1. University of Pennsylvania, Perelman School of Medicine
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

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 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 novo steatosis
(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 8 8

9. Disease Recurrence

10. Recurrence Rates and 5-Yr Patient and Graft Survival
Etiology of Liver Disease
Recurrence Rate
Five-yr Survival (CI)
Five-yr Graft Survival (CI)
Hepatitis C
> 90 %
70 % (67-72 %)
57 % (54-59 %)
Hepatitis B
< 5% with prophylaxis
79 % (74-83 %)
68 % (61-75 %)
Hepatocellular Carcinoma
8-15 %
52 % (35-67 %)
46 % (31-60 %)
Primary Biliary cirrhosis
11-23 %
86 % (83-89 %)
73 % (71-76 %)
Primary Sclerosing Cholangitis
9- 47 %
Autoimmune Hepatitis
16-43 %
77 % (71-82 %)
68 % (63-75 %)
Alcohol induced cirrhosis
~ 5 %
72 % (68-76 %)
65 % (61-68 %)
Nonalcoholic steatohepatitis
11-38 %
73 % (68-77 %)
66 % (61-70 %)
Kotlyar DS et al Am J Gastroenterol 2006;101:

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 years
Probability of hepatic decompensation 50% at 1 year
Risk of mortality 40-60% at 1 year

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

13. Hepatitis C 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

14. Natural History of HCV Immuno- Post-
competent transplant
Fibrosis Progression / yr / yr
Median Time to Cirrhosis yrs yrs
Decompensation after Cirrhosis % in 10 yrs % in 1 yr
Survival after Decompensation % in 5 yrs % in 1 yr 14 14

15. 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

16. AASLD 2013

20. 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

21. 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

22. 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

23. 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%

24. 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

25. 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

26. 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

27. Hepatocellular Carcinoma

28. 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. 28 28

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

30. 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) 30

31. 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

32. Optimizing Immunosuppression
Immunology Product Specialist Training
June 2000
Liver Transplantation
Optimizing Immunosuppression
Infection, Side Effects, Higher Costs
Over
Optimal
Under
Rejection
Leave it to the transplant center!!!!!!!!!!!!!!!!!!!
© The Synapse Group 32 32

33. Advances in Immunosuppression Relative Toxicities
Immunology Product Specialist Training
June 2000
Liver Transplantation
Advances in Immunosuppression Relative Toxicities
Cyclosporine
Renal toxicity
Neurotoxicity
Hypertension
Hyperlipidemia
Hirsuitism
Gingival Hyperplasia
Tacrolimus
Renal toxicity
Neurotoxicity
Diabetes
Diarrhea
Hair loss
Mycophenolate
Diarrhea
N and V
Abdominal pain
Cytopenias
© The Synapse Group 33 33

34. Consequences of Noncompliance
Late Rejection
Widely Variable Immunosuppressive Drug Levels
Failure to comply with post transplant follow-up
Patients at risk
Adolescents
Financial Reasons 34 34

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

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

37. 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
Cumulative Incidence of Chronic Renal Failure
0.20
Heart
0.15
CRF-GFR <30
0.10
Heart-Lung
0.05
0.00 12 24 36 48 60 72 84 96
108
120
Months Since Transplant
Ojo AO et al. N Eng J Med 2003; 349: 37

38. CKD after Transplantation
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
- DM,HTN,HCV
Bloom RD, et al. J Am Soc Nephrol 2007;18: 38

39. Post-Transplant CKD
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 39

40. Chronic kidney disease increased risk of death (RR 4.5, P <0.001)
Risk Factors for CKD
Chronic kidney disease increased risk of death (RR 4.5, P <0.001)
Relative Risk
*P <0.001.
Ojo AO et al. N Eng J Med. 2003;349: 40

41. CV outcomes stratified by GFR
Weiner DE et al. J Am Soc Nephrol 2004; 15: 41

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

43. 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

45. 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)
Ca channel blockers-counteract vasoconstriction effect of CNIs

46. 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

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

48. 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

49. Malignancies

50. 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

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

53. Aberg F, et al. Liver Transpl 2008; 14:1428-36

54. Potential Causes PTLD: EBV
Chronic immunosuppression impairs immunosurveillence
Episodes of graft rejection increase likelihood of developing a cancer (highest risk in heart transplant recipients)
Immunosuppressive agents (AZA, cyclosporine and tacrolimus) damage DNA leading to malignant transformation
Viral Stimulation
Kaposi’s sarcoma: HHV-8 (in both recipient and donor)
Squamous cell skin cancer: HPV detected in 65-90% of skin cancers in transplant recipients
PTLD: EBV

55. Sirolimus mTOR inhibitor
Suppresses the growth and proliferation of tumors in various animal models
Decreases tumor recurrence in transplant recipients with HCC

56. Liang W et al. Liver Transpl 2012; 18: 62-69

57. Skin Cancer
20 fold increase in non-melanoma skin cancer (35% lifetime risk)
SCC > BCC (opposite of general population)
Multiple, more aggressive tumors

58. Skin Cancer Recommend annual Dermatology exam in transplant recipients
Minimize immunosuppression in the setting of diagnosed skin cancer
Use sunscreen/avoid sun exposure

59. Post Transplant Lymphoproliferative Disorder
Second most common cause of de novo malignancy
Incidence in adults is 1-3%
Most commonly EBV associated
Usually occurs within 1 year post-transplant
Treatment
Reduce immunosuppression
Rituximab if CD20 positive, Chemotherapy if CD20 negative
Risk factors-augmented immunos; anti-lymphocyte antibodies; CMV. Donor recipient CMV mismatch

60. Kidney/Liver – 35% 10-year survival
Heart/Pancreas – 15% 10-year survival

61. Malignancies - GI
Upper aerodigestive tract – increased in those with risk factors (alcohol, tobacco)
Colon cancer – increased risk in those with pre-existing risk factors (PSC/UC patients)
Annual colonoscopy with surveillance biopsies

62. Malignancies - Other
Breast, Prostate, Lung cancer – no definite increased risk in those without risk factors
Follow age-appropriate cancer screening guidelines

63. Donor Transmitted Malignancy
With increased age of donors the risk of transplanting unidentified cancers will increase
Cincinnati Tumor Registry
22 patients received donor hearts and/or lungs from patients with a history of malignancy
45% of recipients developed a malignancy
Overall a very small proportion of post-transplant tumors per UNOS data (< 0.001%)

64. Cancer screening Breast Women > 50: mammogram every year Cervical
Pap smear yearly
Prostate
Men >50: rectal and PSA yearly; AA/+ FH: start at age 45
Colorectal
Colonoscopy every yrs*
Yearly in UC patients with random bx
Skin
Annual exam with dermatology

65. Drug-Drug Interactions

66. Anti-Convulsants Antibiotics Other
Drugs and Substances: Lower Levels of cyclosporine, tacrolimus, sirolimus
Anti-Convulsants
Antibiotics
Other
Carbamazepine
Rifabutin
St. John’s Wort
Phenobarbital
Rifampin
Orlistat
Phenytoin
* This list is not all inclusive
McGuire BM et al Am J Transplant 2009;9:

67. Calcium Channel Blockers
Drugs and Substances: Increase Levels of cyclosporine, tacrolimus, sirolimus
Antifungals
Antibiotics
Calcium Channel Blockers
Other
Protease inhibitors for HBV
Caspofungin
Azithromycin
Diltiazem
Fluconozole
Clarithromycin
Verapamil
Protease inhibitors for HIV
Itraconozole
Erythromycin
Nicardipine
Grapefruit products
Ketoconozole
Carvedilol
Danazol
Terbinafine
Voriconozole
McGuire BM et al Am J Transplant 2009;9:

68. Vaccinations

69. Vaccines that are safe in Immunsuppressed Patients or Household Contacts
Diphtheria
Hepatitis A,B, or combination of A and B
Hemophilus influenzae type B
Human papilloma virus
Influenza inactivated
Meningococcal
Pertussis
Pneumococcal
Tetanus
Tick-borne encephalitis
McGuire BM et al Am J Transplant 2009;9:

70. Live Attenuated Vaccines
Bacille calmette-guerin (BCG)
Liver attenuated influenza (LAIV)
Measles
Mumps Polio (oral)
Rotavirus
Rubella
Typhoid (oral-TY21a)
Vaccinia (smallpox vaccine)
Varicella
Yellow fever
McGuire BM et al Am J Transplant 2009;9:

71. Summary
Post-OLT allograft dysfunction can be due to a variety of reasons
Recurrent disease and allograft rejection are major reasons for graft dysfunction
HCV recurrence has emerged as the major cause for allograft failure-therapy is challenging

72. Summary
De novo steatosis and recurrent steatosis/steatohepatitis are not uncommon and present a unique challenge
Awareness of drug-drug interactions is likely to decrease risk of drug toxicity and graft dysfunction
Disease specific preventive strategies are to be in the follow up care of liver transplant recipients

73. The Hospital of the University of Pennsylvania73