International Journal of Molecular Sciences Review Review GastrinGastrin and and the the Moderate Moderate Hypergastrinemias Hypergastrinemias Jens F. Rehfeld Jens F. Rehfeld Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100Department Copenhagen, of Clinical Denmark; Biochemistry, [email protected] Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; [email protected] Abstract: The antral hormone gastrin potently regulates gastric acid secretion and fundic mucosal growth.Abstract: Consequently,The antral hormone appropriate gastrin gastrin potently secretio regulatesn and plasma gastric acidconcentrations secretion and are fundicimportant mucosal for thegrowth. early phases Consequently, of digestion. appropriate This review gastrin describes secretion andas the plasma first concentrationspremise the normal are important biogenesis for of the gastrinearly phasesin the antral of digestion. mucosa, This but review also mentions describes the as theextraantral first premise expression the normal. Subsequently, biogenesis the of gastrin molec- in ularthe nature antral mucosa,and concentration but also mentions levels of thegastrin extraantral in serum expression. or plasma Subsequently,are overviewed. the Third, molecular assays nature for accurateand concentration measurements levels of plasma of gastrin or inserum serum concen or plasmatrations are are overviewed. commented. Third, Finally, assays the problem for accurate of moderatemeasurements hypergastrinemia of plasma or due serum to Helicobacter concentrations pylori are infections commented. and/or Finally, treatment the problem with proton-pump of moderate inhibitorshypergastrinemia (PPI) is discussed. due to Helicobacter The review pylori concludeinfectionss that and/or accurate treatment measurement with proton-pump of the true inhibitorsconcen- trations(PPI) is of discussed. bioactive gastrins The review in plasma concludes is import that accurateant. Moreover, measurement it suggests of thethat true moderate concentrations hypergas- of trinemiasbioactive are gastrins also essential in plasma health is important. issues that Moreover, require serious it suggests attention. that moderate hypergastrinemias are also essential health issues that require serious attention. Keywords: Duodenal ulcer; Gastric cancer; Gastrin; Helicobacter pylori; Hypergastrinemia; Proton- pumpKeywords: inhibitorsduodenal ulcer; gastric cancer; gastrin; Helicobacter pylori; hypergastrinemia; proton- pump inhibitors 1. Introduction 1. Introduction Gastrin is the gastroduodenal hormone that stimulates acid secretion and growth of Gastrin is the gastroduodenal hormone that stimulates acid secretion and growth the fundic mucosa (see Figure 1 and the recent reviews [1,2]). Precisely regulated gastrin Citation: Rehfeld, J.F. Gastrin and of the fundic mucosa (see Figure1 and the recent reviews [ 1,2]). Precisely regulated gas- secretion is essential for normal digestion and, consequently, for good health. In contrast, theCitation: ModerateRehfeld, Hypergastrinemias. J.F. Gastrin and trin secretion is essential for normal digestion and, consequently, for good health. In either total lack of gastrin or the opposite, severe hypersecretion of gastrin, are life-threat- Int.the J. ModerateMol. Sci. 2021 Hypergastrinemias., 22, x. Int. contrast, either total lack of gastrin or the opposite, severe hypersecretion of gastrin, are ening. Complete lack of gastrin is seen in genetically modified “knockout” mice. Such https://doi.org/10.3390/xxxxxJ. Mol. Sci. 2021, 22, 6977. https://doi. life-threatening. Complete lack of gastrin is seen in genetically modified “knockout” mice. mice cannot produce gastric acid [3,4]. However, gastric acid is necessary for killing in- org/10.3390/ijms22136977 Such mice cannot produce gastric acid [3,4]. However, gastric acid is necessary for killing Academic Editor: Alain Couvineau gested bacteria and other pathogenic microorganisms. In the absence of gastric acid, the ingested bacteria and other pathogenic microorganisms. In the absence of gastric acid, stomach, therefore, becomes infected with bacteria that gradually lead to irreversible in- Academic Editor: Alain Couvineau the stomach, therefore, becomes infected with bacteria that gradually lead to irreversible Received: 3 June 2021 testinalintestinal metaplasia metaplasia and and carcinogenic carcinogenic tumor tumor dev developmentelopment [5,6]. [5,6 Vice]. Vice versa, versa, severe severe hyper- hyper- Accepted:Received: 17 3 June 2021 secretion of gastrin as seen in the Zollinger–Ellison syndrome caused by gastrin-produc- Published: date secretion of gastrin as seen in the Zollinger–Ellison syndrome caused by gastrin-producing Accepted: 17 June 2021 ingtumors tumors (gastrinomas) (gastrinomas) is, inis, itsin fulminantits fulminant forms, forms, also also life-threatening—partly life-threatening—partly due todue gross to Published: 29 June 2021 grossgastric gastric hyperacidity hyperacidity with with multiple multiple duodenal duodenal and and jejunal jejunal peptic peptic ulcers, ulcers, diarrhea diarrhea and and se- Publisher’s Note: MDPI stays neu- severe water–electrolyte disturbances and partly because gastrinomas—although mostly tral with regard to jurisdictional vere water–electrolyte disturbances and partly because gastrinomas—although mostly Publisher’s Note: MDPI stays neutral slow-growing—are malignant, metastatic neoplasias [7,8]. In addition to the relatively claims in published maps and institu- slow-growing—are malignant, metastatic neoplasias [7,8]. In addition to the relatively rare with regard to jurisdictional claims in rare neuroendocrine gastrinomas, however, gastrin is also expressed locally in common tional affiliations. neuroendocrine gastrinomas, however, gastrin is also expressed locally in common cancers, published maps and institutional affil- cancers,for instance, for instance, in some in brain some tumors, brain mosttumors, lung most cancers, lung exocrinecancers, pancreaticexocrine pancreatic cancers, gastric, can- iations. cers,colorectal gastric, and colorectal ovarian and adenocarcinomas ovarian adenocarcinomas in which autocrine in which and/or autocrine paracrine and/or gastrin paracrine may gastrinstimulate may carcinogenetic stimulate carcinogenetic growth [9–14 growth]. [9–14]. Copyright: © 2021 by the author. Li- censee MDPI, Basel, Switzerland. ThisCopyright: article is ©an 2021open byaccess the article author. distributedLicensee MDPI,under the Basel, terms Switzerland. and con- ditionsThis articleof the Creative is an open Commons access articleAt- tributiondistributed (CC BY) under license the (http://crea- terms and tivecommons.org/licenses/by/4.0/).conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Figure 1. The structure of gastrin-17, the first identified molecular form of gastrin in antral G cells [15]. 4.0/). Int. J. Mol. Sci. 2021, 22, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6977. https://doi.org/10.3390/ijms22136977 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6977 2 of 12 In between the described extremes of gastrin secretion—from complete lack to ex- cessive overproduction—are the moderate variations of plasma gastrin levels (Table1). In addition to the variations of fasted and fed normogastrinemic healthy persons, they include hypogastrinemias as seen, for instance, after classic Whipple operations (where the antrum, the duodenum, the upper jejunum and the head of the pancreas have been removed [16]) and in achlorhydric patients with pernicious anemia also involving atrophy of the antral mucosa [17]. Frequent moderate hypergastrinemias are, however, seen in Heli- cobacter pylori-infected patients [18–24] and in patients who are treated with proton-pump inhibitors [25–33]. Table 1. Gastrinemias. Basal Plasma Concentration Category Condition Levels (pmol/L) Agastrinemia Genetically modified animals 0 Antroduodenally resected patients Hypogastrinemia 0–5 Antro-mucosal atrophy patients Normogastrinemia Fasting normal subjects and mammals 5–15 Helicobacter pylori-infected subjects Hypergastrinemia (I) Proton-pump inhibitor-treated patients 20–100 (moderate) Early gastrinomas Atrophic gastritis Hypergastrinemia (II) Gastrinomas with fulminant Zollinger–Ellison syndrome >100 (excessive) Gastric polyposis This review discusses, in particular, moderate hypergastrinemias and their possible pathogenetic significance. In order to have such a discussion, an essential premise is first to understand the biogenesis of bioactive gastrin peptides in antral G cells, and then to also consider the cellular expression of gastrin outside the antral mucosa. 2. G Cell Synthesis of Gastrin In healthy adult humans, G cells in the antral and duodenal mucosa are the main site of gastrin synthesis and subsequent release to blood (for a recent review see [2]). A few sporadic G cells are also present in the jejunum and in the ileum. So far, however, gastrin biosynthesis studies have examined antral gastrin production [34–36]. Interpretation of the results of these studies in the light of general knowledge about peptide biosynthesis provides a picture of normal synthesis of antroduodenal gastrin, as shown in Figure2 and as detailed earlier [37,38]. After translation of gastrin mRNA in the rough endoplasmic reticulum and cotransla- tional removal of the signal peptide from preprogastrin, progastrin is transported