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Mean and peak jejunal bile salt concentrations during digestion of a standard fat meal were found to be significantly lower in six Puerto Rican patients with untreated tropical sprue, all of whom had steatorrhoea, than in six asymptomatic subjects who had normal fat absorption. Bile salt pool size and turnover time did not differ significantly in the two groups. It is suggested that bile salt concentrations may be reduced in the proximal small intestine of patients with tropical sprue as a result of excessive dilution by intestinal fluid. The finding of low bile salt concentrations in two asymptomatic subjects indicates that bile salt lack alone may not be sufficient to produce steatorrhoea.

Eleven Puerto Rican children with chronic diarrhea, intestinal malabsorption, abnormal jejunal mucosa, megaloblastic bone marrow, and malnutrition have been studied. The patients were treated with folic acid alone or folic acid and vitamin B 12 ; one patient received oxytetracycline. The results were good to excellent in all but one of 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 manifested at an early age, sometimes as early as the first year of life. The etiology of this disease in children, as well as in adults, remains unknown.

Disaccharidase activities have been studied in biopsy specimens obtained from control Indian and American subjects and from Indian patients with tropical sprue. The values in the Americans were similar to those of Caucasian subjects reported in the literature. Lactase, maltase and trehalase values in the Indian controls were significantly lower than the values in the Americans, but there was no difference in the sucrase. Lactase levels were uniformly low in the Indian controls, indicating a very high prevalence of lactase “deficiency”. In patients with sprue the maltase, sucrase and trehalase levels were significantly lower than in the control groups. Enzyme levels along the length of the intestine of a sprue patient, obtained at post mortem, were decreased to a greater extent in the proximal region.

Steatorrhea associated with advanced cirrhosis of the liver was studied by means of the I131-labeled oleic acid absorption test. The validity of the use of this test as a measure of fat absorption by the small intestine was reviewed. Malabsorption of oleic acid was demonstrated in each of the 6 cirrhotic patients examined. The impaired absorption of oleic acid was attributed to pathologic changes in the mucosa of the small intestine secondary to portal hypertension. The clinical implications of this finding were discussed. The possibility that a protein-losing enteropathy might contribute to the hypoalbuminemia of advanced cirrhosis was investigated by means of intravenously administered I131-labeled polyvinylpyrrolidone and I131-labeled serum albumin. However, no significant loss of protein through the gastrointestinal tract was demonstrated in the 4 cirrhotic patients examined for this condition.

1. If FIGLU is excreted in excessive amounts after histidine loading it indicates a disturbance of folic acid metabolism. This is not necessarily due to a deficiency of folic acid—even a relative one due to the excessive utilisation of folic acid by abnormally active haematopoietic tissue or tumour tissue—but may be the result of a disturbance of folic acid metabolism by anticonvulsants, folic acid antagonists, impaired transferase activity, the unexplained disturbance of metabolism found in patients with megaloblastic anaemia of pregnancy, or some other cause. 2. Not all patients with megaloblastic anaemia and disturbed folic acid metabolism excrete excessive quantities of FIGLU. In some the excretion of FIGLU may be normal, and other workers have found the excretion of urocanic acid excessive in these patients. In some patients investigated in this study in whom the marrow showed megaloblastic erythropoiesis, the serum B12 level was normal and a satisfactory response followed the administration of folic acid, increased excretion of either FIGLU or urocanic acid could not be demonstrated. The nature of the metabolic abnormality in these patients is not understood. 3. Excessive excretion of urocanic acid after histidine loading was demonstrated in all patients with liver disease—all of whom were also anaemic. Two patients also excreted increased amounts of FIGLU. Other workers have found that non-anaemic patients with liver damage may excrete FIGLU and urocanic acid. These findings make the interpretation of excessive excretion of these substances in anaemic patients with liver disease difficult. 4. The histidine loading test does not distinguish between patients with Vitamin B12 deficiency and consequent disturbance of folic acid metabolism from patients with a normal serum B12 level and a disturbance of folic acid metabolism from some other cause. 5. Nearly all patients with a positive histidine loading test have evidence of megaloblastic erythropoiesis; however occasional patients may have normoblastic erythropoiesis. In these patients the histidine loading test may be more sensitive than marrow biopsy in revealing a disturbance of folic acid metabolism.

Summary Total fatty acid, lipide phosphorus, and cholesterol were estimated in the serum of sixteen patients with tropical sprue, and nine normal subjects. These estimations were repeated at intervals after a standard meal containing 18 grammes of fat; from these data twelve fat curves in normal subjects, and thirty-one in patients with sprue, were plotted. It was found that the fasting level of total fatty acid in sprue did not differ significantly from normal values; but phospholipide and cholesterol were significantly lower, while the calculated value for neutral fat was higher than normal. After the fatty meal, the total fatty acids increased less in the sprue patients than in normal subjects; phospholipides showed a smaller increment than neutral fatty acid. The cholesterol, which was little affected by the meal in normal subjects, usually fell in the sprue patients. Sodium glycerophosphate, in a dose of 10 grammes, raised the height of the fat curve in five out of six patients with sprue; a similar effect was not observed with choline or lecithin. No significant change was demonstrated in the fat curve after a period of liver treatment in four patients. Although the results of serial fat estimations in serum are no doubt affected by metabolic changes not directly concerned with fat absorption, the low fat curve in sprue fits in well with the more direct evidence of faulty fat absorption given by stool analysis. The changes in the different lipide fractions are discussed in relation to Stannus's hypothesis that the absorption defect affects only those lipides which are phosphorylated during absorption. The observed results can be well explained on the basis of this hypothesis, but they cannot be said to contribute directly to proving it.

Forty I131 triolein tests using both blood and fecal radioactivity assays were performed in 37 patients with various diseases associated with steatorrhea and in controls.

SummaryThe absorption of medium chain triglycerides (MCT) has been studied in 8 patients with tropical sprue (2 acute, 4 in relapse, 2 in remission). Studies were performed first during a period in which a standard steatorrhea test diet containing long chain animal and vegetable fats was given, and continued while substituting all the fat in the diet for medium chain triglycerides. Normal fat excretion levels were attained by all patients while they were receiving from 80-100 g of medium chain triglycerides in the diet. The average apparent coefficient of fat absorption ranged from 92.3 to 97%. Steatorrhea recurred when the steatorrhea test diet was repeated, and disappeared again when the MCT diet was resumed. Absorption of medium chain triglycerides was accompanied by improved appetite, weight gain, and increased serum lipids. The results of this experiment suggest that medium chain triglycerides may have a place in the management of sprue cases.The authors are indebted to Dr. V. K. Babayan, E. F. Drew ...

Two lifelong residents of the Philadelphia area, with malabsorption of an unclassified type suggestive of tropical sprue, are described. They manifested steatorrhea, a sprue pattern on X-ray examination of the small bowel, compatible small-bowel biopsy findings and bacterial cultures showing coliform growth in the upper small intestine. Other causes of malabsorption were excluded by exhaustive testing. The 1 patient, so tested, manifestedd-xylose malabsorption, while the other showed malabsorption of vitamin B12. Both patients presented with features clearly different from those of celiac sprue or the blind loop syndrome in its widest interpretation. While the evidence is not entirely conclusive, the data suggest that these patients suffered from a malabsorptive syndrome bearing close resemblance to the syndrome of tropical sprue, and that “tropical sprue” may be encountered, though rarely, in lifelong residents of the United States.

A deficiency of the intestinal enzyme sucrase was found in tropical sprue. This deficiency persists even after therapy and is probably responsible for the sucrosuria characteristic of the disease.

Summary1. Plasma copper was determined in 29 patients with sprue in relapse, 27 patients with sprue in remission, and 6 patients with megaloblastic anemia of pregnancy. 2. Mean plasma copper concentration (± 1 S.D.) in patients with sprue in relapse was 87 ± 33 μg%; in treated patients, 114 ± 33; and in patients with megaloblastic anemia of pregnancy, 159 (105 − 242). 3. It is suggested that hypocupremia in sprue may frequently be due primarily to an inability to synthesize the protein portion of ceruloplasmin. In a few patients malabsorption of copper may be a contributing factor.

It has been found that patients with sprue excrete significantly greater quantities of intact sucrose in the urine after an oral dose of sucrose than do normal subjects. The urine of normal persons becomes free of sucrose after a 10-hour fast, but patients with sprue may exhibit sucrosuria throughout a 24-hour fast. Diminished hydrolysis of sucrose and increased intestinal permeability are mentioned as possible explanations for the findings.

The 5-hour urinary xylose excretion test was performed in 158 normal Puerto Rican school children 2½ to 13 years of age after the administration of a 5 gm oral dose of D-xylose. The values ranged from 0.7 to 2.3 gm with a mean of 1.44 gm and a standard deviation of ± 0.35 gm. Seven children excreted 0.9 gm or less (18% of the oral dose), which was the upper limit of excretion by the patients with untreated tropical sprue. All except one of the values below 1.0 gm occurred in children less than 6½ years of age. Thirty children with proven untreated tropical sprue showed a range of 0.2 to 0.9 gm, with a mean of 0.54 gm and a standard deviation of ± 0.20 gm Seventeen patients with tropical sprue treated for 6 months to 2 years showed a xylose excretion of 1.0 to 2.3 gm with a mean of 1.48 gm and a standard deviation of ± 0.36 gm. The lowest value obtained in this group, 1.0 gm, is higher than the seven lowest values in the control group. Our study confirms that the xylose excretion test is a simple and very reliable test of intestinal absorption. It is very useful as a screening test for the diagnosis of tropical sprue and in the follow up of treated patients.

The antigenic properties of various wheat-gluten fractions were investigated and compared with their known harmful and nonharmful properties when ingested by patients with nontropical sprue. Gluten fractions were suspended in complete Freund's adjuvant and injected into the foot pads of rabbits on 5 consecutive days. A final intraperitoneal injection was also given. Investigation of antibodies in their serum 3 and 6 weeks thereafter by means of double gel diffusion showed no correlation between the reported harmful and the antigenic properties of some of the fractions. This indicates that the deleterious properties of gluten and its fractions can not be attributed to their antigenicity.

MONG the published cases of acquired agamA maglobulinemia, a sprue-like syndrome has been reported in at least eight [7-81; Gitlin and associates [9] estimated the incidence of this syndrome in such cases as about 20 per cent. Such an incidence appears to be far too great to be altogether coincidental. Our study of serum globulins in sprue was stimulated by the observation of two cases in which non-tropical sprue and agammaglobulinemia coexisted. It is our aim to report these two cases and to present evidence, obtained from a review of the records in 124 cases of non-tropical sprue, that deficiencies in serum globulin, with or without associated reductions in serum albumin, occur frequently in this disease. These data and also an increase in the concentration of gamma globulin toward normal in one of our patients during a remission of sprue suggest that malabsorption may be an important causative factor in some cases of acquired agammaglobulinemia.

Macroscopic and microscopic photographs of seven jejunal biopsies illustrating the range of morphological changes found in southern Indian control subjects were circulated, together with a questionaire, to observers in different parts of the world. There was general agreement among the observers regarding the ‘normality’ of the biopsy showing the least changes and the abnormality of the two showing the most marked changes, but considerable disagreement over those intermediate between these two extremes. Opinion regarding the prevalence of the different biopsy appearances in control subjects varied significantly between temperate and tropical areas. A hierarchy of abnormality has been drawn up ranking countries in decreasing order of prevalence of the two most abnormal biopsies. Possible factors in the pathogenesis of the morphological changes in the jejunal mucosa in the tropics are discussed.

An abnormal bacterial flora was demonstrated in the upper small intestine of six patients with tropical sprue. Increased numbers of coliforms in the jejunum was the most consistent finding. This was in contrast to eight healthy Bengalis in whom no coliforms could be isolated from the jejunum. Longitudinal studies in two cases demonstrated a direct relationship between the abnormal microflora and mal-absorption of fat and vitamin B 12 .

A comparative study has been made of the urinary excretion of amino acids in free and bound forms in normal South Indian subjects and subjects with sprue. Chromatographic examination showed a quantitative decrease of urinary amino acids in the sprue group, but no qualitative differences between the two groups. A wide range of ninhydrin-positive compounds was noticed in both groups. A number of these compounds remain unidentified. Free α-amino acid excretion was markedly reduced in male sprue patients as compared with normal controls. No such decrease was found in the female subjects. The excretion of bound hydroxyproline was increased in both male and female patients with sprue. A significant lowering in the mean creatinine excretion was noticed in the male sprue patients.

Summary 1. Radiographic evidence of increased calibre or of thickened mucosal folds in the small intestine has been found in 32 per cent of all cases referred for barium-meal examinations in this hospital. 2. A high percentage of such cases suffers from idiopathic malabsorption of essential foods (fat, sugar, vitamins). 3. Minor degrees of flocculation patterns and of alterations in mucosal patterns are described. 4. The importance of distinguishing between constantly dilated loops of gut due to minor organic structures and increased calibre due to motor disorder is stressed. Repeat examinations may be essential and laparotomy may be justified as a diagnostic final court of appeal in some cases. 5. Abnormalities of peristalsis and transit time are described. 6. The possible causes of the above radiographic signs are discussed. 7. Ninety per cent of cases finally diagnosed as idiopathic malabsorption or sprue-like disorder show radiographic signs.

21 consecutive Asian patients in Singapore with megaloblastic anaemia were studied. In 4 the megaloblastic anaemia was due to vitamin B12 deficiency. 3 of these patients were considered to have pernicious anaemia; in the other, vitamin B12 deficiency had arisen as a result of gastrectomy. 2 patients had tropical sprue. One had acute tropical sprue with folate deficiency; the other had chronic tropical sprue with both folate and vitamin B12 deficiency. In the remaining 15 patients the megaloblastic anaemia was considered to be primarily due to folate deficiency, which in turn was thought to be the result of malnutrition.

At the present time the etiology of tropical sprue is undetermined. Manson-Bahr (1948) has indicated that tropical sprue must be infective since malnutrition is not observed in many patients. Frazer (1949) has suggested that an alteration in the small bowel bacterial flora could be a mechanism for impaired absorption by competitive demands for nutrition. Thus, bacterial growth in the small bowel, which is normally bacteria-free (Cregan and Hayward 1953) could possibly lead to impaired absorption by utilization of metabolites, production of antimetabolites and/or production of toxic effects on the mucosa. Since the area of active absorption of foodstuffs is greatest in the jejunum, the present study was undertaken to sample small bowel juice in that segment for bacterial growth. It was hoped that information could be obtained to allow a more definitive conclusion regarding the role of bacteria in the etiology of malabsorption in tropical sprue.

SummaryOur studies indicate that measurement of changes in plasma optical density after a fatty meal is a simple and reliable screening test for patients with malabsorption syndromes. It is of value in following the course of these diseases and in evaluating response to therapy.

Alterations in gastric mucosal morphology were studied in 56 patients before and after a partial gastrectomy graded by the preoperative values of total acid output (MAO) following large doses of histamine.In the group of patients secreting 30 mEq/h or more and who were subjected to a two-thirds gastrectomy, the thickness of the parietal cell layer decreased significantly from a preoperative mean value of 0.71 mm to 0.60 mm at three months and 0.51 mm at twelve months after operation. The thickness of the total mucosa, 1.02 mm, did not show significant alterations. The frequency of gastritis, which was low pre-operatively, increased abruptly, and at twelve months about two-thirds of the cases had moderate or severe atrophic gastritis.In the group of patients secreting less than 30 mEq/h and who received a one-third gastrectomy, significantly lower values were preoperatively found for MAO and the parietal cell layer thickness, while the frequency of gastritis was higher. Twelve months after operation the pa...

There are many identifiable causes of malabsorption in populations living in the tropics. In some patients, however, the etiology of subclinical or overt malabsorption remains unclarified. The frequency with which abnormal bacterial colonization of the upper small bowel, folic acid deficiency, and primary protein malnutrition coexist in these patients tends to confuse the issue of etiologic factor(s) in malabsorption. We have studied malabsorptive states in the Cauca Valley of Colombia for the last 7 years. The present communication reviews the characteristics of the malabsorption syndrome seen in 26 closely controlled adult patients, followed for a long period, who had strictly defined, severe, primary (nutritional) protein malnutrition. Materials and methods

1. (1) Studies of gastro-intestinal function in 10 cases of tropical sprue, 10 cases of coeliac disease and 24 cases of idiopathic steatorrhoea are described. 2. (2) All the cases showed delay and depression of intestinal absorption. 3. (3) Radiographic studies revealed excessive mucus secretion and decreased intestinal tone and motility in all three conditions. 4. (4) Pancreatic enzymes were normal. 5. (5) It is concluded that functional incapacity of the small intestine is the basic pathological fault in tropical sprue, coeliac disease and idiopathic steatorrhoea. 6. (6) Delayed and depressed absorption may cause a calorie deficit, increased growth of intestinal bacteria and modification of intestinal contents. These changes may be responsible for the main features of the syndromes observed. 7. (7) The relationship of possible primary aetiological factors to this basic intestinal fault is reviewed. Adrenal insufficiency, climatic factors and vitamin deficiency do not seem to be primary factors. Infection and hereditary factors may have a causative role in any of the three conditions. Rancid fats may be important in tropical sprue. Dietary wheat gluten is a factor of major importance in coeliac disease.

A case is reported of a patient with intussusception complicating tropical sprue demonstrable over a period of months. There was clinical and laboratory evidence of malabsorption. The chronicity of tropical sprue and its delayed laboratory and histologic response to therapy was demonstrated. Such a case has not been previously reported.