Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away?

Abstract

Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever around the world. At the same time, APAP can cause dose-related hepatocellular necrosis, responsible for nearly 500 deaths annually in the United States (US) alone, as well as 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year. As an over-the-counter and prescription product (with opioids), APAP toxicity dwarfs all other prescription drugs as a cause of acute liver failure in the US and Europe, but it is not regulated in any significant way. In this review the ongoing controversy surrounding the proper role for this ubiquitous pain reliever: its history, pathogenesis, clinical challenges in recognition and management, and current regulatory status are highlighted. A new solution to a 50-year-old problem is proposed.

Keywords: APAP; Acetaminophen; Hepatotoxicity.

Figure 1

Bar graph showing breakdown by percent for each of the major ALF etiologies over 18 years. Over this time period, there has been little change in the percentages for each etiology, save a decline in hepatitis A and B.

Figure 2

Biochemical pathways of acetaminophen metabolism. Only small amounts of NAPQI are formed unless the capacity for glucuronidation and sulfation is exceeded. Even then, glutathione supplies sulfhydryl groups that detoxify NAPQI to mercapturic acid, which is excreted in the urine. When glutathione is exhausted, then NAPQI binds to cell proteins disrupting cell function, the full details of which remain poorly understood.

Figure 3

Diagrammatic representation of events by day (Sankey plot), after registry enrollment/listing for transplantation, according to etiology groups: a: APAP, and b: Drug-induced liver injury (DILI). Most of the deaths and transplants in the APAP group (3a) took place within the first 48-72 hours, while both deaths and transplants evolved more slowly in the non-APAP categories such as DILI (3b).

Figure 3

Diagrammatic representation of events by day (Sankey plot), after registry enrollment/listing for transplantation, according to etiology groups: a: APAP, and b: Drug-induced liver injury (DILI). Most of the deaths and transplants in the APAP group (3a) took place within the first 48-72 hours, while both deaths and transplants evolved more slowly in the non-APAP categories such as DILI (3b).