Extracorporal hemodialysis with acute or decompensated chronical hepatic failure

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.

Toward an Improved Definition of Acute-on-Chronic Liver Failure

BackgroundThe role of artificial and bioartificial liver support systems in acute-on-chronic liver failure (ACLF) is still controversial. We aimed to perform the first network meta-analysis comparing and ranking different liver support systems and standard medical therapy (SMT) in patients with ACLF.MethodsThe study protocol was registered with PROSPERO (CRD42020155850). A systematic search was conducted in five databases. We conducted a Bayesian network meta-analysis of randomized controlled trials assessing the effect of artificial or bioartificial liver support systems on survival in patients with ACLF. Ranking was performed by calculating the surface under cumulative ranking (SUCRA) curve values. The RoB2 tool and a modified GRADE approach were used for the assessment of the risk of bias and quality of evidence (QE).ResultsIn the quantitative synthesis 16 trials were included, using MARS®, Prometheus®, ELAD®, plasma exchange (PE) and BioLogic-DT®. Overall (OS) and transplant-free (TFS) survival were assessed at 1 and 3 months. PE significantly improved 3-month OS compared to SMT (RR 0.74, CrI: 0.6–0.94) and ranked first on the cumulative ranking curves for both OS outcomes (SUCRA: 86% at 3 months; 77% at 1 month) and 3-month TFS (SUCRA: 87%) and second after ELAD for 1-month TFS (SUCRA: 76%). Other comparisons did not reach statistical significance. QE was moderate for PE concerning 1-month OS and both TFS outcomes. Other results were of very low certainty.ConclusionPE seems to be the best currently available liver support therapy in ACLF regarding 3-month OS. Based on the low QE, randomized trials are needed to confirm our findings for already existing options and to introduce new devices.

Low Baseline but Not Delta Cortisol Relates to 28-Day Transplant-Free Survival in Acute and Acute-on-Chronic Liver Failure.

Objective. The CC chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-3 alpha (MIP3-alpha) may be involved in the pathogenesis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). In ALF and ACLF, the molecular adsorbent recirculating system (MARS) has been used to support liver function. Enhancement of MCP-1, as seen in other extracorporeal support systems such as haemodialysis, might thus have mitigated the beneficial effects of the MARS system in acute hepatic failure. Material and methods. Serum concentrations of MCP-1 and MIP3-alpha were measured in 10 patients with ALF or ACLF treated with MARS. Thirteen patients suffering from chronic hepatic failure (CHF) and 15 healthy individuals served as controls. Results. Baseline MCP-1 serum concentrations were significantly increased in ALF and ACLF patients as compared to patients with CHF (p=0.0027 and p=0.0046, respectively) and controls (p=0.0006 and p=0.0012, respectively). MIP3-alpha serum concentrations were also significantly enhanced in the ALF and ACLF groups as compared with those in CHF patients (p=0.0002 and p=0.0003, respectively) and controls (p<0.0001 and p<0.0001, respectively). Moreover, MIP3-alpha levels were significantly increased in CHF patients as compared to controls (p=0.0002). MCP-1 and MIP3-alpha concentrations did not change significantly during MARS treatment in ALF and ACLF patients. Conclusions. The CC chemokines MCP-1 and MIP3-alpha are increased in ALF and ACLF patients. MARS had no effect on MCP-1 and MIP3-alpha serum concentrations in patients with ALF and ACLF, and yielded no evidence of any harmful effects of the increase of these potentially hepatocidal chemokines.

Introduction: Molecular adsorbent recirculating system (MARS) is an artificial albumin dialysis-based liver support system that has been developed for patients with liver failure and has been FDA-approved in the treatment acute liver failure due to drug overdose and poisonings, as well as hepatic encephalopathy (HE) due to decompensation of chronic liver disease. This case series presents 2 subsets of liver failure patients: 1 patient with acute liver failure (ALF) in the setting of autoimmune hepatitis (AIH), and a second patient with acute on chronic liver failure (ACLF) in the setting of ischemic hepatitis on a background of alcoholic cirrhosis. The uniqueness of our case series is that MARS therapy was utilized to stabilize a anhepatic state in both ALF and ACLF for a duration of 96 hours, and subsequently bridge the patients to successful liver transplantation. Our first patient was a 56-year-old female who was transferred to our university hospital for acute liver injury. The patient was started on MARS therapy in the setting of grade 4 hepatic encephalopathy, severe coagulopathy (INR>9), and a profound metabolic acidosis. Cardiopulmonary, neurologic, and metabolic stability was maintained on MARS therapy for 96 hours, and the patient subsequently underwent successful liver transplantation. Of note, the liver explant demonstrated greater than 90% hepatic necrosis. Our second patient was a 67-year-old male with alcoholic cirrhosis, who developed severe ACLF in the setting of profound superimposed ischemic hepatitis due to anaphylactic shock. Clinical parameters were consistent with severe hepatic insufficiency, as evidenced by a profound coagulopathy (INR>10) and grade 4 hepatic encephalopathy. Timely administration of MARS therapy was successful in clinical stabilization of the patient, despite minimal hepatic function. Following approximately 96 hours of MARS therapy, the patient was successfully bridged to liver transplantation. Explant pathology of the native liver demonstrated extensive hepatic necrosis on a background of cirrhosis. These 2 cases demonstrate the efficacy of MARS therapy in stabilizing the clinical status of patients in both ALF and ACLF in the setting of severe hepatic insufficiency. In particular, both these patients were stabilized for 4 days in a virtually anhepatic state while they awaited liver transplantation. Severe hepatic insufficiency is typically characterized by severe multi-organ system failure that is prohibitive for liver transplantation. This case series demonstrates the ability of MARS therapy to prevent multi-organ system failure in the setting of a prolonged anhepatic state, and the opportunity to utilize this therapy as a bridge to liver transplantation. Disclosure - Dr. Ram Subramanian is a consultant for Gambro.

We summarize the therapeutic approach to patients with acute liver failure with the main focus on bioartificial and artificial liver support. We also describe specific and general therapeutic approaches based upon recent advances in the understanding of the pathophysiology of acute liver failure. Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient's circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Although bioartificial liver-assist devices have not been shown to improve the survival of patients with acute liver failure, further development is underway. Artificial liver support systems have been shown to alter several pathophysiological mechanisms involved in the development of acute liver failure but survival data are still limited. Mortality in patients with acute liver failure is still unacceptably high. The most effective treatment, liver transplantation, is a limited resource and so other therapeutic options to bridge patients to recovery or stabilization have to be considered. Better understanding of the pathophysiology of acute liver failure and device development is necessary to achieve the elusive goal of effective extracorporeal liver assist.

Potential conflict of interest: Nothing to report. We read with interest the article by Cardoso et al.,1 who reported that continuous renal replacement therapy for acute liver failure (ALF) was associated with a reduction in serum ammonia level and improved 21‐day transplant‐free survival in a large, multicenter study. First of all, we applaud their efforts for the diagnosis and treatment of ALF and continuous contributions targeting whole fields of ALF as the U.S. ALF Study Group, different from the Japanese one. We realize how difficult these studies are to perform in infrequent and life‐threatening diseases like ALF. We also believe an artificial liver support system sustaining patients in good condition, including restoration of consciousness until recovery of the native liver or performance of liver transplantation, is essential for the improvement of the poor prognosis of ALF, although it does not induce liver regeneration. In European countries, the molecular adsorbent recirculating system has been shown to remove protein‐bound substances and decrease plasma concentrations of bilirubin, ammonia, and creatinine in patients with ALF. But a question is raised about the feasibility of removing substances responsible for hepatic encephalopathy through removal of albumin‐binding toxic ones alone. To the contrary, in Japan, a combination of plasma exchange (PE) and hemodiafiltration (HDF) has been performed. Hemodialysis removes low‐molecular‐weight substances, including amnonia, and hemofiltration removes middle‐molecular‐weight substances, including proinflammatory cytokines, efficiently. Therefore, we concluded that it is desirable to apply HDF for the treatment of patients with ALF. As described in the Discussion, there is still a controversy over the methodology of renal replacement therapy for ALF. However, it is a fact that more than 90% of patients recover consciousness by high‐flow dialysate HDF in combination with PE in leading Japanese liver units.2 Especially, online HDF reduces the cost and simplifies procedures for the management of encephalopathy.4 Therefore, we have not performed intracranial pressure monitor placement, which is reported to be one of major bleeding sites, for more than 20 years.

OBJECTIVES To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU. DESIGN The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. SETTING The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology. INTERVENTIONS We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence. CONCLUSIONS Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.

Acute and chronic liver failure is associated with high mortality. The enormous regenerative potential of the liver has generated a lot of attention. We undertook this work to assess the two-tier regenerative response in liver failure by immunohistochemistry and to correlate such response with liver histology in acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis (CHD). Histological examination and immunohistochemical analysis of proliferating hepatocytes and activated hepatic progenitor cells (HPCs) were performed on the liver tissue of patients with ALF (25), ACLF (70), and CHD (70). Comparative analysis of regenerative markers and correlation with histological parameters were done in ALF, ACLF, and CHD. Hepatocytes proliferated significantly more in ALF in comparison to ACLF (p < 0.001) and CHD (p < 0.001). HPC proliferation was significantly higher in ACLF (p < 0.001) and CHD (p < 0.001) than in ALF. ACLF patients showed the highest HPC proliferation and differentiation. Significantly more intermediate hepatocytes were found in ACLF than in ALF and CHD (p < 0.001). Marked parenchymal replacement by fibrosis and/or necrosis correlated significantly with activation of HPC in ACLF (p = 0.01, odds ratio (OR) 4.95) and in CHD (p = 0.05, OR 4.19). The study of liver regeneration in human acute and chronic liver failure suggests that hepatocyte proliferation, providing the first line of regeneration response, is most active in ALF whereas HPC activation, the second line of defense, is more prominent in ACLF. More HPC differentiate to hepatocytes in ACLF than in CHD, reflecting better regenerative potential in ACLF.

Systematic review of artificial liver support systems: Current clinical challenges

Objective To comparative analyze the influence factors of short-term (6 months) and long-term (10 years) prognosis in patients with HBV-related acute-on-chronic liver failure (ACLF), and to provide some reference values on clinic therapy and follow-up management. Methods The data of 524 hospitalized patients with ACLF from January 2001 to December 2009 were analyzed retrospectively. The follow-up termination time was December 2013. Patients were all given internal medical therapy, and were given antiviral therapy with nucleoside and nucleotide analogs (NAs) (yes/no) and plasma exchange in artificial liver support system (yes/no) according to the patient′s informed choice. The method of Cox regression analysis was used to analyze the short-term prognostic factors and long-term prognosis factors of ACLF. Results The short-term prognosis factors in patients with ACLF were MELD scores, ages, percentage of neutrophils, hepatic encephalopathy, whether to apply NAs or not, HBV DNA levels, times of plasma exchange in artificial liver support system, cholinesterase levels and total bilirubin levels in turn (P<0.05). The long-term prognosis factors were ages, whether to apply NAs or not, MELD scores, cholinesterase levels, concomitant infection, white blood cell counts, gender and hepatic encephalopathy in turn (P<0.05), and antiviral therapy with NAs was a time-dependent independent prognostic factor. Conclusions There are some differences between the short-term prognosis factors and the long-term prognosis factors in patients with ACLF. We should give antiviral therapy with NAs, measures to improve liver function, preventions and treatments of infection and hepatic encephalopathy and other complications from early-stage to long-term follow-up managements. And in early-stage of ACLF we should also give the treatment with artificial liver support system. Key words: Hepatitis B virus; Acute-on-chronic liver failure; Prognosis; Regression analysis

Albumin Regeneration for Extracorporeal Liver Support Using Prometheus: A Step in the Right Direction

We aim to determine the impact of an artificial liver support system (ALSS) treatment before liver transplantation (LT), and identify the prognostic factors and evaluate the predictive values of the current commonly used ACLF prognostic models for short-term prognosis after LT. Data from 166 patients who underwent LT with acute-on-chronic liver failure (ACLF) were retrospectively collected from January 2011 to December 2018 from the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were divided into two groups depending on whether they received ALSS treatment pre-LT. In the observation group, liver function tests and prognostic scores were significantly lower after ALSS treatment, and the waiting time for a donor liver was significantly longer than that of the control group. Both intraoperative blood loss and period of postoperative ICU care were significantly lower; however, there were no significant differences between groups in terms of total postoperative hospital stays. Postoperative 4-week and 12-week survival rates in the observation group were significantly higher than those of the control group. Similar trends were also observed at 48 and 96 weeks, however, without significant difference. Multivariate Cox regression analysis of the risk factors related to prognosis showed that preoperative ALSS treatment, neutrophil–lymphocyte ratio, and intraoperative blood loss were independent predicting factors for 4-week survival rate after transplantation. ALSS treatment combined with LT in patients with HBV-related ACLF improved short-term survival. ALSS treatment pre-LT is an independent protective factor affecting the 4-week survival rate after LT.

Soportes actuales en falla hepática: cuando el trasplante se hace esperar