Ramipril-associated hepatotoxicity

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

Context.-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.

Design.-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.

Conclusion.-Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.

During the last 2 decades, angiotensin-converting enzyme (ACE) inhibitors have been prescribed for an increasing number of cardiovascular1 and renal diseases.2 As a class of drugs, ACE inhibitors are well-tolerated. Liver injury is rare but has been reported in patients receiving captopril,3-5 enalapril,3,6,7 lisinopril,8-10 and fosinopril.11

The ACE inhibitor ramipril was first approved for use in the United States in 1991 and in Canada in 1993 for the treatment of hypertension. It was subsequently approved for the treatment of congestive heart failure occurring after myocardial infarction and for reducing the risk of stroke, myocardial infarction, and death among high-risk patients.1 Despite its widespread use, we believe these are the first 3 reports of hepatic injury associated with ramipril.

REPORT OF CASES

Case 1

The patient was a 51-year-old black man from Jamaica admitted because of painless jaundice for 14 weeks. His past medical history was significant for type 2 diabetes mellitus for 11 years; nephrolithiasis diagnosed 10 years earlier; testicular tuberculosis treated with medications and orchiectomy 5 years earlier; and 3 episodes of right parotid gland bacterial infection, last requiring drainage 1 year earlier, followed by 1 week of oral cephalexin. The patient had no history of liver disease. Five months prior to presentation, he suffered an acute myocardial infarction and was started on ramipril, 2.5 mg once daily, and atorvastatin, 20 mg once daily. One month later, he developed anorexia, jaundice, and pruritus. He also reported dark urine and pale stools. Both ramipril and atorvastatin were discontinued after 6 weeks of use. One month prior to presentation, he began experiencing diarrhea together with a 4.5-kg (10-lb) weight loss. His only other medications were insulin and aspirin. He had no history of over-the-counter or herbal medication use. He also denied any previous alcohol or intravenous drug use and has never received blood transfusions. Laboratory data 1 month after ramipril was started showed a total bilirubin level of 8.4 mg/dL (144 [mu]mol/L) (normal range, 0-1 mg/dL [5-21 [mu]mol/L]) and a serum alkaline phosphatase (ALP) level of 112 U/L (normal range, 35-125 U/ L). Three months later, he was icteric and had a palpable liver edge, but splenomegaly, ascites, and other stigmata of chronic liver disease were absent. His serum bilirubin level had increased to 15.5 mg/dL (266 [mu]mol/L) and ALP increased to 957 U/L. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 99 U/L (normal range, 7-40 U/L) and 103 U/L (normal range, 10-15 U/L), respectively. Hemoglobin level was 11.7 g/dL (normal range, 13-17 g/dL); white blood cell count, 10.5 x 10^sup 3^/[mu]L (normal range, 4-11 x 10^sup 3^/[mu]L); and platelet count, 302 x 10^sup 3^/[mu]L (normal range, 140-100 x 10^sup 3^/[mu]L). There was no peripheral eosinophilia. His international normalized ratio (INR) was 1.22 (normal range, 0.8-1.2) and serum albumin was 2.6 g/dL (normal range, 3.5-5 g/dL). Abdominal ultrasound showed an enlarged liver measuring 19 cm in span, with increased echogenicity. The size of his spleen was normal. Computed tomography showed cholelithiasis but no dilatation of the biliary tree. Serology for hepatitis A, B, and C was negative. Antinuclear antibody, antimitochondrial antibody, anti-smooth muscle antibody, and antimicrosomal liver-kidney antibody were negative. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography were normal.