- Email: [email protected]
Protein-losing enteropathy associated with gastrointestinal allergy
Protein-Losing
Enteropathy
Gastrointestinal NORTON
J.
Associated Allergy*
M.D., JAMES I. TENNENBAUM,
GREENBERGER,
RICHARD
D. RUPPERT,
Columbus,
with
M.D. and
M.D.
Ohio
A case of hypoproteinemia and protein-losing enteropathy occurring in association with gastrointestinal allergy is described. The excessive enteric loss of protein, documented by a C&albumin test, was corrected by corticosteroid therapy with a return of serum proteins to normal levels. A specific food intolerance was correlated with the symptoms of gastrointestinal involvement and changes in the intestinal mucosa. The patient was challenged with various foods in a manner in which he could not identify the food being administered. A bland food produced no symptoms. However, after challenge with a food to which he was intolerant, tachycardia, nausea, emesis, abdominal cramps, diarrhea, leukocytosis and increased eosinophilia developed. Biopsy specimens from the small intestine obtained after challenge demonstrated an increased infiltration of eosinophils but no significant change in jejunal histamine or serotonin concentrations. Since an exhaustive workup failed to reveal any other cause for the patient’s protein-losing enteropathy, it is proposed that the excessive enteric loss of protein was due to injury to the gastrointestinal mucosa by specific food allergens.
I
N 1949 Ingelfinger et al. [7] stated that “Gastrointestinal allergy is a diagnosis frequently entertained, occasionally evaluated, and rarely established. It offers, to its enthusiastic supporters, a reasonable explanation for many obscure abdominal complaints. To the skeptical, it frequently appears as a specious and unwarranted diagnosis. These conflicting views cannot be resolved on the basis of existing knowledge.” Today, seventeen years later, these statements are still valid. As Ingelfinger has emphasized, there are several reasons why the spontaneous occurrence of gastrointestinal allergy in man is still regarded as an inconclusive entity. First, symptoms claimed to be specific or characteristic of gastrointestinal allergy are in fact nonspecific and highly variable. Second, the methods currently available for establishing the diagnosis of gastrointestinal allergy are not sufficiently accurate. In particular, it should be emphasized that specific skin tests are indirect tests. Third, the occurrence of abdominal complaints in patients with other allergic manifestations such as rhinitis, asthma, hives and eczema has led to the
tendency to diagnose such complaints as a gastrointestinal allergy whereas in actuality there is little objective evidence on which to base such a diagnosis. Fourth, with but few exceptions [2,3] no lesions in the gut or abnormalities in intestinal absorptive function have been demonstrated in patients with a diagnosis of gastrointestinal allergy. In the present report an adult patient with hypoproteinemia and a protein-losing enteropathy occurring in association with gastrointestinal allergy is described. The excessive enteric loss of protein was documented by chromium6i (C+)-albumin test and was corrected by corticosteroid therapy with a return of serum proteins to normal levels. METHODS
The concentration of serum total proteins was determined by the biuret method of Gornall et al. [4] and the serum proteins were separated by paper electrophoresis. The serum immunoglobulins were determined by a modification of the method of Fahey and McKelvey [5]. Iron intolerance tests were performed by a modification of the method of Milner
* From the Department of Medicine, Division of Gastroenterology, Ohio State University College of Medicine, Columbus, Ohio. This study was supported in part by Grant FR-34 from the U. S. Public Health Service General Clinical Research Center. Manuscript received September 20, 1966. VOL.
43,
NOVEMBER
1967
777
778
Gastrointestinal
Allergy-GrePnhPr;~P~. ft TABLE
SIJMMARY
al.
I
OF LABORATORY
DATA
Stool Fat
IIrmatocrit (%J)
Hemoglobin (gm./lOO ml.)
1Vhite Blood count (X 103)
Per Cent Eosinophils
Cocficient of Fat Absorption gm.124
1962*
39
11.1
9,800
39
. .
1964f 1964$ 1965 $ 19669
44 39 39 40
14.3 12.2 11.1 11.3
8,000 11,500 10,600 10,300
18 32 30 47
9.9 6.8 . . .
* Cincinnati General Hospital, Cincinnati, Ohio. t Middletown Hospital, Middietown, Ohio.
al. [6]. After a fasting blood specimen was obtained the patient was given 2 tablets of Cytoferrin@ (containing 400 mg. of ferrous sulfate) and blood specimens were procured for serum iron and iron-binding capacity levels at hourly intervals for four hours. The number of eosinophils in the epithelial cells and lamina propria in intestinal biopsy specimens was determined by a pathologist who was unaware of the conditions under which they were obtained. The number of eosinophils per 10 high power fields was recorded after which the code was broken. Demonstration of Gastrointestinal Protein Loss. Cr”r-albumin* was used to demonstrate gastrointestinal protein loss according to the method of Waldmann [7]. The patient received approximately 30 PC. of the labeled macromolecule intravenously. The urine and stools passed during the subsequent four days were collected separately. The stools were placed in a Waring blender, brought to constant volume, and homogenized. Triplicate aliquots of the homogenized stool and of each urine sample were counted with an appropriate standard in a well-type scintillation counter. The results are expressed as a percentage of the dose of administered isotope excreted in the four day stool collection and the four day urine collection. Determination of Histamine and Serotonin in Blood and Intestinal Biopsy Specimens. The histamine concentration in blood and jejunal mucosal homogenates was determined by the method of Shore et al. [a]. The serotonin concentration in intestinal mucosa was determined by the method of Weissbach et al. [9]. Blood eosinophils were determined by direct counting using Randolph’s stain [ 701. et
CASE
REPORT
A twenty-two year old white male student (M.G., OSUH No. 848881), was admitted to the Clinical Research Unit of The Ohio State University Hospital in December 1965 for evaluation of abdominal pain and eosinophilia of many years’ duration. He had been hospitalized elsewhere on three occasions; the * Generously provided by Dr. B. Bruno, Department of Radiopharmaceutical Research, E. R. Squibb RLSons Co.
hr.
Serum
Iron
Serum Iron-Binding Capacity (fig./100 ml.)
(%’
Schilling
Test
(%/24
hr.)
.
.
14 . 91.5
35 43
. . 366 548
f Duke University Hospital, Durham, North $ Ohio State University Hospital, Columbus,
14
Carolina. Ohio.
pertinent data from these hospitalizations are summarized in Table I. Since the age of thirteen the patient had experienced recurrent episodes of abdominal pain. The pain was crampy in nature, epigastric and periumbilical in location, occurred thirty to sixty minutes after meals and frequently was associated with diarrhea. The episodes of pain occurred at least once or twice a week. The patient usually had 1 to 2 stools per day but with attacks of pain he had from 12 to 15 watery stools per day. Several stool examinations failed to reveal ova and parasites but because of persistent abdominal symptoms and eosinophilia he had received two courses of therapy with Delvex@ without effect. The patient had also been treated with iron tablets for an iron deficiency anemia while in his teens. There was no history of febrile episodes, melena, symptoms of joint involvement or perirectal disease. In 1962 the patient was found to have mild atopic dermatitis. In 1964 he was hospitalized with acute bronchitis. There was no history of asthma, seasonal rhinitis, hives or urticaria. However, he had noted intermittent pedal edema. The patient stated that he was intolerant of many foods, including meat products (beef, pork, veal, lamb), oats, wheat products (pastries, cake) and eggs. Ingestion of red meats in particular would consistently precipitate episodes of abdominal pain and accordingly he had not eaten any meat products for five years. He was not intolerant of alcohol and milk products. A trial on a gluten-free diet in 1964 did not appreciably alter his symptoms. Physical examination on admission revealed a thin, well developed, young man in no distress. The temperature was 99O~., the pulse 80 beats per minute, respirations 16 and blood pressure 140/60 mm. Hg. Eczematous and lichenified lesions were present on both antecubital fossae, the left wrist and both ankles. There was no lymphadenopathy. The heart and lungs were normal. No abdominal organs or masses were palpable. There was mild pedal and pretibial edema. Sigmoidoscopic examination was entirely within normal limits. Initial laboratory studies (Table I) revealed a AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
,~llergy--Greerlbel.,~r~r
hematocrit reading of 39 per cent, a hemoglobin of 11.1 gm. per 100 ml., a white blood cell count of 10,600 per cu. mm. with 30 per cent cosinophils and an erythrocyte sedimentation rate of 2 mm. per hour. The urinalysis was normal. Urinary excretion of n-xylose after a 25 gm. oral dose was 11.2 gm. Quantitative stool fat excretion was 6.8 gm. in twenty-four hours with a coefficient of fat absorption of 91.5 per cent (three day collection). The serum albumin was 3.2 gm. per 100 ml. and the serum globulin 1.7 gm. per 100 ml. The immunoglobulins were as follows: 1gG 410 mg. per 100 ml., IgA 105 mg. per 100 ml. and 1 gM 25 mg. per 100 ml. The serum cholesterol was 160 mg. per 100 ml. and the serum calcium 9.2 mg. per 100 ml. The serum iron was 35 pg. per 100 ml. and the iron-binding capacity 366 pg. per 100 ml. A small bowel biopsy revealed minimal eosinophilic infiltration but otherwise was interpreted as normal (Fig. 1). X-ray examinations of the upper gastrointestinal tract, small bowel and colon did not reveal any abnormalities. An augmented histamine gastric analysis was within normal limits with a maximal acid output of 7 mEq. in one hour. The twenty-four hour urinary excretion of 5HIAA was 5.0 mg. A lactose tolerance test was normal. An oral iron tolerance test was also normal, the serum iron level increasing from a fasting value of 50 to 360 pg. per 100 ml. in three hours. The patient ingested 25 gm. of a gluten solution without any untoward effects. Cutaneous scratch tests with eighty-four common food extracts revealed the following positive responses: eggs, oats, wheat, pork, corn and rice. However, cutaneous intradermal tests with the common inhalent allergens and yeasts were negative. A Crsl-albumin test performed while the patient was in relapse resulted in a fecal excretion of 6.6 per cent and a urinary excretion of 20 per cent of the given dose (Table II). The patient was given a ten day course of treatment with prednisone (30 mg. per day). This was followed by marked symptomatic improvement and a significant increase in serum albumin and globulin levels. In a six week period the patient had no gastrointestinal symptoms and gained 28 pounds in weight. A repeat Crsl-albumin
STUDIES
OF SERUM
PRO’I‘EINS
AND
779
et al.
FIG. 1. Jejunal biopsy specimen revealing normal villous structure. tlematoxylin and eosin stain, original magnification X 130. test performed while the patient was in remission revealed a normal fecal excretion of Crsl-albumin (Table II). Several serum albumin determinations were normal, further indicating that the patient no longer had increased enteric loss of protein. SPEIXAL
STUDIES
Special studies were carried out to confirm that the patient did have specific food intolerances and to determine whether administration of certain foods might induce a lesion in the small intestinal mucosa. A Rubin hydraulic biopsy tube was positioned in the proximal jejunum under fluoroscopic control. A No. 16 cardiac catheter was then positioned in the fundus of the stomach. Control mucosal biopsy specimens and blood samples were obtained after which the patient received 10 cc. of a bland food (extract of peas). This was injected via the stomach tube (in this and all subsequent injections the patient did not observe the actual injection and thus he did not know what foods he was receiving). During the next sixty ruinutes the patient had no complaints and one hour
GASTROINTESI‘INAL
PROTEIN
LOSS
CW-Albumin ‘Test (7* of Dose)
~. Date
October 1964 December 1965 February 1966 (after corticosteroid May 1966
NOTE: VOL.
Values
43,
Scrurll
(gm./lOO
ml.)
.4lburnin
Globulin
(3.5-5.5) 3.4 3.2 4.8
(1.5-3.0) 1.6 1.7 2.0
Immunoglobulins IgG (800-l
,400)
410 570
therapy)
in parentheses NOVEMBER
4.1
represent
normal
1967
2.1
values.
. .
(mg./lOO Ig.4
(100-300)
ml.) IgM (30-150)
105 128
25 28
.
...
4 Day Fecal Excretion
(0.1-0.7) 6.6 0.3
4 Day Urinary Excretion
(20-40) 20.5 24.6
780
Allergy-Greenberger
Gastrointestinal
TABLE CHANGES
IN
JEJUNAL
HISTAMINE
AND
SEROTONIN AFTER
Time
ll:oo 11:05 12:oo 12:05 1 :oo 1: 30 2:oo 4 30
:
NOTE:
Food
A.M. A.Y. noon P.M. P.H. P.M. P.M. P.M.
Given
NOIX Peas (10 cc.)
......
Oats (10 cc.) Meat (20 cc.) Meat (30 cc.) ......
......
Symptoms Induced
.. NO NO NO YCS
III
CONCENTRATIONS, CHALLENGE
et al.
WITH
BLOOD VARIOUS
HISTAMINE
LEVELS
AND
BLOOD
EOSINOPHILS
FOODS
(%)
White Blood Count (no./ml. x 108)
Blood Eosinophil COWIt (no./ml.)
(38-52)
(5-10)
(<300)
7,600
1,381
19
0.8
9,400
1,406
31
0.4
0.6 ......
0.104
8,200 13,100
2,214 2,358
............
40
0.6
0.6
0.088
Hematocrit
38 ..I 36 ............... ..................... ..................... 39 40.5
Jejunal Eosinophils (no./10 h.p.f.)
. .
Jejunal Scrotonin
Jejunal Histamine
Blood Histamine
&./pm.)
(cg./gm.)
(w/ml.)
(0.2-0.8)
(0.4-0.8)
.
0.6
(O.Ol0.09) 0.096
.
Figures in parentheses represent normal values
after injection of the extract of peas repeat jejunal biopsy specimens and blood samples were obtained. The patient then received an intragastric injection of 10 cc. of a food (oats) to which he was intolerant. During the next sixty minutes the patient had no complaints. At the start of the third one hour period the patient received an intagastric injection of 20 cc. of a puree of rare steak. After thirty minutes an additional injection of 30 cc. of steak puree was given. After forty minutes the patient noted the onset of nausea and after fifty minutes he was experiencing cramping abdominal pain. One hour after the first intragastric injection of meat extract repeat jejunal biopsy specimens and blood samples were obtained. The experiment was terminated shortly thereafter because of the development of severe nausea, emesis and abdominal pain. Shortly thereafter, the patient had two watery bowel movements. The results of this special study are summarized in Table III. The next day the patient was anorectic and still experiencing nausea, cramps and diarrhea which had not responded to Demerol,@ ChlorTrimeton@ and Pro-Banthine.@ Accordingly, he was given a seven day course of prednisone with complete cessation of symptoms. He has remained asymptomatic on a diet free of meat and wheat products. Special skin tests and passive transfer studies were carried out four months after the food challenge studies. Wheal and erythema skin reactivity to various pure bovine and porcine antigens was determined by the intracutaneous method. The tests were performed with 0.02 ml. of serial dilutions of bovine serum albumin,
bovine gamma globulin, porcine serum, porcine serum albumin and porcine gamma globulin (Mann Laboratories, New York, New York). An intracutaneous test was considered positive if there was at least 20 mm. erythema. The patient’s serum was assayed for skin sensitizing antibody by the Prausnitz-Kustner (P-K) test. 0.1 ml. of Sietz-filtered serum was injected intracutaneously in several sites in a nonsensitive subject. In one half of the sites injections of 0.02 ml. of a 1: 100 dilution of the porcine antigens were made three hours after implantation. Injections in the remaining sites were made twenty-four hours after implantation. The test sites were read for wheal and erythema reactions twenty minutes after injection of the antigen. Identical studies were performed using serum that had been heated to 56’~. for four hours. In Table IV are summarized the results of the direct intracutaneous tests and passive transfer studies. The direct skin reactivity to the porcine antigens was more marked than to bovine antigens as shown by the extremely small amount of porcine antigen required to elicit a positive reaction. The skin reactivity paralleled that of the patient’s food sensitivities in that he was more intolerant of pork products than beef products. Skin sensitizing antibody activity could be demonstrated only to porcine serum when the sites were challenged at three hours. Challenge at twenty-four hours was negative with all five antigens. This finding is in contrast to that of the classic P-K reaction which may be positive for several weeks after transfer. Heating the serum to 56Oc. for four hours destroyed the skin sensitizing antibody activity to porcine serum when AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
Allergy-Greenberger
the site was challenged at three hours. It is of interest that classic skin sensitizing antibody activity is destroyed by this heating process. COMMENTS
In 1957 Citrin et al. [ 7 I] first demonstrated that a lesion of the gastrointestinal tract might be complicated by an increased enteric loss of proteins, resulting in hypoproteinemia. Since that time an increasing number of disorders have been associated with a protein-losing enteropathy and in his recent review Waldmann [3] listed some thirty-five such disorders. Some of the more common causes of increased enteric protein loss are summarized in Table v. The data obtained in this study support the concept that the patient’s protein-losing enteropathy was due to gastrointestinal allergy. It appears less likely that the protein-losing enteropathy was due to other disorders of the small intestine listed in Table IV. However, before concluding that this is so, the following disorders need to be considered in the differential diagnosis: (1) celiac-sprue, (2) regional enteritis, (3) nonspecific granuloma of the bowel, (4) intestinal lymphangiectasia, (5) idiopathic proteinlosing enteropathy with spontaneous recovery and (6) malabsorption associated with eczematous skin disorders. The normal villous structure of the intestinal mucosa, the failure to induce gastrointestinal symptoms with gluten loading and the failure to improve while on a gluten-free diet are inconsistent with a diagnosis of celiac-sprue. The long history of abdominal pain and diarrhea, the mild steatorrhea and the amelioration of abdominal symptoms and enteric protein loss following corticosteroid therapy are all compatible with a diagnosis of regional enteritis. However, the absence of characteristic abnormalities on roentgenograms upon repeated examination of the small bowel and colon, the normal findings on sigmoidoscopic examination and the normal results of the Schilling test do not support this diagnosis. In 1959 Holman et al. [ 721 described a group of adults who had hypoproteinemia for many years before inflammatory involvement of the small intestine and mesentery was discovered. These patients were found to have localized inflammatory and granulomatous disease of the small bowel. In three of these patients resection of the involved small bowel resulted in correction VOL.
43,
NOVEMBER
1967
781
et al.
TABLE IV SPECIAL SKIN TESTS AND PASSIVETRANSFER STUDIES Intracutaneous Tests
;Intigen Bovine serum albumin (40 mg./ml.) Bovine gamma globulin (20 mg./ml.) Porcine serum (60 mg./ml.) Porcine serum albumin (40 mg./ml.) Porcine gamma globulin (20 mg./ml.)
Passive Transfer*
+1:10
Not done
+1:1000
Not done
+1:50,000
+1:100
+1:10,000
-1:lOO
+1:10,000
-1:lOO
* Sites challenged three hours after transfer.
of the hypoproteinemia. It is possible that the present patient does have a localized inflammatory disease of the bowel which is too mild to be recognized but which might still have caused a significant protein-losing enteropathy. In addition, such a disorder might be expected to respond favorably to the administration of corticosteroids. It is apparent that this diagnosis cannot be excluded in the present case, although the long history of symptoms and associated food intolerances do suggest another process. TABLE v DISORDERS ASSOCIATED WITH PROTEIN-LOSING ENTEROPATHY*
1. Cardiac Congestive heart failure Constrictive pericarditis Interatrial septal defect Primary myocardial disease 2. Gastric Gastric carcinoma Giant hypertrophy of the gastric mucosa 3. Small intestine Celiac-sprue, gluten-induced enteropathy Tropical sprue Regional enteritis Whipple’s disease Lymphosarcoma of bowel Nonspecific granuloma of bowel Acute gastrointestinal infection Intestinal lymphangiectasia Allergic gastroenteropathy Idiopathic protein-losing enteropathy 4. Colon Ulcerative colitis Colonic neoplasm * Modified from Waldmann, 422, 1966 [3].
T. A. Gastrocnterokrgy,50:
782
Gastrointestinal
Allergy-Grpetzberger
Since Waldmann’s classic article [ /,7] appeared in 1961 rtlany cases of intestinal lymphangiectasia have been reported. The absence of lymphopenia, the failure to demonstrate dilated lymphatics in biopsy specimens of the small bowel and the lack of effect of a low fat diet on the patient’s symptoms and hypoproteinemia do not support a diagnosis of intestinal lymphangiectasia. In 1963 Donaldson and Holt [ 141 described an adult with a protein-losing enteropathy of uncertain cause who spontaneously went into remission after seven years of well documented hypoproteinemia and malabsorption. In this patient biopsy specimens of the intestinal mucosa were normal and the findings on exploratory laparotomy were nondiagnostic. Donaldson and Holt concluded that he had an idiopathic protein-losing enteropathy and suggest that intestinal lymphangiectasia may not be the only basis for “idiopathic” protein-losing enteropathy. Recently, Schuster and his associates [ 75,161 reported that patients with a variety of eczematous skin lesions may have underlying intestinal disease with malabsorption. In some of these patients the biopsy specimens showed the intestinal mucosa to be blunted and flattened and they responded to a gluten-free diet, suggesting that they had occult nontropical sprue. Of particular interest is the fact that three of four patients with atopic eczema had eosinophilic infiltration of the intestinal mucosa. However, no mention was made of food intolerances, hypoproteinemia or protein-losing enteropathy in these cases. Nevertheless, it is possible that patients with atopic eczema might have an intestinal lesion with an increased enteric loss of protein and this postulate cannot be excluded in the present case. In 1949 Ingelfinger [I] listed the criteria that have to be fulfilled before a diagnosis of gastrointestinal allergy could be considered seriously. These requirements were as follows: (1) the symptoms should be caused by specific substances that are innocuous when given to the bulk of the population; (2) lesions or functional changes in the gut should be demonstrated; and (3) emotional and mechanical factors should be excluded and the role of subjective attitudes minimized by testing various substances under carefully controlled conditions. Specific foods should be given in such a manner that the patient is unaware of the nature of the administered food. Reproducible symptoms, signs or x-ray
et al.
findings should consistently follow administration of the disguised food at a more or less constant interval not greater than two hours. Other innocuous foods given in the same manner should not produce symptoms or functional changes. The patient described in this report appears to have met most of the criteria set forth by Ingelfinger. A food (meat) that the patient stated caused adverse symptoms did in fact precipitate gastrointestinal symptoms (nausea, emesis, cramps, diarrhea) when administered to the patient via an intragastric tube whereas food that the patient was tolerant of had no such effects. The failure to observe a similar response with oats may have been due to the small amount of oats injected. It is of interest that after the injection of meat there was a significantly increased infiltration of eosinophils in the intestinal mucosa (Table III). However, the significance of this observation is uncertain in view of the increase in blood eosinophils occurring at the same time. It is unfortunate that intestinal biopsy specimens could not be obtained twelve and twenty-four hours after the administration of meat for it is possible that additional changes such as mucosal edema and increased infiltration of inflammatory cells might have been demonstrated. The tachycardia, leukocytosis, and increase in blood eosinophils that accompanied the development of gastrointestinal symptoms are an indirect reflection of the presumed allergic reaction occurring in the gastrointestinal mucosa. The significance of the changes in jejunal histamine and serotonin concentrations and blood histamine levels is uncertain. The development of gastrointestinal symptoms within thirty to sixty minutes after challenge with meat is in accord with the earlier observations of Pollard and Stuart [2]. These investigators performed a gastroscopic examination in six patients with specific food intolerances before and after the administration of offending foods. Gastrointestinal symptoms developed in all patients within fifteen to sixty minutes after ingestion of food. In addition, there were marked changes in the gastroscopic appearance of the stomach, with hyperemia, broadening of rugal folds, mucosal edema and decreased peristalsis in all cases. There is additional evidence in support of the thesis that the patient’s protein-losing enteropathy was due to gastrointestinal allergy. It will be recalled that the patient’s fecal loss of C+ albumin was decreased from an abnormally AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
,illlergy--Grpettbe~~p~
elevated level to a normal value following the administration of prednisone for ten days. hloreover, this was accompanied by a significant increase in both serum albumin and globulin levels to normal and amelioration of gastrointestinal complaints. Such a response to corticosteroid therapy has been documented in patients with regional enteritis and ulcerative colitis but not in the remaining disorders listed in Table IV. Since there was no other apparent cause for the patient’s protein-losing enteropathy it appears reasonable to conclude that it was due to gastrointestinal allergy. In a recent review article Waldmann [3] summarized the available data [ 77-231 in six children, three to ten years of age, with proteinlosing enteropathy thought to be due to gastrointestinal allergy. These patients had hypoalbuminemia, hypoglobulinemia, peripheral edema, diarrhea, normal small bowel biopsies*, iron deficiency anemia, eosinophilia and other allergic manifestations such as eczema, asthma and rhinitis. In a few patients it was demonstrated that milk feeding induced an increased enteric loss of protein and this was corrected by a milk-free diet. Some patients received corticosteroid therapy but no data are available concerning the effects of corticosteroids on enteric protein loss in these cases. There are many similarities between these patients and the patient described in this report. These include (1) the onset of symptoms in childhood, (2) a history of iron deficiency anemia, (3) eosinophilia, (4) hypoproteinemia and (5) excessive enteric loss of protein with correction by corticosteroid therapy. It is possible that patients with gastrointestinal allergy have less severe symptoms and less functional abnormalities of the gastrointestinal tract as they grow older. Such a postulate would account for some of the observations in our patient, namely, the absence of anemia and the mild hypoproteinemia. The persistence of low serum iron levels and increased iron-binding capacity of the serum in our patient is of particular interest. In view of the marked increase in serum iron levels after ingestion of 400 mg. of ferrous sulfate, it would appear that the patient could absorb iron normally. In the absence of gross gastrointestinal bleeding and malabsorption of iron the question arises as to the mechanism whereby iron deficiency developed. It is possible that increased amounts of iron * One biopsy specimen showed villous atrophy. VOL.
43,
NOVEMBER
1967
et nl.
783
were “leaking” into tllc intestinal tract together with seruiii albunlin and globulin. In this connection it is pertinent that Wilson, Heimer and Lahey [23], using C+-labeled red blood cells, demonstrated occult gastrointestinal blood loss secondary to milk allergy. The mechanisni of the blood loss in these cases is not clearly understood. The mechanism of the enteric protein loss in patients with gastrointestinal allergy has not been defined. It is possible that after ingestion of foods containing allergens there is a localized hypersensitivity reaction in the intestinal mucosa with the development of mucosal edema. Following this there might be passive diffusion of plasma proteins between mucosal cells or frank exudation through an inflammed mucosa. Such a process could conceivably subside rapidly when the offending agent is removed from the intestinal tract. In this connection, the recent studies of Laster et al. [24] demonstrating a rapid reversal of exudative enteropathy are of interest. These investigators demonstrated that Crjialbumin tests reverted to normal in two patients with Whipple’s disease twelve and sixteen days after initiation of antibiotic therapy. In that study [24] it was also reported that one patient had two episodes of fever, shock, massive diarrhea and oliguria following the administration of Lugol’s solution. These workers suggest that the ingestion of Lugol’s solution was associated with a hypersensitivity reaction in the gastrointestinal mucosa and increased enteric loss of protein and concluded that their case was an example of drug-induced gastroenteropathy. There are similarities between this patient of Laster et al. and the present one after he was challenged with meat. It is evident that further studies are needed to elucidate the mechanism of enteric protein loss in patients with a proteinlosing enteropathy induced by drugs or foods. We wish to thank Dr. FranAckncwledgment: cis Cuppage for performing the jejunal eosinophil counts, Dr. Charles E. Mengel for performing the histamine and serotonin assays, Dr. Jerry S. Trier for reviewing intestinal biopsy specimens and Dr. Malcolm P. Tyor for referring the patient to us. REFERENCES 1. INGPLFINGER,F. J., LOWEI.I., F. C. and FRANKLIN, W. Gastrointestinal allergy. New England J. Med., 241: 303, 337,1949. 2. POLLARD, H. M. and STUART, G. J. Experimental
784
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Gastrointestinal
Allergy-Greenberger
reproduction of gastric allergy in human beings with controlled observations on the mucosa. J. Allergy, 13: 467, 1942. WALDMANN, T. A. Protein-losing enteropathy. Gastroenterology, 50: 422, 1966. GORNALL, A. G., BARDAWILL, C. J. and DAVID, M. M. Determination of serum proteins by means of the biuret reaction. .J. Biol. Chem., 177: 751, 1949. FAHEY, J. L. and MCKELVEY, E. M. Quantitative determination of serum immunoglobulins in antibody-agar plates. J. Immunol., 94: 84, 1965. MILNER, P. F., IRVINE, R. A., BARTON, C. J. BRAS, G. and RICHARDS, R. Intestinal malabsorption in strongyloides stercoralis infestation. Gut, 6: 574, 1965. WALDMANN, T. A. Gastrointestinal protein loss demonstrated by C@-labelled albumin. Lancet,2: 121, 1961. SHORE, P. A., BURKHALTER,A. and COHN, V. H., JR. A method for the fluorometric assay of histamine in tissues. J. Pharmacol. tY Exper. Therap., 127: 182,1959. WEISSBACH,H., WAALKES, T. P. and UDENFRIEND, S. A. Simplified method for measuring serotonin in tissues. Simultaneous assay of both serotonin and histamine. J. Biol. Chem., 230: 864, 1958. RANDOLPH, T. G. Blood studies in allergy. I. The direct counting chamber determination of eosinophils in propylene glycol aqueous stains. J. Allergy, 15: 89, 1944. CITRIN, Y., STERLING, K. and HALSTED, J. A. Mechanism of hypoproteinemia associated with giant hypertrophy of gastric mucosa. New England J. Med., 257: 906, 1957. HOLMAN, H., NICKEL, W. F., JR. and SLEISENGER, M. H. Hypoproteinemia antedating intestinal lesions and possibly due to excessive serum protein loss into the intestine. Am. J. Med., 27: 963, 1959. WALDMANN,T. A., STEINFELD,J. L., DUTCHER,T. F., DAVIDSON,J. D. and GORDON,R. S., JR. The role
14.
15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
et al.
of the gastrointestinal system in “idiopathic hypoproteinemia.” Gastroentno~ogy, 41 : 197, 1961. DONALDSON,R. M., JR. and HOLT, P. R. Idiopathic protein-losing enteropathy in an adult with apparently complete recovery. Am. J. Med., 34: 572, 1963. SCHUSTER,S. and MARKS, J. Dermatogenic enteropathy. A new cause of steatorrhea. Lancet, 1 : 1367, 1965. FRY, L., MCMINN, R. M. H. and SCHUSTER,S. The small intestine in skin diseases. Arch. Dermat., 93: 647, 1966. STURGEON,P. and BRUBAKER,C. Copper deficiency in infants. A syndrome characterized by hypocupremia, iron deficiency anemia, and hypoproteinemia. Am. J. Dis. Child., 92: 254, 1956. ZIPURSKY, A., DEMPSEY, H., MARKOWITZ, H., CARTWRIGHT, G. and WINTROBE, M. M. Studies on copper metabolism. XXIV. Hypocupremia in infancy. Am. J. Dis. Child., 96: 148, 1958. SCHUBERT,W. K. and LAHEY, M. E. Copper and protein depletion complicating hypoferric anemia of infancy. Pediatrics, 24: 710, 1959. ULSTROM,R. A. and KRIVIT, W. Exudative enteropathy, hypoproteinemia, edema and iron deficiency anemia. Am. J. Dis. Child., 100: 509, 1960. WILSON, J. F., HEIMER, D. C. and LAHEY, M. E. Studies on iron metabolism. I. Evidence of gastrointestinal dysfunction in infants with iron deficiency anemia. A preliminary report. J. Pediat., 60: 787, 1962. HEIMER, D. C., WILSON, J. F. and LAHEY, M. E. Sensitivity to cow’s milk. J.A.M.A., 189: 563,1964. WILSON, J. F. and LAHEY, M. E. A unifying concept for the pathogenesis of the syndrome of iron deficiency anemia, hypocupremia and hypoproteinemia in infants. J. Clin. Invest., 44: 1112, 1965. LASTER, L., WALDMANN,T. A., FENSTER,L. F. and SINGLETON, J. W. Albumin metabolism in patients with Whipple’s disease. J. Clin. Invest., 45 : 637, 1966.
AMERICAN
JOURNAL
OF
MEDICINE
Enteropathy
Gastrointestinal NORTON
J.
Associated Allergy*
M.D., JAMES I. TENNENBAUM,
GREENBERGER,
RICHARD
D. RUPPERT,
Columbus,
with
M.D. and
M.D.
Ohio
A case of hypoproteinemia and protein-losing enteropathy occurring in association with gastrointestinal allergy is described. The excessive enteric loss of protein, documented by a C&albumin test, was corrected by corticosteroid therapy with a return of serum proteins to normal levels. A specific food intolerance was correlated with the symptoms of gastrointestinal involvement and changes in the intestinal mucosa. The patient was challenged with various foods in a manner in which he could not identify the food being administered. A bland food produced no symptoms. However, after challenge with a food to which he was intolerant, tachycardia, nausea, emesis, abdominal cramps, diarrhea, leukocytosis and increased eosinophilia developed. Biopsy specimens from the small intestine obtained after challenge demonstrated an increased infiltration of eosinophils but no significant change in jejunal histamine or serotonin concentrations. Since an exhaustive workup failed to reveal any other cause for the patient’s protein-losing enteropathy, it is proposed that the excessive enteric loss of protein was due to injury to the gastrointestinal mucosa by specific food allergens.
I
N 1949 Ingelfinger et al. [7] stated that “Gastrointestinal allergy is a diagnosis frequently entertained, occasionally evaluated, and rarely established. It offers, to its enthusiastic supporters, a reasonable explanation for many obscure abdominal complaints. To the skeptical, it frequently appears as a specious and unwarranted diagnosis. These conflicting views cannot be resolved on the basis of existing knowledge.” Today, seventeen years later, these statements are still valid. As Ingelfinger has emphasized, there are several reasons why the spontaneous occurrence of gastrointestinal allergy in man is still regarded as an inconclusive entity. First, symptoms claimed to be specific or characteristic of gastrointestinal allergy are in fact nonspecific and highly variable. Second, the methods currently available for establishing the diagnosis of gastrointestinal allergy are not sufficiently accurate. In particular, it should be emphasized that specific skin tests are indirect tests. Third, the occurrence of abdominal complaints in patients with other allergic manifestations such as rhinitis, asthma, hives and eczema has led to the
tendency to diagnose such complaints as a gastrointestinal allergy whereas in actuality there is little objective evidence on which to base such a diagnosis. Fourth, with but few exceptions [2,3] no lesions in the gut or abnormalities in intestinal absorptive function have been demonstrated in patients with a diagnosis of gastrointestinal allergy. In the present report an adult patient with hypoproteinemia and a protein-losing enteropathy occurring in association with gastrointestinal allergy is described. The excessive enteric loss of protein was documented by chromium6i (C+)-albumin test and was corrected by corticosteroid therapy with a return of serum proteins to normal levels. METHODS
The concentration of serum total proteins was determined by the biuret method of Gornall et al. [4] and the serum proteins were separated by paper electrophoresis. The serum immunoglobulins were determined by a modification of the method of Fahey and McKelvey [5]. Iron intolerance tests were performed by a modification of the method of Milner
* From the Department of Medicine, Division of Gastroenterology, Ohio State University College of Medicine, Columbus, Ohio. This study was supported in part by Grant FR-34 from the U. S. Public Health Service General Clinical Research Center. Manuscript received September 20, 1966. VOL.
43,
NOVEMBER
1967
777
778
Gastrointestinal
Allergy-GrePnhPr;~P~. ft TABLE
SIJMMARY
al.
I
OF LABORATORY
DATA
Stool Fat
IIrmatocrit (%J)
Hemoglobin (gm./lOO ml.)
1Vhite Blood count (X 103)
Per Cent Eosinophils
Cocficient of Fat Absorption gm.124
1962*
39
11.1
9,800
39
. .
1964f 1964$ 1965 $ 19669
44 39 39 40
14.3 12.2 11.1 11.3
8,000 11,500 10,600 10,300
18 32 30 47
9.9 6.8 . . .
* Cincinnati General Hospital, Cincinnati, Ohio. t Middletown Hospital, Middietown, Ohio.
al. [6]. After a fasting blood specimen was obtained the patient was given 2 tablets of Cytoferrin@ (containing 400 mg. of ferrous sulfate) and blood specimens were procured for serum iron and iron-binding capacity levels at hourly intervals for four hours. The number of eosinophils in the epithelial cells and lamina propria in intestinal biopsy specimens was determined by a pathologist who was unaware of the conditions under which they were obtained. The number of eosinophils per 10 high power fields was recorded after which the code was broken. Demonstration of Gastrointestinal Protein Loss. Cr”r-albumin* was used to demonstrate gastrointestinal protein loss according to the method of Waldmann [7]. The patient received approximately 30 PC. of the labeled macromolecule intravenously. The urine and stools passed during the subsequent four days were collected separately. The stools were placed in a Waring blender, brought to constant volume, and homogenized. Triplicate aliquots of the homogenized stool and of each urine sample were counted with an appropriate standard in a well-type scintillation counter. The results are expressed as a percentage of the dose of administered isotope excreted in the four day stool collection and the four day urine collection. Determination of Histamine and Serotonin in Blood and Intestinal Biopsy Specimens. The histamine concentration in blood and jejunal mucosal homogenates was determined by the method of Shore et al. [a]. The serotonin concentration in intestinal mucosa was determined by the method of Weissbach et al. [9]. Blood eosinophils were determined by direct counting using Randolph’s stain [ 701. et
CASE
REPORT
A twenty-two year old white male student (M.G., OSUH No. 848881), was admitted to the Clinical Research Unit of The Ohio State University Hospital in December 1965 for evaluation of abdominal pain and eosinophilia of many years’ duration. He had been hospitalized elsewhere on three occasions; the * Generously provided by Dr. B. Bruno, Department of Radiopharmaceutical Research, E. R. Squibb RLSons Co.
hr.
Serum
Iron
Serum Iron-Binding Capacity (fig./100 ml.)
(%’
Schilling
Test
(%/24
hr.)
.
.
14 . 91.5
35 43
. . 366 548
f Duke University Hospital, Durham, North $ Ohio State University Hospital, Columbus,
14
Carolina. Ohio.
pertinent data from these hospitalizations are summarized in Table I. Since the age of thirteen the patient had experienced recurrent episodes of abdominal pain. The pain was crampy in nature, epigastric and periumbilical in location, occurred thirty to sixty minutes after meals and frequently was associated with diarrhea. The episodes of pain occurred at least once or twice a week. The patient usually had 1 to 2 stools per day but with attacks of pain he had from 12 to 15 watery stools per day. Several stool examinations failed to reveal ova and parasites but because of persistent abdominal symptoms and eosinophilia he had received two courses of therapy with Delvex@ without effect. The patient had also been treated with iron tablets for an iron deficiency anemia while in his teens. There was no history of febrile episodes, melena, symptoms of joint involvement or perirectal disease. In 1962 the patient was found to have mild atopic dermatitis. In 1964 he was hospitalized with acute bronchitis. There was no history of asthma, seasonal rhinitis, hives or urticaria. However, he had noted intermittent pedal edema. The patient stated that he was intolerant of many foods, including meat products (beef, pork, veal, lamb), oats, wheat products (pastries, cake) and eggs. Ingestion of red meats in particular would consistently precipitate episodes of abdominal pain and accordingly he had not eaten any meat products for five years. He was not intolerant of alcohol and milk products. A trial on a gluten-free diet in 1964 did not appreciably alter his symptoms. Physical examination on admission revealed a thin, well developed, young man in no distress. The temperature was 99O~., the pulse 80 beats per minute, respirations 16 and blood pressure 140/60 mm. Hg. Eczematous and lichenified lesions were present on both antecubital fossae, the left wrist and both ankles. There was no lymphadenopathy. The heart and lungs were normal. No abdominal organs or masses were palpable. There was mild pedal and pretibial edema. Sigmoidoscopic examination was entirely within normal limits. Initial laboratory studies (Table I) revealed a AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
,~llergy--Greerlbel.,~r~r
hematocrit reading of 39 per cent, a hemoglobin of 11.1 gm. per 100 ml., a white blood cell count of 10,600 per cu. mm. with 30 per cent cosinophils and an erythrocyte sedimentation rate of 2 mm. per hour. The urinalysis was normal. Urinary excretion of n-xylose after a 25 gm. oral dose was 11.2 gm. Quantitative stool fat excretion was 6.8 gm. in twenty-four hours with a coefficient of fat absorption of 91.5 per cent (three day collection). The serum albumin was 3.2 gm. per 100 ml. and the serum globulin 1.7 gm. per 100 ml. The immunoglobulins were as follows: 1gG 410 mg. per 100 ml., IgA 105 mg. per 100 ml. and 1 gM 25 mg. per 100 ml. The serum cholesterol was 160 mg. per 100 ml. and the serum calcium 9.2 mg. per 100 ml. The serum iron was 35 pg. per 100 ml. and the iron-binding capacity 366 pg. per 100 ml. A small bowel biopsy revealed minimal eosinophilic infiltration but otherwise was interpreted as normal (Fig. 1). X-ray examinations of the upper gastrointestinal tract, small bowel and colon did not reveal any abnormalities. An augmented histamine gastric analysis was within normal limits with a maximal acid output of 7 mEq. in one hour. The twenty-four hour urinary excretion of 5HIAA was 5.0 mg. A lactose tolerance test was normal. An oral iron tolerance test was also normal, the serum iron level increasing from a fasting value of 50 to 360 pg. per 100 ml. in three hours. The patient ingested 25 gm. of a gluten solution without any untoward effects. Cutaneous scratch tests with eighty-four common food extracts revealed the following positive responses: eggs, oats, wheat, pork, corn and rice. However, cutaneous intradermal tests with the common inhalent allergens and yeasts were negative. A Crsl-albumin test performed while the patient was in relapse resulted in a fecal excretion of 6.6 per cent and a urinary excretion of 20 per cent of the given dose (Table II). The patient was given a ten day course of treatment with prednisone (30 mg. per day). This was followed by marked symptomatic improvement and a significant increase in serum albumin and globulin levels. In a six week period the patient had no gastrointestinal symptoms and gained 28 pounds in weight. A repeat Crsl-albumin
STUDIES
OF SERUM
PRO’I‘EINS
AND
779
et al.
FIG. 1. Jejunal biopsy specimen revealing normal villous structure. tlematoxylin and eosin stain, original magnification X 130. test performed while the patient was in remission revealed a normal fecal excretion of Crsl-albumin (Table II). Several serum albumin determinations were normal, further indicating that the patient no longer had increased enteric loss of protein. SPEIXAL
STUDIES
Special studies were carried out to confirm that the patient did have specific food intolerances and to determine whether administration of certain foods might induce a lesion in the small intestinal mucosa. A Rubin hydraulic biopsy tube was positioned in the proximal jejunum under fluoroscopic control. A No. 16 cardiac catheter was then positioned in the fundus of the stomach. Control mucosal biopsy specimens and blood samples were obtained after which the patient received 10 cc. of a bland food (extract of peas). This was injected via the stomach tube (in this and all subsequent injections the patient did not observe the actual injection and thus he did not know what foods he was receiving). During the next sixty ruinutes the patient had no complaints and one hour
GASTROINTESI‘INAL
PROTEIN
LOSS
CW-Albumin ‘Test (7* of Dose)
~. Date
October 1964 December 1965 February 1966 (after corticosteroid May 1966
NOTE: VOL.
Values
43,
Scrurll
(gm./lOO
ml.)
.4lburnin
Globulin
(3.5-5.5) 3.4 3.2 4.8
(1.5-3.0) 1.6 1.7 2.0
Immunoglobulins IgG (800-l
,400)
410 570
therapy)
in parentheses NOVEMBER
4.1
represent
normal
1967
2.1
values.
. .
(mg./lOO Ig.4
(100-300)
ml.) IgM (30-150)
105 128
25 28
.
...
4 Day Fecal Excretion
(0.1-0.7) 6.6 0.3
4 Day Urinary Excretion
(20-40) 20.5 24.6
780
Allergy-Greenberger
Gastrointestinal
TABLE CHANGES
IN
JEJUNAL
HISTAMINE
AND
SEROTONIN AFTER
Time
ll:oo 11:05 12:oo 12:05 1 :oo 1: 30 2:oo 4 30
:
NOTE:
Food
A.M. A.Y. noon P.M. P.H. P.M. P.M. P.M.
Given
NOIX Peas (10 cc.)
......
Oats (10 cc.) Meat (20 cc.) Meat (30 cc.) ......
......
Symptoms Induced
.. NO NO NO YCS
III
CONCENTRATIONS, CHALLENGE
et al.
WITH
BLOOD VARIOUS
HISTAMINE
LEVELS
AND
BLOOD
EOSINOPHILS
FOODS
(%)
White Blood Count (no./ml. x 108)
Blood Eosinophil COWIt (no./ml.)
(38-52)
(5-10)
(<300)
7,600
1,381
19
0.8
9,400
1,406
31
0.4
0.6 ......
0.104
8,200 13,100
2,214 2,358
............
40
0.6
0.6
0.088
Hematocrit
38 ..I 36 ............... ..................... ..................... 39 40.5
Jejunal Eosinophils (no./10 h.p.f.)
. .
Jejunal Scrotonin
Jejunal Histamine
Blood Histamine
&./pm.)
(cg./gm.)
(w/ml.)
(0.2-0.8)
(0.4-0.8)
.
0.6
(O.Ol0.09) 0.096
.
Figures in parentheses represent normal values
after injection of the extract of peas repeat jejunal biopsy specimens and blood samples were obtained. The patient then received an intragastric injection of 10 cc. of a food (oats) to which he was intolerant. During the next sixty minutes the patient had no complaints. At the start of the third one hour period the patient received an intagastric injection of 20 cc. of a puree of rare steak. After thirty minutes an additional injection of 30 cc. of steak puree was given. After forty minutes the patient noted the onset of nausea and after fifty minutes he was experiencing cramping abdominal pain. One hour after the first intragastric injection of meat extract repeat jejunal biopsy specimens and blood samples were obtained. The experiment was terminated shortly thereafter because of the development of severe nausea, emesis and abdominal pain. Shortly thereafter, the patient had two watery bowel movements. The results of this special study are summarized in Table III. The next day the patient was anorectic and still experiencing nausea, cramps and diarrhea which had not responded to Demerol,@ ChlorTrimeton@ and Pro-Banthine.@ Accordingly, he was given a seven day course of prednisone with complete cessation of symptoms. He has remained asymptomatic on a diet free of meat and wheat products. Special skin tests and passive transfer studies were carried out four months after the food challenge studies. Wheal and erythema skin reactivity to various pure bovine and porcine antigens was determined by the intracutaneous method. The tests were performed with 0.02 ml. of serial dilutions of bovine serum albumin,
bovine gamma globulin, porcine serum, porcine serum albumin and porcine gamma globulin (Mann Laboratories, New York, New York). An intracutaneous test was considered positive if there was at least 20 mm. erythema. The patient’s serum was assayed for skin sensitizing antibody by the Prausnitz-Kustner (P-K) test. 0.1 ml. of Sietz-filtered serum was injected intracutaneously in several sites in a nonsensitive subject. In one half of the sites injections of 0.02 ml. of a 1: 100 dilution of the porcine antigens were made three hours after implantation. Injections in the remaining sites were made twenty-four hours after implantation. The test sites were read for wheal and erythema reactions twenty minutes after injection of the antigen. Identical studies were performed using serum that had been heated to 56’~. for four hours. In Table IV are summarized the results of the direct intracutaneous tests and passive transfer studies. The direct skin reactivity to the porcine antigens was more marked than to bovine antigens as shown by the extremely small amount of porcine antigen required to elicit a positive reaction. The skin reactivity paralleled that of the patient’s food sensitivities in that he was more intolerant of pork products than beef products. Skin sensitizing antibody activity could be demonstrated only to porcine serum when the sites were challenged at three hours. Challenge at twenty-four hours was negative with all five antigens. This finding is in contrast to that of the classic P-K reaction which may be positive for several weeks after transfer. Heating the serum to 56Oc. for four hours destroyed the skin sensitizing antibody activity to porcine serum when AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
Allergy-Greenberger
the site was challenged at three hours. It is of interest that classic skin sensitizing antibody activity is destroyed by this heating process. COMMENTS
In 1957 Citrin et al. [ 7 I] first demonstrated that a lesion of the gastrointestinal tract might be complicated by an increased enteric loss of proteins, resulting in hypoproteinemia. Since that time an increasing number of disorders have been associated with a protein-losing enteropathy and in his recent review Waldmann [3] listed some thirty-five such disorders. Some of the more common causes of increased enteric protein loss are summarized in Table v. The data obtained in this study support the concept that the patient’s protein-losing enteropathy was due to gastrointestinal allergy. It appears less likely that the protein-losing enteropathy was due to other disorders of the small intestine listed in Table IV. However, before concluding that this is so, the following disorders need to be considered in the differential diagnosis: (1) celiac-sprue, (2) regional enteritis, (3) nonspecific granuloma of the bowel, (4) intestinal lymphangiectasia, (5) idiopathic proteinlosing enteropathy with spontaneous recovery and (6) malabsorption associated with eczematous skin disorders. The normal villous structure of the intestinal mucosa, the failure to induce gastrointestinal symptoms with gluten loading and the failure to improve while on a gluten-free diet are inconsistent with a diagnosis of celiac-sprue. The long history of abdominal pain and diarrhea, the mild steatorrhea and the amelioration of abdominal symptoms and enteric protein loss following corticosteroid therapy are all compatible with a diagnosis of regional enteritis. However, the absence of characteristic abnormalities on roentgenograms upon repeated examination of the small bowel and colon, the normal findings on sigmoidoscopic examination and the normal results of the Schilling test do not support this diagnosis. In 1959 Holman et al. [ 721 described a group of adults who had hypoproteinemia for many years before inflammatory involvement of the small intestine and mesentery was discovered. These patients were found to have localized inflammatory and granulomatous disease of the small bowel. In three of these patients resection of the involved small bowel resulted in correction VOL.
43,
NOVEMBER
1967
781
et al.
TABLE IV SPECIAL SKIN TESTS AND PASSIVETRANSFER STUDIES Intracutaneous Tests
;Intigen Bovine serum albumin (40 mg./ml.) Bovine gamma globulin (20 mg./ml.) Porcine serum (60 mg./ml.) Porcine serum albumin (40 mg./ml.) Porcine gamma globulin (20 mg./ml.)
Passive Transfer*
+1:10
Not done
+1:1000
Not done
+1:50,000
+1:100
+1:10,000
-1:lOO
+1:10,000
-1:lOO
* Sites challenged three hours after transfer.
of the hypoproteinemia. It is possible that the present patient does have a localized inflammatory disease of the bowel which is too mild to be recognized but which might still have caused a significant protein-losing enteropathy. In addition, such a disorder might be expected to respond favorably to the administration of corticosteroids. It is apparent that this diagnosis cannot be excluded in the present case, although the long history of symptoms and associated food intolerances do suggest another process. TABLE v DISORDERS ASSOCIATED WITH PROTEIN-LOSING ENTEROPATHY*
1. Cardiac Congestive heart failure Constrictive pericarditis Interatrial septal defect Primary myocardial disease 2. Gastric Gastric carcinoma Giant hypertrophy of the gastric mucosa 3. Small intestine Celiac-sprue, gluten-induced enteropathy Tropical sprue Regional enteritis Whipple’s disease Lymphosarcoma of bowel Nonspecific granuloma of bowel Acute gastrointestinal infection Intestinal lymphangiectasia Allergic gastroenteropathy Idiopathic protein-losing enteropathy 4. Colon Ulcerative colitis Colonic neoplasm * Modified from Waldmann, 422, 1966 [3].
T. A. Gastrocnterokrgy,50:
782
Gastrointestinal
Allergy-Grpetzberger
Since Waldmann’s classic article [ /,7] appeared in 1961 rtlany cases of intestinal lymphangiectasia have been reported. The absence of lymphopenia, the failure to demonstrate dilated lymphatics in biopsy specimens of the small bowel and the lack of effect of a low fat diet on the patient’s symptoms and hypoproteinemia do not support a diagnosis of intestinal lymphangiectasia. In 1963 Donaldson and Holt [ 141 described an adult with a protein-losing enteropathy of uncertain cause who spontaneously went into remission after seven years of well documented hypoproteinemia and malabsorption. In this patient biopsy specimens of the intestinal mucosa were normal and the findings on exploratory laparotomy were nondiagnostic. Donaldson and Holt concluded that he had an idiopathic protein-losing enteropathy and suggest that intestinal lymphangiectasia may not be the only basis for “idiopathic” protein-losing enteropathy. Recently, Schuster and his associates [ 75,161 reported that patients with a variety of eczematous skin lesions may have underlying intestinal disease with malabsorption. In some of these patients the biopsy specimens showed the intestinal mucosa to be blunted and flattened and they responded to a gluten-free diet, suggesting that they had occult nontropical sprue. Of particular interest is the fact that three of four patients with atopic eczema had eosinophilic infiltration of the intestinal mucosa. However, no mention was made of food intolerances, hypoproteinemia or protein-losing enteropathy in these cases. Nevertheless, it is possible that patients with atopic eczema might have an intestinal lesion with an increased enteric loss of protein and this postulate cannot be excluded in the present case. In 1949 Ingelfinger [I] listed the criteria that have to be fulfilled before a diagnosis of gastrointestinal allergy could be considered seriously. These requirements were as follows: (1) the symptoms should be caused by specific substances that are innocuous when given to the bulk of the population; (2) lesions or functional changes in the gut should be demonstrated; and (3) emotional and mechanical factors should be excluded and the role of subjective attitudes minimized by testing various substances under carefully controlled conditions. Specific foods should be given in such a manner that the patient is unaware of the nature of the administered food. Reproducible symptoms, signs or x-ray
et al.
findings should consistently follow administration of the disguised food at a more or less constant interval not greater than two hours. Other innocuous foods given in the same manner should not produce symptoms or functional changes. The patient described in this report appears to have met most of the criteria set forth by Ingelfinger. A food (meat) that the patient stated caused adverse symptoms did in fact precipitate gastrointestinal symptoms (nausea, emesis, cramps, diarrhea) when administered to the patient via an intragastric tube whereas food that the patient was tolerant of had no such effects. The failure to observe a similar response with oats may have been due to the small amount of oats injected. It is of interest that after the injection of meat there was a significantly increased infiltration of eosinophils in the intestinal mucosa (Table III). However, the significance of this observation is uncertain in view of the increase in blood eosinophils occurring at the same time. It is unfortunate that intestinal biopsy specimens could not be obtained twelve and twenty-four hours after the administration of meat for it is possible that additional changes such as mucosal edema and increased infiltration of inflammatory cells might have been demonstrated. The tachycardia, leukocytosis, and increase in blood eosinophils that accompanied the development of gastrointestinal symptoms are an indirect reflection of the presumed allergic reaction occurring in the gastrointestinal mucosa. The significance of the changes in jejunal histamine and serotonin concentrations and blood histamine levels is uncertain. The development of gastrointestinal symptoms within thirty to sixty minutes after challenge with meat is in accord with the earlier observations of Pollard and Stuart [2]. These investigators performed a gastroscopic examination in six patients with specific food intolerances before and after the administration of offending foods. Gastrointestinal symptoms developed in all patients within fifteen to sixty minutes after ingestion of food. In addition, there were marked changes in the gastroscopic appearance of the stomach, with hyperemia, broadening of rugal folds, mucosal edema and decreased peristalsis in all cases. There is additional evidence in support of the thesis that the patient’s protein-losing enteropathy was due to gastrointestinal allergy. It will be recalled that the patient’s fecal loss of C+ albumin was decreased from an abnormally AMERICAN
JOURNAL
OF
MEDICINE
Gastrointestinal
,illlergy--Grpettbe~~p~
elevated level to a normal value following the administration of prednisone for ten days. hloreover, this was accompanied by a significant increase in both serum albumin and globulin levels to normal and amelioration of gastrointestinal complaints. Such a response to corticosteroid therapy has been documented in patients with regional enteritis and ulcerative colitis but not in the remaining disorders listed in Table IV. Since there was no other apparent cause for the patient’s protein-losing enteropathy it appears reasonable to conclude that it was due to gastrointestinal allergy. In a recent review article Waldmann [3] summarized the available data [ 77-231 in six children, three to ten years of age, with proteinlosing enteropathy thought to be due to gastrointestinal allergy. These patients had hypoalbuminemia, hypoglobulinemia, peripheral edema, diarrhea, normal small bowel biopsies*, iron deficiency anemia, eosinophilia and other allergic manifestations such as eczema, asthma and rhinitis. In a few patients it was demonstrated that milk feeding induced an increased enteric loss of protein and this was corrected by a milk-free diet. Some patients received corticosteroid therapy but no data are available concerning the effects of corticosteroids on enteric protein loss in these cases. There are many similarities between these patients and the patient described in this report. These include (1) the onset of symptoms in childhood, (2) a history of iron deficiency anemia, (3) eosinophilia, (4) hypoproteinemia and (5) excessive enteric loss of protein with correction by corticosteroid therapy. It is possible that patients with gastrointestinal allergy have less severe symptoms and less functional abnormalities of the gastrointestinal tract as they grow older. Such a postulate would account for some of the observations in our patient, namely, the absence of anemia and the mild hypoproteinemia. The persistence of low serum iron levels and increased iron-binding capacity of the serum in our patient is of particular interest. In view of the marked increase in serum iron levels after ingestion of 400 mg. of ferrous sulfate, it would appear that the patient could absorb iron normally. In the absence of gross gastrointestinal bleeding and malabsorption of iron the question arises as to the mechanism whereby iron deficiency developed. It is possible that increased amounts of iron * One biopsy specimen showed villous atrophy. VOL.
43,
NOVEMBER
1967
et nl.
783
were “leaking” into tllc intestinal tract together with seruiii albunlin and globulin. In this connection it is pertinent that Wilson, Heimer and Lahey [23], using C+-labeled red blood cells, demonstrated occult gastrointestinal blood loss secondary to milk allergy. The mechanisni of the blood loss in these cases is not clearly understood. The mechanism of the enteric protein loss in patients with gastrointestinal allergy has not been defined. It is possible that after ingestion of foods containing allergens there is a localized hypersensitivity reaction in the intestinal mucosa with the development of mucosal edema. Following this there might be passive diffusion of plasma proteins between mucosal cells or frank exudation through an inflammed mucosa. Such a process could conceivably subside rapidly when the offending agent is removed from the intestinal tract. In this connection, the recent studies of Laster et al. [24] demonstrating a rapid reversal of exudative enteropathy are of interest. These investigators demonstrated that Crjialbumin tests reverted to normal in two patients with Whipple’s disease twelve and sixteen days after initiation of antibiotic therapy. In that study [24] it was also reported that one patient had two episodes of fever, shock, massive diarrhea and oliguria following the administration of Lugol’s solution. These workers suggest that the ingestion of Lugol’s solution was associated with a hypersensitivity reaction in the gastrointestinal mucosa and increased enteric loss of protein and concluded that their case was an example of drug-induced gastroenteropathy. There are similarities between this patient of Laster et al. and the present one after he was challenged with meat. It is evident that further studies are needed to elucidate the mechanism of enteric protein loss in patients with a proteinlosing enteropathy induced by drugs or foods. We wish to thank Dr. FranAckncwledgment: cis Cuppage for performing the jejunal eosinophil counts, Dr. Charles E. Mengel for performing the histamine and serotonin assays, Dr. Jerry S. Trier for reviewing intestinal biopsy specimens and Dr. Malcolm P. Tyor for referring the patient to us. REFERENCES 1. INGPLFINGER,F. J., LOWEI.I., F. C. and FRANKLIN, W. Gastrointestinal allergy. New England J. Med., 241: 303, 337,1949. 2. POLLARD, H. M. and STUART, G. J. Experimental
784
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Gastrointestinal
Allergy-Greenberger
reproduction of gastric allergy in human beings with controlled observations on the mucosa. J. Allergy, 13: 467, 1942. WALDMANN, T. A. Protein-losing enteropathy. Gastroenterology, 50: 422, 1966. GORNALL, A. G., BARDAWILL, C. J. and DAVID, M. M. Determination of serum proteins by means of the biuret reaction. .J. Biol. Chem., 177: 751, 1949. FAHEY, J. L. and MCKELVEY, E. M. Quantitative determination of serum immunoglobulins in antibody-agar plates. J. Immunol., 94: 84, 1965. MILNER, P. F., IRVINE, R. A., BARTON, C. J. BRAS, G. and RICHARDS, R. Intestinal malabsorption in strongyloides stercoralis infestation. Gut, 6: 574, 1965. WALDMANN, T. A. Gastrointestinal protein loss demonstrated by C@-labelled albumin. Lancet,2: 121, 1961. SHORE, P. A., BURKHALTER,A. and COHN, V. H., JR. A method for the fluorometric assay of histamine in tissues. J. Pharmacol. tY Exper. Therap., 127: 182,1959. WEISSBACH,H., WAALKES, T. P. and UDENFRIEND, S. A. Simplified method for measuring serotonin in tissues. Simultaneous assay of both serotonin and histamine. J. Biol. Chem., 230: 864, 1958. RANDOLPH, T. G. Blood studies in allergy. I. The direct counting chamber determination of eosinophils in propylene glycol aqueous stains. J. Allergy, 15: 89, 1944. CITRIN, Y., STERLING, K. and HALSTED, J. A. Mechanism of hypoproteinemia associated with giant hypertrophy of gastric mucosa. New England J. Med., 257: 906, 1957. HOLMAN, H., NICKEL, W. F., JR. and SLEISENGER, M. H. Hypoproteinemia antedating intestinal lesions and possibly due to excessive serum protein loss into the intestine. Am. J. Med., 27: 963, 1959. WALDMANN,T. A., STEINFELD,J. L., DUTCHER,T. F., DAVIDSON,J. D. and GORDON,R. S., JR. The role
14.
15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
et al.
of the gastrointestinal system in “idiopathic hypoproteinemia.” Gastroentno~ogy, 41 : 197, 1961. DONALDSON,R. M., JR. and HOLT, P. R. Idiopathic protein-losing enteropathy in an adult with apparently complete recovery. Am. J. Med., 34: 572, 1963. SCHUSTER,S. and MARKS, J. Dermatogenic enteropathy. A new cause of steatorrhea. Lancet, 1 : 1367, 1965. FRY, L., MCMINN, R. M. H. and SCHUSTER,S. The small intestine in skin diseases. Arch. Dermat., 93: 647, 1966. STURGEON,P. and BRUBAKER,C. Copper deficiency in infants. A syndrome characterized by hypocupremia, iron deficiency anemia, and hypoproteinemia. Am. J. Dis. Child., 92: 254, 1956. ZIPURSKY, A., DEMPSEY, H., MARKOWITZ, H., CARTWRIGHT, G. and WINTROBE, M. M. Studies on copper metabolism. XXIV. Hypocupremia in infancy. Am. J. Dis. Child., 96: 148, 1958. SCHUBERT,W. K. and LAHEY, M. E. Copper and protein depletion complicating hypoferric anemia of infancy. Pediatrics, 24: 710, 1959. ULSTROM,R. A. and KRIVIT, W. Exudative enteropathy, hypoproteinemia, edema and iron deficiency anemia. Am. J. Dis. Child., 100: 509, 1960. WILSON, J. F., HEIMER, D. C. and LAHEY, M. E. Studies on iron metabolism. I. Evidence of gastrointestinal dysfunction in infants with iron deficiency anemia. A preliminary report. J. Pediat., 60: 787, 1962. HEIMER, D. C., WILSON, J. F. and LAHEY, M. E. Sensitivity to cow’s milk. J.A.M.A., 189: 563,1964. WILSON, J. F. and LAHEY, M. E. A unifying concept for the pathogenesis of the syndrome of iron deficiency anemia, hypocupremia and hypoproteinemia in infants. J. Clin. Invest., 44: 1112, 1965. LASTER, L., WALDMANN,T. A., FENSTER,L. F. and SINGLETON, J. W. Albumin metabolism in patients with Whipple’s disease. J. Clin. Invest., 45 : 637, 1966.
AMERICAN
JOURNAL
OF
MEDICINE