Baylor University Medical Center Proceedings July 2017 - 349

a

b

c

Figure 1. Biopsy in Case 1 showing (a) collagenous gastritis (hematoxylin and eosin [H&E] stain, 200×) and (b) collagenous and lymphocytic colitis (H&E, 20×).
(c) Duodenal biopsy in Case 3 showing severe villous atrophy (H&E, 100×).

epithelial reactive changes, severe duodenal villous atrophy,
and intraepithelial lymphocytosis (Figure 1c). Random colon
biopsies showed lymphocytic and collagenous colitis. Diarrhea
resolved 4 days after stopping olmesartan. Two months later,
the patient reported complete resolution of his diarrhea and
had returned to his normal weight.
DISCUSSION
Severe chronic diarrhea and weight loss in the setting of
duodenal villous atrophy presents a broad differential (Table 1)
(2, 4-7). Before further investigation is pursued, celiac disease
must be ruled out. This is most often done with serologic testing with a highly accurate IgA anti-tissue transglutaminase
assay (tTG). If celiac disease is excluded, drug-induced enteropathy is most likely, but several other disorders are possible.
Olmesartan is a common cause for drug-induced enteropathy. Mucosal changes associated with olmesartan include diffuse
duodenal villous atrophy with varying degrees of inflammation
and are indistinguishable from changes seen with celiac disease
(8). Also, increased subepithelial collagen deposition may be
found throughout the entire gastrointestinal tract (8). There
is no confirmatory test for olmesartan-associated enteropathy,
unlike celiac disease and autoimmune enteropathy, in which
serologic testing can be confirmatory. The prompt relief of
symptoms and improved histology when olmesartan is withdrawn is strong evidence for an etiologic association. The cases
in which patients have been rechallenged with olmesartan-

Table 1. Differential diagnosis of villous atrophy in adults
Celiac disease
Drug-induced villous atrophy
Autoimmune enteropathy
Crohn's disease
Giardiasis
Immunodeficiency states
Eosinophilic gastroenteritis
*From references 2, 4-7.

July 2017

Collagenous sprue
Tropical sprue Zollinger-Ellison syndrome
Whipple disease
Graft-versus-host disease
Intestinal lymphoma
Small intestinal bacterial overgrowth

such as Cases 2 and 3 in this report-provide further confirmation that olmesartan was the offending agent.
The pathogenesis of olmesartan-associated enteropathy is not
fully understood, but is thought to involve a cell-mediated immune response causing damage to the intestinal brush border
(2, 8). In Rubio-Tapia's initial study, 15 of 22 patients were found
to be positive for HLA-DQ2 or HLA-DQ8 (1). Both of these genetic alleles predispose patients to celiac disease, but this diagnosis
was an unlikely cause of their symptoms, since highly accurate
serological tests, such as tTG and anti-endomysial antibodies,
were negative and patients did not respond to a gluten-free diet.
All three of our cases were positive for HLA-DQ2 or HLA-DQ8.
This is a nonspecific finding, since about 25% of normal persons
are positive for one of these alleles, but does suggest that an immune process or genetic predisposition may be involved in the
pathogenesis of olmesartan-associated enteropathy. It is unclear
whether olmesartan acts in an analogous fashion as gluten in
celiac disease by activating an autoimmune response directly or
produces this adverse effect by some other mechanism.
Our cases demonstrate the variable presentations of
olmesartan-associated enteropathy (Table 2). In addition to small
bowel involvement, the stomach and colon may be involved:
Cases 1 and 2 had multiple gastric erosions as well as discrete
duodenal ulcers, and Case 1 had lymphocytic and collagenous
colitis. These other areas of involvement also healed promptly
after olmesartan was withdrawn. Case 1 had a high-volume
secretory diarrhea with only mild steatorrhea, whereas Case 2
had marked steatorrhea with less severe secretory diarrhea. This
variability is probably due to differences in the extent of small
bowel and colonic involvement in these patients. Inflammatory
arthritis (Case 1) is a recognized but infrequent complication
of olmesartan-associated enteropathy (9); it too resolved with
discontinuation of the drug. The prolonged latent period of
2 to 2.5 years in Cases 1 and 2 is typical for patients with
olmesartan-associated enteropathy. Nonetheless, it is unusual
for a drug reaction. Case 3 had an almost immediate reaction
to olmesartan, but previously had been exposed to the drug.
Pharmaceutical agents other than olmesartan have been
reported to cause villous atrophy on occasion and are listed
in Table 3 (1-6, 8-23). Olmesartan appears to be the most

Olmesartan-associated enteropathy

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