Hypergastrinemia in Long-Term Use of Proton Pump Inhibitors

Shiotani, Akiko; Katsumata, Ryo; Gouda, Kyousuke; Fukushima, Shinya; Nakato, Rui; Murao, Takahisa; Ishii, Manabu; Fujita, Minoru; Matsumoto, Hiroshi; Sugihara, Takashi

doi:10.1159/000484688

Cited by 26 publications

(19 citation statements)

References 43 publications

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“…The statistical analysis showed that the higher rate of Ki67‐positive cells in the deeper layers of fundic glands and foveolar hyperplastic lesions in patients on PPIs was related to the larger size of FGPs, indicating that PPI treatment promotes proliferation of foveolar type epithelium in the deeper layer of FGPs. In addition to the obstruction of isthmus glands by parietal cell protrusion, a large amount of mucinous product from proliferating foveolar cells, which was promoted by PPI‐induced hypergastrinaemia due to decreased acid secretion and related factors, might enlarge fundic gland cysts and result in FGP enlargement.…”

Section: Discussionmentioning

confidence: 99%

Histological analysis of fundic gland polyps secondary to PPI therapy

et al. 2019

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Aims The aim of this study was to clarify the histopathological features of fundic gland polyps (FGPs) in patients treated with proton pump inhibitors (PPIs) and to investigate the mechanism of enlargement of FGPs after PPI treatment. Methods and results A total of 196 biopsy specimens of FGPs, which consisted of 87 FGPs in patients treated with PPIs (PPI group) and 109 FGPs in patients treated without PPIs (non‐PPI group) were compared histologically using haematoxylin and eosin staining, Ki67 immunohistochemistry and multiplex immunohistochemical stain with Ki67, MUC5AC and MUC6. The significant histological features of FGPs in the PPI group were: larger size of dilated fundic gland cysts, larger number of foveolar and mixture type fundic gland cysts, foveolar cell hyperplasia, parietal cell protrusion, mononuclear cell infiltration and a higher percentage of Ki67‐positive cells in the deeper layers of the glands. Multiplex immunohistochemical stain showed that Ki67‐positive cells were also positive for MUC5AC, and the Ki67‐positive rate was significantly higher in MUC5AC‐positive cells of the PPI group than of the non‐PPI group. Gene mutations of β‐catenin were found in only 9.7% of FGPs in the PPI group. Conclusions Enlargement of fundic gland cysts due to foveolar cell proliferation and parietal cell protrusion might promote the enlargement of FGPs in patients treated with PPIs. β‐catenin gene mutations might not be associated with these histological changes of FGPs after PPI treatment.

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Section: Discussionmentioning

confidence: 99%

Histological analysis of fundic gland polyps secondary to PPI therapy

et al. 2019

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“…Long-term human use of PPIs leads to hypergastrinemia in almost all cases, with fasting serum gastrin (FSG) levels increasing 3 to 5-fold in most subjects, but to much higher levels in 10% to 30% of cases [11]. Higher levels are seen in females and in those with atrophy of the gastric corpus due to CAG, whether auto-immune or due to Helicobacter pylori [27]. Recent studies, however, have shown that FSG levels in PPI users do not reflect the 4-or 5-fold elevations in mean serum gastrin concentrations that occur and persist after meals, particularly in females [28].…”

Section: Observations In Humansmentioning

confidence: 99%

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids—What Is the Relationship?

McCarthy

2020

IJMS

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Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin’s effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

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“…This low incidence may be related to high rates of H. pylori infection in China. However, even in countries with high H. pylori infection rates, FGP frequency may be high, but these polyp have not been observed in several studies [40] . Frequency of FGPs is related to long-term PPI use.…”

Section: Discussionmentioning

confidence: 90%

Evaluation of gastric polyps in patients with upper gastrointestinal endoscopy

zheng¹,

wen²,

Dai³

et al. 2020

Preprint

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Background:According to the study population, incidence of gastric polyps (GPs) varies from 0.33% to 6.7% in various studies. Most GPs consist of hyperplastic polyps (HPs), fundic gland polyps (FGPs), and adenomatous polyps (APs). Despite the high malignant APs potential, sporadic FGPs has no malignant potential. On the contrary, HPs has a lower risk of potential harm. It is not sufficient to perform biopsies to determine the presence of polyp types and displacements, therefore, some polyps may require extensive biopsy or complete resection. MethodsThis retrospective study included GPs patients or polyphenic lesions with polyps or malignant histology found in polyps or gastroscopy at the Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine from 2017 to 2019.ResultsIn a series of 10.000 upper gastrointestinal endoscopy, 384 patients (3.84%) were found to have GPs. Of these patients, 98 (25.5) were male and 286(74.5) were female. The average age of the patients was 62.8±10.4 (36-75) years. HPs, APs and FGPs frequencies were 88.5%, 5.2% and 2.1%, respectively. The polyp size of 274 (71.3%) patients was ≤ 1 cm. Polyp was identified in 262 (68.2%) patients. The most common polyps are the antrum and the corpus. Endoscopic mucosal resection was performed on 128 patients. Bleeding events have been observed and endoscopic treatment is required after ESP.Conclusion: In current study, GPs frequency was low (3.84%), and HP frequency may be high due to high frequency of Helicobacter pylori (HPy) infection in China. Due to the high frequency of HPy infection and the short-term use of proton pump use, FGP frequency may be low.

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Hypergastrinemia in Long-Term Use of Proton Pump Inhibitors

Cited by 26 publications

References 43 publications

Histological analysis of fundic gland polyps secondary to PPI therapy

Histological analysis of fundic gland polyps secondary to PPI therapy

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids—What Is the Relationship?

Evaluation of gastric polyps in patients with upper gastrointestinal endoscopy

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