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LONG-TERM PROTON PUMP INHIBITOR USE AND RISK OF GASTRIC NEUROENDOCRINE NEOPLASMS IN A POPULATION-BASED STUDY FROM THE FIVE NORDIC COUNTRIES

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LONG-TERM PROTON PUMP INHIBITOR USE AND RISK OF GASTRIC NEUROENDOCRINE NEOPLASMS IN A POPULATION-BASED STUDY FROM THE FIVE NORDIC COUNTRIES

Eivind Ness-Jensen 1, Giola Santoni 2, Cecilia Radkiewicz 2, My von Euler-Chelpin 3, Joonas H. Kauppila 4, Helgi Birgisson 5, Reidar Fossmark 6, Jesper Lagergren 7

Affiliations

1 NTNU, Norwegian University of Science and Technology, Levanger, Norway|||Nord-Trøndelag Hospital Trust, Levanger Hospital, Levanger, Norway

2 Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden

3 University of Copenhagen, Copenhagen, Denmark

4 University of Oulu and Oulu University Hospital, Oulu, Finland|||Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden

5 Icelandic Cancer Registry, Reykjavík, Iceland

6 NTNU, Norwegian University of Science and Technology, Trondheim, Norway|||Oslo University Hospital, Oslo, Norway

7 King's College London and Guy’s and St Thomas Foundation Trust, London, United Kingdom|||Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden

Summary

AI Generated

Long-term proton pump inhibitor use was associated with an increased risk of gastric neuroendocrine neoplasms in a dose-dependent manner in a Nordic population-based case-control study of 1,790 cases and 17,897 controls.

The adjusted odds ratio for incident gastric neuroendocrine neoplasms was 1.83 (95% CI 1.56-2.15) in the highest tertile of PPI use (>385 defined daily doses over the entire drug history) compared to no PPI use.
The risk increased in a dose-dependent manner across three tertiles of PPI exposure, with adjusted odds ratios of 1.34, 1.37, and 1.83 for tertiles 1, 2, and 3 respectively.
The risk was higher in younger PPI users (<65 years) than in older users (≥65 years).
Results remained consistent when excluding individuals with chronic atrophic gastritis, other neuroendocrine neoplasms, and Helicobacter pylori infection.
The study was based on nationwide registries from Denmark, Finland, Iceland, Norway, and Sweden, with data collected between 1996 and 2020 and a median follow-up of 11.8 years after a one-year run-in period.

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Abstract

Introduction

Hypergastrinemia, caused by chronic atrophic gastritis or Helicobacter pylori (H. pylori) associated pangastritis, is associated with an increased risk of non-cardia gastric cancer. Recent studies have also found an increased risk of gastric cancer in long-term proton pump inhibitor (PPI) users. Patients with chronic atrophic gastritis also have an increased risk of neuroendocrine neoplasms (NEN) due to hypergastrinemia. However, whether long-term PPI use increases the risk of gastric NEN has not been assessed in the general population.

Aims & Methods

The aim of the present study was to assess the risk of gastric NEN among long-term PPI users in a multinational population-based study from the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). The study was based on the Nordic Gastric and Esophageal Tumor Study (NordGETS), which is a population-based multinational sex, age, calendar year, and country matched case-control study including all adults (≥18 years of age) with a diagnosis of gastric or esophageal tumor in the Nordic countries. In the present study, the cases were incident gastric NEN identified in the cancer registries and the exposure was long-term use of PPI categorised into three equal-sized groups (tertiles) of defined daily doses (DDDs) from the medication registries of the Nordic countries between 1996 and 2020. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for chronic atrophic gastritis, NEN in the duodenum or pancreas, and H. pylori infection identified in the patient registries and medication registries.

Results

In total, 1,790 gastric NEN case patients were compared to 17,897 control participants. After a one-year run-in period, the median follow-up was 11.8 years. The risk of incident gastric NEN increased in PPI users compared to non-users in a dose-dependent manner. The adjusted OR for incident gastric NEN was 1.83 (95% CI 1.56 to 2.15) in the highest tertile of PPI use (>385 DDDs, entire drug history) compared to no PPI use (Table). The risk was higher in the younger age group (<65 years) than the older age group (≥65 years) and the estimates were consistent when excluding individuals with chronic atrophic gastritis, other NENs, and H. pylori.

Table Risk of gastric neuroendocrine neoplasms (NEN) by proton pump inhibitor (PPI) exposure defined by tertiles of defined daily doses (DDD) for the entire drug history between 1996 and 2020.
PPI (DDD)*	Crude odds ratio (95% confidence interval)**	Adjusted odds ratio (95% confidence interval)***
None	1.00 (reference)	1.00 (reference)
Tertile 1	1.46 (1.25-1.70)	1.34 (1.14-1.58)
Tertile 2	1.54 (1.30-1.81)	1.37 (1.15-1.64)
Tertile 3	1.92 (1.65-2.24)	1.83 (1.56-2.15)
* Tertiles: 1 ≤56 DDDs; 2 >56-385 DDDs; 3 >385 DDDs. Matched for sex, age, calendar year, and country. * Matched for sex, age, calendar year, and country, and adjusted for chronic atrophic gastritis, NEN in duodenum or pancreas, and H. pylori.

Conclusion

In this population-based study from the five Nordic countries the risk of gastric NEN was increased in PPI users compared to non-users of PPI in a seemingly dose-dependent manner. The risk was higher in younger age groups of PPI users compared to older age groups.

Disclosure

No conflicts of interest

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy Oesophagus

Submission format

Abstract

Session

From prediction to detection in upper GI

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Victoria Úbeda Vargas

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UEG Presentation

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Who is at risk: Is it all about anticoagulants?

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Who is at risk: Is it all about anticoagulants?

Franco Radaelli 1

Affiliations

1 Valduce Hospital, Como, Italy

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Radiology & Imaging

Session

Crash course: Lower GI bleeding

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Victoria Úbeda Vargas

Whole diet interventions for IBS

Heidi Staudacher

UEG Presentation

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Panel discussion: Therapy update - EoE

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Abstract

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Small Intestine & Nutrition Oesophagus Paediatrics

Session

Therapy update: EoE

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Franco Radaelli

Panel discussion: Therapy update - EoE

Early onset life-long impact: Caustic injury/atresia (Complete Session)

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Christos Tzivinikos

CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

Victoria Úbeda Vargas

Whole diet interventions for IBS

Heidi Staudacher

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Early onset life-long impact: Caustic injury/atresia (Complete Session)

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Early onset life-long impact: Caustic injury/atresia (Complete Session)

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Abstract

Event

UEG Week Berlin 2025

Topics

Oesophagus Paediatrics

Session

Early onset life-long impact: Caustic injury/atresia

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Franco Radaelli

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CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

Victoria Úbeda Vargas

Whole diet interventions for IBS

Heidi Staudacher

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

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Pediatric emergencies

Christos Tzivinikos 1

Affiliations

1 Al Jalila Children's Specialty Hospital, DUBAI, United Arab Emirates

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Nurses Paediatrics Surgery

Session

Crash course: Foreign bodies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Victoria Úbeda Vargas

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UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

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CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

Leticia Rodríguez-Alcolado 1, Emilio Jose Laserna-Mendieta 2, Victoria Úbeda Vargas 3, Sergio Casabona-Francés 4, Edurne Amorena Muro 5, Leonardo Blas 6, Edoardo Vincenzo Savarino 7, Isabel Pérez-Martínez 8, Jesús Barrio Andrés 9, Antonio Guardiola Arevalo 10, Danila Guagnozzi 11, Marina Coletta 12, Laura Martín Asenjo 13, Luisa de la Peña Negro 14, Gaia Pellegatta 15, Alejandro García-Díaz 16, Elena Betoré 17, Anne Lund Krarup 18, Susana de la Riva 19, Silvia Carrión Bolorino 20, María Pipa 21, Sonia Fernandez-Fernandez 22, Carlos Teruel Sanchez - Vegazo 23, Juan Naves 24, BLANCA BELLOC 25, Salvatore Oliva 26, Mónica Llorente-Barrio 27, Carlo Maria Rossi 28, Juan Armando Rodríguez Oballe 29, Maria Luisa Masiques-Mas 30, Raúl Honrubia-López 31, Raffaella Dainese Plichon 32, Alexis González Almeida 33, Luis Bujanda Fernández de Piérola 34, Juan Khaled Bisso Zein 35, Alba Juan-Juan 36, Sara Feo Ortega 3, Verónica Martín Domínguez 4, Jennifer Fernández-Pacheco 4, Oscar Nantes Castillejo 5, Julia Nicolay Maneru 5, Marta Álvarez-García 6, Matteo Ghisa 7, Carmen Díaz-Donado 37, Paula Gil Simón 9, Alicia Granja 10, Ronald Llerena Castro 11, Roberto Penagini 12, Cecilio Santander 4, Alfredo J. Lucendo 2

Affiliations

1 Hospital General de Tomelloso, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Tomelloso, Spain|||University of Alcalá, Alcalá de Henares, Spain

2 Hospital General de Tomelloso, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Tomelloso, Spain|||Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain

3 Hospital General de Tomelloso, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Tomelloso, Spain

4 Hospital Universitario de La Princesa, Madrid, Spain|||Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

5 Hospital Universitario de Navarra. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

6 Fundacion Jiménez Díaz, Madrid, Spain

7 Azienda Ospedaliera Università di Padova, Padua, Italy

8 Hospital Universitario Central de Asturias, Oviedo, Spain|||Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

9 Hospital Universitario Rio Hortega, Valladolid, Spain

10 Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain

11 Hospital Vall d'Hebrón, Barcelona, Spain

12 Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy

13 Hospital Universitario de Álava, Vitoria, Spain

14 Hospital de Viladecans, Viladecans, Spain

15 Humanitas Research Hospital, Rozzano, Italy

16 Hospital Universitario Puerta de Hierro, Majadahonda, Spain

17 Hospital Universitario Miguel Servet, Zaragoza, Spain

18 The North Danish Regional Hospital, Hjørring, Denmark

19 Clínica Universidad de Navarra, Pamplona, Spain

20 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain|||Hospital de Mataró, Mataró, Spain

21 Hospital Universitario de Cabueñes, Gijón, Spain

22 Hospital Universitario Severo Ochoa, Leganés, Spain

23 Hospital Universitario Ramón y Cajal, Madrid, Spain

24 Hospital del Mar, Barcelona, Spain

25 Hospital General de la Defensa, Zaragoza, Spain

26 University Hospital Umberto I - Sapienza University of Rome, Roma, Italy

27 Hospital Santa Bárbara, Soria, Spain

28 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

29 Hospital Universitario Santa María, Lérida, Spain

30 Hospital de Granollers, Granollers, Spain

31 Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Spain

32 Centre Hospitalier d’Antibes Juan-les-Pins, Antibes, France

33 Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain

34 Hospital Universitario de Donostia-Instituto Biodonostia, San Sebastián, Spain

35 Hospital Universitario Costa del Sol, Marbella, Spain

36 Hospital Sant Joan Despí Moisès Broggi, Sant Joan Despí, Spain

37 Hospital Universitario Central de Asturias, Oviedo, Spain

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Abstract

Introduction

Eosinophilic esophagitis (EoE) is type-2 chronic inflammatory disorder usually accompanied by other atopic conditions including rhinitis, conjunctivitis, bronchial asthma, dermatitis, hives or chronic rhinosinusitis with nasal polyps. The influence of these atopies in the response to the EoE therapy has been barely investigated, with opposite results in small cohorts (1,2).

Aims & Methods

We aim to describe atopic concomitances in European EoE patients and to evaluate its influence on effectiveness of first-line therapy, consisting in proton-pump inhibitors (PPIs), swallowed topical corticosteroids (STCs) and food-elimination diets (FEDs).
A cross-sectional analysis of the multicenter EoE CONNECT registry (3) was performed. Demographic and clinical data from patients recruited at 42 hospitals in 4 European countries were extracted on March 25^th, 2025. Concomitant atopies were classified as seasonal or persistent. Clinico-histological response (CHR) was defined as the simultaneous presence of symptomatic remission and a peak eosinophil count <15 eosinophils per high power field after therapy.

Results

Overall, 3,900 patients (75.6% males, mean age 33.3 ±15.1 years) were analyzed (Table). CHR rate after first-line monotherapy with PPIs, STCs or FEDs was 50.4% (n=2,685). PPIs was the only treatment affected by concomitant atopy: presence of asthma and hives significantly reduced CHR rates to PPIs (42.7% vs 49.7%, p=0.005, and 39.3% vs 48%, p=0.044, respectively), and CHR also tended to be lower in presence of conjunctivitis (43.6% vs 48.4, p=0.067) and dermatitis (43.2% vs 48.3%, p=0.081). Seasonal or persistent presentation of atopy did not influence response to treatment. Taking into account age at diagnosis, the effect of concomitant atopy in reducing CHR to PPIs was exclusively observed in adults (≥18 years old) for asthma (43.8% vs 51.3%, p=0.007) and dermatitis (42.6% vs 50.3%, p=0.026), and in children (<18 years old) for hives (17.4% vs 39.9%, p=0.032).
We next analyzed whether the number of concomitant atopies influenced CHR to first-line therapy. While no differences were found among patients who presented only one atopic condition, the presence of 2 or more atopies reduced PPI effectiveness in adults (45.0% vs 50.7%, p=0.032) and to FEDs in children (23.5% vs 59.3%, p=0.020). A reduction in CHR rate after PPI therapy was even greater in adults with 3 or more atopies concomitant to EoE (39.0% vs 50.4%, p=0.001). Effectiveness of first-line STCs were not affected in any of these comparisons.

Age at diagnosis (n=3,705)	<18 years: 19.4%; ≥18 years: 80.6%
Rhinitis (n=3,558)	49.4 %; Seasonal 77.3 %; Persistent 22.7%
Conjunctivitis (n=3,499)	23.8%; Seasonal 88.5%; Persistent 11.5%
Asthma (n=3,526)	28.6%; Seasonal 63.8%; Persistent 36.2%
Dermatitis (n=3,507)	18.7%; Seasonal 43.4%; Persistent 56.6%
Hives (n=3,403)	7.1%; Seasonal 50.7 %; Persistent 49.3%
Chronic rhinosinusitis with nasal polyps (n=3,461)	2.1%; Persistent: 100%
Number of allergies (n=3,353)	At least 1 allergy: 64.7%; ≥2 allergies: 39.1%; ≥3 allergies: 17.4%
Response to 1st treatment option in monotherapy evaluated (n=3,266)	PPI: 82.6%; STC: 11.9%; FED: 5.5%

Conclusion

The coexistence of asthma, dermatitis and hives determined lower response to PPI therapy for EoE. Association of 2 or more atopic condition further decreased effectiveness of PPIs in adults and of FEDs in children.

References

1. Ancellin M, Ricolfi-Waligova L, Clerc-Urmès I, et al. Management of eosinophilic esophagitis in children according to atopic status: a retrospective cohort in northeast of France. Arch Pediatr. 2020;27(3):122-127.
2. Reed WD, Ocampo AA, Xue Z, et al. Eosinophilic esophagitis patients with multiple atopic conditions: clinical characteristics and treatment response to topical steroids. Ann Allergy Asthma Immunol. 2023;131(1): 109-115.e2.
3. Lucendo AJ, Santander C, Savarino E, et al. EoE CONNECT, the European Registry of Clinical, Environmental, and Genetic Determinants in Eosinophilic Esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe. Therap Adv Gastroenterol. 2022;15:17562848221074204.

Event

UEG Week Berlin 2025

Topics

Histopathology Mechanisms & Personalised Medicine Oesophagus

Submission format

Abstract

Session

EoE: From gene to clinic

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Who is at risk: Is it all about anticoagulants?

Franco Radaelli

Panel discussion: Therapy update - EoE

Early onset life-long impact: Caustic injury/atresia (Complete Session)

Pediatric emergencies

Christos Tzivinikos

CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

Victoria Úbeda Vargas

Whole diet interventions for IBS

Heidi Staudacher

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

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Whole diet interventions for IBS

Heidi Staudacher 1

Affiliations

1 The University of Queensland, Melbourne, Australia

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Neurogastroenterology & Motility Primary Care

Session

Diet and disorders of gut-brain interaction: From IBS to IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Franco Radaelli

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Christos Tzivinikos

CONCOMITANT ATOPY INFLUENCES RESPONSE TO PROTON-PUMP INHIBITORS IN EOSINOPHILIC ESOPHAGITIS: AN ANALYSIS OF THE EOE CONNECT REGISTRY

Victoria Úbeda Vargas

Whole diet interventions for IBS

Heidi Staudacher