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 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.

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.

Calcium acetate, an effective phosphorus binder in patients with renal failure.

Calcium salts are increasingly used as phosphorus binders in patients with chronic renal failure. Calcium carbonate is the principal salt presently utilized, however, other calcium salts may be more effective and safer phosphorus binders. Theoretical calculations, in vitro experiments, and in vivo studies in normal subjects have shown calcium acetate to be a more effective phosphorus binder than other calcium salts. This salt has not previously been studied in patients with chronic renal failure. We used a one-meal gastrointestinal balance technique to measure phosphorus absorption, calcium absorption and phosphorus binding in six patients with chronic renal failure. Calcium acetate was compared with calcium carbonate and placebo. Equivalent doses (50 mEq Ca++) of calcium acetate bound more than twice as much phosphorus (106 +/- 23 mg) as calcium carbonate (43 +/- 39 mg) P less than 0.05. When phosphorus binding was factored for calcium absorption, calcium acetate bound 0.44 mEq HPO4 =/mEq absorbed Ca++ compared with 0.16 mEq HPO4 = bound/mEq Ca++ absorbed with calcium carbonate. More efficient phosphorus binding permits serum phosphorus concentration to be controlled with lower doses of calcium salts. The higher phosphorus binding/calcium absorption ratio coupled with a lower dose indicates that less calcium will be absorbed when calcium acetate is used for phosphorus control. Markedly positive calcium balance, hypercalcemia and ectopic calcification should be less likely to occur with this drug than other calcium salts.

Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose.

The purpose of these studies was to gain insight into the pathophysiology of pure osmotic diarrhea and the osmotic diarrhea caused by carbohydrate malabsorption. Diarrhea was induced in normal volunteers by ingestion of polyethylene glycol (PEG), which is nonabsorbable, not metabolized by colonic bacteria, and carries no electrical charge. In PEG-induced diarrhea, (a) stool weight was directly correlated with the total mass of PEG ingested; (b) PEG contributed 40-60% of the osmolality of the fecal fluid, the remainder being contributed by other solutes either of dietary, endogenous, or bacterial origin; and (c) fecal sodium, potassium, and chloride were avidly conserved by the intestine, in spite of stool water losses exceeding 1,200 g/d. Diarrhea was also induced in normal subjects by ingestion of lactulose, a disaccharide that is not absorbed by the small intestine but is metabolized by colonic bacteria. In lactulose-induced diarrhea, (a) a maximum of approximate 80 g/d of lactulose was metabolized by colonic bacteria to noncarbohydrate moieties such as organic acids; (b) the organic acids were partially absorbed in the colon; (c) unabsorbed organic acids obligated the accumulation of inorganic cations (Na greater than Ca greater than K greater than Mg) in the diarrheal fluid; (d) diarrhea associated with low doses of lactulose was mainly due to unabsorbed organic acids and associated cations, whereas with larger doses of lactulose unmetabolized carbohydrates also played a major role; and (e) the net effect of bacterial metabolism of lactulose and partial absorption of organic acids on stool water output was done dependent. With low or moderate doses of lactulose, stool water losses were reduced by as much as 600 g/d (compared with equimolar osmotic loads of PEG); with large dose, the increment in osmotically active solutes within the lumen exceeded the increment of the ingested osmotic load, and the severity of diarrhea was augmented.

Effect of the time of administration of calcium acetate on phosphorus binding.

Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (+/- SE) measured 9.17 +/- 0.36 mmol (78 percent) with placebo but decreased to 3.81 +/- 0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36 +/- 0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00 +/- 0.52 mmol and 1.81 +/- 0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21 +/- 1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40 +/- 4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals.

Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study.

Antacids used to decrease phosphorus absorption in patients with renal failure may be toxic. To find more efficient or less toxic binders, a three-part study was conducted. First, theoretical calculations showed that phosphorus binding occurs in the following order of avidity: Al3+ greater than H+ greater than Ca2+ greater than Mg2+. In the presence of acid (as in the stomach), aluminum can therefore bind phosphorus better than calcium or magnesium. Second, in vitro studies showed that the time required to reach equilibrium varied from 10 min to 3 wk among different compounds, depending upon solubility in acid and neutral solutions. Third, the relative order of effectiveness of binders in vivo was accurately predicted from theoretical and in vitro results; specifically, calcium acetate and aluminum carbonate gel were superior to calcium carbonate or calcium citrate in inhibiting dietary phosphorus absorption in normal subjects. We concluded that: (a) inhibition of phosphorus absorption by binders involves a complex interplay between chemical reactions and ion transport processes in the stomach and small intestine; (b) theoretical and in vitro studies can identify potentially better in vivo phosphorus binders; and (c) calcium acetate, not previously used for medical purposes, is approximately as efficient as aluminum carbonate gel and more efficient as a phosphorus binder than other currently used calcium salts.

Calcium absorption: effect of meal and glucose polymer.

Various nonelectrolyte meal components such as glucose and lysine enhance gastrointestinal calcium absorption under experimental conditions. The effect of a mixed meal on Ca absorption from Ca supplements is unknown. The effect of glucose polymer on Ca absorption when ingested with food also is unknown. Using a single-day method, we measured net Ca absorption from Ca carbonate when ingested in fasting state, with a steak and potatoes meal, and with the meal and 50 g glucose polymer. Eight healthy human subjects were studied after a 500-mg elemental Ca dose. Mean net Ca absorption was 195 +/- 18 mg (4.87 +/- 0.45 mmol) fasting, 213 +/- 21 mg (5.31 +/- 0.52 mmol) with a meal, and 179 +/- 16 mg (4.47 +/- 0.40 mmol) with a meal plus glucose polymer. The differences are not statistically significant. In normal people Ca absorption from Ca carbonate was not significantly enhanced by a meal or by 50 g glucose polymer ingested with food.

Role of vitamin D-dependent and vitamin D-independent mechanisms in absorption of food calcium.

We measured net calcium absorption and the calcium content of the digestive glands secretions in people with widely different serum concentrations of 1,25 dihydroxy vitamin D (hereafter referred to a 1,25-D). Patients with end stage renal disease on hemodialysis served as a model of human 1,25-D deficiency; they were also studied when they had abnormally high serum 1,25-D concentrations as a result of short periods of treatment with exogenous 1,25-D. Normal subjects were studied for comparison. The amount of calcium secreted into the duodenum by the digestive glands was found to be trivial compared to the calcium content of normal or even low calcium meals; therefore, values for net and true net calcium absorption differed only slightly. There was a linear correlation between true net calcium absorption and serum 1,25-D concentration. By extrapolating the short distance to a zero value for serum 1,25-D, D-independent true net calcium absorption was estimated. By subtracting D independent from true net calcium absorption, values for D-dependent absorption were obtained. For a given level of meal calcium intake, D-dependent calcium absorption was found to be directly proportional to serum 1,25-D concentration. At any given value for serum 1,25-D, absorption via the D-dependent mechanism was approximately the same with a low (120 mg) calcium meal as it was when meal calcium intake was increased to 300 mg. We interpret this to mean that the D-dependent mechanism is saturated or nearly saturated by low calcium meals. The D-independent absorption/secretion mechanism resulted in secretion (a loss of body calcium in the feces) when intake was low (120 mg per meal) and absorption when intake was normal. All of the increment in calcium absorption that occurs when low or normal calcium meals are supplemented with extra calcium is mediated by the D-independent mechanism.

The absorption of dietary phosphorus and calcium in hemodialysis patients.

Absorption of dietary phosphorus plays a critical role in the development of metabolic bone diseases in patients with chronic renal failure. However, phosphorus absorption is difficult to quantitate in dialysis patients because the dialysis treatments complicate metabolic balance studies. Utilizing a recently developed technique which permits measurement of net absorption of dietary constituents after a single meal, we measured phosphorus absorption in dialysis patients. The following observations were made: A.) Following a meal containing approximately 300 mg phosphorus, mean phosphorus absorption in five hemodialysis patients (with severe vitamin D deficiency) was only slightly less than in matched controls (186 +/- 35 vs. 242 +/- 30). B.) After dialysis patients were treated with 1,25(OH)2-D3, phosphorus absorption increased from 186 +/- 35 to 272 +/- 16 mg (P less than 0.025). C.) The effect of three aluminum containing antacids on phosphorus absorption was studied; each slightly reduced the absorption of phosphorus compared to placebo (P less than 0.01), but there was no significant difference between them. D.) Aluminum hydroxide and calcium carbonate each reduced dietary phosphorus absorption to approximately the same extent. Calcium carbonate ingestion was associated with sharply increased calcium absorption. The absorption of dietary phosphorus is influenced only modestly by 1,25(OH)2-D3 and is inhibited to an equal but only modest degree by various aluminum antacids and by calcium carbonate.

An evaluation of the significance of microscopic colitis in patients with chronic diarrhea.

Some patients with chronic idiopathic diarrhea have an apparent nonspecific inflammation of colonic mucosa, even though their colons appear normal by barium enema and colonoscopy. This has been referred to as microscopic colitis. However, the significance of this finding is unclear, because the ability of pathologists to accurately distinguish mild degrees of abnormality has not been established. Furthermore, even if the mucosa of these patients is nonspecifically inflamed, it is not known whether this is associated with deranged colonic function that could contribute to the development of chronic diarrhea. To assess these questions, we first examined colonic biopsy specimens in a blinded fashion, comparing biopsy results from patients with microscopic colitis with biopsy specimens from subjects in two control groups. This analysis revealed that colonic mucosa from six patients with microscopic colitis was in fact abnormal. For example, their mucosa contained an excess of both neutrophiles and round cells in the lamina propria, cryptitis, and reactive changes. These and other differences were statistically significant. Second, colonic absorption, measured by the steady state nonabsorbable marker perfusion method, was severely depressed in the patients. For example, mean water absorption rate was 159 ml/h in normal subjects and was reduced to only 26 ml/h in six patients with microscopic colitis. Results of net and unidirectional electrolyte fluxes and of electrical potential difference suggested that colonic fluid absorption was abnormal because of reduced active and passive sodium and chloride absorption and because of reduced Cl/HCO3 exchange. Small intestinal fluid and electrolyte absorption was abnormally reduced in two of the six patients, suggesting the possibility of coexistent small intestinal involvement in some of these patients. We conclude that nonspecific inflammation of colonic mucosa is associated with a severe reduction of colonic fluid absorption, and that the latter probably contributes to the development of chronic diarrhea.

An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium.

Since calcium solubility is a prerequisite to calcium absorption, and since solubility of calcium is highly pH-dependent, it has been generally assumed that gastric acid secretion and gastric acidity play an important role in the intestinal absorption of calcium from ingested food or calcium salts such as CaCO3. To evaluate this hypothesis, we developed a method wherein net gastrointestinal absorption of calcium can be measured after ingestion of a single meal. A large dose of cimetidine, which markedly reduced gastric acid secretion, had no effect on calcium absorption in normal subjects, and an achlorhydric patient with pernicious anemia absorbed calcium normally. This was true regardless of the major source of dietary calcium (i.e., milk, insoluble calcium carbonate, or soluble calcium citrate). Moreover, calcium absorption after CaCO3 ingestion was the same when intragastric contents were maintained at pH 7.4 (by in vivo titration) as when intragastric pH was 3.0. On the basis of these results, we conclude that gastric acid secretion and gastric acidity do not normally play a role in the absorption of dietary calcium. Other possible mechanisms by which the gastrointestinal tract might solubilize ingested calcium complexes and salts are discussed.

Development of a lavage solution associated with minimal water and electrolyte absorption or secretion.

Ingestion of large volumes of a balanced electrolyte solution has previously been shown to be an effective method of cleaning the colon for diagnostic studies. However, in this paper we have shown that total gut perfusion with such a solution results in absorption of 2400 ml water and 375 meq of sodium over 3 hr, which is the approximate time required to clean the colon by this technique. This might be hazardous to patients who are unable to readily excrete a salt and water load. We, therefore, designed a solution containing mainly sodium sulfate that was associated with only trivial amounts of water and sodium absorption or secretion during total gut perfusion. This new solution might be useful in colon cleansing before colonoscopy, barium enema, and surgery. In addition, such a solution may have some therapeutic indications, including bowel cleaning in patients with hepatic encephalopathy or as a rapid washout technique for ingested toxins.

Fecal incontinence in chronic diarrhea. Report of a case with improvement after training with rectally infused saline.

Patients with chronic diarrhea and fecal in continence are unable to retain as much rectally infused saline as patients without incontinence. We explored the effect of training such a patient to retain rectally infused saline. The patient was a 31-yr-old female with chronic diarrhea of obscure etiology who had daily episodes of fecal incontinence which markedly restricted her lifestyle. Training was accomplished by urging the patient to retain as much of a 25-min rectal infusion of 1500 ml saline as possible. After 10 training sessions, the patient increased her ability to hold rectally infused saline almost sevenfold. This increase was well maintained over 10 wk. In spite of continued diarrhea, the patient's incontinence did not recur after the first week of training, and she was able to resume a normal life. Anal sphincter pressure and a test of continence for a solid sphere did not change during or after training. This simple training technique has potential as a treatment for disabling fecal incontinence in patients with chronic diarrhea.

Healing of duodenal ulcer with an antacid regimen.

To determine whether a large-dose antacid regimen is effective in promoting healing of duodenal ulcer, 74 patients with endoscopically proved duodenal ulcer completed a 28-day double-blind clinical trial comparing such a regimen with an inert placebo. The ulcer healed completely in 28 of the 36 antacid-treated as compared to 17 of the 38 placebo-treated patients (P less than 0.005). The antacid regimen was not more effective than placebo in relieving ulcer symptoms. Presence or absence of symptoms during the fourth treatment week was a poor predictor of presence or absence of an ulcer crater. Ulcers of placebo-treated patients who smoked cigarettes were less likely to heal than those of nonsmokers (P = 0.03). Except for mild diarrhea, no side effects of the antacid regimen were observed. We conclude that a large-dose antacid regimen hastens the healing of duodenal ulcer.

Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol.

Calcium absorption in 30-cm segments of small intestine was measured by constant perfusion of test solutions containing different concentrations of calcium gluconate. In both the jejunum and ileum, calcium absorption rates increased progressively as luminal calcium concentration was increased stepwise between 1 and 20 mM. Although calcium transport was not saturable within these limits, unidirectional flux ratios of calcium (47Ca) suggest that calcium absorption is active in both the jejunum and ileum. Calcium absorption in patients with chronic renal disease was markedly depressed in both regions of the small intestine. This was due to decreased flux out of the lumen; flux in the reverse direction was normal. Flux ratios in the renal disease patients showed no evidence for active calcium transport. Treatment of these patients for 1 wk within 2 mug/day of 1alpha-hydroxycholecalciferol [1alpha-(OH)-D3] restored net calcium absorption and unidirectional calcium flux out of the lumen to normal values in the jejunum; in the ileum, 1alpha-(OH)-D3 increased calcium absorption 60-83% of normal at the various luminal calcium concentrations. 1alpha(OH)-D3 had no effect on unidirectional calcium flux into the lumen or on xylose and electrolyte absorption in either area of the small intestine.

Jejunal absorption and secretion of calcium in patients with chronic renal disease on hemodialysis.

10 patients with chronic renal disease on hemodialysis and 8 normals were studied by constant jejunal perfusion of calcium gluconate solutions, using polyethylene glycol as a nonabsorbable marker. Results in normals indicated that calcium absorption from 1 and 5 mM calcium solutions is mainly active. Absorption from 5, 15, and 20 mM solutions was a linear function of luminal calcium concentration, suggesting that the active transport carrier is saturated when luminal calcium concentration is greater than 5 mM and indicating that the increment in absorption at higher luminal concentrations is mainly the result of passive absorption. With 1 mM calcium, normals absorbed calcium against a concentration gradient, whereas the patients secreted calcium. Absorption in the patients was much less than normal with 5, 15, and 20 mM luminal calcium concentrations; however, the slope of this linear (passive) portion of the curve was normal. Unidirectional calcium fluxes were measured with calcium-47. Flux out of the lumen was depressed 2.5-fold in the patients, but flux into the lumen was normal. Xylose, urea, and tritiated water were absorbed normally, indicating no generalized abnormality of jejunal transport in these patients. Endogenous calcium secretion, estimated by the amount of calcium added to a calcium-free solution, was normal in the dialysis patients. These results indicate that active calcium absorption is markedly depressed in patients with chronic renal disease who are receiving hemodialysis therapy. On the other hand, passive calcium movement and endogenous calcium secretions are normal.