Transplant Hepatology Post Transplant Management

What I need to know as the community GI NP/PA

Brenda Appolo PAC, MHSUniversity of Pennsylvania, Perelman School of Medicine

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

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%

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

Causes for Allograft Dysfunction after Liver Transplantation

Abnormal Liver Tests

Recurrent Disease

Bacterial, fungal,and viral infections

Primary non-function(Immediate) Biliary

Complications

Vascular Complications

Medications related including

hyperalimentation

De novo steatosis(Obesity, Diabetes, Hyperlipidemia)

Rejection

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

Don’t panic

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

Disease Recurrence

Recurrence Rates and 5-Yr Patient and Graft SurvivalEtiology of Liver

DiseaseRecurrence 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 % 86 % (83-89 %) 73 % (71-76 %)

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;101:1370-78

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

Hepatitis C

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

• 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

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

AASLD 2013

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

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

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

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%

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

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

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

Hepatocellular Carcinoma

Absence of Macroscopic Vascular InvasionAbsence of Extra-hepatic Spread

1 lesion ≤5 cm 3 or less lesions, none ≥ 3 cm

Liver Transplantation for HCC Milan Criteria

Mazzaferro V, et al. N Engl J Med 1996; 334:693–699.

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

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)

Rejection(Normally dealt with by Transplant Center)

Rejection

Acute cellular rejection common within the first 3 months of transplantation

Late occurrence - low levels of

immunosuppressants or non-compliance

In 10 % of patientsAbnormal hepatic biochemical tests

Chronic ductopenic rejection-late manifestation

Optimizing Immunosuppression

Rejection

Infection, Side Effects, Higher Costs

Under

Over

Optimal

Leave it to the transplant center!!!!!!!!!!!!!!!!!!!

Consequences of Noncompliance

• Late Rejection• Widely Variable Immunosuppressive Drug Levels• Failure to comply with post transplant follow-up• Patients at risk

– Adolescents– Financial Reasons

Immunosuppression-Dark Side

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

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

Chronic Kidney DiseaseCumulative Incidence of Chronic Renal Failure among Persons

Who Received Non-renal Organ Transplants

Ojo AO et al. N Eng J Med 2003; 349: 931-40

12 24 36 48 60 72 84 96 108 12000.00

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CKD after Transplantation

Bloom RD, et al. J Am Soc Nephrol 2007;18:3031-3041

- DM,HTN,HCV

• 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

Risk Factors for CKD

*1.181.15*

*0.74

1.36*(per 10-y

increment) *1.42

2.13*

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RelativeRisk

*P <0.001.

Ojo AO et al. N Eng J Med. 2003;349:931-940.

Chronic kidney disease increased risk of death (RR 4.5, P <0.001)

CV outcomes stratified by GFR

Weiner DE et al. J Am Soc Nephrol 2004; 15:1307-1315

Metabolic Syndrome

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

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

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)

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

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

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

Malignancies

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

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

Post-Transplant Malignancy

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

Potential Causes• 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

Sirolimus• mTOR inhibitor

• Suppresses the growth and proliferation of tumors in various animal models

• Decreases tumor recurrence in transplant recipients with HCC

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

Skin Cancer

20 fold increase in non-melanoma skin cancer (35% lifetime risk)

SCC > BCC (opposite of general population)

Multiple, more aggressive tumors

Skin Cancer

• Recommend annual Dermatology exam in transplant recipients

• Minimize immunosuppression in the setting of diagnosed skin cancer

• Use sunscreen/avoid sun exposure

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

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

Malignancies - Other

• Breast, Prostate, Lung cancer – no definite increased risk in those without risk factors

• Follow age-appropriate cancer screening guidelines

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%)

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 5 -10 yrs*– Yearly in UC patients with random bx

• Skin– Annual exam with dermatology

Drug-Drug Interactions

Drugs and Substances:Lower Levels of cyclosporine, tacrolimus, sirolimus

Anti-Convulsants

Antibiotics Other

Carbamazepine Rifabutin St. John’s Wort

Phenobarbital Rifampin Orlistat

Phenytoin

McGuire BM et al Am J Transplant 2009;9:1988-2003

* This list is not all inclusive

Voriconozole

Terbinafine

DanazolCarvedilolKetoconozole

Grapefruit productsNicardipineErythromycinItraconozole

Protease inhibitors for HIV

VerapamilClarithromycinFluconozole

Protease inhibitors for HBV

DiltiazemAzithromycinCaspofungin

OtherCalcium Channel Blockers

AntibioticsAntifungals

Drugs and Substances:Increase Levels of cyclosporine, tacrolimus, sirolimus

McGuire BM et al Am J Transplant 2009;9:1988-2003

Vaccinations

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;9:1988-2003

Live Attenuated VaccinesBacille 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;9:1988-2003

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

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

The Hospital of the University of Pennsylvania