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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, Universit di Roma Sapienza - P. le A. Moro, 5 Rome, February 17th, 2016

    Stefano Ginanni Corradini

    Liver Transplant Unit Sapienza Universit di Roma

  • Stefano Ginanni CorradiniSapienza Universit di Roma

    Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto dinteresse 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 encephalopathy and make the decision at the time a donor organ

    becomes available

    a) use some set of indicators of a poor prognosis without liver transplantation

    OGrady 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 transplantation 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 encephalopathy within 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 mol/L) and

    creatinine clearance (< 60 mL/minute/1.73

    m2) for Acetaminophen ALF

    serum bilirubin ( 200 mol/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 -

    Kings 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 super-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 super-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;143:12371243

    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 ofunnecessary 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 7480

    LIVER TRANSPLANTATION 21:512523, 2015 Hepatology. 2008 April ; 47(4): 14011415

    Outcome of patients with ALF admitted to the ICU

    Kings 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:Kings 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