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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (25 September 2019) | Viewed by 103477

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Prof. Dr. Helge L. Waldum

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Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7030 Trondheim, Norway
Interests: gastric physiology; gastric carcinogenesis; cell of origin; gastrin; the ECL cell; histamine; gastric acidity
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Special Issue Information

Dear Colleagues,

Proton–pump inhibitors (PPIs) are used by up to 10% of the population in Western countries. They vitually take away a biological function, the production of acidic gastric juice. Normally, gastric acidity is maintained by the Helicobacter pylori regulated release of gastrin from the G cell. Drug-induced hypoacidity induces hypergastrinemia. Gastrin stimulates the ECL cell to release histamine and to proliferate. Based on old animal studies, there has been a fear that long-term profound acid inhibition would also induce gastric neoplasia in humans. In recent years, there have been reports substantiating this view. The present issue of the International Journal of Molecular Sciences will explore all facets related to use of PPIs and particularly the safety aspects.

Prof. Dr. Helge L. Waldum
Guest Editor

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Keywords

gastric acidity
biological function of gastric juice
regulation of gastric acid secretion
acid related disease
inhibitors of gastric acid secretion
PPIs and potassium-competitive acid blockers (P-CABs)
gastritis
Helicobacter pylori
gastrin
ECL cell
gastric neuroendocrine tumors (NETs) and cancer
infections secondary to gastric hypoacidity
treatment of acid related diseases

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Published Papers (7 papers)

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Research

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11 pages, 1245 KiB

Open AccessArticle

The Reduction in Gastric Atrophy after Helicobacter pylori Eradication Is Reduced by Treatment with Inhibitors of Gastric Acid Secretion

by Ryota Niikura, Yoku Hayakawa, Yoshihiro Hirata, Keiji Ogura, Mitsuhiro Fujishiro, Atsuo Yamada, Tetsuo Ushiku, Mitsuru Konishi, Masashi Fukayama and Kazuhiko Koike

Int. J. Mol. Sci. 2019, 20(8), 1913; https://doi.org/10.3390/ijms20081913 - 18 Apr 2019

Cited by 15 | Viewed by 4254

Abstract

Background: Helicobacter pylori (H. pylori) eradication therapy may improve gastric atrophy and intestinal metaplasia, but the results of previous studies have not always been consistent. The aim of this study was to compare the histological changes of intestinal metaplasia and gastric atrophy among the use of acid-suppressing drugs after H. pylori eradication. Methods: A cohort of 242 patients who underwent successful eradication therapy for H. pylori gastritis and surveillance endoscopy examination from 1996 to 2015 was analyzed. Changes in the histological scores of intestinal metaplasia and atrophy according to drug use (proton-pump inhibitors (PPIs), H₂ receptor antagonists (H2RAs), and non-acid suppressant use) were evaluated in biopsies of the antrum and corpus using a generalized linear mixed model in all patients. Results: The mean follow-up period and number of biopsies were 5.48 ± 4.69 years and 2.62 ± 1.67 times, respectively. Improvement in the atrophy scores of both the antrum (p = 0.042) and corpus (p = 0.020) were significantly superior in patients with non-acid suppressant drug use compared with those of PPI and H2RA use. Metaplasia scores in both the antrum and corpus did not improve in all groups, and no significant differences were observed among groups in the antrum (p = 0.271) and corpus (p = 0.077). Conclusions: Prolonged acid suppression by PPIs or H2RAs may limit the recovery of gastric atrophy following H. pylori eradication. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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Review

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12 pages, 874 KiB

Open AccessReview

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

by Denis M. McCarthy

Int. J. Mol. Sci. 2020, 21(2), 662; https://doi.org/10.3390/ijms21020662 - 19 Jan 2020

Cited by 44 | Viewed by 6248

Abstract

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. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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22 pages, 421 KiB

Open AccessReview

The Phylogeny and Biological Function of Gastric Juice—Microbiological Consequences of Removing Gastric Acid

by Tom C. Martinsen, Reidar Fossmark and Helge L. Waldum

Int. J. Mol. Sci. 2019, 20(23), 6031; https://doi.org/10.3390/ijms20236031 - 29 Nov 2019

Cited by 54 | Viewed by 11369

Abstract

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

17 pages, 3239 KiB

Open AccessReview

Problems Associated with Deprescribing of Proton Pump Inhibitors

by Holmfridur Helgadottir and Einar S. Bjornsson

Int. J. Mol. Sci. 2019, 20(21), 5469; https://doi.org/10.3390/ijms20215469 - 2 Nov 2019

Cited by 66 | Viewed by 29219

Abstract

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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15 pages, 955 KiB

Open AccessReview

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

by Reidar Fossmark, Tom C. Martinsen and Helge L. Waldum

Int. J. Mol. Sci. 2019, 20(20), 5203; https://doi.org/10.3390/ijms20205203 - 21 Oct 2019

Cited by 109 | Viewed by 19206

Abstract

Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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45 pages, 2413 KiB

Open AccessReview

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger–Ellison Syndrome

by Lingaku Lee, Irene Ramos-Alvarez, Tetsuhide Ito and Robert T. Jensen

Int. J. Mol. Sci. 2019, 20(20), 5128; https://doi.org/10.3390/ijms20205128 - 16 Oct 2019

Cited by 29 | Viewed by 18690

Abstract

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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11 pages, 631 KiB

Open AccessReview

The Enterochromaffin-like [ECL] Cell—Central in Gastric Physiology and Pathology

by Helge L. Waldum, Øystein F. Sørdal and Patricia G. Mjønes

Int. J. Mol. Sci. 2019, 20(10), 2444; https://doi.org/10.3390/ijms20102444 - 17 May 2019

Cited by 27 | Viewed by 12626

Abstract

Background: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. Methods: This review is based upon literature research and personal knowledge. Results: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. Conclusions: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion. Full article

(This article belongs to the Special Issue Proton-Pump Inhibitors (PPIs))

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