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STATE OF THE ART REVIEW

Extracorporeal Liver Support: Waiting for the Deciding Vote

Adham, Mustapha

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doi: 10.1097/01.MAT.0000093748.55874.BA
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Abstract

In the era of liver transplantation (LT), acute liver cell failure (ALF) remains a serious condition associated with a high mortality and where prospective randomized studies comparing different methods of liver support to standard therapy are scarce. The aim of this review is to present the various methods of extracorporeal liver support systems and to discuss their respective roles in the therapeutic armament of ALF. Other methods of temporary or definitive liver support as liver or hepatocyte transplantation were beyond the scope of this review and therefore not discussed. 1–6

ALF that develops with a previously normal liver within 12 weeks of insult or first sign of jaundice is currently known as fulminant hepatitis (FH). When it develops on chronic liver disease it is known as acute on chronic liver failure (AoCLF).

FH is arising from very heterogeneous etiologies and is associated with a high mortality that ranges from 50–90%. 7–11 It is characterized by an acute metabolic deficit, a hepatic encephalopathy, and coagulopathy resulting from an acute extensive necrosis or dysfunction of liver parenchyma. Here the cause of death is usually herniation secondary to cerebral edema and increased intracranial pressure. Nonetheless, because of the absence of preexisting liver diseases, the mechanism of injury could, in approximately 25% of cases, be reversed with liver regeneration and full recovery. 7,12,13

Chronic liver failure is the most frequent form of liver diseases where the hepatocytes are unable to correctly perform their functions of synthesis and purification. Here, it can be necessary to resort to LT for 60–90% of patients. 14 In these cases, portal hypertension, impaired coagulation, variceal gastrointestinal bleeding, deterioration of mental status, and coma dominate the clinical picture. In case of AoCLF, the causes of death are usually secondary to sepsis and multiorgan failure rather than increased intracranial pressure.

Despite the progress made in the intensive care treatment and the capacity of the liver to regenerate (in case of FH), medical treatment alone is still insufficient to improve the outcome of these patients, 15–17 making LT the only proven therapy that allows a survival rate exceeding 60% and thus remains the treatment of choice. 18–20 Nonetheless, approximately one third of these patients die while waiting in the first line for a graft, whereas recoverable ones might receive needless LT. 17 For these reasons, the recourse to the liver support systems is considered a means of waiting to bring these patients towards LT or regeneration whenever possible. 21,22

Theories and Methods of Liver Support

The initial theory for liver support was based upon the concept that if the liver fails to clear metabolic by-products, extrahepatic organs deteriorate. Thus, if the liver could be temporarily supported, secondary organ failure could be avoided, and the liver might regenerate.

The methods of liver support were classified, historically, in two groups. The first comprises chemical systems, with no cellular components, that aimed at ensuring chemical toxin removal as hemodialysis, hemofiltration, exchange transfusion, plasmapheresis, hemoperfusion, and plasma perfusion. These devices were adapted later to the development of artificial livers with improved purification functions. The second group aimed at a global replacement of liver functions with the use of cross-hemodialysis, cross-circulation, and extracorporeal whole liver perfusion (ECLP). 23

Today, liver support systems are based upon either the albumin bound toxin hypothesis where the cause of liver failure is tightly bound to blood albumin or upon the metabolic support hypothesis that recognizes the need to eliminate protein bound toxins but stresses the importance of a hepatocyte based metabolic support.

For a comprehensive understanding, the present author classified liver support devices in two categories according to the presence or absence of hepatocytes. The term biologic device may refer to the presence of cells or other organic and biochemical components.

Hepatocyte Free Devices

Early liver support systems aimed only at plasma purification through chemical removal of metabolic by-products that accumulate during liver cell failure. These by-products were believed to be responsible for secondary organ failure and to inhibit liver cell regeneration.

Hemodialysis and Hemofiltration

The standard hemodialysis was the first to be suggested for the treatment of hepatic insufficiencies. Kiley et al.24 performed the first tests in 1956, then used the Kolff hemodialyzer for the treatment of hepatic coma with ammonia intoxication in five patients (four, alcoholic liver cirrhosis; one, liver metastasis); all had history of gastrointestinal bleeding. Improvement of metabolic encephalopathy was observed in four patients, but none achieved long-term survival that ranged from 1 day to 1 month. 25 The following reports of liver dialysis confirmed the reduction in the blood ammonia without improving the state of the patients carrying a FH. 26 In 1976, Opolon et al.27 reported the use of a new polyacrylonitrile membrane hemodialysis for the treatment of 24 viral FH patients with grade III or IV coma: recovery of consciousness was fully obtained in 13 and partially in 4 patients; 5 patients had full recovery and were discharged. Patients treated with polyacrylonitril membrane dialysis had a statistically significant improvement of their neurologic state compared with historical controls receiving conventional therapy, but survival rate was identical in both groups. 28–31 The same modality was used by Rakela et al.32 who led three of the five patients treated by hemofiltration to LT, and one survived without LT.

Exchange Transfusion and Plasma Exchange (Plasmapheresis)

Lee and Tink 33 first introduced exchange transfusion in 1958, and it was performed over two episodes of encephalopathy in a 13 year old patient presenting FH of unknown etiology. The multiple uncontrolled trials performed in the 1960s and the beginning of the 1970s suggested the beneficial effects of exchange transfusion in the treatment of hepatic coma. 34–36 This procedure was abandoned after the results of the controlled study published by Redeker and Yamahiro 37 in 1973 that showed the inefficacy of the process to improve survival.

Plasma exchange (plasmapheresis), a more interesting process, consisted in separating the plasma by filtration or centrifugation and its elimination, this one being replaced by fresh frozen plasma. It was introduced to limit the risk related to the use of blood products during the treatment of hepatic coma. 38 It was a nonselective method that allowed the elimination of many toxins present in the serum, in particular, the protein bound toxins, and controlled hemorrhages by the supply of coagulation factors. Initial results showed an improvement of the neurologic state and biologic parameters, as well as a reduction in the bleeding episodes but without survival improvement. 39–41 In spite of apparent efficacy suggesting that plasmapheresis provided temporary liver support, 42 a link appeared between the number of plasma exchanges carried out and the mortality rate 43 with better results in the studies that used plasma exchanges at a lower frequency. 44–46 This technique was reproached for its infectious risk, the elimination of the hepatotrophic growth factors, and the use of a significant quantity of plasma that may inhibit hepatic regeneration, 47 which explained the lack of any significant improvement of survival. 48 In another study, albumin was used instead of plasma during plasmapheresis, suggesting that, in the absence of hemorrhage, the removal of toxic substances was more important than plasma replacement. 40 Others studied the relationship between neurologic status and cerebral blood flow velocity during high volume plasmapheresis in 18 consecutive patients with FH. Results suggested an improvement of neurologic status with an increase in the cerebral oxygen delivery; 11 patients survived, 9 after LT. 49 In a prospective study including 10 patients with FH, cardiac output, systemic vascular resistance, and arterial blood pressure were improved during high volume plasmapheresis. 50 Another study compared 11 patients with chronic liver failure with 16 patients with ALF during high volume plasmapheresis. Results suggested that portosystemic shunting and chronic peripheral vasodilatation contribute to the hyperkinetic syndrome in chronic liver failure patients, whereas in ALF, a humoral factor, which can be removed by plasmapheresis, is a contributing factor. 51

Hemoperfusion and Plasma Perfusion

The hemoperfusion is an old process, which consisted in making blood pass through columns containing the resins or the activated charcoal. 52–56

Hemoperfusion on charcoal column was proposed for the elimination of many water soluble molecules and lipophilic substances associated with metabolic encephalopathy, such as blood ammonia, neurotransmitter metabolites, polypeptides, aromatic amino acids, and bilirubin, but not the protein bound compounds and intracellular molecules. 57–59 Gazzard et al.60 reported a successful treatment of 10 out of 20 FH patients presenting a hepatic coma using charcoal hemoperfusion. Though animal experimentation confirmed the possibility of treating acute ischemic hepatitis by the same process, 61 there was no improvement of results in a controlled study bearing on 137 FH by using the hemoperfusion on charcoal column compared with the standard medical treatment. 62,63 Indeed, the use of the resins in direct contact of total blood was associated with a high complication rate, including leucopenia, hemorrhage caused by thrombopenia, hypotension, and a possible pulmonary embolism. The use of a cytoprotector like prostaglandin-I2 was proposed to prevent thrombopenia and improve the biocompatibility. 64 Other techniques used the principle of the artificial cell to cover resin or charcoal particles by a membrane (e.g., albumin or nitrate of cellulose) to insulate them, avoiding any direct contact with the blood cells. 65,66

Plasma perfusion is another process that consisted in separating the plasma and making it pass on an adsorbent. It avoided the destruction of the platelets and decreased the hemorrhagic complications related to the hemoperfusion. This technique of membrane filtration prevented the direct contact between the blood cells and the adsorbents by using membranes allowing a high plasma flow without hemolysis. Inoue 45 reported the first Japanese study on 26 treated cases with a survival rate of 19.2%. In the study by Kawanishi et al., 55 only one of six patients survived, and no significant improvement of survival was obtained in the study of Tabei et al.67

Combination Treatments

The absence of individual success for each single preceding therapeutic method led to the concept of combination treatment, which is based upon the principle of an association of different systems of liver support. 68,69

In a prospective study, Matsubara et al.70 proposed the combination of plasma exchange and hemofiltration, which allowed survival in 3 of 16 patients and an extension in survival time in patients who died at an average of 15 days.

Artificial Liver Devices

The concept of artificial liver devices was based upon the hypothesis that better blood purification could be sufficient to support ALF patients and to avoid secondary organ failure. This could be achieved by combination therapy, based upon, in one device, the most recent technical advancement of blood purification systems.

Artificial liver support system.

Yoshiba et al.71 treated 27 consecutive patients with FH (six with late onset hepatic failure) using an artificial liver support system consisting of plasma exchange in combination with hemodiafiltration using a high performance membrane (polymethylmetacrylate). Treatment was considered successful for 15 out of 27 treated patient who survived after a mean of 16.1 sessions over a mean of 19.3 days. The effectiveness of this device (55.6% survival) was attributed to its early application. Nonetheless, long term follow-up and survival of those 15 patients was not reported. 71

Hemodiabsorption (Biologic-DT): Hemocleanse Inc.

The hemodiabsorption (Biologic-DT), also known as the Liver Dialysis Unit, is a selective chemical removal process that combines hemodialysis with column of charcoal and resins where blood is actively pumped through membranes of cellulosic plate dialyzer (effective molecular weight cutoff = 5,000) in a single access. The dialysate contains a suspension of activated charcoal and cation exchanger. 72–74 Early trial treatment of 15 patients with acute deterioration of liver function showed statistically significant improvement in neurologic status; 4 patients recovered liver function and another 4 improved enough to receive LT. 75

A randomized controlled study of Biologic-DT sorbent, including 10 patients with FH, showed a significant loss of platelets, a decrease in plasma fibrinogen, and a rise in blood activated clotting time without significant removal of metabolites as ammonia. 76 A later study showed that with better biocompatibility an improvement of side effects was obtained in the treatment of 10 patients with severe acute alcoholic hepatitis. 77 It thus appeared that further development of the system is required for the treatment of such group of patients.

Device development led to the concept of the Biologic-DTPF system that combines the hemodiabsorption Biologic-DT system with push-pull pheresis system (Biologic-PF), in which membranes separate plasma for direct contact between plasma proteins and the sorbents. Treatment of patients with hepatic failure associated to renal and respiratory insufficiency and coma grade III or IV was safe without significant hematologic changes. An improvement of blood pressure and encephalopathy and decreases in bilirubin, aromatic amino acids, ammonium, creatinine, and interleukin-3 (IL-1beta) were observed. 78 Because the reduction of Fischer ratio was incriminated in the pathogenesis of hepatic encephalopathy, small amounts of branched chain amino acids (BCAA) were introduced to the sorbent in the Biologic-DT and PF-Unit to improve the Fischer ratio. Results revealed an improvement of Fischer ratio because of the extraction of aromatic amino acids (AAA) as a result of the strong binding capacity of powered charcoal, as well as an increase in plasma BCAA. 79

One of the largest controlled prospective multicentric trials enrolled 56 patients (31 treated with Liver Dialysis Unit; 25 as control) with acute hepatic encephalopathy grades II to IV. Liver dialysis treatment was done for 6 hours, 1 to 5 days. Control patients received identical measurements and phantom treatment was introduced at a time as if they had been randomized. All patients treated with the Liver Dialysis Unit had an improvement of both neurologic (improvement in the Glascow score and encephalopathy) and physiologic status (increase in mean arterial blood pressure) versus control patients. There were no adverse clinical effects, in particular, no hemodynamic complications. In AoCLF patients, there was a significant increase in the incidence of recovery of hepatic function or improvement for transplantation compared with controls (71.5% treated vs. 35.7% control, p = 0.036). In FH patients, none reached statistical significance as compared with control. 80

Liver Dialysis Unit was used in the treatment of 10 patients with acetaminophen induced hepatitis. Treatment was initiated 12 to 168 hours after acetaminophen ingestion, and the mean number of treatments was 1.6 per patient. Blood level of acetaminophen decreased by an average of 73% at each treatment with an outflow concentration of 50–60% lower than inflow. All patients had stabilization or improvement of liver enzyme by 72 hours after first treatment, and all were discharged after a mean of 5.5 ± 1 days. It does not clearly appear whether patient recovery in this study happened despite or because of the treatment. Indeed, the same results could be obtained with conventional treatment, and this study indicates that acetaminophen posing could be safely treated with the Liver Dialysis Unit. 81

Adsorbent molecular recycling system (MARS).

This system was conceived according to the albumin bound toxin hypothesis. 82 This system was composed of a compartment of hollow fiber membrane, which constitutes the interface of dialysis between the blood of the patient and albumin. This compartment was successively followed by columns of anion exchange, activated charcoal, and hemodialysis. 83 It permitted to eliminate protein bound toxins as well as water soluble ones. The first clinical tests were performed for 13 patients presenting AoCLF with 69% survival rate (nine patients). At 6 months, two patients were electively registered for LT. 84 A recent report confirmed, in a randomized study, its superiority to conventional therapy for treatment of hepatorenal syndrome, whereas the 7 day mortality rate was 100% in the hemodiafiltration control group, and the 7 and 30 day mortality rates in the MARS treated patients were 62.5% and 75%, respectively (Table 1). 85 Retrospective analysis showed that this therapeutic option allows removal of toxins involved in multiorgan dysfunction secondary to liver failure, as well as neurologic and physical improvement in AoCLF patients. 86,87 An analysis of 176 of the MARS registry patients (56% AoCLF, 22% ALF, 15% PNF, 4% post liver surgery, and 3% miscellaneous) confirmed the efficacy and safety of this therapeutic modality. 88

Table 1
Table 1:
Improvement of Hepatorenal Syndrome with MARS Versus HDF Control Group

Hepatocyte Based Devices

The hepatocytes based devices (HBD) were conceived according to the global metabolic support hypothesis where liver support is provided by hepatocytes. They comprise cross-hemodialysis and cross-circulation, extracorporeal whole liver perfusion (ECLP), and bioartificial liver devices (BLD).

Cross-Hemodialysis and Cross-Circulation

Cross-hemodialysis was first reported by Kimoto 89 in 1959. This procedure consisted in a hemodialysis system with two circuits, one for the patients’ blood and the other for a canine blood, both being separated by cellophane tubing. This report demonstrated the implication of dialyzable substances in metabolic encephalopathy and defended the idea that xenogenic liver can support hepatic function in human.

Cross-circulation was first proposed by Burnell et al.90 in 1969, followed by others’ using either human or baboon cross-circulation. 91–93

These liver support methods were abandoned because of unacceptable risks to the second party in case of allogenic cross circulation (e.g., risk of liver failure and viral hepatitis) and also to the high patient risks with the use of xenogenic cross-circulation.

Extracorporeal Whole Liver Perfusion

Otto et al.94 first described experimental ECLP in 1958. One of its first clinical uses was reported by Eisman et al.95 on the treatment of eight patients presenting an aggravation of a chronic hepatic insufficiency (one, viral hepatitis; seven, alcoholic cirrhosis). The time of perfusion was 1 to 6.5 hours, ending in the reduction in the metabolic functions of the perfused livers. Despite neurologic improvements in all patients (five patients had rapid improvement of their encephalopathy), there were no long term survivals. 95 Hickman et al.96 treated four patients presenting a FH by exchange transfusion and porcine ECLP. Two patients obtained a temporary improvement of encephalopathy, but all died secondarily. 96 In these two series, the main complications related to the ECLP were hemorrhages secondary to thrombopenia because of platelets destruction inside the oxygenator and the development of a disseminated intravascular coagulopathy. Abouna et al.97,98 outlined the use of multispecies ECLP in the treatment of hepatic encephalopathy. Ten patients received 33 ECLP using allogenic and xenogenic livers for the treatment of 21 episodes of encephalopathy. Thirteen episodes of encephalopathy were completely reversed (62%), and four were improved (19%). The complications were an anaphylactic shock after repeated perfusion, hyperacute rejection of the hepatic graft, and a gas embolism starting from the venous tank. 99 This study showed that liver perfusion could be maintained for a longer time with the use of allogenic (35–51 hours) than with xenogenic concordant baboon (13–24 hours) than with xenogenic discordant porcine (6–12 hours) livers. Moreover, whereas recovery of encephalopathy was obtained with the use of one to four successive porcine liver perfusions, only one baboon liver could maintain consciousness for the same period of time. Following review of ECLP showed promising results that allowed 42.9% of survival in the event of serious hepatitis. 100 Since then, the ECLP has aimed at providing the total biochemical functions of the failing liver (functions of oxidation, reduction, conjugation, and detoxification).

In the 1990s, experimental studies allowed a better comprehension and definition of optimal methods for ECLP. 101–103 A renewed interest for the ECLP (Table 2) led Fox et al.104 to use allogenic ECLP in the management of three patients with fulminant hepatic failure. Two patients were successfully bridged to LT; the third patient failed to improve neurologically and died 7 days later. This report demonstrated the improvement of serum bilirubin and arterial ammonia levels, a neurologic improvement was observed in 2 cases, and metabolic function of the perfused liver was demonstrated. 104 It is interesting to note that the use of allogenic livers allowed perfusion for 20, 40, and 72 hours for each single liver, which was longer than the previously reported xenogenic liver perfusion.

Table 2
Table 2:
Renewed Interest in Extracorporeal Whole Liver Perfusion in the 1990s

In the series of Chari et al., 105 a xenogenic liver perfusion was attempted in four cases of ALF. Only one patient was successfully bridged to LT after ECLP during 10 days and successive perfusions by five porcine livers. This report reproached its technical insufficiency by using the short cut perfusion only through the portal vein and the transfusion of blood or blood derivative that increased immunologic cross-reaction. Tector et al.106 successfully bridged a FH patient with hepatic coma stage V to LT after xenogenic ECLP. More recently, Levy et al.107 reported the first two cases of ECLP using transgenic porcine liver to overcome a potential immunologic barrier (hCD55/hCD59); both were successfully bridged to LT.

These models of ECLP perfusions allowed a better comprehension of the physiologic and immunologic characteristics during liver xenoperfusion among patients in hepatic insufficiency. 108,109 Because FH patients have a very low complement level, clinical and experimental data tend to show that xenogenic liver perfusion is associated with minimal or no hyperacute rejection, providing that patients do not receive blood or blood derivative immediately before or during xenoperfusion. 110,111 The clinical application of porcine ECLP was also subjected to the same physiologic, immunologic, and virologic restrictions of the xenograft.

Bioartificial Liver Devices

BLD are currently defined as artificial liver support systems housing hepatocytes of animal or human origin. Recent progress in tissue harvesting and preservation, 112 in cell culture with preservation of cellular viability, 113,114 had allowed the development of the BLD. Ideally, BLD should perform the essential biochemical liver functions that ensure patient survival. The objective of such a device was to correct secondary metabolic imbalance associated with liver cell failure while facilitating hepatic regeneration. These are biologically active devices that house a mass of hepatocyte perfused by plasma or blood. They usually involve a hollow fiber cartridge, similar to a hemodialysis device, containing numerous hollow fibers of semipermeable material. The device has two compartments, an intramembrane space (IMS) where blood or plasma is pumped and an extramembrane space (EMS), that house the hepatocytes. The hepatocytes were insulated inside the EMS by a semipermeable membrane, the essential role of which was to prevent the direct contact between the lymphocytes of the patient and the hepatocytes to reduce the immunologic cross-reaction. These membranes were also impermeable to certain proteins, in particular the antibodies. They allow the passage of the blood substances of average molecular weight towards the hepatocytes and the diffusion of vital substances produced by the hepatocytes toward the blood of the patient. The same principle was used to develop the artificial cells, 115 which could contain microsomes, enzymes, or even a group of hepatocytes encapsulated in a similar membrane. 116 Several devices of BLD were proposed. 117 Two approaches have been mainly adopted using either an immortalized hepatocyte cell line or primary hepatocytes (Table 3).

Table 3
Table 3:
The Bioartificial Liver Devices

The Hepatix-Baylor/Vitagen Extracorporeal Liver Assist Device (ELAD) is the first BLD that incorporates immortalized human liver cells (human hepatoblastoma cells, C3A). C3A cells can be reproducibly manufactured; they express normal liver specific metabolic pathways as ureogenesis, gluconeogenesis, P450 activity, and secrete clotting factors. C3A cells are sown inside the EMS of a hemodialysis cartridge, with an average cellular mass of 200 g. 118 Preliminary studies showed the safety of the device and its capacity for supplying at least 20% of total liver function, whereas clotting inside the device remained the major limitation to long term use. 119,120 A pilot controlled study comparing ELAD versus hemoperfusion (Table 4) showed that the encephalopathy grade related deterioration was more frequent in the control than in the ELAD treated patients (58%vs. 25%). Improvements of encephalopathy and survival rate were comparable in both groups (78% ELAD vs. 75% control) because of patient selection in an early stage of the disease. 121 The advantage of this device rested on the hepatocyte mass that is superior to other device based upon primary hepatocytes, the life span of hepatoblastoma cells, and the absence of xenogenic cells. Despite the presence of a plasma filtering system to avoid the dissemination of hepatoblastoma cells into the patients’ circulation, the risk of accidental dissemination of hepatoblastoma cells remains a real potential danger limiting the diffusion of the system. 122 To overcome this potential hazard, other works are currently directed towards the development of other nontumoral human hepatocytes lines capable of replication and with preserved synthetic functions. 123–125

Table 4
Table 4:
Results of Pilot Controlled Study Comparing ELAD versus Conventional (Control) Therapy

The Circe’s bioartificial liver of the W.R. Grace & Co and Cedars-Sinai Medical Center—HepatAssist—used primary pig hepatocytes isolated from fresh liver and maintained in culture. Bioartificial liver (BAL) consists of four parts: a hollow fiber bioreactor containing primary porcine hepatocytes, two charcoal filters, a membrane oxygenator, and a pump. There is a primary separation of plasma from blood by centrifugation in a technique similar to plasmapheresis. Plasma is recirculated into a loop of activated cellulose coated charcoal column then hollow fiber module (bioreactor), where 5 billion viable hepatocytes attached to collagen coated dextran microcarriers are inoculated into the EMS. After return from the BAL, plasma and blood cells are reconstituted and returned to the patient. 126 As primary hepatocytes do not divide in vitro, the need for a steady supply of fresh cells was resolved by Rozga et al.127 with the development of techniques of cell isolation, attachment to microcarriers beads that are stored frozen. In early clinical trials, seven FH patients were successfully bridged to LT. 128 In the phase I study evaluating BAL (Table 5), 16 of 18 FH patients were bridged to LT, 1 had remission without LT, and 1 died. 129 Three patients treated for primary graft nonfunction were successfully bridged to LT, two of ten patients treated for an AoCLF were supported to recovery and were successfully transplanted later on, and the other eight patients were supported temporarily but died later because they were not candidate for LT. 129 Recently, the same team reported the results of eight patients treated for acetaminophen induced FH: three were transplanted, and five survived without transplantation. 130

Table 5
Table 5:
Results of the Phase I Study of BAL Treated Patients

The Monsanto Co and St Louis University School of Medicine’s Surgical Research Institute (Monsanto/St. Louis) bioreactor uses aggregates of cultured hepatocytes entrapped in packed bed of glass beads perfused with nutrients and oxygenated. 131 In this system, cells may remain viable for 15 days. Patient plasma is separated and perfused through the device. 132

The Regenerex Inc and the University of Minnesota (Regenerex/Minnesota) uses 6–7 billion porcine hepatocytes suspended in a collagen solution. The viability of hepatocytes, the main advantage of this device, is maintained by continuous perfusion of nutrients. Patients’ blood is heparinized and perfused within the EMS of the hollow fibers. 133

Discussion

Early results of liver support systems using chemical models showed improvement of the neurologic state and some biologic parameters but showed their inefficacy in improving survival of ALF patients. However, some isolated successes were reported, especially in combination with LT. These studies mainly showed that the dialysis of substances of molecular weight of less than 15,000 improves metabolic encephalopathy but does not affect survival of FH patients, suggesting the need for additional liver functions. Some of these chemical devices are still being used in association as hemodialysis or continuous arteriovenous (or venovenous) hemofiltration for the management of severe metabolic acidosis, hyperkalemia, or fluid overload. Plasmapheresis can also be proposed in the perioperative management of FH patients waiting for a graft or as preparation for LT. 134 Nonetheless, their use in presence of hypotension, coagulopathy, or cerebral edema may be difficult.

Today, the only radical treatment of ALF is orthotopic liver transplantation. Currently, the liver support is directed towards the use of an extracorporeal system as artificial liver, BLD, or ECLP. The choice between these liver support systems is not yet clearly established (Table 6). Indeed, FH and AoCLF are two divergent situations that might require different approaches of liver support. For FH patients, the liver support would ideally lower intracranial pressure and provide temporary purification functions enhancing native liver regeneration 135 or allowing a longer waiting time when liver graft is not rapidly available. For AoCLF patients, because neither hepatic regeneration nor super urgency LT are possible, the liver support would ideally provide synthetic liver functions playing the role of a link that bring these patients to an elective LT.

Table 6
Table 6:
Comparison Between Liver Support Modalities Using ECLP, BLD, MARS, and Biologic-DT

Each liver support system has its own advantages, but their use has raised several areas of concern that are specific to each device. Artificial livers are more rapidly available; they do not comprise a cellular element of tumoral or xenogenic origin that could expose the patient to the carcinologic, immunologic, and virologic risks, as well as those of zoonoses. Nonetheless, it lacks any cellular component and does not provide synthetic hepatocytes function.

The argument in favor of hepatocyte based devices (BLD and ECLP) is the principle of global biologic support. Because BLD systems lack liver architecture and accessory cells, they seems to offer only partial biologic support, which can place them half way between artificial livers and ECLP systems. 136

Another concern in BLD is the estimated hepatocyte mass required to ensure a proper liver support. We know that the average ratio of liver weight relative to body weight is 2% in adult, and recent studies from living related liver transplantation indicated that the estimated donor graft weight to recipient body weight ratio should be more than 0.7%, or a ratio between expected graft weight to recipient liver weight higher than 30% is required to ensure sufficient liver function. 137–139 Accordingly, an efficient liver support device should bring the effective liver mass above this critical threshold. 140,141 In BLD, the hepatocyte mass seems to be defined according to the capacity of the bioreactor and not to the functional requirement. Indeed, hepatocyte mass in BLD is far less than that supposed essential for liver support. In consequence, for an optimal support, we need to define the minimal hepatocyte mass (in correlation with the body weight or, ideally, the degree of hepatic insufficiency), the essential biologic functions that are required for liver support and to control if these functions are achieved by BLD. 142,143 Indeed, normal hepatocyte functions required for the treatment of FH have to be more clearly demonstrated in BLD. The quality of the purification of these BLD will come from the progress made in the fields of hepatocyte culture and the development of the interfaces used. 144–149 Today, there is no artificial or bioartificial device that is able to reproduce all the biochemical synthetic functions of the liver. For these reasons, among HBD, ECLP appears to be the only available method that may offer a global liver support that parallels LT by allowing functions of purifications and synthesis.

In the setting of xenoperfusion (xenogenic ECLP or xenogenic hepatocytes in a BLD), the risk of a possible interspecies immunologic cross-reaction appeared to be the first obstacle. Indeed, the experimental studies showed that the cross-section of the hollow fiber membrane allows the passage of substances of molecular weight up to 100,000, including IgM and complement, which can then initiate a xenogenic immunologic response. 150,151 However, hyperacute rejection is not a major obstacle for biologic support of ALF patients because of their very low complement level and the availability of transgenic pigs. 107,110,111 Beside the currently known zoonosis, another main obstacle is the risk of transmitting a porcine virus or other unknown pathogens from the pig to humans. To control these risks, a specific germ free breeding needs to be developed, and the possibility of viral material transmission needs to be evaluated, in particular the porcine retrovirus. 152–154 The follow-up of patients with previous exposure to xenogenic material did not highlight the risk of porcine viral transmission; these reassuring preliminary results must be confirmed. 107,155,156 To overcome these immunologic and viral risks, most groups choose a cutoff membrane molecular weight of 100 to 150 kd, allowing free transport of large molecules as albumin but not complement, immunoglubulin, viruses, or cells. 136

The physiologic and the possible enzymatic incompatibility as well as the incapacity of the porcine hepatocytes to synthesize human proteins constitutes another limitation for their use. 157,158 The development of transgenic pigs is an interesting approach, and the objectives should not only aim at overcoming the immunologic problems, 108 but should ideally aim at providing livers (or hepatocytes) that can synthesize human proteins. We also need to confirm that the functional capacity of the xenogenic hepatocytes meets the physiologic requirements of human patients. In a recent review of world experience of ECLP in ALF, porcine livers did not appear to be an alternative to standard intensive care therapy. 159 Another alternative is the use of human cadaveric livers, which are not suitable for transplantation, for ECLP. This option is hardly acceptable because it requires a sufficiently bad hepatic graft not to be transplanted, even in situation of super urgency, but to be rather good to perfuse. Indeed, in a situation of super urgency, borderline hepatic grafts can be used, whereas the perfusion of a liver of too low quality could be more toxic for the patient, as in the event of a primary graft nonfunction.

Indications for Liver Support

Recent randomized studies showed an advantage in liver support treatment for FH and AoCLF patients. 160 Indeed, the use of the Liver Dialysis Unit in a multicenter prospective randomized trial, and recent trials with the newly added PF module, had shown their ability to improve clinical outcomes and demonstrated their efficacy particularly in the AoCLF. 160,161 In the same time, MARS treatment of patients with hepatic failure allowed neurologic and physical improvement, as well as the outcome of patient with AoCLF, and allowed an increased survival of patients with hepatorenal syndrome. 78,87 These studies lack power because of the small number of treated patients. The difficulty in the construction and conduction of these randomized multicentric prospective controlled studies, including a large number of patients, remains in the very heterogenous etiologies and nature of these patients, besides the situation of super urgency that lead to LT before treatment success can be affirmed. 162

Indications for liver support should be based upon well established prognostic criteria that can predict not only poor outcome 163 but also can recognize recoverable patients who might regenerate the liver. Indeed, a recent study showed that the fulfillment of King’s College Hospital prognostic criteria usually predicts poor outcome, but a lack of fulfillment does not predict survival. 164 Because there is still a lack of objective criteria for the identification of recoverable patients, and in the absence of real therapeutic outcome, the installation of liver support would be a major leap. If one insists upon defining the criteria that are required to introduce a liver support, none of the reported studies had dealt with the crucial question of defining the criteria for stopping liver support whenever started.

The objectives of liver support can be summarized as follows:

  1. Bridge FH and primary graft nonfunction patients to LT by allowing a longer waiting time. These are two situations that involve a major vital risk. The recourse to LT in super urgency makes it possible to shorten the waiting time. Ideally, the liver support should be used while waiting for hepatic regeneration or as a bridge to LT.
  2. Avoid LT and long term immunosuppression when liver regeneration is achieved for patients with FH. Here, when liver regeneration is achieved, the liver graft will find a better use.
  3. Improve patients’ condition at time of LT. In critical cases and before LT, liver support can be done to improve patients’ outcome and survival rate with earlier hospital discharge and less graft dysfunction, especially when borderline liver graft is used.
  4. Stabilize patients with AoCLF to allow later elective LT. In these cases, one cannot expect a recovery through hepatic regeneration. The only definitive therapeutic outcome is elective LT after patients’ clinical improvement or stabilization. For those patients who are stabilized after liver support, the access to liver graft can be accelerated.
  5. Support patients with cirrhosis undergoing hepatic or nonhepatic surgery, as well as extended hepatectomy for patients without cirrhosis. In these cases, liver support should be electively prepared and started as early as possible, before the onset of cholestasis, infectious complications, and multiorgan failure.
  6. In the future, as for dialysis in patients with chronic renal failure, intermittent long term liver support could be a therapy for end stage liver disease.

Conclusion

Recent randomized studies indicated that liver support systems could now be accepted as an associated therapy for ALF. Because these studies included small numbers of patients, it is necessary to conduct controlled randomized prospective studies, including large numbers of patients, to confirm their superiority compared with standard treatment. There is also a lack of data comparing hepatocyte based and hepatocyte free devices. The choice between both systems could be made according to the etiology for ALF and patients’ status. If hepatocyte based support is required, the choice between whole liver for wider biologic support and BLD for elective biochemical support could be discussed.

To define the potential indications for liver support, the following is necessary:

  1. Clearly define the object of treatment with a reasonable chance for therapeutic outcome and an apparent cost effectiveness.
  2. Recognize patients with acceptable therapeutic outcome and who can benefit from liver support.
  3. Define the clinical criteria for recoverable and nonrecoverable patients that would allow the introduction of liver support as a link for liver regeneration in the first case or as a bridge to LT in the second.
  4. Define treatment success according to therapeutic objectives: LT or regeneration.
  5. Establish the treatment failure criteria to know when to stop liver support.

In clinical practice, liver support can be used in FH patients as a bridge to hepatic regeneration in recoverable ones or to LT for the others, whereas in AoCLF it is used as a link to a later elective LT. As it is now admitted that removal of toxic by-products could reduce secondary organ failure, an extension of indications could be made to support patients with cirrhosis after hepatic and nonhepatic surgery and in cases of extended hepatectomy in patients without cirrhosis.

To date, in all likelihood, only another normal liver graft could adequately substitute for the one that had failed: we are still waiting for the deciding vote.

Acknowledgment

The author acknowledges Mme Isabelle Dujet, Professeur Associée en Anglais au SCEL de Lyon I, Diplômée de l’ETI de Genève.

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