PRINCIPLES OF TOXICOLOGY

124 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVER
To make things more complicated, cells go through a series of morphological changes as they
progress to become a benign or malignant tumor. Thus, groups of cells that represent proliferation of
liver tissue, but are not (or not yet) tumors, may be described as nodular hyperplasia, focal hepatocellular
hyperplasia, or foci of hepatocellular alteration, depending on their morphological characteristics.
The foci of hepatocellular alteration represent the earliest stages that can be detected microscopically.
These foci are small groups of cells that are abnormal, but have no distinct boundary separating them
from adjacent cells. Their growth rate is such that they are producing little or no compression of
surrounding cells. The abnormalities are subtle at this stage, and special stains and markers are
sometimes used to help visualize them. Nodular hyperplasia is more readily observed; the group of
cells is more circumscribed and compression of adjacent cells is apparent. These cells are thought to
represent an intermediate step in tumor development. The significance of these lesions is not that they
are associated with any clinical signs or symptoms of disease, but rather that they may represent an
area from which a tumor may develop. Consequently, their appearance is important in the assessment
of the ability of a drug or chemical to cause cancer. For most chemicals, only a very small
percentage—or perhaps none—of the neoplastic areas will go on to produce a malignant tumor.
Consequently, the issue of how to use data regarding the appearance of these lesions in the assessment
of carcinogencity of a chemical is one of considerable discussion and debate among toxicologists.
Liver tumors from chemical exposure can arise through numerous mechanisms. Some hepatocarcinogens
form DNA adducts leading to mutations. Nitrosoureas and nitrosamines are examples of
hepatocarcinogens thought to produce tumors through this mechanism (see also Chapters 12 and 13
for further discussion of genotoxicity and carcinogenicity). Many chemicals that produce liver tumors
are not genotoxic, however, and appear to work through epigenetic mechanisms. Nongenotoxic
hepatocarcinogens are many and diverse, and include tetrachlorodibenzo-p-dioxin, sex steroids,
synthetic antioxidants, some hepatic enzyme inducing agents (e.g., phenobarbital), and peroxisome
proliferators (e.g., clofibrate). A discussion of the mechanisms underlying epigenetic carcinogenesis
(e.g., inhibition of cell-to-cell communication, recurrent cellular injury, receptor interactions) is
beyond the scope of this chapter, and the reader is referred to Chapter 12 for more information on this
subject.
Despite the many chemicals found to produce benign and malignant liver tumors in mice and rats,
relatively few have been clearly associated with liver tumors in humans. Adenomas have been
associated with the use of contraceptive steroids, and clinical and epidemiologic studies implicate
anabolic steroids, arsenic, and thorium dioxide as causing hepatocellular carcinoma in humans.
Hemangiosarcoma is a rare tumor that has been strongly linked to occupational exposure to vinyl
chloride, and has also been associated with arsenic and thorium dioxide exposure.
5.3 EVALUATION OF LIVER INJURY
Symptoms of Liver Toxicity
As discussed above, liver injury may be either acute or chronic, and may involve liver cell death, hepatic
vascular injury, disruption of bile formation and/or flow, or the development of benign or malignant
tumors. Obviously, the signs and symptoms that accompany this array of types of liver injury can vary
significantly. There are some generalizations that can be made, however. Common symptoms of liver
injury include anorexia (loss of appetite), nausea, vomiting, fatigue, and abdominal tenderness.
Physical examination may reveal hepatomegaly (swelling of the liver) and ascites (the accumulation
of fluid in the abdominal space). Patients whose liver toxicity involves impaired biliary function may
develop jaundice, which results from the accumulation of bilirubin in the blood and tissues. Jaundice
will appear as a yellowish tint to the skin, mucous membranes, and eyes. Pruritis, or an itching sensation
in the skin, will often accompany the jaundice.
If the injury is particularly severe, it may lead to fulminant hepatic failure. When the liver fails,
death can occur in as little as 10 days. There are several complications associated with fulminant hepatic