the paneth cell in disease' - bmj

Gut, 1969, 10, 804-811

The Paneth cell in disease'KLAUS LEWIN2

From the Department ofPathology, Vincent Square Laboratories of Westminster Hospital, London

SUMMARY A systematic study of the distribution of Paneth cells in disease of the small and largeintestine is described. In disease of the small intestine and appendix there is usually a fall in the num-ber of Paneth cells normally present. Occasionally, as in Crohn's disease, there may be proliferation.In disease of the colon the number of Paneth cells is unaltered in functional and developmentaldisorders and increased in the inflammatory and neoplastic diseases. lt is suggested that the Panethcell proliferation originates from stem cells in the colon.The significance of an increase in Paneth cells is discussed and it is suggested that in ulcerative

colitis it may produce a self-perpetuating and destructive state.

Paneth cells were discovered by Schwalbe in 1872 andlater described more fully by Paneth in 1888. Theyare found in the intestinal mucosa of a wide varietyof animals in the fundus of the crypts of Lieberkuhn,and are characterized by large granules visible inboth the fresh and fixed state in the apical supra-nuclear part of the cell. In man they are foundnormally in the small intestine and appendix, andhave been reported in the colon (Hamperl, 1928;Verity, Mellinkoff, Frankland, and Greipel, 1962),the stomach, and the pancreas (Helly, 1905). Theirpresence in the last three sites has not been gen-erally confirmed.

In diseases of the intestinal tract the number ofPaneth cells normally present may be altered. In thestomach there is proliferation in association withgastritis and gastric carcinoma. In the small intestinethe number is diminished in coeliac disease(Creamer and Pink, 1967). In the colon Paneth cellsare found in increased numbers in ulcerative colitis(Watson and Roy, 1960; Paterson and Watson,1961), in 'tuberculous typhlitis' (Hertzog, 1937),in benign tumours (Thorel, 1898; Schmidt, 1905;Lendrum, 1948; Morson, 1955; Gibbs, 1967; andin others), and in carcinoma (Schmidt, 1905; Kerrand Lendrum, 1936; Lauren, 1961; Gibbs, 1967).The purpose of this paper is to report the findings

of a systematic study of the effect of intestinaldisease on the Paneth cell, because most of our

'The subject matter has formed part of a thesis for the MD degreeof the University of London, 1966.'Present address: Department of Pathology, Stanford UniversityHospital, Stanford, California 94305, USA.

present knowledge is restricted to isolated reports inconnexion with other investigations of the intestine.

MATERIAL AND METHODS

The diseases which were studied are listed in Table I.The material consisted of biopsy and resection speci-mens obtained predominantly at operation and occasion-ally at necropsy. Wherever possible, the lesion, mucosaadjacent to the lesion, and normal mucosa were examined.In the specimens involving long segments of bowel,blocks were selected at frequent intervals along theirlength. In every case the diagnosis was made on histo-logical and not on clinical grounds.

All specimens were fixed in 10% formol saline for 24to 48 hours. Representative blocks were embedded inparaffin wax and sectioned in the normal fashion andthen stained in the standard way with Mayer's haematoxy-lin and eosin. Special stains which were used includedLendrum's phloxine tartrazine, Masson's trichrome, anda combined ammoniacal silver and trichrome stain.With haematoxylin and eosin there was poor contrast

between the granules, the nucleus, and the surroundingstroma. The best contrast was obtained with Masson'strichrome stain and Lendrum's phloxine tartrazinemethod. In the former, the Paneth cell granules retainedtheir red colour from the dyes Ponceau 2R and acidfuchsin after differentiation with phosphomolybdic acid.The nuclei were stained blue-black by the haematoxylinand the surrounding stroma took up the counterstain,light green. In Lendrum's phloxine tartrazine method,the Paneth cell granules remained red after differentiationwith tartrazine in cellusolve, but the cytoplasm andcollagen turned a pale yellow. The nuclei were stainedblue black by the haematoxylin. Differentiation wasmuch easier to control in the trichrome method and

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The Paneth cell in disease

TABLE IMATERIAL STUDIED

Specimen No. of SpecimensExamined

Small intestineCrohn's diseaseUlcerative colitis

MucoviscidosisVillous atrophyTumours: primary

secondary

AppendixAcute appendicitisChronic appendicitisUlcerative colitisCrohn's disease

Large intestineCarcinoma: caecum, ascending or transverse colon

descending, sigmoid colon or rectumPolyps: Epithelial: colon

rectumMetaplastic: rectumSimple: rectumPeutz Jegher's: rectumJuvenile

Diverticular diseaseUlcerative colitisCrohn's diseaseNonspecific inflammation of the rectumMiscellaneous: Melanosis coli

MucoviscidosisHirshsprung'sIdiopathic megacolon

more consistent results were obtained. For this reasonthe trichrome method was found to be the most reliablein demonstrating Paneth cells.With the last two stains, the morphology of the Paneth

cell was quite distinct from that of the otherglandularcellsof the intestinal tract, although the argentaffin cellgranules stained in a similar manner to the Paneth cellgranules. This occasionally caused confusion in obliquelycut sections, in which the relationship of the positionof the granules to the nucleus was difficult to assess.(The Paneth cell granules were supranuclear and theargentaffin cell granules were infranuclear.) Whereconfusion as to the nature of the granule occurred, acombined ammoniacal-silver-trichrome stain was helpfulsince the argentaffin cell granules took up the silverstain and appeared black, whereas the Paneth cellgranules were unaffected and took up the Ponceau 2Rand fuchsin stains.

ESTIMATION OF NUMBER OF PANETH CELLS The number ofPaneth cells in each section was estimated by obtaininga Paneth cell count. This was calculated by dividing thenumber of crypts of Lieberkiuhn which contained Panethcells by the total number of crypts of Lieberkuhn in thatsection. The ratio was then expressed as a percentage.For the large intestine an average figure from thoselesions with Paneth cells was calculated for each of thespecial groups. Although the Paneth cell count wasusually related to the total number of Paneth cells persection it was really only an estimate of the number ofcrypts of Lieberkuihn containing Paneth cells. It was there-

ResectionResection of terminal ileum with

large bowelResection and necropsyPeroral biopsyResectionResection

ResectionResectionRemoval with colonRemoval with colon

Right hemicolectomyAbdomino-perineal resectionResectionLocal excisionLocal excisionLocal excisionLocal excisionLocal excisionLocal resectionTotal colectomyResectionBiopsyResectionNecropsyResectionResection

9

1741866

3035293

352915

2316314

5344222633II

fore necessary sometimes to add a rider about thenumber of cells per crypt. This was expressed as decreased,normal, or increased.

OBSERVATIONS

In order to evaluate the influence of disease on thePaneth cell, a preliminary investigation, details ofwhich are published elsewhere (Lewin, 1969), wasundertaken to determine the distribution of thePaneth cell in health. In the small intestine they werefound in the jejunum and ileum in equal numbersand they occurred in almost every crypt of Lieber-kuhn. In the appendix they were found in about75% of specimens, but unlike the frequency in thesmall intestine they occurred only in about 8 % ofthe crypts and the number per crypt was small. Inthe large intestine, Paneth cells were very sparseand were only found in 26% of specimens. Theyoccurred mainly in the caecum and ascending colonand rarely more distally although they couldoccasionally be found as far as the rectum.The morphology of the Paneth cell is highly

characteristic: it is a cone-shaped cell with its baseadjacent to the basement membrane and apexbordering the lumen of the crypts of Lieberkuhn.Its nucleus lies at the base of the cell. The cytoplasmcontains large granules situated in the upper half

Disease

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Klaus Lewin

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FIG. 1. Paneth cell counts in the normal and diseased appendix.

of the cell and variable in number. They take upnumerous dyes, such as eosin, safranine, acid fuchsin,azan stains, phosphotungstic acid haematoxylin, andaniline dyes. In disease the general morphology ofthe cell remains unaltered. The degree of granularity,however, may vary but the changes are not consistent.The influence of disease of the small intestine and

appendix on the Paneth cell is summarized inTable II and Figure 1. In general, diseases of thesmall intestine caused a fall in number of Paneth

TABLE IIINFLUENCE OF DISEASE OF THE SMALL INTESTINE ON

THE PANETH CELL

Disease Effect onNo. ofPaneth Cells

Crohn's disease

Ulcerative colitis with reflux ileitisMucoviscidosisVillous atrophyTumours

Usually decreasedSometimes increasedDecreasedDecreasedDecreasedDecreased

cells normally present. There was one exception,namely, some cases of Crohn's disease in whichthere was an increased number of Paneth cells (Fig. 2).

In Crohn's disease the decrease in number ofPaneth cells occurred in the severely diseased seg-ments. In the less acutely inflamed specimens andin areas where there was evidence of repair, pro-liferation of Paneth cells was seen. The Paneth cellswere often seen high up on the sides of the glandcrypts and occasionally even on the intestinal villi(Fig. 3). These changes occurred only in diseasedsegments.

In villous atrophy there was a diminution innumber of Paneth cells in biopsies with shortenedor absent villi, but no change was seen in biopsieswith spade villi (Fig. 4). In mucoviscidosis therewas also a marked reduction in the number ofPaneth cells and where these were present theycontained fewer, poorly staining granules. Also insome areas Paneth cell depletion appeared to beassociated with cystically dilated gland cryptsfilled with abnormal mucus. In ulcerative colitis

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The Paneth cell in disease2 ~~~~~~~~~~~~~~~~~~~~~... ..... .FIG. a2I tiXFIG. 2.

FIG. 4.

FIG. 2. Ileum in Crohn's disease. Section shows markedproliferation ofPaneth cells. Trichrome x 160.

FIG. 3. Ileum in Crohn's disease showing proliferationofPaneth cells up the sides ofthe crypts ofLieberkuhn. OnePaneth cell is also seen at the base of a villus in the upperright half of the photomicrograph. Trichrome x 160.

FIG. 4. Peroral jejunal biopsy showing villous atrophy.Note the absence of Paneth cells at the crypts ofLieberkuhn. Trichrome x 80.

FIG. 3.

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Klaus Lewin

TABLE IIlDISTRIBUTION OF PANETH CELLS IN DISEASE OF THE LARGE INTESTINE

No. of Specimens ContainingSpecimens Paneth CellsExamined

No. %

Paneth Cell No. of Paneth CellsCount Compared with No.(%) Normally Present

CarcinomaCaxcum, ascending and transverse colonRectum. sigmoid, and ascending colonTotal

PolypEpithelial: Colon

RectumTotal

MetaplasticSimplePeutz Jegher'sJuvenile

Diverticular diseaseDiverticulosisDiverticulitis

Ulcerative colitisDiffuse acuteDiffuse chronic activeProctocolotis: Acute

Chronic activeTotal

Crohn's diseaseTotal colectomyRight hemicolectomyLeft hemicolectomyTotal

Chronic non-specific inflammation o1 rectum

MiscellaneousMelaepsis coliMucoviscidosisHirchsprung's diseaseIdiopathic megacolon

293665

1S2338163

4

3519

111710644

1246

22

22426

64100

0

0

1

212

101795

41

103

14

26

4312

with reflux ileitis and tumours the number of Panethcells was reduced in the diseased segments only.In the case of tumours, there was no difference inbehaviour between primary and secondary lesions.

All the diseases of the appendix, with the excep-tion of appendicitis and some cases of ulcerativecolitis, showed a decrease in number of Paneth cells.In some cases the reduction was due to mucosalulceration, but in the majority this was not the onlyfactor, because in the nonulcerated portions of themucosa, the number ofPaneth cells was also reduced.In chronic appendicitis the number of Paneth cellswas unchanged. In ulcerative colitis, those appen-dices associated with the diffuse chronic form showedproliferation of Paneth cells.The influence of disease of the colon on the Paneth

cell is summarized in Table III and the conditionsassociated with an increased number of Paneth cellsare described briefly below.

In carcinoma there was a moderate increase inthe number of Paneth cells. These were found in the

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2.7 Moderately increased16 Moderately increased

No changeNo changeNo change?Moderately increased

4 No change2 Greatly increased

5-8 Greatly increased

9.9 Greatly increased

Moderately increased

No changeNo changeNo changeNo change

mucosa immediately adjacent to the tumour andoccupied their usual position in the crypts ofLieberkuhn. They were found more frequentlyin carcinoma of the caecum, ascending, and trans-verse colon than in carcinoma ofthe descending colon,sigmoid colon, and rectum. In adenomas there was amoderate increase in the number of Paneth cells, butin contrast to carcinoma, they were found bothwithin the polyps and in the adjacent mucosa. ThePaneth cells occurred at the bases of the glandsand were found twice as commonly in the colonas in the rectum. In the colon all the tumours weresimple adenomas but in the rectum three werevillous papillomas. One villous papilloma consistedmainly of Paneth cells, thus giving an abnormallyhigh average Paneth cell count for the rectal epith-elial polyps (Table III).

In diverticular disease Paneth cells were veryuncommon in uninflamed specimens and abun-dant in inflamed ones. In the latter they occurredmore commonly in healed or chronically inflamed

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The Paneth cell in disease

exact line of demarcation between ileum and rectumwas difficult to locate because ileal villi were blunted,so giving the ileal mucosa a colonic appearance.In none of these specimens was there anyevidence of Paneth cell migration from the smallintestine into the colon.

Paneth cells were found in large numbers inCrohn's disease of the colon and the pattern ofPaneth cell distribution in the diffuse disease wassimilar to that in diffuse chronic active ulcerativecolitis.

DISCUSSION

FIG. 5. Colon inthe numerous PanTrichrome x 100.

diverticula than jative colitis Pannumbers in almdistribution of Pseverity and extdiffuse ulcerativewas diseased, Pa:the caecum andnumber from ca4

were found mor4phase of the disedifferences in P

apparent in spealthough Panethhistologically no:ascending colon,mens of ulcerativ4were also examin

AVERAGE PANETH I1

Severity of Disease

Diffuse acuteulcerative colitis

Diffuse chronic activeulcerative colitis

Distal acute ulcerativecolitis

Distal chronic activeulcerative colitis

3*

- U - S Patzelt (1936) and Morson (1959) stated that thePaneth cells in the small intestine were unaffectedin disease, but did not mention which diseases wereexamined. However, the results of this study haveshown that in disease there is a change in the number

chronic active ulcerative colitis. Note of Paneth cells normally present. Thus there was areth cells within the distorted glands. reduction in the number of Paneth cells in Crohn's

disease, ulcerative colitis with reflux ileitis, primaryand secondary tumours, mucoviscidosis, and severe

in acutely inflamed ones. In ulcer- villous atrophy, and an increase in number inieth cells occurred in very large certain cases of Crohn's disease. The factors re-iost all specimens (Fig. 5). The sponsible for the variation in number of the Paneth'aneth cells varied according to the cells did not appear to be the same in every disorder.;ent of the lesion (Table IV). In In Crohn's disease, ulcerative colitis with refluxcolitis, in which the whole colon ileitis, and tumours the reduction appeared to be

neth cells were most abundant in the result of nonspecific injury due to the diseaseshowed a gradual falling off in process. This was because the reduction occurredecum to rectum. The Paneth cells only in those areas showing disease involving thee frequently in the chronic active crypts of Lieberkuhn and not in the adjacentase than in the acute phase. These healthy segments. In some cases the reduction in'aneth cell distribution were not Paneth cells was actually due to mucosal ulceration.cimens with distal proctocolitis In mucoviscidosis the most important abnormalitycells were frequently seen in the seemed to be an inadequate or abnormal synthesis ofrmal sections from the caecum, granules, because many of the cells contained few orand transverse colon. Four speci- poorly formed granules. This would not be surprisinge colitis with ileorectal anastomoses since specialized cells other than the goblet cells,led. They were all diseased and the for example those in sweat glands, are also ab-

normal in this disease. Pressure atrophy of PanethTABLE IV cells by cystically dilated crypts of Lieberkuhn

CELL COUNTS OF LARGE INTESTINE IN filled with abnormal mucus contributed to a minorULCERATIVE COLITIS extent to a reduction in Paneth cells. In villousPaneth Cell Counts atrophy the small intestine takes on the appearanceCaecum Ascend- Trans- Des- Rectum of colonic mucosa and there is a great diminution

ing verse cending in the number of Paneth cells. Creamer and PinkColon Colon Colon (1967) attributed the mucosal flattening to the ab-

sence of Paneth cells, which they believed played a12 6 3 2 2 10 role in the nutrition of the mucosa. However,11 12 9 8 4 Paneth cell depletion was not necessarily accom-

panied by mucosal flattening, as, for example, in6s 10 44 16 s mucoviscidosis. Therefore it would seem that the10 10 8-7 16 11 most likely reason for the Paneth cell depletion was

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TABLE VFREQUENCY OF PANETH CELL OCCURRENCE IN DISEASE OF THE COLON AND RECTUM

Percentage of Specimens with Paneth Cells

Group 1 Group 2 Group 3(Between 0 and 20%) (Between 20 and 40%) (Between 70 and 80%)

Disease Frequency Disease Frequency Disease Frequency

Diverticulosis 2 of 35 (5%) Carcinoma of colon and 26 of 65 (40 %) Ulcerative colitis 41 of 44 (93%)

Metaplastic polyps 0 of 16 (0%)

Peutz Jegher's 0 of 1 (0%Y)polyps

Simple polyps 0 of 3 (0%)

Melanosis coli 0 of 3 (0%)Hirshsprung's

disease 0 of 1 (0%)Mucoviscidosis 0 of 3 (0%)

rectumAdenoma of colon and 10 of 38 (26%)

rectumNonspecific rectal 6 of 26 (23%)

inflammationJuvenile polyps of colon 1 of 4 (25 %)and rectum

that it formed part of the general mucosal reactionto injury. In summary, in the small intestine thefactors involved in Paneth cell reduction appearedto be an intrinsic abnormality of the Paneth cells asin mucoviscidosis, direct damage as in inflammation,and as part of a general mucosal reaction to injury.The diseases of the large intestine could be divided

into three groups according to the frequency withwhich the Paneth cells were found (Table V). Ingroup 1, which contained the functional and develop-mental disorders, Paneth cells were scanty or absent.Those present were probably part of the normaldistribution in the colon and unrelated to theintestinal abnormality. Although the juvenile polypsfell into group 2, they should probably have beenincluded in this group because only one of the fourspecimens available for examination containedPaneth cells and these appeared to be due to a severeconcomitant inflammation. In groups 2 and 3 thenumber of Paneth cells was increased above normaland the inflammatory conditions were more potentin stimulating Paneth cell production than neo-plasms.The above figures do not altogether reflect the

true position because they failed to take intoconsideration the site of the lesion. This was im-portant in determining the likelihood of findingPaneth cells as these cells were found more frequentlyin the proximal half than in the distal half of thecolon in all diseases, a fact probably related tothe normal distribution of the Paneth cell in thecolon where Paneth cells are rarely found beyondthe splenic flexure. Taking the site of the lesion intoconsideration, it was found that carcinoma of theproximal half of the colon was accompanied by thePaneth cell nearly as frequently as in ulcerativecolitis and Crohn's disease. However, the numberot Paneth cells per specimen was much greater in theinflammations. The relative frequency of these cells

Crohn's disease

Diverticulitis

14 of 22 (64,%)

12 of 19 (63 %)

in diseases of the distal half of the colon remainedunchanged.The explanation for the presence of Paneth cells

in increased numbers in inflammation andneoplasms is not clear. In inflammation repairand regeneration seem to be the most potent stimuli,as seen in chronic active ulcerative colitis (alsonoted by Watson and Roy, 1960) and in diverticu-litis. Acute inflammation or the factors causing itcan also produce Paneth cell proliferation, as thisincrease was found in acute ulcerative colitis in theunaffected areas of the colon.The incidence and significance of Paneth cells in

tumours of the large intestine was discussed byGibbs (1967), who concluded that Paneth cellsoccurred either as a result of sequestration or weretaking part in the neoplastic process. The results ofthis investigation confirmed these findings exceptthat neoplastic proliferation of Paneth cells occurredonly in one case. However, another factor in Panethcell proliferation appeared to be the tumour itselfor something causing the tumour since Paneth cellswere found in increased numbers in the areasadjacent to the neoplasm whether or not these areasshowed inflammation. When inflammation occursit may contribute to proliferation of Paneth cells.It appeared to be responsible for the Paneth cellsfound in the one juvenile polyp since none wasfound in the other hamartomas examined. Thesefindings were not borne out by Gibbs (1967) whofound Paneth cells in juvenile polyposis and Peutz-Jeghers polyps. However, the degree of inflammationpresent in these polyps was not discussed.

SIGNIFICANCE OF CHANGES IN PANETH CELL POPU-LATION IN DISEASE In diseases of the small intestinealteration in the number of Paneth cells did not seemto have any effect on the behaviour of the underlyinglesion.

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The Paneth cell in disease 811

The large intestine reacted to inflammation andtumours by producing an increased number ofPaneth cells. Black and Ogle (1948) suggested thatPaneth cells secreted a protective factor whichinhibited the spread of tumours, because of thefact that carcinomas were so uncommon in the smallintestine where Paneth cells occurred in large num-bers and so common in the colon where Panethcells were sparse. However, there is little evidence infavour of this theory because in tumours of thelarge intestine there are too few Paneth cells adjacentto carcinomas to be of practical significance, andthe extent of the tumour spread is unrelated to thenumber and site of Paneth cells.Large numbers of Paneth cells, as in ulcerative

colitis, may be of some significance. If, as somebelieve, the Paneth cell produces a proteolyticpeptidase, then an excessive number might causemucosal damage by autodigestion, provided that thepeptidase were secreted in sufficient concentrationand in the correct milieu. This may explain thedifferences in clinical behaviour between ulcerativecolitis in which very many Paneth cells are found,and other inflammations in which there are far fewerPaneth cells. Once a sufficient number of Panethcells are produced a self-perpetuating state maydevelop, in which Paneth cells cause tissue destruc-tion and the reparative process gives rise to newPaneth cells. The reason for the chronicity ofulcerative colitis, and why the causative factor ofthe disease has never been found, is presumablybecause by the time the patient is investigated, ithas long since ceased to act.

ORIGIN OF THE PANETH CELLS IN THE DISEASED COLONThe increased number of Paneth cells in the largebowel could either come from cells migrating fromthe small intestine or from cells developing locally.The first possibility is unlikely, because cells migrat-ing along the mucosa should be seen on the surfaceepithelium and they have not been found there.Also there was no evidence of migration of Panethcells from small bowel to large bowel in specimensin which the ileum was anastomosed to the rectum.

Increased numbers of Paneth cells could developlocally either by the multiplication of Paneth cellsnormally resident in the colon or by the stimulationof Paneth stem cells. If the former occurs one wouldperhaps see some Paneth cells in the mitotic phaseand an increased number in the crypts of origin.Mitotic figures were not seen in this material, and

in carcinoma and diverticulitis Paneth cells wereusually found singly in the crypts. Since the Panethcell is a distinctive cell and has never been shownto develop from the transformation of the otherglandular cells of the mucosa, it is most likely tooriginate in the normal and diseased colon fromstem cells in situ.

1 am indebted to Dr Ian Dawson for his constant adviceand encouragement. I should also like to thank Mrs H.Frances for technical assistance.

I gratefully acknowledge a grant towards expenses fromthe Govemors' discretionary fund of WestminsterHospital.

REFERENCES

Black, C. E., and Ogle, R. S. (1948). Influence of local acidification oftissue bordering cancerous growths. Arch. Path., 46, 107-118.

Creamer, B., and Pink, I. J. (1967). Paneth-cell deficiency. Lancet,1, 304-306.

Gibbs, N. M. (1967). Incidence and significance of argentaffin andPaneth cells in some tumours of the large intestine. J. clin.Path., 20, 826-831.

Hamperl, H. (1928). Ober erworbene Heterotopien ortsfremdenEpithels in Magen-Darmtrakt. Beitr. path. Anat., 80, 307-335.

Helly, K. (1905). Acidophil gekbrnte Becherzellen bei Torpedomarmorata. Arch. mikr. Anat., 66,434-439.

Hertzog, A. J. (1937). The Paneth cell. Amer. J. Path., 13, 351-360.Kerr, A. B., and Lendrum, A. C. (1936). A chloride-secreting papil-

loma in the gall-bladder: containing Paneth cells and entero-chromaffine cells and associated with massive chloride loss;with a critical review of papilloma of the gall-bladder. Atumour of heterotopic intestinal epithelium. Brit. J. Surg., 23,615-639.

Lauren, P. (1961). The cell structure and secretion in intestinal cancer.Acta path. microbiol. scand., suppl. 152

Lendrum, A. C. (1948). The surgical significance of some so-calledsimple tumours. Ann. roy. Coll. Surg. Engi., 3, 32-43.

Lewin, K. (1969). The Paneth cell in health and disease. Ibid., 44,23-37.

Morson, B. C. (1955). Gastric polyps composed of intestinal epi-thelium. Brit. J. Cancer, 9, 550-557.(1959). Histopathology of ihe small intestine. Proc. roy. Soc.Med., 52,6-10.

Paneth, J. (1888). Ueber die secernirenden Zellen des Dunndarm-Epithels. Arch. mikr. Anat., 31, 113-191.

Paterson, J. C., and Watson, S. H. (1961). Paneth cell metaplasia inulcerative colitis. Amer. J. Path., 38, 243-249.

Patzelt, V. (1936). Die oxyphilen Panethschen Kbrnchenzellen. InDer Darm: Handbuch der Mikroskopisher Anatomie desMenschen, edited by W. V. Moollendorff. Vol. 5, part 3,pp. 120-137. Springer, Berlin.

Schmidt, J. E. (1905). Beitrage zur normalen und pathologischenHistologie einiger Zellarten der Schleimhaut des menschli-chen Darmkanales. Arch. mikr. Anat., 66, 12-40.

Schwalbe, G. (1872). Beitrage zur Kenntiss der Drusen in den Darm-wandungen ins Besondere der Brunner'schen Drusen. Ibid.,8,92-140.

Thorel, C. (1898). Ueber die hyalinen Korper der Magen-und Darm-schleimhaut. Virchows Arch. path. Anat., 151, 319-345.

Verity, M. A., Mellinkoff, S. M., Frankland, M., and Greipel, M.(1962). Serotonin content and argentaffin and Paneth cellchanges in ulcerative colitis. Gastroenterology, 43, 24-31.

Watson, A. J., and Roy, A. D. (1960). Paneth cells in the large intestinein ulcerative colitis. J. path. Bact., 80, 309-316.



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