Epithelial Cell Proliferation in Duodenal Ulcer

Epithelial cell proliferation in the duodenum was investigated in 50 patients by incubating mucosal biopsy samples with tritiated thymidine, followed by autoradiography. Fifteen patients had a normal duodenum, 15 duodenal ulcer undergoing elective surgery, 10 perforated duodenal ulcer, and 5 severe non-ulcer-associated duodenitis. The mean crypt cell labelling index in the duodenal bulb of controls was 8.8 ± 0.4% (mean ± SEM), at the edge of perforated ulcers 19.1 ± 2.0%, at the edge of elective ulcers 18.6 ± 1.4%, and in biopsy specimens from non-ulcer-associated duodenitis 14.0 ± 1.2%. The mean labelling index in the distal first part of duodenum of control patients was 9.1 ± 0.8 similar to the values found in histologically normal specimens distal to ulcer or duodenitis. The results indicate active epithelial cell proliferation in both duodenal ulcer and duodenitis. There was no evidence of impairment of epithelial cell proliferation in duodenal ulcer patients.     

Epithelial cell proliferation in duodenal ulcer

Epithelial cell proliferation in the duodenum was investigated in 50 patients by incubating mucosal biopsy samples with tritiated thymidine, followed by autoradiography. Fifteen patients had a normal duodenum, 15 duodenal ulcer undergoing elective surgery, 10 perforated duodenal ulcer, and 5 severe non-ulcer-associated duodenitis. The mean crypt cell labelling index in the duodenal bulb of controls was 8.8 +/- 0.4% (mean +/- SEM), at the edge of perforated ulcers 19.1 +/- 2.0%, at the edge of elective ulcers 18.6 +/- 1.4%, and in biopsy specimens from non-ulcer-associated duodenitis 14.0 +/- 1.2%. The mean labelling index in the distal first part of duodenum of control patients was 9.1 +/- 0.8 similar to the values found in histologically normal specimens distal to ulcer or duodenitis. The results indicate active epithelial cell proliferation in both duodenal ulcer and duodenitis. There was no evidence of impairment of epithelial cell proliferation in duodenal ulcer patients.     

Duodenal epithelial thymidine uptake in patients with duodenal ulcer or endoscopic duodenitis

To evaluate the relationship between duodenal ulcer disease and duodenitis, duodenal epithelial cell renewal was measured in mucosal biopsies by the incorporation of [³H]thymidine. When 14 patients with duodenal ulcer were compared to 13 control subjects or 7 with endoscopic duodenitis alone, the crypt size was the same in all groups. Similar to other inflammatory processes of the gastrointestinal tract, patients with endoscopic duodenitis showed increased proliferative indices including a greater number of cells incorporating [³H]thymidine. In contrast, the proliferative indices from the duodenal mucosa of patients with duodenal ulcers did not differ from a control group. In a group of 6 patients with both endoscopic duodenitis and duodenal ulcer, the [³H]thymidine incorporation was intermediate between control subjects or patients with duodenal ulcer alone and those with endoscopic duodenitis alone. When subjects were divided according to the histologic appearance of the duodenal mucosa, those having chronic duodenitis demonstrated enhanced [³H]thymidine incorporation in comparison to a control group or patients with chronic active duodenitis (polymorphonuclear leukocytes present). Although there are many possible explanations of these findings, one may speculate that duodenal ulceration does not stimulate duodenal epithelial proliferation. This project was supported by the Yale Digestive Cancer Research Fund. Dr. Gorelick was supported by a Research Fellowship Award from the National Foundation for Ileitis and Colitis during a portion of this study and is currently a recipient of a Clinical Investigator Award (KO8-AM-00659) from the National Institute of Arthritis, Metabolism and Digestive Diseases.     

Quantitative histological study of mucosal inflammatory cell densities in endoscopic duodenal biopsy specimens from dyspeptic patients using computer linked image analysis.

Inflammatory cell counting in endoscopic biopsy sections was carried out on duodenal mucosal samples from defined sites in patients with duodenal ulcer, duodenitis but no ulcer, non-ulcer dyspepsia, and asymptomatic controls using computer linked image analysis. The variables measured included polymorphonuclear and mononuclear cells per mm of superficial epithelium and per mm2 lamina propria. Duodenal ulcer crater margin and mucosal biopsy specimens from endoscopically inflamed mucosa in the group with duodenitis but no ulcer showed significantly higher inflammatory cell counts than endoscopically normal non-ulcer dyspepsia and control mucosa. Biopsy specimens from non-ulcer dyspepsia patients showed significantly higher lamina propria polymorphs than control group mucosa. Endoscopically normal duodenal ulcer and duodenitis but no ulcer mucosa also showed significantly higher acute and chronic inflammatory cell counts than controls. The prevalence of Helicobacter pylori in duodenal biopsy specimens was low (0-22%) and unrelated to local inflammatory response. Despite histological appearances, duodenal biopsy specimens from non-ulcer dyspepsia patients showed significantly higher inflammatory cell infiltration than control specimens, suggesting that at least some represent part of a spectrum of subclinical peptic disease.     

In vivo cell kinetics studies of the duodenum during and after healing of cysteamine-induced duodenal ulcer in rats using bromodeoxyuridine incorporation

The present study investigated the defect of duodenal defence responsible for the tendency of recurrence of duodenal ulcer. Male Wistar rats were treated with cysteamine-HCl subcutaneously to induce duodenal ulcer, and bromodeoxyuridine (BrdU) was given intraperitoneally 1 h before laparotomy. Serial tissue sections and immunocytochemical staining of BrdU were done to study the cell kinetics during and after healing. Deep ulcers developed in the proximal part of the duodenum 24 h after cysteamine injection, and the ulcer was replaced by scar tissue 1 week later. BrdU-labelling index of normal duodenal mucosa in control rats was 30-34%. On the peripheral part of the regenerative mucosa, BrdU-labelling index increased from 1.5% to 26-27%, 1-4 weeks after injection and remained at this level thereafter. On the central part, except the most central area, the labelling index remained at 0% until 3 weeks, and was 15% 6 weeks after cysteamine treatment. It never achieved the level seen in control normal mucosa. The labelling rate of fibrous cells in scar tissue decreased from 28% to nearly 0% 1-4 weeks after the injection. It is concluded that both the ulcer scar and the regenerative mucosa do not achieve a mature state in the initial scarred stage; they need more time to reach a relatively mature condition. Moreover, the regenerative mucosa will be the weak, easily damaged part of the duodenum.     

Flow cytometric analysis of cell proliferation kinetics during duodenal ulcer healing

Cell proliferation in the gastroduodenal mucosa of patients with duodenal ulcers was evaluated using flow cytometry. Forty patients with duodenal ulcers and 12 normal subjects were investigated. Biopsy samples were obtained during endoscopic examination and subjected to DNA analysis by flow cytometry. Thirty patients with duodenal ulcers were healed within 3 months with H₂ blockers (tractable or responsive ulcers), whereas 10 patients did not respond to treatment (intractable ulcers). The percentage of cells at the DNA-synthetic phase, an index of cell proliferation, was constant in the adjacent duodenal mucosa 2cm from ulcer margin and antral mucosa during duodenal ulcer healing. The index at the margin of tractable ulcers was elevated during the active stage (12.9 ± 1.3), peaked during the healing stage (15.4 ± 2.8) and returned to the same level at the scarring stage (10.9 ± 2.0) as normal controls (10.3 ± 1.7). However, the index was not elevated in intractable ulcers (10.3 ± 1.7 in the healing stage) and was smaller than in tractable ulcers. These data indicate that augmented mucosal cell proliferation at the ulcer margin plays an important role in duodenal ulcer healing and intractable ulcers are characterized by an abnormal failure to accelerate DNA synthesis to achieve ulcer repair.     

Study of the proliferation in human gastric mucosa after in vivo bromodeoxyuridine labelling.

Studies to measure human gastric crypt or gland cell proliferation may have a number of practical clinical applications in relation to both benign and malignant gastric conditions. Bromodeoxyuridine (BrdUrd) labels human gastric mucosal cells in the S phase. Computer aided data analysis of labelled mucosa allows static proliferative indices to be estimated, including the crypt labelling index (LI), the peak labelling position, the distribution of labelled cells and indirectly the crypt growth fraction. Multiparameter flow cytometric analysis of labelled nuclei allows the S phase duration (Ts) of mucosal cells to be estimated. Specimens of histologically normal gastric body (GB, n = 16) and antral mucosa (GA, n = 10) were obtained from 25 patients with gastric carcinomas who received a bolus dose of 250 mg BrdUrd between 3.0 and 15.7 hours before surgery. Tissue sections were stained by an immunohistochemical method and subjected to detailed counting of up to 50 longitudinal crypts per specimen. The total crypt labelling index was calculated by a grid counting method. A significant difference existed between the proliferative compartments of gastric antral and body mucosa measured by a number of criteria. The median lengths of the crypts were 137 cells (GB) and 188 cells (GA). The median peak labelling positions were cell 26 (GB) and cell 61 (GA) from the crypt orifice. The mean crypt labelling indices were 2.8% (GB) and 4.8% (GA). The mean Ts of GA cells was 7.7 hours and of GB cells was 10.8 hours.     

Link betweenHelicobacter pylori-associated gastritis and duodenal ulcer

We examined the interrelationships among the degree of fundic mucosal atrophy, the prevalence ofHelicobacter pylori in the gastric antrum, the gastric juice, and the duodenum with and without gastric metaplasia, in 20 duodenal ulcer patients and 20 non-duodenal ulcer patients. The detection rates ofH. pylori in the antrum, the gastric juice, and the duodenum were significantly higher in duodenal ulcer patients (80%, 65%, and 60%) than in non-duodenal ulcer subjects (50%, 20%, and 5%). The frequency ofH. pylori was significantly lower in the gastric juice (30%) and the duodenum (10%) in non-duodenal ulcer patients with antralH. pylori, compared with those in duodenal ulcer patients with antralH. pylori. All of seven patients with both gastric metaplasia andH. pylori infection in the duodenum had duodenal ulcer, whereas only 1 of 14 patients without either gastric metaplasia orH. pylori infection in the duodenum had duodenal ulcer. There was normal or mild atrophic mucosa in the fundus of duodenal ulcer patients withH. pylori in the antrum, whereas moderate or severe atrophic mucosa in non-duodenal ulcer patients withH. pylori gastritis. These results suggest that the preserved fundic mucosa, gastric metaplasia in the duodenum, and a greater load ofH. pylori to the duodenum through the gastric juice may be prerequisites for the formation of duodenal ulcers.     

Upper gastrointestinal mucosal lesions in chronic renal failure.

The upper gastrointestinal mucosa was studied endoscopically in 182 patients (140 males, 42 females) with chronic renal failure prior to hemodialysis. Endoscopy revealed normal mucosa in 77 patients (42.3%), inflammatory mucosal lesions in 88 (48.4%), peptic ulcer in 16 (8.8%; duodenal 15, gastric 1) and Barrett's ulcer in one patient. Upper gastrointestinal bleeding was noted at presentation in 16 (8.8%) cases and was associated with erosive gastritis, duodenitis and duodenal ulcer in 11, 3 and 2 patients respectively. Thus patients with chronic renal failure had a high prevalence of inflammatory mucosal changes.     

The duodenal mucosa in peptic ulcer disease

Summary The duodenum was evaluated in patients with X-ray negative dyspepsia (6), duodenal ulcer or deformed bulbs (18), duodenitis (3), and normal controls (5), using the peroral small-bowel biopsy instrument of Crosby and Kugler. Specimens from patients with X-ray-negative dyspepsia and normal controls were similar. The majority of patients with duodenal ulcer (14) had normal mucosal biopsies. However, the other 4 patients had marked histological changes, consisting of chronic inflammatory cell infiltration into the submucosa and blunting of the villi. One patient with duodenitis only, demonstrated by X-ray, had pathological findings confirming that diagnosis. No close relationship could be found between pathological material and either clinical or X-ray findings. It is believed that this histological picture is consistent with what has been described pathologically as duodenitis. The significance of these findings awaits further investigation.This paper represents the personal viewpoint of the authors and is not to be construed as a statement of official Air Force policy.     

Duodenal mucosal injury with nonsteroidal antiinflammatory drugs

The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on duodenal mucosa was assessed both retrospectively and prospectively. In 444 patients with duodenal ulcer, the incidence of upper gastrointestinal bleeding was five times higher in 56 patients who were treated with NSAIDs than in those who did not receive NSAIDs. Indomethacin and naproxen had the most potent damaging effects. In a control group of patients with gastric ulcer, nine out of 134 had taken NSAIDs. The incidence of bleeding in these patients was three times higher than in those who were not on NSAIDs. The effect of indomethacin, 150 mg/day, on the upper gastrointestinal tract was examined in a prospective study of 75 patients with acute musculoskeletal disorders. Endoscopy after 1 week of therapy showed that 45% had mucosal damage in the duodenum, and this was as frequent and as severe as the gastric mucosal damage. In most instances, the duodenal damage was erosive duodenitis.     

Helicobacter pylori infection, gastric metaplasia in the duodenum and the relationship with ulcer recurrence

OBJECTIVE: To study the prevalence of Helicobacter pylori (H. pylori) infection and gastric metaplasia (GM) in the duodenum a large group of patients with duodenal ulcer was evaluated to determine whether these factors are related to the number of ulcer recurrences. METHODS: Three hundred and seven patients diagnosed by endoscopy as having active duodenal ulcers were studied. At endoscopy, all patients had gastric biopsies taken for histology, the rapid urease test and culture. Three duodenal biopsies were also taken and processed for histology (haematoxylin & eosin, Giemsa, Warthin-Starry, and PAS stain). RESULTS: GM and H. pylori in the duodenum was identified in 73% (68-78%) and 66% (60-71%) of the cases, respectively. All patients with H. pylori in the duodenum also had GM at this location, while areas with GM but without H. pylori were described. The kappa statistic for concordance between GM and H. pylori at the duodenum was 0.82. The prevalence of GM and H. pylori, depending on the number of ulcer recurrences, was: 1st episode, 34% and 27%, respectively; 2nd episode, 84% and 80%; and > or = 3rd episode, 90% and 79% (P < 0.001 when comparing 1st vs 2nd or > or = 3rd episode). In the multivariate analysis, age and number of ulcer recurrences correlated both with GM and with H. pylori in the duodenum. Chronic duodenitis was demonstrated in all duodenal biopsies, 87% being active chronic duodenitis. H. pylori in the duodenum was more frequent in patients with active duodenitis (73%) than in those with inactive duodenitis (13%) (P < 0.001). CONCLUSIONS: Patients with recurrent ulcer disease have a higher prevalence of both GM and H. pylori infection in the duodenum, suggesting that these two factors are related with the chronicity and recurrence of duodenal ulcer disease. H. pylori infection in the duodenum always appears in areas of GM, although GM is not necessarily colonized by the organism. H. pylori infection cannot be excluded based only on the results of duodenal biopsies, as false negative results at this area are frequent.     

Helicobacter Pylori and Refractory Duodenal Ulcers: Cross-over Comparison of Continued Cimetidine with Cimetidine plus Antimicrobials

Objectives: To determine the distribution of Helicobacter pylori in the antral and duodenal mucosa of patients with duodenal ulcers refractory to 12 wk of treatment with cimetidine and to evaluate the effect of adding antimicrobial agents to cimetidine on the bealing of refractory duodenal ulcers. Methods: A randomized crossover comparison of continued 800 mg of cimetidine at night for 4 wk with cimetidine plus 500 mg of amoxycillin three times a day for the first 2 wk and 250 mg of metronidazole three times a day for the second 2 wk. H. pylori status in the gastric antral and duodenal mucosa was evaluated by histology and bacterial culture before and at the end of each treatment period. Results: Forty-eight patients were studied. Upon entry to the study, all patients had antral colonization with H. pylori . In the duodenum, active chronic duodenitis was present in 66%, duodenal gastric metaplasia in 33%, and H. pylori in 50%, similar proportions to patients with nonrefractory duodenal ulcers. Healing occurred in 70% (30 of 43) of patients during treatment with cimetidine plus antimicrobials but in only 21 % (6 of 28) during treatment with cimetidine alone ( P = 0.0003). In patients who received antimicrobials, neither clearance of H. pylori from the antrum (58% of patients) or duodenum (71% of colonized patients) nor eradication of H. pylori (33%) was significantly correlated with ulcer healing. Conclusions: The distribution of H. pylori in refractory duodenal ulcers is similar to nonrefractory ulcers, and the combination of amoxycillin and metronidazole with cimetidine increases the proportion of refractory duodenal ulcers, which heals.     

Nodular duodenitis

This prospective study evaluated the radiographic, endoscopic, histologic, and clinical characteristics of nodular duodenitis found in 17 of 50 (34%) patients with end-stage renal disease. By comparison, nodular duodenitis was noted in only 23 of 557 (4%) consecutive endoscopies in a general medical population. Endoscopic nodular duodenitis consisted of two or more nodules, 2.5-7.0 mm in diameter, with apical erythema, with or without tip erosions. Eight patients had nodules in the bulb only, eight had diffuse duodenal nodules, and a single patient had nodules only in the second portion of the duodenum. Single-contrast barium x-rays were sensitive in detecting the nodules only when they were 5 mm or greater in diameter. Some degree of inflammatory infiltrate was found in 14 of 17 (82%) of the patients with nodular duodenitis; 10 of 17 had a moderate to severe histologic grade compared to 3 of 18 (P = 0.015) patients with a normal endoscopic appearance to the duodenum. Several patients with endoscopic nodular duodenitis, in whom biopsies were taken both of the nodule and surrounding mucosa, were found to have a focal histologic lesion which consisted of villous blunting and thickening due to fibrosis and a chronic inflammatory infiltrate or lymphoid aggregate in the stroma. A higher incidence of peptic ulcers occurred in the nodular duodenitis group (3 of 17) compared to the remainder of the group (0 of 33) during a mean follow-up of 38 months (P = 0.03). Resolution of the nodules occurred in six patients following successful renal transplant (four patients) and following vagotomy and pyloroplasty (two patients).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell renewal in non-specific duodenitis, ulcer-related duodenitis and duodenal ulcer. Experiments in Mastomys (Praomys natalensis)

Cell renewal in the duodenal mucosa of Mastomys was studied by autoradiography 1 and 24 h after intraperitoneal injection of tritiated thymidine. Non-specific duodenitis and duodenal ulceration were produced with a continuous infusion of histamine. Mucosal renewal in the duodenum of 30 control Mastomys was compared with 30 which received histamine dihydrochloride for 5 days. No abnormality developed in the controls, but 11 of the experimental group developed non-specific duodenitis and 12 duodenal ulcers. The size of the proliferative zone was increased in the Mastomys sacrificed 1 h after injection of tritiated thymidine which received histamine, compared with controls (p = 0.004). The number of labelled nuclei (p = 0.0003) and the size of the columns of labelled nuclei (p = 0.001) were increased in the Mastomys receiving histamine and sacrificed 24 h after injection of tritiated thymidine, compared with controls. The number of labelled nuclei (p = 0.004) and the size of the columns of labelled nuclei (p = 0.01) were increased in the Mastomys with ulcers compared with the other Mastomys which had received histamine. Cimetidine prevented duodenitis and ulceration, normalising the pattern of cell renewal. There was correlation between the severity of non-specific and ulcer-related duodenitis as judged by Lance's system and the number of labelled nuclei (Spearman rank correlation coefficient 0.771, p less than 0.002). Cell renewal increased as duodenitis became more severe and duodenal ulcers were found in duodenal mucosa where cell renewal was fastest.     

Duodenal mucosal architecture in non-specific and ulcer-associated duodenitis.

This study was done to determine the severity and extent of abnormalities of duodenal mucosal architecture in non-specific (non-ulcerative) and ulcer-associated duodenitis. The effect of successful treatment with cimetidine on these changes has also been assessed. A method of microdissection and measurement of villus height, crypt depth, and mitotic figure count per crypt was applied to endoscopic biopsies from the duodenum. Five groups of patients were studied: untreated ulcer-associated duodenitis, untreated non-specific duodenitis, healed ulcer-associated and non-specific duodenitis after cimetidine treatment, and controls. Significant reduction in villus height, increase in crypt length, and increase in mitotic figure count per crypt were all found in both ulcer-associated and severe non-specific duodenitis as compared with controls. These changes were localised to visually inflamed areas and regressed after healing of these lesions with cimetidine. This is the first quantitative comparison of the architectural features between diseased states in the duodenum and control in the same study. Identical morphological changes in the form of crypt hyperplasia and villus atrophy were demonstrated in areas of non-specific and ulcer-associated duodenitis. No evidence could be found from this study that non-specific duodenitis constitutes a different disease from ulcer-associated duodenitis.     

Patterns of inflammation linked to ulcer disease.

Peptic ulcers are accompanied by different patterns of chronic gastritis and duodenitis that generally run parallel to the topography of colonization by Helicobacter pylori (H. pylori). Duodenal ulcers arise on a background of a gastroduodenitis; the gastritis is antrum-predominant while the duodenitis requires acid-induced gastric metaplasia in the duodenal mucosa before bacterial colonization can occur. The colonized and inflamed metaplastic areas in the duodenum (and inflamed pre-pyloric antrum) are the initial sites of ulceration. Proximal gastric ulcers arise in a diffuse (pan-) gastritis or a corpus-predominant H. pylori gastritis when the weakened gastric mucosa (especially in the antrum-body transitional zone) is susceptible to ulceration even in the presence of subnormal acid production. These distinctive patterns of gastritis are sufficiently consistent for them to be used to predict ulcer risk.     

Influence ofHelicobacter pylori on tryptase and cathepsin D in peptic ulcer

We here ascertain whether tryptase (a serine endoprotease released by mast cells) and cathepsin D (CD, a lysosomal hydrolase that seems able to derange the extracellular matrix) play a part in peptic ulcer disease and whether they are linked toHelicobacter pylori (Hp) infection. We studied 13 controls, 25 patients with gastric ulcer, 47 with duodenal ulcer, and 11 with duodenitis. Tryptase and CD were measured in mucosal biopsies (body and antrum of the stomach and duodenum) using IRMA methods. Hp infection was histologically evaluated (Giemsa). Tryptase and CD levels were higher (25%) in patients with active peptic ulcer, whether gastric or duodenal. In Hp-positive patients the CD mucosal content was higher while tryptase mucosal levels were lower than in Hp-negative patients. Tryptase was correlated with gastrin content. CD seems to be mainly related to the phlogistic reaction of the mucosa to Hp infection; tryptase may reflect an indirect link between Hp infection, gastrin release, and the function of mast cells.     

Persistence ofCampylobacter pyloridis despite healing of duodenal ulcer and improvement of accompanying duodenitis and gastritis

Campylobacter pyloridis has been associated with antral gastritis and duodenal ulcer. To study the pathogenetic role of these organisms in duodenal ulcer, endoscopic biopsies, two from the first part of duodenum, four from antrum, and four from body and fundus, were taken before and after four weeks of cimetidine treatment (1.2 g/day) from 67 patients with active duodenal ulcer. The biopsies were examined for the presence and severity of any inflammation by two independent pathologists in the absence of any clinical information and for the occurrence and density of Campylobacter pyloridis by culture and Warthin-Starry stain. Before treatment, inflammation was present in 71.1, 100, and 25.8%, while the organisms were present in 34.3, 91.0, and 79.1% of the duodenal, antral, and fundal biopsies, respectively. With complete healing of duodenal ulcer, inflammation was present in 48.9, 98.2, and 30.2%, while the organisms were present in 25, 76.7, and 63.3% of the respective mucosae. With ulcer healing, duodenitis became significantly milder (P less than 0.05). With improvement of gastritis and duodenitis, there was no significant change in the occurrence and density of Campylobacter pyloridis. These findings indicate that healing of duodenal ulcer is not influenced by the presence of Campylobacter pyloridis, which is frequently found in the gastroduodenal mucosa of patients with duodenal ulcer, but does not appear to be associated with mucosal inflammation except in the antrum.     

Lysolecithin: A factor in the pathogenesis of gastric ulceration?

Lysolecithin is formed when pancreatic juice and bile mix in the duodenum. Lysolecithin concentrations have been measured in intermittent samples of night gastric juice from patients with gastric ulcers and duodenal ulcers and in normal controls. In gastric ulcer patients, the mean of the peak concentrations (444 mug/ml) and mean of concentrations in all samples (199 mug/ml) were significantly higher than in controls (34 mug/ml and 18 mug/ml respectively). Duodenal ulcer patients had normal or moderately raised values. The levels in gastric ulcer patients were as high as those which have been found experimentally to cause severe damage to the gastric mucosal barrier, and it is concluded that lysolecithin may be as important, or more important, than bile salts in the destruction of the gastric mucosal barrier and therefore in the aetiology of gastric ulcer.