Cardiac Intestinal Metaplasia Research Articles

A128 Examining the Prevalence of Cardiac Intestinal Metaplasia in the Pre-operative Bariatric Patient Population

A128 Examining the Prevalence of Cardiac Intestinal Metaplasia in the Pre-operative Bariatric Patient Population

Aberrant DNA methylation and expression of EYA4 in gastric cardia intestinal metaplasia.

Intestinal metaplasia (IM) of the gastric cardia is an important premalignant lesion. However, there is limited information concerning its epidemiological and molecular features. Herein, we aimed to provide an overview of the epidemiological data for gastric cardiac IM and evaluate the role of EYA transcriptional coactivator and phosphatase 4 (EYA4) as an epigenetic biomarker for gastric cardiac IM. The study was conducted in the context of the gastric cardiac precancerous lesion program in southern China, which included 718 non-cancer participants, who undertook endoscopic biopsy and pathological examination in three endoscopy centers, between November 2018 and November 2021. Pyrosequencing and immunohistochemistry were performed to examine the DNA methylation status and protein expression level of EYA4. Gastric cardiac IM presented in 14.1% (101/718) of participants and was more common among older (>50 years; 22.0% [95% CI: 17.8-26.8]) than younger participants (≤50 years; 6.7% [95% CI: 4.5-9.9]; P < 0.001). IM was more common in male participants (16.9% [95% CI: 13.2-21.3] vs. 11.3% [95% CI: 8.3-15.1]; P = 0.04). Pyrosequencing revealed that IM tissues exhibited significantly higher DNA methylation levels in EYA4 gene than normal tissues (P = 0.016). Further, the protein expression level of EYA4 was reduced in IM and absent in intraepithelial neoplasia tissues compared to normal tissues (P < 0.001). Detection rates of gastric cardiac IM increase with age and are higher in men. Our findings highlight the important role of promoter hypermethylation and downregulation of EYA4 in gastric cardiac IM development.

Genome-wide DNA methylation profiling identifies epigenetic signatures of gastric cardiac intestinal metaplasia

BackgroundMeasuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM.MethodsHistopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR.ResultsThe detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ2 test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue.ConclusionsOur results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.

Expression of CDX2 and Villin in Gastric Cardiac Intestinal Metaplasia and the Relation with Gastric Cardiac Carcinogenesis

To determine whether CDX2 and villin protein expression are associated with intestinal metaplasia (IM) in gastric cardiac mucosa and to explore the relationship with evolution of gastric cardiac adenocarcinoma (GCA). We studied 143 gastric cardiac biopsy or resection specimens from Henan province China, including 25 cardiac gastritis specimens with IM, 65 dysplasia specimens with IM and 35 gastric cardiac adenocarcinoma specimens and stained them for CDX2 and villin by the immunohistochemical SP method. 15 normal gastric cardiac biopsy specimens were also collected as control. (1) Normal gastric mucosa presented no CDX2 and villin expression. The positive rates of CDX2 protein in cardiac gastritis with IM, dysplasia with IM, and carcinoma tissues were 84.0% (21/25), 66.7% (32/48) and 36.4% (20/55), respectively. While the positive rates of villin protein in cardiac gastritis with IM, dysplasia with IM, and carcinoma tissues were 76.0% (19/25), 70.8% (34/48) and 45.5% (25/55), respectively.There were significant differences among the three groups for both CDX2 and villin (P<0.01). Spearman's rank correlation coefficient(rho) showed a close correlation between the two proteins (r=0.843, P<0.01) and both were positively related with tumor differentiation (both P<0.05), but not associated with age, sex, invasion and metastasis of lymph node (P>0.05). Our results suggest that ectopic expression of CDX2 and villin may be involved in early-stage IM and tumorigenesis in gastric cardia and the expression of villin may be regulated by CDX2.

The Prevalence of Barrett's Esophagus and the Comparison of Barrett's Esophagus with Cardiac Intestinal Metaplasia in the Health Screening at a Secondary Care Hospital

The purpose of this study was to estimate the prevalence of Barrett's esophagus (BE) and its association with reflux esophagitis (RE) and peptic ulcer disease detected by free charge endoscopy which was covered by the National Health Insurance at a secondary care hospital, and to compare the results of the biopsy of BE with that of cardiac intestinal metaplasia (CIM). A total of 4,002 patients underwent endoscopy from March 2010 to December 2012. BE was diagnosed if there was histologically proven specialized intestinal metaplasia, and CIM was diagnosed if intestinal metaplasia was accompanied with chronic gastritis. Four hundred twenty four patients underwent endoscopic biopsy, and the prevalence of BE was 1.0% (42/4,002). The mean age and the proportion of males in BE were significantly higher than those of the rest of study population, and BE had slight tendency related to RE than the rest of study population. CIM was observed in 34 patients and BE and CIM showed similar results, regarding age, sex and association with RE. The mean length of endoscopic Barrett's mucosa of BE group was 9.2±5.1 mm, and it was similar to that of CIM. The prevalence of BE in the secondary care hospital was not low, and old age and male sex were significantly associated with BE. Because BE was observed in about 10% of biopsied patients and CIM was observed in a similar percentage with BE, the precise targeted biopsy is warranted and the biopsy method should be reestablished through the large prospective study of multiple secondary care hospitals.

Comparison of intestinal metaplasia in gastric cardia and Barrett's esophagus

To evaluate and compare the pathological features and immunostaining pattern (cytokeratin 7 (CK-7), mucin core peptide 1 (Muc-1)) in Barrett's esophagus (BE) and cardiac intestinal metaplasia (CIM). According to endoscopic diagnosis, patients with gastric cardiac inflammation and BE were selected from March 2008 to February 2009 in Renji Hospital, Shanghai Jiaotong University School of Medicine. Those patients who had histological findings of intestinal metaplasia (82 cases of CIM and 64 special type BE) were enrolled in our study. Hematoxylin-eosin, periodic acid-Schiff and Alcian blue staining and an immunohistochemical examination (CK-7, Muc-1) were undertaken in all of them. Squamous mucosa overlying the columnar crypts with intestinal metaplasia, also called buried metaplasia, was often found in the BE group (56.2%), mainly as an incomplete type (85.9%). Inflammation in the gastric antrum was more severe in the CIM group (45.1% vs 26.6%), in contrast, esophagitis was more severe in the BE group (53.1% vs 35.4%). CK-7 was highly expressed in the BE group (84.4%) in contrast to the CIM group (37.8%). There was no difference in the expression of Muc-1 in these two kinds of intestinal metaplasia (14.1% vs 19.5%). Buried intestinal metaplasia, mainly as an incomplete type, is the major predominant type of BE. The degree of inflammation in the gastric antrum and esophagus can differentiate BE from CIM to some extent. CK-7 immunohistochemical staining can help identify BE and CIM but Muc-1 cannot.

The Gene Expression Profile of Cardiac Intestinal Metaplasia Is Similar to Barrettʼs Esophagus, Not Gastric Intestinal Metaplasia

Purpose: The etiology and significance of cardiac intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus (BE) due to reflux or could reflect generalized gastric intestinal metaplasia (GIM) due to H. pylori. The aim of this study was to utilize gene expression data to compare CIM to BE and GIM. Methods: Biopsies were first classified by endoscopic and histologic criteria as CIM (n = 40), BE (n = 26), or GIM (n = 23). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients. H. pylori status was tested in antral biopsies of all patients. After laser-capture microdissection, quantitative RT-PCR was used to measure the expression of a panel of 9 genes that has been shown to differentiate BE from other foregut mucosa (Cox2, Cdx1, Cdx2, VEGF, TSP1, Survivin, TIMP1, Bcl2, CTNNB1). Next, cluster analysis using linear discriminant analysis of logged expression data was used to classify samples into groups based solely on similarity of gene expression. Cluster analysis was performed for 3 groups (CIM vs BE vs GIM) and 2 groups (CIM+BE vs GIM). Results: Median BE length was 4.5 cm. There was no difference in H. pylori infection among groups (p = 0.68). Three group clustering had a misclassification rate of 0.39 (p = 0.001); most errors occurred between CIM and BE (Table 1). Two group clustering had a misclassification rate of 0.18 (p<0.001) (Table 2):[figure 1]Table 1: No Caption available.Table 2: No Caption available.Conclusions: The gene expression profiles of CIM and BE were similar in 91% of patients and differed significantly from that of GIM. Those with misclassification of CIM as GIM may have an alternate etiology such as H. pylori. The similar gene expression profile of CIM and BE suggests a shared reflux etiology in the majority of patients and calls into question the perception that CIM is an innocuous process.

Cytokeratin immunoreactivity patterns in short‐segment Barrett's esophagus in Japanese patients

The origin of intestinal metaplasia at the esophagogastric junction has clinical importance. However, it can be difficult to differentiate between intestinal metaplasia of short-segment Barrett's esophagus and cardiac intestinal metaplasia due to Helicobacter pylori infection. Specific patterns of cytokeratin (CK)7 and CK20 have been detected in long-segment Barrett's esophagus. The aim of the present study was to assess the immunostaining patterns associated with short-segment Barrett's esophagus. Paraffin-embedded biopsy specimens were prepared from 128 patients with intestinal metaplasia of long-segment Barrett's esophagus (n = 3), short-segment Barrett's esophagus without H. pylori infection (n = 22), short-segment Barrett's esophagus with H. pylori infection (n = 22), and cardiac mucosa (n = 49) and gastric mucosa from antrum and fundus (n = 44) with H. pylori infection. Sections were prepared and immunostained for CK7 and CK20. A Barrett's CK7/20 pattern was present in all three patients (100%) with long-segment Barrett's esophagus, 21 of 22 patients (95%) with short-segment Barrett's esophagus without H. pylori infection, and six of 22 patients (27%) with short-segment Barrett's esophagus with H. pylori infection (P < 0.05). Intestinal metaplasia of short-segment Barrett's esophagus in patients without H. pylori infection is thought to be similar to that seen in long-segment Barrett's esophagus.

Distinction between short-segment Barrett’s esophageal and cardiac intestinal metaplasia

To investigate the roles of mucin histochemistry, cytokeratin 7/20 (CK7/20) immunoreactivity, clinical characteristics and endoscopy to distinguish short-segment Barrett's esophageal (SSBE) from cardiac intestinal metaplasia (CIM). High iron diamine/Alcian blue (HID/AB) mucin-histochemical staining and immunohistochemical staining were used to classify intestinal metaplasia (IM) and to determine CK7/20 immunoreactivity pattern in SSBE and CIM, respectively, and these results were compared with endoscopical diagnosis and the positive rate of gastroesophageal reflux disease (GERD) symptoms and H pylori infection. Long-segment Barrett's esophageal and IM of gastric antrum were designed as control. The prevalence of type III IM was significantly higher in SSBE than in CIM (63.33% vs 23.08%, P< 0.005). The CK7/20 immunoreactivity in SSBE showed mainly Barrett's pattern (76.66%), and the GERD symptoms in most cases which showed Barrett's pattern were positive, whereas H pylori infection was negative. However, the CK7/20 immunoreactivity in CIM was gastric pattern preponderantly (61.54%), but there were 23.08% cases that showed Barrett's pattern. H pylori infection in all cases which showed gastric pattern was significantly higher than those which showed Barrett's pattern (63.83% vs 19.30%, P< 0.005), whereas the GERD symptoms in gastric pattern were significantly lower than that in Barrett's pattern (21.28% vs 85.96%, P< 0.005). Distinction of SSBE from CIM should not be based on a single method; however, the combination of clinical characteristics, histology, mucin histochemistry, CK7/20 immunoreactivity, and endoscopic biopsy should be applied. Type III IM, presence of GERD symptoms, and Barrett's CK7/20 immunoreactivity pattern may support the diagnosis of SSBE, whereas non-type III IM, positive H pylori infection, and gastric CK7/20 immunoreactivity pattern may imply CIM.

Utilization of Cytokeratins 7 and 20 Does Not Differentiate between Barrett's Esophagus and Gastric Cardiac Intestinal Metaplasia

Long segment Barrett’s esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains. Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining. We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the “Barrett’s” pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett’s pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences. Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett’s pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.

Metaplasia intestinal en la unión esofagogástrica. Prevalencia y asociaciones en una población sometida a endoscopia

Short segments of intestinal metaplasia (IM) at the esophagogastric junction is an unclear entity. Several studies have reported wide variations in its prevalence and in the factors associated with its development. Recently, this entity has been divided into esophageal IM and cardiac IM, as two different lesions in etiopathogenesis and prognosis. We studied the prevalence of these conditions and their association with gastroesophageal reflux disease (GERD) and Helicobacter pylori infection. In 161 patients, biopsies were obtained from the distal esophagus (2), just below the Z line (3), and in the gastric antrum (4). IM was diagnosed on the basis of staining of goblet cells with Alcian blue and was classified as esophageal if ILZ < IEG or cardiac ILZ = IEG. H. pylori was determined by rapid urease (CLO-test) and histology. Diagnosis of GERD was based on typical symptoms, endoscopy, and histology. In 54 patients with IM (73%) esophageal manometry and 24-hour pH-metry was also performed. IM was detected in 74 patients (46%); IM was esophageal in 33 patients (20.5%) and cardiac in 41 patients (25.4%). Patients with IM were significantly older than those without (p = 0.007) and took proton pump inhibitors more frequently (p = 0.004). No correlation was found between reflux symptoms, esophageal lesions or histological changes with either type of IM. No differences between esophageal or cardiac IM were detected by esophageal pH-metry. H. pylori infection was unrelated to cardiac IM, but these patients had a lower frequency of endoscopic and histological changes in the distal esophagus. Intestinal metaplasia is a common finding in patients sent for gastroscopy and is probably an acquired lesion that increases in prevalence with age. We found no associations between esophageal IM and GERD, evaluated by typical symptoms, endoscopic and histological changes and pH-metry. H. pylori infection showed no relation to cardiac IM.

Characteristics of intestinal metaplasia in the gastric cardia

OBJECTIVE: Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett’s esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. METHODS: Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett’s esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. RESULTS: Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett’s esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett’s esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett’s esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett’s esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. CONCLUSIONS: Intestinal metaplasia of the gastric cardia is different from Barrett’s esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett’s esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.

Characteristics of intestinal metaplasia in the gastric cardia.

Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett's esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett's esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett's esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett's esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett's esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett's esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. Intestinal metaplasia of the gastric cardia is different from Barrett's esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett's esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.