Geographic disparities in access to liver transplant for advanced cirrhosis: Time to ring the alarm!

Decompensated cirrhosis and hepatocellular cancer are major risk factors for mortality worldwide. Liver transplantation (LT), both live-donor LT or deceased-donor LT, are lifesaving, but there are several barriers toward equitable access. These barriers are exacerbated in the setting of critical illness or acute-on-chronic liver failure. Rates of LT vary widely worldwide but are lowest in lower-income countries owing to lack of resources, infrastructure, late disease presentation, and limited donor awareness. A recent experience by the Chronic Liver Disease Evolution and Registry for Events and Decompensation consortium defined these barriers toward LT as critical in determining overall survival in hospitalized cirrhosis patients. A major focus should be on appropriate, affordable, and early cirrhosis and hepatocellular cancer care to prevent the need for LT. Live-donor LT is predominant across Asian countries, whereas deceased-donor LT is more common in Western countries; both approaches have unique challenges that add to the access disparities. There are many challenges toward equitable access but uniform definitions of acute-on-chronic liver failure, improving transplant expertise, enhancing availability of resources and encouraging knowledge between centers, and preventing disease progression are critical to reduce LT disparities.

APASL-ACLF Research Consortium-Artificial Intelligence (AARC-AI) model precisely predicts outcomes in acute-on-chronic liver failure patients.

BACKGROUND AND AIMS: We hypothesized that artificial intelligence (AI) models are more precise than standard models for predicting outcomes in acute-on-chronic liver failure (ACLF). METHODS: We recruited ACLF patients between 2009 and 2020 from APASL-ACLF Research Consortium (AARC). Their clinical data, investigations and organ involvement were serially noted for 90-days and utilized for AI modelling. Data were split randomly into train and validation sets. Multiple AI models, MELD and AARC-Model, were created/optimized on train set. Outcome prediction abilities were evaluated on validation sets through area under the curve (AUC), accuracy, sensitivity, specificity and class precision. RESULTS: Among 2481 ACLF patients, 1501 in train set and 980 in validation set, the extreme gradient boost-cross-validated model (XGB-CV) demonstrated the highest AUC in train (0.999), validation (0.907) and overall sets (0.976) for predicting 30-day outcomes. The AUC and accuracy of the XGB-CV model (%Δ) were 7.0% and 6.9% higher than the standard day-7 AARC model (p < .001) and 12.8% and 10.6% higher than the day 7 MELD for 30-day predictions in validation set (p < .001). The XGB model had the highest AUC for 7- and 90-day predictions as well (p < .001). Day-7 creatinine, international normalized ratio (INR), circulatory failure, leucocyte count and day-4 sepsis were top features determining the 30-day outcomes. A simple decision tree incorporating creatinine, INR and circulatory failure was able to classify patients into high (~90%), intermediate (~60%) and low risk (~20%) of mortality. A web-based AARC-AI model was developed and validated twice with optimal performance for 30-day predictions. CONCLUSIONS: The performance of the AARC-AI model exceeds the standard models for outcome predictions in ACLF. An AI-based decision tree can reliably undertake severity-based stratification of patients for timely interventions.

Safety and Efficacy of Transjugular Intrahepatic Portosystemic Shunt for Non-tumoral Cirrhotic Portal Vein Thrombosis Not Responding to Anticoagulation Therapy.

OBJECTIVES: To evaluate the feasibility, safety, and efficacy of add-on transjugular-intrahepatic-portosystemic shunt (TIPS) for portal vein recanalization (PVR) in cirrhotic patients with non-tumoral chronic portal vein thrombosis (PVT) after 6 months of monitored anticoagulation therapy (ACT). METHODS: We conducted a retrospective search of the hospital database for patients who underwent TIPS for persistent PVT despite 6 months of ACT (January 2011 to August 2021). These patients were compared to control group (ACT group; no TIPS but continued on ACT). Post-TIPS periodic assessment was done to look for clinical outcome, PVR (using contrast-enhanced CT scan), and complications. RESULTS: A total of 90 patients were analyzed. Thirty-six patients in TIPS group and 54 patients in ACT group. TIPS was successfully performed in all patients. TIPS group showed complete recanalization of portal vein in 77.8%, partial recanalization in 16.7%, and stable thrombus in 5.5% of the patients. TIPS thrombosis was seen in 3 patients, all underwent successful endovascular thrombolysis. Seven patients developed post-TIPS hepatic encephalopathy and were managed conservatively. In contrast, no patient in ACT group achieved PVR on 12-month follow-up. After propensity score matching, patients in TIPS group showed significantly lower incidence of variceal re-bleeding (22.2% vs. 77.8%, p = 0.03) and refractory ascites (11.1% vs. 51.9%, p < 0.01) with significantly better 12-month survival as compared to ACT group (88.9% vs. 69.4%, p = 0.04). CONCLUSION: TIPS in cirrhotic patients with PVT result in superior recanalization rates, better control of ascites, and variceal re-bleeding resulting in better survival. TIPS may be considered a preferred therapy after anticoagulation failure. CLINICAL IMPACT: TIPS is associated with good technical and clinical success in patients of cirrhosis with PVT and should be considered in patients not responding to ACT.

Intragastric Balloon in Obese Compensated Nonalcoholic Steatohepatitis Cirrhosis Patients Is Safe and Achieves Significant Weight Reduction at 6-Months.

BACKGROUND AND STUDY AIMS: Weight reduction is the mainstay treatment for Nonalcoholic steatohepatitis (NASH). intragastric balloon (IGB) placement has proven benefit in terms of weight reduction. The aim of the present study is to assess the safety and efficacy of IGB placement in compensated NASH cirrhosis. PATIENTS AND METHODS: Nonalcoholic steatohepatitis cirrhosis patients with CTP ≤ 7, BMI of > 30, and who were unable to achieve weight reduction with lifestyle modification in past 3 months were prospectively enrolled. Spatz3™ adjustable gastric balloon was placed endoscopically. Primary objective was to determine efficacy in weight loss at 6 months, with secondary objectives of reduction in hepatic venous pressure gradient (HVPG), liver fat (controlled attenuation parameter, CAP), liver stiffness measurement (LSM) and clinical events as well as the tolerability and adverse events due to IGB placement. RESULTS: Altogether 56 cirrhosis patients, with a baseline BMI of 35.24 ± 3.92 and a CTP score of 6.27 ± 1.28 underwent IGB placement. The absolute weight reduction achieved was 15.88 kg (- 16.46%) and reduction in BMI was - 10.1% at 6 months. The percentage total body weight loss of ≥ 10% was achieved in 31 (55.35%) patients. The reduction in HVPG at 6-months was 11.12% (n = 16, 14.18 ± 2.12 to 12.60 ± 1.67 mmHg). The mean reduction in LSM was 28.6% and in CAP was 10.09%. Three (5.36%) patients required removal of IGB before 6-months due to persisting vomiting. No patient developed new-onset decompensation or any serious adverse event. CONCLUSION: IGB placement is a safe, well tolerated and effective option for reduction in weight and portal pressure in compensated obese cirrhosis patients. TRIAL REGISTRY: Clinicaltrails.gov identifier no: NCT03753438.

Hepatic artery-related complications after live donor liver transplantation.

BACKGROUND: Hepatic artery-related complications (HARC) after live donor liver transplantation (LDLT) is associated with high morbidity and mortality rate. METHODS: Prospectively maintained data from July 2011 to September 2020 was analyzed for etiology, detection, management, and outcome of HARC. RESULTS: Six hundred fifty-seven LDLT (adult 572/pediatrics 85) were performed during the study period. Twenty-one (3.2%) patient developed HARC; 16 (2.4%) hepatic artery thrombosis (HAT) and 5 (0.76%) non-thrombotic hepatic artery complication (NTHAC). Ninety percent (19/21) HARC were asymptomatic and detected on protocol Doppler. Median time to detection was day 4 (range - 1 to 35), which included 18 early (within 7 days) vs 3 late incidents. Only one pediatric patient had HAT. Seven patients underwent surgical revascularization, 11 had endovascular intervention and 3 with attenuated flow required only systemic anticoagulation. All NTHAC survived without any sequelae. Revascularization was successful in 81% (13/16) with HAT. Biliary complications were seen in 5 (23.8%); four were managed successfully. Overall mortality was 14.8% (3/21). The 1-year and 5-year survival were similar to those who did not develop HARC (80.9% vs 84.2%, p = 0.27 and 71.4% vs 75.19%, p = 0.36 respectively) but biliary complications were significantly higher (23.8% vs 14.2%, p = 0.03). On multivariate analysis, clockwise technique of arterial reconstruction was associated with decreased risk of HAT (1.7% vs 4.1% (p value - 0.003)). CONCLUSION: Technical refinement, early detection, and revascularization can achieve good outcome in patients with HARC after LDLT.

Comparative genomics reveals the diversity of CRISPR-Cas locus in Azotobacter organisms.

Clustered regularly interspaced short palindromic repeats (CRISPRs) are known to provide adaptive immunity to bacteria against invading bacteriophages. In recent years, CRISPR-based technologies have been used for creating improved plant varieties; however, the indigenous CRISPR-Cas elements of plant growth-promoting bacteria are usually neglected. These indigenous genetic cassettes have evolved over millions of years and have shaped the bacterial genome. Therefore, these genetic loci can be used to study the adaptive capability of the bacteria in the environment. This study aims to bioinformatically analyze the genomes of a common free-living nitrogen-fixing Azotobacter spp. to assess their CRISPR-Cas diversity. Strains of Azotobacter vinelandii and Azotobacter chroococcum were found to harbor a large number of spacers. The phylogeny of different Cas and Cse1 proteins revealed a close evolutionary relationship among A. chroococcum B3, A. chroococcum NCIMB 8003 locus II, and A. vinelandii DJ locus I. The secondary structure of the hairpin loop of the repeat was also analyzed, and a correlation was derived between the structural stability of the hairpin loop and the number of spacers acquired by the CRISPR loci. These findings revealed the diversity and evolution of the CRISPR sequences and Cas proteins in Azotobacter species. Although the adaptive immune system of bacteria against bacteriophage, CRISPR-Cas, has been identified in many bacteria, studies of plant growth-promoting bacteria have been neglected. These indigenous CRISPRs have shaped the genome over millions of years and their study can lead to the understanding of the genome composition of these organisms. Our results strengthen the idea of using A. chroococcum and A. vinelandii as biofertilizer strains as they possess more spacers with highly stable repeat sequences, thereby imparting them higher chance of survival against mobile genetic elements like phages and plasmids.

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial.

BACKGROUND: High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS: In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS: ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) µg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION: In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL: gov (identifier: NCT02718079).

Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial.

Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count < 50 × 109 /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy, which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Although 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared with the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. Conclusion: In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared with SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.

Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC.

BACKGROUND AND AIM: Plasma-exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. METHODS: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. RESULTS: ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS-matched cohort (n = 208, [ALS-119; PE-94, FPSA-25)], SMT-89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42-24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5-11.1), and lower liver-failure-related deaths as compared to FPSA and SMT (P < .05). PE cleared inflammatory cytokines, damage-associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) compared to non-responders. PE was associated with lesser adverse effects as compared to FPSA. CONCLUSIONS: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma-exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.

Impact of metabolic risk factors on the severity and outcome of patients with alcohol-associated acute-on-chronic liver failure.

BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.

Omega-3 fatty acid lipid emulsions are safe and effective in reducing endotoxemia and sepsis in acute-on-chronic liver failure: An open-label randomized controlled trial.

BACKGROUND AND AIM: Sepsis is an important determinant of the outcome of acute-on-chronic liver failure (ACLF) patients. Omega-3 fatty acids (FAs) are known to suppress inflammation, reduce morbidity, and mortality in postoperative and critically ill patients. We aimed to evaluate the effect of intravenous omega-6 and omega-3 FA lipid emulsions in ACLF patients. METHODS: Ninety ACLF patients were randomly allocated to three groups: Gr. A received no lipid emulsions, Gr. B received omega-6 FAs, and Gr. C received omega-3 FAs. The primary and secondary aims were to compare the effects of lipid emulsions on immune modulation, the incidence of bacterial sepsis, and mortality at day 28. RESULTS: The baseline characteristics of the patients were comparable. Serum endotoxin levels remained suppressed by 22% in Gr. C compared with a 4% and 12% rise in Gr. B and A (P < 0.001). Omega-3 FAs also suppressed C-reactive protein levels and neutrophil-to-lymphocyte ratio in Gr. C. Compared with Gr. A, omega-3 FAs reduced sepsis by 86% (HR, 0.14; 95% CI 0.04-0.43; P < 0.001). Omega-3 FAs significantly increased the expression of TLR2 and TLR4 on both CD14+ and CD16+ monocytes, and TLR4, on macrophages and neutrophils. There were no serious adverse events, except transient flushing in 20% and 16.6% of patients receiving omega-6 FAs and omega-3 FAs, respectively. CONCLUSION: Omega-3 FAs are safe and effective in reducing systemic inflammation, endotoxemia, and sepsis in patients with ACLF. These lipid emulsions could also be considered as effective sources of immunonutrition in such sick patients.

Heparin-like Effect Associated With Risk of Bleeding, Sepsis, and Death in Patients With Severe Alcohol-Associated Hepatitis.

BACKGROUND & AIMS: Endogenous heparinoids or heparin-like effects (HLEs) can cause coagulation failure in patients with cirrhosis and sepsis. We performed a prospective study of the association between HLE and bleeding events, sepsis, and outcomes of patients with severe alcohol-associated hepatitis. METHODS: Our final analysis comprised 78 patients with severe alcohol-associated hepatitis (44.3 ± 11.7 years; all male; discriminant function >32) who presented without sepsis at a single center in India from August 2015 through August 2016. Blood samples were collected at days 0, 3, and 7 after presentation and assessed by a global coagulation assay; by SONOCLOT (global and heparinase treated); and in assays for factor VIII, von Willebrand factor, protein C, and antithrombin. Patients were followed for sepsis, bleeding and outcome. The primary outcome was association of HLE with survival 28 days after presentation. RESULTS: HLEs were observed in 32 patients (41%) at day 0, 27 patients (34.6%) at day 3, and 28 patients (35.9%) patients at day 7. Factors associated with mortality at day 0 were factor VIII activity >160% (hazard ratio [HR], 3.1; 95% CI, 1.4-9.5; P = .026), level of protein C <34% (HR, 0.7; 95% CI, 0.5-0.8; P = .037), antithrombin activity <28% (HR, 0.7; 95% CI, 0.3-1.1; P = .008) and international normalized ratio >2.6 (HR, 2.3; 95% CI, 1.8-9.7; P = .010). In multivariate analyses, only factor VIII activity (HR, 2.3; 95% CI, 1.6-7.8; P = .046), international normalized ratio (1.9; 95% CI, 1.2-4.3; P = .039), level of protein C (HR, 0.9; 95% CI, 0.7-1.1; P = .052) and model for end-stage liver disease score (HR, 3.2; 95% CI, 1.9-10.2; P = .042) were associated with mortality. Episodes of epistaxis, hemorrhoid bleeding, hemoperitoneum, and pulmonary hemorrhage occurred in 10.2%, 12.3%, 3.4%, and 4.5% of patients respectively. The presence of HLE at day 0 increased the risk of sepsis (HR, 2.5; 95% CI, 2.2-4.3; P = .002), bleeding (HR, 1.4; 95% CI, 1.2-5.3; P = .004) and death (HR, 1.2; 95% CI, 1.4-1.7; P = .044). CONCLUSIONS: In a prospective study of patients with severe alcohol-associated hepatitis, we associated HLE with coagulation abnormalities, risk of sepsis, and mortality. Clinicaltrials.govNCT02307409.

Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy.

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

OBJECTIVES: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

Living Donor Liver Transplantation for Acute Liver Failure: Donor Safety and Recipient Outcome.

In countries where deceased organ donation is sparse, emergency living donor liver transplantation (LDLT) is the only lifesaving option in select patients with acute liver failure (ALF). The aim of the current study is living liver donor safety and recipient outcomes following LDLT for ALF. A total of 410 patients underwent LDLT between March 2011 and February 2018, out of which 61 (14.9%) were for ALF. All satisfied the King's College criteria (KCC). Median admission to transplant time was 48 hours (range, 24-80.5 hours), and median living donor evaluation time was 18 hours (14-20 hours). Median Model for End-Stage Liver Disease score was 37 (32-40) with more than two-thirds having grade 3 or 4 encephalopathy and 70% being on mechanical ventilation. The most common etiology was viral (37%). Median jaundice-to-encephalopathy time was 15 (9-29) days. Preoperative culture was positive in 47.5%. There was no difference in the complication rate among emergency and elective living liver donors (13.1% versus 21.2%; P = 0.19). There was no donor mortality. For patients who met the KCC but did not undergo LT, survival was 22.8% (29/127). The 5-year post-LT actuarial survival was 65.57% with a median follow-up of 35 months. On multivariate analysis, postoperative worsening of cerebral edema (CE; hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.31), systemic inflammatory response syndrome (SIRS; HR, 16.7; 95% CI, 2.05-136.7), preoperative culture positivity (HR, 6.54; 95% CI, 2.24-19.07), and a longer anhepatic phase duration (HR, 1.01; 95% CI, 1.00-1.02) predicted poor outcomes. In conclusion, emergency LDLT is lifesaving in selected patients with ALF. Outcomes of emergency living liver donation were comparable to that of elective donors. Postoperative worsening of CE, preoperative SIRS, and sepsis predicted outcome after LDLT for ALF.

Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: An observational cohort study.

BACKGROUND: Patients with acute-on-chronic liver failure (ACLF) have coagulation failure in the setting of systemic inflammatory syndrome (SIRS), sepsis and extra-hepatic organ failures. METHODS: Consecutive ACLF patients without sepsis at baseline were assessed at days 0, 3 and 7 with thromboelastography (TEG) and specific assays (Factor VIII, von Willebrand factor [vWF], protein C and antithrombin III [ATIII]) and followed for development of sepsis, bleeding and outcome. RESULTS: Of 243 patients, 114 (63% ethanol related; mean age 44.3 ± 11.7 years; 90% male) were recruited. SIRS was noted in 39 (34.2%), 45 (39.5%) and 46 (40%) patients at days 0, 3 and 7 and sepsis in 28 (24%) and 52 (56.1%) patients at days 3 and 7 respectively. The 28- and 90-day survivals were 62% and 51% respectively. A hypocoagulable TEG at baseline was a predictor of bleeding (hazard ratio [HR] 2.1; CI 1.6-4.9; P = 0.050) and mortality (HR 1.9; CI 1.3-7.9; P = 0.043). ACLF patients had increased Factor VIII, vWF, tissue factor levels and tissue plasminogen activator (tPA) activity with reduced protein C and ATIII. Coagulation parameters like Coagulation Index (HR 2.1; CI 1.1-4.5; P = 0.044),clot lysis (HR 3.2; CI 1.9-3.4; P = 0.033), low protein C < 30% (HR 2.1; CI 1.5-2.8; P = 0.017), ATIII (HR 1.4; CI 1.7-3.1; P = 0.052) and tPA (HR 1.5; CI 1.1-2.4; P = 0.052) were predictors of mortality at day 28. Protein C activity <30% (HR 1.3; CI 1.0-2.9; P = 0.042) and tPA >20 ng/mL (HR 1.2; CI 1.1-2.1; P = 0.040) predicted mortality when adjusted for age, gender and baseline MELD. CONCLUSIONS: Dynamic coagulation derangements, measured by TEG, determine the likelihood of bleeding and mortality in ACLF.

SX-Ella Stent Danis Effectively Controls Refractory Variceal Bleed in Patients with Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Almost 10% of bleeding episodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality up to 50%. Severity of liver disease and high portal pressure are mainly responsible for it. TIPS cannot be used in these patients due to high MELD score. We aimed to evaluate the efficacy of self-expandable DE stents for control of refractory variceal bleeds in patients with ACLF. METHODS: Acute-on-chronic liver failure patients (n = 88, mean age 47.3 ± 10.9 years) with refractory variceal bleeds received either DE stent (Gr. A, n = 35) or continued with repeat endotherapy and vasoactive drug (Gr.B, n = 53). Matching by propensity risk score (PRS) was done to avoid selection bias. Competing risk Cox regression analysis was done to identify event-specific, i.e., gastrointestinal bleed-related death. RESULTS: Majority (78.4%) of patients were alcoholic with MELD score of 45.9 ± 20.1. Control of initial bleeding was significantly more in the DE stent group as compared to controls in both pre-match (89 vs. 37%; p < 0.001) and PRS-matched cohorts (73 vs. 32%; 0.007). Further, bleed-related death was also significantly lower in DE group as compared to controls in both pre-match (14 vs. 64%; p = 0.001) and PRS-matched cohorts (6 vs. 56%; p = 0.001). In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both pre-match (p = 0.04, HR 0.36, 95% CI 0.13-0.96) and PRS-matched cohorts (p < 0.001, HR 0.21, 95% CI 0.08-0.51). CONCLUSIONS: Self-expandable DE stents are very effective in control of refractory variceal bleeding and reduced mortality in patients with severe liver failure.

A randomized trial comparing terlipressin and noradrenaline in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: The choice of vasopressor for treating cirrhosis with septic shock is unclear. While noradrenaline in general is the preferred vasopressor, terlipressin improves microcirculation in addition to vasopressor action in non-cirrhotics. We compared the efficacy and safety of noradrenaline and terlipressin in cirrhotics with septic shock. PATIENTS AND METHODS: Cirrhotics with septic shock underwent open label randomization to receive either terlipressin (n=42) or noradrenaline (n=42) infusion at a titrated dose. The primary outcome was mean arterial pressure (MAP) >65 mm Hg at 48 h. RESULTS: Baseline characteristics were comparable between the terlipressin and noradrenaline groups.SBP and pneumonia were major sources of sepsis. A higher proportion of patients on terlipressin were able to achieve MAP >65 mm of Hg (92.9% vs 69.1% P=.005) at 48 h. Subsequent discontinuation of vasopressor after hemodynamic stability was better with terlipressin (33.3% vs 11.9%, P<.05). Terlipressin compared to noradrenaline prevented variceal bleed (0% vs 9.5%, P=.01) and improved survival at 48 h (95.2% vs 71.4%, P=.003). Percentage lactate clearance (LC) is an independent predictor of survival [P=.0001, HR=3.9 (95% CI: 1.85-8.22)] after achieving the target MAP.Therapy related adverse effect were comparable in both the arms (40.5% vs 21.4%, P=.06), mostly minor (GradeII-88%) and reversible. CONCLUSIONS: Terlipressin is as effective as noradrenaline as a vasopressor in cirrhotics with septic shock and can serve as a useful drug. Terlipressin additionally provides early survival benefit and reduces the risk of variceal bleed. Lactate clearance is a better predictor of outcome even after achieving target MAP, suggesting the role of microcirculation in septic shock.

Systemic inflammatory response syndrome in acute-on-chronic liver failure: Relevance of 'golden window': A prospective study.

BACKGROUND AND AIM: Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute-on-chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis. METHODS: Consecutive ACLF patients were monitored for the development of SIRS/sepsis and associated complications and followed till 90 days, liver transplant or death. RESULTS: Of 561 patients, 201 (35.8%) had no SIRS and 360 (64.2%) had SIRS with or without infection. New onset SIRS and sepsis developed in 74.6% and 8% respectively in a median of 7 (range 4-15) days, at a rate of 11% per day. The cumulative incidence of new SIRS was 29%, 92.8%, and 100% by days 4, 7, and 15. Liver failure, that is, bilirubin > 12 mg/dL (odds ratio [OR] = 2.5 [95% confidence interval {CI} = 1.05-6.19], P = 0.04) at days 0 and 4, and renal failure at day 4 (OR = 6.74 [95%CI = 1.50-13.29], P = 0.01), independently predicted new onset SIRS. Absence of SIRS in the first week was associated with reduced incidence of organ failure (20% vs 39.4%, P = 0.003), as was the 28-day (17.6% vs 36%, P = 0.02) and 90-day (27.5% vs 51%,P = 0.002) mortality. The 90-day mortality was 61.6% in the total cohort and that for those having no SIRS and SIRS at presentation were 42.8% and 65%, respectively (P < 0.001). CONCLUSION: Liver failure predicts the development of SIRS. New onset SIRS in the first week is an important determinant of early sepsis, organ failure, and survival. Prompt interventions in this 'golden window' before development of sepsis may improve the outcome of ACLF.

Acute-on-chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a distinct entity that differs from acute liver failure and decompensated cirrhosis in timing, presence of treatable acute precipitant, and course of disease, with a potential for self-recovery. The core concept is acute deterioration of existing liver function in a patient of chronic liver disease with or without cirrhosis in response to an acute insult. The insult should be a hepatic one and presentation in the form of liver failure (jaundice, encephalopathy, coagulopathy, ascites) with or without extrahepatic organ failure in a defined time frame. ACLF is characterized by a state of deregulated inflammation. Initial cytokine burst presenting as SIRS, progression to CARS and associated immunoparalysis leads to sepsis and multi-organ failure. Early identification of the acute insult and mitigation of the same, use of nucleoside analogue in HBV-ACLF, steroid in severe alcoholic hepatitis, steroid in severe autoimmune hepatitis and/or bridging therapy lead to recovery, with a 90-day transplant-free survival rate of up to 50 %. First-week presentation is crucial concerning SIRS/sepsis, development, multiorgan failure and consideration of transplant. A protocol-based multi-disciplinary approach including critical care hepatology, early liver transplant before multi-organ involvement, or priority for organ allocation may improve the outcome. Presentation with extrahepatic organ involvement or inclusion of sepsis as an acute insult in definition restricts the therapy, i.e., liver transplant or bridging therapy, and needs serious consideration. Augmentation of regeneration, cell-based therapy, immunotherapy, and gut microbiota modulation are the emerging areas and need further research.