PHYSICIANS ROLE C.E.Eapen

1. Liver transplant:
Managing complications
Physician’s role
CE Eapen
Hepatology
Christian Medical College
Vellore

2. MELD score 1 yr
survival
3 yr
survival
< 10 90% 84%
11 - 18 90% 83%
19 – 24 88% 81%
> 25 85% 76%
Survival after liver Tx: 1997 – 2004
(UNOS database)
http://optn.transplant.hrsa.gov/converge/
latestData/rptStrat.asp

3. 1 yr
survival
5 yr
survival
After
liver
transplant
90 – 95% 70%
Moreno et al.
Annals of Hepatol 2006

4. Neuberger
Liver Transplant 2009
1 yr survival ~ 90%

5. Neuberger
Liver Transplant 2009

6. Neuberger
Liver Transplant 2009
In UK, adult liver Tx recipients
have 7.7 yr reduction in life
expectancy

7. Survival after liver Tx : 1997 – 2004
(UNOS database)
Roberts et al.
Liver Transplant 2004

8. Survival after liver Tx :
1997 – 2004
(UNOS database)
Roberts et al.
Liver Transplant 2004
cancers
fulminant
HCV
HBV

9. Survival after liver Tx :
1997 – 2004 (UNOS)
Roberts et al.
Liver Tx 2004

10. Survival after liver Tx :
1997 – 2004
(UNOS database)
Roberts et al.
Liver Transplant 2004
cancers
fulminant
HCV
HBV
1st week - 1st month:
important
milestones to cross

11. Better survival after liver Tx
• Better surgical techniques
• Prevent acute rejection

12. Duration of immunosuppression
after transplant
Kidney lifelong
Bone marrow
Liver

13. Duration of immunosuppression
after transplant
Kidney lifelong
Bone marrow 1 – 3 years
Liver

14. Duration of immunosuppression
after transplant
Kidney lifelong
Bone marrow 1 – 3 years
Liver lifelong

15. Triple immunosuppression after liver
transplant
Steroids (stop by Day 100)
Tacrolimus (FK506) / Cyclosporine
Mycophenolate / Azathioprine

16. • Thomas Starzl (Pittsburgh, USA)
• Sir Roy Calne (Cambridge, UK)

17. 12 pts: cyclosporin +
prednisone
(83% : 1 yr survival)
1-Yr Actuarial Survival after Liver Transplant
170 pts: prednisone
(55% : 1 yr survival)
Starzl et al.
N Engl J Med
1981; 305: 266

18. Pre - 1980 After 1980
Steroids
Azathioprine
Steroids
Azathioprine
Cyclosporine /
Tacrolimus
Main
concerns
after liver
transplant
Graft loss,
death (due to
acute rejection)
Side – effects of
immuno-supp.
Recurrent liver
disease
Cyclosporine : the game – changer in survival after liver
transplantation

19. Successful liver transplant with azathioprine,
prednisone, anti-lymphoid globulin (1967)
Azathioprine replaced by Cyclosporine (1979)
Cyclosporine replaced in turn by Tacrolimus (1989)
Starzl, Fung.
Hepatology June 2010

20. acute rejection of liver graft : a multi-step process
Signal 1 Allo-antigen recognition
Signal 2 Lymphocyte activation
Signal 3 Clonal expansion
Graft inflammation

21. Allo-ag recognition Lymphocyte activation
Clonal expansionAg presenting cell
T lymphocyte Target lymphocyte
Immunobiology of acute rejection in liver transplantation

22. Immunobiology of acute rejection
Drugs to prevent / treat
1. Allo-antigen
recognition
Anti-lymphocyte
antibodies
2. Lymphocyte
activation
Calcineurin inhibitors Cyclosporine
Tacrolimus
3. Clonal
expansion
Monoclonal ab against
IL – 2 receptor
Basiliximab
Binds to mTOR
(mammalian target of
Rapamycin)
Sirolimus
Everolimus
Inhibit DNA synthesis Azathioprine
Mycophenolate
Inflammatory
cascade
Steroids

23. Target therapeutic levels for calcineurin inhibitors after
liver transplant
Therapeutic level
Cyclosporine 1st 3mo:s 200 – 250 ng / ml
After 12 mo:s 80 – 120 ng /ml
Tacrolimus 1st 6 mo:s 7 – 10 ng / ml
After 6 mo: s 4 – 6 ng / ml

24. Use of biological agents for induction IS (2000 - 2009) (based on data from the
US Scientific Registry of Transplant Pts).
Induction agents included ATG, OKT3, thymoglobulin, daclizumab, basiliximab,
& alemtuzumab.
Trotter et al.
Liver Transpl. 2013 Aug; 826-42.

25. IS regimen at time of pt. discharge (2000 - 2009) (based on
data from the US Scientific Registry of Transplant Pts.).
Trotter et al.
Liver Transpl. 2013 Aug; 826-42.

26. Maintenance IS regimens (1999 – 2007) (based on data
from the US Scientific Registry of Transplant pts.)
Trotter et al.
Liver Transpl. 2013 Aug; 826-42.

27. 1. Lifelong immunosuppression is needed
2. Low dose immunosuppression in initial post –
op period, to encourage “cross-talk”, facilitate
tolerance.

28. Drug interactions

29. Drug interaction after liver transplant
Immuno-
suppression
New drug
added
Drug interaction consequence
Cyclosporine /
Tacrolimus
Phenytoin Induces CYP 3A4 -
↓ blood level of
CYA / Tac
Can cause
graft
rejection

30. Drug interaction after liver transplant
Immuno-
suppression
New drug
added
Drug interaction Possible
consequence
Cyclosporine
/ Tacrolimus
Phenytoin Induces CYP 3A4 -
↓ blood level of CYA / Tac
graft rejection
Fluconazole Inhibits CYP 3A4 - ↑
blood level of CYA /
Tac
CYA / Tac
toxicity :
eg: renal failure

31. Drug interaction after liver transplant
• 9 months after transplant: on cyclosporine
and azathioprine
• Developed gout
• Started on allopurinol
• Presented with pancytopenia

32. Drug interaction after liver Tx
• 9 mo. after Tx: on cyclosporine + azathioprine
• Gout, started on allopurinol, now pancytopenia
azathioprine
6 m-p
Inactive metabolites

33. Drug interaction after liver transplant
• 9 mo. after Tx: on cyclosporine + azathioprine
• Gout, started on allopurinol, now pancytopenia
azathioprine
6 m-p
Inactive metabolites
Xanthine oxidase
* Allopurinol inhibits xanthine oxidase,
↑ses level of 6m-p in blood

34. Drug interaction after liver transplant
• CYA / Tac → hyperuricemia, gout
azathioprine
6 m-p
Inactive metabolites
Xanthine oxidase
•Allopurinol inhibits xanthine oxidase, ↑ses
level of 6m-p in blood
• MMF : does not interact with allopurinol
Stamp et al.
Drugs 2005;65:2593-611.

35. Drug interaction after liver transplant
Immuno-
suppression
New drug
added
Drug interaction Possible
consequence
Cyclosporine /
Tacrolimus
Phenytoin Induces CYP 3A4 -
↓ blood level of CYA /
Tac
graft rejection
Fluconazole Inhibits CYP 3A4 - ↑
blood level of CYA /
Tac
CYA / Tac
toxicity : eg:
renal failure
Azathioprine Allopurinol Inhibits
metabolism of
azathioprine
Bone marrow
suppression

36. Medical complications of liver Tx
Immediate Late
Primary poor / non
function of graft
Chronic rejection
Acute rejection HT, Diabetes,
↑lipids, Obesity
Recurrent viral hepatitis Renal failure
Infections
Bacterial
Viral
Fungal
Recurrence of native
liver disease
Malignancy