Angiotensin II receptor blockers and acute pancreatitis

BACKGROUND: Acute pancreatitis is a disease with potentially lethal consequences. The hormone angiotensin II inhibits the protective mucosa alkaline secretion in the duodenum via the angiotensin II type 1 receptor. A local pancreatic renin-angiotensin system affects enzyme secretion and inflammatory response in the pancreas. Animal experiments have shown that blocking the angiotensin II type 1 receptor could prevent acute pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) is followed by an increased risk of elevated pancreatic enzymes (hyperenzymemia) and acute pancreatitis, and no pharmacological prevention exists.

METHODS: Paper I. A laboratory study of the response to angiotensin II infusion by measuring the ratio of angiotensin II type 1 and type 2 receptors and the duodenal mucosal alkaline secretion in rats. Paper II and IV. The effect of angiotensin II receptor blockers (ARB) and relative risk of acute pancreatitis was estimated in two case-control studies: a) A matched case-control study among patients with hypertension in 1996-2005, nested within the Health Improvement Network in the United Kingdom (II), and b) A nationwide population-based case-control study during 2006 in Sweden (IV). Paper III. A randomized triple-blind placebo controlled clinical trial at two Swedish hospitals was performed in 2005-2008 to evaluate whether 50 mg of the ARB losartan, given one hour before ERCP, prevents hyperenzymemia 24 hours after ERCP.

RESULTS Paper I. Angiotensin II did not elicit any response in duodenal mucosal alkaline secretion. The expression of angiotensin II type 2 receptor was decreased compared to previous studies. Administration of angiotensin II increased the relative expression of angiotensin II type 2 receptor compared to the type 1 receptor. Paper II. During follow-up of more than 600,00 person-years at risk, 265 cases of acute pancreatitis and 2,000 control people were compared. The risk of acute pancreatitis was statistically non-significantly decreased in ARB users (odds ratio 0.63, 95% confidence interval 0.38-1.03) compared to non-users. Paper III. Among 38 losartan treated patients, 9 developed hyperenzymemia, compared to 7 out of 38 placebo treated individuals. Losartan conferred an OR of 1.6 (95% CI 0.3-7.8) with regard to hyperenzymemia. Paper IV. 1,961 case patients with acute pancreatitis and 20,000 control individuals from the general population were compared. The risk of acute pancreatitis in users of ARB was statistically significantly decreased (odds ratio 0.81, 95% confidence interval 0.69-0.97) after adjustment for age, sex, education, number of distinct drugs and cardiovascular disease.

CONCLUSIONS: Paper I. The response in duodenal mucosal alkaline secretion depends on the level of angiotensin II type 2 receptor expression, which in turn is affected by angiotensin II infusion. Paper II and IV. The use of ARB might decrease the risk of acute pancreatitis. Paper III. An oral dose of 50 mg of the ARB losartan may not prevent post-ERCP hyperenzymemia.

List of scientific papers

I. Ewert S, Sjoberg T, Johansson B, Duvetorp A, Holm M, Fandriks L (2006). "Dynamic expression of the angiotensin II type 2 receptor and duodenal mucosal alkaline secretion in the Sprague-Dawley rat." Exp Physiol 91(1): 191-9.
https://doi.org/10.1113/expphysiol.2005.031401

II. Sjöberg T (2010). "Use of angiotensin II receptor blockers and the risk of acute pancreatitis: a nested case-control study." Pancreatology [Accepted]
https://doi.org/10.1159/000225906

III. Sjöberg T (2010). "Angiotensin II receptor blocker losartan in the prevention of hyperenzymemia after endoscopic retrograde cholangiopancreatography: a randomized clinical trial." [Submitted]

IV. Sjöberg T (2010). "Angiotensin II receptor blockers and risk of acute pancreatitis: a population based case-control study using the Prescribed Drug Register in Sweden." [Manuscript]