Extracorporeal bioartificial liver for treating acute liver diseases

Liver is a vital organ of the human body performing myriad of essential functions. Liver-related ailments are often life-threatening and dramatically deteriorate the quality of life of patients. Management of acute liver diseases requires adequate support of various hepatic functions. Thus far, liver transplantation has been proven as the only effective solution for acute liver diseases. However, broader application of liver transplantation is limited by demand for lifelong immunosuppression, shortage of organ donors, relative high morbidity, and high cost. Therefore, research has been focused on attempting to develop alternative support systems to treat liver diseases. Earlier attempts have been made to use nonbiological therapies based on the use of conventional detoxification procedures such as filtration and dialysis. However, the absence of liver cells in such techniques reduced the overall survival rate of the patients and led to inadequate essential liver-specific functions. As a result, there has been growing interest in the development of biological therapy-based extracorporeal liver support systems as a bridge to liver transplantation or to support the ailing liver. A bioartificial liver support is an extracorporeal device through which plasma is circulated over living and functionally active hepatocytes packed in a bioreactor with the aim to aid the diseased liver until it regenerates or until a suitable graft for transplantation is available. This review article gives a brief overview of efficacy of various liver support systems that are currently available. Also, the development of advanced liver support systems, which has been analyzed for improving the important system component such as cell source and other culture and circulation conditions for the maintenance of the liver-specific functions, have been described. Keywords: liver failure, hepatocytes, liver support devices, bioartificial liver, bioreactor.     

Liver support technology--an update

BACKGROUND: Currently, there is no direct treatment for hepatic failure, and patients must receive a transplant or endure prolonged hospitalization, with significant morbidity and mortality. Because of the scarcity of donor organs, liver support strategies are being developed with the aim of either supporting patients with borderline functional liver cell mass until an appropriate organ becomes available for transplantation or until their livers recover from injury. METHODS: A literature review was performed using MEDLINE and library searches. Only major blood detoxification/purification devices and cell-based techniques are included in this review. RESULTS: Currently, a number of blood purification systems and devices utilizing viable liver cells are in various stages of clinical development. Non-biological systems include plasma exchange, albumin dialysis, hemo(dia)filtration, and sorbent-based devices (charcoal, resin). These systems are able to remove toxins of hepatic failure, and their utility is limited by their inability to provide missing liver-specific functions. In contrast, hepatocyte-based devices are able to provide whole liver functions, including detoxification, biosynthesis, and biotransformation. Molecular adsorbent recycling system (MARS) blood detoxification system has been tested in thousands of patients, but additional well-conducted controlled studies are warranted to better define the role of MARS in the treatment of patients with acute hepatic failure and acute exacerbation of chronic liver disease. HepatAssist was tested in a phase II/III controlled clinical trial that demonstrated safety and proof of concept for use of biological liver support systems to improve patient survival in acute hepatic failure. CONCLUSIONS: Developing an effective liver assist technology has proven difficult, because of the complexity of liver functions that must be replaced, as well as heterogeneity of the patient population. Non-biological systems may have a role in the treatment of specific forms of liver failure where the primary goal is to provide blood detoxification/purification. Biological systems appear to be useful in treating liver failure where the primary objective is to provide whole liver functions which are impaired or lost. It is suggested that there will be a role for hybrid liver support systems that offer liver cell therapy and various forms of blood purification (sorption, hemofiltration and diafiltration) to treat patients with specific forms of liver failure at various stages of their illness.     

Bioartificial liver support

Orthotopic liver transplantation is the only definitive therapy for patients with fulminant hepatic failure (FHF). However, due to shortage of organs, a large number of patients die before a liver can be procured for transplantation. In FHF the need for a liver is particularly urgent because of rapid deterioration in the patients' condition with the onset of cerebral edema and intracranial hypertension leading to irreversible brain damage. It is thus necessary to develop an extracorporeal liver support system to help maintain patients alive and neurologically intact until an organ becomes available for transplantation. Multiple attempts have been made, ranging from the use of plasma exchange to utilization of charcoal columns and extracorporeal devices loaded with liver tissue to develop liver support systems for treating patients with acute severe liver failure. None of these systems has achieved wide clinical use, and FHF due to multiple causes continues to be associated with significant morbidity and mortality. In this paper, the authors review the history of extracorporeal liver support for acute liver failure and discuss their experience with a hollow fiber bioartificial liver support system utilizing porcine hepatocytes in the treatment of patients with acute liver failure. Received: July 7, 2000 / Accepted: October 12, 2000     

Auxiliary Partial Orthotopic Living Donor Liver Transplantation: Kyoto University Experience

Auxiliary partial orthotopic liver transplantation (APOLT) was initially indicated as a potentially reversible fulminant hepatic failure and non-cirrhotic metabolic liver disease to compensate for enzyme deficiency without complete removal of the native liver. We expand our indication of APOLT for small-for-size grafts to support the function of implanted grafts during the early post-operative period, and for ABO-incompatibility to sustain a patient's life if the patient has a graft failure. We retrospectively reviewed 31 patients undergoing APOLT from living donor. The indication of APOLT was fulminant hepatic failure in 6, non-cirrhotic metabolic liver disease in 6, small-for-size grafts in 13 and ABO-incompatible cases in 6. The cumulative survival rate for APOLT at 1 and 5 years was 57.9% and 50.6%, and 78.8% and 73.8% for standard LDLT. None of the patients who underwent transplantation with APOLT for fulminant hepatic failure had long-term patient survival. The incidence of acute cellular rejection was higher in APOLT (58.1%) than standard LDLT (35.0%). Biliary complication was higher and the need for retransplantation was greater in APOLT than standard LDLT (p < 0.01). The results suggest that the indications of APOLT should be reconsidered in view of the risk for complications and retransplantation.     

Development of a Bioartificial Liver Using Isolated Hepatocytes

Abstract: Severe liver disease is very often life-threatening and dramatically diminishes quality of life. Liver support systems based on detoxification alone have been proved ineffective because they cannot correct biochemical disorders. An effective artificial liver support system should be capable of carrying out the liver's essential processes, such as synthetic and metabolic functions, detoxification, and excretion. It should be capable of sustaining patients with fulminant hepatic failure, preparing patients for liver transplantation when a donor liver is not readily available (i.e., bridge to transplantation), and improving the survival and quality of life for patients for whom transplantation is not a therapeutic option. Recent advances in cell biology, tissue culture techniques, and biotechnology have led the way for the potential use of isolated hepatocytes in treating an array of liver disorders. Isolated hepatocytes may be transplanted to replace liver-specific deficiencies or as an important element of an auxiliary hybrid, bioartificial extracorporeal liver support device, which are important therapeutic applications for treating severe liver disease. Recently, several hepatocyte-based liver support systems have been proposed. Although there is no current consensus on its eventual design configuration, the hollow fiber hepatocyte bioreactor shows the greatest promise. Furthermore, application of tissue engineering technology, based on cellsurface interaction studies proposed by our group and others, has enhanced interest in the development of highly efficient hybrid, bioartificial, liver support devices.     

Fulminant liver failure: clinical and experimental study.

Clinical experience of some newer methods of hepatic support is described. The results are unpredictable and far from satisfactory. The need for an animal model in which potential therapeutic methods can be studied is emphasized. Such a model based on carefully imposed ischaemic insult to the liver in the absence of portacaval shunting is described. It is suggested that bacterial presence in the bowel together with a depression of the liver reticuloendothelial function plays an important part in the early and rapid mortality of acute liver failure. Temporary auxiliary liver transplantation using an allograft or a closely related primate heterograft seem to be the 2 best available methods of hepatic support for potentially reversible acute liver failure.     

Liver transplantation for fulminant hepatitis

Liver transplantation has been recognized as an effective therapeutic method for end-stage liver disease in Japan. Fulminant hepatic failure is also an indication for liver transplantation, and the number of patients undergoing liver transplantation has been increasing. Reversibility and urgency are characteristics of fulminant hepatitis. If given appropriate critical support, many patients recover spontaneously. However, many patients develop cerebral edema or multiorgan failure before the liver can regenerate. Indications, operative procedures, and outcome of liver transplantation for fulminant hepatitis are discussed here. At Shinshu University, 23 of 169 cases of liver transplantation were for fulminant hepatitis. One transplantation was from a cadaveric donor and 22 from living donors. The actuarial 5-year patient and graft survival rate was 85.4%. Although some problems remain in liver transplantation for fulminant hepatitis, the results are better than those of conventional therapy. Therefore patients with fulminant hepatic failure should be listed for liver transplantation when grade 2 hepatic encephalopathy develops. Moreover, in cases of severe acute hepatitis, i.e., before patients develop grade 2 encephalopathy, liver transplantation should be considered among choices of therapy in the near future.     

Auxiliary heterotopic partial liver transplantation in pigs with acute liver failure

Fulminant hepatic failure is usually fatal without liver transplantation; however, orthotopic liver transplantation is often difficult to perform due to the high risk of coagulopathy and the development of multiple organ failure. Auxiliary heterotopic partial liver transplantation (APLT), however, has the potential to provide an effective hepatic support system considering that the host liver is left in situ and the surgical procedure is less invasive. In this report, we describe the beneficial effects of performing 60% APLT on the hepatic function and survival of pigs with acute hepatic failure induced by hepatic artery ligation. The pigs were divided into a control group of nine animals (group 1) that had portal vein and hepatic artery ligation with a side-to-side portacaval shunt, and an APLT group of seven animals (group 2) that had portal vein and hepatic artery ligation with APLT. The two left lateral lobes of the donor liver were resected, reducing the liver weight to about 60%, and the graft was placed in the right subhepatic space. No deaths occurred intraoperatively. In group 1, eight pigs died of massive liver necrosis within 48 h and one died between 48 and 72 h (median surivival 23 h). In group 2, two pigs died within 72 h due to preservation or anesthetic problems, but five survived for more than 3 days (median survival 13.4 days), with a significant difference between the two groups (P<0.05). One animal was killed 30 days after APLT and excellent graft function was demonstrated by the synthesis of clotting factors, ammonia detoxification, and glucohomeostasis. Moreover, evidence of hepatic regeneration was found in the transplanted livers. These results indicate that APLT provides metabolic support and improves survival in animals with induced acute liver failure.     

Is the Biological Artificial Liver Clinically Applicable? A Historic Review of Biological Artificial Liver Support Systems

Abstract: Hemoperfusion, hemodiafiltration, plasma exchange, and extracorporeal liver perfusion have already been adopted to treat patients with acute and chronic hepatic failure. However, the survival rate of patients with acute hepatic failure remains at approximately 30% and has not improved as expected. Current advances in biotechnology have opened the way for the development of a biological artificial liver, which is called the hybrid artificial liver because it consists of both biological and artificial materials. Isolated hepatocytes have been investigated for use in various types of hybrid artificial liver. In addition, the role of biomatrices, microcarriers, and the microencapsulation technique has been studied with respect to long-term maintenance of hepatocellular function and development of high-density culture systems for hepatocytes. Before clinical application of hybrid artificial liver support systems becomes possible, many problems have to be resolved, including large-scale preparation and long-term preservation of biomaterials, high-density and stable immobilization of biomaterials on artificial materials, control of immunological hazards, biocompatibility, safe transportation and sterilization of biomaterials, and the high cost. We review the history of biological artificial livers and discuss their future role.     

Fulminant liver failure: etiopathogenesis and therapy

Fulminant hepatic failure (FHF) is a clinical syndrome characterized by the development of encephalopathy within eight weeks from the onset of the first symptoms, in the absence of previous hepatic disease. It is an uncommon but not rare disease, often fatal but potentially reversible. This article looks at the diverse aetiologies, clinical features, and current medical management, including orthotopic liver transplantation, and auxiliary orthotopic or eterotopic liver transplantation, that are the most recently adopted surgical procedures. Clinical experience with bio-artificial liver support systems of two of the most active research Groups in this field, concludes the paper.     

Hepatic Assist: Present and Future

Fulminant hepatic failure due to acute massive liver cell necrosis is a complex pathophysiological entity, and treatment is still unsatisfactory. Artificial liver supports such as hemodialysis, hemoperfusion, and plasmapheresis have recently been used clinically to treat fulminant hepatic failure. However, survival rate has not improved as expected, although the consciousness of the patient has improved frequently. In this article the present status of clinical artificial liver support and basic research of hybrid artificial liver will be discussed. Moreover, the future aspects of total artificial liver support and hepatocyte transplantation for chronic liver failure will be introduced.     

Extracorporeal liver support systems

Acute liver failure is very life-threatening since the conventional medical treatments have little effects on the clinical outcome. Artificial liver support systems based on blood detoxification alone have proven ineffective because they cannot correct the severe biochemical disorders. An effective liver support system should be capable of carrying out essential functions such as phase I reaction in which lipid-soluble toxic substance are rendered water-soluble by the enzyme system of the cytochrome P450 and NADPH-cytochrome reductase, and are therefore conjugated by the phase II reaction, before excretion. Liver support systems should be capable of sustaining patients with fulminant liver failure until an organ is available for liver transplantation (bridging treatment), or improving the survival in patients for whom liver transplantation is not a therapeutic option. Recent advances in cell biology and tissue culture techniques have led the way for potential clinical use of isolated hepatocytes so that they are now an important element of bioartificial liver support devices. Some of these systems are currently under clinical investigation in the USA and Europe, and the results of the prospective controlled trials will be soon available.     

Use of mammalian liver cells for artificial liver support

Advances in orthotopic liver transplantation have improved the survival rate of both acute and chronic liver failure patients to nearly 70%. However, the success of this treatment modality has created an international organ shortage. Many patients die while awaiting transplantation in part due to the minimal capacity to store viable transplantable livers beyond 24 h. Additionally, for many areas of the world, routine use of whole liver transplantation to treat liver disease is impractical due to the demands on both financial and technical resources. Potentially, these issues may be alleviated, at least in part, by the use of liver cell transplantation or cellular-based liver assist devices. The well-documented regenerative capacity of the liver may obviate the need for whole organ transplantation in some instances of acute failure, if the patient may be provided temporary metabolic support. Although other patients ultimately may require transplantation, a longer period of time to find a suitable organ for transplantation may be gained by that supportive therapy. The field of liver cell transplantation may offer solutions to patients with inherited metabolic deficiencies or chronic liver disease. The potential to treat an hepatic disorder by using only a fraction of the whole liver would increase the number of whole organs available for orthotopic liver transplantation. Research in the fields of hepatocyte based intra-and extracorporeal liver support is providing evidence that these therapeutic modalities may ultimately become routine in the treatment of severe liver disease. A historic overview of that technology along with its current status is discussed.     

Biochemical, Hematological and Histological Changes in a Fulminant HeDatic Failure Rat Model for Ahificial Liver Assessment

Galactosamine-induced fulminant hepatic failure rats have been used as a model for statistical assessment of liver support systems. The present study reports in detail the biochemical, hematological and histological changes in these animals. They have been used to study statistically the effects of ACAC charcoal hemoperfusion, cross-circulation and liver perfusion on long-term survival in fulminant hepatic failure.     

Functional portal flow competition after auxiliary partial orthotopic living donor liver transplantation in noncirrhotic metabolic liver disease

Auxilliary partial orthotopic liver transplantation (APOLT) was introduced initially as a tentative or permanent support for patients with potentially reversible fulminant hepatic failure and has extended its indication to congenital metabolic disorder of the liver that has otherwise normal functional integrity. Postoperative management of APOLT is complicated because of functional portal flow competition between the native and graft liver. The native portal vein diversion to the graft is sometimes indicated to prevent functional competition; however, it is still an open question whether this technique can be theoretically indicated for APOLT patients. The authors report a on patient with ornithine transcarbamylase deficiency who received APOLT from a living donor without native portal vein diversion. Because of functional portal vein competition between the native and graft liver, the patient had to have portal vein diversion, portal vein embolization, and finally native hepatectomy to induce the graft regeneration after APOLT. After the experience of the current case, primary portal vein diversion for APOLT with noncirrhotic metabolic liver disease patients to prevent functional portal flow competition is recommended.     

Development and Perspectives of Perfusion Treatment for Liver Failure

To treat patients with severe liver failure, liver transplantation and blood purification therapy, including plasmapheresis, hemodiafiltration, and bioartificial liver support, are available. The two mainstream systems developed for bioartificial liver support are extracorporeal whole liver perfusion (ECLP) and the bioreactor system (BIS). We developed a method of cross-plasma perfusion, in which plasma is exchanged between the blood circuit of the patient and that of a hepatic functioning unit, through which immunologically free whole human blood is perfused. From the aspects of efficacy and epidemic safety, the best system of bioartificial liver support for clinical use is considered to be ECLP in cross-plasma perfusion. In opposition, a social antagonist for zoonosis has consistently been raised, with controversy surrounding the use of xenogeneic organs for human treatment, which might be final obstacle. It is possible that the combination therapy of hemodiafiltration and the administration of human serum albumin and anticoagulant factors, which minimizes the economic and medical resource costs through the development of transgenic livestock that secrete human pharmaceuticals systemically, will become a more desirable and practical treatment for patients with severe liver failure.     

What Should We Expect From a Bioartificial Liver In Fulminant Hepatic Failure?

Fulminant hepatic failure is associated with high mortality. Liver transplantation is an effective therapy that improves survival, and because of donor organ shortage and urgency, a bioartificial liver could act as an effective bridge to liver transplantation in patients with fulminant hepatic failure. We discuss the place of the bioartificial liver in the treatment of other causes of liver failure.     

"Artificial liver"

Acute liver failure is a life-threatening condition since conventional medical treatments have little effect on survival. Artificial liver support systems based on blood detoxification alone have proven to be ineffective. A liver support system should carry out essential functions such as the phase I reaction in which lipid-soluble toxic substance are rendered water-soluble by the enzyme system of the cytochrome P450 and NADPH-cytochrome reductase, and are therefore conjugated by the phase II reaction, before excretion. Liver support systems should be capable of sustaining patients until an organ is available for liver transplantation (bridging treatment), or improving the survival in patients for whom liver transplantation is not a therapeutic option. Recent advances in cell biology and tissue culture techniques have led the way for potential clinical use of isolated hepatocytes so that they are now an important element of bioartificial liver (BAL) support devices. Some of these BAL are currently under clinical investigation in the USA and Europe, and the results of the prospective controlled trials will be soon available.     

Acute liver failure in chronic hepatic disease. Clinico-therapeutic evaluation

Chronic liver diseases are potentially evolving clinical situations which, independently by the etiology, could proceed towards progressive liver structural and functional impairments. The only efficient treatment is orthotopic liver transplantation. Chronic liver diseases, and up to 40% of liver cirrhosis, are initially asymptomatic, but cirrhosis is the most frequent cause of death among non-neoplastic digestive diseases. Important elements complicating a decompensated liver cirrhosis are ascites, hepatic encephalopathy, digestive bleeding and jaundice. Acute liver failure (ALF) is the expression of a clinical state, that is common to many conditions sharing severe liver structural and functional impairments. In patients affected by decompensated liver cirrhosis, ALF could be triggered by several factors, while the death is caused by bleeding episodes, hepato-renal syndrome, spontaneous bacterial peritonitis or hepatocarcinoma. In patients affected by chronic liver diseases, the diagnosis of ALF is based on progressively increasing jaundice, encephalopathy and coagulopathy. Recent clinical trials have evaluated the efficacy of extrahepatic liver support systems, either artificial or bio-artificial, in treating episodes of ALF in chronic liver patients. The preliminary results indicate a potential use of such systems in blood detoxification, but they also showed limits in increasing patient survival.