Cholestatic Hepatitis Associated With Repaglinide

Repaglinide is a fast, short-acting meglitinide analog antidiabetic drug approved for the treatment of type 2 diabetes. Hypoglycemia is a major adverse effect of this drug (1). In rare cases, elevated liver enzymes have been noted (2). We report a patient who developed cholestatic hepatitis while taking repaglinide.

A 72-year-old man had a 2-year history of type 2 diabetes that was initially controlled by diet. He had normal liver function. Two months before presentation, he began taking repaglinide (1 mg/day), and 1 month before presentation, the daily dose was increased to 2 mg. The patient presented because of a 2-week history of itching and jaundice and was admitted to the hospital. He had no toxic habits and denied the use of any other drugs or herbal remedies.

The patient’s physical examination was unremarkable except for jaundice. Aspartate aminotransferase was 83 units/l (normal <37), alanine aminotransferase 183 units/l (normal <40), alkaline phosphatase 307 units/l (normal <136), γ-glutamyltransferase 303 units/l (normal <85), and total bilirubin 12.2 mg/dl with direct bilirubin 9.4 mg/dl. Serum creatinine was 1.3 mg/dl. Serology ruled out viral causes, and screening for autoantibodies was negative. Imaging testing, including a magnetic resonance cholangiography, showed no pathological findings. A liver biopsy showed expanded portal areas with mild proliferation of bile ducts and a moderate inflammatory infiltrate (mainly lymphocytes and some eosinophils) with ballooning of hepatocytes. Repaglinide was discontinued, and laboratory findings were normal within a month.

To our knowledge, this is the first published report of cholestatic hepatitis related to repaglinide. The putative role of repaglinide in this case of acute cholestasis is strongly supported by its temporal eligibility, the careful exclusion of alternative causes, the histological features, and the rapid improvement after drug withdrawal. The presence of some eosinophils in the liver inflammatory infiltrate suggest that an immune mechanism might be operating.

Idiosyncratic hepatic reactions are often associated with partial dose dependence and a relationship to drug metabolism (3). Repaglinide clearance is dependent on liver enzyme activity and secondarily on hepatic blood flow. These two factors are impaired at a variable extent among elderly individuals (4). Furthermore, 8% of a dose is excreted in the urine (1). This patient had an estimate of the creatinine clearance of 46.59 ml/min (Cockcroft and Gault formula). Studies carried out in patients with mild to moderate kidney impairment (30–80 ml/min) have shown higher values for drug concentration over time in both single and multiple dosing compared with those in healthy subjects (1).

The product datasheet states that dose adjustments are unnecessary in geriatric patients, while a dose titration is recommended in patients with hepatic or renal impairment. Indeed, the reduced liver enzyme activity, along with the steady decline in renal function with normal aging that can be further compromised with the presence of underlying chronic conditions such as diabetes (4), indicates that caution should be observed when repaglinide is prescribed to elderly patients. Therefore, we believe that a reduced dose should also be encouraged, and that clinicians should be aware of the potential for hepatotoxicity of repaglinide.