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
• 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
Primary non-function
(Immediate)
Bacterial, fungal,and
viral infections
De novo steatosis
(Obesity, Diabetes, Hyperlipidemia)
Biliary
Complications
Vascular
Complications
Abnormal Liver
Tests
Rejection
Medications related
including
hyperalimentation
Recurrent Disease
Case
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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
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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 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 %)
79 % (74-83 %)
68 % (61-75 %)
Hepatitis B
< 5% with
prophylaxis
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 %)
11-38 %
73 % (68-77 %)
66 % (61-70 %)
Nonalcoholic
steatohepatitis
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
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
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
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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
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.
Robert JP. Liver Transpl 2005; 11: S45-46
Factors associated with HCC Recurrence
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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)
In 10 % of patients
Abnormal hepatic biochemical tests
Chronic ductopenic
rejection-late
manifestation
Rejection
Late occurrence - low
levels of
immunosuppressants
or non-compliance
Acute cellular rejection common within the
first 3 months of transplantation
Optimizing Immunosuppression
Infection, Side Effects, Higher Costs
Over
Optimal
Under
Rejection
Leave it to the transplant center!!!!!!!!!!!!!!!!!!!
Consequences of Noncompliance
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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 Disease
Cumulative Incidence of
Chronic Renal Failure
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
Heart
0.15
0.10
Heart-Lung
0.05
0.00
0
12
24
36
48
60
72
84
Months Since Transplant
Ojo AO et al. N Eng J Med 2003; 349: 931-40
96
108
120
CKD after Transplantation
- DM,HTN,HCV
Bloom RD, et al. J Am Soc Nephrol 2007;18:3031-3041
Post-Transplant CKD
• Approximately 20% of patients undergoing liver
transplantation develop stage IV or V CKD at 5 years posttransplant.
• 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 CNIassociated immunosuppression
Risk Factors for CKD
Chronic kidney disease increased risk of death (RR 4.5, P
<0.001)
2.5
2.0
1.5
Relative
Risk
2.13*
1.36*
(per 10-y
increment)
*1.18
1.15*
*1.42
*0.74
1.0
0.5
Ojo AO et al. N Eng J Med. 2003;349:931-940.
I
A
K
M
Po
st
-o
p
yp
e
H
*P <0.001.
D
rte
ns
io
n
V
C
H
er
en
d
G
A
ge
0.0
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
Post-Transplant Malignancy
Aberg F, et al. Liver Transpl 2008; 14:1428-36
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
AntiConvulsants
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;9:1988-2003
Drugs and Substances:
Increase Levels of cyclosporine, tacrolimus, sirolimus
Antifungals Antibiotics Calcium Channel
Blockers
Other
Protease inhibitors for
HBV
Protease inhibitors for
HIV
Caspofungin
Azithromycin
Diltiazem
Fluconozole
Clarithromycin
Verapamil
Itraconozole
Erythromycin
Nicardipine
Grapefruit products
Carvedilol
Danazol
Ketoconozole
Terbinafine
Voriconozole
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 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;9:1988-2003
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