Intractable Malabsorption With a Flat Jejunal Mucosa and Selective IgA Deficiency

Vol. 67, No . 4

GASTROENTEROLOGY 67:709-716, 1974 Copyright© 1974 by The Williams & Wilkins Co.

Printed in U.S.A.

CASE REPORTS INTRACTABLE MALABSORPTION WITH A FLAT JEJUNAL MUCOSA AND SELECTIVE IgA DEFICIENCY Acase report with immunological and autoradiographic studies KARL E. ANDERSON, M.D ., NIALL D. ELEANOR E . DESCHNER, PH.D.

c.

FINLAYSON, M.D ., CH.B., M.R.C .P., AND

The Gastrointestinal Division, Department of Medicine, and the Department of Radiology, Cornell University Medical College , New York, New York

A 13-year-old male with selective IgA deficiency, a flat jejunal mucosa, and severe, fatal malabsorption is reported. Unlike previously well described cases, there was no reponse to a gluten-free diet, and multiple forms of therapy were not helpful. The mucosal lesion was the only basis demonstrated for malabsorption, and contributing factors, such as giardiasis and bacterial overgrowth, were not pre~:;ent. Infusions offresh-frozen plasma raised the serum IgA from undetectable levels to 14.5 to 16.0 mg per 100 ml, but there was no obvious beneficial effect from this. Investigations of the jejunal mucosa demonstrated proliferation of plasma cells and an increased proliferation of epithelial cells as in gluten-sensitive enteropathy. This case illustrates that in the occasional patient who initially appears to have gluten enteropathy, but does not respond to treatment, correction of coexisting selective IgA deficiency by plasma infusions may not be helpful. Intestinal secretory IgA, which is made locally by plasma cells in the lamina propria, 1 may afford protection against infectious agents and foreign antigenic material presented to the body via the gut. 2 Selective IgA deficiency is the most common immunoglobulin deficiency syn-

drome, with an incidence in the general population of about 1 in 700. 3 Such individuals may be asymptomatic. 4 • 5 In patients with gluten-sensitive enteropathy, the incidence of selective IgA deficiency

Dr. Deschner's present address is: The Memorial Sloan-Kettering Cancer Center, New York, New Received February 9, 1973. Accepted April 26, York 10021. 1974. The authors would like to thank Dr. Alan Mufson Address requests for reprints to: Dr. Karl E. of Denville, New Jersey, for referring this patient, and Anderson, Department of Medicine, F231, The New Dr. Norman B. Javitt, Director of the Gastrointestinal York Hospital-Cornell Medical Center, 525 East 68th Division, and Dr. Frank J. Troncale, for their encourStreet, New York, New York 10021. agement and help during the patient's investigation. The work was supported by United States Public The authors are grateful to Dr. Henry Kunkel (The Health Service Training Grant T01-AM-5430 from Rockefeller University) for looking for serum antithe National institute of Arthritis and Metabolic bodies to lgA, milk proteins, and beef proteins, and to Diseases (Drs. Anderson and Finlayson) and United Dr. George Falk (Cornell University Medical College) States Public Health Service Grant CA-08921 from for looking for lgA in the saliva and intestinal juice, the National Cancer Institute (Dr. Deschner). and to Ms. Florence Long for technical assistance . Dr. Finlayson's present address is: The Royal They acknowledge the work of the many nurses and Infirmary, Edinburgh EH8 9AG Scotland, United physicians in the New York Hospital who helped in the investigations . Kingdom. 709

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appears to be higher than in the general population, 6 • 7 suggesting that loss of the protective role of IgA may sometimes be important in producing a flat jejunal mocosal lesion. We have recently studied a patient with selective IgA deficiency and progressive, severe malabsorption associated with loss of jejunal villi, who did not respond to a gluten-free diet, fresh-frozen plasma infusions, or other therapy. This is in contrast to all other adequately described cases of selective IgA deficiency associated with a flat jejunal mucosa which did respond to gluten withdrawal. 7 - 18 The clinical course, immunological studies, and investigation of DNA synthesis in the diseased small bowel mucosa of this unusual patient form the basis of this report. Case Report The patient was a white male whose growth and development were normal until age 13 when he developed generalized weakness, followed within 2 months by cramping abdominal pain and bulky, foul-smelling diarrhea . Investigations at another hospital, including a small bowel biopsy, indicated a diagnosis of nontropical sprue. Treatment with a gluten-free diet seemed to result in a temporary improvement, but subsequent deterioration led to additional treatment with corticosteroids. This did not benefit him, and he was referred to the New York Hospital. Apart from an allergy to penicillin, the patient had no unusual past medical history, and there was no evidence of increased susceptibility to infection. Both parents reported multiple food allergies, and the mother had had diarrheal episodes in childhood. Milk had produced diarrhea and eczema during infancy in one of the patient's three siblings. The patient was cachetic. Hypotension (blood pressure, 95/60) and tachycardia (120 per min) suggested hypovolemia. There was mild ankle edema. Examination was otherwise normal, and, in particular, no abnormality of lymph nodes, tonsils, or spleen was noted. Laboratory investigation showed a mild normochromic anemia (hematocrit 38%) and a leukocytosis (13,000 cells per em 3 ) with a normal differential count. Low values were found for serum potassium (2.9 mEq per liter), calcium (6.4 mg per 100 ml), magnesium (0.04 mEq per liter), carotene (0.02 mg per 100 ml), and albumin (2.7 g per 100 ml). Other routine

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investigations, including chest X-ray, skeletal survey, liver function tests, and morning and evening plasma cortisol levels, were normal. Malabsorption was demonstrated by the presence of steatorrhea (fecal fat 7 to 13 g per day; diet fat 25 to 35 g per day), and poor d-xylose absorption (5-hr urinary excretion 1.4 g; oral dose 25 g). Radiological examination of the small bowel using nonflocculable barium showed a malabsorption pattern with dilated loops of small bowel and no evidence of nodular lymphoid hyperplasia. Barium studies of the esophagus, stomach, duodenum, and colon were normal. A proximal jejunal biopsy showed total loss of villous structure (fig. 1) with a moderate infiltrate of chronic inflammatory cells and plasma cells (fig. 2) and a few polymorphonuckar leukocytes in the lamina propria. No bacteria were found on Gram stains or aerobic and anaerobic culture of jejunal fluid, and neither this fluid nor s~ool contained Giardia Iamblia. At the time of admission, the patient was already receiving a gluten-free diet and prednisolone; these were continued and isoniazid was added. The patient was in the New York Hospital for 5 1/z months, the last 2 months of which was spent on a metabolic ward. For most of the first 2 months, 20 to 40 mg per day of prednisolone were given; thereafter, the dose was cut gradually to 5 mg per day. After routine malabsorption investigations had been carried out, full sequential courses of tetracycline, neomycin, and sulfisoxazole were administered, as well as metronidazole, in case a giardia infection had been missed. Lactose was elimi· nated from the diet, and supplemental oral medium chain triglycerides, amino acids, and pancreatic enzymes (Cotazyme, Organon, West Orange, N. J.) were also given. None of the above treatments prevented a steady deterioration of the patient. After IgA deficiency was demonstrated (see below) , intravenous hyperalimentation (3300 cal per day), with infusions of fresh-frozen plasma ( > 10 cc per kg of body weight), was carried out. The plasma infusions resulted in an increase in serum IgA levels to 14.5 to 16.0 mg per 100 ml over a 30-day treatment period. Thereafter, the serum IgA level fell gradually, reaching about half its maximum value in 32 days. Transient improve· ment during intravenous feeding, including a 10-kg weight gain, occurred. The effect was short lived, however, and hyperalimentation, which was given twice for periods lasting 22 and 20 days, could not be prolonged because of fevers and an episode of Candida septicemia. Deterioration resumed, and eventually the pa-

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FIG. 1. Proximal jejunal biopsy showing a flat mucosa with loss of villi ( x 100).

Immunological Investigations lgG, lgA, and lgM levels in serum, saliva, and jejunal fluid were measured by single radial immunodiffusion 19 using specific antihuman antisera and special low level immunoplates when lgA levels below 60 mg per 100 ml were found (Kallestad Laboratories , Inc ., Minneapolis, Minn.). The serum results are shown in table 1. No IgA was detectable in the saliva or jejunal fluid (Dr. George Falk, Cornell University Medical College) . Antibodies to milk and beef proteins were demonstrated in high titers in all of several serum samples examined, but antibodies to lgA were not found (Dr . Henry Kunkel, The Rockefeller University) . No anti' ,A_ft;j..41it. ::: .;. ..:/_'~! nuclear, antismooth muscle, antimitochondrial, FIG. 2. An area of the jejunal lamina propria antithyroid, or antireticulin autoantibodies containing a mixture of plasma cells and other mono- were found by the indirect immunofluorescent nuclear cells ( x 470). method 20 ; rat stomach, kidney, liver, aorta, heart, adrenal, thyroid, and placenta were used tient died of an air embolus after insertion for as antigens , and fluorescein-labeled antihuman the third time of a subclavian venous catheter. globulins (Nutritional Biochemicals Corp ., At autopsy, the presence of air in the right Cleveland, 0.) were standardized by the ventricle was confirmed . Lymph nodes, tonsils, method of Hoi borow and Johnson. 21 Serum appendix , and spleen showed few germinal total hemolytic complement, measured by the centers. The esophagus , stomach, duodenum , method of Kent and Fife, 22 was normal. Skin colon, liver, biliary tree, and pancreas were tests with tuberculin (Parke, Davis and Co., normal. The whole small bowel was thin, pale , Detroit, Mich.; purified protein derivative 250 and dilated with macroscopically prominent U.S.P . units), mumps (Eli Lilly and Co ., IndiPeyer's patches. Microscopic evaluation was anapolis, Ind.; 0.1 ml), Candida (Hollister-Stier difficult because of autolysis, but multiple sec- Laboratories, Cincinnati, 0.; Dermatophytin tions of the jejunum and ileum revealed no "0" 0.1 ml of 1: 10 dilution), and streptokinaseevidence of villous structures. Giemsa stains of streptodornase (Lederle Laboratories, Pearl the small intestine did not show coccidiosis. River, N. Y.; 50 streptokinase units) antigens

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CASE REPORTS

712 TABLE

1. Serum immunoglobulin levels" in the

patient and his family Subject

IgG

IgA

IgM

mg/IOOml

Patient• . . Father . .. .. . . . . .. ... Mother . . Sister (age 16) Sister (age 12) Brother (age 7) . .

1275 1650 820 925 1450 1275

0 420 110 117 117 135

92 145 175 145 175 175

a Normal range: IgG, 570 to 1900; IgA, 60 to 330; IgM , 45 to 145. • Prior to therapy with fresh-frozen plasma.

gave no reaction at 6, 12, 24, and 48 hr; the patient was receiving prednisolone, 12.5 mg daily, at the time. Serum lgG, IgA , and lgM levels in both parents and all three siblings were normal (table 1).

Autoradiographic Studies Jejunal biopsy tissue from the patient and from a normal control were cut into fragments containing approximately 10 glands , and incubated for 3 and 19 hr with tritiated thymidine, as previously described . 23 After 3-hr incubation , the normal epithelium was observed to incorporate thymidine into cells only in the mitotic zone, which is the lower two-thirds of the crypt. With a longer period of incubation (fig. 3), labeled cells migrated to the mouth of the crypt and onto the villi. In jejunal mucosa from the patient, however, active DNA synthesis and mitosis occurred along the entire length of the crypt and on the surface epithelium at 3 hr (figs. 4 and 5). In addition , the lamina propria contained many more labeled cells in the patient (fig. 5) than in the normal control. Lightly labeled cells were identified as plasma cells, but heavily labeled cells could not be definitely identified because nuclear morphology was obscured.

Discussion It is well recognized that while a flat

jejunal mucosa can result from a number of causes, 24 most patients with steatorrhea and a flat lesion recover when fed a glutenfree diet, and may, therefore, be regarded as suffering from a gluten-sensitive enteropathy. Previous case reports have indicated 7 - 1 8 that when malabsorption is associated with selective lgA deficiency, a

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flat mucosa is usually found, nodular lymphoid hyperplasia and Giardia are absent, as was true in our patient, but that in contrast to our case, a favorable response to gluten exclusion can be expected. Deficiency of more than one major immunoglobin is also sometimes associated with malabsorption and partial or total loss of jejunal villi . Reported cases commonly have not responded to gluten exclusion. 1 1. 2 5 27 They characteristically differed from our patient, and from those patients in the literature with malabsorption associated with selective lgA deficiency, 7 " 18 because they had reduced or absent plasma cells in the lamina propria, very often had nodular lymphoid hyperplasia and overgrowth of the small bowel by Giardia or bacteria, and they often improved after eradication of these organisms. Only a few case reports of selective lgA deficiency associated with giardiasis and nodular lymphoid hyperplasia, 2 8 bacterial overgrowth, 29 or tropical sprue 30 have appeared. This report extends present knowledge by showing that a patient with selective lgA deficiency and a flat mucosa may not always respond to a gluten-free diet and other therapy, including corticosteroids and fresh plasma. Other exceptional cases of malabsorption, also without other known causes of a flat mucosa, and with what was said to be strict adherence to dietary gluten exclusion , have been claimed to progressively deteriorate due to complicating small intestinal ulcerations, 31 pancreatic insufficiency, 3 2 Paneth cell deficiency, 33 cutaneous vasculitis, 6 • 3 4 • 35 or subepithelial collagen deposition . 6 • 35 • 36' 38 None of these complications were present in our patient. A few similar fatal cases, also without the complications mentioned above, have been reported. 32 • 3 6 • 3 9 • 40 Immunoglobin levels were determined in few of these patients, 40 and the presence of selective lgA deficiency was not previously noted . Fresh-frozen plasma was given to our patient in view of reports that diarrheal illness associated with combined lgG, lgA, and lgM deficiency 41 and selective lgA deficiency with nodular lymphoid

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FIG. 3. Jejunum biopsy from a normal control, after in vitro incubation for 19 hr with tritiated thymidine (x 80). Labeled cells appear at the surface of the crypts (arrows), and on the lower portion of the villus .

hyperplasia 28 may be relieved and kept in remission by infusions of fresh-frozen plasma. No clear benefit occurred in our patient even though serum IgA levels, initially undetectable, rose to 14.5 to 16.0 mg per 100 ml, which is comparable to that achieved by others. 5 • 42 In this regard , the previous patients with diarrhea, who were treated with fresh plasma, 28 • 41 differed from ours by having well preserved jejunal villi and little, if any, steatorrhea. One was also treated with tetracycline. 28 Furthermore, intravenously infused IgA probably does not reach internal secretion, such as bowel fluid , in significant small amounts. 5 • 43 South et al. 44 did report finding some IgA in saliva after plasma infusion, but only after achieving a much higher serum IgA level. Fresh plasma can transmit hepatitis. A severe transfusion reaction may occur when an IgA-deficient individual is given plasma , especially if his serum contains anti-IgA antibodies. 4 5 For these reasons, the value of plasma infusions in patients with IgA deficiency is doubtful. Possibly, the evaluation of oral treatment with colostrum , or with other

material containing secretory lgA, may be warranted in the future. Antibodies to milk and beef proteins, but not to reticulin or basement membranes, were found in our patient's serum. Antibodies to milk and beef proteins, or to reticulin, can be found in asymptomatic individuals with selective IgA deficiency, and in gluten enteropathy or other intestinal diseases whether or not immunoglobin abnormalities are present. 2 • 1 5 • 46 They have not been shown to be of pathogenetic or prognostic importance. Using an in vitro autoradiographic technique, Trier and Browning 47 showed that the rate of epithelial cell proliferation and migration is increased in the jejunum of untreated patients, with gluten-sensitive enteropathy. By a similar method, study of jejunal mucosa after incubation with tritiated thymidine indicated that proliferation of the small intestinal epithelium in our patient was very rapid with active mitosis and DNA synthesis, not only in the crypts, but also on the surface mucosa. Barry et al., 38 • 48 who utilized a nonisotopic method which measures the rate of DNA loss into

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t.... FIG. 4. Patient's jejunal mucosa after 3 hr of in vitro incubation with tritiated thymidine ( x 450). Labeled cells are seen along the entire wall of the crypt.

FIG. 5. Patient's jejunal mucosa also after in vitro incubation with tritiated thymidine for 3 hr ( x 450) . The numbered arrows indicate: (1) labeled epithelial cells at or near the surface; (2) an epithelial cell near the surface undergoing mitosis (metaphase) ; and (3) labeled mononuclear cells in the lamina propria .

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the small bowel lumen, claimed recently that some patients with flat lesions and poor response to therapy may have reduced epithelial cell turnover. But other than mitotic indices, which were not significantly different in those who did or did not respond, 48 direct observations of epithelial turnover in diseased mucosa were not made. Of interest also in our patient was the finding of many DNA-synthesizing mononuclear cells in the lamina propria. They may represent immunocytes multiplying in response to an immunological challenge, and whether they are found in other patients with flat mucosal lesions and contribute to mucosal damage deserves further study. REFERENCES I. Tomasi TB, Bienenstock J : Secretory immuno-

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