APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study.

BACKGROUND AIMS: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence (AI) in a global cohort, we sought to derive and validate an enhanced prognostic model. APPROACH AND RESULTS: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled AH patients per NIAAA criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day post-admission mortality, three AI algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined via Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce post-test probabilities. The ALCoholic Hepatitis Artificial INtelligence (ALCHAIN) Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30-day) and 27.9% (90-day) in the derivation cohort, versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779 - 0.844) and 0.799 (0.769 - 0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, MELD variations, ABIC, Glasgow, and modified Glasgow Scores (p<0.001). ALCHAIN Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCHAIN Ensemble score>0.20 in both derivation and validation cohorts. CONCLUSIONS: Harnessing AI within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/.

Determinants, profile and outcomes of hepatitis A virus-associated severe acute liver injury in adults.

BACKGROUND AND OBJECTIVES: Hepatitis A virus (HAV)-related hepatitis is witnessing an epidemiological transition with increasing trends in adults. While uncomplicated hepatitis remains common, evidence suggests it to be a growing cause for acute liver failure (ALF). In between the two extremes exists severe acute liver injury (s-ALI) which has a propensity to transition to ALF. We aimed at describing the clinical profile of patients with HAV-related s-ALI and identifying potential predictors of progression to ALF. METHODS: This was a single-center retrospective analysis of adult patients admitted with HAV-related s-ALI between April 2022 and December 2023. Demographic and laboratory parameters were compared between patients with only s-ALI and those with ALF. Predictors of progression from s-ALI to ALF were identified using logistic regression. RESULTS: Forty-three patients satisfied criteria of s-ALI, of which 33 (76.7%) had only s-ALI, while 10 (23.3%) had ALF. Patients with s-ALI had lesser leukocytosis (6.3 ± 3 vs. 13.2 ± 4.8), less incidence of acute kidney injury (9.1% vs. 40%) and lower model for end-stage liver disease (MELD) (20 [18-24.5] vs. 31.5 [26-42]), arterial lactate (2.1 [1.3-3.1] vs. 6.3 [5.2-8.0]), arterial ammonia (94 [72-118] vs. 299 [188-573]), procalcitonin (0.5 [0.28-1.25] vs. 3.2 [1.2-6.1]) and ferritin (482 [213-1633] vs. 5186 [1341-11,053]) compared to HAV-ALF (p < 0.05 for all). Three patients (9.09%) with s-ALI progressed to ALF of whom one (3%) died. Baseline ammonia levels (unadjusted odds ratio [OR] 1.03 [1.01-1.06]) and leukocyte count (OR 1.00 [1.00-1.01]) tended to be associated with ALF progression, although none was significant after multi-variable adjustment. Ammonia levels had an area under receiver operating curve of 0.816 (0.64-0.93) (p = 0.009) (cut-off of 144 µmol/L). Additional comorbidities did not impact overall outcomes. CONCLUSION: HAV presents as s-ALI in young adults, with almost one in 10 progressing to ALF. Baseline ammonia may be an important predictor of progression even in s-ALI, but mandates larger well-designed studies.

Randomized, Double-Blind, Placebo-Controlled, Clinical Study of Passiflora incarnata in Participants With Stress and Sleep Problems.

Background and objectives SIVI is a standardized extract prepared using the aerial parts of Passiflora incarnata developed to enhance the quality of sleep. ​​​​​​The objective of the present study was to the evaluate efficacy and safety of SIVI (Passiflora incarnata extract) in the management of stress and sleep problems in Indian participants in a randomized, double-blind, placebo-controlled, clinical study. Materials and methods A total of 65 participants with stress and insomnia were randomized to two groups with 32 in the SIVI (Passiflora incarnata extract) group and 33 in the placebo group. Subjects were asked to take the test substance along with water at bedtime for 30 days. The Perceived Stress Scale, quality of life using the General Health Questionnaire (GHQ-12) scale, and Insomnia Severity Index were assessed on day 1, day 15, and day 30. Results Passiflora incarnata extract showed a statistically significant reduction in the mean score of stress on the Perceived Stress Scale and significantly increased the mean score of total sleep time compared to placebo. The general psychological health was found to be significantly improved in the SIVI (Passiflora incarnata extract) group compared to the placebo group on day 15 and day 30. SIVI (Passiflora incarnata extract) did not show any adverse effects. Conclusions The results of the current study indicate that Passiflora incarnata extract is beneficial in the management of stress and helps to improve sleep quality in subjects with stress and insomnia.

Hepatocellular Carcinoma Screening in a Contemporary Cohort of At-Risk Patients.

Importance: Cohort studies demonstrating an association of hepatocellular carcinoma (HCC) screening with reduced mortality are prone to lead-time and length-time biases. Objective: To characterize the clinical benefits of HCC screening, adjusting for lead-time and length-time biases, in a diverse, contemporary cohort of at-risk patients. Design, Setting, and Participants: This retrospective cohort study of patients with HCC was conducted between January 2008 and December 2022 at 2 large US health systems. Data analysis was performed from September to November 2023. Main Outcomes and Measures: The primary outcome was screen-detected HCC, defined by abnormal screening-intent abdominal imaging or α-fetoprotein level within 6 months before diagnosis. Cox regression analysis was used to characterize differences in overall survival between patients with screen-detected and non-screen-detected HCC; lead-time and length-time adjustments were calculated using the Duffy parametric formula. Results: Among 1313 patients with HCC (mean [SD] age, 61.7 [9.6] years; 993 male [75.6%]; 739 [56.3%] with Barcelona Clinic Liver Cancer stage 0/A disease), HCC was screen-detected in 556 (42.3%) and non-screen detected in 757 (57.7%). Patients with screen-detected HCC had higher proportions of early-stage HCC (393 patients [70.7%] vs 346 patients [45.7%]; risk ratio [RR], 1.54; 95% CI, 1.41-1.70) and curative treatment receipt (283 patients [51.1%] vs 252 patients [33.5%]; RR, 1.52; 95% CI, 1.34-1.74) compared with patients with non-screen-detected HCC. The screen-detected group had significantly lower mortality, which persisted after correcting for lead-time bias (hazard ratio, 0.75; 95% CI, 0.65-0.87) in fully adjusted models. Both groups had similar tumor doubling times (median [IQR], 3.8 [2.2-10.7] vs 5.6 [1.7-11.4] months) and proportions of indolent tumors (28 patients [35.4%] vs 24 patients [38.1%]; RR, 0.93; 95% CI, 0.60-1.43). Adjustment for length-time bias decreased survival estimates, although 3-year and 5-year survival for patients with screen-detected HCC remained longer than that for patients with non-screen-detected HCC. Conclusions and Relevance: The findings of this cohort study suggest that HCC screening is associated with reduced mortality even after accounting for lead-time and length-time biases. However, these biases should be considered in future studies.

Acute-on-chronic liver failure - steps towards harmonization of the definition!

Acute-on-chronic liver failure (ACLF), usually precipitated by alcohol misuse or viral reactivation, is characterised by rapid onset and usually reversible liver failure. Various definitions of ACLF have been proposed and widely used across the globe, including those by APASL, COSSH, EASL-CLIF, Japanese experts, and NACSELD. Although all the definitions have several similarities and connote high short-term mortality, a clear and standardised definition is still lacking, hampering research in this key area. In this review, we discuss the similarities and differences among various definitions and propose steps to harmonise EASL-CLIF, APASL, NACSELD, Japanese, and Chinese definitions of ACLF.

Standard-Volume Is As Effective As High-Volume Plasma Exchange for Patients With Acute Liver Failure.

Background/Aims: Acute liver failure (ALF) is associated with fatal outcomes without liver transplantation. Two randomized studies reported standard volume (SV) and high volume (HV) plasma exchange (PLEX) as effective therapeutic modalities for patients with ALF. However, no studies have compared the safety and efficacy of SV with HV PLEX, which we aimed to assess. Methods: This retrospective study included patients with ALF admitted between March 2021 and March 2023 who underwent PLEX. All patients underwent HV PLEX until May 2022, and then thereafter, SV PLEX was performed. The objectives of the study were to compare transplant-free survival (TFS) at 30 days, efficacy in reducing severity scores, biochemical variables, and adverse events between SV (total plasma volume x 1) and HV (total plasma volume x 1.5-2) PLEX. Results: Forty two ALF patients (median age: 23.5 years; females: 57.1%; MELD Na: 34.67 ± 6.07; SOFA score- 5.24 ± 1.42) underwent PLEX. Of these, 22 patients underwent SV-PLEX, and 20 underwent HV-PLEX. The mean age, sex, etiology distribution, and severity scores were similar between the groups. The median number of PLEX sessions (2) was similar in both groups. On Kaplan-Meier analysis, TFS was 45.5% in SV group and 45% in HV group (P = 0.76). A comparable decline in total bilirubin, PT/INR, ammonia, and MELD Na scores was noted in both groups. The cumulative number of adverse events was similar between the HV group (77.3%) and SV group (54.5%; P = 0.12). Conclusions: SV PLEX is safe and as effective as HV PLEX in patients with ALF. Further randomized controlled trials with a larger sample size are needed to validate these findings.

Machine learning improves the prediction of significant fibrosis in Asian patients with metabolic dysfunction-associated steatotic liver disease - The Gut and Obesity in Asia (GO-ASIA) Study.

BACKGROUND: The precise estimation of cases with significant fibrosis (SF) is an unmet goal in non-alcoholic fatty liver disease (NAFLD/MASLD). AIMS: We evaluated the performance of machine learning (ML) and non-patented scores for ruling out SF among NAFLD/MASLD patients. METHODS: Twenty-one ML models were trained (N = 1153), tested (N = 283), and validated (N = 220) on clinical and biochemical parameters of histologically-proven NAFLD/MASLD patients (N = 1656) collected across 14 centres in 8 Asian countries. Their performance for detecting histological-SF (≥F2fibrosis) were evaluated with APRI, FIB4, NFS, BARD, and SAFE (NPV/F1-score as model-selection criteria). RESULTS: Patients aged 47 years (median), 54.6% males, 73.7% with metabolic syndrome, and 32.9% with histological-SF were included in the study. Patients with SFvs.no-SF had higher age, aminotransferases, fasting plasma glucose, metabolic syndrome, uncontrolled diabetes, and NAFLD activity score (p < 0.001, each). ML models showed 7%-12% better discrimination than FIB-4 to detect SF. Optimised random forest (RF) yielded best NPV/F1 in overall set (0.947/0.754), test set (0.798/0.588) and validation set (0.852/0.559), as compared to FIB4 in overall set (0.744/0.499), test set (0.722/0.456), and validation set (0.806/0.507). Compared to FIB-4, RF could pick 10 times more patients with SF, reduce unnecessary referrals by 28%, and prevent missed referrals by 78%. Age, AST, ALT fasting plasma glucose, and platelet count were top features determining the SF. Sequential use of SAFE < 140 and FIB4 < 1.2 (when SAFE > 140) was next best in ruling out SF (NPV of 0.757, 0.724 and 0.827 in overall, test and validation set). CONCLUSIONS: ML with clinical, anthropometric data and simple blood investigations perform better than FIB-4 for ruling out SF in biopsy-proven Asian NAFLD/MASLD patients.

Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

Myosteatosis for Early Detection of Muscle Disorder in Patients With Liver Cirrhosis.

Background and aims: Muscle disorders in cirrhosis are associated with poor outcome and need early identification. Anthropometric measures lack sensitivity, and CT-based L3-skeletal muscle Index (L3-SMI) may miss early sarcopenia. The study aimed to find if SM-RA can identify more patients with muscle disorder than L3-SMI and anthropometry. Methods: 388 patients with cirrhosis underwent nutritional assessment by anthropometry, short-physical-performance-battery (SPPB) < 9, L3-SMI (<36.5 cm2/m2 (males); <30.2 cm2/m2 (females), and myosteatosis assessment by skeletal muscle radiation attenuation (SM-RA) (<41 HU for body mass index [BMI] <24.9 kg/m2 and <33 HU for ≥25 kg/m2) and results were compared. Results: Sarcopenia based on SPPB was 38.9 % with scores (9 ± 1.48 vs. 10.74 ± 1.25, P = 0.001 in males; and 8.43 ± 1.59 vs. 9.89 ± 1.57, P = 0.001 in females). Mid-arm muscle circumference was lower in sarcopenic males [20.5 ± 2.42 vs. 22.9 ± 2.19 cm, P = 0.001] but not in females [19.4 ± 2.73 vs. 21.1 ± 2.51, P = 0.18]. L3-SMI-based sarcopenia was found in 44.8 % (additional 5.92 %) compared to SPPB, mostly in cryptogenic cirrhosis (19.2 % vs. 35.08 %, δ change +15.9 %). Myosteatosis (71.64 %) identified an additional 26.85 % and 32.74 % of patients with muscle disorder compared to L3SMI and SPPB, respectively, with the majority of new detection in non-alcoholic fatty liver disease (NAFLD) 39.4 % vs. 77.06 %, δ change +37.66 %) CTP-A patients (16.6 % vs. 36.8 %, δ change +20.2 %). Myosteatosis was found in 48.3 % of patients with normal L3-SMI. Conclusion: SM-RA can identify more patients with muscle disorder than L3-SMI and SPPB.

The incidence of adverse outcome in donors after living donor liver transplantation: A meta-analysis of 60,829 donors.

The scarcity of liver grafts has prompted developments in living donor liver transplantations (LDLT), with previous literature illustrating similar outcomes in recipients compared to deceased donor transplants. However, significant concerns regarding living donor morbidity and mortality have yet to be examined comprehensively. This study aims to provide estimates of the incidence of various outcomes in living liver donors. In this meta-analysis, Medline and Embase were searched from inception to July 2022 for articles assessing the incidence of outcomes in LDLT donors. Complications in the included studies were classified into respective organ systems. Analysis of incidence was conducted using a generalized linear mixed model with Clopper-Pearson intervals. Eighty-seven articles involving 60,829 living liver donors were included. The overall pooled incidence of complications in LDLT donors was 24.7% (CI: 21.6%-28.1%). The incidence of minor complications was 17.3% (CI: 14.7%-20.3%), while the incidence of major complications was lower at 5.5% (CI: 4.5%-6.7%). The overall incidence of donor mortality was 0.06% (CI: 0.0%-0.1%) in 49,027 individuals. Psychological complications (7.6%, CI: 4.9%-11.5%) were the most common among LDLT donors, followed by wound-related (5.2%, CI: 4.4%-6.2%) and respiratory complications (4.9%, CI: 3.8%-6.3%). Conversely, cardiovascular complications had the lowest incidence among the subgroups at 0.8% (CI: 0.4%-1.3%). This study presents the incidence of post-LDLT outcomes in living liver donors, illustrating significant psychological, wound-related, and respiratory complications. While significant advancements in recent decades have contributed towards decreased morbidity in living donors, our findings call for targeted measures and continued efforts to ensure the safety and quality of life of liver donors post-LDLT.

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Antibiotics With or Without Rifaximin for Acute Hepatic Encephalopathy in Critically Ill Patients With Cirrhosis: A Double-Blind, Randomized Controlled (ARiE) Trial.

INTRODUCTION: Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE). METHODS: In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed. RESULTS: Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective ( P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections ( P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections. DISCUSSION: Reversal of overt HE in those on ab was comparable with those on ab + r.

Comparing rare variants versus common in the pathogenesis of nonalcoholic fatty liver disease: a whole exome sequencing approach.

BACKGROUND/PURPOSE: Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis. METHODS: This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven nonalcoholic steatohepatitis and persistently elevated liver enzymes were included. Controls were with normal CT/MR fat fraction. DNA was isolated from whole blood, amplified (SureSelectXT Human All Exon V5 + UTR kit) and sequenced (Illumina). Data were filtered for quality, aligned (hg19), and annotated (OpenCRAVAT). Pathogenic (Polyphen-2/SIFT/ClinVar) variants and variants reported to be associated with NAFLD based on published literature were extracted from our data and compared between patients and controls. RESULTS: The mean age of controls (N = 17) and patients (N = 37) was 46.88 ± 6.94 and 37.46 ± 13.34 years, respectively. A total of 251 missense variants out of 89 286 were classified as pathogenic. Of these, 106 (42.23%) were unique to the patients and remaining (n = 145; 57.77%) were found in both patients and controls. Majority (25/37; 67.57%) patients had a minimum of one or more rare pathogenic variant(s) related to liver pathology that was not seen in the controls. CONCLUSION: Elucidating the contribution of rare pathogenic variants would enhance our understanding of the pathogenesis. Including the rarer genes in the polygenic risk scores would enhance prediction power.

Evaluation of terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury using point-of-care echocardiography.

BACKGROUND AND AIMS: Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. APPROACH: Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. RESULTS: One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CONCLUSIONS: CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Proton Pump Inhibitors Increases Longitudinal Risk of Mortality, Decompensation, and Infection in Cirrhosis: A Meta-Analysis.

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are frequently prescribed to cirrhotic patients, but there is limited longitudinal evidence regarding their effects. This study aimed to assess the impact of PPIs on adverse events in cirrhotic patients. METHODS: A comprehensive search was conducted using the Medline and Embase databases to identify relevant articles. Pooled hazard ratios (HRs) using DerSimonian and Laird random-effects model were calculated to evaluate the risk of adverse events such as long-term mortality, hepatic decompensation, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and overall infection in cirrhotic patients with PPI use. RESULTS: The analysis included 28 studies with 260,854 cirrhotic patients. The prevalence of PPI use among cirrhotic patients was 55.93%. The use of PPIs was not significantly associated with short-term mortality in cirrhotic patients. However, long-term mortality (HR 1.321, 95% CI 1.103-1.581, P = 0.002), decompensation (HR 1.646, 95% CI 1.477-1.835, P < 0.001), HE (HR 1.968, 95% CI 1.372-2.822, P < 0.001), SBP (HR 1.751, 95% CI 1.649-1.859, P < 0.001), and infection (HR 1.370, 95% CI 1.148-1.634, P < 0.001) were significantly associated with PPI use. Sensitivity analysis with prospective studies yielded similar results. CONCLUSION: PPIs should be reserved for appropriate indications at lowest effective dose for cirrhotic patients due to the potential harm.

Managing a Prospective Liver Transplant Recipient on the Waiting List.

The management of a patient in the peri-transplantation period is highly challenging, and it is even more difficult while the patient is on the transplantation waitlist. Keeping the patient alive during this period involves managing the complications of liver disease and preventing the disease's progression. Based on the pre-transplantation etiology and type of liver failure, there is a difference in the management protocol. The current review is divided into different sections, which include: the management of underlying cirrhosis and complications of portal hypertension, treatment and identification of infections, portal vein thrombosis management, and particular emphasis on the management of patients of hepatocellular carcinoma and acute liver failure in the transplantation waitlist. The review highlights special concerns in the management of patients in the Asian subcontinent also. The review also addresses the issue of delisting from the transplant waitlist to see that futility does not overtake the utility of organs. The treatment modalities are primarily expressed in tabular format for quick reference. The following review integrates the vast issues in this period concisely so that the management during this crucial period is taken care of in the best possible way.

Human albumin infusion is safe and effective even in patients without acute kidney injury and spontaneous bacterial peritonitis.

BACKGROUND AND OBJECTIVES: Human albumin (HA) solution is currently recommended only for patients with spontaneous bacterial peritonitis (SBP) and acute kidney injury (AKI). However, its use in hospitalized patients is quite frequent. The objective was to compare the outcomes of patients receiving HA in recommended (Gr. A) vs. non-recommended (Gr. B) indications. METHODS: In this prospective study, consecutive hospitalized patients who received HA were included. Apart from comparing the proportion of patients achieving resolution of hyponatremia, infection and hepatic encephalopathy among Gr. A and Gr. B, we also compared the in-hospital survival and performed a sub-group analysis of patients with the European Association for the Study of the Liver (EASL) acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC). RESULTS: Of the 396 hospitalized patients who received HA, 180 had AKI and/or SBP (Gr. A), and 216 received albumin for non-recommended indications (Gr. B). The mean age, sex and etiology distribution were similar. The total dose of HA was higher (88 ± 61.62 g vs. 71.31 ± 488.17 g; p = 0.003) and the duration longer (4 ± 2.37 vs. 3.4 ± 1.82 days; p = 0.005) in Gr. A than B. The resolution of infection and HE was similar among both groups, while hyponatremia resolution was significantly higher in Gr. B (94.7%) than Gr. A (75.6%; p < 0.001). On Kaplan-Meier analysis, survival was significantly higher in Gr. B (94%) than Gr. A (78.9%; p < 0.001). The incidence of albumin-induced fluid overload was comparable (2.8% vs. 1.4%; p = 0.32). Patients with ACLF were sicker with a higher incidence of microbiologically proven infection, hepatic encephalopathy (HE) and hyponatremia than in the DC group. Resolution of infection and hyponatremia and in-hospital survival was significantly lower in the ACLF group (72.5%) than in the DC group (92.7%; p < 0.001). Eighty-six per cent of patients achieved resolution of ACLF. CONCLUSIONS: HA infusion is safe and effective even in patients without AKI and SBP and leads to the resolution of infection, hyponatremia, HE and ACLF.