King's College Criteria Research Articles

Outcomes of patients with acute liver failure not listed for liver transplantation: A cohort analysis.

Acute liver failure (ALF) is a rare condition leading to morbidity and mortality. Liver transplantation (LT) is often required, but patients are not always listed for LT. There is a lack of data regarding outcomes in these patients. Our aim is to describe outcomes of patients with ALF not listed for LT and to compare this with those listed for LT. Retrospective analysis of all nonlisted patients with ALF enrolled in the Acute Liver Failure Study Group (ALFSG) registry between 1998 and 2018. The primary outcome was 21-day mortality. Multivariable logistic regression was done to identify factors associated with 21-day mortality. The comparison was then made with patients with ALF listed for LT. A total of 1672 patients with ALF were not listed for LT. The median age was 41 (IQR: 30-54). Three hundred seventy-one (28.9%) patients were too sick to list. The most common etiology was acetaminophen toxicity (54.8%). Five hundred fifty-eight (35.7%) patients died at 21 days. After adjusting for relevant covariates, King's College Criteria (adjusted odds ratio: 3.17, CI 2.23-4.51), mechanical ventilation (adjusted odds ratio: 1.53, CI: 1.01-2.33), and vasopressors (adjusted odds ratio: 2.10, CI: 1.43-3.08) (p < 0.05 for all) were independently associated with 21-day mortality. Compared to listed patients, nonlisted patients had higher mortality (35.7% vs. 24.3%). Patients deemed not sick enough had greater than 95% survival, while those deemed too sick still had >30% survival. Despite no LT, the majority of patients were alive at 21 days. Survival was lower in nonlisted patients. Clinicians are more accurate in deeming patients not sick enough to require LT as opposed to deeming patients too sick to survive.

Current status of etiology and outcomes of acute liver failure in India-A multicentre study from tertiary centres.

Acute liver failure (ALF) is a medical emergency and liver transplantation (LT) may be required as definitive therapy. The etiology varies across geographical locations and is mostly viral dominant in India. We aimed at evaluating the spectrum, impact of interventions (plasma exchange [PLEx], continuous renal replacement therapy [CRRT]) and outcomes of ALF in India in recent times. A multicentre retrospective study across four major tertiary care centres. As many as 183ALF patients (median age, 23years; females, 43.1%; model for end-stage liver disease [MELD], 32.7) from January 2021 to December 2023 were included. Nineteen percent had infection and 40.4% of patients satisfied King's College criteria (KCC) at admission. Most common cause for ALF was hepatitis A virus (HAV) (44.2%) followed by rodenticide poisoning (10.3%). Approximately 35% of patients each received either PLEx or CRRT. The 7, 14 and 21-day transplant-free survival probability was 65.5%, 60.1%, and 57.3%, respectively. Only 3.8% of patients underwent liver transplantation. On multivariable Cox regression analysis, hemoglobin (HR, 0.74 [0.63-0.87]), lactate (HR, 1.14 [1.03-1.26]), advanced hepatic encephalopathy (HE) (HR, 4.87 [1.89-12.5]) and fulfilling KCC [HR, 10.04 [4.57-22.06]) at admission were the independent predictors of mortality. A model including KCC + lactate + HE ≥ 3 with or without hemoglobin had an AUROC of 0.81-0.84 to predict mortality. In those who underwent PLEx, advanced HE (HR, 4.13 [1.75-9.7]), procalcitonin (HR, 1.18 [1.07-1.30]) and KCC (HR, 4.6 [1.6-13.1), while for those who received CRRT, lactate (HR, 1.37 [1.22-1.54]) and KCC (HR, 6.4 [2.5-15.8]) independently predicted mortality. Hepatitis A virus is currently the most common cause for ALF in India, emphasizing the need for universal vaccination programmes. Spontaneous survival in tertiary care centres is 57%. LT rates were low.

Silent Destruction: Fulminant Hepatitis and the Hidden Danger of Weight Loss Drugs

The use of natural products for therapeutic purposes is a common practice throughout the world, in part, due to the global obesity epidemic and the search for products with appetite suppression and weight loss properties, which include nutritional supplements, vitamins and minerals to herbal products. It is known that such products may be associated with various adverse health effects. Thus, the objective of this study is to report a series of cases of patients, who presented fulminant liver failure (HFI) requiring liver transplantation (LT), related to the consumption of products used for weight loss. This is a retrospective cohort based on the evaluation of patients listed for LT due to IHF at the Hospital das Clínicas of the Universidade Estadual de Campinas, between 1991 and 2022, with patients who had confirmed consumption of products with the aim of loss being selected. During the studied period, 92 patients were listed for HT due to IHF according to the Kings College criteria, with 5 cases being selected with proven consumption of herbal products for weight loss, and other causes that could explain the IHF were excluded. Four (80%) of the patients were female, with a mean age of 40.5 years, and 40% of the cases died. Unlike traditional pharmaceutical medicines, in most countries, the commercialization of these products is not conditioned on clinical and safety evidence or prior approval by regulatory bodies. Hepatoxicity can be related to several factors, such as the presence of toxins naturally found in plants, the presence of heavy metals, contamination during obtaining or processing and the addition of substances omitted from the labels. The use of weight loss products can evolve with IHF, a fact that deserves attention, due to ease of access and growing demand, and it is important to regulate the trade of these products and raise public awareness about the risks of use without professional supervision and guidance.

An international, multicenter, survey-based analysis of practice and management of acute liver failure.

Acute liver failure (ALF) is an acute liver dysfunction with coagulopathy and hepatic encephalopathy in a patient with no known liver disease. As ALF is rare and large clinical trials are lacking, the level of evidence regarding its management is low-moderate, favoring heterogeneous clinical practice. In this international multicenter survey study, we aimed to investigate the current practice and management of patients with ALF. An online survey targeting physicians who care for patients with ALF was developed by the International Liver Transplantation Society ALF Special-Interest Group. The survey focused on management and liver transplantation (LT) practices of ALF. Survey questions were summarized overall and by geographic region. A total of 267 physicians completed the survey with a survey response rate of 21.36%. Centers from all continents were represented. More than 90% of physicians were specialized in either transplant hepatology/surgery or anesthesiology/critical care. Two hundred and fifty-two (94.4%) respondents' institutions offered LT. A total of 76.8% of respondents' centers had a dedicated liver- or transplant- intensive care unit (p<0.001). Median time to LT was within 48 hours in 12.7% of respondents' centers, 72 hours in 35.6%, one week in 37.6%, and more than one week in 9.6% (p<0.001). Deceased-donor liver graft (49.6%) was the most common type of graft offered. For consideration of LT, 84.8% of physicians used King's College Criteria and 41.6% used Clichy Criteria. Significant differences were observed between Asia, Europe, and North America for offering LT, number of LTs performed, volume of ALF patients, admission to a dedicated intensive care unit, median time to LT, type of liver graft, monitoring hepatic encephalopathy and intracranial pressure, management of coagulopathy, and utilization of different criteria for LT. In our study, we observed significant geographic differences in the practice and management of ALF. As ALF is rare multicenter studies are valuable to identify global practice.

Circulating myostatin levels as a prognostic biomarker in patients with acute liver failure and late-onset hepatic failure.

Myostatin is a myokine involved in muscle mass regulation. The associations between circulating myostatin levels and clinical characteristics in patients with acute liver failure (ALF) and late-onset hepatic failure (LOHF) are unclear. In this retrospective study, 51 patients with ALF or LOHF were included. Serum myostatin was measured using an enzyme-linked immunosorbent assay. Myostatin levels were significantly lower in patients with ALF and LOHF than in controls (ALF/LOHF: 2522pg/mL, controls: 3853pg/mL, p=0.003). The prevalence of low myostatin in deceased patients was significantly higher than that in spontaneous survivors and patients who underwent liver transplantation. Patients with low myostatin levels had a high incidence of complications. There was a positive correlation between the psoas muscle index and serum myostatin levels. Patients with low myostatin levels had shorter 1-year transplant-free survival and shorter 1-year overall survival than patients with high myostatin levels. Low serum myostatin levels were associated with poor prognosis independent of the Japanese scoring system for ALF ≥3, King's College criteria, or model for end-stage liver disease score >30.5. The combination of serum myostatin levels and prognostic models for ALF significantly stratified patients according to 1-year prognosis. Low serum myostatin levels were associated with a low psoas muscle index, complication rate, and poor prognosis in patients with ALF and LOHF. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with ALF and LOHF.

Impact of Renal Replacement Therapy on Outcomes of Living Donor Liver Transplantation for Acute Liver Failure: A Cohort Study.

Despite the promising role of renal replacement therapy (RRT) in acute liver failure (ALF), high-risk patients need liver transplantation and remain at risk for death due to cerebral complications. The objective of this study was to report outcomes of living donor liver transplantation (LDLT) for ALF with perioperative RRT. This was a single-center retrospective cohort study. Out of 1167 LDLTs, 24 patients had ALF and met the King's College criteria for transplantation. They were categorized into no-RRT (n = 13) and RRT (n = 11) groups. We looked at 1-year posttransplant survival in these patients. The median serum ammonia level at the time of transplant in the no-RRT and RRT groups was 259.5 mcg/dL (222.7-398) and 70.6 mcg/dL (58.1-92.6) (p = 0.005). In the RRT group, serum ammonia level < 100 mcg/dL was achieved in all patients. Seven (53.8%) patients in the no-RRT group and 11/11 (100%) in the RRT group were extubated and regained full consciousness after LDLT (p = 0.013). The 90-day mortality was 6/13 (46.1%) and 2/11 (18.1%) (p = 0.211). There was no brainstem herniation-related mortality in the RRT group, that is, 5/13 (38.4%) and 0/11 (0%) (p = 0.030). The 1-year posttransplant survival was also significantly higher in the RRT group (p = 0.031). The use of RRT lowers serum ammonia levels and might reduce posttransplant mortality due to brainstem herniation.

Clinical Profile and Outcomes of Children with Acute Liver Failure in a Tertiary Care Center in South India: A Retrospective Study.

In this study, we investigated the clinical profile, survival at discharge, and proportion of children with acute liver failure (ALF) meeting the criteria for, yet surviving without, liver transplantation (LT). Medical case records of children aged >28 days to ≤15 years over a period of 7 years, identified from pediatric admission and discharge registers, were screened. Children satisfying the criteria for ALF were included in this study. A total of 71 records meeting the pediatric ALF (PALF) criteria were included. The survival rate at discharge was 61% (n=44). A considerable proportion of children satisfied the King's College Criteria (KCC) (56.3%) and the European Association for the Study of the Liver (EASL) criteria (7%) for LT at admission. Nonetheless, the survival rate in the absence of LT was 42.5% in children who satisfied the KCC and 20% in those who met the EASL criteria. Infection (29.5%) and paracetamol overdose (19.7%) were the major identifiable causes of PALF. Hepatitis A was the most common infection identified. No significant predictors of poor outcomes were identified in multivariable analysis. Our study highlights the changing survival rates and the clinical and etiological profiles of patients with PALF. In areas with poor access to LT services, survival in these children could be improved through early referral to centers with adequate intensive care facilities. Preventing ALF and referring patients to LT services are paramount to reducing mortality.

Live donor liver transplantation for pediatric acute liver failure: challenges and outcomes.

This study aimed at studying the challenges and outcomes of live-donor liver transplantation (LDLT) for pediatric acute liver failure (PALF). A total of 315 patients with PALF were treated over a period of 11years. 42 underwent LT (41 LDLT and one DDLT), constituting 38% (41/110) of all pediatric transplants during this duration. The outcomes of LDLT for PALF were analyzed. All the 41 children who underwent LT met the Kings College criteria (KCC). The etiology was indeterminate in 46.3% (n = 19) children. 75.6% (n = 31) were on mechanical ventilation for grade 3/4 hepatic encephalopathy. There was presence of cerebral edema on a computed tomography scan of the brain in 50% of the children. One-third of our children required hemodynamic support with vasopressors. Systemic inflammatory response syndrome and sepsis were observed in 46.3% and 41.4% of patients, respectively. Post-LDLT 1- and 5-yr patient and graft survival were 75.6% and 70.9%, respectively. The survival in children satisfying KCC but did not undergo LT was 24% (38/161). Vascular and biliary complication rates were 2.4% and 4.8%, respectively. No graft loss occurred because of acute rejection. In multivariate analysis, pre-LT culture positivity and cerebral edema, persistence of brain edema after transplantation, and resultant pulmonary complications were significantly associated with post-LT death. Thirteen (32%) children who underwent plasmapheresis prior to LT had better post-LT neurological recovery, as evidenced by early extubation. LDLT for PALF is lifesaving and provides a unique opportunity to time transplantation. Good long-term survival can be achieved, despite the majority of patients presenting late for transplantation. Early referral and better selection can save more lives through timely transplantation.

Selection Liver Transplantation and Bridge Therapeutic Modalities in Acute Liver Failure

Introduction: Acute liver failure (ALF) is a condition that can rapidly progress to multiorgan failure. Therefore, different extracorporeal liver support systems have been developed to function as a bridge to transplantation or spontaneous survival. Conversely, the shortage of organs demands a rigorous selection process to determine whom should receive transplantation and several prognostic models have been proposed to identify the patients who would benefit the most from liver transplantation (LT). Objectives: A review of the main selection criteria used for LT in ALF is carried out, focusing mostly on the new proposed prognostic markers, and aiming to identify poor prognosis criteria associated with futility in LT. Extracorporeal liver support systems (ECLS) were also reviewed, including an analysis of their impact on the survival of patients with ALF. Methods: MEDLINE and PubMed databases were searched between 16th October 2021 and 5th December 2021. The inclusion criteria were: adult patients; patients with acute liver injury (ALI) or ALF; observational studies; clinical studies; case series; case-control studies; systematic reviews; meta-analysis. Discussion: King’s College criteria (KCC) have been widely used and despite good specificity, have low sensitivity. Several markers have been used to improve prognostic accuracy, but the results are not sufficiently clear. Patient age, ABO incompatibility, and poor-quality grafting were potential factors that could indicate potential futility in LT. ECLS have a positive influence in clinical and laboratory parameters; however, there is no clear evidence of improvement in survival. Conclusion: ALF is a heterogeneous syndrome, which brings into question of the studies carried out to evaluate prognostic criteria to select patients for LT. It also narrows down the studies performed to evaluate the impact of ECLS on survival.

Acute Liver Failure: Biomarkers Evaluated by the Acute Liver Failure Study Group.

There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King's College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI.

Liver Transplantation for Metamizole induced Acute Liver Failure

Metamizole, or dipyrone, is a frequently prescribed analgetic drug that can cause drug-induced liver injury (DILI). Still, there are only a few metamizole-associated DILI cases (n=61, including our study) described in the literature. So far liver transplantation has been reported in 6 patients with metamizole-induced acute liver failure. In 2020, a German group described a bigger cohort (n=23) of metamizole-related DILI. Shortly thereafter, this issue gained wider attention as the German Federal Institute for Drugs and Medical Devices published a Direct Healthcare Professional Communication, emphasizing DILI as a potential adverse event caused by metamizole. We herein report 2 patients that were admitted to our liver transplant center due to acute liver failure (ALF) in April and May 2021. Both patients reported intake of metamizole as pain medication over a few weeks. After ruling out alternative reasons for ALF and fulfilling the King's College criteria both patients received emergency liver transplantations in our center. Pathology assessment of both explants were consistent with metamizole-associated DILI. As illustrated by our 2 cases of metamizole-induced liver failure with subsequent liver transplantation, this rare but presumably often overlooked adverse drug effect of metamizole should be considered as differential diagnosis in cases of cryptogenic liver failure.

Low platelets: a new and simple prognostic marker for patients with hepatitis E virus-related acute liver failure.

Hepatitis E virus-related acute liver failure (HEV-ALF) rapidly worsens and has a high mortality. However, no simple and specific parameters for predicting short-term mortality are available. A derivation cohort including 97 patients with HEV-ALF and another validation cohort were enrolled. Laboratory and clinical parameters were recorded. Platelet count, model for end-stage liver disease (MELD), and King's College criteria (KCC) were separately used for predicting mortality, and the levels of cytokines associated with systemic inflammation, platelet production, and plateletactivation were measured. Platelet counts were significantly lower in patients with HEV-ALF, and nonsurvivors had lower platelet counts than survivors (p < 0.001). Platelet count was an independent risk factor forpredicting 28- and 90-day mortality in patients with HEV-ALF. The AUROC of the baseline platelet count (cutoff, 131 × 109/L) for 28- and 90-day mortality was 0.786 and 0.764, respectively, which was superior to KCC score (p < 0.05) and comparable to MELD score. Furthermore, the platelet counts at 3 and 7days after ALF diagnosis had similar predictive power for 28- and 90-day mortality. The value of platelet count was also confirmed in the validation cohort. Moreover, platelet-associated cytokines, including thrombopoietin, platelet factor 4, and P-selectin, were increased in patients with HEV-ALF. Decreased platelet count is a simple and reliable indicator for predicting 28- and 90-day mortality in patients with HEV-ALF. Overactivation of platelets is an important risk for platelet countsdecrease, and treatment aiming at platelet count recovery may be considered.

The Role of Predictive Models in the Assessment of the Poor Outcomes in Pediatric Acute Liver Failure.

Objectives: In children, acute liver failure (ALF) is a severe condition with high mortality. As some patients need liver transplantation (LT), it is essential to predict the fatal evolution and to refer them early for LT if needed. Our study aimed to evaluate the prognostic criteria and scores for assessing the outcome in children with ALF. Methods: Data of 161 children with ALF (54.66% female, mean age 7.66 ± 6.18 years) were analyzed based on final evolution (32.91% with fatal evolution or LT) and etiology. We calculated on the first day of hospitalization the PELD score (109 children), MELD, and MELD-Na score (52 children), and King’s College Criteria (KCC) for all patients. The Nazer prognostic index and Wilson index for predicting mortality were calculated for nine patients with ALF in Wilson’s disease (WD). Results: PELD, MELD, and MELD-Na scores were significantly higher in patients with fatal evolution (21.04 ± 13.28 vs. 13.99 ± 10.07, p = 0.0023; 36.20 ± 19.51 vs. 20.08 ± 8.57, p < 0.0001; and 33.07 ± 8.29 vs. 20.08 ± 8.47, p < 0.0001, respectively). Moreover, age, bilirubin, albumin, INR, and hemoglobin significantly differed in children with fatal evolution. Function to etiology, PELD, MELD, MELD-Na, and KCC accurately predicted fatal evolution in toxic ALF (25.33 vs. 9.90, p = 0.0032; 37.29 vs. 18.79, p < 0.0001; 34.29 vs. 19.24, p = 0.0002, respectively; with positive predicting value 100%, negative predicting value 88.52%, and accuracy 89.23% for King’s College criteria). The Wilson index for predicting mortality had an excellent predictive strength (100% sensibility and specificity), better than the Nazer prognostic index. Conclusions: Prognostic scores may be used to predict the fatal evolution of ALF in children in correlation with other parameters or criteria. Early estimation of the outcome of ALF is essential, mainly in countries where emergency LT is problematic, as the transfer to a specialized center could be delayed, affecting survival chances.

The Use of Ischemia Modified Albumin as a Predictive and Prognostic Biomarker in Patients with Non–Acetaminophen-Induced Acute Liver Failure

Background: King College criteria (KCC) and Model for End-Stage Liver Disease (MELD) score are the most commonly used criteria in the follow-up of patients with acute liver failure (ALF). However, these criteria cannot always predict prognosis and the need for liver transplantation (LT). Aim: This study aimed to investigate to usability of ischemia modified albumin (IMA) and IMA/albumin ratio (IMAR) values in the follow-up of ALF patients. Methods: IMA and IMAR values of 23 ALF patients and 43 healthy volunteers were measured. Then IMA and IMAR values were compared with KCC and MELD score to predict LT requirement and prognosis in ALF patients. Results: IMA and IMAR values were significantly higher in ALF patients compared healthy volunteers (p=0.001, p=0.001; respectively). IMA and IMAR values predicted LT requirement in ALF patients such as KCC and MELD (≥30) score (p=0.006, p=0.04, p=0.001, p=0.03; respectively). IMA values were found to better than KCC in predicting mortality (p=0.008, p=0.02; respectively). MELD (≥30) score failed to predict mortality (p=0.44). Conclusion: IMA and IMAR values can be used as diagnostic biomarkers in ALF patients. IMA is a better prognostic biomarker in the follow-up of ALF patients.

Refeeding syndrome in surgical patients post initiation of artificial feeding, a prospective cohort study in a low-income country.

South Africa's inequitable history has contributed to a malnourished population, further aggravated by high levels of violence and economic uncertainty culminating in a population suffering the sequelae of poverty. The perceived notion is that malnutrition places the South African population at greater risk for development of refeeding syndrome. This study aimed to identify the incidence of refeeding syndrome in the South African population. All patients admitted into the surgical intensive care unit from 1 November 2019 to 30 September 2020, were screened using the National Institute for Health and Care Excellence (NICE) refeeding risk criteria. Patients started on artificial feeds with one or more risk factors were included in the study. The syndrome was confirmed using the King's College criteria and compared with the American Society for Parenteral and Enteral Nutrition (ASPEN) criteria for refeeding syndrome. 200 Patients were included in this study. The median age of the sample population was 41 years (IQR 30-58) with a male predominance (63%). All patients included had one or more risk factors and 62 (31%) of patients fulfilled the NICE criteria. The sensitivity of the NICE criteria was 33% and specificity was 70%. The most common risk factors identified were little or no nutritional intake for >5 days (55%) followed by a history of alcohol abuse, drugs including insulin, chemotherapy, diuretics or antacids (18%). Specificity values for all risk factors were >80% apart from little or no nutritional intake for >5 days which had a specificity of 64.2%. Sensitivity values for all risk factors were low. 84.5% of patients received artificial nutritional support in the form of enteral feeds, 9% parenteral and 6.5% both enteral and parenteral feeds. A total of 146 patients required electrolyte supplementation. Three patients fulfilled the King's College criteria and one subsequently died. In comparison, 25 patients fulfilled the ASPEN criteria and 3 demised. Due to the low sensitivity and specificity of the NICE criteria, we advise that it be used merely as a guideline to identify patients at risk of refeeding syndrome and one should remain vigilant in patients with any risk factors present. Due to the small number of patients who fulfilled the King's College criteria and significant difference in incidence when compared to the ASPEN definition, a conclusion regarding the accuracy of both diagnostic criteria could not be made. We recommend a review of the current definition and a global adoption of an agreed criteria for the estimation of the true prevalence.

Use of the Molecular Adsorbent Recirculating System in Acute Liver Failure: Results of a Multicenter Propensity Score-Matched Study.

The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy. Propensity score-matched retrospective cohort analysis. Tertiary North American liver transplant centers. Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry. Molecular adsorbent recirculating system treatment versus standard medical therapy (control). One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all). Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure.

The utility of biomarkers in prognosis assessment of patients with acute liver failure.

Acute liver failure (ALF) is a rare but potential lethal condition characterized by the sudden development of jaundice, coagulopathy and hepatic encephalopathy in patients without underlying liver disease. In selected patients, emergency liver transplantation is required. Selection of these patients is based on clinical criteria such as the Kings College Criteria (KCC) or the Clichy criteria. The aim of this work is to provide an overview of potential biomarkers that could improve the prognostic value of KCC. Several promising biomarkers involved in related pathophysiological processes have been identified. Some could be as stand-alone biomarkers; however, the best prognostic values have been observed in the combination of biomarkers with current models. Among these, the ALFSG Index that combines clinical parameters and circulating blood levels of CK18 claims a higher prognostic value than KCC. In this review, all potential biomarkers for ALF have been summarized to give an overview of the work performed over the last years, and a glimpse of what to expect in this field in the coming years.

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure

Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC= 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC= 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

S2568 DDD: Diagnostic Dilemma in Drug Induced Liver Injury: Adverse Reaction of Abiraterone in Treatment of Metastatic Prostate Cancer

INTRODUCTION: Drug-induced liver injury (DILI) is a benign and reversible form of liver injury that occurs as an adverse reaction to medication use. It is a leading cause of acute liver failure and requires prompt recognition and discontinuation of the offending agent to avoid development of chronic disease. We present a case of severe DILI secondary to Abiraterone use in a patient with prostate cancer. CASE DESCRIPTION/METHODS: A 67 year-old-male without known liver disease was seen for severely elevated liver enzymes, jaundice and abdominal pain. Pertinent history includes stage IV prostate cancer with metastasis to the bone and lymph nodes with initiation of Abiraterone four months prior. He denies excessive alcohol, acetaminophen or herbal supplement use. Initial liver panel results: AST 1668 (peak 2379), ALT 3093 (peak 3330), alk phos 185 (peak 361) and TB 14.3 (peak 29). INR was 1.40 (peak 1.65). While transplant center transfer was considered, given patient's stability and not meeting King's College Criteria for acute liver failure, this decision was deferred and he was placed on NAC for 48 hours. Extensive workup for other causes of elevated liver enzymes were negative including: Wilson’s disease, autoimmune hepatitis, HAV, HBV, HCV, EBV, HSV, CMV, alpha 1 antitrypsin deficiency, portal vasculature thrombosis and acetaminophen toxicity. Core needle biopsies revealed acute hepatitis with confluent and bridging necrosis as well as mild Kupffer cell siderosis with iron accumulation. Serum ferritin level was 28,441 and IgG4 was mildly elevated, which prompted concern for hemophagocytic lymphohistiocytosis(HLH), hemochromatosis and autoimmune cholangiopathy. Patient did not meet criteria for HLH, hemochromatosis types I-IV in the absence of HFE, HFE2, TFR2, HAMP and SLC40A1 gene mutations, nor did MRI or pathology staining reveal IgG4 cholangiopathy. LFTs normalized within four months and ferritin within six months. Abiraterone was not restarted. DISCUSSION: Abiraterone is an antiandrogen that inhibits CYP17. Although the mechanism of hepatic injury is unknown, Abiraterone has been shown to cause elevations in serum aminotransferase levels in up to 13% of patients and ALT elevations above 5x the ULN in 6% of patients, however only few documented cases are known in which patients displayed associated symptoms such as jaundice and no documentation of severe elevations in serum ferritin as seen in our patient. This case also highlights the diagnostic challenge in DILI.Figure 1.: A. Mild to moderate predominantly lymphocytic inflammation. B. Intact bile ducts.Figure 2.: Confluent necrosis with areas of bridging necrosis.Figure 3.: Iron stain with Kupffer cell siderosis.

Acute Liver Failure Secondary to Yellow Phosphorus Rodenticide Poisoning: Outcomes at a Center With Dedicated Liver Intensive Care and Transplant Unit

BackgroundAccidental or suicidal poisoning with yellow phosphorus or metal phosphides (YPMP) such as aluminum (AlP) zinc phosphide (Zn3P2) commonly causes acute liver failure (ALF) and cardiotoxicity. These are used as household, agricultural, and industrial rodenticides and in production of ammunitions, firecrackers, and fertilizers. In absence of a clinically available laboratory test for diagnosis or toxin measurement or an antidote, managing their poisoning is challenging even at a tertiary-care center with a dedicated liver intensive care unit (LICU) and liver transplant facility.MethodsPatients with YPMP-related ALF were monitored using standardized clinical, hemodynamic, biochemical, metabolic, neurological, electrocardiography (ECG), and sequential organ failure assessment (SOFA) score and managed using uniform intensive care, treatment, and transplant protocols in LICU. Sociodemographic characteristics, clinical and biochemical parameters, and scores were summarized and compared between 3 groups i.e. spontaneous survivors, transplanted patients, and non-survivors. Predictors of spontaneous survival and the need for liver transplant are also evaluated.ResultsNineteen patients with YPMP-related ALF were about 32 years old (63.2% females) and presented to us at a median of 3 (0–10) days after poisoning. YPMP-related cardiotoxicity was rapidly progressive and fatal, whereas liver transplant was therapeutic for ALF. Spontaneous survivors had lower-dose ingestion (<17.5 g), absence of cardiotoxicity, < grade 3 hepatic encephalopathy (HE), lactate < 5.8, SOFA score < 14.5, and increase in SOFA score by < 5.5. Patients with renal failure need for continuous veno-venous hemodiafiltration (CVVHDF) and King College criteria positivity on account of prothrombin time and international normalized ratio (PT-INR) > 6.5 had higher mortality risk. Patients undergoing liver transplant and with spontaneous recovery required longer intensive care unit and hospital stay. At median follow-up of 3.4 (2.6–5.5) years, all spontaneous survivors and transplanted patients are well with normal liver function.ConclusionsEarly transfer to a specialized center, preemptive close monitoring, and intensive care and organ support with ventilation, CVVHDF, plasmapheresis, and others may maximize their chances of spontaneous recovery, allowing accurate prognostication and a timely liver transplant.