Liver Support Systems: Will They Ever Reach Prime Time?
Rafael Bañares, María-Vega Catalina & Javier Vaquero
Current Gastroenterology Reports ISSN 1522-8037 Volume 15 Number 3 Curr Gastroenterol Rep (2013) 15:1-7 DOI 10.1007/s11894-013-0312-x
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Author's personal copy Curr Gastroenterol Rep (2013) 15:312 DOI 10.1007/s11894-013-0312-x
LIVER (B BACON, SECTION EDITOR)
Liver Support Systems: Will They Ever Reach Prime Time? Rafael Bañares & María-Vega Catalina & Javier Vaquero
# Springer Science+Business Media New York 2013
Abstract Liver support systems aim to provide temporary support of liver function while maintaining extra-hepatic function in patients with liver failure. Important advances have been achieved in the design of artificial and bio-artificial devices, but the current systems are far from meeting the ideal. Artificial devices provide detoxification through different dialysis procedures, whereas bio-artificial devices add synthetic functions by incorporating a cellular component into the system. Overall, liver support systems have consistently shown beneficial effects on the pathophysiology of liver failure, especially in acute-on-chronic liver failure. However, these beneficial effects have not been translated into an improvement of survival. Our review discusses the current evidence, paying special attention to the clinical aspects of (bio)-artificial liver support devices. Keywords Liver support systems . Artificial liver support . Acute liver failure . Acute-on-chronic liver failure . Randomized clinical trial . Albumin dialysis . Molecular adsorbent recirculating system . Bioartificial liver
This article is part of the Topical Collection on Liver R. Bañares (*) Liver Unit, Facultad de Medicina, Universidad Complutense de Madrid, Hospital General Universitario Gregorio Marañón, IISGM, CIBEREHD, Madrid, Spain e-mail:
[email protected] M.-V. Catalina Liver Unit, Hospital General Universitario Gregorio Marañón, IISGM, CIBEREHD, Madrid, Spain J. Vaquero Hospital General Universitario Gregorio Marañón, IISGM, CIBEREHD, Madrid, Spain
Why do we need Liver Support Systems? Liver failure is a condition frequently observed in clinical practice that includes two types of syndromes: acute liver failure (ALF), which implies normal liver function and histology 2 −8 weeks before the onset of the disease, and acute-on-chronic liver failure (ACLF), when there is an abrupt impairment of liver function in patients with an already damaged liver. Both situations are characterized by the potential for recovering previous liver function. Importantly, patients suffering of liver failure have not only deterioration of liver function but also severe functional impairment of extra-hepatic organs, mainly the brain, the kidney and the circulatory system. Although its prevention and clinical management have improved in recent years, liver failure is still an important cause of morbidity in Europe and the United States [1]. Liver transplantation is the only therapeutic measure that has clearly proven to have a survival benefit in patients with severe liver failure and, therefore, current therapeutic approaches are aimed at stabilizing the patient until a liver graft is available or, rarely, until spontaneous recovery of liver function occurs. Unfortunately, an important proportion of patients die while waiting for a graft due to the shortage of donor organs. Moreover, worsening of the condition of the patients due to progression of the disease and/or the presence of contraindications (i.e. alcohol consumption, advanced age, drug-abuse, etc.) may preclude liver transplantation. Together, these observations emphasize the need for liver supportive strategies aimed at facilitating the complete regeneration of liver mass, while maintaining hepatic and extra-hepatic function. A secondary aim would be to provide a bridge to liver transplantation if a complete liver regeneration or the recovery of previous function is not possible. Liver support devices should also provide support to extra-hepatic organs and, importantly, have an adequate safety profile. The aim of this review is to summarize the current state of liver support systems in patients with ALF and ACLF, paying special attention to emerging clinical aspects
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Pathophysiological Approach to Artificial Liver Support and Types of Liver Support Systems Liver cell damage in liver failure depends on the type, duration, and severity of the action of the noxious agent [2]. Cell damage induces accumulation of various toxic substances, such as ammonia, mediators of oxidative stress, bile acids, nitric oxide, lactate, products of arachidonic acid metabolism, benzodiazepines, indoles, or mercaptans, resulting in a “toxic” state that induces increased susceptibility to infections, circulatory disturbances and end-organ dysfunction. In addition, secondary liver damage occurs as a consequence of the vicious circle that results from the release of inflammatory mediators, oxidative stress and sinusoidal endothelial cell damage, finally leading to hepatocellular apoptosis and necrosis. There are several theoretical pathophysiological approaches to restore liver function in liver failure. The first one would be to increase liver regeneration; another possibility would be to increase the metabolic mass by performing auxiliary liver transplantation or hepatocyte transplantation [3, 4]. These procedures, however, are difficult to perform, require complex logistics and they have still not shown clinical efficacy. Another promising and probably more feasible approach to liver support is the use of extracorporeal systems. These devices are basically divided into biological, non-biological (also called artificial or cell-free techniques), and bio-artificial (hybrid techniques) devices [5]. Most liver support systems incorporate several different “therapeutic units” ranging from conventional hemodialysis or hemofiltration modules to specifically designed adsorption systems. In the case of biological systems, the devices include extracorporeal bioreactors loaded with liver cells [6•]. In the case of extracorporeal nonbiological devices, a variety of designs with different mechanisms of actions (see summary in Table 1) have been
evaluated. Non-biological devices have been more extensively evaluated in clinical studies, especially albumin dialysis. There are two main systems of albumin dialysis: the molecular adsorbent recirculating system (MARS) and the fractionated plasma separation and absorption (Prometheus). In contrast with the single-pass albumin techniques in which the albumin-rich dialysate is discharged after passing through the dialyzer, the MARS system regenerates the albumin in a separate circuit by using low-flux dialysis and different adsorbents to “clean” the albumin dialysate that is then used again for the detoxification process. In the Prometheus system, a special albumin permeable filter is used. Thus, albumin and the protein-bound toxins pass through the membrane and are then directly removed by special adsorbents within a secondary circuit. The native albumin is subsequently returned to the patient, and the process is completed with hemodialysis to eliminate water-soluble toxins.
Clinical Efficacy of Liver Support Systems A number of studies have evaluated the use of artificial liver support (ALS) devices in patients with ALF and ACLF, despite the inherent difficulties of studies in this type of patients (see Table 2). Bioartificial Devices in Acute Liver Failure Several studies have assessed bio-artificial devices in ALF, but the majority of them included a relatively small number of patients. The ELAD device (that incorporates cells from hepatoma lines) has been tested in two small studies [7, 8]. In the first study [8], 24 patients were included after stratification by the absence (group I: n=17 patients; expected mortality 50 %)
Table 1 Mechanisms of action of cell-free liver support systems Type of device
Mode of action
Hemofiltration [29] Hemofiltration [30] High volume plasmapheresis [31] Hemodiafiltration [32, 33]
Exchange diffusion across a semipermeable membrane Continuous convective solute removal across a semipermeable membrane Exchange of high plasma volume Convection (large molecules) and diffusion (small molecules) removal across a semipermeable membrane Perfusion of blood/plasma over charcoal, synthetic neutral resins or anion exchange resins Dialysis against a combination of charcoal and ion exchanger Removal of protein-bound and water-soluble substances across a specialized membrane against albumin-enriched dialysate Hemodiafiltration using albumin dialysate Combination of plasma exchange, hemoperfusion, hemofiltration and hemodialysis Combination of hemodiabsorption with push−pull sorbent-based apheresis
Hemoperfusion [34] Hemodiabsorption [35] Molecular adsorbent recirculating system (MARS) [19, 21, 36] FPSA (Prometheus) [37, 38] Artificial liver support system [39] PF-Liver Dialysis [40] FPSA Fractionated plasma separation and adsorption
ALF with potential recoverable lesion or fulfilment of criteria for liver transplantation
ELAD (median period of 72 h) vs. SMT
HepatAssist (6 h daily)+SMT vs. SMT
MARS+SMT vs. Prometheus+SMT or SMT alone (3 days) Prometheus+SMT vs. SMT Up to 8−11 sessions
MARS+SMT (53) vs. SMT (49) 8 hours session One single 6-h session with Prometheus, MARS or hemodialysis
MARS+SMT vs. SMT Up to 10 sessions (6−8 h)
MARS+SMT Vs. Prometheus+SMT or SMT alone (3 days) MARS+SMT vs. SMT Up to 10 sessions
MARS vs. SMT
MARS+SMT vs. SMT
MARS+SMT vs. SMT
Liver dialysis vs. SMT
Design of the trial
No hemodynamic effects No adverse events Decrease in platelet count Reduction in bilirubin levels (larger in Prometheus) Hemodynamic improvement (larger in MARS patients) No changes in overall survival Survival benefit in post-hoc analysis in type I HRS and MELD score >30 Non-significant improvement in 30-day survival (71 vs. 62 %) Post-hoc multivariate analysis excluding primary nonfunction. Adjusted HR: 0.58; p=0.048 Good biocompatibility Survival similar to SMT DIC or hypersensitivity reaction
Improvement of HE No hemodynamic changes No changes in plasma cytokines and ammonia levels Improved survival Further appropriately sized studies are needed Reduction in bilirubin levels (larger in Prometheus) Hemodynamic improvement (larger in MARS patients) Improved 30-day survival Decrease in bilirubin Improvement in renal failure and HE No changes in survival Improvement in HE Improvement in HRS No differences in overall adverse events Six-month survival rate (84.9 vs 75.5 %; NS)
Improved neurological status and hemodynamic profile Increased bleeding in patients with DIC More frequent and earlier improvement of HE
Clinical results
[8]
[9]
[25••]
[43]
[44]
[17]
[24••]
[21]
[43]
[42]
[41]
[22]
[35]
References
Curr Gastroenterol Rep (2013) 15:312
AAH Acute alcoholic hepatitis, ACLF acute-on-chronic liver failure, ALF acute liver failure, DIC disseminated intravascular coagulation, ELAD extracorporeal liver assist device, FHF fulminant hepatic failure, HE hepatic encephalopathy, HRS hepatorenal syndrome, MARS molecular adsorbent recirculating system, SFHF subfulminant hepatic failure, SMT standard medical therapy
24
ELAD
Fulminant or subfulminant hepatic failure and primary non-function after liver transplantation
ACLF
145
171
ACLF in severe AAH
18
ALF
102
Decompensated cirrhosis
ACLF Bilirubin >20 mg/dl and/or HE greater than grade II and/or HRS
189
24
Decompensated cirrhosis Bilirubin >20 mg/dl not responsive to SMT
24
HepatAssist
Prometheus
Hypoxic liver failure after cardiogenic shock (bilirubin levels >8 mg/dl) ACLF in severe AAH
27
18
HE grade 3 or 4
ACLF in severe AAH (9 MARS, 9 control)
MARS
ACLF and ALF
70
56
Liver dialysis
Study population
18
n
ALS Device
Table 2 Summary of randomized controlled clinical trials of artificial liver support systems in ALF and ACLF
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or presence (group II: n=7 patients; expected mortality 90 %) of liver transplantation criteria. Arterial ammonia decreased marginally in the ELAD group, whereas the rise in serum bilirubin was more pronounced in the controls. In addition, worsening of encephalopathy was less frequent in ELAD-treated patients. These positive effects were not translated into an improved survival (78 vs. 75 % in group I and 33 vs. 25 % in group II). In a more recent randomized controlled phase I trial in patients with fulminant hepatic failure, patients were stratified into those listed for liver transplantation (n=19) and those who were not listed (n=5) [7]. Patients treated with ELAD had an increased probability of undergoing liver transplantation (92 vs 43 %; p
