How to decide when to list a patient with acute liver failure for liver transplantation? Clichy or King’s College criteria, or something else?
2007; Elsevier BV; Volume: 46; Issue: 4 Linguagem: Inglês
10.1016/j.jhep.2007.01.009
ISSN1600-0641
Autores Tópico(s)Liver Disease Diagnosis and Treatment
Resumo1. IntroductionAcute liver failure (ALF) is characterized by massive acute injury to a previously healthy liver associated with development of hepatic encephalopathy. The same clinical syndrome occurring in patients with pre-existing “clinically silent” chronic liver diseases such as autoimmune hepatitis (AIH) or Wilson’s disease is, somewhat imprecisely, often also referred to as ALF. Depending on the time elapsed between appearance of jaundice and development of encephalopathy, ALF is often subdivided in hyperacute (0–7 days), acute (8–28 days) and subacute (29–84 days) forms [[1]O’Grady J.G. Schalm S.W. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 273-275Abstract PubMed Scopus (39) Google Scholar]. With an estimated annual incidence of 2000 cases in the US [[2]Lee W.M. Acute liver failure.N Engl J Med. 1993; 329: 1862-1872Crossref PubMed Scopus (553) Google Scholar], ALF is a relatively rare condition, but carries a short-term (3 week) mortality in excess of 40% [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. If the patient survived, however, the liver typically recovers fully, both structurally and functionally (except in the AIH and Wilson’s cases).Orthotopic liver transplantation (OLT) is the only therapy to date able to substantially alter the survival outcome in patients with ALF. In a recent prospective study, short-term survival of patients listed for OLT was 84% if transplantation was possible in a timely fashion (median within 3.5 days of listing), but only 35% if not [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. Transplantable livers are a scarce resource and OLT, while potentially life saving, carries relevant long-term morbidity and mortality. Appropriate selection of patients for OLT therefore requires tools allowing to accurately prognosticate spontaneous recovery (i.e.: without OLT) early-on during the course of ALF, when results of liver transplantation are best.Conceptually, prognosis in ALF depends on the net sum in time of processes leading to hepatocellular damage and those attempting repair [[4]Blei A.T. Selection for acute liver failure: have we got it right?.Liver Transpl. 2005; 11: S30-S34Crossref PubMed Scopus (45) Google Scholar]. In addition, development of complications, in particular increased intracranial pressure and multiorgan failure (often due to sepsis), affects outcome, cerebral herniation and sepsis remaining the most frequent causes of death in ALF [[5]Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (94) Google Scholar]. Thus, an ideal prognostic test should capture all these features with parameters readily available early during hospital admission and have a high predictive accuracy for death and survival without OLT. Unfortunately, even the best sets of prognostic criteria available today, the King’s College [[6]O’Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar] and the Clichy criteria [7Bernuau J. Goudeau A. Poynard T. Dubois F. Lesage G. Yvonet B. et al.Multivariate analysis of prognostic factors in fulminant hepatitis B.Hepatology. 1986; 6: 648-651Crossref PubMed Scopus (408) Google Scholar, 8Bismuth H. Samuel D. Castaing D. Adam R. Saliba F. Johann M. et al.Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.Ann Surg. 1995; 222: 109-119Crossref PubMed Scopus (278) Google Scholar], fall short of this ideal.2. Clinical factors associated with outcomeTransplant-free survival differs according to etiology of ALF [[1]O’Grady J.G. Schalm S.W. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 273-275Abstract PubMed Scopus (39) Google Scholar]. In a recent series of more than 300 consecutive ALF patients from 17 US centers, paracetamol-induced and hepatitis A associated ALF, as well as shock liver, had transplant-free survival rates over 60%, whereas that of ALF secondary to idiosyncratic drug reactions, hepatitis B, Budd–Chiari syndrome autoimmune hepatitis, as well as ALF of undetermined etiology, ranged from 15% to 20%, only [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. Acute Wilson’s disease had a particularly low transplant-free survival rate (approaching zero) in this relatively recent series.O’Grady et al. have shown that transplant-free survival depends on the subtype of ALF [[1]O’Grady J.G. Schalm S.W. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 273-275Abstract PubMed Scopus (39) Google Scholar]. In general, the shorter the time interval between the onset of jaundice and encephalopathy the better the prognosis. Conversely, subacute liver failure where hepatic encephalopathy often develops only weeks after the onset of jaundice has a particularly low transplant free survival. In the recent US series, transplant-free survival of subacute liver failure was only 14%, compared to 30% for hyperacute and acute liver failure [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. The development of encephalopathy, i.e. reaching the diagnostic criteria for acute liver failure only late during the course of the disease, makes the decision/timing of transplantation particularly challenging in patients with subacute ALF. In selected cases with subacute liver failure, listing may therefore be warranted prior to development of encephalopathy, i.e. prior to fulfilling strict diagnostic criteria for ALF, but this strategy remains a matter of debate.Not too surprisingly, coma grade on admission has been found to be associated with poor outcome [3Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar, 9Bismuth H. Samuel D. Castaing D. Williams R. Pereira S.P. Liver transplantation in Europe for patients with acute liver failure.Semin Liver Dis. 1996; 16: 415-425Crossref PubMed Scopus (135) Google Scholar]. In the large US series, 52% of ALF patients with hepatic coma grades I–II on admission survived 3 weeks without transplant, whereas transplant-free survival dropped to 33% if hepatic coma had already reached stage III or IV on admission. An earlier study by Bismuth et al. also showed that mortality prior to OLT, the proportion of patients transplanted, 1-year survival after OLT, and overall 1-year survival are decreased with higher coma grades on admission [[9]Bismuth H. Samuel D. Castaing D. Williams R. Pereira S.P. Liver transplantation in Europe for patients with acute liver failure.Semin Liver Dis. 1996; 16: 415-425Crossref PubMed Scopus (135) Google Scholar]. This underscores the importance of early referral of ALF patients to a transplant center.Age above 40 and below 10 years has been reported to be associated with poor prognosis in ALF [[6]O’Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar]. The more recent data from the US, however, seem to modify this notion. Overall survival for all age groups (15 years or older) was relatively similar, ranging from 63% to 77%, and decreased to 33% only in the relatively (small number of) patients aged >65 years [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar].3. King’s College criteriaIn their seminal paper [[6]O’Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar], O’Grady et al. explored data from 588 patients with ALF treated between 1983 and 1985 at the Liver Unit of the King’s College in London, UK. Multivariate analysis of this large cohort of patients revealed that separate predictors for transplant-free survival apply to (a) paracetamol-induced and (b) non-paracetamol induced ALF (Table 1). The model was validated in an independent cohort of 175 ALF patients treated between 1986 and 1987 at the same institution. Positive predictive values (i.e. the observed mortality rate in those patients predicted to die) were 84% and 98%, negative predictive values (i.e. the observed survival rate in those patients predicted to survive) 86% and 82% for paracetamol-induced and non-paracetamol induced ALF, respectively. This translates into predictive accuracies of 85% and 95%. The King’s college criteria are based on simple parameters readily available at admission and are widely used for selecting ALF patients for liver transplantation worldwide. They are however derived from a cohort of patients treated now >20 years ago, and critical care management of ALF patients has made dramatic progress over the past two decades. This limitation is somewhat balanced by the fact that, since their first publication, the criteria have been validated in several, but not all [10Gow P.J. Smallwood R.A. Angus P.W. Paracetamol overdose in a liver transplantation centre: an 8-year experience.J Gastroenterol Hepatol. 1999; 14: 817-821Crossref Scopus (41) Google Scholar, 11Larson A.M. Polson J. Fontana R.J. Davern T.J. Lalani E. Hynan L.S. et al.Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.Hepatology. 2005; 42: 1364-1372Crossref PubMed Scopus (1446) Google Scholar], independent cohorts of patients suffering from ALF of paracetamol [12Anand A.C. Nightingale P. Neuberger J.M. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King’s criteria.J Hepatol. 1997; 26: 62-68Abstract Full Text PDF PubMed Scopus (189) Google Scholar, 13Shakil A. Kramer D. Mazariegos G. Fung J. Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria.Liver Transpl. 2000; 6: 163-169PubMed Google Scholar, 14Bernal W. Donaldson N. Wyncoll D. Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study.Lancet. 2000; 359: 558-563Abstract Full Text Full Text PDF Scopus (379) Google Scholar, 15Schmidt L.E. Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.Hepatology. 2002; 36: 281-286Crossref Scopus (187) Google Scholar] and non-paracetamol etiology ([12Anand A.C. Nightingale P. Neuberger J.M. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King’s criteria.J Hepatol. 1997; 26: 62-68Abstract Full Text PDF PubMed Scopus (189) Google Scholar, 13Shakil A. Kramer D. Mazariegos G. Fung J. Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria.Liver Transpl. 2000; 6: 163-169PubMed Google Scholar, 16Pauwels A. Mostefa-Kara N. Florent C. Levy V.G. Emergency liver transplantation for acute liver failure.J Hepatol. 1993; 17: 124-127Abstract Full Text PDF PubMed Scopus (183) Google Scholar]; for review, see also [[17]Riordan S.M. Williams R. Mechanisms of hepatocyte injury, multiorgan failure and prognostic criteria in acute liver failure.Semin Liver Dis. 2003; 23: 203-215Crossref PubMed Scopus (107) Google Scholar]). While not all of these studies showed as good predictive values as the original paper, they by-and-large confirmed that the King’s college criteria have a high positive predictive value (around 80% in paracetamol-induced ALF, 70–>90% in non-paracetamol cases). Their negative predictive value is however lower (70–90% in paracetamol-induced ALF, 25–50%, only, in non-paracetamol induced cases). Thus, adhering to the King’s college criteria allows identifying patients in need for a liver transplant with reasonable accuracy. Nevertheless, the criteria will select around 20% of patients for OLT, who might have survived without. More importantly perhaps, not meeting the criteria does not guarantee survival without a transplant, particularly in non-paracetamol cases.Table 1King’s College criteria for selection of ALF patients for liver transplantation (according to Ref. [6]O’Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar)Paracetamol-induced ALFArterial blood pH < 7.30 (irrespective of grade of encephalopathy)OR all of the following•Prothrombin time >100 s (INR >6.5)•Serum creatinine >300 μmol/L•Grade III or IV hepatic encephalopathyNon-Paracetamol induced ALFProthrombin time >100 s (INR > 6.5) (irrespective of grade of encephalopathy)OR any 3 of the following (irrespective of grade of encephalopathy)•Age 40 years•Etiology: non-A/non-B hepatitis, drug-induced•Duration of jaundice to encephalopathy >7 days•Prothrombin time >50 (INR > 3.5)•Serum bilirubin >300 μmol/L Open table in a new tab 4. Clichy criteriaBernuau et al. reported in 1986 on 115 patients with HBV associated ALF, mostly treated during the 1970s, and showed by multivariate analysis that factor V level, patient’s age, absence of HBsAg in serum and serum α-fetoprotein concentration were independent predictors of survival [[7]Bernuau J. Goudeau A. Poynard T. Dubois F. Lesage G. Yvonet B. et al.Multivariate analysis of prognostic factors in fulminant hepatitis B.Hepatology. 1986; 6: 648-651Crossref PubMed Scopus (408) Google Scholar]. These parameters were adopted by Bismuth et al. for selection of patients for OLT in patients admitted for ALF to the liver unit at Paul Brousse hospital in Paris between 1986 and 1991 [[8]Bismuth H. Samuel D. Castaing D. Adam R. Saliba F. Johann M. et al.Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.Ann Surg. 1995; 222: 109-119Crossref PubMed Scopus (278) Google Scholar]. The so called Clichy criteria are summarized in Table 2. Of 139 patients with ALF who met the criteria, 1 recovered, 22 died awaiting transplantation and 116 were transplanted with a 1-year survival of 81% in those receiving an ABO compatible whole liver graft without steatosis. This data seems to indicate that the Clichy criteria are able to select quite accurately the ALF patients requiring a liver transplant. They are widely used in France for that purpose. The study does however not allow drawing conclusions as to the mortality in those who did not fulfill the criteria.Table 2Clichy criteria for selection of ALF patients for liver transplantation (according to Ref. [8]Bismuth H. Samuel D. Castaing D. Adam R. Saliba F. Johann M. et al.Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.Ann Surg. 1995; 222: 109-119Crossref PubMed Scopus (278) Google Scholar)Presence of hepatic encephalopathyANDFactor V level of <20% (if patient’s age <30 years) OR <30% (if patient’s age ⩾30 years) Open table in a new tab A few studies only have attempted to directly compare the Clichy and the King’s college criteria (for review cf. 17). While confirming their prognostic value, the King’s college group reported that somewhat modified Clichy criteria had an inferior positive predictive value (observed mortality in those patients predicted to die without a transplant) to the King’s college criteria in a cohort of 81 non-transplanted patients with paracetamol-induced ALF and also, albeit less clearly, in a very limited number (n = 17) of non-paracetamol cases [[18]Isuzumi S. Langley P.G. Wendon J. Ellis A.J. Pernambuco R.B. Hughes R.D. et al.Coagulation factor V as a prognostic indicator in fulminant hepatic failure.Hepatology. 1996; 23: 1507-1511Crossref Google Scholar]. A recent meta-analysis of studies in paracetamol-induced ALF also showed that the King’s college criteria were more accurate in predicting outcome than other prognostic indicators [[19]Bailey B. Amre D.K. Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need fro liver transplantation.Crit Care Med. 2003; 31: 299-305Crossref PubMed Scopus (152) Google Scholar]. In another retrospective analysis of 81 non-transplanted patients with non-paracetamol induced ALF from France mortality was 81% [[16]Pauwels A. Mostefa-Kara N. Florent C. Levy V.G. Emergency liver transplantation for acute liver failure.J Hepatol. 1993; 17: 124-127Abstract Full Text PDF PubMed Scopus (183) Google Scholar]. The Clichy and King’s college criteria applied on admission had predictive accuracies of 60% and 80%, respectively, again suggesting superiority of the King’s college criteria.5. Other parameters of prognostic valueA number of further parameters have been studied and found to be of value in predicting transplant-free survival in ALF. Of those, serum lactate, particularly after fluid resuscitation, was shown to be a valuable predictor of transplant-free survival adding to the prognostic value of the King’s college criteria in paracetamol-induced ALF [[14]Bernal W. Donaldson N. Wyncoll D. Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study.Lancet. 2000; 359: 558-563Abstract Full Text Full Text PDF Scopus (379) Google Scholar]. Low serum phosphate concentrations were found to be predictive of survival in ALF in some [15Schmidt L.E. Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.Hepatology. 2002; 36: 281-286Crossref Scopus (187) Google Scholar, 20Chung P.Y. Sitrin M.D. Te H.S. Serum phosphate levels predict clinical outcome in fulminant hepatic failure.Liver Transpl. 2003; 9: 248-253Crossref PubMed Scopus (69) Google Scholar, 21Baquerizo A. Anselmo D. Shackleton C. Chen T.W. Cao C. Weaver H. et al.Phosphorous as an early predictive factor in patients with acute liver failure.Transplantation. 2003; 75: 2007-2014Crossref PubMed Scopus (72) Google Scholar], but not all [[22]Macquillan G.C. Seyam M.S. Nightingale P. Neuberger J.M. Murphy N. Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure.Liver Transpl. 2005; 11: 1073-1079Crossref PubMed Scopus (89) Google Scholar], studies. The extent of necrosis on (transjugular) liver biopsy [23Donaldson B.W. Gopinath R. Wanless I.R. Phillips M.J. Cameron R. Roberts E.A. et al.The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators.Hepatology. 1993; 18: 1370-1376Crossref PubMed Scopus (132) Google Scholar, 24Van Thiel D.H. When should the decision to proceed with transplantation be made in cases of fulminant or subfulminant hepatic failure: at admission to hospital or when a donor organ becomes available?.J Hepatol. 1993; 17: 1-2Abstract Full Text PDF PubMed Scopus (45) Google Scholar], liver volume assessed by CT [[24]Van Thiel D.H. When should the decision to proceed with transplantation be made in cases of fulminant or subfulminant hepatic failure: at admission to hospital or when a donor organ becomes available?.J Hepatol. 1993; 17: 1-2Abstract Full Text PDF PubMed Scopus (45) Google Scholar], the time course of serum α-fetoprotein concentration during the evolution of ALF [25Yang S.S. Cheng K.S. Lai Y.C. Wu C.H. Chen T.K. Lee C.L. et al.Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B.J Gastroenterol. 2002; 37: 626-632Crossref PubMed Scopus (46) Google Scholar, 26Schiodt FV, Ostapowicz G, Murray N, Satyanarana R, Zaman A, Munoz S, Lee WM and the Acute Liver Failure Study Group. Apha-fetoprotein and prognosis in acute liver failure.Google Scholar] and serum concentration of Gc-globulin [27Lee W.M. Galbraith R.M. Watt G.H. Hughes R.D. McINtire D.D. Hoffman B.J. et al.Predicting survival in fulminant hepatic failure using serum Gc protein concentrations.Hepatology. 1995; 21: 101-105PubMed Google Scholar, 28Schiodt F.V. Bondesen S. Petersen I. Dalhoff K. Otto P. Tygstrup N. Admission levels of Gc-glopulin: predictive value in fulminant hepatic failure.Hepatology. 1996; 23: 713-718PubMed Google Scholar, 29Schiodt F.V. Rossaro L. Stravitz R.T. Shakil A.O. Chung R.T. Lee W.M. Acute Liver Failure Study Group. Gc-globulin and prognosis in acute liver failure.Liver Transpl. 2005; 11: 1223-1227Crossref PubMed Scopus (53) Google Scholar], a short-lived, liver derived protein involved in scavenging of actin released by dying liver cells, have also been reported to carry prognostic value, at least in some forms/etiologies of ALF. The number of patients included in most of these studies was however relatively small limiting generalizability of the results. Further work and validation in independent patient cohorts would therefore be required to assess the value of these and other proposed etiology-specific and non-specific parameters/scoring systems [30Dabos K.J. Newsome P.N. Parkinson J.S.A. Davidson J.S. Sadler I.H. Plevris J.N. et al.A biochemical prognostic model of outcome in paracetamol-induced acute liver injury.Transplantation. 2005; 80: 1712-1717Crossref PubMed Scopus (29) Google Scholar, 31Madl C. Grimm G. Ferenci P. Kramer L. Yeganehfar W. Oder W. et al.Serial recording of sensory evoked potentials: a noninvasive prognostic indicator in fulminant hepatic failure.Hepatology. 1994; 20: 1487-1494Crossref PubMed Scopus (43) Google Scholar, 32Zaman M.B. Hoti E. Quasim A. Maguire D. McCormick P.A. Hegarty J.E. et al.MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.Transplant Proc. 2006; 38: 2091-2098Abstract Full Text Full Text PDF Scopus (52) Google Scholar, 33Miyake Y. Sakaguchi K. Iwasaki Y. Ikeda H. Makino Y. Kobashi H. et al.New prognostic scoring system for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.Transplantation. 2005; 80: 930-936Crossref PubMed Scopus (24) Google Scholar, 34Ganzert M. Felgenhauer N. Zilker T. Indication for liver transplantation following amatoxin intoxication.J Hepatol. 2005; 42: 202-209Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 35Elinav E. Ben-Doc I. Hai-AM E. Ackerman Z. Ofran Y. The predictive value of admission and follow up factor V and VII levels in patients with acute hepatitis and coagulopathy.J Hepatol. 2005; 42: 82-86Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] in prognosticating outcome in ALF, either alone or in conjunction with the King’s college or the Clichy criteria.6. ConclusionsCurrent criteria for selection of patients with ALF for OLT are far from being perfect. The King’s college criteria are probably the best validated tool currently available. While they allow identifying patients dying without a liver transplant reasonably well, they do worse in predicting survival in those patients never fulfilling the criteria. Appropriate selection and listing of patients with ALF for OLT therefore remains a challenge. This seems particularly true in subacute ALF where mortality is high, but many patients fulfill the diagnostic criteria for ALF, i.e. develop encephalopathy, only late in the course of the disease. Other parameters including factor V levels and serum lactate, and, importantly, clinical experience remain valuable adjuncts. Our tools for selecting patients with ALF for liver transplantation remain to be improved. This will require state-of-the-art outcome analysis of large cohorts of patients and will only be feasible through large multicentric consortia such as the Acute Liver Failure Study Group in the US. Moreover, tools to be developed in the future should predict not only mortality/survival without a transplant, but also capture survival after liver transplantation, i.e. allow to predict transplant benefit, in individual patients with ALF. 1. IntroductionAcute liver failure (ALF) is characterized by massive acute injury to a previously healthy liver associated with development of hepatic encephalopathy. The same clinical syndrome occurring in patients with pre-existing “clinically silent” chronic liver diseases such as autoimmune hepatitis (AIH) or Wilson’s disease is, somewhat imprecisely, often also referred to as ALF. Depending on the time elapsed between appearance of jaundice and development of encephalopathy, ALF is often subdivided in hyperacute (0–7 days), acute (8–28 days) and subacute (29–84 days) forms [[1]O’Grady J.G. Schalm S.W. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 273-275Abstract PubMed Scopus (39) Google Scholar]. With an estimated annual incidence of 2000 cases in the US [[2]Lee W.M. Acute liver failure.N Engl J Med. 1993; 329: 1862-1872Crossref PubMed Scopus (553) Google Scholar], ALF is a relatively rare condition, but carries a short-term (3 week) mortality in excess of 40% [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. If the patient survived, however, the liver typically recovers fully, both structurally and functionally (except in the AIH and Wilson’s cases).Orthotopic liver transplantation (OLT) is the only therapy to date able to substantially alter the survival outcome in patients with ALF. In a recent prospective study, short-term survival of patients listed for OLT was 84% if transplantation was possible in a timely fashion (median within 3.5 days of listing), but only 35% if not [[3]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H.B. et al.and the U.S. Acute Liver Failure Study GroupResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Int Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. Transplantable livers are a scarce resource and OLT, while potentially life saving, carries relevant long-term morbidity and mortality. Appropriate selection of patients for OLT therefore requires tools allowing to accurately prognosticate spontaneous recovery (i.e.: without OLT) early-on during the course of ALF, when results of liver transplantation are best.Conceptually, prognosis in ALF depends on the net sum in time of processes leading to hepatocellular damage and those attempting repair [[4]Blei A.T. Selection for acute liver failure: have we got it right?.Liver Transpl. 2005; 11: S30-S34Crossref PubMed Scopus (45) Google Scholar]. In addition, development of complications, in particular increased intracranial pressure and multiorgan failure (often due to sepsis), affects outcome, cerebral herniation and sepsis remaining the most frequent causes of death in ALF [[5]Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (94) Google Scholar]. Thus, an ideal prognostic test should capture all these features with parameters readily available early during hospital admission and have a high predictive accuracy for death and survival without OLT. Unfortunately, even the best sets of prognostic criteria available today, the King’s College [[6]O’Grady J.G. Alexander G.J. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar] and the Clichy criteria [7Bernuau J. Goudeau A. Poynard T. Dubois F. Lesage G. Yvonet B. et al.Multivariate analysis of prognostic factors in fulminant hepatitis B.Hepatology. 1986; 6: 648-651Crossref PubMed Scopus (408) Google Scholar, 8Bismuth H. Samuel D. Castaing D. Adam R. Saliba F. Johann M. et al.Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.Ann Surg. 1995; 222: 109-119Crossref PubMed Scopus (278) Google Scholar], fall short of this ideal.
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