1. Care of the Post-OLT Patient
George Makar

2. Overview Immunosuppression Causes of Allograft Failure
Medical Comorbidites
Malignancies
Pregnancy/Sexual Function

3. Figure 1. Timeline for the introduction of immunosuppression medications.
Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp

4. Figure 2. Illustration showing the activation of a T lymphocyte (via 3-signal pathway) by an antigen-presenting cell. Further detail includes the specific sites targeted by the calcineurin inhibitors (TAC and CyA) showing inhibition of IL-2 production. Monoclonal antibodies (basiliximab, daclizumab) target the IL-2 receptor, while OKT3 targets the T-cell receptor. Sirolimus, MPA, MMF, azathioprine, and FK778 interfere with the proliferative phase in the cell cycle. Novel agent FTY720 alters lymphocyte trafficking/homing patterns through modulation of cell surface adhesion receptors inducing a lymphopenic effect.
Immunosuppression in Liver Transplantation. Post et al. Liver Transplantation, Vol 11, No 11,2005: pp

5. Immunosuppression Early – multiple meds, high doses
Pred + CNI* +/- (MMF/AZA)
Late – fewer (1) meds, lower doses
Most patients CNI alone (usually Tac)
Exceptions:
Autoimmune hepatitis, PSC, PBC (usually 2 drugs)
Renal dysfunction (MMF/AZA + lower CNI dose)
*CNI = calcineurin inhibitor = CsA or Tac

6. Cyclosporine Block Calcineurin→ ↓IL-2 →↓T-Cell Activation
Initial dosage 10 to 15 mg/kg/day divided into 2 doses.
Trough Goals
Week ng/mL
Weeks
Weeks ng/mL
Weeks ng/mL
Distant – can tolerate levels <100

7. Cyclosporine – Adverse Effects
Hypertension
Renal dysfunction
Hirsutism
Hyperkalemia
Gingival hyperplasia
Hypomagnesemia

8. Tacrolimus MOA same as CsA Initial dose 0.1 to 0.15 mg/kg/day orally
Trough Goals (variable per patient/disease)
Early Post-OLT – ng/ml
3-6 Months – 8-10
>6 Months – 5-7 (variable)

9. Tacrolimus – Adverse Effects
Posttransplant diabetes mellitus
Nausea, vomiting, diarrhea
Hyperkalemia
Tremor
Hypertension
Hypomagnesemia
Headache
Renal dysfunction

10. Tac vs Csa Dyslipidemia and Gingival hyperplasia – more common in Csa
Diabetes – more common in Tac
Rejection – less common in Tac
Renal Dysfunction – similar

11. Sirolimus
Binds to same immunophilin as Tac (FKBP12) but with a different mechanism of action
blocks response of T and B Cell Activation by cytokines – prevents progression at the juncture of G1 and S phase in these cell lines.
Theoretical (lab based) antineoplastic and antifungal effects.
Early excitement about renal protective effect- subsequent studies have not confirmed this
Meta-analysis of 11 studies suggests a numerical/non-significant improvement in renal function.
Hepatology Oct;52(4):

12. Sirolimus Not FDA approved for Liver Transplants –
The FDA is notifying healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune). The trial was conducted by sirolimus manufacturer, Wyeth.

13. Sirolimus
Black Box warning – possible increased risk of Hepatic Artery Thrombosis in immediate post-OLT setting – usually wait up to 12 weeks post.
Recent study of switch from CNI to SRL suggests possible increased mortality (FDA ALERT [06/11/2009])
Currently using in those intolerant to CNIs, and in some patients for theoretical antineoplastic and renoprotective (controversial) effects.

14. Sirolimus – Adverse Effects
Anemia
Hypercholesterolemia
Hypertriglyceridemia
Leukopenia
Hyperlipidemia
Interstitial lung disease
Thrombocytopenia
Peripheral edema
Wound dehiscence
Hepatic Artery Thrombosis

15. Mycophenylate Mofetil (MMF)/ Mycophenolic Acid (MPA)
inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotides
Leads to blockage of DNA replication in T and B lymphocytes (can’t use salvage pathways).
MPA is a delayed release form of MMF
Dosing –
mg bid MMF or
BID MPA

16. Side effects of MMF/MPA
Nausea, vomiting, diarrhea
Anemia
Leukopenia
Weight loss
Thrombocytopenia

17. Immunosuppression – Drug Interactions
Cytochrome P-450 3A
P-Glycoprotein – cell membrane associated protein transports drugs and plays a role in both absorption (bowel) as well as elimination (liver and kidney)
carvedilol inhibits p-plycoprotein pathway leading to increased CNI levels
Grapefruit – can increase levels of CNIs – mechanism not totally clear

18. Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003

19. Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003

20. Antibody Induction Antithymocyte Globulin – induction/rejection.
Polyclonal antilymphocyte globulin – multiple epitopes on T cell receptor – lead to apoptosis of T-cells
ATGAM (of equine origin)
Thymoglobulin (of rabbit origin)
Monoclonal anti T-Cell antibodies – induction/rejection
Muromonab-CD3 (OKT3) – binds CD3 Antigen on T-Cell receptor – inactivates adjacent T-Cell – leads to rapid drop in T-Cells
IL-2 Receptor Antibodies – induction
Basiliximab (Simulect)
daclizumab (Zenapax).

21. Causes of Allograft Failure
Primary Nonfunction – slightly more common in Living Donors
Vascular Complications – 10% of patients
Hepatic Artery Thrombosis/Stricture
Portal Vein Thrombosis/Stricture
Hepatic Vein Thrombosis/Stricture
Biliary Complications –
Donors after Cardiac Death
Living Donors
Anastomotic vs nonanastomotic strictures

22. Causes of Allograft Failure- Rejection
Antibody Mediated Rejection – hours to days
10-20% Acute Rejection
Risk 1st 3months>1st year>subsequent years
Chronic Rejection – a primary RF is prior episodes of Acute Rejection.
Acute vs Chronic –
time course
pattern of liver enzyme abnormalities
response to therapy

23. Acute Rejection Banff Grading System – each factor 1-3 scale
Portal Inflammation
Bile Duct Inflammation/damage
Venous Endothelial Inflammation

24. Wyatt (2010) Histopathology 57, 333–341

25. Acute Rejection
RFs –
young recipient,
“healthier” recipients,
HLA-DR mismatch,
PSC/PBC/AIH,
long cold ischemia time,
older donor.
Late (>1 year) acute rejection – inadequate immunosuppression.

26. Chronic Rejection Early CR Late CR Small Bile ducts
Duct loss <50% portal triads
Duct loss>50% portal triads
Terminal hepatic venules/zone 3 hepatocytes
Zone 3 necrosis/inflammation
Mild perivenular fibrosis
Focal obliteration
Severe fibrosis – central-central bridging fibrosis
Portal tract hepatic arterioles
loss <25% portal triads
loss >25% portal triads
Adapted/abbreviated from Table 69-9 Features of Early and Late Chronic liver allograft rejection. Pg 1086, Transplantation of the Liver, Busuttil and Klingman, 2nd Edition.

27. Infections that can lead to graft failure
CMV – 1-4 months post-OLT, increased risk of rejection
Other herpes family viruses similar course to lesser extent
HCV
1 in 3 cirrhotic at 5 years
5-10% fibrosing cholestatic HCV
HBV
Controlled in era of HBIG and oral therapies

28. Causes of Allograft Failure – Recurrent Disease
AIH, PBC, PSC – 10-20%
EtOH – 20% with recurrent use
majority of recurrent use not associated with heavy Etoh ingestion or poor outcomes.
HCC – within Milan - 10% risk of recurrence
- higher rates for outside of Milan Criteria

29. Renal Dysfunction 18% Rate of CRF (GFR <30) by 5 years
Pretransplant Factors –
female, HCV, Renal disease pretransplant
Immunosuppression – dose dependent
Reversible – vasoconstriction of Intrarenal Vessels
Irreversible – tubulointerstitial fibrosis
Hypertension
Diabetes

30. Diabetes Prevalence – 33%
RF – obesity, steroids, high TAC doses, pretransplant DM, HCV
De novo post transplant diabetes
27% year 1
9% year 2
1% year 3
Treat in a similar manner as non-OLT patients – lifestyle changes, minimize steroids and lower Tac dosing.
OLT can cure Diabetes in some patients
56% pretransplant DM, resolved DM in one cohort study1
Steinmuller TH,. Liver transplantation and diabetes mellitus. Exp Clin Endocrinol Diabetes 2000; 108: 401–405.

31. Hypertension CsA (25-82%) > Tac (17-64%) Goal BP <=130/80
Thiazide, Loop (if edema)
Calcium channel Blockers*
(not dilt,verapamil, nicardipine – inc levels of CNIs).
Later ACE/ARB, especially in DM (monitor K)
Can use others – doxazosin, clonidine, beta blockers (monitor levels with Coreg).
*Can block intrarenal vasoconstriction caused by CNIs

32. Dyslipidemia Prevalence 16-43%
RF – Female, Cholestatic liver disease, DM, Obesity, pretransplant dyslipidemia
Effects on Lipids:
CSA, Steroids Sirolimus – greatest effect
TAC – minor effect
MMF/AZA – no effect
Treatment – all classes of agents can be used – each with potential for drug interactions/toxicities.
Note – bile acids cannot be used if also on MMF/AZA

33. Obesity 22% Nonobese patients pre-OLT become obese post
Pre-OLT obese gain more weight than non-obese
RF for recurrent (or de novo) NASH
TX – the usual
Orlistat can decrease absorption of CsA

34. Gout Dec Uric Acid excretion by CNIs
RFs – thiazides, ASA, Nicotinic Acid
Prophylaxis – Allopurinol (except if on AZA)
TX – colchicine, steroids
Avoid NSAIDS (nephrotoxic with CNIs)

35. Bone Disease Nadir in Bone Density 6 months Post
Bone density 1 year post similar to bone density at time of OLT
13% fracture rate within 2 years of OLT
RFs for Osteoporosis
ETOH
Tobacco
Low Testosterone
Physical Inactivity
cholestatic liver disease –
unconjug bili inhibits osteoblast proliferation
Patients also at risk of Osteonecrosis of Femoral Head

36. Bone Disease Treatment of Osteoporosis
Calcium 1500mg +vitamin D 800 IU
Bisphosphonates well studied
Other classes not as well studied but no obvious contraindications
Calcitonins, Parathyroid hormone, Selective Estrogen Receptor-Modulators

37. Vaccines

38. Vaccines
Theoretical Risks with Life Attenuated Vaccines due to potential risk of shedding of liver virus – small studies suggest that many of these are safe.
Transplant Center dependent decisions for these (we don’t use)
Use inactivated virus whenever possible

39. Dental Care
Important – can be source of sepsis in peri/post-OLT setting
Gingival Hyperplasia – unique to CSA, may require oral surgery and/or switch to Tac
Antibiotic Prophylaxis for Dental Work - revised
As per AHA guidelines only if at increased risk of endocarditis (prior endocarditis, prosth valve, certain forms congenital heart dz).
Many transplant programs (including ours) still provide antibiotics.

40. Tobacco Increased rates of CAD Stroke
Esophageal/upper aerodigestive Cancer
liver vascular events (Hepatic Artery Thrombosis/Stenosis, Portal Vein Stenosis, DVT)

41. THC
In Nontransplant Patients – reports of increased steatosis/fibrosis in THC users
Contamination with fungal spores – theoretical increased risk of fungal infections.

42. Malignancies – Skin Cancer
100x over general population
Squamous Cell (SCC)> Basal Cell > Melanoma
SCC – multiple, more aggressive, more likely to be associated with metastasis
35% lifetime risk
Rec –
annual Dermatology exam,
minimize immunosuppression in setting of diagnosed skin cancer
use sunscreen/avoid sun exposure

43. Malignancies - PTLD 2% Adults, 15% Kids 80-90% EBV associated
Usually within 1 year post-OLT
2 less common forms (CD20 negative)
Plasmacytic form (similar to multiple myeloma)
T-Cell malignancy
Treatment
Reduce immunsuppresion
Rituximab if CD20 positive, Chemotherapy if CD20 negative

44. Malignancies - GI
Upper aerodigestive tract – increased in those with Risk Factors – ETOH, Tobacco
Colon cancer – increased risk in those with preexisting RFs – ie PSC/UC patients –
Annual colonoscopy with surveillance biopsies

45. Malignancies - Other
Breast, Prostate, Lung, Colon cancer – no definite increased risk (in those without risk factors)
Follow age-appropriate cancer screening guidelines
Role of decreased immunosuppression less clear in these cancers than in virally mediated malignancies (EBV, Kaposi’s, HPV associated (anogenital) malignances)

46. Sexual Function
ESLD is bad for fertility (50% amenorrhea) and for sexual dysfunction (both libido and erectile dysfunction).
>90% recover sexual function post-OLT
Use Contraception!
50% of females transplanted are of child bearing age

47. Pregnancy Wait 1 year post-OLT Most drugs category C
(MMF/AZA category D)
National Transplantation Pregnancy Registry (NTPR) – 2700 pregnancies
Live birth Rate 70%
Congenital anomolies 4-5% vs 3% general population
Premature/Low Birth weights range 10-55%
Tac – lower rates of hypertension/preeclampsia vs CsA

48. Pregnancy – Risk of Rejection
Increased serum proteins that lead to increased binding of CNI’s and decreased levels
10% rate of rejection
Close monitoring of CNI levels throughout pregnancy

49. Summary
CsA, Tac or Sirolimus are the backbone of maintenance immunosuppresion
Addition of other agents (Steroids, MMF, Azathioprine) can be used to decrease risk of rejection or allow for lower doses of the primary agents.
50% of post-OLT deaths are directly/indirectly related to immunosuppressive medications.

50. Summary
Technical Factors and early recurrent Disease responsible for allograft failure in first year
With the possible exception of HCV and HCC patients, after the first year, long-term survival more affected by CV disease and malignancy than allograft failure.
Goal should be aggressive lifestyle measures to control weight and medical comorbidities and ensuring patients are up to date with cancer screening.
Primary additional testing in long-term transplant patients: annual dermatology exams and DEXA scans (especially for those on long-term steroid therapy).

51. Reading
McGuire BM et al. Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor American Journal of Transplantation 2009; 9: 1988–2003
Post DJ. Immunosuppression in Liver Transplantation. Liver Transplantation, 2005; 11: