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.

Conjugated bile acid replacement therapy for short-bowel syndrome.

BACKGROUND & AIMS: Although fat malabsorption in the short-bowel syndrome is caused in part by decreased bile acid secretion, bile acid replacement therapy is not used because of the belief that ingested bile acids would worsen diarrhea, outweighing the benefits of improved fat absorption. This study compared the effect of a natural conjugated bile acid mixture from ox bile with that of cholylsarcosine, a synthetic conjugated bile acid, on fat absorption and diarrhea in a patient with the short-bowel syndrome. Cholylsarcosine is resistant to bacterial metabolism and has no cathartic activity. METHODS: Metabolic balance studies and a clinical trial were performed in an emaciated patient with the short-bowel syndrome and ileostomy in whom parenteral nutrition could not be used. RESULTS: In balance studies, conjugated bile acid replacement therapy with either preparation caused fat absorption to increase by approximately 40 g/day. Calcium absorption also increased. Neither bile acid product caused a clinically significant increase in ileostomy water output. During a 4-month outpatient trial, while the patient ingested 2 g/meal natural bile acids, her weight increased from 80 to 98 lb, without side effects. CONCLUSIONS: Conjugated bile acid replacement therapy should be part of the armamentarium for the treatment of selected patients with the short-bowel 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.

Effect of mineralocorticoid activity on transtubular potassium gradient, urinary [K]/[Na] ratio, and fractional excretion of potassium.

Clinical assessment of potassium derangements may require evaluation of mineralocorticoid status. Several indirect indices of mineralocorticoid activity based on renal electrolyte excretion have been proposed and include the transtubular potassium gradient, urinary [K]/[Na] ratio, and renal fractional excretion of potassium. We studied the impact of high mineralocorticoid activity versus blocked mineralocorticoid activity on these indices in otherwise normal subjects who ingested a defined diet. Eight normal subjects received either fludrocortisone or spironolactone for 4 days. After a washout period of > or = 2 weeks, each subject then received the opposite regimen. Subjects ingested an identical high-potassium diet during both experimental periods. The renal fractional excretion of potassium and transtubular potassium gradient were calculated using standard formulas. Fludrocortisone caused an increase in body weight and no significant reduction in serum potassium concentration, while spironolactone decreased body weight and increased plasma potassium concentration. After 1 or 2 days of treatment with fludrocortisone, the average values for all urinary indices of mineralocorticoid activity were significantly higher than after 1 or 2 days of treatment with spironolactone. However, the differences between these indices in the fludrocortisone and spironolactone test periods diminished by day 3 and were nonexistent by day 4. In conclusion, the transtubular potassium gradient, [K]/[Na] ratio, and renal fractional excretion of potassium reflect acute changes in mineralocorticoid activity. However, these indices do not discriminate between states of high and low mineralocorticoid activity lasting longer than 2 to 3 days.

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.

Determinants of decreased fecal consistency in patients with diarrhea.

BACKGROUND/AIMS: Loose stools are a common and troublesome feature in diarrhea. The purpose of this study was to investigate factors that determine different degrees of stool looseness in diarrhea. METHODS: Fecal consistency was measured visually. Stools were analyzed for content of water and solids. Water-holding capacity of insoluble solids was measured in vitro. RESULTS: Formed stools from normal subjects had a near constant ratio of water to solids despite a sevenfold variation in daily stool weight. In diarrhea, loose consistency was correlated directly with percent fecal water. For any level of percent water, steatorrhea stools were looser than nonsteatorrhea stools. Ingestion of psyllium reduced stool looseness without changing the percent water. Both the effect of fat and psyllium could be explained by consideration of the ratio of fecal water to water-holding capacity of insoluble solids. CONCLUSIONS: (1) The normal intestine delivers stools that differ widely in quantity but maintains percent fecal water within a narrow range. (2) Stool looseness in diarrhea is determined by the ratio of fecal water to water-holding capacity of insoluble solids. (3) In patients with diarrhea with normal stool weight, loose stools are due to low output of insoluble solids without the concomitant reduction in water output that occurs in normal subjects when insoluble solids are low.

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.

Diagnostic value of fasting plasma peptide concentrations in patients with chronic diarrhea.

To evaluate the utility of screening for multiple gastrointestinal peptides in the evaluation of patients with chronic diarrhea, we studied 193 patients referred for evaluation of chronic diarrhea and eight patients with known peptide-secreting tumors as a reference group. Fasting plasma samples were assayed for motilin, neurotensin, pancreatic polypeptide, somatostatin, substance P, vasoactive intestinal polypeptide, gastrin-releasing peptide, and calcitonin during a protocol evaluation for causes of chronic diarrhea. Although none of the referred patients were found to have tumors, abnormal levels of one or more peptides were found in 86 of 193 patients (45%). Abnormal plasma peptide levels were sometimes as high in these patients as in patients with known peptide-secreting tumors and would have led to mistaken diagnoses of tumors much more often than they would have led to correct diagnoses. The positive predictive value of elevation of any assayed peptide was < 2% at realistic prevalence rates for peptide-secreting tumors; the negative predictive value of a series of normal results was > 99%, but much of this was due to the rarity of these tumors. Patients with chronic diarrhea should not be screened routinely with a panel of plasma peptide assays in an effort to detect tumors; instead, peptide levels should be ordered selectively. Elevated fasting concentrations of the plasma peptides measured in this study are most likely epiphenomena due to diarrhea and should not be the sole basis for invasive diagnostic or surgical management of these patients.

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.

Pathophysiology of potassium absorption and secretion by the human intestine.

When normal people ingest 90 mEq/day of K+ in their diet, they absorb about 90% of intake (81 mEq) and excrete an equivalent amount of K+ in the urine. Normal fecal K+ excretion averages about 9 mEq/day. The vast majority of intestinal K+ absorption occurs in the small intestine; the contribution of the normal colon to net K+ absorption and secretion is trivial. K+ is absorbed or secreted mainly by passive mechanisms; the rectum and perhaps the sigmoid colon have the capacity to actively secrete K+, but the quantitative and physiological significance of this active secretion is uncertain. Hyperaldosteronism increases fecal K+ excretion by about 3 mEq/day in people with otherwise normal intestinal tracts. Cation exchange resin by mouth can increase fecal K+ excretion to 40 mEq/day. The absorptive mechanisms of K+ are not disturbed by diarrhea per se, but fecal K+ losses are increased in diarrheal diseases by unabsorbed anions (which obligate K+), by electrochemical gradients secondary to active chloride secretion, and probably by secondary hyperaldosteronism. In diarrhea, total body K+ can be reduced by two mechanisms: loss of muscle mass because of malnutrition and reduced net absorption of K+; only the latter causes hypokalemia. Balance studies in patients with diarrhea are exceedingly rare, but available data emphasize an important role for dietary K+ intake, renal K+ excretion, and fecal K+ losses in determining whether or not a patient develops hypokalemia. The paradoxical negative K+ balance induced by ureterosigmoid anastomosis is described. The concept that fecal K+ excretion is markedly elevated in patients with uremia as an intestinal adaptation to prevent hyperkalemia is analyzed; we conclude that the data do not convincingly show the existence of a major intestinal adaptive response to chronic renal failure.

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.