Drug induced liver injury pathophysiology
Template:Drug-induced hepatitis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both hepatocellular and extracellular mechanisms. The following are some of the mechanisms that have been described:
Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death.
Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.
Cytolytic T-cell activation: Covalent binding of a drug to the P450 enzyme acts as an immunogen, activating T cells and cytokines and stimulating a multifaceted immune response.
Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.
Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis.
Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.
Drug Toxicity Mechanisms
The classic division of drug reactions is into at least 2 major groups,
- Drugs that directly affect the liver
- Drugs that mediate an immune response.
Hypersensitivity
Phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency period of 1-4 weeks.
Idiosyncratic Drug Reactions
Idiosyncratic drug reactions can be subdivided into those that are classified as hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic.
Intrinsic or predictable drug reactions
Drugs that fall into this category cause reproducible injuries in animals, and the injury is dose related. The *injury can be due to the drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.
Metabolic-idiosyncratic
This type of reaction occurs through an indirect metabolite of the offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms may occur with some drugs (e.g., halothane).