Adult-to-adult living donorliver transplantation –

Triumphs and challenges

ST Fan, MS, MD, PhD, DScProfessorSun CY Chair of Hepatobiliary SurgeryThe University of Hong KongHong Kong

Falk Symposium No. 163 on Chronic Inflammation of Liver and Gut

Pioneers of adult-to-child LDLT• Raia S Brazil 1989• Strong R Australia 1989• Nagasue N Japan 1989• Ozawa K Japan 1990• Broelsch C USA 1990

Mother-to-child living donor liver transplantation

Left lobe donation from large body size donor to small body size recipient

The first 6 right liver LDLT recipients in the world. All of their right liver grafts contain the MHV. All except one are surviving in good condition.

Right liver donation from small body size donor to large body size recipient

Right liver graft (MHV) expands applicability of LDLT

Right liver LDLT override body-size mismatch

211 (73.5%)Donor BW < Recipient BW

14 (4.9%)Donor BW = Recipient BW

62 (21.6 %)Donor BW > Recipient BW

Number

0

60

120

180

240

300

360

420

480

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

Year

Publications on LDLT since inception (1989)

Leftliver

Rightliver

Left liver graft with middle hepatic vein Left liver graft with caudate lobe

Right liver graft without middle hepatic vein Right liver graft with middle hepatic vein

Right lateral sector graft

The available graft types for adult-to-adult LDLT. The shaded area represent the graft portion of the liver.

Adult-to-adult living donor liver transplantation using dual grafts

Left lobe Left lobe Left lobeLateral

segment

Left lobe

Right lobe Lateral segment

Posterior segment

Lee SG, Asian J Surg, 2003

Right liver living donor liver transplant in Queen Mary Hospital, Hong Kong

10 (29.4%)33118342007

15 (45.5%)13014332006

6 (18.8%)2.54227322005

13 (31%)44226422004

4 (14.3%)4.56031282003

10 (34.5%)43027292002

564025302001

164220312000

26

32

-

47

MELD score (median)

01564121999

016.57181998

----01997

01115181996

Recipient with no blood

transfusion

Blood transfusion unit

(median)

ICU stay (days)

(median)

Recipienthospital

mortality

NumberYear

287 13 (4.5%)110 consecutive patients without hospital mortality

University of HK

Comparison between living donor liver transplantation (LDLT)and deceased donor liver transplantation (DDLT)

Patient survival at Queen Mary Hospital

6050403020100

100

90

80

70

60

50

40

30

20

100

P = 0.31

LDLT (n = 124)

DDLT (n = 56)

Survival time (months)

Cum

ulat

ive

surv

ival

(%)

University of HK

Results of right liver LDLT (including MHV) at Queen Mary Hospital, University of Hong Kong

3 (7.7%)0.93(0.6 – 1.95)

49.7(35.1 – 86.9)

37 (23 – 52)39CAH acute flare

55(39.7 – 89.4)

47.5(28.5 – 68.9)

47.8 (31.5 – 79.5)

Graft wt to ESLW (%)

0.98(0.74 – 1.92)

0.89(0.49 – 1.32)

0.88(0.55 – 1.41)

Graft wt to recipient body

wt (%)

1 (5.0%)

3 (6.8%)

5 (4.3%)

Hospital mortality

36 (27 – 50)20Fulminanthepatic failure

35 (15 – 59)44Cirrhosis with acute deterioration

16 (7 – 41)117Cirrhosis

MELD scoreNo. of transplant

University of HK

Survival time (years)

Graft survival of adult patients with liver cirrhosis with acute deterioration

9876543210

100

90

80

70

60

50

40

30

20

100C

umul

ativ

e su

rviv

al (%

)

DDLT (n=19)

R lobe LDLT (n=38)

P=0.6705

11109876543210

100

90

80

70

60

50

40

30

20

100

DDLT (n=5)R lobe LDLT (n=29)

P=0.4611

Graft survival of adult patients with chronic hepatitis B with acute flare

131211109876543210

100

90

80

70

60

50

40

30

20

100

DDLT (n=5)

R lobe LDLT (n=18)

P=0.3892

Graft survival of adult recipients with fulminant hepatic failure

Survival time (years)

Cum

ulat

ive

surv

ival

(%)

14131211109876543210

100

90

80

70

60

50

40

30

20

100

Graft survival of adult recipients with cirrhosis

R lobe LDLT (n=101)

DDLT (n=92)

P=0.5323

Cum

ulat

ive

surv

ival

(%)

Survival time (years)

Survival time (years)

Cum

ulat

ive

surv

ival

(%)

University of HK

Survival time (years)

1.87Donation after cardiac death donor

1.36 – 2.32Extended criteria donor

1.0Standard criteria deceased donor

0.78Live donor

Relative riskGraft type

Relative risk of dying after liver transplantation

Emond J, 2007

1211109876543210

100

90

80

70

60

50

40

30

20

100

Disease-free survival of HCC recipients

Cum

ulat

ive

surv

ival

(%)

Survival time (years)

DDLT (n=21)

LDLT (n=59)

P=0.0299

University of HK

Lo CM et al, Br J Surg, 2007

Probability of freedom from HCC recurrence by time since LDLT or DDLT

Fisher RA et al, Am J Transplant, 2007

DDLT (n=34)

LDLT (n=58)

P=0.002

Free

dom

from

Rec

urre

nce

(%)

Year from transplant

Possible reasons for higher incidence of HCC recurrence after LDLT• HCC with aggressive biological behavior are

transplanted early• Less lymph node removal• More liver manipulation• More acute phase injury in small graft • Rapid liver regeneration stimulates HCC growth• More immunosuppression relative to liver graft

size

Tumor Tumor growthgrowth inin small graft small graft (nude mice model)(nude mice model)

Whole graft

Small graft

Day 20 Day 40

Acute phase injury and late phase tumor recurrenceAcute phase injury and late phase tumor recurrence

Liver transplantation using small liver graft

Shear stress

Inflammatory cascades

Angiogenesis (VEGF , HSC activation )

Favorable environment for tumor growth and

metastasis

Liver regeneration

Hepatic sinusoidal injuryMicrovascular barrier dysfunction

Liver parenchyma damageCell adhesion, migration

and invasion(ROCK , RAC , Pyk2 )

Tumor cell proliferation(Ki67 )

Invasive tumor growth in small-for-size liver graftMan K, Liver Transpl, in press

Is the living donor graft to be blamed for higher HCC recurrence?

• Risk factors for recurrence of HCC by multivariate analysis

Transplant year (pre MELD)AFP levelRecipient ageCentre experience

Fisher RA et al, Am J Transpl, 2007

Salvage transplantPathological stage beyond UCSF criteria

CM Lo et al, Br J Surg, 2007

Hyperdynamic portal flow

Endothelial cell damage

Adhesion molecule upregulation

Cytokine release

Macrophage activation and infiltration

Enhanced alloantigen presentation

Exacerbated acute rejection

Initiation of apoptotic pathway

Exacerbation of inflammation

Loss of small-for-size graft

Liver regeneration

Mediator release e.g. VEGF

Possible reasons for loss of small-for-size graft

Generation of reactive oxygen species

Inter-relationship of variables contributing to small-for-size graft injury

↑ portal inflow

impairedvenous outflow

suboptimal graft quality

↓ graft size

Fan ST, Transplantation, 2006

↑ portal inflow

impairedvenous outflow

suboptimal graft quality

↓ graft size

Measures to improve graft outcome

• porta-systemic shunt• FK409• splenic artery ligation

• ↓ ischemia time• avoid fatty graft• avoid elderly graft• FTY720• HO-1 transfer• >35% ESLW

• inclusion of MHVin the graft

• venoplasty

Small-for-size graft injury

Fan ST, Transplantation, 2006

PancreatitisRt liver (w/o MHV)United StatesBrown

Duodeno-caval fistula complicating chronic duodenal ulcer

Rt liver (w/MHV)Hong KongChanCerebral hemorrhageRt liver (w/o MHV)BrazilWiederkehr

Gas gangrene of stomachRt liver (w/o MHV)United StatesMillerPulmonary embolismLt liverGermanyMalagoCongenital lipodystrophyRt liver (w/o MHV)GermanyMalagoNot knownNot knownUnited States-

Massive pulmonary embolismLeft lateral segmentGermanyBroering

Right pleural effusion, multiple organ failure

Rt liver (w/o MHV)FranceBoillotSuspected pulmonary embolismNot knownIndia-Nonalcoholic steatohepatitisRt liver (w/ MHV)JapanAkabayashi

RemarksType of graftCountryAuthor

Known donor mortalities

Cardiac arrhythmiaRt liverBrazilCoelho

Sepsis, bile leakageRt liver EgyptAbofetouhMultiple myclomaRt liverFrance-Cardiac arrest, unknown causeRt liver India-

Liver failure, steatosisRt liverKorea-Heart attackRt liverSingaporePolido

RemarksType of graftCountryAuthor

Known donor mortalities

Donor operationPrinciple

• A donor receives an operation for a disease that he does not have

• To protect the donor and to prevent unnecessary morbidity and mortality, vigilant evaluation and perioperative care is necessary

Donor evaluationPrinciple

• Healthy donor is a completely healthy person

• Any volunteer with concomitant medical disease should not be allowed to donate

• No compromise in donor evaluation and acceptance criteria

Pre-requisite for successful donor hepatectomy

• Experience and skill in liver transection• Knowledge of liver anatomy• Protection of remnant liver• Meticulous post-operative care

Living donor liver transplantation• Major stride in liver transplantation• Donor mortality and morbidity are major

concerns• Further strategies to improve outcome

– small for size graft injury– HCC recurrence– Minimize donor morbidity