Elsevier

Clinics in Liver Disease

Volume 11, Issue 3, August 2007, Pages 563-575
Clinics in Liver Disease

Nonsteroidal Anti-Inflammatory Drug–Induced Hepatotoxicity

https://doi.org/10.1016/j.cld.2007.06.004Get rights and content

Nonsteroidal anti-inflammatory drugs are among the most common drugs associated with drug-induced liver injury, with an estimated incidence of between 3 and 23 per 100 000 patient years. Nimesulide, sulindac, and diclofenac seem to be associated with the highest risk and the only risk factor consistently identified is the concomitant use of other hepatotoxic drugs. Diclofenac-induced liver injury is a paradigm for drug-related hepatotoxicity. Recent studies suggest that genetic factors favoring the formation and accumulation of the reactive acylglucuronide metabolite of diclofenac and an enhanced immune response to the metabolite-protein adducts are associated with increased susceptibility to hepatotoxicity.

Section snippets

Epidemiology

Because the relatively high-risk agents causing hepatotoxicity have been replaced by apparently safer drugs, relatively rare adverse reactions to commonly prescribed low-risk agents have become the most important cause of liver injury. This is exemplified by NSAIDs that are among the most common drugs causing idiosyncratic hepatotoxicity in several recently published series (Table 1) [7], [8], [9], [10], [11], [12], [13]. Despite these reports highlighting the importance of NSAIDs as a cause of

Sulindac

Among NSAIDs, sulindac has been the drug most consistently associated with hepatotoxicity. By 1993 there had been 91 cases of liver injury reported to the FDA with 43% showing a cholestatic pattern of liver blood test abnormalities, 25% a hepatocellular pattern, and the rest a mixed pattern [23]. In these reports the female/male ratio was 3.5:1 and 69% were over the age of 50 years. Most patients (67%) were jaundiced and four patients died. Features of hypersensitivity, such as fever, rash, and

Diclofenac-induced liver injury: a paradigm of idiosyncratic hepatotoxicity

Diclofenac is a widely prescribed NSAID, which can cause rare, but potentially serious, hepatotoxicity. Because of its widespread use, diclofenac hepatotoxicity has been one of the most common causes of hepatic adverse drug reactions, with 180 confirmed cases reported to the FDA during the first 3 years of marketing [19]. Consistent with its worldwide exposure and its association with liver injury, diclofenac on its own is among the most common drugs associated with idiosyncratic hepatotoxicity

The importance of nonsteroidal anti-inflammatory drug–induced liver injury

Because of their common use, NSAIDs contribute significantly to the overall burden of drug-induced liver injury. The importance of any drug as a cause of liver injury lies not in the overall number of cases, however, but in the severity of some reactions. Despite the availability of liver transplantation, 26% (95% CI, 13%–43%) of those who develop jaundice caused by severe NSAID-induced hepatotoxicity die [60]. Adverse hepatic reactions can mimic a wide spectrum of hepatobiliary diseases. Early

References (60)

  • P.A. McCormick et al.

    COX 2 inhibitor and fulminant hepatic failure

    Lancet

    (1999)
  • T.R. Riley et al.

    Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series

    Am J Gastroenterol

    (1998)
  • B. Fromenty et al.

    Inhibition of mitochondrial ß–oxidation as a mechanism of hepatotoxicity

    Pharmacol Ther

    (1995)
  • T. Leemann et al.

    Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4′-hydroxylation in human liver

    Life Sci

    (1993)
  • U.A. Boelsterli

    Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

    Toxicol Appl Pharmacol

    (2003)
  • R. Bort et al.

    Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways

    Biochem Pharmacol

    (1999)
  • A.K. Daly et al.

    Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8 and ABCC2 genotypes

    Gastroenterology

    (2007)
  • A. Kretz-Rommel et al.

    Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes

    Toxicol Appl Pharmacol

    (1993)
  • A. Kretz-Rommel et al.

    Cytotoxic activity of T cells and non-T cells from diclofenac-immunised mice against cultured syngeneic hepatocytes exposed to diclofenac

    Hepatology

    (1995)
  • D. Bougie et al.

    Sensitivity to a metabolite of diclofenac as a cause of acute immune haemolytic anaemia

    Blood

    (1997)
  • R. Paulose-Ram et al.

    Prescription and non-prescription analgesic use among the US adult population: results from the third National health and nutritional examination survey (NHANES III)

    Pharmacoepidemiol Drug Saf

    (2003)
  • C. Lumley

    Clinical toxicity: could it have been predicted? Pre-marketing experience

  • B.H.C.H. Stricher

    Drug-induced hepatic injury

    (1992)
  • Anonymous

    Bromfenac withdrawal

    WHO Drug Inf

    (1998)
  • National Agency for Medicine (Finland).Available at:www.nam.fi/english/news/press_releases/nimed.html. Accessed June...
  • M.A. Macia et al.

    Hepatotoxicity associated with nimesulide: data from the Spanish pharmacovigilance system

    Clin Pharmacol Ther

    (2002)
  • M.I. Lucena et al.

    Comparison of two clinical scales for causality assessment in hepatotoxicity

    Hepatology

    (2001)
  • Y. Meier et al.

    Incidence of drug-induced liver injury in medical inpatients

    Eur J Clin Pharmacol

    (2005)
  • E. Bjornsson et al.

    Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden

    Scand J Gastroenterol

    (2005)
  • J.H. Rubenstein et al.

    Systematic review: the hepatotoxicity of non-steroidal anti-inflamatory drugs

    Aliment Pharmacol Ther

    (2004)
  • Cited by (137)

    • How Are Adjuvant Medications Such as Corticosteroids and NSAIDs Used for Pain Management?

      2023, Evidence-Based Practice of Palliative Medicine, Second Edition
    • Safety assessment of vitacoxib: 180-day chronic oral toxicity studies

      2018, Regulatory Toxicology and Pharmacology
      Citation Excerpt :

      Indeed, it has been documented that coxib-induced hepatotoxicity includes genetic susceptibility to coxib-induced liver damage. On the other hand, a number of NSAIDs have been withdrawn from the human market due to liver failure (Aithal and Day, 2007). Meanwhile, the despair findings of stomach were noted, such as epithelial cells of gastric mucosa shed at 30 mg/kg bw groups on Day 180 (Fig. 3H).

    View all citing articles on Scopus
    View full text