Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion.

To explain the very high frequency of cystic fibrosis (CF) mutations in most populations of European descent, it has been proposed that CF heterozygotes have a survival advantage when infected with Vibrio cholerae or Escherichia coli, the toxins of which induce diarrhea by stimulation of active intestinal chloride secretion. Two assumptions underlie this hypothesis: (1) chloride conductance by the CF transmembrane conductance regulator (CFTR) is the rate-limiting step for active intestinal chloride secretion at all levels of expression, from approximately zero in patients with CF to normal levels in people who are not carriers of a mutation; and (2) heterozygotes have smaller amounts of functional intestinal CFTR than do people who are not carriers, and heterozygotes therefore secrete less chloride when exposed to secretagogues. The authors used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analogue. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less-than-normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results do not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal illnesses mediated by intestinal hypersecretion of chloride.

Discrepancies between effects of recombinant human growth hormone on absorption and secretion of water and electrolytes on the human jejunum compared to results reported on rat jejunum.

Previous studies in rats showed that the administration of recombinant human growth hormone markedly increased intestinal absorption of electrolytes and water and suggested that growth hormone would be a useful antidiarrheal agent. We therefore examined the effect of recombinant human growth hormone on the human jejunum in vivo, using a triple lumen nonabsorbable marker technique. Healthy subjects were studied on two different test days, one as a control and a second where recombinant human growth hormone was injected subcutaneously in a dose of 100 microg/kg. With this dose we achieved equal or higher growth hormone serum levels than in previous rat studies. However the administration of recombinant human growth hormone did not stimulate absorption or inhibit secretion of water and electrolytes in the human jejunum in vivo. We believe that the discrepancy between humans and rats is most likely due to the species difference rather than to differences in methods that were used. Therefore recombinant human growth hormone cannot be considered a useful proabsorptive antidiarrheal agent in humans.

Positive results on tests for steatorrhea in persons consuming olestra potato chips.

BACKGROUND: Olestra is a nonabsorbable fat substitute that consists of fatty acids esterified to a sucrose molecule. OBJECTIVE: To determine the effect of olestra consumption on measurements of fecal fat excretion. DESIGN: Controlled cross-over trial. SETTING: Clinical research center and outpatient research laboratory. PARTICIPANTS: 10 healthy volunteers. INTERVENTION: On days 1 to 6 of the study, participants consumed 5 oz of conventional potato chips per day; on days 7 to 12, they consumed 5 oz of potato chips containing 40 g of olestra per day. MEASUREMENTS: Quantitative measurement of fecal fat by the van de Kamer titration, van de Kamer gravimetric, and Jeejeebhoy gravimetric methods and qualitative assessment of fecal fat by Sudan III staining. RESULTS: Excellent correlation was seen among the three quantitative assays, but the van de Kamer titration method yielded lower measurements than the two gravimetric methods. When participants consumed 40 g of olestra per day, the excretion of fecal fat increased to levels observed in patients with steatorrhea caused by the malabsorption syndrome. CONCLUSION: Consumption of olestra can cause false-positive results on tests for steatorrhea and may therefore lead to an erroneous diagnosis of the malabsorption syndrome.

A comparison of stool characteristics from normal and constipated people.

In people with constipation, it is not known if decreased frequency of defecation is associated with abnormalities in the weight or in the consistency of stools or if the weight or the consistency of stools correlates with the severity of various discomforts associated with bowel movements. In neither normal nor constipated subjects has the consistency of stools been carefully correlated with their relative contents of water and solids. Our aim was to gain insight into these questions. Twenty subjects with idiopathic chronic constipation and 20 age- and sex-matched control subjects were recruited by advertisement. Stools were collected for one week. After each bowel movement, the subject's perception of various discomforts associated with the bowel movement were recorded. The stools were then analyzed. The results and conclusions were as follows: (1) Stool weight per bowel movement was similar in the two groups but stool weight per week was markedly reduced in constipated subjects. (2) Reduced stool weight per week in constipated subjects was due to a nearly proportional reduction in stool water and stool solids output. (3) Using data from both groups, there was a curvilinear correlation between percent insoluble stool solids and stool hardness, as measured by a texture analyzer; hardness increased only slightly as percent insoluble solids increased between 7 and 20%, but hardness increased dramatically when percent insoluble solids exceeded 25%. (4) Only 6% of stools from constipated subjects (2 of 34) had abnormally high values for percent stool solids and physical hardness. (5) In subjects with constipation, the severity of various discomforts associated with bowel movements (such as straining) correlated poorly with the weight or the hardness of stool that was produced by the bowel movement.

Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease.

Hyperkalemia in patients with renal failure is frequently treated with a cation exchange resin (sodium polystyrene sulfonate, hereafter referred to as resin) in combination with a cathartic, but the effect of such therapy on serum potassium concentration has not been established. This study evaluates the effect of four single-dose resin-cathartic regimens and placebo on 5 different test days in six patients with chronic renal failure. Dietary intake was controlled. Fecal potassium output and serum potassium concentration were measured for 12 h. Phenolphthalein alone caused an average fecal potassium output of 54 mEq. The addition of resin caused an increase in insoluble potassium output but a decrease in soluble potassium output; therefore, there was no significant effect of resin on total potassium output. Sorbitol plus resin caused less potassium output than phenolphthalein plus resin. On placebo therapy, the average serum potassium concentration increased slightly (0.4 mEq/L) during the 12-h experiment. This rise was apparently abrogated by some of the regimens that included resin; this may have been due in part to extracellular volume expansion caused by absorption of sodium released from resin. Phenolphthalein regimens were associated with a slight rise in serum potassium concentrations (similar to placebo); this may have been due to extracellular volume contraction produced by high volume and sodium-rich diarrhea and acidosis secondary to bicarbonate losses. None of the regimens reduced serum potassium concentrations, compared with baseline levels. Because single-dose resin-cathartic therapy produces no or only trivial reductions in serum potassium concentration, and because this therapy is unpleasant and occasionally is associated with serious complications, this study questions the wisdom of its use in the management of acute hyperkalemic episodes.

Glucose-stimulated sodium transport by the human intestine during experimental cholera.

BACKGROUND & AIMS: Net sodium absorption from oral rehydration solution is increased by both glucose-sodium cotransport and solvent drag. The aim of this study was to measure the relative importance of glucose-sodium cotransport and solvent drag in the stimulation of net sodium absorption by oral rehydration solution. METHODS: Total intestinal perfusion was used in normal subjects with and without intrajejunal cholera toxin using three test solutions containing 100 mmol/L sodium and either 100 mmol/L mannitol (control), 100 mmol/L glucose, or no additional solute (hypotonic solution). The increase in sodium absorption greater than control with hypotonic solution represented sodium absorption stimulated by solvent drag; the further increase in sodium absorption induced by glucose, greater than that noted with the hypotonic solution, represented sodium absorption stimulated by cotransport. RESULTS: Without cholera toxin, solvent drag and cotransport promoted sodium absorption at rates of 62 and 33 mmol/h, respectively. With cholera toxin, solvent drag and cotransport promoted sodium absorption at rates of 44 and 71 mmol/h, respectively. CONCLUSIONS: Net sodium absorption caused by cotransport increased more than twofold after exposure of the intestine to cholera toxin (P < 0.003). This could be mediated by increased cotransport, a change in the stoichiometry of cotransport, or an increase in chloride permeability.

Validation of polyethylene glycol 3350 as a poorly absorbable marker for intestinal perfusion studies.

Polyethylene glycol (PEG) has been used as a poorly absorbable marker in intestinal perfusion studies, but there is controversy about the absorbability of PEG, particularly when glucose-sodium cotransport is occurring. Total intestinal perfusion studies were done in five normal humans using three solutions containing 1 g/liter PEG 3350 and designed to produce low rates of water absorption, high rates of water absorption, or high rates of glucose-sodium cotransport. Water absorption rates were calculated by traditional nonabsorbable marker equations and by a novel balance technique in which absorption was taken as the difference between the volumes of solution infused and recovered during steady-state conditions. Effluent PEG recovery was 99 +/- 4%, 109 +/- 2%, and 104 +/- 6% of the amount infused with each solution. Water absorption rates measured by use of PEG concentrations were similar to those calculated by the balance technique (r = 0.99). The complete recovery of PEG confirms the poor absorbability of PEG 3350, and the excellent agreement between techniques validates PEG as a poorly absorbed marker, even when glucose-sodium cotransport is occurring.

Effect of fludrocortisone and spironolactone on sodium and potassium losses in secretory diarrhea.

The response of the colon to aldosterone is believed to be an important adaptive mechanism to excessive sodium losses in diarrhea. However, the degree to which mineralocorticoid activity actually influences fecal output of sodium in people with diarrhea is unknown. To gain insight into this question, 10 normal people were treated with placebo, fludrocortisone (an aldosterone agonist), and spironolactone (an aldosterone antagonist) during three experimental periods lasting nine days. On days 5-8, diarrhea was induced by ingestion of phenolphthalein. Diet was controlled. Fecal sodium was 40 meq/day on placebo and 29 meq/day on fludrocortisone, consistent with mineralocorticoid stimulation of intestinal sodium absorption. However, contrary to our expectations, spironolactone therapy was also associated with a fall in fecal sodium output, to 28 meq/day. To explain this paradoxical effect of spironolactone, we suggest that sodium depletion caused by spironolactone's natriuretic action on the kidney caused the release of an unknown stimulant of intestinal sodium absorption, whose action more than overcame the reduced colonic absorption resulting from inhibition of aldosterone activity by spironolactone. This interpretation implies that the intestinal adaptation to sodium depletion in diarrhea involves both aldosterone and an aldosterone independent factor, working in concert to reduce fecal sodium output.

Effect of changing intestinal flow rate on a measurement of intestinal permeability.

BACKGROUND/AIMS: The flow rate of fluid through the proximal small intestine varies widely under normal physiological conditions. The aim of this study was to assess the effect of changes in flow rate on the passive permeability of the aqueous paracellular pathway of the human jejunum. METHODS: Normal subjects were studied in vivo during constant perfusion of 30-cm loops of jejunum at flow rates of 5, 10, or 20 mL/min. The permeability ratio of L-xylose/urea was used to assess apparent permeability of the mucosa and to calculate the average pore radius of the aqueous pathway for passive diffusion. RESULTS: Increasing jejunal flow rate from 5 to 20 mL/min significantly decreased the L-xylose/urea permeability ratio from 0.35 to 0.23 and decreased average calculated pore radius of the diffusion pathway from 13 A to 8 A. CONCLUSIONS: Increases in flow rate in the normal physiological range decrease the estimated pore size of normal healthy jejunal mucosa. Because increasing flow rate is known to increase exposure of luminal fluid to the intervillus space, the results of this study are best explained by postulating that cells lining the sides of villi are less permeable than cells lining the villus tips.

Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion.

BACKGROUND/AIMS: The treatment of hyperkalemia in patients with renal insufficiency often includes the ingestion of sorbitol and a cation exchange resin. Sorbitol alone may be used to remove sodium and water from overloaded patients. The efficacy of these regimens has never been compared with other laxative or laxative-resin combinations. The aim of the study was to compare the relative effect of three laxatives with different mechanisms of action, alone and in combination with resin, on fecal sodium and potassium excretion. METHODS: Sodium, potassium, and water excretion in 12-hour stool collections were analyzed after various laxative-resin combinations in normal subjects. RESULTS: Correctol (yellow phenolphthalein) (Schering Plough Health Care Products, Memphis, TN) was more effective than sorbitol or sodium sulfate in causing fecal sodium and potassium loss. Resin recovery in stool was much greater with phenolphthalein than with other laxatives, and more potassium was excreted in stool with phenolphthalein-resin than with phenolphthalein alone or other laxative-resin combinations. Sorbitol caused more undesirable gastrointestinal symptoms than did sodium sulfate or phenolphthalein. CONCLUSIONS: In normal people, phenolphthalein (1) is preferable to other laxatives in causing fecal sodium and potassium excretion, (2) hastens resin transit through the intestine compared with other laxatives, and (3) produces greater fecal potassium excretion when combined with resin than phenolphthalein alone or other laxative-resin combinations.

Mechanism by which glucose stimulates the passive absorption of small solutes by the human jejunum in vivo.

BACKGROUND/AIMS: Active absorption of glucose stimulates passive absorption of small solutes. Part of this effect may be caused by glucose-induced water absorption. Increased water absorption can enhance passive solute absorption by solvent drag and by passive diffusion if the luminal solute concentration increases as water is removed from the lumen. The purpose of this research was to quantitate the contribution of these two forces when glucose enhances the absorption of L-xylose. METHODS: The effect of solvent drag on L-xylose absorption was determined by measuring the effect of water absorption stimulated by hypotonicity on L-xylose absorption when the L-xylose concentration was constant. The effect of diffusion on L-xylose absorption was determined by measuring the effect of L-xylose concentration on L-xylose absorption when water absorption was nil. RESULTS: Glucose increased L-xylose absorption by 1.8 mmol.h-1 x 30 cm-1 (from 1.4 to 3.2 mmol.h-1 x 30 cm-1). The increase attributable to solvent drag was 1.03 mmol.h-1 x 30 cm-1; the increase attributable to passive diffusion was 0.75 mmol.h-1 x 30 cm-1. CONCLUSIONS: When glucose stimulates the passive absorption of L-xylose, 57% of the increase can be attributed to solvent drag and 42% to passive diffusion. Because the combined effect of these two forces can account for 99% of the observed effect, virtually all of the glucose effect on L-xylose absorption can be explained by glucose-induced water absorption.

Effect of D-glucose on intestinal permeability and its passive absorption in human small intestine in vivo.

BACKGROUND: Based on studies in animals, it has been proposed that carrier-mediated D-glucose absorption markedly enhances passive permeability of the jejunal mucosa, allowing the majority of D-glucose absorption to proceed passively. In this study, we evaluated this hypothesis in the human jejunum in vivo. METHODS: Using the constant perfusion, nonabsorbable marker technique, permeability of jejunal mucosa was assessed by measuring the ratio of diffusion rates of urea/L-xylose and mannitol/L-xylose. Passive D-glucose absorption was quantitated using L-glucose and mannitol as probes for D-glucose. RESULTS: Addition of D-glucose to perfused solutions did not change the diffusion ratios, indicating that D-glucose has no effect on the size of channels for passive diffusion across the jejunal mucosa. The fraction of total D-glucose absorption that could be attributed to a passive mechanism averaged 5%. In the human ileum in vivo, we detected no evidence of passive D-glucose absorption. CONCLUSIONS: Carrier-mediated D-glucose absorption does not increase passive permeability of human jejunal mucosa to solutes with molecular radii between 2.6 and 4.0 A. The amount of D-glucose absorbed passively from the human jejunum is trivial compared with the overwhelmingly dominant mechanism, carrier-mediated transport. Our results do not support the concept that sodium-dependent nutrient transport increases tight junction permeability.

Effect of psyllium, calcium polycarbophil, and wheat bran on secretory diarrhea induced by phenolphthalein.

BACKGROUND: Fiber and water-holding agents are used for the treatment of constipation. In what may appear to be a paradox, they are sometimes also used for the treatment of diarrhea; it has been proposed that they sequester water from liquid stools and/or increase the ratio of fecal solids to fecal water and thereby improve stool consistency. The purpose of the present study was to test the validity of this hypothesis in normal subjects in whom secretory diarrhea was induced by phenolphthalein. METHODS: In random sequence, 9 subjects with phenolphthalein-induced diarrhea were treated with placebo, psyllium, calcium polycarbophil, or wheat bran. RESULTS: Calcium polycarbophil and wheat bran had no effect on fecal consistency or on fecal viscosity. By contrast, psyllium made stools firmer and increased fecal viscosity. In a dose-response study in 6 subjects, doses of 9, 18, and 30 g of psyllium per day caused a near linear increase in fecal viscosity. CONCLUSION: Psyllium, but not calcium polycarbophil or wheat bran, improves fecal consistency and viscosity in subjects with experimentally-induced secretory diarrhea.

Subepithelial collagen table thickness in colon specimens from patients with microscopic colitis and collagenous colitis.

Microscopic colitis and collagenous colitis are similar conditions that are differentiated by the presence or absence of subepithelial collagen table thickening. To better understand the relationship between these two disorders and the role of collagen table thickening in the pathogenesis of diarrhea, colonic mucosal biopsy specimens from 24 patients with microscopic or collagenous colitis and 9 control subjects were analyzed using a computer-assisted morphometric method to evaluate the average thickness of the subepithelial collagen table. The collagen table thickness in colitis patients taken together formed a multimodal rather than a unimodal distribution. There was no tendency for collagen table thickening to increase with age or with duration of symptoms. In general, the types and distribution of inflammatory cells were similar in patients with normal and thickened collagen tables. Stool weight correlated with lamina propria cellularity but not with collagen table thickening. The multimodal distribution of collagen table thickening and the lack of correlation with age, duration of symptoms, or inflammation suggest that microscopic colitis and collagenous colitis are discrete conditions, although the inflammatory changes in the two conditions are similar. Moreover, because stool weight correlates with lamina propria cellularity but not with collagen table thickening, diarrhea probably is caused by the inflammatory changes and not by collagen table thickening per se.

Intestinal absorption of magnesium from food and supplements.

The purpose of this study was to measure magnesium absorption over the wide range of intakes to which the intestine may be exposed from food and/or magnesium-containing medications. Net magnesium absorption was measured in normal subjects after they ingested a standard meal supplemented with 0, 10, 20, 40, and 80 mEq of magnesium acetate. Although absorption increased with each increment in intake, fractional magnesium absorption fell progressively (from 65% at the lowest to 11% at the highest intake) so that absorption as a function of intake was curvilinear. This absorption-intake relationship was almost perfectly represented by an equation containing a hyperbolic function plus a linear function. Our results are statistically compatible with a magnesium absorption process that simultaneously uses a mechanism that reaches an absorptive maximum, plus a mechanism that endlessly absorbs a defined fraction (7%) of ingested magnesium. Compared to previous studies of calcium absorption, much less magnesium that calcium was absorbed at intakes above 8 mEq/meal, apparently due to greater restriction of intestinal permeability to magnesium. We also found that magnesium from a high magnesium-containing food source, almonds, was just as bioavailable as from soluble magnesium acetate. In contrast, magnesium absorption from commercially available enteric-coated magnesium chloride was much less than from magnesium acetate, suggesting that enteric coating can impair magnesium bioavailability.

Diagnosis of magnesium-induced diarrhea.

BACKGROUND: There is no specific method of diagnosing magnesium-induced diarrhea. Therefore, the frequency and clinical importance of diarrhea caused by magnesium are unknown. The purposes of this study were to establish a method for diagnosing magnesium-induced diarrhea and to apply it to patients with chronic diarrhea. METHODS: We measured fecal output of soluble magnesium and fecal magnesium concentration in 19 normal subjects with formed stools (15 collection periods), with non-magnesium-induced diarrhea (36 collection periods), and with diarrhea induced by magnesium hydroxide alone (11 collection periods) or in combination with phenolphthalein (3 collection periods), and in 359 patients with chronic diarrhea. RESULTS: The upper limits of fecal output of soluble magnesium and fecal magnesium concentration in normal subjects were 14.6 mmol per day and 45.2 mmol per liter, respectively. When normal subjects had diarrhea due to the ingestion of magnesium hydroxide alone or in combination with phenolphthalein, fecal magnesium output was always abnormally high. For each millimole increase in fecal magnesium output, fecal weight increased by approximately 7.3 g. The fecal magnesium concentration was very high when magnesium was the only cause of diarrhea but only moderately elevated when diarrhea was induced by magnesium hydroxide plus phenolphthalein. Biochemical and clinical evidence indicated that excessive ingestion of magnesium was an important cause of chronic diarrhea in 15 of the 359 patients with chronic diarrhea (4.2 percent), if not the only cause. CONCLUSIONS: Quantitative fecal analysis for soluble magnesium is an accurate method of diagnosing magnesium-induced diarrhea. Some patients with chronic diarrhea ingest excessive amounts of magnesium (in antacids or food supplements), and physicians may fail to discover this before embarking on an expensive and invasive diagnostic evaluation.

Carbohydrate malabsorption. Its measurement and its contribution to diarrhea.

The major purpose of this research was to gain insight into the effect of carbohydrate malabsorption on fecal water output. To do this we measured daily fecal output of total carbohydrate, reducing sugars, and organic acids (a product of bacterial fermentation). Normal subjects were studied in their native state and when diarrhea was induced by mechanisms that did and did not involve carbohydrate malabsorption. Patients with malabsorption syndrome were also studied. We concluded that: (a) Excretion of carbohydrate and its breakdown products can be expressed as a single number by converting organic acids to their monosaccharide equivalents. (b) Diarrhea per se causes only a trivial increase in fecal carbohydrate excretion. (c) The molar output of osmotic moieties in feces due to unabsorbed carbohydrate can be determined by adding fecal reducing sugars to organic acids and their obligated cations. This expression parallels almost exactly the effect of increasing doses of lactulose (a nonabsorbable sugar) on fecal water output; one excreted millimole obligates 3.5 g of stool water. This relationship can be used to predict the effect of carbohydrate malabsorption on stool water output in patients with diarrhea. (d) 12 of 19 patients with malabsorption syndrome due to various diseases had excessive fecal excretion of carbohydrate and its breakdown products; of the diseases that cause malabsorption syndrome, combined small and large bowel resection is most likely to result in excessive fecal excretion of carbohydrate and monosaccharide equivalents. In 6 of these 19 patients carbohydrate malabsorption appeared to be the major cause of diarrhea.

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea.

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.