Is it time to rethink the burden of non-coeliac gluten sensitivity? A systematic review.

INTRODUCTION: Non-coeliac gluten sensitivity (NCGS) is still a poorly defined clinical condition. This review aims to describe the clinical features of subjects with a symptomatic response to gluten intake, and to estimate the prevalence of NCGS. EVIDENCE ACQUISITION: Literature search was conducted in accordance with PRISMA recommendations. The PubMed database was searched for original articles until 1st June 2020. EVIDENCE SYNTHESIS: We identified 30 relevant articles, including 14 studies that investigated NCGS through a double-blind, placebo-controlled crossover trial (DBPCC), and 16 that examined the role of gluten in causing symptoms without a DBPCC. We found that regardless of the diagnostic work up, gluten-sensitive patients were predominately middle-aged females complaining of abdominal pain, bloating and diarrhea. The pooled prevalence of NCGS after DBPCC was 24% (5-34%). Subjects with irritable bowel syndrome or self-reporting gluten intolerance accounted for the vast majority of the patients who did not start a DBPCC. A symptomatic response to a gluten-free diet (GFD) occurred in between 7% and 93% of patients. No data on long-term outcomes of NCGS individuals were reported. CONCLUSIONS: Clinical features of NCGS patients did not differ among all the included studies, whereas prevalence figures are rather heterogeneous. Long-term benefit of a GFD on these patients still needs to be ascertained.

Effect of prolonged omeprazole administration on segmental intestinal Mg2+ absorption in male Sprague-Dawley rats.

BACKGROUND: The exact mechanism of proton pump inhibitors (PPIs)-induced hypomagnesemia (PPIH) is largely unknown. Previous studies proposed that PPIH is a consequence of intestinal Mg2+ malabsorption. However, the mechanism of PPIs-suppressed intestinal Mg2+ absorption is under debate. AIM: To investigate the effect of 12-wk and 24-wk omeprazole injection on the total, transcellular, and paracellular Mg2+ absorption in the duodenum, jejunum, ileum, and colon of male Sprague-Dawley rats. METHODS: The rats received 20 mg/kg∙d subcutaneous omeprazole injection for 12 or 24 wk. Plasma and urinary Mg2+, Ca2+, and PO4 3- levels were measured. The plasma concentrations of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), epidermal growth factor (EGF), and insulin were also observed. The duodenum, jejunum, ileum, and colon of each rat were mounted onto individual modified Using chamber setups to study the rates of total, transcellular, and paracellular Mg2+ absorption simultaneously. The expression of transient receptor potential melastatin 6 (TRPM6) and cyclin M4 (CNNM4) in the entire intestinal tract was also measured. RESULTS: Single-dose omeprazole injection significantly increased the intraluminal pH of the stomach, duodenum, and jejunum. Omeprazole injection for 12 and 24 wk induced hypomagnesemia with reduced urinary Mg2+ excretion. The plasma Ca2+ was normal but the urinary Ca2+ excretion was reduced in rats with PPIH. The plasma and urinary PO4 3- levels increased in PPIH rats. The levels of 1α,25(OH)2D3 and FGF-23 increased, whereas that of plasma EGF decreased in the omeprazole-treated rats. The rates of the total, transcellular, and paracellular Mg2+ absorption was significantly lower in the duodenum, jejunum, ileum, and colon of the rats with PPIH than in those of the control rats. The percent suppression of Mg2+ absorption in the duodenum, jejunum, ileum, and colon of the rats with PPIH compared with the control rats was 81.86%, 70.59%, 69.45%, and 39.25%, respectively. Compared with the control rats, the rats with PPIH had significantly higher TRPM6 and CNNM4 expression levels throughout the intestinal tract. CONCLUSION: Intestinal Mg2+ malabsorption was observed throughout the intestinal tract of rats with PPIH. PPIs mainly suppressed small intestinal Mg2+ absorption. Omeprazole exerted no effect on the intraluminal acidic pH in the colon. Thus, the lowest percent suppression of total Mg2+ absorption was found in the colon. The expression levels of TRPM6 and CNNM4 increased, indicating the presence of a compensatory response to Mg2+ malabsorption in rats with PPIH. Therefore, the small intestine is an appropriate segment that should be modulated to counteract PPIH.

Pharmacy and therapeutics committees strategy to address olmesartan safety issues at a primary care level.

Background Olmesartan, an antihypertensive drug, has been associated with a severe and potentially life-threatening sprue-like enteropathy, consisting of a serious, chronic diarrhoea and malabsorption syndrome. Treatment with this drug should be discontinued if patients develop such symptoms. Objective To retrospectively determine the reduction in olmesartan prescription following a strategy promoted by pharmacy and therapeutics committees within daily clinical practice to manage updated safety information on olmesartan. Setting Three primary healthcare centres. Method In May 2016, local pharmacy and therapeutics committees integrated by general practitioners, nursing staff and clinical pharmacists sent information about olmesartan safety issues to general practitioners, together with an individual list of their patients who were then being treated with olmesartan. Moreover, information about dose equivalents between angiotensin II receptor blockers and angiotensin II receptor blockers versus angiotensin-converting-enzyme inhibitors was also attached. The strategy aimed to promote individual benefit/risk assessment by general practitioners of the continuation of olmesartan treatment as a means to achieving a decrease in the risk of sprue-like enteropathy. The investigation team retrospectively reviewed the clinical records. Main outcome measure Reduction of olmesartan prescription. Results Olmesartan was discontinued in 44.4% of patients (197/444) in the year after the safety alert e-mail. In their medical records general practitioners registered that, after informing about olmesartan safety warnings, in four cases (0.9%), patients reported gastrointestinal symptoms. Conclusion A multidisciplinary strategy implemented to promote individual benefit/risk assessment regarding continuation of olmesartan treatment showed an important reduction in olmesartan prescriptions 1 year later.

Association of sprue-like enteropathy and angiotensin receptor-1 antagonists.

Over the past 5 years several case reports and cohort studies have been published that describe a sprue-like enteropathy (SLE) with abdominal pain, chronic diarrhea and weight loss, after taking angiotensin type 1 receptor blockers (ARB). The initial case series from the Mayo Clinic, which described 22 cases of olmesartan-induced SLE, was followed by numerous case descriptions for almost all ARBs. A total of 73 case reports have been described so far that show evidence of ARB-associated enteropathy with villous atrophy and full recovery 3-12 months after discontinuation of the sartan in question. Of these, 59 cases were olmesartan-associated cases of SLE, another 14 case reports have been published for telmisartan (4), valsartan (3), losartan (2), candesartan (1) and eprosartan (1). Based on the available cohort studies, ARB-associated intestinal malabsorption occurs in 9.8-14 cases per 100,000 patients treated with ARBs, the number treated to harm is over 31,000 patient-years. Although the majority of case reports have been published with olmesartan, in the cohort studies no clear difference within the ARBs can be ruled out. The SLE is rare but must be suspected and diagnostically investigated in every patient presenting with abdominal discomfort, chronic diarrhea and weight loss who is being treated with an ARB, after other causes have been ruled out. In such cases, discontinuing the ARB leads to a full recovery.

[Olmesartan therapy and enteropathy: About two cases and review of the literature]. / Traitement par olmésartan et entéropathie : à propos de deux cas et revue de la littérature.

INTRODUCTION: Olmesartan is an angiotensin II receptor blocker, used to treat arterial hypertension. Severe digestive manifestations have been associated with olmesartan, including sprue-like enteropathy and lymphocytic colitis. OBSERVATIONS: We report two cases of sprue-like enteropathy associated with olmesartan, leading to malabsorption syndrome related to villous atrophy. After olmesartan discontinuation, patients exhibited resolution of clinical digestive symptoms and disappearance of biochemical abnormalities. CONCLUSION: Our case reports underscore that accurate questioning is crucial in diagnostic approach, allowing to make the diagnosis of sprue-like enteropathy related to olmesartan in our patients. Interestingly, particular attention has recently been drawn to the fact that sprue-like disease may be a class effect of angiotensin II receptor blockers; further investigations are warranted to confirm these latter data.

Severe intestinal malabsorption associated with ACE inhibitor or angiotensin receptor blocker treatment. An observational cohort study in Germany and Italy.

PURPOSE: The angiotensin II receptor blocker (ARB) olmesartan has been recently associated with sprue-like enteropathy (SLE), a gastrointestinal condition characterized by intestinal malabsorption (IM) and severe diarrhea. Whether the increased risk of SLE is substance-specific or a class effect involving all ARBs is uncertain. The aim of this study is to assess the risk of enteropathy associated with ARBs and angiotensin converting enzyme inhibitors (ACE-i) by using data from large administrative and claim databases. METHODS: We obtained data from Italian local health-care units and a large German claim database and included patients treated with olmesartan, other ARBs, and ACE-i. In the absence of a specific diagnosis code for SLE, International Classification of Diseases codes for IM were used. Analysis implemented a Poisson regression with robust error variance procedure, which allowed accounting for different clusters (local health-care units and countries) and correctly estimating the standard error for the relative risk of rare event occurrence. RESULTS: Patients were divided into 3 groups: olmesartan (25.591, 5.5%), other ARBs (104.901, 22.5%), and ACE-i patients (334.951, 72.0%). Baseline characteristics were similar overall. The incidence of unspecified IM in ACE-i patients was not different compared with that of olmesartan, whereas a higher rate ratio was observed when comparing ARB patients with the olmesartan group (RR: 2.50, 95% CI 1.21 to 5.19, P .01). When International Classification of Diseases codes for coeliac disease were included, no differences were observed. CONCLUSIONS: We could not confirm previous findings of a higher risk of malabsorption in olmesartan-only patients, and drug-induced enteropathy should be considered the result of exposure to the class of ARBs rather than a specific drug-related effect.

Unspecified intestinal malabsorption in patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers: a retrospective analysis in primary care settings.

OBJECTIVE: To investigate the possible relationship between the use of Angiotensin II Receptor Blockers (ARBs) or Angiotensin-Converting-Enzyme Inhibitors (ACE-i) and unspecified intestinal malabsorption (IM) within the Italian and German real-life context. RESEARCH DESIGN AND METHODS: a retrospective cohort of patients with a new unspecified IM diagnosis during the period 1 January 2010-31 December 2013 was extracted from Italian IMS Health Longitudinal Patient Database and German IMS Disease Analyzer. Only patients with at least one prescription of ARB or ACE-i medication during the 6 months preceding the IM diagnosis were included and then followed up for 12 months to assess treatment exposure. RESULTS: After stratification by year and molecule, the proportion of patients experiencing an unspecified IM diagnosis on total patients receiving ARBs or ACE-i ranged from 0% to 0.14%, showing no relevant differences between molecules and no time trends. CONCLUSIONS: this study indicates that ACE-i or ARBs were rarely associated to an unspecified IM diagnosis. No relevant difference between each specific ACE-i and ARB was highlighted.

Enteropatía asociada a olmesartán: atención a un fenómeno iatrogénico emergente / Olmesartan-associated enteropathy: attention to an emerging iatrogenic phenomenon

El olmesartán es un antagonista del receptor tipo 1 de la angiotensina II utilizado habitualmente en el tratamiento de pacientes con hipertensión arterial. Recientemente se han descrito varios casos de enteropatía sprue-like asociados al uso de este fármaco, con afectación clínica importante y total remisión tras la retirada del mismo. Se presenta el caso de un varón de 64 años, con antecedentes de hipertensión arterial en tratamiento con olmesartan-amlodipino con clínica de diarrea y pérdida de peso severas, atrofia vellositaria en biopsia duodenal sin criterios de enfermedad celiaca y remisión completa del cuadro tras la supresión del olmesartán. Basado en los hallazgos del caso clínico presentado, se revisan las manifestaciones clínicas e histopatológicas así como el curso evolutivo de una posible causa de enteropatía farmacológica recientemente descrita (AU)

Olmesartan is an angiotensin II type 1 receptor blocker commonly used in the treatment of hypertension. Several cases of sprue-like enteropathy associated with the use of this drug have been described which, even with important signs and limitations for the patient, present a full recovery after discontinuing the use of olmesartan. The case of a 64 year-old patient is presented, diagnosed with hypertension, under treatment with olmesartan- amlodipine, with chronic diarrhoea and villous atrophy on intestinal biopsies without diagnostic criteria for celiac disease and with complete remission after suspending discontinuing the use of olmesartan. Based on the clinical features presented by the case reported, the clinical and anatomopathological findings are described as well as the evolution of drug-induced enteropathy (AU)

Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. METHODS: A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. RESULTS: Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs <0.75 PPI pills/d; P value interaction = .004) and decreased after medication discontinuation (P-trend < .001). Some of the strongest associations were among persons taking >1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. CONCLUSIONS: Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation.

Olmesartan-associated sprue-like enteropathy: a systematic review with emphasis on histopathology.

Sprue-like enteropathy associated with the angiotensin II receptor blocker (ARB) olmesartan was first described in 2012, and a number of cases have since been reported. This syndrome is characterized by severe diarrhea and sprue-like histopathologic findings in the intestine, often with increased subepithelial collagen. The incidence of this adverse drug reaction is not entirely clear, although it is thought to be rare. It is also not well established if other ARBs cause such a syndrome, although case reports suggest they can. The histopathologic features of olmesartan-related injury have only been described in a limited number of cases, and there are no guidelines regarding the histopathologic distinction of olmesartan-associated enteropathy from other causes of sprue (eg, celiac disease, tropical sprue). Herein, we review the histopathologic changes and clinical observations described in recent reports of olmesartan-associated sprue-like enteropathy comprising case series and isolated reports, other relevant literature, and our experience at a referral center specializing in small intestinal disorders. We will review recent literature suggesting other ARBs can be associated with a similar phenotype. Lastly, we will discuss the histopathologic differential diagnosis and provide clues to distinguish this entity from other entities which can cause sprue-like histopathology.

Nutritional consequences of long-term acid suppression; are they clinically important?

PURPOSE OF REVIEW: As acid suppression therapies with proton pump inhibitors are an extremely common practice for common acid-related diseases, there has been increased scrutiny on the safety of this class of therapy. RECENT FINDINGS: There have been increasing reports of allegation of harm with the sustained use of proton pump inhibitors, in particular with potential adverse effects on vitamin and mineral absorption. This has prompted a number of product label changes directed by the US Food and Drug Administration, raising concerns for ongoing continued use among clinicians and patients. SUMMARY: This review highlights the most recent information around these controversies and provides evidence summaries to help guide care providers in their care plans as well as discussions with patients.

Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study.

OBJECTIVES: Severe sprue-like enteropathy associated with olmesartan has been reported, but there has been no demonstration of an increased risk by epidemiological studies. AIM: To assess, in a nationwide patient cohort, the risk of hospitalisation for intestinal malabsorption associated with olmesartan compared with other angiotensin receptor blockers (ARB) and ACE inhibitors (ACEIs). DESIGN: From the French National Health Insurance claim database, all adult patients initiating ARB or ACEI between 1 January 2007 and 31 December 2012 with no prior hospitalisation for intestinal malabsorption, no serology testing for coeliac disease and no prescription for a gluten-free diet product were included. Incidence of hospitalisation with a discharge diagnosis of intestinal malabsorption was the primary endpoint. RESULTS: 4 546 680 patients (9 010 303 person-years) were included, and 218 events observed. Compared with ACEI, the adjusted rate ratio of hospitalisation with a discharge diagnosis of intestinal malabsorption was 2.49 (95% CI 1.73 to 3.57, p<0.0001) in olmesartan users. This adjusted rate ratio was 0.76 (95% CI 0.39 to 1.49, p=0.43) for treatment duration shorter than 1 year, 3.66 (95% CI 1.84 to 7.29, p<0.001) between 1 and 2 years and 10.65 (95% CI 5.05 to 22.46, p<0.0001) beyond 2 years of exposure. Median length of hospital stay for intestinal malabsorption was longer in the olmesartan group than in the other groups (p=0.02). Compared with ACEI, the adjusted rate ratio of hospitalisation for coeliac disease was 4.39 (95% CI 2.77 to 6.96, p<0.0001) in olmesartan users and increased with treatment duration. CONCLUSIONS: Olmesartan is associated with an increased risk of hospitalisation for intestinal malabsorption and coeliac disease.

An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking.

Microvillus inclusion disease (MVID) is a rare intestinal enteropathy with an onset within a few days to months after birth, resulting in persistent watery diarrhea. Mutations in the myosin Vb gene (MYO5B) have been identified in the majority of MVID patients. However, the exact pathophysiology of MVID still remains unclear. To address the specific role of MYO5B in the intestine, we generated an intestine-specific conditional Myo5b-deficient (Myo5bfl/fl;Vil-CreERT2) mouse model. We analyzed intestinal tissues and cultured organoids of Myo5bfl/fl;Vil-CreERT2 mice by electron microscopy, immunofluorescence, and immunohistochemistry. Our data showed that Myo5bfl/fl;Vil-CreERT2 mice developed severe diarrhea within 4 d after tamoxifen induction. Periodic Acid Schiff and alkaline phosphatase staining revealed subapical accumulation of intracellular vesicles in villus enterocytes. Analysis by electron microscopy confirmed an almost complete absence of apical microvilli, the appearance of microvillus inclusions, and enlarged intercellular spaces in induced Myo5bfl/fl;Vil-CreERT2 intestines. In addition, we determined that MYO5B is involved not only in apical but also basolateral trafficking of proteins. The analysis of the intestine during the early onset of the disease revealed that subapical accumulation of secretory granules precedes occurrence of microvillus inclusions, indicating involvement of MYO5B in early differentiation of epithelial cells. By comparing our data with a novel MVID patient, we conclude that our mouse model completely recapitulates the intestinal phenotype of human MVID. This includes severe diarrhea, loss of microvilli, occurrence of microvillus inclusions, and subapical secretory granules. Thus, loss of MYO5B disturbs both apical and basolateral trafficking of proteins and causes MVID in mice.