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  1. 1. Wilson Disease and Liver Transplantation Catherine Frenette, M.D. Department of Transplantation and Hepatology California Pacific Medical Center
  2. 2. Liver Transplantation in the US <ul><li>Since 1988, 95,985 patients transplanted in US </li></ul><ul><li>Current liver transplant listings: 15,859 </li></ul><ul><li>2008: 6,318 patients transplanted </li></ul><ul><ul><li>249 living donor </li></ul></ul><ul><ul><li>6069 deceased donor </li></ul></ul><ul><li>914 OLTs in 2008 in region 5 </li></ul><ul><ul><li>871 deceased donor </li></ul></ul><ul><ul><li>43 living donor </li></ul></ul>
  3. 4. Liver Transplantation for Wilson Disease <ul><li>1971: first successful transplant for Wilson disease </li></ul><ul><li>1.4% of current patients listed are listed for “metabolic disease” </li></ul><ul><li>577 transplants to date for Wilson disease </li></ul><ul><ul><li>34 transplants in 2008 </li></ul></ul><ul><ul><ul><li>4 transplants in Region 5 </li></ul></ul></ul>
  4. 5. Indications for Liver Transplant <ul><li>Acute liver failure: onset of coagulopathy and encephalopathy within 8 weeks of presentation </li></ul><ul><li>End stage liver disease: cirrhosis with complications </li></ul><ul><ul><li>Encephalopathy </li></ul></ul><ul><ul><li>Ascites </li></ul></ul><ul><ul><li>Portal hypertensive bleeding </li></ul></ul><ul><ul><li>Liver cancer </li></ul></ul>
  5. 6. Indications for Liver Transplant: Wilson Disease <ul><li>Acute liver failure </li></ul><ul><ul><li>Can be seen as initial presentation of Wilson disease </li></ul></ul><ul><ul><li>Can occur when chelating medications are stopped </li></ul></ul><ul><li>End stage liver disease </li></ul><ul><ul><li>Wilson disease unresponsive to chelating medications or patients intolerant of medications </li></ul></ul><ul><li>?Neurologic Symptoms </li></ul><ul><ul><li>Controversial whether patients should undergo transplant for this </li></ul></ul>
  6. 7. Liver Transplantation Contraindications <ul><li>Severe cardiopulmonary disease </li></ul><ul><li>Infections or malignancies outside of the liver </li></ul><ul><li>Hepatoma > 6.5 cm or multifocal (>5 lesions) </li></ul><ul><li>Age > 70 years: relative contraindication only </li></ul><ul><li>Active substance abuse (w/in past 6 months) </li></ul><ul><li>Inadequate support or coping mechanisms </li></ul><ul><li>Non-compliance </li></ul>
  7. 8. MELD Score <ul><li>MELD = Model for Endstage Liver Disease </li></ul><ul><ul><li>(0.957 x LN(creatinine) + 0.378 x LN(bilirubin) +1.12 x LN(PT-INR) +0.643) x 10 </li></ul></ul><ul><ul><ul><li>Range 6 - 40* </li></ul></ul></ul><ul><ul><li>Predictive of 3 months and 12 months survival </li></ul></ul><ul><ul><li>Utilized as a disease severity index to prioritize patients listed for liver transplantation </li></ul></ul>
  8. 9. % Mortality MELD Score n=124 n=1800 n=1038 n=295 n=126 2.9 7.7 23.5 60 81 3-Month Mortality based on Listing MELD Score Weisner et al, 2003 0 10 20 30 40 50 60 70 80 90 < 9 10 to 19 20 to 29 30 to 39 > 40
  9. 10. MELD <ul><li>MELD 21-30: </li></ul><ul><ul><li>Mean time to OLT, 128 days </li></ul></ul><ul><li>MELD 31-40: </li></ul><ul><ul><li>Mean time to OLT, 29 days </li></ul></ul><ul><li>Status 1 (acute liver failure): </li></ul><ul><ul><li>Mean time to OLT, 11 days </li></ul></ul>
  10. 12. Wilson Disease and Acute Liver Failure
  11. 13. Acute Liver Failure: Wilson Disease <ul><li>Wilson disease accounts for 4-6% of all liver transplants in US done for acute liver failure </li></ul><ul><li>Female preponderance for acute liver failure and Wilson disease </li></ul><ul><ul><li>?role of hormonal factors </li></ul></ul><ul><li>5% of all Wilson patients present with acute liver failure </li></ul>
  12. 14. Acute Liver Failure: Wilson Disease <ul><li>Often with underlying cirrhosis/advanced fibrosis </li></ul><ul><li>Can occur as initial presentation or in a known Wilson patient with medication non-adherence or treatment failure </li></ul><ul><li>Near 100% mortality without emergency liver transplant </li></ul><ul><ul><li>Early identification is key! </li></ul></ul><ul><li>1 year survival after OLT 79-87% </li></ul>Kormen et al Hepatology 2008
  13. 15. ALF and Wilson disease <ul><li>Relatively low transaminases </li></ul><ul><li>Low alkaline phosphatase (alk phos/bili) </li></ul><ul><li>Coombs negative hemolysis </li></ul><ul><li>Elevated urine and serum copper </li></ul><ul><li>KF in 50% </li></ul><ul><li>Ceruloplasmin not always helpful* </li></ul><ul><li>*ALFSG data </li></ul>
  14. 16. Hemolysis Liver Injury Copper accumulation Loss of antioxidant potential Copper release Release of Heme iron Renal Injury
  15. 17. Diagnosis of Acute Wilson Disease <ul><li>AP:TB <4 </li></ul><ul><li>AST:ALT >2.2 </li></ul>Kormen et al Hepatology 2008
  16. 18. Revised King’s Score for Liver Transplantation Dhawan et al Liver Transpl 2005 <20 >15.4 >401 >2.5 >301 4 21-24 10.4-15.3 301-400 2-2.4 201-300 3 25-33 8.4-10.3 151-300 1.7-1.9 151-200 2 35-44 6.8-8.3 101-150 1.3-1.6 101-150 1 >45 0-6.7 0-100 0-1.29 0-100 0 Albumin WCC AST INR Bilirubin µmole Score
  17. 19. Prospective Application of Scoring System Dhawan et al Liver Transpl 2005
  18. 20. Supportive Measures Awaiting Liver Transplant for Acute Liver Failure <ul><li>Plasma exchange/treatment </li></ul><ul><li>Exchange transfusion Plasmapheresis </li></ul><ul><li>MARS </li></ul><ul><li>Albumin dialysis </li></ul><ul><li>Early institution of renal replacement therapy </li></ul>
  19. 21. Neurologic Disease and Transplantation
  20. 22. Neurological Manifestations and Transplantation <ul><li>OLT reverses neurological deterioration in many Wilson patients </li></ul><ul><ul><li>~80% of patients improve or stabilize </li></ul></ul><ul><li>Combined hepatic and neurological disease must be carefully assessed to determine severity of neurological disease </li></ul>Medici et al Liver Transpl 2005; Stracciari et al, Arch Neurol 2000
  21. 23. Neurological Manifestations and Transplantation <ul><li>Isolated neuropsychiatric symptoms is considered by some experts to be a contraindication for OLT </li></ul><ul><ul><li>May improve with medical therapy </li></ul></ul><ul><ul><li>May worsen compliance with post transplant care and medications </li></ul></ul><ul><ul><li>Should not expose patients to risk of OLT when it may not improve symptoms </li></ul></ul>
  22. 24. Neurological Manifestations and Transplantation Medici et al Liver Transpl 2005
  23. 25. Transplant Options <ul><li>DDLT: deceased donor liver transplant </li></ul><ul><li>LDLT: living donor liver transplant </li></ul><ul><ul><li>60% of liver taken from healthy person to transplant into recipient </li></ul></ul><ul><ul><li>Can occur from relations who are heterozygous for Wilson mutation </li></ul></ul><ul><ul><li>Slower normalization of copper metabolism </li></ul></ul>
  24. 26. Transplant Outcomes in Wilson Dz <ul><li>Copper metabolism normalizes quickly after transplant </li></ul><ul><li>Copper overload slowly resolves in extrahepatic organs </li></ul><ul><ul><li>Within 2-3 months with DDLT </li></ul></ul><ul><ul><li>Within 6 months with LDLT </li></ul></ul>
  25. 27. Changes in Urine Copper Post OLT Wang et al W J Gastro 2003
  26. 28. Copper Changes after Transplant Stracciari et al, Arch Neurol 2000
  27. 29. Survival Post Transplantation <ul><li>Three month survival ~88-90% </li></ul><ul><ul><li>Peri-operative complications </li></ul></ul><ul><ul><li>Post-operative infection </li></ul></ul><ul><li>One year survival ~80-84% </li></ul><ul><li>Three year survival ~67-75% </li></ul><ul><li>Five year survival ~60-70% </li></ul><ul><li>* Depends on age, underlying diagnosis, disease recurrence, other medical problems </li></ul>
  28. 31. OLT outcomes in Wilson Disease Medici et al Liver Transpl 2005
  29. 32. Conclusions <ul><li>Wilson disease can be cured with liver transplantation </li></ul><ul><ul><li>Copper metabolism normalizes </li></ul></ul><ul><ul><li>Neurological symptoms can improve </li></ul></ul><ul><li>Wilson patients do just as well as other patients with liver transplantation </li></ul><ul><li>Compliance with chelating medications is key to avoid transplantation </li></ul>
  30. 33. CPMC Liver Transplantation
  31. 34. Birth Death Hepatic Inflammation Cirrhosis Liver Failure Complications of portal HTN ascites variceal bleeding encephalopathy Non-specific symptoms of liver disease Neuropsychiatric symptoms Natural History of Wilson Disease
  32. 35. Birth Death Hepatic Inflammation Acute Liver Failure Advanced fibrosis Cirrhosis Hemolytic anemia Jaundice Ascites Renal Failure