Histopathology Of Celiac Disease Research Articles

HISTOPATHOLOGY OF CELIAC DISEASE. POSITION STATEMENTS OF THE ITALIAN GROUP OF GASTROINTESTINAL PATHOLOGISTS (GIPAD-SIAPEC)

Celiac Disease (CeD) is an immune-mediated inflammatory disorder of the small intestine, affecting genetically susceptible individuals when exposed to gluten. Small intestinal biopsy interpretation has been the “gold standard” for celiac disease (CeD) for over 50 years. Despite today’s availability of sensitive and specific serological tests, the histopathological features from mucosal biopsy play a key role in diagnosing when CeD is suspected. Such a diagnostic approach requires a multidisciplinary team to optimize both tissue sampling and interpretation via the interaction between the pathologist and the gastroenterologist. Pathologists of the Italian Group of Gastrointestinal Pathology (GIPAD-SIAPEC), together with a member (TR) of the Italian Society of Technicians (AITIC) and an expert gastroenterologist (CC), provide position statements as a practical tool for reading and interpreting the report.Moreover, a position statement was formulated about the recently described condition known as Non-Celiac Gluten Sensitivity (NCGS). Within such a diagnostic setting, both the architectural abnormalities of the duodenal mucosa, namely glandular hyperplasia, and villous atrophy and the number of intraepithelial T-lymphocytes should be well highlighted. Ancillary tests such as anti-CD3 stain are useful for an accurate count of the intraepithelial T lymphocytes when CeD or NCGS is suspected. Moreover, anti-CD3 and anti-CD8 stains are recommended in patients not responding to the gluten-free diet (GFD) to confirm a diagnosis of Refractory Celiac Disease (RCeD). Diagnostic clues about the differential diagnosis of both CeD and RCeD have also been rendered.

Celiac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activation.

BackgroundIn celiac disease (CD), intestinal epithelium damage occurs secondary to an immune insult and is characterized by blunting of the villi and crypt hyperplasia. Similarities between Hedgehog (Hh)/BMP4 downregulation, as reported in a mouse model, and CD histopathology, suggest mechanistic involvement of Hh/BMP4/WNT pathways in proliferation and differentiation of immature epithelial cells in the context of human intestinal homeostasis and regeneration after damage. Herein we examined the nature of intestinal crypt hyperplasia and involvement of Hh/BMP4 in CD histopathology.Methods and FindingsImmunohistochemistry, qPCR and in situ hybridization were used to study a cohort of 24 healthy controls (HC) and 24 patients with diagnosed acute celiac disease (A-CD) intestinal biopsies. In A-CD we observed an increase in cells positive for Leucin-rich repeat-containing G protein-coupled receptor 5 (LGR5), an epithelial stem cell specific marker and expansion of WNT responding compartment. Further, we observed alteration in number and distribution of mesenchymal cells, predicted to be part of the intestinal stem cells niche. At the molecular level we found downregulation of indian hedgehog (IHH) and other components of the Hh pathway, but we did not observe a concurrent downregulation of BMP4. However, we observed upregulation of BMPs antagonists, gremlin 1 and gremlin 2.ConclusionsOur data suggest that acute CD histopathology partially recapitulates the phenotype reported in Hh knockdown models. Specifically, Hh/BMP4 paradigm appears to be decoupled in CD, as the expansion of the immature cell population does not occur consequent to downregulation of BMP4. Instead, we provide evidence that upregulation of BMP antagonists play a key role in intestinal crypt hyperplasia. This study sheds light on the molecular mechanisms underlying CD histopathology and the limitations in the use of mouse models for celiac disease.

The celiac iceberg: from the clinical spectrum to serology and histopathology in children and adolescents with type 1 diabetes mellitus and Down syndrome

Objective: The objective of this study is to investigate the occurrence of gastrointestinal (GI) and extraintestinal symptoms in children and adolescents with type 1 diabetes mellitus (DM1) and Down syndrome (DS) and their association with specific antibodies and histopathology of celiac disease (CelD), representing its clinical forms in the iceberg. Material and methods: Cross-sectional study (November 2009–December 2012) conducted at an outpatient care facility in Northeast Brazil including patients [DM1 (n = 111); DS (n = 77)] aged 10 months–18 years old. Measurement of anti-endomysial (EmA) and anti-tissue transglutaminase (anti-tTG) IgA antibodies was performed, as was that of anti-tTG-IgG in the cases with low serum IgA. The patients with antibody positivity were subjected to small intestine biopsy. Results: GI symptoms occurred in 53.7% of the sample, extraintestinal symptoms in 4.3%, and antibody positivity in 28.2% (n = 53). Of those who underwent biopsy (n = 40), histopathological findings of CelD were found in 37.5% [DM1 = 5/111 (4.5%), DS = 10/77 (13.0%)]. GI symptoms were associated with antibody positivity, but not with the histopathology. The GI (32.5%), silent (5.0%), and potential (62.5%) forms of disease were detected. Conclusions: The prevalence of GI symptoms was high in groups DM1 and DS, and the occurrence of such symptoms was associated with antibody positivity. The lack of association between the symptoms and histopatholological findings points to the inconsistency of the former as indicators of CelD. Although the GI form predominated among the cases with active CelD, its contribution to the celiac iceberg was smaller compared with the potential form, which determined the large and submerged base of the iceberg representing the high-risk groups investigated.

An Update on Celiac Disease Histopathology and the Road Ahead

Celiac disease (CD) is a common immune-mediated disorder that occurs in genetically predisposed individuals (carriers of HLA-DQ2 and DQ8 haplotypes) on consumption of wheat (gluten). It is characterized by inflammation of the small-intestinal mucosa and myriad gastrointestinal and systemic manifestations. Celiac disease is common in the general population (prevalence, 0.5%-1%). Currently, small-bowel biopsy is considered the gold standard for diagnosing CD. However, the role of serologic testing in the diagnosis of CD has evolved, from being a supportive test to supplanting intestinal biopsies in certain patient populations. To summarize key aspects of histopathologic assessment, discuss the benefit of standardized pathology reports, impact of the site and number of small-bowel biopsy samples on diagnosis, and recommendations regarding serologic testing. Literature review of publications on CD and experience with histopathologic review of biopsies at the Department of Pathology and Cell Biology, Columbia University Medical Center, New York-Presbyterian Hospital, New York. Intraepithelial lymphocytosis in the context of villous atrophy is considered a characteristic histologic finding of CD; however, it is a rather nonspecific finding. A growing list of publications has also indicated that the detection of intraepithelial lymphocytosis in the absence of villous atrophy has rather low specificity for CD. Therefore, communication between pathologists and gastroenterologists is paramount, as is knowledge regarding the pertinent clinical and laboratory data, in distinguishing between CD and other disorders with similar histopathologic and clinical manifestations.

Visualization of Transepithelial Passage of the Immunogenic 33-Residue Peptide from α-2 Gliadin in Gluten-Sensitive Macaques

BackgroundBased on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from α2-gliadin in the distal duodenum of gluten-sensitive macaques.Methodology/Principal FindingsSix rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with “leaky” duodenum, the peptide penetrated beneath the epithelium into the lamina propria.Conclusions/SignificanceThe rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.

Strongly Positive Tissue Transglutaminase Antibodies are Associated With Marsh 3 Histopathology in Adult and Pediatric Celiac Disease

Our objective was to determine whether high serologic IgA tissue transglutaminase antibodies (TTGA) are exclusively associated with celiac disease (CD). IgA TTGA are found in the serum of most individuals with CD. This serologic marker is used to screen individuals with suspected CD for duodenal biopsy, the gold standard of CD diagnosis. Data suggest strongly positive IgA TTGA >or= 100 units are highly specific for CD histopathology in pediatric patients and may be sufficient for diagnosis. Records of adult and pediatric subjects in the celiac study at the University of Utah and University of California Irvine were reviewed for strongly positive TTGA. Pathology reports from duodenal biopsies of subjects with IgA TTGA >or= 100 units were graded as 0 to 3 by modified Marsh criteria. From a pool of 1882 subjects with IgA TTGA assayed, 208 had IgA TTGA >or= 100 units. Seventy-six of these, including 28 children and 48 adults, also had duodenal biopsies. Villous atrophy (Marsh 3 histopathology) was found on biopsy in 73 (96%) of these subjects. The remaining 3 subjects had intermediate Marsh histology. One (Marsh 1) had a complete serologic response to a gluten-free diet and 2 had Marsh 2 lesions and positive endomysium, making early CD most likely. IgA TTGA >or= 100 units occur almost exclusively in the setting of Marsh 3 duodenal histopathology in adults and children. Rare cases without villous atrophy were marked by intermediate Marsh changes suggestive of early CD. IgA TTGA >or= 100 arbitrary units indicate duodenal changes consistent with CD.

Correlation of Duodenal Histology With Tissue Transglutaminase and Endomysial Antibody Levels in Pediatric Celiac Disease

IgA antibodies against tissue transglutaminase (TTGA) and endomysium (EMA) are sensitive and specific markers for celiac disease (CD). Data correlating TTGA and EMA levels with degree of villous atrophy are limited. We compared duodenal histopathology in pediatric CD patients with TTGA and EMA serologies, symptoms, height, and weight. We identified 117 pediatric patients retrospectively who had serologic testing for IgA TTGA and IgA EMA and duodenal biopsies graded by modified Marsh criteria as 0-3c. Data were analyzed with Spearman rank correlation and multinomial logistic regression. IgA TTGA (r = .704, P < .001) and IgA EMA (r = 0.740, P < .001) correlated with intestinal villous atrophy in pediatric CD patients by Spearman rank correlation. Similar correlations were found in a subset of 23 patients younger than 3 years of age. Multinomial logistic regression revealed increased probability of Marsh 3a or greater changes with increasing TTGA or EMA levels. Strongly positive antibody levels (TTGA >100 units or EMA titer >1:1280) were highly specific (>98%) for Marsh 3a or greater lesions. Among symptoms, abdominal distention and diarrhea were associated with abnormal histology. IgA TTGA and EMA levels correlate with duodenal villous atrophy in pediatric CD patients. IgA TTGA >100 or EMA >1:1280 were nearly always associated with CD histopathology. With further validation of this observation, strongly positive titers might be considered sufficient for diagnosis of pediatric patients at risk for CD. Symptoms, height, and weight are not reliable predictors of CD.

Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent celiac disease.

Endomysial antibodies (EMA) are a well-known hallmark of celiac disease, but some recent studies showed that the prevalence of these antibodies in clinical practice is lower than expected. The aim of our study was to determine the prevalence of antigliadin (AGA) and EMA antibodies on a consecutive series of subclinical/silent celiac patients. We studied 115 consecutive patients with subclinical (92 patients) or silent (23 patients) forms of celiac disease. AGA and EMA were screened in all patients. Histopathology of celiac disease was expressed according to the Marsh classification. The overall AGA in subclinical form were positive in 77% (14 of 18) of patients with partial villous atrophy (VA), in 84% (21 of 25) of patients with subtotal VA, and in 90% (27 of 30) of patients with total VA, whereas EMA were positive in 88.88% (16 of 18) of patients with partial VA, in 92% (23 of 25) of patients with subtotal VA, and 96.66% (29 of 30) of patients with total VA. On the other hand, AGA were positive in 0% (zero of two) of patients with Marsh I and in 30% (three of 10) of patients with Marsh II, whereas EMA were positive in 0% (zero of two) of patients with Marsh I and in 40% (four of 10) of patients with Marsh II (Marsh I-IIIa vs Marsh IIIb-c, p = < 0.005 in overall AGA-positive patients and p = < 0.0001 in EMA-positive patients). At the same time the overall AGA in silent form were positive in 60% (three of five) of patients with partial VA, in 66.66% (four of six) of patients with subtotal VA, and in 77.77% (seven of nine) of patients with total VA, whereas EMA were positive in 80% (four of five) of patients with partial VA, in 83.33% (five of six) of patients with subtotal VA, and in 88.88% (eight of nine) of patients with total VA. On the other hand, overall AGA were positive in 0% of patients with both Marsh I (zero of one) and Marsh II (zero of two), as well as EMA were positive in 0% with both Marsh I (zero of one) and Marsh II (zero of two) (Marsh I-IIIa vs Marsh IIIb-c, p = < 0.001 in overall AGA-positive patients and p = < 0.007 in EMA-positive patients). At this time small bowel biopsy seems to be the only correct procedure to diagnose a case of suspected celiac disease, especially in patients with mild symptoms or suspected for celiac disease, because they belong to high-risk groups.

Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent celiac disease

OBJECTIVE: Endomysial antibodies (EMA) are a well-known hallmark of celiac disease, but some recent studies showed that the prevalence of these antibodies in clinical practice is lower than expected. The aim of our study was to determine the prevalence of antigliadin (AGA) and EMA antibodies on a consecutive series of subclinical/silent celiac patients. METHODS: We studied 115 consecutive patients with subclinical (92 patients) or silent (23 patients) forms of celiac disease. AGA and EMA were screened in all patients. Histopathology of celiac disease was expressed according to the Marsh classification. RESULTS: The overall AGA in subclinical form were positive in 77% (14 of 18) of patients with partial villous atrophy (VA), in 84% (21 of 25) of patients with subtotal VA, and in 90% (27 of 30) of patients with total VA, whereas EMA were positive in 88.88% (16 of 18) of patients with partial VA, in 92% (23 of 25) of patients with subtotal VA, and 96.66% (29 of 30) of patients with total VA. On the other hand, AGA were positive in 0% (zero of two) of patients with Marsh I and in 30% (three of 10) of patients with Marsh II, whereas EMA were positive in 0% (zero of two) of patients with Marsh I and in 40% (four of 10) of patients with Marsh II (Marsh I–IIIa vs Marsh IIIb–c, p = < 0.005 in overall AGA-positive patients and p = < 0.0001 in EMA-positive patients). At the same time the overall AGA in silent form were positive in 60% (three of five) of patients with partial VA, in 66.66% (four of six) of patients with subtotal VA, and in 77.77% (seven of nine) of patients with total VA, whereas EMA were positive in 80% (four of five) of patients with partial VA, in 83.33% (five of six) of patients with subtotal VA, and in 88.88% (eight of nine) of patients with total VA. On the other hand, overall AGA were positive in 0% of patients with both Marsh I (zero of one) and Marsh II (zero of two), as well as EMA were positive in 0% with both Marsh I (zero of one) and Marsh II (zero of two) (Marsh I–IIIa vs Marsh IIIb–c, p = < 0.001 in overall AGA-positive patients and p = < 0.007 in EMA-positive patients). CONCLUSIONS: At this time small bowel biopsy seems to be the only correct procedure to diagnose a case of suspected celiac disease, especially in patients with mild symptoms or suspected for celiac disease, because they belong to high-risk groups.

Histopathology of celiac disease

The diagnosis of celiac disease (CD) is based upon histologic findings in duodenal or jejunal biopsies. In the past few years it has turned out that the development of CD lesion in the small bowel is a dynamic process which may present in various histologic forms. At one end of the spectrum is a mucosa with normal architecture and an increase in intraepithelial lymphocytes (IEL), at the other end is the classical flat mucosa. Histologic features supporting the diagnosis of CD are architectural changes of the villi and/or crypts, an increase in lamina propria cell density and an increase in IEL counts. For diagnostic purposes and for monitoring CD patients an exact histologic classification of the histologic findings has to be given. This has become possible by using a modified Marsh classification. In the present paper the histologic presentation of CD is presented as well as the modified Marsh classification.