Reduction in index of oxygen saturation at margin of active duodenal ulcers may lead to slow healing

This study tested the hypothesis that reduced perfusion of a duodenal ulcer margin (ie, the mucosa 1–2 mm from the edge of the ulcer base) is associated with slow healing. Reflectance spectrophotometric measurement of indices of mucosal hemoglobin concentration (IHB) and mucosal hemoglobin oxygen saturation (ISO₂) were obtained endoscopically in 21 patients at the ulcer margin and the adjacent mucosa (ie, the mucosa 1–2 cm from the edge of the ulcer base). In 17 patients with adequate follow-up, stepwise multilinear regression analysis revealed a significantly negative correlation (r=s-0.69, P < 0.05) between ISO₂ at the ulcer margin minus ISO₂ at the adjacent mucosa (ISO)₂ and ulcer healing time. In addition, smoking, being black, and early relapse since the last ulcer attack were found to be associated with increased duration required for healing. The results of this pilot study suggest factors, in addition to smoking, that may have to be considered in future studies concerned with duodenal ulcer healing.This work was supported by the National Institute of Arthritis and Metabolism and Digestive Diseases Grant AM34840, American Society for Gastrointestinal Endoscopy Career Development Award H850208, Veterans Administration Medical Research Funds, and UCLA Academic Senate Grant 4063.     

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.     

Gastroduodenal mucosal hemodynamics by endoscopic reflectance spectrophotometry

The reflectance spectrophotometric technique measures an index of mucosal hemoglobin concentration and an index of oxygen saturation by spectral analysis of light reflected from the mucosal surface. Using a commercially available unit, a technique for obtaining reproducible endoscopic measurements with acceptable intraobserver and interobserver variability was developed in the anesthetized dogs. The reflectance spectrophotometric finding that experimentally induced prehepatic portal hypertension did not affect gastric mucosal blood flow was confirmed by hydrogen gas clearance measurements. Endoscopic studies in patients with active duodenal ulcer disease revealed a higher index of mucosal hemoglobin concentration and a normal index of oxygen saturation (i.e., an increase in blood flow) at the margin of the ulcer compared with the adjacent normal appearing mucosa.     

Endoscopic demonstration that vasopressin but not propranolol produces gastric mucosal ischemia in dogs with portal hypertension

Endoscopic reflectance spectrophotometry was used to compare the effect of vasopressin and propranolol on gastric mucosal hemodynamics in dogs with surgically induced esophageal varices and prehepatic portal hypertension. Reflectance spectrophotometry provides indices of mucosal hemoglobin concentration (IHB) and oxygen saturation (ISO2). Hyperemia (increased IHB, normal ISO2), ischemia without congestion (decreased IHB, decreased ISO2), and ischemia with congestion (increased IHB, decreased ISO2) are accompanied by characteristic patterns of IHB and ISO2. Under anesthesia, measurements were obtained on separate days from the gastric corpus mucosa of eight dogs before and 2 to 10 min after either 1 to 5 units of intravenous vasopressin or 1 mg of propranolol. Results revealed that vasopressin (in doses that significantly reduced variceal and portal venous pressure in this animal model) produced a reduction in both IHB and ISO2, indicating gastric mucosal ischemia secondary to splanchnic vasoconstriction. On the other hand, propranolol in a dose that significantly reduced pulse rate by 27 +/- 2% had no effect on IHB or ISO2, suggesting that this dose of propranolol has no direct vasoactive effect on the gastric (splanchnic) circulation.     

Reflectance spectrophotometry in the gastrointestinal tract: limitations and new applications

OBJECTIVES: Reflectance spectrophotometry (RS) assesses blood flow changes by measuring an index of Hb concentration (IHB) and index of Hb oxygen saturation (ISO2). We tested the following hypotheses: 1) endoscopic RS measurements obtained by two observers and with the aid of fiber optic and video endoscopes are similar, and 2) the method is suitable for documenting mesenteric venoconstriction associated with systemic hypoxia and blood flow autoregulation associated with hemorrhagic hypotension. METHODS: Study 1: two investigators obtained baseline gastric mucosal RS measurements in anesthetized rats (n = 3) before and after stepwise reduction of blood pressure induced by arterial hemorrhage. Study 2: subjects were examined by both fiber optic and video endoscopes. Endoscopic RS measurements were obtained at 20 cm from the anal verge. Study 3: video endoscope was used to obtain RS measurements in oxygen-dependent patients on and off oxygen treatment. Study 4: the procedures in study 1 were repeated in five additional rats by one of the investigators. RESULTS: Study 1: there was good agreement between the measurements of IHB and ISO2 between the two investigators. Study 2: video endoscope-assisted measurements were consistently lower. Study 3: cessation of oxygen treatment produced a significant drop in oxygen saturation (pulse oximetry), decline in ISO2, and rise in IHB. Study 4: when blood pressure varied between 90% and 40% of baseline, gastric mucosal blood flow (IHB) was maintained at approximately 70% of baseline level. CONCLUSIONS: We confirmed that reproducible measurement can be obtained by different investigators using standardized techniques. Standardization of endoscopic equipment is also necessary to overcome the significant limitation of endoscopic equipment on RS measurements. RS measurements can document mesenteric venoconstriction associated with systemic hypoxia and blood flow autoregulation associated with hemorrhagic hypotension.     

Tobacco cigarette smoke attenuates duodenal ulcer margin hyperemia in the rat

The hyperemia at the duodenal ulcer margin is important for ulcer healing. We studied the effect of tobacco cigarette smoke on the hyperemia at the margin of mepirizole-induced duodenal ulcer. Duodenal mucosal blood flow values measured by iodo[¹⁴C]antipyrine (IAP) autoradiography and hydrogen gas clearance (HGC) were compared. Twenty-four hours after rats were injected with an ulcerogenic dose of mepirizole, they were exposed to tobacco cigarette smoke and duodenal mucosal blood flow was measured by IAP autoradiography. There is a significant correlation between the blood flow measurements by HGC and IAP autoradiography. The hyperemia at the ulcer margin previously demonstrated in our laboratory is absent after exposure of the rats to tobacco cigarette smoke. We speculate that the inhibition of ulcer margin hyperemia could explain the aggravation of duodenal ulcer by tobacco cigarette smoke.     

Assessment of mucosal hemodynamics in normal human colon and patients with inflammatory bowel disease

Reflectance spectrophotometry measures indices of mucosal hemoglobin concentration (IHB) and oxygen saturation (ISO2). In the rat colon, characteristic patterns of IHB and ISO2 are associated with ischemia with congestion (increased IHB and decreased ISO2) and ischemia without congestion (decreased IHB and decreased ISO2). Endoscopic measurements with acceptable interobserver variability was demonstrated in the canine stomach. In eight healthy subjects, endoscopic measurement in different areas of the colon and rectum revealed significantly lower IHB values in the splenic flexure. These observations are compatible with reduced flow and increased susceptibility to ischemic damage in this watershed area. The endoscopic measurements in 13 patients with active inflammatory bowel disease revealed an increase in IHB and ISO2 values in the involved areas, indicating an increase in mucosal blood flow. In six patients restudied when the disease remitted, these values returned to normal.     

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.     

Catecholamine concentrations in biopsied gastroduodenal tissue specimens of patients with duodenal ulcer

We measured dopamine and norepinephrine concentrations in the biopsied gastroduodenal mucosa obtained from 12 ulcer-free dyspeptic patients, nine patients with active duodenal ulcer, and eight patients with inactive (or healed) duodenal ulcer using a high-performance liquid chromatography with electrochemical detection method. Biopsy specimens were taken from endoscopically normal-appearing mucosa in the gastric body and antrum as well as in the duodenal bulb. Additional specimens were obtained from the outer edge of the ulcer margin in patients with active duodenal ulcer. The mean (±SD) mucosal dopamine concentrations in the gastric body and duodenum (7.6±2.8 and 6.8±2.6 pg/mg tissue) obtained from patients with inactive duodenal ulcer were significantly (P<0.05) lower than those from dyspeptic patients (13.6±6.9 and 10.9±3.5 pg/mg tissue, respectively). In contrast, no significant differences were observed in the mean norepinephrine concentrations in these gastroduodenal tissues among the three study groups. However, the mean mucosal norepinephrine concentration in the outer edge of duodenal ulcer (86.2±125.6 pg/mg tissue) was significantly (P<0.05 and 0.01) reduced as compared with that in the ulcer-free area of duodenum obtained from patients with inactive duodenal ulcer (257.1±188.2 pg/mg tissue) and from dyspeptic patients (276.8±138.3 pg/mg tissue). The results suggest that an alteration in the catecholaminergic system may be associated with one of the pathogenic factors of duodenal ulcer.This study was supported by a grant-in-aid from the Ministry of Human Health and Welfare, Tokyo.     

Changes in Gastric Mucosal Blood Flow during Healing of EMR-Induced Ulcer

Abstract: We used the laser Doppler method to study the difference in gastric mucosal blood flow changes between peptic ulcer (65 cases) and artificial ulcer caused by endoscopic mucosal resection (35 cases) during their respective healing processes. At each endoscopic ulcer stage, blood flow at the ulcer margin and that in the surrounding mucosa were measured. In the artificial ulcer, which heals easily, blood flow at the ulcer margin was still high at the scarring stage as compared with that in the corresponding area of a peptic ulcer, which is prone to relapse. Moreover, the blood flow ratio (blood flow at the ulcer margin/blood flow in the surrounding mucosa) at the S1 stage in artificial ulcers was significantly higher than that in peptic ulcers (p<0.05). These results suggest that blood flow in the SI stage is an important aspect of ulcer healing and relapse.     

Gastroduodenal Perfusion and Mortality in Mechanical Ventilation-Dependent Patients with Systemic Inflammatory Response Syndrome

The role of gastrointestinal blood flow determination in predicting mortality is not known. We tested the hypothesis that when mechanical ventilation-dependent (MVD) patients with systemic inflammatory response syndrome (SIRS) develop a significant reduction in gastroduodenal blood flow, high mortality will ensue. The design was a prospective, observational study at the intensive care unit (study patients) and outpatient endoscopy suite (controls) of a tertiary care Veterans Affairs Hospital. There were 6 study patients and 10 control subjects. Interventions were endoscopic reflectance spectrophotometry recorded indexes of gastroduodenal mucosal oxygen saturation (ISO2) and hemoglobin concentration (IHB). Data for Acute Physiologic and Chronic Health Evaluation (APACHE) II scores were gathered. All study patients had septic SIRS at enrollment. Gastroduodenal blood flow measurements ranged from 32 to 55% (ISO2) and from 42 to 51% (IHB) of those in control subjects. The significant hypoperfusion upgraded diagnosis to severe sepsis. The APACHE II score of 16.8 +/- 2.8 (mean +/- SE) predicted approximately 25% mortality. Observed in-hospital mortality was 83%. Our study confirmed that MVD patients with severe sepsis have a significant impairment of gastroduodenal blood flow. Such a dramatic reduction is associated with a grave prognosis. The impact of these measurements on physicians' predictions of the likelihood of survival in patients receiving intensive care deserves to be assessed.     

The Histological Maturity of Regenerating Mucosa of Healed Duodenal Ulcer and Ulcer Recurrence after Treatment with H2-Antagonist

We investigated the relationship between the histological maturity of regenerating mucosa of healed duodenal ulcer and ulcer recurrence, after treatment with an H2-antagonist. Duodenal ulcer patients were given H2-antagonists (either cimetidine or famotidine) for 4 wk of therapy. Fifty-two (77.6%) of the 67 patients were healed endoscopically. The histological state of the regenerating mucosa of healed duodenal ulcer was divided into three categories: good, fair, and poor patterns. Of the 52 healed patients, 15 achieved a good histological pattern. None of these 15 patients had a recurrence 3 months later. However, nine of the 37 patients with a fair or poor pattern of regenerating mucosa had a recurrence 3 months after healing (p = 0.034). We concluded that a duodenal ulcer should be treated until the regenerating mucosa of the healed ulcer reaches a good histological pattern, so as to prevent the recurrence of the ulcer.     

Occurrence of Campylobacter pylori in patients with gastritis and peptic ulcer

Endoscopic biopsies from the gastric antrum and margin of peptic ulcers (gastric and duodenal) were obtained from 56 patients for histologic and microbiologic studies in order to establish the occurrence of Campylobacter pylori. Thirty nine of them had antral gastritis and in 37 (94.8%) the bacteria was detected. In 17 cases with normal mucosa the culture was positive in only 2 of them (p less than 0.01). Patients with duodenal and gastric ulcer had a 100% and 88.8%, respectively, of positivity to C. pylori at samples from the margin of the lesions. Bacteriologic findings were similar to those described in the literature. At the electronic microscopy bacilli were found near or adhering to the cellular surface without signs of intraepithelial penetration. This study confirms the association between C. pylori and gastritis and peptic gastroduodenal ulcer.     

Omentum and basic fibroblast growth factor in healing of chronic gastric ulcerations in rats

Omentum was shown to exhibit angiogenic activity, but its role in healing of chronic gastric ulcers is unknown. This study was designed to compare the effects of omentum and basic fibroblast growth factor (bFGF), a potent angiogenic factor, on healing of chronic gastric ulcers in rats. Several series of rats with gastric ulcers were used: series A with intact omentum (control), series B with omentum resected, and series C with omentum placed on the serosal side of the ulcer. Series A–C were divided into four groups treated with vehicle (I); indomethacin (II), an inhibitor of prostaglandin formation, difluoromethylornithine (DFMO) (III); an inhibitor of polyamine biosynthesis or bFGF (IV). Seven days after ulcer induction, the animals were anesthetized, the gastric blood flow (GBF) was determined by laser Doppler flowmetry (LDF), and the ulcer area was measured by planimetry. Biopsy samples of the ulcer margin were taken for determination of the number of capillaries and myofibroblasts in the granulation tissue. Attachment of omentum significantly accelerated ulcer healing, whereas omentectomy delayed this process. LDF revealed the decrease in the GBF at the ulcer margin to 45% and at the ulcer bed to 18% of the value recorded in the intact adjacent mucosa. Attachment of the omentum significantly increased the blood flow at the ulcer margin and increased the number of capillaries and myofibroblasts in the granulation tissue. Indomethacin (1 mg/kg/day) that inhibited mucosal PGE₂ by about 85% delayed significantly ulcer healing without affecting the blood flow in the ulcer area. DFMO (200 mg/kg intraperitoneally) suppressed ODC activity in the mucosa but did not influence the ulcer healing. bFGF given subcutaneously accelerated dose-dependently ulcer healing and stimulated angiogenesis to a similar extent as the attached omentum. We conclude that omentum enhances the ulcer healing in similar way as bFGF and that this effect is accompanied by the increased angiogenesis and blood flow in the ulcer area.     

Prostanoid synthesis by cultured gastric and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.     

Deformity of duodenal bulb, gastric metaplasia of duodenal regenerating mucosa and recurrence of duodenal ulcer： A correlated study

AIM: To investigate the correlation among the presence and degree of gastric metaplasia of duodenal regenerating mucosa, the deformity of bulb and the recurrence of duodenal ulcer. METHODS: A total of 99 patients with duodenal ulcer were treated with H2-antagonist with or without antimicrobial therapy. All patients received follow-up endoscopic examinations 6 wk after treatment. When the ulcer(s) were noted to be healed, two biopsies were taken from the ulcer scar for histological study of gastric metaplasia, and 4 biopsies were taken from antrum for Helicobacter pylori (H pylori) study. Out of these cases, 44 received further follow-up endoscopic examinations after 3,6 and 12 mo respectively for studying the recurrence rate of duodenal ulcers. The correlation among ulcer recurrence, degree of gastric metaplasia of regenerating mucosa, bulbar deformity, and colonization of H pylori in the stomach was then studied. RESULTS: The results showed that there was a strong correlation between the deformity of duodenal bulb and the degree of gastric metaplasia of regenerating duodenal mucosa. The recurrence rate of duodenal ulcer had a significant difference between patients with and without H pylori colonization in the stomach (P<0.001). The greater the degree of gastric metaplasia of duodenal regenerating mucosa, the higher the recurrence rate of duodenal ulcer (P= 0.021). The more deformed the duodenal bulb, the higher the incidence of recurrence of duodenal ulcer (P = 0.03). CONCLUSION: There is a correlation among deformity of duodenal bulb, gastric metaplasia of duodenal regenerating mucosa and recurrence of duodenal ulcer. A more severely deformed duodenal bulb is closely related to a greater extent of gastric metaplasia. Both factors contribute to the recurrence of duodenal ulcer.     

Duodenal mucosa synthesis of prostaglandins in duodenal ulcer disease.

Synthesis of prostaglandins (PGE2, PGI2 and PGF2 alpha) and thromboxane A2 was investigated in short term incubates of duodenal mucosa biopsies. Mucosa close to the ulcer site synthesised significantly less PGF2 alpha (p less than 0.001) and PGI2 (p less than 0.002) measured as its stable metabolite 6-oxo-PGF1 alpha than healthy mucosa from non-ulcer patients. In paired biopsies taken from the ulcer site and opposite the ulcer in the same patient PGF2 alpha and PGI2 syntheses were both significantly and similarly depressed when compared with normal mucosa. Synthesis of PGE2 and TxA2 (as its stable metabolite TxB2) was not different in any tissue. There is a defect in the ability of the human duodenal mucosa in duodenal ulcer disease to synthesise PGF2 alpha and PGI2; the defect is not limited to the ulcer site.     

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.     

Phospholipid composition of human gastric mucosa: a study of endoscopic biopsy specimens.

Gastric mucosal phospholipids, and in particular those of the surface layer, play an important part in mucosal barrier function. This study examined whether the phospholipid composition of the full thickness gastric mucosa is changed in peptic ulcer disease and gastritis. The phospholipid composition of gastric mucosa from endoscopic biopsy specimens in 28 subjects (eight healthy controls, 12 patients with duodenal ulcer, and eight with chronic atrophic gastritis) was studied. In addition, the phospholipid composition of gastric mucosa was compared with that of duodenal mucosa in 10 patients with duodenal ulcer. As expected phosphatidylcholine and phosphatidylethanolamine prevailed in all three groups. Lysolecithin was the smallest component in the duodenal ulcer and chronic atrophic gastritis groups. The phosphatidylethanolamine value was higher in duodenal ulcer and lower in chronic atrophic gastritis compared with the control group. In chronic atrophic gastritis there was an appreciable amount of phosphatidylglycerol that was not present in patients with duodenal ulcer or in the control group. There was no significant difference in phospholipid composition between antral and duodenal sites in duodenal ulcer patients. In conclusion, the phospholipid composition of gastric mucosa changes in human gastrointestinal diseases but its relation to cellular functions needs further study.     

Effect of oral epidermal growth factor on mucosal healing in rats with duodenal ulcer

AIM: To investigate the effect of epidermal growth factor (EGF) on mucosal healing in rats with duodenal ulcer.METHODS: Male Sprague-Dawley rats were randomly divided into sham operation without EGF, sham operation with EGF, duodenal ulcer without EGF, or duodenal ulcer with EGF groups. Additionally, normal rats without operation served as the control group. Duodenal ulcer was induced in rats by 300 mL/L acetic acid. Rats with EGF were orally administered at a dose of 60 μg/kg/day in drinking water on the next day of operation (day 1). Healing of duodenal ulcer was detected by haematoxylin and eosin staining. Cell growth of damaged mucosa was determined by the contents of nucleic acids and proteins. The level of EGF in duodenal mucosa was measured by ELISA.RESULTS: The pathological results showed that duodenal ulcer rats with EGF improved mucosal healing compared with those without EGF after day 5. Duodenal ulcer rats with EGF significantly increased duodenal DNA content compared with those without EGF on day 15 (6.44±0.54mg/g VS 1.45±0.52 mg/g mucosa, P＜0.05). Duodenal RNA and protein contents did not differ between duodenal ulcer rats with and without EGF during the experimental period.Sham operation and duodenal ulcer rats with EGF significantly increased duodenal mucosal EGF content compared with those without EGF on day 5 (76.0±13.7 ng/g VS 35.7±12.9ng/g mucosa in sham operation rats, and 68.3±10.9 ng/gVS 28.3±9.2 ng/g mucosa in duodenal ulcer rats, P＜0.05).CONCLUSION: Oral EGF can promote mucosal healing of the rats with duodenal ulcer by stimulating mucosal proliferation accompanied by an increase in mucosal EGF content.