PRINCIPLES OF TOXICOLOGY

assays that are rapid and inexpensive. In fact, the concentrations of each of these proteins are typically
measured as an enzyme activity rate, rather than a true concentration per se.
Aminotransferase activities [alanine aminotransferase (ALT) and aspartate aminotransferase
(AST)], alkaline phosphatase activity, and gamma glutamyltransferase transpeptidase (GGTP) are
included in nearly all standard clinical test suites to assess potential hepatotoxicity. The value of
performing a battery of these tests is that each test responds slightly differently in the various forms
of liver injury, and evaluating the pattern of responses can offer insight into the type of injury that has
occurred. For example, severe hepatic injury from acetaminophen can result in dramatic increases in
serum ALT and ALT activities (up to 500 times normal values), but only modest increases in alkaline
phosphatase activity. Pronounced increases in alkaline phosphatase is characteristic of cholestatic
injury, where increases in ALT and AST may be limited or nonexistent. In alcoholic liver disease, AST
activity is usually greater than ALT activity, but for most other forms of hepatocellular injury ALT
activities are higher. Serum GGTP is an extremely sensitive indicator of hepatobiliary effects, and may
be elevated simply by drinking alcoholic beverages. It is not a particularly specific indicator (it is
increased by both hepatocellular and cholestatic injury) and is best utilized in combination with other
tests. Serum levels of enzymes such as lactate dehydrogenase have been used to evaluate liver toxicity,
but this enzyme has such low specificity for the liver that interpretation of these results is impossible
without other confirming tests. Other enzymes such as sorbitol dehydrogenase (SDH) and ornithine
carbamoyltransferase (OCT) are quite specific to the liver.
5.4 SUMMARY
Both the anatomic location and its role as a primary site for biotransformation make the liver uniquely
susceptible to drug- and chemical-induced injury. Many chemicals encountered in the workplace and
environment are capable of producing toxic effects in the liver:
• There are many types of liver injury, including hepatocellular degeneration and death
(necrosis), fatty liver, cholestasis (decreased or arrested bile flow), vascular injury, cirrhosis,
and tumor development.
• Hepatic injury from drugs and chemicals can arise from a variety of mechanisms. While the
mechanism of toxicity for some chemicals is reasonably well established, many aspects of
toxic mechanisms for most chemicals remain unclear.
• Hepatotoxic chemicals can attack a variety of subcellular targets. Principal organelles and
structures affected include the plasma membrane, mitochondria, the endoplasmic reticulum,
the nucleus, and lysosomes.
• Liver injury can be evaluated morphologically (microscopic examination of liver tissue) or
through blood tests. Blood tests are designed to either measure the functional capacity of
the liver or the appearance of intracellular hepatic contents in the blood.
REFERENCES AND SUGGESTED READING
REFERENCES AND SUGGESTED READING 127
Cullen, J. M., and B. H. Ruebner, “A histopathologic classification of chemical-induced injury of the liver,” in
Hepatotoxicity, R. G. Meeks, S. D. Harrison, and R. J. Bull, eds., CRC Press, Boca Raton, FL, 1991, pp. 67–92.
Delaney, K., “Hepatic principles,” in Goldfrank’s Toxicologic Emergencies, L. R. Goldfrank, N. E. Flomenbaum,
N. A. Lewin, R. S. Weisman, M. A. Howland, and R. S. Hoffman, eds., Appleton & Lange, Stamford, CT, 1998,
pp. 213–228.
Kedderis, G. L. “Biochemical Basis of Hepatocellular Injury.” Toxicologic Pathology, 24 (1): 77–83 (1996).