Introduction

Aspirin or acetylsalicylic acid is perhaps the most commonly used analgesic and antipyretic medication worldwide, having been in clinical use for over 100 years. Aspirin can cause several forms of liver injury: in high doses, aspirin can cause moderate to marked serum aminotransferase elevations occasionally with jaundice or signs of liver dysfunction, and in lower doses in susceptible children with a febrile illness aspirin can lead to Reye syndrome.

Background

Aspirin is a salicylate, but technically is also a nonsteroidal anti-inflammatory drug (NSAID). Like the NSAIDs, salicylates are inhibitors of tissue cyclooxygenases (Cox-1 and -2) which cause a decrease in synthesis of proinflammatory prostaglandins, potent mediators of pain and inflammation. In distinction to other NSAIDs, however, aspirin is a noncompetitive and irreversible inhibitor of Cox-1, so that its effects are longer lasting and less easily reversed than those of typical NSAIDs. Aspirin has potent effects in inhibiting platelet function that lasts for the lifetime of the platelet. Aspirin’s potent and lasting effects on Cox-1 in gastric epithelial cells account for its frequent gastric side effects and association with peptic ulcer disease and gastrointestinal bleeding. Aspirin is indicated for the treatment of mild to moderate pain from headaches, colds, arthritis, menstrual periods, toothaches and joint and muscle aches caused by trauma, osteoarthritis, or rheumatoid arthritis. Higher, more continuous doses of aspirin are effective in therapy of juvenile rheumatoid arthritis, systemic lupus erythematosus, rheumatoid arthritis, acute rheumatic fever and Kawasaki disease. 

Hepatotoxicity

Patients on long term, moderate-to-high dose aspirin therapy frequently have elevations in serum ALT levels. With high doses, ALT elevations are common and can be marked and associated with mild increases in alkaline phosphatase and bilirubin. The more dramatic examples of aspirin hepatotoxicity usually occur with doses of 1,800 to 3,200 mg daily (>100 mg/kg) and with salicylate levels of greater than 25 mg/dL, but mild-to-moderate ALT elevations occur with even lower doses and lower serum levels. These abnormalities resolve rapidly with discontinuation of aspirin, but instances of resolution despite continuation of aspirin in the same or lower doses (adaptation) have also been described. The hepatotoxicity of aspirin is usually mild and asymptomatic, although with higher doses symptoms of nausea, anorexia and abdominal pain and even encephalopathy with signs of hepatic dysfunction (hyperammonemia and coagulopathy) can occur. Bilirubin elevations are usually mild or absent.

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Ibuprofen Increases the Hepatotoxicity of Ethanol through Potentiating Oxidative Stress-NIH

Over 30 million prescriptions of Ibuprofen-NSAIDs (non-steroidal anti-inflammatory drugs) are issued every year. Considering that these drugs are available without a prescription as over the counter (OTC) drugs, their use will be astronomical. With the increasing use of NSAIDs, their adverse effects are drawing attention. Especially, stomach bleeding, kidney toxicity, liver toxicity, and neurological toxicity are reported as common. Ibuprofen, one of the extensively used NSAIDs along with aspirin, can also induce liver toxicity.

In fact, NSAIDs are one of the most notable causes of drug-induced liver injuries, with about 3 to 23 per 100,000 patient years (Aithal and Day, 2007), and as a result, three different NSAIDS, bromfenac, ibufenac, and benoxaprofen, had been removed from the UK and/or US markets because of their hepatotoxic side effects (Goldkind and Laine, 2006). These adverse effects of NSAIDs have been witnessed in children (Cardile et al., 2016) and elderly (Freytag et al., 2014) alike and can be caused or exacerbated by multiple factors, including overconsumption caused by duplicate prescriptions and/or medication overdose, significant drug interactions, and individual patient susceptibilities (Tolman, 1998).