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Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge

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  • Case ReportSeronegative Intestinal Villous Atrophy: A Diagnostic Challenge

    Cludio Martins, Cristina Teixeira, Suzane Ribeiro, Daniel Trabulo,Cludia Cardoso, Joo Mangualde, Ricardo Freire, Ana Lusa Alves,lia Gamito, Isabelle Cremers, and Ana Paula Oliveira

    Department of Gastroenterology, Setubal Hospital Center, Sao Bernardo Hospital, Setubal, Portugal

    Correspondence should be addressed to Claudio Martins; [email protected]

    Received 8 July 2016; Accepted 18 September 2016

    Academic Editor: Maria Teresa Bardella

    Copyright 2016 Claudio Martins et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

    Celiac disease is the most important cause of intestinal villous atrophy. Seronegative intestinal villous atrophy, including thosethat are nonresponsive to a gluten-free diet, is a diagnostic challenge. In these cases, before establishing the diagnosis ofseronegative celiac disease, alternative etiologies of atrophic enteropathy should be considered. Recently, a new clinical entityresponsible for seronegative villous atrophy was describedolmesartan-induced sprue-like enteropathy. Herein, we report twouncommon cases of atrophic enteropathy in patients with arterial hypertension under olmesartan, who presented with severechronic diarrhea and significant involuntary weight loss. Further investigation revealed intestinal villous atrophy and intraepitheliallymphocytosis. Celiac disease and other causes of villous atrophy were ruled out. Drug-induced enteropathy was suspected andclinical improvement and histologic recovery were verified after olmesartan withdrawal. These cases highlight the importance forclinicians to maintain a high index of suspicion for olmesartan as a precipitant of sprue-like enteropathy.

    1. Introduction

    The combination of diarrhea, weight loss, and villous atrophy(VA) is usually associated with celiac disease (CD) [1].The diagnosis of CD is supported by positive serologicaltests, celiac permissive HLA type, and symptomatic andhistologic response to a gluten-free diet (GFD). AlthoughCD is the most common cause of VA, patients with VA andnegative celiac serology are encountered, placing a diagnosticand therapeutic dilemma. Testing for other conditions suchas Crohns disease, autoimmune enteropathy, microscopicenterocolitis, and infectious enteritis should be warranted.Another possible cause of VA has recently garnered moreattentiondrug-induced enteropathy. Reports of damage tothe intestinal villi by pharmaceuticals have been describedpreviously with the use of immunosuppressive drugs, inparticular azathioprine and methotrexate [2, 3]. Recently,a new drug was linked to sprue-like enteropathythe oralangiotensin-receptor blocker (ARB) olmesartan. To date,the pathophysiologic mechanisms of olmesartan-inducedsprue-like enteropathy (OISLE) remain unknown, although

    a cell-mediated immune response and a genetic predisposi-tion are suggested.

    Herein, we report two uncommon cases of severe OISLEand discuss the natural history of this entity.

    2. Case Report 1

    A 53-year-old Caucasian female was admitted to our Depart-ment with a 6-month clinical picture of diarrhea and sig-nificant involuntary weight loss (20% body weight). Shereported between 6 and 10 daily episodes of bulky, watery,and nonbloody diarrhea, abdominal bloating, and, morerecently, severe asthenia. She denied abdominal pain, feveror other symptoms suggestive of local or systemic infections,recent travels or sick contacts, prior exposure to health careenvironments, or changes in her diet habits or medicationswithin the last few years. Apart from arterial hypertensiontreated with olmesartan 40mg/daily for the last six years,her past medical and surgical history were unremarkable.The patient did not respond to initial therapeutic approach,

    Hindawi Publishing CorporationCase Reports in Gastrointestinal MedicineVolume 2016, Article ID 6392028, 4 pageshttp://dx.doi.org/10.1155/2016/6392028

  • 2 Case Reports in Gastrointestinal Medicine

    (a) (b)

    Figure 1: Endoscopic findings. (a) Visible blood vessels on the duodenal bulb. (b) Attenuation of mucosal folds on the second portion ofduodenum.

    including probiotics, an opioid-receptor agonist, and gluten-and lactose-free diet, as well a trial of oral antibiotic forpossible small bowel bacterial overgrowth.

    On admission, physical examination showed pallor andmuscle wasting. Initial blood tests showed mild microcyticanemia (11 g/dL; N: 11.515.5), leukopenia (3.8 109/L;N: 4.510), thrombocytopenia (130 109/L; N: 150400),and hypokalemia (2.8mmol/L; N: 3.55). The rest of thelaboratory study was unremarkable including erythrocytesedimentation rate, C-reactive protein, liver and kidneytests, total protein, albumin, and immunoglobulin lev-els, B12 vitamin, folic acid, thyroid-stimulating hormone,anti-tissue transglutaminase antibodies, and serology forhuman immunodeficiency virus (HIV) and cytomegalovirus.Stool culture for infectious agents and polymerase chainreaction testing for C. difficile toxins A and B werenegative.

    The subsequent workup included abdominopelvic com-puted tomography scan which was negative for pancreaticabnormalities or other suspicious lesions for malignancy;total colonoscopy and terminal ileoscopy with random biop-sies that were normal and with no evidence of inflammatorybowel disease or microscopic colitis; and upper endoscopythat showed attenuation of duodenal folds (Figure 1) andhistopathological examination confirmed a partial villousatrophy and intraepithelial lymphocyte infiltration with nosigns of granulomas, microorganisms, or malignancy (Fig-ure 2).

    A diagnostic hypothesis of OISLE was placed and, there-fore, this drug was withdrawn and switched to lisinopril.Prompt improvement was achieved within 72 h with resolu-tion of diarrhea and normalization of laboratory tests. Upperendoscopy was repeated two months later showing normalduodenal appearance and complete recovery of duodenal villiand no intraepithelial lymphocyte infiltration, on histology.At six-month follow-up, the patient remained asymptomaticwith complete recovery of weight loss.

    3. Case Report 2

    A 65-year-old Caucasian female with arterial hypertensionunder olmesartan 40mg/daily in the last four years wasadmitted to our Department with a 2-month clinical pictureof watery and nonbloody diarrhea (710 stools/day), diffuseabdominal pain, fatigue, anorexia, and involuntary weightloss (10% body weight). She denied fever and any otherrelevant epidemiologic context. She was previously evaluatedby her family doctor who prescribed empiric antibiotic butwith no improvement. On admission, physical examinationshowed dehydration, hypotension, and tachycardia. Labo-ratory evaluations revealed normocytic anemia (10.9 g/dL;N: 11.515), urea 84mg/dL (N: 2143), creatinine 3.63mg/dL(N: 0.61.1), serum potassium (2.5mmol/L; N: 3.55), andalbumin 3.1 g/dL (N: 3.44.8). Serology for celiac diseaseand thyroid hormone levels and stool analysis for infectiousagents (C. difficile, virology, bacteriology, mycobacteriology,and parasitology) and serology forHIV, cytomegalovirus, andherpes simplex virus were all negative. Total colonoscopyrevealed normal mucosa without evidence of microscopiccolitis or inflammatory bowel disease, on histopathology.Upper endoscopy showed normal gastroduodenal mucosa.Duodenal biopsies highlighted partial villous atrophy withsevere intraepithelial lymphocytosis. Given the high sus-picion of OISLE, this drug was suspended and switchedto lisinopril, with replacement of electrolytes. One weekafter admission, the patient was discharged without diar-rhea or need of nutritional/electrolyte support. Two monthslater, a complete recovery of weight was seen along withfull normalization of laboratory tests and histopathologicalchanges.

    4. Discussion

    CD is an immunomediated disorder occurring in peoplegenetically susceptible to gluten and results in variable

  • Case Reports in Gastrointestinal Medicine 3

    (a) (b)

    (c) (d)

    Figure 2: Duodenal histopathological features. (a, b, c) Partial villous atrophy with lymphocytic inflammatory infiltrate in lamina propriaand surface intraepithelial lymphocytosis (H&E). (d) CD3 immunostaining shows pathological increase of intraepithelial lymphocytes (IHC200).

    degrees of VA and an increase in intraepithelial lympho-cytes [1]. The diagnosis of CD is supported by positiveantibody tests (anti-tissue transglutaminase antibodies) andsymptomatic and histologic response to a GFD. When celiacserologies are negative on a gluten-containing diet, alterna-tive etiologies for VA should be considered before diagnosisof seronegative CD to prevent an unnecessary lifelong GFD[4]. Differential diagnosis includes autoimmune enteropathy,Crohns disease, microscopic enterocolitis, hypogammaglob-ulinemic sprue, Whipples disease, tropical sprue, intestinaltuberculosis, HIV-associated enteropathy, infectious enteri-tis, intestinal malignancies, and drugs-induced enteropathy.DeGaetani et al. [5] studied 72 patients with seronegativeVA at a tertiary care center and, interestingly, the two mostcommon diagnoses in these patients were seronegative CD(28%) and drug-induced sprue-like enteropathy (26%).

    Olmesartan is one of the several ARBs commonly pre-scribed for the management of hypertension. The earliestevidence of OISLE was first described in 2012 by Rubio-Tapiaet al. [6], and a few reports were published subsequently,leading Food and Drug Administration to institute labelchanges addressing this adverse event, in July 2013. Based oncases reported to date, this entitymost frequently affects olderadults (mean age, 68 years; range, 4691 years)with no genderpredomina

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