Disclaimer. ZR2019BH023/Shandong Provincal Natural Science Foundation, 81900716/National Natural Science Foundation of China, Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation. doi: 10.1097/HC9.0000000000000179. Third Report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia. In addition, pretreatment baseline liver biochemistries were not available in 5 of the 7 treated patients. BMC Gastroenterol 21, 298 (2021). The changes in laboratory values during hospitalization. The duration of treatment ranged from 556 weeks. & Chen, Yw. Primary biliary cholangitis: Epidemiology, prognosis, and treatment. PMC Eight months later, follow-up examination suggested the liver function was normal. Dig Dis Sci. Fontana RJ, Hayashi PH, Barnhart H, et al. Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernndez N, Ibez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK; International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Hajdu D, Aiglov K, Vinklerov I, et al. -. Nicoletti P, Aithal GP, Bjornsson ES, et al. Department of Pharmacy, eCollection 2023 Jun 1. volume21, Articlenumber:298 (2021) Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Fenofibrate-induced cirrhosis. The locations and principal investigators of the DILIN participating sites are given in the supplementary material. Shandong Rongjun General Hospital, Bethesda, MD 20894, Web Policies Moustafa T, Fickert P, Magnes C, et al. FOIA We report a special case of fenofibrateinduced acute severe DILI with sudden onset and rapid recovery, which is different from those in the LiverTox database. Shandong, The ducts show injury without loss. Ahmed F, Rouhier ML, et al. Mukthinuthalapati PK, Fontana RJ, Vuppalanchi R, Chalasani N, Ghabril M. J Clin Gastroenterol. 2017 Dec;62(12):3596-3604. doi: 10.1007/s10620-017-4812-7. An official website of the United States government. Plasma cells and eosinophils are prominent in the infiltrate. Steatohepatitis with cholestasis and duct injury. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. In the 3 cases that did not go to transplant there were eosinophils present in the portal areas but these were rare, similar to the numbers seen in case 5 who underwent liver transplant. 2001 Sep;152(5):353-4. An official website of the United States government. Federal government websites often end in .gov or .mil. 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. Moderate macrovesicular steatosis in zone 3 associated with mild perisinusoidal fibrosis and small balloon cells. official website and that any information you provide is encrypted Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Clinically significant liver injury from fenofibrate is very rare; indeed less than 0.3% of patients developed serum aminotransferase levels greater than five times the ULN in the FIELD trial that was conducted in almost 5000 patients treated with fenofibrate for an average of 5 years, a rate that was similar to placebo [5]. Additionally the US showed a normal gallbladder size, normal gallbladder wall thickness, and multiple gallstones. Any symptom of fatigue, poor appetite and yellow stained skin and sclera during fenofibrate therapy should trigger prompt withdrawal. The patients presented here have been included in prior publications of the overall features and outcomes of DILI in the prospective DILIN study [20, 21]. 2006 Sep-Oct;64(5):515-6. Liver imaging showed fatty liver without ductal dilation and he underwent endoscopic retrograde cholangiography which was normal. His symptoms persisted and laboratory studies worsened despite a trial of prednisone. The pattern and severity of injury is variable but a chronic progressive cholestatic disease can occur. Roussel Uclaf Causality Assessment Method. Both progressive cases presented in a manner that could be interpreted as acute-on-chronic liver failure with early appearance of ascites and features of hepatic dysfunction but without a previous bout of acute liver failure or marked serum aminotransferase elevations. After transplantation, jaundice resolved rapidly and all liver tests were normal 3 weeks later. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugsII. 2015;89(3):327334. and transmitted securely. 5.2 Hepatotoxicity. National Library of Medicine The patient was found to be free of autoimmune hepatitis, viral hepatitis and infectious hepatitis. He had not been treated with fenofibrate since the diagnosis of hypertriglyceridemia, and there was no allergic history to any drug or food. All evidences suggested that this patients liver injury were attributed to fenofibrate. He took telmisartan, felodipine, arotinolol hydrochloride, allopurinol, and metformin as usual medications. The injury in case 5 involved a 41 year-old male started on fenofibrate 160 mg daily for hypertriglyceridemia. The laboratory result showed alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk P) were all in normal range. The mechanism of hepatotoxicity of fenofibrate is not known but appears to be immunological [7] In case the patient visits again, low-frequency HLA type HLA-A*33:01 shall be tested, which is associated with DILI [8]. Interestingly, this HLA type was not seen in the 2 severe cases nor in the 2 with long latency to onset and autoimmune features. The doses were all in the prescribed range, 48160 mg daily. Hepatology. Ho CY, Kuo TH, Chen TS, Tsay SH, Chang FY, Lee SD. Shandong Provincial Hospital affiliated to Shandong First Medical University, Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. The pattern of liver enzyme elevations (based upon R ratios) was hepatocellular in 2, cholestatic in 3 and mixed in 2 (Table 2). The causality scores were highly likely in 5 and probable in 2. Severe chronic injury and mortality may occur if drug discontinuation is delayed. Gastroenterology. Representative histological changes in case 5. Mild inflammation was present, mainly in portal areas (H&E, 100x). Adenosine cyclophosphate and pantoprazole sodium injection were administered to alleviate the symptoms. All data generated or analyzed during this study are included in this published article. Patterson AD, Shah YM, Matsubara T, et al. Representative histological changes in case 5. doi: 10.1097/MD.0000000000010318. In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 120 mg fenofibrate tablets . Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Clipboard, Search History, and several other advanced features are temporarily unavailable. A. 2013;57(3):873874. He was jaundiced with yellow sclera and skin. The second patient (case 2) recovered from the severe and progressive injury with resolution of jaundice 6 months after onset but had persistence of symptoms of fatigue and weakness, marked elevation in AlkP and ascites. Drug Saf. statement and Efficacy and Safety of Bezafibrate Alone or in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis: Systematic Review and Meta-Analysis. Your privacy choices/Manage cookies we use in the preference centre. 2017;40(9):783787. Unauthorized use of these marks is strictly prohibited. Looks very much like autoimmune hepatitis. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. 2022 Dec 23;45(1):78-91. doi: 10.3390/cimb45010006. Given the variability in presentation the mechanism underlying fenofibrate hepatotoxicity is unclear. CAS Six patients had been taking medications other than the implicated agent within 2 months of onset, ranging from 1 to 10 medications, but in only two cases (2 and 4) were these agents considered even possibly related to the liver injury. Bethesda, MD 20894, Web Policies The site is secure. To assess causality between the drug and liver injury, two methods were employed: a consensus expert opinion by committee using a standardized scoring system [16]: 1 (definite: 95% likelihood), 2 (highly likely: 75%94% likelihood), 3 (probable: 50%74% likelihood), 4 (possible: 25%49% likelihood) or 5 (unlikely: <25% likelihood); and the standardized Roussel Uclaf Causality Assessment Method (RUCAM) [17]. Liver PPAR is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Epub 2011 Jul 8. The patient, who had type II obesity and hypertriglyceridaemia was on fenofibrate [ route not stated] 145 mg/24h from 2 and a half years with good control. Rodrguez-Vilarrupla A, Lavia B, Garca-Calder H, et al. Mild, transient serum aminotransferase elevations may develop in up to 20% of patients receiving fenofibrate. All authors declare that they have no conflicts of interest. Inclusion in an NLM database does not imply endorsement of, or agreement with, Inflammatory, immunological factors and genetic heterogeneity appear to be involved in the onset and progression of fenofibrateinduced DILI, and one recent study demonstrated that HLAA*33:01 may have potent effects on fenofibrateinduced DILI.7, 22, 29, 30, 31 Several clinical studies have reported that some DILI case reports were not . All 7 patients were symptomatic at presentation, the most common symptoms being jaundice (n=6), fatigue (n=3), nausea (n=3), itching (n=3) and abdominal pain (n=2). Laboratory results at presentation showed hepatocellular, mixed and cholestatic injury but 6 cases presented with jaundice. -, Rangnekar AS, Fontana RJ. The authors declare that they have no competing interests. Hepatitis B surface antigen and hepatitis C antibody were negative. Weakness, fatigue and abnormal liver function during fenofibrate therapy should be closely monitored and trigger prompt withdrawal if these symptoms occur. Although there was not a single pattern of injury observed, there were common themes. Liver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Drs. TriCor (fenofibrate) oral micronized capsule: Lipid-lowering agents . Bethesda, MD 20894, Web Policies Fenofibrateis commonly used in the treatment of dyslipidemia. 2004;67(5):2457. Dr. Chalasani receives research grant support from Intercept, Lilly, Gilead, Galectin Therapeutics and Cumberland where his institution receives the funding. Rockey DC, Seeff LB, Rochon J, et al. Reuben A, Koch DG, Lee WM, Acute Liver Failure Study G The study was approved by the Institutional Review Boards at each clinical site and data coordinating center and by a central Data Safety and Monitoring Board appointed by the NIDDK specifically for this study. BMC Gastroenterology All authors have approved the submitted version. Despite the concern for hepatotoxicity and the recommendation to monitor liver tests while on fenofibrate, the FIELD study found no difference in liver test abnormalities between fenofibrate and placebo [5] suggesting that DILI from fenofibrate is a rare event probably arising in fewer than 1:10,000 exposed persons, arguing against routine monitoring of liver tests, particularly as the appropriate interval and frequency is unclear. Fenofibrate is a peroxisome proliferator receptor alpha (PPAR-) activator which is commonly used in the therapy of hypertriglyceridemia and mixed dyslipidemia. 2020 Aug 19;10(9):338. doi: 10.3390/metabo10090338. Funding source: 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). 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