critical care in acute liver failure || selection and results of liver transplantation

124 © 2013 Future Medicine124124 www.futuremedicine.com

Sarah A HughesSarah A Hughes graduated from the University of Cambridge (UK) in 1999. She is currently a Clinical Research Fellow in the Institute of Liver Studies, King’s College Hospital (London, UK). She has clinical interests in both acute and chronic liver diseases, and liver transplantation. Her research is focused on the subject of viral hepatitis, in particular hepatitis D virus.

John O’GradyProfessor John O’Grady graduated from the National University of Ireland (Galway) in 1978. He joined the Liver Unit at King’s College Hospital (London, UK), in 1984 where he currently works as a Consultant Hepatologist with an interest in liver transplantation and hepatology. He was President of the British Association for the Study of the Liver (BASL) from 2007 to 2009. He is also Deputy Editor of the American Journal of Transplantation. He has published over 270 papers in his areas of interest.

About the Authors

For reprint orders, please contact: [email protected]

© 2013 Future Medicine

doi:10.2217/EBO.12.381

125

Selection and results of liver transplantation

Sarah A Hughes & John O’GradyImprovements in medical management and intensive therapy of patients with acute liver failure (ALF) have led to an improved overall prognosis. Mortality in those with severe ALF, however, remains high. Liver transplantation may be life-saving in this group, but is not suitable in all cases. The procedure carries with it its own mortality and morbidity, including the sequelae of long-term immunosuppression. Moreover, in the current era of global donor organ shortage, unnecessary liver transplantation in a patient with ALF who would otherwise have survived represents a missed opportunity for a patient awaiting liver transplantation for the complications of chronic liver disease. The challenge for the clinician, therefore, is to determine which of those patients with ALF are in need of, and, at the same time, will derive benefit from, liver transplantation, and who will survive with medical therapy alone.

Factors influencing prognosis 126

Prognostic models 127

Graft allocation 135

Results of liver transplantation for ALF 136

Auxiliary liver transplantation 137

Chapter 10

Hughes & O’Grady

126 www.futuremedicine.com

Factors influencing prognosisMaking a clinical judgment on the need for emergency liver transplantation in acute liver failure (ALF) requires an understanding of the factors that influence prognosis, and to what extent these predict death or survival. Many such factors have been identified, but in reality relatively few are routinely utilized for this purpose. Given the rapidity with which the ALF syndrome can evolve, and the need to maximize the time for a graft to become available in those who are listed for transplantation, the ideal prognostic marker would be objective, simple to measure, widely applicable and would have prognostic significance early in the course of the illness.

Laboratory parametersLaboratory variables shown to correlate with prognosis in ALF include coagulation factors, in particular, prothrombin time (PT) or international normalized ratio (INR), serum bilirubin, serum creatinine, arterial pH and serum lactate [1–3]. Also of predictive value, but less widely used, are alternative coagulation factors, in particular, nonvitamin K-dependent factors V and VII [4–6], a-fetoprotein [4,7], arterial ammonia [8], serum phosphate [9,10], ketone body ratio [11] and levels of Gc globulin, a liver‑derived component of the actin‑scavenging system [12].

Clinical factorsThe etiology of the disease is an important determinant of outcome. Prog-nosis is much better in ALF that develops in relation to acetaminophen tox-icity, pregnancy, hepatic ischemia or hepatitis A, where transplant‑free sur-vival is in excess of 50%, compared with idiosyncratic drug reactions, seronegative hepatitis, autoimmune hepatitis or Wilson’s disease, where spontaneous survival is generally less than 30% [13,14]. Encephalopathy grade on admission is also clearly linked to outcome, with those in grade 3–4 coma having poorer survival than those with grade 1–2 coma, regardless of the etiology of the liver failure. Prognosis is worse when grade 4 encephalopathy is complicated by cerebral edema, and worse still when there is coexistent renal failure [15]. Cerebral edema occurs less frequently in the current era, owing to improvements in the medical management of encephalopathy and measures to prevent and control intracranial hypertension, but still accounts for up to 25% of all deaths in ALF [16]. The third key clinical determinant of

outcome is age, perhaps owing to the decline in ability to achieve hepatic regeneration with increasing age. Age greater than 40 years is linked to a poorer prognosis [17].

The three most important clinical factors predicting poor prognosis in acute liver failure

are: etiology of liver failure, encephalopathy grade and increasing age.

Selection & results of liver transplantation

127www.futuremedicine.com

Radiological & histological indicesIt is recognized that serial collapse of the liver is a harbinger of poor prognosis in ALF. The ratio of computed tomography‑derived liver volume to standardized liver volume at the time of diagnosis has been shown to predict the outcome of ALF with 76.5% sensitivity and 92.3% specificity [18]. Assessment of the role of transjugular liver biopsy has shown that the percentage of hepatic necrosis in the specimen is of discriminatory prognostic value [19]. The practicalities of implementing these methods as routine markers to evaluate prognosis in a critically ill population of patients render them of doubtful utility.

Prognostic modelsThe feasibility of liver transplantation as a treatment for ALF was established during the 1980s. Although it is now widely accepted practice to undertake transplantation in this condition, no controlled trials have ever been performed to evaluate its efficacy or appropriate indications. A number of prognostic models have therefore been proposed, derived from the analysis of data from retrospective cohorts. The aspiration of these models is to establish simply applied criteria, which enable the clinician to list for emergency transplant all those who will die without this intervention, while sparing those who will survive spontaneously from unnecessary transplantation. The accuracy of such criteria to predict poor prognosis can be validated using various indices, in particular positive predictive value (PPV), negative predictive value (NPV), predictive accuracy, sensitivity and specificity.

The limitations of existing prognostic models have been that although fulfillment of criteria is highly predictive of death, lack of fulfillment does not guarantee survival. Setting the criteria too high will increase the PPV of the model, but with an inevitable reduction in NPV, equating to potentially avoidable deaths in patients who may have benefited from transplantation. The corollary, if criteria are set too low, is the burden of unnecessary transplantation for an individual who may have survived spontaneously, and a wasted organ from the limited donor pool (Figure 10.1). There are a number of reasons for the imperfections in these models, not least of which is the diversity of the ALF syndrome, particularly in relation

Prognostic model: a group of conditions that, when satisfied, predict outcome.

Positive predictive value (PPV): the proportion of patients fulfilling poor prognosis criteria that die.

Negative predictive value (NPV): the proportion of patients not fulfilling poor prognosis criteria that survive.

Predictive accuracy: the overall proportion of cases in which the outcome is correctly predicted.

Sensitivity: the proportion of fatal cases fulfilling criteria.

Specificity: the proportion of survivors not fulfilling criteria.

Hughes & O’Grady


to disease etiology. The apparent paradox that those with hyper‑ALF due to acetaminophen toxicity, who develop a worse coagulopathy and more cerebral edema, have a better outcome than those with seronegative sub-ALF, who are less coagulopathic, and rarely develop cerebral edema but are more jaundiced, is not something that is easily overcome in defining a one‑size‑fits‑all set of selection criteria to enable the crucial decision as to whether to list a patient for transplantation.

King’s College Hospital criteriaThe King’s College Hospital (KCH) criteria were proposed in 1989, and were the first to separate prognostic criteria by etiology of ALF, defining distinct criteria for those with acetaminophen-induced ALF from those with non-acetaminophen-induced causes [1]. The criteria, which include for acetaminophen-related ALF, arterial pH, PT or INR, creatinine and encephalopathy grade, and for non-acetaminophen etiologies, PT or INR, bilirubin, jaundice to encephalopathy time, age and etiology, are shown in Table 10.1. They form the basis of registration for emergency liver transplantation in the UK, and are in widespread use worldwide. The

criteria were originally derived by multivariate analysis of prognostic factors in a retrospective cohort of 588 patients, treated with medical management between

Selection criteria: factors shown to predict outcome in acute liver failure, which can be

used as a basis for selecting patients who need liver transplantation.

Figure 10.1. Schematic representation of the effect of setting a cutoff value for selection criteria.

All those in need transplantedMore unnecessary transplants

Missed deathsFewer avoidable transplants

Criteria cut-off

NPV

PPV

Sensitivity

Specificity

It should be noted that the relationship between the variable and performance indicators is not necessarily linear. PPV: Positive predictive value; NPV: Negative predictive value.



Table 1

0.1. P

ropose

d p

rognost

ic m

odels for th

e pre

dictio

n of poor out

com

e in a

cute

live

r fa

ilure

.

Mod

el (y

ear)

Etiolog

yCriteria fo

r po

or progn

osis

Performan

ceRe

f.

King

’s C

olle

ge

Hos

pita

l cri

teri

a (1

989)

Ace

tam

inop

hen

indu

ced

Non

-ac

etam

inop

hen

indu

ced

Art

eria

l pH

<7.

30 a

fter

flui

d re

susc

itati

on, o

r al

l of t

he

follo

win

g:��

PT >

100/

INR

>6.5

��Cr

eatin

ine

>300

µM

/l (3

.4 m

g/dl

)��

Gra

de 3

/4 e

ncep

halo

path

y

PT >

100/

INR

>6.5

, or

any

3 of

:��

NA

NB/

drug

/hal

otha

ne e

tiolo

gy��

Jaun

dice

to e

ncep

halo

path

y >7

day

s��

Age

<10

or

>40

year

s��

PT >

50/I

NR

>3.5

��Bi

lirub

in >

300

µM/l

(17.

4 m

g/dl

)

PPV

84%

NPV

86%

PPV

98%

NPV

82%

[1]

Clic

hy (1

991)

Vir

al h

epati

tisCo

nfus

ion,

plu

s��

Fact

or V

<20

% if

age

<30

year

s or

��Fa

ctor

V <

30%

if a

ge >

30 y

ears

PPV

90%

NPV

95%

[28]

Art

eria

l lac

tate

(2

002)

Ace

tam

inop

hen

>3.5

mm

ol/l

on

adm

issi

on

>3.0

mm

ol/l

pos

tres

usci

tatio

n

Sens

itivi

ty 6

7%Sp

ecifi

city

95%

Sens

itivi

ty 7

6%Sp

ecifi

city

97%

[3]

[3]

BiLE

sco

re (2

008)

Mix

edBi

lirub

in le

vel (

mm

ol/l

)/10

0 pl

us la

ctat

e (m

mol

/l) p

lus

etiol

ogy

(inde

term

inat

e; B

udd–

Chia

ri =

4;

acet

amin

ophe

n =

2; o

ther

= 0

); sc

ore

>6.9

poo

r pr

ogno

sis

Sens

itivi

ty 7

9%Sp

ecifi

city

84%

[3

5]

MEL

D (2

007)

Ace

tam

inop

hen

MEL

D >

33 a

fter

ons

et o

f enc

epha

lopa

thy

Sens

itivi

ty 6

0%; P

PV 6

5%;

Spec

ifici

ty 6

9%; N

PV 6

3%[3

2]

ALF

SG: A

cute

Liv

er F

ailu

re S

tudy

Gro

up; A

LT: A

lani

ne a

min

otra

nsfe

rase

; AST

: Adm

issi

on a

spar

tate

am

inot

rans

fera

se; A

URO

C: A

rea

unde

r re

ceiv

ing

oper

ator

cur

ve ;

BiLE

: Bili

rubi

n, la

ctat

e an

d eti

olog

y; IN

R: In

tern

ation

al n

orm

alis

ed r

atio;

MEL

D: M

odel

for

end

stag

e liv

er d

isea

se; N

AN

B: N

on‑A

, non

‑B

hepa

titis

; NPV

: Neg

ative

pre

dicti

ve v

alue

; PPV

: Pos

itive

pre

dicti

ve v

alue

; PT:

Pro

thro

mbi

n tim

e.

Hughes & O’Grady


Table 1

0.1. P

ropose

d p

rognost

ic m

odels for th

e pre

dictio

n of poor out

com

e in a

cute

live

r fa

ilure

(co

nt.).

Mod

el (y

ear)

Etiolog

yCriteria fo

r po

or progn

osis

Performan

ceRe

f.

CK‑1

8/M

65‑M

ELD

(2

010)

Mix

edM

-MEL

D >

53.5

(see

ref

eren

ce fo

r fo

rmul

a)O

n ad

mis

sion

for

non-

acet

amin

ophe

n:

sens

itivi

ty 8

1%; s

peci

ficit

y 82

%

[34]

ALF

SG-in

dex

(201

2)M

ixed

Com

a gr

ade

≥2, b

iliru

bin,

INR,

pho

spha

te (≥

3.7

mg/

dl),

log 10

M‑3

0Se

nsiti

vity

85.

6%Sp

ecifi

city

64.

7%[3

6]

Dhi

man

(200

7)V

iral

hep

atitis

Any

3 o

f:��

Age

>50

yea

rs��

Jaun

dice

to e

ncep

halo

path

y >7

day

s��

Gra

de 3

/4 e

ncep

halo

path

y��

Cere

bral

ede

ma

��PT

>35

s��

Crea

tinin

e >1

.5 m

g/dl

(133

µM

/l)

AURO

C 0.

821

[23]

MA

LD (2

012)

Ace

tam

inop

hen

Adm

issi

on: A

ST, A

LT, I

NR,

cre

atini

ne (s

ee r

efer

ence

for

deta

ils)

Sens

itivi

ty 1

00%

; spe

cific

ity

91%

; PPV

67%

; NPV

100

%[3

7]

Live

r bi

opsy

(199

3)M

ixed

Hep

atic

necr

osis

>70

%PP

V 95

%[1

9]

Preg

nanc

y-re

late

d liv

er fa

ilure

(201

0)Pr

egna

ncy

rela

ted

Lact

ate

>2.8

mg/

dl p

lus

ence

phal

opat

hySe

nsiti

vity

90%

Spec

ifici

ty 8

6%[3

9]

Hep

atitis

A (2

006)

H

epati

tis A

ALT

<26

00 IU

/l, c

reati

nine

>2.

0 m

g/dl

(177

µM

/l),

intu

batio

n st

atus

, nee

d fo

r va

sopr

esso

r ag

ents

AURO

C 0.

899

[40]

Gan

zert

(200

5)A

mat

oxin

Prot

hrom

bin

inde

x <2

5%, s

erum

cre

atini

ne >

106

µM/l

(1

.2 m

g/dl

), fr

om d

ay 3

pos

t‑in

gesti

onSe

nsiti

vity

100

%Sp

ecifi

city

98%

[41]

Escu

die

(200

7)A

mat

oxin

Tim

e fr

om in

gesti

on to

dia

rrhe

a <8

hPr

edic

tive

accu

racy

78%

[42]

ALF

SG: A

cute

Liv

er F

ailu

re S

tudy

Gro

up; A

LT: A

lani

ne a

min

otra

nsfe

rase

; AST

: Adm

issi

on a

spar

tate

am

inot

rans

fera

se; A

URO

C: A

rea

unde

r re

ceiv

ing

oper

ator

cur

ve ;

BiLE

: Bili

rubi

n, la

ctat

e an

d eti

olog

y; IN

R: In

tern

ation

al n

orm

alis

ed r

atio;

MEL

D: M

odel

for

end

stag

e liv

er d

isea

se; N

AN

B: N

on‑A

, non

‑B

hepa

titis

; NPV

: Neg

ative

pre

dicti

ve v

alue

; PPV

: Pos

itive

pre

dicti

ve v

alue

; PT:

Pro

thro

mbi

n tim

e.



1973 and 1985. The criteria were validated in a further retrospective cohort of patients from 1986 to 1987, comprising 121 patients with ALF due to acetaminophen and 54 with ALF due to other etiologies.

Many groups have assessed the performance of the KCH criteria in their own ALF cohorts (Table 10.2) [6,19–25]. Interpretation of these, mostly retrospective, reports is made difficult by the small numbers incorporated, the effect of era on the outcome of critically ill patients, and the heterogeneity of the cohorts. For example, reports vary as to whether those who underwent transplant are included in the analysis; the natural history of the illness is censored by intervening with liver transplantation, rendering it difficult to accurately evaluate transplant‑free survival. Two recent meta-analyses of the performance of the KCH criteria have been published. The first, addressing non‑acetaminophen-induced ALF, included 1105 patients in 18 studies and found an overall sensitivity of 68% and specificity of 82% [26]. Specificity was highest in those with higher‑grade encephalopathy and where the criteria were applied dynamically. Sensitivity was lower in studies published after 2005 than before 1995. The second systematic review, addressing acetaminophen-induced ALF, included 1960 patients in 14 studies and found a sensitivity of 58% and specificity of 95% [27].

Clichy criteriaThe Clichy criteria were defined in 1986 and were modeled from a cohort of 115 patients with fulminant hepatitis B. Prognostic indicators were Factor V levels, age, a‑fetoprotein concentration and absence of hepatitis B virus surface antigen [4]. The model incorporated a function of age, Factor V levels and encephalopathy grade (Table 10.1) [28]. The criteria were extended for application to other etiologies of liver failure and are in use across northern Europe. The utility of these criteria are limited in some areas by restricted access to a reliable factor V assay. The assessment of the performance of these criteria in one series of 120 consecutive patients showed a PPV of 75% and NPV of 58%, increasing to 87% and 67%, respectively, when children were included in the analysis [24].

Alternatives & improvements to current prognostic modelsIn the process of assessing the performance of existing prognostic models, and seeking to improve their sensitivity and NPV in particular, many other refinements have been suggested. Bernal and colleagues identified arterial lactate as having prognostic value in identifying patients likely to die without transplantation [3]. A lactate threshold of 3.5 mmol/l early after admission, and 3.0 mmol/l post‑resuscitation had a sensitivity, specificity,

Hughes & O’Grady


positive likelihood ratio and negative likelihood ratio of 67%, 95%, 13 and 0.35, and 76%, 97%, 30 and 0.24, respectively. Combining lactate values at the two time points had similar predictive ability to the KCH criteria, but allowed earlier identification, and therefore listing, of nonsurvivors. Adding post‑resuscitation lactate to the KCH criteria increased its sensitivity to 91%. Other groups have examined the performance of lactate in alternative

Table 10.2. Assessment of the performance of the King’s College criteria in other cohorts of patients with acute liver failure.

Study (year) Etiology Patients (n)

Sensitivity (%)

Specificity (%)

Ref.

Donaldson et al. (1993)

Non-acetaminophen 46 91 82 [19]

Acetaminophen 15 100 100

Pauwels et al. (1993)


Izumi et al. (1996)


Acetaminophen 81 69 96

Shakil et al. (2000)

Non-acetaminophen 144 34†/93‡ 100†/90‡ [22]

Acetaminophen 33 49§/45¶ 99§/94¶

Schmidt and Dalhoff (2002)

Acetaminophen 106 67 97 [9]

Bernal et al. (2002)


Zaman et al. (2006)


Dhiman et al. (2007)


Yantorno et al. (2007)


Schmidt and Larsen (2007)


Bechmann et al. (2010)


Cholongitas et al. (2012)


Criteria are as defined in Table 10.1. †Based on INR criteria. ‡Based on “3 of 5” criteria. §Based on pH criteria. ¶Based on non-pH criteria.



prognostic models, and have not found it to be superior to the existing criteria [29]. The UK Transplant Agency incorporated lactate criteria into minor modifications of its categories for ‘super‑urgent’ listing for acetaminophen-induced liver failure in 2008 [30]. Criteria for listing for non-acetaminophen-induced liver failure, based on those published by O’Grady in 1989 [1], have remained largely unchanged for over 20 years.

The Model for End‑Stage Liver Disease (MELD) score has been adapted for assessment of survival in those with chronic liver disease, and forms the basis of registration for elective liver transplantation in the USA. It incorporates the variables serum bilirubin, serum creatinine and INR, all of which feature in the KCH criteria. It seemed natural, then, to assess its performance in predicting outcome in those with ALF. Several groups have found MELD to perform as well as or better than the KCH or Clichy criteria [24,31], but others have not found it to be superior to the KCH criteria for acetaminophen-induced liver failure [32]. It has been acknowledged that MELD alone is insufficient in providing accurate survival probabilities [33], which is perhaps not surprising, since its component variables do not take into account some of the most important clinical factors influencing survival in ALF, for example, age and etiology, as discussed. Combining MELD with other factors therefore seems logical. An example is the substitution of a cell‑death marker, cytokeratin‑18, for bilirubin within the MELD, which was shown in a prospective cohort of 68 patients to outperform MELD and the KCH criteria in predicting outcome [34].

Other proposed models include the Bilirubin, Lactate and Etiology (BiLE) score, found by retrospective analysis of 102 patients to predict poor outcome better than bilirubin, lactate, MELD or the Simplified Acute Physiology Score III (SAPS-III), but did not conclusively outperform the KCH criteria [35]. A group from India identified six key clinical prognostic indicators: age ≥50 years, jaundice to encephalopathy interval >7 days, grade 3/4 encephalopathy, presence of cerebral edema, PT ≥35 s and creatinine ≥1.5 mg/dl. In their cohort of 144 patients, all of whom had acute viral hepatitis, fulfilling any three of these six factors predicted adverse outcome better than MELD or the KCH criteria [23]. The inclusion of a late complication of ALF, such as cerebral edema, in this study will naturally have increased PPV, but falls short of the aspiration to identify factors that discriminate nonsurvivors at an earlier stage in the course of the illness. Future models

Key determinants of a poor outcome following liver transplantation for acute liver failure

include:�� Recipient age >50 years�� Donor age >60 years�� ABO incompatibility�� Reduced‑size grafts�� BMI ≥30 kg/m2

�� Serum creatinine >2.0 mg/dl�� History of organ support

Hughes & O’Grady


are likely to take into account the evolution of the illness, and to use criteria that are applied dynamically.

Most recently, a model termed the ALF study group (ALFSG) index has been proposed, which incorporates coma grade, bilirubin, INR, phosphate and log10-M30, a cleavage product of cytokeratin‑18 caspase, and a marker of cell death [36]. The model uses values collected from day 1 of admission to a specialist unit and, based on the area under the receiver operating curve, predicted adverse outcome better than the KCH criteria or MELD. Although the model satisfies the need to improve on the sensitivity of the KCH criteria (sensitivity 85.6%), it is at the expense of specificity, particularly in the non-acetaminophen group where specificity was 59.2%.

A recent study by Remien and colleagues has elegantly applied mathematical modeling to evaluate outcome in acetaminophen-induced liver failure, terming it the model for acetaminophen‑induced liver disease (MALD) [37]. They base their model on the fact that size of overdose and time to administration of N-acetylcysteine are important determinants of prognosis, and use mathematical modeling of admission aspartate aminotransferase, alanine aminotransferase and INR, in conjunction with knowledge of the pattern of acetaminophen‑induced liver injury to estimate overdose amount and timing. From that they derive an estimate of outcome, which, with the inclusion of creatinine, predicts survival with 91% specificity, 100% sensitivity, 67% PPV and 100% NPV. This approach is clearly attractive in its use of the very earliest available laboratory values, and warrants further analysis in a prospective multicenter study.

Well‑validated scores of organ dysfunction in critically ill patients have been applied to cohorts of patients with ALF to judge their prognostic performance. Examples include the sequential organ failure assessment (SOFA) score [25], systemic inflammatory response syndrome (SIRS) score [29] and the acute physiology and chronic health evaluation II (Apache‑II) score [38]. Although all were shown to have prognostic value in the setting of ALF, none have been conclusively proven to perform better than existing criteria and, as with other proposed models, require further validation in large prospective cohorts before being considered as the basis for registration for emergency liver transplantation.

Disease-specific prognostic modelsThere are etiologies of ALF for which the KCH criteria were not validated, and separate studies have provided guidance on prognostic criteria in these more rare conditions. A retrospective analysis of 54 patients with pregnancy‑related liver disease found a transplant‑free survival of 80%. A



total of 13% died and 7% underwent transplantation [39]. The KCH criteria did not accurately predict survival, instead an admission lactate of ≥2.8 mg/dl had a sensitivity of 73% and specificity of 75% in predicting death or liver transplantation. These figures increased to 90% and 86%, respectively, with the addition of encephalopathy, concluding that increased lactate in the presence of encephalopathy was the best predictor of poor outcome in this group [39]. A study of 29 patients with hepatitis A‑related ALF from the USA found that a prognostic model incorporating alanine aminotransferase <2600 IU/l, creatinine >2.0 mg/dl, intubation status and need for vasopressor agents best predicted outcome, with an area under the receiver operating curve of 0.899, which was significantly better than the KCH criteria or MELD score [40]. Regarding patients with ALF caused by ingestion of mushrooms containing amatoxins, a series of 198 patients reported that a prothrombin index <25% combined with a serum creatinine >106 µM/l from day 3 post‑ingestion onwards had 100% sensitivity and 98% specificity for the prediction of death [41]. A second series of 27 patients with amanita poisoning found that an interval between ingestion and the onset of diarrhea of less than 8 h was an earlier predictor of fatal outcome, with a predictive accuracy of 78% [42].

Graft allocationWorldwide, approximately 45–50% of those meeting the definition of ALF are transplanted, although when acetaminophen toxicity is the etiology, this figure falls to less than 10%. The remainder survive spontaneously, have contraindications to transplantation, or die before an organ becomes available. Contraindications can include being too sick in relation to the severity of liver failure and associated organ dysfunction, coexisting illnesses conferring a limited life expectancy, for example, malignancy, and psychiatric or substance abuse issues deemed to be complex enough to preclude transplantation. The latter may be contentious, has ethical implications and requires a multidisciplinary team evaluation on an individual case basis [43]. The feasibility of emergency transplantation for ALF is predicated on the timely availability of a suitable graft. In both the USA and Europe, the majority will receive a graft within 48 h of being listed. The need for speed has influenced the type of grafts used, and ABO‑incompatible grafts, steatotic livers, non‑heart‑beating deceased donors and reduced size grafts have all been used in this setting. The ideal scenario would be to individually match recipient and graft, and offer the best quality graft to the sickest patient. In reality, the risk of delaying in the hope that a better graft becomes available results in the acceptance of more marginal grafts. In areas such as Asia, where access to deceased donor transplantation is limited, there is

Hughes & O’Grady


experience of living-related donor transplantation for ALF, with reported 5‑year survival rates of up to 80%. Where the recipient is an adult, the main difficulty is obtaining an adequately sized graft, which usually means the use of a right lobe split graft, which carries more risk for the donor.

Results of liver transplantation for ALFALF accounts for 6–7% of all transplant activity in the USA [44] and 11% in Europe [45]. Despite the improvements in intensive care management of these patients, the outcome of emergency transplantation for ALF remains inferior to that of elective transplantation for chronic liver disease. In the USA, patient survival is seven percentage points less in the former group, and in Europe it is 15 percentage points less [46]. In general, 1-year survival post-emergency liver transplant is approximately 60–80%, with consistent improvement in survival rates over the last 25 years. In the USA, analysis of 1457 patients transplanted for fulminant liver failure over a 15‑year period, identified through the United Network for Organ Sharing, found a 1‑, 5‑ and 10‑year patient and graft survival of 77.1, 67.2 and 60%, and 69.2, 57.1 and 48.3%, respectively [47]. European Liver Transplant Registry data for 4903 patients over a 21‑year period revealed corresponding figures of 74, 68 and 63%, and 63, 57 and 50% respectively [45]. In this analysis, survival in the 2004–2009 period was significantly higher than in earlier time periods, despite the steady increase in age of donors over time, implying that improvements in medical care and surgical techniques surpass the deleterious effects of increasing donor age.

Most series concur that the most common cause of early mortality is sepsis and consequent multiorgan dysfunction [45,47,48]. There are a number of pretransplant donor‑, recipient‑ and graft‑related factors that have been shown by multivariate analysis to predict poor outcome post emergency liver transplant. Although studies vary as to which of these factors has the greatest prognostic relevance, the negative effect of older recipient age is a consistent finding. European registry data identified male recipients, recipient age >50 years, ABO incompatibility, donor age >60 years and reduced size graft as being associated with post‑transplant death or graft loss [45]. The United Network for Organ Sharing data found BMI ≥30 kg/m2, serum creatinine >2.0 mg/dl, recipient age >50 years and a history of life support to be the factors most strongly associated with poor outcome [47]. From these four factors a scoring system was devised, with low-risk patients having a 5‑year survival of 81%, compared with 42% in high‑risk

Characteristics of optimal recipients for auxiliary grafts:

�� Young (<40 years)�� Hyperacute liver failure�� Viral or acetaminophen etiology�� Limited extrahepatic organ dysfunction



patients. In one single‑center study, multivariate analysis of data from 204 patients transplanted over a 17‑year period found that serum creatinine was the single-most important determinant of survival post-liver transplant [48].

Auxiliary liver transplantationIn some situations where resolution of the insult causing liver failure would lead to regeneration of the native liver, auxiliary liver transplantation may be used to bridge the gap to recovery. In this procedure, a partial graft is transplanted heterotopically or orthotopically, leaving all or part of the native liver in situ. A right lobe graft is often preferred in an adult recipient, as it offers a larger liver volume. Splitting a deceased donor liver for use in auxiliary transplantation requires a good‑quality graft. The operation is technically challenging and requires surgical skill and experience. Auxiliary transplantation is an attractive option, since it potentially avoids the need for longer‑term immunosuppression and its various side effects and complications. After an appropriate time period, slow withdrawal of immunosuppression will lead to atrophy of the graft, with the hope that the native liver has regenerated adequately to support normal hepatic function. The success of this will depend on there being a critical mass of surviving native hepatocytes. Histologically, the majority of native livers will regenerate, with particularly high rates in cases of diffuse liver injury, typified by the liver injury caused by acetaminophen toxicity, where, unless there is massive cell loss, hepatocyte proliferation is at its peak in the first week post transplant [49]. In seronegative sub‑ALF, the liver injury is more map‑like, and histological regeneration is rather more unpredictable [49]. Clinically, outcomes after auxiliary transplantation are best in younger recipients (<40 years), those with a hyperacute course of liver failure, and those with viral hepatitis or acetaminophen toxicity [50,51]. Each of these factors has a logical association with hepatic regeneration, which in turn may explain their link to better clinical outcomes.

Overall survival rates in auxiliary transplantation for ALF are between 63 and 72% [50–53]. Technical complications and requirement for retransplantation do appear to be higher when compared with standard transplants, although this does not seem to impact on patient survival [53], and is less apparent in more recent series as experience of the surgical techniques increases. There may be more bacteremia after auxiliary transplantation, and brain death from cerebral edema is more common [53]. The latter observation may be explained by the persistence of circulating factors, generated by the ongoing presence of the diseased necrotic native liver, and auxiliary transplantation is not generally recommended in those with issues

Auxiliary liver transplantion: transplantation of a reduced graft leaving some or all of the native

liver in situ to regenerate.

Hughes & O’Grady


relating to cerebral edema. Individual series are small and heterogeneous, but successful regeneration and permanent withdrawal of immunosuppression in those surviving auxiliary transplantation varied from 10% at 17 years post‑transplant [52] to 60% [51]. Multicenter European experience reports that immunosuppression was permanently stopped in 65% of survivors [54].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Summary.

�� Acute liver failure has a high mortality and liver transplantation can be life‑saving.�� Transplantation may not be suitable in all cases, and decisions regarding contraindications to

transplantation can be difficult.�� Several laboratory and clinical factors have been shown to predict outcome in acute liver

failure.�� Prognostic models are available that help to select those patients who will die without liver

transplantation, but they require modification to improve their prognostic performance.�� Younger patients with limited extrahepatic organ dysfunction, receiving a whole, ABO‑matched

graft from a younger donor have the best outcomes post transplant.�� Auxiliary transplantation offers the opportunity to withdraw long‑term immunosuppression

after regeneration of the native liver.�� Imperfections in existing prognostic models are such that clinical judgment is still required, and

listing for emergency liver transplant should be a multidisciplinary team decision taken on an individual case basis, while using data and knowledge of the factors influencing prognosis to maintain a consistent approach.

References1 O’Grady JG, Alexander GJ,

Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 97(2), 439–445 (1989).

2 Harrison PM, O’Grady JG, Keays RT, Alexander GJ, Williams R. Serial

prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ 301(6758), 964–966 (1990).

3 Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-

induced acute liver failure: a cohort study. Lancet 359(9306), 558–563 (2002).

4 Bernuau J, Goudeau A, Poynard T et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 6(4), 648–651 (1986).



5 Pereira LM, Langley PG, Hayllar KM, Tredger JM, Williams R. Coagulation Factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators. Gut 33(1), 98–102 (1992).

6 Izumi S, Langley PG, Wendon J et al. Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. Hepatology 23(6), 1507–1511 (1996).

7 Karvountzis GG, Redeker AG. Relation of a-fetoprotein in acute hepatitis to severity and prognosis. Ann. Intern. Med. 80(2), 156–160 (1974).

8 Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29(3), 648–653 (1999).

9 Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology 36(3), 659–665 (2002).

10 Baquerizo A, Anselmo D, Shackleton C et al. Phosphorus ans an early predictive factor in patients with acute liver failure. Transplantation 75(12), 2007–2014 (2003).

11 Yamasaki H, Saibara T, Maeda T, Onishi S. The arterial ketone body ratio and serum a‑fetoprotein level in patients with acute hepatic failure. Liver 15(4), 219–223 (1995).

12 Schiodt FV, Bangert K, Shakil AO et al. Predictive value of

actin‑free Gc‑globulin in acute liver failure. Liver Transpl. 13(9), 1324–1329 (2007).

13 O’Grady J. Liver transplantation for acute liver failure. Best Pract. Res. Clin. Gastroenterol. 26(1), 27–33 (2012).

14 Lee WM. Recent developments in acute liver failure. Best Pract. Res. Clin. Gastroenterol. 26(1), 3–16 (2012).

15 O’Grady JG, Gimson AE, O’Brien CJ, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 94(5 Pt 1), 1186–1192 (1988).

16 Stravitz RT, Larsen FS. Therapeutic hypothermia for acute liver failure. Crit. Care Med. 37(Suppl. 7), S258–S264 (2009).

17 O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 342(8866), 273–275 (1993).

18 Yamagishi Y, Saito H, Ebinuma H et al. A new prognostic formula for adult acute liver failure using computer tomography‑derived hepatic volumetric analysis. J. Gastroenterol. 44(6), 615–623 (2009).

19 Donaldson BW, Gopinath R, Wanless IR et al. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators. Hepatology 18(6), 1370–1376 (1993).

20 Pauwels A, Mostefa-Kara N, Florent C, Levy VG. Emergency liver

transplantation for acute liver failure. Evaluation of London and Clichy criteria. J. Hepatol. 17(1), 124–127 (1993).

21 Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King’s criteria. J. Hepatol. 26(1), 62–68 (1997).

22 Shakil AO, Kramer D, Mazariegos GV, Fung JJ, Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl. 6(2), 163–169 (2000).

23 Dhiman RK, Jain S, Maheshwari U et al. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End‑Stage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transpl. 13(6), 814–821 (2007).

24 Yantorno SE, Kremers WK, Ruf AE, Trentadue JJ, Podesta LG, Villamil FG. MELD is superior to King’s College and Clichy’s criteria to assess prognosis in fulminant hepatic failure. Liver Transpl. 13(6), 822–828 (2007).

25 Cholongitas E, Theocharidou E, Vasianopoulou P et al. Comparison of the sequential organ failure assessment score with the King’s College Hospital criteria and the model for end-stage liver disease score for the prognosis of acetaminophen-induced acute liver failure. Liver Transpl. 18(4), 405–412 (2012).

26 McPhail MJ, Wendon JA, Bernal W. Meta‑analysis of performance of Kings’s College Hospital Criteria in prediction of outcome in nonparacetamol-induced

Hughes & O’Grady


acute liver failure. J. Hepatol. 53(3), 492–499 (2010).

27 Craig DG, Ford AC, Hayes PC, Simpson KJ. Systematic review: prognostic tests of paracetamol-induced acute liver failure. Aliment. Pharmacol. Ther. 31(10), 1064–1076 (2010).

28 Bernuau J, Samuel D, Durand F et al. Criteria for emergency liver transplantation in patients with acute viral hepatitis and factor V (FV) below 50% of normal: a prospective study. Hepatology 14(S4), 49A (1991).

29 Schmidt LE, Larsen FS. Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit. Care Med. 34(2), 337–343 (2006).

30 Neuberger J, Gimson A, Davies M et al. Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut 57(2), 252–257 (2008).

31 Zaman MB, Hoti E, Qasim A et al. MELD score as a prognostic model for listing acute liver failure patients for liver transplantation. Transplant. Proc. 38(7), 2097–2098 (2006).

32 Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury. Hepatology 45(3), 789–796 (2007).

33 Kremers WK, van IM, Kim WR et al. MELD score as a predictor of pretransplant and posttransplant survival in OPTN/UNOS status 1 patients. Hepatology 39(3), 764–769 (2004).

34 Bechmann LP, Jochum C, Kocabayoglu P et al. Cytokeratin 18‑based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J. Hepatol. 53(4), 639–647 (2010).

35 Hadem J, Stiefel P, Bahr MJ et al. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Clin. Gastroenterol. Hepatol. 6(3), 339–345 (2008).

36 Rutherford A, King LY, Hynan LS et al. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology 143(5), 1237–1243 (2012).

37 Remien CH, Adler FR, Waddoups L, Box TD, Sussman NL. Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death. Hepatology 56(2), 727–734 (2012).

38 Mitchell I, Bihari D, Chang R, Wendon J, Williams R. Earlier identification of patients at risk from acetaminophen-induced acute liver failure. Crit. Care Med. 26(2), 279–284 (1998).

39 Westbrook RH, Yeoman AD, Joshi D et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am. J. Transplant. 10(11), 2520–2526 (2010).

40 Taylor RM, Davern T, Munoz S et al. Fulminant hepatitis A virus infection in the United States: incidence, prognosis, and outcomes. Hepatology 44(6), 1589–1597 (2006).

41 Ganzert M, Felgenhauer N, Zilker T. Indication of liver transplantation following amatoxin intoxication. J. Hepatol. 42(2), 202–209 (2005).

42 Escudie L, Francoz C, Vinel JP et al. Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation. J. Hepatol. 46(3), 466–473 (2007).

43 Rhodes R, Aggarwal S, Schiano TD. Overdose with suicidal intent: ethical considerations for liver transplant programs. Liver Transpl. 17(9), 1111–1116 (2011).

44 Freeman RB Jr, Steffick DE, Guidinger MK, Farmer DG, Berg CL, Merion RM. Liver and intestine transplantation in the United States, 1997–2006. Am. J. Transplant. 8(4 Pt 2), 958–976 (2008).

45 Germani G, Theocharidou E, Adam R et al. Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database. J. Hepatol. 57(2), 288–296 (2012).

46 Bernal W, Cross TJ, Auzinger G et al. Outcome after wait‑listing for emergency liver transplantation in acute liver failure: a single centre experience. J. Hepatol. 50(2), 306–313 (2009).

47 Barshes NR, Lee TC, Balkrishnan R, Karpen SJ, Carter BA, Goss JA. Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure. Transplantation 81(2), 195–201 (2006).



48 Farmer DG, Anselmo DM, Ghobrial RM et al. Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period. Ann. Surg. 237(5), 666–675 (2003).

49 Quaglia A, Portmann BC, Knisely AS et al. Auxiliary transplantation for acute liver failure: histopathological study of native liver regeneration. Liver Transpl. 14(10), 1437–1448 (2008).

50 Chenard‑Neu MP, Boudjema K, Bernuau J et al. Auxiliary liver transplantation: regeneration of the native liver and outcome in

30 patients with fulminant hepatic failure: a multicenter European study. Hepatology 23(5), 1119–1127 (1996).

51 Jaeck D, Boudjema K, Audet M et al. Auxiliary partial orthotopic liver transplantation (APOLT) in the treatment of acute liver failure. J. Gastroenterol. 37(Suppl. 13), S88–S91 (2002).

52 Girlanda R, Vilca‑Melendez H, Srinivasan P et al. Immunosuppression withdrawal after auxiliary liver transplantation for acute liver failure. Transplant. Proc. 37(4), 1720–1721 (2005).

53 Azoulay D, Samuel D, Ichai P et al. Auxiliary partial orthotopic versus standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single center by a case–control study. Ann. Surg. 234(6), 723–731 (2001).

54 van Hoek B, de Boer J, Boudjema K, Williams R, Corsmit O, Terpstra OT. Auxiliary versus orthotopic liver transplantation for acute liver failure. EURALT Study Group. European Auxiliary Liver Transplant Registry. J. Hepatol. 30(4), 699–705 (1999).

critical care in acute liver failure || selection and results of liver transplantation

Documents