Acetaminophen: Pathology and clinical presentation of hepatotoxicity

Acetaminophen (called paracetamol outside the United States) is a popular and widely used analgesic and antipyretic agent. First synthesized in 1893, it was introduced for prescription use in the United States in 1955 and approved for over-the-counter use in 1960 (1). It is frequently combined with codeine or other analgesic agents, decongestants, and antihistamines. Over 300 different preparations are now available in the United States with more than one billion pills sold annually. Acetaminophen’s popularity has in part arisen from its apparent lack of side effects. Unlike aspirin and other nonsteroidal anti-inflammatory drugs, it does not cause gastric inflammation, ulcers, or coronary ischemia. Although it is remarkably safe when used at usual therapeutic doses, it has a relatively narrow therapeutic window. Acetaminophen overdose is the leading cause for calls to Poison Control Centers (O100,000/yr), and accounts for more than 56,000 emergency room visits, 2600 hospitalizations and an estimated 458 deaths due to acute liver failure (ALF) each year (1). Data from the U.S. Acute Liver Failure Study Group registry of more than 1100 patients with acute liver failure (ALF) from across the United States, suggests that acetaminophen poisoning alone currently constitutes nearly 50% of all ALF [Fig. 1; (2)]. Available in single or combination products, acetaminophen produces more than a billion dollars in annual sales and is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the United States Food and Drug Administration (FDA) to outweigh its risks (3).