Ramipril-associated hepatotoxicity.
BACKGROUND
Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.


OBJECTIVE
To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.


METHODS
Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.


RESULTS
The 3 patients were middle-aged men. In 2 patients, jaundice appeared 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. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.


CONCLUSIONS
Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.
Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada.
Elaine
E
Yeung
Florence S
FS
Wong
Ian R
IR
Wanless
Koji
K
Shiota
Maha
M
Guindi
Supriya
S
Joshi
Geoffrey
G
Gardiner
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D002216:Captopril / Q000009:adverse effects / Q000627:therapeutic use; D056487:Chemical and Drug Induced Liver Injury, Chronic; D002760:Cholangiopancreatography, Endoscopic Retrograde / Q000379:methods; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use; D017328:Fosinopril / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007565:Jaundice / Q000139:chemically induced; D008099:Liver; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D017257:Ramipril / Q000009:adverse effects* / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D002216:Captopril; D017257:Ramipril; D017328:Fosinopril