John S. Fordtran

Gastric Acid Secretion Rate and Buffer Content of the Stomach after Eating. RESULTS IN NORMAL SUBJECTS AND IN PATIENTS WITH DUODENAL ULCER

New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.

Permeability characteristics of the human small intestine.

Relatively little information is available concerning the membrane structure of the mucosal cells of the small intestine. Hdber and Hober (1) and Schanker, Tocco, Brodie, and Hogben (2, 3) studied the absorption of a variety of substances in rats and found that absorption rate increased as lipid solubility increased. From this it has been deduced that mucosal cell membranes are lipoid in nature and that lipid-soluble substances are absorbed by dissolving in the cell membrane. However, it has been known for many years that small molecules, although lipid insoluble, can also be absorbed from the gastrointestinal tract. This has led to the hypothesis that, although essentially lipoidal, cell membranes are interspersed with water-filled pores, through which small molecules can diffuse. Hbber and Hdber (1) tested this hypothesis in the small intestine of the rat by correlating the absorption rate of nonlipid-soluble substances with their molecular size. Their results support the thesis that these molecules are absorbed by diffusion through water-filled pores, since small molecules were absorbed more rapidly than larger ones, and beyond a certain size (molecular weight about 180, which corresponds to a molecular radius of about 4 A) no penetration occurred. Lindemann and Solomons studies (4) are in close agreement, since they experimentally determined, by an independent method, the pore radius of the luminal surface of the rat jejunal cells

Interrelationships of chloride, bicarbonate, sodium, and hydrogen transport in the human ileum

Using a triple-lumen constant perfusion system, the following observations were made in normal subjects. First, chloride, bicarbonate, and sodium were found to exhibit net movement across ileal mucosa against electrochemical gradients. Second, during perfusion with a balanced electrolyte solution simulating plasma, the ileum generally absorbed, but sometimes secreted fluid. A reciprocal net movement of chloride and bicarbonate was noted when sodium movement was zero. Increasing rates of sodium absorption were associated with decreasing bicarbonate secretion rates and finally bicarbonate absorption. Even when bicarbonate was absorbed ileal contents were alkalinized (by contraction of luminal volume). Third, net chloride movement was found to be sensitive to bicarbonate concentration in ileal fluid. For instance, chloride was absorbed from solutions containing 14 or 44 mEq/liter of bicarbonate, but was secreted when ileal fluid contained 87 mEq/liter of bicarbonate. Fourth, when chloridefree (sulfate) solutions were infused, the ileum absorbed sodium bicarbonate and the ileal contents were acidified. Fifth, when plasma-like solutions were infused, the potential difference (PD) between skin and ileal lumen was near zero and did not change when chloride was replaced by sulfate in the perfusion solution. These results suggest that ileal electrolyte transport occurs via a simultaneous double exchange, Cl/HCO2 and Na/H. In this model neither the anion nor the cation exchange causes net ion movement; net movement results from the chemical reaction between hydrogen and bicarbonate. No other unitary model explains all of the following observations: (a) human ileal transport in vivo is essentially nonelectrogenic even though Na, Cl, and HCO3 are transported against electrochemical gradients, (b) the ileum can secrete as well as absorb, (c) ileal contents are alkalinized during absorption of or during secretion into a plasma-like solution, and (d) the ileum acidifies its contents when sulfate replaces chloride. Data obtained with a carbonic anhydrase inhibitor support the proposed model.

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.

The mechanisms of sodium absorption in the human small intestine

The present studies were designed to characterize sodium transport in the jejunum and ileum of humans with respect to the effects of water flow, sodium concentration, addition of glucose and galactose, and variations in aniomic composition of luminal fluid. In the ileum, sodium absorption occurred against very steep electrochemical gradients (110 mEq/liter, 5-15 mv), was unaffected by the rate or direction of water flow, and was not stimulated by addition of glucose, galactose, or bicarbonate. These findings led to the conclusion that there is an efficiently active sodium transport across a membrane that is relatively impermeable to sodium. In contrast, jejunal sodium (chloride) absorption can take place against only the modest concentration gradient of 13 mEq/liter, was dramatically influenced by water movement, and was stimulated by addition of glucose, galactose, and bicarbonate. The stimulatory effect of glucose and galactose was evident even when net water movement was inhibited to zero by mannitol. These observations led to the conclusion that a small fraction of jejunal sodium absorption was mediated by active transport coupled either to active absorption of bicarbonate or active secretion of hydrogen ions. The major part of sodium absorption, i.e. sodium chloride absorption, appeared to be mediated by a process of bulk flow of solution along osmotic pressure gradients. The stimulatory effect of glucose and galactose, even at zero water flow, was explained by a model in which the active transport of monosaccharide generates a local osmotic force for the absorption of solution (NaCl and water) from the jejunal lumen, which, in the presence of mannitol, is counterbalanced by a reverse flow of pure solvent (H(2)O) through a parallel set of channels which are impermeable to sodium. Support for the model was obtained by the demonstration that glucose and bicarbonate stimulated the absorption of the nonactively transported solute urea even when net water flow was maintained at zero by addition of mannitol to luminal contents.

pH dependence of acid secretion and gastrin release in normal and ulcer subjects.

By use of a recently described method, which estimates the rate of gastric acid secretion by measuring the rate of sodium bicarbonate infusion needed to keep intragastric pH constant, gastric acid secretion rates and changes in serum gastrin were measured in five normal subjects while gastric pH was kept at 5.5, 4.0, 3.0, or 2.5. Preliminary experiments revealed that the method did not accurately measure acid secretion at a pH lower than 2.5. Stimulation of acid secretion was produced by gastric instillation of a solution of amino acids and cornstarch. The secretion rate with the amino acid meal was highest at pH 5.5 and was 60% of that produced by a steak meal at the same pH. As the pH of the amino acid meal was decreased, there was a stepwise reduction in acid secretion so that at pH 2.5 the rate was only half as great as at pH 5.5. The amino acid meal produced increases in serum gastrin that were also less marked than those produced by a steak meal. With amino acid stimulation, serum gastrin responses were similar at pH 5.5, 4.0, and 3.0, but no increase in gastrin could be measured when the meal was maintained at pH 2.5. A group of six patients with duodenal ulcers was compared with seven normal subjects at pH 5.5 and 2.5. Ulcer patients released more gastrin and secreted more acid at each time period at both pH values. More important, the degree of inhibition at pH 2.5 was significantly less in ulcer patients. For example, during the 2nd h after stimulation acid secretion was inhibited by only 30% in ulcer patients compared with 70% in normal subjects. These findings suggest a defect in autoregulation of gastrin release and gastric acid secretion at low pH in ulcer patients which may play a role in pathogenesis of this disease.

Effect of Dietary Calcium and Age on Jejunal Calcium Absorption in Humans Studied by Intestinal Perfusion

Jejunal calcium absorption was measured from test solutions containing 1.0, 2.5, 5, and 10 mM calcium (as calcium gluconate). Absorption rates increased progressively as luminal calcium concentration was increased, although there was a tendency toward saturation of the absorptive process at the higher concentrations. Calcium absorption was higher in normal young adults than in normal subjects over age 60. In both groups a 300 mg calcium diet for 4-8 wk enhanced calcium absorption relative to absorption rates after 4-8 wk on a 2,000 mg calcium diet. This adaptation was more definite and dramatic in the young than in the old subjects. Indirect estimates suggest that adaptation to a low calcium diet and the higher absorption in young than old normal subjects are mediated by an increased V(max) rather than a decreased K(m).

A Clinical Study of Patients With Fecal Incontinence and Diarrhea

Clinical and pathophysiologic studies were carried out in 29 patients with chronic diarrhea and incontinence. Most of these patients had been extensively investigated for diarrhea, whereas closer questioning revealed that the major (but previously unmentioned) problem was incontinence for liquid stools. Incontinent patients were, as a group, abnormal with regard to anal sphincter pressure, the ability to retain a solid sphere in the rectum as weights were applied, and the ability to retain saline that had been infused into the rectum. They were, however, no different from control subjects with regard to sphincter length and squeeze duration and with regard to the ability to detect the presence of fluid infused into the rectum. Estimation of sphincter tone by digital examination did not correlate with any objective measure of anal sphincter function or with continence to rectally infused saline. Analysis of the individual data from incontinent diarrhea patients showed that most of these patients had low stool volumes, low sphincter pressures, and an impaired ability to retain saline infused into the rectum. These results would be compatible with a defect in the function of the sphincter muscles. However, some patients had sphincter pressures well within the normal range, low stool volumes, and impaired saline continence. It seems likely that these patients have an abnormality in the continence mechanism other than a muscular weakness of the anal sphincter. Finally, 2 patients had sphincter pressures well within the normal range and good continence to saline, but passed very large amounts of -stool. Such patients probably represent a situation where large volume diarrhea overwhelms a fairly normal mechanism for preserving continence. Our results suggest that measurement of stool volume, sphincter pressure, and ability to retain rectally infused saline may aid in the diagnostic and therapeutic evaluation of patients with chronic diarrhea and fecal incontinence.

A Method for Studying Absorption of Water and Solute from the Human Small Intestine

Summary A triple-lumen intubation technique is described whereby absorption or secretion of water, electrolytes, and other solutes can be studied within specific and defined test segments of the human small intestine. The technique allows correction for endogenous water and solute that enter the test segment from digestive secretions. Experiments that were carried out to test the precision of the method have demonstrated the technique to have a high degree of accuracy when 1-hr study periods are used.

Pathogenesis of fecal incontinence in diabetes mellitus: evidence for internal-anal-sphincter dysfunction.

We studied 16 patients with diabetes and fecal incontinence. The onset of incontinence coincided with the onset of chronic diarrhea in most patients. Episodes of incontinence occurred when stools were frequent and loose; however, 24-hour stool weights were usually within normal limits. All patients had evidence of autonomic neuropathy, and one third had steatorrhea. Incontinent diabetics had a lower mean basal anal-sphincter pressure than 35 normal subjects (63 +/- 4 vs. 37 +/- 4 mm Hg; P less than 0.001), reflecting abnormal internal-anal-sphincter function. The increment in sphincter pressure with voluntary contraction (external-sphincter function) was not significantly different from normal. Incontinent diabetics also had impaired continence for a solid sphere and for rectally infused saline. In contrast, 14 diabetics without diarrhea or incontinence had normal sphincter pressures and normal results on tests of continence, even though 79 per cent had evidence of autonomic neuropathy and nearly half had steatorrhea. We conclude that incontinence in diabetic patients is related to abnormal internal-anal-sphincter function, and that as a group, diabetics without diarrhea do not have latent defects in continence.