Toxic damage to the liver usually presents either as
1) Fatty liver -- an accumulation of lipids that may or may not damage the liver functionally or
2) Necrosis -- direct cellular death

Necrosis usually occurs as a result of direct cellular injury (of the types discussed previously in the course), for instance as with acetaminophen toxicity, or as a result of immune-mediated attack to the hepatocyte.  The specific site of initial necrosis may differ and may reflect the nature of the toxicant.  (RECALL that hepatocytes are arranged in roughly hexagonal lobules around a central vein and surrounded by hepatic vasculature).
Perilobular (periportal) necrosis -- appears around the periphery of the lobule -- often due to toxicants that present to the liver in their active form.

Midzonal necrosis -- appears in the central portion of the lobule -- may be the result of direct toxic action or may reflect the action of hepatotoxic metabolites.

Centrilobular necrosis -- appears around the central vein -- often due to hepatotoxic metabolites that are formed within the lobule itself.

Necrosis may exhibit a dose:response relationship (the lower the dose, the less toxic the compound, with greater toxicity at successively higher doses).  Carbon tetrachloride is a classic hepatotoxic agent that produces necrosis by direct tissue damage (altering cellular membrane permeability and direct lysosomal damage) and through biochemical lesions (uncoupling of oxidative phosphorylation to decrease protein synthesis).  Other agents that may cause biochemical lesions (thus reducing lipo-, structural, or functional proteins) include dimethylnitrosamine and galactosamine.
 

Fatty liver refers to the accumulation of fats (primarily triglycerides, TG) in hepatocytes.  This accumulation may occur by either increased TG synthesis and/or decreased TG secretion.  Again, carbon tetrachloride is a classic example of an hepatotoxin that produces fatty liver (hence it is doubly toxic to the liver) by interfering with VLDL production and inhibiting fatty secretions.  Other hepatotoxins that produce fatty liver include puromycin (decreases carrier protein synthesis thereby decreasing fatty secretion), tetracycline (decreases fatty secretion), and ethanol.  SOME evidence suggests that fatty liver, per se, is NOT DIRECTLY hepatotoxic (it does not cause cell death or reduce hepatic function).  HOWEVER, increased TG within the cell DOES increase the risk of lipid peroxidation which does damage the cellular and organelle membranes leading to necrosis.  Therefore, fatty liver may be indirectly toxic to the organ.  Agents that increase this risk by causing lipid peroxidation include (again) carbon tetrachloride and chloroform.

Hepatotoxicity may also present as a dysfunction of the bile forming and/or secretory function of the liver.  Recall that the liver normally produces bile (which is used in the transport and absorption of lipids from the intestine for re-uptake into the liver) and secretes it, via the bile duct, into the intestines.  Decreases in the bile flow will result in hyperbilirubinaemia (jaundice) and may occur as a result of blocked transport of the bile.  Manganese toxicity and certain drugs (anabolic steroids) commonly cause this type of cholestatic injury.

Cirrhosis -- This chronic hepatic condition (common with certain toxicants such as ethanol) results from deficiencies in the repair mechanisms of the liver and local hypoxia.  As local areas of the liver are damaged, normal repair mechanisms result in fibrotic scar tissue formation.  This repair process may be magnified (often as a result of extensive necrosis or as a direct result of the toxicant itself) such that extensive scarring of sections of the liver into separate nodules (effectively creating many small livers rather than one continuous organ).  This stage of the disease is termed HEPATIC FIBROSIS.  Blood flow is altered during this fibrotic stage creating areas of ischaemia, thus further damaging the liver.  As repair attempts continue, the fibrous tissue contains increasing amounts of collagen, ultimately leading to a highly fibrous, non-functional liver.  Classic examples of compounds that can cause hepatic cirrhosis include carbon tetrachloride, aflatoxins, and ethanol (there is some debate over whether ethanol itself causes the cirrhosis or whether it is ethanol AND a poor diet that results in cirrhosis -- controlled animal studies in which the animals received good nutrition and chronic ethanol never exhibited cirrhosis while those that were nutritionally deprived and were chronically administered ethanol did develop cirrhosis).

Changes in hepatic blood flow may also cause hepatotoxicity.  Haemorrhagic necrosis (hepatic bleeding) such as caused by beryllium and dimethylnitrosamine, will cause reduced blood flow to distal areas of the liver (supplied by the bleeding vessels), thus causing ischaemia and ultimate necrosis.

Biotransformation (either detoxification or bioactivation)

Glutathione levels (the higher the GSH levels, the less likely hepatic damage will occur as a result of free radical damage)

The presence of other hepatotoxins -- for example the presence of both ethanol and acetaminophen greatly increases the risk of hepatic damage than either drug alone.  Additionally, chronic use of one agent will increase the risk of toxic insult by the other.