The King’s prognostic criteria for patients with acute liver failure (ALF) introduced in 1989 have been used worldwide. This distinguished for the ﬁrst time cases with ‘hyper-acute’ course (characteristically paracetamol overdose) where there is a better chance of recovery with medical supportive care alone from those etiologies with a less acute course and paradoxically lower chances of ‘spontaneous’ recovery. Ongoing use showed the limited sensitivity of the criteria to constitute a signiﬁcant practical limitation. Subsequent models including the MELD score and composite ones with markers of necrosis, an apoptotic liver cell death, proposed to improve sensitivity did not have the required high speciﬁcity. Two recent models utilizing new availability of web- and app-based computing delivering outcome predication through sophisticated algorithms are described. The ﬁrst is a dynamic model described for paracetamol-induced ALF based upon admission ﬁndings and sequential variables over the ﬁrst 2 days. The new model of the US Acute Liver Failure group was devised to cover all etiologies of ALF for predicting ‘transplant-free’ survival and accurately predicated spontaneous survival in two-thirds of cases. Improved survival results with medical management, particularly in hyper-acute cases, now approach those obtained with successful liver transplant and have raised the question of transplant beneﬁt. Also considered in the review are new non-transplant approaches to treatment including the use of plasma exchange and based on successful results in acute-on-chronic liver failure, agents to modulate and improve hepatic regeneration. Keywords Acute liver failure King’s criteria Dynamic model ALFSG Plasma exchange Liver transplant Introduction and historical context would be transplanted who would otherwise have recov- ered with medical management alone; variously termed Difﬁculties in determining prognosis in patients with acute ‘transplant-free’ or ‘spontaneous’ survival. liver failure (ALF) from paracetamol hepatotoxicity have The description of the King’s College Criteria (KCC) in been apparent for many years. Initial issues related to the 1989 represented a major step forward in identifying can- difﬁculties in identifying those patients with paracetamol didates for liver transplantation (Text Box 1) . It stres- intoxication who would beneﬁt from antidotal therapy . sed the importance of etiology and mode of presentation in The need for accurate predictive tests of patient outcome the outcome of ALF, recognizing the chances of recovery became even more apparent when the life-saving procedure with medical supportive care alone with rapidly evolving of liver transplant for patients with ALF was introduced in paracetamol hepatotoxicity as being much higher than with the early 1980. Concerns were raised that some patients other etiologies of ALF, particularly those with illness of more gradual onset. Derived and validated in a cohort of 763 patients managed before the introduction of trans- & Roger Williams plantation for ALF, the high speciﬁcity of the KCC meant email@example.com that relatively few cases fulﬁlling criteria would be 1 unnecessarily transplanted. However, their sensitivity was The Institute of Liver Studies, Cheyne Wing, King’s College lower, indicating that a signiﬁcant number of cases not Hospital, Denmark Hill, London SE5 9RS, UK fulﬁlling criteria would progress and die without earlier The Institute of Hepatology London and Foundation for Liver identiﬁcation and consideration for possible liver trans- Research, 111 Coldharbour Lane, London SE5 9NT, UK plantation. For the non-paracetamol cases, both sensitivity Faculty of Life Sciences & Medicine, King’s College, and speciﬁcity were high but within this overall group, London, UK 123 Hepatology International (2018) 12:204–213 205 certain etiologies with rapid illness onset—speciﬁcally These changes in the spectrum of complications and ischemic hepatitis, acute fatty liver of pregnancy and improvement in survival have since been documented in hepatitis A—had similar survival rates with medical man- other large historical series [8–10]. agement alone to that of paracetamol-induced cases. It was In this review, we will consider: ﬁrst, the basis of in those cases with an indolent presentation and ‘sub-acute’ prognostic assessment systems in ALF and the practical phenotype and often ‘indeterminate’ etiology that had the difﬁculties in their application, with focus upon the KCC as worst outcome without transplantation . an example of a system in current use. Second, the improved results currently being obtained with liver Text Box 1 transplantation in these very sick patients are described and third, how new approaches to treatment may impact upon The original Kings College Criteria for poor prognosis in future care and outcome. Acute Liver Failure. Paracetamol: pH<7.3 (irrespective of grade of encephalopathy) Improving prediction of outcome or Prothrombin time >100 s and serum creatinine >300 µmol/L In patients with grade III or IV encephalopathy. A number of different systems are in current use for the evaluation of prognosis in patients with ALF, with clinical Non-paracetamol: experience of their application and operational perfor- Prothrombin time >100 s (irrespective of grade of encephalopathy) mance reported for the KCC and criteria from France and Or Japan [2, 10–12]. Though details of the models used vary, Any 3 of the following variable (irrespective of grade of they share common features (Table 1). All recognize the encephalopathy) key importance of the development of encephalopathy as a Age <10 or > 40 years Etiology –non A, non B hepatitis, halothane hepatitis, marker of critically impaired liver function and retain it as idiosyncratic drug reactions a central criterion of poor prognosis. All also utilize lab- Duration of jaundice before onset of encephalopathy >7 days oratory measures of liver function to quantify severity of Prothrombin time >50 s Serum Bilirubin >300 µmol/L liver injury, most common measures of coagulation status. Source: O’Grady et al. Patient Age is also recognized by all as being of prognostic importance—likely reﬂecting the compromise of physio- Current UK ALF Transplant wait listing criterial found at http://odt.nhs.uk/pdf/liver_selection_policy.pdf logic reserve with increasing age—key to surviving any critical illness, and a possible parallel impairment of hep- atic regenerative ability. An important difference of the KCC from the other established criteria is the distinction Decision making in relation to the use of transplantation between paracetamol and non-paracetamol etiologies, in ALF became even more difﬁcult as improvements in reﬂecting the high volume of paracetamol cases seen in the intensive liver care led to higher survival rates with med- United Kingdom and differences seen in clinical course. ical management alone. In the King’s College Hospital Their clinical simplicity has, however, served them well (KCH) experience of over 3000 patients treated between over time, relying not on complex calculation or use of 1973 and 2008, transplant-free survival had increased to specialized laboratory tests but rather standard bedside 48%, with a near fourfold increase in overall hospital survival rates—including cases transplanted from 16.7 to Table 1 Comparison of elements of prognostic scoring systems in 62.2% .The increase in ‘transplant-free’ survival was current widespread use most apparent in paracetamol cases and associated with a substantial fall in the occurrence of cerebral edema and Factor Criteria intracranial hypertension, which in the past was often the b c d Kings Clichy Japanese cause of death in cases with a ‘hyper-acute’ presentation. Age ?? ? An important contribution to this improvement is likely Etiology ? –– through control of circulating levels of ammonia—the Encephalopathy ?? ? principal neurotoxin in this setting—through interventions Bilirubin -/? – ? that include the earlier and more widespread use of con- tinuous hemoﬁltration [5, 6]. In paracetamol-induced ALF, Coagulopathy ?? ? the narrowing in the gap between survival with medical ? Factor included in criteria. - Factor not included in criteria management alone and survival with transplantation has a b c d Factor common to all criteria. References: , ,  raised doubts about the transplant beneﬁt in such cases . 123 206 Hepatology International (2018) 12:204–213 assessment and readily available routine laboratory both paracetamol and non-paracetamol etiologies sug- measures. gested an overall sensitivity of 59% and speciﬁcity of 79%, Published data illustrate their limitations in current and with better performance values for prediction of non- clinical practice, particularly in relation to hyper-acute survival in paracetamol than in non-paracetamol etiologies disease. Here the initial intensity of critical illness may be . severe but paradoxically the potential for native liver Indications are, therefore, of particular aspects where regeneration is high [4, 9, 11]. In early case series of hyper- diagnostic performance of selection criteria could be acute patients, the dominant clinical issues were those of improved beyond existing systems. First, they should either a failure to identify all patients with a poor prognosis consider etiology of illness and reﬂect the differential in for consideration of transplantation—limited sensitivity— current outcomes of medical care alone. Second, they in concert with that of rapid deterioration of those who would perform sequential rather than single time point fulﬁlled KCC and high risk of death on the transplant estimations of prognosis, a process identiﬁed on meta- waitlist prior to grafts becoming available, late identiﬁca- analysis as having additional diagnostic value and reﬂect- tion [13–15]. Efforts were, therefore, initially focussed on ing the rapidly changing clinical condition seen particularly reﬁning the KCC by improving criteria sensitivity enabling in paracetamol and other hyper-acute etiologies and earlier identiﬁcation of patients with a poor prognosis already utilized in other novel prognostic criteria . through integration of supplemental prognostic markers. Recent studies suggest that in these cases waitlist Initial studies explored the inclusion of arterial blood improvement rather than deterioration may now principally lactate measurements determined using point of care test- confound decision making [9, 11, 12, 15]. Additionally, ing, as hyperlactatemia reﬂects both decreased hepatic any new or supplemental criteria should ideally retain the clearance by a damaged liver and global illness severity clinical simplicity of existing systems. Two recent attempts and multi-organ failure. Initial reports conﬁrmed their to address these issues are discussed below, both of which prognostic value, and their inclusion was found to improve have utilized the recent availability of web- and app-based speciﬁcity, sensitivity and timeliness of the KCC . computing power to deliver outcome predictions through Other studies have also examined arterial blood lactate in sophisticated algorithms. ALF, ﬁnding elevated levels to be strongly and indepen- dently associated with death or transplantation in both paracetamol and non-paracetamol-induced disease Dynamic outcome predictive model [17–19]. Analysis of the performance of the speciﬁc for paracetamol-induced ALF thresholds for arterial lactate introduced into the KCC for paracetamol-induced disease has been less consistent, with Prediction models in hyper-acute disease would be of most one report suggesting that early levels resulted in an beneﬁt if they could be applied sequentially identifying and increase in sensitivity but at the expense of reduction in quantifying both improvement and deterioration [22, 23]. speciﬁcity . However, two other studies found that The latest model from the King’s Liver Intensive Care Unit lactate measurements alone 12 h after admission to trans- is a dynamic outcome prediction model developed and plant centers had high predictive accuracy, with perfor- validated for use in patients with paracetamol-induced ALF mance greater than the KCC alone [18, 19]. Though . It is based on prospective data including analysis of adopted into United Kingdom ALF wait-listing criteria, more than 20 daily variables sequentially assessed for meta-analysis of validation studies to date has failed to 3 days after ICU admission in 912 un-transplanted patients conﬁrm an improvement in diagnostic test performance between 2000 and 2012. The variables included in the ﬁnal through their inclusion . models to predict death-included age, hepatic Two further meta-analyses of the performance of the encephalopathy, cardiovascular failure, INR, creatinine and KCC have further illustrated their potential shortcomings arterial pH on admission and dynamic variables of (Fig. 1). Review of studies of the KCC in predicting out- changing arterial blood lactate and INR. On validation in come of non-paracetamol-induced ALF comprising 1105 independent datasets from four transplant centers, the cases, showed overall sensitivity of 68% and speciﬁcity models showed good discrimination between survivors and 82% . Speciﬁcity was highest (93%) in patients with non-survivors, improving with the inclusion of changes in high-grade HE and where the criteria were sequentially INR and Lactate over time (Fig. 2). Innovative in this determined through the clinical course of illness. Impor- approach was its access though a dedicated website and the tantly, this analysis also described a fall-off in diagnostic generation of continuous survival estimates rather than a performance in more recent studies, reﬂecting the increased binary survival outcome, with the intention that the model success of non-transplant approaches to care. A second, should act as a decision-support tool to support clinical larger meta-analysis examining criteria performance in 123 Hepatology International (2018) 12:204–213 207 Fig. 1 Pooled (a) Sensitivity and (b) Speciﬁcity of Kings College Criteria (Source Ref. ) 123 208 Hepatology International (2018) 12:204–213 Fig. 2 Discrimination and calibration of dynamic prediction model (AUROC) for day 1 model, b AUROC for day 2 model, c Calibration on day 1 and day 2 of admission in 150 patients with paracetamol- curve for day 1 model, d Calibration curve for day 2 model (Source induced ALF. a Area under receiver operating characteristic curve Ref. ) judgement rather than a sole arbiter as to proceeding with transplantation. Model of acute liver failure study group (ALFSG) Elements of this approach were also adopted in the recent analysis by the ALFSG of 1974 subjects enrolled prospectively from 28 academic centers across North America between 1998 and 2013, and managed with and without transplantation . The aim was to devise a mathematical model for all etiologies of ALF to predict transplant-free survival at 21 days, rather than mortality as adopted in other models—making comparison with other Fig. 3 Comparison of the ALFSG model with the Kings College studies adopting more standard approaches more complex. Criteria and MELD score in predicting survival. ALFSG acute liver Clinical features and laboratory values were collected at failure study group, MELD model for end stage liver disease APAP study enrolment and recorded serially up to 7 days. Vari- acetaminophen (paracetamol). AUROC: ALFSG: 0.843, MELD: ables of prognostic value adopted in the predictive model 0.717, KCC APAP 0.560, KCC non-APAP 0.655 (Source Ref. ) included admission coma grade, etiology and vasopressor requirement, and admission bilirubin and INR values. with the model correctly predicting outcome of illness in 66.3% of subjects. Its performance was best in patients Arterial blood lactate was not explored. In this analyses of both paracetamol and non-paracetamol cases, sequential with unfavorable etiologies and high-grade encephalopathy and more limited in those with more favorable etiologies values of the INR did not add to prediction over that on admission. Using AUROC analysis, test discrimination and high-grade encephalopathy. appeared superior to the KCC and MELD scores (Fig. 3) 123 Hepatology International (2018) 12:204–213 209 Though sharing similarities in their use of web-based predictive algorithms, key differences exist between these two predictive systems. One is based on the prediction of mortality and the other survival, with resultant differences in test performance. Further, they are targeted at different patient groups—with the USALF criteria taking a broad approach to all etiologies of ALF, whilst the Dynamic Model is focused upon liver injury from paracetamol where the USALF performs least well. It may be that application of these and other models are complimentary and decision making is based upon the results generated from several prognostic systems [23–25]. Other systems evaluated A variety of other scoring systems and supplemental markers have been proposed to identify candidates for liver transplantation, though in general their performance has been evaluated in patient cohorts of limited size (Table 2). Scores used in this way include non-liver speciﬁc ones such as SOFA and APACHE II that are widely used to quantify severity of multi-organ failure in other forms of critical illness [17, 26, 27]. Reports suggest similar sensi- tivity and speciﬁcity to the King’s criteria in predicting death and they can be applied sequentially. However, though they may identify those patients at risk of death, the multi-organ failure they quantify may not be corrected by transplantation, if for example, it results for other ALF- associated complications such as severe sepsis or pancre- atitis. Consequently, they are not in widespread use to select candidates for transplant. The MELD score is more focused on severity of liver injury and has been assessed more widely in ALF and subjected to meta-analysis [22, 28, 29]. In its unmodiﬁed form, it shows most promise in non-paracetamol etiologies, with diagnostic performance close to that of the KCC . It has also been combined with circulating blood levels of cytokeratin K18 (CK18) a cell death-associated marker measured using the M30 assay which principally reﬂects apoptotic cell death . Also, this measurement in place of bilirubin to give a modiﬁed MELD Score showed superior sensitivity and speciﬁcity to the standard MELD Score and the King’s criteria in predicting outcome of ALF . Other studies have also reported prognostic models combining standard clinical variables with non-standard analytes. By example, the ALFSG index predictive model combined Coma-grade, INR, bilirubin and phosphorus levels with that of blood levels of M30 CK18 . In a 250-strong validation cohort, discrimination between sur- vivors and non-survivors was greater than with the KCC or MELD, though later external validation in a smaller Table 2 Features of illustrative systems for mortality prediction in acute liver failure Study Publication Criteria Era Etiology n Non- Sensitivity Speciﬁcity AUROC Comment year survivors McPhail et al.  2016 KCC 2001–2015 All 2153 Not Given 0.59 0.79 0.76 Meta-analysis (0.56–0.62) (0.77–0.81) Cholongitas et al. 2012 SOFA 1993–2010 Paracetamol 125 58 (46%) 0.67 0.80 0.79 SOFA Score threshold 12  McPhail et al.  2016 MELD 2001–2015 All 2153 Not given 0.74 0.67 0.78 Meta-analysis (0.71–0.77) (0.64–0.69) Bechmann et al.  2010 MELD/CK18 2006–2009 All 68 18 (27%) 0.85 (0.69–1.0) 0.76 (0.6–0.91) 0.94 Peak M65 fragment Koch et al.  2016 ALFSG 1998–2013 All 1974 987 (50%) Not given Not given 0.84 Prediction of survival not death Rutherford et al.  2012 ALFSG/CK18 1998–2011 All 500 251 (50%) 0.86 0.65 0.82 Admission M30 fragment Antoine et al.  2012 Acetylated Not Given Paracetamol 78 27 (35%) Not given Not given 0.87 Admission values HMGB1 KCC Kings College Criteria, SOFA sequential organ failure assessment, MELD model for end-stage liver disease, CK18 cytokeratin 18, ALFGSG Acute liver failure study group, HMGB1 high- mobility group box-1 Non-survivors; cases who died or were transplanted. Figures in parentheses are 95% Conﬁdence Intervals where given 210 Hepatology International (2018) 12:204–213 independent cohort showed no advantage over SOFA or APACHE scoring [32, 33]. However, the primary mechanism of liver cell injury may vary by etiology and necrosis rather than apoptosis may predominate. Antoine and colleagues assessed circu- lating levels of a panel of cell death markers in 78 patients with paracetamol-induced ALF . They found that best prediction of non-survival was with acetylated HMGBI—a biomarker of hepatic necrosis and cellular immunological activation, and to lesser degree with biomarkers of apop- tosis including molecular forms of CK18. To date, vali- dation studies have not indicated prognostic advantage above the standard KCC in predicting survival . Cell death biomarkers do appear to be exquisitely sensitive in predicting clinically signiﬁcant liver injury very early after paracetamol overdose but If they are to be adopted as adjunctive measures to select liver transplant candidates with ALF, key practical issues will need to be overcome [36, 37]. Techniques for their rapid determination will need to be widely available, and it is likely that a panel of biomarkers will need to be assessed to cover etiology- speciﬁc differences in the mechanisms of liver cell injury and death. Other simpler clinical measures have also demonstrated potential for use as prognostic markers: platelet count has been shown to be closely linked to outcome. In a recent study from the USALFSG, the evolution of thrombocy- Fig. 4 a Platelet Counts on days 1–7 after admission in 1598 patients topenia was closely associated with development of multi- with acute liver failure according to outcome at 21 days. SS organ failure and a poor outcome in ALF and linked to the spontaneous survivor, OLT orthotropic liver transplant. Three sym- development of a systemic inﬂammatory response  bols, p \ 0.001; two symbols, p \ 0.01; one symbol, p \ 0.05. *SS (Fig. 4a). Liver volume may be easily determined using vs LT, SS vs death, and LT vs death. SS, spontaneous survival. b Survival According to CT-derived liver volume on admission in 37 analysis of CT images and reﬂect the balance between the non-transplanted patients with non-acetaminophen etiologies. parallel processes of liver collapse with cell death and 3 3 \ 1000 cm n = 11, C 1000 cm n = 26, p \ 0.001 log-rank increase with regeneration. Recent studies suggest that in (Source Ref. [36, 38]) some non-paracetamol etiologies, loss of liver volume in adults to less than 1000 cm may indicate irreversible absolute arbiter, these models should support decision damage and serve as an early indicator of poor prognosis, making and the multifactorial team assessment. often in advance of the development of encephalopathy (Fig. 4b) [39–41]. Other studies have also sought to identify at a very early Current results of liver transplantation stage those patients with acute liver injury (ALI) in the absence of encephalopathy which will later progress to a Life-saving though it was soon seen to be after its intro- poor outcome of death or transplantation. In a study of US duction, overall results not surprisingly for these very sick patients hospitalized with ALI, progression to a poor out- patients were signiﬁcantly lower than for elective trans- come was more common in non-paracetamol etiologies and plants carried out for those with chronic diseases. Several with higher levels of INR and bilirubin, and a prolonged series have now demonstrated a progressive incremental duration of illness . improvement in survival over time, with patient survival Finally, it is important to emphasize that prognostic now approaching that of elective surgery. Recent reports models should be only part of the overall functional eval- for the US and UK are of 1-year patient survival rates of uation of the very sick patient with ALF and an experi- 85–90% . These results reﬂect advances in peri- and enced multi-disciplinary team in an intensive care setting is intra-operative care and the interplay of several factors: the required for correct interpretation. Rather than providing an earlier and more accurate prediction of need for transplant 123 Hepatology International (2018) 12:204–213 211 and identiﬁcation those patients who are too sick for sur- pre-existing sub-clinical non-cirrhotic liver disease upon gery, and a better understanding of the interplay between liver regeneration is currently poorly characterized, for graft and recipient factors in determining patient survival. example, from chronic alcohol use or non-alcoholic Analysis of the European experience of 4903 transplant steatohepatitis. recipients between 1998 and 2009 found death after sur- In cases where the liver injury has progressed ‘beyond gery to relate to both with independent association shown the point of no return’, novel medical therapies are unlikely with male recipients (adjusted OR 1.25), recipient to be of beneﬁt. It would thus be of no surprise that most [ 50 years of age (1.26), incompatible ABO matching efﬁcacy would be seen either in treatment at an early stage (1.93), donors [ 60 years (1.21), and reduced size graft of disease and/or in etiologies with greatest regenerative (1.54). Recipients [ 50 years, combined with donors capacity. By example, the FULMAR trial of the MARS [ 60 years had a 57% mortality/graft loss within the ﬁrst extra-corporeal device in patients with ALF failed to show year after transplant . Matching of graft to recipient is a survival improvement in the overall study cohort but key to ensuring optimal outcome . Case series also now there were indications of potential beneﬁt in patients with conﬁrms the practicality and excellent outcomes obtained paracetamol-related disease . for selected patients transplanted using living donors, and Such caveats may also apply to the use of therapeutic from auxiliary liver grafting in etiologies where native liver plasma exchange (TPE). Through mechanisms thought to regenerative potential exists—though globally, these tech- include removal of deleterious inhibitors of hepatic niques are applied to only a small proportion of recipients regeneration and a complex pattern of immunomodulation, [45, 46]. use of this therapy has recently been demonstrated to Patient survival after transplantation for ALF follows a deliver a survival beneﬁt in non-transplanted patients with characteristic pattern of increased mortality early after ALF. In a multi-center randomized controlled trial on transplant, but in patients who survive this phase, subse- mixed etiologies of disease, three 5-l TPE sessions signif- quent survival parallels closely with that seen in elective icantly improved survival above that seen with standard transplantation . In an early series, the high prevalence medical care, although the survival beneﬁt was inferior to of psychiatric comorbidity and addiction issues seen in that seen with transplantation (Fig. 5). There is recipients of transplantation for paracetamol-induced ALF ongoing debate about the place of this therapy in patients was reﬂected in an increased risk of death due to suicide, with ALF, given that its use normalizes measures of trauma or non-adherence to immunosuppression with over coagulation disturbance and thus precludes their use in half the deaths occurring within 12 months of transplan- prognostic evaluation for later transplantation. Our practice tation . Later series have not demonstrated such an is in accordance with recent EASL guidance, with its early increase in mortality, but it is clear that paracetamol use in patients with ALF with an expected poor prognosis recipients show increased levels of psychotic comorbidity without transplantation but who have clear medical or which may be reﬂected in poor compliance with medica- psychiatric contra-indications to surgery . In addition, tion and follow-up . In these patients, assessment of the use of TPE is associated with signiﬁcant improvements severity of psychiatric illness is a key element of the in cardiovascular status and we also treat patients who are selection of potential recipients and in those transplanted waitlisted for liver transplantation but with worsening follow-up must include close ongoing psychiatric moni- toring and support. New novel non-transplant options A number of novel non-transplant interventions have potential to serve as alternatives to transplantation. A central premise to their use is that the injured liver retains regenerative ability and that this may be augmented by these interventions. A better practical understanding of the processes inﬂuencing both liver injury and regeneration is Fig. 5 Survival in 182 patients with ALF according to treatment with likely to be of clinical importance here, exempliﬁed by the liver transplantation and high-volume plasma exchange. Two groups receiving SMT (standard medical treated group) with and without major clinical and laboratory differences between parac- emergency transplantation (HVP ? LTx vs ?HVPLTx) and the two etamol hepatotoxity from single time point or staggered group receiving SMT with and without emergency transplantation overdoses—and the markedly worse outcomes seen in the (HVPLTx vs. ?HVPLTx) (log rank: p = 0.0058) and Cox propor- latter group . 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Published: Jun 1, 2018