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Care of the Post-OLT Patient George Makar. Overview Immunosuppression Causes of Allograft Failure Medical Comorbidites Malignancies Pregnancy/Sexual Function.

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Presentation on theme: "Care of the Post-OLT Patient George Makar. Overview Immunosuppression Causes of Allograft Failure Medical Comorbidites Malignancies Pregnancy/Sexual Function."— Presentation transcript:

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 1 st 3months>1 st 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 CRLate CR Small Bile ductsDuct loss <50% portal triadsDuct 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 triadsloss >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, 2 nd 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 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 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:


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