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Transplant Hepatology Post Transplant Management What I need to know as the community GI NP/PA

Transplant Hepatology Post Transplant Management What I need to know as the community GI NP/PA. Brenda Appolo PAC, MHS University of Pennsylvania, Perelman School of Medicine. Learning Objectives. Appreciate the frequency and natural history of recurrent disease

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Transplant Hepatology Post Transplant Management What I need to know as the community GI NP/PA

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  1. Transplant Hepatology Post Transplant ManagementWhat I need to know as the community GI NP/PA Brenda Appolo PAC, MHS University of Pennsylvania, Perelman School of Medicine

  2. Learning Objectives Appreciate the frequency and natural history of recurrent disease Recognize the complications of liver transplantation and their management Become aware of unique drug-drug interactions To appreciate the need for and facilitate disease preventive strategies

  3. How many patients are out there? Between 1985-2011 there are 100,000 people in the USA s/p liver transplant 1 year survival = 88% 5 year survival = 78% 10 year survival = 65%

  4. Morbidity/Mortality Most deaths or re-transplants occur early Infection and intraoperative/peri-operative causes account for 60% death/graft loss in the first year Malignancies, cardiovascular causes, and disease recurrence account for late morbidity and mortality Acute or chronic allograft rejection is an uncommon cause of death or retransplantation

  5. Causes for Allograft Dysfunction after Liver Transplantation Primary non-function (Immediate) De novosteatosis (Obesity, Diabetes, Hyperlipidemia) Biliary Complications Vascular Complications Abnormal Liver Tests Bacterial, fungal,and viral infections Rejection Medications related including hyperalimentation Recurrent Disease

  6. Case • 57 M s/p OLT x 7 months prior for HCV cirrhosis; naïve to HCV therapy prior to LT; • “I was told to follow up periodically with my GI provider my primary care providers locally” • Pre LT: Nonbleeding varices, refractory ascites, SBP,HE; transplanted at MELD 30 • Explant: incidental native liver HCC (1cm R lobe; no lymphovascular invasion) • Time Zero LBX: < 5% steatosis, no sig fibrosis; + HBV core donor • Protocol LT Bx 6m: Mild hepatitis; mild space of disse collegenization; no ACR; • Post LT: steroid induced DM • C/o weight gain with prior prednisone • Meds: Tacrolimus 4 mg bid; azathioprine 50 mg qd; DS Bactrim; LAM 100 mg qd • Exam: 145/92; HR 88; well healed incision; exam otherwise unremarkable • Labs: • Cr 1.3; K 5.0; T bil 0.9; AST 98; ALT 88; AP 158; INR 0.9; WBC 3.3; Hg 11.2; Plt 189K; Tac 8.5

  7. Don’t panic

  8. General Approach Immunosuppression Care in prescribing drugs Compliance Graft dysfunction/recurrence of disease Chronic Kidney Disease Cardiovascular risk factors Diabetes Cancer Bone Disease Immunizations Obesity Pregnancy

  9. Disease Recurrence

  10. Recurrence Rates and 5-Yr Patient and Graft Survival Kotlyar DS et al Am J Gastroenterol 2006;101:1370-78

  11. Hepatitis C Hepatitis C accounts for 50% of all transplants Recurrence is universal Recurrence results in decreased patient and allograft survival Cirrhosis noted in up to 30% at 5 years Median time to cirrhosis 8 -10 years Probability of hepatic decompensation 50% at 1 year Risk of mortality 40-60% at 1 year

  12. Hepatitis C Verna et. al. Liver Transplantation 2013;19:78-88

  13. Clinical course of allograft reinfection RNA detectable in serum in first post-operative week Histologic evidence of recurrent disease noted within 1 year in majority Biochemical/ histologic patterns of recurrence Biochemical abnormalities noted between 1-3 months Acute and chronic hepatitis ensue Fibrosing cholestatic hepatitis C seen in up to 10% Aggressive form of recurrence resulting in graft failure without treatment Hepatitis C

  14. Hepatitis C Considerations for Antiviral Therapy Traditionally pre-transplant therapy with interferon considered risky Increase in life threatening adverse events Low SVR reported Post-transplant therapy was less effective With direct acting antivirals with NO concern for drug interactions, treatment for HCV prior to and after transplantation will change radically

  15. AASLD 2013

  16. Hepatitis B Accounts for less than 10% of liver transplants performed in US Declining rate of transplants reflects efficacy of antiviral therapy Combination of Hepatitis B immune globulin (HBIG) and nucleos(t)ide antiviral agents prevents recurrence > 90% of patients undergoing transplantation for hepatitis B HBIG withdrawal can be attempted in patients without HBV viremia at transplant and low risk factors for recurrence

  17. Primary Biliary Cirrhosis Recurrence rates range from 4-33% Though recurrence may be common, less than 5% develop end stage disease Recurrence can occur in the setting of normal liver associated enzymes and there is no correlation with AMA presence or titer Ursodeoxycholic acid may be of use in the treatment of recurrent disease but no data exists for benefit in patient or graft survival

  18. Primary Sclerosing Cholangitis Recurrent PSC is seen in up to 50% of patients at 5 years post-transplant Graft loss occurs in up to 25% with recurrent disease Risk factors Male sex Intact colon prior to transplant Active colitis at time of transplant Steroid resistant rejection Sex mismatch of donor and recipient CMV infection

  19. Autoimmune Hepatitis Recurrence occurs in 10% patients at 1 year and 36-68% at 5 years Risk factors Rapid corticosteroid withdrawal Severity of disease prior to transplant Autoantibodies, hypergammaglobulinemia and histology are important for diagnosis Corticosteroids +/- Azathioprine represents cornerstone of therapy Retransplantation required in 8-23%

  20. Alcoholic Liver Disease Post-transplant survival similar to controls, unless patients have coexisting HCV Relapse rates are 10-20% post-transplant Concomitant tobacco use increases risk for CV death and aerodigestive tract cancers

  21. Non-Alcoholic Steatohepatitis Recurrent and de novo disease are common after liver transplant Risk Factors Obesity Diabetes mellitus Hypertension Hyperlipidemia Steatosis Immunosuppression May lead to fibrosis in the allograft but cirrhosis is uncommon

  22. Recurrence of Pre-existing Malignancy Recurrence rates 0-10% Localized RCC, testicular cancer, cervical cancer, thyroid cancer and lymphomas Recurrence rates 11-25% Carcinomas of the uterus, colon, prostate and breast Recurrence rates >25% Bladder carcinoma, advanced RCC, Sarcoma, Myeloma, Melanoma, non-melanoma skin cancer

  23. Hepatocellular Carcinoma

  24. Liver Transplantation for HCC Milan Criteria 1 lesion ≤5 cm 3 or less lesions, none ≥ 3 cm Absence of Macroscopic Vascular Invasion Absence of Extra-hepatic Spread Mazzaferro V, et al. N Engl J Med 1996; 334:693–699.

  25. Robert JP. Liver Transpl 2005; 11: S45-46

  26. Factors associated with HCC Recurrence Large tumor burden Macrovascular invasion Tumor rupture “Satellite” lesions Lymph node involvement Poor histologic differentiation Elevated AFP (> 400 ng/ml)

  27. Rejection(Normally dealt with by Transplant Center) In 10 % of patients Abnormal hepatic biochemical tests Late occurrence - low levels of immunosuppressants or non-compliance Chronic ductopenic rejection-late manifestation Rejection Acute cellular rejection common within the first 3 months of transplantation

  28. Optimizing Immunosuppression Infection, Side Effects, Higher Costs Over Optimal Under Rejection Leave it to the transplant center!!!!!!!!!!!!!!!!!!!

  29. Consequences of Noncompliance Late Rejection Widely Variable Immunosuppressive Drug Levels Failure to comply with post transplant follow-up Patients at risk Adolescents FinancialReasons

  30. Immunosuppression-Dark Side Lucey MR et al. Liver Transpl 2013; 19:3-26

  31. Lucey MR et al. Liver Transpl 2013; 19:3-26

  32. Chronic Kidney Disease Cumulative Incidence of Chronic Renal Failure among Persons Who Received Non-renal Organ Transplants 0.35 0.30 Liver Intestine 0.25 Lung 0.20 Cumulative Incidence of Chronic Renal Failure Heart 0.15 0.10 Heart-Lung 0.05 0.00 24 48 12 36 72 84 96 108 120 60 0 Months Since Transplant Ojo AO et al. N Eng J Med2003; 349: 931-40

  33. CKD after Transplantation - DM,HTN,HCV Bloom RD, et al. J Am Soc Nephrol 2007;18:3031-3041

  34. Approximately 20% of patients undergoing liver transplantation develop stage IV or V CKD at 5 years post-transplant. CKD in liver transplant recipients is associated with a dramatic increase in cardiovascular risk, hospitalizations, and a 4 fold higher mortality Duration and degree of renal impairment prior to liver transplantation have been associated with post-operative kidney dysfunction. Management involves reduction or withdrawal of CNI-associated immunosuppression Post-Transplant CKD

  35. Risk Factors for CKD Chronic kidney disease increased risk of death (RR 4.5, P <0.001) RelativeRisk *P <0.001. Ojo AO et al. N Eng J Med. 2003;349:931-940.

  36. CV outcomes stratified by GFR Weiner DE et al. J Am Soc Nephrol 2004; 15:1307-1315

  37. Metabolic Syndrome Lucey MR et al. Liver Transpl 2013; 19:3-26

  38. Diabetes Prevalence: 5-16% (de novo post-transplant) Risk factors: corticosteroids, CNIs (tacrolimus > cyclosporine), pre-transplant DM, HCV Goals of treatment are similar to non-transplant patients with target hemoglobin A1C <7.0% Minimizing steroid exposure and conversion from tacrolimus to cyclosporine does improve glycemic control Metformin can be used in patients with normal renal function but sulfonylureas are preferred in patients with kidney disease

  39. Hypertension Post-transplant Hypertension increases risk of CV disease and CKD Goal BP in transplant recipients ≤ 130/80 mmHg Minimization of corticosteroids, CNIs (cyclosporine > tacrolimus) Calcium channel blockers are very effective (avoid diltiazem and verapamil - increase levels of CNIs). ACE-I/ARB should be used as first line therapy in patients with DM,CKD and/or proteinuria (monitor potassium)

  40. Dyslipidemia Prevalence up to 70% in transplant recipients Major risk factor for CV disease Risk factors include age, obesity, DM, pre-transplant dyslipidemia, and immunosuppression Immunosuppression effects on lipids: Cyclosporine, corticosteroids, mTOR inhibitors– greatest effect TAC – minor effect MMF/AZA – no effect Treatment – all classes of agents can be used

  41. Lucey MR et al. Liver Transpl 2013; 19:3-26

  42. Obesity Over 20% lean patients become obese post-transplant Corticosteroids contribute to appetite stimulation All transplant recipients require dietary counseling to avoid obesity Consider weight loss programs, bariatric surgery for morbid obesity

  43. Malignancies

  44. Transplant Related Malignancies De novo Malignancies New cancers identified after transplantation Donor Transmitted Malignancies Cancers identified as arising from the organ donor Recurrence of Pre-Existing Malignancies Cancers managed prior to or simultaneously with transplantation, that recur after chronic immunosuppression

  45. Post-Transplant Malignancy Aberg F, et al. Liver Transpl 2008; 14:1428-36

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