Case Report

Omeprazole increased small intestinal mucosal injury intwo of six disease-free cases evaluated by capsuleendoscopy

Shunji Fujimori, Yoko Takahashi, Atsushi Tatsuguchi and Choitsu Sakamoto

Department of Gastroenterology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan

Recently, a report showed that proton-pump inhibitors (PPI) exac-erbate non-steroidal anti-inflammatory drug-induced small intes-tinal injury in the rat. In the present report of two human cases,small intestinal injuries were probably induced and/or exacer-bated after PPI treatment. Case 1 was a 30-year-old healthy manin whom no small intestinal mucosal break was detected at base-line capsule endoscopy. After 2 weeks of omeprazole given20 mg once daily, he was found to have two small intestinalmucosal breaks. Case 2 was a 40-year-old healthy man in whomsix small intestinal mucosal breaks were detected at baselinecapsule endoscopy. After 2 weeks of omeprazole given 20 mgonce daily, 12 small intestinal mucosal breaks were detected.Follow-up capsule endoscopy carried out 3 weeks after stoppingomeprazole in case 2 showed seven small intestinal mucosalbreaks were detected, showing restitution of the small intestinal

mucosal injury. These two cases were obtained from a pilot studyevaluating the effect of single administration of PPI on small intes-tinal mucosa in humans. In the pilot study, six healthy male vol-unteers were given omeprazole 20 mg for a period of 2 weeks.Small intestinal injury was evaluated before and after PPI treat-ment using capsule endoscopy. In four subjects other than thetwo above-mentioned cases, no small intestinal mucosal breakswere found at both baseline and post-treatment capsule endos-copy. Considering the two cases with increased or newlydetected small intestinal mucosal breaks, omeprazole mayexacerbate/induce small intestinal injury.

Key words: capsule endoscopy, non-steroidal anti-inflammatorydrug (NSAID), omeprazole, proton-pump inhibitor (PPI), smallintestinal injury

INTRODUCTION

CAPSULE ENDOSCOPY AND balloon-assisted endos-copy, advanced modalities that now allow for full inves-

tigation of the entire small intestine, have revealed thatnon-steroidal anti-inflammatory drugs (NSAIDs) cause avariety of abnormalities in the small intestine, includingulcerations, perforations, bleeding and diaphragm-likestrictures.1–3 Recently, several capsule endoscopy studieswere carried out on healthy volunteers, such as comparingtraditional NSAIDs with cyclooxygenase-2 inhibitors forsmall intestinal injury, and evaluating the preventive effect ofconcomitant administration of mucoprotective drugs againstNSAID-induced small intestinal injury.4 Goldstein et al.reported that 55% of subjects developed small intestinalinjuries after 2 weeks of naproxen medication, with a mean

of 2.99 mucosal breaks per subject.5 Japanese studies supportthese findings, showing that over 50% of subjects developedsmall intestinal mucosal breaks after 2 weeks of diclofenacmedication.6,7 These studies suggest that 2 weeks of tradi-tional NSAIDs medication causes small intestinal injuries inover 50% of subjects. A common aspect of all these studieswas that proton-pump inhibitors (PPI) were given along withtraditional NSAIDs to prevent NSAID-induced gastroduode-nal injury. The capsule endoscopy studies have shown thatgiving concomitant PPI failed to prevent NSAID-inducedsmall intestinal mucosal injury in healthy volunteers.4–8

Until recently, most studies of NSAID-associated injuryhave focused on the upper gastrointestinal tract, as thestomach and duodenum are sites generally associated withmajor morbidity and mortality in the clinical setting. There-fore, PPI and prostaglandin analogs have become the estab-lished treatment against NSAID-induced gastroduodenalinjuries.9 Many physicians consider the use of traditionalNSAIDs in combination with a PPI, a recommendationfound in major treatment guidelines for patients with ahistory of gastrointestinal events or for those at high risk ofdeveloping complications.9 However, as mentioned earlier,

Corresponding: Shunji Fujimori, Department of Gastroenterology,Graduate School of Medicine, Nippon Medical School, 1-1-5,Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Email: s-fujimori@nms.ac.jpReceived 21 August 2013; accepted 11 September 2013.

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studies in healthy volunteers have shown that the preventiveeffect of PPI does not extend to the small intestine.4 Further-more, the studies have no information of the effect of PPI onthe small intestine. In addition, there are no reports of singleadministration of PPI to evaluate the effect of PPI on thesmall intestine in humans. Therefore, the purpose of thepresent case report was to introduce two cases in whomsmall intestinal mucosal injuries were exacerbated or newlydiscovered after single administration of PPI using capsuleendoscopy.

CASE REPORTS

Case 1

CASE 1 WAS a healthy 30-year-old, male pack-a-daysmoker, moderate drinker, not associated with any gas-

trointestinal (GI) symptoms. No small intestinal mucosalbreak was detected at baseline capsule endoscopy. After 2weeks of giving omeprazole 20 mg once daily, he was foundto have two small intestinal mucosal breaks at post-treatmentcapsule endoscopy (Fig. 1).

Case 2Case 2 was a healthy 40-year-old, male non-smoker, moder-ate drinker, not associated with any GI symptoms. Six smallintestinal mucosal breaks were detected at baseline capsuleendoscopy. Figure 2a shows the endoscopic images of thetop two severe small intestinal mucosal breaks in the subjectat baseline capsule endoscopy. After 2 weeks of givingomeprazole 20 mg once daily, 12 small intestinal mucosalbreaks were detected at post-treatment capsule endoscopy.Figure 2b shows the endoscopic images of the top two smallintestinal mucosal breaks in the subject at post-treatmentcapsule endoscopy. Follow-up capsule endoscopy was

carried out 3 weeks after stopping omeprazole. Seven smallintestinal mucosal breaks were detected at the follow-upcapsule endoscopy showing restitution of the small intestinalmucosal injury.

These two cases were obtained from a pilot study to evalu-ate the effect of single administration of PPI on small intes-tinal mucosa. The pilot study method was as follows. A totalof six healthy male subjects who had volunteered throughopen recruitment were screened by laboratory tests and inter-views between February 2007 and April 2007. Eligible sub-jects were aged 36.5 ± 4.3 years, had taken no medicationduring the 1-month period prior to the start of the study andhad normal physical examination and laboratory results.Exclusion criteria included failure to access the full length ofthe small intestine by baseline capsule endoscopy. This studywas approved by the Ethics Committee at Nippon MedicalSchool and all subjects provided written informed consentfor enrolment in the study before undergoing baselinecapsule endoscopy examinations.

After evaluation by baseline capsule endoscopy, all eli-gible subjects were given omeprazole 20 mg once dailyimmediately after dinner for a period of 2 weeks. Post-treatment capsule endoscopy was done within 24 h after

Figure 1 Case 1. A healthy male subject in whom small intestinalmucosal breaks were not detected at baseline capsule endos-copy developed two obviously small intestinal mucosal breaksafter omeprazole treatment. Endoscopic images of small intesti-nal mucosal breaks in the subject post-treatment are shown.

Figure 2 Case 2. A healthy male subject in whom six small intes-tinal mucosal breaks were detected at baseline capsule endos-copy developed 12 small intestinal mucosal breaks afteromeprazole treatment. Endoscopic images of the top two severeintestinal mucosal breaks in the subject at (a) baseline and (b)post-treatment are shown.

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completion of the drug regimen. In this study, mucosalbreaks of the small intestine were defined as lesions withslough surrounded by erythema. The number of small intes-tinal mucosal breaks found at capsule endoscopy was calcu-lated for each subject and compared between baseline andpost-treatment capsule endoscopy.

All capsule endoscopy examinations were completed toevaluate the full length of the small intestine. Throughout thestudy none of the subjects complained about clinical symp-toms, nor suffered any side-effects. Four subjects other thanthe above-mentioned two cases were aged 37.3 ± 3.4 years,one was a pack-a-day smoker and the other three were non-smokers, all were moderate drinkers, and all subjects werewithout GI symptoms. In these four subjects, no small intes-tinal mucosal breaks were found at both baseline and post-treatment capsule endoscopy.

DISCUSSION

ONE HEALTHY SUBJECT in whom small intestinalmucosal breaks was not detected at baseline capsule

endoscopy developed two obviously small intestinal mucosalbreaks after omeprazole treatment. Furthermore, onesubject, who had six small intestinal mucosal breaks at base-line capsule endoscopy, developed 12 small intestinalmucosal breaks after treatment. Surprisingly, the small intes-tinal mucosal injury in the second subject was reversed afterstopping omeprazole treatment 3 weeks later. Case 1 did notundergo follow-up capsule endoscopy. The result showedthat omeprazole might induce and exacerbate small intesti-nal injuries in humans.

In our experience of capsule endoscopy studies, 12% (14/115) of Japanese healthy male volunteers had 2.1 ± 2.7(mean ± SD) small intestinal mucosal breaks. The authorsthought it would not be problematic to singly give PPI to thesubject with several small intestinal mucosal breaks beforethe study. The study was carried out approximately 5 yearsago. Nevertheless, the study was not widely published at thetime due to its small size, and the result was not able to beexplained scientifically. Recently, Wallace et al. reported thatPPI exacerbate NSAID-induced small intestinal injury in therat.10 Their study showed that omeprazole and lansoprazoleimpair the ability to disinfect by PPI-induced low acidgastric environment, and resulted in transubstantiation ofintestinal flora exacerbated NSAID-induced small intestinalinjury. Our results support the novel idea that a similar tran-substantiation of intestinal flora might occur by giving PPI toexacerbate NSAID-induced small intestinal injury inhumans. In addition, the results suggested that PPI not onlyexacerbate, but also induce, the small intestinal injury.

If PPI do exacerbate/induce small intestinal injury, mostcapsule endoscopy studies, as previously mentioned, whichevaluated NSAID-induced small intestinal injury with con-comitant administration of PPI, might have overevaluatedthe frequency of NSAID-induced small intestinal injury.Accordingly, giving PPI to prevent NSAID-induced gastro-duodenal injury should be reconsidered to protect the smallintestine from PPI-induced small intestinal injury. Of course,our study had limitations such as small size study and nocontrol study. However, the two cases clearly showed thepossibility that 2-week administration of omeprazoleinduced and/or exacerbated small intestinal injury. Furtherextensive studies are clearly necessary to determine whethergiving PPI exacerbates and/or induces small intestinal injuryregardless of giving concomitant NSAIDs.

CONFLICTS OF INTEREST

DR FUJIMORI SERVES as interpreter for capsuleendoscopy lectures to Given Imaging Ltd. Dr

Sakamoto has served as a consultant and speaker for AstellasPharma Inc., AstraZeneca, Eisai Co., Ltd, Otsuka Pharma-ceuticals Co., Ltd, Pfizer Japan Inc., and Takeda Pharmaceu-ticals Co., Ltd. Dr Sakamoto has also received grant/researchsupport from Astellas Pharma Inc., AstraZeneca, Eisai Co.,Ltd, Otsuka Pharmaceutical Co., Ltd, Pfizer Japan Inc., andTakeda Pharmaceutical Co., Ltd. Remaining authors declareno conflicts of interest.

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