Xanthelasma is a rare benign lesion encountered during upper gastrointestinal (GI) endoscopy examination. As early as 1887, Orth (1) first recorded this entity. Subsequently, some terms such as “xanthoma” and “lipid island” have been successively used to describe this disease (2, 3). Now, the term “xanthelasma” is widely accepted and used (4, 5). It appears as a yellow-white nodule or plaque under endoscopy, with a size ranging from 1 to 10 mm (6). The most common site is the stomach which also occurs in the esophagus and duodenum. The reported prevalence of gastric xanthelasma (GX) ranges from 0.018 to 7.7% (7–13).

As is well known, Helicobacter pylori (H. pylori) is a microaerophilic, gram-negative bacterium commonly found in the stomach (14). The chronic inflammation of gastric mucosa induced by its infection is closely related to the progression of the gastritis-atrophy-metaplasia-dysplasia-cancer sequence (15). In recent decades, limited research has explored the correlation between GX and various factors, such as H. pylori infection, atrophic gastritis (AG), intestinal metaplasia (IM), and gastric cancer (8, 13, 16–19). However, most studies have a small sample size, and the results are still inconclusive. In addition, no study has investigated the clinical significance of esophageal/duodenal xanthelasma.

Consequently, we performed a large retrospective study investigating the relationship between xanthelasma (including gastric and esophageal/duodenal) and upper GI endoscopic or histopathological features. Moreover, we also evaluated whether AG or IM plays some role in the relationship between H. pylori infection and GX.

The present analysis supported that H. pylori infection, AG, and IM were independent risk factors of GX. It also revealed that the GX risk might increase further in individuals with H. pylori-related AG/IM. As for esophageal/duodenal xanthelasma, the connection between it and upper GI diseases was not discovered.

Due to the rarity of esophageal/duodenal xanthelasma, there have been few reports on it. Gencosmanoglu (7) showed that the incidence of xanthelasma in the stomach, esophagus, and duodenum was 76, 12, and 12%, respectively. Although the etiology of xanthelasma is still unknown, most authors believed xanthelasma might be related to inflammation caused by mucosal damage or aging (20, 21). This may explain why xanthelasma incidence in the esophagus was lower than in the stomach, as the esophageal mucosa has better damage tolerance. (7). To date, no research has explored whether esophageal/duodenal xanthelasma has the same significance as GX. Our study found that unlike GX, esophageal/duodenal xanthelasma may not be associated with upper GI diseases, or more specifically, H. pylori infection, AG, IM, and gastric cancer. However, this discovery requires further confirmation from larger sample size studies, and the etiology and specific mechanism still need to be investigated.

It is well known that H. pylori can cause various GI diseases, such as peptic ulcer, AG, IM, and gastric cancer (22). Prior small-sample studies also showed a positive correlation between H. pylori and GX (16, 23). However, other studies did not find a relation between H. pylori and GX (13, 17, 18). This contradiction between studies might be partly due to different rates of H. pylori infection in different regions, small sample sizes, and various detection methods. In 1996, Hori (16) conducted H. pylori antigen localization analysis on 145 xanthelasma biopsy specimens and identified H. pylori infection on the surface of concave cells in 69 (48%) samples. More than half of the antigens were penetrated into the lamina propria. These findings may support the hypothesis that H. pylori infection is the etiology of some xanthelasmas.

Patients with AG/IM raise the risk of gastric adenocarcinoma. For advanced AG or extensive IM, an endoscopic examination every three years is recommended (24). Multiple publications have noted a positive relationship between GX and AG/IM (8, 13, 19, 25). The current study also demonstrated that AG and IM were independent risk factors for GX. However, no relationship was found between the location distribution of AG/IM and GX. To the best of our knowledge, no research has clarified the association between GX and H. pylori-related AG/IM. Therefore, we conducted a further analysis that stratified cases based on H. pylori infection and AG/IM statuses. The results indicated that patients with simple H. pylori infection had a 1.6-fold risk for GX, which increased when H. pylori infection caused AG/IM (OR 4.0–4.6). In addition, our study found that multiple GXs had a higher rate of IG/IM than single GX, which was consistent with the findings of Köksal (8). Our result may indicate that the higher the number of GX, the greater the likelihood of IG/IM.

Moreover, Sekikawa (9, 10) and Shibukawa (26, 27) believed that the presence of GX was a predictive indicator of gastric cancer. Kaiserling (28) speculated that the increased release of oxygen free radicals might simultaneously play a role in the development of gastric cancer and GX. In this analysis, although the Chi-square test indicated that gastric cancer was more common in individuals with GX (1.5 vs. 0.9%, p = 0.038), multivariate analysis did not find an independent correlation between gastric cancer and GX, which might be related to a lower detection rate of gastric cancer in our cohort.

Several limitations of our study must be considered. Firstly, a retrospective single-center study design increased the possibility of bias. Secondly, information on the history of H. pylori eradication was not available. Thirdly, we did not evaluate interobserver variability in assessing endoscopic findings. Furthermore, we could not obtain the specific stages of the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis/Intestinal-Metaplasia Assessment (OLGIM) due to insufficient gastric biopsy sites. Despite these shortcomings, our study elucidated the relationship between GX and upper GI diseases with a relatively large sample size to determine whether xanthelasma could serve as a warning sign for gastric precancerous lesions. Moreover, this is the first report on risk factors for esophageal/duodenal xanthelasma.

In summary, the results demonstrated an increased risk of GX in subjects with H. pylori infection, AG and IM, especially H. pylori-related AG/IM. Although GX is a benign lesion, sufficient attention should be given during the endoscopic examination. Endoscopists should spend more time on patients with gastric xanthelasma, especially those with multiple GXs, to rule out H. pylori infection, precancerous lesions, and even gastric cancer.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by this study has been approved by the Ethical Committees of Tongji Hospital of Tongji Medical College [TJ-IRB20230431]. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because the informed consent was waived as only de-identified data was analyzed.

LF, JG, YZ, RD, and YH conceived and designed this study. JG, YZ, MZ, LF, SX, and JL participated in data collection, interpretation and analysis. LF, MZ, YH, KZ, and FX wrote the first draft of the manuscript. LF, JG, RD, KZ, and SX prepared the figures and tables. JL and FX revised the primary manuscript. All authors contributed to the article and approved the submitted version.

This work is supported by the Subproject of the National Key Research and Development Program (no. 2021YFC2600263).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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