Prognostic Modelling in Paediatric Acute Liver Failure

Vandana Jain1, Anil Dhawan1

1. Paediatric Liver, GI and Nutrition Centre, Kings College Hospital, London, UK

Abstract

Liver Transplantation (LT) is the only proven treatment for paediatric acute liver failure (PALF).

However, over a period of time, spontaneous native liver survival is increasingly reported, making

us wander if we are over-transplanting children with acute liver failure (ALF). An effective

prognostic model for PALF would help direct appropriate organ allocation. Only patients that

would die would undergo liver transplantation (LT), and those who would spontaneously recover,

would avoid unnecessary LT. Deriving and validating such a model for PALF, however,

encompasses numerous challenges. In particular, the heterogeneity of age and aetiology in PALF,

as well as lack of understanding of the natural history of the disease, contributed by the

availability of LT, lead to difficulties in prognostic model development. Several prognostic

laboratory variables have been identified, and incorporation into scoring systems have been

attempted. A reliable targeted prognostic model for ALF in Wilson’s Disease, has been established

and, externally validated. The role of physiological, immunological and metabolomic parameters

in prognosis are being investigated. This review discusses the challenges with prognostic modelling

in PALF and describes predictive methods that are currently available and in development for the

future.
Abbreviations; AIH, autoimmune hepatitis; ALFED, ALF early dynamic model; ALF, acute liver failure;

ALT, alanine transaminase; APACHE II, The Acute Physiology and Chronic Health Evaluation II; AST,

aspartate transaminase; AUC, area under the curve; CK 18, total cytokeratin 18; ELSS, extracorporeal

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/lt.24501

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 Liver Transplantation Page 2 of 27

liver support system; GALD, Gestational Alloimmune Liver Disease INR, International Normalised

Ratio; KCH, Kings College Hospital; HE, hepatic encephalopathy; HLH, haemophagocytic

lymphohistiocytosis; HSV, herpes simplex virus; LIU, Liver Injury Units; LT, liver transplantation;

MELD, Model for End-stage Liver Disease; NH, Neonatal Haemochromatosis; NIH, The National

Institute of Health; ; NPV, negative predictive value; PALF, paediatric acute liver failure; PELD,

pediatric end stage liver disease; PIM , Paediatric Index of Mortality; PPV, positive predictive value;

PRISM, Paediatric Risk of Mortality; PT, Pro-Thrombin Time; PCM, paracetamol; ROC, receiver

operator curve; SOFA , Sequential Organ Failure Assessment; SBR, serum bilirubin; SNL, survival

native liver; UK, United Kingdom;, US, United States, WD, wilson’s disease; WCC, leukocyte count.

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Page 3 of 27 Liver Transplantation

Paediatric acute liver failure (PALF), although rare, is a condition associated with high mortality 1.

Earlier literature on the subject has used adult definitions of acute liver failure (ALF) as well as adult

prognostic criteria to consider liver transplantation (LT). However, with increased experience, it

became clear that PALF differs from adult ALF, in terms of type and diversity of aetiologies and the

later appearance of hepatic encephalopathy (HE). A consensus definition of PALF is “ the acute

onset of liver disease with hepatic-based coagulopathy (Pro-Thrombin Time, PT ≥ 20s; International

Normalised Ratio, INR ≥ 2) not corrected by parenteral vitamin K with or without HE or hepatic-

based coagulopathy (PT 15-19.9s; INR 1.5-1.9) with HE 2. Emergency liver transplantation (LT)

remains the only definitive treatment, with PALF accounting for 10-15% of all paediatric LT1, 3.

Aetiology in PALF varies significantly according to age and worldwide location1-4; identifiable causes

include infection, metabolic, toxin/drug-induced, vascular/ischemic, infiltrative/malignancy and

immune dys-regulation. In the developed world, the commonest cause amongst all age groups

remains indeterminate. Clinical management of PALF entails (i) identifying conditions that have

specific medical treatments (ii) ensuring supportive therapy and (iii) determining the likelihood of

either spontaneous native liver recovery or death. Accurate prognostication in PALF would ensure

that only patients that were likely to die would be listed for emergency LT. Prognostication is also

key in appropriately allocating extra-corporeal liver support systems (ELSS) and auxiliary LT to

patients. However, determining prognosis remains challenging.

PALF outcomes

The creation of multi-centre registries of PALF data have led to a much better understanding of PALF

management in the developed world. The National Institute of Health (NIH) sponsored PALF Study

database 2, initiated in 1999, includes data from 24 participating centres from United States (US),

Canada and the United Kingdom (UK). In the pre-transplantation era, Kings College Hospital (KCH),
5
London reported spontaneous recovery only in 28% PALF patients, albeit with limitation of the

data, whilst the majority (72%) died. Post-LT, the PALF Study database demonstrated a much higher

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 Liver Transplantation Page 4 of 27

spontaneous recovery of 56% (1999-2004). More recently, the Paediatric Health Information System

(PHIS), from the US 6, has reported an increasing spontaneous survival of 73.4% (2008-2012) (Figure

1). Despite these encouraging results, optimal prognostic criteria to decide who will die without LT is

lacking 7. The PALF Study database 2 highlighted 10% of all patients listed for emergency LT were de-

listed due to death or spontaneous recovery in 20 and 80% of cases respectively. The increased

availability of living donor LT could further complicate the natural history of PALF by unnecessary

transplantation where spontaneous liver recovery could have occurred. Auxiliary LT, with native liver

regeneration shown in up to 70% of select patient groups, provides insight into the potential for

native liver recovery 8

Figure 1 Comparison of survival native liver (SNL), LT and death rates (%) in PALF in the pre-LT and

post-LT eras.

Designing an ideal prognostic model for PALF

A prognostic model in medicine is designed to produce indices to enable the estimation of the risk of

future events in individual patients/groups and to risk stratify these patients 9. Figure 2 highlights the

principles behind ideal derivation, assessment and validation of a prognostic model. Prior to deriving

a predictive model, its clinical relevance should be clear, aimed at aiding clinicians in decision-

making. Prognostication in PALF is essential for clinical practice, to accurately differentiate patients

that are likely to survive or die, in order to allocate emergency LT appropriately. The ideal model-

derivation population should be large, representative of the diseased cohort and entail a reasonable

proportion of the outcome measure. The outcome measure(s) should be clearly defined. Ideally,

PALF prognosis should comprise two outcomes; survival and death. However, artificially intervening

with LT skews the data, as the true outcome for patients undergoing LT, is unknown. Variables in a

model should be easy to measure and utilise, ideally objective and not too extensive. Variables for

adult ALF and PALF models are usually derived from uni- and/or multi-variate analyses on historical

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patient cohorts. To test if the variables/model display acceptable predictive reliability, the actual

observed and predicted outcomes need to be plotted and compared, in a process called ‘calibration’.

Subsequently, in a process called ‘discrimination’, the model can be quantified to distinguish

between patients who do or do not experience the event. In order to determine discriminatory

power, the sensitivity and specificity for the model at different threshold settings must be calculated
10
and then plotted on a receiver-operator curve (ROC) . The area under the curve (AUC) or ‘c’-

statistic summarises how good the model is at discriminating between outcomes. AUC or ‘c’-statistic

of ‘1.0’ would be ideal, representing 100% discrimination, however, in practice, AUC/c-statistic > 0.8

is considered acceptable. In PALF, an appropriate balance between sensitivity and specificity is

essential, as reduced sensitivity (low positive predictive value; PPV) could lead to the failure to list a

patient for LT who would have subsequently died, but reduced specificity (low negative predictive

value; NPV) carries a risk of unnecessary LT in a patient who was likely to recover spontaneously.

Once a model demonstrates good calibration and discrimination, it should be tested outside of the
11
derivation dataset, in a process called ‘validation’ . Validation can take place internally, on a

different dataset, either retrospectively or prospectively (temporal validation) but external

validation (i.e different centre) is preferred, in order to test transportability of the model.

Figure 2 Diagram to illustrate the principles of the ideal prognostic model development and

validation. The accuracy of the model developed is summarised by (a) calibration and (b)

discrimination. A well calibrated model shows good correlation between observed and predicted

mortality with a reasonable ‘goodness to fit’. Sensitivity and specificity at different threshold

settings are plotted on a receiver-operator curve (ROC) and discrimination is summarised by the

area under the curve (AUC). AUC as close to 1.0 shows optimal sensitivity and specificity (0.8 is

acceptable in predictive modeling)

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Adult ALF prognostic modelling

Adult ALF, given the higher patient population, fewer aetiologies and strict definition, consists of
12, 13
more literature on prognostic modelling as compared to children . The two most recognised

models (Figure 3) were derived from logistic regression analysis of historical patient cohorts in the

pre-transplantation era 14, 15. The Kings College Hospital (KCH) criteria, first described in 1989, is the

standard upon which other models have been judged, and is currently the basis for the UK NHS

Blood and Transplant emergency LT selection. It incorporates paracetamol (PCM) and non-PCM

aetiologies as well as age, INR, HE, serum bilirubin (SBR), renal function and acidosis. Although a

small number of paediatric patients (n=29) were included in this cohort, details are limited, and
16
infants were excluded. Numerous studies, including a recent meta-analysis , have consistently

demonstrated good specificity (PCM 95%; non-PCM 81%) but poor sensitivity (PCM 58%; non-PCM

68%), hence, not adequately discriminating the patients that would die without LT. The Clichy-
14
Villejuif criteria , was similarly devised in the late 1980’s from an adult cohort of viral hepatitis

patients, and incorporates age, HE and factor V concentration. It is the criteria by which patients are

listed for emergency LT in Northern Europe. However, similar to KCH criteria, sensitivity is low.

Assessment of other variables to supplement existing criteria, e.g. lactate, continues 17. Despite its

initial development for cirrhotic patients, Model for End-stage Liver Disease (MELD) has been
18, 19
evaluated in ALF . McPhail et al 20, in their meta-analysis, revealed higher sensitivity of MELD
21
over KCH criteria, but at the cost of reduced specificity. Kumar et al recently developed, and

validated, the ALF early dynamic (ALFED) model. This model was based on early changes of four

variables (arterial ammonia, INR, HE and serum bilirubin; SBR), over 3 days, as a prediction of

mortality. Good calibration and discrimination (AUC 0.91) were revealed. Although we can learn

from the principles of adult ALF modelling, extrapolation to PALF is challenging, due to fundamental

differences in presentation, definition, age and aetiology.

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Figure 3 Adult ALF prognostic models; King’s College Hospital Criteria and Clichy-Villejuif criteria.

Challenges in PALF prognostication

The pursuit for the ‘ideal’ prognostic model in PALF is undoubtedly crucial, but complex. Figure 4

summarises the interplay of multiple complexities in PALF prognostic modelling.

Figure 4 Factors contributing to the challenges in PALF prognostication

Presentation and definition. Definitions for adult ALF and PALF incorporate different concepts,

highlighting the differences in disease presentation. HE has important prognostic significance in

adult ALF, hence, incorporated into both KCH and Clichy models. However, in PALF, HE is difficult to

incorporate into a model as it is uncommonly present at diagnosis, difficult to diagnose in younger

children and rapidly progressive in some cases1, 22, 23. Another important discrepancy between adult

and paediatric definitions, is that the ‘absence of pre-existing liver disease’ is required in adult ALF,

but in PALF, children can present with an acute de-compensation of a previously unknown

underlying liver disorder (e.g inherited metabolic disorder).

Age and Aetiology. PALF comprises widespread aetiologies and age groups, which carry different

prognostic outcomes. Figure 5a shows overall PALF aetiology, as well as categorisation by age in the
1, 2, 24
developed world. Several paediatric studies have highlighted the contribution of aetiology to

prognosis (Figure 5b), with an increased likelihood of spontaneous recovery in conditions such as,

PCM-toxicity, hepatitis A and ischemic hepatitis and a reduced likelihood of spontaneous recovery in

indeterminate, Wilson’s Disease (WD), idiosyncratic drug reactions, autoimmune hepatitis (AIH), and

multi-systemic conditions (e.g. mitochondrial disease, haemophagocytic lymphohistiocytosis; HLH

and herpes simplex virus; HSV). The PALF Study database comprises a wide range of aetiologies, but

subgroup analysis demonstrates a 94% spontaneous recovery of PCM- induced PALF. PCM toxicity

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accounts for over 50% of adult ALF in the UK 25; O’Grady et al15. (1989) incorporated PCM toxicity

separately within the KCH criteria. This raises the question as to whether aetiology specific scores

would be more appropriate than an overall PALF score. A successful prognostic model for WD,

which is discussed in a later section, further supports this view. Aetiology specific scores would need

to incorporate the variability of a single condition, the variable impact of specific directed therapy in

some disease processes (e.g. AIH, HSV, Neonatal Haemochromatosis; NH) as well as the potential for

score modification if new treatments become available (e.g possible immunosuppression in cases of

indeterminate PALF)26

Young age is associated with poorer PALF outcomes, partly due to comprising higher risk aetiologies

with multi-systemic involvement, but also due to the specific technical challenges posed by younger

infants27. Figure 5a highlights age-dependent aetiologies; NH, HLH and HSV most common in

neonates, metabolic in infancy/early childhood and drugs, WD and AIH in older children 1, 2, 4, 22. The

term, ‘NH’, is being expressed rather than ‘GALD” (Gestational Allo-immune Liver Disease), as only

the phenotypic description of this disease can be inferred and not the allo-immune aetiological

component. The largest aetiological group for PALF across all ages, indeterminate, accounting for
1, 2, 4, 6, 24
over 50% cases in UK . The PALF Study database revealed an increased risk of death/LT

amongst <3 versus ≥ 3 years old groups. Durand et al (2001), in their single-centre retrospective
22
analysis of infants with ALF (n=80, 1986-2000) demonstrated death/LT in 47% cases, which was
28
higher than in older children. Sundaram et al , in particular, highlighted the challenges in very

young infants (< 3 months) from the PALF Study database. They identified 148 young infants (median

age 18 days, range 11-37 days) and compared outcomes to the older group (≥ 3 months).

Spontaneous survival and mortality without LT were 59.5 and 24% respectively in young infants

which was significantly worse than figures for older children in the PALF cohort (79 and 10.5%

respectively). Indeterminate (38%), NH (13.6%) and HSV (12.8%) were the commonest categories in

this young cohort. The same group showed that only 40% of young infants that were listed for LT,

actually received an organ, compared to 66% in the older group, emphasizing potential technical

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issues, such as, lack of suitable size-matched organs. Hence, similar to aetiology, age plays an

essential role in prognostication. The incorporation of age parameters, in particular young age in

prognostic modelling, is vital for accurate scoring. The ‘ideal prognostic model’ would need to be

derived from a cohort of specific aetiology and age.

Figure 5 (a) Overall and age categorised PALF aetiology in the developed world (b) Aetiology

dependent PALF prognosis. Data for overall aetiology adapted from Dhawan et al 4

PALF natural history. A significant limitation in developing the ‘ideal’ model for both adult ALF and

PALF, is the restricted insight into the natural history of the disease, in light of artificially intervening

with LT. Data from the pre-LT era 5 and from countries where LT is not available 29, allows glimpses

into PALF natural history, however, differences in medical care and aetiologies within both these

cohorts make extrapolation to current practice in developed countries, challenging. PALF prognostic

models often incorporate LT and death as a combined measure of poor outcome, but as some

patients undergoing LT would have spontaneously recovered, models comparing native liver survival

to death without LT, are more appropriate. Ideally, parameters of liver function which can determine

the number of remaining parenchymal cells, the level of cell dysfunction and their capacity of

regeneration would help predict the natural history of disease.

Additional model limitations. Decisions regarding optimal threshold cut-offs for a PALF model are

challenging, as sensitivity and specificity need to be balanced appropriately. Most prognostic models

are derived and validated retrospectively, hence, missing information and different time-points for

data collection (admission versus study enrolment data; early versus late transfer to tertiary

centre30), can be confounders. Intensive care procedures, such as ELSS and use of blood products

can affect laboratory and physiological parameters used in prognostic models, however, integrating

these measures into models is difficult. Worldwide, there are differences in organ availability (lack of

donors, less experience with living related techniques). In countries with reduced organ availability

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and increased waiting times, although PALF modelling would still guide management, there may be

more a role for proactive listing for LT as compared to countries with greater organ availability. In

addition, PALF aetiologies and management vary across the world, hence, external validation of PALF

models across different geographic locations need to be interpreted cautiously. Lastly, the

improvement of PALF outcomes over time, with enhanced medical care, suggests the need to

update existing models accordingly.

Prognostic variables in PALF

Despite the above challenges, numerous groups have investigated the role of various prognostic

variables in PALF (Table 1). A retrospective analysis of 31 children with PALF (predominantly viral

aetiology) 5 at KCH in the pre-LT era demonstrated a significantly higher chance of death if the pro-

thrombin time exceeded 90 seconds. Subsequent studies in the post-LT era demonstrated that PT

and INR were significant predictors of death/LT or death alone 24, 27, 31. At KCH, an INR > 4 was shown

to have the best sensitivity (86%) and specificity (73%.) and AUC-ROC 0.79. The PALF study database

revealed an INR ≥ 2.5 to be a predictor of death. Hence, different thresholds may be applicable to

different populations. UK organ allocation is based on INR > 4. Other laboratory variables, namely

SBR, alanine transaminase (ALT), aspartate transaminase (AST), leukocyte count and factor V

concentration, have been studied, in order to supplement INR and improve its discriminative power.

SBR was significantly associated with death/LT and death alone in the PALF study database on

multivariate analysis, along with several other studies. Dhawan et al 27, in a multi-variate followed by

uni-variate analysis, and using ROC methodology, identified a cut-off value of total SBR 235

µmmol/l, with a a sensitivity and specificity of 85 and 65% (AUC 0.76). Leukocyte count (WCC) ≥ 9

x109/L and age < 2 years were identified as additional risk factors. Figure 6 shows the increasing

discriminatory value of combining all 4 parameters (INR, SBR, WCC, age), predicting near 100 %

mortality without LT. Low transaminases 23, 24 and factor V 22, 32, 33 at admission have been associated

with poor outcome. Factor V is used in few European countries, for PALF organ allocation. The

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severity of HE, if present, is a poor prognostic marker, with grade IV HE nearly always associated
2, 24
with fatality . Admission electroencephalogram (EEG) abnormalities in conjunction with clinical

HE grading could add further prognostic advantage34. Currently, INR/PT together with other

laboratory variables, aetiology and young age is the optimal way to assess PALF outcomes. There are

no paediatric studies, which have evaluated the role of type of PALF presentation (e.g acute versus

sub-acute) and prognosis.

Figure 6 Four PALF prognostic variables associated with cumulative risk of mortality. Adapted

from Dhawan et al 27

PALF Scoring Systems

Incorporating PALF prognostic variables into a scoring system would aid clinical staff in making

decisions regarding LT. However, this is proving to be a highly complex task. Several groups have

attempted to apply adult criteria and chronic liver disease scoring systems in PALF. Newer PALF

models have been devised, with the disease specific score, the revised Wilson’s Index, being in

widespread use.

KCH Criteria. The parameters incorporated into KCH criteria are known to be prognostic markers for

death in PALF. KCH criteria was applied to a large cohort of patients (n=522) with non-PCM induced

PALF 35, who did not undergo LT, from the PALF Study database. This cohort comprised 36.8% infants

and 43.1% overall indeterminate aetiology. Of the patients that fulfilled KCH criteria, 66.9% survived,

and of those that did not, 11.8% died. Hence, although specificity for mortality was similar to adult

ALF, sensitivity was lower, at 61%. Missing data, in particular for HE, was a significant limitation to

this study. Several other studies have applied KCH criteria to PALF groups, however, results are
33
difficult to interpret due to small or non-heterogenous cohorts. Ciocca et al demonstrated

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sensitivity and specificity of 72% and 96% respectively, for mortality without LT in their large cohort

(n=210), but infants were excluded and aetiology was dominated by Hepatitis A.

MELD/PELD. The Pediatric End-stage Liver Disease (PELD) score, was derived in 2000, from a

multicentre North American database, in order to aid allocation and prioritisation of LT to children
36
(up to 12 years old) and infants listed with end stage liver disease . It incorporates SBR, INR,

albumin and age and growth failure. It has been validated and approved for use in organ allocation

in many countries outside of USA. After 12 years of age, the MELD scoring system has been

validated. PELD-MELD score at different time-points (admission, PALF diagnosis, peak) was applied

to a small cohort of PALF patients 37 at a single centre in Australia (n=54, median age 17 months, 1

day-15.6 years). Scores were significantly different between spontaneous survivors and non-

transplant death at diagnosis and peak values, but not at admission. Construction of AUC-ROC curves

demonstrated that PELD-MELD score cut-offs >27 and >42 at PALF diagnosis led to sensitivity of 76

and 66% and specificity of 60 and 92% respectively. Another recent study 38, in a small PALF cohort,

demonstrated good sensitivity (86%) and specificity (81%) for poor outcome with a cut-off value of

33. However, missing data, increased prevalence of hepatitis A (43%) and AIH (17.5%) and combined

LT/death as one outcome measure are significant limitations.

Liver Injury Units (LIU). Single centre retrospective analysis in a cohort of PALF patients (n=81)

revealed that peak bilirubin, INR (or PT) and ammonia were significantly associated with death/LT 39.

A score called ‘Liver Injury Units’ (LIU) was developed by weighting the peak values of these

parameters by coefficients obtained from the Cox regression. The score derived from this formula

was stratified into risk categories for likelihood of death or LT (low risk ≤ 85; moderate risk 85-138;

high risk > 139). High specificity and sensitivity of the LIU score for predicting death/LT was
40
demonstrated by an AUC-ROC 90.5%. Lu et al subsequently validated this score internally on

retrospective analysis of a subsequent group of children (n=53). The transportability of this score to

a larger, more heterogenous population (n=461), was assessed by application to the PALF Study

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41
database . In contrast to the preceding studies, LT and death alone were assessed as separate

outcome measure, in addition to the combined death/LT parameter. AUC-ROC values for LIU score

prediction of death/LT, LT alone or death alone was 0.81, 0.84 and 0.76 respectively. Although this

scoring model contains measurable, objective parameters and demonstrates good specificity and

sensitivity for predicting death/LT in the derivation, internal and external validation cohorts, several

limitations exist. The model is only accurate at predicting death or LT, not death alone, which would

be a more reliable outcome measure. Also the model was derived for peak laboratory values,

irrespective of day (i.e. no specific time-point), and score values were divided into low/moderate

and high-risk categories, which would be challenging to apply on a practical, day-to-day level.
41
Admission LIU scores were not predictive of death/LT. Lu et al sought to use the score in a

dynamic way, by calculating the highest daily LIU score within the 21 days of enrolment. Good

discrimination for death/LT (AUR-ROC 0.81) was revealed on using the highest values. Although a

dynamic role for LIU score is suggested, the limitations of using enrolment rather than admission

data, must be considered. In addition, neither age, nor aetiology is incorporated into the model, and

in fact, stratification by age revealed that the LIU score was not reliable in early infancy. To our

knowledge, LIU score is not currently in clinical use.

KCH revised Wilsons index. PALF, is a heterogenous condition, with aetiology-specific therapies and

outcomes. Hence, aetiology- specific prognostic models may be more appropriate than an overall

PALF model. Wilson’s Disease (WD) is autosomal recessive, predominantly presenting in childhood

and early adulthood, characterised by an accumulation of copper in various organs, leading to

hepatic or neuropsychiatric manifestations in the majority of patients. This abnormality of copper

metabolism is a result of a mutation in the ATP7B gene located on the long arm of chromosome 13
42
. In children, WD usually manifests after 3 years of age, with either an incidental finding of

abnormal liver function, chronic liver disease or rarely, as PALF. The rarity of WD associated PALF is

illustrated in the PALF Study database, where only 3% of PALF was secondary to WD 2. WD,
2, 42
presenting with acute decompensation, and associated with HE, has a near-100% mortality .

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Likewise, some patients with acute decompensation, but without encephalopathy, succumb to LT.

The challenge over the past 3 decades, had been to understand who will respond to copper

chelation therapy, and to calculate the risk of mortality in WD PALF not associated with HE, in order

to optimize organ allocation. Nazer et al43, identified SBR, AST and PT as prognostic parameters in

WD ALF, in a small cohort of both adult and paediatric patients at KCH. Dhawan et al 42, at the same

centre, improved the prognostic power of this score, by performing multivariate and ROC curve

analysis in 57 children with WD presenting with acute decompensation, between 1967-2000.

Leukocyte count (WCC) was identified as an additional prognostic marker. Table 2. demonstrates the

incorporation of these parameters into a ‘revised Wilson’s Index’. At a cut-off value ≥ 11, sensitivity

and specificity of 93 and 97% for mortality prediction was achieved, respectively. The revised

Wilson’s Index has been prospectively validated and is widely used in children, including parts of the

developing world. It has also been validated in adult cohorts 44.

Intensive Care scoring in PALF

It is well established, in both adults and children, that ALF is a complex multi-organ illness, and that

mortality increases with severe sepsis and multi-organ failure 45. In an attempt to improve current

prognostic scores, several groups have studied the efficacy of established intensive care unit (ICU)

predictive models, as a means to grade adult ALF and PALF severity. The Acute Physiology and

Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) are
46, 47
validated adult ICU-specific prognostic scores developed from general ICU populations . Both

scores have been validated in patients with cirrhosis 48. Mixed results are available when applying
49
these models to ALF. Cholangitas et al applied APACHE II and SOFA to a single-centre large cohort

(n=125) of PCM-induced ALF. Discrimination between survival and LT/death was better in SOFA

(AUC-ROC 0.79) than KCH criteria, although KCH criteria had higher specificity. Similarly, in

paediatrics, a wide range of general ICU-scoring systems exist; Paediatric Risk of Mortality (PRISM)

and Paediatric Index of Mortality (PIM) have been widely established and validated in conditions

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such as sepsis, meningococcal disease, cardio- and respiratory failure 50. PRISM, first published by

Pollack et al 50 in 1987, is a 14-point score, based on clinical and laboratory parameters, including 23

ranges, and accounting for infants and children separately. Several attempts at applying this score to
51
PALF, have yielded varied results. Admission PRISM scores at a French centre, for a large

heterogenous group of PALF (n=109), did discriminate between survivors and death/LT groups, but

observed and PRISM score based expected mortality demonstrated poor calibration. Matthews et al
52
applied a revised version of the PIM score, PIM2, to assess surival outcomes in PALF, utilising the

PALF Study Database (n=103) cohort. The AUC-ROC for mortality in the non-transplanted patients

was only 0.712, which would not be sensitive or specific enough to minimize the risk of unnecessary

transplantation. Currently, ICU-scoring systems, do not confer extra advantage to PALF prognostic

models, but in conjunction with established PALF criteria, physiological and inflammatory

parameters may add additional accuracy.

Newer prognostic strategies

PALF comprises immune activation and inactivation, apoptosis and liver regeneration, which can all

variably affect its outcome. Biomarkers incorporating these processes are being researched for their

role in prognosis. In adult ALF, IL6 and IL853 and soluble CD154 have been associated with

mortality54. In paediatrics, Bucuvalas et al 55

demonstrated a role for soluble IL2Ra in predicting a

poorer prognosis of PALF. Biomarkers of regeneration, detectable at the time of presentation, might

help determine the likelihood of spontaneous recovery. Specific amino acids and elevated levels of

alpha-fetoprotein, have been associated with native liver survival in PALF, and, studies suggest there
56-58
may be a role for growth factors in prognosis . Conversely, cell death markers have been

investigated as potential prognostic variables for poor outcome. The US ALF Study group59 reported

that the addition of the apoptosis marker M30 of the CK18 molecule improved sensitivity of the KCH

criteria to 86% but specificity was reduced to 69%. In paediatrics, an increased level of M30 epitope

of CK18 in WD PALF compared to chronic presentation of WD60 has been demonstrated.

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 Liver Transplantation Page 16 of 27

Conclusions

Early identification and diagnosis in PALF is paramount, with rapid initiation of disease specific, and

overall supportive therapy. Dynamic prognostic scoring systems for PALF are important for

emergency LT allocation, but must incorporate optimal accuracy before use. To date, no optimal

PALF prognostic model exists, therefore, organ allocation should be based on clinical and

biochemical assessment, adjusted for age and aetiology, as well as taking into consideration any

contraindications for LT. Neither adult nor chronic liver disease-derived scores are suitable for PALF.

The revised Wilson’s Index can be reliably utilised in WD PALF. We suggest that there is an urgent

need for further aetiology and age specific scoring systems, with potential inclusion of physiological,

inflammatory and metabolomic parameters.

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 Liver Transplantation Page 20 of 27

Pre-LT Post-LT
80
72 73.4
70

60 58 56
%
50 SNL

40 Death
31
30 28 28 LT
22
20 15 13
10 4.6
0
1969-1977 1985-1993 1999-2004 2008-2012

Western Hemisphere
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Page 21 of 27 Liver Transplantation

Model Development
Relevant
will model aid medical decisions?
Validation
Population
Internal
The ideal large, represent diseased cohort

prognostic Variable (s)

model measurable, objective, few Temporal
Outcome
well defined
External
Accurate
(a) calibration, (b) discrimination

(a) Calibration (b) Discrimination

40
1
35
observed mortality %

30
ROC
True
25 +ve
20 rate
15 AUC 0.8
10 Goodness to fit
5
0 0
0 10 20 30 40 50 John Wiley & Sons, Inc.
Predicted mortality % This article is protected by copyright. All rights
0 reserved.
False +ve rate 1
 Liver Transplantation Page 22 of 27

Kings College Hospital Criteria

Non-PCM PCM
• Any grade HE and INR ≥ 6.5 • Arterial pH < 7.3 (after adequate
fluid resuscitation)
OR any three of; OR combination of;
• INR > 3.5 • HE ≥ III
• SBR ≥ 300 μmol/l • Creatinine ≥ 300 μmol/l
• Age < 10 or >40 years • INR > 6.5
• Unfavourable cause (DILI,
indeterminate) Lactate >3.0 [Bernal et al. Lancet 2002]

Clichy-Villejuif Criteria
Presence of HE
AND
Factor V level;
< 20% of normal in patients < 30 years old
OR
< 30% of normal in patients > 30 years old
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Page 23 of 27 Liver Transplantation

Age
Presentation
Retrospective validation Aetiology Incorporation bias
Missing data

Incorporation of
Calibration and ICU/ELSS, blood
discrimination cut-offs product interventions

Challenges
Outcome?
In Timepoint?(i)Admission
(i) LT/Death PALF (ii)Peak
(ii) Death alone (iii) multi-centre study
prognosis enrollment

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 Liver Transplantation Page 24 of 27
AIH
(a)
Misc 9% < 90 days < 5 years > 5 years
Indeterminate Haemophagocytic
31% Lymphohistiocytosis Metabolic
Viral 11% Herpes Simplex Virus Metabolic
Autoimmune
Hepatitis
NH
Wilson’s Disease
Metabolic
Metabolic
11%

NH Infection
Drugs
8% Indeterminate

Likely to recover
PCM
(b) Ischemic
spontaneously
Hepatitis A
Indeterminate
Idiosyncratic drug reaction Unlikely to survive
Autoimmune Hepatitis without LT
Wilson’s Disease
Mitochondrial diseases
Haemophagocytic Lymphohistiocytosis
Herpes Simplex Virus John Wiley & Sons, Inc.
Unlikely to survive or
benefit from LT
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Page 25 of 27 Liver Transplantation

Variable % mortality Variable % mortality

Age < 2 years 96 Any 1 variable 76

Peak INR ≥ 4 93 Any 2 variables 93

Peak SBR ≥ 235 μmol 92 Any 3 variables 96

WBC ≥ 9 x109/l 93 Any 4 variables 100

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 Liver Transplantation Page 26 of 27
Study N Aetiology <1y Laboratory Timepoint Clinical Outcomes (%) Predictive ability
r 1 2 3 Comments
Psacharopoulos 31 Mixed Y PT>90s peak HE severity 28 72 - • PT (cut off 90s) statistically
et al. 83% HBV different group 1 vs 2
1980, UK (5) • HE Grade IV

Bhadhuri et al abstract Y INR > 4 peak • 16.6% LT-free survival in INR > 4
1996, UK (31)

Lee et al 97 Mixed, Y PT > 55s admission Symptoms to HE 33 26 41 • All independent prognostic

2004, UK (24) 37% ALT ≤ 2384 IU/l >7d parameters for death/LT
indeterminate

Dhawan et al. 44 Mixed Y INR ≥ 4 peak Age < 2 66 34 - • All independent prognostic
2004, UK (27) SBR ≥ 235 μmol/l HE or no HE parameters for death or survival
WCC ≥ 9 x 109/l HE I/II vs III/IV • Presence of HE not significant
• HE I-II and III-IV mortality risk 44%
and 78% respectively (p=0.002)

Squires et al. 348 Mixed Y INR ≥ 2.55 Admission Gender 56 13 31 • INR, SBR and HE independent
2006, 49% SBR ≥ 5mg/dL and peak HE or no HE prognostic factors for death/LT
US/Canada/UK indeterminate HE III and IV • HE III 33% and HE IV 22% survival
(2) 14% PCM • F>M
10% metabolic

Ciocca et al 210 Mixed Y INR > 4, PT < 22% peak HE III/IV 28 29 43 • Univariate analysis; FV, PT/SBR/HE
2008, Argentina 61% HAV SBR > 17 mg/dL III-IV significantly different for all 3
(2 centres) (33) 32% FV < 30 groups
indeterminate • Multivariate analysis; SBR/INR/HE
III-IV independent predictors for
death/LT and SBR/PT/HE III-IV for
death

Table 1 Paediatric studies identifying prognostic variables for PALF. Outcomes 1. Survival with native liver (SNL) 2. Death without LT 3.
LT

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Page 27 of 27 Liver Transplantation

Score Bilirubin INR AST WCC Albumin

μmol/L (IU/L) (109/L) (g/L)
0 0-100 0-1.29 0-100 0-6.7 >45
1 101-150 1.3-1.6 101-150 6.8-8.3 34-44
2 151-200 1.7-1.9 151-300 8.4-10.3 25-33
3 201-300 2.0-2.4 301-400 10.4-15.3 21-24
4 >301 >2.5 >401 >15.4 <20
Table 2 Revised KCH Wilson’s Index. Adapted from Dhawan et al 42

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