45
Never too late and never too soon: how to decide to list a patient with ALF and the role of hepatological and ICU scores 18 th 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 17 th , 2016 Stefano Ginanni Corradini Liver Transplant Unit Sapienza Università di Roma

Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

Embed Size (px)

Citation preview

Page 1: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 2: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 3: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� THE CURRENTLY USED PROGNOSTIC SCORES

� THE FUTURE PROGNOSTIC SCORES

Page 4: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 5: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 6: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 7: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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

Page 8: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 9: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 10: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 11: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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”

Page 12: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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)

Page 13: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 14: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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)

Page 15: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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

Page 16: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 17: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

The Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores

Page 18: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

The SOFA score to predict outcome in patients with AcetaminophenALF

Aliment Pharmacol Ther 2012;35:705–713

KCC, MELD and SOFA assessed dynamically

Page 19: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� THE FUTURE PROGNOSTIC SCORES

(Better accuracy in the new treatment era)

Page 20: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

• 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

Page 21: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 22: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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)

Page 23: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 24: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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)

Page 25: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� ……. 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

Page 26: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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

Page 27: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 28: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 29: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

The MELD score to predict outcome in patients with ALF

HEPATOLOGY2007;45:789-796

Liver Int. 2007;27:329-34

Page 30: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 31: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 32: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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)

Page 33: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

≥2 SIRS components to predict outcome in patients with AcetaminophenALF

Aliment Pharmacol Ther 2011;34:219–228

SIRS and KCC assessed dynamically

Page 34: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

• 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

Page 35: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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??

Page 36: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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

Page 37: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

Heterogeneity of definitions of ALF in the literature

Aliment Pharmacol Ther 2012;35:1245–1256

Page 38: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

World J Gastroenterol 2016 January 28; 22(4): 1523-1531

Page 39: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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

Page 40: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

� 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

Page 41: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

World J Gastroenterol 2016 January 28; 22(4): 1523-1531

Page 42: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

World J Gastroenterol 2016 January 28; 22(4): 1523-1531

Page 43: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

World J Gastroenterol 2016 January 28; 22(4): 1523-1531

Page 44: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

World J Gastroenterol 2016 January 28; 22(4): 1523-1531

Page 45: Never too late and never too soon: how to decide to list a ... · • Budd-Chiari Syndrome → TIPS or hepatic vein stenting ... → CVVH, antibiotics, mannitol , hypertonic saline,

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