PRINCIPLES OF TOXICOLOGY

5 Hepatotoxicity: Toxic Effects on the
Liver
HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVER
STEPHEN M. ROBERTS, ROBERT C. JAMES, AND MICHAEL R. FRANKLIN
This chapter will familiarize the reader with
• The basis of liver injury
• Normal liver functions
• The role the liver plays in certain chemical-induced toxicities
• Types of liver injury
• Evaluation of liver injury
• Specific chemicals that are hepatotoxic
5.1 THE PHYSIOLOGIC AND MORPHOLOGIC BASES OF LIVER INJURY
Physiologic Considerations
The liver is the largest organ in the body, accounting for about 5 percent of total body mass. It is often
the target organ of chemical-induced tissue injury, a fact recognized for over 100 years. While the
chemicals toxic to the liver and the mechanisms of their toxicity are numerous and varied, several basic
factors underlie the liver’s susceptibility to chemical attack.
First, the liver maintains a unique position within the circulatory system. As Figure 5.1 shows, the
liver effectively “filters” the blood coming from the gastrointestinal tract and abdominal space before
this blood is pumped through the lungs and into the general circulation. This unique position in the
circulatory system aids the liver in its normal functions, which include (1) carbohydrate storage and
metabolism; (2) metabolism of hormones, endogenous wastes, and foreign chemicals; (3) synthesis of
blood proteins; (4) urea formation; (5) metabolism of fats; and (6) bile formation. When drugs or
chemicals are absorbed from the gastrointestinal tract, virtually all of the absorbed dose must pass
through the liver before being distributed through the bloodstream to the rest of the body. Once a
chemical reaches the general circulation, regardless of the route of absorption, it is still subject to
extraction and metabolism by the liver. The liver receives nearly 30 percent of cardiac output and, at
any given time, 10–15 percent of total blood volume is present in the liver. Consequently, it is difficult
for any drug or chemical to escape contact with the liver, an important factor in the role of the liver in
removing foreign chemicals.
The liver’s prominence causes it to have increased vulnerability to toxic attack. The liver can
particularly affect, or be affected by, chemicals ingested orally or administered intraperitoneally (i.e.,
into the abdominal cavity) because it is the first organ perfused by blood containing the chemical. As
discussed in Chapter 2, rapid and extensive removal of the chemical by the liver can drastically reduce
the amount of drug reaching the general circulation—termed the first-pass effect. Being the first organ
Principles of Toxicology: Environmental and Industrial Applications, Second Edition, Edited by Phillip L. Williams,
Robert C. James, and Stephen M. Roberts.
ISBN 0-471-29321-0 © 2000 John Wiley & Sons, Inc.
111