I. T. Beck

Acute exposure of small intestine to ethanol: effects on morphology and function.

There is evidence to indicate that chronic alcoholism may lead to steatorrhea, malnutrition, or simple diarrhea (1). These conditions may arise from impaired intestinal function, from abnormal pancreatic and hepatobiliary secretion, or from a combination of all the above (2). Because of this, it is important to dissect the effects of alcohol on the small intestine from those on other organs. Wilson and Hoyumpa (3) reviewed, in general, the effect of acute and chronic intake of alcohol on intestinal transport processes. However, before one can even hope to understand the effect of chronic alcohol intake on small intestinal function, it is necessary to define the mechanism(s) of action of a single dose of alcohol. Accordingly, in this review, we have examined in detail the effect of acute ingestion of ethanol on small intestinal functions.* To focus on this subject adequately, studies on the effect of chronic ethanol intake are not included.

Effect of Ethanol on Sodium-Dependent Glucose Transport in the Small Intestine of the Hamster

The objective of this study was to investigate the mechanism by which ethanol inhibits intestinal absorption of sugars. In vitro experiments on hamster jejunum have shown that the presence of ethanol in the mucosal solution caused an inhibition of the net transport of water and glucose. There was also a decrease in the intracellular water content and an increase in the intracellular sodium and potassium concentration of the gut tissue. In contrast, the intracellular glucose concentration decreased in the presence of ethanol. These ethanol-induced changes were directly related to the ethanol concentration of the mucosal solution. In the presence of 450 mM (2%) ethanol in the mucosal solution, there was also a significant inhibition of transmural potential difference, estimated glucose metabolism, and both unidirectional fluxes of sodium. The net flux of sodium to the serosal side however did not decrease significantly. These effects of ethanol cannot be fully explained by its osmotic action, and it is suggested that the ethanol-induced reduction in glucose transport could be mainly the result of an interference with the carrier-mediated coupled entrance of glucose and sodium across the brush border. A depression of cellular metabolism could also have played a role in this process.

Ethanol-induced vascular permeability changes in the jejunal mucosa of the dog

We have demonstrated previously that ethanol causes alterations in jejunal morphology and fluid secretion, and that these changes are accompanied by an increase in mucosal arteriolar blood flow, shunting of blood through noncapillary microvessels, hyperemia, hemoconcentration, and an enhanced loss of plasma protein into the gut lumen. All the microcirculatory changes are compatible with an ethanol-induced mucosal microvascular stasis. The present study was undertaken to examine whether these changes are accompanied by an enhanced mucosal microvascular permeability. Using a colloidal carbon vascular labeling technique, we demonstrated that 6% wt/vol intraluminal ethanol caused marked accumulation of carbon particles in the walls of the capillaries and microvenules of the villus tips. The effect of 3% ethanol was much less pronounced, and the extent of carbon entrapment did not significantly differ from microvessels in villi perfused with Krebs-Ringer solution without ethanol. Electron microscopy indicated that the carbon was localized between the endothelial cell and the basal lamina of the microvessels. Because the carbon accumulation was always localized at the vicinity of endothelial cell junctions, the escape of carbon particles from the lumen probably occurred through these cell junctions. This could have been the result of a transient retraction of endothelial cells. Electron microscopic examination also demonstrated that the lumina of some capillaries and venules of the villus tip of jejunal segments perfused with 6% ethanol were clogged with carbon particles. This latter finding indicates that there was stasis in these vessels at the time of carbon injection. Similar intraluminal carbon accumulation was never seen in control jejunum or jejunum perfused with 3% ethanol. Thus the results of this study indicate that 6% (wt/vol) ethanol causes microvascular injury and stasis. The findings with 6% ethanol are reminiscent of those described by others in the early phases of acute inflammation, and thus it is possible that the microvascular changes caused by ethanol may be related to the liberation of some of the chemical mediators of the immediate response to acute injury.

Histamine Is Involved in Ethanol-Induced Jejunal Microvascular Injury in Rabbits

To examine for the possible involvement of histamine in the jejunal microvascular effects of ethanol, we investigated the effects of (a) intraluminal ethanol on histamine release by the jejunum and (b) simultaneous inhibition of both histamine1 and histamine2 receptors (using promethazine and cimetidine, respectively) on ethanol-induced intestinal plasma protein loss in rabbits. Ethanol increased histamine release by the jejunum both in vivo (p less than 0.01) and in vitro (p less than 0.05). To investigate the effect of antihistamines on ethanol-induced plasma protein loss, we determined the dose of blockers that would completely inhibit the histamine1 and histamine2 receptors. In the absence of antihistamines, ethanol caused a 10-fold increase in jejunal protein loss over the controls (p less than 0.001). Simultaneous inhibition of histamine1 and histamine2 receptors attenuated (p less than 0.025), but did not abolish, the ethanol-induced protein loss. These data are discussed in relation to the literature, and it is concluded that histamine may play a role in the jejunal microvascular effects of ethanol. As the ethanol-induced protein loss was not completely inhibited, other mediators or mechanisms were probably involved.

On the mechanism of the inhibitory effect of ethanol on intestinal glucose and water absorption.

Experiments were performed to investigate whether the inhibitory effect of ethanol on intestinal glucose transport is related to its action on the brush border or on the ATPase-dependent sodium pump of the basolateral membrane, of the enterocyte. We compared the effect of ethanol on glucose and water transport when it was added either to the mucosal or to the serosal solution of anin vitro preparation of hamster jejunum. The purpose of the addition of ethanol to the serosal solution was to mimic a situation similar to that produced when ouabain is placed on the serosal side to inhibit the ATPase-dependent sodium pump at the basolateral membrane. The presence of 450 mM ethanol (2.07%) in the mucosal solution depressed glucose and water transport by 40 and 63%, respectively, but the presence of the same concentration of ethanol on the serosal side had no effect on glucose and water absorption. These findings seem to indicate that the depressing effect of ethanol in intestinal glucose and water transport cannot be ascribed to the inhibition of the Na+, K+-sensitive ATPase-dependent sodium pump located at the basolateral membrane.

Mechanism of Ethanol-Induced Jejunal Microvascular and Morphologic Changes in the Dog

To study the mechanism of morphologic and microvascular effects of intraluminal ethanol, we perfused jejunal segments of the dog with 6% (wt/vol) ethanol for 0 (control), 10, 20, 30, 60, and 90 min, and measured the time-dependent changes in (a) the prevalence of villi with epithelial damage (i.e., villi with intact blebs plus those with broken blebs) and those without epithelial damage (undamaged villi), (b) the height of the villus core and the patency of lacteals, (c) jejunal albumin loss, and (d) permeability of microvessels of the villus tip by colloidal carbon vascular labeling. We found that (a) the prevalence of villi with epithelial damage or with intact bleb increased progressively during the first 20 min of ethanol perfusion and then declined gradually; (b) the height of the villus core and the patency of lacteals in the undamaged villi and in those with intact bleb decreased during the first 20 min and then gradually increased; and (c) jejunal albumin loss and the prevalence of villi with carbon labeling increased for the first 30 min, after which the former declined gradually whereas the latter remained at a plateau. These findings suggest that contraction of the villus core and compression of the lymphatics are the primary cause of ethanol-induced epithelial damage, which is accentuated by increased microvascular permeability and consequent protein leakage. The mechanism of recovery of most parameters, in spite of continuous ethanol perfusion, remains to be investigated.

Role of xanthine oxidase-derived oxidants and leukocytes in ethanol-induced jejunal mucosal injury

Previous reports indicate that intestinal intraluminal ethanol increases mucosal permeability (an index of mucosal injury) and histamine release by mast cells, and that the released histamine plays a role in mediating the increased permeability. In the present study, we investigated whether reactive oxygen metabolites and their major sources (xanthine oxidase and leukocytes) were involved in these ethanol effects. In rabbits, segments of the jejunum were perfused with a control solution or with 6% ethanol. In these segments, mucosal permeability was assessed by determining jejunal clearance of i.v. administered51Cr-ethylenediaminetetraacetate (51Cr-EDTA) and125I-bovine serum albumin (125I-BSA), and mast cell histamine release was estimated from the histamine concentration of the gut effluent. Ethanol increased51Cr-EDTA clearance,125I-BSA clearance, and histamine release. These ethanol effects decreased when the animals were given superoxide dismutase plus catalase (scavenger of O2− and H2O2, respectively), allopurinol, or oxypurinol (xanthine oxidase inhibitors). Administration of a monoclonal antibody (R15.7) against leukocyte adhesion molecule, CD18, inhibited completely the ethanol-induced increased51Cr-EDTA and125I-BSA clearances and histamine release. These and supplementary data suggest that (a) ethanol-induced mucosal injury and mast cell histamine release are mediated primarily by leukocytes, and (b) oxy radicals, especially those generated by xanthine oxidase, mediate these ethanol effects mainly by promoting leukocyte infiltration.

Transition from Nutcracker Esophagus to Achalasia. A Case Reprot

We report a middle-aged woman with nutcracker esophagus who progressed to classic achalasia in two years. Several previous reports have documented progression of nutcracker esophagus to diffuse esophageal spasm and diffuse esophageal spasm to achalasia, but the only previous report of nutcracker esophagus progressing to achalasia was in a child. Our case suggests that, in some instances, nutcracker esophagus and achalasia may share the same pathogenesis.

Effect of ethanol on morphology and total, capillary, and shunted blood flow of different anatomical layers of dog jejunum

On the basis of previous studies in our laboratory we postulated that the ethanol-induced alteration in jejunal morphology was the result of its effect on the microcirculation. The present study was undertaken to examine the validity of this hypothesis. Accordingly, the effects of intraluminal ethanol perfusion (3.0 and 6.0% w/v) on mucosal morphology; water, glucose, and sodium transport; and regional blood flow were examined inin vivo jejunal segments of pentobarbital-anesthetized dogs. Compared to control segments, those perfused with ethanol exhibited a significant increase in the prevalence of morphological alterations of the mucosa, consisting of subepithelial fluid accumulation (bleb formation) and exfoliation. Those villi with epithelial damage exhibited villus cores significantly shorter than those with a normal, undamaged epithelium. Segments perfused with ethanol exhibited a depressed net water absorption, to the point that net secretion occurred in the segments perfused with 6% ethanol. Net absorption of glucose was similarly depressed by intraluminal perfusion with ethanol, whereas net absorption of sodium was unaffected. Regional jejunal blood flows were estimated using a dual, radiolabeled microsphere technique. Both total jejunal wall and total mucosal blood flow (in ml/min/100 g dry tissue) in the ethanol-perfused segments were significantly increased over control. Similarly, jejunal wall and mucosal capillary blood flows were increased by ethanol perfusion. Neither submucosal nor muscularis blood flows were affected by intraluminal perfusion with ethanol. Compared to control, shunting or nonentrapment of 9-μm microspheres was increased in the mucosa of the ethanol-perfused segments. In contrast to this, shunting of 9-μm microspheres in the submucosa and muscularis was unaffected by intraluminal perfusion with ethanol. It therefore appears that the ethanolinduced mucosal morphological alterations are accompanied by a localized mucosal hyperemia, and an increased shunting of blood through the mucosa. Based on the results of this and other studies, a microvascular mechanism was tentatively proposed to explain the pathogenesis of the ethanol-induced morphological changes.

Transmural potential difference (PD) in the body of the esophagus in patients with esophagitis, Barrett's epithelium and carcinoma of the esophagus

Esophageal transmural potential difference (PD) was measured from mucosa to subcutaneous tissue (scarified skin) simultaneously with esophageal motility studies in 23 normal volunteers, 10 patients with proven and 6 patients with suspected esophagitis, 3 patients with Barretts epithelium and 8 patients with carcinoma of the esophagus. Of 23 normal subjects, 19 demonstrated a steady PD (baseline) along the body of the esophagus with 7 mV or less deflection from highest to lowest PD. The 10 patients with endoscopically proven esophagitis had abnormal tracings. Of the 6 patients who had esophageal hyperemia and symptoms of esophagitis, but no endoscopic or histologic evidence of inflammation, 4 had almost normal PD configurations. The 3 patients with Barretts epithelium and all 8 patients with carcinoma had abnormal tracings. Esophageal PD can be easily measured simultaneously with motility studies and can be used to demonstrate esophageal mucosal lesions, but the pathologic nature of the mucosal abnormality cannot be determined from the configuration of the PD tracing.