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.

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.

Studies of the mechanism of the antidiarrheal effect of codeine.

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

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.

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.

Review article: anti-diarrhoeal pharmacology and therapeutics.

Anti-diarrhoeal drugs reduce the symptoms of diarrhoea (loose stool consistency, frequency of defecation and excessive stool weight) by effects on intestinal transit, mucosal transport or luminal contents. Opiates and opioids are the most useful antidiarrhoeal agents. Opiates have major effects on intestinal transit; pro-absorptive and anti-secretory effects are less well documented, but may be important for some of these drugs. Alpha-adrenergic agonists, somatostatin analogues and several other agents have had limited clinical use; these drugs may modify mucosal transport in addition to slowing transit. Adsorbents, bismuth and stool texture modifiers are used frequently by the public, but their efficacy is largely unproven. Oral rehydration solutions have had the greatest impact in saving lives and continue to be improved. Many new approaches to the treatment of diarrhoea are yet to be exploited.

Review article: the therapy of constipation.

Constipation is a common symptom that may be idiopathic or due to various identifiable disease processes. Laxatives are agents that add bulk to intestinal contents, that retain water within the bowel lumen by virtue of osmotic effects, or that stimulate intestinal secretion or motility, thereby increasing the frequency and ease of defecation. Drugs which improve constipation by stimulating gastrointestinal motility by direct actions on the enteric nervous system are under development. Other modalities used to treat constipation include biofeedback and surgery. Laxatives and lavage solutions are also used for colon preparation and evacuation of the bowels after toxic ingestions.

Diarrhea.

Diarrhea is a common symptom of many conditions, and making an accurate diagnosis can be daunting. Research efforts have expanded the differential diagnosis of chronic diarrhea and have provided improved methods for the evaluation and management of patients with diarrheal diseases. This article discusses some of these trends and presents the emerging consensus regarding appropriate pathways of caring for patients with diarrheal diseases.

Upper gastrointestinal motility disorders and respiratory symptoms.

The association between upper gastrointestinal (GI) motility disorders and respiratory problems is reviewed. Upper GI motility disorders, such as gastroesophageal reflux disease, gastroparesis, and achalasia, have been associated with respiratory problems, including aspiration, airway obstruction, asthma, bronchospasm, chronic cough, and laryngitis. These associations, which had been based solely on clinical observation, have recently been supported by physiologic studies and treatment trials. The association of reflux disease with asthma has the most support. Up to 80% of persons with asthma have evidence of pathologic gastroesophageal reflux, and in several studies antireflux therapy with prokinetic agents, antisecretory drugs, or fundoplication surgery has been found to reduce asthma symptoms and the need for medication in some patients. Reflux has also been associated with chronic cough and laryngitis, and antireflux therapy can reduce respiratory symptoms. Gastroesophageal reflux, gastroparesis, and achalasia are all associated with aspiration. In addition, in rare instances, the megaesophagus associated with achalasia can produce mechanical airway obstruction. Effective therapy for these GI motility disorders can eliminate complicating respiratory problems.

Secretory diarrhea.

Diarrhea, defined as loose stools, occurs when the intestine does not complete absorption of electrolytes and water from luminal contents. This can happen when a nonabsorbable, osmotically active substance is ingested ("osmotic diarrhea") or when electrolyte absorption is impaired ("secretory diarrhea"). Most cases of acute and chronic diarrhea are due to the latter mechanism. Secretory diarrhea can result from bacterial toxins, reduced absorptive surface area caused by disease or resection, luminal secretagogues (such as bile acids or laxatives), circulating secretagogues (such as various hormones, drugs, and poisons), and medical problems that compromise regulation of intestinal function. Evaluation of patients with secretory diarrhea must be tailored to find the likely causes of this problem. Specific and nonspecific treatment can be valuable.

Clinical pharmacology and use of laxatives and lavage solutions.

Laxatives and lavage solutions are used in the treatment of constipation and toxic ingestion and also for preparation of the colon before endoscopic or surgical procedures. Several different categories of agents are available for use. These include bulking agents, osmotic agents, secretagogues and agents with direct effects on epithelial nerve or smooth muscle cells, and lubricating agents. Each category has different pharmacologic effects, side effects, and clinical indications. This review summarizes current information about these agents.

Microscopic colitis syndrome: lymphocytic colitis and collagenous colitis.

Microscopic colitis is a syndrome consisting of chronic watery diarrhea, a normal or near-normal gross appearance of the colonic lining, and a specific histological picture described as either lymphocytic colitis or collagenous colitis. Since its initial descriptions a quarter of a century ago, microscopic colitis has become a frequent diagnosis in patients with chronic diarrhea. Understanding of the cause and pathogenesis of microscopic colitis remain incomplete, but potentially important clues have been discovered that shed light on predisposing factors. In particular, specific HLA-DQ genotypes may be permissive for the development of microscopic colitis, and suggest a linkage to the pathogenesis of celiac sprue. Although the differential diagnosis of chronic watery diarrhea is broad, the diagnosis of microscopic colitis is straightforward, involving endoscopic inspection of the colonic mucosa and proper pathologic interpretation of biopsy specimens. As the limitations of drugs ordinarily used for other forms of inflammatory bowel disease are being recognized, new approaches, such as the use of bismuth subsalicylate, are being evaluated. The prognosis of patients with microscopic colitis syndrome remains good, and symptomatic improvement can be expected in most patients.

Constipation and fecal incontinence in the elderly.

Although constipation and fecal incontinence are common symptoms in the elderly, relatively little research has been done to differentiate physiologic changes in rectoanal function resulting from aging and pathologic changes resulting from diseases occurring as patients age. Certain physiologic changes occur in many older patients and may predispose them to the development of constipation or fecal incontinence. These symptoms need the same thoughtful evaluation and management in the elderly as in younger patients. Results of therapy often can be good, leading to alleviation of suffering and the ability to lead a fuller life.

Disorders of gastrointestinal motility associated with diabetes mellitus.

Gastrointestinal symptoms such as vomiting, constipation, diarrhea, and fecal incontinence occur frequently in patients with diabetes mellitus. In a survey of 136 diabetic outpatients, 76% had one or more gastrointestinal symptoms, the commonest symptom being constipation (found in 60%). In many cases these symptoms are thought to be due to abnormal gastrointestinal motility that, in turn, may be a manifestation of diabetic autonomic neuropathy involving the gastrointestinal tract. The pathophysiology of these gastrointestinal symptoms, clarified in recent studies, and the clinical features and treatment of these problems in diabetic patients are reviewed.

AGA technical review on the evaluation and management of chronic diarrhea.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. The paper was approved by the committee on September 27, 1998.

Quantification of colonic lamina propria cells by means of a morphometric point-counting method.

The lamina propria of colonic mucosa normally contains eosinophils, lymphocytes, plasma cells, and a few neutrophils. If the number of such cells is judged to be increased, colonic inflammation is said to be present. However, the number of cells present in normal mucosa has not been clearly established. Mild abnormalities are difficult to identify, yet might be associated with colonic dysfunction. We therefore developed a morphometric point-counting method to quantitatively analyze the areas occupied by different structures in the mucosa of the human colon. A computer was used to move a dot in a rectilinear pattern over the X400 magnified image of biopsy specimens obtained from throughout the colon by colonoscopy. The structure on which the dot landed was identified and tabulated by a pathologist. In preliminary studies, we established counting parameters that would yield the most representative results. Based on statistical analysis, it was decided to count 98 points in each of seven regions of six biopsy specimens, i.e., over 4000 points per subject. Results were expressed as percentages of counts landing on a given item, and represented the area of the biopsy specimen covered by that item. Using this method, we determined the range of normal in healthy volunteers. The sensitivity of this method was tested by studying patients with chronic diarrhea previously diagnosed as having or not having mild to moderate mucosal inflammation. In the patient group, colonic fluid absorption measured by a perfusion technique was directly correlated with epithelial cell counts and inversely correlated with lamina propria cellularity and with the counts of lamina propria neutrophils and plasma cells. We conclude that morphometric analysis of colon biopsy specimens can be used to quantitate histologic features of colonic mucosa and to accurately identify even mild abnormalities, and that it can be a useful clinical research tool.

Effect of sham feeding on gastric emptying.

We studied the effect of vagal stimulation by sham feeding on gastric emptying in normal human subjects. When a saline test meal was infused into the stomach, simultaneous sham feeding did not alter the emptying of a nonabsorbable marker added to the meal or the volume of fluid emptied from the stomach. When a homogenized steak meal was infused, sham feeding caused a slight acceleration of emptying (47 +/- 2 vs. 53 +/- 2% marker recovered from the stomach 45 min after the meal, P less than 0.05). Gastric acid secretion in response to both meals was significantly augmented by sham feeding. Our results suggest that vagal stimulation by sham feeding has no effect on the emptying of isotonic saline and only a monor effect on gastric emptying of homogenized food in humans.

Distention-induced gastrin release: effects of luminal acidification and intravenous atropine.

We evaluated whether gastric distention with saline test meals could release gastrin in healthy subjects and whether luminal acidification or atropine would modify this response. Distention with 700 ml saline adjusted to pH 5.0 led to a significant gastrin response (averaging 9 +/- 3 pg/ml above basal levels during the first 15 min after distention, P less than 0.02), whereas distention with 25 ml saline led to no gastrin release. Distention with 700 ml saline adjusted to pH 2.5 also led to a significant gastrin rise, which was nearly identical to that seen at pH 5.0. A small dose of atropine (2.3 micrograms/kg i.v.) significantly enhanced the gastrin response to 700-ml distention at pH 5.0 (average gastrin rise 20 +/- 3 pg/ml, P less than 0.02 vs. 700 ml without atropine). This enhancement of gastrin release by atropine was not due to changes in intragastric pH, because pH was held constant at 5.0 by in vivo intragastric titration. Enhancement was also not due to greater gastric distention after atropine, because gastric volumes after the 700-ml test meal were similar with or without atropine. Although atropine enhanced distention-induced gastrin release, atropine reduced acid secretion by more than 50% (P less than 0.05). Our findings indicate (a) that gastric distention releases significant amounts of gastrin in healthy subjects; (b) this gastrin response is resistant to inhibition by luminal acidification to pH 2.5 and (c) the gastrin response to distention is enhanced by atropine, suggesting that distention may also activate cholinergic pathways that inhibit gastrin release.