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Bile Salts for the Prevention of Rejection Following Liver Transplantation

Bile Salts for the Prevention of Rejection Following Liver Transplantation. Haley Gill VCH-PHC Pharmacy Resident 2009-2010 January 29, 2010. Outline. Learning Objectives Case Background Clinical Question Review of Literature Recommendation Monitoring Follow-up. Learning Objectives.

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Bile Salts for the Prevention of Rejection Following Liver Transplantation

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  1. Bile Salts for the Prevention of Rejection Following Liver Transplantation Haley Gill VCH-PHC Pharmacy Resident 2009-2010 January 29, 2010

  2. Outline • Learning Objectives • Case • Background • Clinical Question • Review of Literature • Recommendation • Monitoring • Follow-up

  3. Learning Objectives • To review the pathophysiology and treatment of acute rejection (AR) and chronic rejection (CR) in liver transplant recipients • To evaluate the literature surrounding the use of Ursodeoxycholic acid (UDCA) in prevention of acute and chronic graft rejection in liver transplantation

  4. Case ID: LS, 38 y/o female ESLD 2o EtOH Shx: From Victoria, divorced, good support from mother, Non-smoker, EtOH: 1-2 drinks/day per patient

  5. Case PMHx: Liver cirrhosis with portal HTN GI bleeds – varicies banded x 3 Exercise induced asthma NKDA MPTA:

  6. Case HPI:

  7. Review of Systems

  8. Review of Systems

  9. Lab Values

  10. Liver Function UDCA 500 BID MP 500 IV X 3 Dec 29 Dec 31 Jan 2 Jan 4 Jan 6 Jan 8 Jan 10

  11. Medications in Hospital

  12. Drug Related Problems • LS is experiencing acute graft rejection despite therapy with methylprednisolone (MP) and would benefit from reassessment of her current therapy • LS is experiencing hypomagnesemia and would benefit from reassessment of her current therapy • LS is experiencing hyperglycemia 2o to high dose MP and would benefit from reassessment of her current therapy

  13. Acute & Chronic Rejection • Incidence: • AR: ~18-30% of patients • CR leading to graft loss: < 3% of patients • Immune reaction to foreign tissue or organ • Antigen presenting cells • T cell activation • May lead to graft dysfunction or failure • Graded based on Rejection Activity Index (RAI)

  14. Acute Rejection • Usually occurs 5 – 30 days after transplant • Signs & Symptoms • ↑ LFT’s/liver enzymes • Fever • Swelling & tenderness at graft site • Change in color & quantity of bile • Re-accumulation of ascites

  15. Chronic Rejection • Obliterative arteriopathy & gradual loss of bile ducts • Irreversible • Signs & Symptoms • ↑GGT & ↑ALP • ↑ bilirubin may lead to jaundice & itching

  16. Acute & Chronic Rejection Treatment • AR: • High dose corticosteroids • Lymphocyte depleting agents - Anti-thymocyte globulin (ATG) • CR: • Optimize immunosuppression

  17. Ursodeoxycholic Acid Gallstone dissolution agent Beneficial in a number of cholestatic liver conditions MOA:  hydrophilicity & viscosity of bile acid pool Replace more toxic bile acids  IL-2 & IL-4 production  stabilize cell plasma membrane Immunomodulatory effects – alters antigens on hepatocyte membranes

  18. Ursodeoxycholic Acid • VGH: 250 mg capsule = $0.86 • Restricted to hematology, gastroenterology • Community: 500 mg capsule = $1.79 • Full benefit for select BC pharmacare groups

  19. Clinical Question • In a 38 y/o female liver transplant recipient does the addition of UDCA compared to standard triple immunosuppressive therapy decrease mortality and reduce the incidence of acute and/or chronic rejection?

  20. Search Strategy • Databases: Medline, Embase, Pubmed • Search terms: liver transplantation, bile salts, ursodiol, ursodeoxycholic acid, rejection • Limited to humans & English language • Results: • 1 systematic review • 5 RCT’s • 1 Review article

  21. Bile acids for liver-transplanted patients (Review) Chen W, Gluud C Cochrane Database of Systematic Reviews 2005, Issue 3

  22. Chen W, Gluud C Design • Systematic Review Objective • Evaluate the beneficial & harmful effects of bile acids for liver transplanted patients

  23. Chen W, Gluund C • Total Studies: 7 • Total Subjects: n=335 • Intervention: 172 • Placebo/control: 163 • Doses of UDCA used • 500 mg/day in 2 divided doses • 10 – 15 mg/kg/day in divided doses • 900 mg/day • 600 mg/day in 2 - 3 divided doses • Co-interventions • Standard triple immunosuppression (steroids, AZA, and CSA or TAC) • Steroids and CSA

  24. Chen W, Gluud C Outcomes • all-cause mortality • acute cellular rejection • death related to rejection • retransplantation • chronic rejection • steroid resistant rejection • adverse effects • serum bilirubin • length of hospital stay

  25. 90 day survival > in UDCA group (p=0.04) ↓ duration of hospital stay in UDCA group (p=0.03) Chen W, Gluud C

  26. No outcomes significant No difference in 1 year survival Chen W, Gluud C

  27. ↓GGT in UDCA group (p=<0.01) Chen W, Gluud C

  28. No difference in rejection incidence or severity Chen W, Gluud C

  29. Chen W, Gluud C

  30. Chen W, Gluud C Results – Acute Rejection

  31. Chen W, Gluud C • Results – Chronic Rejection • Significant reduction with fixed-effects model (RR 0.28, 95% CI 0.08 – 0.95) • Non-significant trend with random-effects model (RR 0.30, 95% CI 0.08 – 1.13)

  32. Chen W, Gluud C Other Outcomes: • Not significant: • All-cause mortality • Mortality related to allograft rejection • Number of retransplantations • Steroid Resistant Rejection • Adverse events • Significant  in length of hospital stay

  33. Chen W, Gluud C • Conclusions • Bile salts do not seem to decrease the incidence of acute rejection • Time to initiation & duration of therapy did not affect outcomes • May have some benefit in reducing incidence of chronic rejection • Therapy with bile salts well tolerated

  34. Chen W, Gluud C • Limitations • None of the trials considered to be of high methodological quality • Small number of patients in trials • Short follow up

  35. Recommendations • UDCA not recommended • If no response to MP pulse, consider ATG • Optimize current IMS • ↑MMF to 1500 mg PO BID • Maintain therapeutic TAC levels

  36. Monitoring

  37. Follow-up • Remained on UDCA 500 mg PO BID • Liver function worsened • Steroid pulse repeated Jan 12 with good result • Liver function worsened again • Recurrent AR treated with ATG

  38. References • Saksena S, Rakesh KT. Ursodeoxycholic acid in treatment of liver diseases. Postgrad Med J 1997;73:75-80 • Chen W, Gluud C. Bile acids for liver-transplanted patients. Cochrane Database of Systematic Reviews 2005, Issue 3 • Fleckenstein JF, et al. A prospective, randomized, double-blind trial evaluating the efficacy of ursodeoxycholic acid in prevention of liver transplant rejection. Liver Transplantation and Surgery 1998;4(4):276-279 • Pageaux GP, et al. Failure of ursodeoxycholic acid to prevent acute cellular rejection after liver transplantation. Journal of Hepatology 1995;23:119-122 • Barnes D, et al. A randomized clinical trial of ursodeoxycholic acid as adjuvant treatment to prevent liver transplant rejection. Hepatology 1997;26:853-857 • Keiding S, et al. The nordic multiventer double-blind randomized controlled trial of prophylactic ursodeoxycholic acid in liver transplant patients. Transplantation 1997;63(11):1591-1594

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