Treatment for celiac disease is a gluten-free diet, which usually results in recovery of the mucosa and return to normal health. Our patient, however, did not respond to this diet, as is the case with 0.3–30 % of patients with celiac disease, who are subsequently diagnosed as refactory celiac disease (RCD) [
9‐
12]. There are two types of RCD: type 1 shows a normal intraepithelial lymphocyte population, whereas type 2 displays a predominantly aberrant intraepithelial lymphocyte phenotype [
13]. Taking all these findings together, our patient could have RCD type I, but I think this diagnosis has to be questioned because she is an elderly woman who might have had trouble following a strict gluten-free diet. Moreover, we speak of non-responsive sprue if patients do not respond to strict gluten-free diet for 6–12 months and of RCD if patients do not respond to strict gluten-free diet for ≥ 12 months and other causes of villous atrophy have been excluded [
14]. Based on the information given in the protocol, our patient had, however, not been on a gluten-free diet long enough and as already mentioned, the elderly patient may not have been able to comply with it. Still, the negative celiac serology and the supposed non-response to a gluten-free diet urge us to consider other non-celiac enteropathies (NCE) presenting with villous atrophy. The diagnostic algorithm for small intestinal villous atrophy (Fig.
2) indicates that other etiologies of NCE have to be considered here [
15]. These include common variable immunodeficiency, food allergies, tropical sprue, post viral enteropathy, eosinophilic gastroenteritis, peptic duodenitis, autoimmune enteropathy, small intestinal bacterial overgrowth, immune-mediated enteropathy, Crohn’s disease, and collagenous sprue [
15]. Other diseases with small intestinal villous atrophy that merit consideration are giardiasis, HIV enteropathy, tuberculosis, radiation enteritis, Zollinger–Ellison syndrome, Whipple’s disease, intestinal lymphoma, food intolerances [
16], alpha chain disease, graft-versus-host disease, hypogammaglobulinemia, severe malnutrition [
5], and certain medications [
17]. The medical history shows no evidence for most of these diseases; there are no further specific histopathological findings and there is no other serological abnormality. This leads us to limit the differential diagnosis to non-responsive sprue, post-gastroenteritis syndrome, small intestinal bacterial overgrowth, autoimmune enteropathy, and Zollinger–Ellison syndrome. A strict gluten-free diet over a longer period of time would show whether the patient suffers from truly non-responsive sprue. A post-gastroenteritis syndrome would be self-limiting (“watch and wait”); small intestinal bacterial overgrowth could be sought with an H
2-breath test and analysis of duodenal aspirate, and treated with oral antibiotics; an autoimmune enteropathy could be diagnosed by an experienced gastrointestinal pathologist’s review of the biopsies and enterocyte antibodies; and in case of Zollinger–Ellison syndrome, serum gastrin would be increased, usually together with a tumor in the pancreas or duodenal wall. Actually, none of these diagnoses really seems to be likely in our patient. According to our list of potential causes for NCE, only a careful review of the patient’s medication is left, because some drugs might have adverse gastrointestinal effects (Table
1). Of the eight different medications our patient took, five document diarrhea as an adverse effect. Diarrhea is indeed a common drug-associated adverse event, and the underlying mechanisms are often unclear [
18]. Diarrhea due to drug-induced enteropathy has been reported for medications such as mycophenolate mofetil [
19,
20], methotrexate [
21,
22], azathioprine [
23] and most recently olmesartan. Among the medications taken by our patient, only one, olmesartan, is associated with villous atrophy resulting in sprue-like enteropathy. Olmesartan is an angiotensin II receptor antagonist that has been commonly prescribed for treatment of hypertension since 2002 [
24]. The association between sprue-like enteropathy and olmesartan was first reported in 2012 [
18]. Clinical features of this enteropathy include gastrointestinal symptoms such as diarrhea, weight loss and steatorrhea, negative IgA tissue transglutaminase antibodies (or endomysial-antibodies), evidence of enteropathy (villous atrophy) with or without collagen deposition or intraepithelial lymphocytes, lack of clinical response to a gluten-free diet, and exclusion of other causes of enteropathy [
18]. Since our patient took olmesartan and presented with unexplained diarrhea, I suggest that she suffers from olmesartan-associated sprue-like enteropathy. Symptoms typically occur after olmesartan has been taken for months or years; this enteropathy can affect almost the entire gut [
18], and can present a spectrum of histological damage (from normal villi to partial or total villous atrophy with variable degrees of mucosal inflammation) [
25]. The mechanisms underlying olmesartan-associated enteropathy are still unclear. Interestingly, approximately 70 % of patients with olmesartan-associated enteropathy are HLA-DQ2 or HLA-DQ8 positive, which is a higher prevalence than expected in the general population (25–30 %) [
26,
27]. This suggests that the presence of HLA-DQ2 or HLA-DQ8 may increase the risk for immune-mediated mucosal damage in these patients, but further studies must clarify this. Withdrawal of olmesartan intake usually results in rapid clinical and histological improvement of the enteropathy. Withdrawal of olmesartan is thus indicated for our patient.