Liver disease is a growing burden. Transplant organs are scarce. Extracorporeal liver support systems (ELSS) are a bridge to transplantation for eligible patients. For transplant-ineligible patients the objective becomes liver recovery.

We review seven decades of non-cell-based ELSS research in humans. Where possible, we emphasize randomized controlled trials (RCTs). When RCTs are not available, we describe the available human clinical data.

There are three broad cell-free approaches to remove protein-bound toxins (PBTs) and treat liver failure. The first is a dialysate binder suspension. A material that binds the PBT (the binder) is added to the dialysate. Binders include albumin, charcoal, and polystyrene sulfonate sodium. The unbound fraction of the PBT crosses the dialyzer membrane along a chemical gradient and binds to the binder. The second approach is using grains of sorbent fixed in a plastic housing to remove PBTs. Toxin-laden blood or plasma flows directly through the column. Toxins are removed by binding to the sorbent. The third approach is exchanging toxin-laden blood, or fractions of blood, for a healthy donor blood product. Most systems lack widespread acceptance, but plasma exchange (PE) is recommended in many guidelines. The large donor plasma requirement of PE creates demand for systems to complement or replace it.

Now that PE has become recommended in some, but not all, jurisdictions, we discuss the importance of reporting precise PE protocols and dose. Our work provides an overview of promising new systems and lessons from old technologies to enable ELSS improvement.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops after an acute insult and is associated with organ failures and high short-term mortality. Plasma exchange (PLEX) is an emerging modality for treating ACLF patients. We aimed to evaluate the efficacy of PLEX in treating ACLF.

We conducted a systematic review and meta-analysis of studies comparing PLEX versus standard medical therapy (SMT) to treat patients with ACLF across different definitions and etiologies. Pooled risk ratios were determined by the Mantel-Haenszel method within a random effect model. The primary outcome studied was survival at 30 days in PLEX group compared to SMT.

Twenty-three studies (5336 ACLF patients with 2724 in PLEX arm, including 4 RCTs) were included. PLEX was associated with a significant reduction in mortality at 30 days (RR 0.70; 95% CI, 0.60-0.81; p < 0.001) and at 90 days (RR 0.81;0.77-0.86; p < 0.001). Six studies (1495 patients; 2 RCTs) with data for 1-year survival showed better outcomes in the PLEX group (RR 0.85; 0.79-0.92; p < 0.0001) compared to SMT. Among HBV-related ACLF and alcohol-related ACLF, there was a significant reduction in mortality among PLEX treated group at 90 days; RR 0.79 (0.74-0.85), p < 0.001 and RR 0.69 (0.52-0.92), p = 0.01 respectively. PLEX was associated with improved 3-month survival across definitions for ACLF. The most common adverse effects were skin rash and allergic reactions (14%).

In this up-to-date meta-analysis, significant 1, 3-month and up to 1-year survival benefit was noted among patients with ACLF treated with PLEX compared to SMT.

Alcohol-related liver disease (ALD) is still to this date one of the leading causes of chronic liver disease globally. ALD comprises a wide disease spectrum, from the benign liver steatosis, to the life-threatening inflammatory acute phenotype of alcoholic hepatitis (AH) and ultimately, advanced liver fibrosis and cirrhosis. AH represents an acute inflammatory liver condition caused by prolonged high quantities of alcohol intake. Disease outcome varies from mild to severe, with systemic implication and high mortality. Although the pathogenesis has been extensively studied over the years, little progress has been made regarding therapeutic options. In over 50 years, steroid treatment is still the cornerstone therapeutic option, albeit having multiple limitations and a low success rate. On the other hand, important progress has been made regarding disease management and severity stratification with the implementation of different prognostic score. Although highly prevalent, AH still has many unmet needs, with a growing necessity for novel non-invasive diagnosis, prognosis biomarkers and impactful treatment options.

In this review, we discuss the pathophysiology and management of acute kidney injury (AKI) in the setting of acute-on-chronic liver failure (ACLF). ACLF is characterised by the occurrence of acute hepatic and/or extrahepatic organ failure, induced by immune dysregulation and systemic inflammation in patients with chronic liver disease. Kidney involvement is common, with AKI occurring in 30% to > 95% of ACLF patients, depending on the definition used. Since there is a lack of kidney biopsy data in these patients, the underlying pathophysiological basis of AKI remains incompletely understood, and systemic inflammation is believed to be the primary driver of organ injury. The management of AKI has been largely extrapolated from studies in decompensated cirrhosis, and there is little data specifically in the ACLF setting. However, available evidence suggests that structural kidney injury is more common in ACLF than in decompensated CLD, and therefore, AKI in ACLF is less likely to respond to volume repletion and vasopressors. Treatment options remain limited for those who are non-responsive to intravenous fluids and vasopressors. Liver transplantation (LT), with or without kidney transplantation, is the definitive treatment for these patients. At present, extracorporeal therapies such as therapeutic plasma exchange and kidney replacement therapies play a supportive role in ACLF as a bridge to LT; however, the optimal timing and dosing remain unclear. While theoretically, extracorporeal therapies have the potential to reverse or halt progression of organ damage in ACLF, there is limited evidence currently.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by organ failure and high short-term mortality. Since its first definition in 2013, many international organizations have defined this syndrome and, till now, there has been no agreement regarding definitions and diagnostic criteria. Although the precise mechanism of ACLF is unknown, precipitant factors and the systemic inflammation response play a major role. Specific management of this high-mortality syndrome is still under development, but a general consensus in the diagnosis and management of ACLF is needed.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

Acute-on-chronic liver failure (ACLF) is defined by acute decompensation, organ failure and a high risk of short-term mortality. This condition is characterized by an overwhelming systemic inflammatory response. Despite treating the precipitating event, intensive monitoring and organ support, clinical deterioration can occur with very poor outcomes. During the last decades, several extracorporeal liver support systems have been developed to try to reduce ongoing liver injury and provide an improved environment for the liver to regenerate or as a bridging therapy until liver transplantation. Several clinical trials have been performed to evaluate the clinical efficacy of extracorporeal liver support systems, but no clear impact on survival has been proven. DIALIVE is a novel extracorporeal liver support device that has been built to specifically address the pathophysiological derangements responsible for the development of ACLF by replacing dysfunctional albumin and removing pathogen and damage-associated molecular patterns (PAMPs and DAMPs). In phase II clinical trial, DIALIVE appears to be safe, and it seems to be associated with a faster time to the resolution of ACLF compared with standard medical treatment. Even in patients with severe ACLF, liver transplantation saves lives and there is clear evidence of transplant benefit. Careful selection of patients is required to attain good results from liver transplantation, but many questions remain unanswered. In this review, we describe the current perspectives on the use of extracorporeal liver support and liver transplantation for ACLF patients.

In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.

Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

Acute on chronic liver failure (ACLF) reflects the development of organ failure(s) in a patient with cirrhosis and is associated with high short-term mortality. Given that ACLF has many different 'phenotypes', medical management needs to take into account the relationship between precipitating insult, organ systems involved and underlying physiology of chronic liver disease/cirrhosis. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (e.g. infection, severe alcoholic hepatitis and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo liver transplantation or recovery. Management of these patients is complex since they are prone to develop new organ failures and infectious or bleeding complications. ICU therapy parallels that applied in the general ICU population in some complications but differs in others. Given that liver transplantation in ACLF is an emerging and evolving field, multidisciplinary teams with expertise in critical care and transplant medicine best accomplish management of the critically ill ACLF patient. The focus of this review is to identify the common complications of ACLF and to describe the proper management in critically ill patients awaiting liver transplantation in our centres, including organ support, prognostic assessment and how to assess when recovery is unlikely.

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.

To describe outcomes of a cohort of patients with paediatric acute liver failure (PALF) treated with either one of two extracorporeal therapies (ECT) - continuous renal replacement therapy (CRRT) and molecular adsorbent recirculatory system (MARS®). Retrospective, observational, cohort study at two European paediatric intensive care units (PICUs) - UK (2006-2017, CRRT) and the Netherlands (2003-2017, MARS® and CRRT). Patients were children (0-18 years) admitted to the PICU with PALF who required CRRT or MARS®. Between each group, we compared baseline characteristics, biochemical parameters at 0 and 24 h after commencing MARS®/CRRT, and clinical outcomes. In total, 95 patients (23 MARS®, 72 CRRT) were included. The median age at admission for the whole cohort was 4.3 years (interquartile range (IQR) 1.0-12.1), and 47/95 (49.5%) of patients had an indeterminate aetiology. A lower proportion of patients in the MARS® group were on inotropes or were ventilated at admission, and they had a lower Pediatric Index of Mortality 3 risk % than the CRRT group (14.5% (7.5-22) vs 20.4% (16.8-26.4), p = 0.002). After treatment, there were no significant differences detected between groups in survival with native liver, or overall survival (15/23 (65.2%) for MARS® and 49/72 (68.1%) for CRRT, p = 0.998).

We did not detect a significant difference in clinical outcomes between PALF patients treated with CRRT or MARS®, despite a relatively sicker cohort in the CRRT group. Further high-quality evidence is necessary regarding the role of extracorporeal therapies in PALF, with consideration of clinical outcomes, feasibility, and cost.

• Outcomes for children with paediatric acute liver failure (PALF) have improved in recent years secondary to improved supportive care aimed at avoiding liver transplantation. • Extracorporeal therapies, in particular continuous renal replacement therapy (CRRT), are increasingly applied in the management of these children; however few studies have compared outcomes between different extracorporeal therapies.

• In this retrospective study across two centres, outcomes between patients with PALF treated with CRRT were compared to patients treated with MARS®. • There was no significant difference in key clinical outcomes between groups, including survival with native liver and overall survival.

Acute-on-chronic liver failure (ACLF) is a rapidly progressive and highly fatal condition. Early identification of critically ill patients is crucial. Hepatitis B virus-related ACLF (HBV-ACLF), the main cause of ACLF in China, is characterized by liver failure and coagulation dysfunction. Dynamic changes in total bilirubin (TB) and international normalized ratio (INR) can reflect disease progression. This study aims to investigate the clinical application of dynamic trajectories of TB and INR in HBV-ACLF patients.

Retrospective data from 194 patients at Taizhou Hospital, China (Jan 2012 - June 2023), meeting COSSH-ACLF criteria, were analyzed. A latent class mixed model (LCMM) identified three trajectory groups (declining, stable, fluctuating) based on bilirubin and INR changes. Clinical applicability of these groups was investigated.

The 194 patients were divided into the trajectory groups mentioned above. The declining group had lower predicted scores and a better prognosis. The stable and fluctuating groups had worse prognosis compared to the declining group (P<0.001). Artificial liver support did not improve short-term prognosis for the stable group; instead, it was a risk factor (OR 2.16, 95% CI [0.23-3.79], P=0.007). Subgroup analysis showed no interaction between predictive models and trajectory groups. Additionally, trajectory grouping improved the predictive effectiveness of existing models.

Based on our trajectory analysis, patients with a continuous declining in bilirubin and INR values showed the best prognosis, highlighting the clinical significance of trajectory grouping in treatment decisions. Trajectory grouping can complement existing scoring models, improving predictive effectiveness.

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by acute liver decompensation in patients with chronic liver disease, marked by systemic inflammation and systemic organ failure. In this review, we discussed sex-related disparities in the incidence, prognosis, and access to liver transplantation (LT) for patients with ACLF, particularly during Intensive Care Unit (ICU) management. Some studies have suggested that ACLF is more prevalent among male patients admitted to the ICU, and they have higher mortality rates than females. Available prognostic scores, such as CLIF-C or TAM-score, lack sex-specific adjustments. Sarcopenia seems to enhance the accuracy of these scores though this is observed only in male individuals. LT is the only effective treatment for patients with ACLF grade 2-3 who do not respond to medical therapies. Sex-related disparities occur in both access to LT and post-transplant outcomes, although the influence of sex on the prevalence, clinical course, and listing for LT in ACLF remains largely undetermined. A sex-orientated analysis of ICU outcomes in ACLF would facilitate the development of sex-orientated management strategies, thereby improving patients' outcomes.

Acute-on-chronic liver failure (ACLF) patients with hepatorenal syndrome (HRS-AKI) have limited response to vasoconstrictors and worse outcomes, requiring biomarkers for early detection.

In a prospective cohort of ACLF patients (n = 240), urine NGAL was performed in patients with the clinical diagnosis of HRS-AKI, while in a subset of patients (n = 30), a complete panel of 17 urinary biomarkers was assessed for identifying terlipressin non-response (T-NR).

ACLF patients with HRS-AKI, aged 45.84 ± 10.6 years, 91.2% males, 74.2% with alcohol etiology, mean urine NGAL of 1541.66 ± 1684.69 ng/ml, AARC score 10.19 ± 1.86, 155 (64.5%) had T-NR at day 4. T-NR was maximal for AARC grade 3 and was associated with a higher need of dialysis (50.3% vs 5.9%; OR 16.21, 6.23-42.19) and 28-day mortality (49.0% vs. 17.9%; HR 3.42, 1.96-5.95). AARC grade 3 (OR 38.21, 2.93-497.74), (HR 5.10, 1.19-21.84) and urine NGAL (OR 11.53, 5.66-23.49; AUROC 0.97, NGAL > 900 ng/ml) (HR 1.23, 1.02-1.49) were independent predictors of T-NR and 28-day mortality, respectively. It was interesting to observe a significant elevation in renal injury and a decrease in the repair markers in T-NR (p < 0.05).

Almost 60% of patients with ACLF and HRS-AKI experience non-response to terlipressin which predicts higher mortality and need for dialysis. High NGAL above 900 ng/ml predicts T-NR with 100% specificity for T-NR. ACLF patients with HRS, with AARC grade 3 and high NGAL have a high likelihood of T-NR and should be considered for alternative therapeutic modalities.

The artificial liver support system (ALSS) has been recruited as an available method for patients with acute-on-chronic liver failure (ACLF), but its impact on the outcome of ACLF remains controversial. This study aimed to investigate the association between ALSS treatment and short-term prognosis of hepatitis B-related ACLF (HBV-ACLF).

This was a retrospective observational cohort study, and data were obtained from the Center of Infectious Diseases, West China Hospital of Sichuan University, between Mar 2015 and December 2021. The primary outcome was 28-day transplant-free mortality and the secondary outcomes were 60- and 90-day transplant-free mortality. Patients were divided into standard medical therapy (SMT) and ALSS groups. Kaplan-Meier survival analysis curves show the 28-day, 60-day and 90-day transplant-free mortality. Based on the feature selection result of univariate logistic, univariate Cox and Boruta algorithm, the univariate and multivariate logistic and COX regression models were used to investigate the association of ALSS with 28-day, 60-day and 90-day outcomes in patients with HBV-ACLF. Subgroup analyses were conducted to test the robustness of the results.

A total of 589 hBV-ACLF patients were enrolled in this study (median age, 48.00 years [IQR,44.00-55.00 years]; 70 [11.9%] female). The 28-day, 60-day and 90-day transplant-free mortality rates were 25.6%, 35.8% and 38.9%, respectively. In the univariate and Kaplan-Meier survival analysis, ALSS could significantly reduce 28-day, 60-day and 90-day transplant-free mortality compared to SMT. Furthermore, an in-depth analysis of our study revealed that the therapeutic benefits of the ALSS were observed exclusively within the end-stage (PT-INR ≥ 2.5) subgroup of HBV-ACLF patients.

Compared to SMT, ALSS demonstrated efficacy primarily in enhancing the short- term prognosis of end-stage HBV-ACLF patients, rather than across the entire spectrum of HBV-ACLF patients.

Acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) is driven by the severity of systemic inflammation, acute portal hypertension driving circulatory dysfunction, hyperbilirubinemia, and toxicity of bile acids. The spectrum is mostly structural, associated with reduced response to vasoconstrictors. The progression is rapid, and need of renal replacement therapy and extracorporeal therapies may be required for the management. The development of renal failure is usually considered when defining the syndrome of ACLF.

In the current review we discuss the pathophysiological basis, natural course, and response to the current therapeutic modalities and challenges in assessing and managing AKI in patients with ACLF. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Scopus using keywords like lactate, NGAL, and PHTN, as well as CRRT, PLEX, ACLF, and AKI phases for our review. Peer-reviewed English papers that addressed our issue were considered.

The difficulties and specific management strategies for AKI in ACLF patients are discussed emphasizing the importance of customized protocols, risk assessment guided by biomarkers, and investigation of extracorporeal therapies that target bile acids.

To systematically review the safety and efficacy of nonbiological (NBAL) or biological artificial liver support systems (BAL) and whole-organ extracorporeal liver perfusion (W-ECLP) systems, in adults with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF).

Eligible NBAL/BAL studies from PubMed/Embase searches were randomized controlled trials (RCTs) in adult patients with ALF/ACLF, greater than or equal to ten patients per group, reporting outcomes related to survival, adverse events, transplantation rate, and hepatic encephalopathy, and published in English from January 2000 to July 2023. Separately, we searched for studies evaluating W-ECLP in adult patients with ALF or ACLF published between January1990 and July 2023.

Two researchers independently screened citations for eligibility and, of eligible studies, retrieved data related to study characteristics, patients and interventions, outcomes definition, and intervention effects. The Cochrane Risk of Bias 2 tool and Joanna Briggs Institute checklists were used to assess individual study risk of bias. Meta-analysis of mortality at 28-30 days post-support system initiation and frequency of at least one serious adverse event (SAE) generated pooled risk ratios (RRs), based on random (mortality) or fixed (SAE) effects models.

Of 17 trials evaluating NBAL/BAL systems, 11 reported 28-30 days mortality and five reported frequency of at least one SAE. Overall, NBAL/BAL was not statistically associated with mortality at 28-30 days (RR, 0.85; 95% CI, 0.67-1.07; p = 0.169) or frequency of at least one SAE (RR, 1.15; 95% CI, 0.99-1.33; p = 0.059), compared with standard medical treatment. Subgroup results on ALF patients suggest possible benefit for mortality (RR, 0.67; 95% CI, 0.44-1.03; p = 0.069). From six reports of W-ECLP (12 patients), more than half (58%) of severe patients were bridged to transplantation and survived without transmission of porcine retroviruses.

Despite no significant pooled effects of NBAL/BAL devices, the available evidence calls for further research and development of extracorporeal liver support systems, with larger RCTs and optimization of patient selection, perfusion durability, and treatment protocols.

Liver failure is the 12th leading cause of death worldwide. Protein-bound toxins such as bilirubin are responsible for many complications of the disease. Binder dialysis systems use albumin or another binding molecule in dialysate and detoxifying sorbent columns to remove these toxins. Systems like the molecular adsorbent recirculating system and BioLogic-DT have existed since the 1990s, but survival benefits in randomized controlled trials have not been consistent. New binder dialysis systems, including open albumin dialysis and the Advanced Multi-Organ Replacement system, are being developed. Optimal conditions for binder dialysis have not been established. We developed and validated a computational model of bound solute dialysis. It predicted the impact of changing between two test setups using different polysulfone dialyzers (F3 and F6HPS). We then predicted the impact of varying the dialysate flow rate on toxin removal. We found that bilirubin removal declines with dialysate flow rate. This can be explained through a linear decline in free bilirubin membrane permeability. Our model quantifies this decline through a single parameter (polysulfone dialyzers). Validation for additional dialyzers and flow rates will be needed. This model will benefit clinical trials by predicting optimal dialyzer and flow rate conditions. Accounting for toxin adsorption onto the dialyzer membrane may improve results further.

Patients with cirrhosis are known to be prone to infections. Infections can trigger organ failures and decompensations in cirrhosis. Septic shock can increase mortality by fourfold and cause hemodynamic imbalances, adding to the already hyperdynamic circulation. Management of septic shock in cirrhosis can be tricky due to this complex interplay of altered hemodynamics, immune function, and coagulation.

In this review, we explore the pathophysiological basis, screening, monitoring and management of septic shock in cirrhosis. We also explore novel biomarkers, the growing challenge of multidrug-resistant pathogens and novel and adjunctive therapies. Finally, we propose an algorithm for the management of septic shock in cirrhosis. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Cochrane Library using the keywords and MeSH terms like 'septic shock,' 'cirrhosis,' 'liver disease,' 'sepsis' among others. The search was restricted to peer-reviewed articles in English.

The difficulties in managing septic shock in cirrhosis are discussed, emphasizing personalized approaches over protocol-driven care. Fluid and vasopressor management, antibiotic timing and selection, the role of adjunctive therapies, the importance of lactate clearance, gut failure, and the need for further research in this population are highlighted.

Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE.

Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE.

A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Acute liver failure (ALF) and acute-on-chronic liver (ACLF) are distinct phenotypes of liver failure and, thus, need to be compared and contrasted for appropriate management. There has been a significant improvement in the outcomes of these patients undergoing liver transplantation (LT). Survival post-LT for ALF and ACLF ranges between 90% and 95% and 80% and 90% at 1 year, futility criteria have been described in both ALF and ACLF where organ failures define survival. Plasma exchange and continuous renal replacement therapy may serve as bridging therapies. Identifying the futility of LT is as necessary as the utility of LT in patients with ALF and ACLF. The role of regenerative therapies such as granulocyte colony-stimulating factors in ACLF and hepatocyte and xenotransplantation in both conditions remains uncertain. Measures to increase the donor pool through increasing deceased donor transplants in Asian countries, living donations in Western countries, auxiliary liver transplants, and ABO-incompatible liver transplants are necessary to improve the survival of these patients. In this review, we discuss the similarities and differences in clinical characteristics and the timing and outcomes of LT for ALF and ACLF, briefly highlighting the role of bridging therapies and providing an overview of recent advances in the management of ALF and ACLF.

Acute-on-chronic liver failure (ACLF) is defined as a clinical syndrome that develops in patients with chronic liver disease characterized by the presence of organ failure and high short-term mortality, although there is still no worldwide consensus on diagnostic criteria. Management of ACLF is mainly based on treatment of "precipitating factors" (the most common are infections, alcohol-associated hepatitis, hepatitis B flare, and bleeding) and support of organ failure, which often requires admission to the intensive care unit. Liver transplantation should be considered in patients with ACLF grades 2 to 3 as a potentially life-saving treatment. When a transplant is not indicated, palliative care should be considered after 3 to 7 days of full organ support in patients with at least four organ failures or a CLIF-C ACLF score of >70. This review summarizes the current knowledge on the management of organ failure in patients with ACLF, focusing on recent advances.

Cirrhosis with complications of liver decompensation and hepatocellular carcinoma (HCC) constitute a leading cause of morbidity and mortality worldwide. Portal hypertension is central to the progression of liver disease and decompensation. The most recent Baveno VII guidance included revision of the nomenclature for chronic liver disease, termed compensated advanced chronic liver disease, and leveraged the use of liver stiffness measurement to categorize the degree of portal hypertension. Additionally, non-selective beta blockers, especially carvedilol, can improve portal hypertension and may even have a survival benefit. Procedural techniques with interventional radiology have become more advanced in the management of refractory ascites and variceal bleeding, leading to improved prognosis in patients with decompensated liver disease. While lactulose and rifaximin are the preferred treatments for hepatic encephalopathy, many alternative treatment options may be used in refractory cases and even procedural interventions such as shunt embolization may be of benefit. The approval of terlipressin for the treatment of hepatorenal syndrome (HRS) in the USA has improved the way in which HRS is managed and will be discussed in detail. Malnutrition, frailty, and sarcopenia lead to poorer outcomes in patients with decompensated liver disease and should be addressed in this patient population. Palliative care interventions can lead to improved quality of life and clinical outcomes. Lastly, the investigation of systemic therapies, in particular immunotherapy, has revolutionized the management of HCC. These topics will be discussed in detail in this review.

Hepatic encephalopathy is described by a broad spectrum of neurological and psychiatric aberrations resulting due to advanced liver dysfunction. It is a neurological disorder due to hepatic insufficiency and/or portosystemic shunts. Its clinical presentation includes neuropsychiatric dysfunction ranging from subclinical changes to comatose state. It is a sign of poor prognosis in cirrhotics with a high 1-year mortality. Each episode of hepatic encephalopathy leads to high hospitalization rate, poor prognosis and raised burden of healthcare. Primary prophylaxis is prevention of initial occurrence and secondary prophylaxis is prevention of reappearance of hepatic encephalopathy in subjects who had prior history. Early detection and management of triggers is very important in the treatment of hepatic encephalopathy. The initial choice of treatment is still lactulose, as it is effective in minimal, overt, and recurrent hepatic encephalopathy. Rifaximin is equally effective as lactulose in managing hepatic encephalopathy and is better tolerated. Branch chain amino acids are beneficial in subjects who are protein intolerant. L-ornithine L-aspartate and probiotics are also useful in the management of hepatic encephalopathy. Rifaximin along with lactulose is effective in managing overt and recurrent hepatic encephalopathy. Large portosystemic shunts embolization and liver transplant is efficacious in certain group of patients. Nutritional therapy and fecal microbiota transplantation are newer therapies for hepatic encephalopathy but the evidences are limited, more research is required to prove their efficacy. Involvement of hospital pharmacists, telemedicine, and providing education are also beneficial in managing hepatic encephalopathy.