mucosa of the small intestine · december i96i holmes,hourihaneandbooth: themucosaofthe...

POSTGRAD. MED. J. (196), 37, 717

THE MUCOSA OF THE SMALL INTESTINER. HOLMES, M.Sc., M.B., PH.D.,*

D. O'B. HOURIHANE, M.B. D.C.P., M.R.C.P.I.,tC. C. BOOTH, M.D., M.R.C.P.

The Postgraduate Medical School of London, W. 2

THE mucosa of the small intestine is intimatelyconcerned with digestive processes and it rapidlydestroys itself after the death of the organismwhich it serves. In studies of the histopathologyof human intestinal mucosa this rapid post-mortem autolysis has considerably limited progress,for until recently it was only possible to obtainsatisfactory histological preparations either whennecropsy was rapidly performed (Manson-Bahr,1915; Adlersberg and Schein, I947) or at lapar-otomy (Paulley, 1954). Such observations, how-ever, demonstrated that abnormalities of the in-testinal mucosa might be present in patients suffer-ing from intestinal malabsorption syndrome andcontradicted Thaysen's view that any changesfound in the intestinal mucosa in tropical sprue oridiopathic steatorrhcea were due only to post-mortem autolysis (Thaysen, 1932).The introduction in recent years of satisfactory

methods for obtaining biopsies of small in-testinal mucosa (Shiner, 1956; Crosby and Kugler,1957; Brandborg, Rubin and Quinton, 1959;Baker and Hughes, i960; Flick, Quinton andRubin, i96i) has confirmed the importance ofmucosal abnormalities in patients with cceliacdisease, idiopathic steatorrhcea and tropical sprueand has led to considerable advances in knowledgeof the histopathology of these conditions (Doniachand Shiner, 1957; Sakula and Shiner, I957;Butterworth and Perez-Santiago, 1958; Smith,Sprinz, Crosby and Sullivan, 1958; Rubin, Brand-borg, Phelps and Taylor, i96oa; Fone, Cooke,Meynell, Brewer, Harris and Cox, i960; Gird-wood, Delamore and Wynn Williams, I96i).These mucosal abnormalities may be recognizedwhen biopsies are examined directly at relativelylow magnification under a dissecting microscope(Rubin, Brandborg, Phelps and Taylor, i96oa;Holmes, Hourihane and Booth, I96I) as well as

* Present address: The Royal Infirmary, Man-chester, 13.

t Present address: The London Hospital, White-chapel, London, E.I.

by conventional histological techniques and elec-tron microscopy.The purpose of this paper is to describe the

appearances of the intestinal mucosa in health andin the two conditions in which intestinal biopsy isof greatest diagnostic value in temperate climates,cceliac disease and idiopathic steatorrhtea. Wehave used the term ' idiopathic steatorrhea ' todescribe those patients in whom malabsorptionfirst presents in adult life, in whom there is noanatomical, hepatic or pancreatic cause forsteatorrhkea and who have no history suggestingcceliac disease in childhood. The biopsies whichare illustrated in the figures were obtained usingthe Crosby biopsy capsule.Normal AppearancesYejunumViewed under the dissecting microscope, freshly-

obtained normal jejunal mucosa is remarkablybeautiful. When biopsy samples are examined inthis way, the shape and appearance of the villiare seen to vary considerably in different in-dividuals. Examples of the different dissectingmicroscope appearances of biopsies from two-normal subjects are illustrated in Figs. Ia and 2a;the corresponding histological sections are shownin Figs. ib and 2b.

Fig. i a shows the characteristic appearances ofa normal jejunal biopsy. The villi project likelong fingers from the mucosa and the blood vesselsare easily seen through the transparent layer ofcolumnar cells which cover them. However,although these long finger-like projections arecharacteristic of the biopsies from many controlsubjects, in others the villi are different, beingbroad, flat and leaf shaped. Such villi are shownin Fig. 2a. These flat, leaf-shaped villi frequentlymingle with those illustrated in Fig. Ia, but some-times the entire mucosa is composed of this typeof villus and occasionally these leaves appear tocoalesce to form distinct ridges within an other-wise villous mucosa. This appearance is com-

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78 POSTGRADUATE MEDICAL JOURNAL December i961

FIG. IA.-Dissecting microscope appearance of normaljejunal mucosa ( X 25). The histological section ofthis specimen is shown in Fig. ib. FIG. IB.-Histological section of jejunal mucosa shown

in Fig. Ia.

FIG. 2A.-Dissecting microscope appearance of normaljejunal mucosa showing leaf-shaped villi (x 25).The histological section of this specimen is shownin Fig. 2b.

·

FIG. 2B.-Histological section of jejunal mucosa shownin Fig. 2a.

monly seen in specimens obtained from theduodenum.

Single histological sections of normal biopsiesdo not reveal the differences in villus shape shownunder the dissecting microscope. Figs. ib and 2billustrate the histological sections taken from thebiopsies shown in Figs. ia and 2a. There is nosignificant difference between these two mucossewhen examined by conventional microscopy.

Histologically, normal villi are long and slender

(Figs. ib and 2b), varying in height between 320 tLand 510 0t, and they project from a thin glandularlayer whose thickness normally measures betweenI20o Land 265 L (Shiner and Doniach, 1958). Underhigher magnification the ' brush' border of theepithelial cells, first described by Brettauer andSteinach (i857), may be seen. Examination of this' brush' border by electron microscopy hasrevealed that it is composed of rows of fine rod-likeprocesses packed closely together like the posts ina palisade (Haubrich, Watson, O'Driscoll andValentine, 1959; Zetterquist and Hendrix, i960;



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December i96I HOLMES, HOURIHANE and BOOTH: The Mucosa of the Small Intestine 719

Add

FIG. 3A.-Dissecting microscope appearance of normalileal mucosa (x 25). The histological section ofthis specimen is shown in Fig. 3b.

FIG. 3B.-Histological section of normal ileal mucosashown in Fig. 3a.

Hartman, Butterworth, Hartman, Crosby andShirai, I960; Padykula, Strauss, Ladman andGardner, i96i). These processes are termedmicrovilli.

IleumThe appearance of normal ileum obtained by

biopsy differs very little from that of the jejunum.An example of normal ileal mucosa is shown inFig. 3 (a and b).Under the dissecting microscope the long,

slender finger-like villi are similar to those seenin the jejunum (Fig. 3a). Leaf-shaped villi mayoccur in this region, but have been seen less oftenthan in the more proximal regions of the smallintestine. Histologically, the villi of the ileumare sometimes rather plumper than those usuallyseen in the jejunum (Fig. 3b).Coeliac Disease and Idiopathic SteatorrhceaJejunum

Jejunal biopsies obtained from patients withcceliac disease or idiopathic steatorrhoea arestrikingly different from those of normal subjects.There is, however, a considerable variation in theappearances of biopsies in different patients andthese differences are apparent both under the dis-secting microscope and on conventional micro-scopy. We have previously classified the differentdissecting-microscope appearances of biopsies frompatients with cceliac disease or idiopathic steator-rhcea as either ' flat' or ' convoluted ' (Holmes,Hourihane and Booth, i96i).

' Flat' Mucosa. Examples of the dissecting-

microscope appearances of two varieties of the' flat' type of mucosa are shown in Figs. 4a and5a; the corresponding histological sections areillustrated in Figs. 4b and 5b.

In some patients the jejunal mucosa under thedissecting microscope is entirely flat and featureless(Fig. 4a). Disorganized blood vessels may be seenthrough the epithelium. Histologically, there iscomplete loss of villi (Fig. 4b), but the glandularlayer of the mucosa is invariably thickened,measuring more than 300 ,t (Doniach and Shiner,1957). This appearance has been termed subtotalvillous atrophy by Doniach and Shiner (I957).Under higher magnification the epithelial cellsmay be seen to be thin; the striated border isoften absent and electron microscopy reveals grossdisorganization and loss of the microvilli (Zetter-quist and Hendrix, I960; Hartman and others,i960; Padykula and others, i96I).

In other patients the dissecting microscopeshows a similarly flat mucosa, but instead of thefeatureless appearance shown in Fig. 4a themucosa may be divided by grooves into round orhexagonal shapes, the whole mucosa appearinglike a mosaic or crazy pavement (Fig. 5a). Histo-logical sections also show the flat mucosa and, inaddition, the deep grooves between the mosaic maybe recognized (Fig. 5b).

Clinically, these ' flat' biopsies are usually seenin children or adult patients with cceliac disease.Of patients who develop symptoms of idiopathicsteatorrhrea in later life, those who present withdiarrhoea and other gastrointestinal symptomsusually also have a ' flat' mucosa.

'Convoluted' mucosa. Examples of the dis-

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720 POSTGRADUATE MEDICAL JOURNAL December i961

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FIG. 4A.-Dissecting microscope appearance of jejunum showing 'flat' mucosa (x 40). Thehistological section of this specimen is shown in Fig. 4b.

FIG. 4B.-Histological section of' flat' mucosa shown in Fig. 4a.



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December 1961 HOLMES, HOURIHANE and BOOTH: The Mucosa of the Small Intestine

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FIG. 5A.-Dissecting microscopeappearance of jejunum showing'flat ' mucosa arranged in amosaic pattern (x 30). Thehistological section of thisspecimen is shown in Fig. 5b.

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FIG. 5B.-Histological section of' flat ' mucosa shown in Fig. 5a.

secting-microscope appearances and histologicalsection of this type of mucosa are shown in Figs.6a and b.

Fig. 6a illustrates the dissecting-microscopeappearance. In contrast to the biopsies shown inFigs. 4a and 5a, this mucosa is not flat. No truevilli are present, but the entire mucosa is arrangedin a series of ridges and whorls reminiscent of theconvolutions of the brain. Histologically, singlesections through such mucosx show what appearto be short, thick, stunted ' villi ' (Fig. 6b), con-trasting with the flat appearances seen in Figs. 4band 5b. This appearance has been termed partialvillous atrophy by Shiner and Doniach (1958).Other workers have referred to these abnormal' villi ' (Fone and others, i960; Rubin and others,i96oa; Doniach and Shiner, I957). However,

single histological sections of these mucosm give afalse impression, for what appear to be ' villi ' are,in fact, transverse sections through the ridgesshown in Fig. 6a, an appearance which the term' convoluted ' seems best to describe. The three-dimensional view obtained under the dissectingmicroscope reveals the nature of these pathologicalabnormalities more clearly and accurately thanhistological examination alone.Although this convoluted type of mucosa appears

entirely different from the ' flat' biopsies shown inFigs. 4a and 5a, the appearances of jejunal speci-mens from other patients suggest that they may berelated. A ridged and convoluted mucosa is oftenarranged in a mosaic form similar to that in the' flat' mucosa shown in Fig. 5a. Furthermore, wehave seen one biopsy taken from a patient with



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722 POSTGRADUATE MEDICAL JOURNAL December 196I

-rnrFIG. 6A.-Dissecting microscope appearance of jejunum

showing ' convoluted ' mucosa ( x 25). The histo-logical section of this specimen is shown in Fig. 6b.

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FIG. 6B.-Histological section of jejunal mucosa shownin Fig. 6a.

FIG. 7A.-Dissecting microscope appearance of ileumshowing 'convoluted' mucosa (x 30). Thehistological section of this specimen is shown inFig. 7b.

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adult cceliac disease who was responding well to agluten-free diet in whom areas of entirely 'flat'mucosa alternated with a convoluted appearance.

Clinically, this 'convoluted' type of mucosararely occurs in patients with untreated cceliacdisease. It is more commonly seen in adult patientssuffering from latent idiopathic steatorrhcea whopresent with deficiency states such as megalo-blastic anaemia or osteomalacia and who haveminimal intestinal symptoms. This is not in-variably the case, for we have encountered twoadult patients with cceliac disease whose jejunalbiopsies have shown the ' convoluted ' appearance.IleumAlthough the changes in the mucosa of the

jejunum in coeliac disease and idiopathic steator-rhcea have been well described, very much less isknown of the pathology of the ileum. Rubin andhis colleagues (Ig6oa) have reported normal ilealhistology in patients whose jejunal biopsies were'flat ', but in other instances ileal changes havebeen similar to those found in the jejunum (Shinerand Doniach, 1958; Mollin, Booth and Chanarin,I958). We have had the opportunity of examiningboth jejunal and ileal mucosa in eight adultpatients suffering from idiopathic steatorrhoea.The mucosal appearances in these patients aredescribed in the accompanying table.Four of these patients (Cases i to 4) had a ' flat'

jejunal mucosa. In the first patient (Case i) itwas possible to examine the entire intestinal tractat autopsy (Hourihane, Holmes and Booth, 1961).The ileum in this patient showed a predominantly' convoluted' appearance, but the changes wereundoubtedly patchy, for there were also areaswhere the ileal mucosa was entirely flat andother smaller areas which appeared normal. Inthe next two patients (Cases 2 and 3) ileal biopsiesshowed a 'convoluted' appearance. The advan-tage of examination under the dissecting micro-scope is illustrated by the ileal biopsy obtained



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December 1961 HOLMES, HOURIHANE and BOOTH: The Mucosa of the Small Intestine 723

TABLETHE CHANGES. IN THE JEJUNUM AND ILEUM IN EIGHT

PATIENTS WITH IDIOPATHIC STEATORRHOEACase Jejunum Ileum

I ' Flat' ' Flat',' convoluted 'and normal

2 ' Flat ' ' Convoluted'3 'Flat' ' Convoluted '4 ' Flat' Normal5 Convoluted ' Normal6 Convoluted ' Normal7 'Convoluted ' Normal8 Convoluted ' Normal

from one of these patients (Case 3). On con-ventional histological examination (Fig. 7b) itmight be difficult to determine the nature of theintestinal lesion, for almost normal ' villi' can beseen. Under the dissecting microscope, however,the characteristic ridged pattern of a ' convoluted '

mucosa is seen (Fig. 7a). The fourth patient (Case4) had a normal ileal biopsy.The remaining four patients (Cases 5 to 8) had

a 'convoluted' jejunal biopsy. The ileum wasnormal in all these four patients.Comment

It is as yet uncertain whether the flat appearancesshown in Figs. 4 and 5 represent a more severedegree of intestinal mucosal change than the ridgedand convoluted abnormalities illustrated in Fig. 6a.That these changes may indicate differences inseverity is best supported by the observation thatareas of the ileum may show a convoluted appear-ance when the jejunum is entirely flat. Thegradation of changes observed between an entirelyconvoluted and a flat mucosa is also in keepingwith this hypothesis. The abnormalities rangefrom a mucosa which is entirely flat at one end ofthe scale (Fig. 4a) to a flat mucosa arranged in amosaic pattern (Fig. 5a), then to a mosaic patternin which there is a ridged and convoluted appear-ance and, finally, to an entirely convoluted mucosaat the other end of the scale (Fig. 6a). This lasttype of mucosa may well merge with the normal,for, as we have pointed out, apparently ridgedareas may be seen in otherwise normal biopsieswhere there is a predominance of leaf-shapedvilli, possibly by fusion of these villi.What causes the mucosal changes in cceliac

disease and idiopathic steatorrhera is not yetknown. It has frequently been reported thatjejunal biopsies show no improvement in manypatients who respond satisfactorily to a gluten-freediet (Rubin, Brandborg, Phelps, Taylor, Murray,Stemler, Howry and Volwiler, g96ob), but morerecent reports have indicated that jejunal histologymay become normal on this regime. Anderson(1960), for example, has demonstrated marked im-

provement in the duodenal biopsies of childrenwith cceliac disease treated with the gluten-freediet, although it is uncertain whether their initiallyflat biopsies returned to an entirely normal villousmucosa. Zetterquist and Hendrix (I960) demon-strated regeneration of the epithelial microvilliusing electron microscopy in two patients withidiopathic steatorrhcea after as little as four monthson a gluten-free diet. These observations suggestthat the intestinal mucosal abnormalities inpatients who respond to this dietary regime aredue to a toxic action of gluten. The finding of anormal or less severely abnormal mucosa in theileum when the jejunum is severely abnormal is inkeeping with the concept that a foodstuff is re-sponsible for the mucosal changes. A crucial ex-periment which appears to clinch the hypothesisthat gluten sensitivity is the cause of these changeshas been carried out by Rubin and his colleagues(Rubin and others, I960c; Rubin, Flick, Mac-Donald and Parmentier, I96I). These workersdemonstrated the development of abnormalities inthe ileal mucosa after instilling gluten directly intothe ileum of coeliac patients whose distal intestinewas initially histologically normal.The nature of these changes is a matter for

speculation. Although the term ' villous atrophy 'is frequently used, there is no evidence that the' flat' mucosa is an atrophic process and it is diffi-cult to conceive how atrophy might lead to the' convoluted ' appearance. Furthermore, asDoniach and Shiner (I957) have pointed out, theglandular layer of the mucosa is hypertrophied andthicker than normal. These observations have ledto the suggestion that the increased mucosal thick-ness is due to compensatory hypertrophy of theglandular layer in an attempt to' maintain a villousepithelium intact in the face of the threatened life-span of the cells ', a situation which is analogous tobone marrow hypertrophy in the presence ofanaemia (Doniach and Shiner, I960). This ideahas recently been supported by Padykula and hercolleagues (I96I).

Further studies of jejunal and ileal histology arenecessary to determine the variations in normalappearances and the cause and nature of the ' flat 'and ' convoluted' mucosa. Although muchremains to be learnt from further studies usingconventional and electron microscopic techniques,it should be emphasized that the three-dimensionalview of biopsy material obtained with a dissectingmicroscope may be of major importance in assess-ing changes in the shape and pattern of thevilli. It also provides the most rapid method ofdiagnosis.We wish to thank Mr. W. Brackenbury for the

preparation of the photographs, and the MedicalResearch Council for their support.



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724 POSTGRADUATE MEDICAL JOURNAL December 1961

REFERENCESADLERSBERG, D., and SCHEIN, J. (1947): Clinical and Pathological Studies in Sprue, J. Amer. med. Ass., i34, 1459.ANDERSON, C. M. (1960): Histological Changes in Duodenal Mucosa in Cceliac Disease: Reversibility During Treat-

ment with a Wheat Gluten-free Diet, Arch. Dis. Childh., 35, 419.BAKER, S. J., and HUGHES, A. (1960): Multiple-retrieving Small-intestinal Biopsy Tube, Lancet, ii, 686.BRANDBORG, L. D., RUBIN, C. E., and QUINTON, W. E. (1959): A Multi-purpose Instrument for Suction Biopsy of

the (Esophagus, Stomach, Small Bowel and Colon, Gastroenterology, 37, I.BRETTAUER, J., and STEINACH, S. (1857): Untersuchagen uber das Cylinder-epithelium der Darmzotten und seine

Bezielung zur Fettrosorption, S.B. Akad. Wiss. Wien, math.-nat. Kl., 23, 303.BUTTERWORTH, C. E., Jr., and PEREZ-SANTIAGO, E. (1958), Jejunal Biopsies in Sprue, Ann. intern. Med., 48, 8.BOLT, R. J., POLLARD, H. M., and STANDAERT, L. (1958): Transoral Small Bowel Biopsy as an Aid in the Diagnosis

of Malabsorption States, New Engl. J. Med., 259, 32.CROSBY, W. H., and KUGLER, H. W. (I957): Intraluminal Biopsy of the Small Intestine; the Intestinal Biopsy Capsule,

Amer. J. dig. Dis., 2, 236.CULVER, P. J., BENSON, J. A., STRAUSS, E., and JONES, C. M. (1959): Some Observations on the Malabsorption Syndrome

Based on Use of Absorption Tests and Biopsy of the Small Intestine, Gastroenterology, 36, 459.DONIACH, I., and SHINER, M. (1957): Duodenal and Jejunal Biopsies: II. Histology, Ibid., 33, 71.

, (I960): Histopathology of the Stomach in Pernicious Anaemia and Jejunum in Steatorrhcea, Brit. J. Radiol.,33, 238.

FLICK, A. L., QUINTON, W. E., and RUBIN, C. E. (1961): A Peroral Hydraulic Biopsy Tube for Multiple Sampling atany Level of the Gastrointestinal Tract, Gastroenterology, 40, 120.

FONE, D. J., COOKE, W. T., MEYNELL, M. J., BREWER, D. B., HARRIS, E. L., and Cox, E. V. (1960): Jejunal Biopsyin Adult Cceliac Disease and Allied Disorders, Lancet, i, 933.

GIRDWOOD, R. H., DELAMORE, I. W., and WYNN WILLIAMS, I. (1961): Jejunal Biopsy in Malabsorptive Disorders ofthe Adult, Brit. med. J., ii, 319.

HARTMAN, R. S., BUTTERWORTH, C. E., HARTMAN, R. E., CROSBY, W. H., and SHIRAI, A. (1960): An Electron Micro-scope Investigation of the Jejunal Epithelium in Sprue, Gastroenterology, 38, 506.

HAUBRICH, W. S., WATSON, J. H. L., O'DRISCOL, W., and VALENTINE, V. (1959): Electron Microscopy of the FreeBorder of Human Intestinal Epithelial Cell, Henry Ford Hosp. Bull., 7, 113.

HOLMES, R., HOURIHANE, O'B. D., and BOOTH, C. C. (1961): Dissecting Microscope Appearances of Jejunal BiopsySpecimens from Patients with Idiopathic Steatorrhcea, Lancet, i, 8I.

HOURIHANE, D. O'B., HOLMES, R., and BOOTH, C. C. (I96I): In preparation.MANSON-BAHR, P. (1915): 'A Report on Research on Sprue in Ceylon, 1912-4 '. London: Cambridge University

Press.MOLLIN, D. L., BOOTH, C. C., and CHANARIN, I. (1958): 'The Pathogenesis of Deficiency of Vitamin B12 and Folic

Acid in Idiopathic Steatorrhcea', Proceedings of World Congress of Gastroenterology, Washington, 1958,p. 483. Baltimore: Williams and Wilkins.

PAULLEY, J. W. (1954): Observations on the )Etiology of Idiopathic Steatorrhcea, Brit. med. Y., ii, 13i8.PADYKULA, H. A., STRAUSS, E. W., LADMAN, A. J., and GARDNER, F. H. (1961): A Morphologic and Histochemical

Analysis of the Human Jejunal Epithelium in Non-tropical Sprue, Gastroenterology, 40, 735.RUBIN, C. E., BRANDBORG, L. L., PHELPS, P. C., and TAYLOR, H. C. (i96oa): Studies of Cceliac Disease, I, Ibid.,

38, 28.,,-, MURRAY, C. V., STEMLER, R., HOWRY, C., and VOLWILER, W. (I96ob): Studies of Coeliac

Disease, II, Ibid., 38, 5I7., , FLICK, A. L., PARMENTIER, C., PHELPS, P., and VAN NIEL, S. (I96oc): The Effect of Wheat Instillation intothe Proximal Ileum of Patients with Idiopathic Sprue, J. Clin. Invest., 39, 1023.

- , FLICK, F. L., MACDONALD, W. C., and PARMENTIER, C. M. (1961): Acute Intestinal Response to Wheat in CceliacSprue, Clin. Res., 9, 89.

SAKULA, J., and SHINER, M. (1957): Cceliac Disease with Atrophy of the Small Intestine Mucosa, Lancet, ii, 876.SHINER, M. (1956): Duodenal Biopsy, Ibid., i, 17.

and DONIACH, I. (1958): ' Histopathologic Studies in Steatorrhoea'. In Proceedings of the World Congressof Gastroenterology, Vol. I, p. 580. Baltimore: Williams and Wilkins.

SMITH, R. B. W., SPRINZ, H., CROSBY, W. H., and SULLIVAN, B. H. (1958): Peroral Small Bowel Mucosal Biopsy,Amer. J. Med., 25, 391.

THAYSEN, T. E. H. (1932):' Non-tropical Sprue'. London: Oxford University Press.ZETTERQUIST, H., and HENDRIX, T. R. (1960): A Preliminary Note on an Ultra-structural Abnormaljty of the Intestinal

Epithelium in Adult Cceliac Disease (Non-tropical $prue) which is Reversed by a' Gluten-free Diet, Bull. JohnsHopk. Hosp., Io6, 240.



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