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.     

A surgical model of fulminant hepatic failure in rabbits.

AIM: Animal models of fulminant hepatic failure (FHF) have been developed for characterization of disease progression and to evaluate the effectiveness of liver-assist devices, some by treatment with hepatotoxic drugs, viral hepatitis or surgical procedures. We have developed a model in the rabbit by combining resection of the three anterior lobes with ligation of the pedicle of the right lateral lobes, resulting in liver necrosis; the remnant quadrate lobes are left intact. MATERIALS AND METHODS: Adult male New Zealand white rabbits (n=16) were used. Six animals were killed to measure the weight of the separate liver lobes. The others (n=10) underwent left neck central line placement to monitor continuous blood pressure and collect blood for laboratory analysis, and a burr hole on the right parietal bone to monitor the intracranial pressure (ICP). Blood laboratory analysis, clinical hepatic encephalopathy and ICP levels were measured in FHF animals (n=6). Animals (n=4) undergoing a sham operation served as controls. RESULTS: All FHF animals died between 12 and 26 h after liver surgery from FHF characterized by a progressive increase in liver enzymes, ammonia, total bilirubin, coagulopathy, hepatic encephalopathy and intracranial hypertension. Histological features of the ischaemic lobes showed coagulative necrosis of hepatocytes with absence of nuclei and collapse of cell plates. Brain histology revealed hypoxic cell damage. CONCLUSION: We have developed a simple, reproducible model of FHF in rabbits that has a number of features comparable with clinical FHF patients and is well suited for testing experimental bioartificial liver systems and investigating the pathogenesis of FHF.     

Separate analysis of asialoglycoprotein receptors in the right and left hepatic lobes using (99m)Tc-GSA SPECT in patients with acute hepatic damage.

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. However, regional expression and clinical significance of the ASGPR in acute hepatic damage is presently unknown. Our aim was to clarify the clinical significance of the regional expression of ASGPR in human livers with acute hepatitis (AH) and fulminant hepatic failure (FHF). Eighteen volunteers, 42 patients with AH and 10 with FHF were studied using a newly developed, conventional (99m)Tc-GSA SPECT analysis. Using Cantlie's line as a guide, ASGPR expression was analyzed separately in the right and left hepatic lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased in accordance with the severity of acute hepatic damage. In the FHF group, the reduction in LUR and LUD values in the right lobes was more significant than in the left lobes. The LUR and LUD values for the whole liver correlated well with hepatic functional reserve and total bilirubin levels. The right LUR and LUD values in particular correlated well with these parameters. A time-course observation of 13 patients with either AH or FHF revealed that the expression of ASGPRs in the right lobe recovered faster than in the left. We first evaluated the regional expression of AGSPRs by (99m)Tc-GSA SPECT analysis in both AH and FHF patients, which is a clinically useful and reliable indicator for assessing the severity of regional hepatic damage and evaluating regional liver regeneration.     

Intensive liver care and management of acute hepatic failure

In describing acute liver failure, the term fulminant hepatic failure (FHF) is used to denote patients with the most rapid progression, normally defined as the onset of encephalopathy within eight weeks of the onset of symptoms. For patients with a slower onset of encephalopathy, ranging from eight weeks to six months after the onset of symptoms, late-onset hepatic failure is the term used to reflect the overlap in clinical features with some patients with FHF. The importance of accurately determining the type of acute liver failure results from increasing evidence of an inverse relationship between the tempo of disease progression and the chances of recovery. Prognosis is also dependent on the underlying etiology. Principles of management are as follows: (1) an accurate recognition of the tempo of the hepatic failure—fulminant, late onset, acute on chronic—and the establishment of a likely etiology; (2) early detection and treatment of complications, particularly metabolic acidosis (early), renal failure, cerebral edema, and infection (late); (3) optimization of conditions for regeneration by maintenance of a near normal metabolic milieu (with removal of toxins by various methods of artificial liver support if necessary); and (4) early consideration of an orthotopic liver transplant for those patients in the poor prognosis group. Variations in the natural history and clinical features of acute liver failure (ALF) have led to a number of different classifications and subgroupings. Knowledge of these is important in relation to the assessment of prognosis and is even more important now that transplantation is a therapeutic option. Fulminant hepatic failure (FHF) is the term used to denote the subgroup where the tempo is greatest and is variously defined as the onset of encephalopathy within four weeks (1), six weeks (EASL, 1979) and eight weeks [as described by Trey and Davidson (2)] of the onset of symptoms, or within two weeks of the onset of jaundice (3). The patients with a more protracted course are designated by the terms subacute or late-onset hepatic failure (LOHF) (4) or subfulminant hepatic failure (3). The etiology of the hepatic failure also has a major influence on the likely prognosis.Presented at the Proceedings of International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Cadaveric liver transplantation for non-acetaminophen fulminant hepatic failure： A 20-year experience

AIM: To investigate the long-term results of liver transplantation (LT) for non-acetaminophen fulminant hepatic failure (FHF). METHODS: Over a 20-year period, 29 FHF patients underwent cadaveric whole LT. Most frequent causes of FHF were hepatitis B virus and drug-related (not acetaminophen) liver failure. All surviving patients were regularly controlled at the out-patient clinic and none was lost to follow-up. Mean follow-up was 101 mo. RESULTS: One month, one-, five- and ten-year patient survival was 79%, 72%, 68% and 68%, respectively. One month, one-, five- and ten-year graft survival was 69%, 65%, 51% and 38%, respectively. Six patients needed early (< 2 mo) retransplantation, four for primary non-function, one for early acute refractory rejection because of ABO blood group incompatibility, and one for a malignant tumor found in the donor. Two patients with hepatitis B FHF developed cerebral lesions peri-transplantion: One developed irreversible and extensive brain damage leading to death, and one suffered from deep deficits leading to continuous medical care in a specialized institution. CONCLUSION: Long-term outcome of patients transplanted for non-acetaminophen FHF may be excellent. As the quality of life of these patients is also particularly good, LT for FHF is clearly justified, despite lower graft survival compared with LT for other liver diseases.     

Pathophysiology of Brain Edema in Fulminant Hepatic Failure,Revisited

We have proposed a combined osmolar-hemodynamic disturbance to explain the presence of brain edema in fulminant hepatic failure, a major cause of death in this disorder. The concept of an osmotic disturbance in the brain, emphasizing the presence of astrocyte swelling and low-grade cerebral edema, has been expanded to the entire spectrum of liver disease. The mechanism of cerebral hyperemia in patients with FHF and brain swelling has been studied in experimental models linking hyperammonemia and glutamine generation in astrocytes to the development of this hemodynamic alteration. Measures to control cerebral hyperemia, such as mild hypothermia, are effective in preventing the development of brain edema in experimental models as well as intracranial hypertension in human disease.     

Fulminant hepatic failure: Summary of a workshop

Fulminant hepatic failure (FHF) is defined by the appearance of severe liver injury with hepatic encephalopathy in a previously healthy person. There are an estimated 2,000 cases of FHF in the United States yearly, representing 0.1% of all deaths and, perhaps, 6% of liver-related deaths. The causes of FHF are many, the chief ones in the United States being hepatitis A; B; non-A, non-B and drug induced liver disease. There are no specific therapies for FHF, however, liver transplantation is recommended for situations in which spontaneous recovery appears unlikely. Factors that are valuable in assessing the likelihood of spontaneous recovery are static features such as patient age and etiology of FHF and dynamic features including encephalopathy grade, prothrombin time, and serum bilirubin. Presently, approximately 7% of all liver transplants are done for FHF and the 1-year patient survival rates average 63%, somewhat less than survival rates for nonfulminant liver disease, averaging 78%. The management of patients with FHF is challenging, particularly important being monitoring and early treatment of infections, hemodynamic abnormalities, and brain edema. Innovative approaches to management and therapy include use of cytoprotective or antiviral medications, hepatic support systems, extracorporeal liver support, hepatocyte transplantation, auxiliary liver transplantation, and xenotransplantation. None of these are of proven benefit, but many are promising as a means to support the patient with FHF until spontaneous recovery occurs or a suitable liver graft is available for transplantation.     

Living donor liver transplantation for fulminant hepatic failure

Aim: The aim of this study was to investigate the safety of living donor liver transplantation (LDLT) for fulminant hepatic failure (FHF) patients. Methods: We reviewed the clinical indications, operative procedures and prognosis of LDLT performed on patients with FHF at the University of Tokyo. From January 1996 to August 2007, 96 patients were referred to our department due to severe acute hepatitis or FHF. Of these, 36 underwent LDLT and were the subjects of this study. Of the 36 patients who underwent LDLT, 32 were over 18 years old. The etiologies of FHF included non‐A, non‐B hepatitis in 23, hepatitis B virus in 11, Wilson's disease in one, and auto‐immune hepatitis in one. Graft type included right liver in 18, left liver in 16 and right paramedian sector in two. Results: Patient and graft survival rates at 5 years were 87% and 82%, respectively. Twenty‐three patients had postoperative complications: acute cellular rejection in 12, biliary stricture in eight, bile leakage in six, peritoneal hemorrhage in six and hepatic arterial thrombosis in four. Conclusion: The LDLT procedure provided satisfactory survival rates for FHF patients.     

Clozapine-induced fatal fulminant hepatic failure: A case report

Fulminant hepatic failure (FHF) refers to the rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in a person who previously had a normal liver or had well-compensated liver disease. The potential causes of FHF are numerous, but viral or toxin-induced hepatitis are the most common. Clozapine-induced hepatotoxicity has rarely been reported in the literature, occurs via an unknown mechanism and results in liver biochemical abnormalities that are usually of no clinical significance. In approximately 30% to 50% of patients treated with clozapine, there is an asymptomatic rise in serum aminotransaminase levels; however, there are no current guidelines for routine monitoring of liver function tests and liver enzymes during its use. Fatal fulminant hepatitis has only been reported in three patients receiving clozapine. A case of fatal FHF that occurred in a schizophrenic woman who began clozapine therapy shortly before her illness developed is described.     

Neurological and neuropsychiatric syndromes associated with liver disease

The clinical presentation of acute liver failure and hepatic encephalopathy (HE) in patients with cirrhosis differs significantly. The most serious neurological complication of acute liver failure is the development of devastating brain oedema. Therefore, intracranial pressure monitoring is urgently needed in these patients. Brain oedema is amplified by hypoglycemia, hypoxia and seizures, which are also frequent complications of acute liver failure. Therefore, these parameters must also be monitored. In contrast to acute liver failure in which cerebral dysfunction progresses rapidly, cognitive decline may be clinically undetectable for a long time in cirrhotic patients, until clinically overt symptoms such as psychomotor slowing, disorientation, confusion, extrapyramidal and cerebellar symptoms or a decrease in consciousness occur. Clinically, overt HE is preceded by minimal alterations of cerebral function that can only be detected by neuropsychological or neurophysiological measures, but which nevertheless interfere with the patient's daily living. Rapidly progressing spastic paraparesis (hepatic myelopathy) is a rare complication of cirrhosis. In contrast to HE, it does not respond to blood ammonia lowering therapies but must be considered as an indication for urgent liver transplantation. Cognitive dysfunction has recently been detected in hepatitis C virus (HCV)-infected patients with normal liver function. The patients presented with severe fatigue, cognitive dysfunction and mood disorders. Alterations in brain metabolites, as detected by magnetic resonance spectroscopy, indicated central nervous system alteration in these patients. In contrast to patients with HE, HCV-infected patients did not show motor symptoms or deficits in visual perception, but considerable deficits in attention and concentration ability.     

Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy and brain edema are important complications in the course of a patient with acute liver failure. Presumed unrelated for many years, increasing evidence suggests that an increase in brain water is seen in all forms of hepatic encephalopathy. Ammonia, traditionally linked to the pathogenesis of hepatic encephalopathy, plays an important role in the increase in brain water. In acute liver failure, an osmotic disturbance in the astrocyte, in combination with an alteration of cerebral blood flow results in overt brain edema and intracranial hypertension. In cirrhosis, magnetic resonance techniques indicate the presence of a brain osmotic disturbance. Several clinical factors modulate the development of brain swelling.     

Major complications of acute and chronic liver disease

Many advances have been made in the understanding, diagnosis, and management of severe complications of liver disease. The pathogenesis of hepatic encephalopathy remains a challenge. Several toxins including ammonia, mercaptans, short-chain fatty acids, benzodiazepine-like substances, GABA-like substances, and impaired glutamatergic neurotransmission are at the top of the list of candidates. Use of the benzodiazepine antagonists is an experimental but promising new therapy in patients with hepatic encephalopathy. In patients with cirrhosis, spontaneous bacterial peritonitis (SBP) remains a common and highly lethal complication. The diagnosis of SBP is based on the polymorphonuclear cell count in the ascites and confirmed by culture of ascitic fluid. Early diagnosis and aggressive treatment has reduced mortality of SBP from greater than 90 per cent to 30 to 50 per cent. The appearance of cerebral edema in severe acute hepatocellular failure is associated with high mortality and conventional neurologic signs may be unreliable indicators of brain swelling. Current management of cerebral edema in fulminant hepatocellular failure may include early placement of an extradural sensor for continuous monitoring of intracranial pressure, so that short-term measures can be instituted making later liver transplantation safer. Coagulopathy remains a serious problem in patients with liver disease. Exchange plasmapheresis is a promising short-term adjuvant therapy. However, liver transplantation should be considered the definitive treatment for fulminant hepatocellular failure. The gastroenterologist often encounters multiorgan failure in patients with severe liver disease. Liver transplantation is now an important therapeutic consideration in almost every patient with severe, irreversible liver disease. Efforts should be targeted to early diagnosis of irreversible disease and coordination of patient care with a liver transplant center.     

Visual and auditory evoked responses in acute severe hepatitis

Evoked responses have not been studied in patients with acute severe hepatitis (ASH) with or without hepatic encephalopathy. This prospective study was undertaken to find out diagnostic as well as prognostic value of visual evoked responses (VER), and brain stem auditory evoked responses (BAER) in patients with ASH with or without encephalopathy. Visual evoked responses and BAER were studied in 20 patients (14 males and six females) with ASH. The patients were diagnosed as having severe hepatitis if acute hepatitis was associated with raised serum bilirubin and serum transaminases, and if they had a prothrombin time index of < 50%. After a detailed neuropsychiatric examination of each patient, the study sample was divided into two groups of 10 patients: ASH without encephalopathy (ASH-WOE), and ASH with encephalopathy (fulminant hepatic failure, FHF). The median P100 latencies of FHF patients were significantly increased compared with controls and patients in the ASH-WOE group. Abnormal P100 latencies, exceeding 95th percentile values of the controls, were present in one patient in the ASH-WOE group and six patients in the FHF group. The median interpeak latencies I-III, III-V and I-V were significantly prolonged in the FHF group. Interpeak latencies III-V were also increased significantly in patients in the ASH-WOE group. While abnormal BAER were seen frequently in both groups, VER abnormalities were largely confined to patients in the FHF group. In the FHF group, six out of 10 patients survived and exhibited clinical improvement in the status of hepatic encephalopathy. Evoked responses were repeated after 2–3 weeks of recovery in these patients and VER abnormalities showed a tendency to normalize, thereby suggesting a prognostic implication. The incidence of abnormal VER in hepatic encephalopathy complicating ASH far exceeded that of abnormal BAER. Markedly prolonged P100 latencies in FHF patients indicate poor prognosis.     

Hypothermia in Acute Liver Failure

The development of encephalopathy in patients with acute liver injury defines the occurrence of liver failure. The encephalopathy of acute liver failure is characterized by brain edema which manifests clinically as increased intracranial pressure. Despite the best available medical therapies a significant proportion of patients with acute liver failure die due to brain herniation. The present review explores the experimental and clinical data to define the role of hypothermia as a treatment modality for increased intracranial pressure in patients with acute liver failure.     

Mercury as a cause of fulminant hepatic failure in a child: case report and literature review

Fulminant hepatic failure (FHF) in children is devastating unless urgent liver transplantation is undergone. Intoxication or drug-related FHF is a well-known group of causes leading to FHF. Mercury intoxication is described in the literature to cause hepatitis but not described to cause DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and FHF in the same patient. We describe a child with mercury intoxication and FHF with clinical features fulfilling DRESS syndrome criteria. To our best knowledge, this is the first case report of fatal acute liver failure secondary to mercury intoxication in the English literature. Mercury intoxication should receive a worldwide attention to its consequences in order to minimize the morbidities and mortalities that arise from its intoxication.     

Technology insight: liver support systems

Emergency orthotopic liver transplantation (OLT) is currently the only standard treatment for fulminant hepatic failure (FHF). The waiting time for transplantation can exceed a week-using a liver assist device to bridge patients with FHF to OLT might therefore decrease the mortality rate. Several liver support systems have been described, but no system has gained FDA approval or widespread clinical acceptance. Although the results of many experimental and clinical trials are encouraging, the field is still in its initial stages. Using nonbiologic liver support is based on the assumption that several toxins that cause hepatic coma can be removed from the circulation by blood or plasma sorption methods. As these toxins could be involved in many FHF complications recovery without the need for transplantation is the ultimate aim. Biologic liver support uses xenogeneic livers or hepatocytes to support the failed human liver, exploiting biological cell functions, namely detoxification, metabolism, and biosynthesis. The classical nonbiologic dialysis methods could decrease mortality in patients with acute-on-chronic liver failure, but definitive conclusions are impossible to draw because of the small number of patients studied and inadequate follow-up. Larger studies performed in specialty centers should provide conclusive data about the role of the bioartificial liver support system as a possible universal bridge to OLT. This article presents an overview of published experience with liver support systems since the 1960s.     

Metastatic liver disease and fulminant hepatic failure: presentation of a case and review of the literature

Although liver metastases are commonly found in cancer patients, fulminant hepatic failure (FHF) secondary to diffuse liver infiltration is rare. Furthermore, clinical presentation and laboratory findings are obscure and far from being pathognomonic for the disease. We report a case of a patient who died in the intensive care unit of our hospital from multiple organ failure syndrome secondary to FHF, as a result of liver infiltration from poorly differentiated small cell lung carcinoma. We also present the current knowledge about the clinical picture, laboratory findings and physical history of neoplastic liver-metastasis-induced FHF.     

Management of hepatic encephalopathy in patients with cirrhosis

The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.     

Serum osteopontin levels in patients with acute liver dysfunction

OBJECTIVE: Fulminant hepatic failure (FHF) is a clinical syndrome of sudden and severe liver dysfunction accompanied by encephalopathy in a previously healthy person. In FHF, hepatocytes are severely damaged and ordinary liver regeneration is impaired. We demonstrated that the expression of osteopontin (OPN), a multifunctional cytokine, was up-regulated in mouse oval cell (a stem-cell progenitor) induction models. MATERIAL AND METHODS: Based on this finding, serum OPN levels were examined in 43 patients with FHF and in 45 patients with acute self-limited hepatitis (AH). To determine the cellular source of OPN, the expression of OPN was studied in a liver specimen derived from an FHF patient. RESULTS: The mean OPN level of patients with FHF was 2.80+/-0.48 ng/ml (log(10), +/-SD), which was significantly higher than that of the patients with AH (2.42+/-0.39 ng/ml) (p=0.003, unpaired t-test). Patients with elevated serum OPN levels had a significantly poorer prognosis than patients whose serum OPN levels were not elevated. In the FHF patient's liver, OPN protein was expressed not only in inflammatory cells but also in regenerating hepatocytes and bile ductular structures. CONCLUSIONS: Our current study indicates that serum OPN levels increased in patients with FHF and that OPN might play an important role in liver regeneration due to activation of hepatic stem cells.     

Role of transfusion-transmitted virus in acute viral hepatitis and fulminant hepatic failure of unknown etiology

BACKGROUND AND AIM: The role of the newly described transfusion-transmitted virus (TTV), a circular single-stranded DNA virus, has been investigated in acute liver disease, comprising 36 patients with acute viral hepatitis (AVH) and 25 with fulminant hepatic failure (FHF), including 50 volunteer blood donors as controls. METHODS: Detection of TTV DNA sequences was carried out by polymerase chain reaction (PCR) using primers derived from the UTR(A) region of the TTV genome. The clinical course and biochemical profile when infected with TTV alone or coinfected with other classical hepatotropic viruses were analyzed. All patients were first evaluated for liver function profile and for the presence of various hepatotropic viruses using serological tests and PCR in serologically negative patients. RESULTS: Transfusion-transmitted virus DNA was detected in 80.6% (29/36) of the AVH cases and in 76% (19/25) of the FHF cases, which were significantly higher levels (P < 0.05) than the 52% (26/50) observed in volunteer blood donors. No significant difference in symptoms, clinical course, liver function and risk factor profile between TTV-positive and TTV-negative patients could be observed in both AVH and FHF patients. TTV was found to coexist with both parenterally and non-parenterally transmitted hepatotropic viruses in similar frequency in both AVH and FHF patients. Further, there was no significant difference in the mortality rates between TTV-positive and TTV-negative FHF patients. Also, there was no difference between patients coinfected by TTV and other hepatotropic viruses and those with TTV infection alone. CONCLUSION: Thus, it appears that TTV, although it exists in a very high frequency in the Indian population, appears to have no significant etiological role in AVH and FHF.