Clofibrate is a fibric acid derivative used in the therapy of hypertriglyceridemia and dyslipidemia. Clofibrate therapy is associated with mild and transient serum aminotransferase elevations and with rare instances of acute liver injury.
Clofibrate (kloe fye' brate) is a fibric acid derivative. The lipid lowering activity of clofibrate 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. Clofibrate increases lipoprotein lipase levels which enhances clearance of triglyceride rich lipoproteins. Clofibrate was available for many years and frequently used in the therapy of hypertriglyceridemia (Fredrickson types IV and V hyperlipidemia) and hypercholesterolemia (Fredrickson types IIa and IIb). Use of clofibrate decreased with the availability of statins for therapy of hyperlipidemia and subsequently it was withdrawn from use in 2002. Clofibrate was available previously in generic forms and under the brand name of Atromid-S as capsules of 500 mg. The recommended dosage was 2 grams daily in divided doses. Common side effects of clofibrate include headache, muscle aches and gastrointestinal upset. Fibrates have multiple drug interactions requiring careful review and use.
Mild, transient serum aminotransferase elevations develop in a small proportion of patients receiving clofibrate, but values above 3 times normal occur in 2% or less. These abnormalities are usually asymptomatic and transient, resolving even with continuation of clofibrate. There have been rare reports of clinically apparent liver injury in patients on clofibrate. Onset of injury is usually after 2 to 3 months of treatment and the pattern of serum enzyme elevations can be either cholestatic or hepatocellular. Symptoms of immunoallergic hepatitis are rare as are autoantibodies. Chronic therapy with clofibrate has also been linked to an increased rate of gallstones, particularly among patients with chronic cholestatic liver disease (primary biliary cirrhosis).
Mechanism of Injury
The mechanism of hepatotoxicity of clofibrate is not known but may relate to formation of toxic intermediates or interference with normal hepatic enzyme function. The development of gallstones during clofibrate therapy may relate to its effects in increasing cholesterol while lowering bile acid secretion in bile, thus favoring cholesterol supersaturation.
Outcome and Management
There have been no reports of acute liver failure, chronic hepatitis, cirrhosis or vanishing bile duct syndrome related to clofibrate therapy. There is likely to be some degree of cross reactivity to hepatotoxic reactions to fibrates, but not to statins.
REPRESENTATIVE TRADE NAMES
Clofibrate – Atromid-S®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 15 May 2014
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Jacobs WH. Intrahepatic cholestasis following the use of Atromid-S. Am J Gastroenterol 1976; 66: 69-71. PubMed Citation (70 year old woman developed jaundice 2 years after starting clofibrate [bilirubin 10.5 mg/dL, ALT 45 U/L, Alk P 125 U/L], biopsy showing intrahepatic cholestasis, degree of recovery not given).
Bateson MC, Maclean D, Ross PE, Bouchier IAD. Clofibrate therapy and gallstone induction. Am J Dig Dis 1978; 23: 623-8. PubMed Citation (Among patients with hyperlipidemia, 9 of 19 on clofibrate compared to 15 of 112 untreated patients had gallstones by oral cholecystograms; biliary cholesterol was higher in clofibrate treated group, saturation index 1.46 vs 1.03 ).
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Migneco G, Mascarella A, La Ferla A, Attianese R. [Clofibrate hepatitis. A case report] Minerva Med 1986; 77: 799-800. PubMed Citation (51 year old developed abdominal pain and fatigue 3 months after starting clofibrate [bilirubin normal, ALT 210 U/L] and rapid resolution on stopping; 4 months later she presented again having taken fenofibrate for 1 month [ALT 76 U/L, Alk P normal], and rapid resolution again on stopping).
Athyros VG, Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Didangelos TP, Carina MV, Kranitsas DF, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80: 608-13. PubMed Citation (389 patients treated with statin and fibrate combination for average of 2.5 years; 1.3% stopped because of ALT >3 times normal, all resolving within 4 weeks; no hepatitis or jaundice reported).
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 was attributed to fenofibrate, but none to clofibrate or gemfibrozil).
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