Gut 1996; 39: 649-653

Marked increase in gastric acid secretory capacityafter omeprazole treatment

H L Waldum, J S Arnestad, E Brenna, I Eide, U Syversen, A K Sandvik

AbstractBackground-In contrast with the hista-mine2 (H2) blockers, proton pump in-hibitors have not been shown to giverebound hypersecretion of acid. Takinginto consideration the hyperplasia of theenterochromaffin-like (ECL) cell pro-voked by hypergastrinaemia secondary toprofound acid inhibition and the centralrole of histamine from ECL cells in theregulation of acid secretion, the lack ofany rebound acid hypersecretion aftertreatment with proton pump inhibitorshas been questioned.Aims-To reassess the effect of treatmentwith omeprazole on post-treatment acidsecretion.Methods and Patients-Basal and penta-gastrin stimulated acid secretion weredetermined in nine patients with refluxoesophagitis before and 14 days aftertermination of a 90 day treatment periodwith the proton pump inhibitor ome-prazole (40 mg daily). Basal gastrin valuesas well as meal stimulated gastrin releasewere determined before and during ome-prazole treatment. Furthermore, biopsysamples from the oxyntic mucosa weretaken before and at the end of thetreatment period for chemical (histamineand chromogranin A (CgA)) evaluation ofthe ECL cell mass.Results-A substantial increase in mealstimulated gastrin release during ome-prazole treatment resulted in an increasedECL cell mass. Furthermore, CgA inserum increased during omeprazole treat-ment suggesting that serum CgA may beused as a test to evaluate ECL cell hyper-plasia. A significant increase in basal anda marked (50%) and significant increase inpentagastrin stimulated acid secretionwere found after treatment with ome-prazole.Conclusions-Increased acid secretionafter a conventional treatment period witha proton pump inhibitor is probably due toECL cell hyperplasia and may havenegative consequences for acid relateddiseases.(Gut 1996; 39: 649-653)

Keywords: acid secretion, acid related diseases, gastrin,hisatmine, proton pump inhibitors.

In humans, gastrin is the main physiologicalregulator of gastric acid secretion.1 In the rat,gastrin stimulates acid secretion by releasing

histamine2 from the enterochromaffin-like(ECL) cell.3 Also in humans6 and otherspecies the stimulation of acid secretion bygastrin is probably mediated by the stimulationof histamine release from the ECL cell.7Gastrin not only regulates the function but alsothe growth of the ECL cell,8 an effect probablymediated by the same receptor, as thefunctional and trophic effects show the sameconcentration dependence in rat2 9 andman.' '° " We have previously shown that inthe isolated rat stomach maximal histaminestimulated acid secretion is higher than maximalgastrin stimulated acid secretion.'2 In vivo, theapparently similar maximal gastrin and hista-mine stimulated acid secretion may be due tothe toxicity of histamine making it impossible toadminister histamine in a dose giving maximalgastric acid secretion.'3 Moreover, we haveshown that gastrin stimulated histamine releasedepends on the ECL cell density or mass.`Furthermore, longterm hypergastrinaemia sec-ondary to profound acid inhibition has beenreported to induce an increased capacity tosecrete acid in the rat.'5 In humans, treatmentwith proton pump inhibitors in conventionaldoses leads to marked hypergastrinaemia6 17and increased density of argyrophil cells(presumably ECL cells).16 7 Thus one wouldexpect that treatment with such drugs shouldinduce a rebound acid hypersecretion also inhumans. The present study was carried out toexamine whether treatment with a proton pumpinhibitor in a conventional dose can increasepost-treatment acid secretory capacity inhumans as such an effect could have a negativeinfluence on acid related diseases. Moreover, wealso wanted to explore whether chromogranin A(CgA) could be used to assess the ECL cellmass not only in patients with Zollinger-Ellisonsyndrome,'8 but also in patients with hyper-gastrinaemia secondary to acid inhibition.

MethodsPatients between 20 and 70 years of age withreflux oesophagitis grade 1-3,'9 were invited toparticipate in the study, if they had not beentaking any proton pump inhibitor during theprevious six months or histamine2 (H2)blockers during the previous two weeks.Patients with malignant disease, liver or kidneydiseases, or serious heart disease as well aswomen of childbearing age were not included.The study was approved by the local ethicalcommittee, and the patients were given writteninformation and gave written consent to par-ticipate. The study was conducted in ac-cordance with the Declaration of Helsinki.

Department ofMedicine, UniversityHospital andDepartment ofPhysiology andBiomedicalEngineering,Norwegian Universityof Science andTechnology,Trondheim, NorwayH J WaldumJ S AmestadE BrennaI EideU SyversenA K SandvikCorrespondence to:Dr H L Waldum,Department of Medicine,University Hospital, N-7006Trondheim, Norway.Accepted for publication1 1 June 1996

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Endoscopy with biopsiesNine men between 39 and 68 years of age

participated. They had had symptoms ofgastro-oesophageal reflux disease for 1-20years. Upper gastrointestinal endoscopy was

performed using a gastroscope GIF IT20(Olympus, Japan) and biopsy specimens were

taken from the oxyntic mucosa (5 cm oral tothe angulus from the anterior and posteriorwall), using biopsy forceps FB-13K E(Olympus, Japan). The examination was

performed after an overnight fast and withoutpremedication or sedation. Two biopsy speci-mens were frozen directly in liquid nitrogen forlater chemical analysis. One of the patients hadoesophagitis grade 3, three had grade 2, andfive grade 1.19

Basal andpentagastrin stimulated acid secretionand meal stimulated gastrin releaseA few days later and after an overnight fast,blood was taken in EDTA tubes for later de-termination of histamine20 and in glass tubes forgastrin and CgA determination. The patientswere then given a test meal consisting of 100 g

beef and 150 ml water taken within 10 minutes,and multiple blood samples were drawn forgastrin determination over a 120 minute period.Within another few days, basal and maximal

acid secretion was determined by a con-

ventional pentagastrin test using pentagastrin(Peptavlon; Zeneca, Cheshire, UK) in a doseof 6 ,ug/kg body weight subcutaneously as

stimulant. Gastric juice was collected for eight15 minute periods after an initial 30 minuteperiod to empty the stomach. The H' con-

centration in the gastric juice was determinedby titration (Radiometer, Copenhagen, Den-mark). Thereafter the patients were given ome-prazole (Losec; Astra, Gothenburg, Sweden)40 mg once daily for 90 days.During the last treatment week and after an

overnight fast, blood sampling and the test mealwere repeated as described above. Moreover,the patients underwent a second gastroscopywith biopsy specimens taken from the same

area ofthe stomach and handled as at inclusion.During the first 14 days after the end of theomeprazole treatment, the patients were

allowed only antacids for symptomatic relief.Then, after an overnight fast, a new penta-gastrin test was caried out as described above.

Blood testsGastrin in serum was determined by a

commercial radioimmunoassay (RIA) method(Becton Dickinson, Orangeburg, NY, USA).Plasma histamine was also determined byan RIA method (Immunotech, Marseilles,France).5 21 Antibody to Helicobacter pylori wasassessed by an enzyme linked immunosorbentassay (ELISA) as previously described.22 CgAwas determined in serum by a commercialELISA method (Dako, Denmark) as previouslyused in our laboratory.23 The serum/plasmasamples were stored at -20°C until analysis.

Assay ofhistamine and CgA in the oxynticmucosa

Biopsy samples taken from the oxyntic mucosaand stored in liquid nitrogen were weighed,dissolved in phosphate buffer at a concen-

tration of 100 mg tissue/ml, and homogenisedusing a rotating knife homogeniser.15 Hista-mine was determined in the homogenate (after10 minutes of boiling) by the commercial RIAmethod used for determination of plasma his-tamine, and CgA was determined by a

commercial ELISA method (Dako, Den-mark).23 The blood tests as well as the biopsyspecimens were examined blindly.

StatisticsWilcoxon's paired signed rank test was used toevaluate statistically the differences induced bythe treatment, and Mann-Whitney test toevaluate the differences in gastrin values be-tween Hpylori positive and negative patients.

ResultsThe oesophagitis was healed in all patients.Three of the patients were positive for H pylorias assessed by serology (Table I).

Plasma gastrinBasal plasma gastrin increased in all subjectsalthough in some only marginally. On the otherhand, basal plasma gastrin increased more thaneightfold in one subject and threefold in twoothers (Table I). Basal gastrin before treatmentwas significantly (p=00238) higher in thethree patients with Hpylori infection compared

TABLE I Effect of three months' treatment with omeprazole 40 mg daily on blood basal CgA, gastrin, and histamine, andmeal stimulated gastrin release in patients with reflux oesophagitis

Patient Basal gastrin Meal stimulated gastrin Peak meal stimulated Plasma histamine Serum CgA(pmoll) release (area under curve) gastrin concentration (nmoUl) (UIl)

(pmol//min/l) (pmoll)Before During Before During Before During Before During Before During

1 14 15 - 2232 25 3-3 4.0 9-2 24-02 13 18 1963 7628 20 86 2-9 5-1 9.1 9.13* 23 75 5060 17095 69 176 3-6 2-6 5-4 24-04 12 101 2148 9908 24 104 3-3 4-2 12-0 34 05 12 17 1453 4345 13 42 2-6 3-6 110 16-06* 23 37 3660 16893 47 172 2-6 3.0 23-0 55 07 12 27 1800 8165 20 93 7-4 4-2 100 13-08* 22 64 2785 13240 28 122 3-6 4-2 22-0 74 09 17 19 1678 7783 20 91 5.9 4-6 5-4 13-0Median 14 27 2056 8165 20 91 3-3 4-2 10 0 24-0

*Helicobactr pylori positive.

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Effect ofomeprazole on gastric acid secretion

with the other six H pylori negative patients.Although plasma gastrin only increasedmarginally in most of the patients, the inte-grated two hour gastrin response to the testmeal increased substantially in all subjects(Table I). The increase in meal stimulatedgastrin release after omeprazole treatmentdepended on the meal stimulated releasebefore treatment and increased threefold tofourfold compared with that before the treat-ment period (Table I). Moreover, integratedmeal stimulated gastrin release before(p=00357) as well as during (p=00238) ome-prazole treatment was significantly increased inpatients with H pylori infection.

Plasma histamine and CgA in serumPlasma histamine did not increase significantlyduring the omeprazole treatment period(Table I). On the other hand, serum CgAincreased in eight of the patients and wasunchanged in the ninth (p=0.002) (Table I).

Gastric acid secretionBasal acid secretion increased significantlyafter omeprazole treatment (p<005). In one ofthe subjects, it became as high as 16 mmol/h(Figure).

Pentagastrin stimulated acid secretionincreased in seven and was unchanged in oneof the eight subjects studied (Figure) (p=0.004).In one patient (patient 3) the acid secretioncould not be assessed owing to heavy duodeno-gastric reflux (dark brown bilirubin stainedgastric juice) on both occasions. Pentagastrinstimulated acid secretion was nearly doubled inpatients 5 and 6, and a substantial increase wasnoted in all but two patients (patients 2 and 8).Median pentagastrin stimulated acid secretionincreased 50% (from 27.9 to 42-4 mmol/h).

70 r

60K

50 H

40 H

30 H

20 H

10 [-

0 0Before After Before After

Basal (left) and pentagastrin stimulated (right) acid secretion before and 14 days after a 90day treatment period with omeprazole 40 mg daily.

Histamine and CgA in the oxyntic mucosaHistamine increased significantly (p=002) inthe oxyntic mucosa over the omeprazole treat-ment period (Table II). The increase in CgAwas even more marked and highly significant(p=0.004) (Table II).

DiscussionFor the first time a marked gastric acid hyper-secretion after treatment with a proton pumpinhibitor has been found in humans. This is inagreement with a previous study in rats wheregastric acid hypersecretion was recorded oneweek after the end of longterm treatment withomeprazole.'5 24 The acid hypersecretion inthese rats persisted for at least 70 days.'5 24Previously, tolerance to H2 blockers has beendescribed whereas no such tolerance has beenreported after treatment with proton pumpinhibitors.25 Rebound acid hypersecretion hasbeen recorded after even a relatively shorttreatment period of four weeks with an H2receptor antagonist.26 The dose of omeprazoleused in the present study (40 mg daily) ishigher than that reported to give maximalinhibition of acid secretion in patients withduodenal ulcer by Sharma et al,27 but lowerthan the dose giving maximal inhibition ofpentagastrin stimulated acid secretion inhealthy volunteers.28 Nevertheless, the doseused probably gave a profound inhibition ofacid secretion in these patients, which issupported by the increased basal and mealstimulated gastrin release. Acid secretion asassessed by the pH in aspirated aliquots ofgastric juice in healthy volunteers after a threeweek treatment period with either ranitidine300 mg or omeprazole 40 mg per day haspreviously been studied up to 21 days aftercessation of treatment without any change innocturnal acidity.29 The apparent discrepancybetween that study and the present one isprobably because the treatment period in thestudy of Prewett and coworkers was tooshort.29 In fact, the ECL cell density as assessedby argyrophil cell density increased markedlyfrom day 30 to day 60 of hypergastrinaemia inrats.30 In agreement with previous studies,3'fasting gastrin and meal stimulated gastrinrelease were higher in patients with H pyloriinfection. One of the patients with H pyloriinfection had marked duodenogastric refluxwith bile stained gastric juice. Although

TABLE II Effect of three months' treatment withomeprazole 40 mg daily on the concentration ofhistamineand CgA in the oxyntic mucosa

Patient Histamine (nmol/g) CgA (U/g)

Before During Before During

1 96 55 0-84 0722 82 91 1-45 3-803* 62 255 0-27 3-104 131 161 2-90 6-005 107 101 2 35 3.306* 91 184 096 4.007 61 120 1.30 4.308* 51 130 0 65 5.009 64 127 0.84 290Median 82 127 096 3.80

*Helicobacter pylori positive.

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duodenogastric reflux is usually quite small,not affecting the clinical value of the gastricacid secretory test, it may vary from 0'1 to22.3% in healthy volunteers.32 Naturally,duodenograstric reflux makes basal gastric acidsecretion less reliable than stimulated values.In the present study basal gastric juice inpatient 3 was not only bile stained, but alsoalkaline. Therefore, it was quite clear that thesecretory data from this patient could not beused in the assessment of rebound acidhypersecretion in this study. Ideally, thispatient should have been removed from thestudy at the initial phase because of theobserved duodenogastric reflux. However,exclusion of this patient would have meant thatonly two patients with Hpylori infection wouldhave had pre- and post-treatment acidsecretion determined. In one of these patients(patient 8) both basal and pentagastrin stimu-lated acid secretion were unaffected by thetreatment with omeprazole whereas it in-creased markedly in the other patient (patient6) with H pylori infection (pentagastrin stimu-lated acid secretion increased from 27.3 to47-8 gmol/h).The effect of omeprazole persists for at least

one week.27 Therefore, it is mandatory to waitfor longer than this to be able to detectrebound acid hypersecretion. In the presentstudy we determined acid secretion two weeksafter the end of treatment with the protonpump inhibitor and detected an increasedpentagastrin stimulated as well as basal acidsecretion. In vivo 24 hour gastric acidityreflects basal as well as food stimulated acidsecretion. Since gastrin is the dominatingsecretagogue for meal stimulated acid se-cretion,1 the described increase in pentagastrinstimulated acid secretion would be expected tolead to an augmented food stimulated acidsecretion. Furthermore, as longterm inhibitionof acid secretion also leads to an increase inantral G cells and decrease in somatostatin (D)cells,30 food stimulated acid secretion afterlong-term treatment with potent inhibitors ofacid secretion could lead to an even moremarked acid hypersecretion than detected bypentagastrin stimulated acid secretion. It is pos-sible that GRP stimulated acid secretion33 couldbe an even more sensitive test for post-treatmentacid hypersecretion. The clinical impact of thispost-treatment acid hypersecretion remains tobe shown. However, gastric acid plays a patho-genetic part in both peptic ulcer disease andreflux oesophagitis. Therefore, it is conceivablethat.the demonstrated acid hypersecretion mayhave a negative effect and contribute to therecurrence of both these diseases. The hyper-gastrinaemia secondary to the inhibition of acidsecretion by omeprazole probably induced thepost-treatment gastric acid hypersecretion.Basal gastrin increased in all subjects duringtreatment. The increase in basal gastrin was,however, slight or moderate with a value above100 pmol/l in only one patient. However, evenmoderate hypergastrinaemia has a significanttrophic effect on the ECL cell.9

Furthermore, as shown in this study, basalgastrin values during treatment with proton

pump inhibitors underestimate the post-prandial hypergastrinaemia, which was greatlyincreased in all subjects during omeprazoletreatment. Thus, the 24 hour gastrin stimu-lation is considerably raised in patients treatedwith proton pump inhibitors. Taking intoconsideration that the maximal trophic effectof gastrin on the ECL cell is reached at a lowerconcentration than previously thought inhumans,'0 as in the rat,9 it is probable that nearmaximal stimulation of ECL cell growth wasobtained during a greater part of the day insome of the patients, for instance patients 3and 6, who both had postprandial gastrinvalues just above 170 pmolll (Table I).

It is now established that the ECL cell playsa central part in the regulation of gastric acidsecretion.7 Furthermore, it is probable thatgastrin induced histamine release is thelimiting factor for gastric acid secretion aftergastrin stimulation as well as meal stimulatedacid secretion.34 We found an increased hista-mine concentration in the oxyntic mucosa afteromeprazole treatment, which probably reflectsan increase in the ECL cell mass, especially asit was accompanied by a similar increase inCgA. An increased ECL cell density in theoxyntic mucosa in humans is well known afteromeprazole treatment. 16 Lamberts et alreported a doubling of the density of argyrophilcells in the oxyntic mucosa in patients withpeptic ulcer treated with omeprazole for one totwo years at the dose of 40 mg daily.'6 Takinginto consideration that the ECL cell, the onlyargyrophilic cell in the oxyntic mucosa wheregastrin has a positive trophic effect,35 normallyrepresents only 35% of these cells,36 a doublingof the density of the argyrophilic cells probablyindicates an even more marked increase in theECL cell density than just a doubling. Further-more, gastrin has a negative trophic effect onthe D cell in the oxyntic mucosa.37 Accord-ingly, the described increase in argyrophilic celldensity represents a massive increase in theECL cell mass and function in the oxynticmucosa. On the other hand, proton pumpinhibitor treatment seems not to induce anincrease in parietal cell density.'5Longterm hypergastrinaemia in humans is

accompanied by gastric acid hypersecretion.38This gastric acid hypersecretion may be con-trolled by treatment with proton pump in-hibitors in normal doses,39 whereas H2 blockershave to be used in greatly increased doses,40suggesting an increase in the histamine concen-tration in the oxyntic mucosa.34 Altogether, thefindings of this study and previousstudies'6 34-40 suggest that increased histaminedue to ECL cell hyperplasia is the mostimportant mechanism for increased acidsecretory capacity after prolonged hyper-gastrinaemia. Furthermore, this study showsthat CgA in blood may be used to assess theneuroendocrine cell mass in the stomachwhereas plasma histamine cannot be used toestimate the ECL cell mass (Table I). Con-tamination of histamine released from granulo-cytes at the blood sampling and preparation ofplasma'o is probably the main reason for thelack of correlation between plasma histamine

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Effect of omeprazole on gastric acid secretion 653

on one hand and serum CgA or ECL cell masson the other.

In conclusion, this study shows for the firsttime that treatment with a proton pumpinhibitor in a conventional dose even inhumans induces post-treatment gastric acidhypersecretion, which may have negativeinfluences on the diseases for which they wereprescribed. Furthermore, this increase in acidsecretion is probably due to an increased ECLcell mass secondary to hypergastrinaemiaduring the treatment period.

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2 SandvikAK, Waldum HL, Kleveland PM, Schulze S0gnen B.Gastrin produces an immediate and dose-dependenthistamine release preceding acid secretion in the totallyisolated, vascularly perfused rat stomach. Scand JGastroenterol 1987; 22: 803-8.

3 Brenna E, Waldum HL. Studies of isolated parietal andenterochromaffin-like cells from the rat. Scand JGastroenterol 199 1; 26: 1295-306.

4 Prinz C, Kajimura M, Scott DR, Mercier F, Helander HF,Sachs G. Histamine secretion from rat enterochromaffin-like cells. Gastroenterology 1993; 105: 459-61.

5 Waldum HL, Sandvik AK, Brenna E, Schulze S0gnen B.Radioimmunoassay of histamine. Scand J Gastroenterol1991; 26 (suppl 180): 32-9.

6 Leth R, Olbe L, Haglund U. The pentagastrin-inducedgastric acid response in humans. Scand J Gastroenterol1988; 23: 224-48.

7 Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrin-histamine sequence in the regulation of gastric acidsecretion. Gut 1991; 32: 698-701.

8 Ryberg B, Tielemans Y, Axelson J, Carlsson E, Hakanson R,Mattson H, et al. Gastrin stimulates the selfreplicationrate of enterochromaffin-like cells in the rat stomach.Gastroenterology 1990; 99: 935-42.

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11 Waldum HL, Sandvik AK, Syversen U, Brenna E. Theenterochromaffin-like (ECL) cell. Physiological andpathophysiological role. Acta Oncol 1993; 32: 141-7.

12 Kleveland PM, Waldum HL, Larsson H. Gastric acidsecretion in the totally isolated, vascularly perfused ratstomach. A selective muscarinic-1 agent does, whereasgastrin does not, augment maximal histamine-stimulatedacid secretion. ScandJ Gastroenterol 1987; 22: 705-13.

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31 Prewett EJ, Smith JTL, Nwokolo CU, Hudson M,Sawyer AM, Pounder RE. Eradication of Helicobacterpylon abolishes 24-hour hypergastrinemia: a prospectivestudy in healthy subjects. Aliment Pharmacol Ther 1991;5: 283-90.

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