The Therapeutic Use of Acetaminophen in Patients with Liver Disease

Abstract

Acetaminophen has been used safely and effectively for many years to manage pain and/or fever in patients of all ages. It is commonly recommended as first-line therapy for a variety of patients and conditions, including the elderly, children with viral illnesses, and patients with osteoarthritis, gastrointestinal conditions, bleeding disorders, cardiovascular disease, or renal disease. However, its use is often avoided in patients with chronic liver disease. The perception that acetaminophen should be avoided in such patients arose from awareness of the association between massive acetaminophen overdose and hepatotoxicity, combined with a lack of understanding of the metabolism of acetaminophen in patients with liver disease. There are various theoretical mechanisms of acetaminophen hepatotoxicity in chronic liver disease including: altered metabolism and depleted glutathione stores that would be expected to increase accumulation of the hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Available studies in patients with chronic liver disease, however, have shown that although the half-life of acetaminophen may be prolonged, cytochrome P-450 activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses. Furthermore, acetaminophen has been studied in a variety of liver diseases without evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.

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“…It is commonly recommended that paracetamol should be used with caution or in reduced doses in patients with active liver disease, history of heavy alcohol intake and glucose-6-phosphate dehydrogenase deficiency. However, others report that it can be used safely in patients with liver disease and is preferred to NSAIDs, and that therapeutic doses of paracetamol, at least for short-term use, are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol (Benson et al, 2005;Oscier & Milner, 2009). There is no evidence that patients who have depleted glutathione stores (eg patients who are malnourished, or who have cirrhosis, hepatitis C or human immunodeficiency virus [HIV]) are at increased risk of liver dysfunction when exposed to therapeutic doses of paracetamol (Benson et al, 2005Oscier & Milner, 2009 …”

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“…APAP overdose is the leading cause of acute liver failure in the US (13,39). APAP is converted by hepatic cytochrome P450 enzymes, primarily CYP2E1, to the toxic intermediate compound NAPQI, which is rapidly detoxified by GSH (40). To examine the ability of Taldo1 -/-mice to resist APAP-induced oxidative stress, 10-weekold Taldo1 +/-, Taldo1 -/-, and Taldo1 +/+ littermates were injected with 100-800 mg/kg APAP i.p.…”

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“…However, at therapeutic doses of Ͻ4 g/day, acetaminophen is generally considered safe, although some experts recommend a lower dose of 2 g/day. 35,36 Nonsteroidal anti-inflammatories should be avoided in patients with cirrhosis because of the potential for hepatorenal syn- Table 4 for dosing). 37,38 Because of impairment in drug metabolism, the use of opioids should be minimized since they can precipitate hepatic encephalopathy.…”