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Digestive Diseases and Sciences

, Volume 62, Issue 12, pp 3596–3604 | Cite as

Identification and Characterization of Fenofibrate-Induced Liver Injury

  • Jawad Ahmad
  • Joseph A. Odin
  • Paul H. Hayashi
  • Naga Chalasani
  • Robert J. Fontana
  • Huiman Barnhart
  • Elizabeth T. Cirulli
  • David E. Kleiner
  • Jay H. Hoofnagle
Original Article

Abstract

Background

Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended.

Aims

The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate.

Methods

All cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed.

Results

Among 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37–61) years, and latency to onset was short (5–8 weeks) in 4 patients but more prolonged (18–56 weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA-A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2.

Conclusions

Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.

Keywords

Fenofibrate Hepatotoxicity Liver injury tests 

Abbreviations

ALT

Alanine aminotransferase

ANA

Antinuclear antibody

Alk P

Alkaline phosphatase

AST

Aspartate aminotransferase

DILI

Drug-induced liver injury

DILIN

Drug Induced Liver Injury Network

INR

International normalized ratio

RUCAM

Roussel Uclaf Causality Assessment Method

ULN

Upper limit of normal

Notes

Funding

The Drug-Induced Liver Injury Network (DILIN) is structured as an U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) with funds provided by the following Grants: U01DK065211 (Indiana University [Purdue]), U01DK065184 (University of Michigan [Ann Arbor]), U01DK065201 (University of North Carolina [Chapel Hill], Asheville, Wake Forest Baptist Medical Center), U01DK083020 (University of Southern California, University of California-Los Angeles [Pfleger Liver Institute]), U01DK083027 (Albert Einstein Medical Center), U01DK100928 (Icahn School of Medicine at Mount Sinai), U01DK065176 (Duke Clinical Research Institute). Additional support was provided by the Intramural Division of the National Cancer Institute (NCI), NIH.

Author’s Contribution

All authors contributed to the collection of clinical data, data analysis, and initial and final drafting of the manuscript. DEK provided expert review of the available liver histopathology.

Compliance with ethical standards

Conflict of interest

Dr. Chalasani has ongoing consulting activities (or had in the preceding 12 months) with NuSirt, Abbvie, Eli Lilly, Afimmune (DS Biopharma), Tobira (Allergan), Madrigal, Shire, Cempra, Ardelyx, Gen Fit and Amarin. These consulting activities are generally in the areas of nonalcoholic fatty liver disease and drug hepatotoxicity. Dr. Chalasani receives research grant support from Intercept, Lilly, Gilead, Galectin Therapeutics and Cumberland where his institution receives the funding. Over the last decade, Dr. Chalasani has served as a paid consultant to more than 30 pharmaceutical companies, and these outside activities have regularly been disclosed to his institutional authorities. Drs. Kleiner and Hoofnagle have no conflicts of interest to disclose.

Supplementary material

10620_2017_4812_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)

References

  1. 1.
    Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol. 1996;77:1179.CrossRefPubMedGoogle Scholar
  2. 2.
    Dewey FE, Gusarova V, O’Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;374:1123.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med.. 2016;374:1134.CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1.CrossRefPubMedGoogle Scholar
  5. 5.
    Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849.CrossRefPubMedGoogle Scholar
  6. 6.
    Jackevicius CA, Tu JV, Ross JS, et al. Use of fibrates in the United States and Canada. JAMA. 2011;305:1217–1224.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ganne-Carrié N, de Leusse A, Guettier C, et al. Autoimmune hepatitis induced by fibrates. Gastroenterol Clin Biol. 1998;22:525–529.PubMedGoogle Scholar
  8. 8.
    Dohmen K, Wen CY, Nagaoka S, et al. Fenofibrate-induced liver injury. World J Gastroenterol. 2005;11:7702–7703.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lucena MI, Andrade RJ, Vicioso L, et al. Prolonged cholestasis after raloxifene and fenofibrate interaction: a case report. World J Gastroenterol. 2006;12:5244–5246.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ho CY, Kuo TH, Chen TS, et al. Fenofibrate-induced acute cholestatic hepatitis. J Chin Med Assoc. 2004;67:245–247.PubMedGoogle Scholar
  11. 11.
    Hajdu D, Aiglová K, Vinklerová I, et al. Acute cholestatic hepatitis induced by fenofibrate. J Clin Pharm Ther. 2009;34:599–602.CrossRefPubMedGoogle Scholar
  12. 12.
    Rodríguez-Vilarrupla A, Laviña B, García-Calderó H, et al. PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J Hepatol. 2012;56:1033–1039.CrossRefPubMedGoogle Scholar
  13. 13.
    Montagner A, Polizzi A, Fouché E, et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut. 2016;65:1202–1214.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hegade VS, Khanna A, Walker LJ, et al. Long-term fenofibrate treatment in primary biliary cholangitis improves biochemistry but not the UK-PBC risk score. Dig Dis Sci. doi: 10.1007/s10620-016-4250-y. 2016 Jul 19. [Epub ahead of print].
  15. 15.
    Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther. 2016;43:283–293.CrossRefPubMedGoogle Scholar
  16. 16.
    Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel–Uclaf causality assessment method. Hepatology. 2010;51:2117–2126.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causalityassessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46:1331–1336.CrossRefPubMedGoogle Scholar
  18. 18.
    Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf.. 2009;32:55–68.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kleiner DE, Chalasani NP, Lee WM, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014;59:661–670.CrossRefPubMedGoogle Scholar
  20. 20.
    Fontana RJ, Hayashi PH, Barnhart H, et al. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury. Am J Gastroenterol. 2015;110:1450–1459.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chalasani N, Bonkovsky HL, Fontana R, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148:1340–1352.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nicoletti P, Aithal GP, Bjornsson ES, et al. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a Genome-Wide Association study. Gastroenterology. 2017;152:1078–1089.CrossRefPubMedGoogle Scholar
  23. 23.
    Patterson AD, Shah YM, Matsubara T, et al. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. Hepatology. 2012;56:281–290.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology. 2012;142:140–151.CrossRefPubMedGoogle Scholar
  25. 25.
    https://livertox.nih.gov. Accessed 2 May 2017.

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Jawad Ahmad
    • 1
  • Joseph A. Odin
    • 1
  • Paul H. Hayashi
    • 1
  • Naga Chalasani
    • 1
  • Robert J. Fontana
    • 1
  • Huiman Barnhart
    • 1
  • Elizabeth T. Cirulli
    • 1
  • David E. Kleiner
    • 1
  • Jay H. Hoofnagle
    • 1
  1. 1.Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkUSA

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