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ACG: ACE Inhibitor Use Linked to Liver Toxicity
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By Charles Bankhead, Staff Writer, MedPage Today
Action Points
* Explain to patients that a review of medical literature has shown that liver toxicity may be an uncommon adverse effect of treatment with ACE inhibitors.
* Note that the findings were based on a literature review, not a controlled clinical study, and that the studies reviewed were not recent publications.
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
SAN DIEGO -- Use of ACE inhibitors may confer a risk of hepatotoxicity, data from a literature review suggest.
The review identified 52 cases of ACE inhibitor-associated hepatotoxicity. However, the most detailed study was published in 1993. Given the widespread, chronic use of ACE inhibitors, the frequency could be greater than currently recognized, Saurabh Sethi, MD, reported here at the American College of Gastroenterology meeting.
"More than 50 million prescriptions for ACE inhibitors are written each year," Sethi, of Wayne State University in Detroit, said in an interview. "Hepatotoxicity usually is reversible upon cessation of therapy, but severe liver toxicity is certainly a potential if the treatment continues."
"We really don't know how often hepatotoxicity occurs in patients taking ACE inhibitors," he added. "The best data available are several years old. More studies are needed to better define the frequency, to identify possible risk factors, and to understand better the mechanisms of hepatotoxicity."
The 1993 review -- the most extensive to date -- involved 19 cases of ACE inhibitor-associated hepatotoxicity (Ann Pharmacother 1993; 27: 228-31).
Another report in 2001 detailed two additional cases and reviewed 13 prior cases, all involving use of captopril (Am J Med Sci 2001; 322: 236-40).
Although most episodes of hepatotoxicity resolved uneventfully after discontinuation of the ACE inhibitor, serious complications have arisen, such as a case of acute fulminant hepatitis (Gastroenterol 1990; 99: 1832-33).
In effort to update and describe cases of ACE inhibitor-related hepatotoxicity, Sethi and colleagues reviewed literature databases including publications from 1966 to 2009.
The initial search revealed 463 publications, which the investigators trimmed to 138 after a preliminary review. More detailed study led to additional culling and resulted in 52 case reports limited to hepatotoxicity in patients taking ACE inhibitors.
The investigators could get complete information on 44 of the 52 reports, which showed that 26 of the cases resulted from captopril use, nine involved enalapril, and three each involved lisinopril, ramipril, and fosinopril.
Biopsy findings from 31 cases showed prominent cholestasis in 21, dominant hepatocellular injury in eight, and mixed in two.
Time course to hepatotoxicity ranged from five days to three years. In two-thirds of cases, hepatotoxicity was detected within eight weeks of beginning low-dose therapy, said Sethi.
Most patients improved within a week after stopping the ACE inhibitors, but jaundice persisted for as long as six months in some patients.
The case reports included three cases of liver failure involving captopril, lisinopril, and enalapril, and three cases of ACE inhibitor-related cirrhosis in patients treated long term with lisinopril, ramipril, and enalapril.
The publications cited three potential mechanisms of ACE inhibitor-associated hepatotoxicity:
* Hypersensitivity
* ACE inhibitors' intrinsic ability to inhibit bradykinin activation, leading to increased conversion of arachidonic acid to prostaglandins and reduced rates of bile flow
* Metabolic idiosyncrasy involving the sulfhydryl group of captopril or the terminal proline ring common to captopril, lisinopril, and enalapril, leading to bile stasis.
Sethi said metabolic idiosyncrasy involving captopril was the most common mechanistic explanation.
Sethi and co-investigators reported no disclosures.
Primary source: American Journal of Gastroenterology
Source reference:
Sethi S, et al "A review on ACE inhibitor-associated hepatotoxicity" Am J Gastroenterol 2009; 104(suppl): Abstract 372.
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