UPDATE AND INNOVATIONS IN

LIVER TRANSPLANTATION
Lewis Teperman, M.D.
Director of Transplantation
Vice Chairman of Surgery
NYU School of Medicine
Annual Presentation to Nurses
June 28, 2013
1

Number of Patients on UNOS Liver Waiting List

3/14/2011 = 16,853)

(as of

Transplant
s

Sources:(1)2007OPTN/SRTRAnnualReportTables1.3and1.7;and(2)http://optn.transplant.hrsa.gov/ar2009/

Causes of Death in 262 Donors

New York Organ Donor Network

New York is safer

Crime is down
Vehicular accidents are down

OrganDonation
LivingDonation20%
DeceasedDonation10%
ImportOrganOffers75%
5

Doctors Confirm West Nile in a 4th

Transplant Patient

Doctors have confirmed that a woman in Florida is the fourth person

to have contracted West Nile virus after receiving an organ
transplanted from a single donor who had the virus, a federal health
official said last night.

Finding the virus in all four organ recipients "very strongly suggests
that the disease was transmitted by the organs rather than by
mosquito bites, said the official, Dr. Lyle Petersen, a West Nile expert
at the Centers for Disease Control and Prevention.

--- The New York Times

6

WEST NILE VIRUS

West Nile, a flavivirus, is a relatively

new pathogen to the U.S.

Other flaviviruses include:

- Yellow fever
- Dengue
- Saint Louis Encephalitis
LWTeperman,MD,TDiflo,MD,AFahmy,MB,GRMorgan,MD,etal.WestNileVirusInfectionsinOrganTransplantRecipients
NewYorkandPennsylvania,AugustSeptember,2005.MMWRDisptachofCDCOctober5,2005:54(Dispatch);13.
7

West Nile Virus

Approximate Geographic Range in 1998

 2,949 cases

2005

628 counties
42 states

10

1137

PATIENT COURSE
400

AST

311
300

Neurologic
40.6 C

40.3 C

37.6 C

Temp Curve

43

IgG

35

OMR-IgG-am

Treatment

OLTX

FK/SM/ZENEPAX
CELLCEPT

DCd
Cellcept

WNV
T 105 Weakness
FK / DCd

Flaccid
Seizures Paralysis

68 days

11

expired

Tumor Conveyance
Teen Organ Donor's Gift Turns Tragic1
Transmission of Anaplastic Large Cell
Lymphoma via Organ Donation After
Cardiac Death2
1.SAGHARBOR,N.Y.,April1,2008,NancyCordes,CBSNewsCorrespondent
2.JWHarbell,TBDunn,MFaudia,DGJohn,ASGoldenbergandLWTeperman..AmericanJournalofTransplantation,
January2008;Vol.1;IssueI;238244.
12

Transmission of Anaplastic
Large Cell Lymphoma via
Organ Donation After
Cardiac Death

J.W.Harbell,T.B.Dunn,M.Fauda,D.G.John,A.S.Goldenberg,L.W.Teperman;
AJT:2008;8,pps238244.

14

Donor-Derived Disease Transmission Events

in the United States: Data Reviewed
by the OPTN/UNOS Disease Transmission
Advisory Committee
M. G. Ison,*, J. Hager, E. Blumberg,
J. Burdick, K. Carney, J. Cutler, J. M. DiMaio,
R. Hasz, M. J. Kuehnert, E. Ortiz-Rios,
L. Teperman and M. Nalesnik

American Journal of Transplantation 2009; 9: 17

15

Table5:ReportsmadetoDTACregardingapotentialdonor
derivedmalignancytransmission
20052007
Malignancies

Donor
Reports1

Confirmed
Recipients2

Recipient
Deaths3

Lung adenocarcinoma

Glioblastoma
multiforme
Lymphoma

Metastatic Melanoma

Prostate
adenocarcinoma
OTHERS

TOTALS

55

15

Renal Cell Carcinoma

25

1.Numberofdonorsreportedpossibledonorderiveddiseasetransmission.2.Numberofrecipientswithconfirmed(proven,probableorpossible)donorderived
disease.3.Numberofrecipientswhodiedastheresultofadonorderiveddiseasetransmission.

The liver does not

undergo senescence.
-Hans Popper, MD

The Successful Use of Older

Donors for Liver
Transplantation
L. Teperman, L. Podesta, L. Mieles, T. Starzl JAMA
1989; 262:2837

Donor Factors

Age Barrier > 80 Years

Fat Content:
macro vs. micro
Length of stay > 10 days
Hypernatremia

19

Expanded Criteria Donor

Define Relative Risk(RR) of Failure

RR 1.7: 70% greater risk of failure

Factor
Donor Age 40 to 49

RR
1.16

P-Value
0.0006

Donor Race Black

1.19

0.0001

DCD Liver

1.52

0.0006

Partial / Split Liver

1.53

0.0001

Donor Age 70 or Above

1.63

0.0001
20

Obesity Trends* Among U.S. Adults

BRFSS, 1991, 1996, 2004
(*BMI 30, or about 30 lbs overweight for 54 person)
1991

1996

2004

No Data

<10%

Source Mokdad A.H., et all JAMA 2003,289-1

10%14%

15%19%

20%24%

25%
21

Obesity Trends* Among U.S. Adults

BRFSS, 2011

http://feww.files.wordpress.com/2011/07/obesity2011feww1.png

22

23

RetransplantRates(%)

Retransplant Rates in Region

vs. the US

NYU
5%
24

Utility vs. Equity

Old Allocation System

Child-Turcotte-Pugh Scoring System to Assess

the Severity of Liver Disease
Points

None

1-2

3-4

Absent

Slight or
controlled
by diuretics

At least
moderate
despite diuretics

<2

2-3

>3

Albumin

>3.5

2.8-3.5

<2.8

Prothrombin time
(seconds prolonged)
or INR

<1.7

1.7-2.3

>2.3

<4

4-10

>10

Encephalopathy
Ascites

Bilirubin(mg/dL)

For PBC, PSC or other

cholestatic liver diseases:
Bilirubin (mg/dL)*

* For cholestatic liver diseases, these values for bilirubin are to be submitted for the values above.

26

Problems with CTP Score

Limited number of categories

Limited discriminating ability
Uses subjective parameters - gaming
Laboratory variability (protime, albumin)
Never validated
Creatinine not included
27

Q: What is MELD?
A: Disease Severity Score

MELD MODEL:
Predicts Survival in TIPS Patients

90% Survival Probability on the waitlist

Variables
Bilirubin
Creatinine
INR
?
CHANGE REAGENT
Liver disease etiology (deleted)

29

MELD Equation

MELD = (0.957 x LN (creatinine) + 0.378 x

LN (bilirubin) + 1.12x LN(INR) + 0.643) x 10
Capped at 40

30

HCC: Extra Credit

Patients meeting criteria receive 22 points.

After a three-month reevaluation patients
receive additional points.
Thereafter they receive additional points
every three months.

31

Indications for Transplantation

NYUCTxps2007

32

Hepatitis C Tumor Burden

4 million US Patients
1 million Cirrhotics (10 years)
1/4 million HCC (10 years)

33

Lewis Teperman, M.D.

Abdominal Organ Cluster

Transplantation for the Treatment of
Upper Abdominal Malignancies
Thomas E Starzl MD, PHD; Satoro Todo MD; Andreas Tzakis MD; Luis Podesta MD; Luis
Mieles MD, Anthony Demetris MD, Lewis Teperman MD; Rick Selby MD; William
Stevensen MD; Andre Steiber MD; Robert Gordon MD; Shunzaburo Iwatzuki MD

35

36

OLT Survival Milan Criteria

10
0

Probability
(%)

80
60

40
20
0
0

12

18

24

30

Months

36

42

48

Mazzaferro, V. N Engl
J
37
Med 1996

HCC

While we wait, the tumor grows!

Treatment is appropriate
Are 6 cm lesions really more deadly than 5 ?
Exceptional case review (RRB)

John Roberts, UCSF, AJT 2006;

Yao, et al. Am J Transplant. 2007;7:2587-2596.

38

HCC Recurrence after OLT

1.

Recurrence

.9
.8

Vascular
Invasion

.7
.6
.5
.4
.3
.2

No Vascular
Invasion

.1
0

10

20

30

Months

40
50
60
Hemming, A. Ann Surg
39

Hepatomas

Initial MELD Exception

29 points
~ 20% of transplants
20-24 points
Excellent Survival
MELD is Evolving!
Consider living donation
40

Strategies for Long Waiting

Time
TACE
Living Donor Transplant

41

Chemoembolization (CE) for

HCC

Femoral artery Catheterization

3 Elements

Lipiodol
Chemotherapeutic agent(adriamycin, cisplatinum)
Embolizing Agent(Gelform, Avitene)

Selective hepatic arterial localization

Kill Rates
Without significant complications
*Neo adjuvant: Thalidomide (-)

(+) NEXAVAR MULTI-CENTER

TRIAL 2012
42

43

44

Chemoembolization
Random Effects Model
OR (95% CI)

0.0
1

0.1

0.5 1

Lin, Gastroenterology 6
1988
3
9
GETCH NEJM
5
1995
8
Bruix, Hepatology
0
1998
Pelletier, J Hepatology 7
1998
3
7
Lo, Hepatology
9
2002
11
Lovett, Lancet
2
2002
Overall
50
3
Llovet, J Hepatology
2003

2 10

100

P=0.017

Favors
Treatment

Favors45
Control

Patient Survival after liver

transplantation:
Benign vs. Malignant disease

Months after transplantation

46

TRANSPLANTATION FOR HEP

B HBIG TREATMENT

Months

HBIG

HBIG

HBIG
47

There is NO consensus on optimal

duration of HBIG, dose, or mode of
administration.
- Lewis Teperman
10/15/2006

48

Viral DNA Chain Terminators

Ganciclovir
Famciclovir
Lamivudine
Adefovir
Entecevir
Tenofovir
Emtricitabine

49

A Randomized Trial of HBIG

Withdrawal Using
Emtricitabine/Tenofovir DF in
Post-Liver Transplant Recipients
L Teperman1, J Spivey2, F Poordad3, T Schiano4, N Bzowej5,

S Pungpapong6, P Martin7, D Coombs8, K Hirsch8, J Anderson8 and F Rousseau8

The Mary Lea Johnson Richards Organ Transplantation Center,
New York University Medical Center, New York, NY; 2Emory Healthcare, Atlanta, GA;
3
Cedars-Sinai Medical Center, Los Angeles, CA; 4Recanati/Miller Transplantation Institute,
Mount Sinai Hospital, New York, NY; 5California Pacific Medical Center, San Francisco, CA;
6
Mayo Clinic Jacksonville, Jacksonville, FL; 7 Schiff Liver Institute, University of Miami,
Miller School of Medicine, Miami, FL; 8Gilead Sciences Inc., Durham, NC
1

Background

HBIG prophylaxis is routinely prescribed to

prevent HBV recurrence post-orthotopic liver
transplantation (OLT)
HBIG prevents recurrence by neutralizing HBsAg
Long-term prophylaxis with HBIG is inconvenient
and expensive, but is the mainstay of posttransplant therapy.
51

Cost of HBIG in Relation with HBIG Dosing and Strategy of

Administration in Patients Receiving HBIG + Lamivudine

Di Paolo et al. Transplantation 2004; 77: 12031208. cost of different schedules of HBIg administration in Euros. The on demand schedule using
Yearly
52
2,000 IU of HBIg allows a savings of over 50% compared with fixed monthly doses of 5,000 IU.

Aim

This ongoing randomized study (Study 107)

evaluates the safety and efficacy of TVD
with/without HBIG in preventing recurrence of
CHB post OLT

The aim of this interim analysis is to evaluate the

efficacy, safety and tolerability of TVD in this
population
53

Patient Disposition
Screened
N=51
Enrolled
N=40
Discontinued N=3

Randomized at Week 24
N=37
TVD+HBIG
N=19
Discontinued N=1

Completed Week 72 N=15

Completed Week 96 N=11

TVD
N=18
Discontinued N=1
Death N=1

Completed Week 72 N=14

Completed Week 96 N=12

Virologic Outcomes

No detectable HBV DNA (169 copies/mL;

lower limit of quantitation) in either group
No HBsAg positivity

55

Hepatitis C

Most common indication for

transplantation 25 - 45%

95% of recipients persist with antibody to C

At least 50% develop active hepatitis on
biopsy
It is unknown how many progress to a chronic
state

56

Treatment for Hepatitis C

Interferon
Ribavirin

Pegylated - Interferon

Pegasys
PEG-Intron
Protease Inhibitors 2011
NYU post tx pilot 7/15 neg

-TIMING-

57

November 2005
Baylor Zenapax Trial
Randomized Controlled Trial
Steroid Sparing
I L 2 Receptor Antagonist Induction
Results:
No Difference in Hepatitis C Recurrence,
Diabetes, or Rejection
Fasola,CG.,Heffron,T.G.,Sher,L.,Douglas,D.D.,Brown,R.,Ham,J,.Teperman,L.,etal.MulticenterRandomizedHepatitisC
(HCV)ThreeTrialPostLiverTransplantation(OLT):APreliminaryReport.Transplantation.78(2)Supplement1:146,July27,2004.
58

ARandomizedMulticenterStudy
ComparingEfficacyandSafetyof
SteroidFreeandStandard
ImmunosuppressionforLiver
TransplantationRecipientswith
ChronicHepatitisC
(submitted)

Goran B. Klintmalm1, Gary L. Davis1, Lewis Teperman2, George J. Netto3, Ken Washburn4, Steven Rudich5, Elizabeth Pomfret6, Hugo
E. Vargas7, Robert Brown8, Devin Eckhoff9, Timothy Pruett10, John Roberts11, David C. Mulligan7, Michael Charlton12, Thomas G.
Heffron13, John Ham14, David Douglas7, Linda Sher15, Prabhakar Baliga16, Milan Kinkhabwala8, Baburao Koneru17, Michael Abecassis18,
Michael Millis19, Linda W. Jennings1, Carlos G. Fasola13
1
Baylor University Medical Center, Dallas, TX; 2 New York University Medical Center, NY; 3 Johns Hopkins Medical Institutions,
Baltimore, MD; 4 University of Texas Health Science Center at San Antonio; 5 University of Cincinnati, Cincinnati, OH; 6 Lahey Clinic,
Burlington, MA; 7 Mayo Clinic, Scottsdale, AZ; 8 New York Presbyterian Hospital, New York, NY; 9 University of Alabama Birmingham, AL; 10
University of Virginia, Charlottesville, VA; 11 University of California, San Francisco, CA; 12 Mayo Clinic, Rochester, MN; 13 Emory University
School of Medicine, Atlanta, GA (current address: Scott and White Clinic, Temple, TX); 14 Oregon Health Sciences University, Portland, OR; 15
University of Southern California, Los Angeles, CA; 16 Medical College of South Carolina, Charleston, SC; 17 University of Medicine and
Dentistry of New Jersey, Newark NJ; 18 Northwestern Memorial Hospital, Chicago, IL; 19 University of Chicago, Chicago, IL

59

The challenge of
transplant surgery is NOT
the surgery

60

61

Immunologic Armamentarium
(Arsenal)

Vietnam Conflict

Ground Troops
Light Artillery

Cyclosporine
Okt3

F16
Tactical warhead / cruise missile

Smart Bomb
Modified F16
B2 stealth bomber
X - Plane
Osprey Transport
Modified Osprey Transport

Biologic Weapon
Modified Biologic Weapon

Desert Storm

Cold War

Imuran
Steroids

Prograf
Neoral
Cell Cept
IL2 Receptor Abs
Rapamycin
Rapamune

War on Terror

Thymoglobulin
Campath

62

Risk of Chronic Renal Failure

A 15-year experience at Baylor Medical

Center found that at 13 years after liver
transplantation

Incidence of severe renal dysfunction of

18.1%
Chronic renal failure in 8.6% of patients
ESRD in 9.5% of patients

Gonwa TA et al. Transplantation 2001;72:1934-1939.

63

Risk of Chronic Renal Failure

Cumulative Incidence
of Chronic Renal Failure

0.35
0.30

Liver
Intestine

0.25

Lung

0.20

Heart

0.15
0.10

Heartlung

0.05
0.00

12

24

36

48
60
72
84
Months since Transplantation

Number at Risk
Heart576
375
295
219
194
156
lung
Heart
24,014 19,885 17,238 14,687 12,341 10,022
Intestine 228
152
110
84
57
33
Liver
36,849 28,495 24,041 19,508 15,724 12,564
Lung
7,643 5,633
4,316 3,184 2,327 1,629

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

96

108

120

133

107

72

46

30

7,997
23
9,844
1,136

6,104
13
7,345
745

4,526
8
5,292
468

3,096
5
3,614
258

1,991
5
2,261
133

64

Calcineurin inhibitor-free
maintenance with
mycophenolate
mofetil/sirolimus in liver
transplant recipients: Savethe-Nephron Trial
(submitted)

L.Teperman,1 D. Moonka,2 A.Sebastian,3 L. Sher,4 P. Marotta,5 C. Marsh,6 B. Koneru,7 J. Goss,8 D. Preston,9 and J. Roberts10
New York University School of Medicine, New York, New York; 2Henry Ford Health Systems, Detroit, Michigan; 3Integris Baptist Medical
Center, Oklahoma City, Oklahoma; 4University of Southern California, Los Angeles, California; 5London Health Sciences Hospital,
London, Ontario, Canada; 6Scripps Green Hospital, La Jolla, California; 7University of Medicine and Dentistry of New Jersey, Newark,
New Jersey; 8Saint Lukes
Lukes Episcopal Hospital, Houston, Texas; 9Genentech, South San Francisco, California; 10University of California, San
Francisco, California
Lew, This version contains comments from LS, JR, and DM. PM provided feedback of no comments.
65

STN Trial Design

Pre-randomization
MMF + tacrolimus
corticosteroids

MMF + cyclosporine
corticosteroids
Screening

Stable

Post-randomization

4 12

MMF + tacrolimus

W
E
E
K
S

MMF + sirolimus

P
O
S
T
T
X

MMF + cyclosporine
MMF + sirolimus

Enrollment

1 year

2 years

66

Mean % Increase in Calculated

GFR
Baseline to Month 6
40

Mean Percent Increase

(SEM)

35
MMF/SRL

30
25

MMF/CNI

29.2

20
15
10
5
3.2

0
Baseline GFR SEM (mL/min)

N = 84
55.8 1.9

N = 86
50.6 1.9
67

Conclusions

At least 62% of individuals are able to tolerate a

maintenance regimen of MMF/SRL and will
benefit
In the short term, MMF/SRL improves renal
function when compared to CNI-containing
regimens
The addition of lipid-lowering agents may be
necessary in patients receiving MMF/SRL
Complete follow-up of the 294 patients will
provide a more statistically robust conclusion
about the long-term effect of this regimen
68

Donor and NYU Timeline

New Transplant Regulations
1999 Living Donation (Right Lobe Adult)
1990 Living Donation Lateral
Segment (peds)
1965 1st Successful
Liver Transplant

1997 Split Livers (peds) (Adult)

1988 Reduced Sized Grafts (peds)

1963 University Hospital Built

69

DONOR RISKS

NewYorkNewsday,March13,2002

70

Transplant Chief at Mt. Sinai Quits Post in

Wake of Inquiry

A week after Mount Sinai Medical Center was cited by

the state for dozens of serious violations, the chief of its
liver transplant center has stepped down and the entire
program will be restructured, hospital officials
announced yesterday.

--- The New York Times

71

Summer of 2010

2 Recent U.S. Deaths

Colorado
Massachusetts

72

New York State

Report of the Subcommittee on Donor
Perioperative Care and Facility Report
Lewis Teperman M.D., Chair

73

New Preoperative Care Regs

1.
2.
3.

4.

5.

Psychiatric Evaluation
Bank Blood
Staff
1.
2 donor surgeons*
2.
A third transplant surgeon*
3.
Anesthesia (2 attendings)
Post operative care
1.
ICU (days 0 - 1)
1 Nurse / 2 Patients
2.
Floor 1 Nurse / 4 patients
3.
Residents
(pgy2) / NP 24/7
Registry
1.
Outcome

* Qualified

74

Living Donor Recipients

Inclusion
Listed with UNOS and must have a significant
complication of liver disease
Relative Exclusions
MELD > 25
Cholangio Carcinoma
Exclusions
AFHF
Retransplant for C
Acute Alcoholic Hepatitis
75

HCC: Extra Credit

Is Living Donation justified?

Patients meeting criteria receive 22

points.
After a three-month reevaluation
patients receive additional points.
Thereafter they receive additional
points every three months.
76

Recipient life expectancy

(years)

Hepatoma Predictor
LDLT and Waiting List Time

14

12
Immediate LDLT

10

DLT drop out

2%/month

5 yr survival after DLT

70%

DLT drop out

4%/month

4
2

0
0

10

12

14

16

18

20

22

24

Waiting list time

(months) Sarasin, F. Hepatology
77

NoSellingofOrgans

$
78

Donor Candidacy
Requirements (1)

Emotionally related
Age 18 - 60
Blood Type Compatible

A
O

A
O, B, A, AB

79

MELD Score Comparison of Cadaveric

vs. Living Related Donors

Average Living Donor MELD Score:

17.4

Average Cadaveric MELD Score:

32
80

81

1% Rule

70kg recipient needs a 700cc liver graft

(1% GRWR)
1% mortality
(Actually ~0.05% but over emphasize to
define risk)

82

Living Donor

Right Hepatic resection

50% - 65% of the hepatic mass

Right is Right
Left hepatic resections will have
more complications

83

Living Donors
What the Surgeon Needs to Know:

Liver Parenchyma

Hepatic arteries

Right lobe volume

Exclude fatty
infiltration
Characterize lesions
Arterial variants
RHA origin

Portal veins

PV variants, RPV
origin

Hepatic veins

RHV length
MHV branches to right
lobe
Inferior accessory HV

Biliary ducts

Biliary variants
Rt lateral duct origin

84

Volumetric MR
Cholangiography

Lee VS, Teperman L, et Al. AJR, 2001.

85

CT Cholangiography

Higher Spatial
Resolution than MR
Shorter Exam Time
Radiation Dose
Contrast Agent

86

Safety
Donor Rule #2

Know the donors anatomy prior to the

procedure

Donor Rule #1

Do not hurt the donor

See Rule #2
87

Living Donor Biliary

Technique
1.
2.
3.
4.
5.

Demonstrate anatomy prior to OR

Confirm anatomy with an on table
cholangiogram
Exclude right to left cross over
Perform a duct to duct anastomosis
Utilize a t-tube for post operative studies and
drainage
88

Picture of on table cholangiogram prior

to splitting

89

90

91

92

93

NYU Donor Complications

7 Bile leaks requiring intervention
1 non-occlusive PV thrombus
3 peripheral neuropathies
1 pleural effusion drained

5 Required blood transfusions

2 late laparotomies for SBO
94

NYU Recipient Biliary

Complications

100 right lobectomies

8 patients experienced early biliary complications
4 leaks
2 - ERCP and internal stent; 2 - JP drainage
1 stricture (following a leak treated by ERCP and
internal stent)
Endoscopic dilation
13 patients experienced late biliary complications
All requiring PTC and Dilation
95

Comparative Living Donor Liver

Transplant Survival Rates
Survival Categories
Patient Survival
Graft Survival

NYU
Medical
Center

National
Average

Difference

91%

86.5%

+ 4.5%

88.4%

80.6%

+ 7.8%

96

Results

97

ExtracorporealLiverAssistDevice
(ELAD)

98

ExtracorporealLiverAssistDevice
(ELAD)

99

100