Ramipril-associated hepatotoxicity

Archives of Pathology & Laboratory Medicine, Nov 2003 by Yeung, Elaine, Wong, Florence S, Wanless, Ian R, Shiota, Koji, Et al

The patient underwent transjugular liver biopsy 3 weeks after the onset of jaundice; wedged and free hepatic vein pressures were normal. The biopsy showed cholestasis with bile duct necrosis, consistent with drug-induced injury (Figures 4 through 6) and no evidence of amyloidosis. There was moderate fibrosis with portal expansion and early septation typical of cholestatic disease. Ramipril was discontinued and nifedipine restarted for blood pressure control. In addition, ursodeoxycholic acid and cholestyramine were given for the cholestasis. Six weeks after discontinuing ramipril, the patient's ALP level had fallen to 177 U/L, transaminase and bilirubin levels had normalized, and symptoms had improved. At latest follow-up, the patient was still on clonidine, metoprolol, nifedipine, cyclophosphamide, prednisone, and thalidomide.

Case 3

A 51-year-old, previously healthy Chinese man, on no medications, was incidentally found to have proteinuria of 1.3 g/24 h, associated with a serum creatinine level of 1.4 mg/dL (123.76 [mu]mol/L) (normal range,

COMMENT

The temporal profile of hepatitis with or without jaundice in relation to ramipril, the exclusion of other causes of jaundice, and similar histologic findings in the 2 liver biopsies suggest ramipril-induced liver dysfunction in our patients. Patient 1 received atorvastatin at the same time as ramipril. Atorvastatin is uncommonly associated with asymptomatic elevation of serum transaminases.12 Patient 1, however, had persistent cholestatic jaundice after being on ramipril for 6 weeks and despite discontinuation of ramipril for 14 months. He also had evidence of cirrhosis with decompensation. Our second patient was receiving various antihypertensive medications concurrently with ramipril at the onset of jaundice, but cholestasis resolved on discontinuing ramipril and continuing the other drugs. In addition, various antibiotics were administered while he was on ramipril. However, it is unusual for 1 dose of trimethoprim-sulfamethoxazole, a known hepatotoxin, to cause significant cholestasis. Furthermore, cholestasis did not improve until ramipril was discontinued. Vancomycin and ceftriaxone do not cause cholestatic hepatitis. This patient had peripheral eosinophilia prior to the onset of jaundice. He had almost total resolution of cholestasis 6 weeks after discontinuation of ramipril. Our third patient was not on any other medications except ramipril, and the rise and fall in his aminotransferases coincided with starting and stopping ramipril.

While we know of no previous reports of ramipril-induced liver injury, at least 32 cases of captopril-induced liver injury have been reported and reviewed in the English language literature since 1982.3-5 Twelve additional cases involving enalapril,3,6,7 lisinopril,8-10 and fosinopril11 have also been reported. The majority of cases had cholestatic liver tests with clinical findings of jaundice and pruritus. Fever was seen in 11 cases,3-5,10 rash in 9,3 and eosinophilia in 5.3,4 The duration of use before detection of hepatotoxicity ranged from 5 days to 3 years, but the majority of cases presented within 8 weeks of starting the drug at low doses. Three patients tolerated 1 ACE inhibitor after experiencing a hepatic adverse event to another.3,11 Two other patients experienced liver injury with both captopril and enalapril3; one of these patients was able to tolerate delapril at a later date.3 Complete recovery occurred in the majority of cases from days to months after discontinuing the offending agent. In none of the patients who recovered was a rechallenge attempted. Two cases of fulminant hepatitis were reported. The first patient died of massive hepatic necrosis 6 weeks after the captopril dose was increased from 25 mg to 50 mg.7 The second case involved lisinopril with improvement of liver enzymes after withdrawal of the drug, but the patient died of complications related to prolonged illness.11