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There is a strong imperative to develop valid and accurate prognostic modeling for acute liver failure (ALF). Despite the numerous clinical models that have been proposed thus far and the use of some such models, that is, King's College Criteria and Model for End-Stage Liver Disease, in clinical practice to aid decision-making, there is a significant need for improvement for determining patients' clinical course, survival, and requirement for liver transplantation. Future prognostic models shall need a stronger statistical foundation and accountability for time and variability in the clinical course of ALF and be applied for pretransplant and posttransplant outcomes.

Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry.A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT).Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P.001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P.001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P.001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86).TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.

Although rare, death from amanitin exposure poses a significant health risk and a diagnostic challenge to the clinician due to its rarity. This is one of the few conditions to be voluntarily reported by healthcare professionals. No antidote exists for this poisoning and, perhaps due to its rarity or lack of attention, the United States has lagged behind Europe for almost three decades in treatment, diagnostics and experimentation. This regrettable fact warrants the formation of a centralized agency for education, the advancement of research and the collection of data, to provide better treatment for the population.

Acetaminophen toxicity is common and is characterized by hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require hepatic transplant. While there are various criteria to predict patients who might benefit from transplant, the King's College criteria remain one of the most widely used. However, the King's College criteria have several limitations and do not incorporate glucose, an important marker of hepatic function.The primary objective of this study is to compare the presence of hypoglycemia, coagulopathy, and metabolic acidosis with the King's College criteria for predicting a composite endpoint of death or transplant.This study is a retrospective cohort study of adult patients admitted with a discharge diagnosis of acetaminophen-induced liver failure.The patients were admitted at one of six university-affiliated teaching hospitals in the United States.A total of 334 subjects were identified who met inclusion criteria. Fifty-one subjects (15.3%) met the composite endpoint of death or transplant. Ninety-six (28.7%) subjects met the King's College criteria for transplant. The presence of hypoglycemia increased the odds of reaching the composite endpoint by 3.39-fold. This model performed better than the King's College criteria (pseudo RThe combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King's College criteria for predicting death or transplant.

Acute liver failure (ALF) is an indication for emergency liver transplantation (LT). Although centers performing only deceased donor liver transplants (DDLT) have shown improved outcomes in this situation, they still have relatively long waiting lists. An alternative would be living donor liver transplantation (LDLT), which has shown equivalent outcomes in the elective situation but there is limited evidence of its results in ALF. The purpose of this study was to assess the outcomes in patients with ALF undergoing emergency LDLT in our center in Delhi, India. We prospectively collected data on 479 patients who underwent LT in our hospital between January 2009 and December 2015 to evaluate the outcomes of those with ALF. The ALF patients were listed for transplantation after they met the Kings’ College criteria and rapid evaluation was done following a protocol consisting of three phases. Patients with grade III/IV encephalopathy were put on mechanical ventilation. Data regarding their postoperative course, morbidity, and mortality were analyzed. Thirty-six (7.5%) out of the 479 patients underwent emergency LT for ALF. Their mean age was 27.5 years (range 4–59 years) and the male to female ratio of 2:3. Preoperative intubation was required in 15 of 25 patients who had encephalopathy. Wilson’s disease was the most common cause of ALF in children while in adults, it was acute viral hepatitis. The time interval between listing and transplantation was a mean of 36 ± 12.4 h. The mean graft to recipient weight ratio (GRWR) was 1.06 ± 0.3. The recipients were extubated postoperatively after a mean period of 2.6 days and their mean ICU stay was 6.3 days. Postoperative infection was the most common complication and required upgradation of antifungal and antibiotic treatments. Neurological complications occurred in five patients. Thirty-one of 36 (86.1%) patients survived and progressive cerebral edema and sepsis were the most common causes of mortality. Patients who died had higher model for end-stage liver disease scores, longer cold ischemia time (CIT), and higher grades of encephalopathy (though 80% patients with encephalopathy survived). There was no donor mortality. At long-term follow up of a median of 56 months, 29 (80.5%) of 36 patients were still alive. In our experience, LDLT is an alternative procedure to DDLT in patients with ALF and is associated with good outcomes even in patients with high grades of encephalopathy.

Acute-on-chronic hepatitis B liver failure is a devastating condition that is associated with mortality rates of over 50% and is consequent to acute exacerbation of chronic hepatitis B in patients with previously diagnosed or undiagnosed chronic liver disease. Liver transplantation is the definitive treatment to lower mortality rate, but there is a great imbalance between donation and potential recipients. An early and accurate prognostic system based on the integration of laboratory indicators, clinical events and some mathematic logistic equations is needed to optimize treatment for patients. As parts of the scoring systems, the MELD was the most common and the donor-MELD was the most innovative for patients on the waiting list for liver transplantation. This review aims to highlight the various features and prognostic capabilities of these scoring systems.

Dear Editor,The recent article by Levine raises numerous questions about the use of hypoglycemia as a prognostic factor for severe outcomes following acetaminophen-induced hepatotoxicity, in compar...

Acute liver failure (ALF) is an unpredictable and rapidly progressive, life-threatening multisystem condition that ensues when an insult causes diffuse necrosis of liver parenchyma disrupting hepatocyte function in patients who have no preexisting liver injury. The subsequent development of encephalopathy and coagulopathy within days or weeks represents the key features of ALF, but critically often culminates with multi-organ failure (MOF), which impacts significantly on mortality. Timely referral to specialist centres with expertise in the management of ALF and liver transplantation is crucial.

Division of Transplantation, Box 40, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA Department of Surgery, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK Department of Biostatistics, University of Michigan, Ann Arbor, USA Department of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Liver Unit, Favaloro Foundation and University, Buenos Aires, Argentina

Acute liver failure (ALF) is characterized by massive acute injury to a previously healthy liver associated with development of hepatic encephalopathy. The same clinical syndromeoccurring in patientswith 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]. With an estimated annual incidence of 2000 cases in the US [2], ALF is a relatively rare condition, but carries a short-term (3 week) mortality in excess of 40% [3]. 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]. Transplantable livers are a scarce resource and OLT, while potentially life saving, carries relevant long-termmorbidity 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]. In addition, development of complications, in particular increased intracranial pressure and multiorgan failure (often due to sepsis), affects outcome, cerebral herniation and sepsis remaining themost frequent causes of death inALF [5]. 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] and the Clichy criteria [7,8], fall short of this ideal.

Background & Aims Several prognostic factors are used to identify patients with acute liver failure (ALF) who require emergency liver transplantation. We performed a meta-analysis to determine the accuracy of King's College criteria (KCC) versus the model for end-stage liver disease (MELD) scores in predicting hospital mortality among patients with ALF. Methods We performed a systematic search of the literature for articles published from 2001 through 2015 that compared the accuracy of the KCC with MELD scores in predicting hospital mortality in patients with ALF. We identified 23 studies (comprising 2153 patients) and assessed the quality of data, and then performed a meta-analysis of pooled sensitivity and specificity values, diagnostic odds ratios (DORs), and summary receiver operating characteristic curves. Subgroups analyzed included study quality, era, location (Europe vs non-Europe), and size; ALF etiology (acetaminophen-associated ALF [AALF] vs nonassociated [NAALF]); and whether or not the study included patients who underwent liver transplantation and if the study center was also a transplant center. Results The DOR for the KCC was 5.3 (95% confidence interval [CI], 3.7–7.6; 57% heterogeneity) and the DOR for MELD score was 7.0 (95% CI, 5.1–9.7; 48% heterogeneity), so the MELD score and KCC are comparable in overall accuracy. The summary area under the receiver operating characteristic curve values was 0.76 for the KCC and 0.78 for MELD scores. The KCC identified patients with AALF who died with 58% sensitivity (95% CI, 51%–65%) and 89% specificity (95% CI, 85%–93%), whereas MELD scores identified patients with AALF who died with 80% sensitivity (95% CI, 74%–86%) and 53% specificity (95% CI, 47%–59%). The KCC predicted hospital mortality in patients with NAALF with 58% sensitivity (95% CI, 54%–63%) and 74% specificity (95% CI, 69%–78%), whereas MELD scores predicted hospital mortality in patients with NAALF with 76% sensitivity (95% CI, 72%–80%) and 73% specificity (95% CI, 69%–78%). In patients with AALF, the KCC's DOR was 10.4 (95% CI, 4.9–22.1) and the MELD score's DOR was 6.6 (95% CI, 2.1–20.2). In patients with NAALF, the KCC's DOR was 4.16 (95% CI, 2.34–7.40) and the MELD score's DOR was 8.42 (95% CI, 5.98–11.88). Conclusions Based on a meta-analysis of studies, the KCC more accurately predicts hospital mortality among patients with AALF, whereas MELD scores more accurately predict mortality among patients with NAALF. However, there is significant heterogeneity among studies and neither system is optimal for all patients. Given the importance of specificity in decision making for listing for emergency liver transplantation, MELD scores should not replace the KCC in predicting hospital mortality of patients with AALF, but could have a role for NAALF.

Zinc phosphide (ZnP) containing rodenticide poisoning is a recognized cause of acute liver failure (ALF) in India. When standard conservative measures fail, the sole option is liver transplantation. Records of 41 patients admitted to a single centre with ZnP-induced ALF were reviewed to identify prognostic indicators for requirement of liver transplantation. Patients were analyzed in two groups: group I (n = 22) consisted of patients who either underwent a liver transplant (n = 14) or died without a transplant (n = 8); group II (n = 19) comprised those who survived without liver transplantation. International normalized ratio (INR) in group I was 9 compared to 3 in group II (p

We report a case of 32-year-old man with Acetaminophen induced liver failure who did not meet King’s College criteria for liver transplantation but showed progressive worsening cerebral edema and encephalopathy despite improving biochemical parameters. The patient was managed with urgent liver transplantation and made an excellent recovery. To our knowledge, there is no literature or reported cases for worsening cerebral edema in the setting of acuter liver failure and improving liver function tests.

Background & Aims Patients with acute liver failure (ALF) have high mortality and frequently require liver transplantation (LT); few reliable prognostic markers are available. Levels of M30, a cleavage product of cytokeratin-18 caspase, are significantly increased in serum samples from patients with ALF who die or undergo LT. We developed a prognostic index for ALF based on level of M30 and commonly measured clinical variables (called the Acute Liver Failure Study Group [ALFSG] index) and compared its accuracy with that of the King's College criteria (KCC) and Model for End Stage Liver Disease (MELD). We also validated our model in an independent group of patients with ALF. Methods Serum levels of M30 and M65 antigen (the total cytokeratin-18 fragment, a marker of apoptosis and necrosis) were measured on 3 of the first 4 days following admission of 250 patients with ALF. Logistic regression was used to determine whether the following factors, measured on day 1, were associated with LT or death: age, etiology; coma grade; international normalized ratio (INR); serum pH; body mass index; levels of creatinine, bilirubin, phosphorus, arterial ammonia, and lactate; and log 10 M30 and log 10 M65. The area under the receiver operating characteristic (AUROC) was calculated for the ALFSG and other indices. Results Coma grade, INR, levels of bilirubin and phosphorus, and log 10 M30 value at study entry most accurately identified patients who would require LT or die. The ALFSG index identified these patients with 85.6% sensitivity and 64.7% specificity. Based on comparison of AUROC values, the ALFSG Index (AUROC, 0.822) better identified patients most likely to require LT or die than the KCC (AUROC, 0.654) or MELD (AUROC, 0.704) ( P = .0002 and P = .0010, respectively). We validated these findings in a separate group of 250 patients with ALF. Conclusions The ALFSG index, a combination of clinical markers and measurements of the apoptosis biomarker M30, better predicts outcomes of patients with ALF than the KCC or MELD; ClinicalTrials.gov, number NCT00518440.

Background & Aims: Among the potentially helpful indicators of poor prognosis in acute liver failure (ALF) are etiology, encephalopathy grade, blood lactate, and King's College Criteria (KCC). The accuracy of these parameters in predicting transplantation or death shows significant variation in different countries. Methods: We retrospectively analyzed 102 patients with ALF treated at our institution between 1996 and 2005. Baseline parameters, simplified acute physiology score III (SAPS-III), KCC, Model for End-Stage Liver Disease (MELD) score, and a novel score of bilirubin, lactate, and etiology (BiLE score) were compared between transplant-free survivors and patients who required liver transplantation or died, by using multivariate linear regression analysis and receiver operating characteristics (ROC). Results: The most common causes of ALF were indeterminate liver failure (21%), acute hepatitis B (18%), acetaminophen ingestion (16%), and Budd-Chiari syndrome (9%). Transplantation-free survival was 38%, 44% of patients underwent liver transplantation, and 18% died without transplantation. Eight-week survival was 77%. The BiLE score was the best predictor of death or need of transplantation, with 79% sensitivity and 84% specificity. ROC analysis revealed a better performance of BiLE score when compared with bilirubin, lactate, MELD score, and SAPS-III (area under the curve: 0.87 ± 0.04, 0.73 ± 0.51, 0.73 ± 0.52, 0.71 ± 0.05, and 0.68 ± 0.59, respectively). Conclusions: The simple, combined BiLE score emerged as the best predictor of poor outcome in our patient cohort and should be prospectively evaluated in other populations.

Introduction Several prognostic scores attempt to aid in the selection of patients with acute liver failure (ALF) to be treated either medically or by liver transplantation; however, their lack of fulfillment does not predict spontaneous survival in ALF and refined prognostic criteria are needed to improve such selection. Our aim was to evaluate and compare a new ALF in-hospital mortality prediction score versus King’s College Criteria (KCC) and model for End-Stage Disease (MELD) score. Methods First-time ALF-diagnosed individuals admitted to our institution (n = 58) were grouped according their final outcome as “alive” or “death,” and those significantly different variables between groups entered into a logistic regression and lineal regression models. An ALF in-hospital mortality score (ALFIHMS) was produced and its sensitivity, specificity, and area under receiver operator characteristics were compared with those of KCC and MELD scores. Results Since no significant differences (P = .81) in mortality rates between fulminant and subfulminant hepatic failure were found, no further analysis according to ALF’s classification was performed. After obtaining and comparing ALFIHMS with KCC and MELD, we found that ALFIHMS prediction accuracy is higher than that of KCC and MELD score and that an ALFIHMS cutoff point >15 points is associated with an in-hospital mortality probability >50%. Conclusions ALFIHMS has higher prognostic accuracy than KCC and MELD scores in ALF.

A cu te Li ve r Fa ilu re from malnutrition, a host factor known to cause reduced immunocompetence leading to greater risk of multiple viral infections. Aims: To evaluate the role of maternal nutritional factors in acute viral hepatitis (AVH) and acute liver failure (ALF) patients with HEV infection during pregnancy. Methods: The study included 180 pregnant cases of which 72 HEV infected pregnant cases, 78 Non-HEV pregnant cases and 30 control cases were recruited in the study during February 2011 to December 2012. Serological evaluation of virological markers like IgM anti-HAV, HBsAg, anti-HCV Ab and IgM anti-HEV was done by ELISA. Nutritional factors were evaluated by measuring the anthropometric parameters such as body mass index (BMI), height, weight, triceps skin fold thickness, mid arm circumference (MAC), arm span using appropriate readings. Results: The meanmaternal age, gestational age at delivery and hemoglobin levels of HEV infected pregnant patients were 24.32+4.25years, 33.41+3.94weeks and 10.4+1.87 g/ dl respectively. BMI, mid arm circumference and tricep skin fold thickness were found to be significantly lower in ALF pregnant patients compared to their AVH counterparts in the HEV group (P

Background & Aims Acute liver failure (ALF) is a severe form of acute liver injury that can progress to multiple organ failure. We investigated causes and outcomes of ALF. Methods Eleven university medical centers in Germany were asked to report patients with (primary) severe acute liver injury (sALI) (international normalized ratio [INR] >1.5 but no hepatic encephalopathy) and primary ALF (INR >1.5 with overt hepatic encephalopathy) treated from 2008 to 2009. Data were analyzed from 46 patients with sALI and 109 patients with ALF. Results The most frequent etiologies of primary ALF were non-acetaminophen drug-induced (32%), indeterminate (24%), and viral (21%); acetaminophen ingestion was the cause of ALF in only 9% of patients. The support of a ventilator was required by 44% of patients with ALF, vasopressors by 38%, and renal replacement by 36%. Seventy-nine patients with ALF (72%) survived until hospital discharge, 38 (35%) survived without emergency liver transplantation (ELT), and 51 received ELT (47%); 80% of patients who received ELT survived until discharge from the hospital. Conclusions In Germany, drug toxicity, indeterminate etiology, and viral hepatitis appear to be the major causes of primary ALF, which has high mortality. Patients with ALF are at great risk of progressing to multiple organ failure, but 80% of patients who receive ELT survive until discharge from the hospital.

Introduction Outcome prediction is a cornerstone of the management of Acute Liver Failure (ALF) where Emergency Liver Transplantation (ELT) is indicated for predicted death. The King9s College Criteria (KCC) for paracetamol overdose (POD) and non-POD ALF are the benchmark prognostic scores but recent reports have suggested the Modified End Stage Liver Disease (MELD) score could replace KCC. Aim To meta-analyse and compare diagnostic performance for outcome prediction of KCC and MELD in ALF. Method A systematic database search was performed and retrieved articles graded according to a pre-agreed proforma of methodological quality. Collated data were meta-analysed for summary sensitivity, specificity, Diagnostic OR, DOR meta-regression and ROC curve analysis. Pre-specified subgroup analysis was performed on the basis of methodological quality, the severity of hepatic encephalopathy (HE) of reported patients, and exclusion of those who underwent ELT. Results 32 studies published between 1992 and 2009 with data on 3008 patients (2464 from KCC and 544 MELD) were available for production of 2×2 tables. Taking data where transplanted patients were excluded summary sensitivity for KCC was 63 (95% CI 60 to 66) %, specificity 91 (90 to 93) % and DOR 18 (8.9 to 37). Summary sensitivity for MELD was 82 (95% CI 77 to 86) %, specificity 65 (59to71) % and DOR 11 (5.3 to 23; RDOR 0.75 (0.18 to 3.13))). Despite different MELD cut-offs between studies no statistical evidence of threshold was found and the AUROC for MELD was 0.83 (SE 0.05) and 0.88 (0.03) for KCC. A lack of patient level data prevented statistical comparison between these areas. The DOR for KCC in POD ALF was 27 (9–83) and 13 (5–31) in non-POD ALF. Heterogeneity (using the I 2 statistic) in the DOR for MELD was 49% and 80% for KCC although this was not dependent on aetiology. The lower sensitivity for KCC could be overcome by dynamic application of the criteria. Conclusion MELD is not superior to KCC on the basis of quantitative analysis of published evidence. While both scores may give complementary sensitivity and specificity (particularly in cases where bilirubin may have more prognostic value) the DOR and AUROC superiority of KCC suggest they should remain the preferred method of outcome prediction and listing decision for ELT in ALF, particularly in cases of POD-ALF.

The successful use of orthotopic liver transplantation in fulminant hepatic failure has created a need for early prognostic indicators to select the patients most likely to benefit at a time when liver transplantation is still feasible. Univariate and multivariate analysis was performed on 588 patients with acute liver failure managed medically during 1973-1985, to identify the factors most likely to indicate a poor prognosis. In acetaminophen-induced fulminant hepatic failure, survival correlated with arterial blood pH, peak prothrombin time, and serum creatinine--a pH less than 7.30, prothrombin time greater than 100 s, and creatinine greater than 300 mumol/L indicating a poor prognosis. In patients with viral hepatitis and drug reactions three static variables [etiology (non A, non B hepatitis or drug reactions), age less than 11 and greater than 40 yr, duration of jaundice before the onset of encephalopathy greater than 7 days] and two dynamic variables (serum bilirubin greater than 300 mumol/L and prothrombin time greater than 50 s) indicated a poor prognosis. The value of these indicators in determining outcome was tested retrospectively in a further 175 patients admitted during 1986-1987, leading to the construction of models for the selection of patients for liver transplantation.

Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition.To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure.Prospective cohort study.17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group.308 consecutive patients with acute liver failure, admitted over a 41-month period.Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission.73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not.Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.