Immune-mediated Liver Damage

Primary biliary cirrhosis is characterized by progressive inflammatory destruction of the bile ducts. Immune-mediated inflammation of intrahepatic bile ducts results in remodeling and scarring, causing retention of bile within the liver and subsequent hepatocellular damage and cirrhosis. The number of patients affected with primary biliary cirrhosis is difficult to estimate because many people are asymptomatic and incidental diagnosis during routine health care visits is common. 

In the absence of IL-4, the Th1 response established during the period of infection before egg production persists, and continues to promote classical macrophage activation and NO production (Brunet et al., 1999 La Flamme et al., 2001a). This type of immune response is apparently incompatible with the ongoing insult to the liver caused by egg deposition, and in combination these factors lead to severe hepatic damage and death. It is important to note that severe disease in IL-4 deficient mice and in other animals that cannot makeTh2 responses, is not associated with an increased parasite burden but rather is the result of immune-mediated damage (Brunet et al., 1997). 

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

Hepatic damage related to isoflurane anesthesia has very occasionally been described (9,10), including one report of hepatic necrosis and death (11). Hepatitis or hepatocellular injury has been described with all current volatile anesthetics. Among these, halothane-associated hepatitis has been best characterized and is probably caused by an immune reaction induced by hepatocyte proteins that have been covalently trifluoroacetylated by the trifluoro-acetyl metabolite of halothane. The reactive acyl-halide metabolite of trifluoroacetic acid can trifluoroacetylate liver proteins, resulting in immune-mediated hepatic necrosis (12). However, isoflurane biotransformation to trifluoroacetate is less than 0.2%, compared with 15-20% for halothane. 

While the demonstration that the immune suppression by a given chemical is mediated by a metabolite, and not the parent compound, is an important observation, it does not in itself account for the mechanism of action. One indirect mechanism of action, which is consistent with a role for metabolism, involves a primary consequence of the generation of many reactive intermediates, that is, liver damage. Among many different types of adaptive responses, the liver is capable of secreting a number of soluble factors. Some of these soluble factors are capable of affecting immune responses. Most notably, as pointed out in Table 1, TGF- S is capable of modulating both T- and B-cell effector... 

Liver injury can be a result of both direct cytotoxicity and antibody-dependent cellular toxicity. Alcoholic liver disease is another example of possible immune-mediated damage. Acetaldehyde, produced by the metabolism of ethanol, forms adducts with hepatic proteins similar to halothane, resulting in higher antibody titers, to which some of the liver damage following ethanol ingestion may be attributed (Ramaiah et al., 2004). However,... 

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