AGA Clinical Practice Update on the Use of Vasoactive Drugs and Intravenous Albumin in Cirrhosis: Expert Review.

DESCRIPTION: Cirrhosis is a major cause of morbidity and mortality in the United States and worldwide. It consists of compensated, decompensated, and further decompensated stages; median survival is more than 15 years, 2 years, and 9 months for each stage, respectively. With each stage, there is progressive worsening of portal hypertension and the vasodilatory-hyperdynamic circulatory state, resulting in a progressive decrease in effective arterial blood volume and renal perfusion. Vasoconstrictors reduce portal pressure via splanchnic vasoconstriction and are used in the management of variceal hemorrhage. Intravenous (IV) albumin increases effective arterial blood volume and is used in the prevention of acute kidney injury (AKI) and death after large-volume paracentesis and in patients with spontaneous bacterial peritonitis (SBP). The combination of vasoconstrictors and albumin is used in the reversal of hepatorenal syndrome (HRS-AKI), the most lethal complication of cirrhosis. Because a potent vasoconstrictor, terlipressin, was recently approved by the US Food and Drug Administration, and because recent trials have explored use of IV albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and IV albumin in the following 3 specific scenarios: variceal hemorrhage, ascites and SBP, and HRS. METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. It underwent internal peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Some of the statements are unchanged from published guidelines because of lack of new evidence in the literature. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality and evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Vasoactive drugs should be initiated as soon as the diagnosis of variceal hemorrhage is suspected or confirmed, preferably before diagnostic and/or therapeutic endoscopy. BEST PRACTICE ADVICE 2: After initial endoscopic hemostasis, vasoactive drugs should be continued for 2-5 days to prevent early rebleeding. BEST PRACTICE ADVICE 3: Octreotide is the vasoactive drug of choice in the management of variceal hemorrhage based on its safety profile. BEST PRACTICE ADVICE 4: IV albumin should be administered at the time of large-volume (>5 L) paracentesis. BEST PRACTICE ADVICE 5: IV albumin may be considered in patients with SBP. BEST PRACTICE ADVICE 6: Albumin should not be used in patients (hospitalized or not) with cirrhosis and uncomplicated ascites. BEST PRACTICE ADVICE 7: Vasoconstrictors should not be used in the management of uncomplicated ascites, after large-volume paracentesis or in patients with SBP. BEST PRACTICE ADVICE 8: IV albumin is the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with AKI. BEST PRACTICE ADVICE 9: Vasoactive drugs (eg, terlipressin, norepinephrine, and combination of octreotide and midodrine) should be used in the treatment of HRS-AKI, but not in other forms of AKI in cirrhosis. BEST PRACTICE ADVICE 10: Terlipressin is the vasoactive drug of choice in the treatment of HRS-AKI and use of concurrent albumin can be considered when accounting for patient's volume status. BEST PRACTICE ADVICE 11: Terlipressin treatment does not require intensive care unit monitoring and can be administered intravenously through a peripheral line. BEST PRACTICE ADVICE 12: Terlipressin use is contraindicated in patients with hypoxemia and in patients with ongoing coronary, peripheral, or mesenteric ischemia, and should be used with caution in patients with acute-on-chronic liver failure grade 3. The benefits may not outweigh the risks in patients with serum creatinine >5 mg/dL and in patients listed for transplantation with a Model for End-stage Liver Disease ≥35.

Full adherence to cirrhosis quality indicators is associated with lower mortality in acute variceal bleeding: Nationwide audit.

BACKGROUND AND AIMS: Acute variceal bleeding (AVB) is a major complication in patients with cirrhosis. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB. APPROACH AND RESULTS: We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all 5 QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-week mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6 weeks (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) ( p <0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, nonadherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence to the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality. CONCLUSIONS: Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Comparing serial and current liver stiffness measurements to predict decompensation in compensated advanced chronic liver disease patients.

BACKGROUND AND AIMS: The utility of serial liver stiffness measurements (LSM) to predict decompensation in patients with compensated advanced chronic liver disease (cACLD) remains unclear. We aimed to validate whether comparing serial LSM is superior to using the current LSM to predict liver-related events (LRE) in patients with cACLD. APPROACH AND RESULTS: In this retrospective analysis of an international registry, patients with cACLD and serial LSM were followed up until index LRE. We compared the performance of both the dynamic LSM changes and the current LSM in predicting LRE using Cox regression analysis, considering time zero of follow-up as the date of latest liver stiffness measurement. In all, 480 patients with cACLD with serial LSM were included from 5 countries. The commonest etiology of cACLD was viral (53%) and MASLD (34%). Over a median follow-up of 68 (IQR: 45 -92) months, 32% experienced a LSM decrease to levels below 10kPa (resolved cACLD) and 5.8% experienced LRE. Resolved cACLD were more likely to be nondiabetic and had better liver function. While a higher value of the current LSM was associated with higher LREs, LSM changes over time (LSM slope) were not associated with LRE. In multivariable Cox regression, neither the prior LSM nor the LSM slope added predictive value to latest liver stiffness measurement. CONCLUSIONS: Once the current LSM is known, previous LSM values do not add to the prediction of LREs in patients with cACLD.

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis.

OBJECTIVE: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. DESIGN: In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). RESULT: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. CONCLUSIONS: We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Predicting survival in patients with 'non-high-risk' acute variceal bleeding receiving ß-blockers+ligation to prevent re-bleeding.

BACKGROUND & AIMS: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13). Nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation for secondary prophylaxis. We investigated prognostic factors for re-bleeding and mortality in 'non-high-risk' AVB to identify subgroups who may benefit from more potent treatments (i.e., TIPS) to prevent further decompensation and mortality. METHODS: A total of 2,225 adults with cirrhosis and variceal bleeding were prospectively recruited at 34 centres between 2011-2015; for the purpose of this study, case definitions and information on prognostic indicators at index AVB and on day 5 were further refined in low-risk patients, of whom 581 (without failure to control bleeding or contraindications to TIPS) who were managed by non-selective beta-blockers/endoscopic variceal ligation, were finally included. Patients were followed for 1 year. RESULTS: Overall, 90 patients (15%) re-bled and 70 (12%) patients died during follow-up. Using clinical routine data, no meaningful predictors of re-bleeding were identified. However, re-bleeding (included as a time-dependent co-variable) increased mortality, even after accounting for differences in patient characteristics (adjusted cause-specific hazard ratio: 2.57; 95% CI 1.43-4.62; p = 0.002). A nomogram including CTP, creatinine, and sodium measured at baseline accurately (concordance: 0.752) stratified the risk of death. CONCLUSION: The majority of 'non-high-risk' patients with AVB have an excellent prognosis, if treated according to current recommendations. However, about one-fifth of patients, i.e. those with CTP ≥8 and/or high creatinine levels or hyponatremia, have a considerable risk of death within 1 year of the index bleed. Future clinical trials should investigate whether elective TIPS placement reduces mortality in these patients. IMPACT AND IMPLICATIONS: Pre-emptive transjugular intrahepatic portosystemic shunt placement improves outcomes in high-risk acute variceal bleeding; nevertheless, some 'non-high-risk' patients have poor outcomes despite the combination of non-selective beta-blockers and endoscopic variceal ligation. This is the first large-scale study investigating prognostic factors for re-bleeding and mortality in 'non-high-risk' acute variceal bleeding. While no clinically meaningful predictors were identified for re-bleeding, we developed a nomogram integrating baseline Child-Turcotte-Pugh score, creatinine, and sodium to stratify mortality risk. Our study paves the way for future clinical trials evaluating whether elective transjugular intrahepatic portosystemic shunt placement improves outcomes in presumably 'non-high-risk' patients who are identified as being at increased risk of death.

Porto-sinusoidal vascular liver disorder with portal hypertension: Natural History and Long-Term Outcome.

BACKGROUND & AIMS: Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine natural history and prognostic factors using a large multicenter cohort of PSVD patients. METHODS: Retrospective multicentric study of PSVD patients and signs of portal hypertension (PH) prospectively registered in 27 centers. RESULTS: 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patient had an associated condition, that was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients; ascites in 117 and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was of 15% at 5 years, with a 5-year rebleeding rate of 18%. Five-year cumulative incidence of new or worsening ascites was of 18% and of developing PVT of 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver related death. Transplant-free survival was 97%, and 83% at 1 and 5 years. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed the creation of a Nomogram that accurately predicted prognosis. CONCLUSIONS: Prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function.

Cost Effectiveness of the Baveno VI Criteria Compared With Endoscopy for High-Risk Varices in Patients With Child-Pugh A Cirrhosis.

BACKGROUND & AIMS: Although upper gastrointestinal endoscopy (EGD) remains the gold standard for detecting varices in cirrhosis, the Baveno VI criteria proposed a combination of transient elastography and platelet count that could rule out high-risk varices, therefore sparing the need for an endoscopy, with significant potential cost savings. We performed a cost-effectiveness analysis of the Baveno VI criteria compared with EGD in the diagnosis of high-risk varices in cirrhosis. METHODS: We built an analytical decision model to estimate the cost and benefits of using the Baveno VI criteria compared with EGD in patients with Child-Pugh A cirrhosis. The analysis was performed from the UK National Health Service perspective, over 1, 5, and 20 years. A Markov model was populated with data from published evidence. Outcomes were measured in terms of quality-adjusted life years (QALYs) and avoided deaths. The analyses were repeated for Canada and Spain, using relevant cost inputs. RESULTS: The Baveno VI criteria were cost effective compared with endoscopy in all analyses. For 1000 patients, they produced 0.16 additional QALYs at an incremental cost of £326 ($443.41) over 5 years, resulting in an incremental cost of £2081 ($2830) per additional QALY gained. The incremental net monetary benefit of Baveno VI compared with EGD was £2808 ($3819) over 5 years per patient. Baveno VI criteria also were cost effective in Canada and Spain. Deterministic and probabilistic sensitivity analysis supported these findings. CONCLUSIONS: The findings demonstrate that the Baveno VI criteria are cost effective, suggesting that they should be considered for widespread implementation on the basis of safety, appropriateness, and economic grounds.

A model including standardized weight improved predicting waiting list mortality in adolescent liver transplant candidates: A US national study.

The Model for End-Stage Liver Disease (MELD) score has been employed to identify adolescents eligible for liver transplantation since 2004. However, the optimal model for prioritizing adolescent candidates is uncertain. In our study, we aimed at evaluating the value of adding anthropometric variables to liver transplantation allocation models among adolescents. We conducted a retrospective cohort study using the data from the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research to identify adolescent patients registered on the liver transplant waiting list in the United States between January 1, 2003, and December 31, 2022. Adolescents (12-17 y) who were listed for their first liver transplantation were included. We evaluated the performance of different models including pediatric end-stage liver disease with Na and creatinine, MELD, and MELD 3.0. Furthermore, we evaluated whether adding anthropometric variables ( z -score for weight and height) would improve the models' performance for our primary outcome (mortality at 90 days after listing). We identified 1421 eligible adolescent patients. Adding a z -score of weight (MELD-TEEN) improved the performance and discrimination of the MELD score. The final model including weight z -score (MELD-TEEN) had better discriminative power compared to MELD 3.0 and pediatric end-stage liver disease with Na and creatinine in the overall cohort and in different age groups (ages 12-14 and 15-17). MELD-TEEN could improve the accuracy of allocation of liver transplants among adolescents by incorporating the weight z -score compared to MELD 3.0 and pediatric end-stage liver disease with Na and creatinine.

Noninvasive assessment of hepatic decompensation.

Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs' wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management.

Quantifying the benefit of nonselective beta-blockers in the prevention of hepatic decompensation: A Bayesian reanalysis of the PREDESCI trial.

BACKGROUND AND AIMS: Beta-blockers have been studied for the prevention of variceal bleeding and, more recently, for the prevention of all-cause decompensation. Some uncertainties regarding the benefit of beta-blockers for the prevention of decompensation remain. Bayesian analyses enhance the interpretation of trials. The purpose of this study was to provide clinically meaningful estimates of both the probability and magnitude of the benefit of beta-blocker treatment across a range of patient types. APPROACH AND RESULTS: We undertook a Bayesian reanalysis of PREDESCI incorporating 3 priors (moderate neutral, moderate optimistic, and weak pessimistic). The probability of clinical benefit was assessed considering the prevention of all-cause decompensation. Microsimulation analyses were done to determine the magnitude of the benefit. In the Bayesian analysis, the probability that beta-blockers reduce all-cause decompensation was >0.93 for all priors. The Bayesian posterior hazard ratios (HR) for decompensation ranged from 0.50 (optimistic prior, 95% credible interval 0.27-0.93) to 0.70 (neutral prior, 95% credible interval 0.44-1.12). Exploring the benefit of treatment using microsimulation highlights substantial treatment benefits. For the neutral prior derived posterior HR and a 5% annual incidence of decompensation, at 10 years, an average of 497 decompensation-free years per 1000 patients were gained with treatment. In contrast, at 10 years 1639 years per 1000 patients were gained from the optimistic prior derived posterior HR and a 10% incidence of decompensation. CONCLUSIONS: Beta-blocker treatment is associated with a high probability of clinical benefit. This likely translates to a substantial gain in decompensation-free life years at the population level.

Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis.

BACKGROUND AND AIMS: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients. APPROACH AND RESULTS: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance [C-index of 0.808 (CI95% 0.735-0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites. CONCLUSIONS: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.

Prophylactic antibiotics in patients with alcohol-associated hepatitis receiving steroids: A systematic review and meta-analysis.

BACKGROUND & AIMS: The benefits of prophylactic antibiotics in patients with alcohol-associated hepatitis (AH) receiving steroids remain unclear. We aimed to assess the clinical impact of prophylactic antibiotics in AH patients receiving steroids. METHODS: We systematically reviewed four electronic databases from inception to 30 November 2023. Pooled estimates were analysed using random-effects models. The primary outcome was 90-day survival. Secondary outcomes included infection at days 30 and 90 days, hepatorenal syndrome (HRS), acute kidney injury (AKI), hepatic encephalopathy (HE) and drug-related adverse events (AE). Trial sequential analyses were performed for the primary outcome of 90-day mortality. RESULTS: We screened 419 articles and included six eligible studies (four RCTs and two matched cohort studies) with a total of 510 patients. Compared to standard medical treatment (SMT), prophylactic antibiotics were associated with a lower risk of infection at 30 days (OR: 0.35, 95%CI: 0.20-0.59, I 2 = 0%), infection at 90 days (OR: 0.26, 95%CI: 0.10-0.67, I 2 = 0%) and a lower rate of HE (OR: 0.32, 95%CI: 0.12-0.87, I 2 = 0%). However, prophylactic antibiotics did not improve 90-day survival, sepsis-related mortality, HRS, or AKI. The risks of drug-related AE and fungal infections were similar in patients with AH who received prophylactic antibiotics or SMT. Using trial sequential analysis, the minimum sample size required to detect a 15% relative risk reduction in 90 days mortality with prophylactic antibiotics was 1171. CONCLUSIONS: In hospitalized AH patients receiving steroid therapy, prophylactic antibiotics reduced the risk of infection and HE, but did not improve survival or prevent AKI compared to SMT.

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

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

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Hepatic encephalopathy is not a contraindication to pre-emptive TIPS in high-risk patients with cirrhosis with variceal bleeding.

BACKGROUND: A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE. PATIENTS AND METHODS: This is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation. RESULTS: 671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients. CONCLUSION: pTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission.

Update in the Treatment of the Complications of Cirrhosis.

Cirrhosis consists of 2 main stages: compensated and decompensated, the latter defined by the development/presence of ascites, variceal hemorrhage, and hepatic encephalopathy. The survival rate is entirely different, depending on the stage. Treatment with nonselective ß-blockers prevents decompensation in patients with clinically significant portal hypertension, changing the previous paradigm based on the presence of varices. In patients with acute variceal hemorrhage at high risk of failure with standard treatment (defined as those with a Child-Pugh score of 10-13 or those with a Child-Pugh score of 8-9 with active bleeding at endoscopy), a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) improves the mortality rate and has become the standard of care in many centers. In patients with bleeding from gastrofundal varices, retrograde transvenous obliteration (in those with a gastrorenal shunt) and/or variceal cyanoacrylate injection have emerged as alternatives to TIPS. In patients with ascites, emerging evidence suggests that TIPS might be used earlier, before strict criteria for refractory ascites are met. Long-term albumin use is under assessment for improving the prognosis of patients with uncomplicated ascites and confirmatory studies are ongoing. Hepatorenal syndrome is the least common cause of acute kidney injury in cirrhosis, and first-line treatment is the combination of terlipressin and albumin. Hepatic encephalopathy has a profound impact on the quality of life of patients with cirrhosis. Lactulose and rifaximin are first- and second-line treatments for hepatic encephalopathy, respectively. Newer therapies such as L-ornithine L-aspartate and albumin require further assessment.

Point-of-Care Noninvasive Prediction of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Individual risk prediction of liver-related events (LRE) is needed for clinical assessment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) patients. We aimed to provide point-of-care validated liver stiffness measurement (LSM)-based risk prediction models for the development of LRE in patients with NAFLD, focusing on selecting patients for clinical trials at risk of clinical events. METHODS: Two large multicenter cohorts were evaluated, 2638 NAFLD patients covering all LSM values as the derivation cohort and 679 more advanced patients as the validation cohort. We used Cox regression to develop and validate risk prediction models based on LSM alone, and the ANTICIPATE and ANTICIPATE-NASH models for clinically significant portal hypertension. The main outcome of the study was the rate of LRE in the first 3 years after initial assessment. RESULTS: The 3 predictive models had similar performance in the derivation cohort with a very high discriminative value (c-statistic, 0.87-0.91). In the validation cohort, the LSM-LRE alone model had a significant inferior discrimination (c-statistic, 0.75) compared with the other 2 models, whereas the ANTICIPATE-NASH-LRE model (0.81) was significantly better than the ANTICIPATE-LRE model (0.79). In addition, the ANTICIPATE-NASH-LRE model presented very good calibration in the validation cohort (integrated calibration index, 0.016), and was better than the ANTICIPATE-LRE model. CONCLUSIONS: The ANTICIPATE-LRE models, and especially the ANTICIPATE-NASH-LRE model, could be valuable validated clinical tools to individually assess the risk of LRE at 3 years in patients with NAFLD/NASH.

Frailty is associated with increased risk of cirrhosis disease progression and death.

BACKGROUND AND AIMS: The Liver Frailty Index (LFI) is a well-studied tool that evaluates frailty in patients with cirrhosis. Consisting of grip strength, chair stands, and balance testing, the LFI has been associated with increased mortality in patients awaiting liver transplant. We aimed to extend our understanding of frailty in cirrhosis by exploring the relationship between the LFI and the risk of (1) cirrhosis progression, (2) mortality, and (3) unplanned hospitalizations, in both compensated and decompensated disease. APPROACH AND RESULTS: Adult patients with cirrhosis from four centers in North America and one in India were included. Frailty was measured at baseline using the LFI and categorized as robust (LFI < 3.2), prefrail (LFI 3.2-4.5), and frail (LFI > 4.5). Progression of cirrhosis was defined by an increase in clinical stage, ranging from 1 to 5, from baseline using the D'Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate regression models, with transplant as a competing risk. In total, 822 patients with cirrhosis were included. Average Model for End-Stage Liver Disease (MELD) score was 15.5 ± 6.0. In patients with compensated cirrhosis, being frail versus robust was associated with increased risk of progression to the next cirrhosis stage or to death (HR, 2.45; 95% CI, 1.14-5.29) and with an increased risk of unplanned hospitalizations (2.32; 95% CI, 1.13-4.79), after adjusting for age, sex, and MELD score. Similar HRs were observed in patients with decompensated cirrhosis. CONCLUSIONS: Frailty was an independent predictor of cirrhosis progression or death and unplanned hospitalization across patients with compensated and decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.