Systematic review of artificial liver support systems: Current clinical challenges

Artificial liver systems are used to bridge between transplantation or to allow a patient's liver to recover. They are used in patients with acute liver failure (ALF) and acute-on-chronic liver failure. There are five artificial systems currently in use: molecular adsorbent recirculating system (MARS), single-pass albumin dialysis (SPAD), Prometheus, selective plasma filtration therapy, and hemodiafiltration. The aim is to compare existing data on the efficiency of these devices. A literature search was conducted using online libraries. Inclusion criteria included randomized control trials or comparative human studies published after the year 2000. A systematic review was conducted for the five individual devices with a more detailed comparison of the biochemistry for the SPAD and MARS systems. Eighty-nine patients were involved in the review comparing SPAD and MARS. Results showed that there was an average reduction in bilirubin (-53μmol/L in MARS and -50μmol/L in SPAD), creatinine (-19.5μmol/L in MARS and -7.5μmol/L in SPAD), urea (-0.9mmol/L in MARS and -0.75mmol/L in SPAD), and gamma-glutamyl transferase (-0.215μmol/L·s in MARS and -0.295μmol/L·s in SPAD) in both SPAD and MARS. However, there was no significant difference between the changes in the two systems. This review demonstrated that both MARS and SPAD aid recovery of ALF. There is no difference between the efficiency of MARS and SPAD. Because of the limited data, there is a need for more randomized control trials. Evaluating cost and patient preference would aid in differentiating the systems.

See “Effect of Molecular Adsorbents Recirculating System Treatment in Children With Acute Liver Failure Caused by Wilson Diseas” by Rustom et al on page 162. Molecular adsorbents recirculating system (MARS) is a form of dialysis using albumin-enriched dialysate to remove albumin-bound toxins via a specialised membrane. The dialysate is then regenerated through activated charcoal and anion exchange resin columns. Haemofiltration is required simultaneously to control the blood and dialysate circuits. Single-pass albumin dialysis is another form of albumin dialysis, without a perfusion pump. The accumulation of albumin-bound toxins (eg, bilirubin, bile salts) in liver failure has led to the curiosity behind the potential use of MARS in improving the overall clinical condition for successful bridging to transplantation, or even avoiding transplantation, in cases of acute liver failure (ALF) or acute-on-chronic liver failure (AoCLF). In this study, Rustom et al (1) have set out to show that MARS therapy may be useful as a bridge to transplantation in acute Wilson disease (WD) in children. The concept of MARS as a method for removing liver failure–associated albumin-bound toxins, as well as the increased fraction of toxic albumin-bound copper in acute WD, is the basis for their hypothesis. Data were retrospectively analysed (2004–2009) for all of the children who presented with acute WD and had MARS treatment in a single centre. All of the patients (n = 4) had encephalopathy, renal failure, and a Wilson prognostic index >11. Hence, all of the patients were listed for transplantation. Biochemical data were available for 3 patients and showed reduction in bilirubin, ammonia, aspartate aminotransferase, creatinine, and serum copper levels after MARS sessions. Data available for 2 patients showed an improvement in the Fischer index. All 4 patients were reported to have stable or improved encephalopathy after MARS treatment. Platelet count was significantly reduced in all of the patients and 1 patient had an adverse incident secondary to vascular catheter insertion. There was no improvement in hepatic synthetic function. The median time for transplantation was 5.5 days. Rustom et al suggest that the observed improvement in biological and clinical parameters render MARS a promising treatment modality in acute WD in children; however, the group recognises the shortcomings of such a small sample size and the incomplete dataset. They also acknowledge that the treatment effect is difficult to determine in the absence of a control group and the presence of simultaneous haemofiltration. The exact methodology of encephalopathy measurement in the 2 ventilated cases was unclear. Furthermore, although there is a postulated association with a higher Fischer index and improved encephalopathy, this is, as yet, not a known validated tool in liver failure. Most crucially, this article is unable to shed further light on the following clinically relevant question: Do the observed improved biological and clinical parameters correlate to improved survival and/or morbidity outcomes? Small randomised controlled trials (2–4) in adult studies of AoCLF concur with Rustom et al, namely, biological and clinical improvement is demonstrated in the MARS treatment group compared with the standard medical treatment group. Similarly, some small uncontrolled adult studies of ALF (5) and MARS therapy have observed such improvement. With respect to acute WD, case reports (using MARS or single-pass albumin dialysis) (6–8) have documented enhanced biochemical parameters with or without improved encephalopathy while being successfully bridged to transplantation. One common feature among all of the studies was the acceptable safety profile of MARS, with only complications of thrombocytopaenia and vascular catheter insertion being noted. Two recent large multicentre randomised controlled trials have shown that the survival benefit of MARS remains uncertain. Bañares et al (9) have shown no beneficial effect on survival at 28 days in MARS compared with a standard medical treatment group for AoCLF, despite improved biochemistry and encephalopathy in this group. Saliba et al (10) did show a statistically nonsignificant improved 6-month posttransplant and nontransplant survival rate in patients with ALF in the MARS therapy group, but no improvement in biochemical or clinical parameters. In paediatrics, Dhawan et al (11) revealed a median time of 3.5 days for transplantation of acute WD. This brief period to transplantation raises the question of the need for MARS as a bridging technique. Paediatric data for MARS are limited. Auth et al (12) used MARS as a bridging technique to transplantation for 2 paediatric cases of acute WD. They demonstrated that the MARS circuit could extract toxic metabolites; however, this was not consistently reflected by reduced serum levels of certain metabolites (copper, ammonia, bilirubin), suggesting saturation of the albumin-binding capacity. Essential growth factors and precursors to glutathione synthesis were also noted to be extracted by the albumin circuit, which could negatively affect mortality and liver regeneration. MARS does not prevent transplantation, and survival outcome posttransplantation is unclear. There is no robust evidence to justify the financial implications of this intervention in a clinical setting. The present role of MARS remains within the research setting. Alas, the quest for “life on MARS” continues.

Acute liver failure (ALF) and acute on chronic liver failure (AoCLF) carry a high mortality. The rationale for extracorporeal systems is to provide an environment facilitating recovery or a window of opportunity for liver transplantation. Recent technologies have used albumin as a scavenging molecule. Two different albumin dialysis systems have been developed using this principle: MARS (Molecular Adsorbent Recirculation System) and SPAD (Single-Pass Albumin Dialysis). A third system, Prometheus (Fractionated Plasma Separation and Adsorption), differs from the others in that the patient's albumin is separated across a membrane and then is run over adsorptive columns. Although several trials have been published (particularly with MARS), currently there is a lack of controlled studies with homogenous patient populations. Many studies have combined patients with ALF and AoCLF. Others have included patients with different etiologies. Although MARS and Prometheus have shown biochemical improvements in AoCLF and ALF, additional studies are required to show conclusive benefit in short- and long-term survival. The appropriate comparator is standard medical therapy rather than head-to-head comparisons of different forms of albumin dialysis.

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

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) both have high mortality rates without liver transplantation. Artificial liver support systems may benefit patients with liver failure, serving as a bridge to transplantation or as a destination therapy allowing recovery. There are currently two types of artificial liver support systems: non-biological and biological. Non-biological artificial liver (NBAL) support systems primarily focus on detoxification by removing toxins through selective membranes and adsorbent materials. Well-known NBAL systems are plasma exchange, Molecular Adsorbent Recirculating System (MARS), Single-Pass Albumin Dialysis (SPAD), and the Fractionated Plasma Separation and Adsorption System (Prometheus). NBAL therapies consistently reduce bilirubin and improve encephalopathy; however, pivotal randomized controlled trials such as RELIEF (MARS) and HELIOS (Prometheus) did not confirm a survival advantage, although plasma exchange improved transplant-free survival in acute liver failure. Biological artificial liver (BAL) support systems use human or animal-derived hepatocytes to temporarily replace liver function, including the Extracorporeal Liver Assist Device (ELAD), HepatAssist, and stem-cell-based systems. Early BAL studies showed biochemical and neurological improvements, but large trials such as VTL-308 failed to demonstrate a significant survival benefit over standard medical therapy. Overall, while NBAL and BAL therapies can improve encephalopathy, renal function, and cholestasis, current evidence does not show a clear mortality benefit, and artificial liver support systems remain supportive rather than curative.

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.

BackgroundThe aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure.MethodsPatients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4 % albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model.ResultsSixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median −68 μmol/L, interquartile range [IQR] −107.5 to −33.5, p = 0.001; SPAD: −59 μmol/L, −84.5 to +36.5, p = 0.001). However, bile acids (MARS: −39 μmol/L, −105.6 to −8.3, p < 0.001; SPAD: −9 μmol/L, −36.9 to +11.4, p = 0.131), creatinine (MARS: −24 μmol/L, −46.5 to −8.0, p < 0.001; SPAD: −2 μmol/L, −9.0 to +7.0/L, p = 0.314) and urea (MARS: −0.9 mmol/L, −1.93 to −0.10, p = 0.024; SPAD: −0.1 mmol/L, −1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10 %, −0.8 to +20.9 %, p < 0.001; SPAD: +7 %, −7.5 to +15.5 %, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD.ConclusionsBoth procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation.Trial registrationGerman Clinical Trials Register (www.drks.de) DRKS00000371. Registered 8 April 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1159-3) contains supplementary material, which is available to authorized users.

Acute liver failure (ALF) and acute on chronic liver failure (ACLF) represent severely compromised clinical conditions, characterised by high mortality and often candidates for liver transplantation. Recently, non-biological extracorporeal treatments (ECLSD) have gained an increasing role as temporary support through the removal of water-soluble and albumin-bound toxins. This paper provides an overview of the main available devices, including SPAD (single pass Albumin Dialysis), MARS (Molecular Adsorbent Recirculation System), Prometheus (Fractionated Plasma Separation and Adsorption), Cytosorb, CPFA (Coupled Plasma Filtration Adsorption) and DPMAS (Dual Plasma Molecular Adsorption System), illustrating their technical characteristics, efficacy and limitations. Cytosorb, although originally designed for the treatment of systemic inflammatory conditions, has shown surprising efficacy in reducing bilirubin and bile acids, surpassing the results of MARS in some retrospective studies. Special attention is given to our centre's experience with the RAED (Recirculated Albumin Extended Dialysis) and RHENOB (Reemplazo Hepático No Biológico) techniques, based on recirculated albumin circuits, with or without regeneration by DPMAS. In a series of seven patients with ALF or ACLF treated with RHENOB, a significant reduction in bilirubin (25-50%) was observed after only a few sessions, without haemodynamic adverse events. One patient subsequently received a successful liver transplant, completing the biochemical stabilisation course. The RAED and RHENOB techniques appear to be innovative, effective, cost-effective approaches that can be applied even in centres without advanced technology. However, controlled prospective studies are needed to consolidate their use in clinical practice.

Introduction: Molecular adsorbent recirculating system (MARS) for albumin liver dialysis has been used as a bridge to liver transplantation in patients with fulminant hepatic failure (FHF). This review examines the available data on its clinical use, its technical aspects and present gaps in knowledge. Methods: Peer-reviewed journals and monographs on the subject were covered. Results: FHF is associated with elevation in various substances including bilirubin, ammonia, lactate, free fatty acids and aromatic amino acids. Some of these toxic metabolites, such as ammonia and bilirubin, are believed to be central to the clinical manifestations of hepatic encephalopathy and acute renal failure. MARS ameliorates both biochemical and clinical manifestations of FHF by removing both water-soluble and protein-bound toxins. Among the benefits of MARS is the attenuation of severe cerebral oedema and raised intracranial pressure found in FHF, possibly through reduction in high concentrations of these toxins. Although MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant hepatic failure and less severe forms of acute liver failure (ALF) remains uncertain. The current literature also suggests that it may be beneficial to treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic chemistries can be similarly ameliorated, but the impact of MARS on the natural history of AoCLF remains uncertain. The difficulty lies in being able to accurately quantify residual liver function and variability in the course of acute intercurrent events. The broader question is whether MARS can favourably change the natural history of ALF and FHF. For this, large multi-centre, randomised controlled trials are needed. Furthermore, it is also uncertain how hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver-assist devices which have both synthetic and excretory hepatic functions in ALF treatment in intensive care unit patients. Nevertheless, MARS has proven to be a valuable homeostatic tool that may be useful in restoring the biochemical and clinical status quo in much the same way that continuous veno-venous haemofiltration and mechanical ventilation provide temporary artificial organ support while these organs are in distress. This is the evolving concept of multi-organ support therapy. Other major unresolved issues with MARS include the timing of initiation of albumin liver dialysis, the clinical and/or biochemical parameters to base this decision on, the intensity of MARS therapy (continuous versus intermittent) and the saturation capacity of the system for different metabolites in intermittent MARS. Conclusions: MARS is an effective and, thus far, safe homeostatic tool in treating FHF. More studies are needed to delineate its role as a homeostatic tool in less severe forms of ALF, including that which occurs in multi-organ failure and in AoCLF. Other studies need to focus on the optimal timing of initiation of and intensity of MARS albumin liver dialysis. The larger issue is to compare MARS with bio-assist liver devices in treating the whole spectrum of ALF.

Liver failure is a life-threatening condition, and an artificial liver is highly desirable to replace the failing liver-functions in the waiting time for liver regeneration to happen or until liver transplantation can be undertaken. This review focuses on the efficacy of using artificial extracorporeal liver support devices. Artificial liver support devices such as the molecular adsorbent recirculating system (MARS), fractionated plasma separation and adsorption, and therapeutic plasma exchange (TPE) are well tolerated. MARS and TPE improve systemic haemodynamics and the grade of hepatic encephalopathy. However, randomized, controlled trials of MARS and fractionated plasma separation and adsorption have failed to show improvement in survival in patients with acute liver failure (ALF) and patients with acute-on-chronic liver failure (ACLF). Only TPE improves survival in patients with ALF by ameliorate the release of ammonia, damage-associated molecular patterns and sB7 (CD80/86) from the necrotic liver. No randomized, controlled trials on survival in patients with ACLF using TPE have been done. Liver support systems such as MARS and TPE may temporarily improve systemic haemodynamics and the degree of encephalopathy. However, TPE is the only procedure that improves survival in patients with ALF. The role of TPE in ACLF remains unknown.

Nucleosome Serum Levels in Acute Hepatic Failure and MARS Treatment

To identify prognostic factors for survival in patients with liver failure treated with a molecular adsorbent recirculating system (MARS). MARS is a liver-assisting device that has been used in the treatment of liver failure to enable native liver recovery, and as a bridge to liver transplantation (LTX). We analyzed the 1-year outcomes of 188 patients treated with MARS, from 2001 to 2007, in an intensive care unit specializing in liver disease. Demographic, clinical and laboratory parameters were recorded before and after each treatment. One-year survival and the number of LTXs were recorded. Logistic regression analysis was performed to determine factors predicting survival. The study included 113 patients with acute liver failure (ALF), 62 with acute-on-chronic liver failure (AOCLF), 11 with graft failure (GF), and six with miscellaneous liver failure. LTX was performed for 29% of patients with ALF, 18% with AOCLF and 55% with GF. The overall 1-year survival rate was 74% for ALF, 27% for AOCLF, and 73% for GF. The poorest survival rate, 6%, was noted in non-transplanted patients with alcohol-related AOCLF and cirrhosis, whereas, patients with enlarged and steatotic liver had 55% survival. The etiology of liver failure was the most important predictor of survival (P < 0.0001). Other prognostic factors were encephalopathy (P = 0.001) in paracetamol-related ALF, coagulation factors (P = 0.049) and encephalopathy (P = 0.064) in non-paracetamol-related toxic ALF, and alanine aminotransferase (P = 0.013) and factor V levels (P = 0.022) in ALF of unknown etiology. The etiology of liver disease was the most important prognostic factor. MARS treatment appears to be ineffective in AOCLF with end-stage cirrhosis without an LTX option.

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6 h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92 ± 7.79 mmol/L to 7.16 ± 5.64 mmol/L (P < 0.05). The concentration decreased in all amino acids with the exception of the branched‐chain amino acids. Fischer's ratio of branched‐chain to aromatic amino acids increased from 0.73 ± 0.47 to 0.91 ± 0.54 (P < 0.05). A net cerebral efflux of amino acids in patients with FHF (8.94 ± 8.34 μmol/100 g/min) as well as AoCLF (7.35 ± 24.97 μmol/100 g/min) was not affected by the MARS treatment. MARS had no effect on the cerebral metabolic rate of any single amino acid in either group. Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.

Background:Acute-on-chronic liver failure (ACLF) is a common complication of cirrhosischaracterized by single or multiple organ failures and high short-termmortality. Treatment of ACLF consists of standard medical care (SMC) andorgan(s) support. Whether the efficacy of artificial liver support (ALS)depends on the severity of ACLF or on the intensity of this treatment, orboth, is unclear. This study aimed to further assess these issues.Methods:We performed an individual patient data meta-analysis assessing the efficacyof Molecular Adsorbent Recirculating System (MARS) in ACLF patients enrolledin prior randomized control trials (RCTs). The meta-analysis was designed toassess the effect of patient severity (ACLF grade) and treatment intensity[low-intensity therapy (LIT), SMC alone or SMC plus ⩽ 4 MARS sessions,high-intensity therapy (HIT), SMC plus > 4 MARS sessions] onmortality.Results:Three RCTs suitable for the meta-analysis (n = 285, ACLFpatients = 165) were identified in a systematic review. SMC plus MARS(irrespective of the number of sessions) did not improve survival comparedwith SMC alone, neither in the complete population nor in the ACLF patients.Survival, however, was significantly improved in the subgroup of patientsreceiving HIT both in the entire cohort (10-day survival: 98.6%versus 82.8%, p = 0.001; 30-daysurvival: 73.9% versus 64.3%, p = 0.032)and within the ACLF patients (10-day survival: 97.8% versus78.6%, p = 0.001; 30-day survival: 73.3%versus 58.5%, p = 0.041). Remarkably,HIT increased survival independently of ACLF grade. Independent predictorsof survival were age, Model for End-Stage Liver Disease (MELD), ACLF grade,number of MARS sessions received, and intensity of MARS therapy.Conclusion:HIT with albumin dialysis may improve survival in patients with ACLF.Appropriate treatment schedules should be determined in future clinicaltrials.

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