Best Practice & Research Clinical Gastroenterology 28 (2014) 953e965

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Best Practice & Research ClinicalGastroenterology

1

Gastric acid secretion: Changes during a century

Francesco Di Mario, MD, Full Professor of Gastroenterology *,Elisabetta Goni, MD, Assistant fellow 1

Department of Clinical and Experimental Medicine, University of Parma, School of Medicine, Via Gramsci 14,43125, Parma, Italy

Keywords:Gastric acid secretionGastric physiologyGERDDyspepsiaPeptic ulcer diseaseHelicobacter pylori infectionChronic atrophic gastritisGastric cancer riskAcid regulatory drugs

* Corresponding author. Tel.: þ39 0521 033564.E-mail addresses: francesco.dimario@unipr.it (F

1 Tel.: þ39 0521 033564.

http://dx.doi.org/10.1016/j.bpg.2014.10.0061521-6918/© 2014 Elsevier Ltd. All rights reserved

a b s t r a c t

The advances in knowledge of gastric physiology within the pastcentury have been the most exciting and important in this area ofinterest for many decades.The aim of this presentation consists of a comprehensive review ofthe extensive recent literature on this topic in order to highlightmilestones in the field of gastric physiology, in particular in gastricacid secretion, gastric pathophysiology, acid-related diseases anduse of acid regulatory drugs. Moreover, in the 21st century therehave been many epidemiologic changes as well as a decrease ofHelicobacter pylori infection and gastric cancer together with anincrease of gastroesophageal reflux disease and the related in-crease of pomp proton inhibitor wide use.

© 2014 Elsevier Ltd. All rights reserved.

Introduction

The present review is focusing on gastric acid secretion and its changes during the last century. Inparticular, wewill analyse the role ofHelicobacter pylori (H. pylori) infection and IL1 beta in acid-relateddiseases such as peptic ulcer disease and gastroesophageal reflux disease (GERD), as well as thedevelopment of new techniques in the measurement of gastric acid secretion.

Moreover, in gastroenterology, as in other medical specialities, new potential therapies, bothpharmaceutical and invasive, continually appear on the horizon, always with great initial enthusiasm.

. Di Mario), elisabetta.goni@gmail.com (E. Goni).

.

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Over time, these either will prove to be failures or will find their appropriate level of use in ourtherapeutic armamentarium. When faced with promising new therapies, we should always wonderwhether they are effective and safe and whether they are really better than the current ones. Althoughacid suppression therapy has stood the test of time, the final chapter on the pharmacological treatmentof acid-related diseases has not yet been written.

Which factors could change gastric acid secretion?

Environmental factor: H. pylori infection

In 1910 was “no acid, no ulcer”, since 1984 it became “no H. pylori no ulcer” following the discov-ering of the role of H. pylori [1].

As a classic example of epidemiology, John Snow was able to identify tainted water as the cause ofthe London cholera epidemic in 1854, because disease occurrence clustered amongst householdsserved by a singular water pump at Broad Street [2]. Similarly, the recurrent clustering of deafnessamong subjects born shortly after rubella epidemics led to the discovery of rubella embryopathy [3].The frequent occurrence of gastric cancer among coal miners in Europe was partly related to their highsalt intake as a means to cope with profuse sweating while working underground [4,5]. Other suchexamples abound. The present review is focused on clustering in time and especially on the historicperiod and cohort effects of gastrointestinal diseases associated with H. pylori.

The incidence and mortality of many diseases increase with age. Because of the cumulative expo-sure to environmental risk factors over time and the age-related decline in physiological repair, olderpeople are more prone to develop most types of disease and die from them. After becoming infectedwith H. pylori, it takes decades for the gastric mucosa to develop intestinal metaplasia, gastric atrophy,mucosal dysplasia and, ultimately, gastric cancer [6,7]. The increased incidence of a disease in aparticular age group can also point at time when the risk exposure to an environmental agent wasespecially high. Nowadays, gastric and duodenal ulcers tend to occur in older people, who were morelikely to have been exposed to H. pylori in their childhood than recently born generations [8]. Periodeffects are caused by environmental influences that change during a given time period and simulta-neously affect most or large portions of the population. Acute ulcer attacks became more common, forinstance, during the air raids of London by the German air force during World War II or after earth-quakes in Japan [9,10]. Period effects are also brought forth by the introduction of new diagnostictechniques, public health measures or medical therapies, which typically affect all age groups at thesame time. Therefore, period effects tend to reveal themselves as rise or fall occurring in all age groupsalike during the same time period. In contradiction to period effects, the concurrence of divergenttrends among period-age contours of consecutive age groups is generally suggestive of underlyingbirth-cohort effects. Cohort effects are caused by risk exposure during early childhood that influencessubsequent disease behaviour throughout life. The acquisition of H. pylori infection during earlychildhood and the ensuing risk for the future development of peptic ulcer or gastric cancer represents atypical example for a cohort effect in digestive diseases.

The recent decline in peptic ulcer and gastric cancer is easy to explain by similar trends of H. pyloriinfection in the general population. Although the route of transmission of H. pylori has still remainedsomewhat of a mystery, the drop in infection rate is generally assumed to have resulted from increasingstandards of hygiene [11,12]. The initial rise in the occurrence of peptic ulcer and gastric cancer hasremained the true mystery. H. pylori is found to have infected all human populations worldwide, andthere appears to be no population free of any H. pylori infection. Based on genetic analysis of H. pyloriobtained from populations throughout the world, its origin can be traced back to Africa, and it is nowassumed that H. pylorimigrated inside the stomachs of the first humans out of Africa [13]. If this is true,how could there have been any sudden rise in the occurrence of H. pylori -related diseases throughoutthe nineteenth century?

As its competitors vanished, the ecologic niche ofH. pylori in the stomach and upper gastrointestinaltract expanded, resulting in more ulcers and gastric cancers. Subsequently, further improvements inhygiene ultimately led also to the downfall of H. pylori and its associated diagnoses. It has been sug-gested, for instance, that pasteurisation of milk eliminated acidophilic lactobacilli as potential gastric

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commensals (Richard H. Hunt, personal communication). Pasteurisation became widely implementedonly after the turn of the century and could not have accounted for the initial rise. Different kinds ofpublic health measures could have similarly affected other types of intragastric organisms. At thepresent time, however, this explanation is mostly hypothetical, as no specific bacteria to fit this patternhave been characterized [14].

Acid-related diseases

Peptic ulcer disease (PUD)

Occasional reports of well-documented instances of perforated gastric ulcer reach as far back as theepoch of the Renaissance in Europe [15]. Many such instances were accompanied by the typical symp-toms of acute peritonitis and a subsequent necropsy that confirmed the existence of a punctured hole inthe stomach. Although physicians between 1400 and 1800were familiar with this cause of sudden death,itwas still a rare disease until the early nineteenth centurywhen it suddenly started to rise. In a landmarkarticle published by the Lancet in 1940, Jennings summarised the statistics available on the early timetrends of gastric and duodenal ulcer [16,17]. As the nineteenth century progressed, gastric ulcer becamemore common in middle-aged women and men. Shortly before the turn of the century, physiciansstarted to notice a sudden increase in the occurrence of perforations from duodenal ulcers. Differentlyfrom the preceding PUD epidemic, this second wave of duodenal ulcers affected primarily young menand generally less female patients. These temporal changes were not restricted to Britain, but weresimilarly observed in the countries of Scandinavia and Central Europe. During the first half of thetwentieth century, PUD inflicted more than 10% of the adult population. Because duodenal ulcer diseaseand its sequelae incapacitated many young males who would serve in the armies of World War I and II,means to contain the epidemic became an issue of military defence and national interest [18e21].

In the last quarter of the twentieth century, a slew of investigators started to notice a decline in theoccurrence of PUD [14e25].

Sonnenbertg et al aimed to follow the time trends of mortality from ulcerative colitis and comparethem with those of gastric and duodenal ulcer. They study mortality data from 21 different countriesbetween 1941 and 2004 were analysed. The birth-cohort pattern indicates that exposure to the rele-vant risk factors of ulcerative colitis occurs during early life. As the model of H. pylori and its associatedbirth-cohort patterns of PUD and duodenal ulcer suggest, an enteric infection provides a possibleexplanation for such temporal trends of ulcerative colitis as well [26].

Moreover, the same group studied analysed mortality data in countries outside Europe andcompared them with previous reports of ulcer mortality from Europe and North America.

Mortality data from eight different countries were analysed, including Argentina, Australia, Chile,Hong Kong, Japan, Mexico, Singapore, and Taiwan. The age-standardized death rates of individualcountries were followed from 1971 to 2004. Japan and Australia had mortality data for more than 50years that provided the opportunity to conduct a birth-cohort analysis. The ubiquitous decline in ulcermortality in countries fromdifferent parts of theworld is likely to be associatedwith aworldwide declinein the occurrence of H. pylori infection. The events accompanying the receding infection in developedcountries must have similarly affected populations exposed to increasing standards of hygiene [21].

GERD

GERD includes a spectrum of disorders ranging from non-erosive reflux disease (NERD) to erosiveoesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. NERD is associated with themost frequent complaints, but barely leads to hospitalisations, let alone death. Because, comparedwithPUD and gastric cancer, erosive oesophagitis and oesophageal adenocarcinoma are relatively rare di-agnoses, their time trends tend to be less well documented than those of PUD or gastric cancer. In spiteof these limitations, physicians nevertheless started to notice a marked increase in their patientpopulation with GERD symptoms since the 1970s [18,27e29]. This rise was partly responsible for thetremendous success of various newly developed antisecretory drugs, such as histamine-2 receptorantagonists and proton pump inhibitors, even though PUD was already becoming less common. The

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rise was also documented by hospitalisation statistics of erosive oesophagitis, as well as the incidence,hospitalisation and mortality data pertaining to oesophageal adenocarcinoma. Early on, it was spec-ulated that this rise was secondary to a decline in H. pylori infection. As long-term infection with H.pylori results in gastritis with a concomitant drop in acid output, H. pylori infection may function as anatural antisecretory mechanism that protects against all forms of GERD. The continuing rise in theoccurrence of oesophageal adenocarcinoma has been themost worrisome consequence of vanishing H.pylori infection [30]. Because the prevalence of H. pylori has already reached low levels of 10%, it isforeseeable that, in the near future, the rise of oesophageal adenocarcinoma will ultimately level off.

On a population level, the inverse relationship between H. pylori and all forms of GERD is easy tosubstantiate [31e35]. In the individual patient, such an inverse association has been difficult to verify.After an H. pylori infection becomes eradicated, few, if any, patients go on to develop GERD, let aloneerosive oesophagitis or Barrett's oesophagus. One simple reason for such lack of immediate influencemay be that several additional factors besides acid secretion must contribute to the development ofGERD [36]. Aside from NERD, moreover, erosive oesophagitis and oesophageal adenocarcinoma arerelatively rare diseases that take long time periods to develop in an individual patient. Onewould needto recruit a large case population and follow the cases over a prolonged time period to be able to trulyappreciate any influence of H. pylori eradication on oesophageal disease. Lastly, it is not fully clearwhether the interaction between H. pylori infection and Barrett's oesophagus is solely explicable by theinhibitory influence of H. pylori on gastric acid output. Overweight and obesity have repeatedly beenshown to constitute a significant risk for the development of all forms of GERD [37e39]. It isconceivable that the fattening of western populations has contributed to the rise of GERD.

However, overwhelming epidemiologic evidence unmistakably points at inverse relationships be-tween H. pylori infection and all forms of GERD. The rise in GERD appears to have preceded the weightepidemic by at least two decades. There is obviously a substantial portion of reflux patients withnormal weights, attesting to the influence of other risk factors besides body mass index or abdominalgirth. It remains safe to say that the falling time trends ofH. pylori infection in the populationmust havecontributed substantially the concomitant rise in GERD [14].

The role of gastric acid today

The importance of gastric acid in the 21st century is relatedwith thewide use of antisecretory drugsadministered to the patients for a large spectrum of upper GI symptoms not ever supported by a trueacid hypersecretion, like dyspepsia, functional esophageal disorders, gastroprotection etc.

Direct measurement of gastric acid production is out of order in clinical practice but a lot ofsymptoms, mainly aspecific, are claimed to be related with an acid disorder and then empirically curedby over the counter drugs like antacids and buffer preparations.

On the other hand, low level of acid is strongly related with precancerous gastric conditions as wellas chronic atrophic gastritis.

Gastric physiology

Cells anatomy

Anatomically, the stomach consists of three regions: fundus, body, and antrum (Fig. 1). Functionally,there are two glandular regions: oxyntic and pyloric mucosa. The oxyntic glandmucosa, the hallmark ofwhich is the oxyntic or parietal cell, comprises 80% of the fundus and body. The pyloric gland mucosa,the hallmark ofwhich is the G cell, comprises 20% of the antrum. There is debate as towhether the cardiaexists as a normal anatomic structure or develops as a result of abnormal reflux of gastric_contents [40].

The glandular mucosa is organized in vertical tubular units that consist of four regions: the pitregion, consisting mainly of columnar surface mucous cells; the isthmus, where the multipotentprogenitor cells reside; and the actual gland region [41e43], which forms the lower part of the unit. Thelatter consists of a neck and a base. The mucous-producing pit cells migrate upward from the pro-genitor cell toward the gastric lumen. Acid-secreting parietal cells migrate downward to the middleand lower regions of the gland [42,44e46].

Fig. 1. Anatomic and functional areas of the stomach. Legend ECL cells ¼ enterochromaffin like cells H2 ¼ histamine H2 receptorSSTR2 ¼ Somatostatin receptor type 2.

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Chief cells predominate at the base and secrete pepsinogen and leptin [47].A variety of distinct neuroendocrine cell types are contained within the gland, but only some of

their products have been assigned physiologic functions. These cells include: a) enterochromaffin(EC) cells, contain atrial natriuretic peptide (ANP), contain somatostatin serotonin, and adrenome-dullin [48,49]; b) enterochromaffin-like (ECL) cells, which contain histamine [50,51]; c) D cells, whichand amylin [52,53]; d) A-like or Gr cells, which contain ghrelin and obestatin [54e63].

Parietal cell and Hþ/KþATP-ASE

Parietal cells secrete hydrochloric acid at a concentration of approximately 160 mMol or pH 0.8. Acidis produced from the hydration of CO2 to formHþ andHCO3

�, a reaction catalysed by carbonic anhydrase.The acid-secretory process requires functional receptors, signalling pathways, channels and trans-porters, and acid-secreting pumps (i.e., Hþ/Kþ-ATPase). After exit from the parietal cell, acid is thought togain access to the gastric lumen via channels in the mucous layer created by the relatively high intra-glandular hydrostatic pressures (approximately 17 mmHg) generated during secretion [64].

In parietal cells, acid secretion is increased by intracellular elevation of cAMP, calcium, or bothfollowed by a cascade that activates downstream protein kinases that trigger the translocation of Hþ/Kþ-ATPase from cytoplasmic tubulovesicles to the apical plasma membrane, with concomitantactivation of luminal membrane conductances for Kþ and Cl�. Binding of histamine to the parietal cellH2 receptor evokes an increase in cAMP (and some species also an increase in calcium), whereasbinding of gastrin to the CCK 2 and acetylcholine to the M3 receptor elicits an increase in intracellularcalcium [65e71,73,74].

Acid secretion regulation

In conjunction with a meal, gastric acid secretion can be considered to occur in three phases:cephalic, gastric and intestinal. The major portion of secretion occurs during the gastric phase, whenthe meal is present in the stomach. Secretion of other gastric products usually parallels that of the acid.

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Cephalic phaseEven before the meal is ingested, the stomach is readied to receive it by the so-called cephalic phase

of secretion. Indeed, during the cephalic phase, the functions of several gastrointestinal systems inaddition to the stomach begin to be regulated, including the pancreas and gallbladder. The existence ofa cephalic phase of secretion was demonstrated by experiments called “sham feeding.” Likewise, theexperiments of Pavlov, where dogs were conditioned to associate the ringing of a bell with a meal,showed that the anticipation of food alone is a powerful trigger for an increase in gastric secretion [72].

Gastric phaseThe gastric phase of secretion is quantitatively the most important. In addition to vagal influences

continuing from the cephalic phase, secretion is now amplified further by mechanical and chemicalstimuli that arise from the presence of the meal in the lumen. The gastric phase of secretion is alsoaccompanied by amarked increase in gastric blood flow, which supplies the metabolic requirements ofthe actively secreting cell types. Moreover, many dietary substances, including proteins, are highlyeffective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumenmay rise to pH 5. This ensures that the rate of acid secretion during the gastric phase is not attenuatedby an inhibition of gastrin release that would otherwise be mediated by somatostatin [72].

Intestinal phaseAs the meal moves out of the stomach into the duodenum, the buffering capacity of the lumen is

reduced and the pH begins to fall. This feedback response is believed to involve several endocrine andparacrine factors, including GIP and CCK, the latter of which binds to CCK1 receptors on D cells [72].

The principal gastric function: acid secretion

The source of gastric acid secretion is the parietal cell, located in the glands of the fundic mucosa.This cell type is remarkably specialized for its function, which is probably the most energetically costlyof any electrolyte transport process anywhere in the body. High rates of secretion by the parietal cellare sustained by redundant regulatory inputs. Thus, the basolateral membrane of the cell containsreceptors for histamine, gastrin, and ACh, which cause potentiated secretion when all are presentsimultaneously (Fig. 2). The downstream targets of the signalling pathways linked to receptor occu-pancy are emerging, and include cytoskeletal elements, the machinery controlling vesicular trafficking,ion channels, and the receptors themselves; the latter representing a mechanism of negative feedback.

Fig. 2. Regulation mechanisms in gastric acid secretion. Legend CNS ¼ central nervous system.

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Cytoskeletal rearrangements are implied by the dramatic morphological changes that occur as parietalcells transition from rest to secretion. When the parietal cell is stimulated, the canaliculi fuse with theapical plasma membrane. The intracellular tubulovesicles, in turn, fuse to the canaliculi, massivelyamplifying the surface area of the apical membrane that is in contact with the gland lumen by a factorof approximately five-to 10-fold. These fusion events require the participation of the cytoskeleton tomove membrane structures together, as well as the activation of specific signalling proteins thatpromote membrane fusion.

The morphological change that occurs in parietal cells during the transition from the resting to thesecretory state is also accompanied by a biochemical change. At rest, the tubulovesicles are the site forstorage of the majority of a membrane-bound transporter, the Hþ, Kþ ATPase, or proton pump, where itis therefore sequestered from the lumen. Following fusion of the tubulovesicles and canaliculi, how-ever, their membranes are brought into continuity with the apical membrane, and thus the density ofproton pumps in that pole of the cell is massively increased. These pumps are the site of active pumpingof protons into the gastric lumen.

Protons are generated adjacent to the apical membrane as a result of the activity of the enzymecarbonic anhydrase II. This enzyme generates protons and bicarbonate ions from the reaction of waterand carbon dioxide. Protons are then pumped out of the cell across the apical membrane in exchangefor potassium ions, with the consumption of cellular energy in the form of ATP. The potassium ions arebelieved to originate also from the cell cytosol, where they are maintained at levels above theirchemical equilibrium by the activity of a basolateral transporter, the Naþ, Kþ ATPase, and a sodium/potassium/chloride cotransporter, NKCC1. They can therefore readily exit across the apical membranethrough potassium channels that are also localized to the tubulovesicles, and which are opened whenthe parietal cell is stimulated. Recent evidence from knockout mice suggests that KCNE2/KCNQ1channels fullfill this role. Chloride channels are also present in this site, and serve to allow the apicalexit of chloride ions to match the protons pumped from the cell. The molecular identity of thesechloride channels remains the subject of debate, although there is some evidence for involvement ofCFTR, the protein that is mutated in patients with cystic fibrosis. Chloride derives from the blood-stream, transported by NKCC1 and also in exchange for bicarbonate. The final secretory product istherefore hydrochloric acid, and the process overall is electrically silent due to the complementarycharges carried by these two solutes.

The massive rates of secretion conducted by parietal cells represent a considerable challenge tocellular homeostasis. This is because a bicarbonate ion is generated for every proton that is secreted,and if these were allowed to accumulate in the cytosol, deleterious effects on cellular metabolismwould result from the resulting increase in pH. Thus, as the protons are secreted apically, the parietalcells also discharge bicarbonate ions across the basolateral membrane to maintain cytosolic pH withinnarrow limits. At least a portion of this bicarbonate transport occurs in exchange for the chloride ionsthat are needed for apical secretion, via chloridee bicarbonate exchangers. Some bicarbonate is likelyalso lost secondary to pumping into intracellular vesicles (distinct from the tubulovesicles) that thenmove to the basolateral membrane and fuse with it, discharging their contents. The bicarbonateeffluxed from the cell by either mechanism is then picked up by the bloodstream, resulting in ameasurable increase in circulating pH values when gastric secretory processes are active. Thearrangement of the microvasculature in the gastric mucosa also carries a portion of this bicarbonate upto the basolateral pole of surface epithelial cells, which secrete bicarbonates to defend themselvesagainst the potentially injurious effects of acid and pepsin. This movement of bicarbonate into thebloodstream during gastric secretion is referred to as the alkaline tide.

In addition to those already mentioned earlier the basolateral membrane contains sodiumehy-drogen exchangers (NHE-1 and NHE-4), which expel protons from the cell in exchange for sodium ions,a process driven secondarily by the low intracellular sodium concentration established by the Naþ, Kþ

ATPase.The Hþ, Kþ ATPase, in particular, has been shown to consist of two subunits. The transporting

a-subunit contains many membrane-spanning regions, and the sites for proton and potassium bindingand translocation as well as ATP hydrolysis. The smaller b-subunit, on the other hand, only passesthrough themembrane a single time, and does not possess any catalytic or transport functions. Instead,the b-subunit appears to be critical for the appropriate targeting of newly synthesized a-subunits to the

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tubulovesicles, and stabilization of the pump at the apical membrane. Drugs capable of inhibiting thepump, known as proton pump inhibitors, or PPIs, have become the mainstay of treatment for digestivedisorders involving inappropriate acid secretion. These PPIs bind either reversibly or irreversibly to asite on the extracellular face of the a-subunit, thereby preventing transport activity [72].

Pathophysiology of HCl production

In gastrointestinal physiology, acid production is crucial first of all in nutrients digestion. Moreover,HCl is important in order to create an antibacterial barrier.

If HCl secretion is inadequate, it could manifest in three different ways (Fig. 3):

� DECREASED ACID SECRETION: chronic atrophic gastritis, dyspepsia and/or infections (e.g. intestinalbacterial overgrowth), autoimmune gastritis, gastric cancer Symptoms could be epigastric fullness,nausea or asymptomatic Hypo or achloridria are crucial condition in gastric pathophysiology and ingastric carcinogenesis (Fig. 3)

� INCREASED ACID SECRETION: GERD, typical and atypical form Symptoms could be epigastric pain,reflux, heartburn

� NORMAL ACID SECRETION: GERD, peptic ulcer disease, gastric cancer

Methods for measurement of gastric acid secretion

Gastric secretory testing by aspiration and titration

Gastric secretory testing assesses the basal and maximal capacity of the stomach to produce acid.The gold standard methodology is to place a nasogastric tube into the most dependent portion of thestomach of a fasted volunteer and aspirate juice by suction. The Hþ concentration in a sample can bedetermined by back-titration to pH 7 with sodium hydroxide or by measuring the pH of the samplewith an electrode and converting the activity to concentration by using a table of activity coefficientsfor Hþ in gastric juice [66].

Basal acid output (BAO), which estimates resting secretion, is expressed as the sum of the measuredacid output, expressed asmMol Hþ per hour, for four consecutive 15-minute periods. The upper limit ofnormal for BAO is about 10 mmol Hþ per hour in men and 5 mmol H per hour inwomen [67]. BAOmayvary from one hour to the next in an individual. The highest BAOs occur during phase III of the gastric

Fig. 3. From normal stomach to gastric cancer and relation with gastric acid secretion. The role of gastric acid secretion changes ingastric carcinogenesis. It could manifest in three different ways. Stomach cancers tend to develop slowly over many years. Invasivegastric carcinoma is preceded by a cascade (Correa's Cascade) of precancerous lesions. The first recognized histologic change isactive chronic inflammation, which may persist as such: non-atrophic chronic gastritis or advance to multifocal atrophic gastritis,the first real step in the precancerous cascade. The following steps are: intestinal metaplasia, dysplasia first low grade and then highgrade. The following step is invasive carcinoma, which is thought to be associated with degradation of the intercellular matrix.Correa's Cascade is inversely related with gastric acid secretion rate.

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migrating motor complex and in the evenings [68]. Maximal acid output (MAO) and peak acid output(PAO) estimate the acid secretory response to an exogenous secretagogue, usually pentagastrin, amanufactured analog of gastrin that contains the biologically active C-terminus sequence. MAO is thesum of acid output of four consecutive 15-minute collection periods and PAO, which correlates withparietal cell mass and is calculated by multiplying the sum of the two highest outputs recorded in thefour test periods by two. The range for MAO is 5e50 mMol Hþ per hour and for PAO the range is10e60 mMol Hþ per hour [69,70].

Other methods used to measure gastric acid secretion

Because of the complexity, formal gastric acid secretory testing is not widely performed. Instead, apH electrode is used to estimate acid concentration. Median fasting pH is 1.5 with a normal range of0.3e2.9 [71,73,74]. Recently, similar results have been obtained using a wireless transmitting capsulethat records luminal pH, temperature, and pressure during transit through the gastrointestinal tract[72]. Other promising, but unproven, methods include electrical impedance 13-epigastrography andC-labeled calcium carbonate breath test [78,79]. A relatively simple test for hypo or achlorhydria is theendoscopic application of Congo red, a pH-sensitive dye that changes colour from red to blue-black inthe presence of acid, combined with intravenous pentagastrin [75e82].

Pepsinogens

Today, the best non-invasive test in order to measure acid secretion is Pepsinogene1 [72,83,84].Recently, in the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took

active part and examined key clinical aspects in three subdivided workshops: (1) Indications andcontraindications for diagnosis and treatment, focusing on dyspepsia, non-steroidal anti-inflammatorydrugs or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of theinfection. (2) Diagnostic tests and treatment of infection. (3) Prevention of gastric cancer and othercomplications. The results of the individual workshops were submitted to a final consensus voting toall participants. Recommendations are provided on the basis of the best current evidence andplausibility to guide doctors involved in the management of this infection associated with variousclinical conditions.

Maastricht IV consensus conference established “Validated serological tests for H pylori andmarkers of atrophy (i.e, pepsinogens) are the best available non-invasive tests to identify subjects athigh risk of gastric cancer (Level of evidence 1� and Recommendation level B)” [85].

Moreover, H. pylori serology combined with serum pepsinogen I/II ratio may constitute anon-invasive method to detect premalignant conditions, although it has a limited sensitivity [86].

After eradication a significant reduction in cancer incidence was seen only in subjects with normalserum pepsinogen levels. This suggests that cancers developing after eradication are related to thepresence of extensive atrophic gastritis present before the eradication treatment was given. H. pylorieradication is beneficial in most subjects who have normal serum pepsinogen I and those with onlymild atrophy [87].

Acid regulatory drugs

The identification of the cellular regulators of acid secretion culminated in the development ofnovel pharmacotherapeutic agents, namely the H2-receptor antagonists (H2RAs) and the PPIs, whichallowed effective and safe treatment of PUD and other acid-related disorders [88,89]. Althoughantisecretory therapy has advanced dramatically since the introduction of cimetidine in themid-1970s,there are several identifiable unmet needs especially in the management of GERD, where an anti-secretory therapy with rapid onset of action and sustained antisecretory effect would be desirable[90,91].

A meta-analysis [92] has shown that in about two-thirds of patients reflux symptoms are notadequately controlled after the first dose of PPI, and nearly half of the patients are still bothered bysymptoms after three days standard dose PPI therapy. A rapid onset of actionwould be desirable also in

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the management and prevention of nonvariceal upper GI bleeding and may be increasingly importantin patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) [91e94].

PPIs profoundly affect the stomach and have been associated with carcinoid tumours in female rats.There is now sufficient experiencewith this class of drugs to allow reasonable estimation of their safetyin terms of cancer development.

Long term PPIs use is associated with an increase in gastric inflammation and development of at-rophy among those with active H. pylori infections. The actual risk is unknown but is clearly low.However, it can be markedly reduced or eliminated by H. pylori eradication leading to the recom-mendation that patients considered for long term proton pump inhibitor therapy be tested for H. pyloriinfection and if present, it should be eradicated. Oxyntic cell hyperplasia, glandular dilatations, andfundic gland polyps may develop in H. pylori uninfected patients, but these changes are believed to bereversible and without significant cancer risk [95].

More study is needed in order to better understand long time PPIs administration adverse effects.

Conflict of interest statement

No conflict of interest.

Practice points

� In the last century, H. pylori infection, PUD and gastric cancer were decreased, on the other

hand there is a GERD increase in general population

� Eradication of H. pylori infection is mandatory in order to prevent peptic ulcer disease (PUD),

chronic atrophic gastritis (a precancerous condition) and gastric cancer

� Discovery of H2 gastric receptor and Hþ/Kþ ATP-ase are milestones in gastric pathophysi-

ology and gastric therapy

Research agenda

� What is the best test in order to early detect gastric precancerous conditions?

� How should interact environmental and genetic factors leading to gastric cancer?

� What is the role of gastric microbiota in acid gastric secretion, in gastric pathophysiology and

in gastric carcinogenesis?

� Is long term PPIs use is associated with an increase in gastric inflammation and development

of atrophy among those with active Helicobacter pylori infections?

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