![]() 10, 17 Soon there were reports that methionine 18 and cysteamine 19 (two medications known to restore hepatic glutathione) could prevent acetaminophen-induced hepatic injury. 16 Studies in animals described the metabolism of acetaminophen to NAPQI and showed that as long as hepatic glutathione was present, toxic effects could be prevented. ![]() In the late 1960s, clinicians recognized that acute acetaminophen overdose caused a dose-related liver injury and that without treatment many patients die. ![]() 14 The exact mechanism of these effects is not clear, but it may involve scavenging of free radicals or changes in hepatic blood flow. 10 In addition, in patients with acetaminophen-induced liver failure, acetylcysteine improves hemodynamics and oxygen use, 12 increases clearance of indocyanine green (a measure of hepatic clearance), 13 and decreases cerebral edema. Acetylcysteine, in contrast, is readily absorbed and rapidly enters cells, where it is hydrolyzed to cysteine, thus providing the limiting substrate for glutathione synthesis.Īcetylcysteine (also known as N-acetylcysteine) prevents hepatic injury primarily by restoring hepatic glutathione ( Fig. However, cysteine itself is not well absorbed after oral administration. Glutamate and glycine are present in abundance in hepatocytes the availability of cysteine is the rate-limiting factor in glutathione synthesis. Glutathione is synthesized from the amino acids cysteine, glutamate, and glycine by means of the pathway shown in Panel B. If glutathione is depleted, NAPQI interacts with various macromolecules, leading to hepatocyte injury and death. Ordinarily, NAPQI is rapidly detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates. Approximately 5% of a therapeutic dose is metabolized by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). The primary pathways for acetaminophen metabolism (Panel A) are glucuronidation and sulfation to nontoxic metabolites. The Metabolism of Acetaminophen and the Synthesis of Glutathione 3, 6 Patients who are not treated until hepatic injury has developed have a variable prognosis, 3, 4 and patients who present with hepatic failure have a mortality rate of 20 to 40%. Transient liver injury may develop in patients who are treated during the preclinical stage, but they recover fully. ![]() This categorization is useful because each stage has a different prognosis and is managed differently. Regardless of whether it occurs as a result of a single overdose or after repeated supratherapeutic ingestion, the progression of acetaminophen poisoning can be categorized into four stages: preclinical toxic effects (a normal serum alanine aminotransferase concentration), hepatic injury (an elevated alanine aminotransferase concentration), hepatic failure (hepatic injury with hepatic encephalopathy 5), and recovery. Repeated supratherapeutic ingestion is increasingly recognized as a significant clinical problem. 2 Acetaminophen poisoning can be due to ingestion of a single overdose (usually as an attempt at self-harm) or ingestion of excessive repeated doses or too-frequent doses, with therapeutic intent. 1 According to poison centers in the United States, acetaminophen poisoning was responsible for more than 70,000 visits to health care facilities and approximately 300 deaths in 2005. Acetaminophen (known as paracetamol outside the United States) is a commonly used analgesic and antipyretic agent, and its use is one of the most common causes of poisoning worldwide.
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