Assessment of Potential Hepatotoxicity of Low Dose Aspirin in Chronic Use

만성적 저용량 아스피린 사용의 잠재적 간독성 평가

  • Received : 2013.08.20
  • Accepted : 2013.10.30
  • Published : 2013.10.31

Abstract

Aspirin is widely used for treatment or prophylaxis of many diseases. Although aspirin is used chronically for preventing cardiovascular diseases especially, liver function is rarely monitored because of unpredictable and uncommon hepatotoxicity induced by aspirin. We evaluated changes in liver function indicators and compared to acetaminophen and NSAIDs. We retrospectively analyzed EMR data (n=28788) of patients who took study drugs and had liver function tests (LFT) during study period from 2009.7.1 to 2010.6.30 at a tertiary hospital and evaluated the above information. Patients not having LFT results at these three standard points of time (baseline, during medication, and after finishing medication) were excluded. During medication, mean changes of Alanine transaminase (ALT), Aspartate transaminase (AST), Total Bilirubin (TB) were increased and that of serum albumin (Alb) was decreased, with the largest effect from aspirin (n=461; 16.8, 14.9, 0.28, -0.24) and the smallest from celecoxib (n=127; 3.4, 5.2, 0.11, -0.16). In addition, aspirin caused more changes of blood liver function indicators in patient group with liver disease (n=128, 27.4, 26.9, 0.53, -0.3) than those in patient group without liver disease (n=357, 12.5, 13.1, 0.23, -0.24). Taking low dose aspirin for prophylaxis purpose with long-term medication may be associated with liver injury. Our study is just a signal regarding the possibility of hepatotoxicity among patients taking low dose aspirin in a hospital setting, and thus it needs to be further investigated.

Keywords

References

  1. Campbell, C. L., Smyth, S., Montalescot, G. and Steinhubl, S. R. : Aspirin dose for the prevention of cardiovascular disease. JAMA 297, 2018 (2007). https://doi.org/10.1001/jama.297.18.2018
  2. Bartolucci, A. A., Tendera, M. and Howard, G. : Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am. J. Cardiol. 107, 1796 (2011). https://doi.org/10.1016/j.amjcard.2011.02.325
  3. Vane, J. R. and Botting, R. M. : Mechanism of action of nonsteroidal anti-inflammatory drugs. The American Journal of Medicine 104, 2S (1998).
  4. Imaeda, A. B., Watanabe, A., Sohail, M. A., Mahmood, S., Mohamadnejad, M., Sutterwala, F. S., Flavell, R. A. and Mehal, W. Z. : Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305 (2009).
  5. Glaser, K. B. : Cyclooxygenase selectivity and NSAIDs: cyclooxygeanse-2 selectivity of etodolac. Inflamopharmacology 3, 335 (1995). https://doi.org/10.1007/BF02668029
  6. Teoh, N. C. and Farrell, G. C. : Hepatotoxicity associated with non-steroidal anti-inflammtory drugs. Clin Liver Dis. 7, 401 (2003). https://doi.org/10.1016/S1089-3261(03)00022-9
  7. Vane, J. R. and Botting, R. M. : Mechanism of action of antiinflammatory drugs. Scand J. Rheumatology 102, 9 (1996).
  8. Charles, F. L., Lora, L. A., Morton, P. G. and Leonard, L. L. : Drug information handbook. 19th ed. Ohio: Lexi-CompInc. (2010).
  9. Marmura, M. J., Hopkins, M., Andrel, J., Young, W. B., Biondi, D. M., Rupnow, M. F. and Armstrong, R. B. : Electronic medical records as a research tool: Evaluating topiramate use at a headache center. Headache 50, 769 (2010). https://doi.org/10.1111/j.1526-4610.2010.01624.x
  10. Elizabeth, H. H. : Elevated liver function tests in type 2 diabetes. Clinical Diabetes 23, 115 (2005). https://doi.org/10.2337/diaclin.23.3.115
  11. Koda-kimble, M. A., Young, L. Y., Alldredge, B. K., Corelli, R. B., Guglielmo, B. J., Kradjan, W. A. and Williams, B. R. : Applied therapeutics-The clinical use of drugs (9th Ed). Baltimore, Philadelphia: Lippincott Williams&Wilkins (2009).
  12. Mary, L. : Basic skills in interpreting laboratory test, 4th ed. (2009).
  13. Banichou, C., Dana, G. and Flahault, A. : Causality assessment of adverse reactions to drug-II. An original model for validation of drug causality assessment methods: case reports with positiverechallenge. J. Clin. Epidemol. 4, 1331 (1993).
  14. Dana, G. and Benichou, C. : Causality assessment of adverse reactions to drugs- I.A novel method based on the conclusions of international consensus meetings:application to druginduced liver injuries. J. Clin. Epidemol. 46, 1323 (1993). https://doi.org/10.1016/0895-4356(93)90101-6
  15. Liss, G., Rattan, S. and Lewis, J. H. : Predicting and preventing actue drug-induced liver injury; what's new in 2010? Expert. Opin. Drug Metab. Toxicol. 6, 1047 (2010). https://doi.org/10.1517/17425255.2010.503706
  16. Stine, J. G. and Lewis, J. H. : Drug-induced liver injury: a summary of recent advances. Expert. Opin. Drug Metab. Toxicol. 7, 875 (2011). https://doi.org/10.1517/17425255.2011.577415
  17. Nachimuthu, S., Volfinzon, L. and Gopal, L. : Acute hepatocellular and cholestatic injury in a patient taking celecoxib. Postgrad Med. J. 7, 548 (2001).
  18. Watkins, P. B. : Biomarkers for the diagnosis and management of drug-induced liver injury. Semin Liver Dis. 24, 393 (2009).
  19. Treeprasertsuk, S., Huntrakul, J., Ridtitid, W., Kullavanijata, P. and Bjornsson, E. : The predictors of complications in patients with drug-induced liver injury caused by antimicrobial agents. Alimentary Pharmacol. Ther. 31, 1200 (2010). https://doi.org/10.1111/j.1365-2036.2010.04292.x
  20. Zimmerman, H. J. : The spectrum of hepatootxicity. PerspectBiol. Med. 12, 135 (1968).
  21. O'Connor, N., Dargan, P. I. and Jones, A. L. : Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM 96, 787 (2003). https://doi.org/10.1093/qjmed/hcg138
  22. Bessone, F. : Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage. WJG 16, 5651 (2010). https://doi.org/10.3748/wjg.v16.i45.5651
  23. Agundez, J. A., Lucena, M. I., Martinez, C., Andrade, R. J., Blanca, M., Ayuso, P. and Garcia-Martin, E. : Assessment of nonsteroidal anti-inflammatory drug-indcued hepatotoxicity. Expert. Opin. Drug Metab. Toxicol. 7, 817 (2011). https://doi.org/10.1517/17425255.2011.574613
  24. Tolman, K. G. : Hepatotoxicity of Non-Narcotic Anagesics. Am. J. Med. 105, 13S (1998). https://doi.org/10.1016/S0002-9343(98)00070-9
  25. Elzouki, A. N. and Lindgren, S. : Granulomatous hepatitis induced by aspirin-kodein analgesics. J. Intern. Med. 239, 279 (1996). https://doi.org/10.1046/j.1365-2796.1996.408761000.x
  26. Laine, L., White, W. B., Rostom, A. and Hochberg, M. : COX- 2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 38, 165 (2008). https://doi.org/10.1016/j.semarthrit.2007.10.004
  27. Travers, F. L. and Hughes, G. R. : Salicylate hepatotoxicity in systemic lupus erythematosus: a common occurrence? Br. Med. J. 2, 1532 (1978).
  28. Kuffner, E. K., Dart, R. C., Bogdan, G. M., Hill, R. E., Casper, E. and Darton, L. : Effect of maximal daily doses of acetaminophen on the liver of alcohol patients. Arch. Intern. Med. 161, 2245 (2001).
  29. Haviv, Y. S. : Low-dose paracetamol probably associated with hepatic injury in a patients with chronic renal failure. Clin. Drug. Invest. 19, 389 (2000). https://doi.org/10.2165/00044011-200019050-00010
  30. Boelsterli, U. A. : Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide. Drug. Saf. 25, 633 (2002). https://doi.org/10.2165/00002018-200225090-00003
  31. Ackerman, Z., Flugelman, M. Y., Wax, Y., Shouval, D. and Levy, M. : Hepatitis during measles in young adults: possible role of antipyretic drugs? Hepatology 10, 203 (1989). https://doi.org/10.1002/hep.1840100214
  32. Alam, I., Ferrell, L. D. and Bass, N. M. : Vanishing bile duct syndrome temporally associated with ibuprofen use. Am. J. Gastroenterol. 91, 1626 (1996).
  33. Benson, G. D. : Hepatotoxicity following the therapeutic use of antipyretic analgesics. Am. J. Med. 75, 85 (1983).
  34. Goldkind, L. and Laine, L. : A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol. Drug. Saf. 15, 213 (2006).
  35. Prescott, L. F. : Effects of non-narcotic analgesics on the liver. Drugs 32, 129 (1986). https://doi.org/10.2165/00003495-198600324-00010
  36. Masubuchi, Y., Saito, H. and Horie, T. : Sturctural Requirements for the Hepatotoxicity of Nonsteroidal Antiinflammatory Drugs in isolated rat hepatocytes. J. Pharmacol. Exp. Ther. 287, 208 (1998).
  37. Mukherjee, D., Nissen, S. E and Topol, E. J. : Risk of Cardiovascular events associated with selective COX-2 inhibitors. JAMA 286, 954 (2001). https://doi.org/10.1001/jama.286.8.954
  38. Paik, Y. H., Kim, J. K., Lee, J. I., Kang, S. H., Kim, D. Y., An, S. H., Lee, S. J., Lee, D. K., Han, K. H., Chon, C. Y., Lee, S. I., Lee, K. S. and Benner, D. A. : Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats. Gut 58, 1517 (2009). https://doi.org/10.1136/gut.2008.157420
  39. Silverstein, F. E., Faich, G., Goldstein, J. L., Simon, L. S., Pincus, T., Whelton, A., Makuch, R., Eisen, G., Agrawal, N. M., Stenson, W. F., Burr, A. M., Kent, J. D., Lefkowith, J. B., Verburg, K. M. and Geis, G. S. : Gastrointestinal toxicity with celecoxibvsnonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib long-term arthritis safety study. JAMA 284, 1247 (2000). https://doi.org/10.1001/jama.284.10.1247
  40. Matsumura, T., Suzuki, T., Aizawa, K., Sawaki, D., Munemasa, Y., Ishida, J. and Nagai, R. : Regulation of transforming growh factor-b-dependent cyclooxygenase-2 expression in fibroblasts. Journal of Biological Chemistry 284, 35861 (2009). https://doi.org/10.1074/jbc.M109.014639