Liver Disease Caused by Anesthetics, Chemicals, Toxins, and Herbal and Dietary Supplements
CCl4 is a classic example of a zone 3 hepatotoxin that causes necrosis leading to hepatic failure (seeTable 89.4). Injury is mediated by its metabolism to a toxic trichloromethyl radical catalyzed by CYP2E1.18,64 Alcohol potentiates the injury through induction of this cytochrome.2 Most cases have been the result of industrial or domestic accidents, such as inhalation of CCl4-containing dry cleaning fluids that are used as household reagents or ingestion of these compounds by alcoholics who mistake them for potable beverages.2,65 At the cellular level, direct damage to cellular membranes results in leakageof intracellular enzymes and electrolytes, leading in turn to calcium shifts and lipid peroxidation.18 Hepatic steatosis develops as a result of triglyceride accumulation caused by haloalkylation-dependent inhibition of lipoprotein micelle transport out of the hepatocyte.64 CCl4 is more toxic than other haloalkanes and haloalkenes because toxicity correlates inversely with the level of bond dissociation energy, number of halogen atoms, and chain length (Table 89.5).2,64 In older series, complete clinical and histologic recovery from CCl4-induced liver damage was the rule with modest exposures, but supervening acute tubular necrosis and GI hemorrhage were associated with a case-fatality rate of 10% to 25%.2,5 Activation of endonucleases, causing chromosomal damage and mutations, may result in carcinogenesis.
Chloroform (trichloromethane) remains an important experimental hepatotoxin, although its use as an anesthetic has long been abandoned (see earlier).2,5,8,65 Hepatic injury, including chronic hepatitis, has been reported with 1,1,1-trichloroethane,66 which has been used as an inhaled treatment for trigeminal neuralgia, and instances of jaundice and hepatic necrosis are described in as many as 10% of workers exposed to the compound during its manufacture.8
Hydrochlorofluorocarbons (HCFCs) have been associated with liver injury in several industrial workers exposed to Tetrachloroethylene and 1-chlorotetrafluoroethane (HCFC-124), both of which are metabolized to reactive trifluoroacetyl halide intermediates similar to those implicated in halothane toxicity.57 Zone 3 necrosis is present on liver biopsy specimens, and autoantibodies against CYP2E1 or P58 protein disulfide isomerase isoform are detected in the serum of many affected persons. As with halothane, liver toxicity may be potentiated by ethanol.