bronchopulmonary disease in coeliac patients · in the basal segments of the k'$~z%v.skleft...

J Clin Pathol 1985;38:361-367

Bronchopulmonary disease in coeliac patientsC EDWARDS,* A WILLIAMS,t P ASQUITHt

From the Departments of *Histopathology, tChest Medicine, and tGastroenterology, East BirminghamHospital, Bordesley Green East, Birmingham

SUMMARY This paper describes the necropsy changes in a patient with coeliac disease andrespiratory disease and the pulmonary biopsies from 13 other coeliac patients with physiologicalevidence of a parenchymal lung disorder. Postmortem examination showed partial fibrous oblit-eration of small airways and dilatation of larger airways, -and the biopsies suggested similarchanges in the other patients. We were unable to find any evidence of granulomatous or primaryinterstitial lung disease.

During the past 15 years there have been reports ofseveral pulmonary disorders coexisting with coeliacdisease.'-9 In most cases cryptogenic fibrosingalveolitis or bird fancier's lung have been diag-nosed,'-6 but idiopathic pulmonary hae-mosiderosis,' sarcoidosis,8 and farmer's lung9 havealso been implicated. These diagnoses have gener-ally been made on clinical and radiological groundsalone; few patients have been biopsied.

Recently, we have found that sonme patients withgluten sensitive enteropathy have physiological evi-dence of a gas transfer defect,'0 and our investiga-tions suggest that the pulmonary lesion in such casesis a chronic inflammatory and fibrotic process affect-ing bronchioles and distal bronchi, with minimalinvolvement of the parenchyma. The first part of thispaper reports the necropsy findings in a patient withcoeliac disease and lung disease. The second partdeals with the appearances in transbronchial biop-sies from 13 coeliac patients with abnormal gastransfer.

Case reports

CASE 1Clinical summaryA 48 year old woman presented in December 1965with a one month history of dyspnoea and a drycough. She had kept a budgerigar for four years.There were inspiratory crackles throughout bothlung fields, most pronounced at the bases, but noother abnormal physical signs were detected. Achest radiograph showed bilateral lower and leftmid-zone shadowing, and spirometry revealed a

Accepted for publication 4 December 1984

pure restrictive defect. Precipitins were shown tobudgerigar serum and droppings and to hen's eggyolk. A diagnosis of interstitial lung disease due toavian exposure was made. The patient disposed ofher budgerigar, and was treated with a daily dose of10 mg of prednisolone. Three months later hersymptoms had improved, but further shadowing wasseen in the right mid-zone. With continued pred-nisolone treatment there was some resolution at thebases but the mid-zone shadowing persisted.By February 1967 her condition had deteriorated.

She had become more breathless, and radiologicallythe basal shadowing had increased. Her daily doseof prednisolone was increased to 30 mg, andalthough there was no bacteriological evidence oftuberculosis, she was given a course of streptomycin,p-aminosalicylic acid, and isoniazid. Four monthslater her clinical and radiological condition hadimproved; her prednisolone was reduced to 15 mgper day, and the p-aminosalicylic acid and strep-tomycin were withdrawn. She continued withisoniazid for two years, and remained on 10 to15 mg of prednisolone daily for nine years. Duringthis period the lung shadowing persisted but did notprogress, and there was no symptomatic deteriora-tion.

In 1976 she was admitted to hospital again, thistime with a three month history of diarrhoea andabdominal pain. She had lost 9 kg in weight duringthis period. On direct questioning she admitted to asimilar episode as a child, which had cleared spon-taneously. Results of investigations showed lowserum iron and folate concentrations and a haemo-globin concentration of 12-3 g/dl. A jejunal biopsyshowed sub-total villous atrophy. No avian precipi-tins were found in the serum on this or subsequent

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fused and there was complete palsy of the left facial_A \ ' .. >',ei->'!Xnerve. Her left arm was weak, and there was wasting

of the intrinsic muscles of the left hand. Reflexeswere abnormally brisk in all four limbs, and the leftplantar response was extensor. Proprioception wasimpaired, she had a positive Romberg's sign, andvibration sense over the left ankle was reduced.Over the next two months she slowly deterio-

rated, became more confused, and she died inOctober 1982.

Necropsy findingsThe lungs were examined after fixation withformol-saline through the trachea. The main bron-chi contained muco-pus. There was fibrosis of thelingula, which was reduced to a tag 3 x 2 x 1.5 cmcontaining dilated airways. Contiguous with thisthere was a shrunken fibrotic area 4 cm long and up

V.,i;.+sw;to 0 7 cm wide running along the anterior border ofthe upper lobe (Fig. 1). In the basal segments of the

%v.k'$~ZsKleft lower lobe peripheral airways were dilated andsurrounded by grey-white fibrotic areas up to 03 cmin diameter (Fig. 2). Similar changes were present inthe basal segments of the right lower lobe. On thesurface of the lower lateral part of the right upperlobe there was a depressed area 4 cm across, andbeneath this, a wedge of fibrosis containing dilatedairways extended into the lung parenchyma forabout 5cm.

Fig. 1 Case l. The lingula, showing fibrosisand dilatationofairways.

occasions. A diagnosis of adult coeliac disease was9VA0'

made, and she was started on a gluten free diet. She bregained her normal weight over the ensuing eightmonths, although a further jejunal biopsy at the endof this period still showed sub-total villous atrophy.The next year her diarrhoea returned, she lost

10kg in weight, and a third jejunal biopsy againshowed sub-total villous atrophy. She had adheredstrictly to her diet, and it was apparent that she hadunresponsive coeliac disease. Her daily dose ofprednisolone was therefore increased to 20 mg, andon this regimen her bowel symptoms subsidedand'A .she gradually regained weight. A jejunal biopsYtaken a few months later showed only minor villousabnormalities.She remained well until August 1982, when she

becamo lethargic, her dyspnoea increased, and sheagain lost weight. She also complained of paras- _thesiae in the left hand and arm. Her bowels wereregular, and her stools were normally formed. On _'examination there were coarse inspiratory crackles Fig. 2 Case 1. The base ofthe lower lobe. Small airwaysthroughout both lung fields. She was slightly con- are dilated and are surrounded by finn white foci offibrosis.

362 Edwards, Williams, Asquith

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363Bronchopulmonary disease in coeliac patients

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containing neither glands nor cartilage. Haematoxylin andeosin. x 43.

Histologically, the walls of the dilated airwaysconsisted of cellular fibrous tissue and lacked muc-ous glands and cartilage (Fig. 3). In longitudinal sec-tions these airways terminated abruptly in the fibro-tic foci seen on naked eye examination (Fig. 4) andwhich consisted of cellular fibrous tissue extending

Fig. 4 Case 1. A dilated airway terminating abruptly in afocus ofinterstitial fibrosis. There is a moderatebronchopneumonia. Haematoxylin and eosin. Originalmagnification x 43.

into the adjacent lung parenchyma in a stellate fash-ion (Fig. 5). The fibrous tissue contained spaceslined by cuboidal non-ciliated epithelium, whichappeared to have budded off the parent airway (Fig.5). In some areas there was proliferation of granularpneumocytes, and distal air spaces often containedfoamy macrophages. Similar changes were seen inthe upper lobes, but the lower lobes, and particu-larly the basal segments, were more severelyaffected. Basal bronchopneumonia was also present.

In the lingula and the lower lateral part of the

Fig. 5 Case 1. A fibrotic focuscontaining spaces lined bycuboidal, non-ciliated epithelium.The fibrosis extends for a shortdistance into the adjacentinterstitium. Haematoxylin andeosin. Original magnificatonx 43.

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364

right upper lobe, dilatation of airways was particu-larly pronounced, and again there was extensivefibrosis of their walls. Intervening pulmonary tissuewas compressed, but there was only minimalfibrosis.The changes in the central nervous system were

similar to those which have been previouslydescribed in association with coeliac disease." In thespinal cord, and in particular in the lumbar region,there was loss of large motor neurones anddegenerative changes were present in the posteriorcolumns. There was slight cuffing of pial vessels. Aninfiltrate of lymphocytes, plasma cells, and occa-sional neutrophils was present in nerve roots anddorsal ganglia, and there was extensive loss ofmyelin sheaths. The pia overlying the cerebralhemispheres, midbrain, and cerebellum showed asubacute meningitis. There was perivascular lym-phocytic cuffing in the cerebral cortex and whitematter, together with astrocytic proliferation andmarginal gliosis. Perivascular cuffing, astrocytic pro-liferation, and neuronal loss were seen in the hip-pocampus, basal ganglia, paraventricular nuclei,hypothalamus, and olivary nuclei. There was slightpial infiltration over the cerebellum, the folia ofwhich were normal; there was no loss of Purkinje orgranular cells but the dentate nucleus showedneuronal degeneration and astrocytic proliferation.There was no villous abnormality in the small

bowel, multiple blocks from which were examined.Sections of the cardia and body of the stomachshowed dilatation of occasional glands and degranu-

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Fig. 6 Case 5. Transbronchial biopsy. Non-specificperibronchiolar fibrosis. Haematoxylin and eosin. x 107.

Edwards, Williams, Asquithlation of chief cells. The colon, appendix, liver, andpancreas were normal. No significant abnormalitywas seen in the heart, thyroid, kidney, uterus, orspleen.

CASES 2 TO 14In 18 of 73 patients with gluten sensitiveenteropathy there was an abnormality of gas trans-fer'0; in 13 patients the respiratory problem was ofsufficient severity to justify transbronchial biopsy.One patient subsequently came to open biopsy.

Clinical and radiological findingsThere were eight women and five men, aged 30-69years. All had gluten sensitive enteropathy, diag-nosed on the basis of jejunal villous atrophy whichhad returned to normal or shown considerableimprovement on a gluten free diet. The mainrespiratory complaints were dyspnoea (ninepatients), a dry or productive cough (five and fourpatients respectively), and wheeze (six patients). Sixpatients were cigarette smokers, three were ex-smokers, and four had never smoked. One patienthad been treated many years previously for tuber-culosis, but there was nothing of relevance in themedical histories of the other patients. No abnor-mality was found on clinical examination, with theexception of one patient, who had finger clubbingand bilateral basal crackles. There was focalcalcification in the apices of both upper lobes in thepatient who had had tuberculosis; the chest radio-graphs of the other members of the group werenormal.

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Fig. 7 Case 9. Transbronchial biopsy. Fibrosis ofthe wallsofterminal airways. Haematoxylin and eosin. Originalmagnification x 107.

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365

kPa). The three ex-smokers had reduced forcedexpiratory volume in one second (FEV1) to forcedvital capacity (FVC) ratios at 67, 61, and 53% of thepredicted values, indicative of mild airflow obstruc-tion; in one of these patients the total lung capacity(TLC) was double the predicted value.Among the six smokers, four had evidence of

airflow obstruction. The FEV,:FVC ratio wasreduced to 58 and 64% of predicted value in two,and in three the TLC was increased to 135, 120, and125%. Three of the smokers were hypoxic, witharterial oxygen tensions of 8-7, 8-9, and 9 5 kPa.

SerologyThere was no consistent abnormality of the serumimmunoglobulins, and the prevalence of autoanti-bodies and immune complexes did not differsignificantly from that found in the 54 patients withnormal gas transfer.'0 Four patients had precipitinsto hen's egg yolk. Precipitins to other avian antigenswere negative.

Transbronchial biopsyBiopsy material was fixed in formol-saline for 24 hand embedded in hydroxyethyl methacrylate; sec-tions were cut at 2,um and stained with haematoxy-lin and eosin, periodic acid-silver, and Perls' stain.'2

Fig. 9 Case 2. Open lungbiopsy. A bronchiolesurrounded by fibrous tissueinfitrated by chronicinflammatory cells.Haematoxylin and eosin.x 107.

Bronchopulmonary disease in coeliac patients

Fig. 8 Case 6. Transbronchial biopsy. Fibrotic thickeningofalveolar septa. Haematoxylin and eosin. Originalmagnification x 43.

Respiratory physiologyAll patients had a reduced single breath transfer fac-tor for carbon monoxide, corrected for lung volumeand anaemia. The four non-smokers had normal sta-tic and dynamic lung volumes, but one had a slightlyreduced arterial carbon dioxide tension (pCO2 46

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366

The changes were generally mild and non-specific,and in two patients the lung parenchyma was nor-mal. In the others there were varying degrees ofinterstitial, peribronchiolar, and perivascular fibrosis(Figs. 6 and 7); adjacent lung parenchyma showedpatchy thickening of the alveolar septa (Fig. 8), andsometimes prominence of granular pneumocytes.No granulomata were present, and there was no

inflammation and no evidence of pulmonaryhaemosiderosis. Arteries, arterioles, and veins werenormal, and there was no abnormality of the capil-lary basement membranes.

Open biopsyThis showed fibrosis and thickening of alveolar wallsand an excess of intra-alveolar macrophages. Bron-chioles were surrounded by cuffs of fibrous tissuecontaining an infiltrate of lymphocytes and plasmacells (Fig. 9), but the extensive peribronchiolarfibrosis seen in case 1 was not present. The musclecoat of these airways was well preserved, and thelining epithelium was of columnar ciliated type. Alittle mucoid material was sometimes present in thelumen.

Discussion

A number of investigators have reported lungchanges in association with coeliac disease. In 1969Scadding' described a patient with coeliac diseasewho had been exposed to pigeons. At biopsy therewere sarcoid like granulomata in the lung paren-chyma; a Kveim test was negative. The disease pro-gressed despite steroid treatment. The next yearHood and Mason2 reported two patients with coeliacdisease, dyspnoea, diffuse pulmonary opacities, andreduced gas transfer. A diagnosis of interstitialfibrosis was made, but no biopsies were taken. In1971 Lancaster-Smith and others3 found diffuselung disease in three of 24 patients with coeliac dis-ease, but again these cases were not biopsied. Later,the same group investigated a further 33 coeliac sub-jects, but found no respiratory disorder.'3 Thebiopsy findings in later cases vary, and include des-quamative interstitial pneumonitis,'4 idiopathicpulmonary haemosiderosis,' non-specific pleuralfibrosis and chronic bronchitis,'5 granulomataassociated with avian exposure,'6 and sarcoidosis.8We found no granulomata in any of our subjects,

and although a few haemosiderin laden mac-rophages were sometimes present in -the alveoli,they did not justify a diagnosis of pulmonaryhaemosiderosis. The changes in the lungs of case 1were not those of a fibrosing alveolitis: instead, theysuggested chronic inflammation of the walls of thesmaller air passages, extending into the adjacent

Edwards, Williams, Asquith

lung parenchyma. A similar process in some of thelarger airways had caused dilatation rather than nar-rowing.The mild interstitial, perivascular, and peribron-

chiolar fibrosis in the biopsy material was non-specific. Most of the patients were cigarette smokersor ex-smokers, and similar appearances are oftenfound in emphysema. Nevertheless, the changes areconsistent with the presence of lesions resemblingthose in the necropsy case. Such lesions would notbe demonstrable in small distorted transbronchialbiopsies. The non-specific chronic pneumonitisfound in the open biopsy may have been obstructivein nature and could well have been caused by dam-age to the airways.

Interference with gas transfer is classically associ-ated with fibrosing alveolitis, but it also occurs in anycondition causing a ventilation to perfusion mis-match, such as emphysema.'' The low gas transfer inour patients could therefore be due to damage to theperipheral airways, and the obstructive elementcould be attributed to involvement of larger airwaysby a similar process. Tarlo's group5 found thatasthma, chronic cough, and airway obstruction wasmore frequent in coeliac than control subjects. Noneof their eighteen cases had interstitial lung disease.All of our patients with physiological evidence ofairways obstruction were current or ex-smokers,however, and the obstruction may be a manifesta-tion of chronic bronchitis.The pathogenesis of the respiratory disorder in

our patients remains obscure. There are no constantimmunological abnormalities and their prevalencein coeliac patients with a low gas transfer was nodifferent from that of those with a normal gas trans-fer.'0 Coeliac patients often have a raised serum IgAand low IgM concentrations, and IgE may also beincreased'8; immune complexes are found in theserum of those who have been exposed to gluten'8and autoantibodies occur more often.'9An association between bird fancier's lung and

coeliac disease has been suggested,' 2 16 20 but this hasnot been confirmed. Hendrick and others2' foundonly one case of bird fancier's lung in 61 patientswith coeliac disease, and jejunal villous abnor-malities were seen in only five of 143 cases of birdfancier's lung in a recent multicentre study carriedout by the British Thoracic Society.22 Furthermore,it has been shown that although avian precipitinsoccur in 35% of patients with coeliac disease, theirpresence is related to abnormal absorption of pro-tein by the damaged intestinal mucosa, because theycross react with hen's egg yolk.23 The avian precipi-tins in our patients were of this type.Thus although our patients show -physiological

evidence of interference with gas transfer,

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Bronchopulmonary disease in coeliac patientspathological findings suggest that this is due to dis-turbed ventilation to perfusion relation consequenton airway rather than alveolar disease. Detailednecropsy studies of the lungs of further cases ofadult coeliac disease are required.

We are grateful to Mrs Ruth Fry for secretarial assis-tance, and Dr Ruth Cayton for help in interpretingthe respiratory physiology tests.

References

'Scadding JG. Lung biopsy in the diagnosis of duffuse lung dis-ease. Br Med J 1970;ii:557-64.

2 Hood J, Mason AMS. Diffuse pulmonary disease with transferdefect occurring with coeliac disease. Lancet 1970;i:445-8.

'Lancaster-Smith MJ, Benson MK, Strickland ID. Coeliac diseaseand diffuse interstitial lung disease. Lancet 1971;i:473-6.

Eade OE, Berrill WT. Coeliac lung disease. Lancet1978;i: 1262-3.

Tarlo SMM, Broder I, Prokipchuk EJ, Peres L, Mintz S. Associa-tion between coeliac disease and lung disease. Chest198 1;80:715-8.

Konig G, Albert E, Dewait M, et al. Extrinsic allergic alveolitiscombined with celiac disease in childhood. Respiration1982;43:444-51.

'Wright PH, Menzies IS, Pounder RE, Kneeling PWN. Adultidiopathic pulmonary haemosiderosis and coeliac disease. Q JMed 1981;50:95-102.

'Douglas JG, Gillon J, Logan RFA, Frant IWB, Crompton GK.Sarcoidosis and coeliac disease: an association? Lancet1984;ii: 13-5.

9Robinson TJ. Coeliac disease with farmer's lung. Br Med J1976;i:745-6.

Williams A, Asquith P, Edwards C, Stableforth DE. Alveolitis inadult coeliac disease-a new syndrome. Thorax 1984;39:219.

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"Kinney HC, Burger PC, Hurwitz BJ, Hijman JC, Grant JP.Degeneration of the central nervous system associated withceliac disease. J Neurol Sci 1982; 53:9-22.

12 Edwards C, Krypczyk A, Brownhill A. Plastic embedding oftransbronchial biopsy specimens for light microscopy. J ClinPathol 1979;32:1294-8.

" Lancaster-Smith MJ, Perrin J, Swarbrick ET, Wright JT. Coeliacdisease and autoimmunity. Postgrad Med J 1974;50:45-8.

4 Fitzgerald MX, Hegarty J, Brennan NJ. Desquamative intersti-tial pneumonia (DIP) and adult coeliac disease.Am Rev RespDis (suppl) 1977; 115:105.

"Cummiskey J, Keelan P. Coeliac disease and diffuse pulmonarydisease (letter). Br Med J 1976,i: 1401.

Birrell WT, Eade OE, Fitzpatrick TF, Hyde I, McLeod WM,Wright R. Bird fancier's lung and jejunal villous atrophy. Lan-cet 1975;ii:1006-8.

Cotes JE. Lung function. Assessment and application in medicine.Oxford: Blackwell, 1979.

K Cooke WT, Holmes GKT. Coeliac disease. Edinburgh: ChurchillLivingstone, 1984.

Kumar P, Oliver RTD, O' Donoghue DP, et al. The relationshipof HLA-A, B status to the clinical findings and autoimmunityin coeliac disease. In: McConnel RB, ed. The generics ofcoeliac disease. Lancaster: MTP Press, 1981.

20 Morris JS, Read AE, Jones B, Cotes JE, Edwards JH. Coeliacdisease and lung disease (letter). Lancet 1971;i:754.

21 Hendrick DJ, Faux JA, Anand B, Piris J, Marshall R. Is birdfancier's lung associated with coeliac disease? Thorax1978;33:425-8.

22 British TMoracic Society. A national survey of bird fanciers' lung:including its possible association with jejunal villous atrophy.Br J Dis Chest 1984;78:75-87.

23 Faux JA, Hendrick DJ, Anand BS. Precipitins to different avianserum antigens in bird fancier's lung and coeliac disease. ClinAllergy 1978;8:101-8.

Requests for reprints to: Dr CW Edwards, Department ofHistopathology, East Birmingham Hospital, BordesleyGreen East, Birmingham B9 5ST, England.

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