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.

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.

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.

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.

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.

Impacts of the feed contaminant deoxynivalenol on the intestine of monogastric animals: poultry and swine.

Deoxynivalenol (DON) is one of the most prevalent cereal contaminants with major public health concerns owing to its high toxigenic potentials. Once ingested, DON first and foremost targets epithelial cells of the gastrointestinal tract, whose proper functioning, as the first line of defence, is of paramount importance for the host's health. Emerging evidences, summarized in this article, suggest that DON produces its toxicity primarily via activation of the mitogen-activated protein kinases (MAPKs) signalling pathway and alteration in the expression of genes responsible for key physiological and immunological functions of the intestinal tissue of chickens and pigs. The activation of MAPKs signalling cascade results in disruption of the gut barrier function and an increase in the permeability by reducing expression of the tight junction proteins. Exposure to DON also down-regulates the expression of multiple transporter systems in the enterocytes with subsequent impairment of the absorption of key nutrients. Other major intestinal cytotoxic effects of DON described herein are modulation of mucosal immune responses, leading to immunosupression or stimulation of local immune cells and cytokine release, and also facilitation of the persistence of intestinal pathogens in the gut. Both of the last events potentiate enteric infections and local inflammation in pigs and poultry, rendering enterocytes and the host more vulnerable to luminal toxic compounds. This review highlights the cytotoxic risks associated with the intake of even low levels of DON and also identifies gaps of knowledge that need to be addressed by future research.

Olmesartan: sprue-like enteropathy.

Olmesartan exposes patients to the risk of sometimes serious chronic intestinal disorders with diarrhoea (sprue-like enteropathy). As of late 2013, this adverse effect has not been reported with other angiotensin II receptor blockers (ARBs).

Miglustat-induced intestinal carbohydrate malabsorption is due to the inhibition of α-glucosidases, but not ß-galactosidases.

Miglustat is an oral medication that has approved indication for type I Gaucher disease and Niemann pick disease type C. Usually treatment with Miglustat is associated with occurrence of gastrointestinal side effects similar to carbohydrate maldigestion symptoms. Here, we studied the direct influence of Miglustat on the enzymatic function of the major disaccharidases of the intestinal epithelium. Our findings show that an immediate effect of Miglustat is its interference with carbohydrate digestion in the intestinal lumen via reversible inhibition of disaccharidases that cleave α-glycosidically linked carbohydrates. Higher non physiological concentrations of Miglustat can partly affect lactase activity. We further show that the inhibition of the disaccharidases function by Miglustat is mainly competitive and does not occur via alteration of the enzyme folding.

Metformin associated B12 deficiency.

According to the ADA guidelines, metformin and lifestyle modifications are the first line therapies in the treatment of type 2 diabetes mellitus. Metformin does, however, cause vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency--a clinically important and treatable condition. Here we report a case of 60 year old diabetic male presenting with clinical features of Vitamin B-12 deficiency on long term metformin therapy, which was confirmed on investigations. Patient showed symptomatic improvement with change in treatment.

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.

[Chronic use of proton pump inhibitors: is the risk of osteoporosis and fractures real?]. / ¿Es real el riesgo de osteoporosis y riesgo de fracturas con el uso crónico de inhibidores de la bomba de protones?

Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and their potential toxicity is periodically reviewed, emphasizing aspects originally considered secondary. The present review analyzes the physiological and pharmacological bases and the scarce clinical evidence for a potential association between the continued administration of PPI and the development of osteoporosis and bone fractures. Both disorders are clearly related to calcium homeostasis and are highly important in elderly patients due to their poor general prognosis and disabling consequences.

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.

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.

[Adverse effects of non-steroidal anti-inflammatory drugs in the lower gastrointestinal tract]. / Nemszteroid gyulladásgátlók alsó tápcsatornai mellékhatásai.

Non-steroidal antiinflammatory drugs (NSAID) are among the most commonly used drugs worldwide. Together with the beneficial effects, several adverse effects have become evident in the past decades. NSAIDs may damage any part of the gastrointestinal (GI) tract. The adverse effect in the lower GI tract was thought to be less important, but more and more data confirm that NSAIDs can cause equally severe lesions in the lower GI tract as well, only the diagnostic procedures are limited. NSAIDs may damage the intact mucosa, and they also may cause flare-up of a preexisting disease. Adverse events in the lower GI tract are caused mainly by the dual (COX-1 and COX-2) inhibitors. Besides the inhibiting of the cyclooxygenase enzymes, an important step is the local effect of the drug that initiates the chain reaction with the damage of the epithelial cells (increase of mucosal permeability, influx of luminal factors, produce of inflammatory mediators etc.). The spectrum of adverse effects of NSAIDs on the lower GI are reviewed according to the latest literature and the available prevention and therapeutic strategies.

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.