Introduction
This topic covers liver injury caused by poisons and drugs (toxic hepatitis) and its most severe form, acute toxic degeneration (dystrophy) of the liver, in which massive hepatocyte necrosis causes acute liver failure. Viral and chronic hepatitis, and cirrhosis, belong to neighbouring topics.
Definition and causes
Toxic hepatitis is liver damage, with hepatocyte degeneration and necrosis and often inflammation, produced by chemicals, drugs or natural toxins. The liver is exposed because it receives all absorbed substances by the portal vein and converts them in hepatocytes.
- Predictable (dose-dependent) toxins: paracetamol (acetaminophen) overdose, carbon tetrachloride, yellow phosphorus, the mushroom Amanita phalloides (amatoxins), aflatoxin, and ethanol.
- Idiosyncratic (unpredictable) drug reactions: halothane, isoniazid, rifampicin, methyldopa, chlorpromazine, amoxicillin-clavulanate, phenytoin, valproate, and many others; they may be metabolic or immune-mediated, and can appear at normal doses.
- Industrial chemicals such as vinyl chloride and arsenic, and herbal remedies.
Pathogenesis
- Many agents are converted by cytochrome P450 in hepatocytes to reactive metabolites. In paracetamol poisoning the toxic metabolite NAPQI is normally neutralized by glutathione; when glutathione is exhausted, NAPQI binds to cell proteins and causes necrosis. Carbon tetrachloride yields free radicals that cause lipid peroxidation of membranes.
- Other mechanisms: mitochondrial injury, inhibition of protein synthesis (amatoxin blocks RNA polymerase II), damage to bile canaliculi (cholestasis), and immune reactions in which the drug acts as a hapten.
- The site of injury follows enzyme distribution: centrilobular hepatocytes (zone 3) have the highest P450 content and low oxygen, so they are damaged first by paracetamol and CCl4.