lack of gamma a-immunoglobulin in of patients · to the hospital on 5 february 1965 for a study of...

Gut, 1966, 7, 11

Lack of gamma A-immunoglobulin in serum ofpatients with steatorrhoealP. A. CRABBt1 AND J. F. HEREMANS

From the Research Department of Internal Medicine and the Department of ClinicalMedicine, The University Clinic of St. Pierre, Louvain, Belgium

EDITORIAL SYNoPsis The possibility is put forward that the deficiency ofgamma A-immunoglobulinin the patients described might be a primary defect and not secondary to impaired proteinsynthesis due to reduced intestinal absorption.

The human intestinal mucosa is known to contain alarge population of plasma cells. In the course of animmunohistochemical study on intestinal biopsiesfrom normal subjects, we have recently shown thatthe majority of these mucosal plasma cells containthe yA-type of immunoglobulin (Crabbd, Car-bonara, and Heremans, 1965). It seemed to us ofinterest to extend this kind of analysis to patientssuffering from various intestinal diseases, especiallyidiopathic steatorrhoea, where the intestinal mucosais heavily infiltrated with plasma cells. The resultsobtained in such patients prompted us to study inmore detail the immunoglobulins present in theirserum.The present report deals with three patients who

have in common the presence of steatorrhoea andthe absence or severe decrease ofyA-immunoglobulinin the serum. Two of these patients have a normallevel of serum 'y globulin', as judged by paperelectrophoresis, while the third is hypogamma-globulinaemic.

CASE REPORTS

CASE 1 A 59-year-old unmarried woman was admittedto the hospital on 5 February 1965 for a study of in-testinal absorption function. The family history was notremarkable and the patient denied any symptoms ofcoeliac disease during childhood. She had been very well,working as an employee, until 1961, when she noted theprogressive onset of weight loss, anorexia, fatigue, andswelling of the ankles. She began to complain of bonepain which was at first restricted to the left groin, butlater spread to other bones. She was treated, withoutsuccess, for 'neuritis' and 'rheumatism'. In 1963, an x-rayexamination disclosed a diffuse decrease in density of thebones and a non-consolidated fracture of the left femoralneck. Hypocalcaemia and increased activity of serum

'This investigation was supported by grant no. 585 of the Fonds dela Recherche Scientifique M6dicale, Brussels, Belgium.

alkaline phosphatase were present. Despite the absenceof diarrhoea, a malabsorption syndrome was suspectedand the presence of steatorrhoea was confirmed by themicroscopic examination of a stool specimen. The patientwas given injections ofcalcium gluconate and supplementsof vitamin preparations with some benefit, but theadministration of large doses of pancreatic extractsfailed to correct the steatorrhoea.On admission the patient appeared as a pale, active,

middle-aged woman in no apparent distress. Her weightwas 51 kg. and her height was 150 cm. The blood pressurewas 11-5/7 cm. of Hg and her pulse was 76 per minute andregular. A soft, apical systolic murmur was present. Theabdomen was slightly protuberant; bowel sounds werenot hyperactive. Mild bilateral pitting ankle oedema waspresent. Digital pressure on several bones and vertebraewas painful. The neurological examination was withinnormal limits.The relevant laboratory data are presented in Tables I

and II. The absorption of D-xylose was evaluated fromthe cumulative amount excreted at five hours after an oraldose of 25 g. None of the three patients described hereshowed any sign of renal insufficiency. Quantitativedetermination of faecal fat was performed by the methodof van de Kamer, ten Bokkel Huinink, and Weijers (1949)on a four-day stool collection, the patient receiving a dietcontaining 80 g. of fat.The radiological examination of the small bowel

showed very slight diffuse dilatation of the loops andsome flocculation of the contrast medium. No localizedlesion was recognized. These changes were interpreted asbeing minimal and non-specific. A jejunal biopsy wasperformed by means of the Crosby-Kugler capsule. Thespecimen was obtained a few centimetres beyond theligament of Treitz. Under the dissecting microscope themucosa appeared to be completely flat. The histologicalexamination showed so-called 'subtotal villous atrophy'with increased infiltration with lymphocytes and plasmacells in the lamina propria. Adequately stained sectionsrevealed the absence of P.A.S.-positive material in thechorion. The changes were considered compatible withthe diagnosis of idiopathic steatorrhoea.The patient was placed on a strict gluten-free diet and

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P. A. Crabbe and J. F. Heremars

Case Red Haemo-No. Blood Cells globin

(per c.mm.) (g./100 ml.)

TABLE ILABORATORY DATA FOR THE THREE CASES

White Calcium Alkaline Pro- SerumBlood Cells Phosphorus Phos- thrombin Iron(per (mg./100 nil.) phatase Time (ls-g/c.mm.) (Bodansky (% of the 100 ml.)

units) normal)

3,480,000 1054,150,000 12 5

3,3706,530

TABLE 1LTOTAL SERUM PROTEINS AND ELECTR

THE THREE PATIENTS

Case Total Paper ElectrophoresiNo. Proteins

(g./lOOml.) Albumin Globulin

CVI

5-645 185-95

58 5 3-663-13 5-9949-67 5-57

8-52 4-08 4-09 828-42 4-25 3-67 594-8 - - -

3290

141*9168

269205145

FlatFlat

follicle was found in the chorion of the histologicatOPHORETIC DATA FOR preparation. The cellular population of the lamina propria

of the biopsy specimen consisted mostly of small lympho-is (as ° of total protein) cytes, histiocytes, and eosinophils. Very few typicalplasma cells could be recognized. A biopsy of theFractions rectal mucosa showed the presence of many plasma cells

under the surface epithelium and between the glandulara2$ crypts. A radiological examination of the small bowel

8-3 12 2 17-4 showed diffuse enlargement of the intestinal loops, with11-65 13-56 5-64 some flocculation of the barium paste. The picture was.13-61 8-61 22-53 that of a deficiency pattern. A radiograph of the chest

failed to reveal the presence of any bronchial dilatation.was given supplements of vitamins, iron, and folic acid.After three months of this regimen, a slight subjectiveimprovement was noted and the abdominal distensionhad definitely decreased. Total serum proteins had in-creased to 7 29 g./100 ml., R.B.C.s to 4,290,000 perc.mm., and haemoglobin to 12 3 g./100 ml.

CASE 2 A 57-year-old widow was admitted on 8 March1965, in order better to define the origin of her steator-rhoea. No history of coeliac disease in childhood couldbe elicited and the family study was not contributory.The patient admitted to having frequent upper respira-tory infections for many years. Any skin wounds wereeasily infected. These problems, however, were neversevere enough to be incapacitating. In 1948 she noted theonset of intermittent, crampy abdominal pain which wasfollowed by the passage of frequent, liquid, pale stools.In 1951, a diagnosis of steatorrhoea and anaemia wasproposed. Except for an episode of acute intestinal infec-tion of unknown aetiology in 1962, she has continuedpassing two to three loose, offensive stools daily.Anaemia, general weakness, and back pain becameprogressively more severe.The patient appeared as a middle-aged, slender, pale

woman in no acute distress. Her weight was 46 kg. andher height was 160 cm. Clubbing of the finger and toenails, abdominal distension, and a painless, regular liveredge palpable 2 cm. below the right costal margin were

the only abnormal findings on physical examination. Theblood pressure was 13-5/9 cm. of Hg.The results of the laboratory examinations are given in

Tables I and II. The 1311-PVP test indicated 1-6% faecalexcretion in four days, a result which is slightly abnormaland of the order of magnitude obtained in intestinal mal-absorption of any aetiology. Bacteriological examinationof a specimen of stool failed to show any pathologicalmicroorganism. The jejunal biopsy displayed a com-pletely flat mucosa under the dissecting microscope. Sub-total villous atrophy was present. A single lymphoid

The patient was placed on a strict gluten-free dietsupplemented by vitamins, and received a course of oralterramycin therapy.

CASE 3 This patient is a 61-year-old man who formany years has been suffering from diarrhoea, markedgeneral weakness, and intermittent spontaneous tetany.He had been critically ill in 1963 when an episode ofbronchopneumonia complicated the underlying disease.A definite improvement in his condition was obtained bytreatment consisting of antibiotics and steroids givenorally. He recently suffered a relapse, while still takingthese drugs.

Physical examination was almost within normal limits,except for the presence of clubbing of the finger nails, apositive Trousseau's sign, and a low systolic bloodpressure at 10 cm. of Hg.The few laboratory data available are listed in Tables I

and II. The presence of steatorrhoea was evident as judgedby the macroscopic appearance of the stools and has beenconfirmed by microscopic examination. Radiographsshowed a pronounced and diffuse increase in the radio-lucency of the bones. The loops of the small intestinewere much dilated and a prominent deficiency patternwas evident on the films. A proximal jejunal biopsyshowed a flat mucosa which, on microscopic examination,assumed the appearance of 'partial villous atrophy' withheavy infiltrates of plasma cells and tissue eosinophils.

METHODS

ANALYSIS OF THE SERUM PROTEINS Electrophoresis of theserum proteins was carried out in agar-gel according tothe technique of Wieme (1959). Immunoelectrophoresiswas performed according to Scheidegger (1955), using amultivalent horse antiserum directed against total humanserum (Pasteur Institute, Paris), as well as specific rabbitantisera directed against each of the three humanimmunoglobulins. For quantitative determination of the

23

D-Xylose(g. ex-cretedin 5 hr.)

C/ho/-sterol(mg./100 nil.)

Glucose FaecalTolerance FatCurve (g. per

24 hr.)

9 1516

23

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Lack ofgamma A-immunoglobulin in serum ofpatients with steatorrhoea

immunoglobulins present in the sera, the method ofsingle radial immuno-diffusion in agar-gel, recentlydescribed by Mancini, Vaerman, Carbonara, andHeremans (1964), was used.

IMMUNOHISTOCHEMICAL TECHNIQUES The methods usedfor immunohistochemical studies of the intestinal mucosalspecimens have been extensively described in a previousarticle (Crabbe et al., 1965). The specific antisera directedagainst each of the three types of immunoglobulins werelabelled with fluorescein isothiocyanate. The number ofcells containing each type of immunoglobulin wasevaluated from planimetric measurements on enlargedphotographs of microscopic sections, by means of themathematical formula presented in our previous publica-tion (Crabbe et al., 1965).

RESULTS

IMMUNOELECTROPHORESIS OF THE SERUM PROTEINSThe common finding in the three sera was theabsence of the precipitin line corresponding toyA-immunoglobulin (Fig. 1). The line of the yG-immunoglobulin was well developed in the sera ofcases 1 and 3, whereas it was very weak in case 2.A weak line corresponding to yM-immunoglobulin

II

could be recognized in cases 1 and 3, but wasapparently absent in case 2.

QUANTITATIVE DETERMINATION OF THE THREE IM-MUNOGLOBULINS The concentrations of the threeimmunoglobulins in the sera of our patients aregiven in Table III. The normal values indicated forcomparison are unpublished data obtained byMancini. No yA-immunoglobulin was detected insera 1 and 3, and only trace amounts (10 mg./ 100 ml.)in serum 2, whereas yM-immunoglobulin was verylow in serum 2 (7 mg./100 ml.) and normal in sera 1and 3.

TABLE IIIQUANTITATIVE VALUES FOR THE THREE IMMUNOGLOBULINS

IN THE SERA OF THE PATIENTS

Immunoglobulin Values (mg./100 ml.)

yA yM yG

Normals1Males

Females

MeanS.D.MeanS.D.

230-8 130 4 1,203-978-0 63 1 160-7277-3 168 5 1,228-3111 5 58 6 287-9

CasesI 0 120 1,2602 10 7 2603 0 180 2,192The mean values found in normal subjects are given for comparison.

The serum of each of the three patients was usedto absorb a multivalent horse antiserum, in a ratioof 3:7 (vol./vol.). In each case, this treatment failedto remove the anti-yA activity of the antiserum.

IMMUNOFLUORESCENT STUDIES OF THE INTESTINALMUCOSA The results obtained for the patients 2 and 3with each antiserum are shown in Figures 5 to 11.Figures 2 to 4 represent, for comparison, the aspectof a normal specimen treated with the same antisera.In Table IV are given the values for the population

TABLE IVPOPULATION DENSITIES (NUMBER OF CELLS PER C.MM.) OFTHE THREE TYPES OF IMMUNOGLOBULIN-CONTAINING

PLASMA CELLS PRESENT IN THE INTESTINAL MUCOSA

yA yM yG

FIG. 1. Immunoelectrophoretic patterns of the sera ofthe three patients, after reaction with multivalent horseantiserum directed against total human serum proteins.Note the precipitin line corresponding to yA-immuno-globulin (arrow) in the normal control (lower part of eachdiagram); this line is absent in the sera of the threepatients. The yG-immunoglobulin precipitin line is well-definedfor cases I and 3, but much weaker in the serum ofcase 2. The precipitin line corresponding to yM-immuno-globulin is not clearly visible on the photograph.

Normal'

Case 12

Case 2

Mean 352,290 51,490 15,450S.D. 122,348 22,271 14,680

77,594 431,628 17,249

Jejunum 3,423 2,057 17,611Rectum 320,402 43,038 28,723

Case 3 26,094 581,535 12,264'Normal values are average obtained on 60 fields from 10 normalsubjects.2Each figure represents the mean value from six high-power fielddeterminations.

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inG. 2. FIG. 3.

FIG. 2. Section of a normal human jejunal mucosalbiopsy after incubation with specific anti-yA-immuno-globulin fluorescent antiserum. Note the large number offluorescent cells under the epithelium of the villi andbetween the crypts ofLieberkuhn.

FIG. 3. Same biopsy as in Fig. 2; section incubated withspecific anti-yM-immunoglobulin antiserum. Fluorescentcells are relatively few.

FIG. 4. Same biopsy as in Figs. 2 and 3, after incubationwith anti-yG-immunoglobulin antiserum. Fluorescent cellsare very few. The narrow fluorescent lining extendingalong the basal part of the epithelium corresponds to thecapillary network.

FIG. 4.

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FIG. O. FIG. 6.

FIG. 5. Biopsy specimen obtained from case 3. Thissection has been incubated with specific anti-yA antiserumand shows a strikingly small number of specificallyfluorescent cells in the chorion. Many small brilliantlyfluorescent spots on the photograph correspond to tissueeosinophils.

FIG. 6. Biopsy specimen of the same patient, afterincubation with anti-yM-antiserum. Note the large numberof specifically fluorescent cells in the densely cellularchorion under the surface epithelium.

FIG. 7. Same biopsy as in Figures 5 and 6. This sectionhas been incubated with anti-yG-immunoglobulin anti-serum. The photograph shows a diffuse fluorescence in theinterstitial spaces, a feature which complicates the defi-nition offluorescent cells at this magnification. The capillarynetwork under the epithelium is well outlined (low magnifi-cation).

F1IG. I.

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FIG. 8. FIG. 9.

FIG. 8. Jejunal biopsy obtainedfrom case 2. This sectionhas been incubated with anti-yA-antiserum. The photo-graph shows the chorion(located under the surface epithe-lium to be devoid of any specifically fluorescent cells. Thetwo brilliantly fluorescent spots correspond to tissleeosinophils (high magnification).

FIG. 9. Section of intestinal mucosa incubated with anti-yM-immunoglobulin antiserum (case 2). One verj weaklyfluorescent cell is located near the centre of the photo-graph. The other fluorescent spots are tissue eosinophils(high magnification).

FIG. 10. Same biopsy as in Figs. 8 and 9, incubated withanti-yG-antiserum. Two specifically fluorescent cells maYbe seen in the chorion under the epithelium. Note thefaintlyfluorescent capillarv network (high magniificationi).

FIG. 10.

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FIG. 11. Rectal mucosal biopsy obtained from case 2.After incubation with anti-yA-antiserum, the section showsmany fluorescent cells located between the glandularcrypts.

densities of the cells containing each type of immuno-globulin, in each of the three patients, as well as innormal controls.

DISCUSSION

The three patients described here are suffering froma malabsorption syndrome which seems to besecondary to a diffuse involvement of the smallintestine, as evidenced by the radiological pattern,low D-xylose absorption, and histological ap-

pearance of the jejunal mucosa.Case 2 is an example of the association of hypo-

gammaglobulinaemia and steatorrhoea. The simul-taneous occurrence of these two conditions in thesame patient has been described in the literature.In acquired hypogammaglobulinaemia, Gitlin,Gross, and Janeway (1959) estimate the incidence ofdiarrhoea or a 'sprue-like' syndrome to be approxi-mately 20%. The presence of steatorrhoea in thecongenital type of hypogammaglobulinaemia hasalso been described (Allen and Hadden, 1964). Whilethe patients often have a long history of respiratory

infections before the malabsorption syndromebecomes apparent, this was not the case in ourpatient who was incapacitated much more by theintestinal condition than by any bronchopulmonaryproblem. The same finding has also been reported inother patients (Cohen, Paley, and Janowitz, 1961).The aetiology of the malabsorption syndrome in

hypogammaglobulinaemic patients is not clear.Pathogenic microorganisms were not found in thefaeces in our case nor in other cases reported in theliterature (Firkin and Blackburn, 1958). Yet, it hasbeen assumed that a decreased resistance to infectionwith possible invasion of the small intestine by micro-organisms could play a role in the pathogenesis ofthe steatorrhoea (Kabler, 1960). As far as we know,no direct evidence for such a concept has beenbrought forward. These patients are often resistantto a gluten-free diet and it is not unusual for anti-biotics, associated or not with injections of gammaglobulins, to fail in correcting the steatorrhoea (Allenand Hadden, 1964; Kabler, 1960).The small intestinal mucosa in such cases has

shown a variable picture. Shortening, clubbing, oreven fusion of the villi is not uncommonly found(Forssman and Herner, 1964; Cohen et al., 1961)and, in some patients, the lamina propria has beenreported to be heavily infiltrated with lymphoid cells(Case record of the Massachusetts General Hospital,1963). The presence in the mucosa of an activelymphoid follicle, as seen in our case, was alsoreported by Allen and Hadden (1964) in one of theirpatients. The most striking change in the mucosa ofour patient was the almost complete absence ofplasma cells in the lamina propria. Most of the inter-stitial cells assumed the appearance of small lympho-cytes and histiocytes. Many tissue eosinophils werealso present. Obviously, these changes did not affectthe entire intestinal tract, since many plasma cellscould be recognized under the epithelium of therectal mucosa.Using immunohistochemical methods, we have

previously shown that most of the plasma cellspresent in the normal intestinal mucosa contain yA-immunoglobulin (Crabbe et al., 1966). The sameobservation has been made by Rubin, Fauci,Sleisenger, and Jeffries (1965). The mean populationdensities for cells containing yA-, yM-, and yG-immunoglobulins have been found to be respectively352,290 per c.mm., 51,490 per c.mm., and 15,450 perc.mm. (Crabbe and Heremans, 1966). In contrast, itis interesting to note that the specimen of jejunalmucosa obtained from case 2 was very poor in cellscontaining immunoglobulins. It may be inferredfrom the data shown in Table IV that the very lowplasma cell count was essentially due to the scarcityof yA- and yM- immunoglobulin-containing cells.

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Again, this was localized in parts of, or in the wholelength of, the small intestine, since in the rectalmucosa the respective proportions of yA-, yM-, andyG-immunoglobulin-containing plasma cells were

normal (Table IV).The deficiency in the serum of case 2 of yA- and

yM-immunoglobulins is not surprising since theseproteins are often lacking in the serum of cases ofhypogammaglobulinaemia (West, Hong, and Hol-land, 1962). It was more surprising to find a completeand isolated absence of yA-immunoglobulin in thesera of cases 1 and 3. On clinical, biological, andhistological grounds, these two patients would beconsidered as having idiopathic steatorrhoea. Thatmost patients suffering from this disease are speci-fically sensitive to the proteins of gluten has oftenbeen reported. As yet we have no evidence that our

patients are indeed responding to the elimination ofthese proteins from their diet, and no history ofcoeliac disease during childhood could be obtainedfrom any of them. Yet the return to normal of serumproteins as well as the progressive correction of theanaemia as seen in case 1, three months after theinstitution of a gluten-free diet, suggest that thispatient might be sensitive to the proteins in wheatflour.The histological appearance of the jejunal mucosa

in cases 1 and 3 was very similar and consisted in animportant flattening and widening of the villi,associated with a heavy infiltration, mostly withplasma cells, in the lamina propria. The similaritybetween these two cases extended to the immuno-histochemical pattern of the lamina propria, wherethe densities for yA- cells were inferior to thoseobtained for yM- cells, and only slightly higher thanthose found for yG-immunoglobulin-containingcells. In our experience, this is the only situationwhere this reversal of the yA:yM cell ratio has beenencountered in the human jejunal mucosa. Thepresent results are different from those obtained byRubin et al. (1965) in patients with adult coeliacdisease. In their cases the yA-immunoglobulin-containing cells were stated to predominate, as theydo in normal subjects.

Gilbert and Hong (1964) have described a patientwith a malabsorption syndrome whose serum con-

tained almost no yA- immunoglobulin, whereas theyM- and yG-immunoglobulins were moderatelyreduced. In children, West et al. (1962) found a mal-absorption syndrome in two patients among 13having low serum levels of yA-immunoglobulin withnear-normal values for the other two immuno-globulins. On the other hand, a congenital disordercharacterized by ataxia, telangiectasia, and the fre-quent absence of yA-immunoglobulin has beendescribed (Peterson, Kelly, and Good, 1964;

Fireman, Boesman, and Gitlin, 1964), but, as far aswe know, no intestinal absorption studies have beenreported on such patients. The isolated deficiency ofyA-immunoglobulin has also been described infemale relatives of patients with congenital agamma-globulinaemia (Heremans, 1960; Burtin, Buffe, andGrabar, 1964), in a very small number of apparentlyhealthy adults (Rockey, Hanson, Heremans, andKunkel, 1964), and in one patient with systemic lupuserythematosus (Bachmann, Laurell, and Svenonius,1965). In a study on an unselected population com-prising 6,995 adults, Bachmann (1965) found theincidence of a-yA-globulinaemia to be of 1: 700. Wedo not know of any report of the association in theadult of a malabsorption state with a-yA-globulinae-mia as the only detectable defect in the immunesystem'. It should be noted, however, that the lack ofthis protein is entirely missed on paper electro-phoresis and that such cases might be more frequent,were immunoelectrophoretic analyses of serumproteins carried out on every patient suffering fromidiopathic steatorrhoea.

In 1961, Huizenga, Wollaeger, Green, andMcKenzie noted that the hypogammaglobulin-aemia seen in certain cases of non-tropical spruecould be secondary to impaired synthesis of proteinsdue to the poor intestinal absorption of certainnutrients. That the absence of yA-immunoglobulincannot be explained by such a mechanism in ourpatients is suggested by the fact that case 1 stillcompletely lacked yA-immunoglobulin at a timewhen her serum proteins had returned to a normalconcentration after a period on a gluten-free diet.It is indeed difficult to imagine an isolated defect inthe synthesis of a single protein that would be dueto a state of malnutrition. For all we know, thedeficiency of yA-immunoglobulin in the patientsdescribed here may be a primary defect.The possible relationship between the disease of

our patients and idiopathic steatorrhoea, adultcoeliac disease, or gluten-induced enteropathyremains to be elucidated. The results of this studysuggest that it may be profitable to examine theimmunoglobulins of every patient suffering from thispoorly understood syndrome.

SUMMARY

Three adult patients suffering from chronic steator-rhoea were found to have a serum deficient in yA-immunoglobulin. Two of them had normal levels of'y-globulins', as seen on paper electrophoresis, thethird one being hypogammaglobulinaemic. Immuno-

'Since the submission of this manuscript two such patients have beenmentioned in an article by Hermans, Huizenga, Hoffman, Brown andMarkowitz (1966).

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histochemical studies performed on the jejunalmucosal biopsy of these patients showed that thehypogammaglobulinaemic subject had almost noplasma cells containing yA- and yM-immuno-globulins in the lamina propria. The other twopatients showed a reversal in the ratio of yA-cells:yM-cells. The number of cells containing yM-immunoglobulin was greatly increased, while thedensity of yA-containing cells was reduced to verylow levels. It is suggested that every patient sufferingfrom idiopathic steatorrhoea be studied for thepresence of yA-immunoglobulin in the serum.

We are grateful to Dr. G. Isaac and Dr. A. Mortiaux forallowing us to study their patients.

ADDENDUM

Since our manuscript was submitted for publication,we have been able to re-evaluate the condition ofcase 1, six months after the institution of a gluten-free diet. The following results have been obtained.The weight is unchanged at 51 kg. The R.B.C.s arenow at 4,080,000 per c.mm. and haemoglobin is124 g. per 100 ml.; the serum iron level has risento 90 jig. per 100 ml. (no parenteral therapy has beengiven). The total serum proteins are at 7.41 g. per100 ml.; the paper electrophoretic pattern is normalbut no precipitation line corresponding to yA-immunoglobulin is seen on immunoelectrophoreticanalysis. The urinary excretion of D-xylose is 4.32 g.after a 25 g. oral load. The daily faecal fat excretion(calculated from a four-day collection) is 2-3 g.Finally, the upper jejunal biopsy shows a coarselyconvoluted aspect under the dissecting microscope;histologically, several villi are present, still very shortand broad. Immunohistochemical examinationshows that most of the plasma cells present in thejejunal biopsy and in a rectal mucosal specimencontain yM-immunoglobulin.

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Allen, G. E., and Hadden, D. R. (1964). Congenital hypogamma-globulinaemia with steatorrhoea in two adult brothers. Brit.med. J., 2, 486-490.

Bachmann, R. (1965). Studies on the serum yA-globulin level. 111. Thefrequency of a-yA-globulinaemia. Scand. J. clin. Lab. Inivest.,17, 316-320.

, Laurell, C. B., and Svenonius, E. (1965). Studies on the serumy1A-globulin level. 11. yIA-deficiency in a case of systemic lupuserythematosus. Scand. J. clin. Lab. Invest., 17, 46-50.

Burtin, P., Buffe, D., and Grabar, P. (1964). Les hypogamma-globulin6mies atypiques (hypogammaglobulinemies recessivesnon liees au sexe). Itude immunochimique et g6n6tique. Ann.Inst. Pasteur, 106, 519-542.

Case record of the Massachusetts General Hospital. Case 6-1963.(1963). New Engl. J. Med., 268, 204-213.

Cohen, N., Paley, D., and Janowitz, H. D. (1961). Acquired hypo-gammaglobulinemia and sprue: report of a case and reviewof the literature. J. Mt Sinai Hosp., 28, 421-427.

Crabb6, P. A., Carbonara, A. 0., and Heremans, J. F. (1965). Thenormal human intestinal mucosa as a major source of plasmacells containing y-A-immunoglobulin. Lab. Invest., 14,235-248.and Heremans, J. F. (1966). etude immunohistochirnique desplasmocytes de la muqueuse intestinale humaine normale.Rev. franf. Etud. clin. biol., in the press.

Fireman, P., Boesman, M., and Gitlin, D. (1964). Ataxia telangiec-tasia: a dysgammaglobulinemia with deficient YIA (192A)-globulin. Lancet, 1, 1193-1195.

Firkin, B. G., and Blackburn, C. R. B. (1958). Congenital andacquired agammaglobulinaemia. Quart. J. Med., 27, 187-205.

Forssman, 0., and Herner, B. (1964). Acquired agammaglobulinaemiaand malabsorption. Acta med. scand., 176, 779-786.

Gilbert, C., and Hong, R. (1964). Qualitative and quantitativeimmunoglobulin deficiency. Amer. J. Med., 37, 602-609.

Gitlin, D., Gross, P. A. M., and Janeway, C. A. (1959). The gammaglobulins and their clinical significance. II. Hypegamma-globulinemia. New Fngl. J. Med., 260, 72-76.

Herernans, J. F. (1960). Les globulines seriques du systmn1e gamma.Leur nature et leur pathologie. Arscia, Brussels, an1 Masson,Paris.

Hermans, P. E., Huizeinga, K. A., Hoffman, H. W., Brown, A. L. Sr.,and Markowitz, H. (1966). Dysgamma. globulinemia associatedwith nodular lymphoid hyperplasia of the small intestine.Amer. J. Med., 40, 78-89.

Huizenga, K. A., Wollaegers, E. E., Green, P. A., and McKenzie, B. F.(1961). Serum globulin deficiences in non-tropical sprue, withreport of two cases of acquired agammaglobulinemia. Amer.J. Med., 31, 572-580.

Kabler, J. D. (1960). Rare malabsorption syndromes. Ann. intern.Med., 52, 1221-1235.

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