Extracorporeal Liver Assist Device Research Articles

314: EXTRACORPOREAL LIVER ASSIST DEVICE FOR ACUTE LIVER INJURY DUE TO LIKELY PARTIAL UREA CYCLE DISORDER

Introduction: Extracorporeal liver assist device (ELAD) is used to bridge patients in acute liver failure to transplant or in severe acute liver injury until spontaneous recovery. ELAD employs an albumin circuit to dialyze albumin-bound toxins from the blood stream. Urea is an albumin bound molecule formed in the liver as a result of nitrogen breakdown. Urea Cycle Disorders (UCDs) are a rare group of genetic enzymatic deficiencies that typically manifest early in life but partial enzymatic deficiencies can present later in life in times of metabolic stress. Description: A 38-year-old female presented with progressive encephalopathy 2 months after being diagnosed with alcoholic hepatitis at which time she had stopped drinking alcohol. She had no prior liver disease. Initial labs showed an elevated ammonia level of 87 mcmol/L, despite decrease in total bilirubin from 33 mg/dL to 3.5mg/dL, and INR of 1.9 to 1.4 since the peak of her alcoholic hepatitis. She had no imaging evidence of cirrhosis and had normal aminotransferases, platelets, and renal function. Initial head CT, infectious evaluation, and work-up for alternate etiologies of acute liver injury were unremarkable. She was intubated for progressive hepatic encephalopathy on hospital day 9. Her ammonia level significantly rose to 203 mcmol/L and a repeat head CT showed diffuse cerebral edema. Due to a rising ammonia level to 247 mcmol/L and CT evidence of progressive cerebral edema despite mannitol, therapeutic hyperventilation, and sedation. She was started on MARS (TM) therapy on hospital day 11. After one 7-hour session, her ammonia level decreased to 101 mcmol/L, mental status improved and head CT showed improved cerebral edema. A urinary orotic acid level was elevated at 1.8 mmol per mol of creatinine. Discussion: A partial UCD was suspected due to atypical time course of encephalopathy and hyperammonemia in the context of improving liver synthetic function and absence of cirrhosis. Genetic testing is pending however, a partial UCD is likely given the elevated urinary orotic acid. A single case report exists of confirmed acquired glutamine synthetase deficiency after orthotopic liver transplant that also improved after a single MARS session. Our report adds to the scarce literature on this topic.

Efficacy and safety of liver support devices in acute and hyperacute liver failure: a systematic review and network meta-analysis

Acute liver failure (ALF) is a potentially life-threatening condition. Liver support therapies can be applied as a bridging-to-transplantation or bridging-to-recovery; however, results of clinical trials are controversial. Our aim was to compare liver support systems in acute and hyperacute liver failure with network meta-analysis. After systematic search, randomized controlled trials (RCT) comparing liver support therapies in adults with acute or hyperacute liver failure were included. In-hospital mortality was the primary outcome, the secondary outcomes were hepatic encephalopathy and mortality-by-aetiology. A Bayesian-method was used to perform network meta-analysis and calculate surface under the cumulative ranking curve (SUCRA) values to rank interventions. Eleven RCTs were included. BioLogic-DT and molecular adsorbent recirculating system (MARS) resulted in the lowest mortality (SUCRAs: 76% and 73%, respectively). In non-paracetamol-poisoned patients, BioLogic-DT, charcoal hemoperfusion and MARS may be equally efficient regarding mortality (SUCRAs: 53%, 52% and 52%, respectively). Considering hepatic encephalopathy, extracorporeal liver assist device (ELAD) may be the most effective option (SUCRA: 78%). However, in pairwise meta-analysis, there were no statistically significant differences between the interventions in the outcomes. In conclusion, MARS therapy seems to be the best available option in reducing mortality. Further research is needed on currently available and new therapeutic modalities. (CRD42020160133).

Extracorporeal renal and liver support in pediatric acute liver failure.

The liver is the only organ which can regenerate and, thus, potentially negate the need for transplantation in acute liver failure (ALF). Cerebral edema and sepsis are leading causes of mortality in ALF. Both water-soluble and protein-bound toxins have been implicated in pathogenesis of various ALF complications. Ammonia is a surrogate marker of water-soluble toxin accumulation in ALF and high levels are associated with higher grades of hepatic encephalopathy, raised intracranial pressure, and mortality. Therefore, extracorporeal therapies aim to lower ammonia and maintain fluid balance and cytokine homeostasis. The most common and easily available modality is continuous kidney replacement therapy (CKRT). Early initiation of high-volume CKRT utilizing an anticoagulation regimen minimizing treatment downtime and delivering the prescribed dose is highly desirable. Ideally, extracorporeal liver-assist devices (ECLAD) should perform both synthetic and detoxification functions of the liver. ECLAD may temporarily replace lost liver function and serve as a bridge, either to spontaneous recovery or liver transplantation. Various bioartificial and biologic liver-assist devices are described in specialty literature, including molecular adsorbent recirculating system (MARS), single pass albumin dialysis (SPAD), and total plasma exchange (TPE); however, clinicians commonly use modalities easily available in intensive care units. There is a lack of standardization of indications for ECLAD, availability of different extracorporeal devices with varied technical approaches, and, of note, the differences in doses of ECLAD provided in clinical practice. We review the practicalities and evidence regarding these four artificial liver support devices in pediatric ALF.

1275

Introduction: Extracorporeal liver assist device has been described in the literature as a promising strategy for acute liver failureIntroduction: Extracorporeal liver assist device has been described in the literature as a promising strategy for acute liver failure in the setting of acetaminophen toxicity as a bridge to liver transplant. In the largest study of paracetamol overdose treated with MARS™ therapy, patients with Grade 2 encephalopathy (n=14) had a mean MELD score 23 ± 13[1]. There was a higher rate of native liver recovery and 6 month survival with Molecular Adsorbent Recirculating System (MARS™) than the control group. However, there is a lack of uniform protocols to guide clinical management. Therefore, the use has not been widely disseminated in the USA, despite acetaminophen toxicity as the leading cause of acute liver failure and a leading cause of drug fatalities. We present a case where extracorporeal liver assist device, MARS, was used in fulminant liver failure secondary to acetaminophen toxicity with recovery of hepatic and neurologic function without organ transplantation. Case Description: A 39 year-old woman with past medical history of chronic pancreatitis status post pancreatectomy and splenectomy, roux-en-y bypass with malnutrition requiring tube feeds, pulmonary emboli on anticoagulation, and bipolar disorder, presented with acute on chronic left abdominal pain for which she takes oxycodone. She also reported dark bloody fluid from her PEG, epistaxis, nausea and vomiting for one day. She was noted to have an elevated INR of 6.3, WBC 15.9 x109/L, hemoglobin 8 g/dL, glucose of 20's mg/dL, and lactate of 8.8 mmol/L. She was given dextrose and antibiotics then transferred for ICU admission. She continued to have abdominal pain out of proportion to her exam and became hypotensive with BP 80's/40's. Recheck of INR was >10 and AST was 700 U/L. Abdominal CT and ultrasound were negative. Despite adequate fluid resuscitation and timely antibiotics, her lactate remained elevated. Acetaminophen level was found to be 42 mcg/mL. Over the phone, her mother noted 75 missing Percocet pills of her own prescription. After 12 hours, she had increasing somnolence with rising ammonia 268 mcg N/dL, a MELD score 24, and rising transaminases (AST 8150 U/L, ALT 3450 U/L). Within hours after intubation, she exhibited decorticate posturing and ICP monitor was emergently placed. Opening pressure was 45 mmHg then decreased within seconds to 6 to 7 mmHg, and later increased episodically >25 mmHg which responded to mannitol bolus. Through multidisciplinary discussion, she was not considered for liver transplant due to complex psychosocial and medical issues. MARS™ was initiated on day 1 with a second session on day 2. Ammonia dropped to 165 mcg N/dL after the first session then to 40 mcg N/dL after the second. She slowly improved and ICP monitor was removed on day 5 and extubated on day 7. She remained on hemodialysis but never required vasopressors. After 3 weeks, she recovered synthetic and metabolic liver function (Albumin 2.7, INR 1.9, AST 70 u/L, ALT 42u/L, glucose 103, Alkaline phosphatase 141 u/L, total bilirubin 25.2 mg/dL from a peak of 42 on day 9, MELD score of 39, platelets 239 x109/L), was neurologically intact, and discharged to a psychiatric unit. Discussion: With limited organ donation, other modalities could be considered for patients with fulminant liver failure, namely extracorporeal liver assist device (ELAD). It is generally well tolerated except for thrombocytopenia, which our patient exhibited but normalized in a week. With two sessions, neurologic and hepatic function recovery was remarkable considering her initial neurological symptoms. The change of ammonia was more dramatic than previously described. One can hypothesize that early initiation of ELAD in fulminant liver failure could be a bridge to transplantation as well as aiding native hepatic recovery in non-organ transplant candidates.

Cell Transplantation in the Treatment of Acute Liver Injury: Effect But No Clear Mechanism

Liver transplantation is the current treatment of choice for end-stage liver disease. Nevertheless, cell-based therapy is emerging as an alternative to whole-organ transplantation. It is less invasive and can be performed repeatedly. Hepatocyte transplantation has been used to bridge patients to whole-organ transplantation, which has been done using bioartificial liver techniques such as extracorporeal liver assist device (ELAD), molecular adsorbent recirculating system (MARS), and plasmapheresis. However, these methods are not achieving the desirable goal of effectively reducing mortality in acute liver failure[ 1 O'Grady J. Modern management of acute liver failure. Clin Liver Dis. 2007; 11: 291 Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar ]. An alternative to the primary hepatocyte is stem cell derivative or hepatocyte precursors, which are available within each patient. Research into the ability of these cells to replace hepatocytes and their function is ongoing [ 2 Nussler A. Konig S. Ott M. et al. Present status and perspectives of cell-based therapies for liver diseases. J Hepatol. 2006; 45: 144 Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar ].

Polyelectrolyte Nano-scaffolds for the Design of Layered Cellular Architectures

The design of in vitro multilayered cellular architectures that resemble the stratified, lattice-like structure in tissues poses a significant challenge for tissue engineering. There is currently no generally applicable methodology to design multilayered cellular constructs that mimic the structure of tissues in vivo. We report a novel and generalizable approach to create multilayered cellular constructs that addresses these issues. These in vitro constructs comprise alternating layers of cells and nano-scale biocompatible polyelectrolyte (PE) scaffolds. We apply this methodology to address two specific problems in hepatic tissue engineering: the design of in vitro liver sinusoidal structures and the critical need to increase viable cell mass in extracorporeal liver-assist devices. We assembled ultrathin polymer scaffolds on the top of a confluent monolayer of cells by the sequential deposition of oppositely charged PEs. The thickness of the PE scaffold lies in the nanometer range. The PE scaffold plays a dual role. First, it is a technique to culture hepatocytes in vitro that maintains their morphology, cytoskeletal structure, and liver-specific functions. Second, the nano-scaffold provides a cell-adhesive surface on which a second layer of cells can be cultured, resulting in layered architectures. We have used this approach to design layered three-dimensional hepatocyte-PE-hepatocyte constructs, hepatocyte-PE-endothelial cell constructs, and hepatocyte-PE-fibroblast constructs. As a result of its versatility, this approach can, in principle, be used to design layered cellular constructs of any tissue type, and therefore has potentially wide applications in tissue engineering, bioreactor devices, and in drug delivery. This methodology has the potential to generate realistic in vitro constructs of any tissue type.

Bioartificial Liver: Current Status

Liver failure remains a life-threatening syndrome. With the growing disparity between the number of suitable donor organs and the number of patients awaiting transplantation, efforts have been made to optimize the allocation of organs, to find alternatives to cadaveric liver transplantation, and to develop extracorporeal methods to support or replace the function of the failing organ. An extracorporeal liver support system has to provide the main functions of the liver: detoxification, synthesis, and regulation. The understanding that the critical issue of the clinical syndrome in liver failure is the accumulation of toxins not cleared by the failing liver led to the development of artificial filtration and adsorption devices (artificial liver support). Based on this hypothesis, the removal of lipophilic, albumin-bound substances, such as bilirubin, bile acids, metabolites of aromatic amino acids, medium-chain fatty acids, and cytokines, should be beneficial to the clinical course of a patient in liver failure. Artificial detoxification devices currently under clinical evaluation include the Molecular Adsorbent Recirculating System (MARS), Single-Pass Albumin Dialysis (SPAD), and the Prometheus system. The complex tasks of regulation and synthesis remain to be addressed by the use of liver cells (bioartificial liver support). The Extracorporeal Liver Assist Device (ELAD), HepatAssist, Modular Extracorporeal Liver Support system (MELS), and the Amsterdam Medical Center Bioartificial Liver (AMC-BAL) are bioartificial systems. This article gives a brief overview on these artificial and bioartificial devices and discusses remaining obstacles.

Convective flow through a hollow fiber bioartificial liver.

A study of open shell flow through a hollow fiber bioartificial liver with a cell packed shell region (the extracapillary space between the fibers) was performed. Previous analyses of flow through a hollow fiber bioartificial liver have ignored the porous nature of the shell region. Existing analytic expressions were used to describe the flow through the porous hollow fibers, and the flow through the shell region was described using Darcy's law. The operational parameters were taken from clinical trials of the Hepatix extracorporeal liver assist device (ELAD). From the experimental parameters, the permeability value of the cell packed shell region of the ELAD was determined. The results suggest the possible formation of preferential flow channels and hypoperfusion of many cells leading to an inadequately functioning bioreactor. Some simple design changes may improve the performance of the ELAD.

Auxiliary liver transplantation and bioartificial bridging procedures in treatment of acute liver failure.

The aim of this review is to discuss the place of auxiliary liver transplantation (ALT) and other cellular based bridging procedures such as hepatocyte transplantation, ex vivo liver perfusion, and bioartificial livers, in the treatment of acute liver failure, vis à vis conventional orthotopic liver transplantation. Hepacocyte transplantation, and ex vivo pig or human liver perfusion are still experimental procedures. Bioartificial livers using human tumoral hepatocytes or porcine hepatocytes have been used in clinical situations as a bridge to transplantation, i.e. to gain the time required to find a high-quality graft for conventional or auxiliary liver transplantation. None of these techniques have yet proved capable of keeping a patient alive long enough for the native liver to recover. Conversely, ALT has been shown to be effective in the treatment of acute liver failure and now appears to be a satisfactory bridging procedure pending native liver (NL) regeneration. We report personal experience of 18 ALT procedures performed in 17 patients between October 1992 and December 1999. The ALT procedure was indicated when patients met criteria for conventional transplantation; it was ultimately selected when a fresh frozen biopsy of the NL did no show any fibrosis. Six patients died within the first 2 postoperative months. The remaining 11 patients are alive, with a follow-up ranging from 2 to 7 years. Regeneration of the NL occurred in 11 of the 17 patients (65%) and in 8 of the 11 survivors (72%), 6 of whom have permanently stopped immunosuppressive therapy. We conclude that liver failure should no longer be handled outside centers where all types of transplantation can be offered, and where innovative therapies such as hepatocyte transplantation and extracorporeal liver-assist devices are being developed and evaluated.

ARTIFICIAL LIVER SUPPORT DEVICES FOR FULMINANT LIVER FAILURE

Artificial liver-support devices attempt to bridge patients with fulminant hepatic failure until either a suitable liver allograft is obtained for transplantation or the patient's own liver regenerates sufficiently to resume normal function. It is thought that toxins contribute to the clinical picture of fulminant hepatic failure. The earliest reports of successful toxin removal were blood- and plasma-exchange transfusions. Given these successful case reports, mechanical liver-support devices were designed to filter toxins. These mechanical devices used hemodialysis, charcoal hemoperfusion, hemoperfusion through cation-exchange resins, hemodiabsorption, and combinations of all of these techniques as in the MARS liver-support device. Despite promising case reports and small series, no controlled studies of mechanical devices have ever showed a long-term survival benefit. Thus, the removal of presumed toxins seems to be insufficient to support patients with fulminant hepatic failure, and the biologic function of the liver must also be replaced. Attempts at replacing the biologic function have included extracorporeal liver perfusion, cross-circulation, and hepatocyte transplantation. Current technologies have combined mechanical and biologic support systems in hybrid liver-support devices. The mechanical component of these hybrid devices serves both to remove toxins and to create a barrier between the patient's serum and the biologic component of the liver-support device. The biologic component of these hybrid liver support devices may consist of liver slices, granulated liver, or hepatocytes from low-grade tumor cells or porcine hepatocytes. These biologic components are housed within bioreactors. Currently the most clinically studied bioreactors are those that use capillary hollow-fiber systems. Both the bioartificial liver by Demetrious and the extracorporeal liver-assist device by Sussman and Kelly are in clinical trials. Although the trials seemed to have yielded good survival data when the devices are used as a bridge to transplantation, the type and degree of liver support provided by these devices remains uncertain. Thus, despite decades of great progress in the field of artificial liver support, no one technique alone yet provides sufficient liver support. A hybrid system seems to be the best option at present. Still to be determined is the best tissue to use, how much liver tissue should be used, and the optimal design of the bioreactor.

Treating Acute Liver Failure with an Extracorporeal Liver-Assist Device

Treating Acute Liver Failure with an Extracorporeal Liver-Assist Device

A novel stable reproducible model of hepatic failure in canines.

Stable and reproducible large animal models of hepatic failure, which allow the assessment of liver-assist devices, are not available. Our objective was to develop a physiologically stable animal model of hepatic failure on which the safety and efficacy of an extracorporeal liver-assist device can be tested. We hypothesized that a surgical model which consists of an end-to-side portocaval shunt combined with common bile duct ligation and transection would create hepatic failure with: (1) elevations in amino transferases, total bilirubin, and ammonia; (2) a decrease in the ratio of branched chain to aromatic amino acids; and (3) histologic evidence of hepatic injury. Eleven mongrel dogs underwent common bile duct transection and an end-to-side portocaval shunt. Aminotransferases (AST, ALT), total bilirubin, ammonia, and branched chain and aromatic amino acids were measured prior to operation (baseline) and after 9 days. A necropsy was performed on Postoperative Day 9 and liver biopsies were obtained for histology. By Postoperative Day 9, AST, ALT, total bilirubin, and ammonia values were significantly elevated compared to baseline (P < 0.02). The ratio of branched chain to aromatic amino acids was significantly reduced compared to baseline (P < 0.003). There was histologic evidence of cholestasis and inflammation. Portocaval shunt with common bile duct transection produces liver failure with elevations in aminotransferases, total bilirubin, and ammonia, a decreased branched chain to aromatic amino acid ratio, and histologic inflammation. Unlike ischemic or chemically induced models of liver failure, the dogs were hemodynamically and neurologically stable. This model can be used to test the safety and efficacy of liver-assist devices aimed at temporizing the detoxification functions of the failing liver.

Acute hepatic failure: a Western perspective.

Acute hepatic failure (AHF) is an uncommon, devastating syndrome, which results in death or the need for liver transplantation in more than 50% of cases. While AHF has numerous causes, most cases are due to viral hepatitis and drug toxicity or idiosyncratic reactions. A significant group with indeterminate causation remains, despite careful investigation. In many of these cases a viral aetiology is suspected, although yet not proven. Major differences exist in the aetiology of AHF between the West and Eastern countries. A wider range of aetiologies exists in the West. Common causes include acetaminophen toxicity and idiosyncratic drug reactions, while viral hepatitis is less frequent. Hepatitis E infection is rarely seen in Western countries in contrast to its high prevalence in the East. The mainstay of AHF management is supportive care in an intensive care unit. Liver transplantation is now the standard of care in many Western liver units for individuals who have a less than 20% probability of survival. Lack of availability of donor livers at short notice remains a significant problem. Methods of liver support used while waiting for a donor liver or for the native liver to regenerate include bioartificial livers, extracorporeal liver-assist devices, extracorporeal whole organ perfusion (human and transgenic pig) and hepatocyte transplantation. The effectiveness of these methods remains unproven and awaits controlled clinical trials. Both transplantation and liver-support methods require specialized units and expensive and complicated equipment. Further research is necessary to identify modalities of therapy that would be effective as well as widely accessible.

Extracorporeal liver support: Cell-based therapy for the failing liver

It is perhaps self-evident to state that a liver support device is possible as long as the artificial organ provides liver function. This basic concept has received woefully little attention, mainly because “liver function” escapes precise definition. We have seen a variety of liver-assist devices that have little to do with liver function over the past 30 years. Recent work has focused on the liver as a biochemical reactor, rather than an excretory organ, and the paradigm has shifted away from blood purification and toward metabolic support. This new generation of devices includes viable liver cells, which provide the necessary biochemical function without needing to identify the numerous metabolic pathways necessary to support the patient with a failing liver. This approach is the most effective and least invasive method available with current technology, and it has yielded exciting data. Questions about the mass of cells required to provide adequate support, the timing and length of treatment, and the source of cellular material continue to be debated. Here we address theoretical and practical problems in developing an extracorporeal liver-assist device (ELAD) and suggest the future role of extracorporeal liver support in the management of liver failure.

Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure

Abstract The objective of this pilot controlled study was to evaluate the extracorporeal liver assist device (ELAD) in patients with acute liver failure who were judged to still have a significant chance of survival (approximately 50%) and in those who had already fulfilled criteria for transplantation. Twenty-four patients were divided into two groups, 17 with a potentially recoverable lesion (group I) and 7 listed for transplantation (group II), and then randomly allocated to ELAD haemoperfusion or control. The median period of ELAD haemoperfusion was 72 hours (range 3-168 h). Biocompatibility of the device was good, with no acceleration in platelet consumption, and haemodynamic stability was maintained. Two patients were withdrawn from the study because of worsening of preexisting disseminated intravascular coagulation in one case and a hypersensitivity reaction in the other. Deterioration with respect to encephalopathy grade was more frequent in the control patients, 7 of 12 (58%), than in the ELAD-treated patients, 3 of 12 (25%). In group I where survival for the ELAD cases was 7 of 9 (78%), there was a higher than expected survival in the controls, 6 of 8 (75%). For group II cases, survival was 1 of 3 (33%) for the ELAD- treated patients, and 1 of 4 (25%) for the controls. Both of the survivors underwent transplantation. Assessment of additive function for the device revealed an improvement in galactose elimination capacity after 6 hours of haemoperfusion. Based on the results of this pilot-controlled trial, better indices of prognosis will be required, in addition to those used to select for transplantation, if patients at an earlier stage of clinical deterioration are to be included in future studies. (Hepatology 1996 Dec;24(6):1446-51)

Novel strategies for liver support in acute liver failure.

At present, the treatment of a patient in acute liver failure is based upon scrupulous intensive care. In those patients whose condition deteriorates, emergency liver transplantation must be considered. There would be great benefit if it were possible to provide treatment which would stabilise the condition of a patient in acute liver failure. Thus, there is great incentive to develop a means of artificial liver support. Over many years, a considerable array of therapeutic strategies has been investigated. These can be considered in four main categories: plasma exchange, haemofiltration, extra-corporeal liver assist devices (ELAD), extra-corporeal liver perfusion (ECLP). Finally, the role of xenotransplantation is considered.

Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure

The objective of this pilot controlled study was to evaluate the extracorporeal liver assist device (ELAD) in patients with acute liver failure who were judged to still have a significant chance of survival (approximately 50%) and in those who had already fulfilled criteria for transplantation. Twenty-four patients were divided into two groups, 17 with a potentially recoverable lesion (group I) and 7 listed for transplantation (group II), and then randomly allocated to ELAD haemoperfusion or control. The median period of ELAD haemoperfusion was 72 hours (range 3-168 h). Biocompatibility of the device was good, with no acceleration in platelet consumption, and haemodynamic stability was maintained. Two patients were withdrawn from the study because of worsening of preexisting disseminated intravascular coagulation in one case and a hypersensitivity reaction in the other. Deterioration with respect to encephalopathy grade was more frequent in the control patients, 7 of 12 (58%), than in the ELAD-treated patients, 3 of 12 (25%). In group I where survival for the ELAD cases was 7 of 9 (78%), there was a higher than expected survival in the controls, 6 of 8 (75%). For group II cases, survival was 1 of 3 (33%) for the ELAD- treated patients, and 1 of 4 (25%) for the controls. Both of the survivors underwent transplantation. Assessment of additive function for the device revealed an improvement in galactose elimination capacity after 6 hours of haemoperfusion. Based on the results of this pilot-controlled trial, better indices of prognosis will be required, in addition to those used to select for transplantation, if patients at an earlier stage of clinical deterioration are to be included in future studies. (Hepatology 1996 Dec;24(6):1446-51)

Effect of ELAD Liver Support on Plasma HGF and TGF–β1 in Acute Liver Failure

The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-beta 1 (TGF-beta 1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 +/- SEM 1.76 ng/ml) compared with normal subjects (0.10 +/- 0.02 ng/ml, p < 0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 +/- 6.19 ng/ml, p < 0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-beta 1 determined by ELISA were significantly increased in the ALF patients (43.4 +/- 5.9 ng/ml) compared with normal subjects (25.1 +/- 2.3 ng/ml, p < 0.01), but there was no change in plasma TGF-beta 1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.

In vivo evaluation of a hollow fiber liver assist device

Orthotopic liver transplantation is the only effective form of therapy currently available for patients with fulminant hepatic failure (FHF). The use of an extracorporeal (EC) liver assist device (LAD) may result in improved presurgical clinical management. Alternatively, patients treated with LADs could avoid the transplantation procedure if they are able to regenerate a critical mass of hepatocytes that will sustain functional viability. In this study, the efficacy of a prototype hollow fiber LAD seeded with rabbit hepatocytes was assessed in vivo by the use of two different animal models: (1) normal rabbits injected with diazepam or lidocaine, and (2) a galactosamine (Gal)-intoxicated rabbit model of FHF. The EC LAD clearly decreased the blood levels of the two drugs and significantly generated diazepam and lidocaine metabolites indicating the maintenance of active P450 forms in the cellular component of the devices. A 6-hour EC treatment significantly increased the survival time and delayed the onset of hepatic encephalopathy (HE) in the Gal-intoxicated rabbits. Histological evaluations of postmortem livers showed greater hepatocyte regenerative activity in the animals treated with hepatocyte-seeded LADs than in the two control groups, e.g., rabbits not treated or treated with unseeded devices. These findings support the concept that a microporous hollow fiber LAD seeded with rabbit hepatocytes is able to sustain drug detoxification in vivo as well as to modify the course of FHF in a well-characterized animal model.

In vivo evaluation of a hollow fiber liver assist device

Orthotopic liver transplantation is the only effective form of therapy currently available for patients with fulminant hepatic failure (FHF). The use of an extracorporeal (EC) liver assist device (LAD) may result in improved presurgical clinical management. Alternatively, patients treated with LADs could avoid the transplantation procedure if they are able to regenerate a critical mass of hepatocytes that will sustain functional viability. In this study, the efficacy of a prototype hollow fiber LAD seeded with rabbit hepatocytes was assessed in vivo by the use of two different animal models: (1) normal rabbits injected with diazepam or lidocaine, and (2) a galactosamine (Gal)-intoxicated rabbit model of FHF. The EC LAD clearly decreased the blood levels of the two drugs and significantly generated diazepam and lidocaine metabolites indicating the maintenance of active P450 forms in the cellular component of the devices. A 6-hour EC treatment significantly increased the survival time and delayed the onset of hepatic encephalopathy (HE) in the Gal-intoxicated rabbits. Histological evaluations of postmortem livers showed greater hepatocyte regenerative activity in the animals treated with hepatocyte-seeded LADs than in the two control groups, e.g., rabbits not treated or treated with unseeded devices. These findings support the concept that a microporous hollow fiber LAD seeded with rabbit hepatocytes is able to sustain drug detoxification in vivo as well as to modify the course of FHF in a well-characterized animal model.