Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Halothane (2-bromo-2-chloro-1:1:1-trifluoroethane) is a volatile, nonflammable anaesthetic agent which has been widely used for the last 20 years. Halothane hepatitis has been a matter of continuing controversy, but now it seems to be generally accepted as a clinical entity. Characteristically the halothane hepatitis occurs after multiple exposures to halothane within short time. The pathogenesis of the liver cell damage is obscure. It is estimated that the incidence of halothane hepatitis is about one per 8000 halothane anaesthesias and the lethality about one per 40000. Prophylaxis consists of avoiding repeated halothane anaesthesias within short time and to avoid re-exposure to halothane if otherwise unexplained liver damage has occurred after halothane.
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PMID:Halothane hepatitis. 27 92

During the past years there has been increasing concern regarding potential hazards to the anaesthetist presented by, e.g., anaesthetic agents, exposure to X-rays, virus hepatitis. Chronic exposure to inhalational anaesthetics, in particular, has been held responsible for a variety of complants and disorders. Investigations at the Technical University, Munich, have shown no appreciable difference in the sick rate between the staff of the Department of Anaesthetics and the Department of Medicine. Whereas exposure to X-radiation cannot be regarded as a health hazard provided the prescribed safety measures are adhered to, virus hepatitis still constitutes a major risk. There is also some evidence of an increased incidence of miscarriages amoung the female anaesthetic personnel. The causes are unknown. Halothane hepatitis is very rare and does not present a major risk.
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PMID:[Health hazards to the anaesthesist]. 96 86

Halothane hepatitis is now a well-recognized distinct entity in adults, but there prevails an often-taught "axiom" that halothane hepatitis "does not occur" in children. We describe 2 children who developed cholestatic hepatitis following halothane anesthesia. The first patient had no antecedent liver disease, and presented with anorexia, abdominal pain and delayed onset of jaundice after multiple halothane exposures. Halothane-specific antibodies were positive, and liver tests resolved completely. The second patient had antecedent liver disease and presented with delayed onset of unexplained high fevers for 10 days following a single halothane exposure. Gradually increasing cholestasis ensued in the absence of other causes of liver disease. Halothane antibodies were negative. These cases illustrate different clinical presentations of halothane hepatitis, such as delayed onset of jaundice or fever following halothane exposure. The difficulties in making a definitive diagnosis and the need to exclude other causes of liver disease are detailed. Risk factors and other presentations are discussed. While halothane hepatitis appears to be an uncommon entity in children, it does occur, and may present with manifestations less than fulminant hepatic failure. A high index of suspicion and a detailed history of the time sequence of events are necessary as the diagnosis is primarily clinical. Halothane-specific antibodies are helpful if positive. In any child developing unexplained jaundice or high fevers following halothane anesthesia, further exposures should be avoided and halothane-specific antibodies obtained.
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PMID:Halothane hepatitis in children. 178 63

Two halogenated anesthetics, enflurane and isoflurane, have been associated with an allergic-type hepatic injury both alone and following previous exposure to halothane. Halothane hepatitis appears to involve an aberrant immune response. An antibody response to a protein-bound biotransformation product (trifluoroacetyl adduct) has been detected on halothane hepatitis patients. This study was performed to determine cross-reactivity between enflurane and isoflurane with the hypersensitivity induced by halothane. The subcellular and lobular production of hepatic neoantigens recognized by halothane-induced antibodies following enflurane and isoflurane, and the biochemical nature of these neoantigens was investigated in two animal models. Enflurane administration resulted in neoantigens detected in both the microsomal and cytosolic fraction of liver homogenates and in the centrilobular region of the liver. In the same liver, biochemical analysis detected fluorinated liver adducts that were up to 20-fold greater in guinea pigs than in rats. This supports and extends previous evidence for a mechanism by which enflurane and/or isoflurane could produce a hypersensitivity condition similar to that of halothane hepatitis either alone or subsequent to halothane administration. The guinea pig would appear to be a useful model for further investigations of the immunological response to these antigens.
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PMID:Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies. 764 82

Exposure of human individuals to halothane causes, in about 20% of all cases, a mild transient form of hepatotoxicity. A small subset of exposed individuals, however, develops a potentially severe and life-threatening form of hepatic damage, coined halothane hepatitis. Halothane hepatitis is thought to have an immunological basis. Sera of afflicted individuals contain a wide variety of autoantibodies against hepatic proteins, in both trifluoroacetylated form (CF3CO-proteins) and, at least in part, in native form. CF3CO-proteins are elicited in the course of oxidative biotransformation of halothane, and include the trifluoroacetylated forms of protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78, and ERp99. Current evidence suggests that CF3CO-proteins arise in all halothane-exposed individuals; however, the vast majority of individuals appear to immunochemically tolerate CF3CO-proteins. The lack of immunological responsiveness of these individuals towards CF3CO-proteins might be due to tolerance, induced through the occurrence of structures in the repertoire of self-determinants, which immunochemically and structurally mimic CF3CO-proteins very closely. In fact, lipoic acid, the prosthetic group of the constitutively expressed E2 subunits of the family of mammalian 2-oxoacid dehydrogenase complexes and of protein X, was shown by immunochemical and molecular modelling analysis to be a perfect structural mimic of N6-trifluoroacetyl-L-lysine (CF3 CO-Lys), the major haptenic group of CF3CO-proteins. As a consequence of molecular mimicry, autoantibodies in patients' sera not only recognize CF3CO-proteins, but also the E2 subunit proteins of the 2-oxoacid dehydrogenase complexes and protein X, as autoantigens associated with halothane hepatitis. Furthermore, a fraction of patients with halothane hepatitis exhibit irregularities in the hepatic expression levels of these native, not trifluoroacetylated autoantigens. Collectively, these data suggest that molecular mimicry of CF3CO-Lys by lipoic acid, or the impairment thereof, might play a role in the susceptibility of individuals for the development of halothane hepatitis.
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PMID:Molecular mimicry in halothane hepatitis: biochemical and structural characterization of lipoylated autoantigens. 771 87

Halothane hepatitis appears to result from an inappropriate immune response to the products of halothane metabolism. Attempts to produce an animal model for halothane hepatitis have been largely unsuccessful. Although guinea pigs produce neoantigens following treatment with halothane, the subsequent antibody response is weak, possibly accounting for the failure to produce halothane hepatitis in these animals. In order to increase the antibody response to halothane neoantigens, three methods for trifluoroacetylating proteins were used. Guinea pigs were either treated with S-ethylthiotrifluoroacetate, autologous lymphocytes trifluoroacetylated ex vivo, or immunized with trifluoroacetylated mycobacterial protein, followed by exposure to halothane, and examined for anti-halothane metabolite antibodies (anti-TFA antibodies). Animals treated with S-ethylthiotrifluoroacetate developed anti-TFA antibodies, and following exposure to halothane exhibited an enhanced antibody response. Treatment with trifluoroacetylated lymphocytes also resulted in an enhanced anti-TFA antibody response following halothane exposure. Immunization with trifluoroacetylated mycobacterial proteins resulted in very high anti-TFA antibody titers. However, subsequent exposure to halothane had no observable effect on specific antibody titers. Exposure to halothane, regardless of treatment, resulted in the production of anti-microsomal protein antibodies. Signs of halothane hepatitis were not observed, indicating that enhancement of the humoral immune response does not appear to be sufficient for production of halothane hepatitis.
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PMID:Trifluoroacetylation potentiates the humoral immune response to halothane in the guinea pig. 775 72

Halothane hepatitis can be life-threatening, and this severe adverse reaction may arise via an immune process. We have detected autoantibodies to purified human liver microsomal carboxylesterase in sera of 17 out of 20 patients with halothane hepatitis (85%) but not in 9 halothane-exposed controls and in only 2 (at low levels) of 33 patients with liver disease due to other causes. Immunohistochemical studies localised the carboxylesterase predominantly to the centrilobular region of liver sections, which is consistent with the area affected by halothane hepatitis. Human hepatic microsomal carboxylesterase is a target antigen in halothane hepatitis, and an immune response to this protein may be involved in the liver damage observed.
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PMID:Autoantibodies to hepatic microsomal carboxylesterase in halothane hepatitis. 810 17

Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intracellular proteins such as alanine aminotransferase and occurs late in the time course following a hepatotoxic dose of a direct toxin. Prior to this disruption, there appears to be a large number of proteins covalently modified by a reactive metabolite. There are at least two possible mechanisms that may cause the toxicity. First, some critical protein is a target of the reactive metabolite. Disruption of the enzymatic function (or a critical pathway for a regulatory protein) may lead directly to cell death. With the direct hepatotoxin acetaminophen, there is a decrease in the activity of several of the early target proteins, but how this disruption of critical proteins leads to the toxicity is still unclear. The early targets appear to be proteins with accessible nucleophilic sulfhydryl groups, and usually the target has a high concentration of the protein within the cell. It is possible that the binding to some of these proteins represents a detoxification protecting more critical targets within the cell. A second mechanism for the direct toxicity is that more and more proteins become targets in the time course following administration of a direct toxin, and eventually the cells machinery is overwhelmed. The cell can then no longer function, or there is a disruption the redox balance within the cell due to the decreased function of numerous proteins. In contrast to the direct-acting toxins, the chemical-protein conjugates that initiate toxicity through an activation of the immune system appear to have a limited number of target proteins and are localized within one subcellular fraction. Halothane produces adducts almost exclusively in the microsomal fraction, and these adducts appear to be limited to selective proteins with high concentrations in this fraction. The substitution level is an important factor in the development of an immune response. Halothane hepatitis patients' antibodies primarily recognize proteins with a high substitution level. For halothane and diclofenac, the proteins are accessible to the immune system through exposure on the plasma membrane. Trichloroethylene binds primarily to a 50-kDa microsomal protein, and preliminary evidence has been presented which indicates that a trichloroethylene-protein conjugate is released into the blood following exposure, where contact with the immune system can occur. In order to elicit an immune response the immune system requires multiple exposure to the chemical-protein conjugates. With halothane hepatitis and with diclofenac hepatitis, as well as occupational and environmental exposure to trichloroethylene, there are multiple exposures leading to repeat presentation of the protein adducts to the immune system; this situation is not generally found with acetaminophen overdose patients. In summary, direct toxicants such as acetaminophen covalently bind to selected targets which may be critical to the development of hepatotoxicity, and they later form adducts with numerous proteins which may overwhelm the cell's capacity to maintain homeostasis, leading to loss of vital function and cell death (Fig.3). In contrast, indirect toxicants that elicit an immune-mediated toxicity such as halothane, and possibly diclofenac and trichloroethylene, appear to have a limited number of protein targets with a high substitution level, and the immune system is exposed repeatedly to the modified proteins.
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PMID:Covalent binding of xenobiotics to specific proteins in the liver. 918 10

Halothane, an effective and usually safe anaesthetic agent, is rarely associated with the development of fulminant hepatic failure. Guidelines have been developed to reduce the probability of a patient developing halothane hepatitis. However, cases continue to occur and, in some cases, the guidelines have been ignored. Stricter adherence to the guidelines will reduce, but not totally prevent, further cases from occurring. Once halothane hepatitis has developed, there are no specific treatments and liver replacement may be required. Halothane hepatitis is a paradigm for immune mediated adverse drug reactions. The mechanism appears to be related to development of sensitization to both autoantigens (including CYP2D6) and halothane-altered liver cell determinants.
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PMID:Halothane hepatitis. 974 90

Halothane hepatitis occurs because susceptible patients mount immune responses to trifluoroacetylated protein antigens, formed following cytochrome P450-mediated bioactivation of halothane to trifluoroacetyl chloride. In the present study, an in vitro approach has been used to investigate the cytochrome P450 isozyme(s) which catalyze neoantigen formation and to explore the protective role of non-protein thiols (cysteine and reduced glutathione). Significant levels of trifluoroacetyl protein antigens were generated when human liver microsomes, and also microsomes from livers of rats pre-treated with isoniazid, phenobarbital or beta-naphtoflavone, were incubated with halothane plus a nicotinamide adenine dinucleotidephosphate (NADPH) generating system. Immunoblotting studies revealed that the major trifluoroacetyl antigens expressed in vitro exhibited molecular masses of 50-55 kDa and included 60 and 80 kDa neoantigens recognized by antibodies from patients with halothane hepatitis. Much lower concentrations of halothane were required to produce maximal antigen generation in isoniazid-induced rat microsomes, as compared with phenobarbital or isosafrole-induced microsomes (0.5 vs 12.5 microl/ml). In isoniazid-induced microsomes, antigen generation was inhibited > 90% by the nucleophiles cysteine and glutathione and by the CYP2E1-selective inhibitors diallylsulfide and p-nitrophenol, but was unaffected by inhibitors of other P450 isozymes (furafylline, sulfaphenazole or triacetyloleandomycin). Neoantigen formation in six human liver microsomal preparations was inhibited in the presence of diallylsulfide, but not by furafylline, sulfaphenazole or triacetyloleandomycin, and exhibited marked variability which correlated with CYP2E1 levels. These results suggest that the balance between metabolic bioactivation by CYP2E1 and detoxication of reactive metabolites by cellular nucleophiles could be an important metabolic risk factor in halothane hepatitis.
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PMID:Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis. 987 5


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