Olmesartan-Induced Enteritis Mimicking Small Bowel Crohn's Disease

ABSTRACT

Drug-induced enteritis and colitis are commonly included in the differential diagnosis for inflammatory bowel disease and olmesartan, an angiotensin-II receptor blocking antihypertensive medication, has been implicated in numerous cases. Typical findings of olmesartan-associated enteropathy mimic that of celiac disease with histology revealing villous blunting or atrophy, though a minority of patients present with an inflammatory phenotype that may be characterized by erythematous patches, cobblestoning, and ulceration. We present a case of olmesartan-associated enteropathy in a 79-year-old woman who initially presented with severe malabsorption and was found to have features initially concerning for upper gastrointestinal Crohn’s disease.

INTRODUCTION

Drug-induced enteritis and colitis are commonly included in the differential diagnosis for inflammatory bowel disease, with common culprit medications including non-steroidal anti-inflammatory drugs, immune checkpoint inhibitors, and mycophenolate. Since the first report in 2012, olmesartan, an angiotensin-II receptor blocking antihypertensive, has been associated with many cases of drug-induced enteritis and colitis.¹ The typical histologic pattern includes villous blunting or atrophy with a minority of patients presenting with inflammatory features on endoscopy including erythematous patches, cobblestoning, and ulceration.² We present a case of olmesartan-associated enteropathy (OAE) mimicking upper gastrointestinal Crohn's disease (CD).

CASE REPORT

A 79-year-old woman with hypertension presented to clinic for evaluation of weight loss and chronic diarrhea. Two years before, she visited an emergency department for diarrhea and abdominal pain, where computed tomography (CT) imaging of the abdomen showed diffuse enteritis, and she was managed conservatively for viral gastroenteritis (Figure 1). One year later, she developed recurrent, severe nonbloody diarrhea and a 20-pound weight loss. Stool testing was positive for Clostridioides difficile toxin, and she was treated with 2 weeks of oral metronidazole without resolution in symptoms.

Figure 1.

(A) Initial coronal contrast-enhanced CT demonstrating subtle abnormal fold thickening of a long segment of ileum (arrows), referred to as jejunalization, because it appears similar to normal jejunum (arrowheads). Fourteen months later a repeat coronal (B) and axial (C) CT in lung windows shows ileal pneumatosis (arrows) along with generalized small bowel dilation. A very small amount of pneumoperitoneum is seen anteriorly (arrowhead). CT, computed tomography.

She was again seen in the emergency department where repeat CT imaging revealed dilated small bowel with pneumatosis (Figure 1), leading to exploratory laparoscopy that failed to identify a perforation or bowel ischemia. Upper endoscopy and colonoscopy days later revealed numerous large ulcers in the second and third portions of duodenum with cobblestoning (Figure 2) and normal-appearing terminal ileum and colon. Pathologic examination of the gastric antrum revealed chronic gastritis with negative immunochemistry staining for Helicobacter pylori and a few intramucosal epithelioid granulomas (Figure 3). Bi, periodic acid-Schiff, acid-fast bacillus, and Grocott’s methenamine silver immunostains were also negative for organisms. Duodenal biopsies revealed chronic, moderately active duodenitis; cytomegalovirus immunostaining was negative (Figure 3). Random colon biopsies were normal. Fecal calprotectin was 62 μg/g, and anti-transglutaminase immunoglobulin A (IgA) and total IgA were normal. Anti-nuclear antibody testing was positive with a 1:640 titer with positive SCL-70 and ribonucleoprotein. Supportive treatment with anti-diarrheal medications and a proton pump inhibitor were started. Owing to hypotension, her home anti-hypertensive, olmesartan, was held at the time of discharge.

Figure 2.

Endoscopic image of (A) duodenal bulb, (B) and (C) second and (D) third portion of duodenum with diffuse nodularity, granularity, and deep ulceration in second and third portions of the duodenum with a cobblestone appearance.

Figure 3.

Duodenal biopsies, H&E stain magnification ×40 (A) with active inflammation, villous effacement, focal crypt dropout, and reactive epithelial changes with nuclear hyperchromasia and pseudostratification. H&E stain, magnification ×100 (B) with patchy active cryptitis with crypt abscess formation (arrows). The affected crypt contains intraluminal neutrophil clusters (inset, magnification ×200). (C) Gastric biopsy, H&E stain, magnification ×20. Gastric antral mucosa showed chronic inflammation and a few epithelioid granulomas. An arrow indicates one non-necrotizing granuloma. No Helicobacter pylori organisms, intestinal metaplasia, or dysplasia were identified. The Grocott methenamine silver and acid-fast bacilli stains were negative for fungal organisms and acid-fast bacilli, respectively (not shown). H&E, hematoxylin and eosin.

She was readmitted to the hospital 2 weeks later with ongoing diarrhea, abdominal pain, and new anasarca. Laboratory test results were notable for an albumin of 2.6 g/dL. CT imaging showed resolving pneumatosis and push enteroscopy revealed marked improvement in duodenal findings, with healing of the deep ulcerations. Duodenal and jejunal biopsies revealed chronic, mild to moderately active enteritis with mild crypt depletion. Treatment with steroids starting with intravenous methylprednisolone 80 mg daily and transition to oral prednisone 40 mg daily was initiated for suspected CD. Her symptoms resolved over time with steroid tapering of prednisone by 5 mg each week. The patient was found to be vitamin B12 and iron deficient, and these were replaced. Subsequent testing for thiamine, 25-OH vitamin D, vitamin B6, zinc, and INR were all normal. She was not started on additional therapy for CD given uncertainty around her diagnosis.

Five months after this hospitalization, the patient's olmesartan was resumed for hypertension. Within 2 weeks, she developed recurrent severe nonbloody diarrhea, weight loss, hypotension, acute encephalopathy attributed to severe electrolyte derangements, and starvation ketosis necessitating intensive care unit admission. Stool bacterial and viral panels including testing for C. difficile were negative. C-reactive protein was 15 mg/L, fecal calprotectin was elevated at 1,177 μg/g, with a low stool pH and elevated stool osmotic gap, consistent with malabsorption. Olmesartan was held due to hypotension and intravenous methylprednisolone 80 mg daily was reinitiated. Esophagogastroduodenoscopy revealed erosive duodenitis and pathology confirmed active duodenitis. She was transitioned to oral prednisone starting at 30 mg daily for 2 weeks followed by a taper of 5 mg per week. Following this admission, she was seen by an inflammatory bowel disease specialist who felt that the presentation was unusual for Crohn's and noted the temporal relationship between olmesartan use and hospitalizations. The patient was advised to avoid olmesartan indefinitely. Repeat endoscopy performed 6 months after completion of the steroid taper was entirely normal with normal biopsies. The patient has not experienced a recurrence of her gastrointestinal symptoms for over 2 years since discontinuing olmesartan.

DISCUSSION

Olmesartan is an antihypertensive belonging to the angiotensin-II receptor blocker class and has been reported to cause severe protein losing enteropathy. Nearly 200 cases of OAE have been reported in the literature since 2012 which has resulted in a black-box warning on the Federal Drug Administration drug label. OAE presents an average of 3 years after initiation and symptoms include profound non-bloody diarrhea and weight loss, often requiring hospitalization. Laboratory testing can reveal electrolyte derangements, hypoalbuminemia, normal celiac serologies, negative stool cultures, and sometimes elevated stool calprotectin. Imaging findings described in this entity may be normal or include nonspecific findings of enteritis.^1,3 Endoscopy typically reveals nodular or atrophic duodenal mucosa with villous atrophy, intraepithelial lymphocytes, and subepithelial collagen deposition on pathology. Patients do not respond to a gluten-free diet.

Our patient had atypical clinical and pathologic features that initially resulted in a suspicion for Crohn's enteritis, including significant small bowel ulceration. This has been described in case series of OAE but appears to be a rare finding.^2,4 To our knowledge, small bowel pneumatosis has not been described in OAE, and the pathologic mechanism in our case was unclear given no operative findings of bowel ischemia or perforation. Furthermore, pathologic findings in our patient did not include the villous blunting typical of OAE.² Despite this, our patient appears to have experienced malabsorption with hypoalbuminemia, iron, and B12 deficiency. Although her terminal ileum appeared normal on colonoscopy, it is possible that she had more proximal small bowel involvement as an explanation for B12 deficiency or this may have been the result of poor oral intake Our patient scored a 9 on the Naranjo Adverse Reaction Probability Scale, consistent with a definite drug reaction.⁵ The fact that diarrhea resolved after discontinuation of Olmesartan and hospitalization recurred within weeks of restarting the drug further supports this conclusion.

As demonstrated in our patient, the pathologic findings in OAE do not always result in sprue-like enteropathy with villous blunting.^2,6 Our patient's histologic finding of gastric granulomata is also rarely described.⁷ While entrapped air can induce a granulomatous reaction, gastric pneumatosis was not seen on initial imaging. It is possible that villous atrophy, while reported as a hallmark finding in OAE, is overrepresented in the literature due to reporting bias. While the mechanism of OAE is poorly understood, it is thought to be an immune-mediated drug injury.⁸ Whether immunosuppressive therapy, such as steroids, accelerates or aids in recovery along with withdrawal of Olmesartan is not known. This case serves as a reminder that the immunopathology in OAE can be varied and may mimic inflammatory bowel disease and reinforces the importance of a good medication history in the management of patients with enteritis.

DISCLOSURES

Author contributions: G. Monti, A. Thompson, and EK Boden performed literature review. B. Foster and R. Freund reviewed and edited the manuscript and provided clinical images. EK Boden provided direct care for the patient described. G. Monti is the article guarantor.

Acknowledgments: Dr Eizaburo (Sabu) Sasatomi, for assistance in preparation of histology images and captions.

Financial disclosure: None to report.

Previous presentation: This case was presented at Advances in Inflammatory Bowel Disease; November 2023; Orlando, Florida.

Informed consent was obtained for this case report.

ABBREVIATIONS:

AFB

acid-fast bacillus

CD

Crohn′s disease

CT

computed tomography

GMS

Grocott's methenamine silver

Iga

immunoglobulin A

INR

International Normalized Ratio

OAE

olmesartan associated enteropathy

PAS

Periodic Acid-Schiff

RNP

ribonucleoprotein

TTG

transglutaminase.