Postgrad Med J (1991) 67, 446 - 449 i) The Fellowship of Postgraduate Medicine, 1991

Granulomatous enteropathy in common variableimmunodeficiency: a cause ofchronic diarrhoea

N. Mike, T.T. Hansel, J. Newman and P. Asquith

Departments ofGastroenterology, Immunology and Histopathology, East Birmingham Hospital, BordesleyGreen East, Birmingham B9 SST, UK.

Summary: Gastrointestinal disease is a well recognized feature in patients with common variableimmunodeficiency, and is often due to infection with a variety of organisms. Symptoms usually improvewith appropriate antibiotic therapy and replacement gammaglobulin. We describe three middle-agedfemale patients with common variable immunodeficiency who had protracted diarrhoea and weight loss.Despite extensive investigation no infectious cause was found.

All patients had granulomas distributed throughout the gastrointestinal tract, but no features ofinflammatory bowel disease. There was a poor response to gammaglobulin replacement therapy,antibiotics or symptomatic treatment. We suggest that granulomatous enteropathy is another gastrointes-tinal manifestation of common variable immunodeficiency.

Introduction

A large number of gastrointestinal manifestationsare recognized in patients with common variableimmunodeficiency (acquired hypogammaglobul-inaemia), and form a major component of thecondition.'`" These include infectious complica-tions such as giardiasis, small intestinal bacterialovergrowth and bacterial and viral enteritis. Gas-tritis, pernicious anaemia and gastric malignancyare well recognized complications.4 Nodular lym-phoid hyperplasia is found in 20-60% of thesepatients, and other associations include hypogam-maglobulinaemic sprue and ulcerative jejunitis. Wedescribe three patients with common variableimmunodeficiency and chronic gastrointestinalsymptoms in whom a granulomatous enteropathywas found.

Case reports

Case I

A 55 year old female had recurrent infections over aperiod of 25 years with episodes ofpneumonia, andthe latter had resulted in bronchiectasis. In 1973 shewas found to have panhypogammaglobulinaemia(IgG 0.22 g/l, IgA and IgM not detected). Delayedhypersensitivity skin tests to recall antigens werenegative and lymphocyte transformation studies

gave subnormal responses. Common variableimmunodeficiency was diagnosed5 and treatmentstarted with weekly intramuscular gammaglobulinand postural drainage.

She remained well until 1984 when asympto-matic hypercalcaemia was noted, with correctedcalcium 2.88 mmol/l (normal 2.33-2.66 mmol/l).Parathyroid hormone levels have repeatedly beennormal, and the hypercalcaemia has persisted. In1986 she developed extensive erythema nodosumwhich lasted 4 months. Chest X-ray showed bron-chiectasis but no features of sarcoidosis. Angioten-sin converting enzyme was not elevated and aKveim test was negative.At this stage the patient developed diarrhoea

lasting for 9 months, during which time she lost10 kg in weight. Immunoglobulin levels were satis-factory on replacement therapy. Tests of poly-morph function (nitroblue tetrazolium reductionfollowing phorbol myristic acetate stimulation)gave normal responses. No organisms were iso-lated or grown from numerous faecal and jejunalaspirate specimens. Tests of absorption were nor-mal, and there was no steatorrhoea. Flexiblesigmoidoscopy revealed normal looking bowelmucosa. On rectal biopsy (Figure 1) the glandarchitecture was mildly distorted and there werenon-caseating granulomata including giant cells.Barium enema demonstrated a normal appearanceof the colon and terminal ileum. At endoscopy theupper gastrointestinal tract looked normal. Duo-denal biopsy had a normal villous pattern but anill-defined granuloma was seen (Figure 2). Trans-bronchial biopsy showed normal lung parenchyma

Correspondence and present address: N. Mike, M.D.,M.R.C.P., Stoke Mandeville Hospital, Aylesbury,Buckinghamshire HP21 8AL, UK.Accepted: 30 August 1990

GRANULOMATOUS ENTEROPATHY 447

Figure 1 Gastric pyloric mucosa. The arrow indicates asmall granuloma. H&E x 100.

Figure 2 Duodenal mucosa. The arrow indicates an

epithelioid cell granuloma. H&E x 100.

with acute and chronic inflammatory cells andoccasional giant cells in the bronchial mucosa.Symptoms slowly improved with anti-diarrhoealagents and dietary supplements, though she re-mains underweight.

Case 2

This 35 year old housewife developed persistentdiarrhoea in 1975 with weight loss of 16 kg. Overthe next 2 years she had recurrent chest, ear andsinus infections. There was vitiligo and spleno-megaly on examination. Investigations revealedpanhypogammaglobulinaemia (IgG 0.2 g/l, IgAand IgM undetectable) and treatment with intra-muscular gammaglobulin was started. Despite thisthe diarrhoea continued 3-4 times daily and shefailed to gain weight. Further investigation showedno evidence of malabsorption or a protein losingenteropathy. Stool cultures were repeatedly nega-tive and no organisms were seen or cultured from ajejunal aspirate. Jejunal biopsy was histologicallynormal. Serum B12 was very low at 8 ng/l (normal150-800 ng/1) with megaloblastic erythropoiesisand treatment with hydroxycobalamin was com-menced. No gut pathogens were isolated despiteextensive testing. By 1986, as well as the diarrhoea,she complained of abdominal pain and vomiting.At endoscopy the upper gastrointestinal tractlooked normal. However, biopsy of the stomachdemonstrated a few non-caseating granulomataincluding giant cells within the lamina propria(Figure 3). No acid-fast bacilli were seen. There wasno evidence of sarcoidosis and polymorph functiontests were normal. Symptomatic treatment withantiemetics, antidiarrhoeal agents and dietary sup-plements have caused little improvement.

Case 3

This 46 year old woman had attacks of severeabdominal pain associated with marked diarrhoea(20-30 times in 24 hours) for 6 years. Theseepisodes lasted about 1 week and recurred every 3months. Endoscopy, barium enema and sig-moidoscopy revealed no cause for her symptoms.She had a panhypogammaglobulinaemia: IgG1.85 g/l, IgA 0.45 g/l, IgM 0.25 g/l. Lymphocytetransformation responses were impaired and com-mon variable immunodeficiency was diagnosed. Abarium follow-through showed nodular lymphoidhyperplasia in the jejunum.

She was commenced on intramuscular gamma-globulin replacement following an episode ofwhooping cough. She was asymptomatic on thisuntil 1988 when she developed sinusitis and ananaerobic lung abscess which responded to tinid-azole and erythronmycin. Intravenous immuno-globin was commenced. In 1989 she had diarrhoea

448 N. MIKE et al.

is ..* . .I

Figure 3 Colonic mucosa. The arrow indicates an ill-formed epithelioid granuloma just beneath the surfaceepithelium. H&E x 100.

for 8 months, accompanied by erythema nodosum.No infectious cause was found for this. A hydrogenbreath test showed normal intestinal transit withno evidence of small intestinal bacterial over-growth. At flexible sigmoidoscopy there were atleast 10 small nodules, 2- 3 mm in diameter, in therectum and sigmoid colon. Histology of theselesions showed an altered glandular pattern with apatchy increase in mononuclear inflammatorycells. An ill-defined focus of epithelioid cells,without giant cells, was seen. There were nofeatures of nodular lymphoid hyperplasia. Atendoscopy no abnormality was seen in the stomachor duodenum. However, histological examinationrevealed ill-defined granulomas and giant cells inthe gastric mucosa. Duodenal biopsies were nor-mal. A prolonged course of therapy with metro-nidazole and erythromycin had no effect on hergastrointestinal symptoms which have persisted.

Discussion

These three patients with common variableimmunodeficiency have had a protracted diarr-hoeal illness with weight loss. None of the recog-nized infective causes or other gastrointestinalmanifestations of hypogammaglobulinaemial"2were found to account for this, though the firstpatient had concurrent pernicious anaemia and thethird had nodular lymphoid hyperplasia, bothcommon in this disease.4 All three patients hadgranulomas in the gastrointestinal tract, requiringcareful scrutiny at multiple levels to identify, and

associated with unique clinicopathological fea-tures.7'8 The major differential diagnosis for granu-lomatous disease ofthe intestine is Crohn's disease,and this has occasionally been reported in patientswith common variable immunodeficiency.9 11These patients had typical features of Crohn'sdisease with strictures in the small and largeintestine resulting in intestinal obstruction. Theinflammation was transmural with granuloma for-mation. None of the three patients described herehas any definite radiological or endoscopic featuresof Crohn's disease. An uncommon cause of intes-tinal granulomas and recurrent infections ischronic granulomatous disease'2 exluded in ourpatients by virtue of normal nitroblue tetrazoliumtests.A sarcoid-like syndrome occurs in some patients

with common variable immunodeficiency.' 3 Thesepatients have a reticular pattern on chest X-raywith hilar lymphadenopathy and reduced gastransfer. Non-caseating granulomas are found inthe lungs, liver, spleen and skin, but gastrointes-tinal involvement is not described in this condi-tion. 4 The Kveim test is negative in the presence ofactive disease, and the condition is considered to bedifferent from true sarcoidosis. Erythema nodo-sum, however, is a well recognized finding insarcoidosis, and also in inflammatory boweldisease and with specific infections,'" but it is veryrare in common variable immunodeficiency. Thepresence of erythema nodosum in two of ourpatients suggests some similarities with classicalsarcoidosis. On the other hand involvement of thegastrointestinal tract in association with activesarcoidosis is very rare.'6"17 Diarrhoea and weightloss are the presenting symptoms and these patientsmay have jejunal villus atrophy with malabsorp-tion and non-caseating granulomas in the smalland large intestine.'8 However, true sarcoidosiswith a positive Kveim test, raised angiotensinconvertase level, and response to steroids is ex-tremely uncommon in patients with hypogamma-globulinaemia.'9 Steroids have been used in suchpatients with the sarcoid-like syndrome and pul-monary involvement, and have had a beneficialeffect both on symptoms, impaired gas transfer andradiological changes."' ' This treatment was notused in the three patients described because aninfectious cause was suspected (though not iden-tified) for their gastrointestinal symptoms.Granuloma formation can be an immune

mechanism against poorly degradable or poorlysoluble substances including a large variety ofmicro-organisms.'2 A number of such organismscommonly cause gastrointestinal infection inimmunodeficient patients, including Giardia lamb-lia, cryptosporidium, rotavirus, as well as the moreusual intestinal organisms."2'20 In particular, cam-pylobacter enteritis may have a prolonged clinical

GRANULOMATOUS ENTEROPATHY 449

course, and be difficult to eradicate with anti-biotics.4'2 A hypogammaglobulinaemic patient hasbeen described in whom chronic campylobacterinfection was associated with granulomas on rectalbiopsy.22 In two further hypogammaglobulinaemicpatients with chronic diarrhoea and mild steatorr-hoea, rod-shaped organisms were isolated from thestools which reacted with an antiserum raisedagainst Campylobacterjejuni.4 This organism couldnot be cultured in vitro, suggesting that the diarr-hoea may have been due to a previously unrecog-nized campylobacter.

Finally, a single patient has been described withmalakoplakia of the colon complicating acquiredhypogammaglobulinaemia.23 This disease is quitedistinct from the granulomatous lesions found inthe three patients described here. We suggest thatthe granulomatous enteropathy is a novel gastro-

intestinal manifestation of common variableimmunodeficiency. It is important to recognizebecause of its morbidity and its poor response totherapy such as prolonged antibiotic treatment.Particularly striking is the lack of improvementwith intravenous gammaglobulin. The finding ofthis enteropathy in three patients with commonvariable immunodeficiency in this centre suggeststhat this disorder may not be uncommon in suchpatients. The underlying cause, which may beinfectious, remains to be elucidated.

Acknowledgements

We are grateful to Dr R.A. Thompson for permission toreport on patients under his care, and to Ms Tracey Greenand Mrs Karen Platt for typing the manuscript.

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