Development of urinary incontinence after therapy with proton pump inhibitors 199 Klinični primer Development of urinary incontinence after therapy with proton pump inhibitors 1 Unit of Gastroenterology and Hepatology, Division of Paediatrics, University Medical Centre Ljubljana, Ljubljana 2 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana Korespondenca/ Correspondence: Janez eržen, e: janezer1@yahoo.com Ključne besede: gastroezofagealna refluksna bolezen; otrok; inhibitorji protonske črpalke; H2-blokatorji; eozinofilni ezofagitis; na inhibitor protonske črpalke odzivna ezofagealna eozinofilija id 1541 r eprodukcija človeka Klinični primer Zdrav Vestn | maj – junij 2017 | l etnik 86 Development of urinary incontinence in a 7-year old boy after therapy with proton pump inhibitors and complete resolution of his clinicopathologic features of eosinophilic esophagitis after H2-receptor antagonist treatment: A case report Klinični primer razvoja urinske inkontinence pri 7-letnem fantu med zdravljenjem z inhibitorjem protonske črpalke in izginotje kliničnopatoloških znakov eozinofilnega ezofagitisa po zdravljenju z antagonisti H2 receptorjev r ok Orel, 1 Janez eržen, 1 Zvezdana Dolenc Stražar 2 Abstract Background: Several diseases result in profound infiltration of esophageal mucosa by eosinophil- ic granulocites, with gastroesophageal reflux disease (GERD), eosinophilic esophagitis (EoE) and proton-pump-inhibitor-responsive esophageal eosinophilia (PPI-REE) being the most prevalent. Proton-pump-inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Case presentation: A 7-year old Slovenian male presented with a few-month history of chest pain, regurgitation and heartburn. First endoscopy was performed and revealed pronounced longitudinal furrows, and on hystology examination > 70 eosinophils per high power field were found through the entire thickness of epithelium and in the submucosis with eosinophilic microabscess forma- tion. Results of 24-hour pH-monitoring (without impedance monitoring) excluded pathologic acid reflux. All allergy tests were negative. The patient started treatment with proton pump inhibitors (PPIs) for three times, twice with pantoprazole before the endoscopy and once with esomeprasole after it to exclude the diagnosis of GERD and PPI-REE. Urinary incontinence reappeared each time just few days after starting treatment and disapeared few days after stopping it. Therefore, urinary incontinence was considered as a plausible adverse effect of therapy with PPIs. As treatment with PPIs was not tolerated, a therapy with H2-receptor antagonists ranitidine was applied for more than 2 months followed by a second endoscopy. Both symptoms and esophageal eosinophilia completely resolved with ranitidine. The resolution of esophageal eosinophilia in PPI-REE has been atributed to proton pump independent antiinflammatory effects of PPIs. No such effects have been described in H2-receptor antagonists. Conclusions: Two unique phenomena were observed in the pediatric patient with profound esoph- ageal eosinophilia: urinary incontinence as an adverse effect of therapy with PPIs, and complete resolution of esophageal eosinophilic inflammation with typical features of EoE after treatment with H2-receptor antagonists. 200 Zdrav Vestn | maj – junij 2017 | l etnik 86 repr ODuKciJa čl OVeKa Key words: gastroesophageal reflux disease; child; proton pump inhibitors; H2- blocker; eosinophilic esophagitis; ppi- responsive esophageal eosinophilia Citirajte kot/Cite as: Zdrav Vestn. 2017; 86:199–206. prispelo: 5. 5. 2016 Sprejeto: 7. 3. 2017 Izvleček Izhodišča: Mnoge bolezni lahko privedejo do obsežne infiltracije sluznice požiralnika z eozino- filnimi granulociti. Med njimi so najbolj pogoste gastroezofagealna refluksna bolezen, eozinofilni ezofagitis in na inhibitor protonske črpalke odzivna ezofagealna eozinofilija. Prikaz primera: 7-letni fantek iz Slovenije je imel več mesecev trajajoče epizode bolečin v prsnem košu, regurgitacije in pekočega občutka za prsnico. Izvedena je bila prva endoskopija, ki je prikazala izrazite vzdolžne brazde, histološki izvid je prikazal več kot 70 eozinofilcev na polje velike povečave, ki so bili prisotni čez celotno debelino epitela, v submukozi pa so bili pristoni eozinofilni mikroab- scesi. 24-urno merjenje pH (brez merjenja impedance) je izključilo patološki kisli refluks. Vsa aler - gološka testiranja so bila negativna. Bolnik je prejemal terapijo z inhibitorji protonske črpalke trikrat, dvakrat je prejemal pantoprazol pred prvo endoskopijo in enkrat esomeprazol po prvi endoskopiji za izključitev gastroezofagealne refluksne bolezni in na inhibitor protonske črpalke odzivne ezofa- gealne eozinofilije. Pri bolniku se je nekaj dni po začetku terapije z inhibitorjem protonske črpalke vedno pojavila urinska inkontinenca, ki je izginila nekaj dni po prenehanju jemanja zdravil. Zato se je le-ta zdela zelo verjeten stranski učinek zdravljenja. Glede na slabo prenašanje zdravljenja z inhibitorjem protonske črpalke smo uvedli zdravljenje z antagonistom H2-receptorjev ranitidinom. Simptomi in ezofagealna eozinofilija so po zdravljenju z ranitidinom izginili. Dobro znani so protivnetni učinki inhibitorjev protonske črpalke, v smislu resolucije ezofagealne eo- zinofilije pri bolnikih, odzivnih na ezofagealno eozinofilijo po jemanju inhibitorja protonske črpalke. Pri antagonistih receptorjev H2 takšnih učinkov še niso opisali. Zaključek: Pri bolniku smo opazili dva pojava: urinsko inkontinenco kot stranski učinek zdravljenja z inhibitorji protonske črpalke in popolno remisijo ezofagealnega eozinofilnega vnetja po zdravlje- nju z antagonisti H2-receptorjev. 1 Introduction The range of GERD prevalence esti- mates in adults is 8.8 %-25.9 % in Euro- pe and is considerably lower than that in the population of children over 1 year of age (1). Until mid-nineties, infiltration of esophageal mucosa with eosinophils has been regarded as hallmark of ga- stroesophageal reflux disease (GERD) as several studies revealed a correla- tion between the density of esopha- geal eosinophilia and esophageal acid exposure  (2,3). Esophageal eosinophilic infiltration(EEI) is observed in several conditions, including gastroesophage- al reflux disease(GERD), eosinophilic esophagitis(EoE), celiac disease, infec- tions, Crohn’s disease, achalasia, drug hypersensitivity, vasculitis and graft-ver- sus-host disease (4). Observations that a proportion of these patients who did not respond to anti-secretory therapy got into remission when put on the elemen- tal formula eliminating all food antigens lead to a discovery of a novel disease, EoE (5). According to current guidelines, EoE is defined as a chronic, immune/an- tigen-mediated esophageal disease cha- racterized clinically by symptoms related to esophageal dysfunction and histolo- gically by esophageal infiltration with at least 15 eosinophils per high-power field(HPF)  (6,7). Immune reactions to food antigens, and in some cases maybe also to aeroalergens, are regarded to play crucial role in its development  (6,8,9). For confirming a diagnosis of EoE, other diseases that may result in esophageal eosinophilia, especially GERD, should be excluded. While previous guidelines required exclusion of GERD by nega- tive results of esophageal pH-monito- ring (10), this is not necessary any more, as both diseases may be present simul- taneously. Consequently, absence of re- Development of urinary incontinence after therapy with proton pump inhibitors Development of urinary incontinence after therapy with proton pump inhibitors 201 Klinični primer sponse – both symptomatic and histo- logic – to acid suppression with proton pump inhibitors (PPIs) became a re- commended method for discrimination between EoE and GERD (6,7). However, a proportion of patients with apparent clinical and histologic signs of EoE and normal esophageal acid exposure (ab- sence of GERD) get into remission with PPI therapy  (11,12). This recently reco- gnized entity of esophageal eosinophilia is defined as PPI-responsive esophageal eosinophilia (PPI-REE)  (6,7). Retro- spective studies have demonstrated that 39 % to 71 % of children and adults with EEI have PPI-REE (13). At the moment, it is not clear whether it represents a part of EoE spectrum, GERD spectrum or a completely independent disease. More than forty patients with EoE were treated at our Pediatric Gastroenterology Unit in recent years, as a majority of patients with EoE in our country are treated at a tertiary level hospital. It has been proposed that anti-in- flammatory effects of PPIs in addition to their inhibition of acid secretion may be involved in PPI-REE (14-19). To the best of our knowledge, resolution of extreme esophageal eosinophilia including other typical hallmarks of EoE with H2-recep- tor antagonists has never been reported. Therefore, we present a case of a boy with extensive esophageal eosinophilia in whom therapy with PPIs was impos- sible due to a peculiar adverse reaction, urinary incontinence, and was therefore treated with alternative anti-secretory drug, H2-receptor antagonists, and got into complete clinical and histologic re- mission. 2 Case Presentation A 7-year-old white Slovenian male presented with a history of approxima- tely one year of chest pain, regurgitation and heartburn with worsening in the last few months. In the past, he had several episodes of laryngitis and pneumonia that remained etiologically unexplained despite comprehensive diagnostic wor- kout by pulmologist, allergologist and otorhynolaryngologist. Family history was negative for gastrointestinal disea- ses but positive for allergic diseases (his father has hay fever). According to the symptoms sugge- stive for GERD, one-month therapeutic trial with PPI (pantoprazole 1 mg/kg) was prescribed by the boy’s primary pe- diatrician. Symptoms improved, howe- ver, approximately a week after starting therapy, nighttime and daytime urinary incontinence appeared, with the boy re- porting loss of feeling for the fullness of the bladder and urge for urination. As he had no previous history of urinary incontinence, the parents attributed in- continence to the adverse effects of pan- toprazole and stopped the medication. Few days after cessation of the therapy incontinence disappeared, but soon after GERD symptoms reappeared. Thus, the boy was referred to the Pediatric Gastro- enterology Unit. Considering good symptomatic re- sponse to the short treatment and no data in the literature about urinary in- continence being an adverse effect of PPIs, therapy with pantoprazole was reconsidered. Again, a week after pan- toprazole introduction urinary inconti- nence reappeared and parents stopped the therapy with the disappearance of incontinence few days after that. Becau- se of persistent chest pain, regurgitation and heartburn the boy was admitted to the hospital 2 months later for esopha- gogastroduodenoscopy under sedation. Endoscopy was performed which reve- aled pronounced longitudinal furrows but no erosions of the esophagus, while stomach and duodenal mucosa appea- Development of urinary incontinence after therapy with proton pump inhibitors 202 Zdrav Vestn | maj – junij 2017 | l etnik 86 repr ODuKciJa čl OVeKa Figure 1: esophageal biopsy of our patient before treatment with H2-receptor antagonists, eosin hematoxylin staining. High number of eosinophils (1) through entire thickness of esophageal epithelium with degranulation and eosinophilic microabscesses (3), basal cell hyperplasia and elongation of papillae (2). red normal. A diagnosis of EoE was su- spected and biopsies were taken from the duodenum, stomach and esophagus, two from the distal and two from the proximal third. On histology examina- tion of the esophageal biopsy specimen, eosinophils were prominent through the entire thickness of the epithelium and eosinophils were also found in the submucosa with peak eosinophil count of 70 eosinophils per HPF. In addition, eosinophilic microabscesses in the sur- face layers, degranulation of eosinophils, basal cell hyperplasia and elongation of lamina propria papillae were confirmed (Figure 1). With strong suspicion of EoE, the boy was referred to an allergologist. Labora- tory testing revealed slightly elevated se- rum immunoglobulin E level (81 kU/L), however specific IgEs, as well as skin prick and patch tests for food allergens were negative. Because of the history of urinary incontinence during PPI the- rapy, a comprehensive nephrologic and urologic workout was performed. All examinations were normal, including abdominal and urinary tract ultrasound, urinalysis and kidney function tests. No invasive urologic procedures were per- formed. In accordance with the recommen- dations, a two-month treatment with PPI was prescribed to exclude PPI-REE. However, despite the use of esomepra- zole instead of pantoprazole, a week af- ter the beginning of treatment urinary incontinence reappeared, and the tre- atment was stopped. Nine months after PPI treatment, a 24-hour esophageal pH-monitoring (without impedance monitoring) excluded pathologic acid reflux (GERD) as reflux index was 3.6 % (normal <5 %) and DeMeester score was 12.59 (normal 14.7). As urinary inconti- nence occurred after the treatment with two different types of PPIs, a treatment with ranitidine 75 mg/day was proposed. The patient had no urinary incontinence and his esophageal symptoms resolved completely. A control endoscopy was performed four months after the first one while the patient was treated with H2-receptor antagonist for more than two months. Macroscopic appearance of the esopha- gus as well as of the rest of the upper GI tract was completely normal. Four biopsy specimens of the proximal and distal esophagus revealed changes su- ggesting GERD, while no changes su- ggesting esophageal eosinophilia were found (there were no eosinophils in the epithelium or in the submucosa, no microabscesses in the surface layers and no degranulation of eosinophils was fo- und). The peak eosinophil count was < 5 per HPF . The patient continues with H2- -blocker therapy and is symptom free. Development of urinary incontinence after therapy with proton pump inhibitors Development of urinary incontinence after therapy with proton pump inhibitors 203 Klinični primer Figure 2: control esophageal biopsy of our patient after treatment with H2-receptor antagonists, Kreyberg staining. There are no eosinophils, no microabscesses, basalification is absent. 3 Discussion The presented case is interesting for two reasons. The first is day- and night- -time urinary incontinence appearing for three times only a few days after starting PPI therapy and disappearing shortly after its cessation, regardless of whether pantoprazole or esomeprazole was used. The patient had never experi- enced urinary incontinence before and complete diagnostic workout for poten- tial urologic or neurologic disorders was negative. Although potential “placebo” adverse reaction to drugs could be a pos- sible explanation, it does not seem very probable, as there was no incontinence during a several-month therapy with H2-receptor antagonists ranitidine, and the boy was much too young to discri- minate between pharmaceutical aspec- ts of PPIs and H2-receptor antagonists. Therefore, urinary incontinence could be considered as a plausible but extre- mely rare adverse effect of therapy with PPIs. PPIs have proven to have a very fa- vorable safety profile. It is known that they can cause dark-colored urine, inter- stitial nephritis, urinary tract infection and frequent urination  (20-22), but to the best of our knowledge and available data, this is the first report of a possible association between urinary incontinen- ce and treatment with PPIs. The under- lying mechanism remains unexplained. It has been revealed that both gastric and non-gastric type of hydrogen/po- tassium adenosine triphosphatase (H+/ K+-exchanging ATPase) is present in various tissues including cochlear late- ral wall, polymorphonuclear leukocytes, kidney, brain, placenta and colon but its functional role has not been well studi- ed (14,23,24). However, it is our second observation in this patient, the disappearance of both symptoms and esophageal eosinophi- lia with H2-receptor antagonist thera- py that may be even more interesting. Esophageal eosinophilia is present in many different diseases of the esopha- gus, with GERD, EoE and PPI-REE be- ing the most prevalent ones. Patient’s symptoms were suggestive of GERD and they always practically disappeared with a short-term anti-secretory therapy. However, the symptoms of EoE, especial- ly in young children, can be very atypical and practically indistinguishable from GERD symptoms (25,26). In addition, all other features, such as acid exposure wi- thin normal limits during 24-hour pH- -monitoring, endoscopic appearance of the esophagus with longitudinal furrows and particularly histology findings, favo- red the diagnosis of EoE. On the other side, EoE is regarded an immune aller- gen-driven disease. With the exception of a weak family and potential personal (recurrent laryngitis) history as well as Development of urinary incontinence after therapy with proton pump inhibitors 204 Zdrav Vestn | maj – junij 2017 | l etnik 86 repr ODuKciJa čl OVeKa slightly elevated immunoglobulin E le- vel, there was no evidence supporting such etiology. All specific allergen hyper- sensitivity tests were negative and both clinical and histologic remission was achieved without therapies recognized as effective in EoE, elimination diet or steroids. Since recognition that a subgro- up of patients with typical features of EoE without evidence of GERD achi- eve clinicopathologic remission with PPI treatment, this has been defined as PPI-REE  (5,6). In addition to the inhibition of the proton pump in the parietal gastric cells, a number of po- tential direct anti-inflammatory effects of PPIs have been suggested (16-19). It was demonstrated that PPIs inhibit the secretion of eotaxin-3, the most po - tent chemo-attractant for eosinophils, by esophageal epithelial cells (15). PPIs have been found to have anti-oxidant properties and direct effects on gra- nulocytes, endothelial and epithelial cells that might prevent inflammation and they may reduce esophageal eosi- nophilia, at least in part, by inhibiting VCAM-1 production by esophageal endothelial cells  (18). They inhibit the production of pro-inflammatory cyto- kines that recruit inflammatory cells to diseased tissues, block IL-8 production, possibly by interfering with the nuclear factor-κB and they decrease levels of a number of proinflammatory cytokines including IL-6, IL-8 and tumor necrosis factor-α (18). The possibility that three very short treatment courses with PPIs, with two of them even before the first endosco- py revealing profound esophageal eosi- nophilia, played an important role in our case is practically negligible. Therefore, the remission should be attributed to the therapy with ranitidine. However, we could not find any evidence of anti-in- flammatory properties of H2-receptor antagonists on esophageal mucosa other than their acid-secretion inhibition in the literature. This brings us to reconsider the role of GERD, eventually even the one not reaching the arbitrarily set upper limits of normal esophageal acid exposure, as an important factor in the development of EoE. Several mechanisms which may predispose GERD patients for the de- velopment of EoE have been described, such as acid peptic damage to the tight junctions between epithelial cells affec- ting permeability of the esophageal epi- thelium for allergens  (27,28), as well as enhancement of expression of adhesion molecules and production of inflamma- tory mediators and cytokines that attract and recruit inflammatory cells including eosinophils in the esophagus (29,30). In conclusion, the presented case su- pports the potential importance of ga- stroesophageal reflux in the pathogene- sis of EoE. The relations between GERD and EoE are only partially understood and worthwhile to be studied intensively in the future. 4 Consent Written informed consent was obta- ined from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. 5 Authors’ contributions RO and JE carried out the clinical and laboratory evaluation of the pati- ent, esophagogastroduodenoscopy and drafted the manuscript. ZDS carried out the histopathological examination of the biopsy specimen and co-drafted the ma- nuscript. 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