase. Journal of
  Bioenergetics and Biomembranes, 34(5) 339-349
• Hoogenraad, T.U. (2006) Paradigm Shift in
  Treatment of Wilsons Disease Zinc Therapy now
  Treatment of Choice. Brain and Development, 28
  141-146
• Hoogenradd, T.U., Van Hattum, J., and Van den
  Hamer, C.J. (1987) Management of Wilsons
  Disease with Zinc Sulphate Experience in a
  series of 27 patients. Journal of the
  Neurological Sciences, 77 137-146
• Leggio, L., Malandrino, N., Loudianos, G.,
  Abenavoli, L., Lepori, M.B., Capristo, E., De
  Virgiliis, S., Gasbarrini, G., and Addolorato, G.
  (2007) Analysis of the T1288R Mutation of the
  Wilson Disease ATP7B Gene in Four Generations of
  Family Possible Genotype-Phenotype Correlation
  with Hepatic Onset. Digestive Diseases and
  Sciences, 52 2570-2575
• Lutsenko, S., and Cooper, M.J. (1998)
  Localization of the Wilsons Disease Protein
  Product to Mitochondria. Proceedings of the
  National Academy of Science of the United States
  of America, 95 6004-6009
• Lutsenko, S., Efremov, R.G., Tsivkovskii, R., and
  Walker, J.M. (2002) Human Copper-Transporting
  ATPase ATP7B (The Wilsons Disease Protein)
  Biochemical Properties and Regulation. Journal
  of Bioenergetics and Biomemebranes, 34(5)
  351-362
• Medici, V., Rossaro, L., and Sturniolo, G.C.
  (2007) Wilson Disease A Practical Approach to
  Diagnosis, Treatment, and Follow-up. Digestive
  and Liver Diseases, 39 601-609
• Menkes, J.H. (2003) Chapter 31 Wilson Disease.
  Genetics of Movement Disorders. Elsevier Science
  341-352
• Sinha, S., and Taly, A.B. (2008) Withdrawal of
  Penicillamine from Zinc Sulphate-Penicillamine
  Maintenance Therapy in Wilsons Disease
  Promising, Safe, and Cheap. Journal of the
  Neurological Sciences, 264 129-132
• Straube, A., and Swanson, P. (2003) Chapter 80
  Wilsons Disease. Neurological Disorders
  Course and Treatment (2nd Edition) Elsevier
  Science 1157-1163
• The Mayo Clinic Wilsons Disease,
  http//www.mayoclinic.org/wilsons-disease/treatmen
  t.html retrieved January 19, 2008
• Waggoner, D.J., Bartnikas, T.B., and Gitlin, J.D.
  (1999) The Role of Copper in Neurodegenrative
  Disease. Neuroiology of Disease, 6 221-230.