Small intestine & ampulla
Inflammatory disorders
Olmesartan enteropathy

Editor-in-Chief: Debra L. Zynger, M.D.
David Hernandez Gonzalo, M.D.

Topic Completed: 27 September 2019

Minor changes: 19 November 2020

Copyright: 2019-2021,, Inc.

PubMed Search: Olmesartan injury

David Hernandez Gonzalo, M.D.
Page views in 2020: 764
Page views in 2021 to date: 488
Cite this page: Hernandez Gonzalo D. Olmesartan enteropathy. website. Accessed May 11th, 2021.
Definition / general
  • A sprue-like enteropathy associated with olmesartan, initially reported in 2012 by Rubio-Tapia et al (Mayo Clin Proc 2012;87:732)
  • Although less frequent, it can be seen with other angiotensin II receptor antagonists
Essential features
  • Reversible sprue-like enteropathy with chronic diarrhea and weight loss
  • Negative celiac serology
  • Variable villous atrophy (with or without collagen deposition), increased intraepithelial lymphocytes, crypt hyperplasia and variable active inflammation
  • No clinical response to gluten free diet
  • Fast clinical and histologic improvement after suspension of olmesartan
  • Sprue-like enteropathy associated with olmesartan
ICD coding
  • ICD-10: K63.9 - disease of intestine, unspecified
  • Frequency not really known; in a large study done by DeGaetani et al, several cases of unclassified sprue were later reclassified as olmesartan enteropathy (Am J Gastroenterol 2013;108:647)
  • Mainly duodenum but stomach (lymphocytic or collagenous gastritis) and colon (lymphocytic or collagenous colitis) also can be involved (Mayo Clin Proc 2012;87:732)
  • IL15 expression is increased in response to olmesartan medoxomil treatment
  • ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil treated Caco-2 cells (human colonic epithelial line) (Aliment Pharmacol Ther 2015;42:1303)
  • Olmesartan medoxomil (trade names of Benicar, Benicar HCTZ, Azor and Tribenzor)
  • Most taking 40 mg/day before onset of diarrhea (mean: 3.1 years) (Mayo Clin Proc 2012;87:732)
Clinical features
  • Severe diarrhea (often following a dose increase; sudden onset in some cases), steatorrhea, weight loss, nausea, vomiting, abdominal pain, bloating and fatigue (Virchows Arch 2017;470:245)
  • High index of suspicion is needed; diagnosis can be made in hypertensive patients on olmesartan who have clinical, endoscopic and histologic sprue-like enteropathy who have negative celiac serology and no clinical improvement following a gluten free diet
  • May be misdiagnosed as refractory celiac disease if medication induced injury is not considered
  • May be misdiagnosed as refractory celiac disease if medication list is not reviewed by the pathologist
  • Negative IgA tissue transglutaminase antibody testing
  • Negative endomysial antibodies
  • Anti-enterocyte antibody can be rarely positive (linear / apical pattern)
  • HLA DQ2 more frequently positive than in general population (68% versus 25%) (Mayo Clin Proc 2012;87:732)
  • Normocytic normochromic anemia
  • Hypoalbuminemia
  • Small bowel bacterial overgrowth can be seen in a subset of cases
Radiology images

Images hosted on other servers:

Thickened bowel wall

Prognostic factors
  • No patients have recurrence of symptoms after restarting a diet containing gluten once olmesartan is discontinued
Case reports
  • Discontinuation of olmesartan
  • Antibiotics not helpful even if small bowel bacterial overgrowth is noted
Clinical images

Images hosted on other servers:

Normal colonoscopy

Duodenal villous atrophy

Duodenal fold attenuation

Gross description
Microscopic (histologic) description
  • Partial or total villous atrophy
  • Increased intraepithelial lymphocytes (> 25 - 30 IEL/100 enterocytes)
  • Crypt hyperplasia
  • Variable active inflammation
  • With or without thick band of subepithelial collagen deposition (collagenous sprue pattern)
Microscopic (histologic) images

Contributed by David Hernandez Gonzalo, M.D.

Moderate villous atrophy and crypt hyperplasia

Increased intraepithelial lymphocytes

Focal active inflammation

Complete histologic recovery

Positive stains
Sample pathology report
  • Duodenum, biopsy:
    • Duodenal mucosa with (mild / moderate / severe) villous blunting, crypt hyperplasia, increased intraepithelial lymphocytes and increase in lymphoplasmacytic infiltrate within lamina propria (see comment)
    • Comment: The above histopathologic findings are in keeping with a malabsorption pattern of injury. The findings can be seen in medication induced injury (such as olmesartan, NSAIDs, methotrexate, azathioprine, colchicine), gluten sensitive enteropathy, reactive duodenopathy, bacterial overgrowth, tropical sprue, chronic malnutrition, hypersensitivity reaction to nongluten proteins (cow's milk, soy, egg, etc.) and immune related disorders (including CVID and autoimmune enteropathy). Correlation with the clinical, endoscopic and serologic findings (including IgA TTG antibodies in non-IgA deficient patients) is needed.
Differential diagnosis
  • Gluten sensitive enteropathy
    • Responds to gluten free diet
    • Celiac serology frequently positive, particularly tTGA (sensitivity: 98%)
  • Tropical sprue
    • GI symptoms with temporal relationship to travel history to tropical regions
    • Responds to antibiotics
  • Collagenous sprue
    • Can be a pattern of injury seen in olmesartan enteropathy (exclusion of celiac disease is key)
  • Autoimmune enteropathy
    • Marked reduction of goblet cells or Paneth cells
    • Crypt apoptoses more prominent
    • Anti-enterocyte antibody can be positive in both entities
    • Responds to immusuppressive agents
  • Common variable immunodeficiency
    • 2/3 of patients show loss of plasma cells in duodenal biopsy
    • Prominent lymphoid aggregates commonly seen
    • Immunoglobulin replacement indicated (does not improve olmesartan enteropathy)
  • Medication associated injury (eg. mycophenolate mofetil, NSAIDs)
    • Mycophenolate mofetil most prominent feature is increase in apoptotic bodies, while celiac-like features are unusual in duodenal biopsies (12%); history of kidney heart or liver transplant is key (Am J Surg Pathol 2009;33:1355)
    • NSAIDs are associated with mucosal erosions and ulcerations in jejunum and ileum and GI bleeding
Board review style question #1
An 84 year old woman presents to your hospital with chronic watery diarrhea (15 months) and 30 lbs of unintentional weight loss. Celiac serology is negative. The patient is on 20 mg on Benicar (olmesartan medoxomil) 1 tablet by mouth daily for her hypertension. She tried a gluten free diet for one year with no response. A duodenal biopsy demonstrates the following findings (see image). After switching to valsartan the patient has a dramatic improvement of her diarrhea within days. Which of the following is true about this entity?

  1. Histopathologic findings can mimic gluten sensitive enteropathy
  2. HLA DQ2 is always negative in these patients
  3. IgA tissue transglutaminase antibody testing is positive in most patients
  4. Onset of diarrhea is typically within days or weeks after initiation of olmesartan
Board review style answer #1
A. Histopathologic findings can mimic gluten sensitive enteropathy.
A. Villous atrophy, increased intraepithelial lymphocytes and crypt hyperplasia can be seen in duodenal biopsies, mimicking celiac disease.
B. HLA DQ2 appears to be more frequently positive in these patients than in the general population.
C. IgA tissue transglutaminase antibody testing is negative.
D. Onset of diarrhea is typically within months or years after initiation of olmesartan.

Reference: Small intestine - Olmesartan enteropathy

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Board review style question #2
Which of the following is true about olmesartan enteropathy?

  1. Clinical and histologic resolution is slow and it takes years for the duodenal mucosa to recover after discontinuation of olmesartan
  2. It is an important diagnostic consideration in patients with presumed refractory celiac disease
  3. Olmesartan associated injury can only be seen in duodenum
  4. Subset of patients with bacterial overgrowth respond to antibiotics
Board review style answer #2
B. It is an important diagnostic consideration in patients with presumed refractory celiac disease.
A. Clinical and histologic recovery is fast compared with celiac disease patients.
B. It is important for the pathologist to correctly diagnose these patients. You can change the patient's life just by checking the medication list. Gluten free diet can be miserable for many patients.
C. Changes can be seen in duodenum, stomach and colon.
D. A subset of patients on olmesartan can demonstrate bacterial overgrowth. These patients don't respond to antibiotic treatment.

Reference: Small intestine - Olmesartan enteropathy

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