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In a prospective study jejunal absorption rates of glucose (from a 200 mmol 1-1 solution) and glycine (from a 100 mmol 1-1 solution) were measured, using a perfusion technique, in nine patients with clinical evidence of post-infective tropical malabsorption (TM group) and in 10 others with trivial symptoms who had also visited the tropics (control group); all were of northern European origin. Seven and one in the two groups, respectively, had Giardia lamblia infections. Mean glucose absorption rate was significantly impaired by TM (P less than 0.01); mean rate for glycine was also depressed but not significantly. Presence of G. lamblia did not affect the severity of malabsorption although numbers studied were small.

The bacterial flora of the upper intestine has been examined in symptomatic expatriate adults with mild tropical malabsorption, without steatorrhoea, persisting for many months after return to a western environment. Seven of the 11 patients had enterobacteria in luminal fluid or mucosal samples in numbers ranging from 10 3 to 10 8 per ml or per g. The most common isolate was Klebsiella pneumoniae (in four cases); Citrobacter freundii, Serratia marcescens and Pseudomonas spp . were also detected. The significance of bacterial colonization in the pathogenesis of mild tropical malabsorption is discussed.

A morphometric study confirmed that increasing severity of the jejunal mucosal morphologic lesion is accompanied by increased crypt height and reduced villus length in patients with tropical sprue. Mitotic activity in the crypts was increased. Pulse labeling of jejunal mucosal biopsies cultured in vitro with [3H]thymidine confirmed that there was increased uptake of label in tropical sprue with more rapid migration of labeled cells to the villi. The label was also lost more rapidly. Earlier ultrastructural studies have shown enterocyte damage and extrusion in the crypt and villus epithelium. The present data suggest that in the jejunal mucosa of patients with tropical sprue, the loss of damaged enterocytes leads to villus shortening and increased cell production in the crypts, with hypertrophy of the crypts.

Tropical sprue, a primary malabsorption syndrome affecting residents and visitors to several tropical regions, occurs in southern India in endemic and epidemic forms. The stomach, the small intestine and colon are affected and malabsorption results in nutrient deficiency. Enterocyte damage, the primary lesion in southern Indian tropical sprue, is the result of a persistent lesion of the stem cell compartment. This lesion occurs on a background of tropical enteropathy and the available evidence suggests that an immunity conferring agent may be responsible for initiating the damage.

A defect in colonic absorption of electrolytes and water was demonstrated in patients with tropical sprue by perfusing the colon with normal saline containing a non-absorbable marker. Colonic water absorption correlated negatively with stool weight and was abnormal in patients with steatorrhoea. The possible mechanisms producing this defect are discussed. This defect may be related to colonocyte damage produced by unabsorbed unsaturated fatty acids in patients with steatorrhoea.

Idiopathic enteropathy in the rural population of Iran was investigated through evaluation of 100 randomly selected apparently normal subjects. The evaluation included quantitation of the nutrient loss, presence of malabsorption, and small intestinal morphological abnormalities. The results show that: 1) there was no significant loss of major nutrients, 2) severe malabsorption was not present, 3) an enteropathy of unknown etiology was found in nearly one-third of the subjects, and 4) abnormalities in morphology did not necessarily mean presence of malabsorption.

The factors responsible for colonization of the small intestine by enterotoxigenic coliform bacteria in Puerto Ricans with tropical sprue are unknown, but epidemiological observations have suggested that they may be related to an increased dietary intake of long-chain unsaturated fatty acids, particularly linoleic acid, which is known to exert an inhibitory effect on the growth of gram-positive organisms that normally comprise the flora of the small intestine. We have examined, by using a glucose-limited continuous-culture system, what effect this fatty acid exerts on the growth relationships of enteric gram-positive and coliform bacteria. In this system, colonization by an invading strain of Klebsiella pneumoniae was prevented by the presence of an established culture of Lactobacillus acidophilus, principally by virtue of a lowered pH of the medium that was incompatible with Klebsiella growth. However, when the population density of L. acidophilus was reduced by the presence of a sufficient concentration of linoleic acid, the invading K. pneumoniae successfully colonized the system and, once established, suppressed the growth of L. acidophilus. These observations indicate that, under the conditions of our chemostat, gram-positive enteric bacteria suppress coliform growth and that this effect is reversible by the presence of linoleic acid. It remains to be established, however, what pertinence these in vitro observations have to conditions within the intestinal tract of persons living in the tropics.

Concentrations of various gut hormones were measured after a test breakfast in eight patients with severe tropical malabsorption and 12 controls. The patients with tropical malabsorption had greatly raised basal plasma motilin and enteroglucagon concentrations, but their postprandial release of both gastric inhibitory polypeptide and insulin was significantly reduced. The pattern of gut hormone release differed from that found in coeliac disease. The measurement of gut hormones, each of which has a specific site and function, thus throws new light on the pathophysiology of tropical malabsorption and may suggest approaches of treatment.

Pancreatic functions were studied in 15 patients with tropical sprue. The diagnosis of tropical sprue was made on accepted criteria of demonstrating malabsorption of at least two unrelated food substances in the absence of any other cause for malabsorption in patients residing in a tropical zone. Exogenous secretion (Boots) in a dose of one clinical unit per kg was employed for direct stimulation of exocrine pancreatic secretion. Of the 15 patients, 12 showed normal pancreatic functions. In two patients, volume output was marginally low i.e. 1.6 and 1.6 ml/kg/hr respectively (Normal value greater than 1.8 ml/kg/hr). In the third patient, volume output was normal but maximum bicarbonate concentration in pancreatic juice was 61.6 mEq/litre (Normal value greater than 80 mEq/litre). None of these three patients, however, had abnormalities in both the parameters of exocrine pancreatic function. Although pancreatic hyposecretion has been reported in patient with tropical sprue when indirect stimulation with Lundh meal was applied to pancreas, yet on direct stimulation with secretin, we found pancreatic functions to be normal. It is therefore concluded that the pancreas is not primarily involved in tropical sprue.

Intestinal absorption of glycine 20 mmol/1, glycyl-glycine 10 mmol/1 plus L-leucine 10 mmol/1, and glycyl-L-leucine 10 mmol/1 has been studied by intestinal perfusion in 11 patients with tropical sprue and 10 control subjects. The patients with sprue had a significant reduction in the rate of absorption of glycine from a 20 mmol/1 solution, but there were no significant differences in the absorption of the other substances. The failure to demonstrate any difference in the absorption of these substances is probably related to their low concentration relative to the maximum absorptive capacity of the intestine. In both groups of subjects the kinetic advantage of glycyl-glycine absorption as compared with glycine absorption was maintained. When the dipeptides were perfused, free amino acids appeared in the perfusate presumably by "back diffusion" from the mucosal cells. In the case of glycyl-L-leucine considerably more glycine and leucine were found in the perfusate in patients with sprue than in the control subjects. There was no correlation between peptide absorption and the concentration of total glycly-glycine hydrolase and glycyl-L-leucine hydrolase, measured as combined brush border and cytosol enzymes. The concentrations of these enzymes were similar in both groups of subjects.

Jejunal absorption of sodium and water has been investigated in 10 normal Indians and 11 patients with chronic tropical sprue. Normal saline and solutions containing amino acids and dipeptides were studied. In both groups little absorption of sodium and water from normal saline was seen. Mean water and sodium absorption from the free amino acid or dipeptide solutions showed no significant difference between the groups and was similar to absorption from normal saline. These results differ from data obtained in normal English subjects where at these concentrations significant stimulation of sodium and water absorption was seen. In a proportion of subjects in both groups net secretion was observed. However, no correlation was seen between mucosal histology or luminal bacteriology and sodium or water movement. These findings in patients with chronic tropical sprue are similar to findings in normal Indians and suggest that jejunal handling of sodium and water is abnormal when compared with normal English subjects, but that the mucosa is not in a secretory phase as seen in certain other diarrhoeal states or in the acute early phase of sprue.

There is a lot of diversity in the observations on jejunal histology between light and discretion microscopy in tropical sprue. In order to compare the light and dissection microscopic appearances, a three-dimensional model of the villous pattern was constructed after a study of 350 serial sections of jejunal biopsy from a patient with tropical sprue. There was considerable variation in the morphological appearance of the villi in different sections. The changes seen varied from mild to partial villous atrophy. Broad synechia and bridge formation between adjoining villi due to fusion was frequently observed. It is postulated that the process of fusion of villi may be partly responsible for the development of features of partial villous atrophy seen in jejunal biopsies in tropical sprue. Normal jejunal pattern reported by some workers in patients with tropical sprue could possibly be due to inadequate sampling of the total biopsy piece.

The respective roles of reduced dietary intake and malabsorption in the pathogenesis of weight loss in persons with chronic tropical sprue have been evaluated . Dietary intake was found to be significantly (P less than 0.001) less in a group of 45 patients with tropical sprue, all of whom had anorexia due to deficiency of folate and/or vitamin B12, than in a group of 51 healthy Puerto Ricans. Weight loss was equally prominent in those patients with tropical sprue who had normal absorption of fat and protein as in those who had excessive fecal loss and reduced absorption of these nutrients. Treatment of five sprue patients with folic acid or vitamin B12 for 2 weeks resulted in improved appetite and increased in dietary intake with weight gain in the absence of significant improvement in intestinal absorption. Treatment with oral tetracycline for a similar period of time in five other patients was not associated with vitamin repletion, return of appetite or weight gain. These observations indicate that reduced dietary intake resulting from anorexia caused by vitamin deficiency is a significant, and sometimes the most important, factor in the pathogenesis of weight loss in persons with chronic tropical sprue.

Summary A man with a gastrojejunostomy and intestinal malabsorption was found to be excreting large numbers of coronavirus-like particles in his stools over a period of at least eight months. Coronavirus-like particles were found in vesicles in degenerating jejunal enterocytes in all of five jejunal biopsies. In a review of electron micrographs, similar structures were found in biopsies from three of 12 patients with classical chronic tropical sprue and in one patient with a sprue-like syndrome associated with agammaglobulinaemia. The hypothesis is advanced that infection with this virus may produce enterocyte damage and may be one cause of the syndrome of tropical sprue.

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.

Epithelial lymphocytes comprise a compartmentalised and specialised population of presumed effector cells which, in general, express the surface phenotypes (Lyt-2+; OX2+; OKT8+) of suppressor/cytolytic (Ts/c) cells. Granular cells within this population (gEL) morphologically resemble the circulating large granular lymphocytes (LGL) which subserve spontaneous (NK) cytolytic activity. Recent in vitro results indicate that gEL can develop this function after prolonged in vitro culture; the relevance of this, in vivo, remains to be decided. EL also appear to be able to mediate ADCC with sIgA against enteric micro-organisms. This is the kind of integrated activity that might be anticipated from local immunocytes within the intestinal mucosa. Other recent work suggests that gEL are not precursors of mucosal mast cells. EL also appear to be capable of inducing Ia-like expression in surface and crypt enterocytes, a property enjoyed both by highly purified Th, but also Ts/c, cells as well. This raises the interesting prospect that enterocytes may display antigen in macrophage-like fashion to other adjacent cells within the inter-epithelial cell spaces. These latter observations might be more consistent with the presence of 'activated' and 'blast-transformed' lymphocytes in such conditions as coeliac disease and tropical sprue. Another emergent view that demands appropriate attention is that the infiltrate of Ts/c cells into surface, and crypt, epithelium of coeliac mucosa does not necessarily cause injury or damage to the jejunal tissues. Nevertheless the role, either primary or secondary, that EL play either in coeliac disease or tropical sprue still remains obscure.

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 .