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Objectives 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. Design Propensity score-matched retrospective cohort analysis. Setting Tertiary North American liver transplant centers. Patients 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. Interventions Molecular adsorbent recirculating system treatment versus standard medical therapy (control). Measurements and main results 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). Conclusions 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.

Transjugular intrahepatic portosystemic shunt (TIPS) is well established as a salvage therapy for refractory esophageal variceal hemorrhage (EVH). A more controversial issue is the upper limit of Model for End-Stage Liver Disease (MELD) scores at which this procedure can be performed safely. We present 2 cases of TIPS performed for EVH in patients with severely high MELD scores as a successful intervention for hemostatic and hemodynamic stabilization, and as a bridge to urgent liver transplantation. Both patients had endoscopically confirmed EVH with high blood product transfusion and vasopressor needs despite standard medical therapy. Each received narrow bore TIPS at MELD 42 and 44, respectively, with subsequent resolution of hemorrhage despite worsening synthetic liver function. Detrimental consequences of metabolic acidosis associated with minimal residual hepatic function were avoided via continuous renal replacement therapy and mechanical ventilation, with a goal to maintain cardiopulmonary stability and favorable acid base balance. Liver transplant followed TIPS 4 and 3 days, respectively, with both patients maintaining good functional status at discharge. Both cases suggest that in patients deemed otherwise appropriate for liver transplantation, a severely high MELD score alone should not preclude TIPS as salvage therapy for refractory EVH bleeds.

BACKGROUND: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility. METHODS: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement. RESULTS: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or 1 μg/kg per minute and a serum lactate level >9 mmol/L. CONCLUSIONS: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented., SCOPUS: ar.j, info:eu-repo/semantics/published

Hepatic hydrothorax (HH) remains a difficult-to-treat complication of cirrhosis. To define the mortality, length of stay (LOS), and risk of ACLF in patients admitted with HH. We utilized the North American Consortium for the Study of End-stage Liver Disease, a prospective cohort of 2868 non-electively hospitalized patients with cirrhosis from 14 tertiary care hepatology centers in North America. A total of 121 patients who required an inpatient thoracentesis (HH group) were compared to 736 patients with refractory ascites without HH, and to 1639 patients without these complications (Other). Patients with a TIPS before or during admission were excluded. There were no differences between the groups in age, gender, or liver disease etiology. Admission MELD (20.5, 21.6 vs. 18.7; p

Introduction Readmission and death in cirrhosis are common, expensive, and difficult to predict. Our aim was to evaluate the abilities of multiple artificial intelligence (AI) techniques to predict clinical outcomes based on variables collected at admission, during hospitalization, and at discharge. Methods We used the multicenter North American Consortium for the Study of End-Stage Liver Disease (NACSELD) cohort of cirrhotic inpatients who are followed up through 90-days postdischarge for readmission and death. We used statistical methods to select variables that are significant for readmission and death and trained 3 AI models, including logistic regression (LR), kernel support vector machine (SVM), and random forest classifiers (RFC), to predict readmission and death. We used the area under the receiver operating characteristic curve (AUC) from 10-fold crossvalidation for evaluation to compare sexes. Data were compared with model for end-stage liver disease (MELD) at discharge. Results We included 2,170 patients (57 ± 11 years, MELD 18 ± 7, 61% men, 79% White, and 8% Hispanic). The 30-day and 90-day readmission rates were 28% and 47%, respectively, and 13% died at 90 days. Prediction for 30-day readmission resulted in 0.60 AUC for all patients with RFC, 0.57 AUC with LR for women-only subpopulation, and 0.61 AUC with LR for men-only subpopulation. For 90-day readmission, the highest AUC was achieved with kernel SVM and RFC (AUC = 0.62). We observed higher predictive value when training models with only women (AUC = 0.68 LR) vs men (AUC = 0.62 kernel SVM). Prediction for death resulted in 0.67 AUC for all patients, 0.72 for women-only subpopulation, and 0.69 for men-only subpopulation, all with LR. MELD-Na model AUC was similar to those from the AI models. Discussion Despite using multiple AI techniques, it is difficult to predict 30- and 90-day readmissions and death in cirrhosis. AI model accuracies were equivalent to models generated using only MELD-Na scores. Additional biomarkers are needed to improve our predictive capability (See also the visual abstract at http://links.lww.com/AJG/B710).

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor–adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor–adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Little is known about patients discharged to hospice following hospitalization for complications of cirrhosis. We sought to understand the current pattern of hospice utilization in patients with cirrhosis by evaluating the North American Consortium for the Study of End-stage Liver Disease (NACSELD) cohort. Patients with cirrhosis from 14 tertiary-care hepatology centers across North America non-electively hospitalized and prospectively enrolled were evaluated. Exclusion criteria included HIV infection, transplantation or non-hepatic malignancy. Random computer-based propensity score matching was undertaken in a 1:2 ratio based on admission MELD score ± 3 points. Totally, 2718 patients were enrolled, 5% (N = 132) were discharged to hospice, 6% (N = 171) died, and the rest were discharged alive. Patients discharged to hospice were older (60 vs. 57 years, p = 0.04), less likely to have had SBP (13% vs. 28%, p = 0.002) and be listed for liver transplantation (11% vs. 26%, p = 0.0007). Features, on multivariable modeling, associated with increased probability of discharge to hospice as opposed to being discharged alive: grade-3–4 hepatic encephalopathy, a higher Child–Turcotte–Pugh (CTP) score, and a higher discharge serum creatinine; however, a higher serum sodium, being listed for transplant and being prescribed rifaximin or a statin were protective from hospice discharge. Patients with more advanced liver disease, hepatic encephalopathy, renal dysfunction, and those not candidates for liver transplantation were more likely to be discharged to hospice. However, in this sick multinational cohort of cirrhotic inpatients, it seems that hospice is markedly underutilized (5%) since 25% of patients not discharged to hospice died within 6 months.

Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure. We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence. We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain. ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.

Nosocomial infections (NIs) can be a major cause of morbidity and mortality in cirrhosis. This study aims to define the determinants of NI development and its impact on 30-day outcomes among hospitalized patients with cirrhosis.North American Consortium for the Study of End-Stage Liver Disease enrolled patients with cirrhosis who were admitted nonelectively. Admission variables and 30-day outcomes were compared between patients with and without NI. These were also compared based on whether there was an isolated admission infection, NI, or both. Models were created for NI development using admission variables and for 30-day mortality.The study included 2,864 patients; of which, 15% (n = 436) developed NI. When comparing NI vs no NI, 1,866 patients were found to be infection free, whereas 562 had admission infections only, 228 had only NI, and 208 had both infections. At admission, patients with NI were more likely to be infected and have advanced cirrhosis. NIs were associated with higher rates of acute-on-chronic liver failure, death, and transplant regardless of admission infections. Patients with NI had higher respiratory infection, urinary tract infection, Clostridium difficile infection, fungal infections, and infection with vancomycin-resistant enterococci compared with patients without NI. Risk factors for NIs were admission infections, model for end-stage liver disease (MELD)20, systemic inflammatory response syndrome criteria, proton pump inhibitor, rifaximin, and lactulose use, but the regression model (sensitivity, 0.67; specificity, 0.63) was not robust. Age, alcohol etiology, admission MELD score, lactulose use, acute-on-chronic liver failure, acute kidney injury, intensive care unit, and NI increased the risk of death, whereas rifaximin decreased the risk of death.NIs are prevalent in hospitalized patients with cirrhosis and are associated with poor outcomes. Although higher MELD scores and systemic inflammatory response syndrome are associated with NI, all hospitalized patients with cirrhosis require vigilance and preventive strategies.

Background & Aims 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. Methods 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. Results 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. Conclusions 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. Lay summary 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.

Supplemental Digital Content is available in the text., Background. The current surge of coronavirus 2019 (COVID-19) cases in certain parts of the country has burdened the healthcare system, limiting access to tertiary centers for many. As a result, COVID-19-positive Solid Organ Transplant (SOT) recipients are increasingly being managed by local healthcare providers. It is crucial for community providers to understand disease severity and know if COVID-19-impacted SOT recipients have a different clinical course compared with COVID-19-negative SOT recipients with a similar presentation. Methods. We conducted a retrospective analysis on SOT recipients suspected to have COVID-19 infection tested during March 14, 2020–April 30, 2020. Patients were followed from time of testing to May 31, 2020. Results. One hundred sixty SOT recipients underwent testing: 22 COVID-19 positive and 138 COVID-19 negative. COVID-19-positive patients were more likely to have rapid progression of symptoms (median 3 vs 6 d, P = 0.002), greater hospitalizations (78% vs 64%, P < 0.017), and need for intensive care unit care (45% vs 17%, P < 0.001) Severe COVID-19 infection was not observed in patients on Belatacept for immunosuppression (30% vs 87%,P = 0.001). COVID- 19 positive patients in the intensive care unit were more likely to have multifocal opacities on radiological imaging in comparison to those admitted to the medical floor (90% vs 11%). Survival probability was similar in both cohorts. Conclusion. COVID-19-infected SOT recipients have a propensity for rapid clinical decompensation. Local providers need to be work closely with transplant centers to appropriately triage and manage COVID-19 SOT recipients in the community.

Objective: Warfarin is the most commonly prescribed oral anticoagulant, although having a narrow therapeutic index and wide interindividual variability. The aim of this study was to replicate the utility of VKORC1 (−1639G>A) rs9923231 genotyping in predicting the mean daily dose and to evaluate its ability to categorize warfarin-treated patients to high-, intermediate-, or low-dose categories in the South Indian population. Materials and methods: A cohort of 222 warfarin-treated patients was genotyped using restriction fragment length polymorphism method. The influence of the rs9923231 polymorphism on the variations in the mean daily dose was compared using one-way analysis of variance and linear regression analysis. Discriminatory ability of the rs9923231 polymorphism to group the patients into ordered dose categories was assessed by estimating the proportional odds ratios using the ordered logit regression analysis. Results: The frequency of AA genotype and A allele in the study sample was found to be 1.8% and 9.23%, respectively, which was similar to reports from other South Indian populations. The mean daily dose required to achieve the optimum international normalized ratio was significantly lower in AA homozygous genotype carriers (3.99 ± 1.67 mg/day) and GA heterozygous (4.26 ± 1.57 mg/day) compared to the GG genotype carriers (5.51 ± 2.13 mg/day), p = 0.003. The A allele carriers (GA+AA genotypes) had a 3.23 higher odds of being grouped as a low-dose requiring category compared to non-carriers (95% CI 1.49–6.98, p = 0.003). Conclusions: These preliminary results strongly support the use of VKORC1 (−1639G>A) rs9923231 polymorphism for genetically guided initial warfarin dosing in South Indian patients with heart valve replacements. Keywords: VKORC1, Polymorphism, Warfarin, Pharmacogenetics, Regression

The North American Consortium for the Study of End-Stage Liver Disease's definition of acute-on-chronic liver failure (NACSELD-ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD-ACLF's ability to predict 30-day survival (defined as in-hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol-induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End-Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD-ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End-Stage Liver Disease score, and presence of infection. The c-statistics were 0.8073 for the training set and 0.8532 for the validation set. Conclusion Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30-day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (Hepatology 2018;67:2367-2374).

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] μg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting.OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

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.

The International Ascites Club (IAC) recently defined Stage 1 acute kidney injury (AKI) for cirrhosis as an acute increase in serum creatinine (SCr) by ≥0.3 mg/dl or by ≥50% in48 h from a stable value within 3 months. The baseline SCr may influence AKI risk and patient outcomes. The objective of this study is to determine in cirrhosis whether the baseline SCr has any effect on the in-hospital AKI course and patient survival.North American Consortium for the Study of End-Stage Liver Disease is a consortium of tertiary-care hepatology centers prospectively enroling non-elective cirrhotic inpatients. Patients with different baseline SCr levels (≤0.5, 0.51-1.0, 1.01-1.5,1.5 mg/dl) were evaluated for the development of AKI, and compared for AKI outcomes and 30-day survival.653 hospitalized cirrhotics (56.7±10years, 64% men, 30% with infection) were included. The incidence of AKI was 47% of enrolled patients. Patients with higher baseline SCr were more likely to develop AKI, with significantly higher delta and peak SCr (P0.001) than the other groups, more likely to have a progressive AKI course (P0.0001), associated with a significantly reduced 30-day survival (P0.0001). Multivariate logistic regression showed that the delta SCr during an AKI episode to be the strongest factor impacting AKI outcomes and survival (P0.001), with a delta SCr of 0.70 mg/dl having a 68% sensitivity and 80% specificity for predicting 30-day mortality.Admitted cirrhotic patients with higher baseline SCr are at higher risk for in-hospital development of AKI, and more likely to have AKI progression with reduced survival. Therefore, such patients should be closely monitored and treated promptly for their AKI.

Background & Aims Inpatients with cirrhosis have high rates of acute-on-chronic failure (ACLF) development and high mortality within 30 days of admission to the hospital. Better biomarkers are needed to predict these outcomes. We performed metabolomic analyses of serum samples from patients with cirrhosis at multiple centers to determine whether metabolite profiles might identify patients at high risk for ACLF and death. Methods We performed metabolomic analyses, using liquid chromatography, of serum samples collected at time of admission to 12 North American tertiary hepatology centers from 602 patients in the North American Consortium for the Study of End-Stage Liver Disease sites from 2015 through 2017 (mean age, 56 years; 61% men; mean model for end-stage liver disease score, 19.5). We performed analysis of covariance, adjusted for model for end-stage liver disease at time of hospital admission, serum levels of albumin and sodium, and white blood cell count, to identify metabolites that differed between patients who did vs did not develop ACLF and patients who did vs did not die during hospitalization and within 30 days. We performed random forest analysis to identify specific metabolite(s) that were associated with outcomes and area under the curve (AUC) analyses to analyze them in context of clinical parameters. We analyzed microbiomes of stool samples collected from 133 patients collected at the same time and examined associations with serum metabolites. Results Of the 602 patients analyzed, 88 developed ACLF (15%), 43 died in the hospital (7%), and 72 died within 30 days (12%). Increased levels of compounds of microbial origin (aromatic compounds, secondary or sulfated bile acids, and benzoate) and estrogen metabolites, as well as decreased levels of phospholipids, were associated with development of ACLF, inpatient, and 30-day mortality and were also associated with fecal microbiomes. Random forest analysis and logistic regression showed that levels of specific microbially produced metabolites identified patients who developed ACLF with an AUC of 0.84 (95% confidence interval [CI] 0.78–0.88; P = .001), patients who died while in the hospital with an AUC of 0.81 (95% CI 0.74–0.85; P = .002), and patients who died within 30 days with an AUC of 0.77 (95% CI 0.73–0.81; P = .02). The metabolites were significantly additive to clinical parameters for predicting these outcomes. Metabolites associated with outcomes were also correlated with microbiomes of stool samples. Conclusions In an analysis of serum metabolites and fecal microbiomes of patients hospitalized with cirrhosis at multiple centers, we associated metabolites of microbial origin and lipid moieties with development of ACLF and death as an inpatient or within 30 days, after controlling for clinical features.

Background & Aims Insurance, race, and ethnicity can affect outcomes of patients with cirrhosis, but findings from prospective studies are unclear. We investigated the role of insurance status and race and ethnicity (race/ethnicity) on inpatient and 90-day post-discharge outcomes in a large inpatient cohort of patients with cirrhosis. Methods We used data from the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) database, from 13 tertiary-care centers. Insurance status (uninsured, Medicare, Medicaid, private, and Canadian), race, and ethnicity, were analyzed independent of clinical co-variates for their association with transfer to the intensive care unit, acute on chronic liver failure (ACLF), length of hospital stay, inpatient and 90-day death or liver transplantation, and readmission to the hospital within 90 days. Multi-variable analyses and interaction terms were created for insurance, race/ethnicity, and for each outcome, with or without Canadian patients. Results We analyzed data from 2640 patients in the NACSELD database (971 with private insurance, 770 with Medicare, 456 Canadians, 265 with Medicaid, 178 uninsured, 540 non-Caucasian and 220 Hispanic); 23% required admittance to the intensive care unit, 12% developed NACSELD-defined ACLF, 7% died, 5% underwent liver transplantation. Of the 2288 patients discharged from hospital, 13% underwent liver transplantation, 19% died, and 42% were readmitted within 90 days. In the univariate model, uninsured patients accounted for the highest percentage of alcohol- or bleeding-related admissions and the lowest proportion of outpatient cirrhosis-related medication users. Canadians had the lowest rifaximin use and but higher proportions had hepatic encephalopathy, compared with other groups. Lack of insurance was higher among non-Caucasians, regardless of Hispanic ethnicity. In multi-variable analysis, lack of insurance was associated with ACLF (P=.02) and inversely associated with inpatient liver transplant (P=.05) and 90-day liver transplant (P=.02), regardless of whether Canadians were included or specific insurance type. Race or ethnicity were not significantly associated with outcomes. Conclusions In analyzing the NACSELD database, we found that insurance status, but not race or ethnicity, were independently associated with ACLF and inpatient or 90-day liver transplantation, regardless of inclusion of Canadian patients.

Circulatory and cardiac compromise in cirrhosis has been well studied. The primary pathophysiology stems from portal hypertension, which is induced from an increased resistance to flow secondary to distorted sinusoidal architecture and is further sustained from an increase in portal venous flow.1 Portal hypertension induces both progressive splanchnic and systemic vasodilation mediated via nitric oxide and other vasoactive molecules secondary to endothelial stretching and sheer stress.2 A hyperdynamic state then ensues with an increase in cardiac output, increase in heart rate, and a low systemic vascular resistance secondary to systemic vasodilatation. The decreased effective arterial blood volume activates neurohormonal systems such as the renin‐angiotensin‐aldosterone system (RAAS), leading to further volume expansion via sodium and water retention. However, because of portosystemic shunting and splanchnic vasodilatation, effective central blood volume remains low and the hyperdynamic state continues, eventually leading to high‐output heart failure (Fig. ​(Fig.1).1). A lower mean arterial pressure (MAP) of 60 to 65 mm Hg is often tolerated in compensated and stable patients through these compensatory mechanisms, which allow end‐organ perfusion to be maintained.1, 2 Any degree of insult to this system can result in significant hypotension and decompensation. Open in a separate window Figure 1 Pathophysiology of hypotension in cirrhosis.

BackgroundHepatic encephalopathy (HE) can adversely affect outcomes in both in-patients and out-patients with cirrhosis.AimTo define targets for improving quality of care in HE management in the multi-centre North American Consortium for End-Stage Liver Disease (NACSELD) cohort.MethodNACSELD in-patient cohort was analysed for (a) medication-associated precipitants, (b) aspiration pneumonia development, (c) HE medication changes, and (d) 90-day HE recurrence/readmissions. Comparisons were made between patients on no-therapy, lactulose only, rifaximin only or both. Ninety-day HE-readmission analysis was adjusted for MELD score.ResultsTwo thousand eight hundred and ten patients (1102 no-therapy, 659 lactulose, 154 rifaximin, 859 both) were included. HE on admission, and HE rates during hospitalisation were highest in those on lactulose only or dual therapy compared to no-therapy or rifaximin only (P&nbsp

ObjectivesAntibiotic prophylaxis is recommended for prevention of the first episode of spontaneous bacterial peritonitis (SBP; primary prophylaxis 1°) and subsequent episodes (secondary prophylaxis 2°). We aimed to compare outcomes in cirrhotic inpatients on 1° vs 2° SBP prophylaxis.MethodsData from North American Consortium for the Study of End-Stage Liver Disease were evaluated for cirrhosis details, reasons for admission/medications, inpatient course recorded, and outcomes over 90 days. Outcomes (intensive care units, acute kidney injury, inpatient/90-day mortality) were compared between the 2 groups after propensity-matching on admission model for end-stage liver disease (MELD) score and serum albumin.ResultsAmong the 2,731 patients enrolled, 305 were on 1° and 187 on 2° SBP prophylaxis. After propensity-matching, 154 patients remained in each group. Patients on 1° prophylaxis were more likely to have admission systemic inflammatory response syndrome (P = 0.02), with higher intensive care unit admissions (31% vs 21%; P = 0.05) and inpatient mortality (19% vs 9%; P = 0.01) than the 2° prophylaxis group. Patients on 2° prophylaxis had higher total (22% vs 10%; P = 0004), readmission (16% vs 9%; P = 0.03), and nosocomial (6% vs 0.5%; P = 0.01) SBP rates with predominant Gram-negative organisms compared to 1° prophylaxis patients. At 90 days, 1° prophylaxis patients had a higher mortality (35% vs 22%; P = 0.02) and acute kidney injury incidence (48% vs 30%; P = 0.04) compared to 2° prophylaxis patients.DiscussionIn this inpatient cirrhosis study, despite prophylaxis, a high proportion of patients developed SBP, which was associated with mortality. Cirrhotic inpatients on 1° prophylaxis had worse outcomes than those on 2° prophylaxis when propensity-matched for the MELD score and serum albumin during the index admission and 90-day follow-up.

Progression of stages 2 and 3 acute kidney injury (AKI) in cirrhosis has not been characterized adequately. Patients with higher stages of AKI are believed to have worse outcomes. We assessed outcomes and factors associated with stages 2 and 3 AKI in patients with cirrhosis in the North American Consortium for the Study of End-stage Liver Disease cohort.We collected data from 2297 hospitalized patients with cirrhosis and ascites from December 2011 through February 2017. Our final analysis included 760 patients who developed AKI per the International Ascites Club 2015 definition (419 with maximum stage 1 and 341 with maximum stage 2 or 3; 63% male; mean age, 58 y). We compared demographic features, laboratory values, AKI treatment response, and survival between patients with maximum stage 1 vs patients with stage 2 or 3 AKI.Patients with stage 2 or 3 AKI had higher Model for End-Stage Liver Disease scores (25.9 ± 7.3) than patients with stage 1 AKI (21.9 ± 7.5) (P.0001). More patients fulfilled systemic inflammatory response syndrome criteria on admission, and more developed a second nosocomial infection (P.05 for both comparisons). More patients with stage 2 or 3 AKI also had progression of AKI and required dialysis and admission into intensive care units when compared to stage 1 AKI patients (P.0001 for both). A lower proportion of patients with stage 2 or 3 AKI survived their hospital stay (80% vs 99% with stage 1 AKI; P.0001), or survived for 30 days without a liver transplant (56% vs 81%; P.0001). The development of stage 2 or 3 AKI was associated with a higher Model for End-Stage Liver Disease score at the time of admission (P.0001), presence of systemic inflammatory response on admission (P = .039), and second infection (P.0001).Based on an analysis of data from the North American Consortium for the Study of End-stage Liver Disease cohort, we found that patients with cirrhosis and more advanced liver disease, as well as a second infection, are more likely to develop stages 2 or 3 AKI, with a progressive course associated with decreased 30-day transplant-free survival. Prevention of AKI progression in patients with cirrhosis and stage 2 or 3 AKI might improve their outcomes.

Background In potential liver transplant candidates, pulmonary vascular diseases, including portopulmonary hypertension (PoPH) and pulmonary venous hypertension (PVH), can be associated with high morbidity and mortality. Although there are clear guidelines regarding management and transplant listing criteria for patients with PoPH, the listing criteria for PVH are not well defined. Objective The aim of this study was to describe and compare the perioperative and postoperative morbidity and mortality associated with PoPH and PVH in patients undergoing liver transplantation. Methods We conducted a retrospective observational study of all patients referred for liver transplantation to our center between 2005 and 2015 who underwent a right heart catheterization (RHC) for screening for pulmonary hypertension as suggested by initial echocardiography. Based on the RHC data, the patients were grouped into no pulmonary hypertension (No PH), PoPH, and PVH categories. In patients who underwent liver transplantation, we recorded vital status intraoperatively and at 30 days and 1-year post-transplant, and we recorded the incidence of postoperative cardiopulmonary and renal complications. Results Of the 134 patients who underwent RHC as part of the initial transplant evaluation, 50 patients were successfully transplanted. There was 1 intraoperative death in the PoPH group. No significant difference in mortality was noted between the No PH, PoPH, and PVH groups intraoperatively and 30 days after liver transplantation. At 1 year, the survival rates were 100%, 69.2%, and 94.1% in the No PH, PoPH, and PVH groups, respectively. With respect to cardiopulmonary and renal complications, no statistically significant difference was noted among the groups, though there was a trend toward increased post-transplant reversible pulmonary complications in the PVH group. Conclusion Our findings suggest that the post-transplant outcomes of patients with PoPH and PVH are similar. In light of the growing recognition of diastolic dysfunction and cirrhotic cardiomyopathy in decompensated cirrhotic patients at the time of transplant, the issue of pulmonary hypertension related to PVH will gain increasing importance as we assess these patients for transplantation. Therefore, future studies are needed to define evidence based guidelines to determine candidacy for liver transplantation in the context of PVH.

Acute liver failure (ALF) caused by hepatitis B virus (HBV) infection can occur after immunosuppressive treatment and be fatal, although it might be preventable. We aimed to characterize the causes, clinical course, and short-term outcomes of HBV-associated ALF after immune-suppressive therapy, compared with patients with HBV-associated ALF without immunosuppression (control subjects).We performed a retrospective multicenter study of 156 consecutive patients diagnosed with HBV-associated ALF (22 with a solid or blood malignancy) enrolled in the Acute Liver Failure Study Group registry from January 1998 through April 2015. We collected data on results of serologic and hepatic biochemistry analyses, grade of hepatic encephalopathy, Model for End-Stage Liver Disease score, and King's College criteria. We also collected data on clinical features, medical therapies, and complications in the first 7 days following study enrollment. Logistic regression was used to identify factors associated with transplant-free survival at 21 days in HBV-associated ALF (the primary outcome).Among patients with HBV-associated ALF, 28 cases (18%) occurred after immunosuppressive therapy (15 patients received systemic corticosteroids and 21 received chemotherapy); and 128 cases did not (control subjects, 82%). Significantly greater proportions of patients with HBV-associated ALF after immunosuppression were nonwhite persons, and had anemia or thrombocytopenia than controls (P.02 for all). The serologic profile of HBV infection, severity of liver failure (based on MELD score), and complications (hepatic encephalopathy or need for mechanical ventilation, vasopressors, or renal replacement therapy) were similar between the groups (P.17 for all). Factors associated with 21 day transplant-free survival were increased MELD score (odds ratio ∼OR, 0.894 (95% confidence interval 0.842-0.949 per increment), requirement for mechanical ventilation (OR 0.111(0.041-0.300), and immunosuppressive therapy (OR 0.274(0.082-0.923)).Within a cohort study of patients with HBV-associated ALF, 18% had received immunosuppressive therapy. Significantly smaller proportions of patients with HBV-associated ALF after immunosuppression survive beyond 21 days than patients with HBV-associated ALF who did not receive immunosuppression. Patients undergoing chemotherapy should be screened for HBV infection and given appropriate antiviral therapies to reduce preventable mortality.

Identification of patients with cirrhosis at risk for death within 3 months of discharge from the hospital is essential to individualize postdischarge plans. The objective of the study was to identify an easy-to-use prognostic model based on the Karnofsky Performance Status (KPS). The North American Consortium for the Study of End-Stage Liver Disease consists of 16 tertiary-care hepatology centers that prospectively enroll nonelectively admitted cirrhosis patients. Patients enrolled had KPS assessed 1 week postdischarge. KPS was categorized into low (score 10-40), intermediate (50-70), and high (80-100). Of 954 middle-aged patients (57 ± 10 years, 63% men) with a median Model for End-Stage Liver Disease (MELD) score of 17 (interquartile range 13-21), the mortality rates for the low, intermediate, and high performance status groups were 23% (36/159), 11% (55/489), and 5% (15/306), respectively. Low, intermediate, and high performance status was seen in 17%, 51%, and 32% of the cohort, respectively. Low performance status was associated with older age, dialysis, hepatic encephalopathy, longer length of stay, and higher white blood cell count or MELD score at discharge. A model was derived using the three independent predictors of 3-month mortality: KPS, age, and MELD score. This score had better discrimination (area under the receiver operating characteristic curve = 0.74) than a model using MELD (area under the receiver operating characteristic curve = 0.62) or MELD and age (area under the receiver operating characteristic curve = 0.67) to predict 3-month mortality. Conclusions Cirrhosis patients at risk for 3-month postdischarge mortality can be identified using a novel KPS-based score; this score may be adopted in practice to guide postdischarge early interventions, including the integrated provision of active and palliative management strategies. (Hepatology 2017;65:217-224).

Artificial (nonbiological) extracorporeal liver support devices aim to remove albumin-bound and water-soluble toxins to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while hepatic recovery or liver transplant occurs. The following beneficial effects have been documented: improvement of jaundice, amelioration of hemodynamic instability, reduction of portal hypertension, and improvement of hepatic encephalopathy. The only randomized prospective multicenter controlled trial to show an improvement in transplant-free survival was for high-volume plasmapheresis. Biological (cell-based) extracorporeal liver support systems aim to support the failing liver through detoxification and synthetic function and warrant further study for safety and benefit.

Severe hyponatremia can complicate the pretransplantation management of patients with decompensated cirrhosis while they await liver transplantation. Before the liver transplant, it is critical to correct severe hyponatremia to an appropriate level to reduce the risks of perioperative complications such as central pontine myelinolysis, cerebral edema, and seizures. Vasopressin receptor antagonists, and in particular tolvaptan, offer a therapeutic modality that can correct severe refractory hyponatremia in a timely and predictable manner before liver transplantation. In this case report, we describe a patient with decompensated cirrhosis and severe hyponatremia in whom administration of tolvaptan led to an optimal correction of preoperative severe hyponatremia and allowed for successful liver transplantation with no associated postoperative complications. In light of the increasing pretransplantation disease severity and higher risk of severe hyponatremia, the use of tolvaptan in the pretransplant period may gain increasing importance as a therapeutic intervention for maintaining peritransplant sodium homeostasis.

BACKGROUND Intravenous contrast-enhanced imaging is invaluable in diagnosing pathology following liver transplantation. Given the potential risk of contrast nephropathy associated with iodinated computed tomography contrast, alternate contrast modalities need to be examined, especially in the setting of renal insufficiency. The purpose of this study was to examine the renal safety of MRI with gadolinium following liver transplantation. METHODS The study involved a retrospective analysis of 549 cases of abdominal MRI with low-dose gadobenate dimeglumine in liver transplant recipients at a single center. For each case, serum creatinine values before and after the MRI were compared. In addition, cases were analyzed for the development of nephrogenic systemic fibrosis. RESULTS Pre-MRI creatinine values ranged from 0.32 to 6.57 mg/dL (median, 1.28 g/dL), with 191 cases having values ≥1.5 mg/dL (median, 1.86 g/dL). A comparison of the pre- and post-MRI creatinine values showed no significant difference, including those patients with pre-MRI values ≥1.5 mg/dL (mean change of -0.04 [95% confidence interval, -0.07 to -0.01; P = 0.004]). No cases of nephrogenic systemic fibrosis were noted. CONCLUSIONS Our findings suggest that, irrespective of baseline renal function, MRI with gadobenate dimeglumine is a nonnephrotoxic imaging modality in liver transplant recipients. Importantly, this intravenous contrast-enhanced imaging modality can be considered in those posttransplant patients who have a contraindication to computed tomography contrast due to renal insufficiency.

We hypothesize that the prevalence of chronic kidney disease (CKD) among patients with cirrhosis has increased due to the increased prevalence of CKD-associated comorbidities, such as diabetes. We aimed to assess the characteristics of hospitalized patients with cirrhosis with CKD and its impact on renal and patient outcomes. The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) prospectively enrolled nonelectively admitted patients with cirrhosis and collected data on demographics, laboratory results, in-hospital clinical course, and postdischarge 3-month outcomes. CKD positive (CKD+) patients, defined as having an estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease-4 variable formula) of ≤60 mL/minute for >3 months, were compared with chronic kidney disease negative (CKD-) patients for development of organ failures, hospital course, and survival. There were 1099 CKD+ patients (46.8% of 2346 enrolled patients) who had significantly higher serum creatinine (2.21 ± 1.33 versus 0.83 ± 0.21 mg/dL in the CKD- group) on admission, higher prevalence of nonalcoholic steatohepatitis cirrhosis etiology, diabetes, refractory ascites, and hospital admissions in the previous 6 months compared with the CKD- group (all P < 0.001). Propensity matching (n = 922 in each group) by Child-Pugh scores (9.78 ± 2.05 versus 9.74 ± 2.04, P = 0.70) showed that CKD+ patients had significantly higher rates of superimposed acute kidney injury (AKI; 68% versus 21%; P < 0.001) and eventual need for dialysis (11% versus 2%; P < 0.001) than CKD- patients. CKD+ patients also had more cases of acute-on-chronic liver failure as defined by the NACSELD group, which was associated with reduced 30- and 90-day overall survival (P < 0.001 for both). A 10 mL/minute drop in eGFR was associated with a 13.1% increase in the risk of 30-day mortality. In conclusion, patients with CKD should be treated as a high-risk group among hospitalized patients with cirrhosis due to their poor survival, and they should be monitored carefully for the development of superimposed AKI.

In this chapter, we would like to focus on four cases which highlight presentation and management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and complications observed in the post-liver transplantation period.

Acute-on-chronic liver failure (ACLF) characterized with ≥2 extrahepatic organ failures in cirrhosis carries a high mortality. Outcomes of patients listed for liver transplantation (LT) after ACLF and after LT are largely unknown. The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled 2793 nonelectively hospitalized patients with cirrhosis; 768 were listed for LT. Within 3 months, 265 (35%) received a LT, 395 remained alive without LT, and 108 died/delisted. Compared with nonlisted patients, those listed were younger and more often had ACLF, acute kidney injury, and a higher admission Model for End-Stage Liver Disease (MELD) score. ACLF was most common in patients who died/delisted, followed by those alive with and without LT respectively, (30%, 22%, and 7%, respectively; P < 0.001). At LT, median MELD was 27.9% and 70% were inpatients; median time from hospitalization to LT was 26 days. Post-LT survival at 6 months was unchanged between those with and without ACLF (93% each at 6 months). There was no difference in 3- and 6-month mean post-LT creatinine in those with and without ACLF, despite those with ACLF having a higher mean pre-LT creatinine and a higher rate of perioperative dialysis (61%). In conclusion, patients with and without ACLF had similar survival after transplant with excellent renal recovery in both groups.

Liver transplantation (LT) for acute liver failure is an uncommon occurrence in the setting of pregnancy given the risk of fetal demise, and rarely is it undertaken with a viable fetus. Maternal hyperthyroidism increases fetal risk in the setting of LT, particularly in the setting of thyrotoxicosis. We report the first case of propylthiouracil-induced acute liver failure in a hyperthyroid patient in her second trimester resulting in LT. The multidisciplinary management led to a favorable outcome for the patient and the subsequent delivery of a healthy infant at 38-weeks' gestation.

OBJECTIVE: To assess the epidemiology and outcome of patients with cirrhosis following critical care unit (CCU) admission. DESIGN: Retrospective cohort study. SETTING: CCUs in England, Wales and Northern Ireland participating in the United Kingdom Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme (CMP) PATIENTS: 31,363 patients with cirrhosis identified out of 1,168,650 total CCU admissions (2.7%) admitted to UK CCUs between 1998 and 2012. INTERVENTIONS: none MEASUREMENTS AND MAIN RESULTS: 10,936 patients had alcohol-related liver disease (ARLD, 35%). 1.6% of CCU admissions in 1998 had cirrhosis rising to 3.1% in 2012. The crude CCU mortality of patients with cirrhosis was 41% in 1998 falling to 31% in 2012 (p

This article discusses the intensive care unit management of patients with acute liver failure. It focuses on the clinical presentation, identification, and management of the myriad of complications seen in patients with acute liver failure.

In smaller single-center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3-month readmissions among inpatients with cirrhosis using the prospective 14-center North American Consortium for the Study of End-Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3-month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection-related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3-month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver-related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End-Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End-Stage Liver Disease and diabetes (c-statistic = 0.64, after split-validation 0.65). The discharge model included Model for End-Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c-statistic = 0.65, after split-validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver-related readmissions consistently had index-stay nosocomial infections as a predictor for HE, renal/metabolic, and infection-associated readmissions (odds ratio = 1.9-3.0). Conclusions: Three-month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (Hepatology 2016;64:200–208)

Because Model for End-Stage Liver Disease (MELD) scores at the time of liver transplantation (LT) increase nationwide, patients are at an increased risk for delisting by becoming too sick or dying while awaiting transplantation. We quantified the risk and defined the predictors of delisting or death in patients with cirrhosis hospitalized with an infection. North American Consortium for the Study of End-Stage Liver Disease (NACSELD) is a 15-center consortium of tertiary-care hepatology centers that prospectively enroll and collect data on infected patients with cirrhosis. Of the 413 patients evaluated, 136 were listed for LT. The listed patients' median age was 55.18 years, 58% were male, and 47% were hepatitis C virus infected, with a mean MELD score of 2303. At 6-month follow-up, 42% (57/136) of patients were delisted/died, 35% (47/136) underwent transplantation, and 24% (32/136) remained listed for transplant. The frequency and types of infection were similar among all 3 groups. MELD scores were highest in those who were delisted/died and were lowest in those remaining listed (25.07, 24.26, 17.59, respectively; P < 0.001). Those who were delisted or died, rather than those who underwent transplantation or were awaiting transplantation, had the highest proportion of 3 or 4 organ failures at hospitalization versus those transplanted or those continuing to await LT (38%, 11%, and 3%, respectively; P = 0.004). For those who were delisted or died, underwent transplantation, or were awaiting transplantation, organ failures were dominated by respiratory (41%, 17%, and 3%, respectively; P < 0.001) and circulatory failures (42%, 16%, and 3%, respectively; P < 0.001). LT-listed patients with end-stage liver disease and infection have a 42% risk of delisting/death within a 6-month period following an admission. The number of organ failures was highly predictive of the risk for delisting/death. Strategies focusing on prevention of infections and extrahepatic organ failure in listed patients with cirrhosis are required.

Hyponatremia is associated with poor outcomes in cirrhosis independent of MELD. While intravenous albumin has been used in small series, its role in hyponatremia is unclear. The aim of this study is to determine the effect of albumin therapy on hyponatremia.Hospitalized cirrhotic patients included in the NACSELD (North American Consortium for End-Stage Liver Disease) cohort with hyponatremia (Na130mmol/L) were divided into those receiving intravenous albumin or not. Determinants of hyponatremia resolution (Na ≥135 meq/L) and 30-day survival were analyzed using regression and ANCOVA models.Overall, 2435 patients, of whom 1126 had admission hyponatremia, were included. Of these, 777 received 225 (IQR 100,400) g of albumin, while 349 did not. Patients given albumin had a higher admission MELD score, and serum creatinine and lower admission Na and mean arterial pressure (MAP). However they experienced a higher maximum Na and hyponatremia resolution (69% vs 61%, p = 0.008) compared to those who did not. On regression, delta Na was independently associated with admission creatinine, MAP and albumin use. On ANCOVA with logistic regression, there was a significant difference in hyponatremia resolution between those who did or did not receive albumin, even after adjustment for admission Na and GFR (85.41% vs 44.78%, p = 0.0057, OR: 1.50 95% CI: 1.13-2.00). Independent predictors of 30-day survival were hyponatremia resolution, age, ACLF, and admission GFR.Hospitalized patients with cirrhosis and hyponatremia who received intravenous albumin had a higher rate of hyponatremia resolution independent of renal function and baseline sodium levels, which was in turn associated with a better 30-day survival.

Artificial (non-biological) extracorporeal liver support (ECLS) devices aim to remove albumin-bound and water soluble toxins in order to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while either hepatic recovery or liver transplant occurs. Current artificial ECLS devices differ primarily in selectivity of the membrane utilized; dialysis based techniques such as the molecular adsorbent recirculating system (MARS®) combine renal replacement therapy with albumin dialysis and a highly selective (

We report a case of a 26-year-old man with no significant medical history, who presented with fatigue, pruritus, jaundice, dark urine and clay colored stool for one month. He had been taking methyl-1-etiochoenolol-epietiocholanolone, an androgenic anabolic steroid (AAS). He was initially found to have a total bilirubin (Tbili) of 6 mg/dL. He discontinued the AAS but the patients’ symptoms worsened and Tbili increased to 36 mg/d. This prompted inpatient management of his drug-induced liver injury (DILI). Molecular adsorbent recirculating system (MARS) is an extracorporeal liver support system that replaces the detoxification function of the liver. The patient was initiated on a 4-day trial of MARS therapy. Over the course of his therapy, he clinically improved and his Tbili decreased to 20.7 mg/dL. At follow-up, his symptoms resolved and Tbili was 3.3 mg/dl. This case demonstrates the efficacy of MARS in treating severe cholestatic DILI refractory to standard medical therapy.

The critical care management of cirrhotic patients involves a multidisciplinary team approach, including the hepatologist and intensivist, to address life-threatening complications and to provide comprehensive care for multi-organ failure commonly seen in these patients. A systematic approach to the diagnosis and therapy of multi-organ system dysfunction is essential to optimize the intensive care management of these complex patients, with a goal to stabilize them for possible liver transplantation. This review provides a system-based approach for the intensive care management of critically ill cirrhotic patients.

Background & Aims Evaluation of patients with acute liver injury (ALI) or acute liver failure (ALF) often includes measurement of plasma levels of acetaminophen, to determine exposure and/or toxicity. However, once liver injury has developed, acetaminophen might be undetectable in plasma. We investigated the association between level of acetaminophen measured and outcomes of patients designated as having ALF or ALI due to acetaminophen toxicity. Methods We performed a retrospective analysis of data from 434 subjects in the Acute Liver Failure Study Group who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) or ALI (severe liver injury with coagulopathy but no encephalopathy) due to acetaminophen toxicity from January 1, 2010 through December 31, 2014. We collected data on patient demographics, biochemical features, reported acetaminophen use, N-acetylcysteine therapy, liver transplant, and outcomes. Descriptive statistics were used to assess patient demographics, clinical characteristics, and outcomes whereas differences in continuous variables between patients with vs without acetaminophen detection on admission were analyzed using the Wilcoxon rank-sum test. The primary aim was to determine the proportion of patients with detectable plasma levels of acetaminophen. Results Acetaminophen was undetectable in serum samples from 227 patients (52%). There were no significant differences between groups of patients with detectable vs undetectable levels in demographic features, alcohol use, median levels of alanine aspartate, or use of N-acetylcysteine (given to 94.7% of patients with detectable acetaminophen vs 95.9% of those with undetectable acetaminophen; P=.63). We observed a significant difference in median dose taken between patients with detectable (29,500 mg; interquartile range, 15,000 mg–50,007 mg) vs no detectable parent compound (14,950 mg; interquartile range, 3960 mg–25,000) (P=.003). A lower proportion of patients with detectable plasma levels of acetaminophen (72.3%) survived without a liver transplant than of patients with undetectable levels (86.3%) in univariate analysis (P=.0006), although this was not significant in multivariable analysis (P=.12). Although most patients had unintentional overdoses, a higher proportion of patients with suicidal overdoses (43%) had detectable levels of acetaminophen than patients with accidental overdoses (29.3%; P=.01). Conclusion More than half of patients who present at the hospital with acetaminophen-induced ALI or ALF have undetectable levels of acetaminophen. Clinicians should not exclude acetaminophen toxicity because of undetectable levels or withhold N-acetylcysteine for patients with ALI or ALF when acetaminophen toxicity is suspected.