physicians role c.e.eapen

Liver transplant:Managing complications Physician’s role

CE EapenHepatology

Christian Medical CollegeVellore

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

1 yr survival

5 yr survival

After liver

transplant90 – 95% 70%

Moreno et al.Annals of Hepatol 2006

Neuberger Liver Transplant 2009

1 yr survival ~ 90%


In UK, adult liver Tx recipients have 7.7 yr reduction in life expectancy

Survival after liver Tx : 1997 – 2004 (UNOS database)

Roberts et al.Liver Transplant 2004

Survival after liver Tx : 1997 – 2004

(UNOS database)


cancers

fulminantHCV

HBV

Survival after liver Tx : 1997 – 2004 (UNOS)

Roberts et al.Liver Tx 2004

Survival after liver Tx : 1997 – 2004

(UNOS database)


cancers

fulminant

HCVHBV

1st week - 1st month: important milestones to cross

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

Duration of immunosuppression after transplant

Kidney lifelongBone marrowLiver


Kidney lifelongBone marrow 1 – 3 yearsLiver


Kidney lifelongBone marrow 1 – 3 yearsLiver lifelong

Triple immunosuppression after liver transplant

Steroids (stop by Day 100)Tacrolimus (FK506) / CyclosporineMycophenolate / Azathioprine

• Thomas Starzl (Pittsburgh, USA)

• Sir Roy Calne (Cambridge, UK)

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

Pre - 1980 After 1980

Steroids Azathioprine

Steroids Azathioprine Cyclosporine / Tacrolimus

Main concerns after livertransplant

Graft loss, death (due to acute rejection)

Side – effects of immuno-supp.

Recurrent liver disease

Cyclosporine : the game – changer in survival after liver transplantation

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

acute rejection of liver graft : a multi-step process

Signal 1 Allo-antigen recognitionSignal 2 Lymphocyte activationSignal 3 Clonal expansion

Graft inflammation

Allo-ag recognition Lymphocyte activation

Clonal expansionAg presenting cell

T lymphocyte Target lymphocyte

Immunobiology of acute rejection in liver transplantation

Immunobiology of acute rejectionDrugs to prevent / treat

1. Allo-antigen recognition

Anti-lymphocyte antibodies

2. Lymphocyte activation

Calcineurin inhibitors CyclosporineTacrolimus

3. Clonal expansion

Monoclonal ab against IL – 2 receptor

Basiliximab

Binds to mTOR (mammalian target of Rapamycin)

SirolimusEverolimus

Inhibit DNA synthesis AzathioprineMycophenolate

Inflammatory cascade

Steroids

Target therapeutic levels for calcineurin inhibitors after liver transplant

Therapeutic levelCyclosporine 1st 3mo:s 200 – 250 ng / ml

After 12 mo:s 80 – 120 ng /mlTacrolimus 1st 6 mo:s 7 – 10 ng / ml

After 6 mo: s 4 – 6 ng / ml

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.

http://www.ncbi.nlm.nih.gov/pubmed/23696464




IS regimen at time of pt. discharge (2000 - 2009) (based on data from the US Scientific Registry of Transplant Pts.).






Maintenance IS regimens (1999 – 2007) (based on data from the US Scientific Registry of Transplant pts.)






1. Lifelong immunosuppression is needed

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

Drug interactions

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


Immuno-suppression

New drug added

Drug interaction Possible consequence


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


• 9 months after transplant: on cyclosporine and azathioprine

• Developed gout• Started on allopurinol• Presented with pancytopenia

Drug interaction after liver Tx

• 9 mo. after Tx: on cyclosporine + azathioprine• Gout, started on allopurinol, now pancytopenia

azathioprine

6 m-p

Inactive metabolites

Drug interaction after liver transplant• 9 mo. after Tx: on cyclosporine + azathioprine• Gout, started on allopurinol, now pancytopenia

azathioprine

6 m-p

Inactive metabolitesXanthine oxidase

* Allopurinol inhibits xanthine oxidase, ↑ses level of 6m-p in blood

Drug interaction after liver transplant• CYA / Tac → hyperuricemia, gout

azathioprine

6 m-p

Inactive metabolitesXanthine 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.


Immuno-suppression

New drug added

Drug interaction Possible consequence


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

Medical complications of liver TxImmediate Late

Primary poor / non function of graft

Chronic rejection

Acute rejection HT, Diabetes, ↑lipids, Obesity

Recurrent viral hepatitis Renal failureInfectionsBacterialViralFungal

Recurrence of native liver disease Malignancy

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