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Fetal and Pediatric Pathology, Early Online:1–4, 2014 Copyright C Informa Healthcare USA, Inc. ISSN: 1551-3815 print / 1551-3823 online DOI: 10.3109/15513815.2014.970262

ARTICLE Co-Occurrence of Celiac Disease and Ulcerative in a 12-Year-Old Girl

Orjena Zaja,ˇ 1 Maja Popovic,´ 1 Tatjana Lesar,1 Ivana Pavic,´ 2 and Iva Hojsak3

1Department of Pediatric , and Nutrition, Clinical Hospital Center Sestre milosrdnice, Croatia, Zagreb, Croatia; 2Department of Pathology, Clinical Hospital Center Sestre milosrdnice, Croatia, Zagreb, Croatia; 3Children’s Hospital Zagreb, Zagreb, Croatia

Celiac disease (CD) and inflammatory bowel diseases (IBD) are separately well-described entities, but the co-occurrence in children has been very rarely reported until today. According to the litera- ture, this case about 12-year-old girl would be the fifth case ever published about co-occurrence in children. We presume that there should be a higher comorbidity prevalence than that described. Distinguishing both diseases in one patient could be difficult due to the overlapping symptoms, but it is very important considering completely different therapeutic approaches. Keywords: celiac disease, IBD, ulcerative colitis, co-occurrence,

For personal use only. INTRODUCTION Celiac disease (CD) and inflammatory bowel diseases (IBD) are separately well described entities. CD is one of the most common lifelong disorders, affecting approx- imately 1% of the general population [1, 2]. The comorbidity between CD and other au- toimmune disorders has been clearly established [3]. However, the associated occur- rence of CD and ulcerative colitis (UC) in children has been very rarely reported until today, referring only to four case reports with confirmed diagnosis [4]. Distinguishing both diseases in one patient could be difficult due to the overlapping symptoms, but it is very important considering completely different therapeutic approaches. We report our experience in a 12-year-old girl with co-occurrence of CD and UC. Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Zagreb on 10/30/14

CASE REPORT A 12-year-old girl was admitted due to chronic , looking chronically ill and se- riously underweight (BMI 12.6 kg/m2, Z-score –3.7). She complained about diarrhea lasting for 3 weeks, without vomiting and loss of appetite. Laboratory testing revealed , mildly elevated sedimentation rate (27 mm/h) and C-reactive protein (6.3 mg/l), lower albumins (32.8 g/l) and very low serum vitamin D3 levels

Received 28 May 2014; Revised 23 September 2014; accepted 24 September 2014. Address correspondence to Dr Maja Popovic,´ Clinical Hospital Center Sestre milosrdnice, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Vinogradska 29, Zagreb, Croatia, Zagreb, 10000 Croatia. E-mail: [email protected]

  Orjena Zajaˇ et al.

Figure 1. Duodenal mucosa; partial villous atrophy, increased inflammatory infiltrate in lamina propria and intraepitheliosis in “crescendo” pattern (H&E 100×); inset: immunohistochemistry (CD3 × 200).

(23 nmol/l). The benzidine was positive. The results of other laboratory tests were in reference intervals. Infective etiology was excluded. Considering the high values of IgA anti-tissue transglutaminase antibodies (anti- For personal use only. TG2; 163.3 RU/ml), and IgG antibodies to deamidated gliadin (anti-DGP; 41 RU/ml), we performed an esophagogastroduodenoscopy (EGD) along with the duodenal that revealed histopathological changes typical for CD (Marsh IIIA) (Figure 1). A gluten-free diet (GFD) was initiated. In the period that followed bloody, loose stools appeared. Repeated microbiological testing re-excluded infective etiology. was performed due to the significantly elevated fecal (FC, 1296 μg/g). The endoscopic, as well as the histopathological findings of colon were typical for UC (Figure 2). MR enterography findings confirmed the UC. After the defini- tive diagnosis of UC (Pediatric UC Activity Index – PUCAI score 60), along with the CD, and therapy was started, and GFD was continued. Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Zagreb on 10/30/14 The patient reacted rapidly to the treatment. Her stools normalized in a fewdays. She gained some weight and strength. At discharge her clinical feature was normal (PUCAI score 5). The clinical course in the following 12 months showed excellent phys- ical condition of the patient. After discontinuation, there were no signs of UC relapse, so we continued only with 5-ASA and a GFD. Follow-up laboratory test- ing revealed a significant decrease of anti-TG2 levels (50.7 RU/ml), and normalization of all laboratory findings. The patient continued to gain weight and on her last visit her body weight was 43.2 kg (BMI 18.1 kg/m2; Z-score –0.25).

DISCUSSION In 2005, when Yang [5] published the first database cohort study that referred to co-occurrence of CD, and IBD in adult patients, there have been only a few isolated

Fetal and Pediatric Pathology Co-Occurrence of CD and Ulcerative Colitis (UC) in a 12-Year-Old Girl 

Figure 2. Colon mucosa; distortion of crypt architecture, of crypts (cryptitis), frank crypt abscesses and inflammatory cells in the lamina propria (H&E 100×), inset: depletion of sur- face mucous secretion (H&E 200×).

For personal use only. reports about this comorbidity. Results of the study showed that in 10 out of 455 patients with CD, IBD was confirmed (5 UC and 5 Crohn’s disease). They proved that IBD is more common in patients with CD than in the general population. The first case report regarding the associated occurrence of CD and UC in children was published in 1999 by Day and Abbott [6]. They described a 7-year-old New Zealand girl with simultaneous presentation of CD and UC with severe clinical course. Over an 18 month following discharge, she required frequent courses of corticosteroid ther- apy and initiation of in addition to ongoing measalazine therapy. In 2004, Sykora [7] described a case of a 15-year-old patient with simultaneous presentation of CD, UC and autoimmune thyroiditis and favorable clinical course over a 1-year follow- up period. The third case was different. A 7-year-old boy was diagnosed with CD,UC Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Zagreb on 10/30/14 and primary sclerosing cholangitis virtually simultaneously, which led to a more ag- gressive phenotype of IBD, that in turn required an immunomodulatory therapy [8]. The fourth case report, published by Cheng [9] described an 8-year-old boy withahis- tory of anemia and failure to thrive who presented with bloody diarrhea. Eventually, CD and UC colitis were diagnosed. This male patient as well as, the female patient in ourcasereport,hadabenigndiseasecourseonaGFDandmesalaminetherapyfor 2 years after corticosteroid tapering with no need for immunomodulators. In our case, the patient who was diagnosed with CD had high levels of FC, accom- panied with persisting diarrhea, regardless of following a GFD. This led us to suspect an IBD associated disease. Following a confirmative colonoscopy diagnosis of UC, we prescribed prednisone and mesalazine therapy in continuation of GFD. A rapid re- sponse to the therapy was observed through normalization of laboratory tests and stools, weight gain and a favorable clinical course even after the discontinuation of

Copyright C Informa Healthcare USA, Inc.  Orjena Zajaˇ et al.

corticosteroid therapy. There was no need for immunomodulatory therapy over the 12 months following discharge. Recently, a case-control study conducted at two tertiary referral hospitals in the USA among adults with CD and IBD has been published. Results showed that pan- colitis was more common in celiac – UC patients when compared with controls, with a trend towards increased use of immunomodulators. On the other hand, coexisting CD did not influence natural history of Crohn’s disease. These results suggest more aggressive phenotype in case of CD and UC co-occurrence [4]. In conclusion, due to the high incidence of each of these diseases, as well as pos- sibility of shared genetic risks, we assume there should be higher comorbidity preva- lence than those described in the literature [10]. Further studies are required to assess the prevalence of this association in children. Whether the shared genetic risk between both diseases predisposes a more aggressive phenotype of IBD remains to be seen. We hope this report will bring new cases to light and give us more information about phenotype differences in cases of CD and UC co-occurrence which would lead tofur- ther discussions about optimal diagnostic and therapeutic approaches.

Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible forthe content and writing of the paper.

REFERENCES [1] Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for Pediatric Gastroenterology, Hep- atology, and Nutrition Guidelines for the Diagnosis of . J Pediatr Gastroenterol Nutr 2012;54:136–160. [2] Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of celiac disease over time. Aliment Pharmacol Ther 2007;26:1217–1225.

For personal use only. [3] Fasano A. Systemic autoimmune disorders in celiac disease. Curr Opin Gastroenterol 2006;22(6):674–679. [4] Oxford EC, Nguyen DD, Sauk J, et al. Impact of coexistent celiac disease on phenotype and natural history of inflammatory bowel disease. Am J Gastroenterol 2013;108(7):1123–1129. [5] Yang A, Chen Y, Scherl E, et al. Inflammatory bowel disease in patients with celiac disease. Inflamm Bowel Dis 2005;11:528–532. [6] Day AS, Abbott GD. Simultaneous presentation of coeliac disease and ulcerative colitis in a child. J Paediatr Child Health 1999;35:204–206. [7] Sykora J, Varvarovska J, Pomahacova R, et al. Simultaneous presentation of coeliac disease, ulcerative colitis and autoimmune thyroidits in childhood. J Clin Gastroenterol 2004;38:613–614. [8] Cadahia V, Rodrigo L, Fuentes D, et al. Celiac disease, ulcerative colitis and primary sclerosing cholangitis in one patient: a family study. Rev Esp Enferm Dig 2005;97:907–913. [9] Cheng SX, Raizner A, Phatak UP, et al. Celiac disease in a child with ulcerative colitis: A possible Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Zagreb on 10/30/14 genetic association. J Clin Gastroenterol 2013;47:127–129. [10] Glas J, Stallhofer J, Ripke S, et al. Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis with IL23R and suggest a common genetic background for ulcerative colitis and celiac disease. Am J Gastroenterol 2009;104(7):1737–1744. doi: 10.1038/ajg.2009.163

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