Endoscopic diagnosis of Helicobacter pylori infection
Article information
Abstract
Accurate prediction of Helicobacter pylori infection status based on endoscopic findings is essential for optimizing management. This review emphasizes the importance of accurate endoscopic diagnosis of H. pylori infection. The endoscopic findings categorized in the Kyoto classification provide valuable indicators of infection status. Specifically, findings such as atrophic gastritis, intestinal metaplasia, nodular gastritis, enlarged folds, sticky mucus, xanthoma, and map-like redness are associated with H. pylori infection. Regular arrangement of collecting venules and linear red streaks are reliable indicators of non-infection. Selective testing based on endoscopic findings can optimize diagnosis and treatment of H. pylori infection and minimize unnecessary procedures. However, some findings overlap and do not clearly distinguish between current and past infections, indicating a need for further research.
Introduction
Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach [1]. H. pylori infection is associated with chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer [2], and with various extragastric conditions, including iron deficiency anemia and immune thrombocytopenia [3,4]. Significantly, H. pylori infection plays a pivotal role in gastric carcinogenesis, and accumulating evidence suggests that H. pylori eradication therapy can reduce the risk of gastric cancer [5,6]. Therefore, timely diagnosis and treatment of H. pylori infection is crucial for the prevention of associated pathologies, including gastric cancer [7].
An accurate diagnosis of H. pylori infection is essential to identify those who require H. pylori eradication therapy. Although Western guidelines recommend testing and treatment strategies, this approach may lead to considerable economic burden and emerging antimicrobial resistance if implemented in countries with a high prevalence of H. pylori infection [8-10]. Diagnostic attempts are usually performed selectively, except in situations where H. pylori eradication treatment is clearly beneficial, such as peptic ulcers, gastric MALT lymphoma, and gastric neoplasms. Therefore, it is important to determine the patients who should be tested for infection.
In countries such as Korea, where a national cancer screening program provides biennial upper endoscopy screening in subjects aged ≥40 years [11], predicting H. pylori infection status during endoscopic examination can help decide whether to perform diagnostic tests for H. pylori infection. Recently, several studies have reported endoscopic findings suggestive of current and previous H. pylori infection [12-14]. This review briefly introduces the diagnostic methods for H. pylori infection and summarizes gastric mucosal changes and endoscopic findings related to H. pylori infection, based on recent advancements.
Diagnostic methods for H. pylori infection
Methods for confirming H. pylori infection are generally divided into noninvasive and invasive methods. Noninvasive methods include serology or the stool antigen test (SAT) that detects antibodies against H. pylori, and the urea breath test (UBT) using 13C or 14C isotopes that detects urease activity [15]. Invasive methods are endoscopy based, including histology, bacterial culture, rapid urease test (RUT), and molecular biological techniques such as polymerase chain reaction (PCR) [15]. Each test has advantages and disadvantages and has varying diagnostic abilities. Therefore, when accurate diagnosis of H. pylori infection is crucial for clinical decision making, such as in patients with gastric MALT lymphoma, simultaneous application of at least two diagnostic tests improved the detection rate of H. pylori infection [16].
Among the noninvasive methods, serology is a simple, safe, and economical test that is not influenced by gastrointestinal bleeding or medication use and has a high negative predictive value. However, because the antibody persists for a long duration after treatment, the test cannot distinguish between current and past infections [17,18]. SAT is a simple method with high sensitivity and specificity of >95% and is most useful in pediatric patients [17,19,20]. UBT is widely used for both the initial diagnosis and confirmation of eradication of infection after therapy. UBT is especially valuable in clinical settings because it allows for the quantitative assessment of urease activity in the entire stomach [9,17,21,22]. Because SAT and UBT results can be affected by use of antibiotics or acid-suppressive agents (such as histamine H2-blockers, proton pump inhibitors, and potassium-competitive acid blockers), leading to false-negative results, it is generally recommended to stop using acid-suppressive agents 2 weeks before the tests and antibiotics 4 weeks before the tests [9,21,22].
Invasive testing methods require tissue or fluid samples from the stomach, and have a high specificity of 95% to 100%. Antibiotic susceptibility testing can be performed with bacterial culture, but is time-consuming, requires a specific environment and skills, and has low sensitivity [8]. H. pylori can be identified through the histological evaluation of tissue samples with/without special staining or immunohistochemical staining, with sensitivity ranging from 60% to 93%. Along with diagnosis, histological evaluation is beneficial for the simultaneous identification of changes in gastric mucosa, such as atrophic gastritis or intestinal metaplasia [8,21]. RUT, with a sensitivity of 84% to 95% and a specificity >95%, is the most commonly used test in clinical practice. However, it does not provide information on antibiotic susceptibility profiles or underlying pathology, and can be affected by gastrointestinal bleeding or medication use [8,17,21]. In addition, the presence and severity of atrophic gastritis and/or intestinal metaplasia can affect the diagnostic performance of RUT [23]. Therefore, it is recommended to obtain samples from areas where the possibility of atrophic gastritis or intestinal metaplasia is low, or both the antrum and body, to avoid false-negative RUT results [24]. Recently, molecular diagnostic methods such as PCR have gained popularity owing to their high sensitivity, specificity, and ability to detect point mutations associated with antibiotic resistance [8,17,21].
Gastric mucosal changes after H. pylori infection
H. pylori is a unique pathogen that can survive in the acidic environment of the stomach and cause pathological changes in the gastric mucosa after infection [25]. During the initial infection, H. pylori mainly settles in the gastric antrum, where it penetrates the mucus layer and attaches to the gastric epithelial cells [26]. During this process, H. pylori damages the gastric mucosa and induces an inflammatory response via various molecular mechanisms [26].
First, H. pylori secretes the enzyme urease, which decomposes urea into ammonia and carbon dioxide (CO2) in the stomach. The ammonia then diffuses into stomach and neutralizes the acidic environment of the stomach and helps bacteria survive, whereas CO2 diffuse into the blood and is subsequently exhaled. The tolerance of H. pylori to gastric acid is largely dependent on urease activity, while the ammonia is toxic to gastric mucosal cells and causes cell damage [27]. Second, H. pylori secretes pathogenic factors such as cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) [28]. CagA is injected into cells through the type IV secretion system, disrupting signaling pathways, and causing structural changes that amplify inflammatory responses [29]. Additionally, CagA activates the nuclear factor kappa B (NF-κB) pathway to promote the secretion of inflammatory cytokines [30]. VacA can enter cells, form vacuoles, disrupt cellular functions, and induce apoptosis [31].
These molecular mechanisms induce acute gastritis following H. pylori infection. Acute gastritis is characterized by mucosal congestion, edema, and neutrophil infiltration, and may cause symptoms such as abdominal pain, nausea, and vomiting [32]. Persistent acute gastritis may progress to chronic gastritis, in which atrophy and structural changes occur in the gastric mucosa due to continuous inflammatory response [33]. During this process, gastric mucosal cells can undergo intestinal metaplasia, a phenomenon wherein gastric mucosal cells transform into intestinal cells, which is considered a precursor lesion of gastric cancer [34].
The long-term consequences of H. pylori infection include peptic ulcers and gastric cancer [2]. Peptic ulcers occur when the balance between aggressive factors and mucosal protective mechanisms is disrupted. Gradually, chronic inflammation leads to continuous damage and regeneration of the gastric mucosa, eventually causing DNA damage and increasing the risk of gastric cancer [6].
Endoscopic findings associated with H. pylori infection
H. pylori infection induces various changes in the gastric mucosa. These changes directly and indirectly indicate the presence or absence of H. pylori infection, which is crucial for assessing the degree of infection and pathological alterations [25]. The recently proposed Kyoto classification of gastritis categorizes 19 endoscopic findings according to H. pylori infection status (H. pylori infected, after H. pylori eradication, and H. pylori uninfected) and suggests a scoring system for estimating potential gastric cancer risk [35-40]. The endoscopic findings outlined in the Kyoto classification and those of recent studies are summarized in Table 1 and are discussed below.
Helicobacter pylori infection status and representative endoscopic findings
1. Endoscopic findings unrelated to H. pylori infection
1) Regular arrangement of collecting venules
Regular arrangement of collecting venules (RAC) refers to the appearance of multiple regular small veins in the gastric body and is a useful indicator for identifying gastric mucosa uninfected by H. pylori (Fig. 1A, 1B) [41]. With the development of high-definition white light, image-enhanced and magnifying endoscopy, RAC has been confirmed as a finding of non-infection [41,42]. A meta-analysis also found that the presence of RAC on endoscopy is a reliable marker for excluding H. pylori infection [42-44].
Examples of endoscopic images from individuals without Helicobacter pylori infection. Regular arrangement of collecting venules (A, B), linear red streaks (C) and hematin (D).
2) Linear red streak
During endoscopy, linear and hyperemic streaks are frequently observed on the gastric mucosa in patients without H. pylori infection (Fig. 1C) [39]. This finding also helps differentiate patients without H. pylori infection, thereby avoiding unnecessary diagnostic tests [45]. Linear erythema can sometimes be observed together with erosion or hematin (Fig. 1D) [45].
2. Endoscopic findings observed in current H. pylori infection
1) Atrophic gastritis and intestinal metaplasia
Atrophic gastritis refers to a progressive condition with increasing loss of gastric glands due to chronic H. pylori infection [46]. The endoscopic findings of atrophic gastritis include thinning of the mucosa, visible blood vessels, and flattening or loss of wrinkles on the mucosal surface (Fig. 2A) [46]. These changes generally begin in the pyloric antrum and progress to the gastric body [47]. Intestinal metaplasia is a phenomenon where gastric mucosal cells transform into intestinal cells, which is a precancerous condition [48]. Endoscopically, intestinal metaplasia may appear as flat elevated lesions with a white or yellowish-white color, an irregular surface, and villi (Fig. 2B).
Examples of endoscopic images from individuals with current Helicobacter pylori infection. Atrophic gastritis (A), intestinal metaplasia (B), nodular/lymphofollicular gastritis (C, D), enlarged folds (E, F), sticky mucus (G, H), spotty redness (I), diffuse redness (J), and foveolar hyperplastic polyps (K, L).
2) Nodular/lymphofollicular gastritis
Nodular gastritis is characterized by numerous small nodules in the mucosa on endoscopy, which are usually found in the pyloric region (Fig. 2C, 2D). Nodular gastritis is considered an immune response to H. pylori infection and is particularly common among younger individuals [49]. Histologically, densely packed lymphocytes or monocytic infiltration have been observed [49]. These nodular changes are usually restored after H. pylori eradication therapy [50]. Observational studies on adults with nodular gastritis have suggested an association between nodular gastritis and gastric cancer, particularly diffuse-type gastric cancer [50,51]. Therefore, if nodular gastritis is observed endoscopically, diagnostic tests for H. pylori infection and subsequent eradication therapy are necessary [50].
3) Enlarged folds and sticky mucus
Enlarged fold or rugal hyperplasia is characterized by the thickening of the gastric fold width by >5 mm, which is not or partially flattened under air inflation (Fig. 2E, 2F) [35]. Sticky mucus is a condition in which excessively secreted mucus is attached to the gastric mucosal surface, and is commonly found in the gastric corpus (Fig. 2G, 2H) [14,52]. These conditions disappear after successful eradication therapy. Notably, enlarged or tortuous folds along with sticky mucus, diffuse redness, and/or nodular gastritis, are typically associated with active H. pylori infection and an increased risk of developing diffuse-type gastric cancer [35,53,54].
4) Spotty or diffuse redness
Spotty redness refers to small red spots scattered irregularly on the gastric mucosal surface resulting from a local inflammatory reaction (Fig. 2I). Spotty redness typically disappears after H. pylori eradication treatment (Fig. 3) [12,13]. Diffuse redness reflects excessive congestion of the mucosa, appearing as hyperemic mucosa with clearly visible blood vessels on endoscopy [55,56]. Diffuse redness is observed in the gastric corpus mucosa without atrophic changes (Fig. 2J). This finding is associated with an acute inflammatory reaction and is an early sign of H. pylori infection [13].
Examples of spotty redness before (A) and after Helicobacter pylori eradication (B).
5) Foveolar hyperplastic polyp
Foveolar polyp is a benign tumor in the gastric mucosa observed as a small bump on the mucosal surface during endoscopy (Fig. 2K, 2L). These polyps are associated with atrophic gastritis and are frequently observed in the presence of H. pylori infection [57]. Because these polyps sometimes regress after H. pylori eradication, eradication therapy may be considered depending on their size [58].
3. Endoscopic indicators of past infection of H. pylori
1) Xanthoma
Xanthoma is a condition in which lipid-laden histiocytes are deposited in the gastric mucosa, appearing as small yellow or yellowish-white spots, or nodules on endoscopy (Fig. 4A) [59]. It is the result of a chronic inflammatory response, due to current or previous H. pylori infection, and is often accompanied by background mucosal atrophy [58]. A recent retrospective study reported that gastric xanthomas were more frequently observed in the precancerous lesion (8.39%) or gastric cancer groups (5.44%) than in the chronic gastritis group (2.29%) [60]. Therefore, in addition to identifying H. pylori infection, careful examination of precancerous gastric lesions and early gastric cancer is necessary when gastric xanthomas are observed during endoscopy.
Endoscopic images of individuals previously infected with Helicobacter pylori. Xanthomas (A) and map-like redness (B).
2) Map-like redness
Map-like redness is identified by irregular, patchy areas of redness in the gastric mucosa (Fig. 4B) [37]. This endoscopic finding has a high specificity for indicating previous H. pylori infection and is histologically associated with intestinal metaplasia [61]. The distinctive appearance of map-like redness is attributed to the loss of diffuse redness in the non-atrophic mucosa after successful eradication therapy, which enhances the contrast between the non-atrophic and atrophic mucosa [37].
Recent studies on the diagnosis of H. pylori infection based on endoscopic findings
With the increasing number of endoscopic examinations and growing awareness among endoscopists, H. pylori infection status is now frequently predicted and estimated during endoscopy [13,62]. Furthermore, the clinical application of Kyoto classification and advancements in endoscopic techniques have led to numerous studies focusing on the clinical diagnosis of H. pylori infection using endoscopic findings.
In a previous study, Watanabe et al. [63] investigated the accuracy of diagnosing H. pylori infection based on endoscopic findings in 77 patients. Eleven endoscopic findings, including RAC, linear erythema, rugal hypertrophy, spotty redness, edema, hemorrhage, fundic gland polyps, and mottled patchy erythema, were used to categorize patients into H. pylori-uninfected, H. pylori-infected, and H. pylori-eradicated groups. They found that the diagnostic accuracy was highest in the H. pylori-uninfected group (88.9%), followed by H. pylori-infected (62.1%), and H. pylori-eradiated groups (55.8%). This study also analyzed the diagnostic results based on the experience level of the endoscopist, revealing that inter-observer agreement was low among beginners (<500 endoscopies). The low diagnostic yield improved significantly after 2 years of daily training on endoscopic findings, suggesting that continuous education and training are important for enhancing the diagnostic performance.
A recent prospective multicenter study involving 650 patients investigated the accuracy and robustness of the Kyoto classification for diagnosing H. pylori infection [64]. This study analyzed not only 17 endoscopic findings of the Kyoto classification but also the disappearance of the boundary of atrophic gastritis and the recovery of RAC. In cases of active infection, nodularity and diffuse redness showed high diagnostic accuracy, whereas RAC was identified as a finding specific to non-infection. Additionally, the disappearance of the boundary of atrophic gastritis and reappearance of the RAC pattern in atrophic mucosa partially supplemented the diagnosis of past infection. Another study that included 836 patients confirmed that the Kyoto classification system and RAC findings are essential tools for predicting H. pylori infection [52]. Mucosal swelling and sticky mucus also demonstrated high positive predictive values for H. pylori infection. However, the predictive value was low when open-type atrophic gastritis or intestinal metaplasia was present, indicating that the role of endoscopic diagnosis is limited in such conditions.
Because the Kyoto classification utilizes several endoscopic findings, attempts have been made to develop a simple scoring system. Seo et al. [45] proposed a new scoring system based on three endoscopic findings to predict H. pylori infection: loss of RAC, nodularity, and diffuse or spotty redness. This scoring system had a high prediction accuracy for H. pylori infection in the validation set, with a prediction rate of 96% when two findings were present and 99% when all three were present. Therefore, they suggested that H. pylori testing should be considered when these findings are observed.
Two recent studies highlighted the scratch sign as a helpful marker for diagnosing H. pylori infection [65,66]. The scratch sign, a longitudinal scrape mark visible during endoscopy, is predictive of H. pylori non-infection with high specificity and predictive value (Fig. 5) [65]. Another study confirmed this finding, showing a significant negative association between the scratch sign and sticky mucus, a common feature of H. pylori infection [66]. Scratch signs on endoscopy can therefore effectively predict a low likelihood of H. pylori infection.
Endoscopic images of the “scratch sign.” These findings were observed as a longitudinal scrape mark visible during endoscopy. (A) Close view and (B) far view.
The feasibility of endoscopic prediction of H. pylori infection during screening endoscopy was also investigated. In a prospective cohort study that included 1,784 subjects without eradication history of H. pylori, endoscopic estimation of H. pylori infection status using the Kyoto classification was compared with the ABC methods that combine serology and pepsinogen I and II tests [67]. Using the ABC method as the reference standard, the false-negative rate of endoscopic diagnosis of H. pylori infection was 16.3%. Most of these cases were in group B, which included patients with mild mucosal atrophy. Thus, although endoscopic diagnosis of H. pylori infection is generally reliable in mass gastric cancer screening programs, false-negative results can occur in cases with mild atrophy. The authors further investigated the reliability of the Kyoto classification combined with serum anti-H. pylori antibody testing and found that combined endoscopic diagnosis and serology showed the highest hazard ratio for gastric cancer detection compared to endoscopic diagnosis or ABC method [68].
Considering recent evidence, the presence of RAC or scratch signs on endoscopy is the primary indicator for diagnosing H. pylori status, particularly for non-infection status. Subsequently, if nodularity in the gastric antrum, mucosal swelling, or spotty or diffuse redness in the gastric corpus is observed, the possibility of current H. pylori infection should be considered. However, in cases with advanced atrophic gastritis or intestinal metaplasia, differentiating between active and past infections based solely on endoscopic findings is challenging, and a comprehensive approach using various diagnostic methods for H. pylori infection in conjunction with endoscopic findings should be considered.
Conclusions
Although its prevalence is reportedly declining, H. pylori infection remains a concern for many individuals worldwide. Endoscopic characteristics associated with H. pylori infection are increasingly recognized as useful indicators for predicting the H. pylori infection status. Because invasive methods for the diagnosis of H. pylori infection usually require tissue samples, selective testing in patients with a high probability of infection based on endoscopic findings, rather than large-scale screening, would be beneficial. Notably, identifying the endoscopic features indicative of the non-infection status of H. pylori, such as RAC or linear red streaks, can help avoiding unnecessary testing. Further studies are needed to improve the accuracy of endoscopic diagnosis, particularly in differentiating between current and previous H. pylori infection, and in the presence of atrophic gastritis and/or intestinal metaplasia.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This research was supported by a National Research Foundation (NRF) grant funded by the Korean government (MIST) (NRF-2021R1C1C1010631).
Author contributions
Conceptualization: KJ, EJG. Investigation: KJ, EJG. Supervision: KJ. Writing - original draft: KJ. Writing, review, and editing: EJG. Approval of the final manuscript: all authors.