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 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

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

IndicationsIndications

Hepatic disease (or first choice?)

Neurological disease

Penicillamine side effects

TrientineTrientine

Neurological patients?Tetrathiomolybdate?Tetrathiomolybdate?

Neurological disease

Maintenance treatment

Pregnancy

ZincZinc

Hepatic diseasePenicillaminePenicillamine

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