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Current Clinical Status of the Extracorporeal Liver Support Devices
The liver is a vital organ with more than 500 functions, including protein synthesis, detoxification, regulation, metabolic functions, and biliary production.
Liver failure, whether occurring without preexisting liver disease (acute liver failure [ALF]) or as an acute decompensation of a chronic liver disease (acute-on-chronic liver failure [ACLF]), is characterized by a sudden deterioration of the liver function leading to accumulation of toxins and reduction of protein synthesis. The clinical manifestations of liver failure include encephalopathy, jaundice, coagulation dysfunction, hemodynamic instability, increased susceptibility to infections, hepatorenal syndrome, and eventually multiorgan failure. Despite improvements in recent years in the clinical management of liver failure, morbidity and mortality remain very high.
A remarkable characteristic of the liver is its capacity to regenerate. In liver failure, if the regenerative capacity is lost during the liver injury and the liver is not able to regenerate, the only lifesaving therapeutic option for these patients is orthotopic liver transplantation (OLT). However, due to the shortage of human donors, currently in the United States 16,562 patients are waiting for an OLT (based on Organ Procurement and Transplant Network data as of October 4, 2013, http://optn.transplant.hrsa.gov ). Because of the donor shortage, the limited time to obtain a suitable organ, and the fact that many ACLF patients are not eligible for OLT, approximately 1 million people worldwide die every year from liver failure, and the incidence is increasing, making liver failure the tenth most common cause of death worldwide.
Extracorporeal liver support devices (ELSD), a therapeutic option for patients with liver failure, have been the focus of both basic and clinical research for the last 3 decades. The concept is attractive because patients with liver failure may be supported either until a donor is available for OLT or the patient’s liver sufficiently regenerates to restore liver function.
ELSD include all measures of extracorporeal liver treatments aimed at supporting the functions of the liver, preventing progression of secondary organ failure, and prolonging the patient’s survival.
The aim of this chapter is to review the ELSD and to analyze the results of the current ELSD clinical studies in patients with liver failure.
Rationale for the Use of Extracorporeal Liver Support Devices in Liver Failure
The goals of the ELSD are to remove the toxins from the blood to prevent organ failure, to stimulate the regeneration of the damaged liver, and to provide temporary liver function until either functional recovery occurs or an organ is available for transplantation.
Elimination of Toxins
Liver cell damage in liver failure depends on the type, duration, and severity of the toxic agent. The deterioration of liver functions, including detoxification and metabolic and regulatory functions, leads to accumulation of various toxic substances such as bilirubin, bile acids, ammonia, protein breakdown products (aromatic amino acids, phenol, mercaptans), lactate, glutamine, mediators of oxidative stress, free fatty acids, endogenous benzodiazepines, and proinflammatory cytokines. These toxins are known to play a key role in the pathogenesis of liver failure. The accumulation of toxins and proinflammatory mediators might further enhance liver damage, preventing hepatic regeneration, leading to hepatocellular apoptosis and necrosis and eventually to multiorgan failure. The fact that the multiorgan dysfunctions can be reversed following OLT has led to the hypothesis that the hepatic dysfunction is central to the pathogenesis of multiorgan failure.
The rationale for using the ELSD is the assumption that decreasing the load of these toxins might reverse or improve the degree of liver dysfunction and improve the liver capacity to regenerate.
Improved Portal and Systemic Hemodynamics
Liver failure, irrespective of its cause, is frequently associated with hemodynamic instability, characterized by a reduced systemic vascular resistance and mean arterial pressure, causing multiorgan dysfunction.
ELSDs are able to remove vasoactive substances and improve systemic hemodynamic instability, improving mean arterial pressure and portal pressure.
Improved Liver Regeneration
Liver failure has a high mortality, but the capacity of the liver to regenerate can allow spontaneous recovery during ALF and ACLF. Therefore, if this period of liver failure can be bridged, and the liver function improves, including the regenerative capacity, the final outcome of these patients can improve.
When the regeneration capacity of the liver is lost by the severity of liver injury, the objective of the ELSD is to support the native liver until a suitable organ is available for transplantation.
Types of Extracorporeal Liver Support Devices
ELSD have increasingly been the focus of both basic and clinical research, but this has been a daunting challenge because of the many complex functions that the liver performs. The concept is attractive because patients with ALF may be supported until native liver regeneration occurs or, by optimizing their condition, until transplantation.
The ELSD can be classified into the following ( Table 107-1 ):
- 1.
Artificial liver support (ALS), also known as nonbiological or cell-free techniques. ALS is based on the principles of adsorption and filtration to remove the toxins and consists of blood purification or detoxification systems using membranes and adsorbents.
- 2.
Biological extracorporeal liver perfusion (BLP) incorporates whole extracorporeal animal or human livers.
- 3.
Bioartificial liver support (BALS) are hybrid techniques that additionally use liver cells to support the failing synthetic and regulative liver functions.
-
An effective ELSD should include three primary functions: detoxification, biosynthesis, and regulation.
TABLE 107-1
Types of Extracorporeal Liver Support Devices
| 1. Artificial Liver Support (ALS) |
|
| 2. Biological Extracorporeal Liver Perfusion (BLP) |
| 3. Bioartificial Liver Support (BALS) |
|
ALS , Artificial liver support; BALS , bioartificial liver support; HBAL , hybrid bioartificial liver; MARS , molecular adsorbent recirculating system; SPAD , single-pass albumin dialysis; UCLA , University of California, Los Angeles.
Artificial Liver Support
The aim of the ALS is to eliminate the toxins accumulated during liver failure. ALS is based on existing dialysis-derived techniques, removing both albumin-bound and water-soluble substances. However, the efficiency of ALS as ELSD is limited by their inability to provide missing liver synthetic functions.
The detoxifying efficiency of the various liver dialysis systems depends on the combination of several factors: material, pore size and placement of filters, amount and active surface of adsorbers, as well as albumin concentration and flow rates in the plasma circuits.
Types of Artificial Liver Support (See Table 107-1 )
Artificial Liver Support Based on Conventional Extracorporeal Procedures
Hemodialysis and Hemofiltration
Conventional dialysis techniques, such as hemodialysis and hemofiltration, are effective in removal of small, water-soluble toxins such as ammonia and urea, but they cannot eliminate large or protein-bound molecules. Hemodialysis is effective in removing water-soluble small molecules that are less than5000 MW, and hemofiltration in removing larger molecules (5000 to 10000 MW). However, the efficacy is low because most toxic substances, such as bilirubin, endotoxin, and cytokines, are protein bound or have a high molecular weight. They can be used in patients with hepatorenal syndrome, but there is no evidence to suggest any improvement in survival in liver failure patients.
A preliminary report in patients with ALF showed total recovery of consciousness in 6 of 10 patients and partial recovery of consciousness in 2 patients. In another report by the same author, the use of high-permeability membrane hemodialysis and hemofiltration in 39 patients led to total recovery of consciousness in 43.6% of the patients; 9 patients survived. Other authors have described partial improvement with dialysis procedures, but in all the cases no improved survival was observed.
Plasmapheresis and High-Volume Plasmapheresis/Plasma Exchange With or Without Hemodiafiltration
Plasmapheresis removes a smaller amount of plasma, usually less than 15% of the patient’s blood volume, and therefore does not require replacement of the removed plasma.
High-volume plasmapheresis/plasma exchange is a procedure in which a large volume of plasma is removed from a patient. The volume removed is such that if it were not replaced, significant hypovolemia resulting in vasomotor collapse would occur. As a result, the removed plasma must be replaced with some form of replacement fluid, including albumin and fresh frozen plasma. It can successfully remove both protein-bound and large molecules such as inflammatory mediators; however, it is nonselective and other relevant molecules, such as clotting factors, are removed at the same time.
Clinical Applications
Plasmapheresis studies have demonstrated improvement in liver and cerebral blood flow, and in hepatic encephalopathy, but did not improve survival.
In patients with ALF, high-volume plasmapheresis improved cardiac output, systemic vascular resistance, and arterial blood pressure ; increased cerebral perfusion pressure ; decreased arterial ammonia level ; and improved coagulopathy and liver functions.
A large randomized controlled trial (RCT) ( ClinicalTrials.gov ), including 92 ALF patients treated with high-volume plasma exchange compared with 90 patients treated with standard medical treatment (SMT) was presented in an abstract form. The study showed significantly higher survival to hospital discharge in the high-volume plasma exchange group (58.7% versus 47.8%). No beneficial survival effect was found in patients who received an OLT, and the incidence of severe adverse events was similar in the two groups. The authors concluded that treatment with high-volume plasma exchange increases survival in patients with ALF by increasing liver transplant–free survival.
Liu et al recently reported two patients with drug-induced ALF who were successfully treated with high-volume plasma exchange without OLT.
Hemodiafiltration studies, convection (large molecule), and diffusion (small molecule) removal across a membrane have shown improved biochemical parameters and neurological status.
Hemoperfusion and Plasma Perfusion
The removal of toxins is obtained by circulating blood or plasma through absorbent systems, using resin or activated charcoal changing ions. This method removes water-soluble and lipophilic substances associated with hepatic encephalopathy, but no protein-bound substances. It is partially beneficial in hepatic coma but includes a high risk for leucopenia, thrombocytopenia, hypotension, and pulmonary embolism. Plasma perfusion decreased the hemoperfusion risks.
Clinical Applications
Considerable experience has been obtained with activated charcoal as an adsorbent of possible toxins. In an early study in which charcoal hemoperfusion was performed in ALF patients, cerebral edema improved. In a later RCT of charcoal hemoperfusion in 137 ALF patients there was no significant difference in overall survival rate between patients treated by charcoal hemoperfusion (10 hours daily) and control patients.
Hemodiabsorbtion and the Liver Dialysis Unit (Formerly BioLogic-DT)
Hemodiabsorbtion is a method that combines hemodialysis with absorption. The patient’s blood actively passes through a flat dialyzer with cellulose membrane (efficient for molecules up to 5000 MW), and the dialysate, continuously renewed, contains activated charcoal suspension and cation changing resin. The two advantages of this method are a large exchange surface and no direct contact between blood and absorbent substances.
To improve the results, a technical modification was introduced that included a plasma filtration with an absorbent wrapping of membranes (“push-pull pheresis system”). The BioLogic-DT device, also known as Liver Dialysis Unit 2 (HemoCleanse Inc, West Lafayette, IN) is based on hemodiabsorbtion with powdered-activated charcoal. The Food and Drug Administration (FDA) approved the Liver Dialysis Unit for the treatment of hepatic encephalopathy in 1997. However, the Liver Dialysis System is not currently marketed because it is being redesigned. HemoCleanse is working on a replacement based on carbon block technology and methods for creating filtration beds from powdered sorbents. They currently envision the technology as a dialysate or plasma regenerating column fitting into dialysis or continuous venovenous hemodialysis (CVVHD) machines used in the hospital ( http://www.hemocleanse.com ).
Clinical Applications
Ash et al reported 15 patients with ALF, with an average coma level of 3.9. The patients were treated for 8 to 12 hours daily with the BioLogic-DT system. A statistically significant improvement in neurological status during individual treatments was observed. Four patients recovered liver function, and another four improved enough to receive a liver transplant operation. The BioLogic-DT system was safe to treat ALF patients.
A RCT was conducted in 10 ALF patients with grade IV encephalopathy to evaluate the safety and biocompatibility of the Biologic-DT. A total of 18 treatments were performed in 5 patients. Hemodynamic stability was maintained throughout. Decreased platelets and plasma fibrinogen was observed in the study group; however, no significant decrease of ammonia level was observed in this sick group of patients after treatment with the Biologic-DT.
A prospective RCT in 56 ALF patients (31 treated with the Liver Dialysis Unit) showed a physiological and neurological improvement, regardless of cause. In ACLF 71.5% of cases had hepatic functional recovery, compared to 35.7% in the control group. However, there was an insignificant improvement in ALF patients. The device proved its utility in acetaminophen intoxication cases.
The nonspecific target of ALS based on conventional extracorporeal procedures is thought to be one of the reasons for its limited success. Currently these conventional ALS are used in conjunction with other ALS and BALS.
Artificial Liver Support Using Albumin Dialysis
Although conventional extracorporeal procedures are highly effective in removal of small, water-soluble toxins such as ammonia and urea, they cannot eliminate large or albumin-bound molecules relevant in liver failure.
Liver toxins bound to albumin include steroid acids (e.g., bile acids), open and closed tetrapyrroles (e.g., bilirubin or protoporphyrin), amino acids (mainly aromatic amino acids), glycoside derivatives (e.g., indoxylsulfate), phenols (e.g., para-cresol), lipids (short- and medium-chain fatty acids such as octanoate), and heterocyclic organic compounds (such as furancarboxylic acid).
However, in liver failure and cirrhosis the albumin-binding capacity is decreased due to a disproportion between available albumin molecules caused by decreased hepatic synthesis and an increase in hydrophobic toxins; therefore the ability of albumin to function as a detoxification agent is severely compromised.
The rationale for albumin dialysis is to use albumin as a carrier to remove protein-bound toxins. Albumin dialysis is based on the fact that liver toxins bound to albumin can be dialyzed through a regular dialysis membrane if the dialysate contains clean albumin as a molecular acceptor. Additionally, albumin dialysis removes smaller water-soluble proteins such as cytokines, ammonia, creatinine, and urea by conventional dialysis.
Several albumin-dialysis systems have been developed and applied in clinical studies.
Single-Pass Albumin Dialysis
The single-pass albumin dialysis (SPAD) system (Fresenius Medical Care AG, Bad Homburg, Germany), designed to remove protein-bound toxins, is the simplest form of albumin dialysis using the basic principles of hemodialysis or hemodiafiltration. The patient’s blood flows through a standard high-flux albumin-impermeable dialyzer and is dialyzed against an albumin-containing dialysate (2%-5% albumin concentration), which is discarded after a single pass. It allows the removal of albumin-bound molecules that are small enough to pass through the membrane pores as well as water-soluble toxins. This technique is similar to continuous venovenous hemofiltration; the difference is the dialysate composition and the time of treatment. In general, SPAD is easy to establish because it can be accomplished with standard dialysis equipment and is therefore widely applicable.
Clinical Applications
There are only case reports of its clinical use. It has been reported that it efficiently cleared bilirubin and copper in a case of fulminant Wilson’s disease, successfully bridged to OLT, and was effective in reducing bilirubin in patients with liver failure.
In a case-control study of SPAD in 13 acetaminophen-induced ALF patients (6 SPAD-treated, 7 controls), Karvellas et al reported that although the SPAD was well tolerated, it was not associated with differences in clinical outcomes.
Molecular Adsorbent Recirculating System
The molecular adsorbent recirculating system (MARS; Gambro AB, Lund, Sweden), developed by Stange and Mitzner in 1993, combines albumin dialysis with conventional dialysis to remove both water-soluble and protein-bound toxins.
The MARS system ( Fig. 107-1 , A and B ) consists of three compartments: a blood circuit, an albumin circuit, and an open-loop single-pass dialysate circuit. The MARS requires standard hemodialysis or hemofiltration equipment to control the blood and dialysate circuits. A pump removes blood from the patient’s venous access site to the MARS cartridge at a rate of 150 to 250 mL/min. In the primary circuit, patient’s blood flows through the MARSflux filter, an albumin-impermeable membrane with a pore size of less than 60 kDa, retaining albumin on the blood side. In a secondary circuit, which is separated from the patient’s blood by the MARSflux filter, a 20% albumin solution (200 g/L, concentration five to seven times that in the plasma) is circulated in a counterdirectional flow and acts as the dialysate and acceptor of the toxins that cross the membrane. The passage of albumin-bound toxins from the patient’s blood is facilitated by active competition from the MARS membrane–bound albumin. Albumin bound to the polymers of the MARS membrane has a greater affinity for the plasma albumin-bound toxins. The principle is that toxins bound to albumin in the patient’s blood will detach and bind to the albumin impregnated on the MARS membrane, because albumin, when attached to polymers, has a higher affinity for albumin-bound toxins. Because the MARSflux membrane is impermeable to albumin, only the free fraction of toxins can cross the membrane, which is the limiting factor for elimination of compounds with strong albumin binding such as unconjugated bilirubin. The albumin in the dialysate carrying the toxins, is then cleansed by perfusion over activated charcoal (diaMARS AC250), and anion-exchange resin (diaMARS IE250). These take up most of the albumin-bound substances. The dialysate is thus regenerated and once more circulated in the MARSflux filter to take up more toxins from the blood. This recirculation component of the MARS system, using a fixed volume (600 mL) of albumin, is considerably more cost-effective than a SPAD. Water-soluble toxins are removed by passage through a hemodialysis/hemofiltration module, which is run in conjunction with the albumin dialysis module. One MARS session lasts 6 to 8 hours, and after that time the albumin-regeneration capacity of the adsorbers decreases significantly.
Clinical Applications
MARS is the most widely developed and applied ALS system. Over 200,000 treatments have been performed in more than 5000 patients. The main indications have been ACLF, ALF, removal of specific exogenous toxins, and drug-refractory pruritus ( Table 107-2 ).
TABLE 107-2
Common Indications for Molecular Adsorbent Recirculating System Treatment
| Acute liver failure |
| Acute-on-chronic liver failure |
|
|
|
|
| Intractable pruritus in cholestasis |
| Drug overdose/intoxication with substances bound to albumin |
| Other indications for liver failure |
|
|
|
HRS , Hepatorenal syndrome; PNF , primary graft nonfunction.
Acute-on-Chronic Liver Failure
MARS has been evaluated predominantly in ACLF. The first clinical treatment with MARS was reported by Stange et al in 1999 in 13 patients with ACLF. The overall survival was 69% and a decrease in bilirubin, bile acid levels, and hepatic encephalopathy was observed.
Although most of the studies published are noncontrol or case reports, few RCT have been performed. A RCT performed in Germany included 24 patients with ACLF and severe cholestasis (bilirubin level >20 mg/dL). MARS treatment was associated with a significant improvement of 30-day survival compared with the SMT group; however, the 3-month mortality was identical in both groups. The effectiveness was also shown on hepatic encephalopathy, bilirubin, biliary acids, arterial pressure, and creatinine level.
A meta-analysis of four RCTs and two nonrandomized studies did not show a survival benefit of MARS in ACLF. A beneficial effect of MARS was shown in the nonrandomized studies. A more recent meta-analysis included nine RCTs and three nonrandomized comparative studies. MARS resulted in a significant decrease in total bilirubin levels ( P < .001) and in an improvement in the West-Haven grade of hepatic encephalopathy ( P < .001). There was no beneficial effect on mortality ( P = .62).
A prospective multicenter RCT including 70 patients with advanced cirrhosis and grade III-IV hepatic encephalopathy compared MARS with SMT. The primary end point was the difference in improvement proportion of hepatic encephalopathy between the two groups. The study showed that the improvement proportion of hepatic encephalopathy was higher in MARS than in the SMT group ( P = .044) and was reached faster and more frequently than in the SMT group ( P = .045). However, this 5-day study was not designed to examine the impact of MARS on survival.
Recently a large European multicenter RCT evaluated the results of MARS in ACLF compared with SMT (RELIEF trial). A total of 189 patients were randomized to be treated with either MARS and SMT or SMT alone. Up to 10 MARS sessions were scheduled (6-8 hours each session). Although MARS-treated patients showed a significant improvement in serum creatinine levels, bilirubin levels, and hepatic encephalopathy, no difference in 28-day mortality was demonstrated (40.8% versus 40%). Severe adverse events were similar in the groups.
Acute Liver Failure
Although most studies using MARS have been performed in patients with ACLF, MARS has also been evaluated in ALF in several studies with heterogeneous results.
Clinical studies in the last decade have demonstrated reduction in bilirubin levels, improvement in encephalopathy and cerebral edema, and improved systemic hemodynamics and renal function.
A recent multicenter RCT in 16 French OLT centers (FULMAR) compared MARS plus SMT versus SMT alone in ALF patients fulfilling criteria for OLT. Fifty-three patients received MARS treatment, whereas 49 had SMT. A non–statistically significant trend for improved 6-month survival (84.9% versus 75.5%) was observed in the MARS group, mainly in acetaminophen-induced ALF (85% versus 68.4%). However, a major confounder was that the median listing-to-transplant time in this study was only 16.2 hours, and 75% of patients enrolled were transplanted within 24 hours. In patients with acetaminophen-related ALF, the 6-month survival rate was 68.4% with SMT and 85.0% with MARS ( P = .46) in the modified intention-to-treat population. Among patients with acetaminophen-induced ALF, 41.0% had OLT versus 79.4% among patients with non–acetaminophen induced ALF ( P < .001). ALF not caused by acetaminophen was associated with greater 6-month patient survival. Adverse events did not significantly differ between groups.
Common Indications for MARS
Clinical studies in the last decade have demonstrated that MARS has been indicated in different settings, as summarized in Table 107-2 .
Hepatic Encephalopathy and Cerebral Edema
Multiple studies have shown improvement in hepatic encephalopathy and decreased intracranial pressure during treatment with MARS.
Kidney Dysfunction/Hepatorenal Syndrome
Improvement of kidney function during MARS treatments, including decreased creatinine and urea levels, increased urine output, and resolution of hepatorenal syndrome, has been reported by several authors.
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