Elsevier

Digestive and Liver Disease

Volume 48, Issue 2, February 2016, Pages 154-161
Digestive and Liver Disease

Alimentary Tract
Potential coeliac disease markers and autoimmunity in olmesartan induced enteropathy: A population-based study

https://doi.org/10.1016/j.dld.2015.09.014Get rights and content

Abstract

Aims

(1) Assess the population-based incidence of severe olmesartan-associated enteropathy. (2) To describe patients of the Spanish registry. (3) Evaluate markers of potential coeliac disease and associated autoimmunity.

Methods

Crude incidence rates in the area of Terrassa (Catalonia) were calculated. Clinical characteristics of patients in the Spanish registry were collected. Duodenal lymphocyte subpopulations and anti-TG2 IgA deposits were assessed in a subset of patients.

Results

Annual incidence rates (2011–2014) ranged from 0 to 22 cases per 104 treated patients. Twenty patients were included in the Spanish registry. Nineteen (95%) exhibited villous atrophy and 16 (80%) had severe enteropathy. Lupus-like disease occurred during olmesartan treatment in 3 patients. HLA-DQ2/DQ8 was positive in 64%. Markers of potential coeliac disease were present in 4 out of 8 patients (positive anti-TG2 deposits and/or increased CD3+gammadelta+ intraepithelial lymphocytes and reduced CD3−). Histopathological changes and clinical manifestations including autoimmune disorders improved after olmesartan discontinuation but not after gluten-free diet, irrespective of the presence or absence of coeliac markers.

Conclusions

Incidence of severe olmesartan-associated enteropathy was low. Autoimmune phenomena were present in a subset of cases and reversed after olmesartan removal. A genetic coeliac disease background and the presence of potential coeliac markers might uncover predisposing factors.

Introduction

In 2012 a new non-coeliac sprue-like enteropathy associated with olmesartan was characterized [1]. Since then more than 100 cases have been reported [2], [3], including a cohort of 36 patients in a national survey in France [2]. The clinical picture includes severe diarrhea, frequently life-threatening, requiring hospitalization and treatment in intensive care units. The incidence of this enteropathy in olmesartan-treated patients and the whole spectrum of severity are unknown [4]. It is noteworthy that large phase III trials did not detect gastrointestinal adverse reactions in olmesartan-treated patients compared with those treated with placebo [5], [6]. This discrepancy might be either the short duration of clinical trials, rendering them unable to detect a complication that occurs in medium- or long-term sustained treatment and/or the rarity of this severe entity [4], [5].

The mechanism underlying olmesartan-associated enteropathy is unknown but a high proportion of the reported patients had a genetic predisposition for coeliac disease (CD), ranging from 68 to 77% [1], [2], which is clearly higher than that described in the general population. It was speculated that the presence of HLA-DQ2 or HLA-DQ8 might increase the risk of immune-mediated damage [1]. In addition, a number of patients in the French series had a past history of immune-mediated diseases [2]. However, to the best of our knowledge autoimmune phenomena associated with olmesartan administration have not been reported to date.

Olmesartan is an angiotensin II receptor blocker (ARB) widely used in the treatment of hypertension [7]. Apart from the known vascular effects, angiotensin II receptor AT [2] interferes with proinflammatory pathways including inhibition of cell growth, modulation of extracellular matrix, apoptosis and cellular differentiation [8].

The aims of this study were to: (1) determine the population-based incidence rate of olmesartan enteropathy in the area of Terrassa, Catalonia, Spain, (2) describe the clinical picture of olmesartan-induced enteropathy and other immune disorders, and (3) assess the genetic predisposition of CD and duodenal CD markers that could predispose to olmesartan damage.

Section snippets

Study setting for incidence calculation

The study period for estimating the annual population-based incidence of enteropathy associated with olmesartan was January 2011 to December 2014 and the setting was the catchment area of the Hospital Universitari Mutua Terrassa (HUMT). The hospital is located in north-eastern Spain (Catalonia), and it is of a mixed rural-urban type. On August 15, 2014, the population residing in this geographical area was 251,225 inhabitants (data obtained from the 2014 population census, ‘Institut

Annual incidence rates (period 2011–2014) in the catchment area of Terrassa, Catalonia (Spain)

Between January 2011 and December 2014, 6 patients resident in the catchment area of the HUMT were attended due to severe enteropathy associated with olmesartan. The first case was admitted to the hospital with severe diarrhea and dehydration in May 2011. It was not until 2012, after the publication of Rubio-Tapia [1], that the patient was properly diagnosed. Annual incidence rates (period 2011–2014) are detailed in Table 1. No other similar cases were found among residents in the study area

Discussion

The particular setting of HUMT providing both private and public health services allowed us to learn the epidemiological characteristics of enteropathy associated with olmesartan in the period 2011–2014. Annual cumulative incidence rates showed that might affect up to 22 cases per 10,000 patients treated for at least 6 months. This low incidence may explain why this severe entity has not previously been detected, either in pivotal trials (2232 diabetics treated for 3.2 years in ROAMAP study [5]

Conflict of interest

None declared.

Acknowledgements

The authors are grateful to Mónica Roldán and Meritxell Vendrell (Autonomous University of Barcelona) for their assistance in microscopic visualization, to Natalia Berenice for her technical laboratory support, and to Núria Rubies, Maite Roldan, Olga Benítez, Anabel Polo, and Rosa Tomás for their helpful technical assistance.

The ‘Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas’ (CIBERehd) is an initiative of the Instituto de Salud Carlos III, Madrid, Spain.

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