| Abstract|| |
Aims: Duodenal nodularity is an uncommon endoscopic appearance of numerous visible mucosal nodules in the proximal duodenum. In this retrospective study we aimed to determine the clinical significance and histopathologic features of duodenal nodularity in children. Materials and Methods: The medical records of the patients who were defined to have duodenal nodularity by endoscopy were reviewed. Statistical Analysis Used: The data were expressed as mean ± SD and percentages (%). Results: Seventeen patients with endoscopically defined duodenal nodularity were chosen. The mean age at diagnosis was 12.1 years (range: 6-17 years), 9 males. Abdominal pain (47%) was the most common clinical symptom and antral nodularity (41%) was the most common endoscopic finding in children with duodenal nodularity. Histopathologic evaluation of duodenal nodules revealed chronic inflammation in all patients, increased intercryptal and intraepithelial numbers of eosinophils in 70.5%, and villous atrophy in 47% of patients. Giardia infestation was demonstrated in 6 patients by histologic examination and/or Giardia lamblia-specific antigen positivity in stools. The clinical diagnoses of the patients have shown variations, such as celiac disease, giardiasis, secretory IgA deficiency, and Helicobacter pylori gastritis, and some of them were associated with the others. Conclusions: Although the endoscopic appearance is similar, clinical spectrum and pathologic features are not so similar and there are no specific histomorphologic findings for nodularity. The most demonstrative findings we observed in children were increased lymphocyte and/or eosinophil infiltration in the duodenal mucosa. We suggested that care should be taken in the evaluation of microbiological and immunologic etiologies causing this prominent inflammatory reaction.
Keywords: Celiac disease, child, duodenal nodularity, giardiasis, Helicobacter pylori, nodular lymphoid hyperplasia
|How to cite this article:|
Gönül ÇD, Bilge C, Gazi KA, Filiz K. Duodenal nodularity in children: A clinical and pathologic study of 17 cases. Indian J Pathol Microbiol 2011;54:312-7
|How to cite this URL:|
Gönül ÇD, Bilge C, Gazi KA, Filiz K. Duodenal nodularity in children: A clinical and pathologic study of 17 cases. Indian J Pathol Microbiol [serial online] 2011 [cited 2013 May 22];54:312-7. Available from: http://www.ijpmonline.org/text.asp?2011/54/2/312/81611
| Introduction|| |
Nodular duodenum is endoscopically characterized by numerous visible mucosal nodules in the proximal duodenum. The size of the nodules ranges from 0.2 to 0.5 cm in diameter. This nodular pattern is not seen commonly and the exact etiology is not known. They are supposed to be caused by duodenal inflammation. Infectious agents, environmental, nutritional, or other individual factors might be the causative factors contributing to a nodular duodenum. ,
Duodenal nodularity is also an uncommon endoscopic finding in children. Clinically, we observe quite a few patients with diffuse duodenal nodularity in routine. In this retrospective study we aimed to define the frequency, clinical significance, and histopathologic features of duodenal nodularity in pediatric patients undergoing upper endoscopy. To the best of our knowledge, no study of clinical, endoscopic, and pathologic features of nodular duodenum has been reported in the pediatric population.
| Material and Methods|| |
We reviewed the endoscopic records of the patients who underwent upper gastrointestinal endoscopy due to various gastrointestinal complains or intestinal biopsy between 2003 and 2009. We identified 20 children with duodenal nodularity via analyzing their endoscopic records. These patients were studied retrospectively with detailed review of medical records for age, sex, type and duration of symptoms, final diagnosis, associated diseases and histopathologic features. Hemoglobin, mean cell volume, serum ferritin, albumin, immunoglobulins, acute phase parameters, celiac autoantibodies, and stool analysis for ova-parasites and ELISA for Giardia lamblia-specific antigen tests were also recorded at the time of diagnosis. None of the patients had associated end-stage renal disease and malignancy.
Duodenal nodularity is defined as the presence of multiple, discrete, 0.2-0.5 cm in diameter, mucosal nodules in the proximal duodenum visible on endoscopic examination [Figure 1]. In addition, any other abnormalities in the esophagus, corpus, antrum, or duodenum was recorded. The biopsies had been taken from the nodular areas of the duodenum in 17 patients and from antrum in 11 patients by biopsy forceps.
|Figure 1: Endoscopic view of duodenal nodularity. Multiple small nodular lesions at the duodenal bulb|
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The histologic evaluation was performed on hematoxylin-eosin and Periodic acid-Schiff (PAS)-alcian blue-stained samples by a single pathologist who knew the endoscopic appearance of the duodenum but unaware of the patients' history, clinical findings, and the results of previous investigations.
The villous/crypt ratio was analyzed on a 0-4 scale, which can be defined as normal (0) or one of 4 grades of villous atrophy.  Intraepithelial lymphocytes (IELs) were counted on the tip of the villi in areas distant from lymphoid follicles. Both chronic and acute inflammation were graded as follows: 0, normal; 1, mild; 2, moderate; 3, severe, modified by Guarder et al.  Nodular lymphoid hyperplasia (NLH) is defined as heavy infiltration with apparent lymphoid follicles with germinal center formation. Gastric mucin-cell (foveolar) metaplasia is defined as the presence of surface epithelial cells containing PAS-positive neutral mucin and lack of a brush border. Brunner's gland hyperplasia (BGH) was considered to be positive when prolapment of Brunner's glands to the mucosa is seen. Heterotopic gastric mucosa is defined as the presence of gastric glands containing parietal cells and often chief cells. Eosinophils identified by hematoxylin/eosin stain were counted at least one high-power field (hpf) area on fields of maximum eosinophil infiltration. Abnormal eosinophilic infiltration is defined as the presence of >20 intramucosal eosinophils/hpf with accompanying infiltration to the surface and/or to crypts.
The data are expressed as mean ± SD and percentages (%).
| Results|| |
From February 2003 through March 2009, approximately 1040 upper gastrointestinal tract endoscopies were performed in our clinic. Nodular duodenum was demonstrated in 20 children (1.9%) endoscopically. Of the 20 cases, 3 were excluded because of unavailable duodenal tissue samples. Seventeen patients were enrolled to the study [Table 1]. There were 9 male (53%) and 8 female (47%) patients with an age range of 6-17 years (mean 12.1 ± 2.7 years).
|Table 1: Summary of patients details, clinical presentations, endoscopic and histopathologic evaluations|
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The most common presenting symptom was abdominal pain, seen in 8 (47%) patients, 37.5% of them were described at epigastric localization [Table 2]. The duration of pain varied from 0.7 to 24 months (mean 10 ± 7.3 months), commonly intermittent and progressive.
Antral nodularity (41%) was the most common endoscopic finding in children in addition to duodenal nodularity. Whole mucosal erythema was seen in 1 (6%) patient. Stool examination was performed in 11 children for G. lamblia-specific antigen and 5 were found to be positive. The clinical and laboratory features and endoscopic findings of patients are shown in [Table 1].
Histopathologic evaluation of duodenal nodules revealed chronic inflammatory infiltration ranging from mild to severe in all patients (100%). Six of them were grade 1, 4 grade 2, and 7 grade 3 chronic inflammation with hyperplasic lymphoid follicles that were suggestive of NLH. Eight biopsies showed varying degrees of villous atrophy, 4 of them (3 were severe) were diagnosed as celiac disease with compatible clinics and celiac autoantibody tests. In 12 of 17 biopsies (70.5%), an increased number of eosinophils was observed in intercryptal and intraepithelial area, but there was no correlation between increased number of eosinophils and G. lamblia positivity [Table 1]. Besides, in these patients investigation of stools for other parasites was negative. Gastric metaplasia and BGH were not prominent in our patients. The histopathologic findings of the patients are shown in [Table 3].
G. lamblia trophozoites were demonstrated on the surface of the duodenal mucosa on histologic examination in 3 patients [Figure 2]. Two of them were found positive for G. lamblia-specific antigen on stool examination. No cases of other protozoal pathogens, such as Cryptosporidia, were identified by light microscopy.
|Figure 2: Groups of Giardia lamblia overlying duodenal surface. (Gomori's trichrome, ×400)|
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None of them had mucosal erosion or ulceration. Plasma cells were easily identified in lamina propria in all biopsies, except that the biopsy of 1 patient with IgA deficiency showed a marked decrease in mucosal plasma cells. Well-formed granulomas or small collections of histiocytes were not recognized. Hyperplastic or adenomatous polyps or any other malign or premalign histopathologic changes were not identified.
Gastric biopsy samples obtained from 11 patients and 9 of them had Helicobacter pylori on antral mucosal surface [Table 1]. In 6 cases with antral nodularity on endoscopy we observed NLH and H. pylori on antral mucosa. Three of them had also NLH on duodenal biopsy.
| Discussion|| |
Duodenal nodularity is an uncommon endoscopic finding, especially in children and we know little about the pathogenesis of the nodularity. In previous studies, nodular duodenum was seen in certain diseases, such as hypogammaglobulinemia, end-stage kidney disease, and celiac disease. ,,, Some studies also had focused on the association between this finding with some agents, such as H. pylori and G. lamblia. ,
In 1980, Langkemper et al,  reported radiologic and endoscopic findings of 22 adult patients with nodular appearance of duodenum. They histopathologically showed that all the patients had the characteristic appearance of duodenal bulb caused by heterotopic gastric mucosa except one. Fernandez-Melone et al,  reported that the incidence of nodular duodenitis was 4% in adult population. They speculated that this appearance was visually distinct, morphologic variant of nonspecific duodenitis. Triadafilopoulos  reported the clinical and histopathologic features of 83 male veterans (prevalence 4%) with nodular duodenum and concluded that nodular duodenum might be a variant of duodenitis, probably related with acid-peptic disease and that histopathologic features were variable. All these study groups included adult patients and the prevalence was suggested to be approximately 4%. We observed quite a few patients with nodular duodenum, and the frequency was 1.9% in our pediatric population.
It was reported previously that nodular duodenum was one of the endoscopic markers of celiac disease in adults. , In our study there were 4 celiac patients with duodenal nodularity and the frequency was 4.6% in pediatric celiac patients who were followed-up in our department. So, it may be postulated that, this appearance can be an endoscopic marker of celiac disease also in children.
In hypogammaglobulinemic disease, patients have an increased risk of infections, predominantly originated in upper and lower gastrointestinal tracts. The intestinal histopathologic features of the immunodeficiency syndromes are variable but NLH and villous atrophy are described as the most frequent findings.  In a previous study, 32 adult patients with common variable immune deficiency underwent gastrointestinal endoscopy and 31% of them had nodular duodenum.  Histologic assessment of duodenal specimens revealed villous atrophy and NLH besides normal histology of duodenal mucosa. We have 2 patients with selective IgA deficiency (patient 6 and 17). The histologic examinations of the duodenum revealed marked lymphocytic inflammation in both, with NLH in one and villous atrophy in the other. Although G. lamblia trophozoides were detected in biopsy in one patient, cysts and antigens of this parasite were found in stool samples of the others. IgA antiendomysial antibodies and IgA and IgG tissue transglutaminase (tTG) antibodies were not compatible with celiac disease for these patients. H.pylori was also observed on antral gastric mucosa histopathologically. They were treated for G. lamblia and H. pylori. Although abdominal pain and diarrhea were resolved in patient 6, there was no difference in the nodular appearance and histopathologic findings of the duodenum, in the second endoscopy after 1 year.
It has been suggested that NLH represents a local immune response to antigens of the microorganisms in immunodeficient patients whose intestine is exposed to bacterial overgrowth.  On the other hand, NLH is not a genuine finding in immunodeficient patients. It has also been diagnosed in giardiasis without immunodeficiency, intestinal bacterial overgrowth, and celiac disease in adults. ,,
In the present series there were 6 patients with giardiasis. Two of them had IgA deficiency as mentioned above, and the others had normal gammaglobulin levels. Although routine stool examinations might fail in detecting G. lamblia trophozoites or cysts, enzyme-linked immunosorbent assay (ELISA) procedures for the presence of G. lamblia antigen in the stool are reported to be more sensitive.  In our study, giardiasis was diagnosed by detecting G. lamblia antigen in stool by ELISA in 5 patients and it was also demonstrated on duodenal mucosa in 3 patients. Although there are no specific histopathologic findings of Giardia infestation, various degrees of villous atrophy, increased intraepithelial lymphoid count, and NLH were previously described. ,, We observed increased lymphoid infiltration in 5 patients, villous atrophy in 4 (1 also celiac, patient 7), and NLH in 3 patients.
NLH, which is defined by heavy infiltration of lymphocyte-resembling lymphoid follicles with germinal center formation, might be a causative explanation of duodenal nodularity. However, our histopathologic findings revealed that NLH was observed in 41% of patients, not all of them, despite the same appearance in endoscopic examination. On the other hand, increased IEL infiltration and chronic inflammation were observed in higher frequencies (59% and 100%, respectively). Besides the chronic inflammation, we noticed that, our study population had increased eosinophilic infiltration in the duodenal mucosa. Although it was not high enough to conclude as eosinophilic gastroenteropathy,  70.5% of our patients had heavy infiltration of eosinophils in the duodenum. Recent studies showed that eosinophilic counts can be naturally higher in pediatric population compared with adults.  Our study group consists of pediatric population, which may account for the resultant eosinophilia or else geographic differences may be the reason. Further investigations are needed to conclude this statement.
The last of our impressing data were that 7 patients had also antral nodularity on endoscopic examination. We obtained gastric biopsy samples from 11 patients (6 of them had antral nodularity) and found that 9 of them had H. pylori on antral mucosa. In 6 patients who had antral nodularity, we observed NLH and H. pylori on antral mucosa. It was suggested previously that there was a very close relationship between H. pylori infection and antral nodular gastritis, particularly in children. , We also see antral nodularity in children with H. pylori gastritis frequently in our practice, but not duodenal nodularity.
Li et al.  studied 86 patients with nodular duodenitis to investigate the association between H. pylori infection, gastric metaplasia, and nodular duodenitis. They found that the prevalence of H. pylori infection and gastric metaplasia were 58.1% and 57% in nodular duodenitis, respectively. In successfully treated patients, gastric metaplasia was significantly regressed but they found no change in the appearance of the endoscopic duodenal nodularity. They suggested that H. pylori infection was related to the gastric metaplasia, but not to the presence of nodularity in duodenum. Gastric metaplasia was not a prominent finding in our study as expected. And it is not clear that H. pylori gastritis (with or without antral nodularity) was related with nodular duodenitis or their relationship was coincidental.
In summary, we reported our clinical and pathologic findings of a series of 17 pediatric patients with nodular duodenum. Although the endoscopic appearance of duodenum is similar, distinct clinical entities and pathologic features can cause this. There are no specific histomorphologic findings for nodularity. We observed in children that the most demonstrative histomorphology is increased lymphocyte and eosinophil infiltration in duodenal mucosa. Although additional studies with larger patient groups will be needed to confirm our findings, care should be taken in the evaluation of microbiological and immunologic etiologies causing this prominent inflammatory reaction.
| References|| |
|1.||Fernandez-Melone JH, Triadafilopoulos G, Chandler JG. Nodular duodenitis and single duodenal nodules. Am Surg 1990;56:175-7. |
|2.||Triadafilopoulos G. Clinical and pathologic features of nodular duodenum. Am J Gastroenterol 1993;88:1058-64. |
|3.||Drut R, Rúa EC. Histopathologic diagnosis of celiac disease in children without clinical evidence of malabsorption. Int J Surg Pathol 2007;15:354-7. |
|4.||Guarner J, Herrera-Goepfert R, Mohar A, Sanchez L, Halperin D, Ley C, et al. Interobserver variability in application of the revised Sydney classification for gastritis. Hum Pathol 1999;30:1431-4. |
|5.||Luzi G, Zullo A, Iebba F, Rinaldi V, Sanchez Mete L, Muscaritoli M, et al. Duodenal pathology and clinical-immunological implications in common variable immunodeciency patients. Am J Gastroenterol 2003;98:118-21. |
|6.||Zukerman GR, Mills BA, Koehler RE, Siegel A, Harter HR, DeSchryver-Kecskemeti K. Nodular duodenitis. Pathologic and clinical characteristics in patients with end-stage renal disease. Dig Dis Sci 1983;28:1018-24. |
|7.||Sotoudehmanesh R, Ali Asgari A, Ansari R, Nouraie M. Endoscopic findings in end-stage renal disease. Endoscopy 2003;35:502-5. |
|8.||Piazzi L, Zancanella L, Chilovi F, Merighi A, De Vitis I, Feliciangeli G, et al. Diagnostic value of endoscopic markers for celiac disease in adults: A multicentre prospective Italian study. Minerva Gastroenterol Dietol 2008;54:335-46. |
|9.||Li XB, Ge ZZ, Chen XY, Liu WZ. Duodenal gastric metaplasia and Helicobacter pylori infection in patients with diffuse nodular duodenitis. Braz J Med Biol Res 2007;40:897-902. |
|10.||Perez-Roldan F, Mate-Valdezate A, Villafanez-Garcia MC, González Carro P, Legaz Huidobro ML. Nodular lymphoid hyperplasia by Giardia lamblia. Endoscopy 2008;40:E116-7. |
|11.||Langkemper R, Hoek AC, Dekker W, Op den Orth JO. Elevated lesions in the duodenal bulb caused by heterotopic gastric mucosa. Radiology 1980;137:621-4. |
|12.||Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc 2003;57:187-91. |
|13.||Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol 1996;20:1240-52. |
|14.||Webster AD, Kenwright S, Ballard J, Shiner M, Slavin G, Levi AJ, et al. Nodular lymphoid hyperplasia of the bowel in primary hypogammaglobulinaemia: Study of in vivo and in vitro lymphocyte function. Gut 1977;18:364-72. |
|15.||Rubio-Tapia A, Hernández-Calleros J, Trinidad-Hernández S, Uscanga L. Clinical characteristics of a group of adults with nodular lymphoid hyperplasia: a single center experience. World J Gastroenterol 2006;12:1945-8. |
|16.||Kasýrga E, Gülen H, Þimsek A, Ayhan S, Yilmaz O, Ellidokuz E. Coexistence of symptomatic iron-deficiency anemia and duodenal nodular lymphoid hyperplasia due to giardiasis: Case report. Pediatr Hematol Oncol 2009;26:57-61. |
|17.||Rambaud JC, De Saint-Louvent P, Marti R, Galian A, Mason DY, Wassef M, et al. Diffuse follicular lymphoid hyperplasia of the small intestine without primary immunoglobulin deficiency. Am J Med 1982;73:125-32. |
|18.||Vesy CJ, Peterson WL. Review article: The management of Giardiasis. Aliment Pharmacol Ther 1999;13:843-50. |
|19.||Eren M, Saltik-Temizel I, Yuce A, Caðlar M, Koçak. Duodenal appearance of giardiasis in a child with selective immunoglobulin A deficiency. Pediatr Int 2007;49:409-11. |
|20.||Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. Allergic eosinophilic gastroenteritis with protein-losing enteropathy: Intestinal pathology, clinical course, and long-term follow-up. J Pediatr Gastroenterol Nutr 2006;42:516-21. |
|21.||Lowichik A, Weinberg AG. A quantitative evaluation of mucosal eosinophils in the pediatric gastrointestinal tract. Mod Pathol 1996;9:110-4. |
|22.||Cohen H, Laine L. Endoscopic methods for the diagnosis of Helicobacter pylori. Aliment Pharmacol Ther 1997;11:3-9. |
|23.||Riddell RH. Pathobiology of Helicobacter pylori infection in children. Can J Gastroenterol 1999;13:599-603. |
Çaltepe Dinler Gönül
Department of Pediatrics, Division of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Ondokuz Mayis University, Kurupelit 55139 Samsun
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]