Treatment of Wilson Treatment of Wilson disease disease Valentina Medici, M.D. Division of Gastroenterology and Hepatology UC Davis May 2 nd , 2009
Treatment of Wilson diseaseTreatment of Wilson disease
Valentina Medici, M.D.Division of Gastroenterology and Hepatology
UC DavisMay 2nd, 2009
OutlineOutline
• Treatment options
• Mechanism of action
• Side effects
• Strategies for better management
• New prospectives
OptionsOptions
• Chelating agents (Penicillamine, Trientine)• Zinc• Tetrathiomolybdate (?)
• Diet • Liver Transplantation
intestine
Copper
Albumin
Blood
Ceruloplasmin
ATP7BATP7B
intestine
Copper
CeruloplasminPenicillamine/Trientine
urine
Chelating Chelating agentsagents: Penicillamine : Penicillamine and Trientineand Trientine
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”)
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
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
intestine
Copper
Albumin Ceruloplasmin
Zinc
metallothionein
Zinc Acetate/SulfateZinc Acetate/Sulfate
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
Combination therapyCombination therapy
• Penicillamine + Zinc dubious efficacy
• Trientine + Zinc yes for decompensated cirrhosis
Askari, JLabClinMed, 2003
Brewer, JAmCollNutr, 1993
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
• 23 pts on Trientine• 25 pts on TM
8 weeks
Trientine26% risk of neuro deterioration
TM 4% risk of neuro deterioration
Tetrathiomolybdate (TM) for Tetrathiomolybdate (TM) for neurological symptomsneurological symptoms
Brewer GJ, Arch Neurol, 2006
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
ALT 85 349 1207 842 87Alk phos 221 299 346 338 358
Chol 171 642 486 327 150
IndicationsIndicationsPenicillaminePenicillamine Hepatic disease
TrientineTrientine Hepatic disease (or first choice?)
Neurological disease
Penicillamine side effects
ZincZinc Neurological disease
Maintenance treatment
Pregnancy
Tetrathiomolybdate?Tetrathiomolybdate? Neurological patients?
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
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
ComplianceCompliance
Sudden interruption of therapy in Wilson
disease can result in Acute Liver Failure
Walshe, Lancet, 1986
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
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
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
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