Systematic Review: Ibuprofen-induced Liver Injury

Miguel E. Zoubek; María Isabel Lucena; Raúl J. Andrade; Camilla Stephens


Aliment Pharmacol Ther. 2020;51(6):603-611. 

In This Article

Abstract and Introduction


Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a leading cause of drug-induced liver injury (DILI) across the world. Ibuprofen is one of the most commonly used and safest NSAIDs, nevertheless reports on ibuprofen-induced hepatotoxicity are available.

Aim: To analyse previously published information on ibuprofen-induced liver injury for a better characterisation of its phenotypic expression.

Method: A systematic search was performed and information on ibuprofen-induced liver injury included in case series and case reports, in terms of demographic, clinical, biochemical and outcome data, was analysed.

Results: Twenty-two idiosyncratic ibuprofen hepatotoxicity cases were identified in the literature, suggesting a very low prevalence of this type of DILI. These patients had a mean age of 31 years and 55% were females. Mean cumulative dose of ibuprofen and time to onset were 30 g and 12 days, respectively. Hepatocellular injury was the most frequently involved liver injury pattern. Six cases developed vanishing bile duct syndrome. Full recovery occurred in 11 patients after a mean time of 14 weeks, whereas five cases evolved to acute liver failure leading to death/liver transplantation.

Conclusions: When assessing potential hepatotoxicity cases, physicians should keep in mind that ibuprofen has been associated with hepatotoxicity in the literature. Ibuprofen-associated DILI presents commonly as hepatocellular damage after a short latency period. Published reports on ibuprofen hepatotoxicity leading to liver failure resulting in liver transplantation or death are available. However, due to the apparent low absolute risk of ibuprofen-induced liver complications, ibuprofen can be regarded as an efficacious and safe NSAID.


Nonsteroidal anti-inflammatory drugs (NSAIDs) belong to a group of chemically heterogeneous compounds, and their therapeutic effect relies on the strong anti-cyclooxygenase activity and ability to block pro-inflammatory substance formation. The main indications for NSAID therapy range from mild/moderate forms of pain to chronic inflammatory processes.[1,2]

In the United States, 6% of the population declared taking at least one prescription NSAID a month and over 30 million people around the world take NSAIDs daily.[3] Conventional NSAIDs are generally well tolerated, but adverse effects, such as cardiovascular, gastrointestinal and renal events may occur in a small proportion of users.[4] NSAID-associated hepatotoxicity is considered rare and the incidence is estimated to be 1–23 cases per 100 000 patient-years.[5] In addition, previous systematic reviews have found low level of liver-related hospitalisation involving NSAID intake.[6,7] Nevertheless, the common use of NSAIDs emphasises the importance of understanding NSAID-associated liver toxicity, which is responsible for approximately 10% of drug-induced liver injury (DILI) cases in developed countries.[8–10] Interestingly reports from prospective DILI cohorts around the world demonstrate differences in relative frequency of individual NSAIDs responsible for DILI (Table 1). Diclofenac was the most common causative NSAID in the United States (63%) and Iceland (100%), while nimesulide more frequently caused DILI in Latin America (38%) and Italy (39%).[10–13] Ibuprofen, on the other hand, was the NSAID responsible for most DILI cases in the Spanish DILI Registry (29%) and was also highly represented in an Indian DILI study (25%), although the latter study presented a more equal distribution between different NSAIDs than the former study.[12,14] Caution should however be taken when interpreting these results due to lack of sales/prescription data.

Ibuprofen is a propionic acid derivative available under medical prescription and as an over-the-counter medication. It has been available in the UK since 1969 and was introduced on markets worldwide during the 1970s. It is currently the most frequently prescribed NSAID with over 20 million prescriptions per year in the USA, apart from its vast self-medication use.[11] The recommended therapeutic dose for adults varies from 800 to 1200 mg per day for over-the-counter self-medication use and 1800–2400 mg per day for chronic treatments under medical supervision.

Short plasma half-life and absence of prolonged retention in the organism contribute to a better gastrointestinal safety profile of ibuprofen compared to other NSAIDs.[15] Nevertheless, ibuprofen has been linked to instances of clinically apparent liver injury with injury patterns varying from moderate elevations of aminotransferases to vanishing bile duct syndrome (VBDS) and even acute liver failure (ALF) resulting in death.[16–34] While most reported ibuprofen-induced hepatotoxicity cases to date are idiosyncratic, some cases of liver injury due to ibuprofen overdose have also been described.[35–37]

The large consumption of ibuprofen worldwide together with the fact that only limited information is available on ibuprofen-induced hepatotoxicity to date, prompted us to look deeper into the phenotypic presentation of this type of DILI. In the present study, we aimed to review previously reported cases of ibuprofen-induced liver injury in the literature in order to enhance the understanding of ibuprofen hepatotoxicity with regard to frequency and phenotypic expression.