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Never too late and never too soon: how to decide to list a patient with ALF and the role of
hepatological and ICU scores
18th
AISF Pre-Meeting Course “Update on the Management of Acute Liver Failure”
Aula Magna, Università di Roma “Sapienza” - P. le A. Moro, 5 Rome, February 17th, 2016
Stefano Ginanni Corradini
Liver Transplant Unit Sapienza Università di Roma
Stefano Ginanni CorradiniSapienza Università di Roma
Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione
e
che la presentazione non contiene discussionedi farmaci in studio o ad uso off-label
� THE CURRENTLY USED PROGNOSTIC SCORES
� THE FUTURE PROGNOSTIC SCORES
Which patient with ALF should be transplanted and when ?
“there are two approaches to listing patients with ALF for liver transplantation:
a) list all patients with encephalopathyand make the decision at the time a donor organ
becomes available
a) use some set of indicators of a poor prognosis without liver transplantation
O’Grady J Best Practice & Research Clinical Gastroenterology 2012; 26: 27-33
• in Italy the mean (± SD) waiting time until organ offer was 11± 18 hours in 2015 (CNT data)
• In UK is nowadays possible to list patients with ALF without encephalopathy for super-urgent transplantation
1. failure to list a patient with ALF for liver tran splantation who subsequently dies
[“TOO LATE!”] is a visible and regrettable event
2. transplanting a patient who would likely have survived [“TOO SOON!”] is a much
less visible but equally regrettable outcome
Hepatic Encephalopathy: is that enough? Is it a “condition sine qua non?”
USA (UNOS)• Status 1A : Fulminant liver failure, without
pre-existing liver disease and currently in the intensive care unit (ICU), defined as the onset of hepatic encephalopathywithin 56 days of the first signs or symptoms of liver disease, and has at least one of the following criteria:
i. Is ventilator dependent ii. Requires dialysis, continuous veno-
venous hemofiltration (CVVH), or continuous veno-venous hemodialysis (CVVHD)
iii. Has an international normalized ratio (INR) greater than 2.0
• Data suggest that pediatric cases can be listed without developing HE
HEPATOLOGY2008;47:1401-1415Donnelly MC et al. Liver Transpl 2016 Jan 28
http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf#nameddest=Policy_09
VariablesKing's College Criteria (KCC)Acetaminophen
King's College Criteria (KCC)
Non-Acetaminophen
Clichy-Villejuif
MELD ALFSG APACHE II SOFA
Age X X X
Etiology X
Encephalopathy X X X X X
Onset of encephalopathy X
Arterial pH X X
Arterial lactate X (modified KCC)
Factor V X
PT-INR X X X X
Serum creatinine X X X X
Serum bilirubin X X X X
Serum sodium and potassium X
Serum phosphorus X
Serum M30 (hepatocyte apoptosis) X
White blood cell count X
Hematocrit X
Platelet count X
Serum alanine aminotransferase
Serum cholinesterase
Vital signs (BT, BP, HR, RR) X X
Oxygenation X X
Mechanical ventilation X
Vasopressors X
Urine output X
Acute kidney insufficiency X
ALF prognostic scores (hepatological vs ICU)
Abbreviations: ALFSG, acute liver failure study group; APACHE , acute physiology and chronic health evaluation; BT, body temperature; BP, blood pressure; HR, heart rate; MELD , model for end-stage liver disease; PT-INR , prothrombin time-international normalized ratio; RR, respiratory ratio; SOFA, sequential organ failure assessment
� many studies equate liver transplantation with death (falsely elevates the
positive predictive value of scoring systems)
� inconsistencies in reproducibility and prognostic accuracy
� the many causes of ALF have different clinical courses
� spontaneous survival rates have improved over time for
many etiologies; however prognostic models have not
been adapted to account for this
Bias in the literature of ALF prognostic scores
Hepatology 1986;6:648-651
� the Clichy criteria could be improved (a
prospective study is needed) incorporating:
• serum bilirubin (≥ 200 µmol/L) and
creatinine clearance (< 60 mL/minute/1.73
m2) for Acetaminophen ALF
• serum bilirubin (≥ 200 µmol/L) for Non-
Acetaminophen ALF
� As currently applied the Clichy criteria
appear to have a limited prognostic capacity
Liver Transpl 2015;21:512-523
The Clichy-Villejuif (CV) to predict outcome in patients with ALF
Gastroenterology 1989; 97:439-445
Etiology Sensitivity Specificity DOR AUCCraig 2010Systematic review
Acetaminophen ALF 58.2% 94.6% 27.7 0.91
Cholongitas 2012Retrospective analysis
Acetaminophen ALF 47% 83% - 0.65
McPail 2015Meta-analysis
Acetaminophen ALF 58% 89% 10.4 -
McPail 2010Meta-analysis
Non-Acetaminophen ALF
68% 82% 12.6 -
McPail 2015Meta-analysis
Non-Acetaminophen ALF
58% 74% 4.2 -
King’s College Criteria (KCC) to predict outcome in patients with ALF
Abbreviations: DOR, diagnostic odds ratio (the ratio of the odds of the test being positive if the subject has the disease relative to the odds of the test being positive if the subject does not have the disease); AUC, area under the curve
Lancet 2002;359:558-63
Updated criteria to list a patient with ALF in UK for sup er-urgent liver transplantation:encephalopathy is not a “condition sine qua non”
http://www.odt.nhs.uk/pdf/Super_Urgent_Liver_FRM4324_DRAFT_v2.pdf. Accessed 03/08/2015
Donnelly MC Liver Transpl 2016 Jan 28
http://www.odt.nhs.uk/pdf/Super_Urgent_Liver_FRM4324_DRAFT_v2.pdf. Accessed 03/08/2015
Donnelly MC Liver Transpl 2016 Jan 28
Updated criteria to list a patient with ALF in UK for sup er-urgent liver transplantation:encephalopathy is not a “condition sine qua non”
The Acute Liver Failure Study Group (ALFSG) index to predict outcomein patients with mixed etiologies ALF
GASTROENTEROLOGY 2012;143:1237–1243
AUROC P (ALFSG vs other criteria)
ALFSG Index derivation set 0.822
KCC derivation set 0.654 0.002
MELD derivation set 0.704 0.001
ALFSG Index validation set 0.839
KCC validation set 0.684 0.003
MELD validation set 0.717 0.0005
ALFSG Index (mixed etiologies):• sensitivity 81%• specificity 72% GASTROENTEROLOGY 2013;144:e25– e26
Same accuracy of ALFSG Index vs
APACHE II and SOFA(However 76% with
Acetaminophen ALF)
Low sensitivity:
number of true positivesnumber of true positives + number of false negatives
=number of true positives
total number of affected individuals in population
A certain number of patients not meeting criteriado not survive (increases the risk of failure to lista patient who subsequently die)
Sensitivity is the probabilityof a positive test given thatthe patient has the disease
High specificity:
number of true negativesnumber of true negatives + number of false positives
=number of true negatives
total number of well individuals in population
↓
Patients fulfilling the criteria are very likely to die ifthey do not receive a transplant (reduces the risk of‘unnecessary transplantation’ in a patient who was likely to recover spontaneously)
Specificity is the probabilityof a negative test given thatthe patient is well
↑
Unpublished data Sapienza Liver Transplant Unit
0
10
20
30
40
50
60
70
80
Spontaneous Survival Transplanted Death without Transplant
France (1997-2010) USA (1998-2007) UK KCH (2004-2008) Sapienza Italy (2006-2015)
%
Journal of Hepatology 2013vol. 59j 74–80
LIVER TRANSPLANTATION 21:512–523, 2015 Hepatology. 2008 April ; 47(4): 1401–1415
Outcome of patients with ALF admitted to the ICU
King’s College criteria(lower sensitivity =avoidable deaths)
Clichy-Villejuif criteria
(lower specificity =unnecessary
transplantations)
� First meta-analysis comparing outcome prediction in ALF of KCC and MELD
� No publication bias
� Caution because particular heterogeneity for MELD related to differing thresholds for poor outcome despite
analysis to explore threshold effects (summary receiver operator curve: sROC)
� Lack of MELD data on each patient → impossible to calculate a pooled MELD cut-off value and make a
combined model of MELD and KCC
� MELD may give improved prognostic accuracy in Non-Acetaminophen ALF
� Neither KCC nor MELD are optimal in all circumstances so there remains an urgent need for more
accurate outcome prediction systems in ALF
Meta-analysis comparing predictive scores for ALF prognosis:King’s College Criteria (KCC) vs MELD
Abbreviations: DOR, diagnostic odds ratio (the ratio of the odds of the test being positive if the subject has the disease relative to the odds of the test being positive if the subject does not have the disease); AUC, area under the curve
Sensitivity Specificity DOR AUC
KCC all patients 59% 79% 5.3 0.762MELD all patients 74% 67% 7.0 0.782
KCC Acetaminophen ALF 58% 89% 10.4 -MELD Acetaminophen ALF 80% 53% 6.6 -
KCC Non-Acetaminophen ALF 58% 74% 4.2 -MELD Non-Acetaminophen ALF 76% 73% 8.4 -
McPhail MJ Clin Gastroenterol Hepatol 2015 Oct 20
Prognosis in patients with ALF
Physiopathological factors affecting prognosis in patients with ALF
Severity of liver injurySeverity of systemic inflammatory
response syndrome (SIRS)
Severity of compensatory anti-inflammatoryresponse syndrome (CARS)
Severity of cerebral edema
Severity of multisystemorgan failure (MOF)
Kamath PS Clin Gastroenterol Hepatol 2015 Dec 24
The Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores
The SOFA score to predict outcome in patients with AcetaminophenALF
Aliment Pharmacol Ther 2012;35:705–713
KCC, MELD and SOFA assessed dynamically
� THE FUTURE PROGNOSTIC SCORES
(Better accuracy in the new treatment era)
• Acetaminophen, mushroom and Non-Acetaminophen with grade I-II Encephalopathy→ N-
acetylcysteine (NAC)
• HBV → nucleos(t)ide analogues
• HEV → Ribavirin
• Wilson D. (without encephalopathy) → penicillamine or trientine
• Autoimmune Hepatitis low grade encephalopathy, MELD <27 → steroids
• DILI with “drug rash with eosinophilia and systemic symptoms” syndrome or autoimmune
reaction → steroids
• Budd-Chiari Syndrome → TIPS or hepatic vein stenting
• Alcoholic hepatitis → steroids
• Acute fatty liver of pregnancy and “hemolysis, elevated liver enzymes, low platelets”
(HELLP) syndrome → early delivery of the fetus
• Ischemic hepatitis→ cardiovascular support and resuscitative measures
• Infection, Systemic Inflammatory Response Syndrome (SIRS) and cerebral edema
→ CVVH, antibiotics, mannitol , hypertonic saline, therapeutic hypothermia, ICP
monitoring
→ High-volume (15% of ideal body weight) plasma exchange (plasmapheresis with fresh
frozen plasma) within 24 hours from encephalopathy grade II development
Larsen FS J Hepatol 2016 64;69:78Donnelly MC Liver Transpl 2016 Jan 28
Non-transplant management options of ALF and future prognosic scores
VariablesKing's College Criteria (KCC)Acetaminophen
King's College Criteria (KCC)
Non-Acetaminophen
Clichy-Villejuif
MELD ALFSG APACHE II SOFA
Age X X X
Etiology X
Encephalopathy X X X X X
Onset of encephalopathy X
Arterial pH X X
Arterial lactate X (modified KCC)
Factor V X
PT-INR X X X X
Serum creatinine X X X X
Serum bilirubin X X X X
Serum sodium and potassium X
Serum phosphorus X
Serum M30 (hepatocyte apoptosis) X
White blood cell count X
Hematocrit X
Platelet count X
Serum alanine aminotransferase
Serum cholinesterase
Vital signs (BT, BP, HR, RR) X X
Oxygenation X X
Mechanical ventilation X
Vasopressors X
Urine output X
Acute kidney insufficiency X
ALF prognostic scores (hepatological vs ICU)
Abbreviations: ALFSG, acute liver failure study group; APACHE , acute physiology and chronic health evaluation; BT, body temperature; BP, blood pressure; HR, heart rate; MELD , model for end-stage liver disease; PT-INR , prothrombin time-international normalized ratio; RR, respiratory ratio; SOFA, sequential organ failure assessment
Modified from Donnelly MC Liver Transpl 2016 Jan 28
Platelet count reduction day 2 vs day 7
(mixed etiologies)[Stravitz LT Clin Gastroenterol Hepatol
2015 Dec 10]
Changes (admission vs day 3) in serum AFP
(mixed etiologies)[Schiødt FV Liver Transpl. 2006 12:1776-81]
Monocyte HLA-DR ≤ 15%(Acetaminophen)
[Antoniades GC. Hepatology. 2006 44:34-43]
More recent ALF prognostic variables / scores
2012
2011
2007
2007
2012
2013
2011
2015
2005
2000
2009
Serum Galectin-9 (DILI)
[Rosen HR Clin GastroenterolHepatol 2015 Oct 20]
(mixed etiologies)
(mixed etiologies)
(mixed etiologies)
(APAP-ALF)
(mixed etiologies)
(mixed etiologies)
(mixed etiologies)
(mixed etiologies)
Subjects were classified into latent subgroups based on the dynamic trajectories of several key clinical and laboratory measurements using growth mixture modeling (GMM), a multilevel random effect modeling framework
Dynamic trajectories of clinical and laboratory variables in pediatric patients with ALF of mixed etiologies
Li R J Pediatr. 2016 Jan 28
� Accuracy of previously validated prognostic scores for ALF is poor and undermined
by recently developed non-transplant management options of ALF [i.e. high volume
plasma exchange (HVP)] which have changed disease prognosis and the dynamic
applicability of scores
� Prospective studies (with standardized hepatological/ICU management, including
HVP, and accurate patient stratification according to etiology) are needed to test
new composite scores (hepatological + ICU), even in the absence of encephalopathy,
which include also baseline and dynamic trajectories of serum bilirubin, creatine,
hepatocyte apoptosis serum markers, arterial lactate, platelet count,
(microparticles?), AFP, TSH and total thyroid hormones and liver volume
measurement
� In the meantime ….
Conclusions (1)
� ……. for Acetaminophen ALF use KCC and/or SOFA
� for Non-Acetaminophen ALF list the patient when grade II or greater
encephalopathy or any grade encephalopathy together with worsening over time of
MELD and/or liver volume
� Do this in a very frequent multidisciplinary (anesthesiologist, surgeon, etc…)
exchange
� Think that the decision is very difficult but that the hardest thing to do is ……
Conclusions (2)
� ……. explain everything to the patient’s relatives
� acceptable specificity (patients fulfilling the criteria are very likely to die without OLT)
� low sensitivity (some patients not meeting criteria do not survive)
� better performance in Acetaminophen than in Non-Acetaminophen ALF
� most effective if grade 3-4 encephalopathy
� reduced accuracy if criteria applied non-dynamically or dynamically in Centers with use of plasma
infusion
� In Acetaminophen ALF:
• better accuracy in studies originating from King’s College Hospital (KCH) vs those outside KCH
• decreased sensitivity with staggered vs single time point APAP overdose
King’s College Criteria (KCC) to predict outcome in patients with ALF
Unpublished data Sapienza Liver Transplant Unit
0
10
20
30
40
50
60
70
80
Spontaneous Survival Transplanted Death without Transplant
France (1997-2010) USA (1998-2007) UK KCH (2004-2008) Sapienza Italy (2006-2015)
%
Journal of Hepatology 2013vol. 59j 74–80
LIVER TRANSPLANTATION 21:512–523, 2015 Hepatology. 2008 April ; 47(4): 1401–1415
MELD criteria(higher sensitivity =
reducedavoidable deaths)
Outcome of patients with ALF admitted to the ICU
Different components of ALF definition used by the studies
Aliment Pharmacol Ther 2012;35:1245–1256
interval between HE and onset of liver disease• 19 studies did not report any interval
• 38 studies did not report how the absence of a pre-existing liver disease was determined
The MELD score to predict outcome in patients with ALF
HEPATOLOGY2007;45:789-796
Liver Int. 2007;27:329-34
The APACHE II and SOFA scores to predict outcome in patients with AcetaminophenALF
HEPATOLOGY2005;42:1364-13
KCC assessed only at entry (not dynamically)
HEPATOLOGY, Vol. 43, No. 4, 2006
LIVER TRANSPLANTATION 18:405-412, 2012
Is there a transplant benefit in patients with Acetaminophen-ALFnowadays ?
Larson AM Hepatology 2005;42:1364–1372
� patients with paracetamol-related ALF and placed on the waiting list who did not receive a
transplant had a survival rate of 52% (King’s College Hospital experience, with grade 3 or
4 encephalopathy ) and 59% (US Acute Liver Failure Group prospective study)
� patients listed for liver transplantation with paracetamol-related ALF had a 2.5-fold higher
risk of death on the waiting list as compared with other aetiologies (King’s College Hospital
experience)
� there is a 24% increase in risk of death after liver transplantation (suicide, trauma or non-
adherence to immunosuppression), mostly within 12 months of transplantation (ELTR)
� There is need of randomised controlled trials
Bernal W J Hepatol 2013;59:74–80
Bernal W J Hepatol 2009;50:306–313 Germani G J Hepatol 2012;57:288–296
Adults with sub-acute liver failure represent a subgroup thatarguably is disadvantaged by the need to demonstrable encephalopathy prior to being listed for liver transplantation. This moreindolent variant of ALF typically manifests a less severe derangement of coagulation, often with INR <2, as the serum bilirubin risesand the disease progresses. Infection is a well recognised trigger forworsening encephalopathy in ALF[57]. This observation is particularly pertinent in sub-acute liver failure because when the onsetof encephalopathy is precipitated by infection this may delay eligibility for liver transplantation or contribute to poorer outcomesafter transplantation. Earlier prediction of the poor outcome insub-acute liver failure to facilitate more timely intervention is currently an un-met need. At present, the best pre-emptive information may be liver volume, as a poor prognosis is suggested by aprogressive reduction as assessed by CT scanning. One study founda 97% death or transplantation rate when the liver volume was lessthan 1,000 ml
Un-met need: earlier prediction of poor outcome in sub-acute liver failure (Grossi)
≥2 SIRS components to predict outcome in patients with AcetaminophenALF
Aliment Pharmacol Ther 2011;34:219–228
SIRS and KCC assessed dynamically
• Lake previously reported that as many as 20% of patients with ALF may be
transplanted unnecessarily. A recent systematic review identified survival was 24% in
non-transplanted APAP-ALF patients meeting the Kings College Hospital Poor
Prognostic Criteria (KCC)
• Spontaneous survival rates have improved over time for many etiologies but
prognostic models have not been adapted
• There is a desperate need for better prognostic criteria to maximise the
transplant benefit afforded to patients with ALF
Which patient with ALF should be transplanted and when ?
“failure to list a patient with ALF for liver trans plantation who subsequently dies is a
visible and regrettable event, but transplanting a patient who would likely have survived
is a much less visible but equally regrettable outcome”
Hepatology 1995;21:879-882
O’Grady J Best Practice & Research Clinical Gastroenterology 2012; 26: 27-33
Aliment Pharmacol Ther 2010;31:1064-1076
� ALF and septic shock have striking similarities [systemic inflammatory response
syndrome (SIRS) and a compensatory anti-inflammatory response syndrome
(CARS), which predisposes to infection]
� Prognosis in ALF depends on severity of liver injury, as well as severity of SIRS,
CARS, cerebral edema and multisystem organ failure
� Prognostic scores predictive of mortality in ALF should consequently include many
or all these elements at entry, after initial resuscitation and later on as the disease
progresses
Kamath PS Clin Gastroenterol Hepatol 2015 Dec 24
why does the SOFA score, which is a non–liver-specific assessment of organ failure, discriminate better than liver-specific models for ACAP-induced ALF, and are patients who are identified in this way salvageable??
� ALF and septic shock have striking similarities. The salient features of ALF include
a systemic inflammatory response syndrome (SIRS) which follows the acute liver
injury, and a compensatory anti-inflammatory response syndrome (CARS) which
predisposes to infection. Studies from the Acute Liver Failure Study Group
demonstrate that in patients with acetaminophen-induced ALF (AALF), infection
and increased leukocyte count at admission are predictive of worsening hepatic
encephalopathy.
� By contrast, in patients with non-acetaminophen-related liver failure (NAALF),
infection may occur several days after progression of hepatic encephalopathy,
reflecting the higher risk of infection in patients with coma.
� Mortality increases in patients with severe sepsis and, in those patients who have
septic shock following ALF, mortality is inevitable. Thus, prognosis in ALF depends
on severity of liver injury, as well as severity of SIRS, CARS, cerebral edema and
multisystem organ failure. Prognostic scores predictive of mortality in ALF should
consequently include many or all these elements.
Kamath PS Clin Gastroenterol Hepatol 2015 Dec 24
Heterogeneity of definitions of ALF in the literature
Aliment Pharmacol Ther 2012;35:1245–1256
World J Gastroenterol 2016 January 28; 22(4): 1523-1531
The positive predictive value (PPV):
number of true positivesnumber of true positives + number of false positives
=number of true positivesnumber of positive calls
sensitivity x prevalencesensitivity x prevalence + (1- specificity) x (1- prevalence)
↑
↓
The negative predictive value (NPV):
number of true negativesnumber of true negatives + number of false negatives
=number of true negativesnumber of negative calls
specificity x (1- prevalence)(1- sensitivity) x prevalence + specificity x (1- prevalence)
↑
↓
High probability that a positive test (perform OLT! )will truly reflect the need for OLT
High probability that a negative test (do not perform OLT!)will truly identify which patient will survive with out OLT
PPV is the percentage of patientswith a positive test who actuallyhave the disease
NPV is the percentage of patientswith a negative test who do nothave the disease
� The criteria have a clinically acceptable specificity, in that patients fulfilling
the criteria are very likely to die if they do not receive transplants
�
� Sensitivity is less, as a certain number of patients not meeting criteria do not
survive
World J Gastroenterol 2016 January 28; 22(4): 1523-1531
World J Gastroenterol 2016 January 28; 22(4): 1523-1531
World J Gastroenterol 2016 January 28; 22(4): 1523-1531
World J Gastroenterol 2016 January 28; 22(4): 1523-1531
Accurate prognostic models are vital to identify those patients who are most
likely to benefit from emergency OLT, at a time when transplant is still
feasible
Similarly, the timely prediction of patients likely to survive spontaneously
prevents unnecessary OLT and long term immunosuppressant therapy
Spontaneous survival rates have improved over time for many etiologies;
however prognostic models have not been adapted to account for this
There is a desperate need for better prognostic criteria to maximise the
transplant benefit afforded to patients with ALF