Amyloidosis associated with primary agammaglobulinemia, severe diarrhea and familial hypogammaglobulinemia

Amyloidosis Associated with Primary Agammaglobulinemia, Severe Diarrhea and Familial Hypogammaglobulinemia* CLAUDE MAWAS, M .D ., CHRISTIAN SORS, M .D . and JEAN-JACQUES BERNIER, M .D . Paris, France A twenty-five year old man, who had had recurrent respiratory tract infections from the age of eight, was found to have primary agammaglobulinemia . Its congenital character was ascertained by the discovery in the proband's family of a twelve year old niece who since the age of five had had superinfected bronchiectases and was found to have a deficiency in serum immunoglobulins . Gastrointestinal disturbances in the proband were associated with widespread amyloid involvement of the digestive tract, liver and kidneys . Mild malabsorption was present, with giardiasis and moderate microbial overgrowth in the intestinal aspirate . The intestinal submucosa showed an absolute lack of IgA-containing plasma cells . The coexistence of primary agammaglobulinemia and amyloidosis has been reported in detail in five of more than 300 published cases of primary agammaglobulinemia . The cases in question, including our own, illustrate the development of amyloidosis in the absence of immunoglobulin synthesis, and raise pertinent questions regarding the pathogenesis of amyloid .

OON after the original description by Colonel Ogden Bruton [1] in 1952 of sex-related agammaglobulincmia in children, the first of many subsequent cases of primary hypogamtnaglobulinemia occurring in male and female subjects with onset of symptoms in adult life was described by Olhagen in 1953 [2], followed by Sanford in 1954 [3] . This has been termed "acquired hypogammaglobulinemia ." The clinical pictures of this disorder in adults, i .e ., infectious, pulmonary, hematologic, digestive, were described by Rosecan [4], Good [5] and Cattan [6-8] . The familial correlated diseases, mainly rheumatoid arthritis, have been noted by Fudenberg [9] ; and its congenital nature, despite the late onset of the disease, was first demonstrated by Wollheim [10] . An abnormal frequency of associated malignant lymphomas in such patients or their close relatives has been recorded by Good [11] and Miller [12] . The association of primary agammaglobulinemia with amyloidosis has been reported with full details in five cases [13-17] . This association

S

appears to occur rarely in primary agamntaglobulinemia of late onset, judged by the cases published to date (more than 200 up to now) . The data presented herein demonstrate a genetic predisposition to agammaglobulineinia in the family of the patient described, indicated by the discovery of hypogammaglobulineinia in a twelve year old niece who has suffered from superinfected bronchiectases since the age of five . The complex gastrointestinal disturbances of the patient will be discussed in the light of agammaglobulinemia and of amyloidosis .

CASE REPORT When seen for the first time in October 1966 the patient, a male, was twenty-five years old . The first clinical manifestations of agammaglobulinemia were noted at seven years of age : repeated bilateral otitis, pneumonia at eight years, resulting in persistent bronchitis ; a generalized epileptic seizure occurred at the age of twelve, well controlled since that time by anticonvulsant drugs . He was treated for two successive episodes of pneumococcal meningitis when he was fifteen . From 1957 to 1963 the patient was

* From the Service de Pneumophtisiologie, Division Rambuteau, Hopital de la Salpetriere, Paris XIII°, and the Service de Gastroenterologie, Hopital St . Lazare, Paris IX", France. Requests for reprints should be addressed to Christian Sors, M .D . at the Hopital de la Salpetriere . Manuscript received April 10, 1968 . 624

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1B

1A

Fic . 1 .

A and B, bronchograms showing extensive bilateral bronchiectases .

hospitalized repeatedly because of bronchiectases . The diagnosis of agammaglobulinemia was first made by Prof. Galy (Lyon) during a hospitalization for a left-sided pleural tubercular effusion (tubercle bacilli were cultured from the pleural effusion in 1963) . This observation was published at the time ([18], Case 4) . When admitted to the HSpital de la Salpetriere, Paris (October 1966) for the first time, an extensive study of the pulmonary disease was made with the view of surgical intervention, following failure of the conventional treatment of the bronchiectases . The patient, 51 kg . in weight and 1 .74 in height, exhibited symptoms of severe general infection : the rectal temperature was 39 .5 °c ., 150 or 250 cc . of mucopurulent sputum was evacuated over a period of twenty-four hours, and bacteriologic study of the sputum showed enterococci without tubercle bacilli . Cyanosis of the lips and nailbeds was noted with evident clubbing of the fingers ; the pulse rate was elevated to correspond to the fever, the respiratory rate was 22 cycles per minute . Rhonchi and medium-sized crepitant rales were heard in both lungs, the heart sounds were of good quality with accentuation of the pulmonic second sound . Bilateral maxillary sinusitis . pyorrhea and numerous decayed teeth were present . An enlarged liver, firm, nontender, without hepatojugular reflux, was palpated below the costal margin, measuring 22 cm . in the anterior axillary line ; no splenomegaly or adenomegaly was present ; the lower limbs were free of edema . 'Ihe red cell count was 4 .44 million per cu . mm . ; hemoglobin 14 gm . per cent ; hematocrit 42 per cent ; white blood cell count 8,400 per cu . mm . with 75 per cent neutrophils, 3 per cent small lymphocytes, 22 per cent large lymphocytes ; platelets were 250,000 per cu . mm . ; sedimentation rate was 12 mm . in one hour (WesterVOL . 46, APRIL 1969

gren) ; fasting blood sugar concentration was 100 mg . per 100 ml . : serum urea concentration 20 mg . per 100 ml . ; Total proteins 5 .6 gm, per 100 ml . ; albumin 67 per cent : alpha, globulin 3 per cent ; alpha 2 globulin 19 per cent ; beta globulin 11 per cent ; gamma globulin 0 per cent . Urinalysis gave normal results (October 1966) . From October 1966 to July 1967 he clinical picture was mainly dominated by the rapid enlargement of the liver and the onset of proteinuria with mild biologic stigmata of renal insufficiency (February 1967i . At this time the twenty-four hour proteinuria was 2 gm . ; clearance of endogenous creatinine 115 ml . per minute ; calciuria was very low (15 mg . per twenty-four hours) but this result must be considered in the light of osteomalacia, confirmed by an iliac crest bone biopsy (Prof. de Seze, Hopital Lariboisiere, Paris) . This proteinuria finally led us to the diagnosis of amyloidosis . Diarrhea had been present for some time and became worse . The patient was discharged from the hospital in July 1967 on a regimen consisting of 2 gm, ampicillin per twenty-four hours and one injection of standard gamma globulin every fortnight (1 ml . per kg . of a 16 .5 per cent solution) . It was possible to maintain this substitution therapy despite the allergic manifestations to gamma globulin injections encountered during hospitalization by the protective action of epsilon-aminocaproic hydrochloride (20 gm . per twenty-four hours of Capramol (W given orally for three days) . SPECIAL STUDIES

X-ray studies of the chest and bronchogratns showed bilateral bronchiectases (Fig . 1), predominant in the lower lobes and on the right



626

Primary Agammaglobulinemia with Amyloidosis-Mawas et al . TABLE I RADIOIODINATED TRIOLEIN ( 1311) A . Absorption Studies

Data

Plasma Patient Normal values*

2 hr .

4hi

5-8

5 .0

6 .5-10 .5

6 hr.

3 .9

9 hr .

3 .5

10 .0-16 .5 6 .5 13 .0 4 .5 8 .5

24 hr.

1 .4 1 .0-2 .0

B. Excretion Studies Data

Feces (%) Urine (%)

1st day 2nd day 3rd day

7 .0 38 .7

0 .6 6 .8

0 .3 1 .5

Total

Normal Valuest

7 .9 47 .0

<5 of given dose >50 7. ofgicen dose

* Per cent of given dose . t For three days.

side with a spread into the middle lobe and the lingula of the right lung . Respiratory insufficiency was severe, with both restriction of the vital capacity (V .C .) (about 35 per cent) and an obstructive component, as shown by the forced expiratory volume in one second (F .V .E .) barely above 1 L . and by the Tiffeneau ratio (F .V .E ./V.C . = 37 per cent) . Furthermore, overexpansion of the lungs was present with an absolute and relative increase in the residual volume (R .V .) . This ventilatory impairment was severe as shown by the blood gas abnormalities ; carbon dioxide (C0 2) content at rest (volumes per cent) 53 .6 ; P0 2 (mm . Hg) 49 ; PCO2 (mm. Hg) 50 ; hematocrit 45 per cent . The electrocardiogram was consistent with chronic cor pulmonale . Cardiac catheterization (H6pital Marie Lannelongue, Paris) gave a

FIG . 2 . Small intestinal mucosa (2.10 M .) . Subatrophic mucosa with few cells in the submucosa, no plasma cells . Hematoxylin and eosin stain .

systolic pulmonary artery pressure of 48 min . Hg (mean pressure of 35 mm . Hg) . Gastrointestinal studies were performed in the gastrointestinal department of Dr . J. J . Bernier (H6pital St . Lazare, Paris) . During an active period the patient had four to six stools a day ; on a five day average, the weight of the stools was 800 gin . per twenty-four hours . The rest of the time the average weight of the stools was 350 gm . per twenty-four hours, with two stools a day . According to Dr. Goiffon, the feces contained partly digested muscle fibres, a small excess of neutral fat, stercobilin, undigested cellulose, intracellular starch and degraded albumin (pus) . The iodophil flora was scant . Microscopic examination of the feces revealed the presence of Giardia lamblia . Coli bacilli and Proteus vulgaris grew out of the coproculture . Culture of the duodenal aspirate showed 23,200 colonies of colimorphs with 200 colonies of fungi (Candida albicans) . The excretion rate of electrolytes in the feces during excessive bowel activity were sodium 30 mEq . per twenty-four hours ; potassium 80 to 100 mEq . per twenty-four hours with hyperhydration of the stools . The average daily excretion of fat was about 3 .5 gin . (range 2 .18 to 5 .70 gin .) . After an oral dose of 25 gin . of xylose, 2 .78 gm . appeared in the urine in five hours (urine volume : 250 ml .) . The Schilling test and the absorption of tritiated radioactive vitamin D were normal . Absorption of radioiodinated triolein and oleic acid gave low plasma concentrations and excessive elimination of radioactivity in the feces (Table i) . Aspiration of pancreatic juice before and after injection of pancreozymin and secretin yielded normal results for tryptic and lipasic activity with normal bicarbonate excretion . Gastric juice analysis showed a normal secretion rate and a normal concentration of free hydrochloric acid . Biopsy specimens of the shall intestines, obtained with the Debray intestinal sampling cup, showed (Dr . C . Bognel) at 2 .1 M . from the nose a subatrophic inucosa with few cells (Fig . 2) ; (Congo red stain was positive in a small vessel of the submucosa .) Histochemical studies of the enzymatic activity of the small intestinal mucosa showed a deficit in ATPase activity (all other enzymes tested were present (Dr . .1 . C . Bognel) . IgA-containing plasma cells could not be found by immunofluorescent methods in the submucosa of the small intestine (Dr . L . Hartmann, Faculte de Medecine, Paris) . The albumin turnover measurements according to AMERICAN JOURNAL O F MEDICINE

Primary Agarnrnaglobulinemia with Ainvloidosis--atlawas ct al .

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specimen showing Fic . 3. Liver biopsy arnyloid involvement of the parenchyma . Congo red stain .

Fu ; . 4 . Rectal biopsy specimen . Anlyloid deposits appear flunrescent with thioflavinc • .

the methods of Veal and Vetter ( 131 1-labeled serum albumin) gave the following results : 4 .98 gin . per kg . ; catabolic rate 9 .64 gin . per twentyfour hours (0 .166 gm . per kg . per twenty-four hours) ; serum albumin half-life 9 .1 days . The stomach and colon appeared to be normal on roentgenographic examination . A roentgenogram of the small bowel showed segmentation and accelerated transit of the barium (carmine index six hours) . Liver scanning showed an enlarged but normally patterned liver . MacLagan and Kunkel zinc turbidity tests, serum glutamic oxalacetic and serum glutamic pyruvate transaminase levels, total and esterified cholesterol, total bilirubineinia and the prothroulbin time were in the normal range . Bromsulfonphthalein clearance was normal (with a slope of 15 .4 per cent) . A hepatic needle biopsy specimen (Menghini) showed amyloid involvement of one third of the parenchyma . (Fig . 3 .) The Congo red test was strongly positive . Specific histologic stains for amyloidosis (Congo red, ntetachromatic stains, thioflavine fluores-

sense , on rectal, jejunal, hepatic and renal biopsies (Dr . L . Morel-Maro,ger, Hopital T(1nors, Paris and Dr . Duhainel, Paris) v,ere all positive (Fig . 4, 5 and 6) . Immunologic Studies . Immurioglohulins Agantmaglobulineinia was demonstrated, as already noted by paper electrophoresis . Immunoelectrophoresis (Fig . 7) demonstrated the lack or great reduction of the three main inununoglobttlins . Immediately after an injection of gamma globulin, the level of serum IgM was nearly undetectable . Fifty-three days after the last injection, it rose to detectable levels (Fig . 7) . These results were confirmed by quantitative determination of the itnmunoglobulins (Mancini's antibody agar plate, Dr. F . Danon, Hopital St . Louis, Paris) (Table n) . Immunoelectrophoresis (Dr . Burtin, V'illejuif) of an intestinal juice solution, concentrated to approximately 5 tug . per ml . of proteins, revealed only two plasma proteins of alpha mobility, without any iulmunoglobulin . In the sputum, only three plasma proteins of mobility

FIG . 5 . Intestinal biopsy specimen . Amyloicl deposits are stained by Congo red (high magnification) .

FIG . 6 . Renal biopsy specimen . Crystal violet stains the amorphous suhstancr • in the glomerulus .

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7A

7E

7C

Immunoelectrophoresis patterns two (a), thirty (b) and fifty-three (c) days since last injection of gamma globulin . The quantitative determinations for 1gG, IgA and IgM are given in Table n . The IgM level rose with the disappearance of the injected gamma globulins . FIG . 7 .

alpha,, alpha 2 and beta, were present; inllnunoglobulins were absent . Immunoelectrophoresis of the tuberculous pleural effusion, performed in 1963, showed no immunoglobulins ; all other plasma proteins were present (Institut Pasteur, Lyon) . Immunoelectrophoretic analysis of the urinary proteins was not performed . Circulating antibody : The patient's blood group was AB, cc, Dee, Kell negative (no isohenlagglutinins were present) . Antistreptolysin 0 was 35 units, antistaphyloccocal 0 .02 unit per ml ., antipneumococcal titre negative (Institut Pasteur, Paris) . Antibodies induced by vaccination during childhood were tetanus 1/300 antitoxin unit per ml . ; diphtheria 1/100 antitoxin unit per ml . ; antipoliomyelitis type I 1/10, type ii and type III 1/10 (Institut Pasteur, Paris) . Before antityphoid-paratyphoid revaccination, specific antibodies against Salmonella (S .) typhi (0 and H), S . paratyphi A (0 and H), S . TABLE II QUANTITATIVE DETERMINATION OF THE THREE IMMUNOGLOBULINS (MANCINI AGAR ANTIBODY IMMUNOPLATE)

Time Since Last Injection of Gamma Globulin

IgG

IgA

1gM

Undetectable (<50 pg.) Undetectable 100 µg. 1 .2 ± 0 .5 0 .5-2 .7

2 days

960 µg .

30 days 53 days

500 µg . 300 µg .

Undetectable (<87 pg .) Undetectable Undetectable

11 .7 ± 2 .7 6 .5-17 .5

2 .2 ± 0 .8 0 .8-4 .5

Normal values (mg ./ml .) Range

p aratyphi B (O and H) and o . paratyphi C (0 and H) were absent . After a booster vaccination (T .A.B . vaccine from Institut Pasteur 0 .5 ml ., 1 ml . and 1 .5 ml . each fortnight) no rise in specific antibodies titres occurred (Dr . Christol, Hopital Claude Bernard, Paris) . Antiricketsial antibodies (Prowasecki, Mooseri, Conori, Burneti) were also absent . Paul and Bunnel test yielded negative results . Viral tests for adenovirus, ornithosis, psittacosis, measles, influenza A and B, sendai were all negative. Autoantibodies : Antired blood cells, antiwhite blood cells, antiplatelets, antiDNA and antigamlnaglobulins (human and rabbit) were absent (Dr. Dausset, Hopital St . Louis, Paris) . Antiliver, antithyroid, antigastric, antismall intestine and anticolon antibodies (immunofluorescent methods, Dr . Eyquem, Paris) were absent . All these studies demonstrated the lack or very low level of immunoantibodies and the absence of any rise of specific antibodies after a booster vaccination ; low levels of antidiphtheritic antibodies were in accordance with a positive Schick reaction on the seventh day (antigen of Institut Pasteur) . Hypersensitivity reaction : Contact with common antigens used in the allergic tests failed to reveal any immediate hypersensitivity type of reaction . The delayed hypersensitivity type of reaction was tested with intradermic tuberculin (positive), streptokinase (negative) and candidin (negative) . Host versus graft reaction was tested by a skin allograft provided by a female donor (blood group 0 rhesus plus) and was compared to a skin homograft : delayed rejection occurred on the twentieth day (Fig . 8) . Lymphoplasmocytic system : No lymph nodes could be palpated . Histologic study of the rectal biopsy specimen did not reveal any follicular organization, only a sheet of reticular and lymphoid cells without any plasma cells . No plasma cells could be demonstrated on histologic sections of the small intestine . No plasma cells were found in the bone marrow aspirate (among 1,000 cells) ; lymphopenia (300 small lymphocytes per ml .) was noted in the blood . Culture of the patient's lymphocytes in presence of phytohemagglutinin (P .H .A .) was impaired ; no mitosis or blastic transformation occurred (Medecin Commandant Gineste, Hopital Percy, Paris) . Familial studies : Paper electrophoresis, imInunoelectrophoresis and tests for antigammaglobulin factors were performed on the serum AMERICAN

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Primary Agaunnaglobuline niia with .Amvloidosis--

~Vf (7 zc a,s et al .

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8D

Fin . 8 . Full thickness skin grafts performed in our patient : left, autograft ; right, allograft . A, graft on day 8 after the transplantation . B, graft on day 10 . C, graft on day 15 . 1), graft on day 20 . Rejection i,, eompletr for the allograft ; the autograft shows a wrinkled epidermis .

of the close relatives of the patient (J .C .H .) ; the results are summarized in Figure 9 . The patient's father had rheumatoid arthritis and antigautmaglobulin factors were present, with hyper IgG globulinemia and hyper alpha 2 globulinemia . The patient's mother and three brothers were normal . The patient's sister had suffered from polyarthritis, considered to be due to rheumatic fever ; no antigarnmaglobulin factors could be detected ; hyperganrmaglobulinemia, with normal alpha2 globulin, was present . Her daughter, the patient's niece, suffered from the age of five from superinfected bronchiectases and her serum was found to be hypogammaglobulinemic : gamma globulin fraction 500 mg . per 100 n il . a t age 12 . A ten year old nephew of the patient was suspected of having bronchiectases but without bronchographic control ; his immunoglobulin level was normal for his age . COMMENTS

We shall discuss only three points in this case report : the association of primary agamrnaglobulinemia and amyloidosis, the results of the family inquiry, and the complex gastrointestinal disturbances shown by the patient . v0L .

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.1myloidosis and Primary Agammaglohuhnemia .

The published cases of the acquired type of aganunaglobulinemia associated with amyloidosis are few . Gras et al . L131 described the first such case in 1954 in a forty year old man . Three years before, this man had had pneumonia which recurred one year later . Seven paper electrophoretic analyses performed within one month showed very low levels of gamma globulin (range : 1 .45 gin . per L . to undetectable amounts) . The Congo red test was positive . Postmortem examination showed hepatic, splenic and renal ainyloidosis with fibrocaseous tuberculous involvement of the mesenteric lymph nodes . Teilum [14] in 1964 described a thirty-one year old man whose infectious disease began at age twenty-seven . This patient had seven attacks of pneumonia during the four months before his first hospitalization (1952) . No gamma globulins could be detected in the patient's serum by electrophoresis . An antidiphtheria and antityphoparatyphoid booster vaccination elicited no rise in specific antibodies . No plasma cells were found in the sternal hone marrow aspirate . Repeated gram-positive infections of



630

Primary Agammaglobulinemia with Amyloidosis--Mawas et al . 0

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AGE BB SILICOSIS RHEUMATOID ARTMROSIS

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40AMMAGLOB UL IN EMIA

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AGE 35 JOINT PAINS WAALER ROSE NEGATIVE

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AGE 12 BRONCHIECTASIS

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N!NORMAL LEVEL $

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9.

UNDETECTABLE LEVEL

Patient family tree .

his bronchiectases occurred from 1952 to 1956 ; at this time mild proteinuria was first noted . Death occurred in 1957 from renal insufficiency . Pathologic findings were renal and splenic amyloidosis, the liver and suprarenals being free of disease . Forssman and Herner [15] in their four case reports of acquired agammaglobulinemia and malabsorption (1964) described a fifty year old woman (Case 2) in whom pronounced albuminuria developed one year prior to her death in 1962 with the clinical picture of suspected amyloidosis . Frequent upper respiratory tract infections developed at age thirty-five ; bronchiectases were verified roentgenographically at age forty-five ; diarrhea developed fifteen months prior to death and three months before the onset of albuminuria. The gamma globulin fraction was markedly reduced (0.1 to 0 .2 mg . per 100 Inl .) . At autopsy, amyloid deposits were found in the liver, spleen and kidneys but not in the small bowel . Conclusive proof is lacking that

this case deserves the designation of acquired agammaglobulinemia . But the very pronounced decrease in the gamma globulin fraction, when the other globulin fractions were substantially normal, deviates from the electrophoretic patterns in malabsorption . Booth [16] in 1965 described a forty-two year old man with acquired hypogammaglobulinemia, pernicious anemia and amyloidosis . The infectious manifestations started at the age of twenty-one, bronchiectases were demonstrated at the age of twenty-five . At age thirty-four, gamma globulin levels were normal . Numerous bacterial infections occurred between his thirtyfourth and thirty-ninth year, when he was rehospitalized . The diagnosis was nephrotic syndrome secondary to amyloidosis, which had developed because of chronic superinfected bronchiectases . At this time gamma globulin levels were low (2 .15 gun . per L .) . Death occurred at the age of forty-two . Pathologic findings included widespread amyloid involveAMERICAN

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Primary Agamrnaglobulinernia with Ainvloidosis- :Ilate as ,neat of the liver, the spleen, both kidneys, ti u° intestinal tract aid the suprarenals . Despite the relatively high gamma globulin levels, histologic examinations could not demonstrate any plasma cells in the patient's bone marrow or lymph nodes, while in the appendix, removed at the age of sixteen, numerous plasma cells could be seen in the histological section . C .omr and Quintiliani [17] described a seventy-four year old Caucasian man admitted to the West Haven Veterans Administration Hospital in 1965 because of recurrent episodes of bronchitis and pneunronitis of five years' duration and frequent episodes of diarrhea for almost two years . The serum total protein ranged from 5 to 5 .8 gin . per '100 ml . and albumin 3 .2 to 3 .6 . Paper electrophoresis showed diminished gamma globulins which averaged approximately 0 .3 gin . per 100 ml . The concentrations of IgG, IgA and IgM determined immunologically were 145, 50 and 20 mg . per 100 nil . The Schick test was positive, typhoid and paratyphoid antibodies were absent before and after immunization, purified protein derivative skin test was positive . There was no proteinuria . In 1931 the patient had had an appendectomy . Review of the histologic material disclosed an abundance of plasma cells . At . postmortem examination the only significant abnormality in the gastrointestinal tract was the presence of amyloid, also found in the spleen, adrenal and thyroid nodules but not elsewhere . A few other published cases could be found in the literature, but without detailed data [11,20] . The five case reports mentioned and the case described herein record the development of amyloidosis in patients without hurnoral immunoglobulins . In recent studies Gueft [21], Cathcart [22] and Sorenson [23] cite evidence for the local production of amnyloid, as first suggested by Teilum in 1964 [24] . Amyloid, whatever its origin, has a fibrillar structure, as shown by electron microscopy . Immunologic studies indicate that at least one part of the amyloid structure is identical with a circulating plasma protein of alpha mobility (component P of Cathcart [25]) . The other proteins described after injection of rabbits with amyloidosis seem to be contaminants (IgG, IgA, fibrinogen) . Gueft [21], Cathcart [22] and Sorenson [23] have shown that amryloidosis usually starts extra-cellularly at the periphery of fibroblasts, not of plasma cells exclusively . Gueft has shown ai nyloidosis to occur at the periphery of histiov-~r . . 46, APRIL 1969

el al .

01

cytes . According to the biphasic theory of Teiliun [24], after an initial pyroninophilic phase 'pith proliferation of reticuloendothelial pyroninophilic cells and plasma cells with ati increase in serum gamuaa globulins) . the amyloid phase begins after suppression of the proliferating pyroninophilic cells (serum ganuna globulin levels decrease at that time), the fundamental defect lying in a dysfixnctioit of the protein .synthetizing capacity of the reticuloendothelial cells, while antigenic stimulation persists . Cohen [26] in a recent general review on amyloidosis advanced the hypothesis that the production of the amyloid fibril is related to the ubiquitous reticuloendothelial cell . The fibril is deposited in the ground substance and at least part of the amyloid fibril may be solubilized and identified as an alpha globulin . In the many diseases associated with amyloidosis (chronic infectious . dvsglobulinemias, prolonged steroid or nitrogen mustard therapy, familial Mediterranean fever2 the common characteristic could bc° iinpainnent of the protein-synthesizing capacity of the individual, of whatever cause . Ebbeseii and Raske Nielsen 127] have shown that in certain strains of mice sometimes paraproteinemia occurred, sometimes amyloidosis, suggesting a genetic predisposition in conditions leading to amyloidosis . One is struck by the rarity of amyloidosis in primary agammaglobulinetnia of the late onset type (108 cases reviewed by Comings in 1965 [28]) . According to the theory of Teilunr, one would, on the contrary, expect this association to occur frequently . This apparent contradiction supports the hypothesis of a distinct genetic predisposition leading to the development of both abnormalities . The prognosis is generally poor when amyloidosis develops in such patients, since death occurs in less than two years, mainly front renal insufficiency . Modern treatment, i .e ., antibiotic therapy and substitutive gamma globulin therapy, will prolong the survival of such agammaglobulinemic patients. Familial studies : Wolheim [101 1901 first described two patients with hypogammaglobulinenria in the same family, but distantly related . Benign polyclonal hyperglobulinemnias are frequently seen in families with agaimnaglobulinemia [29-31] and are considered by Larsen and Leonhardt [32] to be of genetic origin . Connective tissue diseases, notably rheumatoid arthritis, have frequently been found in patients with



632

Primary Agammaglobulinemia with Amyloidosis-Mawas et al .

agammaglobulinemia and in their relatives [9] . Antiglobulins are commonly detected in relatives, as noted in familial studies of macroglobulinemia [33] . In families with atypical agammaglobulinemia (or dysgammaglobulinemia) Burtin found isolated and asyrnptomatic absence of one or two iminunoglobulins [34] . Malignant lymphomas and pernicious anemia frequently occur in patients with agammaglobulinemia and among their relatives [11,12, 31,35] . A genetic background is strongly suggested by such a diversity of abnormalities in close relatives of patients with agammaglobulinemia [36] . In our case, hypogarnmaglobulinemia affecting the patient's twelve year old niece demonstrates the congenital character of our patient's agammaglobulinemia . It is common for patients with agammaglobulinemia to have clinical manifestations long before the discovery of hypogarnmaglobulinemia, and only regular survey of this child's serum will show if her immunoglobulin levels will fall steadily, reaching undetectable amounts . In this family the genetic abnormality is not sex-related . The rheumatoid arthritis of the patient's father with positive antigammaglobulin factor, the rheumatic manifestation of the patient's sister without antiglobulin factors but with benign polyclonal hypergammaglobulinemia are the same as previously described in other families with agammaglobulinemia [37,38] . Gastrointestinal disturbances in agammaglobulinemia and the possible role of amyloidosis : The onset

of diarrhea in patients with agammaglobulinemia is well known . Sanford et al . [3] in 1954 mentioned diarrhea in their case report and Gitlin [36] estimates diarrhea to be present in 20 per cent of the reported cases . The diarrhea usually develops after the onset of recurrent infection, mainly of the upper respiratory tract ; sometimes diarrhea and abnormal susceptibility to infections appear at the same time ; and in some instances diarrhea precedes the infections . Of its mechanism little was known until recently . An infectious pathogenesis is commonly suspected, and in several patients an infectious agent was indeed discovered, i .e ., chronic salmonellosis, shigellosis or staphylococcal enteritis [39] . Giardia lamblia is commonly found in such patients [40] and its significance in causing diarrhea deserves further investigation [41,42] . In most cases the diarrhea subsides following antibiotic therapy and/or substitutive gamma

globulin therapy [6] . When iualabsorption is present, marked alterations of the gastrointestinal mucosa are described [43] . These inucosal atrophies seem to be related to the lack of immunoglobulins, and to the chronic enteritis . An associated celiac disease is less probable, since few patients improve on a gluten-free diet [44] . In Cattan's observations [45] there was improvement of the pathologic changes in the inucosa after long-terra antibiotic therapy . Heremans [46,47] recently described a new syndrome which associates enteropathy, isolated absence of IgA globulin in the serum and disappearance of the IgA-containing plasma cells in the small intestinal submucosa . As IgA seems to be the main immunoglobulin of the intestinal secretions in normal man [48], Heremans suggested that this lack of IgA may play a role in the pathogenesis of such enteropathy, thus favoring infections . Our patient showed Giardia lamblia, moderate microbial overgrowth in the intestinal aspirate, moderate jejuno-ileal mucosa alterations and, in the gastrointestinal submucosa, an absolute lack of IgA-containing plasma cells . There was, as shown by radioactive tracers, a moderate exudative enteropathy . Diarrhea was of the hyperkinetic type which subsided under antibiotic therapy . The role of the absence of ATPase activity in the small bowel inucosa is of unknown significance for the intestinal disturbances . In the pathogenesis of our patient's diarrhea the role of amyloidosis must be discussed . Actually, diarrhea is a common feature of secondary amyloidosis when extensive, and, in a smaller proportion of cases, of primary arrryloidosis, since Rukavina estimates that it is present in 15 per cent of the 150 cases reported up to 1956 [49] . Schein [50], studying intestinal changes in sprue-like syndromes, found two patients with intestinal amyloidosis among forty with primary or secondary amyloidosis . Two theories have been advanced to explain the diarrhea : (1) Infiltration of the intestinal wall with amyloid [51-53], despite the lack of parallelism between the degree of intestinal involvement by amyloid deposits and the intensity of the diarrhea . Pancreatic function is rarely mentioned in the literature yet the involvement of pancreas by ainyloidosis is frequent [53] . (2) French [54] demonstrated in his patient that the uncontrollable diarrhea was caused by amyloid involvement of the subAMERICAN JOURNAL OF MEDICINE



Primary Againmaglobulinemia with Auivloidosis-- Mawas mucosal autonomic nerve plexeses and lumbar ganglia . A similar pathogenesis is encountered in the diarrhea of diabetic patients, as a result of diabetic neuropathy [55] . This observation could explain the changes in the clinical picture of our patient's diarrhea . Antibiotic therapy and treatment of the lamblia by Flagyl ® has much decreased the diarrhea, but it still persists to some- extent . Acknowledgment : We are much indebted to Dr . Francoise Danon who made many suggestions and gave us critical advice which permitted us to make this study .

13 .

14. 15 .

16.

17 .

ADDENDUM 18 .

Since we submitted this paper, one additional case [56] and a review on agammaglobulinemia and amyloidosis [57] have been published .

19 .

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