Background/Aims: Many medications can cause diarrhea by increasing motility, inflammation or enteropathy. Olmesartan and mycophenolic acid (CellCept) are drugs that are capable of increasing inflammation and enteropathy in some individuals and, if not recognized, can lead to chronic diarrhea. It is this type of drug-induced diarrhea that is the focus of this review. Methods: A summary of our findings (recent and earlier published) as well as a review of published works from other centers were conducted. Results: There is increasing evidence that olmesartan use is associated with enteropathy in a small number of individuals who use angiotensin receptor II blockers, and that this enteropathy is characterized by severe diarrhea capable of inducing severe dehydration and, in some instances, failure of organs such as the kidney. Typical patient demographics are Caucasian individuals who are older (>50 years old) and obese or overweight prior to weight loss. Prolonged exposure to olmesartan use for 1-2 years is typical, although case reports of irbesartan and valsartan have been reported as well. Discontinuing olmesartan leads to improvement of symptoms; however, the period for healing is variable, with some patients requiring steroid therapy and even prolonged parental nutrition support. In addition, many histological features of olmesartan-associated enteropathy are also present in celiac disease, including villi shortening and lymphocyte infiltration. Other drug-associated enteropathies have also been reported with mycophenolate mofetil used in transplantation. Conclusions: Of the drug-associated enteropathies discussed in this review, olmesartan can generate the most severe symptoms, albeit quite rare. Therefore, with patients who present with severe diarrhea and weight loss, one should consider olmesartan-associated enteropathy. In addition, many of the features associated with olmesartan-associated enteropathy are also found in celiac disease enteropathy; as such, one should review any celiac disease diagnosis for any use of olmesartan at the time of diagnosis.

Structured Summary Background Olmesartan-associated enteropathy (OAE) is characterized by diarrhea, nausea, vomiting, abdominal pain, weight loss, and severe sprue-like enteropathy, all of which is resolved after olmesartan medoxomil discontinuation. Aim To determine the mechanistic similarities with celiac sprue. Methods Duodenal biopsies were extracted from OAE patients before (n=11) or after (n=17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were 7 “on/off” paired samples. Formalin fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R, and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R, and ZO-1. Results In the “on olmesartan medoxomil” duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells. Conclusions OAE shares many features with celiac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effect of gluten upon the epithelium of celiac patients.

Background & Aims: Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. Methods:We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titers were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval of 8.8 years), from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis.Results: Of the serum samples collected at the first timepoint, 15,398 were negative for tTGA and were 153 positive for tTGA (>4 U/mL). Based on medical records, 6 subjects received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% CI, 0.01%-0.11%). Forty-nine subjects with a negative result from the first serologic test for tTGA

INTRODUCTION: Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure. METHODS:Sixty subjects (n 5 20 treated, healed CeD; n 5 20 treated NCGS; n 5 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up.Twelve serial questionnaires (100 mm visual analog scale; pain, bloating, nausea, and fatigue) and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactulose-13 C mannitol ratios and endoscopic mucosal impedance. RESULTS:Thirty-five of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS) and sham (9 CeD, 9 NCGS) compared with 9 of 20 (45%) controls after gluten (n 5 6) and sham (n 5 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge despite no significant intestinal permeability change from baseline. DISCUSSION:Symptoms do not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates a rapid-onset gluten-induced T-cell activation in CeD despite long-standing treatment. The effector site is unknown, given no increased intestinal permeability after gluten.