Artículo de Revisión

Fredy Ariza Cadena*, Luis Felipe Carmona Serna**, Iván Fernando Quintero C.***, Luis Armando Caicedo*, Carlos A. Vidal Perdomo*, Luis Fernando González*.

* Departamento de Trasplante de Órganos Sólidos, Fundación Valle del Lili, Cali, Colombia. Correspondencia: Carrera 98 No. 18-49 Cali, Colombia. Correo electrónico: fredyariza@hotmail.com

** Anestesiólogo, Hospital de la Misericordia. Bogotá, Colombia. Correo electrónico: pipecarmonaserna@gmail.com

*** Residente de Anestesiología. Universidad del Valle. Cali, Colombia.

Recibido: noviembre 16 de 2010. Enviado para modificaciones: noviembre 22 de 2010. Aceptado: mayo 18 de 2011.

Background. Extracorporeal liver support systems (ELS) have emerged as an alternative to liver transplant (LT), given the growing incidence of acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and the limited organ supply.

Objective. Review of literature about Extracorporeal Liver Support Systems.

Methodology. A literature search was conducted on the main medical databases including MEDLINE, SciELO and EMBASE for papers published between July 1990 and November 2010 looking at technologies associated with liver support systems, their technical specifications, their use, and evidence regarding their effectiveness in patients with some forms of liver failure requiring support.

Results. These systems may be divided into artificial (hemofiltration, MARS) and bioartificial (such as the Hepatassist™). They work by replacing detoxification processes associated specifically with bilirubins, aromatic aminoacids, and inflammatory agents, and the elimination of breakdown products of coagulation. Recent advances in bioengineering and biogenetics have brought these technologies closer to the ideal, enabling their use in humans with a relative degree of success. ELS systems, most of them still under development, are designed not only to act as a bridge for LT but may also become the cornerstone of treatment in specific cases while the ALF resolves.

Acute liver failure (ALF), fulminant hepatic failure (FHF) and acute-on-chronic liver failure (ACLF) are a growing reason for admission to pediatric and adult intensive care units. Although their incidence is low (1-6 cases/million/yr), the risk of multiple organ dysfunction, severe illness and death is high, as are also high the healthcare costs associated with these diseases. (1). The incidence of FHF is probably higher in those areas where infectious hepatitis is common, although toxicity induced by medications such as acetaminophen and, in our setting, the accidental intake of white phosphorus or attempted suicide with this substance, are also significant causes (2,3,4).

Considering the shortage of donors and the frequent ineffectiveness of conventional medical management for supporting life while these patients wait for liver transplant (LT) (5,6), new life support technologies are being developed to help these patients and act as bridges to transplantation or, in some cases, as definitive therapy while the LF resolves (7,9). These systems, called “extracorporeal liver support systems” (ELS), are designed mainly to effectively remove toxic metabolites such as bilirubins and other biologically-active catabolic by-products that would otherwise cause serious effects on organic and hemodynamic function in patients with LF (9-13).

PHYISIOLOGY OF LIVER FAILURE: BASICS

ALF occurs as a result of a direct injury to the liver, sufficiently severe as to produce massive hepatocyte dysfunction and hemorrhagic diathesis. Certain systemic conditions such as sepsis and cardiogenic shock may cause hepatocyte failure and multiple organ failure as part of their clinical manifestations (3). For all practical purposes, ALF may be classified according to onset as fulminant (< 2 weeks after the onset of jaundice), and subfulminant (2 weeks to 3 months after the onset of jaundice). FHF is the most lethal form of ALF, with almost 100 % mortality when associated with acute renal failure, one of the two most important complications together with the onset of severe cerebral edema (1,4,15). The most frequent chemical abnormalities in these patients include increased serum concentration of bilirubins, bile salts, ammonium, lactate, free fatty acids, aromatic aminoacids, gamma-aminobutiric acid (false neurotransmmitter) and mercaptanes. Of these, ammonium appears to play a key role in the pathogenesis of hepatic encephalopathy and cerebral edema, while bilirubins have shown to be toxic for polymorphonuclear neutrophils because they inhibit their cytotoxic response to bacteria (14).

The principles on which conventional medical therapy for ALF is based consist of three fundamental pillars (7,8,10,16): metabolic support, coagulation support and detoxification.

a. M M etabolic support: nutrients and electrolytes may be provided in the form of parenteral and enteral nutrition.

b. Coagulation support: this form of support is provided basically through transfusion therapy, despite the inherent risk of reactions.

c. Detoxification: it may be possible to achieve partial detoxification using lactulose and modified renal replacement therapies such as hemofiltration.

When conventional medical therapy is insufficient, strategies based on biomedical engineering are required in order to replace functions associated specifically with detoxification processes. These relate, in particular, to the bilirubin system, the removal of aromatic aminoacids and the elimination of breakdown products of the coagulation system. ELS systems may be artificial (without biological elements) and bioartificial (containing human or animal cell lines, usually cultured hepatocytes). (8,17). Unlike the former, whose sole function is to detoxify the patient, bioartifical ELS performs certain synthesis functions (plasma proteins and coagulation factors).

A literature search was conducted on the main medical databases including MEDLINE, SciELO and EMBASE for papers published between July 1990 and November 2010 looking at technologies associated with liver support systems, their technical specifications, their use, and evidence regarding their effectiveness in patients with some forms of liver failure requiring support. The MeSH terms (Medical Subject Headings) used for the search included “Hepatic Insufficiency/therapy”, “Life Support Systems/instrumentation”, “Liver Failure”, “Sorption Detoxification”, “Liver, Artificial” and “bioartificial liver”, alone or in combination. The search was also expanded to potential ongoing research that might be included in registries such as clinicaltrials.gov and abstracts reported at international gastroenterology, hepatology or liver transplant meetings.

The review of the literature was done on the basis of levels of evidence by order of importance, starting with clinical trials, followed by prospective and retrospective cohorts and, finally, case series. Case reports or publications whose scope did not cover the topic under review were discarded.

ARTIFICAL EXTRACORPOREAL LIVER SUPPORT SYSTEMS (AELS)

Hemofiltration systems

These systems are based on the natural physical convection principle (diffusion facilitated by centripetal forces that carry anions through a semipermeable membrane). The main difference with hemodialysis is that no dialysatetype substance used to mediate molecular exchange is present at the extracorporeal interface. (12,16). (The term ‘dialysate’ is defined as a chemical substance that enables metabolite and toxin exchange and clearance).

The use of this replacement therapy focuses on the elimination of fluids and toxic substances while maintaining the patient’s hemodynamic stability. It requires a hemofiltration machine, vascular lines with two-way hemodialysis catheters, and staff trained in the management of these systems (Figure 1). It has been shown to be useful in the management of renal failure associated with ALF and encephalopathy; however, published results are not conclusive regarding its true therapeutic effectiveness (8,18).

Molecular Adsorbents Recirculating System (MARS)

The MARS is the next step in the evolution of hemofiltration systems. This system incorporates two additional interfaces aside from the hemofilter: an albumin interface to adsorb certain aminoacids and other toxic substances, and an activated charcoal interface for the adsorption of ionic elements. (The term ‘adsorption’ refers to a substance’s ability to attract and trap other materials or particles on its surface.) (11,19,20).

It has been shown to be effective at reducing serum levels of aromatic aminoacids, bilirubins, triptophane, nitric oxide, interleukins 3 and 6, and tumor necrosis factor, resulting in a significant impact on the progression to hepatic encephalopathy in ALF and the reduction of its severity. Moreover, it has been shown to facilitate hepatic “recovery” while the triggering insult is resolved (21-25).

The situations where the MARS system has produced the best results include toxic FHF, FHF secondary to sepsis or circulatory failure, and also in ACLF (26-29).

The MARS system’s ability to remove toxic substances and help improve electrochemical balance is determined by the combination of its interfaces, including the following (Figure 2):

a. Albumin hemodialyzer: It acts as a dialysate through a hollow chamber and permits the removal of toxic substances bound to proteins in the form of water-soluble toxic substances. Later, this albumin is dialyzed and filtered again, returning to the system free of toxins.

b. P P rototype hemodialyzer: The MARS flow hemodialyzer has a surface area of 2.1 m2, the membrane is 100 nm thick, and the molecular weight is 50kDa. This circuit is connected to a dialysis column with dialysate and an activated charcoal column. It is considered that the hemodialysis is of low flow and that the diffusion gradient is maintained because of the constant albumin recirculation.

c. Active activated charcoal interface: It contributes to organic anion detoxification.

d. Anion exchange resin interface: It helps establish electroneutrality and electrochemical balance.

Results obtained with MARS in the different series include improved hemodynamic profile with increased systemic vascular resistance, as well as a lower need for vasopressors and reduced renal vascular resistance, probably due to cytokine clearance (30-32). Likewise, there is evidence of lower serum bilirubin leves (in particular conjugated bilirubins), azoates and creatinine, reduced intracranial pressure and portal hypertension, and improvement of encephalopathy, renal perfusion and pruritus (24,30,31,33-36).

Despite the apparent benefits of this extracorporeal therapy, very few studies have been conducted using an adequate methodology to assess its actual benefit. Cases have been described of patients with hepatic insufficiency treated with MARS with no liver transplant, avoiding high mortality rates (78-100 %). For this reason, it is indicated to serve as a bridge before transplant, since it allows to optimize and maintain the patient’s clinical condition at the same time. Moreover, it is indicated for management after graft dysfunction (7,19,26,33,37,38).

There are reports describing a worsening of coagulopathy and bleeding with the use of MARS, and for this reason anticoagulation must be minimized during the process of dialysis (39-41). Although it has been proposed that the only contraindication to the use of this system is the presence of disseminated intravascular coagulation, many patients with ALF show increased fibrinolysis and it is frequent to find mild states of disseminated intravascular coagulation (3,40). Faybik et al. (42), showed that, despite an association with low platelet counts and fibrinogen levels, the kynetics of the clot, studied by means of thromboelastography, did not change significantly in patients treated with MARS; additionally, the system was not found to worsen fibrinolysis and it was well tolerated even by patients with severe coagulopathy.

Finally, as far as cost-effectiveness is concerned, despite the high cost of MARS and all other liver support therapies (6,000 euros in average), these systems are promising for the management of ACLF (43,44). Advocates of these systems have suggested that, in some cases, the acute liver dysfunction may resolve, avoiding the need for liver transplant and the costs associated with follow-up. (27,28,33,45,46).

DIALYSIS USING FRACTIONATED PLASMA SEPARATION AND ADSORPT ION (FPSA):

The Prometheus system, developed by Fresenius Medical, is an evolution of a high-flow dialysis system connected to a module that performs fractionated plasma separation and adsorption (FPSA). The areas of application of this system do not only include the management of ALF or ACLF as a bridge before transplantation or until the failure resolves, but also support in cases of broad resections of tumors or other liver lesions, or event as combined support in patients with hepatorenal syndrome (7,8,11,47,48).

The FPSA system consists of an albumin-permeable membrane that allows passage of albumin-bound toxins. Unlike what happens with MARS, these toxins are adsorbed in 2 columns (neutral resin and ion exchanger) and then the albumin returns to the patient toxin-free (11,48,49) (Figure 3).

The FPSA system is more efficient at clearing toxins (urea nitrogen, creatinine, ammonium and bilirubins) than MARS, although the same is not true for bile salts and cytokines (50). Several studies have reported low effectiveness for cytokine clearance, and this explains why it is associated with little improvement of the hemodynamic profile when compared with MARS (30,50,51).

The progression of hepatic encephalopathy, as relates to the use of FPSA, has not been assessed extensively, and the studies available lack adequate methodological design. At present, there are only case reports pointing to a slight improvement of hepatic encephalopathy after FPSA therapy (47).

BIOARTIFICIAL LIVER SUPPORT SYSTEMS (BAL)

These systems were designed to support vital hepatic functions and became a bridge therapy that does not only adsorb toxic solutes but also plays a role in metabolism and synthesis. Its main difference with AELS is the use of live hepatocytes in the interfaces (8). Apart from the elements that may be integrated into a conventional bioartificial system, hepatocyte columns are included in an interface called bioreactor (Figure 4). Plasma enters the bioreactors where it undergoes a process of ultrafiltration, metabolic exchange, oxygenation and allogenic plasma addition before entering the patient again (10).

Depending on the origin of the hepatocytes, three different cell lines may be placed inside the bioreactors: a. human hepatoblastomaderived C3A lines; b. lines derived from organs that are not candidates for transplantation; and c. porcine lines (HepatAssist 2000™).

Hepatoblastoma-derived cell lines, although they retain acceptable functionality, there are doubts regarding overgrowth control, not to mention the fear of potential transfusion of malignant cells to the patients.

Bioreactors consisting of cell lines derived from livers that are not candidates for transplantation have shown to be safer than those that use hepatoblastoma or animal tissue-derived cell lines. However, the issue of in vitro multiplication and the short survival of these cell cultures inside bioreactors have resulted in lower efficiencies than expected (16).

Porcine tissue-derived cells (HepatAssist 2000™; Circe Biomedical, Lexington, Massachusetts 02173, USA) have been studied for their carcinogenic potential with no findings of increased incidence. Functional activity inside the bioreactor has also been studied, with good performance results (11). The experience with these types of cell lines has been satisfactory in terms of safety and adverse events, but there is fear regarding the potential retroviral infection transmission, which is something that has not been well documented (52). This system consists of an activated charcoal line, an oxygenator, the hepatocyte interface and a perfusion pump, all included in a conventional plasmapheresis system.

AELS AND EVIDENCE

There are few systematic reviews published so far looking at the effectiveness of BAELS and AELS. Kjaergard et al. (53) conducted a review to evaluate 12 studies (with 483 patients) that compared BAELS and EALS with conventional treatment, as well as two additional studies comparing artificial with bioartificial systems (in 105 patients). The conclusion was that only AELS resulted in lower mortality in cases of ACLF while, in overall terms, there were no differences in mortality when its effectiveness in ALF was assessed. Regarding its effective use as a bridge to liver transplant (LT) and cases of encephalopathy, the authors did not specify the number of patients analyzed and they just determined the relative risk, making it difficult to interpret the outcomes.

Liu et al. (16) again confirmed Kjaergard ‘s finding one year later when they published, with the Cochrane collaboration, a systematic review with a strikingly similar design, with the same number of patients. Compared with conventional medical therapy, ELS was not associated with a significant effect on mortality, and no big differences were found in the use of these systems as bridge therapy to liver transplant. However, there was a significant reduction in the severity of the encephalopathy. Again, the biggest effect on reduced mortality was found in the group with ACLF, but it was not significant in the ALF group.

PRESENT AND FUTURE

The main barriers to the implementation of these technologies and those that may come in the future are financial, but they are also associated with the scant experience available among hepatobiliary support and intensive care practitioners. However, these technologies will probably become more accessible in the near future, allowing practitioners to gain more experience, and resulting in a larger number of publications on the subject. There is no doubt that the growing incidence of ALF, FHF and ACLF, together with the shortage of organs for donation, will drive the development of this type of support therapies.

In conclusion ELS systems are a developing technology that holds great promise for patients with ALF and ACLF of different etiologies, for use as a bridge while patients are on the waiting list for liver transplant or, in the best of situations, as part of the overall treatment while the LF resolves. Additional studies are required for determining the cost/benefit ratio of these systems. Also needed are additional developments in bioengineering and genetic engineering. Recent advances in the knowledge and manipulation of stem cells have opened the door to a new line for development of these systems, concerning the current problems with immunohistocompatibility and undesirable genetic and/or cellular transmission.

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