Prospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2015; 21(24): 7545-7552
Published online Jun 28, 2015. doi: 10.3748/wjg.v21.i24.7545
Evolution of nonspecific duodenal lymphocytosis over 2 years of follow-up
Giuseppe Losurdo, Domenico Piscitelli, Antonio Giangaspero, Mariabeatrice Principi, Francesca Buffelli, Floriana Giorgio, Lucia Montenegro, Claudia Sorrentino, Annacinzia Amoruso, Enzo Ierardi, Alfredo Di Leo
Giuseppe Losurdo, Domenico Piscitelli, Antonio Giangaspero, Mariabeatrice Principi, Francesca Buffelli, Floriana Giorgio, Lucia Montenegro, Claudia Sorrentino, Annacinzia Amoruso, Enzo Ierardi, Alfredo Di Leo, Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
Author contributions: Losurdo G, Ierardi E and Di Leo A conceived the study; Giangaspero A, Montenegro L and Amoruso A followed the patients; Principi M performed endoscopy; Piscitelli D and Buffelli F performed immunohistochemistry evaluation; Losurdo G and Giorgio F performed statistical analysis; Losurdo G, Ierardi E and Sorrentino C wrote the manuscript; all the authors read and approved the final version of the manuscript.
Ethics approval: The study was reviewed and approved after a meeting of all the authors working in the Gastroenterology Unit of the University Hospital Policlinico of Bari (Italy).
Clinical trial registration: This study was not a clinical trial but only an outpatient follow-up of subjects referred to the Gastroenterology Unit of the University Hospital Policlinico of Bari (Italy) and affected by duodenal lymphocytosis. The names of the patients were listed in the registers of either the outpatient clinic/day hospital and the service of digestive endoscopy of the University Hospital Policlinico of Bari (Italy). As required by Italian law, each patient gave written informed consent for endoscopic examination. No ethical committee approval was required because all procedures were provided by routine clinical patient management.
Informed consent: All study participants provided informed written consent prior to endoscopic investigation. Additional oral consent to perform immunohistochemical staining of intraepithelial lymphocytes was obtained. Subjects with intraepithelial lymphocytosis were invited to undergo the follow-up and the follow-up was agreed with the practitioners of reference for each patient.
Conflict-of-interest: No author received fees for this study. There is no conflict of interest.
Data sharing: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Enzo Ierardi, Professor, Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari, Policlinico, Piazza Giulio Cesare, 70124 Bari, Italy. ierardi.enzo@gmail.com
Telephone: +39-80-5592577 Fax: +39-80-5593088
Received: January 22, 2015
Peer-review started: January 24, 2015
First decision: March 10, 2015
Revised: March 31, 2015
Accepted: May 7, 2015
Article in press: May 21, 2015
Published online: June 28, 2015
Abstract

AIM: To assess the evolution of duodenal lymphocytosis (DL), a condition characterized by increased intraepithelial lymphocytes (IELs), over 2 years of follow-up.

METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease (CD) were included. Evaluation of IELs infiltrate in duodenal biopsy samples was carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: IgG and IgA anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance imaging were performed when necessary. Risk factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR.

RESULTS: Eighty-five patients (16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed IgG anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity (GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn’s disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence. At multivariate analysis, the evolution towards CD was associated with an IELs infiltrate > 25 (OR = 1640.4) or 15-25 (OR = 16.95), human leukocyte antigen (HLA) DQ2/8 (OR = 140.85) or DQA1*0501 (OR = 15.36), diarrhea (OR = 5.56) and weakness (OR = 11.57). GS was associated with IELs 15-25 (OR = 28.59), autoimmune thyroiditis (OR = 87.63), folate deficiency (OR = 48.53) and diarrhea (OR = 54.87).

CONCLUSION: DL may have a multifactorial origin but the IELs infiltrate and HLA are strong predictive factors for CD development and a clinical diagnosis of GS.

Keywords: Duodenal lymphocytosis, Celiac disease, Gluten sensitivity, Seronegative celiac disease, Intraepithelial lymphocytes, Immunohistochemistry

Core tip: Duodenal lymphocytosis may pose a diagnostic challenge since it could be associated with different pathological conditions, which may or may not be related to gluten. In the present study, we demonstrated that during 2 years of follow-up of 85 patients with duodenal lymphocytosis, 27% developed celiac disease and 22% had a clinical diagnosis of gluten sensitivity; the remaining patients were affected by non-gluten-related conditions. At multivariate analysis, the haplotype DQ2/8 and the density of the intraepithelial CD3 lymphocyte infiltrate were the best predictors of the future development of gluten-related disorders.