Multisorbent plasma perfusion in fulminant hepatic failure: effects of duration and frequency of treatment in rats with grade III hepatic coma

Using the model of galactosamine-induced fulminant hepatic failure in the rat, the effects of multisorbent plasma perfusion over Asahi uncoated spherical charcoal, Plasorba (BR-350) resin, and an endotoxin removing adsorbent (polymyxin B-sepharose) were determined in Grade III hepatic coma animals by studying survival as influenced by timing, duration, and frequency of treatment. The effects of treatment on liver cell proliferation and endotoxin removal also were examined. The results demonstrate that duration and frequency of treatment are major contributing factors in the successful application of nonbiological membrane-based multisorbent liver support systems. Examination of the regenerative activity in the liver indicates an enhanced proliferative response following multisorbent plasma perfusion compared with untreated fulminant hepatic failure (FHF) paired controls. Utilizing an endotoxin removal adsorbent alone, a marked reduction in systemic levels of endotoxin in FHF was demonstrated compared with nonperfused FHF paired controls. Despite current emphasis on bioartificial liver support systems, plasma purification by multisorbent systems offers a simple method for the removal of circulating toxic metabolites in general together with specific toxin removal.     

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     

Comparative study of bioartificial liver support and plasma exchange for treatment of pigs with fulminant hepatic failure

Recently, bioartificial liver (BAL) treatment was reported to provide beneficial effects for patients with fulminant hepatic failure (FHF). Some success in experimental or clinical trials has been reported; however, the evaluation of BAL efficacy remains unclear, especially in comparison with other treatments for FHF. The purpose of this study was to compare the efficacy between BAL and plasma exchange (PE) in experimentally induced FHF in pigs. Pigs undergoing hepatic devascularization (HD) were placed into the following groups: no treatment (control; n = 6), BAL treatment (BAL; n = 5), and plasma exchange (PE; n = 5). Each treatment was initiated 6 h after HD and lasted for 4 h. BAL treatment significantly improved liver functions in FHF pigs. The decrease in cerebral perfusion pressure was also significantly suppressed in the pigs with BAL, and their survival time was prolonged compared with the results in pigs with PE. The effects of BAL outperform those of PE in the treatment of experimental FHF model.     

First Report of Cryopreserved Human Hepatocytes Based Bioartificial Liver Successfully Used as a Bridge to Liver Transplantation

Cryopreserved human hepatocytes could be the best type of cells to be used in a bioartificial liver (BAL) device due to reduced biosafety and biocompatibility risks. Banking of primary human hepatocytes, obtained from livers unwanted for transplantation at harvesting, could be used as a source of human liver cells for BAL treatment. We describe herein for the first time the case of a patient affected by fulminant hepatic failure (FHF) due to acute HBV infection that was successfully bridged to emergency liver transplantation by BAL treatment using cryopreserved primary human hepatocytes. The use of cryopreserved primary human hepatocytes as the biological part of the BAL device has never been described before and might be considered as a possible alternative to xenogenic material or human tumoral cell lines due to reduced biosafety and biocompatibility risks.     

Predictors of clinical outcome in children undergoing orthotopic liver transplantation for acute and chronic liver disease.

The current United Network for Organ Sharing (UNOS) policy is to allocate liver grafts to pediatric patients with chronic liver disease based on the pediatric end-stage liver disease (PELD) scoring system, while children with fulminant hepatic failure may be urgently listed as Status 1a. The objective of this study was to identify pre-transplant variables that influence patient and graft survival in those children undergoing LTx (liver transplantion) for FHF (fulminant hepatic failure) compared to those patients transplanted for extrahepatic biliary atresia (EHBA), a chronic form of liver disease. The UNOS Liver Transplant Registry was examined for pediatric liver transplants performed for FHF and EHBA from 1987 to 2002. Variables that influenced patient and graft survival were assessed using univariate and multivariate analysis. Kaplan-Meier analysis of FHF and EHBA groups revealed that 5 year patient and graft survival were both significantly worse (P < 0.0001) in those patients who underwent transplantation for FHF. Multivariate analysis of 29 variables subsequently revealed distinct sets of factors that influenced patient and graft survival for both FHF and EHBA. These results confirm that separate prioritizing systems for LTx are needed for children with chronic liver disease and FHF; additionally, our findings illustrate that there are unique sets of variables which predict survival following LTx for these two groups.     

A biodialysis system for liver support tested in a porcine hepatic failure model

BACKGROUND: A practical liver support system for patients in fulminant hepatic failure (FHF) remains a needed therapeutic modality. A new method of bioartificial liver support, the liver biodialysis system (LBDS), is described. METHODS: Porcine hepatocytes, removed from direct contact with the treated subject's circulation, are in culture in a bioreactor which is combined in a dialysis circuit for patient treatment. The LBDS was tested in a porcine ischaemic hepatic failure model. RESULTS: The viable hepatocyte content of the bioreactor was 2.49 +/- 0.72 x 10(10). Cells remained viable in culture throughout the experiments (30 +/- 3 h) without evidence of immunological damage. A decrease in the degree of accumulation in the blood of ammonia (P < 0.02) and of 14 amino acids (P < 0.001) was achieved by the LBDS. Cerebral perfusion pressure was maintained at significantly higher levels in LBDS-treated animals (P < 0.05). CONCLUSIONS: In the LBDS, hepatocytes in large numbers and satisfactory culture conditions in a bioreactor have sustained viability and function. When combined in a dialysis circuit for the treatment of FHF pigs, immune reactions between the blood and hepatocytes were prevented and beneficial metabolic effects were observed.     

Fulminant hepatic failure from primary hepatic lymphoma: successful treatment with orthotopic liver transplantation and chemotherapy

Systemic lymphomas may involve the liver but rarely cause fulminant hepatic failure (FHF). Acute liver failure from primary hepatic lymphoma (PHL) is even less common with most patients succumbing to the sequelae of FHF before the correct diagnosis is made. We report a patient who underwent successful orthotopic liver transplant (OLT) and chemotherapy for FHF secondary to PHL. This previously-well male developed profound coagulopathy and encephalopathy 6 weeks after the onset of jaundice and fatigue. Workup failed to reveal the underlying cause of his liver failure and the patient soon required urgent OLT. Pathologic evaluation of his explanted liver revealed a malignant T-cell rich, large B-cell non-Hodgkin's lymphoma with widespread hepatocellular necrosis. The patient made an excellent clinical recovery and is undergoing CHOP-Rituxan chemotherapy. This scenario demonstrates that lymphoma should be considered in the differential diagnosis of FHF without clear etiology because of the potential for intervention with transplant and chemotherapy.     

S100 beta protein: the preoperative new clinical indicator of brain damage in patients with fulminant hepatic failure

The aim of this study was to clarify the role of serum S100 beta on the accurate assessment of reversibility of brain damage after fulminant hepatic failure (FHF). Among the 13 patients with FHF enrolled in this study, 12 underwent living donor liver transplantation; one patient could not the procedure because of volvulus of the sigmoid colon. Serum S100 beta was serially measured using a chemiluminescent immunoassay. Preoperative serum S100 beta in patients with diffuse brain edema was significantly higher than that in patients with localized brain edema (P < 0.05). Patients with preoperative brain death showed serum S100 beta levels over 7.0 microg/L. Serum S100 beta levels correlated with the degree of brain edema of FHF. It has the potential to be a new clinical, noninvasive indicator of brain damage due to FHF.     

Bioartificial liver support. Review and personal experience

End-stage liver disease is treated successfully by liver transplantation. In spite of the recent advances in transplantation techniques, donor organ shortage remains a serious problem. Conditions such as fulminant hepatic failure are still burdened by a high mortality rate. This has prompted the design of an extracorporeal liver assist device, to "bridge" patients over until they either recover or receive a liver transplant. In these devices, various types of liver cells are inserted and different device designs have been proposed. The paper will review different models of bioartificial liver and will describe ongoing clinical trials. At the end we will report our experimental experience with a newly designed bioartificial liver, evaluating its beneficial effect on acute liver failure.     

Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure.

Patients with acetaminophen-induced fulminant hepatic failure (FHF) who meet the King's College Hospital criteria have a high mortality risk (>90%) if they do not undergo liver transplantation. We have developed a treatment strategy for these patients based on the use of an extracorporeal bioartificial liver (BAL) support system. In this study, we report the results of the clinical application of BAL support in patients with acetaminophen-induced FHF. All patients were admitted to a dedicated surgical intensive care unit. They were evaluated for urgent liver transplantation and received the standard medical measures, including N-acetylcysteine administration and intracranial pressure monitoring. Moreover, they underwent daily 6-hour BAL treatments. Eight patients were treated. Three patients were bridged to liver transplantation, and five patients recovered without a transplant. All patients experienced neurological and metabolic improvement after treatments with the BAL support system. The BAL support system seems to improve the outcome of high-risk patients with acetaminophen-induced FHF, even in the absence of liver transplantation. Avoiding liver transplantation is particularly important in an era of organ shortage and high cost of transplants.     

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.     

Fulminant hepatic failure from herpes simplex virus: post liver transplantation acyclovir therapy and literature review

INTRODUCTION: Herpes simplex virus (HSV) is seen throughout the world and can be treated with acyclovir. We present a case of fulminant hepatic failure (FHF) as a result of disseminated HSV infection in a pregnant patient during the second trimester. METHODS: The medical records of a patient suffering from HSV-related fulminant hepatic failure were collected. A review of the literature was collected and reported. RESULTS: A previously healthy female presented with fulminant hepatic failure at a local emergency room complaining of a 5-day history of fever, nausea, vomiting, and right side abdominal pain that radiated to the back. She was diagnosed with fulminant hepatic failure and progressed into a coma. The patient underwent orthotopic liver transplantation (OLT) prior to the diagnosis of HSV and then treated successfully with acyclovir. CONCLUSION: Treatment of HSV fulminant hepatitis is dependent up on early suspicion and prompt intervention. In addition, antiviral therapy may need to be lifelong.     

Bioartificial liver treatment prolongs survival and lowers intracranial pressure in pigs with fulminant hepatic failure

Intracranial hypertension leading to brainstem coning is a major cause of death in fulminant hepatic failure (FHF). We have developed a bioartificial liver (BAL) utilizing plasma perfusion through a bioreactor loaded with porcine hepatocytes and a column with activated charcoal. In a Phase I clinical trial, we observed a decrease in intracranial pressure (ICP) in FHF patients. However, these patients received BAL therapy together with other measures. We therefore examined whether BAL therapy alone could prevent development of intracranial hypertension in pigs with surgically induced FHF. Pigs (40-60 kg) underwent end-to-side portacaval shunt, transection of all hepatic ligaments, and placement of slings around the hepatic artery and bile duct. After 3 days, the slings were tightened to induce liver necrosis. After 4 h, Group 1 pigs (n = 6) underwent a 6 h treatment with the BAL utilizing 10 billion cryopreserved pig hepatocytes and a charcoal column, Group 2 pigs (n = 6) with the BAL containing charcoal but no cells, and Group 3 pigs (n = 6) with the BAL containing neither cells nor charcoal. Group 1 pigs maintained a normal ICP during BAL treatment and for 14 h afterward and because of this effect they survived longer than Groups 2 and 3 animals. In contrast, Groups 2 and 3 pigs showed an early (6-8 h) rise in ICP.     

Efficacy of double-filtration plasmapheretic cross-circulation with a high-permeability membrane using canine harvested liver in porcine fulminant hepatic failure model

INTRODUCTION: The use of bioartificial liver devices requires. A sufficient liver cell mass to provide adequate metabolic support, reduction of xenogeneic immune reactions, and avoidance of viral transmission. We have developed a plasmapheresis system using a semipermeable membrane combined with canine whole liver perfusion (PMCWLP). In this study, we investigated the efficacy of our system in a porcine fulminant hepatic failure (FHF) model. METHODS: The porcine FHF model was established by intraportal administration of alpha-amanitin (0.1 mg/kg) and lipopolysaccharide (1 microg/kg). Nine hours after drug injection, xenogenic perfusion treatment was performed twice within 6 hours (n = 5). As the plasmapheresis device, we used a hollow-fiber module with cellulose diacetate porous fibers (pore size, 0.05 microm, surface area, 2 m2). The canine whole liver was perfused with modified Krebs solution, which is commonly used in many laboratories, containing albumin (2 g/dL) and glucose (300 mg/dL). Control pigs (n = 10), had the circuit not connected to the whole canine liver. RESULTS: The survival of FHF pigs was significantly increased by the treatment (58.9 +/- 21.8 hour) compared with the controls (22.3 +/- 8.1 hour). Mean blood ammonia levels and intracranial pressure during treatment were significantly lower compared with control groups. CONCLUSION: Treatment of FHF pigs with the system significantly increased survival time, suggesting that this method may have applications as a clinical liver assist device.     

The Effects of Homologous Cross-Circulation and In Situ Liver Perfusion on Fulrninant Hepatic Failure Rats

A galactosamine-induced fulminant hepatic failure (FHF) rat model was used to study the effects of homologous cross-circulation and in situ liver perfusion. Cross-circulation with homologous donors did not significantly improve the survival time or recovery rate of grade II hepatic coma rats. Homologous in situ liver perfusion significantly improved the survival time and recovery in FHF only when started in grade II coma; it has no effect in the later stage of coma.     

Isoniazid-related fulminant hepatic failure in a child: assessment of the native liver’s early regeneration after auxiliary partial orthotopic liver transplantation

We report the first case of auxiliary partial orthotopic liver transplantation (APOLT) in a patient with isoniazid (INH)-related fulminant hepatic failure (FHF) with the aim to determine the ability of the native liver (NL) to recover after this particular toxic event. A 10-year-old boy with INH-related FHF underwent APOLT after left hepatectomy on the NL. Neurological status and liver function rapidly improved, but, on postoperative day 22, urgent re-transplantation was needed for graft–hepatic artery thrombosis (HAT) and the NLs incapacity to sustain adequate liver function. Histological examination of the NL showed signs evident of its regeneration, however. In conclusion, though we faced the clinical failure of the NL functionally to sustain the patient in the presence of the graft HAT 3, weeks after APOLT, such a failure may be interpreted as time related. In fact, the histological picture in this particular case may suggest the potential for NL recovery after INH-related FHF.     

Bioengineering of liver assist devices

Over 30 000 patients die annually in the United States from liver failure. In fulminant hepatic failure, a clinical syndrome associated with high mortality, orthotopic liver transplantation is the primary therapeutic option for patients not responding to supportive therapy. However, the persistent scarcity of donor organs has limited this therapeutic modality, resulting in a continued increase in the number of patients who die waiting for a donor liver. An extracorporeal bioartificial liver device could provide vital support to a liver failure patient until a donor liver was available or until the patient's own liver regenerated. Although it is unclear which liver-specific functions must be provided by such a device to be effective, a constant challenge has been to obtain stable, well-differentiated, and normally functioning hepatocytes that can be cultured at high cell densities. Many of the devices currently undergoing clinical trials are limited by designs which are prone to substrate limitations, resulting in compromised hepatocyte function. In devices that avoid substrate limitations, hepatocyte functions can be optimized, thereby leading to increased device efficiency. In this overview, the authors describe the critical issues involved in bioartificial liver development and discuss their experiences in hepatocyte culture optimization within the context of a microchannel, flat-plate bioartificial liver device with an internal membrane oxygenator. Received: March 20, 2002 / Accepted: April 15, 2002 Acknowledgment. The authors thank Dr. Harihara Baskaran for the preparation of Figure 2. This work was partially funded by grants from the National Institutes of Health (DK43371) and The Whitaker Foundation. Offprint requests to: M. Toner     

In vivo efficacy of a bioartificial liver in improving spontaneous recovery from fulminant hepatic failure: a controlled study in pigs

BACKGROUND: Bioartificial liver may be useful as a bridge to liver transplantation but there are no data of its efficacy in successfully bridging to spontaneous recovery in fulminant hepatic failure. The aim of our study was to evaluate the efficacy of a bioartificial liver in increasing the spontaneous recovery of pigs with hepatic failure. METHODS: The bioartificial liver consisted in a semipermeable dialyzer with 0.6 x 10(9) cryopreserved allogenic hepatocytes. Hepatic failure was induced by portacaval shunt plus 70% hepatectomy and 1 hour occlusion of the hepatic artery. Forty-one pigs were distributed 24 hr after liver failure induction to a group treated with the bioartificial liver (4 hr daily) until recovery or death (n=16), or to a control group (n=25). Intracranial pressure was monitored in 18 additional pigs, before and 4 hr after treatment with the bioartificial liver with (n=12) or without hepatocytes (n=6). RESULTS: Fifteen days after induction of hepatic failure, 44% of the treated animals had survived and recovered from liver failure versus 22% controls (P=0.030). Intracranial pressure decreased from 13.13+/-5.1 to 7.19+/-2.06 mmHg (P=0.02) in treated animals, and remained unchanged in sham-treated animals (14.08+/-1.92 to 12.54+/-3.82, ns). CONCLUSIONS: Bioartificial liver increases survival and allows spontaneous recovery in pigs with fulminant hepatic failure.     

Isoniazid-related fulminant hepatic failure in a child: assessment of the native liver's early regeneration after auxiliary partial orthotopic liver transplantation

Abstract We report the first case of auxiliary partial orthotopic liver transplantation (APOLT) in a patient with isoniazid (INH)-related fulminant hepatic failure (FHF) with the aim to determine the ability of the native liver (NL) to recover after this particular toxic event. A 10-year-old boy with INH-related FHF underwent APOLT after left hepatectomy on the NL. Neurological status and liver function rapidly improved, but, on postoperative day 22, urgent re-transplantation was needed for graft-hepatic artery thrombosis (HAT) and the NL's incapacity to sustain adequate liver function. Histological examination of the NL showed signs evident of its regeneration, however. In conclusion, though we faced the clinical failure of the NL functionally to sustain the patient in the presence of the graft HAT 3, weeks after APOLT, such a failure may be interpreted as time related. In fact, the histological picture in this particular case may suggest the potential for NL recovery after INH-related FHF