Olmesartan-induced enteropathy causing chronic diarrhea in an elderly female

Olmesartan-induced enteropathy causing chronic diarrhea in an elderly female | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Olmesartan-induced enteropathy causing chronic diarrhea in an elderly female Akash Mathur, Naincy Rastogi, Nidhi Pasricha, Gopal Singh Negi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8450012/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Olmesartan-induced enteropathy (OIE) is an uncommon but increasingly recognised cause of chronic diarrhea that closely resembles celiac disease in both clinical presentation and histopathology. Because symptoms often develop months to years after drug initiation, diagnosis may be delayed unless clinicians maintain a high index of suspicion. A 55-year-old woman presented with two months of chronic diarrhea, abdominal cramps, and 8 kg weight loss. She was on Olmesartan for hypertension. Examination showed mild pallor and edema, with anemia and hypoalbuminemia on laboratory testing. Endoscopy was normal, but duodenal biopsy revealed villous atrophy with intraepithelial lymphocytosis. Celiac serology and HLA-DQ2/DQ8 were negative. Suspecting Olmesartan-induced enteropathy, the drug was discontinued, leading to complete symptom resolution within two weeks. OIE is a key differential diagnosis in patients with chronic diarrhea and celiac-like histology but negative celiac serology and HLA typing. Histologic findings may overlap significantly with celiac disease, making a detailed medication review essential. Drug withdrawal typically results in rapid clinical improvement, serving both diagnostic and therapeutic purposes. This case underscores the importance of considering Olmesartan-induced enteropathy in the evaluation of chronic diarrhea, particularly when endoscopy is normal and celiac investigations are negative. Early recognition can prevent misdiagnosis, unnecessary dietary restrictions, and unwarranted invasive testing. Olmesartan drug-induced enteropathy sprue-like enteropathy villous atrophy chronic diarrhea celiac disease mimic Figures Figure 1 Introduction Olmesartan medoxomil is an angiotensin II receptor blocker widely prescribed for hypertension due to its efficacy and generally favourable safety profile ( 1 ). Over the past decade, olmesartan has been recognised as a distinct cause of sprue-like enteropathy, characterised by chronic diarrhoea and villous atrophy that closely mimics celiac disease ( 2 ). Multiple case series and systematic reviews have since strengthened this association and have positioned olmesartan-induced enteropathy (OIE) within the growing spectrum of drug-induced small intestinal disorders ( 3 – 5 ). In 2013, the United States Food and Drug Administration (FDA) updated product labelling to include a warning about severe enteropathy linked to olmesartan use ( 6 ). Clinically, OIE presents with chronic watery diarrhea, abdominal discomfort, and significant weight loss, often accompanied by biochemical features of malabsorption such as anemia, hypoalbuminemia, and micronutrient deficits ( 7 ). Endoscopic findings are often normal or show subtle mucosal changes, whereas histology typically reveals villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, findings that closely mimic those of celiac disease ( 5 ). Although the exact mechanism remains unclear, proposed theories include cell-mediated immune injury, alterations in cytokine pathways, and T-cell–driven mucosal damage triggered by chronic Olmesartan exposure ( 2 ). Because of this clinicopathological overlap, OIE is now considered part of the broader category of "celiac mimickers" and seronegative villous atrophy ( 8 ). Patients are frequently misdiagnosed with seronegative or refractory celiac disease. They may be exposed to unnecessary gluten-free diets, immunosuppressive therapies, or repeated invasive procedures before a drug-related cause is considered ( 4 , 9 ). Current literature strongly recommends a thorough review of medications including antihypertensives such as Olmesartan when evaluating patients with unexplained villous atrophy and negative celiac serology ( 4 ). Recent studies suggest that while other angiotensin receptor blockers may rarely cause similar enteropathy, olmesartan remains the most frequently implicated, with cases reported across North America, Europe, and Asia ( 10 ). Despite growing evidence, awareness remains limited, and many patients experience prolonged symptoms before the diagnosis is recognised ( 2 ). We describe a case of olmesartan-induced enteropathy in a middle-aged woman who presented with chronic diarrhea, weight loss, and duodenal villous atrophy but had negative celiac serology and HLA-DQ2/DQ8. This case reinforces the importance of considering OIE in the differential diagnosis of seronegative villous atrophy. It highlights a critical, yet often overlooked, clinical lesson: medication review is essential before diagnosing seronegative celiac disease ( 3 ). Case Presentation A 55-year-old woman presented to the gastroenterology clinic with a two-month history of chronic loose stools occurring 6–7 times per day, associated with intermittent crampy abdominal pain and progressive unintentional weight loss of 8 kg. Her symptoms were non-bloody and were not related to meals. She denied fever, vomiting, recent antibiotic use, travel, or sick contacts. There was no history of joint pains, skin rash, or known autoimmune disorders. Her dietary intake had declined due to postprandial discomfort. She had a background of hypertension, well controlled on olmesartan 40 mg once daily for the preceding 18 months. She was not taking nonsteroidal anti-inflammatory drugs, proton pump inhibitors, or herbal supplements. There was no family history of celiac disease, inflammatory bowel disease, or gastrointestinal malignancy. On physical examination, she appeared pale and mildly dehydrated, with bilateral pedal edema. Vital signs were stable, and abdominal examination was unremarkable, with no tenderness, organomegaly, or palpable masses. Initial laboratory investigations demonstrated microcytic anaemia with a haemoglobin of 9.6 g/dL (reference range 13–16 g/dL) and a mean corpuscular volume of 73 fL (reference range 80–100 fL). Serum albumin was low at 3.1 g/dL (reference 3.5–5.5 g/dL). Serum electrolytes, liver function tests, renal function, and thyroid profile were normal. Stool testing for ova, cysts, parasites, and opportunistic infections was negative, and fecal occult blood testing was non-reactive. Given the persistent symptoms, an esophagogastroduodenoscopy was performed and revealed normal-appearing duodenal folds (Fig. 1 A). Colonoscopy also demonstrated normal mucosa throughout the colon and terminal ileum (Fig. 1 B and 1 C). Despite endoscopically normal mucosa, duodenal biopsies showed moderate villous atrophy, crypt hyperplasia with a crypt–villous ratio of 3:1, and more than 30 intraepithelial lymphocytes per 100 epithelial cells, features suggestive of celiac disease (Fig. 1 D, 1 E and 1 F). A detailed evaluation for celiac disease was undertaken. Anti-tissue transglutaminase IgA antibody was negative, and total immunoglobulin levels (IgA, IgG, IgM) were within normal limits, ruling out IgA deficiency as a cause of false-negative serology. Importantly, HLA-DQ2 and HLA-DQ8 genotyping were negative, making classical celiac disease highly unlikely. In light of negative celiac investigations and the patient's prolonged exposure to olmesartan, olmesartan-induced enteropathy (OIE) was considered. After excluding other causes of villous atrophy, such as autoimmune enteropathy, infections, Crohn's disease, and microscopic colitis, a therapeutic trial of drug withdrawal was initiated. Olmesartan was discontinued and replaced with an alternative antihypertensive agent. The clinical response was rapid and striking. The patient reported complete resolution of diarrhea within two weeks of stopping olmesartan, with improvement in appetite and energy levels. At a follow-up visit four weeks later, she had begun to regain weight, her bowel habits were regular, and her edema had resolved. The prompt symptomatic recovery following olmesartan cessation supported the diagnosis of olmesartan-induced enteropathy, eliminating the need for a gluten-free diet or further invasive investigations. Discussion Olmesartan-induced enteropathy (OIE) has emerged as an important, though rare, cause of chronic diarrhea and villous atrophy. Reports consistently show that OIE closely mimics celiac disease in both clinical presentation and histopathological features, making it a key consideration in patients with seronegative villous atrophy ( 11 ). The overlap is striking: both conditions may present with chronic diarrhea, abdominal pain, weight loss, anemia, and hypoalbuminemia, and both show varying degrees of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes on biopsy. Despite these similarities, distinguishing between the two entities is essential because their management differs fundamentally, gluten restriction has no role in OIE, whereas discontinuation of olmesartan results in rapid symptomatic improvement. Our case contributes to the growing body of literature by demonstrating a classic presentation of OIE in a patient with a normal endoscopic appearance but histology strongly suggestive of celiac disease. Like prior reports, this patient had negative anti-tissue transglutaminase antibodies and lacked HLA-DQ2/DQ8, both of which effectively exclude classical celiac disease and highlight the diagnostic challenge of seronegative villous atrophy ( 3 ). The complete resolution of symptoms within 2 weeks of discontinuing olmesartan further reinforces the causal association and provides therapeutic confirmation of the diagnosis. Notably, our case adds value from an Indian clinical setting, where reporting of OIE remains relatively scarce, and clinicians' awareness may still be limited. Several diagnostic pitfalls exist when evaluating chronic diarrhea with villous atrophy. OIE is frequently misdiagnosed as seronegative or refractory celiac disease, leading to unnecessary dietary restrictions, prolonged morbidity, or even immunosuppressive therapy. Other important differentials include Crohn's disease, microscopic colitis, autoimmune enteropathy, and enteropathies caused by other medications such as mycophenolate mofetil or NSAIDs ( 12 ). In our patient, the absence of endoscopic abnormalities, normal immunoglobulin levels, negative HLA typing, and lack of systemic features helped narrow the differential diagnosis. Recognition of the temporal association with olmesartan exposure, symptoms developing 18 months after initiation, is also consistent with literature showing that symptom onset may occur months to years after drug exposure ( 4 ). The pathophysiology of OIE remains incompletely understood, though current hypotheses suggest a delayed, cell-mediated immune response with mucosal injury mediated by T-cell activity and cytokine imbalance. Some studies indicate that olmesartan may trigger epithelial cell apoptosis or modulate transforming growth factor-β pathways, leading to villous atrophy and mucosal inflammation ( 5 ). Further research is needed to clarify underlying mechanisms and to determine whether genetic or environmental factors modulate susceptibility. A significant strength of this case is the comprehensive workup, including biopsy, celiac serology, immunoglobulins, and HLA typing, which allowed confident exclusion of classical and seronegative celiac disease. The rapid and complete response to drug withdrawal strengthens the causal inference. A limitation is the lack of repeat biopsy to document histological recovery, although clinical improvement remains the most widely accepted marker of resolution in OIE. Overall, this case reinforces several key clinical lessons. First, OIE should be routinely considered in the differential diagnosis of chronic diarrhea, especially when biopsy suggests celiac disease but serology and HLA typing are negative. Second, a thorough review of medications, particularly antihypertensive agents such as Olmesartan, is essential to avoid misdiagnosis. Finally, recognition of this reversible condition can prevent unnecessary investigations and provide a simple, effective therapeutic intervention. Conclusions Olmesartan-induced enteropathy is a reversible cause of chronic diarrhea that closely mimics celiac disease, making early recognition critical. Clinicians should suspect OIE when villous atrophy coexists with negative celiac serology and HLA typing, particularly in patients receiving long-term olmesartan. A careful medication history can prevent unnecessary testing and guide rapid, effective management through drug discontinuation. This case emphasises the importance of considering iatrogenic causes in seronegative villous atrophy. Declarations Ethical Approval and accordance Ethical approval was not required for this study as it is a single patient case report. The study was conducted in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent to participate Written informed consent was obtained from the patient for participation in this study. Consent to publish Written informed consent was obtained from the patient for publication of this case report and any accompanying images or clinical information. Data Availability All data generated or analysed during this study are included in this published article. Clinical trial number: Not applicable Consent for publication Written informed consent was obtained from the patient for publication of the case details and accompanying images. Competing interests The authors declare that they have no competing interests. Funding No funding was received for the preparation of this case report. Authors' contributions A.M. evaluated and managed the patient, performed the endoscopic procedures, interpreted the clinical and histopathological findings, and drafted the manuscript. All authors reviewed the manuscript, contributed to critical revisions, and approved the final version. Acknowledgements The authors thank the pathology department for providing high-quality histology images and technical assistance. References Brousil JA, Burke JM. Olmesartan medoxomil: an angiotensin II-receptor blocker. Clin Ther. 2003;25(4):1041–55. Rubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, Wu TT et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012;87(8):732–8. DeGaetani M, Tennyson CA, Lebwohl B, Lewis SK, Abu Daya H, Arguelles-Grande C, et al. Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma. Am J Gastroenterol. 2013;108(5):647–53. Kamboj AK, Oxentenko AS. Clinical and Histologic Mimickers of Celiac Disease. Clin Transl Gastroenterol. 2017;8(8):e114. Ianiro G, Bibbò S, Montalto M, Ricci R, Gasbarrini A, Cammarota G. Systematic review: Sprue-like enteropathy associated with olmesartan. Aliment Pharmacol Ther. 2014;40(1):16–23. Research C, for DE and. Drug Safety Communications. FDA [Internet]. 2025 Aug 28 [cited 2025 Dec 22]; Available from: https://www.fda.gov/drugs/drug-safety-and-availability/drug-safety-communications Marthey L, Cadiot G, Seksik P, Pouderoux P, Lacroute J, Skinazi F, et al. Olmesartan-associated enteropathy: results of a national survey. Aliment Pharmacol Ther. 2014;40(9):1103–9. Aziz I, Peerally MF, Barnes JH, Kandasamy V, Whiteley JC, Partridge D, et al. The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000–2015). Gut. 2017;66(9):1563–72. Schiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. 2022 Nov 1 [cited 2025 Dec 25]; Available from: https://gut.bmj.com/content/71/11/2218 Marietta EV, Cartee A, Rishi A, Murray JA. Drug-induced enteropathy. Dig Dis Basel Switz. 2015;33(2):215–20. Adike A, Corral J, Rybnicek D, Sussman D, Shah S, Quigley E. Olmesartan-Induced Enteropathy. Methodist DeBakey Cardiovasc J. 2016;12(4):230–2. Yamaguchi Y, Miwa T, Murakami R, Sugimura A, Yamamoto K, Sugiyama T, et al. A case report of olmesartan-associated sprue-like enteropathy: Diagnosis and healing confirmed by capsule endoscopy. DEN Open. 2023;3(1):e142. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8450012","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":576184328,"identity":"8af5ab4e-21c2-406e-86d3-1ca21d6e1b67","order_by":0,"name":"Akash Mathur","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYDCCA0DM2AAkeBgYmBkqgAxm5gbCWg7CtZwBaWEkRQtjGwPMUtyA7/bpxM8fdxzO5+85/Phz4bzaaP52oJYfFdtwapE8l7tZ4uCZw5YzzraZSc/cdjx3xmHGBsaeM7dxajE4w7tB4mDbYQOG8wxmzLzbjuU2ALUAXYhXy+YfIC3y59k/f+adcyx3PhFatoFtMTjbYyDN21CTu4GQFkmgFouzbekGhmfOlEnzHDuQuxGo5SA+v/ABHXajss3aQO5M+ubPPDV1ufPOHz744EcFbi3o4DCYPEC0eiCoI0XxKBgFo2AUjBAAAEd6Y7vmskf4AAAAAElFTkSuQmCC","orcid":"","institution":"Geetanjali Institute Of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Akash","middleName":"","lastName":"Mathur","suffix":""},{"id":576184332,"identity":"b5bc4b27-dafd-4e30-bc92-0001fd28677b","order_by":1,"name":"Naincy Rastogi","email":"","orcid":"","institution":"Geetanjali Institute Of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Naincy","middleName":"","lastName":"Rastogi","suffix":""},{"id":576184337,"identity":"8c2c2844-ed7f-498c-b57c-9e2b4d5e2d95","order_by":2,"name":"Nidhi Pasricha","email":"","orcid":"","institution":"Reliable Diagnostic Centre","correspondingAuthor":false,"prefix":"","firstName":"Nidhi","middleName":"","lastName":"Pasricha","suffix":""},{"id":576184338,"identity":"32722c0e-95e3-4e12-8d46-314f48002961","order_by":3,"name":"Gopal Singh Negi","email":"","orcid":"","institution":"Geetanjali Institute Of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Gopal","middleName":"Singh","lastName":"Negi","suffix":""}],"badges":[],"createdAt":"2025-12-25 15:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8450012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8450012/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100673241,"identity":"a783b39a-d4d6-42fd-b93d-5d62d2fd0208","added_by":"auto","created_at":"2026-01-20 10:47:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":275093,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptFile.docx","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/9fc9a8d6265405610e155165.docx"},{"id":100672889,"identity":"d0161544-b2ce-4c68-9e5e-f96b93b5e6c1","added_by":"auto","created_at":"2026-01-20 10:43:25","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5802,"visible":true,"origin":"","legend":"","description":"","filename":"bea2fed1965d48f587d4f5955ec67b3f.json","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/8664301167ca867a509eba0f.json"},{"id":100672994,"identity":"bb31661d-3427-4057-884e-3f92e2aefae0","added_by":"auto","created_at":"2026-01-20 10:44:59","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":28500,"visible":true,"origin":"","legend":"","description":"","filename":"CAREChecklistOIE.docx","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/5fbf9aa87c1671f9f158e09e.docx"},{"id":100673157,"identity":"bf90c357-34a9-43d9-a531-b3c7256019ee","added_by":"auto","created_at":"2026-01-20 10:46:33","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":41251,"visible":true,"origin":"","legend":"","description":"","filename":"bea2fed1965d48f587d4f5955ec67b3f1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/b80dc5a33ae0945a3d3afed8.xml"},{"id":100672992,"identity":"d30429a6-7b83-4915-af63-5d4c496ca4dd","added_by":"auto","created_at":"2026-01-20 10:44:56","extension":"pptx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":8891818,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/520dc3b3595b10dbf1271a9b.pptx"},{"id":100672993,"identity":"30fb06a6-c4bf-4364-8568-c49a8a606a48","added_by":"auto","created_at":"2026-01-20 10:44:58","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1018655,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/1df6d44a7cc99b12125f77eb.jpeg"},{"id":100672914,"identity":"8371ed25-7618-40a9-ac22-18a50c212ba6","added_by":"auto","created_at":"2026-01-20 10:43:44","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":385140,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/d6cc296542a0fd1b2a111395.png"},{"id":100672890,"identity":"20a5bb6f-c21e-46fa-8049-1cbe9dcad481","added_by":"auto","created_at":"2026-01-20 10:43:26","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39792,"visible":true,"origin":"","legend":"","description":"","filename":"bea2fed1965d48f587d4f5955ec67b3f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/2afe8f117c32c42afa142eb1.xml"},{"id":100673004,"identity":"e2f97104-9d39-455d-b30f-5c8b9b11b84f","added_by":"auto","created_at":"2026-01-20 10:45:33","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":46760,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/e462f1ba9130c92dd9f7ccb7.html"},{"id":100673194,"identity":"9c0442be-e1b9-4be6-9105-b83386bf2ece","added_by":"auto","created_at":"2026-01-20 10:47:03","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1660756,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e1A: \u003c/strong\u003eUpper gastrointestinal (GI) endoscopy image showing normal duodenal folds\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1B and C:\u003c/strong\u003e Colonoscopy image demonstrating normal colonic mucosa\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1D and E \u003c/strong\u003e(H\u0026amp;E, ×400), \u003cstrong\u003e1F \u003c/strong\u003e(H\u0026amp;E, ×100): Photomicrographs showing moderate villous atrophy with crypt hyperplasia (crypt–villous ratio 3:1) and more than 30 intraepithelial lymphocytes/100 epithelial cells\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/98eda5f7b9fbed4fde898c8d.jpg"},{"id":104874265,"identity":"9d803196-6ae3-461d-b92f-b2ec037e623b","added_by":"auto","created_at":"2026-03-18 08:29:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2014305,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8450012/v1/489af759-a4a6-4a56-9df7-61b2f671d2bf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Olmesartan-induced enteropathy causing chronic diarrhea in an elderly female","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOlmesartan medoxomil is an angiotensin II receptor blocker widely prescribed for hypertension due to its efficacy and generally favourable safety profile (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Over the past decade, olmesartan has been recognised as a distinct cause of sprue-like enteropathy, characterised by chronic diarrhoea and villous atrophy that closely mimics celiac disease (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Multiple case series and systematic reviews have since strengthened this association and have positioned olmesartan-induced enteropathy (OIE) within the growing spectrum of drug-induced small intestinal disorders (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In 2013, the United States Food and Drug Administration (FDA) updated product labelling to include a warning about severe enteropathy linked to olmesartan use (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinically, OIE presents with chronic watery diarrhea, abdominal discomfort, and significant weight loss, often accompanied by biochemical features of malabsorption such as anemia, hypoalbuminemia, and micronutrient deficits (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Endoscopic findings are often normal or show subtle mucosal changes, whereas histology typically reveals villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, findings that closely mimic those of celiac disease (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Although the exact mechanism remains unclear, proposed theories include cell-mediated immune injury, alterations in cytokine pathways, and T-cell\u0026ndash;driven mucosal damage triggered by chronic Olmesartan exposure (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBecause of this clinicopathological overlap, OIE is now considered part of the broader category of \"celiac mimickers\" and seronegative villous atrophy (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Patients are frequently misdiagnosed with seronegative or refractory celiac disease. They may be exposed to unnecessary gluten-free diets, immunosuppressive therapies, or repeated invasive procedures before a drug-related cause is considered (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Current literature strongly recommends a thorough review of medications including antihypertensives such as Olmesartan when evaluating patients with unexplained villous atrophy and negative celiac serology (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecent studies suggest that while other angiotensin receptor blockers may rarely cause similar enteropathy, olmesartan remains the most frequently implicated, with cases reported across North America, Europe, and Asia (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Despite growing evidence, awareness remains limited, and many patients experience prolonged symptoms before the diagnosis is recognised (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe describe a case of olmesartan-induced enteropathy in a middle-aged woman who presented with chronic diarrhea, weight loss, and duodenal villous atrophy but had negative celiac serology and HLA-DQ2/DQ8. This case reinforces the importance of considering OIE in the differential diagnosis of seronegative villous atrophy. It highlights a critical, yet often overlooked, clinical lesson: medication review is essential before diagnosing seronegative celiac disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 55-year-old woman presented to the gastroenterology clinic with a two-month history of chronic loose stools occurring 6\u0026ndash;7 times per day, associated with intermittent crampy abdominal pain and progressive unintentional weight loss of 8 kg. Her symptoms were non-bloody and were not related to meals. She denied fever, vomiting, recent antibiotic use, travel, or sick contacts. There was no history of joint pains, skin rash, or known autoimmune disorders. Her dietary intake had declined due to postprandial discomfort.\u003c/p\u003e \u003cp\u003eShe had a background of hypertension, well controlled on olmesartan 40 mg once daily for the preceding 18 months. She was not taking nonsteroidal anti-inflammatory drugs, proton pump inhibitors, or herbal supplements. There was no family history of celiac disease, inflammatory bowel disease, or gastrointestinal malignancy.\u003c/p\u003e \u003cp\u003eOn physical examination, she appeared pale and mildly dehydrated, with bilateral pedal edema. Vital signs were stable, and abdominal examination was unremarkable, with no tenderness, organomegaly, or palpable masses.\u003c/p\u003e \u003cp\u003eInitial laboratory investigations demonstrated microcytic anaemia with a haemoglobin of 9.6 g/dL (reference range 13\u0026ndash;16 g/dL) and a mean corpuscular volume of 73 fL (reference range 80\u0026ndash;100 fL). Serum albumin was low at 3.1 g/dL (reference 3.5\u0026ndash;5.5 g/dL). Serum electrolytes, liver function tests, renal function, and thyroid profile were normal. Stool testing for ova, cysts, parasites, and opportunistic infections was negative, and fecal occult blood testing was non-reactive.\u003c/p\u003e \u003cp\u003eGiven the persistent symptoms, an esophagogastroduodenoscopy was performed and revealed normal-appearing duodenal folds (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Colonoscopy also demonstrated normal mucosa throughout the colon and terminal ileum (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Despite endoscopically normal mucosa, duodenal biopsies showed moderate villous atrophy, crypt hyperplasia with a crypt\u0026ndash;villous ratio of 3:1, and more than 30 intraepithelial lymphocytes per 100 epithelial cells, features suggestive of celiac disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eD, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eE and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003eA detailed evaluation for celiac disease was undertaken. Anti-tissue transglutaminase IgA antibody was negative, and total immunoglobulin levels (IgA, IgG, IgM) were within normal limits, ruling out IgA deficiency as a cause of false-negative serology. Importantly, HLA-DQ2 and HLA-DQ8 genotyping were negative, making classical celiac disease highly unlikely.\u003c/p\u003e \u003cp\u003eIn light of negative celiac investigations and the patient's prolonged exposure to olmesartan, olmesartan-induced enteropathy (OIE) was considered. After excluding other causes of villous atrophy, such as autoimmune enteropathy, infections, Crohn's disease, and microscopic colitis, a therapeutic trial of drug withdrawal was initiated. Olmesartan was discontinued and replaced with an alternative antihypertensive agent.\u003c/p\u003e \u003cp\u003eThe clinical response was rapid and striking. The patient reported complete resolution of diarrhea within two weeks of stopping olmesartan, with improvement in appetite and energy levels. At a follow-up visit four weeks later, she had begun to regain weight, her bowel habits were regular, and her edema had resolved.\u003c/p\u003e \u003cp\u003eThe prompt symptomatic recovery following olmesartan cessation supported the diagnosis of olmesartan-induced enteropathy, eliminating the need for a gluten-free diet or further invasive investigations.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOlmesartan-induced enteropathy (OIE) has emerged as an important, though rare, cause of chronic diarrhea and villous atrophy. Reports consistently show that OIE closely mimics celiac disease in both clinical presentation and histopathological features, making it a key consideration in patients with seronegative villous atrophy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The overlap is striking: both conditions may present with chronic diarrhea, abdominal pain, weight loss, anemia, and hypoalbuminemia, and both show varying degrees of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes on biopsy. Despite these similarities, distinguishing between the two entities is essential because their management differs fundamentally, gluten restriction has no role in OIE, whereas discontinuation of olmesartan results in rapid symptomatic improvement.\u003c/p\u003e \u003cp\u003eOur case contributes to the growing body of literature by demonstrating a classic presentation of OIE in a patient with a normal endoscopic appearance but histology strongly suggestive of celiac disease. Like prior reports, this patient had negative anti-tissue transglutaminase antibodies and lacked HLA-DQ2/DQ8, both of which effectively exclude classical celiac disease and highlight the diagnostic challenge of seronegative villous atrophy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The complete resolution of symptoms within 2 weeks of discontinuing olmesartan further reinforces the causal association and provides therapeutic confirmation of the diagnosis. Notably, our case adds value from an Indian clinical setting, where reporting of OIE remains relatively scarce, and clinicians' awareness may still be limited.\u003c/p\u003e \u003cp\u003eSeveral diagnostic pitfalls exist when evaluating chronic diarrhea with villous atrophy. OIE is frequently misdiagnosed as seronegative or refractory celiac disease, leading to unnecessary dietary restrictions, prolonged morbidity, or even immunosuppressive therapy. Other important differentials include Crohn's disease, microscopic colitis, autoimmune enteropathy, and enteropathies caused by other medications such as mycophenolate mofetil or NSAIDs (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In our patient, the absence of endoscopic abnormalities, normal immunoglobulin levels, negative HLA typing, and lack of systemic features helped narrow the differential diagnosis. Recognition of the temporal association with olmesartan exposure, symptoms developing 18 months after initiation, is also consistent with literature showing that symptom onset may occur months to years after drug exposure (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathophysiology of OIE remains incompletely understood, though current hypotheses suggest a delayed, cell-mediated immune response with mucosal injury mediated by T-cell activity and cytokine imbalance. Some studies indicate that olmesartan may trigger epithelial cell apoptosis or modulate transforming growth factor-β pathways, leading to villous atrophy and mucosal inflammation (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Further research is needed to clarify underlying mechanisms and to determine whether genetic or environmental factors modulate susceptibility.\u003c/p\u003e \u003cp\u003eA significant strength of this case is the comprehensive workup, including biopsy, celiac serology, immunoglobulins, and HLA typing, which allowed confident exclusion of classical and seronegative celiac disease. The rapid and complete response to drug withdrawal strengthens the causal inference. A limitation is the lack of repeat biopsy to document histological recovery, although clinical improvement remains the most widely accepted marker of resolution in OIE.\u003c/p\u003e \u003cp\u003eOverall, this case reinforces several key clinical lessons. First, OIE should be routinely considered in the differential diagnosis of chronic diarrhea, especially when biopsy suggests celiac disease but serology and HLA typing are negative. Second, a thorough review of medications, particularly antihypertensive agents such as Olmesartan, is essential to avoid misdiagnosis. Finally, recognition of this reversible condition can prevent unnecessary investigations and provide a simple, effective therapeutic intervention.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOlmesartan-induced enteropathy is a reversible cause of chronic diarrhea that closely mimics celiac disease, making early recognition critical. Clinicians should suspect OIE when villous atrophy coexists with negative celiac serology and HLA typing, particularly in patients receiving long-term olmesartan. A careful medication history can prevent unnecessary testing and guide rapid, effective management through drug discontinuation. This case emphasises the importance of considering iatrogenic causes in seronegative villous atrophy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and accordance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this study as it is a single patient case report. The study was conducted in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images or clinical information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of the case details and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for the preparation of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.M. evaluated and managed the patient, performed the endoscopic procedures, interpreted the clinical and histopathological findings, and drafted the manuscript. All authors reviewed the manuscript, contributed to critical revisions, and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the pathology department for providing high-quality histology images and technical assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrousil JA, Burke JM. Olmesartan medoxomil: an angiotensin II-receptor blocker. Clin Ther. 2003;25(4):1041\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, Wu TT et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012;87(8):732\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeGaetani M, Tennyson CA, Lebwohl B, Lewis SK, Abu Daya H, Arguelles-Grande C, et al. Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma. Am J Gastroenterol. 2013;108(5):647\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamboj AK, Oxentenko AS. Clinical and Histologic Mimickers of Celiac Disease. Clin Transl Gastroenterol. 2017;8(8):e114.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIaniro G, Bibb\u0026ograve; S, Montalto M, Ricci R, Gasbarrini A, Cammarota G. Systematic review: Sprue-like enteropathy associated with olmesartan. Aliment Pharmacol Ther. 2014;40(1):16\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eResearch C, for DE and. Drug Safety Communications. FDA [Internet]. 2025 Aug 28 [cited 2025 Dec 22]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/drugs/drug-safety-and-availability/drug-safety-communications\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/drugs/drug-safety-and-availability/drug-safety-communications\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarthey L, Cadiot G, Seksik P, Pouderoux P, Lacroute J, Skinazi F, et al. Olmesartan-associated enteropathy: results of a national survey. Aliment Pharmacol Ther. 2014;40(9):1103\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAziz I, Peerally MF, Barnes JH, Kandasamy V, Whiteley JC, Partridge D, et al. The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000\u0026ndash;2015). Gut. 2017;66(9):1563\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. 2022 Nov 1 [cited 2025 Dec 25]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gut.bmj.com/content/71/11/2218\u003c/span\u003e\u003cspan address=\"https://gut.bmj.com/content/71/11/2218\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarietta EV, Cartee A, Rishi A, Murray JA. Drug-induced enteropathy. Dig Dis Basel Switz. 2015;33(2):215\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdike A, Corral J, Rybnicek D, Sussman D, Shah S, Quigley E. Olmesartan-Induced Enteropathy. Methodist DeBakey Cardiovasc J. 2016;12(4):230\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi Y, Miwa T, Murakami R, Sugimura A, Yamamoto K, Sugiyama T, et al. A case report of olmesartan-associated sprue-like enteropathy: Diagnosis and healing confirmed by capsule endoscopy. DEN Open. 2023;3(1):e142.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Olmesartan, drug-induced enteropathy, sprue-like enteropathy, villous atrophy, chronic diarrhea, celiac disease mimic","lastPublishedDoi":"10.21203/rs.3.rs-8450012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8450012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOlmesartan-induced enteropathy (OIE) is an uncommon but increasingly recognised cause of chronic diarrhea that closely resembles celiac disease in both clinical presentation and histopathology. Because symptoms often develop months to years after drug initiation, diagnosis may be delayed unless clinicians maintain a high index of suspicion.\u003c/p\u003e \u003cp\u003eA 55-year-old woman presented with two months of chronic diarrhea, abdominal cramps, and 8 kg weight loss. She was on Olmesartan for hypertension. Examination showed mild pallor and edema, with anemia and hypoalbuminemia on laboratory testing. Endoscopy was normal, but duodenal biopsy revealed villous atrophy with intraepithelial lymphocytosis. Celiac serology and HLA-DQ2/DQ8 were negative. Suspecting Olmesartan-induced enteropathy, the drug was discontinued, leading to complete symptom resolution within two weeks.\u003c/p\u003e \u003cp\u003eOIE is a key differential diagnosis in patients with chronic diarrhea and celiac-like histology but negative celiac serology and HLA typing. Histologic findings may overlap significantly with celiac disease, making a detailed medication review essential. Drug withdrawal typically results in rapid clinical improvement, serving both diagnostic and therapeutic purposes.\u003c/p\u003e \u003cp\u003eThis case underscores the importance of considering Olmesartan-induced enteropathy in the evaluation of chronic diarrhea, particularly when endoscopy is normal and celiac investigations are negative. Early recognition can prevent misdiagnosis, unnecessary dietary restrictions, and unwarranted invasive testing.\u003c/p\u003e","manuscriptTitle":"Olmesartan-induced enteropathy causing chronic diarrhea in an elderly female","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-20 09:22:12","doi":"10.21203/rs.3.rs-8450012/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c858632c-58b0-47f7-bd0e-fde022b3d9b2","owner":[],"postedDate":"January 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-18T08:28:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-20 09:22:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8450012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8450012","identity":"rs-8450012","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}