Potassium-competitive acid blocker-associated gastric mucosal lesions

Kimitoshi Kubo; Noriko Kimura; Mototsugu Kato

doi:10.5946/ce.2023.279

Clin Endosc > Epub ahead of print

Kubo, Kimura, and Kato: Potassium-competitive acid blocker-associated gastric mucosal lesions

Review

Clin Endosc 2024; ce.2023.279.

Published online: February 29, 2024

DOI: https://doi.org/10.5946/ce.2023.279

Potassium-competitive acid blocker-associated gastric mucosal lesions

Kimitoshi Kubo¹

, Noriko Kimura²

, Mototsugu Kato^1,³

¹Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, Japan

²Department of Pathology, National Hospital Organization Hakodate National Hospital, Hakodate, Japan

³Hokkaido Cancer Society, Sapporo, Japan

Correspondence: Kimitoshi Kubo Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, 18-16 Kawahara-cho, Hakodate, 041-8512 Hokkaido, Japan E-mail: kubotti25@yahoo.co.jp

Received November 2, 2023 Revised November 23, 2023 Accepted November 27, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Since the introduction of vonoprazan, a potassium-competitive acid blocker (P-CAB), it has been demonstrated to reversibly inhibit gastric acid secretion by engaging in potassium-competitive ionic binding to H⁺/K⁺-ATPase. In contrast, proton pump inhibitors (PPIs) achieve H⁺/K⁺-ATPase inhibition through covalent binding to cysteine residues of the proton pump. Reported cases have indicated an emerging trend of P-CAB-related gastropathies, similar to those associated with PPIs, as well as unique gastropathies specific to P-CAB use, such as the identification of web-like mucus. Pathologically, parietal cell profusions, which show a positively correlated with hypergastrinemia, have a higher incidence in P-CAB users compared to PPI users. Thus, this review aims to summarize the endoscopic and pathological findings reported to date concerning P-CAB-related gastric mucosal lesions. Additionally, it seeks to discuss the differences between the PPIs and P-CABs in terms of the formation and frequency of associated gastropathies. This review highlights the evident differences in the mechanism of action and potency of acid inhibition between P-CABs and PPIs, notably contributing to differences in the formation and frequency of associated gastropathies. It emphasizes the necessity to distinguish between P-CAB-related and PPI-related gastropathies in the clinical setting.

Keywords: Acid-related disorders; Adverse effects; Potassium-competitive acid blocker; Proton pump inhibitors; Vonoprazan

INTRODUCTION

Proton pump inhibitors (PPIs) have been used worldwide to treat acid-related disorders, such as gastroesophageal reflux disease and peptic ulcer disease, as well as for preventing gastroduodenal mucosal damage induced by nonsteroidal anti-inflammatory drugs.¹ Recently, vonoprazan, a potassium-competitive acid blocker (P-CAB), has been developed and approved for clinical use in Japan.² It acts by reversibly inhibiting gastric acid output through K⁺-competitive ionic binding to H⁺/K⁺-ATPase,³ distinguishing itself from PPIs that inhibit the gastric H⁺/K⁺-ATPase via covalent binding to cysteine residues of the proton pump, thereby impeding acid output. Notably, PPIs exhibit certain characteristics, including: (1) a delayed onset of acid inhibition; (2) a short blood half-life resulting in insufficient inhibition of acid secretion throughout the day and night; and (3) intragastric pH achieved with a PPI that depends on the CYP2C19 genotype status.⁴ In contrast, the P-CAB is characterized by its ability to rapidly suppress acid secretion and provide sustained acid-suppressing effect from the first day of administration. Thus, since its introduction, the frequency of P-CAB use has increased. A comparative study, assessing the 24-hour pH ≥4 holding time between the P-CAB and PPIs, demonstrated a more potent acid-inhibitory property for the P-CAB than for PPIs.⁵ Moreover, although both PPIs and P-CAB induce a low acid state in the stomach, prompting gastrin secretion from antral G cells,⁶ a comparative study on long-term administration revealed notably higher serum gastrin levels in individuals receiving P-CAB (median, 870 pg/mL; range, 120–3,000 pg/mL) compared to those receiving PPIs (median, 440 pg/mL; range, 87–2,000 pg/mL).⁷ Thus, P-CAB demonstrates greater potency in inhibiting acid secretion corresponding with elevated serum gastrin levels compared to PPIs.

PPI-induced hypergastrinemia has been reported to result in histopathological changes, including parietal cell protrusion (PCP) into the gland lumen and cystic dilation of the gastric fundic gland. These changes are associated with characteristic endoscopic findings known as PPI-related gastropathies.⁸^-¹³ Recent reports have highlighted similar and novel gastropathies associated with P-CABs, suggesting the importance of recognizing these P-CAB-related gastropathies in clinical setting. Thus, this review aimed to summarize the endoscopic and pathological findings reported to date on P-CAB-related gastric mucosal lesions (Table 1) and to discuss the differences between PPIs and P-CABs in the formation and frequency of associated gastropathies.

P-CAB-ASSOCIATED GASTRIC MUCOSAL LESIONS

Fundic gland polyps

Fundic gland polyps (FGPs) occur in the gastric corpus and fundus, characterized by their small size (<1 cm), whitish-reddish appearance, and smooth-surfaced texture with clear boundaries (Fig. 1A). A meta-analysis of 12 studies established a notable association between the use of PPIs and an increased prevalence of FGPs (odds ratio [OR], 2.46; 95% confidence interval [CI], 1.42–4.27). This association was observed with long-term PPI use (PPI use ≥6 months: OR, 4.71; 95% CI, 2.22–9.99; PPI use ≥12 months: OR, 5.32; 95% CI, 2.58–10.99).¹⁴ Notably, FGPs may develop and increase in frequency with long-term PPI administration, showing a tendency to decrease following PPI discontinuation. Equally noteworthy are two recent case reports documenting the regression of FGPs following P-CAB discontinuation.¹⁵^,¹⁶ Of the two case reports, Iwamuro et al.¹⁵ reported a case wherein FGPs regressed after transitioning from P-CAB to a histamine-2 (H2) blocker. The other case report by Nishimura et al.¹⁶ discussed the notable decrease and regression of FGPs subsequent to P-CAB discontinuation in a patient with anemia, with a concomitant reduction in serum gastrin levels compared to that before drug discontinuation. Moreover, Haruma et al.¹⁷ conducted a multicenter prospective study (VISION trial) and reported a noteworthy increase in the prevalence of FGPs from 43.7% to 66.1% over a three-year period following the initiation of P-CAB therapy. Additionally, Shinozaki et al.¹⁸ found a notably higher prevalence of FGPs among patients receiving P-CAB for more than one year compared to that in non-P-CAB users. Their association with P-CAB use was further validated through multivariate analysis (OR, 2.20; 95% CI, 1.41–3.44).

Hyperplastic polyps

A hyperplastic polyp (HP) is identifiable as a reddish lesion with a papillary surface, often involving swelling of the crypt epithelium (Fig. 1B). In a study by Hongo et al.,¹⁹ it was reported that HP was present in 8.9% of long-term PPI users and that new instances of HP occurred in 5.9% and 22.2% of patients with FGP and HP, respectively. HP has been observed to develop and increase in frequency with long-term PPI administration, a trend that decreases following PPI discontinuation. In line with these observations, two recent case reports underscore the regression of HP following P-CAB discontinuation.¹⁵^,²⁰ Of the two case reports, Iwamuro et al.¹⁵ detailed a case of HP regression after transitioning from the P-CAB to an H2 blocker, while Goto et al.²⁰ reported a case where HP notably reduced after switching from P-CAB to an H2 blocker in a patient with severe anemia, subsequently improving the anemia condition. Results from the VISION trial¹⁷ highlighted a notable increase in the prevalence rate of HPs from 3.7% to 14.7% over a three-year period in patients initiating P-CAB treatment. Additionally, Shinozaki et al.¹⁸ reported a notably higher prevalence of HP among patients receiving P-CAB for more than one year compared to that of non-P-CAB users. The association of HP with P-CAB use was reaffirmed through multivariate analysis (OR, 3.37; 95% CI, 1.44–7.90).

Multiple white and flat elevated lesions

Multiple white and flat elevated lesions (MWFELs) are characterized by white, round, and slightly elevated mucosa with a smooth surface, appearing circumscribed and sharply marginated (Fig. 1C, D).²¹ These lesions are distributed in various locations in the upper corpus and, histologically, represent hyperplastic changes in the foveolar epithelium with normal fundic glands.²² In an observational study by Hatano et al.,²¹ MWFELs were notably associated with PPI use (OR, 3.58; 95% CI, 1.94–6.61) and Helicobacter pylori eradication therapy. The VISION trial¹⁷ demonstrated an increase in the prevalence of MWFELs from 2.2% to 6.4% over a three-year period following the initiation of P-CAB treatment. Moreover, Shinozaki et al.²³ reported a notably higher prevalence of MWFELs among patients receiving P-CAB for more than one year compared to that in non-P-CAB users, with its association with P-CAB use reaffirmed through multivariate analysis (OR, 1.77; 95% CI, 1.14–2.74).

Cobblestone-like mucosa

Cobblestone-like mucosa (CLM) is characterized by gastric mucosa displaying a cobblestone-like appearance, endoscopically detected as multiple smooth, elevated lesions in the corpus under white-light imaging (Fig. 1E). Histologically, CLM is identified by PCP and cystic dilatation of the fundic glands, with these changes typically observed in non-atrophic mucosa with abundant fundic glands.²⁴ In an observational study by Hatano et al.,²¹ CLM demonstrated a notable association with PPI use (OR, 4.57; 95% CI, 2.34–9.96). Notably, Miyamoto et al.²⁵ reported a case of CLM exhibiting similar endoscopic and pathological findings after six months of P-CAB use. The VISION trial¹⁷ reported a notable increase in the prevalence of CLMs from 3.0% to 14.7% over a three-year period in patients initiating P-CAB treatment. Additionally, Shinozaki et al.¹⁸ reported a notably higher prevalence of CLM in patients using P-CAB for more than one year compared to that in non-P-CAB users, with its association shown with P-CAB use confirmed through multivariate analysis (OR, 2.55; 95% CI, 1.03–6.32).

Black spots

Black spots (BS), characterized as black pigmentations within the gastric mucosa observed during conventional endoscopy, are exclusively identified in the fundic gland region (Fig. 1F). Histologically, BS consists of eosinophilic contents and brownish pigmentations within fundic gland cysts.²⁶ Kiso et al.²⁷ reported the frequency of BS to be 5.7% among PPI users and 3.2% among non-PPI users. An observational study by Hatano et al.²¹ demonstrated a notable association between BS and PPI use (OR, 2.94; 95% CI, 1.66–5.21) and H. pylori eradication therapy (OR, 3.01; 95% CI, 1.73–5.24). Notably, the VISION trial¹⁷ indicated an increase in the prevalence of BS from 0.7% to 5.5% over a three-year period following the initiation of P-CAB treatment. However, the components of BS and its mechanism of formation remain unknown.

Gastric mucosal redness

Gastric mucosal redness (GMR) is characterized by linear and spotty redness in the gastric body and was initially reported as a P-CAB-related gastropathy (Fig. 2A–C). Kubo et al.²⁸ reported four cases of GMR emerging after the initiation of P-CAB treatment and subsequently disappearing upon its discontinuation. Histologically, GMR is characterized by the presence of inflammatory cell infiltration, PCP, oxyntic gland dilatation, congestion, focal hemorrhage with congestion beneath the basement membrane, and vacuolar degeneration of parietal cells.²⁹ The mechanism of GMR formation is suspected to involve hypergastrinemia, given that serum gastrin levels are elevated in patients with GMR. Notably, Shinozaki et al.²³ reported a higher prevalence of GMR in patients receiving the P-CAB and PPIs for over one year compared to that in non-P-CAB/non-PPI users, with its association with P-CAB use (OR, 3.42; 95% CI, 1.48–7.90) and PPI use (OR, 2.67; 95% CI, 1.14–2.74) confirmed through multivariate analysis.

White spots

White spots (WS) is characterized by a small, white hemispheric protrusion, with its surface exhibiting regular microscopic vesicles under magnifying narrow-band imaging (Fig. 2D–F). WS was first identified as a P-CAB-related gastropathy.³⁰^,³¹ Histologically, WS is characterized by a dilated gland containing either eosinophilic material with necrotic epithelial fragments or a mucus pool.³⁰^-³³ Iwamuro et al.³⁴ reported two cases of WS in P-CAB and PPI users. Miwa et al.³⁵^,³⁶ reported a case of WS emerging after the initiation of P-CAB treatment and subsequently disappearing after transitioning to a PPI. The findings by Yoshizaki et al.³² revealed a notably higher prevalence of WS in P-CAB used compared to that in non-P-CAB users (4.9% vs 0.2%, p<0.001), with an association of >205 days of P-CAB use (OR, 6.99; 95% CI, 4.60–10.88), confirmed through multivariate analysis. Shinozaki et al.²³ also reported a notably higher prevalence of WS in patients receiving a P-CAB and a PPI for more than one year compared to non-P-CAB/non-PPI users, with its association with P-CAB use (OR, 192.69; 95% CI, 60.20–616.77) and PPI use (OR, 23.19; 95% CI, 6.55–82.08) verified through multivariate analysis. Moreover, Nishiyama et al.³³ demonstrated a notably larger number of patients with high serum gastrin levels among patients positive for WS (18/31) compared to that in patients negative for WS (5/43) (p<0.001). This suggests an association between WS and hypergastrinemia, implying that P-CAB-related hypergastrinemia may be involved in the formation of WS. Mechanistically, it may be hypothesized that hypergastrinemia induces structural disruption in the area extending from the isthmus to the neck of the gland, leading to the obstruction of mucus outflow from the gland, ultimately resulting in cystic dilation of the gland.

Web-like mucus

Web-like mucus is characterized by white, transparent mucus that proves challenging to remove through water rinsing. This mucus is predominantly observed in the area from the fundus to the greater curvature of the body (Fig. 2G–I).³⁷ The mechanism of its formation has been speculated to be linked to the strong and sustained inhibition of acid secretion by the P-CAB.

Histopathology of the gastric mucosa during P-CAB and PPI therapy

PCP, a pathological finding associated with PPI-related gastropathy, has been reported to be positively correlated with hypergastrinemia.⁹ The VISION trial provided information on the histopathology of the gastric mucosa during a three-year period of P-CAB maintenance therapy. PCP was observed in 102/109 (93.6%) patients in the P-CAB group, compared to 45/57 (78.9%) patients in the PPI group, based on gastric mucosal biopsies performed three years after the administration of either drug. Moreover, one patient in the P-CAB group developed hyperplastic endocrine cell micro nests, but none developed gastric neuroendocrine tumors.

CONCLUSIONS

The emergence of P-CAB-related gastropathies, shared with PPIs (FGPs, HP, MWFEL, CLM, and BS) and unique to P-CABs (GMR and WS), marks a notable development since the introduction of P-CABs. Additionally, web-like mucus has also been reported as a gastropathy specific to P-CABs. The observed differences in the mechanism of action and potency of acid inhibition between P-CABs and PPIs greatly contribute to the differences in the formation and frequency of associated gastropathies, indicating the need to promote recognition of the differences between P-CAB-related and PPI-related gastropathies in clinical setting. However, it is important to note that the endoscopic findings of the P-CAB-associated gastropathies described here were derived from the users of vonoprazan and that, to date, no similar endoscopic features have been reported in the users of other P-CABs, such as tegoprazan and fexuprazan.

NOTES

Conflicts of Interest

The authors have no potential conflicts of interest.

Funding

None.

Author Contributions

Conceptualization: KK; Investigation: all authors; Methodology: all authors; Supervision: KK; Validation: KK, MK; Writing–original draft: KK; Writing–review and editing: all authors.

Fig. 1.

Endoscopic findings of potassium-competitive acid blocker-related gastric mucosal lesions. (A) Fundic gland polyps. (B) Hyperplastic polyps. (C, D) Multiple white and flat elevated lesions. (E) Cobblestone-like mucosa. (F) Black spots. Written informed consent was obtained from the patients for publication of the case report as part of the review and any accompanying images included.

Fig. 2.

Endoscopic findings of potassium-competitive acid blocker-related gastric mucosal lesions. (A, B, C) Gastric mucosal redness observed on white-light imaging (WLI) was highlighted on texture and color enhancement imaging (TXI) mode 1 and narrow-band imaging (NBI), respectively. (D, E, F) White spots observed on WLI were highlighted on NBI. Magnifying endoscopy with NBI showed the mucosal surface of white spots to be rich in microscopic vessels. (G, H, I) Web-like mucus observed on WLI was highlighted on TXI mode 1 and NBI, respectively. Written informed consent was obtained from the patients for publication of the case report as part of the review and any accompanying images included.

Table 1.

Summary of PPI/P-CAB-related gastropathies reported to date

	PPI-related gastropathy	P-CAB-related gastropathy	Endoscopic findings	Pathological findings
Fundic gland polyps	〇	〇	Small, whitish-reddish, and smooth-surfaced polyps with clear boundaries	PCP and cystic dilatation of fundic glands
Hyperplastic polyps	〇	〇	Reddish, and its surface is papillary and crypt epithelium is swelling	Foveolar epithelial hyperplasia
Multiple white and flat elevated lesions	〇	〇	White, round, and slightly elevated mucosa with smooth surface	Foveolar epithelial hyperplasia
Cobblestone-like mucosa	〇	〇	Gastric mucosa that has cobblestone-like appearance	PCP and cystic dilatation of fundic glands
Black spots	〇	〇	Black pigmentations in the gastric mucosa	Eosinophilic contents and brownish pigmentations in fundic gland cysts
Gastric mucosal redness	△	〇	Linear and spotty redness	Inflammatory cell infiltration, PCP, oxyntic gland dilatations, congestion, focal hemorrhage with congestion beneath the basement membrane, and vacuolar degeneration of parietal cells
White spot	△	〇	A small white hemispheric protrusion	Dilated gland containing eosinophilic material with necrotic epithelial fragments or a mucus pool
Web-like mucus	×	〇	White, transparent mucus	Unclear

PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker; PCP, parietal cell protrusion.

REFERENCES

1. Strand DS, Kim D, Peura DA. 25 Years of proton pump inhibitors: a comprehensive review. Gut Liver 2017;11:27–37.

2. Arikawa Y, Nishida H, Kurasawa O, et al. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyrid in-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem 2012;55:4446–4456.

3. Parsons ME, Keeling DJ. Novel approaches to the pharmacological blockade of gastric acid secretion. Expert Opin Investig Drugs 2005;14:411–421.

4. Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther 2000;14:1259–1266.

5. Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects: a randomised open-label cross-over study. Aliment Pharmacol Ther 2015;42:719–730.

6. Jansen JB, Klinkenberg-Knol EC, Meuwissen SG, et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990;99:621–628.

7. Kojima Y, Takeuchi T, Sanomura M, et al. Does the novel potassium-competitive acid blocker vonoprazan cause more hypergastrinemia than conventional proton pump inhibitors?: a multicenter prospective cross-sectional study. Digestion 2018;97:70–75.

8. Wang TC, Koh TJ, Varro A, et al. Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest 1996;98:1918–1929.

9. Cats A, Schenk BE, Bloemena E, et al. Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum Pathol 2000;31:684–690.

10. Kumar KR, Iqbal R, Coss E, et al. Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors. Hum Pathol 2013;44:2706–2710.

11. Stolte M, Bethke B, Seifert E, et al. Observation of gastric glandular cysts in the corpus mucosa of the stomach under omeprazole treatment. Z Gastroenterol 1995;33:146–149.

12. Declich P, Ambrosiani L, Bellone S, et al. Parietal cell hyperplasia with deep cystic dilations: a lesion closely mimicking fundic gland polyps. Am J Gastroenterol 2000;95:566–568.

13. Kim GH. Proton pump inhibitor-related gastric mucosal changes. Gut Liver 2021;15:646–652.

14. Martin FC, Chenevix-Trench G, Yeomans ND. Systematic review with meta-analysis: fundic gland polyps and proton pump inhibitors. Aliment Pharmacol Ther 2016;44:915–925.

15. Iwamuro M, Shiraha H, Okada H. Gastric polyps’ regression after potassium-competitive acid blocker cessation. J Gen Fam Med 2022;23:358–359.

16. Nishimura N, Mizuno M, Matsueda K. Gastroduodenal intussusception due to vonoprazan-induced gastric polyps. Intern Med 2022;61:1305–1306.

17. Haruma K, Kinoshita Y, Yao T, et al. Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis. BMC Gastroenterol 2023;23:139.

18. Shinozaki S, Osawa H, Hayashi Y, et al. Changes in gastric morphology during long-term use of vonoprazan compared to proton pump inhibitors. Singapore Med J 2022;63:283–287.

19. Hongo M, Fujimoto K; Gastric Polyps Study Group. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan. J Gastroenterol 2010;45:618–624.

20. Goto C, Okimoto K, Matsusaka K, et al. Long-term vonoprazan administration causes gastric fundic gland-type hyperplastic polyps and chronic bleeding. Clin J Gastroenterol 2023;16:159–163.

21. Hatano Y, Haruma K, Kamada T, et al. Factors associated with gastric black spot, white flat elevated mucosa, and cobblestone-like mucosa: a cross-sectional study. Digestion 2018;98:185–193.

22. Uedo N, Yamaoka R, Yao K. Multiple white flat lesions in the gastric corpus are not intestinal metaplasia. Endoscopy 2017;49:615–616.

23. Shinozaki S, Osawa H, Miura Y, et al. The effect of proton pump inhibitors and vonoprazan on the development of ‘gastric mucosal redness’. Biomed Rep 2022;16:51.

24. Miyamoto S, Kudo T, Kato M, et al. Endoscopic ultrasonography features of gastric mucosal cobblestone-like changes from a proton-pump inhibitor. Clin J Gastroenterol 2017;10:220–223.

25. Miyamoto S, Matsuno Y, Kato M, et al. Parietal cell protrusions and dilated oxyntic glands from use of vonoprazan. Am J Gastroenterol 2017;112:1899–1901.

26. Hatano Y, Haruma K, Ayaki M, et al. Black spot, a novel gastric finding potentially induced by proton pump inhibitors. Intern Med 2016;55:3079–3084.

27. Kiso M, Ito M, Boda T, et al. Endoscopic findings of the gastric mucosa during long-term use of proton pump inhibitor - a multicenter study. Scand J Gastroenterol 2017;52:828–832.

28. Kubo K, Kimura N, Matsuda S, et al. Vonoprazan-associated gastric mucosal redness: a report of four cases. Intern Med 2020;59:507–511.

29. Kubo K, Kimura N, Watanabe R, et al. Vonoprazan-associated gastric mucosal redness in non-Helicobacter pylori-infected and Helicobacter pylori-eradicated stomach. Case Rep Gastroenterol 2021;15:751–758.

30. Kinoshita Y, Yamasaki T, Saruta M. Numerous white nodules during continuous administration of a potent gastric acid suppressor. Gastrointest Endosc 2021;93:766.

31. Nishiyama N, Kobara H, Kagawa S, et al. Vonoprazan may cause white globe appearance in nonatrophic mucosa of stomach. Gastrointest Endosc 2021;93:767–768.

32. Yoshizaki T, Morisawa T, Fujinami M, et al. Propensity score matching analysis: incidence and risk factors for “stardust” gastric mucosa, a novel gastric finding potentially induced by vonoprazan. Aliment Pharmacol Ther 2021;53:94–102.

33. Nishiyama N, Kobara H, Ayaki M, et al. White spot, a novel endoscopic finding, may be associated with acid-suppressing agents and hypergastrinemia. J Clin Med 2021;10:2625.

34. Iwamuro M, Tanaka T, Sakae H, et al. Two cases of white globe appearance in non-cancerous stomach. Ecancermedicalscience 2018;12:856.

35. Miwa W, Hiratsuka T, Sato K, et al. Development of white globe appearance lesions in the noncancerous stomach after vonoprazan administration: a report of two cases with a literature review. Clin J Gastroenterol 2021;14:48–58.

36. Miwa W, Hiratsuka T, Sato K, et al. Marked reduction in the number of white globe appearance lesions in the noncancerous stomach after exchanging vonoprazan for esomeprazole treatment: a follow-up case report. Clin J Gastroenterol 2021;14:1046–1051.

37. Haruma K, Kato M, Inoue K, et al. Kyoto classification of gastritis. 3rd ed. Tokyo: Nihon Medical Center; 2023.

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