LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), are a family of agents that bind to and inhibit the angiotensin II type 1 receptor (AT1) and thus inhibit the renin-angiotensin system and its cascade of effects in causing arteriolar contraction and sodium retention. While angiotensin converting enzyme (ACE) inhibitors block the cleavage of angiotensin I to angiotensin II, the active peptide that causes a pressor response, the ARBs inhibit its peripheral action. The ARBs reduce blood pressure in animal models as well as in humans. Since their introduction in 1995, these agents have been used widely in the therapy of hypertension and to reduce the complications of hypertensive cardiovascular disease and diabetic nephropathy. The ARBs in clinical use in the United States include eight agents of similar chemical structure and activity, but somewhat different pharmacokinetics: losartan (Cozaar: 1995), valsartan (Diovan: 1996), irbesartan (Avapro: 1997), eprosartan (Teveten: 1997), candesartan (Atacand: 1998), telmisartan (Micardis: 1998), olmesartan (Benicar: 2002) and azilsartan (Edarbi: 2011). All of these agents have been associated with a minimal rate of serum enzyme elevations during chronic therapy (0.2% to 2%) which are usually mild-to-moderate in severity, self limited, and rarely require dose modification or discontinuation. As a class, the ARBs have been associated with rare instances of acute liver injury that is usually self limited in duration, but varies in clinical expression, being usually hepatocellular but occasional cholestatic in nature. The most common presentation of liver injury due to these agents is a cholestatic hepatitis arising within 1 to 8 weeks of starting and resolving as rapidly with stopping. Rare instances of prolonged jaundice have been described but not acute liver failure or autoimmune chronic hepatitis. Several Individual case reports of clinically apparent liver injury have been published in the literature for losartan, valsartan, irbesartan olmesartan and candesartan, but not specifically for azilsartan, eprosartan, and telmisartan, probably because these three have been in use for a shorter period of time and in fewer subjects. Most ARBs and particularly olmesartan have been linked to rare instances of severe sprue-like enteropathy. The enteropathy typically presents with severe diarrhea and weight loss with variable degrees of fatigue, nausea and abdominal discomfort arising 6 months to many years after starting the ARB. Small intestinal histological findings resemble those of celiac disease with flattening of the duodenal villuous pattern and villous atrophy. However, anti-transglutaminase and endomysial antibodies (the serologic markers of celiac disease) are negative and there is little or no response to a gluten-free diet. Withdrawal of the ARB, however, results in prompt improvement in the diarrhea and gradual resolution of duodenal villous flattening. Some cases of this drug induced enteropathy have had accompanying serum aminotransferase elevations and fatty liver by imaging or liver biopsy, which, along with the diarrhea, resolve rapidly with stopping the medication.