Source: Diabetes  |  Posted 8 years ago

Ramipril may cause prolonged cholestatic hepatitis and biliary cirrhosis, say researchers.

Angiotensin-converting enzyme (ACE) inhibitors are generally well tolerated and, while liver injury is rare, it has been reported in patients receiving captopril, enalapril, lisinopril, and fosinopril.

Elaine Yeung, MD, with the Toronto General Hospital, Ontario, Canada, and colleagues describe the cases of 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.

The patients were all middle-aged men, 2 of whom experienced jaundice 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. In addition, aminotransferase levels were mildly elevated. No bile duct obstruction was found.

Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, extravasation of bile, ductular proliferation, and portal inflammation.

Cholestasis improved 6 weeks after ramipril was stopped in 1 of the patients. In the other patient, cholestasis continued for 14 months and biliary cirrhosis was present on biopsy.

The third patient developed hepatitis without jaundice 3 weeks after starting ramipril. Symptoms resolved after the drug was discontinued.

"Ramipril-associated liver injury is similar to that seen with other ACE inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously," Dr. Yeung and colleagues note.

According to the researchers, it is unknown if each ACE inhibitor produces hepatotoxicity via a separate mechanism or if a common mechanism exists.

"It has been suggested that hypersensitivity may be a mechanism of injury, as supported by the low incidence, occurrence at low dosages, and the clinical features of fever, rash, myalgias, or eosinophilia," they point out.

Another mechanism may be metabolic idiosyncrasies involving the sulfhydryl group of captopril or the terminal proline ring shared by captopril, lisinopril, and enalapril. An alternative mechanism may be the ability of ACE inhibitors to inhibit the inactivation of bradykinin, leading to increased production of prostaglandins that favour bile stasis, they suggest.