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Chapter: Clinical Cases in Anesthesia : Liver Disease

Describe acetaminophen- and halothane-associated hepatitis

Radical and reactive intermediates have been implicated in the hepatotoxicity of ethanol, acetaminophen (APAP), and halogenated hydrocarbons.

Describe acetaminophen- and halothane-associated hepatitis.


Acetaminophen Toxicity


Radical and reactive intermediates have been implicated in the hepatotoxicity of ethanol, acetaminophen (APAP), and halogenated hydrocarbons. Both radicals and reactive intermediates may result in the interruption of cell function. Toxicity secondary to radical/reactive intermediates is complex and is probably the result of multiple intracellular interactions. One mechanism whereby a drug can become deleterious is via metabolic activation to a toxic metabolite. For example, APAP can cause liver damage. Glucuronidation and sulfation are the major pathways used by the liver to metabolize APAP. APAP is also metabolized by CYP to a reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) of which CYP1A2, 2E1 and 3A4 have the highest activity. Under normal conditions, e.g., an adult ingesting 650–1000 mg of APAP, only trace amounts of NAPQI are produced. However, under different conditions, e.g., a suicide attempt with ingestion of 6,500–10,000 mg (12–20 Extra Strength Tylenol®), or enhanced enzyme activity, e.g., chronic alcohol consumption, the production of NAPQI is greatly increased and hepatotoxicity can be produced even with a therapeutic dose. The effects of chronic ethanol consumption on APAP toxicity can be complex. In the presence of ethanol, APAP-mediated hepa-totoxicity is actually decreased. Ethanol acts as a competi-tive inhibitor of CYP. The toxic intermediate, NAPQI, is usually neutralized by intracellular glutathione (GSH). Nonetheless, under these extreme conditions intracellular GSH is rapidly depleted and NAPQI can then react with other intracellular constituents to cause cell damage. NAPQI has been shown to initiate lipid peroxidation, to damage DNA, as well as to alter cell proteins. In the event that the patient’s GSH is not replenished by treatment with N-acetylcysteine (a precursor of GSH), the end result can be severe liver necrosis that results in the need for liver transplantation, or even death. Accidental overdose and hepatotoxicity remain major clinical problems.

Halothane Toxicity


Halothane is a potent inhaled anesthetic that is in com-mon clinical use worldwide. Its use has declined over recent years for several reasons. Other than the fact that less toxic agents are available today, it is also known that halothane can cause hepatotoxicity. Nonetheless, its use outside the United States is common and its toxicity remains a concern.


There are two main theories as to how halothane causes hepatotoxicity. The first suggests that halothane toxicity is related to CYP’s ability to metabolize halothane via two pathways, an oxidative pathway and a reductive pathway. There are three major CYPs involved in the metabolism of potent inhaled anesthetics: CYP2E1, CYP3A4, and CYP2A6. It appears that halothane and other inhalational anesthetics are largely metabolized by the ethanol-inducible CYP, CYP2E1. CYP3A4, the most abundant isoform found in the liver (and responsible for the metabolism of many drugs), is one of the main isoforms responsible for the reductive metabolism of halothane in human microsomes. CYP2A6 can metabolize halothane via both the reductive and the oxidative pathway. Under normoxic conditions halothane is mostly metabolized via the oxidative pathway. Under conditions of low oxygen tension (e.g., decreased hepatic blood flow, hypoxemia), metabolism is via a reduc-tive pathway that produces a halothane radical. This radical can either react with a number of intracellular molecules or abstract a hydrogen to form 2-chloro-1,1,1-trifluoroethane (CTE) or undergo further reduction to form 2-chloro-1,1-difluoroethane (CDE). This radical probably causes toxicity in the same way that acetaminophen causes toxicity. Under conditions of oxidative stress and/or hypoxia, ATP and NADPH stores may be limited, which can result in a decrease in intracellular GSH. The relationship of GSH to halothane toxicity is dependent on the model being studied. In cultured rat hepatocytes, GSH status is not associated with halothane toxicity. In the guinea pig model, depletion of GSH increased protein-adduct formation and potenti-ated halothane toxicity that could be diminished by replen-ishing the GSH. The combination of decreased intracellular GSH with cellular stress secondary to increased halothane radicals can lead to cellular dysfunction and/or cell death, which may ultimately lead to liver necrosis.

The second theory of halothane toxicity is the immune theory. Severe halothane hepatotoxicity usually occurs fol-lowing a second exposure. Pohl and others (1988) have shown that exposure to halothane can lead to production of trifluoroacetyl chloride, a compound that is capable of reacting with several intracellular proteins and forming tri-fluoroacetyl (TFA) adducts. These adducts are expressed on the cell surface and are capable of inducing the production of antibodies to these altered cell proteins. The antibody-antigen complex is capable of initiating immune reactions that can result in cell death. Indeed, patients who exhibit halothane toxicity have TFA adducts expressed in their liver, as well as antibodies to these adducts in their serum.


The latter theory has been postulated for the rare, ful-minant, and often fatal immune-mediated hepatotoxicity. The former theory addresses the common nonfatal hepa-totoxicity secondary to locally produced reactive interme-diates. Regardless of whether halothane is metabolized via a reductive or an oxidative pathway, the result is reactive intermediates that could disrupt cell function.

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