Acute liver failure: Bridging to transplant or recovery– are we there yet?
2007; Elsevier BV; Volume: 46; Issue: 4 Linguagem: Inglês
10.1016/j.jhep.2007.01.010
ISSN1600-0641
AutoresAmit Singhal, James Neuberger,
Tópico(s)Drug-Induced Hepatotoxicity and Protection
Resumo1. IntroductionThe main goal in the management of patients with acute liver failure (ALF) is to provide support until the liver regenerates sufficiently to restore normal function or, if this is not achievable, until a graft becomes available. Despite advances, overall mortality remains high. To date, only liver transplantation has been convincingly shown to improve outcome in ALF [[1]Bernal W. Wendon J. Liver transplantation in adults with acute liver failure.J Hepatol. 2004; 40: 192-197Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. However, orthotopic liver transplant (OLT) in setting of ALF is not without its problems: a significant number of patients may die while waiting for graft [[2]Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H. et al.Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar]. Furthermore, life after transplantation is reduced both in length [[3]Barber K, Blackwell J, Collett D, Neuberger J. Life expectancy of adult liver allograft recipients in the UK. Gut 2006, (Epub ahead of print).Google Scholar] and quality, due, largely to the consequences of immunosuppression. After transplantation, the patient’s quality of life, while usually excellent, rarely reaches the level seen prior to the onset of liver failure and this, together with the inevitable lack of patient education, may lead to problems of adjustment. In contrast, where recovery does occur, the liver usually returns to normal structure and function and the patient returns to the quality and length of life that was present before the onset of liver failure. Balancing the risks and benefits of transplantation is difficult: prognostic models have only limited sensitivity and specificity [2Ostapowicz G. Fontana R.J. Schiodt F.V. Larson A. Davern T.J. Han S.H. et al.Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med. 2002; 137: 947-954Crossref PubMed Scopus (1681) Google Scholar, 4Macquillan G.C. Seyam M.S. Nightingale P. Neuberger J.M. Murphy N. Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure.Liver Transpl. 2005; 11: 1073-1079Crossref PubMed Scopus (89) Google Scholar].There has, therefore, been considerable interest in developing techniques that provide liver support during the acute phase of liver failure, that will act either as a bridge to transplant (supporting the patient through the acute illness and allow time to find suitable donor organ before the onset of complications that make the procedure futile) or as a bridge to recovery (allowing the native liver to recover so liver replacement is unnecessary). Demonstrating the benefit of such techniques is difficult and best assessed in the setting of controlled clinical trials but undertaking such trials in the context of ALF is a formidable challenge: trials need to be adequately powered with clearly defined inclusion criteria; survival (with or without liver replacement) should be the primary end point [[5]Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar]. Generating adequate numbers of defined cohorts of patients, the variable impact of liver transplantation and the level of funding required make large multi-centre studies very difficult to establish. Surrogate markers of survival are often used in assessing the impact of liver support mechanisms but these have not been validated and must be interpreted with caution.2. ‘Bridging Options’The aim of bridging devices is to provide adequate liver function and maintain the patient well enough until recovery of native liver function occurs or until a graft is found. The many and diverse functions of the liver (metabolic, immunologic, physiologic) make the task of developing simple devices a major challenge: the effects of the ‘toxic liver’ itself also require consideration.Bridging devices can be classed into four categories: (1) auxiliary transplant; (2) liver support devices (biological and non-biological); (3) hepatocyte transplantation; (4) innovative/experimental techniques.The role of auxiliary transplantation is covered in the article by Dr. Jaeck in this forum and will not be discussed any further here.3. Liver support devicesExtracorporeal liver support devices have been attempted for more than 40 years. These devices can broadly be grouped as bioartificial and artificial or non-biological devices. While biological devices aim to replace all the essential functions of the liver, the artificial devices provide mainly detoxification [6Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar, 7Allen J.W. Hassanein T. Bhatia S.N. Advances in bioartificial liver devices.Hepatology. 2001; 34: 447-455Crossref PubMed Scopus (301) Google Scholar].3.1 Bioartificial devicesBioartificial liver (BAL) devices typically incorporate isolated cultured hepatocytes in the bioreactors. The important issues are choice of cellular component, stabilization of hepatocyte phenotype, the amount and efficacy of the biomass, the design of bioreactor and its safety [[7]Allen J.W. Hassanein T. Bhatia S.N. Advances in bioartificial liver devices.Hepatology. 2001; 34: 447-455Crossref PubMed Scopus (301) Google Scholar]. Various bioartificial devices used in clinical trials and their characteristics are summarised in Table 1.Table 1Summary of characteristics of bioartificial liver support systemsBioartificial deviceCell typeCell amountDetoxification moduleDemetriou’s Hepatassist Bioartificial Liver (BAL) [9]Rozga J. Williams F. Ro M.S. Neuzil D.F. Giorgio T.D. Backfisch G. et al.Development of a bioartificial liver: properties and function of a hollow-fiber module inoculated with liver cells.Hepatology. 1993; 17: 258-265Crossref PubMed Scopus (264) Google ScholarPorcine (cryopreserved)5–7 × 109Charcoal column pre-bioreactorAmsterdam Medical Centre Bioartificial Liver (AMC-BAL) [10]Flendrig L.M. la Soe J.W. Jorning G.G. Steenbeek A. Karlsen O.T. Bovee W.M. et al.In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates.J Hepatol. 1997; 26: 1379-1392Abstract Full Text PDF PubMed Scopus (216) Google ScholarPorcine (fresh isolated)10 × 109NoExtracorporeal liver assist device (ELAD) [12]Sussman N.L. Chong M.G. Koussayer T. He D.E. Shang T.A. Whisennand H.H. et al.Reversal of fulminant hepatic failure using an extracorporeal liver assist device.Hepatology. 1992; 16: 60-65Crossref PubMed Scopus (304) Google ScholarHuman, tumour derived (cultured C3A)200–400 gNoModular Extracorporeal Liver Support (MELS) [13]Sauer I.M. Gerlach J.C. Modular extracorporeal liver support.Artif Organs. 2002; 26: 703-706Crossref PubMed Scopus (50) Google ScholarHuman (fresh isolated)Upto 600 gSingle pass albumen dialysisBioartificial liver support system (BLSS) [47]Patzer J.F. Mazariegos G.V. Lopez R. Preclinical evaluation of the Excorp Medical, Inc, Bioartificial Liver Support System.J Am Coll Surg. 2002; 195: 299-310Abstract Full Text Full Text PDF PubMed Scopus (29) Google ScholarPorcine (fresh isolated)70–120 gNo Open table in a new tab In the normal liver, the hepatocytes account for about 70% of the cell mass: other cell types are, however, important not only to support and maintain hepatocellular function but also have their own functional roles. Thus, devices that consist of just hepatocytes may not be adequate to replace hepatic function. Furthermore, the mass of hepatocytes required to sustain life is unknown: in the allograft, a 0.8–1% weight/body weight ratio is considered a minimum to prevent small-for-size syndrome [[8]Ben-Haim M. Emre S. Fishbein T.M. Sheiner P.A. Bodian C.A. Kim-Schluger L. et al.Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient’s disease.Liver Transpl. 2001; 7: 948-953Crossref PubMed Scopus (243) Google Scholar]; but the minimum mass of hepatocytes required for bioartificial devices is not established. Most studies suggest that 150–450 g (1010 hepatocytes) is required to support the failing liver [[7]Allen J.W. Hassanein T. Bhatia S.N. Advances in bioartificial liver devices.Hepatology. 2001; 34: 447-455Crossref PubMed Scopus (301) Google Scholar].The ideal hepatocellular component is human hepatocyte which are of limited availability and cannot be stored for long term use as the cells become phenotypically unstable and rapidly lose many liver specific functions [[7]Allen J.W. Hassanein T. Bhatia S.N. Advances in bioartificial liver devices.Hepatology. 2001; 34: 447-455Crossref PubMed Scopus (301) Google Scholar]. Primary porcine liver cells are much more commonly used in the clinical trials and are used in the HepatAssist BAL device [[9]Rozga J. Williams F. Ro M.S. Neuzil D.F. Giorgio T.D. Backfisch G. et al.Development of a bioartificial liver: properties and function of a hollow-fiber module inoculated with liver cells.Hepatology. 1993; 17: 258-265Crossref PubMed Scopus (264) Google Scholar] and the bioartificial device developed by Amsterdam Medical Centre (AMC-BAL) [[10]Flendrig L.M. la Soe J.W. Jorning G.G. Steenbeek A. Karlsen O.T. Bovee W.M. et al.In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates.J Hepatol. 1997; 26: 1379-1392Abstract Full Text PDF PubMed Scopus (216) Google Scholar]. Porcine hepatocytes are easily prepared and can be satisfactorily cryopreserved, thus simplifying availability, storage and transportation. However there are ongoing concerns regarding immune cross-reactions to foreign antigens, the consequences of the hepatocytes generating circulating porcine rather than human proteins and the possibility of xeno-zoonosis in the form of cross species infection with porcine endogenous retrovirus [5Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar, 11Nyberg S.L. Hibbs J.R. Hardin J.A. Germer J.J. Persing D.H. Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver.Transplantation. 1999; 67: 1251-1255Crossref PubMed Scopus (68) Google Scholar]. Clinical trials with porcine hepatocytes are permitted in USA but not in many parts of Europe.Sussman’s extracorporeal liver assist device (ELAD) incorporates C3A hepatocyte line, a sub-clone of HepG2 hepatoblastoma cell line [[12]Sussman N.L. Chong M.G. Koussayer T. He D.E. Shang T.A. Whisennand H.H. et al.Reversal of fulminant hepatic failure using an extracorporeal liver assist device.Hepatology. 1992; 16: 60-65Crossref PubMed Scopus (304) Google Scholar]. Concerns regarding the functional capacity and escape of tumorigenic cells into the patient are a potential hazard [[6]Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar]. The modular extracorporeal liver support (MELS) utilizes primary human hepatocytes from donor livers found unsuitable for transplantation [[13]Sauer I.M. Gerlach J.C. Modular extracorporeal liver support.Artif Organs. 2002; 26: 703-706Crossref PubMed Scopus (50) Google Scholar].The most basic design of a bioreactor consists of a column containing hollow fibre capillaries through which the patient’s blood circulates while hepatocytes are located in the extra-capillary space. The principle is that the hepatocytes extract nutrients and detoxify putative toxins from the plasma and their metabolites are simultaneously passed back into the plasma. Bioartificial devices differ in designs for support for the hepatocytes, oxygenation of blood and extracorporeal removal of toxins [5Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar, 6Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar, 14Barshes N.R. Gay A.N. Williams B. Patel A.J. Awad S.S. Support for the acutely failing liver: a comprehensive review of historic and contemporary strategies.J Am Coll Surg. 2005; 201: 458-476Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Most include an element of dialysis and some with charcoal column filtration: thus, some of the changes may be related to the dialysis rather than any effect of the hepatocytes.Numerous small trials and case series have reported on the use of bioartificial devices in patients with ALF with varying results. Some of the larger and more recent studies are summarised in Table 2. The only prospective, randomized, multi-centre, controlled trial with bioartificial liver support device reported so far has not shown any survival benefit [[15]Demetriou A.A. Brown Jr., R.S. Busuttil R.W. Fair J. McGuire B.M. Rosenthal P. et al.Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.Ann Surg. 2004; 239: 660-667Crossref PubMed Scopus (527) Google Scholar]. The HepatAssist BAL was assessed in 171 patients in 20 centres (9 European) (147 patients with ALF and 24 patients with primary graft non-function) over a 3 year period. The primary end point was patient survival, with or without OLT. The 30 day survival was 71% in the BAL group and 62% in the control arm but this difference was not statistically significant (p = 0.26). The primary end point was confounded by the impact of OLT. When the survival was analysed accounting for various confounding factors, the ALF subgroup (excluding those with graft non-function) treated with BAL had significantly higher 30 day survival (44% reduction in mortality). It is interesting to note that apart from decrease in serum bilirubin, no statistically significant improvement was noted in neurological status, haemodynamic parameters or other biochemical values.Table 2Summary of important studies evaluating bioartificial liver in acute liver failureStudyPatient populationSystem usedStudy designEnd pointOutcomeDemetriou (2004) [15]Demetriou A.A. Brown Jr., R.S. Busuttil R.W. Fair J. McGuire B.M. Rosenthal P. et al.Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.Ann Surg. 2004; 239: 660-667Crossref PubMed Scopus (527) Google ScholarALF (n = 147)BALMulti-center, RCT30 day mortality30 day survival. ALL patients: BAL 71%, control 62% (p = 0.26) Subgroups: ALF 73%, control 59% (p = 0.18)PNF (n = 24)Survival after accounting for various confounding factors: 44% reduction in mortality in ALF groupSamuel (2002) [16]Samuel D. Ichai P. Feray C. Saliba F. Azoulay D. Arulnaden J.L. et al.Neurological improvement during bioartificial liver sessions in patients with acute liver failure awaiting transplantation.Transplantation. 2002; 73: 257-264Crossref PubMed Scopus (83) Google ScholarALF (n = 10)BALProspective case seriesOLTAll bridged to OLT (8 alive at 18 months).Neurological improvementSignificant improvement in Glasgow coma score and bilirubin levels but not other liver parameters60% had hemodynamic instability50% had bleeding complicationsEllis (1996) [48]Ellis A.J. Hughes R.D. Wendon J.A. Dunne J. Langley P.G. Kelly J.H. et al.Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure.Hepatology. 1996; 24: 1446-1451Crossref PubMed Google ScholarALF (n = 24) Group 1: not fulfilling OLT criteria (n = 17)ELADSingle centre, RCTOLT or in hospital mortalitySurvival: Group 1 – ELAD 78%, controls 75%Group 2 (fulfilling OLT criteria (n = 7)Group 2 – ELAD 33% controls 25%Clear survival advantage not documentedvan de Kerkhove (2002) [49]van de Kerkhove M.P. Di F.E. Scuderi V. Mancini A. Belli A. Bracco A. et al.Phase I clinical trial with the AMC-bioartificial liver.Int J Artif Organs. 2002; 25: 950-959PubMed Google ScholarALF (n = 7) with grade 3–4 comaAMC-BALPhase 1 studyOLT6/7 patients safely bridged to OLT.Neurological improvement in all casesSauer (2002) [50]Sauer I.M. Zeilinger K. Obermayer N. Pless G. Grunwald A. Pascher A. et al.Primary human liver cells as source for modular extracorporeal liver support – a preliminary report.Int J Artif Organs. 2002; 25: 1001-1005PubMed Google ScholarSix patients fulfilling OLT criteria ALF (n = 2), ACLF (n = 2), PNF (n = 2)MELSPhase 1 studyOLTAll 6 patients safely bridged to OLTNeurological improvementNeurological improvement in all cases Open table in a new tab Most of the studies show variable improvements in surrogate markers such as Glasgow coma scores, bilirubin and ammonia levels (Table 2). None of the studies show major improvement in the synthetic function [[5]Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar]. Further, most of the benefit observed with bioartificial devices claim successful bridging to transplantation rather than bridging to recovery. However in most of these studies, significance of survival has been confounded by intervention with LT and selection of the choice of patient, with inclusion criteria limited to those who were stable [20Khuroo M.S. Khuroo M.S. Farahat K.L. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure: a meta-analysis.Liver Transpl. 2004; 10: 1099-1106Crossref PubMed Scopus (156) Google Scholar, 21Kjaergard L.L. Liu J. ls-Nielsen B. Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review.JAMA. 2003; 289: 217-222Crossref PubMed Scopus (312) Google Scholar].Most of the studies including larger trials have shown a good safety profile of bioartificial devices. The majority of the side effects reported were haemodynamic, metabolic and coagulation related consequences to extracorporeal circulation of blood [5Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar, 15Demetriou A.A. Brown Jr., R.S. Busuttil R.W. Fair J. McGuire B.M. Rosenthal P. et al.Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.Ann Surg. 2004; 239: 660-667Crossref PubMed Scopus (527) Google Scholar, 16Samuel D. Ichai P. Feray C. Saliba F. Azoulay D. Arulnaden J.L. et al.Neurological improvement during bioartificial liver sessions in patients with acute liver failure awaiting transplantation.Transplantation. 2002; 73: 257-264Crossref PubMed Scopus (83) Google Scholar]. To date no humans have been reported infected with porcine endogenous retrovirus [14Barshes N.R. Gay A.N. Williams B. Patel A.J. Awad S.S. Support for the acutely failing liver: a comprehensive review of historic and contemporary strategies.J Am Coll Surg. 2005; 201: 458-476Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 15Demetriou A.A. Brown Jr., R.S. Busuttil R.W. Fair J. McGuire B.M. Rosenthal P. et al.Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.Ann Surg. 2004; 239: 660-667Crossref PubMed Scopus (527) Google Scholar].3.2 Artificial devicesThe safety concerns and high costs associated with biological devices have led to a renewed interest in artificial liver support devices. These are essentially detoxifying devices which use membranes and adsorbents that will remove potential toxins. Whole blood exchange, haemodialysis and haemofiltration, haemoperfusion over charcoal, solely or in various combinations, have been tried but clinical success was, at best, modest [[17]Stockmann H.B. Hiemstra C.A. Marquet R.L. IJzermans J.N. Extracorporeal perfusion for the treatment of acute liver failure.Ann Surg. 2000; 231: 460-470Crossref PubMed Scopus (78) Google Scholar]. The newer systems, based on albumin for transporting toxins and utilising a membrane having a sufficiently small pore size, are substantially more effective as regards their detoxifying capacity when compared to earlier devices [6Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar, 14Barshes N.R. Gay A.N. Williams B. Patel A.J. Awad S.S. Support for the acutely failing liver: a comprehensive review of historic and contemporary strategies.J Am Coll Surg. 2005; 201: 458-476Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. These devices are thus specific for albumin bound substances which form the majority of the toxins accumulated in liver failure, while larger molecules (immunoglobulins, growth factors) are retained.3.2.1 MARSThe Molecular Adsorbents Recirculating System (MARS) (Teraklin AG, Rostock, Germany) is probably the most widely used artificial device. Developed in 1993 by Stange and Mitzner and first used in humans in 1996 [[18]Stange J. Mitzner S. A carrier-mediated transport of toxins in a hybrid membrane. Safety barrier between a patients blood and a bioartificial liver.Int J Artif Organs. 1996; 19: 677-691PubMed Google Scholar], it is a very effective detoxification device which uses a hollow fibre dialysis module in which patient’s blood is dialyzed across an albumin-impregnated polysulfone membrane (cut off at 50 kDa) while maintaining a constant flow of 600 ml of 20% albumin as dialysate in the extra-capillary compartment. Dialysate carrying toxins is cleansed sequentially by a haemodialysis/haemofiltration module (removing water soluble substances) and adsorber columns containing activated charcoal and anion exchange resins (removing albumin bound toxins). The dialysate is thus regenerated and is once more capable of taking up more toxins from the blood [[5]Sen S. Williams R. New liver support devices in acute liver failure: a critical evaluation.Semin Liver Dis. 2003; 23: 283-294Crossref PubMed Scopus (31) Google Scholar].To date, more than 4500 patients have been treated with MARS for various indications such as acute or chronic liver failure (ACLF), severe alcoholic hepatitis, intractable intra-hepatic cholestasis and intoxication from protein bound substances [6Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar, 19Laleman W. Wilmer A. Evenepoel P. Verslype C. Fevery J. Nevens F. Review article: non-biological liver support in liver failure.Aliment Pharmacol Ther. 2006; 23: 351-363Crossref PubMed Scopus (53) Google Scholar]. Most of the trials with MARS have been in patients with ACLF and comparatively only few large studies have reported the role of MARS in ALF. Two meta-analyses have been published and both failed to show any survival benefit with MARS in acute liver failure [20Khuroo M.S. Khuroo M.S. Farahat K.L. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure: a meta-analysis.Liver Transpl. 2004; 10: 1099-1106Crossref PubMed Scopus (156) Google Scholar, 21Kjaergard L.L. Liu J. ls-Nielsen B. Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review.JAMA. 2003; 289: 217-222Crossref PubMed Scopus (312) Google Scholar]. Khuroo and colleagues analysed 4 randomized controlled trials (2 in ALF and 2 in ACLF) involving 67 patients with survival as primary end point. They concluded that MARS treatment did not have significant survival advantage in ALF or ACLF. However the study was criticised for pooling together small number of patients with diverse indications, with different primary end points and different treatment protocols [[22]Stange J. Meta-analysis in albumin dialysis: are we really ready for it?.Liver Transpl. 2004; 10: 1107-1108Crossref PubMed Scopus (11) Google Scholar]. Kjaergard analysed 12 RCTs involving 483 patients and 7 types of support systems (5 artificial and 2 bioartificial), both in ALF and ACLF. Of the 12 trials included, 10 assessed artificial systems for ALF or ACLF and 2 assessed bioartificial systems for ALF. In the primary meta-analysis, support systems did not have any benefit on mortality compared with standard medical therapy. However in the subgroup analysis, the support systems were associated with a significantly reduced mortality in ACLF but not in ALF [[21]Kjaergard L.L. Liu J. ls-Nielsen B. Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review.JAMA. 2003; 289: 217-222Crossref PubMed Scopus (312) Google Scholar]. However this meta-analysis included a wide range of support systems in diverse patient groups and may be under-powered to provide a clear answer to the role of support devices in liver failure [[20]Khuroo M.S. Khuroo M.S. Farahat K.L. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure: a meta-analysis.Liver Transpl. 2004; 10: 1099-1106Crossref PubMed Scopus (156) Google Scholar].More recently, larger studies have looked not only at survival but also surrogate markers of survival as primary end points. Novelli studied the impact of MARS in 116 patients with liver failure, of whom 24 had ALF. They demonstrated significant improvement in serum bilirubin, ammonia, lactate, creatinine and in the Glasgow Coma Score after 1–24 sessions (mean 6) of MARS treatment [[23]Novelli G. Rossi M. Pretagostini M. Pugliese F. Ruberto F. Novelli L. et al.One hundred sixteen cases of acute liver failure treated with MARS.Transplant Proc. 2005; 37: 2557-2559Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Similarly, Camus reported significantly improved liver function tests (bilirubin, coagulation) but not Glasgow Coma Score or encephalopathy in 22 patients with ALF who fulfilled the criteria for transplantation. They further demonstrated transplant free recovery rate of 29% compared with an expected rate of 9% [[24]Camus C. Lavoue S. Gacouin A. Le T.Y. Lorho R. Boudjema K. et al.Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation.Intensive Care Med. 2006; 32: 1817-1825Crossref PubMed Scopus (51) Google Scholar].Koivusalo also reported very promising results of MARS therapy in 56 patients with ALF where 30 (53%) recovered. The best results were seen in 25 patients with a toxic aetiology: 76% had evidence of hepatic regeneration when MARS was used as soon as possible after ingestion of toxins [[25]Koivusalo A.M. Vakkuri A. Hockerstedt K. Isoniemi H. Experience of Mars therapy with and without transplantation in 101 patients with liver insufficiency.Transplant Proc. 2005; 37: 3315-3317Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. In contrast, Lee found a very poor outcome with MARS in 13 cases of toxin induced ALF [[26]Lee K.H. Lee M.K. Sutedja D.S. Lim S.G. Outcome from molecular adsorbent recycling system (MARS) liver dialysis following drug-induced liver failure.Liver Int. 2005; 25: 973-977Crossref PubMed Scopus (37) Google Scholar]. All the patients included had met the criteria for urgent liver transplantation and the overall mortality was 85% (median time to death was 8 days). It is likely that different inclusion/exclusion criteria in the two studies are responsible for different outcomes, once again highlighting problems with conducting as well as interpreting trials related to ALF.Current data indicate that MARS treatment itself is safe [19Laleman W. Wilmer A. Evenepoel P. Verslype C. Fevery J. Nevens F. Review article: non-biological liver support in liver failure.Aliment Pharmacol Ther. 2006; 23: 351-363Crossref PubMed Scopus (53) Google Scholar, 20Khuroo M.S. Khuroo M.S. Farahat K.L. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure: a meta-analysis.Liver Transpl. 2004; 10: 1099-1106Crossref PubMed Scopus (156) Google Scholar, 23Novelli G. Rossi M. Pretagostini M. Pugliese F. Ruberto F. Novelli L. et al.One hundred sixteen cases of acute liver failure treated with MARS.Transplant Proc. 2005; 37: 2557-2559Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The MARS registry maintained by University of Rostock shows MARS is well tolerated with thrombocytopenia as only consistent adverse finding [[27]Steiner C. Mitzner S. Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry.Liver. 2002; 22: 20-25Crossref PubMed Scopus (85) Google Scholar]. Some have also suggested that established disseminated intravascular coagulopathy and uncontrolled bleeding are relative contra-indications to MARS therapy [[6]Jalan R. Sen S. Williams R. Prospects for extracorporeal liver support.Gut. 2004; 53: 890-898Crossref PubMed Scopus (64) Google Scholar].3.2.2 Prometheus systemThe Prometheus system (Fresenius Medical Care AG) is a variant of albumin dialysis and like MARS removes both protein bound and water soluble toxins. It is a potent extracorporeal liver detoxification device which works on the principle of fractionated plasma separation and adsorption (FPSA) coupled with high flux haemodialysis [[28]Rifai K. Ernst T. Kretschmer U. Bahr M.J. Schneider A. Hafer C. et al.Prometheus – a new extracorporeal system for the treatment of liver failure.J Hepatol. 2003; 39: 984-990Abstract Full Text Full Text PDF PubMed Scopu
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