Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers.

The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute-on-chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis-associated immune dysfunction (CAID). Gut-derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF.Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.

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.

Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial.

INTRODUCTION: Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites. METHODS AND ANALYSIS: ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis. ETHICS AND DISSEMINATION: The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion. TRIAL REGISTRATION NUMBER: NCT05056220 EU CT: 2022-501006-34-01.

The assessment and management of cirrhotic patients with encephalopathy.

Hepatic encephalopathy (HE) is a debilitating complication associated with both acute and chronic liver injury. It is associated with a greater risk of death than any other significant hepatic decompensation event. It manifests as a wide spectrum of neuropsychological abnormalities ranging from subtle impairments in higher cognitive function, to confusion and coma. The pathophysiological role of ammonia in the development of HE is well known, but there is increasing recognition that the gut microbiome, gut-derived systemic inflammation and development of infection can serve as drivers of HE in patients with cirrhosis. The development of HE portents to the severity of cirrhosis and the prognosis is poor without liver transplantation. A referral for liver transplantation should therefore be considered early in those who are eligible. This review covers the pragmatic assessment of HE in patients with cirrhosis, as well as the current evidence base for the best practice management of HE in such patients.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 3: special circumstances.

The prevalence of cirrhosis has risen significantly over recent decades and is predicted to rise further. Widespread use of non-invasive testing means cirrhosis is increasingly diagnosed at an earlier stage. Despite this, there are significant variations in outcomes in patients with cirrhosis across the UK, and patients in areas with higher levels of deprivation are more likely to die from their liver disease. This three-part best practice guidance aims to address outpatient management of cirrhosis, in order to standardise care and to reduce the risk of progression, decompensation and mortality from liver disease. Part 1 addresses outpatient management of compensated cirrhosis: screening for hepatocellular cancer, varices and osteoporosis, vaccination and lifestyle measures. Part 2 concentrates on outpatient management of decompensated disease including management of ascites, encephalopathy, varices, nutrition as well as liver transplantation and palliative care. In this, the third part of the guidance, we focus on special circumstances encountered in managing people with cirrhosis, namely surgery, pregnancy, travel, managing bleeding risk for invasive procedures and portal vein thrombosis.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 1: compensated cirrhosis.

The prevalence of cirrhosis has risen significantly over recent decades and is predicted to rise further. Widespread use of non-invasive testing means cirrhosis is increasingly diagnosed at an earlier stage. Despite this, there are significant variations in outcomes in patients with cirrhosis across the UK, and patients in areas with higher levels of deprivation are more likely to die from their liver disease. This three-part best practice guidance aims to address outpatient management of cirrhosis, in order to standardise care and to reduce the risk of progression, decompensation and mortality from liver disease. Here, in part one, we focus on outpatient management of compensated cirrhosis, encompassing hepatocellular cancer surveillance, screening for varices and osteoporosis, vaccination and lifestyle measures. We also introduce a compensated cirrhosis care bundle for use in the outpatient setting. Part two concentrates on outpatient management of decompensated disease including management of ascites, encephalopathy, varices, nutrition as well as liver transplantation and palliative care. The third part of the guidance covers special circumstances encountered in managing people with cirrhosis: surgery, pregnancy, travel, managing bleeding risk for invasive procedures and portal vein thrombosis.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 2: decompensated cirrhosis.

There are two distinct phases in the natural history of cirrhosis: compensated disease (corresponding to Child Pugh A and early Child Pugh B disease), where the patient may be largely asymptomatic, progressing with increasing portal hypertension and liver dysfunction to decompensated disease (corresponding to Child Pugh late B-C), characterised by the development of overt clinical signs, including jaundice, hepatic encephalopathy (HE), ascites, renal dysfunction and variceal bleeding. The transition from compensated cirrhosis to decompensated cirrhosis (DC) heralds a watershed in the nature and prognosis of the disease. DC is a systemic disease, characterised by multiorgan/system dysfunction, including haemodynamic and immune dysfunction. In this second part of our three-part series on the outpatient management of cirrhosis, we address outpatient management of DC, including management of varices, ascites, HE, nutrition, liver transplantation and palliative care. We also introduce an outpatient DC care bundle. For recommendations on screening for osteoporosis, hepatocellular carcinoma surveillance and vaccination see part one of the guidance. Part 3 of the guidance focusses on special circumstances encountered in patients with cirrhosis, including surgery, pregnancy, travel, management of bleeding risk for invasive procedures and portal vein thrombosis.

The clinical relevance of acute-on-chronic liver failure in medical procedures: Endoscopy, interventions and surgery.

Acute-on-chronic liver failure (ACLF) is a specific, but complex and multifactorial form of acute decompensation (AD) of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure and high short-term mortality. In daily clinical practice, patients with liver cirrhosis and decompensation have indications for different medical procedures such as endoscopies, interventional treatments like transjugular intrahepatic portosystemic shunt (TIPS) or even surgical procedures. In these situations, clinicians often need to balance the expected benefits of such procedures with the risks of causing acute decompensation or ACLF. This review summarizes the evidence of medical procedures and their role in precipitating or preventing ACLF and highlights the aspects to consider during patient selection.

Diagnosis and management of ectopic varices in portal hypertension.

Ectopic variceal bleeding is a rare cause of gastrointestinal bleeding that can occur in settings of cirrhotic and non-cirrhotic portal hypertension and is characterised by its development at locations remote from the oesophagus and stomach. Ectopic varices can be difficult to identify and access, and, although a relatively uncommon cause of portal hypertensive bleeding, can represent a difficult diagnostic and therapeutic challenge associated with considerable mortality. Low incidence and variance in variceal anatomy preclude large randomised controlled trials, and clinical practice is based on experience from case reports, case series, and specialist centre expertise. Optimisation of survival outcomes relies on understanding a patient's portal venous anatomy and functional hepatic reserve to guide timely and targeted endoscopic and endovascular interventions to facilitate the rapid control of ectopic variceal bleeding.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis.

BACKGROUND & AIMS: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. METHODS: This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. RESULTS: Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. CONCLUSIONS: In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. IMPACT AND IMPLICATIONS: In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.

Modulation of the Gut Microbiota to Control Antimicrobial Resistance (AMR)-A Narrative Review with a Focus on Faecal Microbiota Transplantation (FMT).

Antimicrobial resistance (AMR) is one of the greatest challenges facing humanity, causing a substantial burden to the global healthcare system. AMR in Gram-negative organisms is particularly concerning due to a dramatic rise in infections caused by extended-spectrum beta-lactamase and carbapenemase-producing Enterobacterales (ESBL and CPE). These pathogens have limited treatment options and are associated with poor clinical outcomes, including high mortality rates. The microbiota of the gastrointestinal tract acts as a major reservoir of antibiotic resistance genes (the resistome), and the environment facilitates intra and inter-species transfer of mobile genetic elements carrying these resistance genes. As colonisation often precedes infection, strategies to manipulate the resistome to limit endogenous infections with AMR organisms, as well as prevent transmission to others, is a worthwhile pursuit. This narrative review presents existing evidence on how manipulation of the gut microbiota can be exploited to therapeutically restore colonisation resistance using a number of methods, including diet, probiotics, bacteriophages and faecal microbiota transplantation (FMT).

Real-world evidence of long-term survival and healthcare resource use in patients with hepatic encephalopathy receiving rifaximin-α treatment: a retrospective observational extension study with long-term follow-up (IMPRESS II).

Objective: To describe survival of patients with hepatic encephalopathy (HE), up to 5 years after initiation of rifaximin-α (RFX) treatment. Design/Method: A retrospective, observational extension study within 9 National Health Service secondary/tertiary UK care centres. All patients had a clinical diagnosis of HE, were being treated with RFX and were included in the previous IMPRESS study which reported the 1-year experience. Demographics, clinical outcomes, selected cirrhosis-related complications, hospital admissions and attendances up to 5 years from RFX initiation were extracted from patient medical records and hospital electronic databases. The primary outcome measure was survival at 5 years post-initiation of RFX treatment. Results: The study included 138 patients. The survival rate at 5 years post-initiation of RFX was 35% (95% CI 28.2% to 44.4%) overall and 36% (95% CI 26.1% to 45.4%) for patients with alcohol-related liver disease. Median survival from RFX initiation was 2.8 years (95% CI 2.0 to 3.8; n=136). Among 48 patients alive at 5 years, 69% remained on RFX treatment at the end of the observation period, 74% reported no cirrhosis-related complications and 24% (9/37) had received a liver transplant. Between 1 and 5 years post-initiation, total numbers of liver-related emergency department visits, inpatient admissions, intensive care unit admissions and outpatient visits were 84, 194, 3 and 709, respectively; the liver-related 30-day readmission rate was 37%. Conclusion: Within UK clinical practice, RFX use in HE was associated with a 35% survival rate with high treatment adherence, 76% transplant-free survival rate, minimal healthcare resource and low rates of complications at 5 years post-initiation.