PRINCIPLES OF TOXICOLOGY

5.2 TYPES OF LIVER INJURY 117
cause disarrangement of chromatin material within the nucleus. Morphologically, damage to the
nucleus appears as alterations in the nuclear envelope, in chromatin structure, and in arrangement of
nucleoli. 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 are
important in degrading damaged or aging cellular constituents. In hepatocytes injured by chemical
toxicants, their numbers and size are often increased. Typically, this is not because they are a direct
target for chemical attack, but rather reflects the response of the cell to the need to remove increased
levels of damaged cellular materials caused by the chemical.
Not all hepatocellular toxicity leads to cell death. Cells may display a variety of morphologic
abnormalities in response to chemical insult and still recover. These include cell swelling, dilated
endoplasmic reticulum, condensed mitochondria and chromatin material in the nucleus, and blebs on
the 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 necrosis
are massive swelling of the cell, marked clumping of nuclear chromatin, extreme swelling of
mitochondria, breaks in the plasma membrane, and the formation of cell fragments.
Necrosis from hepatotoxic chemicals can occur within distinct zones in the liver, be distributed
diffusely, or occur massively. Many chemicals produce a zonal necrosis; that is, necrosis is confined
to a specific zone of the hepatic acinus. Table 5.1 provides examples of drugs and chemicals that
produce hepatic necrosis and the characteristic zone in which the lesion occurs. Figure 5.4 shows an
example of zone 3 hepatic necrosis from acetaminophen. Confinement of the lesion to a specific zone
is thought to be a consequence of the mechanism of toxicity of these agents and the balance of activating
and inactivating enzymes or cofactors. Interestingly, there are a few chemicals for which the zone of
necrosis can be altered by treatment with other chemicals. These include cocaine, which normally
produces hepatic necrosis in zone 2 or 3 in mice, but in phenobarbital-pretreated animals causes
necrosis in zone 1. Limited observations of liver sections from humans experiencing cocaine hepatotoxicity
are consistent with this shift produced by barbiturates. The reason for the change in site of
necrosis with these chemicals is unknown.
Necrotic cells produced by some chemicals are distributed diffusely throughout the liver, rather
than being localized in acinar zones. Galactosamine and the drug methylphenidate are examples of
chemicals that produce a diffuse necrosis. Diffuse necrosis is also seen in viral hepatitis and some
forms of idiosyncratic liver injury. The extent of necrosis can vary considerably. When most of the
cells of the liver are involved, this is termed massive necrosis. As the name implies, this involves
destruction of most or all of the hepatic acinus. Not all the acini in the liver are necessarily affected to
the same extent, but at least some acini will have necrosis that extends across the lobule from the portal
triad to the hepatic vein, called bridging necrosis. Massive necrosis is not so much a characteristic of
specific hepatotoxic chemicals as of their dose.
Because of the remarkable ability of the liver to regenerate itself, it is able to withstand moderate
zonal or diffuse necrosis. Over a period of several days, necrotic cells are removed and replaced with
new cells, restoring normal hepatic architecture and function. If the number of damaged cells is too
great, however, the liver’s capacity to restore itself becomes overwhelmed, leading to hepatic failure
and death.
Another form of cell death is apoptosis, or programmed cell death. Apoptosis is a normal
physiological process used by the body to remove cells when they are no longer needed or have become
functionally abnormal. In apoptosis, the cell “commits suicide” through activation of its endonucleases,
destroying its DNA. Apoptotic cells are morphologically distinct from cells undergoing
necrosis as described above. Unlike cells undergoing necrosis, which swell and release their cellular
contents, apoptotic cells generally retain plasma membrane integrity and shrink, resulting in condensed
cytoplasm and dense chromatin in the nucleus. There are normally few apoptotic cells in liver, but the
number may be increased in response to some hepatotoxic chemicals, notably thioacetamine and
ethanol. Also, some chemicals produce hypertrophy, or growth of the liver beyond its normal size.