Treatment of Wilson disease Valentina Medici, M.D. Division of Gastroenterology and Hepatology UC Davis May 2 nd , 2009
Outline <ul><li>Treatment options </li></ul><ul><li>Mechanism of action </li></ul><ul><li>Side effects </li></ul><ul><li>S...
Options <ul><li>Chelating agents (Penicillamine, Trientine) </li></ul><ul><li>Zinc </li></ul><ul><li>Tetrathiomolybdate (?...
intestine Copper Albumin Blood Ceruloplasmin ATP7B
intestine Copper Ceruloplasmin Penicillamine/Trientine urine Chelating  agents : Penicillamine  and Trientine
Penicillamine   <ul><ul><ul><li>Copper chelator:    Cu urinary excretion </li></ul></ul></ul><ul><ul><ul><li>Dose : 750-1...
Penicillamine  side effects <ul><ul><ul><li>Fever, rash, lymphoadenopathy </li></ul></ul></ul><ul><ul><ul><li>Aplastic ane...
Trientine <ul><li>Cu chelator </li></ul><ul><li>New “first choice” </li></ul><ul><li>Fewer side effects than penicillamine...
intestine Copper Albumin Ceruloplasmin Zinc metallothionein Zinc Acetate/Sulfate
Zinc Sulfate/Acetate   <ul><li>“ Blocks” Cu absorption </li></ul><ul><ul><ul><li>Prevents Cu toxicity </li></ul></ul></ul>...
Combination therapy <ul><li>Penicillamine + Zinc     dubious efficacy </li></ul><ul><li>Trientine + Zinc     yes for dec...
Tetrathiomolybdate <ul><li>Forms a complex with copper and protein </li></ul><ul><li>Taken with meals   complexes Cu in t...
<ul><li>23 pts on Trientine </li></ul><ul><li>25 pts on TM </li></ul><ul><li>8 weeks </li></ul><ul><li>Trientine  26% ris...
Medici V, Mov Disord, 2006 33 yo, man, with severe neurological WD TTM  120 mg/day TTM  180 mg/day stop TTM   150 327 486 ...
Indications Hepatic disease (or first choice?)  Neurological disease Penicillamine side effects Trientine Neurological pat...
Management during follow up <ul><li>Depends on the severity of the neurological or hepatic features </li></ul><ul><li>Asse...
Management of hepatic WD <ul><li>About 30% of patients have mildly increased transaminase level   benign </li></ul><ul><l...
Compliance <ul><li>Sudden interruption of therapy in Wilson disease can result in Acute Liver Failure </li></ul>Walshe, La...
<ul><li>Gene therapy </li></ul><ul><li>Lentiviral gene transfer (ATP7B) </li></ul><ul><li>Increased levels of ceruloplasmi...
Allen KJ, Cell Transplant, 2004 TOXIC MILK MOUSE (N° 46) Sublethal radiation Transplant with bone marrow stem cells  N°11 ...
Hepatocytes transplantation <ul><li>6 months after transplant: liver was extensively repopulated with hepatocytes </li></u...
Conclusions <ul><li>WD is a very peculiar medical situation   genetic but treatable disorder, almost complete resolution ...
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  • 1) To learn the mechanisms of action of anticopper agents 2) To learn indications, contraindications, and side effects of different anti copper agents 3) To learn about different strategies when one treatment is not effective
  • First was the BAL (British Anti-lewisite), injected intra-muscolarly and now we have much more practical and effective treatments.
  • Elastosis perforans serpiginosa (EPS) is a rare skin disease in which abnormal elastic tissue fibers, other connective tissue elements, and cellular debris are expelled from the papillary dermis through the epidermis (transepithelial elimination). The first stage of the granulomatous inflammation is the destruction of normal connective tissue. Small papules erupt and are grouped in a confined area, eventually becoming serpiginous. The central core of each papule contains a compressed aggregate of fibrous material and cellular debris that, eventually, is disgorged to the surface, after which the papule subsides and disappears .
  • Make sure that the 2 doses are well separated throu out the day (5-6 hours) Experimental approach
  • Address combination therapy
  • Change!!
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    1. 1. Treatment of Wilson disease Valentina Medici, M.D. Division of Gastroenterology and Hepatology UC Davis May 2 nd , 2009
    2. 2. Outline <ul><li>Treatment options </li></ul><ul><li>Mechanism of action </li></ul><ul><li>Side effects </li></ul><ul><li>Strategies for better management </li></ul><ul><li>New prospectives </li></ul>
    3. 3. Options <ul><li>Chelating agents (Penicillamine, Trientine) </li></ul><ul><li>Zinc </li></ul><ul><li>Tetrathiomolybdate (?) </li></ul><ul><li>Diet </li></ul><ul><li>Liver Transplantation </li></ul>
    4. 4. intestine Copper Albumin Blood Ceruloplasmin ATP7B
    5. 5. intestine Copper Ceruloplasmin Penicillamine/Trientine urine Chelating agents : Penicillamine and Trientine
    6. 6. Penicillamine <ul><ul><ul><li>Copper chelator:  Cu urinary excretion </li></ul></ul></ul><ul><ul><ul><li>Dose : 750-1500 mg/daily + pyridoxine (B6) daily </li></ul></ul></ul><ul><ul><ul><li>30% discontinued for side effects </li></ul></ul></ul><ul><ul><ul><li>Can worsen neurological symptoms (up to 50%) </li></ul></ul></ul><ul><ul><ul><li>Rare birth defects (“ cutis laxa ”) </li></ul></ul></ul>
    7. 7. Penicillamine side effects <ul><ul><ul><li>Fever, rash, lymphoadenopathy </li></ul></ul></ul><ul><ul><ul><li>Aplastic anemia, neutropenia and thrombocytopenia </li></ul></ul></ul><ul><ul><ul><li>Late side effects : elastosis perforans serpiginosa, arthropathy, lupus-like reaction, nephrotic syndrome, myastenia gravis, Goodpasture syndrome </li></ul></ul></ul>Scheinberg IH, Sternlieb I. Wilson’s disease. In: Smith LH Jr., Ed. Philadelphia: W.B. Saunders, 23;1984
    8. 8. Trientine <ul><li>Cu chelator </li></ul><ul><li>New “first choice” </li></ul><ul><li>Fewer side effects than penicillamine </li></ul><ul><li>More tolerable for neurological symptoms </li></ul><ul><li>Dose : 750 -1500 mg/daily </li></ul><ul><li>Side effects  rare pancytopenia </li></ul>
    9. 9. intestine Copper Albumin Ceruloplasmin Zinc metallothionein Zinc Acetate/Sulfate
    10. 10. Zinc Sulfate/Acetate <ul><li>“ Blocks” Cu absorption </li></ul><ul><ul><ul><li>Prevents Cu toxicity </li></ul></ul></ul><ul><ul><ul><li> Cu Urinary Excretion </li></ul></ul></ul><ul><ul><ul><li>Minor side effects (dyspepsia): </li></ul></ul></ul><ul><ul><ul><li>Acetate is better tolerated </li></ul></ul></ul><ul><ul><ul><li>Dose : 150 mg daily of elemental zinc </li></ul></ul></ul><ul><ul><ul><li>Slow action (4-6 months) </li></ul></ul></ul><ul><ul><ul><li>No concerns during pregnancy, safe for neurological symptoms </li></ul></ul></ul>Brewer GJ, J Lab Clin Med, 1999
    11. 11. Combination therapy <ul><li>Penicillamine + Zinc  dubious efficacy </li></ul><ul><li>Trientine + Zinc  yes for decompensated cirrhosis </li></ul>Askari, JLabClinMed, 2003 Brewer, JAmCollNutr, 1993
    12. 12. Tetrathiomolybdate <ul><li>Forms a complex with copper and protein </li></ul><ul><li>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 </li></ul><ul><li>More efficacy for neurological symptoms </li></ul><ul><li>Not yet approved </li></ul>
    13. 13. <ul><li>23 pts on Trientine </li></ul><ul><li>25 pts on TM </li></ul><ul><li>8 weeks </li></ul><ul><li>Trientine  26% risk of neuro deterioration </li></ul><ul><li>TM  4% risk of neuro deterioration </li></ul>Tetrathiomolybdate (TM) for neurological symptoms Brewer GJ, Arch Neurol, 2006
    14. 14. Medici V, Mov Disord, 2006 33 yo, man, with severe neurological WD TTM 120 mg/day TTM 180 mg/day stop TTM 150 327 486 642 171 Chol 358 338 346 299 221 Alk phos 87 842 1207 349 85 ALT
    15. 15. Indications Hepatic disease (or first choice?) Neurological disease Penicillamine side effects Trientine Neurological patients? Tetrathiomolybdate? Neurological disease Maintenance treatment Pregnancy Zinc Hepatic disease Penicillamine
    16. 16. Management during follow up <ul><li>Depends on the severity of the neurological or hepatic features </li></ul><ul><li>Assess any sign of hepatic decompensation </li></ul><ul><li>24-h urinary Cu excretion (denotes adequate treatment) </li></ul><ul><li>Monitor penicillamine side effects </li></ul>
    17. 17. Management of hepatic WD <ul><li>About 30% of patients have mildly increased transaminase level  benign </li></ul><ul><li>Liver biopsy </li></ul><ul><li>Try an alternative anti-copper agent </li></ul><ul><li>Add Vitamin E (antioxidant effect) </li></ul>von Herbay A, J Hepatol, 1994 Iorio, J Pediatr Gastroenterol Nutr, 2004
    18. 18. Compliance <ul><li>Sudden interruption of therapy in Wilson disease can result in Acute Liver Failure </li></ul>Walshe, Lancet, 1986
    19. 19. <ul><li>Gene therapy </li></ul><ul><li>Lentiviral gene transfer (ATP7B) </li></ul><ul><li>Increased levels of ceruloplasmin </li></ul><ul><li>Reduced hepatic copper </li></ul><ul><li>Improved hepatic fibrosis </li></ul>Merle, Scand J Gastro, 2006 LEC rats
    20. 20. 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 cells
    21. 21. Hepatocytes transplantation <ul><li>6 months after transplant: liver was extensively repopulated with hepatocytes </li></ul><ul><li>ATP7B expression, increased Cp, reduced hepatic Cu </li></ul><ul><li>Improved liver histology </li></ul>Joseph, Gastro, 2009 Spleen Liver Hepatocytes LEC rats Cholic acid, radiation, partial hepatectomy
    22. 22. Conclusions <ul><li>WD is a very peculiar medical situation  genetic but treatable disorder, almost complete resolution of symptoms with appropriate and timely therapy </li></ul><ul><li>Early diagnosis and early therapy are mandatory </li></ul><ul><li>Compliance to medical treatment is crucial </li></ul>

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