Fenofibrate – LiverTox – NCBI Bookshelf

Introduction

Fenofibrate is a fibric acid derivative used in the therapy of hypertriglyceridemia and dyslipidemia. Fenofibrate therapy is associated with mild and transient serum aminotransferase elevations and with rare instances of acute liver injury, which can be severe and prolonged and lead to significant hepatic fibrosis.

Background

Fenofibrate (fen” oh fye’ brate) is a fibric acid derivative. Its lipid lowering activity is probably mediated by its interactions with and activation of the peroxisome proliferator activated receptor alpha (PPARα), which regulates gene expression of enzymes involved in fatty acid oxidation. These changes induced by fenofibrate cause an increase in lipoprotein lipase levels which enhance clearance of triglyceride-rich lipoproteins. Fenofibrate is recommended for therapy of adults with severe hypertriglyceridemia and for adults with primary hypercholesterolemia when use of standard agents for lowering low-density lipoprotein cholesterol (LDL-C) is not possible. It has been used off-label to treat primary biliary cirrhosis and sclerosing cholangitis. Fenofibrate was approved for use in Europe in 1975 and in the United States in 1993. Fenofibrate is available in multiple generic forms and under the brand names of Antara, Lipofen, Lofibra, TriCor and Triglide as capsules and tablets of multiple concentrations, typically ranging from 48 to 200 mg each. The recommended initial dosage in adults is 48 to 145 mg daily with dose adjustment to as high as 200 mg daily (depending upon the formulation). Common side effects of fenofibrate include nausea, gastrointestinal upset, headache, muscle cramps, rhinitis, and rash. Laboratory abnormalities can include increases in serum aminotransferase, creatine kinase, and creatinine levels. Fibrates have multiple drug interactions requiring careful review and use. Potential severe adverse events include myopathy and rhabdomyolysis, renal dysfunction, gallstones and their complications, and hypersensitivity reactions including angioedema and anaphylaxis.

Hepatotoxicity

Mild, transient serum aminotransferase elevations develop in up to 20% of patients receiving fenofibrate, but values above 3 times normal in only 3% to 5%. These abnormalities are usually asymptomatic and transient, resolving even with continuation of fenofibrate, but they occasionally may require drug discontinuation. Monitoring of aminotransferase levels is recommended at baseline and periodically during therapy and discontinuation if enzymes persist above 3 times the upper limit of normal (ULN) or if symptoms of liver injury arise.

There have also been multiple reports of clinically apparent liver injury in patients on fenofibrate. Onset of injury is variable; cases resembling acute hepatitis usually arise within a few weeks or months of starting therapy (Case 2), whereas cases resembling chronic hepatitis and cirrhosis typically arise after more than 6 months or even years of treatment (Case 1). The pattern of serum enzyme elevations is typically hepatocellular, but both mixed and cholestatic patterns have also been described. Some instances of acute injury with a short latency (2 to 8 weeks) are associated with fever, rash and eosinophilia, suggesting immunoallergic hepatitis. Cases with a longer latency typically present with nonspecific symptoms of weakness and fatigue, have autoimmune features with hyperglobulinemia, smooth muscle or antinuclear antibody, and a chronic hepatitis-like clinical and histological picture that is sometimes prolonged and associated with significant fibrosis or cirrhosis.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of hepatotoxicity of fenofibrate is not known but appears to be immunologic. Cases of autoimmune-like hepatitis due to fenofibrate suggest that there is induction of immune reactivity to altered metabolites or fenofibrate-protein haptens in the liver. One small series found the rare, extended HLA haplotype A*33:01, B*14:02, C*08:02, in 3 of 7 patients, all of whom had acute self-limited disease and presented with jaundice and cholestatic or mixed enzyme elevations within 5 to 7 weeks of starting fenofibrate for hypertriglyceridemia. The 4 cases with longer durations of therapy did not share this HLA haplotype.

Outcome and Management

Several instances of chronic liver injury and fibrosis have been reported with fenofibrate use, typically in patients who were continued on therapy despite evidence of liver injury. However, in most cases, serum aminotransferase levels fall to normal within 2 to 12 months of stopping. Rechallenge is usually followed by recurrence of liver injury and should be avoided. While many cases of fenofibrate associated liver injury have been prolonged and severe, there have been no instances of acute liver failure due to the fibrates. Chronic injury with vanishing bile duct syndrome may underlie many of the instances of chronic liver disease due to fenofibrate. In other instances, features of autoimmune hepatitis are present (ANA, SMA or high immunoglobulin levels). Corticosteroids have been used with apparent effect on serum enzyme levels, but their efficacy in altering the outcome of injury is less clear. If corticosteroids are used, the dose and duration of therapy should be kept to a minimum. Although not proven, there may be some degree of cross sensitivity to hepatic injury among the different fibrates.

Drug Class: Antilipemic Agents, Fibrates

Case 1. Acute hepatitis due to fenofibrate therapy.(1)

A 74 year old woman developed jaundice having been on oral therapy with fenofibrate (200 mg daily) for two years. She was not taking other medications and had no history of liver disease, alcohol use, or exposures to hepatitis. On hospital admission, physical examination revealed jaundice but no fever or rash. Laboratory findings included marked elevations in serum aminotransferase levels (Table) and bilirubin of 4.7 mg/dL. Tests for hepatitis A and B were negative, as were autoantibodies. Abdominal ultrasound and endoscopic retrograde cholangiopancreatography showed no evidence of biliary obstruction. During the first week in the hospital, serum bilirubin rose to 13.3 mg/dL and prothrombin time decreased to 46% of normal. At this point, fenofibrate was stopped and she then began to improve, with rapid regression of jaundice, allowing her to be discharged after 25 days in the hospital. In follow up over the next year, all abnormal liver tests returned to normal.

Case 2. Acute hepatitis due to fenofibrate.(2)

A 61 year old man with diabetes, hyperlipidemia and hypertension was started on fenofibrate (300 mg daily) and developed dark urine and fatigue two weeks later. After another two weeks, he presented to his physician and was found to be jaundiced. Fenofibrate was stopped, and he was admitted for evaluation. Serum aminotransferase and alkaline phosphatase levels were elevated, and total bilirubin was 9.3 mg/dL (Table). Tests for markers of acute hepatitis A, B and C were negative. Serum autoantibodies were not detected. An abdominal ultrasound and endoscopic retrograde cholangiography showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis, mild degrees of steatosis, and inflammatory cells and mild fibrosis in portal areas. His liver tests improved slowly and were normal two months later.