Liver Toxicity and Hepatic Necrosis

Types of Liver Toxicity

• Toxicant-induced liver injury involves mechanisms leading to cell death or necrosis.
• Acetaminophen and CCl4 toxicity is commonly bio-activated by CYP-450, predominantly causing centrilobular necrosis (Zone 3 where CYP-450 is abundant).
• Co-administration of enzyme inducers like ethanol enhances the toxicity of Acetaminophen and CCl4.
• Activation of Kupffer cells by factors such as Vitamin A or endotoxins exacerbates Acetaminophen toxicity due to intercellular signaling between damaged hepatocytes and activated Kupffer cells.

Mechanisms of Hepatic Necrosis

• N-acetyl-cysteine serves as an antidote for Acetaminophen toxicity by promoting the synthesis of glutathione (GSH).
• Hepatic necrosis is characterized by mitochondrial dysfunction as a result of Peroxynitrite (OONO-) binding to macromolecules like hepatic cell proteins and DNA.
• Key underlying mechanisms include lipid peroxidation, cellular macromolecule binding, mitochondrial damage, and calcium influx.

Target Organ Toxicity

• A target organ is typically the organ most affected by a toxicant, rather than the one responsible for absorption.
• Target organ toxicity results from toxins distributed via the bloodstream or lymphatics, influenced by factors such as blood supply, enzyme abundance, organ function, repair ability, and metabolic activity.
• Chemicals may have multiple target organs; for example, DDT (a chlorinated hydrocarbon) primarily affects the CNS without causing direct toxicity to adipose tissue.

Hepato-toxicity

• The liver is particularly vulnerable to toxic injuries due to its substantial blood supply and position in the portal circulation.
• First organ to encounter ingested substances, the liver significantly interacts with nutrients, metals, and toxins absorbed from the gastrointestinal tract.
• Bile secretion increases toxicity from drugs excreted in bile via enterohepatic circulation.
• Acute necrosis leads to functional liver failure, which is often irreversible.

Patterns of Liver Necrosis

• Focal necrosis involves localized damage to small clusters of hepatocytes.
• Zonal necrosis occurs in specific functional regions of the liver.
• Massive necrosis results in extensive cell death throughout the liver, affecting centrilobular, midzonal, and periportal areas.

Causative Agents of Liver Toxicity

• Known agents that cause necrosis include CCl4, acetaminophen, chloroform, halogenated hydrocarbons, and bromobenzene.
• The mechanism of CCl4 hepatotoxicity primarily leads to fatty liver and centrilobular necrosis due to its lipid solubility and subsequent metabolic activation by CYP-450.