PRINCIPLES OF TOXICOLOGY - Biology East Borneo

5.2 TYPES OF LIVER INJURY 117cause disarrangement of chromatin material within the nucleus. Morphologically, damage to thenucleus appears as alterations in the nuclear envelope, in chromatin structure, and in arrangement ofnucleoli. Examples of chemicals that produce nuclear alterations include aflatoxin B, beryllium,ethionine, galactosamine, and nitrosamines.5. Lysosomes. These subcellular structures contain digestive enzymes (e.g., proteases) and areimportant in degrading damaged or aging cellular constituents. In hepatocytes injured by chemicaltoxicants, their numbers and size are often increased. Typically, this is not because they are a directtarget for chemical attack, but rather reflects the response of the cell to the need to remove increasedlevels of damaged cellular materials caused by the chemical.Not all hepatocellular toxicity leads to cell death. Cells may display a variety of morphologicabnormalities in response to chemical insult and still recover. These include cell swelling, dilatedendoplasmic reticulum, condensed mitochondria and chromatin material in the nucleus, and blebs onthe plasma membrane. More severe morphological changes are indicative that the cell will not recover,and will proceed to cell death, that is, undergo necrosis. Examples of morphological signs of necrosisare massive swelling of the cell, marked clumping of nuclear chromatin, extreme swelling ofmitochondria, breaks in the plasma membrane, and the formation of cell fragments.Necrosis from hepatotoxic chemicals can occur within distinct zones in the liver, be distributeddiffusely, or occur massively. Many chemicals produce a zonal necrosis; that is, necrosis is confinedto a specific zone of the hepatic acinus. Table 5.1 provides examples of drugs and chemicals thatproduce hepatic necrosis and the characteristic zone in which the lesion occurs. Figure 5.4 shows anexample of zone 3 hepatic necrosis from acetaminophen. Confinement of the lesion to a specific zoneis thought to be a consequence of the mechanism of toxicity of these agents and the balance of activatingand inactivating enzymes or cofactors. Interestingly, there are a few chemicals for which the zone ofnecrosis can be altered by treatment with other chemicals. These include cocaine, which normallyproduces hepatic necrosis in zone 2 or 3 in mice, but in phenobarbital-pretreated animals causesnecrosis in zone 1. Limited observations of liver sections from humans experiencing cocaine hepatotoxicityare consistent with this shift produced by barbiturates. The reason for the change in site ofnecrosis with these chemicals is unknown.Necrotic cells produced by some chemicals are distributed diffusely throughout the liver, ratherthan being localized in acinar zones. Galactosamine and the drug methylphenidate are examples ofchemicals that produce a diffuse necrosis. Diffuse necrosis is also seen in viral hepatitis and someforms of idiosyncratic liver injury. The extent of necrosis can vary considerably. When most of thecells of the liver are involved, this is termed massive necrosis. As the name implies, this involvesdestruction of most or all of the hepatic acinus. Not all the acini in the liver are necessarily affected tothe same extent, but at least some acini will have necrosis that extends across the lobule from the portaltriad to the hepatic vein, called bridging necrosis. Massive necrosis is not so much a characteristic ofspecific hepatotoxic chemicals as of their dose.Because of the remarkable ability of the liver to regenerate itself, it is able to withstand moderatezonal or diffuse necrosis. Over a period of several days, necrotic cells are removed and replaced withnew cells, restoring normal hepatic architecture and function. If the number of damaged cells is toogreat, however, the liver’s capacity to restore itself becomes overwhelmed, leading to hepatic failureand death.Another form of cell death is apoptosis, or programmed cell death. Apoptosis is a normalphysiological process used by the body to remove cells when they are no longer needed or have becomefunctionally abnormal. In apoptosis, the cell “commits suicide” through activation of its endonucleases,destroying its DNA. Apoptotic cells are morphologically distinct from cells undergoingnecrosis as described above. Unlike cells undergoing necrosis, which swell and release their cellularcontents, apoptotic cells generally retain plasma membrane integrity and shrink, resulting in condensedcytoplasm and dense chromatin in the nucleus. There are normally few apoptotic cells in liver, but thenumber may be increased in response to some hepatotoxic chemicals, notably thioacetamine andethanol. Also, some chemicals produce hypertrophy, or growth of the liver beyond its normal size.