Diclofenac‐associated hepatotoxicity: Analysis of 180 cases reported to the food and drug administration as adverse reactions

Diclofenac is a nonsteroidal anti–inflammatory drug approved in the United States in 1988 for the treatment of patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis. To characterize the clinical, biochemical, and histological features and possible mechanisms of hepatic injury associated with its use, a retrospective analysis was undertaken of 180 patients whose cases were reported to the Food and Drug Administration from November 1988 through June 1991, as having had possible adverse reactions to diclofenac. Of the reported 180 cases, 79% were female, 71% were 60 years of age or older, and 77% had osteoarthritis. Sixty‐seven percent of the cases were detected by symptoms and the remainder by abnormal laboratory tests. Seventy‐five percent of the symptomatic patients (90 of 120) were jaundiced. Seven of the 90 icteric patients died. The biochemical pattern of injury was hepatocellular or mixed hepatocellular in 66% of cases. Only 8% had a pattern of cholestatic injury. The remainder, with modestly increased values of both transaminases and alkaline phosphatase, were considered “indeterminate,” i.e., either mild hepatocellular or anicteric “cholestatic” injury. Sections of liver from 21 cases were available for study. Hepatic injury was apparent by 1 month after starting the drug in 24% by 3 months in 63%, and by 6 months in 85% of cases. The latent period in 12% was 6 to 12 months, whereas in 3% it was greater than 12 months. A combination of rash, fever, and eosinophilia, all hallmarks of immunological idiosyncrasy (hypersensitivity), was not reported in any case; additionally, the long latent period in most of the patients led to the inference that the mechanism is probably metabolic idiosyncrasy. The data suggest that diclofenac‐related liver injury is particularly likely to involve osteoarthritic females, presenting with jaundice 1 to 6 months after starting diclofenac, with injury that is predominantly hepatocellular and presumably caused by metabolic idiosyncrasy. (Hepatology 1995; 22:820‐827.)

[1]  U. Boelsterli,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. , 1993, Toxicology and applied pharmacology.

[2]  R. Barr,et al.  Diclofenac induced hepatitis , 1993, Digestive diseases and sciences.

[3]  K. Ishak,et al.  Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration. , 1993, Gastroenterology.

[4]  D. V. van Thiel,et al.  Hepatotoxicity of nonsteroidal anti-inflammatory drugs. , 1992, The American journal of gastroenterology.

[5]  H. Jick,et al.  Liver Disease Associated With Diclofenac, Naproxen, and Piroxicam , 1992, Pharmacotherapy.

[6]  J. Berenguer,et al.  [Biliary calculi resistant to dissolution with bile acids: their heterogeneous composition and diversity of treatment response]. , 1992, Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva.

[7]  G. Schmitz,et al.  Toxicity of diclofenac to isolated hepatocytes. , 1992, Journal of hepatology.

[8]  H. Paulus,et al.  Therapeutic applications of NSAIDs : subpopulations and new formulations , 1992 .

[9]  J. Bondeson,et al.  Diclofenac‐induced thrombocytopenic purpura with renal and hepatic involvement , 1991, Journal of internal medicine.

[10]  A. West,et al.  Reversible hepatitis associated with diclofenac. , 1991, Journal of clinical gastroenterology.

[11]  D. Zakim,et al.  Diclofenac-associated hepatotoxicity. , 1990, JAMA.

[12]  R. Chapman,et al.  Diclofenac associated hepatitis. , 1990, Journal of hepatology.

[13]  C. Rogier,et al.  [Cholestatic hepatitis and acute kidney insufficiency during treatment with diclofenac]. , 1989, Annales de gastroenterologie et d'hepatologie.

[14]  P. Diggory,et al.  Renal and hepatic impairment in association with diclofenac administration. , 1989, Postgraduate medical journal.

[15]  Mazeika Pk,et al.  Chronic active hepatitis associated with diclofenac sodium therapy. , 1989 .

[16]  T. Winkler,et al.  A new metabolite of diclofenac sodium in human plasma. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  P. Collet,et al.  Changing the class of NSAID in cases of hepatotoxicity. , 1988, Annals of the rheumatic diseases.

[18]  B Leijnse,et al.  Alterations in carbohydrate composition of serum IgG from patients with rheumatoid arthritis and from pregnant women. , 1988, Annals of the rheumatic diseases.

[19]  I. ClarosGonzález,et al.  Acute hepatitis and diclofenac sodium , 1986 .

[20]  J. Mcnicholl,et al.  Fatal hepatitis associated with diclofenac. , 1986, Gut.

[21]  W. O'Brien,et al.  Adverse reactions to nonsteroidal anti-inflammatory drugs. Diclofenac compared with other nonsteroidal anti-inflammatory drugs. , 1986, The American journal of medicine.

[22]  D. Schapira,et al.  Diclofenac-induced hepatotoxicity. , 1986, Postgraduate medical journal.

[23]  J. Bernuau,et al.  Hépatite fulminante chez une femme prenant de la glafénine et du diclofénac. , 1985 .

[24]  V. Levy,et al.  [Acute fatal hepatitis during treatment with diclofenac (Voltarène)]. , 1984, Gastroenterologie clinique et biologique.

[25]  E. Bercoff,et al.  [Diclofenac hepatitis. A case]. , 1984, Presse medicale.

[26]  Lewis Jh.  Hepatic toxicity of nonsteroidal anti-inflammatory drugs. , 1984 .

[27]  D. Pessayre,et al.  [Hepatitis caused by diclofenac]. , 1983, Gastroenterologie clinique et biologique.

[28]  H. Paulus.  FDA Arthritis Advisory Committee meeting. , 1983, Arthritis and rheumatism.

[29]  E. Jähnchen,et al.  Elimination and distribution of phenylbutazone in rats during the course of adjuvant-induced arthritis. , 1976, The Journal of pharmacology and experimental therapeutics.