Pathophysiology and modern treatment of ulcer disease.

This is an overview of the pathophysiological abnormalities of gastroduodenal (GD) ulcers [duodenal ulcer (DU), gastric ulcer (GU) and Dragstedt ulcers (combined DU and GD)], as well as the effects of the different treatments (surgical, medicinal and physiological) described since the introduction of stomach resections. The intention is to demonstrate whether the peptic ulcer diseases are a homogeneous entity with a characteristic pathophysiology or whether they represent the final expression of many heterogeneous causes including impairment of upper gastrointestinal motility. The review also asks whether DU and GU have a common or different pathogenesis and whether ulcers in the stomach might be predominantly due to impaired mucosal resistance and the DU to gastric hypersecretion. The symptoms of both diseases are also compared with the findings in the normal controls.

The influence of neural signal transduction on EEC gene expression under consideration of chromatin, following myenteric ablation (review).

Significant numerical and spatial changes in 5-HT i.r. cells, CCK i.r. I-cells, glucagon and glicentin i.r. I-cells, somatostatin i.r. D-cells and neurotensin i.r. N-cells occur after a 98% myenteric ablation in the rat. Signal transduction from G-protein-coupled crypt cell receptors (m2, m3; VCAP1 and 2, CAP1; Y2, Y5, Y4) stimulates a cAMP-responsive transcription machinery in which phosphorylation of the cAMP-responsive elements (e.g. CREB) is the first step in initiation of transcription. A DNA pre-initiation complex (PIC), consisting of DNA transcription activators, general activators (TFIID, IIA, IIB, IIF, IIE, II-I and IIH), at least 14 different TAFIIs and CBP/300 coactivators which contain multiple enzymatic activities, associated with the central TBP (TATA-binding protein), which together bind to the RNA-polymerase II holoenzyme disrupts chromatin blockade over the promoter with or without the intervention of activated chromatin remodeling factors. CBP/p300 contains several highly conserved domains e.g., KIX, whose methylation by CARM-1 represses CREB transcription activation, but the bromo-binding domain of CBP increases CREB transcription. A similar positive/negative switch occurs in the regulation of gastrointestinal hormones by transcription factors, from Myc/Max to Mad/Max + corepressor mSin3A, during terminal differentiation of the cell. From these observations we conclude that the primary targets for neural signals are factors of the basal DNA transcriptional apparatus, whose promoter factors then activate chromatin induction, which facilitates transcription positively or negatively.

Influence of the intramural innervation on the morphogenesis of the enteroendocrine cells and the genetic construct involved (review).

The influence of intramural intestinal innervation on the morphogenesis of the mucosa and in particular of the enteroendocrine cells (EECs) has been studied on male Wistar rats with morphometric, autoradiographic and immuno-histochemical methods in the duodenum, proximal and distal jejunum and ilium before and after myenteric ablation with benzalkonium chloride (BAC). Twenty-one days after denervation alterations were observed in the mucosal structure with thickening of the mucosa, increase in the proliferation rate and with changes in numerical and spatial distribution of D-cells, I-cells, N-cells, glucagon and glicentin i.r. L-cells and 5-HT i.r. cells which myenteric ablation caused. Analysis of the genetic constructs involved in the alterations of EECs on the EECs provide evidence for the cAMP responsive elements as the main mediator.

Different endogenous opioid effects on delta- and mu-receptor subtypes in antral and duodenal motility of conscious dogs.

To evaluate the role of endogenous opioids in regulation of upper gastrointestinal motility in unanesthetized dogs and to differentiate the actions on mu- and delta-opioid receptors, seven strain gauges and five platinum electrodes were chronically implanted at the serosa along the antrum and duodenum and connected to a plug in the neck of the dog. Signals were processed by a Hellige AC amplifier, a rectilinear recorder, and a data aquisition system. A motility index (MI) was calculated and together with the electrical data a contractile activity percentage (CAP) was determined for consecutive 30 min periods. The delta-opioid antagonist ICI 741 864 and the mu-receptor blocker naloxone were injected intraarterially through a chronic Groshong catheter placed in the pyloric region and connected to a subcutaneous port. After a meal of solid food, ICI 174 864 increased motility relative to controls in the antrum averaged over 5 hr by 144.4%+/-26 for the MI and 73%+/-26 for CAP; after naloxone MI increased by 222%+/-60 and CAP 121%+/-76. In the duodenum, ICI 174 864 decreased MI over a range of 57% to 22% (P < 0.05). Naloxone increased MI and CAP significantly after 2.5 hr. We interpreted the results of ICI 174 864 in the duodenum to reflect suppression of a tonic opioid influence at the delta-receptor mainly at the prevertebral ganglion. In the interdigestive state in 56% of the dogs, naloxone delayed the occurrence of phase III of the migrating myoelectric complex (MMC) for up to 370 min, while under ICI 174 864, normal interdigestive cycles were present. Disturbance of the timing of the interdigestive cycles at central mu-opioid receptors may by involved in the effect.

Changes in muscularis externa of rat small intestine after myenteric ablation with benzalkonium chloride: electron microscopic and morphometric study.

The influence of the intrinsic innervation on the muscularis externa of the rat small intestine was studied by chemical ablation of the myenteric plexus with benzalkonium chloride (BAC). The resulting severe hypertrophy (cell hypertrophy of 96-133% and hyperplasia) differs from working hypertrophy by the distribution and degree of muscle thickening and by characteristics of the extracellular matrix: narrowing of muscle interspaces of 43%; lack of increased collagen; changes in the ratio of interstitial cells of Cajal (ICCs) to fibroblasts from 1.6:1 to 0.8:1 with no numerical decrease in either type of cell; decreased interconnections of ICCs to muscles and nerves due to deformed ICCs; a 197% increase in vascularization (capillaries, venules) and lymphatics in both muscle layers and in the myenteric plexus cleft, possibly initiated by release of fibroblast growth factor from myelin fragmentation after nerve damage; and increased macrophages, plasma cells, monocytes and mast cells in the myenteric plexus cleft. These all signify the neural influence on the morphodifferentiation of the muscularis externa in concert with the extracellular matrix components.

Effect of 17-norleucine-VIP on gastroduodenal motility relative to serum VIP concentration and blockade of NOS.

Mechanical and electrical activity in the antrum, pylorus, and duodenum was evaluated in the conscious dog, instrumented with seven strain gauges and five platinum electrodes. 17-Norleucine-vasoactive intestinal peptide (17-N-Leu-VIP) or 17-N-Leu-VIP plus NG-nitro-L-arginine methyl ester (L-NAME) was injected intra-arterially close to the pylorus to identify influences of nitric oxide (NO) on effects of VIP. VIP concentration was measured by radioimmunoassay in serum samples collected from the cubital and portal veins before and up to 2 h after VIP injection. VIP (0.004-0.006 mg.kg-1.10 min-1) abolished phasic contractions in the interdigestive state for 16.8 min and in the digestive state for 14.4 min, whereas whole serum VIP concentration rose above 42.4 +/- 13 pmol/l. Administration of L-NAME did not significantly influence the effects of VIP. Aftereffects of VIP, consisting of a reduced motility index, lasted 33 +/- 10.6 min in the interdigestive state and 44.5 +/- 42 min in the digestive state. This VIP aftereffect in the interdigestive state was shortened in time by the addition of L-NAME. The results overall suggest that NO release is a factor only in the aftereffects of VIP.

Intrinsic corporoantropyloric coordination of motility and gastric emptying.

This study examined changes in gastric motility after interruption of the intramural nervous circuitry from the proximal portion of the stomach to the antrum by a circumferential gastric myotomy. Seven extraluminal strain gauge force transducers and five platinum electrodes were implanted along the antropyloroduodenal region, and gastric emptying was studied by X-ray after a 280-g solid meat meal mixed with barium. The motility index increased aboral to the myotomy by 106 and 69% in the distal antrum and pylorus, respectively, in the first postprandial 30-60 min because of the loss of an inhibitory neural influence from the proximal part of the stomach. Destabilization of the basic electrical rhythm occurred in 50% of the dogs. This was apparent as tachyarrhythmia or bradyarrhythmia and an early postprandial 2-11% decrease in slow-wave frequency and a 100% increase in slow-wave amplitude. Coordination of corporoantropyloric contractions was disorganized. Frequent segmenting and antidromic contractions were associated with reduced periods of optimal emptying and disturbed intragastric chyme transport into the constricted antrum. A 10-30% gastric emptying delay of approximately 50 min was a consequence of myotomy despite an increased antroduodenal motor gradient after myotomy. The overall results suggest that intact intramural innervation and muscular continuity are essential for coordination of corporoantropyloric motility and normal gastric emptying.

Histologic, immunohistochemical and morphometric study of the mucosa of the total gastric antrum in patients with carcinoma of the stomach.

Examination of gastrin-immunoreactive G-cells, somatostatin-immunoreactive D-cells, enterochromaffin cells and 5-hydroxytryptamine-immunoreactive (5-HT-immunoreactive) cells of the completely mapped histologic antrum (70 to 100 tissue blocks) was done in 20 normal stomachs of persons between 17 and 94 years of age (from forensic autopsy). Results were compared with those of nine patients between 48 and 76 years of age with total gastrectomy for carcinoma of the proximal part of the stomach. Cell counts and morphometric examinations were performed. Results were summarized for the proximal (I), middle (II) and distal (III) one-third of the antrum and for the major (A) and minor (B) curvature side. In normal stomachs, the G-cell count was 2.52 percent of the total gland cell count in AI; 4.25 percent in AII and 4.77 percent in AIII. In BI, the numbers were 2.5 percent, in BII, 3.73 percent and 4.06 percent in BIII. The D-cell count was 0.47 percent in AI, 0.62 percent in AII and 0.58 percent in AIII. The numbers were 0.44 percent in BI, 0.51 percent in BII and 0.51 percent in BIII. In the antrum of the stomach with carcinoma, the G-cells revealed a non-significant 20 to 70 percent lower cell count, while the D-cell count was reduced insignificantly by as much as 35 percent in all areas. The 5-HT-immunoreactive cell count in normal stomachs is 0.25 percent in AI of the total gland cells, 0.32 percent in AII and 0.39 percent in AIII. In B, it shows numerically no difference to that of A. Contrary to the cell count in normal stomachs, the carcinoma antrum revealed a 200 to 400 percent increase in 5-HT-immunoreactive cell count, highly significant in every area of the antrum. Because 5-HT is known as a growth stimulant, especially for tumors, an increase in 5-HT-immunoreactive cells may be a factor that contributes to the initial histologic changes observed during the early phase of gastric tumor.

Innervation of pylorus in control of motility and gastric emptying.

The motility index (MI) and contractile frequency were determined for the gastric antrum, pylorus, and duodenum during digestive and interdigestive states in eight dogs before and after resection of the ramus pyloricus nervi vagi (NR) and after selective proximal vagotomy (SPV) subsequent to NR. Neither NR nor subsequent SPV altered the migrating motor complex in the interdigestive state. In the digestive state, NR decreased the MI in the antrum, pylorus, and duodenum. The MI did not further change after SPV subsequent to NR. The cholecystokinin antagonist L364,718 decreased MI in the antrum, pylorus, and duodenum. After NR, L364,718 caused a further reduction in the MI during administration. Gastric emptying was accelerated after NR. SPV subsequent to NR increased gastric emptying further. L364,718, in the absence of NR, accelerated gastric emptying but only during the initial period of emptying. After NR, L364,718 also decreased the time required for emptying of 50 and 100% of the meal. After SPV subsequent to NR, no additional acceleration of emptying occurred.

Effects of erythromycin in the dog upper gastrointestinal tract.

The effects of erythromycin on motor and electrical behavior of the antrum, pylorus, and duodenum were determined in chronically instrumented, awake dogs. Erythromycin infusion resulted in an abrupt, powerful increase in motility. The motility index increased 18-fold in the antrum, 15-fold in the pylorus, and 8-fold in the duodenum. Bradyarrhythmia with a 30% decrease in slow-wave frequency occurred in all animals. Retrograde giant contractions in association with retching and vomiting occurred in 88% of the dogs. Neostigmine was less potent than erythromycin in increasing motility. Hexamethonium given intra-arterially during erythromycin infusion abolished motility for 7.2 +/- 2.9 min and intra-arterial atropine did so for 51 +/- 25 min. Hexamethonium or atropine restored the electrical slow-wave frequency. The results provide evidence that erythromycin action involves cholinergic pathways including ganglionic transmission.

Changes in the structure and regeneration mode of the rat small intestinal mucosa following benzalkonium chloride treatment.

Tritiated thymidine was administered IP to rats that had been exposed to benzalkonium chloride in the duodenum, jejunum, and ileum, resulting in neuronal ablation. Epithelial cell proliferation and migration were studied 21 and 7 days after treatment. Significant hyperplasia and hypertrophy of the villi and crypts was seen from day 7 on. This was half as pronounced as that of the muscle layer, whose maximal percent increase was not seen until day 21. In the crypt, the proliferation had increased significantly (65% 3H index corrected) and its zone had expanded proportionally to the total crypt depth. After an average of 36 hours in the ileum (48 hours in normal rats), labeled cells reached the tip of the lengthened villi, reflecting significantly accelerated migration. Concerning the distributional pattern of the labeled cells in the crypt, a nonsignificant shift to the lower two thirds of the crypt could be distinguished. From this the author concludes that treatment with benzalkonium chloride influences the proliferation and migration of the epithelial cells in the treated area. These alterations may result from loss of the myenteric plexus, but other factors cannot be excluded.

Myoelectric activity of small intestine after chemical ablation of myenteric neurons.

Ablation of the myenteric plexus was performed by serosal application of 0.062% benzalkonium chloride (BAC) in the duodenum, proximal and distal jejunum, and ileum. The thickness of muscle layers and the number and sizes of ganglia and neurons of the myenteric plexus were evaluated before and 21-28 days after treatment. Electrodes were implanted on the treated segments and on segments orad and aborad to the treated segment. The electromyogram of each segment was recorded daily for periods of 2-3 h. The number of myenteric neurons in the BAC-treated segment was decreased significantly by 85 to 98% relative to segments removed before BAC application. Significantly, thickening of longitudinal plus circular muscle layers amounted to 113% in the duodenum and 261% in the ileum in the treated segment. No changes were observed in electrical slow-wave frequency in treated segments. Spike activity (percentage of slow waves with spikes) increased in the BAC-treated segment by 92% compared with recording sites orad and aborad to the treated segment and to the small intestine in untreated control animals. We interpreted the increase in spike activity in treated segments to reflect the loss of inhibitory neuronal influence. The hyperplasia and hypertrophy of the longitudinal and circular muscle coat could have resulted from a direct influence of the altered innervation or from work-induced hypertrophy in the treated segment secondary to uncoordinated hyperactivity of the disinhibited musculature.

Effects of superior mesenteric and coeliac ganglionectomy on peptide-producing cells of the small intestinal mucosa in the Hanford mini pig. II. Immunohistochemical study.

Superior mesenteric and coeliac ganglionectomy was performed in 5 Hanford mini pigs and cholecystokinin (CCK)-immunoreactive I-cells, neurotensin (NT)-immunoreactive N-cells, glucagon (Glu)-immunoreactive L-cells, glicentin (Glic)-immunoreactive L-cells and somatostatin (Som)-immunoreactive D-cells were quantitatively evaluated in the duodenum, the upper, middle and lower jejunum and the ileum before, 3 weeks and 6 months after ganglionectomy. Three additional animals served as controls. After ganglionectomy, I-cell numbers increase by 110% in the upper jejunum and duodenum; N-cells increase by 86% in the lower jejunum. Glu- and Glic-immunoreactive L-cells decrease slightly in the jejunum. In contrast, D-cells decrease in all sections of the small intestine by 44-76% (P less than 0.05 and P less than 0.001). All the examined entero-endocrine cells, except the D-cells in the duodenum and upper jejunum, develop hypertrophy after ganglionectomy. No changes either in number or size are found in the ganglia and neurons of the myenteric plexus. From these and the recently described increase in villus height and absorptive cells and absorptive cell enzymes after ganglionectomy (Holle, G.E. et al. Effects of superior mesenteric and coeliac ganglionectomy on the mucosa of the small intestine in the Hanford mini pig. I. Histological and enzymhistochemical study, J. Auton. Nerv. Syst., 26 (1988) 135-145), we conclude that the extrinsic nervous system takes suppressive influence on structure and probably function of the small intestinal mucosa by modifying its cellular organization.

Effects of superior mesenteric and coeliac ganglionectomy on the small intestinal mucosa in the Hanford mini pig. I. Histological and enzyme-histochemical study.

The effects of total superior mesenteric and coeliac ganglionectomy on the thickness of the mucosa, the cell composition of the epithelium and the enzyme activity of the absorptive cells was studied in 10 Hanford mini pigs 3 weeks and 6 months after ganglionectomy. The mucosal thickness increased after ganglionectomy by 10-33% (P less than 0.02) mainly due to increase in the villus height. Differential cell counts showed a postganglionectomy decrease in percentage of goblet cells of 20-40%. Absorptive cell counts increased significantly (P less than 0.05). Enterochromaffin cells (stained with the Masson-Fontana method) and 5-hydroxytryptamine (5-HT)-immunoreactive cells did not change significantly in the small intestine. The activity of L-leucine-amino-peptidase, non-specific alkaline phosphatase, adenosintriphosphatase, non-specific acid phosphatase, non-specific esterase and succinate dehydrogenase, as assessed by absorption photometry, increased by 2-18% (P less than 0.01) after ganglionectomy. Total ganglionectomy thus results in a rise in villus height and in an increase in the number of absorptive cells which, by their enzymatic activity, appear to be fully mature.

Recurrence of peptic ulcer after selective proximal vagotomy and pyloroplasty in relation to changes in clinical signs and symptoms between 1969 and 1983.

Only those patients who were examined endoscopically were evaluated. Concomitant examinations, such as biopsy, histologic studies, roentgenograms, scintiscanning, acid secretion, serum gastrin and review of the operative reports, were done. Duodenal ulcers (1,219) and gastric ulcers (421) were examined preoperatively. Of these, selective proximal vagotomy and pyloroplasty and excision of the ulcer were performed for 1,018 duodenal ulcers. Forty-three per cent were examined postoperatively. Selective proximal vagotomy and pyloroplasty and excision of ulcer were performed for 315 gastric ulcers. Thirty-nine per cent were examined postoperatively. Recurrence was calculated in relation with the patients examined postoperatively. Recurrence of duodenal ulcer occurred in 6.3 per cent; of these, 0.9 per cent had duodenal ulcers develop into gastric ulcers. The recurrence rate of gastric ulcer is 8.1 per cent; of these, 0.8 per cent developed into duodenal ulcers, and 0.8 per cent to carcinoma of the stomach. Data of recurrent ulcers were compared with the data for the total number of patients who underwent surgical treatment. The possible causes for a recurrence are demonstrated. In duodenal ulcers, 79 per cent of recurrences are due to technical error (inadequate vagotomy and incomplete drainage); in gastric ulcers, 90 per cent of recurrences are due to technical error. In both duodenal and gastric ulcers, causes are partly based on advanced clinical symptoms. Recurrence rates showed a tendency to increase between 1969 and 1975 and 1976 and 1983. This correlated directly with the deterioration of the clinical signs and symptoms between 1969 and 1983, shown in increased acid secretion, increase and shift of ulcers and stenoses, increase in bleeding and changed epidemiologic findings.

Effect of selective proximal vagotomy without and with pyloroplasty on gastroduodenal motility.

The effect of selective proximal vagotomy (SPV) was examined in six dogs on the gastric emptying of solid food and the motility of the antrum and duodenum (basic rhythm, motility index, and contractile activity percentage). Emptying and motility were also examined in three dogs after additional submucosal pyloroplasty (SMP). Electrical and motor activities were tested in fasted and fed states. The meal consisted of 300 g of standard protein-mixed meal. Determination of gastric emptying by X ray were conducted with the same meal mixed with barium sulfate. All animals showed delayed emptying of solid food after SPV. Antral motility increased nonsignificantly in the digestive state, whereas duodenal motility decreased, resulting in an increased antroduodenal motor gradient. In the interdigestive state the motility of the antrum decreased significantly. Additional SMP normalized the emptying delay, but decreased digestive and interdigestive motility below the normal values. In conclusion, the emptying delay after SPV is caused at least in part by the altered functional condition of the immediate pyloric region.

Diffuse somatostatin-immunoreactive D-cell hyperplasia in the stomach and duodenum.

This paper presents the first case of extensive, diffuse, somatostatin-immunoreactive D-cell hyperplasia in the human stomach and duodenum. It occurred in a 37-yr-old woman, who showed clinical signs of dwarfism, obesity, dryness of the mouth, and goiter. The density of the distribution of D cells was increased 39-fold in the stomach fundus, 23-fold in the proximal antrum, 25-fold in the distal antrum, and 31-fold in the upper duodenum in comparison with normal values. At the same time, the gastrin-immunoreactive cells were increased 2.3-fold in the antrum. Although the range in size of the D cells was within normal limits in all regions examined, the G cells showed pronounced hypertrophy of up to 127%. A possible relationship between the immuno-histochemical findings and the clinical picture is discussed.

Behavior of somatostatin-immunoreactive cells in the gastric mucosa before and after selective proximal vagotomy and pyloroplasty in treatment of gastric and duodenal ulcers.

Antral somatostatin-immunoreactive cells (D cells) were counted pre- and postoperatively in 20 patients with duodenal ulcer and in 8 patients with gastric ulcer. Counts were obtained either over a 2-yr postoperative period (duodenal ulcer patients) at intervals of 0.5, 1, and 2 yr or over a greater than or equal to 4-yr postoperative period (gastric ulcer patients) at intervals of 1-2 yr. In patients with a normal population of gastrin-immunoreactive cells (G cells), the D cells were within the normal range (mean value 0.53% in duodenal ulcer patients and 0.67% in gastric ulcer patients). High G-cell values were accompanied by high D-cell values (e.g., in gastrin-cell hyperplasia) and low G-cell values were accompanied by low D-cell values. The G-cell to D-cell ratio was 8:1 and 6.6:1 in duodenal and gastric ulcer patients, respectively. After selective proximal vagotomy and pyloroplasty, the following observations were made: the relation of number of G cells to number of D cells remained unchanged; the postoperative rise in G-cell population was accompanied by a rise in D-cell population; hypertrophy of the D cells was apparent as was postoperative hyperplasia, with a postoperative increase in D-cell size. Morphologic coupling of the gastrin-somatostatin system in the antrum is assumed. This is constant in ulcer disease both before and after vagotomy.

Changes of cell population in the antrum after selective proximal vagotomy and pyloroplasty in gastroduodenal ulcer.

A marked increase in the number and size of the antral gastrin cells and parietal cells could be shown in long term examinations of the antrum mucosa after SPV and pyloroplasty. Twenty-five patients with UD, 12 with UV and five with Dragstedt combination (UV and UD) were examined over a period of five to seven years. A significant correlation of parietal cell increase and a positive reaction to insulin was found. The findings were compared with the changes in the fundic mucosa, where a marked decrease of parietal cells occur after SPV.

[Pathophysiology of ulcer disease]. / Die Pathophysiologie der Ulcuskrankheit.

The pathophysiological structure shows aggressors like increased acid and pepsin, an impaired defence system of the mucosa (mucus, mucosal circulation and possibly PG's and epidermal growth hormone). Disturbances in the interdigestive and digestive motility brings about most clearly the pathophysiological differences between GU and DU. Therapeutic corrections of the high secretion lead to pathological reactions in other parts of the system (gastrin). SPV is the only therapeutic procedure which reduces irreversibly the enlarged secretory capacity of the gastric mucosa (parietal cell reduction). This surgical treatment should therefore have priority in the treatment also of uncomplicated duodenal ulcers and with some exceptions of GU.