gastric andduodenal mucosa in 'healthy' individualsgastric andduodenalmucosain...

Journal of Clinical Pathology, 1978, 31, 69-77

Gastric and duodenal mucosa in 'healthy' individualsAn endoscopic and histopathological study of 50 volunteers

J. KREUNING1, F. T. BOSMAN2, G. KUIPER', A. M. v.d. WAL2, ANDJ. LINDEMAN2

From the Department of Gastroenterology' and the Department ofPathology2, University Medical Centre,Wassenaarseweg 62, Leiden, The Netherlands

SUMMARY The results of histological and immunohistochemical examination of gastric and duo-denal biopsy specimens from 50 volunteers without a clinical history of gastrointestinal disease arereported. Multiple specimens of tissue from standard sites in the stomach and duodenum werecarefully orientated, and serially sectioned for examination by light microscopy and for immuno-histochemical characterisation of plasma cells within the lamina propria.The antrum and fundus were normal in 32 of the 50 subjects but the other 18 showed histo-

pathological evidence of gastritis in either the antrum or fundus. The latter appeared to be age-related.

There was considerable variation in the appearance of the surface epithelium of the duodenumwithin as well as among individual subjects. Superficial gastric metaplasia in one or more biopsyspecimens from the duodenal bulb was found in 64% of individuals. Histopathological examina-tion of the duodenum revealed signs of chronic inflammation in 12% of the subjects. In two individ-uals there was active inflammation but in only one of these was the diagnosis made on endoscopicappearances. Histological criteria important for the diagnosis of duodenitis are discussed.The number of plasma cells in different biopsy specimens from subjects not showing histological

signs of inflammation was variable. The ratio IgA :IgG :IgM producing plasma cells was remarkablyconstant from subject to subject as well as from specimen to specimen.

The advent of fibreoptic endoscopy in recent yearshas enormously extended the diagnostic possibilitiesin gastroenterology. Endoscopic appearances maybe valuable in diagnosis but more accurate anddetailed information results from histological ex-amination of mucosal biopsy specimens. In severalpapers (Whitehead, 1973; Wolff, 1974; Chaput et al.,1974; Whitehead et al., 1975; Cheli and Aste, 1976)the significance of histological examination of biopsyspecimens has been stressed and classificationschemes for different types of gastritis and duodenitishave been proposed. Little attention has so far beenpaid to the histological spectrum of gastric andduodenal mucosa that may be found in individualswithout a clinical history of gastrointestinal disease(Siurala et al., 1968; Whitehead, 1973; Korn and

Received for publication 11 July 197769

Foroozan, 1974). In biopsy specimens where histo-logical examination reveals slight abnormalities it isimportant to know whether changes are correlatedwith specific complaints or are merely a variation ofnormal appearances. Variation of 'normal' gastricand duodenal mucosa taken in multiple biopsies hasnot been extensively studied. In order to establishdiagnostic criteria for borderline lesions, for example,in chronic simple gastritis and duodenitis, know-ledge of the variation in appearance of normalmucosa is of the utmost importance. Similarly, thediagnostic significance of changes in the density ofcellular infiltrate in the lamina propria and inrelative numbers of different immunoglobulin-producing plasma cells can be established only ifvariation of these values in normal mucosa isknown. For this reason gastric and duodenal biopsyspecimens taken from multiple standardised sites in50 'healthy' volunteers have been studied.

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J. Kreuning, F. T. Bosman, G. Kuiper, A. M. v.d. Wal, and J. Lindeman

Material and methods

TISSUE SPECIMENSFifty healthy volunteers, 31 of whom were membersof the hospital staff, were examined. Their agesranged from 20 to 58 years with an average of 33years (Fig. 1). There were 23 women and 27 men.Volunteers with any clinical history of gastro-intestinal disease were excluded. In all individualsendoscopy was performed with an Olympus GIF-K300 forward-oblique-viewing fibrescope. Biopsyspecimens were obtained from seven standard sitesin the stomach and also from six standard sites inthe duodenum (Fig. 2). The specimens were immedi-ately examined with a stereomicroscope to judgemucosal thickness and surface structure. Somespecimens were weighed.

TISSUE PROCESSINGSpecimens were fixed in formol sublimate for sixhours at room temperature (Bosman et al., 1977).They were processed routinely in an autotechnicon,embedded after careful orientation in paraplast andsectioned at 4 ,u. Multiple sections were mounted oneach of three slides and stained with haematoxylinana eosin. runtner aujacent sections werJames' reticulin method and the periodimethod.

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re stnleUi Uy Fig. 2 Standard biopsy sites within the stomach andc-acid Schiff duodenum:

I prepyloric2 minor curvature just above the angulus3 major curvature opposite to 24 high up the minor curvature, just below the cardia5 antrum6 middle of corpus, posterior wall

MALES 7fundusI pars descendens next to papilla

2FEMALES II pars descendens opposite to IIII superior curvature of the bulbIV inferior curvature of the bulbV anterior wall of the bulbVI posterior wall of the bulb

IMMUNOHISTOCHEMISTRYImmunoperoxidase staining for IgA, IgG, IgM, IgD,IgE, and K and A light chain immunoglobulin-producing cells was performed as described byBosman etal. (1977). The sections were deparaffinisedand rehydrated in phosphate buffered saline at pH7-4. Sections were given three washes of five minuteseach in phosphate buffered saline and then incubatedin antiserum for 30 minutes. The following com-mercially available antisera were used: rabbit anti-human IgA, IgM, IgG, and IgE (Behring) and anti-

)-59 human K and A light chain and IgD (Nordic).The method of Sternberger (1974) was used as acontrol for the first and second layers of the im-

?rs munological reagents. As a final control the sera were

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20-29 30-39 40-49 5(AGE IN YEARS

Fig. 1 Age and sex distribution of voluntee

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Gastric and duodenal mucosa in 'healthy' individuals

Table 1 Grading of density of infiltration in the laminapropria

Grade I Few scattered mononuclear cells, mainly localisedbetween the crypts

It Fair number of mononuclear cells more diffuselydistributed through the lamina propria

III Large number of mononuclear cells, often in com-bination with short and broad villi

IV Very heavy infiltrate with short and broad villi orabsence of villi

Lymphoid follicles were excluded.

tested on bone marrow cell preparations from IgA,IgG, IgM, IgD, and Bence-Jones K and A myelomasas recommended by Hijmans et al. (1969). Thesecond layer consisted of a goat anti-rabbit y-

globulin conjugated to horseradish peroxidase(Sigma Chemicals C, type 6) using the method ofAvrameas and Ternynck (1971). Peroxidase stainingwas performed with diaminobenzidine using themethod of Graham and Karnovsky (1966). Sectionswere counterstained with haematoxylin.

Biopsy specimens taken from 12 randomly selectedindividuals with no histopathological changes were

used for quantitative evaluation of numbers ofdifferent immunoglobulin-bearing plasma cells usinga modification (Vermeer et al., 1977) of the methoddescribed by Skinner and Whitehead (1974).

HISTOPATHOLOGYAll gastric biopsy specimens were classified accord-ing to the criteria of Whitehead (1973). All duodenalbiopsy specimens were evaluated with regard to (1)shape of villi, (2) inflammatory infiltration andsuperficial gastric metaplasia in surface epithelium,(3) depth of crypts, depletion or hyperplasia ofPaneth cells, and mitotic index in crypts, (4) localisa-tion of Brunner's glands above or below the muscu-

laris mucosae, (5) cellular infiltrate in the laminapropria (see Table 1), and (6) fibrosis of the laminapropria.

Results

STOMACH (Fig. 3)Most volunteers showed no abnormality in thestomach on endoscopic examination. In two subjects,however, the suspicion of severe atrophic gastritiswas confirmed on histological examination. Allbiopsy specimens were of adequate size, the meanweight being 7-2 mg (range 6-0-104 mg). Normalgastric mucosa was found in 64% of the subjectswhereas in the other 36%, that is, 18 individuals,there was evidence of gastritis. In two cases this wasrestricted to the antrum. In the others the inflam-mation was present in both antrum and fundus. The

findings are summarised in Table 2. The age and sexdistribution of those subjects showing gastritis isgiven in Table 3.

DUODENUM (Fig. 4)Endoscopy revealed a distorted bulb with mucosalerosions in one instance. In this case biopsies showeddegeneration and regeneration of surface epitheliumand infiltration by neutrophil polymorphonuclearleucocytes. In another subject nodules were found onthe posterior wall of the bulb, and histology revealedthese to be areas of fundic-type mucosa with parietaland chief cells. Almost all biopsy specimens were ofadequate size in that they included submucosa andmore than four villi per section. The shape of thevilli in the bulb was variable, some appearing finger-like and others leaf-like or ridge-like.

Table 4 shows the grading of the density ofcellular infiltrate in the lamina propria. In only twobiopsy specimens was migration of neutrophil poly-morphonuclear leucocytes into the surface epitheliumseen. Table 5 shows the relative frequency of histo-logical changes found in duodenal tissue. In sixpatients a combination of histological changes waspresent. It is noteworthy that in 16 cases gastricmetaplasia was present in one duodenal specimen,in nine it was seen in two, in four in three, and inthree subjects it was present in all biopsy specimens.Gastric metaplasia was most frequent in the bulb,and only on one occasion was it noticed in thedescending part of the duodenum. Brunner's glandswere found above the muscularis mucosae in 48subjects. In only 17 subjects were they present in thedescending part of the duodenum. In four patientsabnormal duodenal mucosa occurred simultaneouslywith gastritis.

IMMUNOHISTOCHEMISTRYThe number of plasma cells per unit area in thelamina propria in 12 subjects with no histopatho-logical changes in any of the biopsy specimens isgiven in Fig. 5. The numbers vary considerably fromperson to person but, in general, the duodenumshowed the highest and the fundus the lowestcounts. The absolute numbers of IgG, IgM, and IgAproducing plasma cells showed considerable inter-individual variation. The relative numbers exhibiteda constant pattern in all specimens in all individuals(Fig. 6). The average ratio IgA :IgG :IgM was10:2-4:1 1.

Discussion

STOMACHIn 50 apparently healthy volunteers histologicalevidence of inflammation was found in gastric

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Fig. 3 (a) Normal fundus mucosa ( x 50). (b) Superficial fundus gastritis ( x 75). (c) Normal pyloric mucosa( x 125). (d) Antrum gastritis (x 125).

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Table 2 Type of gastritis found in 18 subjects

Diagnosis No. ofpersons

Superficial antrum gastritis with superficialfundus gastritis 1 (1)

Atrophic antrum gastritis (AAG) with normalfundus mucosa 2

AAG with superficial fundus gastritis 1 (1)AAG with fundus gastritis with slight atrophy 8 (5)AAG with fundus gastritis with moderate atrophy 4 (2)AAG with fundus gastritis with severe atrophy 2 (1)Total 18

The numbers of cases with active gastritis are given in parentheses

Table 3 Age and sex distribution of individuals withhistological evidence of gastritis

Age (yr) Female Male

20-29 2 230-39 2 2 (1)40-49 6 (3) 2 (1)50-59 1 (1)

The numbers of cases with moderate to severe atrophy are given inparentheses.

biopsy specimens in 18 individuals. Histological signsare not always paralleled by symptoms. Atrophicgastritis appeared to be an age-related process, themajority of subjects with moderate to severe formsof the condition being over 40 years. The severity ofgastritis also increased with age. These findings are inagreement with those reported elsewhere by Siuralaet al. (1968) and Wolff (1974). These authors alsoconcluded that women over the age of 50 years wereaffected more frequently than men, and the findingsin the present investigation support this contention.It is noticeable that gastritis is more frequent andmore severe in the distal part of the stomach, whichis a pattern also found in the gastric mucosa inpatients with duodenal ulcer (Meikle et al., 1976). Anincreased number of lymphocytes and plasma cellsin the lamina propria may be the only histologicalsign of inflammation in the gastric mucosa but itshould be borne in mind that in normal healthyindividuals there is a fairly considerable variation inthe number ofplasma cells within the lamina propria.

DUODENUMDirect vision endoscopic biopsies of duodenalmucosa yield sufficient material for histologicalexamination provided that specimens are adequatelyorientated and serially sectioned. The shape ofduodenal villi varied considerably in the biopsyspecimens reported here and also in those reported

by Korn and Foroozan (1974). Unless changes invillous shape are of an extreme nature theyshouldnotbe used as a criterion for the diagnosis of duodenitis.

In the present investigation the density of cellularinfiltrate in the lamina propria was classified accord-ing to visual impression. Reliable cell counting isdifficult to accomplish as considerable variationsexist from specimen to specimen and also within agiven biopsy specimen from villus to villusandindeedfrom section to section of the same villus. Gradingaccording to visual impression appeared to bereasonably reproducible and this is in agreement withthe findings of Beck et al. (1965). Owing to samplingdifficulties it was not possible to use the density ofcellular infiltrate in the lamina propria as a singleindication of inflammation but it had to be employedin combination with other abnormalities such asincreased numbers of plasma cells, extension of theinfiltrate between Brunner's glands, and changes inthe surface epithelium. Because of sampling variationduodenal disease cannot be excluded on a singlenormal biopsy. Lesions are often focal and found inonly one or two of the four specimens of tissue takenfrom the bulb. Perera et al. (1975) regard superficialgastric metaplasia as a lesion of questionable signifi-cance. The frequent occurrence of this phenomenonin our material in specimens which showed no othersigns of inflammation indicates, contrary to theopinion of Whitehead et al. (1975), that it cannot beconsidered a finding indicative of duodenitis. Super-ficial gastric metaplasia has a focal distribution, andin only three instances was it found in all fourspecimens from the duodenal bulb. Heterotopicgastric mucosa in the duodenum, which has beenreported to occur more frequently in duodenalulceration (Hoedemaeker, 1970), was encountered ononly one occasion.

In no less than 96% of the biopsies from theduodenal bulb Brunner's glands occurred bothabove and below the muscularis mucosae. This ismuch more frequent than the incidence reported byKorn and Foroozan, probably due to the greaternumber of biopsies taken from each individual in thepresent series. In the descending part of the duo-denum the presence of Brunner's glands was found in34% of cases and this should be regarded as a normalphenomenon not related to duodenal disease.Slightly increased cellularity of the lamina propria,referred to as 'minimal inflammatory change' byPerera et al. (1975), pseudostratification of entero-cytes, and slight variations in the shape of entero-cytes are phenomena which are readily influenced bythe orientationand thickness of sections and thereforeneed very cautious interpretation. Without othercriteria of inflammation these phenomena should beregarded as variations of normal. Based on our

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Fig. 4 (a) Chronic duodenitis ( x 50). (b) Villus with pseudostratification ofsurface epithelium and infiltrategrade III ( x 125). (c) Extension of infiltrate between Brunner's glands ( x 300). (d) Superficial gastric meta-plasia ( x 300).

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Table 4 Histological grading of cellular infiltrate induodenal biopsies

Grade No. of subjects

I 23II 20II-III 3III 4IV 0Total 50

Table 5 Histological findings in duodenal biopsyspecimens

Characteristic No. of subjects

Superficial gastric metaplasia 32Fibrosis 5Degeneration and/or regeneration of surface

epithelium 4Polymorphs in the lamina propria 4Infiltrate grade III 4Extension of infiltrate between Brunner's glands 6

results we propose the following classification of non-specific duodenitis.

(i) Chronic duodenitisGrade III to IV cellularity of lamina propria (seeTable 1)Extension of infiltrate between Brunner's glandsSlight degeneration or regeneration of surfaceepitheliumFibrosis of lamina propria

8 FUNDUS

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(ii) Silent chronic duodenitisAs in (i) but withGrade I or II cellularity of lamina propria (seeTable 1)Absence of surface epithelial changes

(iii) Active chronic duodenitisAs in (i) but withMarked degeneration or regeneration of surfaceepitheliumInvasion of epithelium by neutrophil polymorpho-nuclear leucocytes.

Evaluation of duodenal biopsies in patients withsuspected duodenal disease will have to prove thevalue of this classification.The association between gastritis and duodenitis

is still debatable. In peptic ulcer of the duodenum,aniral gastritis is quite frequent (Meikle et al., 1976).Cheli and Aste (1976) reported the simultaneousoccurrence of gastritis and duodenitis but rejected acausal relationship between the two conditions. Thedata presented here do not allow a firm conclusionto be drawn.

In all biopsy specimens from the 12 individualsselected for plasma cell counting a constant relation-ship was found between the number of IgA, IgG,and IgM producing cells regardless of the absolutenumber, which showed a considerable variation.S0ltoft (1969) reported a differing ratio from ours inplasma cells counted in jejunal mucosa. This differ-ence could well be due to the difference in the type ofmucosa studied. It is important, in comparing such

ANTRUM

>30

Fig. 5 Plasma cell numbers in12 individuals withouthistological signs ofgastric orduodenal disease.

TOTAL NO. OF PLASMA CELLS

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1 PARS DESCENDENS2 BULB3 ANTRUM4 FUNDUS

Fig. 6 Relative numbers of IgA, IgG,and IgM producing plasma cellsexpressed as percentages of total plasmacell counts. Bars indicate standarddeviation.

IgA IgM IgG

differences, to take note of variation of plasma cellcounts within and between individuals if only alimited number of sections from a single biopsy isstudied. The diagnostic value of changes in relativenumbers of plasma cell types in gastric and duodenaldisease remains to be investigated.The present study reveals that histological evidence

of severe gastritis or of severe duodenitis may existwithout clinical symptoms. It also shows that induodenal mucosa a slight increase in cellularity ofthe lamina propria, variation in villous shape andsize, gastric metaplasia, and the occurrence ofBrunner's glands above the muscularis mucosae mayall be regarded as within normal limits.

Mrs E. M. de Groot-van der Hoeven typed themanuscript; Mr K. van der Ham prepared thephotographs; and Mr G. Flippo prepared thegraphs.

References

Avrameas, S., and Ternynck, T. (1971). Peroxydaselabelled antibody and Fab conjugates with enhancedintracellular penetration. Immunochemistry, 8, 1175-1179.

Beck, I. T., Kahn, D. S., Lacerte, M., Solymar, J.,Callegarini, U., Geokas, M. C., and Phelps, E. (1965).'Chronic duodenitis': a clinical pathological entity?Gut, 6, 376-383.

Bosman, F. T., Lindeman, J., Kuiper, G., Van der WalA. M., and Kreuning, J. (1977). The influence offixation on immunoreactivity of plasma cells inroutinely processed intestinal biopsy specimens. Histo-chemistry, 53, 57-62.

Chaput, J. C., Petite, J. P., Rain, B., Buffet, C., Camillieri,J. P., and Eitenne, J. P. (1974). Les duodenites nonspecifiques. Archives FranVaises des Maladies del'Appareil D.gestif, 63, 611-623.

Cheli, R., and Aste, H. (1976). Duodenitis. GeorgThieme,Stuttgart.

Graham, R. C., and Karnovsky, M. J. (1966). Theearly stages of absorption of injected horseradish peroxi-dase in the proximal tubules of mouse kidney: ultra-structural cytochemistry by a new technique. Journal ofHistochemistry and Cytochemistry, 14, 291-302.

Hijmans, W., Schuit, H. R. E., and Klein, F. (1969). Animmunofluorescence procedure for the detection ofintracellular immunoglobulins. Clinical and Experi-mental Immunology, 4, 457-472.

Hoedemaeker, Ph. J. (1970). Heterotopic gastric mucosain the duodenum. Digestion, 3, 165-173.

Korn, E. R. and Foroozan, P. (1974). Endoscopicbiopsies of normal duodenal mucosa. GastrointestinalEndoscopy, 21, 51-54.

Meikle, D. D., Taylor, K. B., Truelove, S. C., andWhitehead, R. (1976). Gastritis duodenitis, andcirculating levels of gastrin in duodenal ulcer beforeand after vagotomy. Gut, 17, 719-728.

Perera, D. R., Weinstein, W. M., and Rubin, C. E. (1975).Small intestinal biopsy. Human Pathology, 6, 157-217.

Siurala, M., Isokoski, M., Varis, K., and Kekki, M.

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(1968). Prevalence of gastritis in a rural population.Scandinavian Journal of Gastroenterology, 3, 211-223.

Skinner, J. M., and Whitehead, R. (1974). The plasma cellsin inflammatory disease of the colon: a quantitativestudy. Journal of Clinical Pathology, 27, 643-646.

S0ltoft, J. (1969). Immunoglobulin-containing cells innormal jejunal mucosa and in ulcerative colitis andregional enteritis. Scandinavian Journal of Gastro-enterology, 4, 353-360.

Sternberger, L. A. (1974). Immunocytochemistry, p. 53.Prentice Hall Inc., Englewood Cliffs, New Jersey.

Vermeer, B. J., Lindeman, J., van de Harst-Oostveen,

C. J. G. R., Penia, A. S., and van Vloten, W. A. (1977).The immunoglobulin-bearing cells in the lamina pro-pria and the clinical response to a gluten-free diet indermatitis herpetiformis. Archives for DermatologicalResearch, 258, 223-230.

Whitehead, R. (1973). Mucosal Biopsy of the Gastro-intestinal Tract. Saunders, London.

Whitehead, R., Roca, M., Meikle, D. D., Skinner, J., andTruelove, S. C. (1975). The histological classification ofduodenitis in fibreoptic biopsy specimens. Digestion,13, 129-136.

Wolff, G. (1974). Chronische Gastritis. J. A. Barth,Leipzig.

The December 1977 IssueTHE DECEMBER 1977 ISSUE CONTAINS THE FOLLOWING PAPERS

History of cytodiagnosis ARTHUR I. SPRIGGS

National Health Service laboratories in England,1966-74 M. A. BUTTOLPH

The Birmingham Histopathology Data Pool: a co-operative project among 10 laboratories B. W.CODLING, M. K. ALEXANDER, R. G. F. PARKER, ANDR. C. CURRAN

An on-line computor system for histopathologyreporting B. W. CODLING, J. C. MACARTNEY, ANDR. C. CURRAN

Incidence in South-west Scotland of hepatitis Bsurface antizen in the liver of patients with hep-atocellular carcinoma M. L. TURBITT, R. S. PATRICK,R. B. GOUDIE, AND W. M. BUCHANAN

Alpharl-fetoprotein in the diagnosis of hepatoma:statistical and cost benefit aspects P. J. PHILLIPS,R. ROWLAND, D. P. REID, AND M. E. COLES

'Psuedocirrhosis' in hereditary haemorrhagic telan-giectasia T. COONEY, E. C. SWEENEY, R. COLL, ANDM. GREALLY

Immune complexes and abnormal liver function inhaemophilia B. A. MCVERRY, JENNIFER VOKE, I.MOHAMMED, KATHRINE M. DORMANDY, AND E. J.HOLBOROW

Severe coagulation defect due to a dietary deficiencyof vitamin K B. T. COLVIN AND M. J. LLOYD

Granuloma formation in patients after injection ofmethamol extraction residue (MER-BCG) A.BARTAL, H. KERNER, Y. COHEN, AND E. ROBINSON

An enzyme inhibition assay for 2,4-diamino-5-(3'4'-dichlorophenyl)-6-methylpyrimidine (DDMP,NSC 19494) A. H. CALVERT, J. S. CRIDLAND, ANDK. R. HARRAP

Rapid screening for significant bacteriuria using aCoulter Counter R. SMITHER

Gas liquid chromatography in the rapid diagnosisof meningitis I. R. FERGUSON AND P. V. TEARLE

Continuous-flow automation of the Lactobacilluscasei serum folate assay G. B. TENNANT

Technical methodEstimation of serum folate by a radioassay and acontinuous-flow method, compared with an estab-lished microbiological tube assay J. E. O'DONNELL,G. B. TENNANT, AND B. M. JONES

Letter to the Editor

Book reviews

Index to Volume 30

Copies are still available and may be obtained from the PUBLISHING MANAGER,BRITISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, LONDON WCIH 9JR, price £300, including postage

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