Gemfibrozil is a fibric acid derivative used in the therapy of hypertriglyceridemia and dyslipidemia. Gemfibrozil therapy is associated with mild and transient serum aminotransferase elevations and with rare instances of acute liver injury.
Gemfibrozil (jem fye' broe zil) is a fibric acid derivative and lipid lowering agent. The lipid lowering activity of gemfibrozil is probably mediated by its interactions with the peroxisome proliferator activated receptor alpha (PPARα), which regulates gene expression of enzymes involved in fatty acid oxidation. Gemfibrozil increases lipoprotein lipase levels, which enhance clearance of triglyceride rich lipoproteins. Gemfibrozil was approved for use in the United States in 1981 and it is still widely used with more than 5 million prescritions filled yearly. Gemfibrozil is recommended for therapy of hypertriglyceridemia (Fredrickson type IV and V hyperlipidemia) and hypercholesterolemia (type IIb). Gemfibrozil therapy has been shown to lower rates of myocardial infarction and stroke, most likely as a result of its effects on HDL cholesterol and triglyceride levels. Gemfibrozil is available in multiple generic forms and under the brand name of Lopid as tablets of 600 mg. The recommended dosage is 600 mg twice daily before morning and evening meals. Common side effects of gemfibrozil include gastrointestinal upset, diarrhea, constipation and fatigue. Fibrates have multiple drug interactions requiring careful review and use.
Mild, transient serum aminotransferase elevations develop in approximately 20% of patients receiving gemfibrozil, but values above 3 times normal in 5% or less. These abnormalities are usually asymptomatic and transient, resolving even with continuation. However, there have also been rare reports of clinically apparent liver injury in patients on long term gemfibrozil. The clinical presentation was highly variable. The onset of injury varied from a few weeks to several years after starting the medication and the pattern of serum enzyme elevations ranged from hepatocellular (Case 1) to mixed to cholestatic. Cases have not been associated with signs of immunoallergic (fever, rash, eosinophilia) or autoimmune hepatitis and recovery has been prompt and complete with stopping therapy.
Mechanism of Injury
The mechanism of hepatotoxicity of the gemfibrozil is not known, but is likely due to an immunologic response to an intermediate of its metabolism.
Outcome and Management
The few published instances of clinically apparent hepatotoxicity due to gemfibrozil have been mild and self-limited. There have been no published reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome related to gemfibrozil. It is unclear whether liver injury is a class effect of the fibrates. There is little evidence for cross sensitivity to hepatotoxicity among the various fibrates.
Case 1. Mild acute hepatitis due to gemfibrozil.
[Modified from: Domínguez Tordera P, Comellas Alabern JF, Ronda Rivero F. Gemfibrozil
hepatotoxicity: a case report. Int J Clin Pharm 2011; 33: 730-2. PubMed Citation]
A 55 year old woman developed nausea and fatigue one month after starting gemfibrozil (600 mg daily). Several months before this she had been involved in a motor vehicle accident and was admitted to the hospital for management of thoracic and ankle trauma. At that time, all liver tests were normal and an ultrasound of the abdomen (done to assess trauma) showed small gallstones, but no abnormalities of intra- or extra-hepatic bile ducts. She was treated for trauma and fractures and was started on enoxaparin, esomeprazole, venlafaxine and metamizol (an analgesic and antipyretic not available in the United States). During follow up after the admission, she was found to have hypertriglyceridemia (239 mg/dL), but normal cholesterol levels and was started on gemfibrozil, which she had not taken previously. She had no history of liver disease, alcohol use, or known risk factors for viral hepatitis. She denied rash, fever and abdominal pain. Blood tests at the time of onset of fatigue showed marked elevations in serum aminotransferase levels (ALT 1142 U/L, AST 656 U/L), modest increase in alkaline phosphatase (331 U/L) and GGT (420 U/L),
and a total serum bilirubin of 2.7 mg/dL (2.2 mg/dL direct). Tests for hepatitis A, B and C were negative. Tests for autoantibodies were not mentioned. Abdominal ultrasound showed the previously described gallstones, but no evidence of biliary obstruction. Gemfibrozil was discontinued, but her other medications were not. Serum enzyme abnormalities rapidly improved and were largely normal 2 weeks later (Table).
||Gemfibrozil (600 mg daily)
||2+ (mild jaundice)
||Enoxaparin, esomeprazole, venlafaxine, metamizol
|Time After Starting
||Time After Stopping
||Alk P (U/L)
|- 2 months
||Admission for trauma
||Started on gemfibrozil (600 mg daily)
Acute hepatocellular injury arose within a month of starting gemfibrozil therapy. The patient was taking several other drugs that might cause liver injury (enoxaparin, venlafaxine and even esomeprazole), but these were continued and only the gemfirbrozil was held. She improved rapidly which was evident within 2 days and nearly complete within 2 weeks. The acute hepatocellular injury with mild jaundice and rapid recovery (<1 month) on stopping the drug are typical of gemfibrozil induced liver injury.
REPRESENTATIVE TRADE NAMES
Gemfibrozil – Generic, Lopid®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 17 March 2014
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Bustamante Balén M, Plumé Gimeno G, Bau González I, Berenguer Lapuerta J. Acute hepatitis caused by gemfibrozil. Gastroenterol Hepatol 1998; 21: 419-20. PubMed Citation (69 year old woman developed dark urine after 2 years of therapy with gemfibrozil [bilirubin 3.1 mg/dL, ALT 1931 U/L], falling to normal within one month of stopping).
de Diego Lorenzo A, Catalina V, García Sánchez A, Escudero M, Cos E, Clemente G. Cholestatic hepatitis caused by gemfibrozil. Rev Esp Enferm Dig 2001; 93; 610-1. PubMed Citation (67 year old man developed jaundice 2 years after starting gemfibrozil [bilirubin 8.2 mg/dL, ALT 524 U/L, Alk P 551 U/L], resolving rapidly with stopping drug).
Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004; 94: 935-8. PubMed Citation (Review of adverse event reports to FDA for gemfibrozil and fenofibrate from 1999-2003; hepatotoxicity report rates were 13 per million for gemfibrozil vs 14.6 per million for fenofibrate).
Grubisić-Cabo F, Vrdoljak E. Drug-induced hepatitis in a patient with malignant melanoma treated with interferon alfa 2b adjuvantly who had been administered gemfibrozil in therapy. Med Oncol 2006; 23: 121-4. PubMed Citation (61 year old with melanoma was treated with interferon alfa [15 mu thrice weekly] for 3 months and then developed rises in ALT [34 to 708 U/L] and bilirubin [0.7 to 1.3 mg/dL] within a few weeks of starting gemfibrozil, resolving within a few weeks of stopping both).
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Andrade RJ, Lucena MI, Kaplowitz N, García-Muņoz B, Borraz Y, Pachkoria K, García-Cortés M, et al. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006; 44: 1581-8. PubMed Citation (28 of 493 [5.7%] cases of drug induced liver disease were found to have evidence of chronic injury; 2 chronic cholestatic cases were attributed, at least in part, to fibrates; gemfibrozil/lovastatin and fenofibrate/raloxifen).
Akoglu H, Yilmaz R, Kirkpantur A, Arici M Altun B, Turgan C. Combined organ failure with combination antihyperlipidemic treatment: a case of hepatic injury and acute renal failure. Ann Pharmacother 2007; 41: 143-7. PubMed Citation (56 year old woman developed fatigue and red urine 1 month after starting combination of fluvastatin and gemfibrozil [bilirubin normal, ALT 2100 U/L, Alk P normal, creatinine 1.8 mg/dL, CPK 45,758 U/L, and myoglobin >3000 ng/dL], resolving rapidly upon stopping both drugs).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 1 case attributed to fenofibrate; none to clofibrate or gemfibrozil).
Domínguez Tordera P, Comellas Alabern JF, Ronda Rivero F. Gemfibrozil
hepatotoxicity: a case report. Int J Clin Pharm 2011; 33: 730-2. PubMed Citation (55 year old woman developed fatigue 1 month after starting gemfibrozil for hypertriglyceridemia [bilirubin 2.7 mg/dL, ALT 1142 U/L, Alk P 331 U/L], resolving within 2 weeks of stopping: Case 1).
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