intestinal permeability: the basicsdownloads.hindawi.com/journals/cjgh/1995/826518.pdf ·...

Intestinal permeability:The basics

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possible, with the introduction ofnonmetabolized sugars as test sub-stances, to assess intestinal permeabil-ity reliably and noninvasively in hu-mans (1). Acceptance of the techniquewas initially slow, mainly because ofthe confusion around the use of poly-ethylene glycol (�� 400) (2,3), but inthe past few years there has been a pro-liferation of published studies, from awide range of research workers, thathave used these tests to assess variousaspects of gastrointestinal diseases.Tests of intestinal permeability may re-late to at least five purposes: diagnosticscreening for intestinal disease; con-firming diagnosis – indication of thera-peutic response and prognosis; evaluat-ing the role of drug-related, dietary andenvironmental factors upon the intes-tine; determining the effect of variousphysiological factors on intestinal bar-rier function – for instance, related todiet (eg, level of food intake and osmo-lar content), level of nutrition andstate of bloodflow; and assessing theimportance of the intestinal barrierfunction in the etiology, pathophysiol-ogy and pathogenesis of intestinal andsystemic disease.

A detailed discussion of all of theabove is beyond the scope of this paper.However, a noticeable feature of manypublications involving tests of intesti-nal permeability is a frequent failure torealize the importance of factors relat-ing to the preparation of test solutionsand conduct of test procedures.

PREDISPOSING FACTORS IN IBD: BUGS, DRUGS AND LEAKS

I BJARNASON, A MACPHERSON, IS MENZIES. Intestinal permeability: Thebasics. Can J Gastroenterol 1995;9(4):203-212. The authors review some ofthe more fundamental principles underlying the noninvasive assessment of intes-tinal permeability in humans, the choice of test markers and their analyses, andthe practical aspects of test dose composition and how these can be changed to al-low the specific assessment of regional permeability changes and other intestinalfunctions. The implications of increased intestinal permeability in the patho-genesis of human disease is discussed in relation to findings in patients withCrohn’s disease. A common feature of increased intestinal permeability is the de-velopment of a low grade enteropathy, and while quantitatively similar changesmay be found in Crohn’s disease these seem to predict relapse of disease. Moreo-ver, factors associated with relapse of Crohn’s disease have in common an actionto increase intestinal permeability. While increased intestinal permeability doesnot seem to be important in the etiology of Crohn’s disease it may be a centralmechanism in the clinical relapse of disease.

Key Words: Crohn’s disease, Intestinal permeability, Noninvasive assessment, Testmarker, Test marker analysis

Perméabilité intestinale : éléments de base

RÉSUMÉ : Les auteurs passent en revue certains des principes les plus fonda-mentaux de l’évaluation non effractive de la perméabilité intestinale chez l’hu-main, le choix des marqueurs diagnostiques et leur analyse, et les aspectspratiques de la composition des doses utilisées et de la façon dont elles peuventêtre modifiées pour permettre une évaluation spécifique des changements région-aux de perméabilité et autres fonctions intestinales. Les répercussions d’uneperméabilité intestinale accrue dans la pathogenèse de la maladie chez l’humainsont abordées en lien avec les résultats observés chez des patients atteints demaladie de Crohn. Une caractéristique chronique de la perméabilité intestinale

Departments of Clinical Biochemistry and Medicine, King’s College School of Medicine andDentistry; and Department of Chemical Pathology, St Thomas’s Hospital, London, UnitedKingdom

Correspondence: Dr Ingvar Bjarnason, Department of Clinical Biochemistry, King’s CollegeSchool of Medicine & Dentistry, Bessemer Road, London SE5 9PJ, United Kingdom. Telephone0171-274-6222 ext 4108, Fax 0171-737-7434

This paper was presented at the Basic Research and Clinical Implications in IBD meeting,April 6 to 9, 1994, held in Victoria, British Columbia. This paper has also been published inSutherland LR, et al, eds. Inflammatory Bowel Disease: Basic Research, Clinical Implicationsand Trends in Therapy. Boston, Dordrecht and London: Kluwer Academic Publishers, 1994

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C�� J G�� V�� 9 N� 4 J�� 1995 203

Furthermore, many practical prob-lems encountered when setting up thenecessary clinical and laboratory pro-cedures require attention to special de-tails. It is important to discuss these

issues to ensure that such noninvasivetest procedures may be successfully ex-ploited to assess intestinal permeabilityand related aspects of intestinal func-tion.

CHOICE OF MARKER:PRINCIPLE OF THE URINARY

EXCRETION OF ORALLYADMINISTERED TEST

SUBSTANCESTesting intestinal permeability

sounds simple: the subject fasts over-night, drinks a solution containing testsubstances the following morning, andthe subsequent timed recovery of testsubstances in the urine indicates intes-tinal permeation of the administeredprobes.

The choice of probe employed forassessing intestinal permeability haschanged somewhat through the years.Initially a single probe, such as lactu-lose or other nonmetabolized disaccha-ride (melibiose), trisaccharide (raffi-nose) or polysaccharide (dextrans), wasused alone (1,4-6). Properties such asmolecular size, water and lipid solubil-ity, susceptibility to metabolic degrada-tion, affinity for transport systems andtoxicity, are important and requirecareful definition to ensure that renalexcretion of the probe is determinedmainly by the state of intestinal perme-ability (7-12).

However, even when recovery inurine following intravenous admini-stration was complete – indicatingminimal systemic loss – recovery of theprobe following ingestion (usually ex-pressed as percentage of the dose) was,as indicated in Table 1, influenced by anumber of factors in addition to intesti-nal permeability.

To increase specificity the principleof ‘differential urinary excretion’ ofseveral simultaneously ingested testsubstances was formulated. Table 1 de-tails the basis of this principle, whichproposes that two test substances, thebehaviour of which differ only in re-spect to the pathway of permeationacross the intestinal mucosa, should beused together, for instance a monosac-charide (�-rhamnose) and a disaccha-ride (lactulose). In these circumstancesthe differential urinary excretion of di-saccharide/monosaccharide after si-multaneous ingestion provides a muchmore specific indication of the stateof mucosal permeability, in this in-stance specifically large/small pore in-cidence (13), than would be indicated

TABLE 1Factors affecting the urinary excretion of orally administered test substances:The principle of the differential urinary excretion of ingested test substances

Factors affecting the urinary excretion oforally administered test substances

Mono-saccharide

Nonhydrolyzeddisaccharide

Hydrolyzeddisaccharide

Premucosal Completeness of inges-tion

= = =

Gastric dilution = = =Gastric emptying = = =Intestinal dilution = = =Intestinal transit = = =Bacterial degradation = = =Unstirred water layer = = =Digestion-hydrolysis 0 0 ++

Mucosal Route of permeation A B BIntestinal bloodflow = = =

Postmucosal Metabolism 0 0 0Endogenous production* 0 0 0Tissue distribution C D DRenal function = = =Timing and completeness

of urinary collection†= = =

Bacterial degradation = = =Analytical performance‡ = = =

*There may be some but minimal endogenous production of mannitol; †Roughly equal for themonosaccharides and disaccharides; ‡Equal if thin-layer chromatography is used; =Identical or af-fects all the test substances equally; 0 Does not take place; + Determined mainly by intestinal disac-charidase activities; A and B Different routes of permeation; C and D Monosaccharides anddisaccharides have a different volume of distribution following intravenous administration andhence there is a slight difference in the speed and completeness of their urinary excretions. This is forpractical purposes not of major importance.When a nonhydrolyzed disaccharide (ie, lactulose) and a monosaccharide (L-rhamnose or manni-tol) are ingested together all the above factors will contribute to their excretion in urine (percent-age of oral dose). However, as all the pre- and postmucosal determinants of their excretion affectthe two test substances equally the urinary excretion ratio (lactulose:L-rhamnose) will only be mini-mally or not at all affected by these variables. The two probes differ significantly only in their routesof permeation across the intestine. The permeation pathways are affected to a different extent insmall intestinal disease and are subject to specific modification to physiological stress (hyperosmo-larity), damage by drugs (ie, nonsteroidal anti-inflammatory drugs) and inflammation. The urinaryexcretion ratio of lactulose:L-rhamnose thereby becomes a specific index of intestinal permeabilitywhich is not affected to an appreciable extent by nonmucosal factors.The simultaneous administration of a nonhydrolyzed (lactulose) and a hydrolyzed disaccharide(lactose, sucrose or palatinose), with subsequent analysis in urine, to assess the efficacy of intestinaldisaccharidase activities (lactase, sucrase and isomaltase, respectively) is an extension of theabove principle. The disaccharides differ only in respect of their rate of hydrolysis in the intestinewhich, in turn, governs the amount of intact disaccharide available for transport across the mu-cosa. In normal subjects the urinary excretion (percentage of dose) ratio of hydrolyzable:nonhydro-lyzable disaccharides is less than 0.3 but with increasing severity of disaccharidase deficiency(primary or secondary) this ratio approaches 1.0, at which time there is no disaccharide hydrolysis

accrue est l’installation d’une entéropathie de bas bruit et, bien que des modifica-tions quantitativement similaires puissent être observées dans la maladie deCrohn, elle semble pouvoir servir de facteur de prévisibilité de la rechute. Deplus, les facteurs associés à la rechute de la maladie de Crohn semblent exercerune influence à la hausse sur la perméabilité intestinale. Bien que la perméabilitéintestinale accrue ne semble pas importante dans l’étiologie de la maladie deCrohn, elle pourrait se révéler être un mécanisme central dans la rechute cliniquede la maladie.

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by the urinary recovery of either probealone.

Usually lactulose, melibiose or raffi-nose has been employed in combina-tion with either �-rhamnose ormannitol. Cellobiose has also been pro-posed, but the suitability of this probehas been questioned because of thepresence of some intestinal cellobiaseactivity (14). $�Cr� �, which apartfrom resistance to bacterial degrada-tion has properties almost identical tothose of lactulose, can be substitutedfor lactulose but this is not ideal be-cause small intestinal bacterial over-growth (causing degradation of�-rhamnose and mannitol) or a par-ticularly rapid intestinal transit (reduc-ing the effective mucosal contact timeof �-rhamnose) may give rise to an in-creased $�Cr� �: monosaccharideurinary excretion ratio in the absenceof a genuine alteration of permeability.

�� 400 should be avoided whentesting for intestinal permeability forthe following reasons. First, �� 400polymers, despite physicochemicalsimilarities (eg, size and solubility) tononmetabolized disaccharides andmonosaccharides, permeate the smallintestine 10 to 50 times more readilythan saccharides of similar mass. Theprecise reason for such atypical per-meation is uncertain, but discussionhas centred on the question of molecu-lar shape or lipid solubility (10,15-19).In any case a readily permeating testsubstance is inappropriate for assessingbarrier function. Second, recovery of

�� 400 in human urine following in-travenous administration is incompleteand varies between 26% and 72% ofthe administered dose excreted within5 h (13). As �� 400 is not known to bemetabolized it is surprising that recov-ery in the urine is so low and ceaseswithin 10 h of intravenous administra-tion. Such a brief and incomplete re-covery suggests that these polymersmust be retained in the tissues. Third,�� 400 is not appropriate for assessingthe profile of intestinal permeabilitybecause this range of polymers appearsto use the same diffusion pathway. Di-agnostically meaningful alterations inpermeation ratio have not yet been de-scribed. Fourth, altered permeation of�� 400 recorded in various diseasesdoes not correlate in a logical fashionwith any aspect of intestinal physiologyor pathology. Finally, the �� 400 testlacks sensitivity, and only a marginalimprovement is achieved by mathe-matical manipulation (filter functionor N�

�) (20-23).

TEST DOSE COMPOSITIONIt is the purpose of the investigation

that determines test dose composition.It is informative to review the main de-velopments of test dose composition ina historical context: first, with respectto the use of ‘osmotic fillers’, the effectsof which have been responsible forconsiderable confusion, and then testmarker composition.Effects of poorly absorbed solute onintestinal absorption: Inclusion of

slowly absorbed solutes, such as lactu-lose, mannitol and �-rhamnose, in thepreparation of test solutions induces re-tention of fluid within the intestinal lu-men and stimulates peristaltic activity,which by reducing concentration gradi-ents and duration of contact with theabsorptive surfaces reduces absorptiveuptake (otherwise permeation) of alltest substances (24). In the presence ofsmall intestinal malabsorption it shouldbe remembered that solutes normallywell absorbed often become poorly ab-sorbed and behave in a similar way.Effects of hyperosmolar solutions –‘hyperosmolar stress’: Early investiga-tors (1) indicated the importance ofcontrolling the osmolarity of ingestedtest solutions in relation to urinary ex-cretion of lactulose and other oligosac-charides. ‘Hyperosmolar stress’, repre-sented by ingestion of a solution of 100mL volume above 1500 mOsm/L, wasfound to increase intestinal permeationof disaccharide but not monosaccha-ride in healthy human subjects(l,4-6,25). The observation that hy-perosmolar stress at the 1500 mOsm/Lthreshold produced no significant ef-fect on normal intestine of controls,while patients with villus atrophy dem-onstrated a significant rise in perme-ability, led to the use of hyperosmotictest solutions in the belief that theywould increase diagnostic discrimina-tion. Several osmotic fillers were used: amixture of sucrose and lactose, glycerol,glucose, etc. Unfortunately osmoticfillers tend to differ in their behaviour

TABLE 2Content of lactulose/mannitol test solutions employed by various authors: Comparison of urine lactulose, mannitol andlactulose/mannitol with test solution osmolarity and poorly absorbed solute (PAS) content of test solution

Author (reference)

Content of test solution Durationof urinesave (h)

# of sub-jects

Osmolarity(mOsm/L)

Urinary excretion

Lac (g) Other solutesVol-ume(mL)

Lac(% dose)

Mannitol(% dose)

PAScontent*

Lac/mannitol

Ukabam et al (32) 10.0 Nil 100 6 33 320 0.16 15.6 32 0.16Murphy et al (31) 5.0 Nil 65 5 42 580 0.26 13.2 42 0.26Andre et al (28) 5.0 Nil 65 5 100 658 0.30 14.3 42 0.30Wyatt et al (34) 10.0 Glucose 22 g 150 5 30 1300 0.22 12.7 57 0.22Elia et al (27) 10.0 Lactose 1.5 g 50 6 35 1300 0.26 13.3 57 0.26Kapembwa et al (30) 10.0 Nil 50 6 19 1350 0.28 11.4 57 0.28van der Hulst et al (33) 10.0 Xylose 5.0 g 65 6 12 1474 0.4 17.6 32 0.40Juby et al (29) 5.0 Glucose 22.3 g 100 5 12 1500 0.44 28.5 26 0.44Blomquist et (26) 5.0 Glycerol 2.0 g 50 6 28 1700 0.60 15.7 35 0.60

*mOsm per test dose; Lac Lactulose

C�� J G�� V�� 9 N� 4 J�� 1995 203

Intestinal permeability

in the intestine and consequent os-motic potency. Furthermore, the osmo-larity of test solutions employed by dif-ferent workers (26-34) varied widelyand, as a consequence, results obtainedfailed to correspond. This problem iswell illustrated in Table 2. The choiceof osmotic filler needs very careful at-tention to avoid additional unwantedvariables. Variations in hydrolysis oflactose and sucrose are particularly li-able to complicate the action of thesesugars which are best avoided as os-motic fillers. The absorption of -gl-ucose, which is sodium coupled, mayalso represent a variable that is bestavoided. Although the effect of osmoticfillers, which may be poorly absorbed,would not alter disaccharide: monosac-charide permeation ratios, the percent-age of monosaccharide recovery inurine (which provides a valuable assess-ment of absorptive capacity) is cer-tainly reduced. Probes for the latter pur-pose (3-o-methyl--glucose, -xyloseand �-rhamnose) are critically depend-ent on test dose composition, as well asthe completeness and accurate timingof urine collections. Perhaps the bestadvice would be to avoid osmotic fillersbecause their use has not, in general,achieved a better diagnostic discrimi-nation.Test markers: $�Cr� � can be usedalone, but 24 h urinary excretionincludes a substantial amount of theprobe passing across the colon andsmall intestine. $�Cr� � alone doesnot allow the specific assessment of in-testinal permeability. Nevertheless, in-creased urinary excretion of this markerin diseases has almost invariably beenshown to be associated with increaseddisaccharide:monosaccharide urinaryexcretion ratios (29,35-41).

Lactulose is the most widely used di-saccharide in tests of intestinal perme-ability. It resists action of smallintestinal disaccharidases and is notwidely distributed in foods althoughcommonly used as a laxative and in thetreatment of hepatic encephalopathy.Prohibitively expensive when pur-chased as powder, lactulose is availableas a reasonably priced syrup. (The addi-tional osmolarity of the syrup should benoted when preparing test solutions.)

Melibiose also resists intestinal disac-charidase and has been successfully em-ployed as an alternative to lactulose,particularly in liver failure patients,many of whom take lactulose. Raffi-nose, a trisaccharide, can also be used.There is little to choose between themonosaccharides �-rhamnose andmannitol. The latter has theoreticaladvantages because urinary excretionfollowing intravenous administrationsimulates urinary excretion following$�Cr� � and lactulose more closelythan that of �-rhamnose (13,42-45),but mannitol is present in certain foodsand cannot be quantitatively estimatedby thin-layer chromatography becausethe colour reaction lacks sufficient sen-sitivity. Lactulose and monosaccharideprobes should be administered in lowdoses because these substances havelimited intestinal permeation and thuscause osmotic fluid retention withinthe bowel as already described (24).

For routine assessment of small in-testinal permeability in humans a 100mL test solution should include lactu-lose or equivalent nonhydrolyzable oli-gosaccharide (not more than 5 g) and�-rhamnose (1.0 g) or mannitol (nomore than 2 g). A 5 h urine collectionshould be made into a container withsufficient preservative (eg, merthiolate100 mg) to prevent bacterial degrada-tion of sugars. For the combined assess-ment of intestinal permeability andabsorptive capacity 3-o-methyl--gl-ucose (0.2 g), which assesses an activecarrier mediated process in the entero-cytes, and -xylose (0.5 g), which as-sesses a passive carrier mediatedtransport system, should be added tothe above test solution.

A complete and accurate urine re-covery is essential because an incom-plete collection will underestimateabsorptive capacity. The adequacy ofboth renal function and urine collec-tion can be confirmed by estimating se-rum and urine creatinineconcentrations and calculating a cre-atinine clearance index.

ANALYSES OF TEST MARKERSReliable analysis of sugar markers in

urine requires great care and experi-ence. Column chromatography (gas-

liquid chromatography and high per-formance liquid chromatography) hasproven to be difficult to control, butquantitative thin-layer chromatogra-phy has proved a reliable method (stillrequiring adequate experience andmanual skill), enabling samples to be‘batched’. Introduction of a techniqueof ‘multiple application’ enables pre-cise analysis of the very low urine disac-charide concentrations obtained withthese tests (46,47). Enzyme analyses forlactulose has had some proponents.Stability and specificity of the enzymepreparation are important, and a ‘co-ntrol’ analysis to make due allowancesfor preexisting monosaccharides pres-ent in urine is essential. For estimationof lactulose it should be rememberedthat it is necessary to estimate fructoserather than the galactose generated byincubation with beta-galactosidase,otherwise any lactose present will bemistakenly included. Radiolabellingthe probes is yet another possibility.However, because these sugars are in-ert, the radiolabel needs to be incorpo-rated into its basic structure.��C-labelled �-rhamnose and mannitolare available. There is a substantialproblem if $�Cr� � is used concomi-tantly with ��C because both isotopeshave a similar beta radiation spectrumthat is difficult to separate. Whatevertechnique is used the analytical per-formance (accuracy and sensitivity)should be clearly stated.

EXPANDING THE PRINCIPLEOF URINARY EXCRETION OF

ORALLY ADMINISTERED TESTPROBES

Assessment of colonic permeability:By noting the principle of urinary ex-cretion of orally administered testprobes it is possible to combine the useof commonly used markers of intestinalpermeability with specially selectedones that allow various other intestinalfunctions to be assessed noninvasively.One such modification is to administer$�Cr� � with lactulose and �-rha-mnose followed by a 5 and 24 h urinecollection for marker analyses (48,49).The principle is that lactulose and�-rhamnose are both rapidly degradedby colonic bacteria while $�Cr� � is

204 C�� J G�� V�� 9 N� 4 J�� 1995

B�� et al

not. Additionally, in most aspects$�Cr� � has physicochemical proper-ties identical to those of lactulose (apartfrom the bacterial degradability of thelatter). Certainly in ileostomy patientsequal amounts appear in urine follow-ing simultaneous oral administration.However, when $�Cr� �, lactuloseand �-rhamnose are ingested togetherand urine collected for the next 5 h,there is always a bit more $�Cr� �than lactulose (13). This is almost cer-tainly due to presence and availabilityof $�Cr� � to permeate across part ofthe intestine where the concentrationof lactulose has been eliminated by bac-terial degradation, namely the colon.When the total 24 h urinary excretionof lactulose is subtracted from that of$�Cr� � the difference representswhat has permeated through the colon(or more precisely that part of the intes-tine containing an active bacterialflora, which may also include the lowerileum). The technique has only beenused in a limited number of diseases, butits simplicity suggests that it may havemuch wider application.Localizing intestinal permeabilitychanges: The above technique allowsthe simultaneous assessment of smalland large bowel permeability. A morelabour-intensive and accurate tech-nique has been used that may be usefulfor assessing the precise intestinal loca-tion of various absorptive processes(such as iron and calcium absorption)and perhaps for assessing the efficacy ofdrug delivery systems.

The principle of the technique isthat a range of test substances, whoseabsorptive site is well defined to a par-ticular region of the intestine, are givenorally with subsequent serum analyses(50). The absorption profile of the testsubstance, in this case $�Cr� �, isthen compared with that of the othermarkers, which allows the site of in-creased intestinal permeability to be as-sessed. The test substances are:3-o-methyl--glucose, absorbed pre-dominantly from the jejunum; $%Co vi-tamin B��, absorbed from the terminalileum; and sulfasalazine, which passesunchanged into the cecum where it iscleaved into 5-aminosalicylic acid andsulphapyridine by azo reductase con-

taining bacteria. Sulphapyridine is rap-idly absorbed, and its appearance inserum indicates when the test solutionenters the cecum.

The absorption profile from patientswith untreated celiac disease shows in-creased serum levels of $�Cr� � cor-responding to the3-o-methyl--glucose absorptioncurve. Similarly the peak serum levelsof $�Cr� � in patients with ilealCrohn’s disease correspond to the ap-pearance of the ileal and colonicmarker, while patients with severe totalcolitis have peak levels following theappearance of these markers. This is inkeeping with the idea that the mainsite of increased intestinal permeabilityin patients with celiac and inflamma-tory bowel disease is the diseased intes-tinal mucosa.Assessment of intestinal disacchari-dase activities: By noting the principleof the differential urinary excretion oforally administered test substances it ispossible to design noninvasive teststhat specifically quantify intestinal di-saccharidase activities (51,52,unpub-lished data). Table 1 shows thevariables that determine the amount ofintact disaccharide excreted in urinefollowing oral administration.

Simultaneous ingestion of lactuloseand melibiose, which both resist muco-sal hydrolysis, gives a urine excretion(percentage dose) ratio of melibiose-lactulose of 1.0 because these oligosac-charides do not differ in theirproperties and permeation pathways.However, if a hydrolyzable disaccha-ride is substituted for melibiose all thevariables in Table 1 will affect the twotest substances equally except the enzy-matic degradation of the hydrolyzabledisaccharide. The amount available forpermeation is, in this case, determinedby the rate of intestinal hydrolysis (di-saccharidase activities) relevant forthat sugar. Sucrose, lactose and palati-nose, being substrates for sucrase, lac-tase and isomaltase, respectively, canbe given with lactulose. Normal uri-nary excretion ratios of sucrose, lactoseor palatinose to that of lactulose in 5 or10 h urines following their oral admini-stration are 0.3 or below in subjectswith active intestinal disaccharidase

hydrolysis. Ratios of 0.3 to 1.0 indicateincreasing impairment of intestinal hy-drolysis. Clinically relevant impair-ments of lactase activity are usuallyassociated with lactose:lactulose uri-nary excretion ratios of 0.45 or greaterin 10 h urine. The technique has beenused to demonstrate transient lactasedeficiency following rotavirus enteritisin children (53), combined sucrase andpalatinase deficiency in asucrasia(51,52,53) and effectiveness of alpha-glucosidase inhibitors on sucrose hy-drolysis, and to quantify total small in-testinal hydrolytic activity in patientswith celiac disease (unpublished data).The technique seems to have potentialas a routine noninvasive screening testfor intestinal disaccharidase deficiencyand may discriminate between isolated,usually genetically determined, disac-charidase deficiency and acquiredpan-disaccharidase deficiency associ-ated with small intestinal disease. Be-cause excretion of dietary lactose andsucrose is a natural phenomenon innormal subjects, it is necessary to ex-clude all dietary sources of lactose andsucrose for at least 18 h before and dur-ing the period of urine collection.

INTESTINAL PERMEABILITYIN CROHN’S DISEASE

The intriguing question, however, iswhether altered intestinal permeabilityplays an etiological or pathogenic rolein Crohn’s disease (54-56). The prob-lem is familiar to clinical investigatorsinterested in inflammatory bowel dis-ease: deciding whether the abnormali-ties are the cause or result of pathology(40). In this case the problem has notso much to do with the interpretationof data as the importance of looking atthe problem from a different perspec-tive and in context of results obtainedin other diseases, a feature lacking frommuch recent, uncritical and high pro-file work.

PATHOGENIC IMPORTANCEOF INCREASED INTESTINAL

PERMEABILITYTests of intestinal permeability were

specifically designed to assess the intes-tinal barrier function. It is the integrityof this barrier that is thought to be im-

C�� J G�� V�� 9 N� 4 J�� 1995 203


portant for limiting macromolecularpermeation. Increased macromolecularpermeation may play a role in systemicand local disease (57,58). In the lattersituation it is important to assess andintegrate all available data to assesswhether a story is emerging.

It is suggested that increased intesti-nal permeability allows mucosal expo-sure of luminal aggressive factors, andan inflammatory reaction consequen-tially sets in because of the generationof or exposure to neutrophil chemotac-tic factors (59-61). The present authorshave suggested that this is a central pa-thophysiological mechanism in anumber of small intestinal diseases. In-deed there may be three ways of initiat-ing intestinal damage, all of which leadto increased intestinal permeability,the prerequisite for an intestinal in-flammatory reaction. The threemechanisms are broadly classified as:primary permeability breakers; factorsor disease associated with enhancedluminal aggressiveness; or diminishedmucosal defence. It is of interest tocompare the changes in intestinal per-meability with quantitate intestinal in-flammation in these diseases.Intestinal permeability breakers –NSAID-induced small intestinal dam-age: Following ingestion of nonsteroi-dal anti-inflammatory drugs (��s)there is a uniform and consistent in-crease in intestinal permeability. Thisoccurs within 12 h of ingestion of thedrugs and occurs predominantly duringdrug absorption when the enterocytesare exposed to the highest concentra-tion of the drugs (40,62-66).

Quantitatively the increased intes-tinal permeability in response to ��

ingestion does not differ from that seenin other small intestinal disorders suchas Crohn’s or celiac disease. Moreoverthere is no significant difference in thepermeability changes following shortor long term ingestion of ��s.

Three lines of evidence show that��s cause small intestinal inflam-mation, namely ��In-labelled leuko-cytes, enteroscopy and postmortemstudies (61,67-70). Collectively thedata show that 65% of patients on longterm ��s develop small intestinalinflammation. The fecal excretion of

��In shows that most patients have alow grade enteropathy with a fecal ex-cretion of 1 to 6% (normal less than1%). Once the inflammation is presentpatients bleed from the inflammatorysite and lose protein, both of which areclinically relevant in patients with ar-thritis because they are prone to irondeficiency and hypoalbuminemia.

In short, ��s have a specific det-rimental biochemical action on en-terocytes which is not evident to thesame extent in other tissue because oflower drug concentrations. Theultrastructural-biochemical alterationslead to increased intestinal permeabil-ity, resulting in a low grade enteropa-thy or substantial inflammation whennormal intestinal defence mechanismsare intact or disrupted, respectively.Alcohol-induced intestinal damage:Only a few studies have assessed intesti-nal permeability in alcoholic patients.The permeability changes were compa-rable with those found in Crohn’s andceliac disease (38). Increased intestinalpermeability, unlike that observed with��s, was not seen following singledoses of alcohol (1,71). Very limiteddata were available on possible intesti-nal inflammation in these patients. Infive of eight heavy drinkers the authorsfound a low grade enteropathy, with fe-cal excretions ranging from 1.2 to 4.3%(unpublished data).Enteropathy of chronic renal failure:There are formidable difficulties associ-ated with the noninvasive measure-ment of intestinal permeability inpatients with chronic renal failure.The authors found increased intestinalpermeability (lactulose/�-rhamnose)in a small group of patients (unpub-lished data). These patients had anenteropathy with a fecal excretion of��In ranging from 2 to 9%. It is sug-gested that the uremia or other circu-lating toxins somehow interfere di-rectly with enterocyte function oralter mucosal defence processes (spe-cific or nonspecific), resulting in in-creased intestinal permeability with itsconsequences.Miscellaneous: Antineoplastic agentsincrease intestinal permeability (72-75), and increased intestinal perme-ability is also evident in patients with

diabetes mellitus (76) and in patientsundergoing major surgery or experienc-ing intestinal ischemia (77-79), or fol-lowing major burns or abdominalradiation (80-82). Apart from abdomi-nal radiation where there is evidence ofan inflammatory reaction (personalcommunication) of severity compara-ble with that of �� enteropathy, itremains to a large extent to be exploredwhether the increased intestinal per-meability in these situations leads to aninflammatory response.Luminal aggressive factors: Variousexogenous microbial infections in-crease intestinal permeability to an ex-tent similar to that seen with thepermeability breakers and in Crohn’sand celiac disease (53). The increasedintestinal permeability may be an es-sential component in the pathogenesisof the intestinal infection, allowingmucosal exposure of the microbe, or itmay be the consequence of neutrophil-induced tissue damage as detailedabove or due to cytokine release. What-ever the mechanism there is a moder-ately severe inflammatory responseevident in these patients with ��In leu-kocyte excretion levels between 1 and9% (83).

Patients with cystic fibrosis havestriking increases in intestinal perme-ability (84-87), possibly because theviscous mucous provides a nidus forsmall intestinal microbial proliferation.Again the possibility that these pa-tients develop an enteropathy remainsto be examined.Altered mucosal defence: Patientswith hypogammaglobulinemia havebeen studied in some detail. Increasedintestinal permeability is a universalfeature and the fecal excretion of ��Inleukocytes in these patients ranges from1.1 to 14.5%, mean 6.9% (88).

Patients with the acquired immuno-deficiency syndrome (��) have in-creased intestinal permeability regard-less of subgrouping (89,90). Studieswith ��In leukocytes showed thatall those with increased intestinal per-meability had a low grade enteropathysimilar in severity to that found in�� enteropathy (unpublisheddata).

The above data conform to buttress

204 C�� J G�� V�� 9 N� 4 J�� 1995

B�� et al

a central importance of the intestinalbarrier function. They show that bywhatever means one disrupts the integ-rity of this barrier there is a uniform in-flammatory response, presumably andpredominantly to luminal factors. It isnow appropriate to reexamine thesituation in Crohn’s disease.

INTESTINAL PERMEABILITYAND INFLAMMATION IN

CROHN’S DISEASETests of intestinal permeability pro-

vide noninvasive functional assess-ment of the small intestine in patientswith Crohn’s disease (36,91) and ul-cerative colitis. Most patients withsmall intestinal involvement ofCrohn’s disease who have not under-gone intestinal resection have in-creased intestinal permeability, asassessed by the differential urine excre-tion of disaccharides/ monosaccharidesand $�Cr� �, and 50% of patientswith colonic Crohn’s disease are abnor-mal (28,31,36,91-105). The perme-ability changes relate to the extent ofdisease as well as activity. Of particularimportance is the fact that the perme-ability changes are of equal magnitudeto those of the above-mentioned dis-eases.

Similarly, studies with ��In leuko-cytes show all patients with activeCrohn’s disease have increased fecalexcretion of neutrophils. However, un-like that seen in ��-induced en-teropathy and other diseases, the fecalexcretion of labelled neutrophils isalmost an order of magnitude higher,averaging 18%, range 10 to 60% de-pending on disease activity. It is the in-

tensity of the neutrophil response thatneeds explanation.

Most researchers feel confident thatpreliminary reports of increased intesti-nal permeation of �� 400 in first-degree relatives of patients withCrohn’s disease are incorrect (106-108). Intestinal permeability is nor-mal in relatives tested with the differ-ential urinary excretion of sugars or$�Cr� � (106,109) with the occa-sional subject (12,106,109-111) beingabnormal, presumably because of alco-hol, ��s, etc.

Recent evidence indicates that nor-mal intestinal permeability in patientswith Crohn’s disease predictswell-being (34,99,102); as permeabilityimproves following treatment (98,99)it has been suggested that the main im-portance of increased intestinal perme-ability in patients with inflammatorybowel disease is that it is the centralmechanism of relapse of the disease.This would then expose patients to thesame luminal aggressive factors as inthe other enteropathies, but the sever-ity of the neutrophil response, whichmay relate to the underlying immunederangement of the disease, is what dis-tinguishes Crohn’s disease clinicallyand pathophysiologically from the oth-erwise low grade enteropathies. The re-lapse of Crohn’s disease is then not anactivation of the disease process itselfbut a nonspecific, unchecked acute in-flammatory response to normal intesti-nal flora caused by a breach inintestinal permeability and amplifiedby the disease itself. This hypothesiscertainly provides a comprehensive,

logical and testable framework for fur-ther investigations.

CONCLUSIONSTests of intestinal permeability have

come a long way in the 20 years sincethey were introduced. Their use is sim-ple, and they are accurate, sensitiveand provide information not obtain-able noninvasively by the use of singlemarkers. There are nevertheless manypractical aspects of their use that needspecial attention, lest unpublishabledata are obtained and time wasted. Wehave outlined many of the commonpitfalls involved when deciding on testdose composition and the method ofurinary analyses of the markers. Mostimportant, prospective workers are welladvised to confer with establishedworkers before embarking on theirprojects. By exploiting the details ofthe underlying principles of the differ-ential urinary excretion of orally ad-ministered test markers, new tests havebeen introduced that allow the specificassessment of regional permeabilitychanges and the noninvasive assess-ment of disaccharidase activities of thewhole of the small intestine. It seemsclear that further development of othernoninvasive techniques for assessingother intestinal functions is limitedonly by the ingenuity of the investiga-tor. An integrated approach to thestudy of intestinal permeability and in-flammation in various diseases and inclassic inflammatory bowel disease pro-vides insight into the basic mecha-nisms of a common final pathway for anintestinal inflammatory response.

REFERENCES1. Menzies IS. Absorption of intact

oligosaccharide in health anddisease. Biochem Soc Trans1974;2:1040-6.

2. Chadwick VS, Phillips SF, HofmanAF. Measurements of intestinalpermeability using low molecularweight polyethylene glycols (PEG400). I. Chemical analysis andbiological properties of PEG400. Gastroenterology1977;73:241-6.

3. Chadwick VS, Phillips SF, HofmanAF. Measurements of intestinalpermeability using low molecularweight polyethylene glycols (PEG400). II. Application to study of

normal and abnormal permeabilitystates in man and animals.Gastroenterology 1977;73:247-51.

4. Laker MF, Menzies IS. Increase inhuman intestinal permeabilityfollowing ingestion of hypertonicsolutions. J Physiol (Lond)1977;273:881-94.

5. Laker MF. The effect of hypertonicsolutions on intestinal permeability.University of London, 1978.(Thesis)

6. Wheeler PG, Menzies IS, Creamer B.Effect of hyperosmolar stimuli andcoeliac disease on the permeability ofthe human gastrointestinal tract. ClinSci Mol Med 1978;54:495-501.

7. Bjarnason I, Peters TJ, Levi AJ.

Intestinal permeability: Clinicalcorrelates. Dig Dis 1986;4:83-92.

8. Hamilton I. Small intestinalpermeability. In: Pounder RE, ed.Recent Advances in Gastroenterology,vol 6. Edinburgh: ChurchillLivingstone, 1986:73-91.

9. Cooper BT. The small intestinalpermeability barrier. In: Losowski MH,Heatley RV, eds. Gut Defences inClinical Practice. Edinburgh: ChurchillLivingstone, 1986:117-32.

10. Menzies IS. Transmucosal passage ofinert molecules in health and disease.In: Skadhauge E, Heintze K, eds.Intestinal Absorption and Secretion.Falk Symposium 36. Lancaster: MTPPress, 1984:527-43.

C�� J G�� V�� 9 N� 4 J�� 1995 203


11. Hollander D. The intestinalpermeability barrier. A hypothesis as toits regulation and involvement inCrohn’s disease. Scand J Gastroenterol1992;27:721-6.

12. Hollander D. Permeability in Crohn’sdisease – Altered barrier function inhealthy relatives? Gastroenterology1993;104:1848-51.

13. Maxton DG, Bjarnason I, ReynoldsAP, Catt SD, Peters TJ, Menzies IS.Lactulose, ��CrEDTA, �-rhamnose andpolyethylene glycol 400 as probemarkers for “in vivo” assessment ofhuman intestinal permeability. ClinSci 1986;71:71-80.

14. Dahlqvist A. Specificity of humanintestinal disaccharidases andimplications for hereditary disaccharideintolerance. J Clin Invest1962;41:463-70.

15. Hollander D, Rickets D, Boyd CAR.Importance of ‘probe’ moleculargeometry in determining intestinalpermeability. Can J Gastroenterol1988;2(Suppl A):35A-8A.

16. Ma TY, Hollander D, Krugliak P, KatzK. PEG 400, a hydrophillic molecularprobe for measuring intestinalpermeability. Gastroenterology1990;98:39-46.

17. Krugliak P, Hollander D, Ma TY,et al. Mechanism of polyethyleneglycol 400 permeability of perfused ratintestine. Gastroenterology1989;97:1164-70.

18. Krugliak P, Hollander D, Le K, Ma T,Dadufalza VD, Katz KD. Regulation ofpolyethylene glycol 400 intestinalpermeability by endogenous andexogenous prostanoids. Influence ofnon-steroidal anti-inflammatory drugs.Gut 1990;31:417-21.

19. Iqbal TH, Lewis KO, Cooper BT.Diffusion of polyethylene glycol-400across lipid barriers in vitro. Clin Sci1993;185:111-5.

20. Magnusson KE, Sundqvist T.Mathematical modelling fordetermining intestinal permeabilityusing polyethylene glycol. Gut1983;25:428-9.

21. Magnusson KE, Sundqvist T.Modelling of intestinal permeability inman to polyethylene glycols (PEG 400and PEG 1000). Acta Physiol Scand1985;125:289-96.

22. Sundqvist T, Tageson C, MagnussonKE. Simulation of a multicompartmentmodel for the intestinal permeability tolow-molecular-weight probes(polyethylene glycol 400). Math Biosci1981;56:287-309.

23. Irving CS, Lifschitz CH, Marks LM,Nichols BC, Klein PD. Polyethyleneglycol polymers of low molecularweight as probes of intestinal

permeability. I. Innovations in analysesand quantitation. J Lab Clin Med1986;107:290-8.

24. Menzies IS, Jenkins AP, Heduan E,Catt SD, Segal MB, Creamer B.The effect of poorly absorbed solute onintestinal absorption. Scand JGastroenterol 1990;25:1257-64.

25. Menzies IS, Pounder R, Heyer S, et al.Abnormal intestinal permeability tosugars in villus atrophy. Lancet1979;ii:1107-9.

26. Blomquist L, Bark T, Hedenborg G,Svenberg T, Norman A. A comparisonbetween the lactulose/mannitol and��CrEDTA/� C-mannitol methods forintestinal permeability. Scand JGastroenterol 1993;28:274-80.

27. Elia M, Beherens R, Northrop C,Wraight P, Neale G. Evaluation ofmannitol, lactulose and ��Cr labelledethylenediaminetetraacetate as markersof intestinal permeability in man. ClinSci 1987;73:197-204.

28. Andre F, Andre C, Emery Y.Assessment of the lactulose-mannitoltest in Crohn’s disease. Gut1988;29:511-5.

29. Juby LD, Rothwell J, Axon ATR.Lactulose/mannitol test. An idealscreening test for coeliac disease.Gastroenterology 1989;96:79-85.

30. Kapembwa MS, Fleming SC,Sewankambo N, et al. Alteredsmall-intestinal permeability associatedwith diarrhoea in human-immunodeficiency-virus-infectedCaucasian and African subjects. ClinSci 1991;81:327-34.

31. Murphy MS, Eastham EJ, Nelson R,Pearson ADJ, Laker MF. Intestinalpermeability in Crohn’s disease. ArchDis Child 1989;64:321-5.

32. Ukabam SO, Homeda MA, Cooper BJ.Small intestinal permeability inSudanese subjects: Evidence of tropicalenteropathy. Trans R Soc Trop MedHyg 1986;40:204-7.

33. van der Hulst PRWJ, Kreel BK,Meyenfelt MF, et al. Glutamine andthe preservation of gut integrity.Lancet 1993;341:1363-5.

34. Wyatt J, Vogelsang H, Hubl W,Waldhoer T, Lochs H. Intestinalpermeability and the predictor ofrelapse in Crohn’s disease. Lancet1993;341:1437-9.

35. Bjarnason I, Peters TJ, Veall N.A persistent defect of intestinalpermeability in coeliac disease asdemonstrated by a ��Cr-labelled EDTAabsorption test. Lancet 1983;i:323-5.

36. Bjarnason I, O’Morain C, Levi AJ,Peters TJ. The absorption of ��CrEDTA in inflammatory boweldisease. Gastroenterology1983;85:318-22.

37. Bjarnason I, Williams P, So A, et al.

Intestinal permeability andinflammation in rheumatoid arthritis:effects of non-steroidal anti-inflammatory drugs. Lancet1984;ii:1171-4.

38. Bjarnason I, Ward K, Peters TJ. Theleaky gut of alcoholism: possible routeof entry for toxic compounds. Lancet1984;i:179-82.

39. Bjarnason I, Goolamali SK, Levi AJ,Peters TJ. Intestinal permeability inpatients with atopic eczema. Br JDermatol 1985;112:291-7.

40. Bjarnason I, Peters TJ. Helping themucosa make sense of macromolecules.Gut 1987;28:1057-61.

41. Hamilton I, Fairris GM, Rothwell J,Cunliffe WJ, Dixon MF, Axon ATR.Small intestinal permeability indermatological disease. Q J Med1985;56:559-67.

42. Laker MF, Bull HJ, Menzies IS.Evaluation of mannitol for use as aprobe marker of gastrointestinalpermeability in man. Eur J Clin Invest1982;12:485-91.

43. Cobden I, Hamilton I, Rothwell J,Axon ATR. Cellobiose/mannitol test:Physiological properties of probemolecules and influence of extraneousfactors. Clin Chim Acta1985;148:53-62.

44. Dominguez R, Corcoran AC, Page IH.Mannitol: kinetics of distribution,excretion and utilization in humanbeings. J Lab Clin Med1947;32:192-202.

45. Newman EV, Bordlay J, Winternitz J.The interrelationship of glomerularfiltration rate (mannitol clearance),extracellular fluid volume, surface areaof the body, and plasma concentrationof mannitol. Bull Johns HopkinsHospital 1944;75:253-68.

46. Menzies IS. Quantitative estimation ofsugars in blood and urine by paperchromatography using directdensitometry. J Chromatogr1983;81:109-27.

47. Menzies IS, Mount JN, Wheeler MJ.Quantitative estimation of clinicallyimportant monosaccharides in plasmaby rapid thin layer chromatography.Ann Clin Biochem 1978;15:65-76.

48. Jenkins AP, Nukajam WS, Menzies IS,Creamer B. Simultaneousadministration of lactulose and��Cr-ethylenediaminetetraacetic acid.A test to distinguish colonic fromsmall-intestinal permeability change.Scand J Gastroenterol 1992;27:769-73.

49. Jenkins AP, Trew DR, Crump BJ,Menzies IS, Creamer B. Dononsteroidal anti-inflammatory drugsincrease colonic permeability? Gut1991;32:66-9.

50. Teahon K, Smith T, Smethurst P,Bjarnason I. A technique for localizing

204 C�� J G�� V�� 9 N� 4 J�� 1995

B�� et al

alterations of intestinal permeability inman. Gastroenterology1991;100:A251.

51. Maxton DG, Catt SD, Menzies IS.Intestinal disaccharidases assessed incongenital asucrasia by differentialurinary disaccharide excretion. Dig DisSci 1989;34:129-31.

52. Maxton DG, Catt SD, Menzies IS.Combined assessment of intestinaldisaccharidases in congenital asucrasiaby differential urinary disaccharideexcretion. J Clin Pathol 1990;43:406-9.

53. Ford RPK, Menzies IS, Phillips AD,Walker-Smith JA, Turner MW.Intestinal sugar permeability:Relationship to diarrhoeal disease andsmall bowel morphology. J PediatrGastroenterol Nutr 1985;4:568-74.

54. Hollander D. Crohn’s disease –A permeability disorder of the tightjunctions? Gut 1988;26:1621-4.

55. Hollander D, Vadheim C, Brettholz E,Pattersen GM, Delahunty T, Rotter JI.Increased intestinal permeability inpatients with Crohn’s disease and theirrelatives. Ann Intern Med1986;105:883-5.

56. Shorter RG, Huizenga GA, SpencerRJ. A working hypothesis for theetiology and pathogenesis ofnonspecific inflammatory boweldisease. Dig Dis Sci 1972;17:1024-31.

57. Walker AW, Isselbacher KJ. Uptakeand transport of macromolecules by theintestine. Possible role in clinicaldisorders. Gastroenterology1974;67:531-50.

58. Walker WA. Mechanisms of antigenhandling by the gut. Clin ImmunolAllergy 1982;2:15-34.

59. Bjarnason I, Macpherson A,Somasundaram S, Teahon K.Nonsteroidal anti-inflammatorydrugs and inflammatory bowel disease.Can J Gastroenterol 1993;7:160-9.

60. Bjarnason I, Macpherson AJS,Somasundaram S, Teahon K.Non-steroidal anti-inflammatory drugsand Crohn’s disease. In: Scholmeric J,Kruis W, Goebbell H, Hohenberger W,Gross V, eds. Inflammatory BowelDiseases: Pathophysiology as Basis ofTreatment. Falk Symposium no 67.Lancaster: Kluwer AcademicPublishers, 1993:208-22.

61. Bjarnason I, Hayllar J, Macpherson AJ,Russell AS. Side effects of nonsteroidalanti-inflammatory drugs on the smalland large intestine. Gastroenterology1993;104:1832-47.

62. Auer IO, Habscheid W, Hiller S,Gerhards W, Eilles C. Nicht-steroidaleantiphlogistika erhöhen diedarmpermeabilität. Dtsch MedWochenschr 1987;112:1032-7.

63. Bjarnason I, Williams P, Smethurst P,Peters TJ, Levi AJ. The effect ofNSAIDs and prostaglandins on the

permeability of the human smallintestine. Gut 1986;27:1292-7.

64. Bjarnason I, Smethurst P, Clarke P,Menzies IS, Levi AJ, Peters TJ. Effectof prostaglandins on indomethacininduced increased intestinalpermeability in man. Scand JGastroenterol 1989;29(Suppl 164):97-103.

65. Bjarnason I, Fehilly B, Smethurst P,Menzies IS, Levi AJ. The importanceof local versus systemic effects ofnonsteroidal anti-inflammatorydrugs to increase intestinalpermeability in man. Gut1991;32:275-7.

66. Bjarnason I, Smethurst P, MacphersonA, et al. Glucose and citrate reduce thepermeability changes caused byindomethacin in humans.Gastroenterology 1992;102:1546-50.

67. Bjarnason I, Zanelli G, Smith T, et al.Nonsteroidal antiinflammatory druginduced intestinal inflammation inhumans. Gastroenterology1987;93:480-9.

68. Morris AJ, Wasson LA, Mackenzie JF.Small bowel enteroscopy inundiagnosed gastrointestinal blood loss.Gut 1992;33:887-9.

69. Rooney PJ, Jenkins RT, Smith KM,Coates G. 111-Indium-labelledpolymorphonuclear scans inrheumatoid arthritis – an importantclinical cause of positive results.Br J Rheumatol 1986;15:167-70.

70. Allison MC, Howatson AG, TorranceCJ, Lee FD, Russell RI.Gastrointestinal damage associatedwith the use of nonsteroidalanti-inflammatory drugs. N Engl J Med1992;327:749-54.

71. Smethurst P, Menzies IS, Levi AJ,Bjarnason I. Is alcohol directly toxic tothe small bowel mucosa? Clin Sci1988;75:50P-1P.

72. Parrilli G, Iaffaioli RV, Martorano M,et al. Effects of anthracycline therapyon intestinal absorption in patientswith advanced breast cancer. CancerRes 1989:49:3689-91.

73. Pledger JV, Pearson ADJ, Craft AW,Laker MF, Eastham EJ. Intestinalpermeability during chemotherapy forchildhood tumors. Eur J Pediatr1988;147:123-7.

74. Pearson ADJ, Craft AW, Pledger JV,Eastham EJ, Laker MF, Pearson CS.Small bowel function in acutelymphoblastic leukemia. Arch DisChild 1984;59:460-5.

75. Selby PJ, Lopes N, Mundy J, Crofts M,Millar JL, McElwain TJ.Cyclophosphomide priming reducesintestinal damage in man followinghigh dose melphalan chemotherapy.Br J Cancer 1987;55:531-3.

76. Cooper BT, Ukabam SO, O’BrienIAD, Hara JPO, Corrall RJM.

Intestinal permeability in diabeticdiarrhoea. Diabet Med1987;4:49-52.

77. Ohri SK, Somasundaram S, Koak Y,et al. The effect of intestinalhypoperfusion during cardiopulmonarybypass surgery on saccharidepermeation and intestinal permeabilityin man. Gastroenterology1994;106:318-23.

78. Otamiri T, Sjodahl R, Tagesson C.An experimental model for studyingreversible intestinal ischemia. ActaChir Scand 1987;153:51-6.

79. Roumen RM, van der Vliet JA, WeversRA, Goris RJ. Intestinal permeability isincreased after major vascular surgery. JVasc Surg 1993;17:734-7.

80. Coltart RS, Howard GC, Wraight EP,Bleehen NM. The effect ofhyperthermia and radiation on smallbowel permeability using ��Cr EDTAand � C mannitol in man. Int JHyperthermia 1988;4:467-77.

81. Ruppin H, Hotze A, During A, et al.Reversible funktionsstörungen desintestinaltraktes durch abdominellestrahlentherapy. Z Gastroenterol1987;25:261-9.

82. Yeoh EK, Horowitz M, Russo A,Muecke T, Robb T, Chatterton BE.Gastrointestinal function in chronicradiation enteritis-effects ofloperamide-N-oxide. Gut1993;34:476-82.

83. Kardossis T, Joseph AEA, Gane JN,Bridges CE, Griffin GE. Fecalleucocytosis. Indium-111 labelledautologous polymorphonuclearleucocyte abdominal scanning, andquantitative fecal indium-111excretion in acute gastroenteritis andenteropathogen carriage. Dig Dis Sci1988;33:1383-90.

84. Leclercq-Foucart J, Forget P,Sodoyez-Gouffaux F, Zappitelli A.Intestinal permeability to ��CrEDTAin children with cystic fibrosis.J Pediatr Gastroenterol Nutr1986;5:284-7.

85. Leclercq-Foucart J, Forget P, VanCutsem JL. Lactulose-rhamnoseintestinal permeability in children withcystic fibrosis. J Pediatr GastroenterolNutr 1987;6:66-70.

86. Dalzell AM, Freestone NS, BillingtonD, Heaf DP. Small intestinalpermeability and orocaecal transit timein cystic fibrosis. Arch Dis Child1990;65:585-8.

87. Escobar H, Perdomo M, Vasconez F,Camarero C, del Olmo MT, Suarez L.Intestinal permeability to ��Cr-EDTAand orocecal transit time in cysticfibrosis. J Pediatr Gastroenterol Nutr1992;14:204-7.

88. Teahon K, Webster AD, Price AB,Bjarnason I. Studies of gastrointestinal

C�� J G�� V�� 9 N� 4 J�� 1995 203


structure and function in patients withprimary hypogammaglobulinaemia.Gut 1994;35:1244-9.

89. Keating J, Bjarnason I, SomasundaramS, et al. Intestinal absorptive capacity,intestinal permeability and jejunalhistology in HIV infected patients andtheir relation to diarrhoea. Gut. (Inpress)

90. Lim SG, Menzies IS, Lee CA, JohnsonMA, Pounder RE. Intestinalpermeability and function in patientsinfected with humanimmunodeficiency virus. Scand JGastroenterol 1993;28:573-80.

91. Ukabam SO, Clamp JR, Cooper BT.Abnormal intestinal permeability tosugars in patients with Crohn’s diseaseof the terminal ileum and colon.Digestion 1982;27:70-4.

92. Casellas F, Aguade S, Soriano B,Accarino A, Molero J, Guarner L.Intestinal permeability to ��Tcdiethylene-tetraaminopentaacetic acidin inflammatory bowel disease. Am JGastroenterol 1986;81:767-70.

93. Resnick RH, Royal H, Marshall W,Barron R, Werth T. Intestinalpermeability in gastrointestinaldisorders. Dig Dis Sci 1990;35:205-11.

94. O’Morain C, Abelon AC, Chervli LR,Fleischner GM, Das KM. ��CrEDTA –a useful test in the assessment ofinflammatory bowel disease. J Lab ClinMed 1986;108:430-5.

95. Jenkins RT, Jones DB, Goodacre RL, etal. Reversibility of increased intestinalpermeability to ��CrEDTA in patientswith gastrointestinal inflammatorybowel disease.J Rheumatol 1987;82:1159-64.

96. Turck D, Ythier H, Maquet E, et al.Increased intestinal permeability to

��CrEDTA in children with Crohn’sdisease and coeliac disease. J PediatrGastroenterol Nutr 1987;6:535-7.

97. Pironi L, Miglioli M, Ruggeri E, et al.Relationship between intestinalpermeability to (��Cr)EDTA andinflammatory activity in asymptomaticpatients with Crohn’s disease. Dig DisSci 1990;35:582-8.

98. Sanderson IR, Boulton P, Menzies IS,Walker-Smith JA. Improvement ofabnormal lactulose rhamnosepermeability in active Crohn’s diseaseof the small bowel by an elementaldiet. Gut 1987;28:1073-6.

99. Teahon K, Smethurst P, Levi AJ,Bjarnason I. The effect of elementaldiet on intestinal permeability andinflammation in Crohn’s disease.Gastroenterology 1991;101:84-9.

100. Jenkins RT, Ramage JK, Jones DB,Collins SM, Goodacre RL, Hunt RH.Small bowel and colonic permeabilityto ��CrEDTA in patients with activeinflammatory bowel disease. ClinInvest Med 1988;11:151-5.

101. Pearson AD, Eastham EJ, Laker ME,Craft AW, Nelson R. Intestinalpermeability in children with Crohn’sdisease and coeliac disease. BMJ1982;285:20-1.

102. Teahon K, Smethurst P, MacphersonAJ, Levi AJ, Menzies IS, Bjarnason I.Intestinal permeability in Crohn’sdisease and its relation to diseaseactivity and relapse followingtreatment with elemental diet.Eur J Gastroenterol Hepatol1993;5:79-84.

103. Adenis A, Colombel JF, Lecouffe P,et al. Increased pulmonary andintestinal permeability in Crohn’sdisease. Gut 1992;33:678-82.

104. Howden CW, Robertson C, Duncan A,Morris AJ, Russell RI. Comparison ofdifferent measurements of intestinalpermeability in inflammatory boweldisease. Am J Gastroenterol1991;86:1445-9.

105. Wallaert B, Colombel JF, Adenis A,et al. Increased intestinal permeabilityin active pulmonary sarcoidosis. AmRev Respir Dis 1992;145:1440-5.

106. Teahon K, Smethurst P, Levi AJ,Menzies IS, Bjarnason I. Intestinalpermeability in patients with Crohn’sdisease and their first degree relatives.Gut 1992;33:320-3.

107. Ruttenberg D, Young GO, Wright JP,Isaacs S. PEG 400 excretion in patientswith Crohn’s disease, their first degreerelatives, and healthy volunteers. DigDis Sci 1992;37:705-8.

108. Munkholm P, Langholz E, HollanderD, et al. Intestinal permeability inpatients with Crohn’s disease andulcerative colitis and their first degreerelatives. Gut 1994;35:68-72.

109. Ainsworth M, Eriksen J, RasmussenJW, Schaffalitzkydemuckadel OB.Intestinal permeability of ��Cr-labelledethylenediaminetetra-acetic acid inpatients with Crohn’s disease and theirfirst degree relatives. Scand JGastroenterol 1989;24:993-8.

110. Katz KD, Hollander D, Vadheim CM, et al.Intestinal permeability in patients withCrohn’s disease and their healthy relatives.Gastroenterology 1989;97:927-31.

111. May GR, Sutherland LR, Meddings JB.Is small intestinal permeability reallyincreased in relatives of patients withCrohn’s disease? Gastroenterology1993;104:1627-32.

204 C�� J G�� V�� 9 N� 4 J�� 1995

B�� et al

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