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Tropical sprue in children
TROPICAL
PEDIATRICS
Derrick B. Jelliffe, Editor
Tropical sprue in children Eleven Puerto Rican children with chronic diarrhea, intestinal malabsorption, abnormal jejunal mucosa, megaIoblastir bone marrow, and malnutrition have been studied. The patients were treated with [olic acid alone or folic acid and vitamin BI,; one patient received oxytetracydine. The results were good to excellent in all but one o[ the children. This symptomatic, "hematologic, and gastrointestinal responses were similar to those reported in adult patients with tropical sprue. The evidence presented here suggests that this syndrome in children is the same disease as tropical sprue in adults mani[ested at an early age, sometimes as early as the first year o[ li[e. The etiology o[ this disease in children, as well as in adults, remains unknown.
Pedro J. Santiago-Borrero, M.D., Norman Maldonado, M.D., and Enrique Horta,
M.D. CAPARRA
HEIGHTS,
PUERTO
RICO
S P R U lg iS a disease c h a r a c by anorexia, weakness, chronic diarrhea, intestinal malabsorption , abnormal jejunal mucosa, malnutrition, glossitis, and megaloblastic anemia. One or more of the characteristic signs may be absent in some patients? -4 This disease has been described in adults of all ages, but very few patients under the age of 15 years have been described in the medical literature?, 5-~ No relation between T R O P I C A L terized
From the Hematology Section, the Department of Medicine and Pediatrics, the University o[ Puerto Rico School of Medicine. This study was supported by National Institutes o] Health Hematology Training Grant No. T I A M 5302-05, National Institute of Arthritis and Metabolic Diseases Grant No. 02776-10, and by N I H Grant No. FR-63-05 [rom the Division o[ Research Facilities and Resources. This work was presented at the Twel[th Congress o[ the International Society o[ Hematology held ih New York City during September, 1968. Vol. 76, No. 3, pp. 470-479
tropical sprue in adults and intestinal realabsorption or chronic diarrhea in children has been reported. Textbooks of pediatrics 1~ 11 and recent reviews of the literature on malabsorption syndromes in children 12, 13 do not mention tropical sprue as one of the causes of this disorder in the pediatric age group. Therefore this relatively common tropical condition remains largely unknown to the physicians engaged in the care of children. It is the purpose of this report to present clinical data and response to therapy in 11 children with tropical sprue. M A T E R I A L AND M E T H O D S Eleven Puerto Rican children with chronic diarrhea and malnutrition admitted to the University Hospital in Rio Piedras, Puerto Rico, from 1962 to 1968 were studied. Baseline work-up included complete history and physical examination, complete blood counts, bone marrow aspiration, stool examinations
Volume 76 Number 3
for ova, parasites, and occult blood, and radiographic examination of the small intestine. The xylose absorption was measured by the urinary excretion of D-xylose during 5 hours after the oral ingestion of 5 Gm. of that pentose? ~ The vitamin A absorption test was performed by measuring the maxim u m ~increment of vitamin A in the serum at 5 or 7 hours after the oral ingestion of a standard dose of 300,000 I. U. of Oleum Percomorphum.*~ Serum carotene was determined on a blood specimen obtained after fasting for 8 hours. .5 T h e jejunal biopsy was obtained with the pediatric Crosby-Kugl e r capsule 16 at a distance of 75 cm. from the lips in children below 10 years of age, and at 90 cm. in children over 10 years. The histologic picture of the jejunal mucosa was evaluated blindly, by an experienced pathologist not participating in this study, according to Swanson and Thomassen's criteriaY The serum folic acid level was determined by the LactobacilIus casei assay *s and the serum vitamin B,2 concentrations by the Euglena gracilis method. .9 T h e serum immunoglobulin concentration was determined by the radial immunodiffusion technique using Hyland Laboratory's immunodiffusion plates. Serum iron, cholesterol, calcium, phosphorus, total proteins and A / G ratio, and prothrombin time were determined by conventional methods. After completion of base-line studies, 7 patients were treated with folic acid 5 rag. 3 times daily orally, and 30 /xg of vitamin B12 daily for 7 days followed by the same dose intramuscularly at weekly intervals. One patient was treated only with folic acid orally, and another patient was treated with oxytetracycline 250 mg. 4 times per day for one month and then twice daily for 5 months. T w o patients were first treated with a glutenfree diet for 10 weeks while kept in a metabolic ward. They were then challenged with gluten, and afterward they were kept on a regular diet while receiving folic acid and vitamin B,2. T h e patients were followed in the outpatient clinics and were re-evaluated with complete blood counts, radiographic examination of the small intestine, xylose
Tropical sprue
471
absorption tests, and peroral jejunal biopsies 6 months or more after initiation of therapy. RESULTS
Seven male and 4 female children ranging in age from 2 to 16 years were evaluated. Four of the 11 patients studied had close relatives with tropical sprue, diagnosed and treated in our clinics. T h e father of Patient 9 and the father and brother of Patient 3 had tropical sprue. Patients 2 and 6 were sisters, and their younger brother was also recently found to have tropical sprue (not included in this series). The approximate age at onset of symptoms ranged from 7 months to fourteen years. The duration of symptoms before the diagnosis was established varied from 2 months to 6 years, and the age at time of diagnosis varied from 2 to 16 years. T h e oldest patient in this series, Patient 11, was included because he had had symptoms since age 10. The clinical findings of these patients at the time of admission are summarized in Table I. Most of the patients had a history of anorexia, weakness, pallor, chronic diarrhea and weight loss, or failure to gain weight. Some also complained o f abdominal pains and burning of the tongue. Glossitis was present in most patients, but it was usually mild. Mild to moderate malnutrition was present in all of them, but neither kwashiorkor n o r specific nutritional deficiencies were noted. All patients but one were below the third percentile in weight. Five children were below the third percentile in heightY ~ 10
Table I. Incidence of signs and symptoms of tropical sprue in 11 children
Signs and symptoms Weight loss or failure to gain weight Anorexia Weakness Pallor Chronic diarrhea Glossitis, mild Abdominal pains Abdominal distension Burning of tongue Vomiting
] No. I1 10 10 10 10 8 4 3 2 1
4 7 2 Santiago-Borrero, Maldonado, and Horta
The Journal o[ Pediatrics March 1970
T a b l e I I . T r o p i c a l sprue in children: h e m a t o l o g i c d a t a
Patient
1 Ag e (yrs.)
Hem~176 [ MCV~ (Gm./lO0 mL) (a s)
] Serum [olate I Serum B2~ (mtzgm/ml.) (##g/ml.)
Bone marrow
1. F. O.M.
14
4.0
122
--
65 43
MegalobIastic
2. F. O.R.
13
6.7
113
2.5
43 I00
Megaloblastic
3. C. O.O.
9
10.0
124
4.0 2.9
84 84
Megaloblastic
4 E. R . V .
2~
8.2
I 11
1.3 1.5
--
Megaloblastic
5. R. B.B.
14
5.7
108
1.0 2.0
--
Megaloblastic
6. J. O.R.
14
10.3
100
4.0
--
Partially megalobIastic
7. E. S.R.
9
11.1
121
2.0 3.0
200 200
Partially megaloblastic
8. I. R.A.
2
9.2
--
3.5
--
Megaloblastic
9. R. H.P.
9
8.5
--
--
150
Megaloblastic
10. E. V.O.
I0
13.4
123
2.7
--
Megaloblastic
1 I. J. L.S.
16
13.2
111
4.5
80
Megaloblastlc
Normal values
--
12.5-14.5
82-92
5-12
200-800
~'MCV = mean corpuscular volume.
None of the patients h a d hepatosplenomegaly, jaundice, edema, o r dermatitis. No p u l m o n a r y abnormalities were detected on physical or roentgenologic examination. T h e h e m a t o l o g i c d a t a are presented in T a b l e I I . All our patients h a d macrocytosis in the p e r i p h e r a l blood smear a n d m e g a loblastosis of variable degrees with a d e q u a t e stores of iron in the bone m a r r o w , as det e r m i n e d by the ~Prussian blue reaction. T h e h e m o g l o b i n concentration v a r i e d f r o m 4.0 to 13.4 Gm. p e r 100 ml., a n d in 7 patients it was less t h a n 10.0 Gm. p e r 100 ml. T h e serum folate level was low in all 9 patients tested. I n 5 o u t of 6 the serum vitamin B12 concentration was low. Eight of o u r patients h a d intestinal p a r a sites. Five h a d m i l d a n d one m o d e r a t e infestation with Trichuris trichiura, one h a d mild m i x e d trichuriasis a n d uncinariasis, a n d one h a d m i l d uncinariasis. T h e results of gastrointestinal studies are summarized in Tabt~ I I I . T h e xylose absorp-
tion test using the 5 Gm. dose was below 1.2 Gm. p e r volume in all the patients. 14, 21 T h e v i t a m i n A absorption test was a b n o r m a l in the 9 patients tested, a n d the serum carotene was low in 7 out of 9. T h e r a d i o g r a p h i c e x a m i n a t i o n of the small intestine was obt a i n e d in 8 children, a n d 6 of t h e m h a d changes of malabsorption. Peroral intestinal biopsy with the C r o s b y - K u g l e r p e d i a t r i c capsule was p e r f o r m e d w i t h o u t complications in all the patients. H o w e v e r , the biopsy m a terial o b t a i n e d in Patient 9 was lost. Gross a n d microscopic e x a m i n a t i o n of the intestinal m u c o s a o b t a i n e d in 10 patients showed changes c o m p a t i b l e with tropical sprue: 4 h a d m o d e r a t e , 5 h a d severe, a n d one h a d a t r o p h i c changes. T h e specimen o b t a i n e d in Patient 8 was f r o m the ileum. However, the ileal a b n o r m a l i t y seen in this p a t i e n t has been also d e m o n s t r a t e d in tropical sprueY 2 Fig. 1 shows the p h o t o m i c r o g r a p h s of the j e j u n a l m u c o s a before t h e r a p y in Patients 3 a n d 10. T h e r e was over-all t h i n n i n g of the
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Tropical @rue
473
T a b l e I I I . T r o p i c a l sprue in children: intestinal studies
Patient 1. F. O.M.
absorption (Gm./5 hr./5 Gin. dose) 0.40
carotene (#g %) 39
Vitamin A absorption (#g % increment) +31
2. F . O . R .
0.90
15
+64
Changes of malabsorption
Severe tropical sprue
3. C. O.O.
0.51
8.0
+8
Normal
Moderate tropical sprue
4. E. R.V.
0.20
2.0
+18
Changes of malabsorption
Atrophic tropical sprue
5. R. B.B.
0.77
18
+31
Changes of malabsorption
Moderate tropical sprue
6. J. O.R.
1.10
18
+10
Changes of malabsorptlon
Severe tropical sprue
7. E. S.R.
0.32
+10
Changes of malabsorption
Severe tropical sprue
8. I. R.A.
0.42
--
9. R. H.P.
0.90
54
10. E. V.O.
0.52
11. J. L.S.
0.70
Normal values
1.20
Xylose
Serum
0.0
Jejunal biopsy Small bowel series Severe tropical Normal sprue
+7
0.0
--
Moderate ileitis
--
Biopsy report not available
Changes of malabsorption
+13
--
Moderate tropical sprue
--
38-76
Severe tropical sprue
--
75
T a b l e I V . S e r u m i m m u n o g l o b u l i n levels in children with tropical sprue
Immunoglobulin IgG IgM
Levels (mg./lO0 ml.) Patient No.
Normal values (mg./lOOml.) 1[ 21314 [ 5 I 1718 600-1,200 1,050 2,200 1,550 1,200 1,300 1,800 1,100 70-200
65
270
300
165
210
260
155
40-100
63
54
75
60
63
90
45
mucosa, flattening a n d shortening of the villi, lengthening of the crypts, inversion of the ratio between the length of the villi a n d the crypts, a n d m a r k e d infiltration of the mucosa with lymphocytes, p l a s m a cells, a n d eosinophils. T a M e I V presents the i m m u n o g l o b u l i n levels in our patients. D e t e r m i n a t i o n s of serum i m m u n o g l o b u l i n c o n c e n t r a t i o n showed I g G r a n g i n g f r o m 1,050 to 3,350 mg. p e r 100 ml., I g A from 65 to 270, a n d I g M f r o m 40
19110111 3,300 1,150 240 180 65 60 45 35
--
2,100 160 140
to 140. Some patients h a d an elevation of immunoglobulins, b u t n o n e h a d evidence of i m m u n o g l o b u l i n deficiency. T h e serum cholesterol, total pf0teiffs, albumin, a n d globulin, a n d p r o t h r o m b i n time in o u r patients are presented in T a b l e V. T h e cholesoerol level was below 100 rag. p e r 100 ml. in one t h i r d of the patients tested. T h e t o t a l proteins were below 6.0 Gin. p e r 100 ml. in one, a n d the serum a l b u m i n
4 74
Santiago-Borrero, MaIdonado, and Horta
A
Fig. 1. Photomicrographs of the jejunal mucosa of Patients 3 (A) and 10 (B) before therapy, showing changes of moderate and severe tropical sprue, respectively. (Hematoxylin and eosin, xl00.)
The journal o[ Pediatrics March 1970
below 4 Gm. p e r 100 ml. in 2 of 9 patients studied. T h e p r o t h r o m b i n time was slightly p r o l o n g e d in 2 a n d m o d e r a t e l y p r o l o n g e d in 1 of 6 cases tested. F o u r of t h e patients h a d serum calcium a n d phosphorus d e t e r m i n a tions; they were all within n o r m a l limits. T h e clinical response to t h e r a p y with folic acid a n d v i t a m i n B12 was good to excellent in all patients, except in P a t i e n t 6. P a t i e n t 11 was t r e a t e d with oxytetraeycline a n d h a d an excellent response. Most patients h a d r a p i d i m p r o v e m e n t in general well-being, strength, body weight, a n d h e m o g l o b i n concentration d u r i n g the first m o n t h of treatment. T h e bowel m o v e m e n t s b e c a m e less frequent, less bulky, less foul smelling, a n d acquired a n o r m a l color within 1 t o 2 months of therapy. However, in some p a tients the stools r e m a i n e d soft in consistency. T w o patients who were t r e a t e d w i t h a strict gluten-free diet, Patients 3 a n d 7, h a d a fair response in general well-being, intestinal symptoms, body weight, a n d xylose absorption; however, the h e m o g l o b i n concentration actually decreased a n d the j e j u n a l mucosa r e m a i n e d unchanged. R e i n t r o d u c t i o n of gluten in the diet p r o d u c e d no detectable changes in the clinical picture. F u r t h e r thera p y with folic acid a n d v i t a m i n B12 p r o d u c e d a n d m a i n t a i n e d h e m a t o l o g i c a n d gastrointestinal remissions while on a regular diet.
T a b l e V. S e r u m cholesterol a n d p r o t e i n values a n d p r o t h r o m b i n time in children w i t h tropical sprue
Patient No. 1 2 3 4 5 6 7 8 9 10 11
Cholesterol (mg./lO0 ml.) 122 93 88 85 130 146 151 -130 -136
Total proteins (Gm./lO0 rnI.) 6.1 6.1 6.8 6.1 7.6 -6.1 7.0 6.2 5.3 --
Albumin (Gm./lO0 ml.) 4.5 4.2 4.2 4.3 5.0 -4.5 4.3 3.6 3.6 --
Globulin (Gm./lO0 ml.) 1.6 1.9 2.6 1.8 2.7 -1.6 2.7 2.6 1.7 --
Average
120
6.4
4.2
2.1
Prothrombin time (sees.) (patient~control) 14/13 15/14 23/15 19/13 19/15 14/13
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Tropical sprue
T h e r e was a r a p i d increase in body weight d u r i n g the first few month.s of t h e r a p y in most of the patients. T h r e e c h i l d r e n r e a c h e d the fiftieth weight percentile, 1 the twentyfifth, 3 the tenth, a n d 2 the t h i r d percentile after 6 months of treatment. T w o children r e m a i n e d below the third percentile in spite of s{gnificant gain in weight} ~ 10 T a b l e V I summarizes the c l i n i c a l a n d l a b o r a t o r y d a t a before a n d after therapy. T h e h e m o g l o b i n concentration increased r a p i d l y in all p a tients who were anemic, except in one (Patient 6) who did not take the m e d i c a t i o n s regularly. O n e child ( P a t i e n t 4) d e v e l o p e d evidence of iron deficiency after the hemoglobin h a d increased from 5.8 to 10.3 G m . p e r 100 ml. with t r e a t m e n t with folic a c i d a n d v i t a m i n B12. D u r i n g the 9 m o n t h s of t h e r a p y his body weight c h a n g e d f r o m 22 to 34 pounds, a 55 p e r cent increase. I m p r o v e m e n t in xylose absorption was r e m a r k a b l e
4 75
in 9 patients, b e c o m i n g n o r m a l in 7 a n d increasing f r o m 0.2 a n d 0.3 to 0.9 Gm. in Patients 4 a n d 7, respectively. T w o o t h e r p a tients with only mild a b n o r m a l i t y of the xylose absorption test before t h e r a p y rem a i n e d essentially unchanged. ~Peroral biopsy of t h e j e j u n a l mucosa was o b t a i n e d for reevaluation in all patients. I m p r o v e m e n t in the a p p e a r a n c e of the m u c o s a occurred in 7 children. I n one, the mucosol lesions c h a n g e d from a t r o p h i c to m o d e r a t e involvement of tropical sprue, 2 from severe to m o d e r a t e , 2 f r o m severe to mild, a n d 2 from m o d e r a t e to mild. T h r e e patients h a d no i m p r o v e m e n t in the a p p e a r a n c e of the j e j u n a l m u c o s a after 6 to 9 months of t h e r a p y ; a n o t h e r p a tient h a d no p r e t r e a t m e n t biopsy specimen for comparison. T h e small bowel series was r e p e a t e d in the 6 patients w h o h a d an abn o r m a l p a t t e r n before biopsy. It r e m a i n e d a b n o r m a l in 3 children after therapy. Fig.
T a b l e V I . T r o p i c a l sprue in children: resonse to t h e r a p y
Xylose~
Patient 1. F. O.M.
Age (yr.) ~ 14 18
Hgb. ~ (Gm./lO0 ml.) 6.5 14.9
Welght ~ (pounds) 60 118
2. F. O.R.
13
15.5
5.6
12.0
57
102
0.9
1.4
Mild Severe tropical sprue tropical sprue
3. C. O.O.
9
9.5
8.2
11.8
41
50
0.5
2.3
Moderate Moderate tropical sprue tropical sprue
4. E. R.V.
2.5
3.33
5.8
i0.3
22
34
0.2
0.9
Moderate Atrophic tropical sprue tropical sprue
(Gin.~5 hr./ 5 Gin. dose) Jejunal biopsy~ Moderate 0.4 1.4 Severe tropical s_prue tropical sprue
5. R. B.R.
14
14.5
5.7
13.2
78
103
0.8
1.9
Moderate Moderate tropical sprue tropical sprue
6. J. O.R.
14
14.5
10.3
I0,6
51
57
I.I
1.0
Severe Severe tropical sprue tropical sprue
7. E. S.R.
9
9.5
9.0
12.3
41
55
0.3
0.9
Mild Severe tropical sprue tropical sprue
8. I. R.A.
2
2.5
9.2
12.2
22
30
0.4
1.6
Moderate ileitis
9. R. H.P.
9
8.5
12.0
48
78
0.9
1.1
10. E . V . O .
10
10.5
13.4
12.7
51
81
0.5
1.5
11. J. L.S.
16
16.16 13.2
13.1
93
110
0.7
14
--
Mild tropical sprue Moderate tropical sprue
Moderate Severe tropical sprue tropical sprue
Mild Moderate tropical sprue tropical sprue "~The first and second figures in each column represent the values before and after therapy, respectively. 1.4
476
Santiago-Borrero, Maldonado, and Horta
A
B
Fig. 2. Photomicrographs of biopsies of the jejunal mucosa of Patients 3 (A) and 10 (B) showing mild to moderate improvement of the mucosal lesions. Patient 10 (B) was treated with folio acid and vitamin B12 for 8 months. The jejunal biopsy of Patient 3 (A) was obtained after 19 months of therapy with vitamin BI~ and folic acid, plus sulfasuxidine during the last 12 months of the course. (Hematoxylin and eosin, xl00.)
2 shows photomicrographs of the jejunal mucosa of 2 children (Patients 3 and 10) after therapy. DISCUSSION
Tropical sprue is the most prevalent primary malabsorption disorder in m a n y tropical areas? It has been recognized as a welldefined medical entity since first described over two h u n d r e d years ago by Hillary in the island of Barbados, one of the West Indies. 23 T h e r e are only 4 case reports of tropical sprue in ,children in the medical literature, most of them inadequately docu-
The Journal of Pediatrics March 1970
mented. 5s However, children are reported to have been affected in epidemics of tropical sprue in South India, 2 and Baker and M a t h a n 24 studied 20 pediatric.patients affected by this disorder. T h e pathogenesis of tropical sprue is still unknown. Gluten intolerance has been proved not to be an etiologic factor. 22 Folic acid and vitamin B12 deficiency are not the cause of the alterations in the small intestinal mucosa, but folic acid and B12 therapy usually result in rapid clinical improvement, hematologic remission, and decrease in the abnormality of the jejunal m u c o s a ? -3, 26 An infectious cause of tropical sprue has been suspected for m a n y years, but no etiologic agent has been isolated from the stools or intestinal contents of these patients? 7, 2s It is rare to see megaloblastic anemia in children outside the age group of 2 to 17 months. 2~ Very few of the malabsorption disorders in children are accompanied by macrocytic anemia and subnormal levels of serum folic acid and vitamin B12.30 T h e presence of these findings in our patients made us suspect that they belonged to a separate group, probably tropical sprue. There is a high incidence of intestinal parasitosis in tropical areas. A few types of parasitic infestations have been shown to cause intestinal malabsorption, especially infestation with Giardia lamblia al and Strongyloides stercoralis? 2 Uncinariasis has been shown not to cause malabsorption? s T h e type and degree of intestinal parasitic infestation present in our patients is not expected to cause malabsorption, megaloblastic anemia, and malnutrition. T h e blind loop syndrome and anatomic defects or malformations of the intestine causing stagnation, bacterial overgrowth, or short circuiting of ingested food and nutrients have been shown to cause malabsorption? 4 These entities were excluded in our patients by the radiographic examination of the small intestine. Immunoglobulin deficiencies associated with intestinal malabsorption have been reported by several authors,3~, a6 but none of our patients h a d deficiency of immunoglobulins. Food allergy,
Volume 76 Number 3
hepatobiliary disease, severe iron deficiency, severe malnutrition, mucoviscidosis, intestinal lymphangiectasia, a-beta-lipoproteinemia, congenital disaccharidase deficiencies, giardiasis, and strongyloidiasis have all been reported to cause malabsorption. 2' 12, la The presence of adequate stores of iron in the bone marrow of all of our patients, the fairly normal serum proteins and A / G ratio, the serum cholesterol above 85 rag. per 100 ml. in the cases tested, the normal chest films, and negative stools for giardia and strongyloides, besides the clinical picture and response to therapy, make these diagnoses very unlikely. The peroral intestinal biopsy is one of the most reliable and most important tests in the etiologic diagnosis of intestinal malabsorption.2, a, 12, i3 Intestinal biopsy specimens were examined in 10 of our patients before therapy and all of them showed changes similar to those encountered in the jejunal mucosa of adult patients with tropical sprue?7, 37 The abnormality of the jejunal mucosa in tropical sprue is characteristic, but not pathognomonic of this disease. Occasionally, other conditions, like severe protein malnutrition, 3~, as, 39 intestinal infestation with Giardia lamblia 31 or Strongyloides stercoralis, 32 and celiac disease, 17 may cause similar findings. However, the history and physical and laboratory findings usually make the differentiation easy. In most patients with tropical sprue the abnormality of the jejunal mucosa is less severe and clearly different from that of children with untreated celiac disease. Rarely, patients with tropical sprue may have atrophic changes in the mucosa which are almost indistinguishable from those of gluten-induced enteropathy. However, some authors 3, 17 believe that the gross appearance is different, and that if attention is paid to some details in the histologic picture these conditions can be differentiated. Gluten-induced enteropathy or celiac disease usually presents with microcytic hypochromic anemia, a~ Cooke 4~ reported megaloblastic anemia in only 8 out of 50 patients with celiac disease. The consistent occurrence of macrocytosis, megaloblastic bone marrow,
Tropical sprue
4 77
and low levels of serum folic acid in our patients, and i n addition the good response to folic acid and vitamin B12 in most of them, provided evidence against the diagnosis of celiac disease. T h e absence of a clear-cut clinical response after l0 weeks of therapy with a gluten-free diet in Patients 3 and 7, the worsening of the anemia and the unchanged appearance of the jejunal mucosa, plus the failure to induce a clinical exacerbation of the disease upon reintroduction of gluten to the diet, clearly eliminated the possibility of celiac disease. Partial improvement in patients with tropical sprue treated with a gluten-free diet has been reported by Bayless and associates 2s and by Cancio and associates. 41 The clinical response of tropical sprue to folic acid and vitamin B~2 has been well documented.a, 2G However, the remission is frequently incomplete, the relapse rate is relatively high, and abnormalities in the jejunal mucosa persist in about two thirds of the patients treated with folio acid and vitamin B12.~2, 42 More complete clinical remission and better histologic improvement of the jejunal mucosa have been achieved by longterm therapy with broad-spectrum antibiotics and nonabsorbable sulfonamides.43, 44 However, the onset of the hematologic remission appears earlier with folic acid and vitamin Bz2.43, 44 All the patients included in this series, with the possible exception of Patient 6, had a good response to therapy with folic acid and vitamin B~2, and one with oxytetracycline. We feel that this therapeutic response confirmed the diagnosis of tropical sprue in the children presented in this report. SUMMARY
Tropical sprue is a common disease of adults in Puerto Rico and other tropical areas. Some investigators have observed a disease in children similar to that seen in adults. However, only a few reports in the medical literature describe this disease in childhood. We have studied 7 boys and 4 girls whose ages ranged from 2 to 16 years with anorexia, weakness, pallor, chronic
478
Santiago-Borrero, Maldonado, and Horta
diarrhea, weight loss or failure to gain weight, glossitis, a n d m a l n u t r i t i o n . T h e symptoms were present from 2 months to 6 years. Macrocytosis, megaloblastic bone marrow, a n d a b n o r m a l absorption of xylose were present in all. T h e intestinal mucosa showed changes compatible with tropical sprue in 10 patients in w h o m biopsy material was studied. T h e v i t a m i n A absorption test was a b n o r m a l in 9, a n d the serum carotene level was low in 7 of 9 patients studied. T h e serum folic acid level wag low in 8 patients tested. T w o patients h a d partial i m p r o v e m e n t o n a gluten-free diet, b u t the mucosal abnormality r e m a i n e d u n c h a n g e d , a n d the clinical findings did n o t relapse when challenged with gluten. N i n e patients h a d a good response to therapy with folic acid a n d vitam i n B12; one h a d excellent i m p r o v e m e n t with oxytetracycline therapy. T h e r e were rapid increases in hemoglobin concentrations a n d in body weight a n d improved control of diarrhea. R e p e a t studies 6 m o n t h s or more after initiation of therapy showed normalization in absorption of xylose in 7 children a n d m a r k e d i m p r o v e m e n t in 2. T h e r e was considerable i m p r o v e m e n t of the j e j u n a l mucosa in 7 patients. W e believe that the syndrome described in these patients is the same disease as tropical sprue in adults.
The Journal o[ Pediatrics March 1970
9.
10. 11. 12. 13. 14.
15. 16.
17. 18.
19. 20.
REFERENCES
1. P6rez-Santiago, E., and Butterworth, C. E.: Definition and diagnosis of sprue, Amer. J. Dig. Dis. 2: 225, 1957. 2. Bockus, H. L.: Secondary malabsorption syndromes: nasologic and diagnostic aspects, Bol. Asoc. Med. P. Rico 58: 112, 1966. 3. Klipstein, F. A.: Progress in gastroenterology: tropical sprue, Gastroenterology 54: 275, 1968. 4. Rodriguez-Molina, R.: Sprue in Puerto Rico--10 years later, P. Rico J. Pub. Health Trop. Med. 18: 314, 1943. 5. Bahr, P. H.: A report on researches on sprue in Ceylon, Cambridge, 1915, Cambridge University Press, p. 122. 6. Johnson, J., and Breidigan, F. T.: Tropical sprue in a child six years of age, Amer. J. Med. Sci. 170: 364, 1925. 7. Miller, R.: A case of sprue commencing at the age of eleven and a half years, Trans. Roy. Soc. Trop. Med~. Hyg. 27: 413, 1934. 8. Mathew, K., Ignatius, M., Meenakshiammal,
21. 22.
23. 24. 25. 26.
27.
and Baker, S. J.: Tropical sprue in children, Indian Pediat. 1: 271, 1964. Baker, S. J., Mathan, V. I., and Joseph, I.: The epidemiology of tropical sprue, in Malabsorption syndromes, Symposium, Second World Congress on Gastroenterology, New York, I963, Karger, p. 4. Nelson, W. E. : Textbook of pediatrics, ed. 8, Philadelphia, 1964, W. B. Saunders Co. Brenneman, J., and Kelley, V. C.: Practice of pediatrics, Hagerstown, Md., 1966, W. F. Prior Co., Inc. Gerrard, J. W., and Lubos, M. C.: The realabsorption syndromes, Pediat. Clin. N. Amer. 14: 73, 1967. Anderson, C. M.: Intestinal malabsorption in childhood. Review articIe, Arch. Dis. Child. 41: 571, 1966. Santini, R., Jr., Sheehy, T. W., and Martlnezde Jesfis, J.: The xylose tolerance test with a five gram dose, Gastroenterology 40: 772, 1961. Consolazio, C. F., Johnson, R. E., and Mareck, M. A.: Metabolic methods, St. Louis, 1951, The C. V. Mosby Company, p. 179. Crosby, W. H., and Kugler, H. W.: Intraluminal biopsy of small intestine: IntestinaI biopsy capsule, Amer. J. Dig. Dis. 2: 236, 1957. Swanson, V. L., and Thomassen, R. W.: Pathology of the jejunal mucosa in tropical sprue, Amer. J. Path. 46: 511, 1965. Baker, H., Herbert, V., Frank, O., Pasher, I., Hunter, S. H., Wasserman, L. R., and Sobotka, H.: A microbiological method for detecting folic acid deficiency in man, Clin. Chem. 5: 275, I959. Ross, G. I. M.: Vitamin B-12 assay in body fluids using Euglena gracilis, J. Clin. Path. 5: 250, 1952. Knott, V. B.: Stature, leg girth and body weight of Puerto Rican private school children measured in 1962, Growth 27: 157, 1963. Santiago, P. J., Santinl, R., Jr., and Maldonado, N.: Xylose absorption test in Puerto Rican children. Unpublished. Sheehy, T. W., Baggs, B., P6rez-Santiago, E., and Flock, M. H.: Prognosis of tropical sprue: A study of the effect of folic acid on the intestinal aspects of acute and chronic sprue, Ann. Intern. Med. 57: 892, 1962. Booth, C. C.: The first description of tropical sprue (William Hillary), Gut 5, 45, 1964. Baker, S. J., and Mathan, V. I.: Syndrome of tropical sprue in South India, Amer. J. Glin. Nutr. 21: 984, 1968. Bayless, T. M.: Tropical sprue: A comparison with celiac disease, Amer. J. Dig. Dis. 9: 779, 1964. Su~rez, R. M., Spies, T. D., Hern~ndezMorales, F., and P6rez-Santiago, E.: A note on the effectiveness of vitamin B-12 in the treatment of tropical sprue in relapse, Blood 4: 1124, 1949. Nadel, H., and Gardner, F. H.: Bacterial as-
Volume 76 Number 3
28.
29. 30. 31. 32. 33.
34.
35. 36.
say of small bowel secretion in tropical sprue, Amer. J. Trop. Med. 5: 686, 1956. Bayless, T. M., Guardiola-Rotger, A., and Wheby, M. S.: Tropical sprue: viral cultures of rectal swabs, Gastroenterology 51: 32, 1966. Luhby, A. L.: Megaloblastic anemia in infancy: Clinical considerations and analysis, J. PEDIAT, 54: 617, 1959. Smith, C. tI.: Blood diseases of infancy and childhood, ed. 2, St. Louis, 1966, The C. V. Mosby Company, pp. 226-239. Cortner, J. A.: Giardiasis, a cause of celiac syndrome, Amer. J. Dis. Child. 98: 311, 1959. Jones, G. H.: Clinical studies in human strongyloidiasis, Gastroenterology 16: 743, 1950. Mayoral, L. G., Tripathy, K., Garcla, F. T., Bolafios, O., and Ghitis, J.: Protein malnutrition-induced malabsorption and other enteropathies in Colombia, Amer. J. Clin. Nutr. 21: 1053, 1968. Thompson, R. B., and Ungley, C. C.: Megaloblastic anemia .associated with anatomic lesions in the small intestine, Blood 10: 771, 1955. Crabb6, P. A., and Haremans, J. F.: Lack of gamma-A immunoglobulin in serum of patients with steatorrhea, Gut 7: 119, 1966. Pelkonen, R., Siurala, M., and Vuopio, P.:
Tropical sprue
37. 38. 39.
40. 41. 42. 43. 44.
479
Inherited agammaglobulinemia with malabsorption and marked alterations in the gastrointestinal mucosa, Acta Med. Scand. 173: 549, 1963. Butterworth, C. E., and P6rez-Santiago, E.: Jejunal biopsies in sprue, Ann. Intern. Med. 48: 8, 1958. Stanfield, J. P., Hutt, M. S. R., and Tunnicliffe, R.: Intestinal biopsy in kwashiorkor, Lancet 2: 5t9, 1965. Brunser, O., Reid, A., Monckerberg, F., Maccioni, A., and Contreras, I.: Jejunal mucosa in infant malnutrition, Amer. J. Clin. Nutr. 21: 976, 1968. Cooke, W. T.: Adult celiac disease, Amer. J. Dig. Dis. 7: 957, 1962. Cancio, M. R., Rodrlguez-Molina, R., and Asenjo, C. F.: Gluten and tropical sprue, Amer. J. Trop. Med. 10: 782, 1961. Bayless, T. M., Wheby, M. S., and Swanson, V. L.: Tropical sprue in Puerto Rico, Amer. J. Clin. Nutr. 21: 1030, 1968. Guerra, R., Wheby, M. S., and Bayless, T. M.: Long-term antibiotic therapy in tropical sprue, Ann. Intern. Med. 63: 619, 1965. Maldonado, N., Horta, E., Guerra, R., and P6rez-Santiago, E.: Poorly absorbed sulfonamide in the treatment of tropical sprue, Gastroenterology. In press.
PEDIATRICS
Derrick B. Jelliffe, Editor
Tropical sprue in children Eleven Puerto Rican children with chronic diarrhea, intestinal malabsorption, abnormal jejunal mucosa, megaIoblastir bone marrow, and malnutrition have been studied. The patients were treated with [olic acid alone or folic acid and vitamin BI,; one patient received oxytetracydine. The results were good to excellent in all but one o[ the children. This symptomatic, "hematologic, and gastrointestinal responses were similar to those reported in adult patients with tropical sprue. The evidence presented here suggests that this syndrome in children is the same disease as tropical sprue in adults mani[ested at an early age, sometimes as early as the first year o[ li[e. The etiology o[ this disease in children, as well as in adults, remains unknown.
Pedro J. Santiago-Borrero, M.D., Norman Maldonado, M.D., and Enrique Horta,
M.D. CAPARRA
HEIGHTS,
PUERTO
RICO
S P R U lg iS a disease c h a r a c by anorexia, weakness, chronic diarrhea, intestinal malabsorption , abnormal jejunal mucosa, malnutrition, glossitis, and megaloblastic anemia. One or more of the characteristic signs may be absent in some patients? -4 This disease has been described in adults of all ages, but very few patients under the age of 15 years have been described in the medical literature?, 5-~ No relation between T R O P I C A L terized
From the Hematology Section, the Department of Medicine and Pediatrics, the University o[ Puerto Rico School of Medicine. This study was supported by National Institutes o] Health Hematology Training Grant No. T I A M 5302-05, National Institute of Arthritis and Metabolic Diseases Grant No. 02776-10, and by N I H Grant No. FR-63-05 [rom the Division o[ Research Facilities and Resources. This work was presented at the Twel[th Congress o[ the International Society o[ Hematology held ih New York City during September, 1968. Vol. 76, No. 3, pp. 470-479
tropical sprue in adults and intestinal realabsorption or chronic diarrhea in children has been reported. Textbooks of pediatrics 1~ 11 and recent reviews of the literature on malabsorption syndromes in children 12, 13 do not mention tropical sprue as one of the causes of this disorder in the pediatric age group. Therefore this relatively common tropical condition remains largely unknown to the physicians engaged in the care of children. It is the purpose of this report to present clinical data and response to therapy in 11 children with tropical sprue. M A T E R I A L AND M E T H O D S Eleven Puerto Rican children with chronic diarrhea and malnutrition admitted to the University Hospital in Rio Piedras, Puerto Rico, from 1962 to 1968 were studied. Baseline work-up included complete history and physical examination, complete blood counts, bone marrow aspiration, stool examinations
Volume 76 Number 3
for ova, parasites, and occult blood, and radiographic examination of the small intestine. The xylose absorption was measured by the urinary excretion of D-xylose during 5 hours after the oral ingestion of 5 Gm. of that pentose? ~ The vitamin A absorption test was performed by measuring the maxim u m ~increment of vitamin A in the serum at 5 or 7 hours after the oral ingestion of a standard dose of 300,000 I. U. of Oleum Percomorphum.*~ Serum carotene was determined on a blood specimen obtained after fasting for 8 hours. .5 T h e jejunal biopsy was obtained with the pediatric Crosby-Kugl e r capsule 16 at a distance of 75 cm. from the lips in children below 10 years of age, and at 90 cm. in children over 10 years. The histologic picture of the jejunal mucosa was evaluated blindly, by an experienced pathologist not participating in this study, according to Swanson and Thomassen's criteriaY The serum folic acid level was determined by the LactobacilIus casei assay *s and the serum vitamin B,2 concentrations by the Euglena gracilis method. .9 T h e serum immunoglobulin concentration was determined by the radial immunodiffusion technique using Hyland Laboratory's immunodiffusion plates. Serum iron, cholesterol, calcium, phosphorus, total proteins and A / G ratio, and prothrombin time were determined by conventional methods. After completion of base-line studies, 7 patients were treated with folic acid 5 rag. 3 times daily orally, and 30 /xg of vitamin B12 daily for 7 days followed by the same dose intramuscularly at weekly intervals. One patient was treated only with folic acid orally, and another patient was treated with oxytetracycline 250 mg. 4 times per day for one month and then twice daily for 5 months. T w o patients were first treated with a glutenfree diet for 10 weeks while kept in a metabolic ward. They were then challenged with gluten, and afterward they were kept on a regular diet while receiving folic acid and vitamin B,2. T h e patients were followed in the outpatient clinics and were re-evaluated with complete blood counts, radiographic examination of the small intestine, xylose
Tropical sprue
471
absorption tests, and peroral jejunal biopsies 6 months or more after initiation of therapy. RESULTS
Seven male and 4 female children ranging in age from 2 to 16 years were evaluated. Four of the 11 patients studied had close relatives with tropical sprue, diagnosed and treated in our clinics. T h e father of Patient 9 and the father and brother of Patient 3 had tropical sprue. Patients 2 and 6 were sisters, and their younger brother was also recently found to have tropical sprue (not included in this series). The approximate age at onset of symptoms ranged from 7 months to fourteen years. The duration of symptoms before the diagnosis was established varied from 2 months to 6 years, and the age at time of diagnosis varied from 2 to 16 years. T h e oldest patient in this series, Patient 11, was included because he had had symptoms since age 10. The clinical findings of these patients at the time of admission are summarized in Table I. Most of the patients had a history of anorexia, weakness, pallor, chronic diarrhea and weight loss, or failure to gain weight. Some also complained o f abdominal pains and burning of the tongue. Glossitis was present in most patients, but it was usually mild. Mild to moderate malnutrition was present in all of them, but neither kwashiorkor n o r specific nutritional deficiencies were noted. All patients but one were below the third percentile in weight. Five children were below the third percentile in heightY ~ 10
Table I. Incidence of signs and symptoms of tropical sprue in 11 children
Signs and symptoms Weight loss or failure to gain weight Anorexia Weakness Pallor Chronic diarrhea Glossitis, mild Abdominal pains Abdominal distension Burning of tongue Vomiting
] No. I1 10 10 10 10 8 4 3 2 1
4 7 2 Santiago-Borrero, Maldonado, and Horta
The Journal o[ Pediatrics March 1970
T a b l e I I . T r o p i c a l sprue in children: h e m a t o l o g i c d a t a
Patient
1 Ag e (yrs.)
Hem~176 [ MCV~ (Gm./lO0 mL) (a s)
] Serum [olate I Serum B2~ (mtzgm/ml.) (##g/ml.)
Bone marrow
1. F. O.M.
14
4.0
122
--
65 43
MegalobIastic
2. F. O.R.
13
6.7
113
2.5
43 I00
Megaloblastic
3. C. O.O.
9
10.0
124
4.0 2.9
84 84
Megaloblastic
4 E. R . V .
2~
8.2
I 11
1.3 1.5
--
Megaloblastic
5. R. B.B.
14
5.7
108
1.0 2.0
--
Megaloblastic
6. J. O.R.
14
10.3
100
4.0
--
Partially megalobIastic
7. E. S.R.
9
11.1
121
2.0 3.0
200 200
Partially megaloblastic
8. I. R.A.
2
9.2
--
3.5
--
Megaloblastic
9. R. H.P.
9
8.5
--
--
150
Megaloblastic
10. E. V.O.
I0
13.4
123
2.7
--
Megaloblastic
1 I. J. L.S.
16
13.2
111
4.5
80
Megaloblastlc
Normal values
--
12.5-14.5
82-92
5-12
200-800
~'MCV = mean corpuscular volume.
None of the patients h a d hepatosplenomegaly, jaundice, edema, o r dermatitis. No p u l m o n a r y abnormalities were detected on physical or roentgenologic examination. T h e h e m a t o l o g i c d a t a are presented in T a b l e I I . All our patients h a d macrocytosis in the p e r i p h e r a l blood smear a n d m e g a loblastosis of variable degrees with a d e q u a t e stores of iron in the bone m a r r o w , as det e r m i n e d by the ~Prussian blue reaction. T h e h e m o g l o b i n concentration v a r i e d f r o m 4.0 to 13.4 Gm. p e r 100 ml., a n d in 7 patients it was less t h a n 10.0 Gm. p e r 100 ml. T h e serum folate level was low in all 9 patients tested. I n 5 o u t of 6 the serum vitamin B12 concentration was low. Eight of o u r patients h a d intestinal p a r a sites. Five h a d m i l d a n d one m o d e r a t e infestation with Trichuris trichiura, one h a d mild m i x e d trichuriasis a n d uncinariasis, a n d one h a d m i l d uncinariasis. T h e results of gastrointestinal studies are summarized in Tabt~ I I I . T h e xylose absorp-
tion test using the 5 Gm. dose was below 1.2 Gm. p e r volume in all the patients. 14, 21 T h e v i t a m i n A absorption test was a b n o r m a l in the 9 patients tested, a n d the serum carotene was low in 7 out of 9. T h e r a d i o g r a p h i c e x a m i n a t i o n of the small intestine was obt a i n e d in 8 children, a n d 6 of t h e m h a d changes of malabsorption. Peroral intestinal biopsy with the C r o s b y - K u g l e r p e d i a t r i c capsule was p e r f o r m e d w i t h o u t complications in all the patients. H o w e v e r , the biopsy m a terial o b t a i n e d in Patient 9 was lost. Gross a n d microscopic e x a m i n a t i o n of the intestinal m u c o s a o b t a i n e d in 10 patients showed changes c o m p a t i b l e with tropical sprue: 4 h a d m o d e r a t e , 5 h a d severe, a n d one h a d a t r o p h i c changes. T h e specimen o b t a i n e d in Patient 8 was f r o m the ileum. However, the ileal a b n o r m a l i t y seen in this p a t i e n t has been also d e m o n s t r a t e d in tropical sprueY 2 Fig. 1 shows the p h o t o m i c r o g r a p h s of the j e j u n a l m u c o s a before t h e r a p y in Patients 3 a n d 10. T h e r e was over-all t h i n n i n g of the
Volume 76 Number 3
Tropical @rue
473
T a b l e I I I . T r o p i c a l sprue in children: intestinal studies
Patient 1. F. O.M.
absorption (Gm./5 hr./5 Gin. dose) 0.40
carotene (#g %) 39
Vitamin A absorption (#g % increment) +31
2. F . O . R .
0.90
15
+64
Changes of malabsorption
Severe tropical sprue
3. C. O.O.
0.51
8.0
+8
Normal
Moderate tropical sprue
4. E. R.V.
0.20
2.0
+18
Changes of malabsorption
Atrophic tropical sprue
5. R. B.B.
0.77
18
+31
Changes of malabsorption
Moderate tropical sprue
6. J. O.R.
1.10
18
+10
Changes of malabsorptlon
Severe tropical sprue
7. E. S.R.
0.32
+10
Changes of malabsorption
Severe tropical sprue
8. I. R.A.
0.42
--
9. R. H.P.
0.90
54
10. E. V.O.
0.52
11. J. L.S.
0.70
Normal values
1.20
Xylose
Serum
0.0
Jejunal biopsy Small bowel series Severe tropical Normal sprue
+7
0.0
--
Moderate ileitis
--
Biopsy report not available
Changes of malabsorption
+13
--
Moderate tropical sprue
--
38-76
Severe tropical sprue
--
75
T a b l e I V . S e r u m i m m u n o g l o b u l i n levels in children with tropical sprue
Immunoglobulin IgG IgM
Levels (mg./lO0 ml.) Patient No.
Normal values (mg./lOOml.) 1[ 21314 [ 5 I 1718 600-1,200 1,050 2,200 1,550 1,200 1,300 1,800 1,100 70-200
65
270
300
165
210
260
155
40-100
63
54
75
60
63
90
45
mucosa, flattening a n d shortening of the villi, lengthening of the crypts, inversion of the ratio between the length of the villi a n d the crypts, a n d m a r k e d infiltration of the mucosa with lymphocytes, p l a s m a cells, a n d eosinophils. T a M e I V presents the i m m u n o g l o b u l i n levels in our patients. D e t e r m i n a t i o n s of serum i m m u n o g l o b u l i n c o n c e n t r a t i o n showed I g G r a n g i n g f r o m 1,050 to 3,350 mg. p e r 100 ml., I g A from 65 to 270, a n d I g M f r o m 40
19110111 3,300 1,150 240 180 65 60 45 35
--
2,100 160 140
to 140. Some patients h a d an elevation of immunoglobulins, b u t n o n e h a d evidence of i m m u n o g l o b u l i n deficiency. T h e serum cholesterol, total pf0teiffs, albumin, a n d globulin, a n d p r o t h r o m b i n time in o u r patients are presented in T a b l e V. T h e cholesoerol level was below 100 rag. p e r 100 ml. in one t h i r d of the patients tested. T h e t o t a l proteins were below 6.0 Gin. p e r 100 ml. in one, a n d the serum a l b u m i n
4 74
Santiago-Borrero, MaIdonado, and Horta
A
Fig. 1. Photomicrographs of the jejunal mucosa of Patients 3 (A) and 10 (B) before therapy, showing changes of moderate and severe tropical sprue, respectively. (Hematoxylin and eosin, xl00.)
The journal o[ Pediatrics March 1970
below 4 Gm. p e r 100 ml. in 2 of 9 patients studied. T h e p r o t h r o m b i n time was slightly p r o l o n g e d in 2 a n d m o d e r a t e l y p r o l o n g e d in 1 of 6 cases tested. F o u r of t h e patients h a d serum calcium a n d phosphorus d e t e r m i n a tions; they were all within n o r m a l limits. T h e clinical response to t h e r a p y with folic acid a n d v i t a m i n B12 was good to excellent in all patients, except in P a t i e n t 6. P a t i e n t 11 was t r e a t e d with oxytetraeycline a n d h a d an excellent response. Most patients h a d r a p i d i m p r o v e m e n t in general well-being, strength, body weight, a n d h e m o g l o b i n concentration d u r i n g the first m o n t h of treatment. T h e bowel m o v e m e n t s b e c a m e less frequent, less bulky, less foul smelling, a n d acquired a n o r m a l color within 1 t o 2 months of therapy. However, in some p a tients the stools r e m a i n e d soft in consistency. T w o patients who were t r e a t e d w i t h a strict gluten-free diet, Patients 3 a n d 7, h a d a fair response in general well-being, intestinal symptoms, body weight, a n d xylose absorption; however, the h e m o g l o b i n concentration actually decreased a n d the j e j u n a l mucosa r e m a i n e d unchanged. R e i n t r o d u c t i o n of gluten in the diet p r o d u c e d no detectable changes in the clinical picture. F u r t h e r thera p y with folic acid a n d v i t a m i n B12 p r o d u c e d a n d m a i n t a i n e d h e m a t o l o g i c a n d gastrointestinal remissions while on a regular diet.
T a b l e V. S e r u m cholesterol a n d p r o t e i n values a n d p r o t h r o m b i n time in children w i t h tropical sprue
Patient No. 1 2 3 4 5 6 7 8 9 10 11
Cholesterol (mg./lO0 ml.) 122 93 88 85 130 146 151 -130 -136
Total proteins (Gm./lO0 rnI.) 6.1 6.1 6.8 6.1 7.6 -6.1 7.0 6.2 5.3 --
Albumin (Gm./lO0 ml.) 4.5 4.2 4.2 4.3 5.0 -4.5 4.3 3.6 3.6 --
Globulin (Gm./lO0 ml.) 1.6 1.9 2.6 1.8 2.7 -1.6 2.7 2.6 1.7 --
Average
120
6.4
4.2
2.1
Prothrombin time (sees.) (patient~control) 14/13 15/14 23/15 19/13 19/15 14/13
Volume 76 Number 3
Tropical sprue
T h e r e was a r a p i d increase in body weight d u r i n g the first few month.s of t h e r a p y in most of the patients. T h r e e c h i l d r e n r e a c h e d the fiftieth weight percentile, 1 the twentyfifth, 3 the tenth, a n d 2 the t h i r d percentile after 6 months of treatment. T w o children r e m a i n e d below the third percentile in spite of s{gnificant gain in weight} ~ 10 T a b l e V I summarizes the c l i n i c a l a n d l a b o r a t o r y d a t a before a n d after therapy. T h e h e m o g l o b i n concentration increased r a p i d l y in all p a tients who were anemic, except in one (Patient 6) who did not take the m e d i c a t i o n s regularly. O n e child ( P a t i e n t 4) d e v e l o p e d evidence of iron deficiency after the hemoglobin h a d increased from 5.8 to 10.3 G m . p e r 100 ml. with t r e a t m e n t with folic a c i d a n d v i t a m i n B12. D u r i n g the 9 m o n t h s of t h e r a p y his body weight c h a n g e d f r o m 22 to 34 pounds, a 55 p e r cent increase. I m p r o v e m e n t in xylose absorption was r e m a r k a b l e
4 75
in 9 patients, b e c o m i n g n o r m a l in 7 a n d increasing f r o m 0.2 a n d 0.3 to 0.9 Gm. in Patients 4 a n d 7, respectively. T w o o t h e r p a tients with only mild a b n o r m a l i t y of the xylose absorption test before t h e r a p y rem a i n e d essentially unchanged. ~Peroral biopsy of t h e j e j u n a l mucosa was o b t a i n e d for reevaluation in all patients. I m p r o v e m e n t in the a p p e a r a n c e of the m u c o s a occurred in 7 children. I n one, the mucosol lesions c h a n g e d from a t r o p h i c to m o d e r a t e involvement of tropical sprue, 2 from severe to m o d e r a t e , 2 f r o m severe to mild, a n d 2 from m o d e r a t e to mild. T h r e e patients h a d no i m p r o v e m e n t in the a p p e a r a n c e of the j e j u n a l m u c o s a after 6 to 9 months of t h e r a p y ; a n o t h e r p a tient h a d no p r e t r e a t m e n t biopsy specimen for comparison. T h e small bowel series was r e p e a t e d in the 6 patients w h o h a d an abn o r m a l p a t t e r n before biopsy. It r e m a i n e d a b n o r m a l in 3 children after therapy. Fig.
T a b l e V I . T r o p i c a l sprue in children: resonse to t h e r a p y
Xylose~
Patient 1. F. O.M.
Age (yr.) ~ 14 18
Hgb. ~ (Gm./lO0 ml.) 6.5 14.9
Welght ~ (pounds) 60 118
2. F. O.R.
13
15.5
5.6
12.0
57
102
0.9
1.4
Mild Severe tropical sprue tropical sprue
3. C. O.O.
9
9.5
8.2
11.8
41
50
0.5
2.3
Moderate Moderate tropical sprue tropical sprue
4. E. R.V.
2.5
3.33
5.8
i0.3
22
34
0.2
0.9
Moderate Atrophic tropical sprue tropical sprue
(Gin.~5 hr./ 5 Gin. dose) Jejunal biopsy~ Moderate 0.4 1.4 Severe tropical s_prue tropical sprue
5. R. B.R.
14
14.5
5.7
13.2
78
103
0.8
1.9
Moderate Moderate tropical sprue tropical sprue
6. J. O.R.
14
14.5
10.3
I0,6
51
57
I.I
1.0
Severe Severe tropical sprue tropical sprue
7. E. S.R.
9
9.5
9.0
12.3
41
55
0.3
0.9
Mild Severe tropical sprue tropical sprue
8. I. R.A.
2
2.5
9.2
12.2
22
30
0.4
1.6
Moderate ileitis
9. R. H.P.
9
8.5
12.0
48
78
0.9
1.1
10. E . V . O .
10
10.5
13.4
12.7
51
81
0.5
1.5
11. J. L.S.
16
16.16 13.2
13.1
93
110
0.7
14
--
Mild tropical sprue Moderate tropical sprue
Moderate Severe tropical sprue tropical sprue
Mild Moderate tropical sprue tropical sprue "~The first and second figures in each column represent the values before and after therapy, respectively. 1.4
476
Santiago-Borrero, Maldonado, and Horta
A
B
Fig. 2. Photomicrographs of biopsies of the jejunal mucosa of Patients 3 (A) and 10 (B) showing mild to moderate improvement of the mucosal lesions. Patient 10 (B) was treated with folio acid and vitamin B12 for 8 months. The jejunal biopsy of Patient 3 (A) was obtained after 19 months of therapy with vitamin BI~ and folic acid, plus sulfasuxidine during the last 12 months of the course. (Hematoxylin and eosin, xl00.)
2 shows photomicrographs of the jejunal mucosa of 2 children (Patients 3 and 10) after therapy. DISCUSSION
Tropical sprue is the most prevalent primary malabsorption disorder in m a n y tropical areas? It has been recognized as a welldefined medical entity since first described over two h u n d r e d years ago by Hillary in the island of Barbados, one of the West Indies. 23 T h e r e are only 4 case reports of tropical sprue in ,children in the medical literature, most of them inadequately docu-
The Journal of Pediatrics March 1970
mented. 5s However, children are reported to have been affected in epidemics of tropical sprue in South India, 2 and Baker and M a t h a n 24 studied 20 pediatric.patients affected by this disorder. T h e pathogenesis of tropical sprue is still unknown. Gluten intolerance has been proved not to be an etiologic factor. 22 Folic acid and vitamin B12 deficiency are not the cause of the alterations in the small intestinal mucosa, but folic acid and B12 therapy usually result in rapid clinical improvement, hematologic remission, and decrease in the abnormality of the jejunal m u c o s a ? -3, 26 An infectious cause of tropical sprue has been suspected for m a n y years, but no etiologic agent has been isolated from the stools or intestinal contents of these patients? 7, 2s It is rare to see megaloblastic anemia in children outside the age group of 2 to 17 months. 2~ Very few of the malabsorption disorders in children are accompanied by macrocytic anemia and subnormal levels of serum folic acid and vitamin B12.30 T h e presence of these findings in our patients made us suspect that they belonged to a separate group, probably tropical sprue. There is a high incidence of intestinal parasitosis in tropical areas. A few types of parasitic infestations have been shown to cause intestinal malabsorption, especially infestation with Giardia lamblia al and Strongyloides stercoralis? 2 Uncinariasis has been shown not to cause malabsorption? s T h e type and degree of intestinal parasitic infestation present in our patients is not expected to cause malabsorption, megaloblastic anemia, and malnutrition. T h e blind loop syndrome and anatomic defects or malformations of the intestine causing stagnation, bacterial overgrowth, or short circuiting of ingested food and nutrients have been shown to cause malabsorption? 4 These entities were excluded in our patients by the radiographic examination of the small intestine. Immunoglobulin deficiencies associated with intestinal malabsorption have been reported by several authors,3~, a6 but none of our patients h a d deficiency of immunoglobulins. Food allergy,
Volume 76 Number 3
hepatobiliary disease, severe iron deficiency, severe malnutrition, mucoviscidosis, intestinal lymphangiectasia, a-beta-lipoproteinemia, congenital disaccharidase deficiencies, giardiasis, and strongyloidiasis have all been reported to cause malabsorption. 2' 12, la The presence of adequate stores of iron in the bone marrow of all of our patients, the fairly normal serum proteins and A / G ratio, the serum cholesterol above 85 rag. per 100 ml. in the cases tested, the normal chest films, and negative stools for giardia and strongyloides, besides the clinical picture and response to therapy, make these diagnoses very unlikely. The peroral intestinal biopsy is one of the most reliable and most important tests in the etiologic diagnosis of intestinal malabsorption.2, a, 12, i3 Intestinal biopsy specimens were examined in 10 of our patients before therapy and all of them showed changes similar to those encountered in the jejunal mucosa of adult patients with tropical sprue?7, 37 The abnormality of the jejunal mucosa in tropical sprue is characteristic, but not pathognomonic of this disease. Occasionally, other conditions, like severe protein malnutrition, 3~, as, 39 intestinal infestation with Giardia lamblia 31 or Strongyloides stercoralis, 32 and celiac disease, 17 may cause similar findings. However, the history and physical and laboratory findings usually make the differentiation easy. In most patients with tropical sprue the abnormality of the jejunal mucosa is less severe and clearly different from that of children with untreated celiac disease. Rarely, patients with tropical sprue may have atrophic changes in the mucosa which are almost indistinguishable from those of gluten-induced enteropathy. However, some authors 3, 17 believe that the gross appearance is different, and that if attention is paid to some details in the histologic picture these conditions can be differentiated. Gluten-induced enteropathy or celiac disease usually presents with microcytic hypochromic anemia, a~ Cooke 4~ reported megaloblastic anemia in only 8 out of 50 patients with celiac disease. The consistent occurrence of macrocytosis, megaloblastic bone marrow,
Tropical sprue
4 77
and low levels of serum folic acid in our patients, and i n addition the good response to folic acid and vitamin B12 in most of them, provided evidence against the diagnosis of celiac disease. T h e absence of a clear-cut clinical response after l0 weeks of therapy with a gluten-free diet in Patients 3 and 7, the worsening of the anemia and the unchanged appearance of the jejunal mucosa, plus the failure to induce a clinical exacerbation of the disease upon reintroduction of gluten to the diet, clearly eliminated the possibility of celiac disease. Partial improvement in patients with tropical sprue treated with a gluten-free diet has been reported by Bayless and associates 2s and by Cancio and associates. 41 The clinical response of tropical sprue to folic acid and vitamin B~2 has been well documented.a, 2G However, the remission is frequently incomplete, the relapse rate is relatively high, and abnormalities in the jejunal mucosa persist in about two thirds of the patients treated with folio acid and vitamin B12.~2, 42 More complete clinical remission and better histologic improvement of the jejunal mucosa have been achieved by longterm therapy with broad-spectrum antibiotics and nonabsorbable sulfonamides.43, 44 However, the onset of the hematologic remission appears earlier with folic acid and vitamin Bz2.43, 44 All the patients included in this series, with the possible exception of Patient 6, had a good response to therapy with folic acid and vitamin B~2, and one with oxytetracycline. We feel that this therapeutic response confirmed the diagnosis of tropical sprue in the children presented in this report. SUMMARY
Tropical sprue is a common disease of adults in Puerto Rico and other tropical areas. Some investigators have observed a disease in children similar to that seen in adults. However, only a few reports in the medical literature describe this disease in childhood. We have studied 7 boys and 4 girls whose ages ranged from 2 to 16 years with anorexia, weakness, pallor, chronic
478
Santiago-Borrero, Maldonado, and Horta
diarrhea, weight loss or failure to gain weight, glossitis, a n d m a l n u t r i t i o n . T h e symptoms were present from 2 months to 6 years. Macrocytosis, megaloblastic bone marrow, a n d a b n o r m a l absorption of xylose were present in all. T h e intestinal mucosa showed changes compatible with tropical sprue in 10 patients in w h o m biopsy material was studied. T h e v i t a m i n A absorption test was a b n o r m a l in 9, a n d the serum carotene level was low in 7 of 9 patients studied. T h e serum folic acid level wag low in 8 patients tested. T w o patients h a d partial i m p r o v e m e n t o n a gluten-free diet, b u t the mucosal abnormality r e m a i n e d u n c h a n g e d , a n d the clinical findings did n o t relapse when challenged with gluten. N i n e patients h a d a good response to therapy with folic acid a n d vitam i n B12; one h a d excellent i m p r o v e m e n t with oxytetracycline therapy. T h e r e were rapid increases in hemoglobin concentrations a n d in body weight a n d improved control of diarrhea. R e p e a t studies 6 m o n t h s or more after initiation of therapy showed normalization in absorption of xylose in 7 children a n d m a r k e d i m p r o v e m e n t in 2. T h e r e was considerable i m p r o v e m e n t of the j e j u n a l mucosa in 7 patients. W e believe that the syndrome described in these patients is the same disease as tropical sprue in adults.
The Journal o[ Pediatrics March 1970
9.
10. 11. 12. 13. 14.
15. 16.
17. 18.
19. 20.
REFERENCES
1. P6rez-Santiago, E., and Butterworth, C. E.: Definition and diagnosis of sprue, Amer. J. Dig. Dis. 2: 225, 1957. 2. Bockus, H. L.: Secondary malabsorption syndromes: nasologic and diagnostic aspects, Bol. Asoc. Med. P. Rico 58: 112, 1966. 3. Klipstein, F. A.: Progress in gastroenterology: tropical sprue, Gastroenterology 54: 275, 1968. 4. Rodriguez-Molina, R.: Sprue in Puerto Rico--10 years later, P. Rico J. Pub. Health Trop. Med. 18: 314, 1943. 5. Bahr, P. H.: A report on researches on sprue in Ceylon, Cambridge, 1915, Cambridge University Press, p. 122. 6. Johnson, J., and Breidigan, F. T.: Tropical sprue in a child six years of age, Amer. J. Med. Sci. 170: 364, 1925. 7. Miller, R.: A case of sprue commencing at the age of eleven and a half years, Trans. Roy. Soc. Trop. Med~. Hyg. 27: 413, 1934. 8. Mathew, K., Ignatius, M., Meenakshiammal,
21. 22.
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and Baker, S. J.: Tropical sprue in children, Indian Pediat. 1: 271, 1964. Baker, S. J., Mathan, V. I., and Joseph, I.: The epidemiology of tropical sprue, in Malabsorption syndromes, Symposium, Second World Congress on Gastroenterology, New York, I963, Karger, p. 4. Nelson, W. E. : Textbook of pediatrics, ed. 8, Philadelphia, 1964, W. B. Saunders Co. Brenneman, J., and Kelley, V. C.: Practice of pediatrics, Hagerstown, Md., 1966, W. F. Prior Co., Inc. Gerrard, J. W., and Lubos, M. C.: The realabsorption syndromes, Pediat. Clin. N. Amer. 14: 73, 1967. Anderson, C. M.: Intestinal malabsorption in childhood. Review articIe, Arch. Dis. Child. 41: 571, 1966. Santini, R., Jr., Sheehy, T. W., and Martlnezde Jesfis, J.: The xylose tolerance test with a five gram dose, Gastroenterology 40: 772, 1961. Consolazio, C. F., Johnson, R. E., and Mareck, M. A.: Metabolic methods, St. Louis, 1951, The C. V. Mosby Company, p. 179. Crosby, W. H., and Kugler, H. W.: Intraluminal biopsy of small intestine: IntestinaI biopsy capsule, Amer. J. Dig. Dis. 2: 236, 1957. Swanson, V. L., and Thomassen, R. W.: Pathology of the jejunal mucosa in tropical sprue, Amer. J. Path. 46: 511, 1965. Baker, H., Herbert, V., Frank, O., Pasher, I., Hunter, S. H., Wasserman, L. R., and Sobotka, H.: A microbiological method for detecting folic acid deficiency in man, Clin. Chem. 5: 275, I959. Ross, G. I. M.: Vitamin B-12 assay in body fluids using Euglena gracilis, J. Clin. Path. 5: 250, 1952. Knott, V. B.: Stature, leg girth and body weight of Puerto Rican private school children measured in 1962, Growth 27: 157, 1963. Santiago, P. J., Santinl, R., Jr., and Maldonado, N.: Xylose absorption test in Puerto Rican children. Unpublished. Sheehy, T. W., Baggs, B., P6rez-Santiago, E., and Flock, M. H.: Prognosis of tropical sprue: A study of the effect of folic acid on the intestinal aspects of acute and chronic sprue, Ann. Intern. Med. 57: 892, 1962. Booth, C. C.: The first description of tropical sprue (William Hillary), Gut 5, 45, 1964. Baker, S. J., and Mathan, V. I.: Syndrome of tropical sprue in South India, Amer. J. Glin. Nutr. 21: 984, 1968. Bayless, T. M.: Tropical sprue: A comparison with celiac disease, Amer. J. Dig. Dis. 9: 779, 1964. Su~rez, R. M., Spies, T. D., Hern~ndezMorales, F., and P6rez-Santiago, E.: A note on the effectiveness of vitamin B-12 in the treatment of tropical sprue in relapse, Blood 4: 1124, 1949. Nadel, H., and Gardner, F. H.: Bacterial as-
Volume 76 Number 3
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34.
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say of small bowel secretion in tropical sprue, Amer. J. Trop. Med. 5: 686, 1956. Bayless, T. M., Guardiola-Rotger, A., and Wheby, M. S.: Tropical sprue: viral cultures of rectal swabs, Gastroenterology 51: 32, 1966. Luhby, A. L.: Megaloblastic anemia in infancy: Clinical considerations and analysis, J. PEDIAT, 54: 617, 1959. Smith, C. tI.: Blood diseases of infancy and childhood, ed. 2, St. Louis, 1966, The C. V. Mosby Company, pp. 226-239. Cortner, J. A.: Giardiasis, a cause of celiac syndrome, Amer. J. Dis. Child. 98: 311, 1959. Jones, G. H.: Clinical studies in human strongyloidiasis, Gastroenterology 16: 743, 1950. Mayoral, L. G., Tripathy, K., Garcla, F. T., Bolafios, O., and Ghitis, J.: Protein malnutrition-induced malabsorption and other enteropathies in Colombia, Amer. J. Clin. Nutr. 21: 1053, 1968. Thompson, R. B., and Ungley, C. C.: Megaloblastic anemia .associated with anatomic lesions in the small intestine, Blood 10: 771, 1955. Crabb6, P. A., and Haremans, J. F.: Lack of gamma-A immunoglobulin in serum of patients with steatorrhea, Gut 7: 119, 1966. Pelkonen, R., Siurala, M., and Vuopio, P.:
Tropical sprue
37. 38. 39.
40. 41. 42. 43. 44.
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Inherited agammaglobulinemia with malabsorption and marked alterations in the gastrointestinal mucosa, Acta Med. Scand. 173: 549, 1963. Butterworth, C. E., and P6rez-Santiago, E.: Jejunal biopsies in sprue, Ann. Intern. Med. 48: 8, 1958. Stanfield, J. P., Hutt, M. S. R., and Tunnicliffe, R.: Intestinal biopsy in kwashiorkor, Lancet 2: 5t9, 1965. Brunser, O., Reid, A., Monckerberg, F., Maccioni, A., and Contreras, I.: Jejunal mucosa in infant malnutrition, Amer. J. Clin. Nutr. 21: 976, 1968. Cooke, W. T.: Adult celiac disease, Amer. J. Dig. Dis. 7: 957, 1962. Cancio, M. R., Rodrlguez-Molina, R., and Asenjo, C. F.: Gluten and tropical sprue, Amer. J. Trop. Med. 10: 782, 1961. Bayless, T. M., Wheby, M. S., and Swanson, V. L.: Tropical sprue in Puerto Rico, Amer. J. Clin. Nutr. 21: 1030, 1968. Guerra, R., Wheby, M. S., and Bayless, T. M.: Long-term antibiotic therapy in tropical sprue, Ann. Intern. Med. 63: 619, 1965. Maldonado, N., Horta, E., Guerra, R., and P6rez-Santiago, E.: Poorly absorbed sulfonamide in the treatment of tropical sprue, Gastroenterology. In press.