Gut 1994; 35: 1244-1249

Studies on the enteropathy associatedwith primary hypogammaglobulinaemia

K Teahon, A D Webster, A B Price, J Weston, I Bjarnason

AbstractTwelve patients with primary hypo-gammaglobulinaemia with diarrhoea notassociated with known microbialpathogens were investigated. Histologicalevidence of inflammation was commonin the stomach and jejunum. Moreover,eight of 10 patients undergoingcolonoscopy had low grade 'microscopiccolitis' with raised intraepithelial lym-phocytes and an intact crypt architecture.Five of 12 patients had small intestinalinflammation on 111indium leucocytescintigrams and all had increased faecalexcretion (normal <1%) of 11indium(over four days), which varied in intensityfrom mild (faecal excretion of"1 indium = 1-3%) to that comparable withmoderately active (7-14.5%) Crohn'sdisease. Three patients had small intes-tinal strictures superficially resemblingCrohn's disease. Histologically, however,these lacked characteristic diagnosticfeatures of Crohn's disease in two and thethird patient had non-steroidal anti-inflammatory drug induced diaphragmlike strictures. Six ofseven who were mostseverely symptomatic were successfullytreated with an elemental diet with rapidimprovement of symptoms. The faecalexcretion of 111indium was repeated infive and all improved but histologicallythe colitis remained unchanged. Thesestudies show that some patients withprimary hypogammaglobulinaemia haveintestinal inflammation unlike that foundin classic inflammatory bowel disease.Elemental diet is a useful temporarymeasure in the treatment of thesepatients.(Gut 1994; 35: 1244-1249)

A variety of intestinal abnormalities have beendescribed in patients with primary hypo-gammaglobulinaemia. Patients with selectiveimmunoglobulin A deficiency have an increasedprevalence of coeliac diseasel 2 and patientswith common variable immunodeficiency oftendevelop atrophic gastritis and are at increasedrisk of gastric carcinoma.3-5 In the small intes-tine, lymphoid nodular hyperplasia occurs withsome regularity but is generally thought to bebenign and of no clinical significance.1 3 4 6 Atleast 10% of patients, however, with hypo-gammaglobulinaemia have unexplained severediarrhoea, abdominal pain, or wasting, or allthree, clinically reminiscent of that seen inpatients with the acquired immunodeficiencysyndrome.7

In 1972 Ament reported a gastrointestinalstudy of 39 patients with either x-linkedagammaglobulinaemia or common variableimmunodeficiency.8 Thirty were asympto-matic and of these three had Giardia lambliaand nine had a low grade colitis. Eight of ninesymptomatic patients had Giardia lamblia.Most of the published work on intestinalfunction is confined to individual casereports.4 9-19 Collectively these suggest thatpatients with common variable immuno-deficiency have jejunal histological findingsranging from normal to subtotal villousatrophy. Those with the most severe abnor-malities may or may not respond to a glutenfree diet. The precise relation to coeliac diseaseis, however, confounded by the fact that inonly one patient was the diagnosis establishedwith jejunal biopsies after gluten withdrawaland challenge.19 Curiously there have been sixcase reports of Crohn's like lesions in patientswith x-linked agammaglobulinaemia or com-mon variable immunodeficiency.22-25 Thesehave usually presented as diarrhoea withintestinal strictures and histological examina-tion has shown transmural inflammation,usually without granulomata.The natural history of hypogammaglobu-

linaemia has been radically changed over thelast decade by the use of intravenous gamma-globulins.7 This seems to have virtuallyeradicated Giardia lamblia as an intestinalpathogen in patients in the United Kingdom asin our clinic only one in about 100 patients hasbeen positive during the past six years. Theincidence, however, of other causes ofdiarrhoea and weight loss have not changed.We therefore investigated a group of patientswith significant symptoms to define the natureof gastrointestinal pathology and to test theeffect of treatment with an elemental diet thathas been effective in Crohn's disease.26 27

Methods

SUBJECTSThe immunodeficiency clinic at NorthwickPark Hospital has a special interest in x-linkedagammaglobulinaemia and common variableimmunodeficiency with about 100 outpatientsattending for regular follow up. Over a 12month period all adult patients with panhypogammaglobulinaemia presenting withpersistent or intermittent gastrointestinalsymptoms of abdominal pain or diarrhoea, inwhom repeated courses of antimicrobialtreatment had been ineffective wereinvestigated. Evidence of small intestinalbacterial overgrowth, which included both a

Department ofClinicalPharmacology,University ofNewcastle upon TyneK Teahon

Departments ofClinical ImmunologyA D Webster

and Histopathology,MRC ClinicalResearch Centre,Harrow, MiddlesexA B PriceJ Weston

Department of ClinicalBiochemistry, King'sCollege School ofMedicine, LondonI Bjarnason

Correspondence to:Dr K Teahon, Wolfson Unitof Clinical Pharmacology,University of Newcastleupon Tyne, ClaremountPlace, Newcastle upon TyneNE2 4LP.Accepted for publication21 December 1993

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TABLE I Clinical details and investigationalfindings in patients with hypogammaglobulinaemia

Faecal Upper smallexcretion of Localisation of intestine

Clinical "'indium (%) inflammation on Duodenum (D)No Sex Diagnosis presentation (n<1-0%) scintigraphy Stomach J'ejunum (7) Colon Specialfeatures

1 F CVID Weight loss 4-3 Indeterminate Increased IEL Subtotal villous Colitis (UC like)diarrhoea atrophy excess excess IEL

IEL (D +J)2 M CVID Weight loss 7-2 Indeterminate Erosive pan Subtotal villous Microscopic pan

diarrhoea gastritis atrophy (D +J) colitis3 F CVID Weight loss 5-9 Indeterminate Normal Normal (D +J) Microscopic pan

diarrhoea colitis excess IEL4 F CVID Weight loss 10-9 Ileal Normal Mild partial villous Microscopic distal Extensive lymphoid

diarrhoea atrophy (D) colitis excess IEL nodular hyperplasiaabdominal pain

5 F CVID Weight loss 14-5 Ileal Normal Mild partial villous Normal Postmortem examination ofabdominal pain atrophy and the ileum showed thinreceiving inflammation (D) walled band like stricturesprednisolone J: normal and non-specific transmural10 mglday inflammation

6 F CVID Weight loss 12-7 Ileal Atrophic Normal (D) Microscopic pan Ileoscopy showed typicaldiarrhoea gastritis colitis excess IEL NSAID strictures withreceiving ulcerationNSAID

7 M XLA Weight loss 10-8 Small bowel Not done Not done Not done Resected jejunum hadabdominal pain multiple strictures and

non-specific transmuralinflammation

8 M XLA Recurrent 8-8 Ileal Not done Not done Not donediarrhoea

9 F CVID Asymptomatic 2-2 Normal Normal Mild duodenitis Excess IELrecurrent (D)diarrhoea

10 M CVID Asymptomatic 1-6 Normal Atrophic HP Mild duodenitis Microscopic panrecurrent gastritis (D) colitis excess IELdiarrhoea Dysplasia

11 M CVID Asymptomatic 1.1 Normal Not done Not done Mild distal colitisrecurrent excess IELdiarrhoea

12 F CVID Asymptomatic 2-3 Normal Not done Not done Proctitis excessrecurrent IELanaemia

HP: Helicobacter pylori; IEL: intraepithelial lymphocytes; CVID: common variable immunodeficiency; XLA: x-linked agammaglobulinaemia; UC: ulcerative colitis.

14C carbon labelled glycocholic acid breathtest and urinary indicans had been negativeand there was no evidence of intestinalinfection (stool for salmonella, shigella,campylobacter, ova, cysts, and parasitesrepeatedly negative) or enterotoxins in stool.Twelve patients were studied (seven femalesand five males), mean (SD) age 53 (13) years.Table I shows the clinical details. All werereceiving regular intravenous gammaglobulins(Sandoglobulin, Sandoz Pharmaceuticals,Frimley, Surrey, UK), which containsimmunoglobulin G and only traces ofimmunoglobulin A and M.

Informed consent was obtained from allpatients and the studies were approved byHarrow Health Authority ethical committee.

antrum, and body. A Crosby capsule jejunalbiopsy specimen was subsequently taken underx ray control adjacent to the ligament of Trietz.Patients with abdominal pain had smallintestinal barium examinations (followthrough or enteroclysis) and all had a lactosetolerance test.

TREATMENTPatients 1-7 (Table I), with the most severesymptoms were treated with an elemental dietas previously described in patients withCrohn's disease.26 27 Patients were dischargedfrom hospital when they could manage the dietthemselves.

ResultsINVESTIGATIONSAll patients were admitted to a metabolicresearch ward for the studies. All underwent1 'indium autologous leucocyte studiesentailing abdominal scans within four hours ofreceiving the cells, to localise the inflammationand a four day faecal collection to quantitatethe inflammatory activity as previouslydescribed.28 The estimated radiation dosereceived, assuming that 300 mCi (11 MBq)dose of llindium leucocytes is injected is8-5 milli Sieverts.Ten patients had a full colonoscopy with

serial biopsies after completion of the abovestudies and a gastroduodenoscopy with abiopsy specimen taken from the duodenum,

I IIINDIUM LEUCOCYTE STUDIES111Indium leucocyte scintigrams showed earlylocalisation of inflammation in five patients(ileal in four and small intestinal in one).Figure 1 shows a representative scintigram. Ina further three patients the 20 hour abdominalscintigrams were abnormal but preciselocalisation to the small intestine was notpossible. Table I shows that the four day faecalexcretion of 11'indium leucocytes wasincreased in all (n<1%), ranging from mildinflammation (1llindium excretion 1-3%) tothat comparable with moderately activeCrohn's disease and ulcerative colitis(7-14.5%).

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Teahon, Webster, Price, Weston, Bjarnason

Figure 3: A small intestinal follow through showingjejunalstrictures and separatedjejunal loops because ofa centrallylocated inflammatory mass.

Figure 1: An abdominal "'indium leucocyte scintigramfrom a patient with primary hypogammaglobulinaemia anddiarrhoea (above) showing normal hepatic, splenic, andbony uptake of the labelled cells and an inflamed intestinalsegment corresponding to ileum. The lower scintigram showsgreatly reduced intestinal inflammation after treatment withelemental dietforfour weeks.

HISTOPATHOLOGICAL STUDIESTable I shows the main histological findings.In all but one patient, and at all sites, plasmacells were absent or occasional cells found onlyafter prolonged searching. Nine patients hadgastric biopsies of which five were normal. Ofthe four with abnormal biopsies two showed a

mild pangastritis, but in two there was severe

atrophy in corpus and antrum. Helicobacter

Figure 2: A low grade colitis from a patient with hypogammaglobulinaemia resemblinglymphocytic colitis with surface epithelial degeneration and increased numbers ofintraepithelial lymphocytes in the cryptal epithelium (haematoxylin and eosin, originalmagnificationX181).

pylori like organisms were identified in onepatient.

Duodenal biopsies were available in eightpatients. Two had villous atrophy with raisednumber of intraepithelial lymphocytes, twoshowed mild villous atrophy, two were inflamedbut had intact villi, and two were normal.Of the four patients in whom the jejunum

was biopsied two were normal and two wereflat and both had a positive lactose tolerancetest (a flat blood glucose curve after 50 g oflactose) with diarrhoea. These two patientshad had flat duodenal biopsy specimens.Ten of the patients had a series of colonic

biopsies in only one of whom were theynormal. In one the picture was indistinguish-able from ulcerative colitis apart from theabsence of plasma cells and increased numberof intraepithelial lymphocytes. In five of theremaining eight there was a total colitis, withthe other three showing inflammationrestricted to the sigmoid colon and rectum.The inflammation was mild in all cases andmostly restricted to the superficial half of themucosa. It was predominantly lymphocyticwith neutrophil polymorphs and eosinophils.Figure 2 shows the representative histology.In four the numbers of intraepithelial lympho-cytes was considerably raised and in threemildly raised. The crypt architecture wasintact, and crypt abscesses were not a feature.

Patients 5-7 (Table I) were particularlyinteresting as they had small intestinalstrictures. Figure 3 shows a representativebarium follow through from patient 7 (patientno 5 was similar). Loops are separated by aninflammatory mass and there are multiple tightjejunal strictures. The radiological findings aresuggestive of Crohn's disease.

Patient 7 had a resection of the diseasedintestinal segment and in patient 5 the

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Figure 4: A small intestinal resection segmentfrom a patient with primaryhypogammaglobulinaemia. There is a broad basedfibrous stricture with proximal ulcers.There are scattered, small inflammatory pseudopolyps.

strictures were shown at necropsy. Figure 4shows the macro and microscopic appear-ances. There were multiple broad smallintestinal strictures, which were based onsubmucosal fibrosis, fibromuscular hyperplasiaof the muscularis, and a degree of neuralhyperplasia. No transmural inflammation orgranulomas were seen. Patient 6 had beenreceiving non-steroidal anti-inflammatorydrugs (NSAIDs) for control of rheumatoidarthritis for six years and at ileoscopycharacteristic changes of NSAID enteropathywere seen with diaphragm formation.29

TREATMENTFive patients had mild or intermittentsymptoms at the time of study and were nottreated. Seven (no 1-7) were treated with anelemental diet and stopped all normal foodintake during the four week treatment period.Six patients had a similar response to that seenin acute Crohn's disease26 27 with rapidimprovement in well being, loss of lethargy,which was a prominent symptom in mostcases, and cessation of diarrhoea. One patientdid not improve significantly although thefrequency of diarrhoea was reduced. Figure 1shows a representative abdominal scintigrambefore and after successful treatment with anelemental diet. In five patients the faecalexcretion of "'1indium was assessed at the endof the treatment period. Table II shows that

TABLE II Effect of elemental diets on intestinalinflammation in patients with primaryhypogammaglobulinaemia

Faecal excretion of 1" lindium(%/0) injected dose)

Patient no Before After

2 7-2 3-03 5.9 3.95 14-5 5-96 12-7 9-37 10-8 1-8

there was a reduction of intestinal inflamma-tion in each case. Repeat gastroduodenoscopyand colonoscopy, however, showed nohistological improvement.

Patients 1 and 3 are well at six and 12months, patient 2 had a relapse at sevenmonths. He started the diet again and is wellsix months later. Patients 4-7 relapsed withinone month of resuming food. One had anintestinal resection, two required large dosesof antibiotics, one of whom died fromfulminating pneumonia and sepsis. Thepatient receiving NSAIDs was treated withmetronidazole30 with a reduction in the faecalexcretion of "llindium leucocytes from 9.7 to3.5% and the diarrhoea is partially controlledwith cholestyramine.

DiscussionBefore the introduction of intravenousimmunoglobulin treatment, the diarrhoea inmany patients with primary hypogammaglobu-linaemia was most often associated withGiardia lamblia, campylobacter or salmonella.7Such pathogens are now rarely found in thesepatients. It is not clear whether protectionresults from the infused immunoglobulin Gappearing in the saliva, or whether it crossesthe intestinal mucosa to 'neutralise' luminalorganisms. Despite 'high dose' intravenousimmunoglobulin treatment, however, chronicsevere diarrhoea remains an important clinicalproblem.

While there were mild and inconsistenthistological changes in the stomach andproximal small intestine there was a highprevalence of a low grade colitis. All had anacute enteritis as shown by the "'1indiumleucocyte studies. Those with abdominal painas the main feature were found to have lumi-nal obstruction resulting from strictures.Significantly, in the patients with the mostsevere symptoms, treatment with elementaldiet led to considerable, albeit temporarily,improvement in well being.The upper gastrointestinal histopathologi-

cal findings are in keeping with that previ-ously reported. The gastritis was withoutactivity in most cases and the jejunal morpho-logical findings were perhaps less noticeablethan expected. This contrasts with the fre-quency of lower small intestinal inflammationand colitis. The "11indium leucocyte scinti-grams and faecal excretion show that most ofthese patients have an enteropathy, which hasnot previously been suspected when investi-gated by conventional techniques. Theinflammatory activity is usually greater thanthat seen in intestinal infections31 and inNSAID induced enteropathy28 and is similarto that seen in classic quiescent or moderatelyactive inflammatory bowel disease.26 28 Thecause of the acute small intestinal inflamma-tion is not evident. In the context of patientswith hypogammaglobulinaemia it is temptingto relate the pathogenesis of the inflammationto deficient IgA production and secretion. Inpatients with Crohn's disease there isdecreased (possibly primary) spontaneous

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1248 Teahon, Webster, Price, Weston, Bjarnason

secretion of mucosal IgA and greatly increasedIgG secretion and it has been suggested thatthis may play an important pathogenic part inthe disease.32-34 This is probably not the wholestory, however, as patients with selectiveimmunoglobulin A deficiency do not normallyhave significant gastrointestinal problems apartfrom the occasional patient with coexistingcoeliac disease.The pattern of colitis was always of mild

degree, and in all but one, in whom itresembled ulcerative colitis, it fell within thespectrum of microscopic or lymphocyticcolitis.35 36 Characteristically such patientsshow a total colitis detected only by biopsy.There was a mild low grade inflammatory cellinfiltrate throughout the mucosa with verylittle crypt damage or abscesses. A highproportion showed increased numbers ofintraepithelial lymphocytes. Histologicallythere is some overlap with the condition ofcollagenous colitis37 but no evidence of anincreased collagen plate was seen in any of thepatients reported here. The aetiology of thispattern of colitis is unknown but there hasbeen speculation about it being an abnormalresponse to luminal antigens akin to that ofcoeliac disease,38 as a relation between the twohas been described.39

In the past there may have been a tendencyto classify the gastrointestinal changes inpatients with hypogammaglobulinaemia intothe diagnostic category of classic inflammatorybowel disease, which bears with it the connota-tion that a change in mucosal immunoglobulinsecretion was important in the pathogenesis ofulcerative colitis and Crohn's disease. In thisseries there was a superficial clinical and radio-logical resemblance with classic inflammatorybowel disease but the histopathology lackeddiagnostic features, apart from one patient whohad features of ulcerative colitis. It would seemthat hypogammaglobulinaemia is associated,in its own right, with a specific form ofintestinal inflammation with variablemanifestations.A consensus has emerged from published

works that a gluten free diet is not of particularbenefit to symptomatic patients withhypogammaglobulinaemia. Our patients inthis category have, however, respondedsymptomatically to treatment with anelemental diet with significant reductions inthe excretion of Illindium leucocytes, similarto that seen in Crohn's disease,27 but with nosignificant change in mucosal histology. Itwould seem that treatment with elementaldiets is a valuable temporary measure inseverely symptomatic patients with hypo-gammaglobulinaemia, which should be triedwhen empirical treatment with antibiotics andcorticosteroids have failed.

In summary a high prevalence of smallintestinal inflammation and microscopic colitiswas found in a group of patients with diarrhoeaand hypogammaglobulinaemia treated withintravenous immunoglobulins. The histo-pathological features suggest a pattern ofinflammation distinguishable from classicinflammatory bowel disease. In severely

symptomatic patients with diarrhoea a trial ofelemental diets may be advisable.

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