A prognostic score for patients with acute-on-chronic liver failure treated with plasma exchange-centered artificial liver support system.

Artificial liver support system (ALSS) therapy is widely used in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). We aimed to develop a predictive score to identify the subgroups who may benefit from plasma exchange (PE)-centered ALSS therapy. A total of 601 patients were retrospectively enrolled and randomly divided into a derivation cohort of 303 patients and a validation cohort of 298 patients for logistic regression analysis, respectively. Five baseline variables, including liver cirrhosis, total bilirubin, international normalized ratio of prothrombin time, infection and hepatic encephalopathy, were found independently associated with 3-month mortality. A predictive PALS model and the simplified PALS score were developed. The predicative value of PALS score (AUROC = 0.818) to 3-month prognosis was as capable as PALS model (AUROC = 0.839), R score (AUROC = 0.824) and Yue-Meng' score (AUROC = 0.810) (all p > 0.05), and superior to CART model (AUROC = 0.760) and MELD score (AUROC = 0.765) (all p < 0.05). The PALS score had significant linear correlation with 3-month mortality (R2 = 0.970, p = 0.000). PALS score of 0-2 had both sensitivity and negative predictive value of > 90% for 3-month mortality, while PALS score of 6-9 had both specificity and positive predictive value of > 90%. Patients with PALS score of 3-5 who received 3-5 sessions of ALSS therapy had much lower 3-month mortality than those who received 1-2 sessions (32.8% vs. 59.2%, p < 0.05). The more severe patients with PALS score of 6-9 could still benefit from ≥ 6 sessions of ALSS therapy compared to ≤ 2 sessions (63.6% vs. 97.0%, p < 0.05). The PALS score could predict prognosis reliably and conveniently. It could identify the subgroups who could benefit from PE-centered ALSS therapy, and suggest the reasonable sessions.Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032055. Registered 19th April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52471 .

Update in intensive care medicine: acute liver failure. Initial management, supportive treatment and who to transplant.

PURPOSE OF REVIEW: Acute liver failure (ALF) is associated with significant mortality. Although specific therapies may be available, the evidence base for these and for many aspects of supportive therapy has been slow to emerge. Liver transplantation continues to be a cornerstone of treatment, and the management of ALF, therefore, remains the domain of the specialist ICU. The purpose of this review is to identify and critically appraise the recent evidence and to inspire those who strive to provide excellent care for a difficult patient cohort. RECENT FINDINGS: Effective vaccination programmes have reduced the incidence of viral hepatitis in Europe and the USA. Spontaneous survival has improved in causes such as acetaminophen toxicity. Early recognition and proactive intensive management have reduced the incidence of early neurological death. The use of artificial liver assist devices and therapeutic plasma exchange is controversial, yet intriguing, with some early evidence of efficacy. SUMMARY: Increasingly sophisticated prognostication tools are evolving, which have the potential to transform clinical decision-making. A review of the indications for transplantation in acetaminophen toxicity is overdue. The use of therapeutic plasma exchange and extracorporeal liver support in ALF requires further investigation.

Liver support strategies: cutting-edge technologies.

The treatment of end-stage liver disease and acute liver failure remains a clinically relevant issue. Although orthotopic liver transplantation is a well-established procedure, whole-organ transplantation is invasive and increasingly limited by the unavailability of suitable donor organs. Artificial and bioartificial liver support systems have been developed to provide an alternative to whole organ transplantation, but despite three decades of scientific efforts, the results are still not convincing with respect to clinical outcome. In this Review, conceptual limitations of clinically available liver support therapy systems are discussed. Furthermore, alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies, including the repopulation of decellularized organs and the biofabrication of entirely new organs by printing techniques or induced organogenesis are analysed with respect to clinical relevance. Whereas hepatocyte transplantation shows promising clinical results, at least for the temporary treatment of inborn metabolic diseases, so far data regarding implantation of engineered hepatic tissue have only emerged from preclinical experiments. However, the evolving techniques presented here raise hope for bioengineered liver support therapies in the future.

Bridging the gap: advances in artificial liver support.

KEY POINTS: 1. The goals of liver support therapy include the following: To provide detoxification and synthetic function during liver failure. To remove or reduce the production of proinflammatory cytokines to correct the systemic inflammatory response of liver failure. To stimulate the regeneration of the injured liver and increase the likelihood of spontaneous recovery. 2. There is a large unmet need for a liver support device because of the shortage of organs for liver transplantation and the risks of major surgery. 3. Liver support devices can be divided into 2 groups: purely mechanical artificial devices and cell-based bioartificial devices. Both provide detoxification, but bioartificial liver devices provide the option of synthetic function and biotransformation activities that are not possible with a purely mechanical device. 4. An abundant high-quality supply of human hepatocytes is not currently available for liver cell therapy. However, such a supply is essential for successful bioartificial liver therapy. Novel options are under development for the unlimited production of high-quality human hepatocytes.

Clinical uses of liver stem cells.

Liver transplantation offers a definitive cure for many liver and metabolic diseases. However, the complex invasive procedure and paucity of donor liver graft organs limit its clinical applicability. Liver stem cells provide a potentially limitless source of cells that would be useful for a variety of clinical applications. These stem cells or hepatocytes generated from them can be used in cellular transplantation, bioartificial liver devices and drug testing in the development of new drugs. In this chapter, we review the technical aspects of clinical applications of liver stem cells and the progress made to date in the clinical setting. The difficulties and challenges of realizing the potential of these cells are discussed.

Bioartificial liver devices: Perspectives on the state of the art.

Acute liver failure remains a significant cause of morbidity and mortality. Bioartificial liver (BAL) devices have been in development for more than 20 years. Such devices aim to temporarily take over the metabolic and excretory functions of the liver until the patients' own liver has recovered or a donor liver becomes available for transplant. The important issues include the choice of cell materials and the design of the bioreactor. Ideal BAL cell materials should be of good viability and functionality, easy to access, and exclude immunoreactive and tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet these requirements. One of the challenges in BAL development is the improvement of current materials; another key point concerning cell materials is the coculture of different cells. The bioreactor is an important component of BAL, because it determines the viability and function of the hepatocytes within it. From the perspective of bioengineering, a successful and clinically effective bioreactor should mimic the structure of the liver and provide an in vivo-like microenvironment for the growth of hepatocytes, thereby maintaining the cells' viability and function to the maximum extent. One future trend in the development of the bioreactor is to improve the oxygen supply system. Another direction for future research on bioreactors is the application of biomedical materials. In conclusion, BAL is, in principle, an important therapeutic strategy for patients with acute liver failure, and may also be a bridge to liver transplantation. It requires further research and development, however, before it can enter clinical practice.

Artificial liver support: quo vadis?

BACKGROUND: Approximately 2 million persons worldwide die each year from hepatic failure. Because of the scarcity of donor organs, artificial liver support systems 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. MATERIAL/METHODS: A literature review was performed using MEDLINE, PubMed, EMBASE, and library searches. Only major liver support techniques are included in this review. RESULTS: A number of extracorporeal liver assist systems are in various stages of clinical development. Published data indicate that patients with acute and acute-on-chronic liver failure may benefit from treatment with some of these therapeutic measures. Results from large prospective randomized trials have shown that treatment with MARS® and PROMETHEUS® may not confer a survival advantage, despite positive effects on blood toxemia and improvement in hepatic encephalopathy. Currently, hemofiltration using albumin-leaking membranes is being explored as a novel promising approach to blood purification in liver 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 hold promise for treating liver failure where the primary objective is to provide whole liver functions which are impaired or lost.

Bioartificial liver support systems.

A variety of bioartificial liver support systems were developed to replace some of the liver's function in case of liver failure. Those systems, in contrast to purely artificial systems, incorporate metabolically active cells to contribute synthetic and regulatory functions as well as detoxification. The selection of the ideal cell source and the design of more sophisticated bioreactors are the main issues in this field of research. Several systems were already introduced into clinical studies to prove their safety. This review briefly introduces a cross-section of experimental and clinically applied systems and tries to give an overview on the problems and limitations of bioartificial liver support.

Artificial and bioartificial liver devices: present and future.

Liver failure is associated with high morbidity and mortality without transplantation. There are two types of device for temporary support: artificial and bioartificial livers. Artificial livers essentially use non-living components to remove the toxins accumulated during liver failure. Bioartificial livers have bioreactors containing hepatocytes to provide both biotransformation and synthetic liver functions. We review here the operating principles, chemical effects, clinical effects and complications of both types, with specific attention paid to bioartificial systems. Several artificial support systems have FDA marketing authorisation or are CE labelled, but the improvement they provide in terms of patient clinical outcome has not yet been fully demonstrated. At present, different bioartifical systems are being investigated clinically on the basis of their promises and capacity to provide and replace most liver functions. However, important issues such as cost, cell availability, maintenance of cell viability and functionality throughout treatment, and regulatory issues, as well as difficult challenges, including implementing cell-housing devices at the patient's bedside on an emergency basis, have delayed their appearance in intensive care units and on the market. Bioreactors are, nevertheless, when combined with artificial components, a pragmatic approach for future treatment of liver failure.

Progress and future challenges in stem cell-derived liver technologies.

The emergence of regenerative medicine has led to significant advances in the identification and understanding of human stem cells and adult progenitor cells. Both cell populations exhibit plasticity and theoretically offer a potential source of somatic cells in large numbers. Such a resource has an important role to play in the understanding of human development, in modeling human disease and drug toxicity, and in the generation of somatic cells in large numbers for cell-based therapies. Presently, liver transplantation is the only effective treatment for end-stage liver disease. Although this procedure can be carried out with high levels of success, the routine transplant of livers is severely limited by organ donor availability. As a result, attention has focused on the ability to restore liver mass and function by alternative approaches ranging from the bioartificial device to transplantation of human hepatocytes. In this review we will focus on the generation of human hepatic endoderm from different stem/progenitor cell populations with a view to its utility in regenerative medicine.

What clinical alternatives to whole liver transplantation? Current status of artificial devices and hepatocyte transplantation.

Shortage of organ donors limits the number of possible liver transplantations. Alternative therapies for treatment of liver failure are currently being developed: (i) extracorporeal artificial liver devices; (ii) bioartificial liver devices using hepatocytes; and (iii) hepatocyte transplantation. The objective of these strategies is to bridge patients with liver failure until a suitable liver allograft is obtained for transplantation or the patient's own liver regenerates sufficiently to resume normal function. In this review, we discuss these strategies and summarize the current status of clinical experience.

Role of artificial liver support in hepatic encephalopathy.

Hepatic encephalopathy (HE) refers to the reversible neuropsychiatric disorders observed in acute liver failure and as a complication of cirrhosis and/or portal hypertension. This review aims to describe the pathophysiology of HE, the rationale for the use of artificial liver support in the treatment of HE, the different concepts of artificial liver support and the results obtained. Ammonia has been considered central to its pathogenesis but recently an important role for its interaction with inflammatory responses and auto-regulation of cerebral hemodynamics has been suggested. Artificial liver support might be able to decrease ammonia and modulate inflammatory mediators and cerebral hemodynamics. Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient's circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Clinical studies have shown that artificial liver support, especially albumin dialysis, is able to improve HE in acute and acute-on-chronic liver failure. Further studies are required to better understand the mechanism, however, artificial liver support can be added to the therapeutic bundle in treating HE.

Stem cells for end stage liver disease: how far have we got?

End stage liver disease (ESLD) is a health problem worldwide. Liver transplantation is currently the only effective therapy, but its many drawbacks include a shortage of donors, operative damage, risk of rejection and in some cases recidivism of the pre-transplant disease. These factors account for the recent growing interest in regenerative medicine. Experiments have sought to identify an optimal source of stem cells, sufficient to generate large amounts of hepatocytes to be used in bioartificial livers or injected in vivo to repair the diseased organ. This update aims to give non-stem cell specialists an overview of the results obtained to date in this fascinating field of biomedical research.

[Primry research of separation and culture of adult hepatocytes].

OBJECTIVE: To explore the separation and culture method of adult hepatocytes. METHODS: The isolated adult hepatocytes were cultivated by RPMI 1640 medium at 37 degrees C in vitro. The characteristics of the growing hepatocytes were observed. Their synthesis of urea was detected. The transformation efficiency and density's change of lidocaine were analyzed. RESULTS: Hepatocytes were successful separated from adult liver. And they were cultivated in common condition and hollow fiber reactor. The functional capacity of hepatocytes was for lidocaine metabolism and urea excretion. CONCLUSION: The adult hepatocytes have been successful separated from liver. And they can be cultivated in common condition and hollow fiber reactor. And it could provide a great quantity and high activity of hepatocytes for bioartificial liver.

Artificial and bioartificial liver support: a review of perfusion treatment for hepatic failure patients.

Liver transplantation and blood purification therapy, including plasmapheresis, hemodiafiltration, and bioartificial liver support, are the available treatments for patients with severe hepatic failure. Bioartificial liver support, in which living liver tissue is used to support hepatic function, has been anticipated as an effective treatment for hepatic failure. The two mainstream systems developed for bioartificial liver support are extracorporeal whole liver perfusion (ECLP) and bioreactor systems. Comparing various types of bioartificial liver in view of function, safety, and operability, we concluded that the best efficacy can be provided by the ECLP system. Moreover, in our subsequent experiments comparing ECLP and apheresis therapy, ECLP offers more ammonia metabolism than HD and HF. In addition, ECLP can compensate amino acid imbalance and can secret bile. A controversial point with ECLP is the procedure is labor intensive, resulting in high costs. However, ECLP has the potential to reduce elevated serum ammonia levels of hepatic coma patients in a short duration. When these problems are solved, bioartificial liver support, especially ECLP, can be adopted as an option in ordinary clinical therapy to treat patients with hepatic failure.

Bioartificial liver systems: current status and future perspective.

Because the liver is a multifunctional and a vital organ for survival, the management of acute liver failure requires the support of a huge number of metabolic functions performed by the organ. Many early detoxification-based artificial liver techniques failed to treat the patients owing to the inadequate support of the many essential hepatic functions. For this reason, a bioartificial liver (BAL) comprising of viable hepatocytes on a mechanical support is believed to more likely provide these essential functions than a purely mechanical device. From 1990, nine clinical studies of various BAL systems have been reported, most of which utilize a hollow fiber technology, and a much larger number of various BAL systems have been suggested to show an enhanced performance. Safety issues such as immunological reactions, zoonosis and tumorgenicity have been successfully addressed for regulatory approval, but a recent report from a large-scale, randomized, and controlled phase III trial of a leading BAL system (HepatAssist) failed to meet our expectation of efficacy in terms of the overall survival rate. In this paper, we review the current BAL systems actively studied and discuss critical issues such as the hepatocyte bioreactor configuration and the hepatocyte source. On the basis of the insights gained from previously developed BAL systems and the rapid progress in stem cell technology, the short-term and long-term future perspectives of BAL systems are suggested.

Artificial liver support: future aspects.

Liver transplantation and blood purification therapy, including plasmapheresis, hemodiafiltration, and bioartificial liver support, are available to treat patients with severe liver failure. 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 plasma cross-perfusion, in which plasma is exchanged between the blood circuit of the patient and that of a hepatic function unit, that is, whole liver or a bioreactor through which immunologically free whole human blood is perfused. From the aspects of efficacy and safety, the best system of bioartificial liver support for clinical use is considered to be ECLP in cross plasma perfusion. However, a social objection about zoonosis has consistently been raised, with controversy surrounding the use of xenogeneic organs for human treatment, and this might be a final obstacle to the development of system efficacy. The combination therapy of hemodiafiltration with the administration of human serum albumin and anticoagulant factors can minimize the economic and medical resource costs through the development of transgenic livestock that secrete human pharmaceuticals systemically. It is possible that this therapy will become the most practical treatment for patients with severe hepatic failure.