Intrinsic versus idiosyncratic drug-induced hepatotoxicity--two villains or one?

Abstract

"Intrinsic" and "idiosyncratic" drug-induced liver injury reactions are commonly thought to arise by different modes of action. Intrinsic toxicity is reproducible in animals and occurs dose-dependently at sublethal doses. Environmental and genetic sensitivity factors can influence the toxicity of intrinsic hepatotoxicants. Among these is inflammatory stress. For example, exposure of mice to inflammatory bacterial lipopolysaccharide (LPS) causes a leftward shift in the dose-response relationship for acetaminophen hepatotoxicity; that is, acetaminophen toxicity is enhanced by LPS-induced inflammatory stress. Idiosyncratic reactions present themselves very differently than intrinsic ones; they happen in a minority of patients, with variable time of onset and no obvious relationship to drug dose, and they are not reproducible in usual animal tests. Although these characteristics seem to distinguish them from intrinsic reactions, consideration of fundamental principles of dose response can explain the differences. For a drug that causes idiosyncratic hepatotoxicity, the liver may not be a typical target for toxicity because the dose-response curve for hepatotoxicity lies to the right of the lethal dose. However, a sporadically occurring sensitivity factor, such as an inflammatory episode, could shift the dose-response curve for hepatotoxicity to the left, thereby bringing hepatotoxic doses into the therapeutic range. This hypothesis can account for the bizarre characteristics of idiosyncratic reactions and is supported by recent results showing that several drugs associated with human idiosyncratic reactions can be rendered hepatotoxic to rodents upon interaction with an inflammatory stimulus. In light of this view, intrinsic and idiosyncratic reactions may not be that different after all.

Fig. 1.

Intrinsic toxicity. To be a useful drug, pharmacologically effective doses must lie to the left of those that cause toxicity and death. The asterisk represents a therapeutically useful dose that is nontoxic. As dose of a drug or other toxicant increases, a threshold is reached, above which injury occurs to one or more organs. The severity of injury is dose-related, and tissues vary in their sensitivity to toxicants. Here, the liver is represented as a “target organ,” inasmuch as it responds with injury at doses smaller than those that cause death or injury to less sensitive organs.

Fig. 2.

Initiation and progression events in acetaminophen (APAP) hepatotoxicity.

Fig. 3.

Simplified view of the inflammatory response. Inflammation is often initiated by agonists such as LPS that bind to Toll-like receptors on various inflammatory cells. In the liver, this activates Kupffer cells and sinusoidal endothelial cells, resulting in release of numerous inflammatory mediators. Some of these mediators can feed back to enhance these responses and activate other cells. The resulting “inflammatory stress” entails an alteration in tissue homeostasis that can either be beneficial (e.g., microbial killing), harmful (e.g., septic shock, multiple organ injury), or harmless depending on its magnitude.

Fig. 4.

Susceptibility to intrinsic (A) and idiosyncratic (B) hepatotoxicities: a dose-response perspective. For drugs that cause intrinsic hepatotoxicity (e.g., APAP), substantial differences in individual sensitivity can occur. One way in which such differences arise is through stresses such as inflammation that can change one's sensitivity to the toxic effects of the drug. This manifests as a leftward shift in the dose-response curve for hepatotoxicity (A). Drugs that cause idiosyncratic toxicity do not cause liver injury in most patients. This may be because the dose-response curve for hepatotoxicity lies to the right of the lethal dose of a drug, so that hepatotoxicity is not seen. However, an episode of hepatic stress from an inflammatory response or other causes may shift the dose-response curve to the left to expose a hepatotoxic response in the range of therapeutic drug doses (B).

Fig. 5.

Drugs may increase susceptibility to inflammatory liver injury. Humans and animals are typically exposed to inflammagens such as LPS at doses far below those that cause injury to liver or other tissues (star). Drugs can increase the risk of inflammatory liver injury by increasing the sensitivity of the liver to inflammatory injury (a) or by increasing exposure to an inflammagen (b). The latter can happen, for example, if the drug affects the intestine to increase the translocation of LPS or bacteria into the portal circulation.