Diflunisal is a salicylic acid derivative that is used in the therapy of chronic arthritis and mild to moderate acute pain. Diflunisal has been linked mild, transient elevations in serum aminotransferase levels during therapy as well as to rare instances of idiosyncratic drug-induced liver disease.
Diflunisal (dye floo' ni sal) is a difluorophenol derivative of salicylic acid that has anti-inflammatory, analgesic and antipyretic actions similar to aspirin. Diflunisal is metabolized by the liver but not to salicylate. Diflunisal is considered a non-steroidal anti-inflammatory agent (NSAID) and is believed to act by inhibition of tissue cyclo-oxygenases (Cox-1 and Cox-2) which leads to a decrease in synthesis of proinflammatory prostaglandins, important mediators in inflammatory and pain pathways. Diflunisal was approved for use in the United States in 1982 and current indications are for chronic arthritis due to osteoarthritis or rheumatoid arthritis and for mild-to-moderate pain. Diflunisal has been shown to stabilize transthyretin variants which are involved in the pathogenesis of amyloidosis which has led to the off-label use of diflunisal in familial amyloidosis. Diflunisal is available as tablets of 500 mg in generic forms and formerly under the brand name of Dolobid. Diflunisal is available by prescription only. The recommended regimen in adults is an initial dose of 1000 mg, followed by 500 to 1500 mg daily in two to three divided doses based upon response and tolerance. Diflunisal, like most NSAIDs, is generally well tolerated but side effects can include intestinal upset, nausea, heartburn, headache, somnolence, dizziness, peripheral edema and hypersensitivity reactions.
Diflunisal therapy is reported to be associated with a low rate of asymptomatic and transient serum aminotransferase elevations, which may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur rarely. Clinically apparent liver injury with jaundice from diflunisal is uncommon; only case reports have been published. The clinical and histologic features of diflunisal hepatotoxicity, however, are distinct and resemble an immunoallergic hepatitis which is quite different from the liver injury that occurs with aspirin or other salicylates. The latency to onset ranges from 1 to 4 weeks and the pattern of enzyme elevations is typically cholestatic but can also be mixed. Most patients have immunoallergic manifestations such as rash, fever and arthralgias; eosinophilia or atypical lymphocytosis are also common. A history of aspirin allergy has not been reported among cases with allergic reactions to diflunisal. Diflunisal is not a commonly used drug and is not mentioned in large case series on drug-induced liver injury or acute liver failure.
Mechanism of Injury
The mechanism of diflunisal hepatotoxicity is likely hypersensitivity and is different from that of acetylsalicylic acid (aspirin).
Outcome and Management
Severity ranges from asymptomatic elevations in serum aminotransferase levels, to symptomatic cholestatic hepatitis with or without jaundice. It is not clear if there is cross-sensivitiy to liver injury between diflunisal an other salicylates.
Case 1. Cholestatic jaundice arising after a few days of diflunisal therapy.
[Modified from: Geoffroy P, Carteret E, Salagnac V, Kalis B, Zeitoun P. [Hepatitis caused by diflunisal (Dolobis). Apropos of a case]. Therapie. 1987; 42: 253. French. PubMed Citation.
A 65 year-old woman with venous stasis ulcers was given diflunisal (750 mg daily) for leg pain while being treated with intravenous penicillin for suspected cellulitis. When therapy was started, serum enzymes and bilirubin levels were normal (Table). Diflunisal was stopped after 3 days because of gastrointestinal intolerance. Five days later blood tests showed marked elevations of alkaline phosphatase with mild hyperbilirubinemia. There was eosinophilia but no rash, lymphadenopathy or further fever. She had had a cholecystectomy in the past, but no history of liver disease or risk factors for viral hepatitis were mentioned. Ultrasound of the abdomen and endoscopic retrograde cholangiopancreatography were unrevealing. A liver biopsy showed portal inflammation with eosinophils and lobular histocytic granulomas. Over the next weeks laboratory test abnormalities fell toward normal despite continuation of penicillin and her medications for depression (clorazepam and viloxazine). Four months later all blood test results were normal.
|Medication:||Diflunisal (750 mg daily for 3 days)|
|Pattern:|| Cholestatic (R=0.3)|
||3+ (Jaundice and prolongation of hospitalization)
||3 Days to symptoms, 8 days to detection of jaundice
|Other medications:||Penicillin (iv), clorazepam, viloxazine|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
Despite absence of some clinical information, this is a convincing case of cholestatic jaundice caused by diflunisal. As in other cases, the latency was quite short and there was at least some evidence for an immunoallergic reaction (eosinophilia). Granulomas found on liver biopsy do not indicate “granulomatous hepatitis” but are rather further evidence of a generalized immunoallergic reaction. The rapid clinical recovery (1 month) but delayed fall of alkaline phosphatase to the normal range (between 2 and 5 months) is typical of cholestatic drug-induced liver injury.
REPRESENTATIVE TRADE NAMES
FDA product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References Last Updated: 22 July 2013
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and tenoxicam [0.03]; diflunisal is not discussed).
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