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Treatment of Wilson diseaseTreatment of Wilson disease
Valentina Medici, M.D.Division of Gastroenterology and Hepatology
UC DavisMay 2nd, 2009
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OutlineOutline
• Treatment options• Mechanism of action• Side effects• Strategies for better management• New prospectives
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OptionsOptions
• Chelating agents (Penicillamine, Trientine)• Zinc• Tetrathiomolybdate (?)
• Diet • Liver Transplantation
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intestine
Copper
Albumin
Blood
Ceruloplasmin
ATP7BATP7B
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intestine
Copper
CeruloplasminPenicillamine/Trientine
urine
Chelating Chelating agentsagents: Penicillamine : Penicillamine and Trientineand Trientine
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PenicillaminePenicillamine
• Copper chelator: ↑ Cu urinary excretion• Dose: 750-1500 mg/daily + pyridoxine (B6)
daily• 30% discontinued for side effects• Can worsen neurological symptoms (up to 50%)• Rare birth defects (“cutis laxa”)
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Penicillamine Penicillamine side effectsside effects
• Fever, rash, lymphoadenopathy• Aplastic anemia, neutropenia and
thrombocytopenia• Late side effects: elastosis perforans serpiginosa,
arthropathy, lupus-like reaction, nephrotic syndrome, myastenia gravis, Goodpasture syndrome
Scheinberg IH, Sternlieb I. Wilson’s disease. In: Smith LH Jr., Ed. Philadelphia: W.B. Saunders, 23;1984
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TrientineTrientine
• Cu chelator• New “first choice”• Fewer side effects than penicillamine• More tolerable for neurological symptoms• Dose: 750 -1500 mg/daily• Side effects rare pancytopenia
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intestine
Copper
Albumin Ceruloplasmin
Zinc
metallothionein
Zinc Acetate/SulfateZinc Acetate/Sulfate
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Zinc Sulfate/AcetateZinc Sulfate/Acetate
“Blocks” Cu absorption• Prevents Cu toxicity∀↓ Cu Urinary Excretion• Minor side effects (dyspepsia): Acetate is better tolerated• Dose: 150 mg daily of elemental zinc• Slow action (4-6 months)• No concerns during pregnancy, safe for neurological
symptoms
Brewer GJ, J Lab Clin Med, 1999
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Combination therapyCombination therapy
• Penicillamine + Zinc dubious efficacy
• Trientine + Zinc yes for decompensated cirrhosis
Askari, JLabClinMed, 2003
Brewer, JAmCollNutr, 1993
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TetrathiomolybdateTetrathiomolybdate
• Forms a complex with copper and protein• Taken with meals complexes Cu in the
food and is secreted into the intestine; between meals it is absorbed and complexes Cu in the blood with albumin
• More efficacy for neurological symptoms• Not yet approved
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• 23 pts on Trientine• 25 pts on TM8 weeksTrientine26% risk of
neuro deteriorationTM 4% risk of neuro
deterioration
Tetrathiomolybdate (TM) for Tetrathiomolybdate (TM) for neurological symptomsneurological symptoms
Brewer GJ, Arch Neurol, 2006
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0
1000
2000
3000
4000
5000
6000
7000
8000
basal 1 2 3 4 5 6 7 9 11 13
weeks
ug/2
4 h
0
200
400
600
800
1000
1200
1400
U/L
24h-urine copper
24h-urine zinc
serum ALT
Medici V, Mov Disord, 2006
33 yo, man, with severe neurological WD33 yo, man, with severe neurological WD
TTM TTM 120 mg/day120 mg/day
TTM TTM 180 mg/day180 mg/day
stop TTMstop TTM
150327486642171Chol
358338346299221Alk phos
87842120734985ALT
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IndicationsIndications
Hepatic disease (or first choice?)
Neurological disease
Penicillamine side effects
TrientineTrientine
Neurological patients?Tetrathiomolybdate?Tetrathiomolybdate?
Neurological disease
Maintenance treatment
Pregnancy
ZincZinc
Hepatic diseasePenicillaminePenicillamine
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Management during follow upManagement during follow up
• Depends on the severity of the neurological or hepatic features
• Assess any sign of hepatic decompensation
• 24-h urinary Cu excretion (denotes adequate treatment)
• Monitor penicillamine side effects
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Management of hepatic WDManagement of hepatic WD
• About 30% of patients have mildly increased transaminase level benign
• Liver biopsy• Try an alternative anti-copper agent• Add Vitamin E (antioxidant effect)
von Herbay A, J Hepatol, 1994
Iorio, J Pediatr Gastroenterol Nutr, 2004
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ComplianceCompliance
Sudden interruption of therapy in Wilson
disease can result in Acute Liver Failure
Walshe, Lancet, 1986
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Gene therapyGene therapy
Lentiviral gene Lentiviral gene transfer (ATP7B)transfer (ATP7B)
Increased levels of ceruloplasmin
Reduced hepatic copper
Improved hepatic fibrosis
Merle, Scand J Gastro, 2006
LEC ratsLEC rats
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Allen KJ, Cell Transplant, 2004
TOXIC MILK MOUSE
(N° 46)
Sublethal radiation
Transplant with bone marrow
stem cells
N°11 (24%): liver ripopulation + Reduction of
hepatic copper accumulation
Bone marrow stem cellsBone marrow stem cells
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Hepatocytes transplantationHepatocytes transplantation
Joseph, Gastro, 2009
Spleen
LiverHepatocytes
LEC rats
• 6 months after transplant: liver was extensively repopulated with hepatocytes
• ATP7B expression, increased Cp, reduced hepatic Cu
• Improved liver histology
Cholic acid, radiation, partial hepatectomy
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ConclusionsConclusions• WD is a very peculiar medical situation genetic
but treatable disorder, almost complete resolution of symptoms with appropriate and timely therapy
• Early diagnosis and early therapy are mandatory
• Compliance to medical treatment is crucial