Assessment of bioartificial liver support in acute liver failure.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R D Hughes
Publications and source records attributed to R D Hughes.
Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure.
The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-beta 1 (TGF-beta 1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 +/- SEM 1.76 ng/ml) compared with normal subjects (0.10 +/- 0.02 ng/ml, p < 0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 +/- 6.19 ng/ml, p < 0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-beta 1 determined by ELISA were significantly increased in the ALF patients (43.4 +/- 5.9 ng/ml) compared with normal subjects (25.1 +/- 2.3 ng/ml, p < 0.01), but there was no change in plasma TGF-beta 1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.
Adolescent↗
Protective effects of Osbeckia octandra against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage.
Ayurvedic and other 'traditional' medical practitioners in Sri Lanka use the mature leaves of the plant Osbeckia octandra for its hepatoprotective properties. In this study the effects of an aqueous extract of Osbeckia octandra against injury induced by D-galactosamine and tert-butyl hydroperoxide (TBH) were investigated in freshly isolated rat hepatocytes. The plant extract (500 micrograms/ml) significantly reduced the inhibition of protein synthesis (as assessed by the incorporation of 14C-leucine into protein) in hepatocytes incubated for 1 h with 10 mM galactosamine by a mean of 25.6 +/- 3.6% and decreased the release of cellular lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzyme activities into the medium by 55.3% and 32.8%, respectively. With TBH, the plant extract decreased lipid peroxidation (estimated from malondialdehyde formation) by a mean of 29.9 +/- 1.1% together with a 46.8% and 54.7% decrease in the release of LDH and AST, respectively into the incubation medium. Significant protection was also obtained when the Osbeckia extract was added to the incubation medium up to 30 min after pre-exposure of the hepatocytes to either galactosamine or, to a lesser extent, TBH. The results support the use of Osbeckia as a hepatoprotective agent.
Animals↗
Evaluation of extracorporeal bioartificial liver devices.
The initial clinical studies on artificial liver support were performed at King's College Hospital, London during the late 1970s. Initially using charcoal haemoperfusion, and subsequently resin haemoperfusion, and these studies culminated in a controlled clinical trial of charcoal haemoperfusion in which overall survival was high, but no statistically significant benefit was found. From this study, much information was also obtained about the clinical importance of the various complications of acute liver failure, and the experience of King's over the last 2 decades exceeds 1,000 patients. The aim of this article is to review the potential of the exciting new developments in this field of bioartificial liver support incorporating hepatocytes. It focuses on the published findings of early clinical use of these systems and attempts to identify what is needed in further studies. It is of paramount importance that future trials are designed to give the greatest information on the effects of bioartificial liver support. For these, the biocompatibility of the systems should to be confirmed with detailed assessment and sensitive tests need to be developed to determine the metabolic functional efficacy of these devices. The possible relationship of treatment to liver regeneration has been considered, because without this these systems will in many cases be limited to use as a bridge to liver transplantation. Finally, some of the possible future modifications of the cell-based liver support systems are discussed.
Animals↗
The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy.
BACKGROUND/AIMS: Quinolinic acid is an endogenous neuroexcitant derived from tryptophan. Brain quinolinic acid concentrations are reportedly elevated in chronic liver failure. The aim of this study was to determine if brain quinolinic acid levels correlate with the severity of hepatic encephalopathy. METHODS: Postmortem samples of selected brain regions and plasma samples taken at several stages of encephalopathy were obtained from patients with acute and chronic liver failure. Quinolinic acid levels were measured by mass spectroscopy using [18O]quinolinic acid. RESULTS: Plasma quinolinic acid levels were significantly increased by stage I encephalopathy in patients with acute liver failure and by stages II and III in patients with chronic liver failure. Brain quinolinic acid levels were elevated only in patients with acute liver failure and were uniformly distributed at concentrations below those observed in plasma. CONCLUSIONS: The uniform distribution of quinolinic acid at subplasma concentrations in the brains of patients with acute liver failure suggests that it is synthesized peripherally and enters the brain across a permeabilized blood-brain barrier. Whereas the elevation of brain quinolinic acid levels in patients who died of acute but not chronic liver failure suggests that the involvement of quinolinic acid in the pathogenesis of hepatic encephalopathy is minimal, it could predispose these patients to seizures.
Acute Disease↗
Protective effects of Osbeckia octandra against paracetamol-induced liver injury.
1. Osbeckia octandra is a plant used in traditional medicine to treat jaundice and other liver disorders. In this study, the effects of Osbeckia leaf extract on paracetamol-induced liver injury were investigated both in vivo in mice and in rat hepatocytes in vitro. 2. Oral administration of Osbeckia extract (330 mg/kg) at the same time as paracetamol (450 mg/kg) to mice, resulted in a significant protection (p < 0.05) against liver damage, as assessed by improvements in the blood Normotest (39.1 +/- 1.9 versus 46.3 +/- 2.0 s), total liver glutathione (730 +/- 39 versus 574 +/- 27 micrograms/250 mg liver), plasma aspartate aminotransferase level (916 +/- 225 versus 1965 +/- 291 iu/l), and liver histopathology at 24 h after paracetamol administration. 3. In experiments to assess the direct effects of Osbeckia extract, significant protection was also found in freshly isolated rat hepatocytes against damage induced by 185 microM 2,6-dimethyl N-acetyl p-quinoneimine (2,6-diMeNAPQI, an analogue of NAPQI, the toxic metabolite of paracetamol) in vitro. When Osbeckia extract (500 micrograms/ml) was added to the incubation medium at the same time as 2,6-diMeNAPQI significant changes in cell viability (78.4 +/- 3.3 versus 47.2 +/- 5.8% of control, p < 0.001), cell reduced glutathione (GSH) level (35.0 +/- 3.1 versus 23.8 +/- 1.5%, p = 0.009), and reduced release of lactate dehydrogenase (129.9 +/- 6.6 versus 224.6 +/- 12.1%, p < 0.001) were demonstrated after 1 h incubation as compared with 2,6-diMeNAPQI alone. 4. Significant protection was still obtained against 2,6-diMeNAPQI in vitro when addition of Osbeckia extract was delayed by 20 min. These results indicate that Osbeckia extract can protect against paracetamol-induced liver injury.
Acetaminophen↗
Fibrinolytic abnormalities following liver transplantation in patients with fulminant hepatic failure.
OBJECTIVE: To evaluate the fibrinolytic system after liver transplantation in patients with fulminant hepatic failure. DESIGN: Seven patients were studied prior to, and for 4 days after, liver transplantation. METHODS: Both activators and inhibitors of the fibrinolytic system were investigated in seven patients with fulminant hepatic failure who underwent liver transplantation. RESULTS: alpha 2-antiplasmin and C1-inhibitor levels increased rapidly after transplantation (81 and 53% of normal on day 1; 106 and 99% on day 2, respectively). Plasminogen levels remained low throughout the 4-day study period. Plasminogen activator inhibitor-1 was higher than normal before transplantation (21.0 compared with 7.4 U/ml) and increased further on the first day after operation (37.5 U/ml; P < 0.05 versus pre-transplantation). Tissue plasminogen activator levels remained normal (pre-operative, 7.0 IU/ml; Day 4, 0.2 IU/ml). D-dimer remained elevated during the postoperative period showing increased fibrinolytic activity. Thrombin-antithrombin III complex was also elevated during the study period. Antithrombin III was greatly reduced prior to transplantation (13.7% of normal) and plasma levels were less than 50% of normal values during the study. CONCLUSIONS: Measures of fibrinolytic activity are raised after liver transplantation in patients with fulminant hepatic failure. This is probably due to increased fibrin formation caused by a coexisting hypercoagulable state.
Adult↗
Acute phase response after liver transplantation for fulminant hepatic failure and cirrhosis.
The hepatic acute phase response after orthotopic transplantation (OLT) was studied in patients with fulminant hepatic failure (FHF) and with cirrhosis, in relation to the pre-existing disease. Plasma levels of C-reactive protein (CRP) increased significantly on day 1 after OLT in both the FHF (delta = 58 micrograms/ml) and cirrhosis (delta = 94 micrograms/ml) groups and reached a peak 4-5 days post surgery. alpha 1-Antitrypsin reached normal levels on day 1 post-transplant and fibrinogen reached normal levels on the 3rd day. The main stimulator of acute phase protein synthesis IL-6 was significantly increased pre-OLT in plasma in both FHF (median 54 pg/ml) and cirrhosis (median 8.7 pg/ml) patients compared to controls (2.35 pg/ml, P < 0.05). After OLT, IL-6 decreased rapidly in patients with FHF, indicating either removal of the source of IL-6 or clearance by the transplanted liver. In patients with cirrhosis, plasma IL-6 remained low, except in three patients who developed infection/rejection and whose IL-6 levels rose above 100 pg/ml. In conclusion, there is a marked acute phase response in the liver graft after transplantation, irrespective of the aetiology of the liver disease for which the transplant was performed.
Acute-Phase Reaction↗
Predicting survival in fulminant hepatic failure using serum Gc protein concentrations.
Plasma Ge protein sequesters actin released into the circulation after massive hepatocyte necrosis, but is greatly depleted in the process. In fulminant hepatic failure (FHF), Gc is present in serum both as a complex with actin and as unbound protein, the latter becoming completely exhausted in those patients with the most severe FHF. In the present study, 47 consecutive patients with FHF, 39 of whom were the result of acetaminophen (AC) overdose, were evaluated to determine whether measurement of Gc protein levels could be used to predict survival. Using serum samples obtained shortly after admission as well as later samples, levels for total Gc protein, percentage of Gc complexed with actin, and calculated unbound Gc remaining in serum were compared for survivors and those who died of their illness. The most marked changes were present in unbound Gc levels in nonsurvivors, the mean of which for follow-up samples was 10% of normal mean values, as compared with 23% of normal mean values in those who survived (P < .01). Using a cutoff value for unbound Gc protein of > or = 34 micrograms/mL to predict survival, outcome was correctly predicted in 32 of 47 (68%) patients using early samples, and in 24 of 27 (89%) patients using later sera. No differences were observed between values and/or outcome in AC and non-AC cases. Measurement of Gc protein level correctly predicted all patients dying of hepatic failure. This single measurement compares favorably with multifactorial predictive models, such as the King's College model, and might be a useful test for patients being considered for transplantation.
Forecasting↗
Plasma hepatocyte growth factor and biliprotein levels and outcome in fulminant hepatic failure.
Plasma levels of growth factors may be important in determining the extent of liver regeneration in patients with fulminant hepatic failure and in this study human hepatocyte growth factor and biliprotein (bilirubin covalently bound to albumin) were determined in patients with fulminant hepatic failure, mainly as a result of acetaminophen overdose. Admission values for plasma human hepatocyte growth factor were significantly raised, although with a wide range in acetaminophen-induced fulminant hepatic failure (median 7.4 ng/ml, range 0.45-48.4 ng/ml, n = 34) and in fulminant hepatic failure from other causes (3.8 ng/ml, 1.72-25.1 ng/ml, n = 9) as compared to normal subjects (0.24 ng/ml, 0-0.5 ng/ml, n = 30). Higher plasma human hepatocyte growth factor was observed in patients who died (10.1 ng/ml, 3.8-48.4 ng/ml, n = 19) than in those who survived (4.3 ng/ml, 0.45-25.1 ng/ml, n = 22, p < 0.02), which may reflect lack of hepatic clearance in the former group. The median plasma biliprotein on admission (13.2 mg/l, range 6.3-100.7 mg/l, n = 43) was significantly increased compared to normal subjects (1.3 mg/l, 0-4.1 mg/l, n = 7, p < 0.001) with no difference between patients who survived or died, although when plasma biliprotein results were expressed as a percentage of the total bilirubin, the values were slightly higher in survivors (median 14.4%, range 10.8-40.5%, n = 23) compared to those who died (12.1%, 7.7-20.9%, n = 20, p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Extent of the acute phase response in fulminant hepatic failure.
The extent of the acute phase response and the relation between acute phase proteins and cytokines in plasma was investigated in 50 patients with fulminant hepatic failure. On admission, C reactive protein was significantly higher in fulminant hepatic failure (median: 12.4 micrograms/ml, range:0.2-112 micrograms/ml) than in 20 controls (median: 0.8 microgram/ml, range: 0.3-2.9 micrograms/ml, p < 0.001). Serial measurements showed that plasma C reactive protein increased daily after admission until day 5, the end of the study period. alpha 1-Antitrypsin (AAT) (median: 69.1%, range: 27.5-124%) and fibrinogen (median: 1.10 g/l, range: 0-2.82 g/l) were significantly lower in fulminant hepatic failure on admission than in controls (AAT: median: 126%, range: 75.4-149%; fibrinogen: median 2.48 g/l, range: 1.82-3.39 g/l, p < 0.001) and did not change subsequently. Both AAT and fibrinogen were maintained at significantly higher concentrations in survivors than in those who did not. Bacterial infection occurred in 23 patients during the course of fulminant hepatic failure, but did not influence the concentrations of these three proteins. Interleukin 6 was significantly higher in fulminant hepatic failure (median: 21.2 pg/ml, range: 0-871 pg/ml) than in controls (median: 2.4 pg/ml, range: 1.5-8.2 pg/ml, p < 0.001). There was a significant correlation between interleukin 6 and the C reactive protein concentrations in patients with viral hepatitis on admission and in all patients 48 hours later, consistent with other evidence that interleukin 6 stimulates synthesis of this acute phase protein.
Acetaminophen↗
Evaluation of the BioLogic-DT sorbent-suspension dialyser in patients with fulminant hepatic failure.
The BioLogic-DT sorbent suspension dialyser was developed to remove toxic substances from the blood of patients with liver failure. In the present study a randomised controlled trial was carried out in 10 patients with fulminant hepatic failure who had developed grade 4 encephalopathy to evaluate the safety and biocompatibility of the dialyser in such severely ill patients. A total of 18 treatments were performed in 5 patients. Haemodynamic stability was maintained throughout. There was a significant loss of platelets (163 +/- 34 to 101 +/- 13 x 10(9)/l) and decrease in plasma fibrinogen (0.53 +/- 0.09 to 0.31 +/- 0.08 g/l) with a rise in blood activated clotting time (190 +/- 17 to 223 +/- 22 sec)--not seen in the controls--, which was a result of the dialysis being carried out without the use of heparin as anticoagulant. Removal of metabolites by treatment was limited, with no significant effect on blood ammonia level and further developments of the system will be needed for this very sick group of patients.
Adult↗
Hepatocyte growth factor and plasminogen activation in fulminant hepatic failure.
Human hepatocyte growth factor (hHGF) has considerable sequence homology with plasminogen and both proteins can be activated by plasminogen activators. The aim of this study was to investigate the relationship between plasma hHGF and fibrinolysis in patients with fulminant hepatic failure (FHF), in whom proteases of coagulation are known to be activated and hHGF levels have been shown to be raised as a consequence of hepatic regeneration. Serum hHGF measured by ELISA was increased in FHF (median 6.67 ng/ml, range 1.2-62 ng/ml), but the values did not correlate with the decreased plasminogen level (median 9%., range 0.7-35.5%) or the level of t-PA which was normal. There was a significant correlation between serum hHGF and increased plasma D-dimer (median 2,163 microgram/l, range 39-7 311 microgram/l), produced by the action of plasmin on fibrin and increased plasma thrombin-antithrombin III complexes (TAT, median 31.7 microgram/l, range 3.7-105 microgram/l). These relationship could be indicative of an involvement of blood coagulation, possibly a specific serine protease, in hHGF activity. After liver transplantation, plasma hHGF was rapidly cleared to almost normal levels, whereas D-dimer and TAT continued to be at elevated levels.
Adolescent↗
Humoral inhibitor of rat hepatocyte DNA synthesis from patients with fulminant liver failure.
Sera and ultrafiltrates (relative molecular mass < 10,000 Da) from patients with fulminant liver failure inhibit hepatocyte DNA synthesis in vivo. In this study the effects of ultrafiltrates from pooled sera from fulminant liver failure patients in the United Kingdom and plasma ultrafiltrates from fulminant liver failure patients in Japan have been investigated in primary cultured rat hepatocytes, with incubation for up to 72 hr. Both types of ultrafiltrate inhibited the incorporation of [3H]thymidine into acid-precipitable material and reduced the cell labeling index as determined on autoradiography in hepatocytes stimulated by epidermal growth factor and insulin compared with normal sera/plasma ultrafiltrates. The inhibitory effects observed were dose dependent, reversible when the fulminant liver failure ultrafiltrate was removed and were not associated with increased release of lactate dehydrogenase or suppression of protein synthesis as assessed on the basis of the incorporation of [3H]leucine. The effects appeared to be specific for hepatocytes; in preliminary experiments DNA synthesis was not inhibited in cultured fibroblasts (NIH 3T3 cells). These experiments are further evidence of the presence of an inhibitory factor of relative molecular mass less than 10,000 Da in the blood of patients with fulminant liver failure.
Adolescent↗
Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy.
Levels of benzodiazepine receptor ligands were measured in plasma samples from 25 patients in various stages of hepatic encephalopathy due to fulminant liver failure who were not exposed to pharmaceutical benzodiazepines immediately before or during hospitalization. Chromatographic analysis of extracted plasma samples revealed one to nine fractions containing material that competitively inhibited [3H]flumazenil binding to benzodiazepine receptors with the pharmacological properties of benzodiazepine receptor agonists. Two of these peaks were positively identified as the 1,4-benzodiazepines diazepam and N-desmethyldiazepam on the basis of chromatographic, ultraviolet and mass spectral evidence. The plasma levels of diazepam and N-desmethyldiazepam were significantly increased above control values in stage 4 hepatic encephalopathy, whereas total benzodiazepine receptor ligand concentrations were increased above control in stages 1 through 4. A significant but weak linear correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor ligands and the severity of hepatic encephalopathy. Thus increased concentrations of benzodiazepine receptor ligands appear to contribute to the enhancement of GABAergic neurotransmission in hepatic encephalopathy, particularly in stage 4. These results constitute further support for a role for benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy associated with acute liver failure.
Adult↗
Controlled trial of antithrombin III supplementation in fulminant hepatic failure.
Patients with fulminant hepatic failure have severe circulatory disturbances which may be due to fibrin and cellular plugs in micro-vessels which are a consequence of intravascular coagulation and which can lead to multiorgan failure. Since antithrombin III supplementation has been shown to be beneficial in animal models of septic shock with disseminated intravascular coagulation, a controlled study was performed to investigate the effect of antithrombin III supplementation in fulminant hepatic failure. Twenty-five patients in grade III or IV coma were selected on the basis of evidence of sepsis, intravascular coagulation and a high risk of developing multiorgan failure. Thirteen patients received 3000 units of antithrombin III (Kybernin P; Behringwerke), followed by a further 1000 units every 6 h. Antithrombin III activity increased from 0.26 +/- 0.04 SE U/ml to 0.82 +/- 0.07 U/ml at 3 h post infusion (normal range 0.80-1.20 U/ml) and remained greater than 0.80 U/ml throughout the study without any apparent increase in the frequency of bleeding. However, survival was not improved and markers of intravascular coagulation remained similar between the two groups. Thus, although the antithrombin III deficiency in fulminant hepatic failure can be corrected by supplementation with antithrombin III concentrate, its use in the prevention of intravascular coagulation and to avoid microvessel plugging needs to be studied at an earlier stage in the disease.
Adolescent↗
Clearance and tissue distribution of staphylococcal enterotoxin A in the rat and potential use of adsorbents for removal from plasma.
Many of the profound effects of staphylococcal septicaemia are thought to be the result of entry of enterotoxins into the systemic circulation. The aim of this study was to investigate the disposition of staphylococcal enterotoxin A (SEA) in the rat and its possible removal from blood. SEA labelled with 125I was administered intravenously (250 micrograms/kg) to rats. The blood clearance of SEA showed a biphasic pattern; an initial fast disappearance (half-life c. 3 min) was followed by a slower one (half-life c. 2 h). Thirty minutes after injection of 125I-labelled SEA, most of the radioactivity was concentrated in the kidneys, indicating that renal excretion was the main route of elimination of SEA. The adsorption capacities of polymer-coated activated charcoal (DHP-1 and Adsorba 150C), uncharged resin (Amberlite XAD-7), anion exchange resin (Dowex-1) and polymyxin B matrix were assessed by measurement of the equilibrium adsorption isotherms for SEA. DHP-1 charcoal, Amberlite XAD-7 resin and Dowex-1 resin adsorbed similar amounts of SEA in human plasma. Plasma perfusion experiments were performed in vitro with small columns containing either charcoal or resin adsorbents. Over 4 h perfusion, DHP-1 charcoal removed 50% of the initial amount of 125I-SEA, Adsorba 150C charcoal 8.1% of SEA and Amberlite XAD-7 resin 32.5% of SEA. These results suggest that it may be feasible to develop the adsorbent columns for direct removal of SEA from the plasma of patients with staphylococcal septicaemia.
Adsorption↗
Use of sorbent columns and haemofiltration in fulminant hepatic failure.
Artificial liver support systems were developed to remove potential toxins from the circulation of patients with liver failure. A wide range of substances have been implicated in the toxic manifestations of liver failure, but no substance(s) has been identified as being of key importance. Charcoal haemoperfusion appeared to be beneficial in early studies, but when clinical trials were performed in 137 patients at King's College Hospital there was no significant improvement in survival over intensive care alone. There have been many studies using haemodialysis/filtration systems, where an improvement in conscious level of the patient was reported, but the effect on survival was less clear. Recently in Japan, continuous high volume haemofiltration with the addition of plasma exchange has been used to support liver failure patients. In liver failure, endotoxaemia and increased cytokine production are important in the pathogenesis of circulatory failure. Experiments on adsorbents to remove cytokines have shown that Amberlite XAD-7 resin can remove significant amounts of tumour necrosis factor and interleukin-6 from liver failure plasma. The development of hepatocyte bioreactors with synthetic and metabolic function for clinical use will be a major advance in liver support.
Adsorption↗