A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure.

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.

Waitlist and posttransplant outcomes of pregnancy-related acute liver failure in the United States.

Data on the liver transplant (LT) outcomes of women with acute liver failure (ALF) due to liver diseases unique to pregnancy (P-ALF) are limited. Using United Network of Organ Sharing (UNOS) data (1987-2021), we analyzed waitlist and post-LT outcomes of ALF in women of childbearing age comparing P-ALF versus ALF due to liver diseases not unique to pregnancy. Baseline characteristics were compared between groups at the time of listing for LT. Of 3542 females aged 16-43 years and listed for LT for ALF, 84 (2%) listed for P-ALF were less likely to be Black (11 vs. 21%, p =0.033), have lower international normalized ratio (2.74 vs. 4.53 p <0.002), but more likely to have respiratory failure (56% vs. 41%, p <0.005), be on pressors (58% vs. 43%, p <0.005), and require dialysis (23% vs. 10%, p <0.001). The cumulative 90-day waitlist mortality (WLM) was lower in P-ALF vs. ALF due to liver diseases not unique to pregnancy (7.4 vs. 16.6%, p <0.001). Posttransplant survival rates at 5 years were similar (82% vs. 79%, p =0.89). In a Fine and Gray regression model controlled for listing year and Model for End-Stage Liver Disease score, 90-day WLM was lower in P-ALF with a sub-HR of 0.42 (95% CI: 0.19-0.94, p =0.035). Of 84 women with P-ALF and listed for LT, 45 listed for hemolysis-elevated liver enzymes-low platelets (HELLP) versus 39 for acute fatty liver of pregnancy had higher 90-day WLM (19.3% vs. 5.7% p <0.005). The 90-day WLM was about 10-fold higher in HELLP versus acute fatty liver of pregnancy with a sub-HR of 9.97 (95% CI: 1.64-60.55, p =0.013). In this UNOS database analysis of ALF among women of childbearing age, the waitlist outcome is better in women with P-ALF compared to women with ALF due to liver diseases not unique to pregnancy. Among women with P-ALF, the 90-day WLM is worse for HELLP versus acute fatty liver of pregnancy. Further studies are needed to improve the management of HELLP and prevent the development of ALF in this subgroup population.

Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes.

OBJECTIVE: To develop neonate-specific prediction models for survival with native liver (SNL) in neonatal acute liver failure (ALF) and to determine if these prediction models have superior accuracy to existing models for older children with ALF. STUDY DESIGN: A single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction). Statistical analysis included comparison of patients by outcome of SNL and generalized linear modeling to derive prediction models. The predictive accuracy of variables was evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis. RESULTS: A total of 51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). Overall SNL rate was 43% (n = 22). Alpha fetoprotein levels were higher in SNL patients (P = .034) and differed more significantly by SNL status among nongestational alloimmune liver disease patients (n = 21, P = .001). An alpha fetoprotein < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in nongestational alloimmune liver disease patients with an area under the ROC curve of 0.81. A neonate-specific admission model (international normalized ratio and ammonia) and peak model (prothrombin time and ammonia) also predicted SNL with good accuracy (area under the ROC curve = 0.73 and 0.82, respectively). CONCLUSIONS: We identified neonate-specific prognostic variables for SNL in ALF. Findings from our study may help early risk stratification to guide medical decision-making and consideration for liver transplantation.

Ammonia and urea metabolism in acute liver failure: A multicentre cohort study.

BACKGROUND & AIMS: Ammonia is metabolized into urea in the liver. In acute liver failure (ALF), ammonia has been associated with survival. However, urea variation has been poorly studied. METHODS: Observational cohort including ALF patients from Curry Cabral Hospital (Lisbon, Portugal) and Clinic Hospital (Barcelona, Spain) between 10/2010 and 01/2023. The United States ALF Study Group cohort was used for external validation. Primary exposures were serum ammonia and urea on ICU admission. Primary endpoint was 30-day transplant-free survival (TFS). Secondary endpoint was explanted liver weight. RESULTS: Among 191 ALF patients, median (IQR) age was 46 (32; 57) years and 85 (44.5%) were males. Overall, 86 (45.0%) patients were transplanted and 75 (39.3%) died. Among all ALF patients, following adjustment for age, sex, body weight, and aetiology, higher ammonia or lower urea was independently associated with higher INR on ICU admission (p < .009). Among all ALF patients, following adjustment for sex, aetiology, and lactate, higher ammonia was independently associated with lower TFS (adjusted odds ratio (95% confidence interval [CI]) = 0.991 (0.985; 0.997); p = .004). This model predicted TFS with good discrimination (area under receiver operating curve [95% CI] = 0.78 [0.75; 0.82]) and reasonable calibration (R2 of 0.43 and Brier score of 0.20) after external validation. Among transplanted patients, following adjustment for age, sex, actual body weight, and aetiology, higher ammonia (p = .024) or lower (p < .001) urea was independently associated with lower explanted liver weight. CONCLUSIONS: Among ALF patients, serum ammonia and urea were associated with ALF severity. A score incorporating serum ammonia predicted TFS reasonably well.

Outcomes and management in paediatric autoimmune hepatitis presenting as acute liver failure: Individual patient data meta-analysis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF). METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. RESULTS: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04). CONCLUSION: While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.

Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Clinical Features of Hepatic Manifestations among Adult Patients with Hemophagocytic Lymphohistiocytosis: A Retrospective Study.

INTRODUCTION: Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH. METHODS: A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. RESULTS: The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥60 years (p = 0.016), blood urea nitrogen (BUN) ≥7 µmol/L (p < 0.001), and malignancy-associated HLH (p < 0.001) at the diagnosis of HLH were identified as being strongly correlated with 30-day prognosis. An excellent predictive power was found. Among the predictive scores used to assess early death of HLH patients with liver injury, the prognostic efficiency of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) (AUROC: 0.936 ± 0.0211) and SOFA score (0.901 ± 0.026) were significantly better than those of the APACHE II (p < 0.001), model for end-stage liver disease score (p < 0.001) and CTP scores (p < 0.001). CONCLUSION: Patients with old age, elevated BUN, and malignancy had inferior survival. CLIF-SOFA and SOFA enable more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

Role of high-volume plasmapheresis in the management of paediatric acute liver failure.

OBJECTIVES: Paediatric acute liver failure (PALF) is a life-threatening disease. Management aims to support hepatic regeneration or to bridge to liver transplantation. High-volume plasmapheresis (HVP) removes protein-bound substances, alleviates inflammation, and improves survival in adult acute liver failure. However, experience with HVP in PALF is limited. Aim of this study is to report on feasibility, safety, efficacy and outcomes of HVP in PALF. METHODS: Retrospective observational study in children with PALF. HVP was performed upon identification of negative prognostic indicators, in toxic aetiology or multiorgan failure (MOF). Exchanged volume with fresh-frozen plasma corresponded to 1.5-2.0 times the patient's estimated plasma volume. One daily cycle was performed until the patient met criteria for discontinuation, that is, liver regeneration, liver transplantation, or death. RESULTS: Twenty-two children with PALF (body weight 2.5-106 kg) received 1-7 HVP cycles. No bleeding or procedure-related mortality occurred. Alkalosis, hypothermia and reduction in platelets were observed. Haemolysis led to HVP termination in one infant. Seven children (32%) survived with their native livers, 13 patients (59%) underwent liver transplantation. Two infants died due to MOF. Overall survival was 86%. International normalization ratio (INR), alanine aminotransaminases (ALT), bilirubin and inotropic support were reduced significantly (p < 0.05) after the first HVP-cycle (median): INR 2.85 versus 1.5; ALT 1280 versus 434 U/L; bilirubin 12.7 versus 6.7 mg/dL; norepinephrine dosage 0.083 versus 0.009 µg/kg/min. Median soluble-interleukin-2-receptor dropped significantly following HVP (n = 7): 2407 versus 950 U/mL (p < 0.02). CONCLUSIONS: HVP in PALF is feasible, safe, improves markers of liver failure and inflammation and is associated with lowering inotropic support. Prospective and controlled studies are required to confirm efficacy of HVP in PALF.

Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China.

Neonatal acute liver failure (NALF), as a rare disease with high mortality, has limited relevant literature reports in China. We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28 days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group (P < 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48 days; 26 days for hypoxic/ischemic injury and 43 days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients (P = 0.018).   Conclusion: Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology. What is Known: • Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China. • Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations. • There are no reliable biochemical markers to predict the outcome of NALF. What is New: • In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF. • The overall prognosis of NALF is poor, and its etiology determines the short-term outcome.

Is there a role for extracorporeal membrane oxygenation in children with acute liver failure? A retrospective analysis of the Extracorporeal Life Support Organization Registry.

Data describing the use of extracorporeal membrane oxygenation (ECMO) in pediatric acute liver failure (PALF) are scarce. Thus, we aimed to describe the use of ECMO in patients with PALF using the data from the Extracorporeal Life Support Organization (ELSO) Registry between January 1, 2010, to December 31, 2022. We described patients' characteristics at ECMO initiation, outcome, and factors associated with mortality. A total of 335 children underwent ECMO support in the context of PALF. Veno-arterial (VA) ECMO was the most prevalent mode (66.6%), followed by veno-venous (VV) ECMO (33.4%). Extracorporeal cardiopulmonary resuscitation (ECPR) was used in 21.5% of the cardiac arrest. In-hospital mortality was 66.6%. Both higher lactate (OR 1.128, CI 1.06-1.209, p < 0.001) and PaCO2 (OR 1.022, CI 1.001-1.047, p 0.05) levels before ECMO reported greater odds of mortality. Low body weight, persistence of hyperlactatemia (OR 0.985, CI 0.973-0.997, p 0.013), and hyperbilirubinemia (OR 2.477, CI 1.042-6.100, p 0.045) after 24 h from ECMO deployment were associated to greater odds of mortality. CONCLUSIONS: Our results suggest that the use of ECMO for the management of respiratory and cardiac failure in patients with PALF should be considered with caution and that further research is needed to understand its role in this specific high-risk population. WHAT IS KNOWN: • Pediatric acute liver failure (PALF) is a clinical syndrome associated with significant morbidity and mortality. • Data on the use of extracorporeal membrane oxygenation (ECMO) in the context of PALF are scarce and controversial. WHAT IS NEW: • ECMO to manage acute respiratory and/or cardiac failure in the context of PALF should be considered with caution. • Bleeding and thrombotic complications in children with acute liver failure receiving ECMO are similar to the ones reported in the general pediatric population.

Continuous renal replacement therapy and therapeutic plasma exchange in pediatric liver failure.

Patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) have significant morbidity and mortality. They require extracorporeal blood purification modalities like continuous renal replacement therapy (CRRT) and therapeutic plasma exchange (TPE) as a bridge to recovery or liver transplantation. Limited data are available on the outcomes of patients treated with these therapies. This is a retrospective single-center study of 23 patients from 2015 to 2022 with ALF/ACLF who underwent CRRT and TPE. We aimed to describe the clinical characteristics and outcomes of these patients. Median (IQR) age was 0.93 years (0.57, 9.88), range 16 days to 20 years. Ten (43%) had ALF and 13 (57%) ACLF. Most (n = 19, 82%) started CRRT for hyperammonemia and/or hepatic encephalopathy and all received TPE for refractory coagulopathy. CRRT was started at a median of 2 days from ICU admission, and TPE started on the same day in most. The liver transplant was done in 17 (74%), and 2 recovered native liver function. Four patients, all with ACLF, died prior to ICU discharge without a liver transplant. The median peak ammonia pre-CRRT was 131 µmol/L for the whole cohort. The mean (SD) drop in ammonia after 48 h of CRRT was 95.45 (43.72) µmol/L in those who survived and 69.50 (21.70) µmol/L in those who did not (p 0.26). Those who survived had 0 median co-morbidities compared to 2.5 in non-survivors (aOR (95% CI) for mortality risk of 2.5 (1.1-5.7), p 0.028). Conclusion: In this cohort of 23 pediatric patients with ALF or ACLF who received CRRT and TPE, 83% survived with a liver transplant or recovered with their native liver. Survival was worse in those who had ACLF and those with co-morbid conditions. What is Known: •  Pediatric acute liver failure is associated with high mortality. •  Patients may require extracorporeal liver assist therapies (like CRRT, TPE, MARS, SPAD) to bridge them over to a transplant or recovery of native liver function. What is New: • Standard volume plasma exhange has not been evaluated against high volume plasma exchange for ALF. • The role, dose, and duration of therapeutic plasma exchange in patients with acute on chronic liver failure is not well described.

Prevalence, Associated Factors, and Outcomes of Severe Acute Kidney Injury in Pediatric Acute Liver Failure: Single-Center Retrospective Study, 2003-2017.

OBJECTIVES: Our aim was to determine the prevalence and explanatory factors associated with outcomes in children with acute liver failure (ALF) admitted to the PICU, who also develop severe acute kidney injury (AKI). DESIGN: Retrospective cohort, 2003 to 2017. SETTING: Sixteen-bed PICU in a university-affiliated tertiary care hospital. PATIENTS: Admissions to the PICU with ALF underwent data review of the first week and at least 90-day follow-up. Patients with stages 2-3 AKI using the British Association of pediatric Nephrology definitions, or receiving continuous renal replacement therapy (CRRT) for renal indications, were defined as severe AKI. We excluded ALF cases on CRRT for hepatic-only indications. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics, proportion with severe AKI, illness severity and interventions, and outcomes (i.e., transplant, survival with native liver, overall survival, duration of PICU stay, and mechanical ventilation). Ninety-four children with ALF admitted to the PICU were included. Over the first week, 29 had severe AKI, and another eight received CRRT for renal/mixed reno-hepatic indications; hence, the total severe AKI cohort was 37 of 94 (39.4%). In a multivariable logistic regression model, peak aspartate aminotransferase (AST) and requirement for inotropes on arrival were associated with severe AKI. Severe AKI was associated with longer PICU stay and duration of ventilation, and lower spontaneous survival with native liver. In another model, severe AKI was associated with greater odds of mortality (odds ratio 7.34 [95% CI, 1.90-28.28], p = 0.004). After 90 days, 3 of 17 survivors of severe AKI had serum creatinine greater than the upper limit of normal for age. CONCLUSIONS: Many children with ALF in the PICU develop severe AKI. Severe AKI is associated with the timecourse of PICU admission and outcome, including survival with native liver. Future work should look at ALF goal directed renoprotective strategies at the time of presentation.

Therapeutic plasma exchange provides native liver survival benefit in children with acute liver failure: A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the safety and efficacy of therapeutic plasma exchange (TPE) in pediatric acute liver failure (PALF). METHODS: All children aged 2-18 years with PALF were included. The intervention cohort included a subset of PALF patients undergoing complete three sessions of TPE, whereas the matching controls were derived by propensity score matching from the patient cohort who did not receive any TPE. Propensity matching was performed based on the international normalized ratio (INR), grade of hepatic encephalopathy (HE), age, bilirubin, and ammonia levels. The primary outcome measure was native liver survival (NLS) in the two arms on day 28. RESULTS: Of the total cohort of 403 patients with PALF, 65 patients who received TPE and 65 propensity-matched controls were included in analysis. The 2 groups were well balanced with comparable baseline parameters. On day 4, patients in the TPE group had significantly lower INR (P = 0.001), lower bilirubin (P = 0.008), and higher mean arterial pressure (MAP) (P = 0.033) than controls. The NLS was 46.15% in the TPE arm and 26.15% in the control arm. The overall survival (OS) was 50.8% in the TPE arm and 35.4% in the control arm. Kaplan-Meier survival analysis showed a significantly higher NLS in patients receiving TPE than controls (P = 0.001). On subgroup analysis, NLS benefit was predominantly seen in hepatitis A-related and indeterminate PALF. CONCLUSION: TPE improved NLS and OS in a propensity-matched cohort of patients with PALF. Patients receiving TPE had lower INR and bilirubin levels and higher MAP on day 4.

Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome.

BACKGROUND AND AIMS: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. APPROACH AND RESULTS: A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients. CONCLUSIONS: Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.

Contrast-Enhanced Ultrasonography-Based Hepatic Perfusion for Early Prediction of Prognosis in Acute Liver Failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker. APPROACH AND RESULTS: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively. CONCLUSIONS: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making.

VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure.

BACKGROUND AND AIMS: Recent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of patients with well-characterized ALF from the Acute Liver Failure Study Group. APPROACH AND RESULTS: Citrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (international normalized ratio ≥2.0 without hepatic encephalopathy) were used to determine levels of von Willebrand factor (VWF), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity, thrombomodulin-modified thrombin generation, and clot lysis time (CLT) and compared with the levels in 40 healthy controls. Patients had 3-fold increased VWF levels, 4-fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4-fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared with transplant-free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and nonbleeding patients. CONCLUSIONS: Rebalanced hemostatic status was confirmed in a large cohort of patients with acute liver injury/ALF, demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggests that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy.

Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure.

BACKGROUND AND AIMS: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival. APPROACH AND RESULTS: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver. CONCLUSIONS: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

Prognostic Value of the 13 C-Methacetin Breath Test in Adults with Acute Liver Failure and Non-acetaminophen Acute Liver Injury.

BACKGROUND AND AIMS: The 13 C-methacetin breath test (MBT) is a noninvasive, quantitative hepatic metabolic function test. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13 C-MBT in predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI). APPROACH AND RESULTS: The 13 C-MBT BreathID device (Exalenz Biosciences, Ltd.) provided the percent dose recovery (PDR) for a duration of 60 minutes after administration of 13 C-methacetin solution as the change in exhaled 13 CO2 /12 CO2 compared with pre-ingestion ratio on study days 1, 2, 3, 5, and 7. Results were correlated with 21-day transplant-free survival and other prognostic indices. A total of 280 subjects were screened for enrollment between May 2016 and August 2019. Median age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian, 76% had ALF with the remaining 24% having ALI. The mean PDR peak on day 1 or day 2 was significantly lower in nonsurvivors compared with transplant-free survivors (2.3%/hour vs. 9.1%/hour; P < 0.0001). In addition, serial PDR peaks were consistently lower in nonsurvivors versus survivors (P < 0.0001). The area under the receiver operating characteristic curve (AUROC) of the 13 C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King's College (AUROC = 0.70) and Model for End-Stage Liver Disease scores (AUROC = 0.83). The 13 C-MBT was well tolerated with only two gastrointestinal adverse events reported. CONCLUSIONS: The 13 C-MBT is a promising tool to estimate the likelihood of hepatic recovery in patients with ALF and ALI. Use of the PDR peak data from the 13 C-MBT point-of-care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill patients with ALF and ALI.

Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.