Abnormal small intestinal permeability in patients with idiopathic malabsorption in tropics (tropical sprue) does not change even after successful treatment.

BACKGROUND: Though tropical sprue (TS) is common in tropics, studies on small intestinal permeability (SIP) in TS are scant. METHOD: SIP was evaluated using (1)H nuclear magnetic resonance (NMR) spectroscopy of urinary lactulose and mannitol in 24 patients with TS (22 before and 15 after treatment with tetracycline and folate) and in 31 healthy subjects (HS). Effect of treatment of TS on SIP and its relationship with outcome were studied. RESULT: Subjects were comparable in terms of age and gender. Before treatment, urinary lactulose (0.24 mmol, 0-1.09 mmol versus 0.09 mmol, 0-0.68 mmol, P=0.02) and lactulose-to-mannitol (L/M) ratio (0.11, 0-0.41 versus 0.042, 0-0.26, P=0.001) were higher in TS than in HS, though mannitol was comparable (2.7 mmol, 0.61-10.5 mmol versus 3.8 mmol, 1.3-16.4 mmol, P=0.08). Patients improved after treatment [stool frequency (9, 4-20/day versus 1, 1-2/day, P<0.0001), weight (44.4, 32-69 kg, versus 56, 39-84 kg, P<0.0001), fecal fat (10.1, 6-26 g/24 h versus 4.4, 3.0-6.7 g/24 h, P<0.0001), D-xylose (0.57, 0.28-1.2 g/5 g/5 h versus 1.1, 0.2-2.1 g/5 g/5 h, P<0.0001), and small intestinal bacterial overgrowth (SIBO) resolved in 10/24 (41.7%) versus 1/15 (6.6%), P=0.02]. Though urinary lactulose (0.17, 0-4.3 mmol versus 0.09, 0-0.68 mmol, P=0.11) and mannitol (2.17, 0.8-36.7 mmol versus 3.84, 1.3-16.4 mmol, P=0.06) were comparable, L/M ratio was higher in TS than in HS (0.09, 0-0.22 versus 0.042, 0-0.26, P=0.002). L/M ratio was more often abnormal (cutoff 0.078) in TS than in HS [14/22 (63.6%) versus 3/31 (9.7%); P=0.0001], which persisted even after treatment [9/15 (60%) as compared with HS; P=0.0006]. Persistently abnormal SIP was associated with less weight gain and frequent stools following treatment. CONCLUSION: SIP is often abnormal in TS and remains unchanged even after successful treatment that was associated with less weight gain and more frequent stool.

Age-related association of small intestinal mucosal enteropathy with nutritional status in rural Gambian children.

Small bowel enteropathy (assessed by the lactulose (L) : mannitol (M) permeability test) is a major factor in infant growth faltering and malnutrition in The Gambia. However, little is known about its persistence and nutritional effect beyond 2 years of age. This was addressed by two cross-sectional studies of intestinal permeability and nutritional status in 162 residents, aged 2-60 years, living in three villages in rural Gambia. L:M ratio was found to be highest in the youngest children and although there was a significant improvement with age (P<0.0001), values were always greater than the range found in UK counterparts. M recovery (mean value 5.68 (se 0.12) %) was at all times between one-third and one-half of expected UK values and showed no improvement with age. Gut barrier function, assessed by L uptake, improved with age (P<0.001) and fell within the UK normal range beyond age 10 years. Both the L:M permeability ratio and L recovery were significantly associated with height-for-age z-scores and -0.22 respectively, P<0.001), a relationship that persisted throughout childhood and into adulthood. Change in height-for-age z-score between the two visits was also related to the L:M ratio P=0.018). The close within-subject correlation of permeability variabilities between the two visits suggests a long-term persistence of enteropathy within individuals. It appears that the small bowel enteropathy previously described in Gambian infants persists through to adulthood. Although the lesion improves with age, the relationship between attained height and L:M permeability raises the possibility that enteropathy may continue to limit growth throughout childhood and puberty.

Jejunal and ileal glucose-stimulated water and sodium absorption in tropical enteropathy: implications for oral rehydration therapy.

Intestinal glucose and water absorption in response to glucose has been studied in tropical enteropathy with a view to determine the optimum glucose concentration in oral rehydration solutions for use in the tropics. Maximum jejunal water and sodium absorption occurred from an 80-mM glucose-sodium chloride solution (-285.7 +/- 46.0 ml/30 cm/h and -31.8 +/- 3.8 mM/30 cm/h, respectively) during in vivo steady-state jejunal perfusion. At perfusate glucose concentrations greater than 250 mM, however, jejunal water and sodium secretion occurred. In the ileum, maximum glucose-stimulated water absorption (-91.1 +/- 27.1 ml/30 cm/h) was significantly less than in the jejunum. Glucose absorption demonstrated saturation kinetics in both the jejunum and ileum. The half-saturation concentration was higher in the jejunum (167 mM) compared to the ileum (28 mM). This study suggests that the optimal glucose concentration for oral rehydration solutions used in the tropics should be 80 mM, as lower and higher concentrations result in diminished jejunal water absorption.

Jejunal surface pH measurements in tropical sprue.

The mucosal surface pH of jejunal biopsy samples incubated in vitro in Krebs-phosphate buffer was measured. Biopsies from 7 healthy individuals or tropical sprue subjects in complete remission had a mean surface pH of 5.8 +/- 0.09, similar to values for normal Caucasian subjects living in the UK. The mean surface pH of biopsies from 20 sprue patients, 6.0 +/- 0.08, was significantly higher (P less than 0.05) than that of the control subjects. Sprue patients could be sub-divided into those with 2 or more abnormal results in 3 intestinal function tests, and those with one or no abnormal test. The 9 low scorers showed a mean surface pH of 5.75 +/- 0.06 resembling the control mean, whereas the 11 high scorers had a higher (P less than 0.01) mean surface pH of 6.17 +/- 0.08. Mucosal surface pH correlated directly with 3 d mean faecal fat excretion and inversely with xylose and vitamin B12 absorption values but not with the nutritional indicators serum albumen, folate or blood haemoglobin levels. As in coeliac disease, mucosal surface pH in the jejunum is elevated above normal in tropical sprue and may reflect the extent to which normal ion transport processes are affected.

Absorption of water and sodium and activity of adenosine triphosphatases in the rectal mucosa in tropical sprue.

In 10 southern Indian patients with tropical sprue, in vivo dialysis showed a defect of absorption of water and sodium from the rectum, when compared with 11 healthy volunteers. Sodium-potassium-ATPase activity, measured in homogenates of rectal biopsies, was significantly diminished in patients with sprue. Magnesium-ATPase and alkaline phosphatase were normal in biopsy homogenates. Decreased activity of colonic sodium-potassium-ATPase may contribute to diarrhoea in some patients with tropical sprue.

Role of bacterial toxins, bile acids, and free fatty acids in colonic water malabsorption in tropical sprue.

Colonic perfusion studies in 10 southern Indian patients with tropical sprue and nine matched healthy adults revealed a defect of water and sodium absorption from the colon in sprue. Heat-labile and heat-stable enterotoxin production was not detected in coliforms cultured from the feces of any of the 19 subjects. The 24-hr fecal bile acid output was increased in patients with sprue, but fecal aqueous bile acid concentrations remained within normal limits, and these did not correlate with defects in colonic water and sodium absorption. Fecal free fatty acid excretion was markedly increased in sprue. There was a negative correlation between fecal excretion of unsaturated free fatty acids and colonic water and sodium absorption.

Intestinal absorption and unmediated permeation of sugars in post-infective tropical malabsorption (tropical sprue).

Differential absorption of D-xylose and 3-O-methyl-D-glucose, and unmediated intestinal permeation of lactulose and L-rhamnose has been investigated in 14 patients with diarrhoea following tropical exposure and in 16 healthy control subjects. Five had malabsorption of fat, D-xylose and B12 ('tropical malabsorption' (TM) group), and that was absent or minimal in the others ('tropical diarrhoea' (TD) group). After combined ingestion of the four test sugars in iso-osmolar solution a marked depression in plasma D-xylose concentration (with a slow rise) occurred in all of the TM group; the TD group did not differ significantly from the controls. In contrast, 3-O-methyl-D-glucose absorption was similar in all three groups. Urine analysis demonstrated that intestinal permeation of lactulose was increased and that of rhamnose decreased in the TM group compared with the controls. Ingestion as a hyperosmotic solution further enhanced abnormal lactulose permeation in the TM group. Although some of the TD group showed one or the other of these changes, discrimination of the TM group from the TD and control groups was improved when results were expressed as lactulose/rhamnose differential permeation ratios, especially when using a hyperosmotic stress. Similar abnormalities have previously been demonstrated in untreated gluten-induced enteropathy (coeliac disease). The magnitude of the absorption defects demonstrated in TM are more severe than would be anticipated from the jejunal mucosal abnormalities alone; this suggests that there is probably significant pathology in the distal small intestine (including the ileum) in TM.

The kinetics of D3-3H metabolism in tropical sprue.

The metabolism of vitamin D3-3H was studied in a small group of controls and subjects with tropical sprue after the oral or intravenous administration of 8 to 10 microCi of D3-3H. The biological half life of D3-3H upon the administration of the isotope by the intravenous route was normal in 2 controls, very low in a subject with tropical sprue who had steatorrhea, and decreased in a subject with tropical sprue who did not present steatorrhea. After the administration of the isotope by the oral route, the biological half life was 35 hours in the control and no radioactivity could be detected in the plasma of the subject with tropical sprue who had steatorrhea. Twenty four hours after the intravenous dose the percentage of radioactivity in the plasma as HCC-3H was two times higher in the tropical sprue subjects than in the controls. When the dose was given orally the net absorption was 50.5% in the subject with tropical sprue and steatorrhea and 86.8% in the subject with tropical sprue who was partially treated. These results showed rapid clearance of the D3-3H in the subject with tropical sprue and steatorrhea indicating depletion of vitamin D stores in the tissues and decrease in the net absorption of the dose when given orally. The presence of a higher percentage of the dose in the plasma as HCC-3H after the intravenous and oral administrations in the tropical sprue subjects when compared to controls indicates that the diseased state does not alter vitamin D3 metabolism.

The kinetics of D3-3H metabolism in tropical sprue

El metabolismo de vitamin D3 rotulada con titrio (D3-3H) fue estudiado en un grupo pequeño de sujetos controles y sujetos con esprú tropical, al cual les fue administrado de 8 a 10 microcuries del isotopo por vía oral o intravenosa. La media vida del isotopo (D3-3H) fue hallada normal en 2 controles, baja en un sujeto con esprú tropical que presentaba esteatorrea y disminuída en un sujeto con esprú tropical sin esteatorrea. Cuando la dosis fue administrada por vía oral la media vida de D3-3H fue de 35 horas en el control, y no se detectó ninguna radioactividad en el plasma del sujeto con esprú tropical y esteatorrea. A las 24 horas de haber recibido la dosis por vía intravenosa el porciento de radioactividad en el plasma como HCC-3H fue dos veces mayor en los sujetos con esprú tropical que en los controles. La absorción oral del D3-3H fue de 50,5% en el sujeto con esprú tropical y esteatorrea y 86,8% en el sujeto con esprú tropical parcialmente tratado. Estos resultados demostraron una depuración rápida del D3-3H en el sujeto con esprú tropical y esteatorrea indicando depleción de las reservas de vitamina D3 en los tejidos y una disminución de la absorción oral del D3-3H. La presencia de un porciento de la radioactividad en el plasma como HCC-3H dos veces mayor en los sujetos con esprú tropical que en los controles, al administrarse la dósis por vía intravenosa y oral indica que no existe ninguna alteración en el metabolismo de vitamina D3 en esprú tropical

Absorption of nutrient energy in southern Indian control subjects and patients with tropical sprue.

Fecal energy excretion was measured by bomb calorimetry, in a group of 30 healthy volunteers and 15 patients with tropical sprue, to determine the absorption of nutrient energy. The mean energy absorption in the healthy volunteers (91.6%) was less than in similar subjects in temperate climates. The reduction of energy absorption in the volunteers, who all have tropical enteropathy, suggests that this condition leads to wastage of 5% of energy intake. In patients with tropical sprue the energy absorption was significantly lower. A strict metabolic balance study was not essential to detect energy malabsorbers.

Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract.

A means of estimating human enteroglucagon (glucagon-like immunoreactivity of intestinal origin) in tissues and plasma is described, based on the subtraction of RIA values obtained with the C-terminal-directed glucagon antiserum RCS5 from the total glucagon-like immunoreactivity determined with the N-terminal- to midmolecule-directed glucagon antiserum R59. Gel filtration on Sephadex G-50 of human plasma and extracts of normal human intestine separated the R59 immunoreactivity into three peaks: a small peak of void volume material, a major peak coeluting with porcine glicentin, and a smaller peak coeluting with pancreatic glucagon. No RCS5 immunoreactivity was detected in the human gut, except for a small amount constituting less than 2% of the total glucagon-like immunoreactivity in the ileum and rectum only. In extracts of human pancreas, the chromatographic profiles obtained with RCS5 and R59 assays differed from the intestinal patterns, but were identical to each other, giving no evidence of a significant amount of pancreatic R59 immunoreactivity that was not also reactive with RCS5. Chromatography of plasmas from healthy subjects and patients with dumping syndrome, active coeliac disease, and tropical sprue showed that only the second major peak of R59 immunoreactivity reflected the basal or postnutrient increases in the plasma enteroglucagon concentration. In patients with exaggerated enteroglucagon release, the rise was again found to be entirely due to an increase in this peak of immunoreactivity. This major molecular form of human enteroglucagon, similar in size to porcine glicentin, is, thus, the form most likely to be of physiological and pathophysiological significance.

Faecal free fatty acids in tropical sprue and their possible role in the production of diarrhoea by inhibition of ATPases.

Faecal excretion of fatty acids is increased in patients with tropical sprue because of unabsorbed dietary fatty acids. The excretion of fatty acids correlates well with faecal wet weight. In vitro unsaturated fatty acids inhibited Na K-ATPase and Mg-ATPase isolated from basolateral membranes of enterocytes and colonocytes. These findings are a possible explanation for the observed abnormalities in water and electrolyte absorption by the colon in patients with tropical sprue and steatorrhoea.

Water and electrolyte absorption by the colon in tropical sprue.

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.

Antibiotic-responsive malabsorption: a tropical sprue-like syndrome in countries with temperate climates.

Antibiotic-responsive malabsorption is prevalent in the tropics, but has been seen only sporadically in countries with temperate climates. We describe a 19-year-old Israeli patient who has never left the country and was hospitalized with shigellosis and malabsorption of fat and D-xylose. A short course of ampicillin reversed the malabsorption. The syndrome of antibiotic-responsive malabsorption in countries with temperate climates may well be underdiagnosed and should be looked for more actively.

Jejunal absorption rates of glucose and glycine in post-infective tropical malabsorption.

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.

Impaired intestinal absorption of dipeptide in tropical sprue patients in India.

1. Intestinal absorption of glycylglycine was studied in four control subjects and six patients with tropical sprue by using a direct technique of intestinal perfusion. 2. The patients with tropical sprue showed significant impairment in the absorption of the dipeptide.