Ezetimibe-induced acute pancreatitis.

Abstract: Ezetimibe is a lipid-lowering agent that inhibits the intestinal absorption of cholesterol and other related phytosterols. It is used alone or in combination with other lipid-lowering agents in the treatment of various forms of hypercholesterolemia. Since its FDA approval in 2002, there are no known citations of ezetimibe-induced pancreatitis.

Key Words: ezetimibe, acute pancreatitis

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Drugs are an uncommon, but important, cause of acute pancreatitis. The case of a 64-year-old African-American female who developed pancreatitis soon after she was started on ezetimibe is presented. Her pancreatitis resolved clinically and biochemically after ezetimibe was stopped. Other possible causes of pancreatitis were excluded clinically and by abdominal imaging.

Case Report

A 64-year-old African-American female came to our facility because of a three day history of epigastric pain. The pain was 8/10 in severity, radiated to her back and was partially alleviated by leaning forward. Pain was associated with nausea and nonbloody, profuse, non-projectile vomiting. She denied any fever, diarrhea, constipation or bleeding per rectum. She reported eating rice and chicken soup from a local Chinese restaurant with her son, who had no medical complaints. She denied any recent alcohol intake and in fact, was abstinent of alcohol use for 10 years. Before that, she was a social drinker, drinking only occasionally. Her past medical history was significant for diabetes, hypertension, dyslipidemia, cerebrovascular accident, and chronic kidney disease. Her medications included furosemide, aspirin, pioglitazone, diltiazem, carvedilol and insulin aspart. There were no changes in the dosage of any of these medications. However, two weeks before presentation, her simvastatin (at a dosage of 20 mg) was changed to a combined formulation of simvastatin and ezetimibe in a dosage of 20 mg and 10 mg, respectively. Her lipase at the time of admission was 576 (30-130). Abdominal ultrasound showed no evidence of gallstones with a normal common bile duct. Her serum calcium was 8.2 (8.8-10.5), serum albumin was 3.3 (3.4-5.0) and serum triglyceride was 198 (30-130). She was hemodynamically stable and a diagnosis of ezetimibe-induced pancreatitis was made, and she was switched back to 20 mg a day of simvastatin. She improved clinically and was discharged home. Lipase was repeated three weeks later and was found to be normal.

Discussion

The clinical diagnosis of acute pancreatitis was based on the patient's characteristic abdominal pain and nausea, combined with elevated serum levels of pancreatic enzymes. Serum amylase levels that are more than three times the upper limit of normal, in the setting of typical abdominal pain, are almost always caused by acute pancreatitis. Lipase levels were also elevated and paralleled the elevation in the amylase levels. Excessive alcohol use and gallstones, the two most frequent causes of acute pancreatitis in adults, (1,2) were ruled out in this patient by history and ultrasound examination, respectively. Very high serum triglyceride levels (greater than 1000) are also associated with acute pancreatitis. (3) In our case, there was mild elevation of the serum triglyceride level, which is extremely unlikely to have precipitated an attack of acute pancreatitis. Hypercalcemia resulting from any etiology can cause acute pancreatitis. (4) In our case, corrected serum calcium was normal. Simvastatin, furosemide and aspirin all have been shown to be associated with acute pancreatitis. However, in our case, the patient was on all of these medications for several years, and there was no recent change in their dosages. In fact, her symptoms resolved and her lipase level normalized despite continuation of aspirin, furosemide and simvastatin. All of these factors ruled these medications out as a cause of acute pancreatitis in this particular case.

Drugs are responsible for about 2% percent of pancreatitis cases. (5-7) It is important to identify them as a cause for pancreatitis to limit and prevent any ongoing pancreatic damage. Many drugs have been implicated as etiologic agents, and the list continues to grow. Proposed criteria for classifying drugs as having an association with pancreatitis include the following (8)

* Pancreatitis develops during treatment with the drug.

* Other likely causes of pancreatitis are not present.

* Pancreatitis resolves upon discontinuation of the drug.

* Pancreatitis usually recurs upon readministration of the drug.

By using the above criteria, as well as the Naranjo adverse drug reaction probability scale (9) (our patient had a score of 6), ezetimibe was the most probable cause of her pancreatitis.

The pathogenesis of drug-induced pancreatitis may be due to an idiosyncratic response in some circumstances (eg, 6-mercaptopurine, aminosalicylates, sulfonamides) or to direct toxicity (eg, diuretics, sulfonamides). (5-7,10) Pancreatitis associated with angiotensin-converting enzyme inhibitors is thought to reflect angioedema of the gland.

Drug-induced pancreatitis has no distinguishing clinical features. A high index of suspicion and careful drug history are therefore essential for making the diagnosis. The time course of developing the disorder depends upon the drug involved. As an example, pancreatitis may develop within a few weeks of beginning a drug with an immunologically mediated adverse reaction, and hence, may also be associated with a rash and eosinophilia. In contrast, patients taking valproic acid, pentamidine or didanosine may not develop pancreatitis until after many months of use, presumably due to the chronic accumulation of toxic metabolites. Proving the association with a particular drug may not always be straightforward, even in suspected cases. In most circumstances, re-challenge with the same drug may be harmful, if not fatal.

The prognosis of drug-induced pancreatitis is generally excellent. In one report of 22 cases, 19 were associated with interstitial pancreatitis; none of them exhibited pancreatic necrosis of more than 30% of the entire gland on computed tomography or ultrasound. Furthermore, there were no fatalities. (10) Mortality has also been rare in other reviews, although there are reports of a few deaths directly related to drug-induced pancreatitis.

Although the exact pathophysiology of this disease process may not be completely defined, the timeline of events in association with the temporal administration of ezetimibe suggests that it is a rapid, easily reversible and immunologically mediated cause of acute pancreatitis. This distinguishes it from the prolonged damage that may occur due to the protracted accumulation of toxic metabolites of drugs like pentamidine, valproic acid and didanosine. Subsequent documentation of the occurrence of ezetimibe-induced pancreatitis will pave the way for a hypothesis explaining the exact mechanism of this phenomenon.

References

1. Lankisch PG, Lowenfels AB, Maisonneuve P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 2002;25:411-412.

2. Venneman NG, Buskens E, Besselink MG, et al. Small gallstones are associated with increased risk of acute pancreatitis: potential benefits of prophylactic cholecystectomy? Am J Gastroenterol 2005;100:2540-2550.

3. Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990;19:783-791.

4. Brandwein SL, Sigman KM. Case report: milk-alkali syndrome and pancreatitis. Am J Med Sci 1994;308:173-176.

5. Ruenzi M, Layer P. Drug-associated pancreatitis: facts and fiction. Pancreas 1996;13:100-109.

6. Wilmink T, Frick TW. Drug-induced pancreatitis. Drug Saf 1996;14:406-423.

7. McArthur KE. Review article: drug-induced pancreatitis. Aliment Pharmacol Ther 1996;10:23-28.

8. Mallory A, Kem F Jr. Drug-induced pancreatitis: a critical review. Gastroenterology 1980;78:813-820.

9. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

10. Lankisch PG, Droege M, Gottesleben F. Drug-induced acute pancreatitis: incidence and severity. Gut 1995;37:565-567.

Imran Ahmad, MD, Edward Ruby, MD, Harris Usman, MD, Mateen Hotiana, MD, Mehnaz Hussain, MD, and Fahd Rahman, MD

From Mercy Fitzgerald Hospital, Darby, PA.

Reprint requests to Dr. Imran Ahmad, 151 S. Bishop Avenue, Apt B17, Secane, PA, 19018. Email: [e-mail]

Accepted September 7, 2006.

RELATED ARTICLE: Key Points

* Drugs are an important, but rare, cause of acute pancreatitis.

* Ezetimibe, a lipid-lowering drug, can cause acute pancreatitis.

* Identification and discontinuation of the offending drug is of great importance in cases of drug-induced acute pancreatitis.