Care of the Post-OLT Patient
George Makar
Overview
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Immunosuppression
Causes of Allograft Failure
Medical Comorbidites
Malignancies
Pregnancy/Sexual Function
Figure 1. Timeline for the introduction of immunosuppression medications.
Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005:
pp 1307-1314
Figure 2. Illustration showing the activation of a T lymphocyte (via 3-signal pathway) by an antigenpresenting 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 13071314
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
Cyclosporine
• Block Calcineurin→ ↓IL-2 →↓T-Cell Activation
• Initial dosage 10 to 15 mg/kg/day divided into 2 doses.
• Trough Goals
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Week 1-2
250-350 ng/mL
Weeks 3-4
200-300
Weeks 5-24
150-250 ng/mL
Weeks 25+
100-200 ng/mL
Distant – can tolerate levels <100
Cyclosporine – Adverse Effects
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Hypertension
Renal dysfunction
Hirsutism
Hyperkalemia
Gingival hyperplasia
Hypomagnesemia
http://jorthod.maneyjournals.org/content/vol30/issue1/images/large/ClocFig1b.jpeg
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 – 10-15 ng/ml
– 3-6 Months – 8-10
– >6 Months – 5-7 (variable)
Tacrolimus – Adverse Effects
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Posttransplant diabetes mellitus
Nausea, vomiting, diarrhea
Hyperkalemia
Tremor
Hypertension
Hypomagnesemia
Headache
Renal dysfunction
Tac vs Csa
• Dyslipidemia and Gingival hyperplasia – more
common in Csa
• Diabetes – more common in Tac
• Rejection – less common in Tac
• Renal Dysfunction – similar
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 effectsubsequent studies have not confirmed this
– Meta-analysis of 11 studies suggests a numerical/nonsignificant improvement in renal function.
Hepatology. 2010 Oct;52(4):1360-70.
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.
Sirolimus
• Black Box warning – possible increased risk of
Hepatic Artery Thrombosis in immediate postOLT 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.
Sirolimus – Adverse Effects
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Anemia
Hypercholesterolemia
Hypertriglyceridemia
Leukopenia
Hyperlipidemia
Interstitial lung disease
Thrombocytopenia
Peripheral edema
Wound dehiscence
Hepatic Artery Thrombosis
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 –
– 1000-1500mg bid MMF or
– 360-720 BID MPA
Side effects of MMF/MPA
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Nausea, vomiting, diarrhea
Anemia
Leukopenia
Weight loss
Thrombocytopenia
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
Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003
Drug Interactions
American Journal of Transplantation 2009; 9:
1988–2003
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).
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
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
Acute Rejection
• Banff Grading System – each factor 1-3 scale
– Portal Inflammation
– Bile Duct Inflammation/damage
– Venous Endothelial Inflammation
Wyatt (2010) Histopathology 57, 333–341
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.
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.
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
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
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
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.
Hypertension
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CsA (25-82%) > Tac (17-64%)
Goal BP <=130/80
Thiazide, Loop (if edema)
Calcium channel Blockers*
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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
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
Obesity
• 22% Nonobese patients pre-OLT become
obese post
• Pre-OLT obese gain more weight than nonobese
• RF for recurrent (or de novo) NASH
• TX – the usual
• Orlistat can decrease absorption of CsA
Gout
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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)
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
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ETOH
Tobacco
Low Testosterone
Physical Inactivity
cholestatic liver disease –
unconjug bili inhibits osteoblast proliferation
• Patients also at risk of Osteonecrosis of Femoral Head
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
Vaccines
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
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.
Tobacco
• Increased rates of
– CAD
– Stroke
– Esophageal/upper aerodigestive Cancer
– liver vascular events (Hepatic Artery
Thrombosis/Stenosis, Portal Vein Stenosis, DVT)
THC
• In Nontransplant Patients – reports of
increased steatosis/fibrosis in THC users
• Contamination with fungal spores –
theoretical increased risk of fungal infections.
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
Malignancies - PTLD
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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
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
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)
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
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
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
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.
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).
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: 1307-1314