Journal of Hepatology
Volume 46, Issue 4 , Pages 557-564, April 2007

Acute liver failure: Bridging to transplant or recovery– are we there yet?

The Liver Unit, Queen Elizabeth Hospital, Birmingham and University of Birmingham, UK

published online 05 February 2007.

Article Outline

Abbreviations: ALF, acute liver failure, ACLF, acute on chronic liver failure, OLT, orthotopic liver transplant, ALT, suxiliary liver transplant, APOLT, auxiliary partial orthotopic liver transplant, HALT, heterotopic auxiliary liver transplant, BAL, bioartificial liver, MARS, Molecular Adsorbents Recirculating System, HT, hepatocyte transplantation, PNF, primary graft non-function

 

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1. Introduction 

The 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]. 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]. Furthermore, life after transplantation is reduced both in length [3] 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 [2], [4].

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]. 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.

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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.

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3. Liver support devices 

Extracorporeal liver support devices have been attempted for more than 40years. 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 [6], [7].

3.1. Bioartificial devices 

Bioartificial 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]. Various bioartificial devices used in clinical trials and their characteristics are summarised in Table 1.

Table 1. Summary of characteristics of bioartificial liver support systems
Bioartificial deviceCell typeCell amountDetoxification module
Demetriou’s Hepatassist Bioartificial Liver (BAL) [9]Porcine (cryopreserved)5–7×109Charcoal column pre-bioreactor
Amsterdam Medical Centre Bioartificial Liver (AMC-BAL) [10]Porcine (fresh isolated)10×109No
Extracorporeal liver assist device (ELAD) [12]Human, tumour derived (cultured C3A)200–400gNo
Modular Extracorporeal Liver Support (MELS) [13]Human (fresh isolated)Upto 600gSingle pass albumen dialysis
Bioartificial liver support system (BLSS) [47]Porcine (fresh isolated)70–120gNo

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]; but the minimum mass of hepatocytes required for bioartificial devices is not established. Most studies suggest that 150–450g (1010 hepatocytes) is required to support the failing liver [7].

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]. Primary porcine liver cells are much more commonly used in the clinical trials and are used in the HepatAssist BAL device [9] and the bioartificial device developed by Amsterdam Medical Centre (AMC-BAL) [10]. 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 [5], [11]. 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]. Concerns regarding the functional capacity and escape of tumorigenic cells into the patient are a potential hazard [6]. The modular extracorporeal liver support (MELS) utilizes primary human hepatocytes from donor livers found unsuitable for transplantation [13].

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 [5], [6], [14]. 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]. 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 3year period. The primary end point was patient survival, with or without OLT. The 30day 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 30day 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 2. Summary of important studies evaluating bioartificial liver in acute liver failure
StudyPatient populationSystem usedStudy designEnd pointOutcome
Demetriou (2004) [15]ALF (n=147)BALMulti-center, RCT30day mortality30day 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 group
Samuel (2002) [16]ALF (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 parameters
60% had hemodynamic instability
50% had bleeding complications
Ellis (1996) [48]ALF (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 documented
van de Kerkhove (2002) [49]ALF (n=7) with grade 3–4 comaAMC-BALPhase 1 studyOLT6/7 patients safely bridged to OLT.
Neurological improvement in all cases
Sauer (2002) [50]Six patients fulfilling OLT criteria ALF (n=2), ACLF (n=2), PNF (n=2)MELSPhase 1 studyOLTAll 6 patients safely bridged to OLT
Neurological improvementNeurological improvement in all cases

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]. 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 [20], [21].

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 [5], [15], [16]. To date no humans have been reported infected with porcine endogenous retrovirus [14], [15].

3.2. Artificial devices 

The 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]. 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 [6], [14]. 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. MARS 

The 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], 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 50kDa) while maintaining a constant flow of 600ml 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].

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 [6], [19]. 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 [20], [21]. 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]. 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]. 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].

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]. 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].

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]. In contrast, Lee found a very poor outcome with MARS in 13 cases of toxin induced ALF [26]. All the patients included had met the criteria for urgent liver transplantation and the overall mortality was 85% (median time to death was 8days). 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 [19], [20], [23]. The MARS registry maintained by University of Rostock shows MARS is well tolerated with thrombocytopenia as only consistent adverse finding [27]. Some have also suggested that established disseminated intravascular coagulopathy and uncontrolled bleeding are relative contra-indications to MARS therapy [6].

3.2.2. Prometheus system 

The 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]. Some studies suggest that it might be more effective than MARS [29]. A recent study evaluated the role of FPSA/high flux haemodialysis in 25 patients of ALF who were urgently listed for transplantation and demonstrated good safety profile and efficacy as a ‘bridge’ to transplantation [30]. However most of the studies have been done in context of ACLF and to date there are only few reported trials of role of Prometheus in ALF.

3.2.3. Plasmapheresis and high volume plasmapheresis 

During plasmapheresis, large molecular weight substances bound to albumen are removed, the patient’s plasma containing potentially toxic mediators is discarded and exchanged for fresh frozen plasma. Small studies have reported improved coagulation and decreased cytokine load, but no significant benefit in either acute or chronic liver failure is reported [31]. High volume plasmapheresis is a more extreme form of plasma exchange, exchanging more than 10L of plasma daily. There are reports of reduction in serum bilirubin and arterial ammonia with improvement in haemodynamic state in those with liver failure [32]. Multi-centre trials are underway to evaluate its role in ALF with encephalopathy grades 2–4. At present there is no clear role for plasmapheresis.

3.2.4. Where are we today? 

Artificial systems are simpler, cheaper and possibly safer than bioartificial devices. Relying only on exogenous detoxification, artificial support systems seem to facilitate an environment needed for hepatic regeneration and clinical recovery. The average cost of MARS in UK for full treatment is £4000–7000 whereas bioartificial devices may cost up to £60,000 [6]. Bioartificial devices have failed to show any significant benefit in synthetic function and benefit seen in association with these devices may primarily be due to extracorporeal detoxification [33]. A major hurdle in the widespread clinical acceptability of these devices remains the selection of optimal bio-component.

Over the past 10years, numerous exciting developments have taken place in the field of liver support devices both artificial and bioartificial. But the data are conflicting and less promising in ALF: to date no large well-controlled randomized trial has shown any clinically significant benefit in patients with ALF. The search for an ideal liver support device will continue. However until controlled clinical trials show a clear benefit in long term outcome, safety and cost effectiveness, the liver support devices cannot be recommended as standard therapy in ALF.

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4. Hepatocyte transplantation 

Hepatocyte transplantation (HT) offers, at least in principle, an attractive therapy for patients with ALF. Liver repopulation from hepatocyte infusion could ‘bridge’ the patient until recovery or transplantation. Hepatocyte suspensions could be cryopreserved and made readily available as needed: several patients could receive enough hepatocytes isolated from a single donor liver [14]. Extensive studies in animal models of ALF have shown the feasibility of HT with promising results [34]. However to date no large controlled clinical trials have been reported in the role of HT in patients with ALF. There are very few, small individual series with less conclusive results [35], [36]. Strom used HT in 5 patients with liver failure with grade IV encephalopathy and ‘bridged’ 3 patients in the study group to transplantation [35]. However 3 of the patients in this series had ACLF, so extrapolation to those with ALF may be inappropriate. More recently, Bilir studied safety and feasibility of HT in 5 cases of advanced ALF who were not candidates for liver transplantation [36]. Each patient received cryopreserved human hepatocytes obtained from human livers procured but rejected for OLT. Immunosuppression with cyclosporin was required to prevent rejection of the allogeneic donor hepatocytes. Two patients died within 48h and three survived 14, 20 and 52days. Those who survived more than 48h showed striking improvement in encephalopathy score, ammonia levels and prothrombin time. Successful engraftment of transplanted hepatocytes was shown in the liver and spleen. Even though all the patients in the study group eventually died, the authors concluded that HT from cryopreserved hepatocytes is feasible in humans and warrants further clinical trials.

At present there are several unanswered questions in relation to HT and research is underway to determine optimum quantity of hepatocytes needed to support liver function, the optimum source of hepatocytes, route of administration and techniques of cryopreservation. Different sources give varying quantities of hepatocyte mass required to provide adequate liver function. Nussler stated that 1–5% of total liver mass (1.8–8.8×109 hepatocytes) can be expected to support liver function [37] whereas others estimate at least 10–20% of normal hepatic mass is needed [14], [38]. Clinical studies of HT in ALF have been criticised for using too few hepatocytes to demonstrate any significant benefit [36], [38].

The ideal route of administration in humans is uncertain. Nussler preferred direct intra-portal hepatocyte infusion in ALF and suggested direct intra-splenic injection when there is evidence of abnormal liver architecture with portal hypertension. Splenic artery infusion was not promoted as it may cause splenic necrosis with vascular occlusion [37]. However others have used splenic artery infusions without any complications [35], [36]; further, the 2 cases of ALF in Bilir’s study who received intraportal infusions, developed hypoxaemia with pulmonary infiltrates suggestive of hepatocyte emboli [36].

There are no protocols established as regards to choice, dosage or duration of immunosuppression [37]. However because the necrotic native liver remains in situ, patients with ALF after HT remain at greater risk of septic complications with immunosuppressive therapy. Indeed, up to 80% patients in study by Bilir had major infective complications [36].

The major limitation of cell based therapy in liver diseases, including HT is the ready availability of functional human hepatocytes [34], [37]. Most of the clinical studies so far have isolated human hepatocytes from donor livers unsuitable for transplant. This raises important question that if the organ itself is not suitable for OLT, how good its cells can be for HT. Is this in part, a reason for suboptimal liver function demonstrated post HT? Baccrani, in an attempt to answer this question, showed that viable functioning hepatocytes can be isolated from marginal livers and proposed that modifications in hepatocyte isolation and conservation protocols along with centralization of hepatocyte banking facility in a nationwide service would improve obtainable results [39].

Finally, exciting developments have taken place in recent years in hepatocyte progenitor cells including foetal liver cell progenitors [40], multi-potent hepatic stem cells [41] and bone marrow derived stem cells [42]. Research is underway to determine whether these can be regarded as genuine functional hepatocytes. The future studies will tell us whether HT has any role in ALF but at present it remains very much in experimental stage.

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5. Innovative/experimental techniques 

Total emergency hepatectomy may improve outcome in a subset of patients with ALF by removing potential source of ‘toxins’ and can act as ‘bridge’ until a liver allograft becomes available [43]. Ringe and colleagues described total hepatectomy with portocaval shunting and delayed liver transplantation upon graft availability as a two stage procedure in 19 patients of ALF. They proposed that this procedure may be beneficial in a subset of patients of ALF who are likely to die with standard medical therapy and immediate non-availability of graft [43].

Animal experiments have shown that portal vein arterialization (PVA) enhances the regenerative capacity of the hepatocytes by increasing the oxygen supply to the liver after hepatectomy or in toxin induced animal models [44]. Nardo and colleagues have also reported symptomatic improvement after PVA in two patients with toxin induced ALF [44]. Schleimer and colleagues reported an improved technique of heterotopic auxiliary liver transplant (HALT) with PVA in the rats and demonstrated good results regarding microcirculation, morphology and function of the graft [45]. In yet another innovation of bio-engineering, Nishio recently reported a new approach to hepatocyte transplantation resulting in generation of an auxiliary liver in vivo [46]. Isolated primary hepatocytes were encapsulated in isolated spleens and then transplanted by attaching the spleens to the livers of recipient animals by bio-degradable adhesive. The transplanted hepatocytes migrated successfully into the liver parenchyma and authors proposed that encapsulation of the hepatocytes significantly improves their survival and hence functional capacity.

However despite the progress in medical, surgical and bio-technical innovations, the quest for ideal liver support technique remains a Holy Grail for the researchers in this area.

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6. Conclusions 

Patients with ALF have a high mortality. OLT remains the only therapy shown to be effective in improving survival. Auxiliary transplantation has a beneficial role in selected patients as immunosuppression can be withdrawn in some. At present, liver support devices, while effective in those with acute on chronic liver failure, appear, at best, to help support the patient until a graft becomes available and, to date, have not shown to provide a bridge to recovery (Table 3).

Table 3. Status of bridging techniques
‘Bridging techniques’Are we there yet?
Auxiliary partial orthotopic liver transplantPerhaps
Heterotopic auxiliary liver transplantNo
Bioartificial support devicesNo
Artificial support devicesNo
Hepatocyte transplantationNo

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PII: S0168-8278(07)00051-7

doi:10.1016/j.jhep.2007.01.010

Journal of Hepatology
Volume 46, Issue 4 , Pages 557-564, April 2007

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