Primary esophageal motility disorders: incisive decisions.
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Combined Modality Therapy↗
Biomedical subjects
G Triadafilopoulos
Publications and source records attributed to G Triadafilopoulos.
Features of symptomatic gastroesophageal reflux disease in elderly patients.
OBJECTIVES: Gastroesophageal reflux disease (GERD) is considered common in the elderly and may present with various symptoms, such as heartburn, regurgitation, dysphagia, or chest pain. In this study, we evaluated the patterns of symptomatic GERD and the spectrum of disease activity in the elderly. METHODS: We prospectively studied 476 predominantly male veterans who were referred for upper endoscopy because of symptoms or signs suggestive of upper gastrointestinal disease. All patients were interviewed immediately before the procedure by a physician who used a standardized symptom questionnaire. Endoscopic findings were categorized and graded according to their extent and severity. The prevalence, nature, and severity of esophageal symptoms and their relationship to endoscopic disease severity were then analyzed. Comparisons were made between two age groups, the young (age less than 65 yr old, mean age 55 yr, age range 30-65 yr), and the elderly (more than 66 yr old, mean age 72 yr, age range 66-90 yr). RESULTS: Heartburn without esophagitis was noted in 28% of young and 24% of elderly patients. Hiatal hernia without esophagitis was noted in 15 % of young and 18% of the elderly. The prevalence of various stages of GERD was similar in the two groups (p > 0.1, chi2 test; odds ratio: 0.983; 95% CI: 0.651-1.48). Quantitative esophageal symptom analysis revealed remarkably similar symptom severity scores for both groups for GERD stages I-IV, as well as for symptomatic controls. However, elderly patients with Barrett's esophagus were significantly less symptomatic than the young (symptom index 2.4 +/- 0.6 vs. 4.88 +/- 1.01, p < 0.02). CONCLUSIONS: Among symptomatic adults undergoing upper endoscopy, the elderly appear to have prevalence rates, patterns, and features of symptomatic GERD that are generally similar to those of their younger counterparts. Nevertheless, the severity of symptoms in the subgroup of elderly with Barrett's esophagus is significantly less than in the young and may contribute to poor or delayed recognition of disease.
Adult↗
Dynamic effects of acid on Barrett's esophagus. An ex vivo proliferation and differentiation model.
Barrett's esophagus (BE), or specialized intestinal metaplasia, is a premalignant heterogeneous epithelium associated with reflux and an increased risk for adenocarcinoma. Since acid is a major component of refluxate, we investigated its effects ex vivo on cell differentiation as determined by villin expression; and on cell proliferation, as determined by tritiated thymidine incorporation and proliferating cell nuclear antigen expression. To mimic known physiological conditions, endoscopic biopsies of normal esophagus, BE, and duodenum were exposed, in organ culture, to acidified media (pH 3-5) either continuously, or as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h. Before culture, villin expression was noted in 25% of BE samples, and increased after 6 or 24 h of continuous acid to 50% or 83% of BE samples, respectively. Increased villin expression correlated with ultrastructural maturation of the brush border. In contrast, an acid-pulse followed by culture at pH 7.4, did not alter villin expression in BE. Moreover, continuous acid exposure blocked cell proliferation in BE, whereas, an acid-pulse enhanced cell proliferation, as compared to pH 7.4. Based on our ex vivo findings, we propose a model in which the diverse patterns of acid exposure in vivo may contribute to the observed heterogeneity and unpredictable progression to neoplasia of BE.
Barrett Esophagus↗
Multifocal heterogeneity in villin and Ep-CAM expression in Barrett's esophagus.
Barrett's esophagus (BE) is a metaplastic change of the squamous esophageal epithelium to columnar gastric or intestinal-like epithelium. BE is associated with long-standing gastroesophageal reflux disease and carries an increased risk for dysplasia and adenocarcinoma. Little if any is known regarding the differentiation state of esophageal metaplasia and its relationship to carcinogenesis. In this study, we investigated the potential of villin, a cytoskeletal protein, and Ep-CAM, a glandular epithelial glycoprotein, to serve as markers for enterocytic differentiation in BE at the molecular level. Endoscopic mucosal biopsy samples of normal esophagus, BE, stomach and duodenum were collected from 23 patients with BE. Biopsies were analyzed for villin and Ep-CAM expression by immunoblotting, and in some cases for the presence of microvilli by electron microscopy. By mapping of BE segments in 6 patients, correlations were also made between the histologic evidence of metaplasia and villin expression. Villin was uniformly expressed in all duodenal samples but was not detected in normal esophagus and stomach. In BE biopsies, villin expression was limited to the subset of patients whose adjacent biopsies showed microvilli by electron microscopy. In several patients studied, however, the expression of villin and the epithelial glycoprotein Ep-CAM differed among various regions of esophageal metaplasia within the same patient. Mapping studies failed to reveal any correlation among histologic evidence of metaplasia, dysplasia and villin expression and confirmed the multifocal heterogeneity of villin expression in BE. Preliminary data of 4 adenocarcinoma patients studied showed that villin expression was absent in 3 and very low in 1 patient. Ep-CAM was highly expressed in all adenocarcinoma patients. Our results show that BE represents a complex epithelium with significant heterogeneity in antigen expression and ultrastructural morphologic features. This molecular heterogeneity supports the presence of different stages of differentiation within the same epithelium.
Adenocarcinoma↗
Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis.
Many patients with interstitial cystitis (IC) also have irritable bowel syndrome (IBS), both of which occur overwhelmingly in women, are characterized by pain, and worsen under stress. Bladder and colon biopsies of a female patient with both IC and IBS were evaluated immunohistochemically. There were 40 +/- 10 mast cells (MC)/mm2 (normal, less than 10) in the bladder, which were degranulated. The colon contained 148 +/- 11 MC/mm2 (normal, less than 50), mostly close to numerous substance P (SP)-positive nerves. Histamine, methylhistamine, and the unique MC enzyme tryptase were evaluated in 24-hour urine during two flare-ups. These results may help explain the concurrent presentation and the painful nature of these syndromes.
Chymases↗
Esophageal mucosal eicosanoids in gastroesophageal reflux disease and Barrett's esophagus.
OBJECTIVE: Eicosanoids (prostaglandins and leukotrienes) may contribute to the clinical manifestations of gastroesophageal reflux disease (GERD). In this cross-sectional study, our purpose was to assess the role of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in the clinical, endoscopic, and histological manifestations of GERD. METHODS: Using RIA, we measured ex vivo LTB4 and PGE2 content in esophageal mucosal biopsies from 141 patients with or without gastroesophageal reflux disease who underwent upper endoscopy. Patients were classified as normal symptomatic controls(n = 70), esophagitis stages 1-4 (n = 60), and Barrett's esophagus (n = 11), using clinical, endoscopic, histological, manometric, and esophageal 24-h ambulatory pH criteria. RESULTS: Mean LTB4 levels were significantly higher in both endoscopically and histologically identified erosive esophagitis and Barrett's esophagus patients, compared with normal controls. In contrast, PGE2 levels did not differ significantly among endoscopic or histological groups. When eicosanoid levels and composite symptom score (frequency score x severity score summed over five symptoms) were analyzed, no significant associations were found between LTB4 or PGE2 levels and the composite symptom score. There was no correlation between tissue eicosanoid levels and either the degree of esophageal acid exposure by ambulatory pH monitoring or the lower esophageal sphincter resting pressure as assessed by esophageal motility. Treatment with omeprazole 20 mg by mouth daily for 6 wk significantly reduced both LTB4 and PGE2 levels (p < 0.05) and was associated with significant improvement of symptoms and the endoscopic and histological appearance of the esophagus in 25 patients. CONCLUSIONS: These results suggest that LTB4, a prominent product of arachidonic acid metabolism in neutrophils, mediates the inflammatory phenomena of reflux esophagitis. The role of LTB4 and PGE2 in the induction of symptoms in patients with GERD and Barrett's esophagus remains unclear.
Adult↗
Olfactory stimuli provoke diffuse esophageal spasm: reversal by ipratropium bromide.
Diffuse esophageal spasm (DES) is a motor disorder of the esophageal smooth muscle characterized by multiple spontaneous contractions and by swallow-induced contractions that are of simultaneous onset, large amplitude, long duration, and repetitive occurrence. Although the pathogenesis of DES is unknown, provocative studies with cholinergic stimulation, esophageal balloon distention, or acid instillation have suggested involvement of both sensory and motor mechanisms. This report describes a patient with DES who would predictably become symptomatic with dysphagia and chest pain upon inhalation of perfume or other strong odors. Using esophageal scintigraphy to quantitate and analyze esophageal transit in this patient, we report for the first time that olfactory stimulation triggers episodes of DES and that such phenomena are mediated through the vagus nerve, because they can be ameliorated by the administration of ipratropium bromide. These observations suggest a new (sensory) pathway for the induction of DES and raise the intriguing possibility that inhaled anticholinergics may have a therapeutic role in the management of spastic esophageal motility disorders.
Administration, Inhalation↗
Esophageal submucosal gland duct adenoma.
An 81-year-old man with a 3-year history of dysphagia underwent endoscopic resection of a 1-cm-diameter distal esophageal mass. Examination revealed a submucosal neoplasm with a circumscribed growth pattern composed of tubules, cysts, and papillae in association with a marked interstitial lymphoid infiltrate. The cyst lumens and papillae were lined by two to six layers of cytologically bland cuboidal to columnar cells with rare mitotic figures. The basal layer of cells was uniformly positive for smooth-muscle actin. Mucin-positive intracytoplasmic lumens were focally present, but cytoplasmic mucin was not seen. There was no evidence of Barrett's metaplastic epithelium. These features are similar to those in two, possibly three, previously reported cases of esophageal adenomas and bear a resemblance to sialadenoma papilliferum, a rare neoplasm of the minor salivary glands. Their clinicopathologic and immunohistologic features suggest that these neoplasms derive from the submucosal gland ducts. Comparison with the previously reported cases indicates that although the proportions of the various components (tubules, cysts, and papillae) may vary, all cases appear to pursue a slowly growing, clinically indolent course with no evidence of recurrence after complete resection.
Actins↗
Early dysphagia after placement of a self-expanding esophageal stent: severe esophagitis mimicking luminal occlusion.
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Adenocarcinoma↗
E-cadherin expression in gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma: an immunohistochemical and immunoblot study.
BACKGROUND/AIMS: Cadherins are cell adhesion molecules that are thought to play a vital role in cell-cell adhesion; loss or down-regulation of their expression has been implicated in neoplasia. Barrett's esophageal columnar metaplasia (BE) is a premalignant lesion for esophageal adenocarcinoma with clinical symptoms similar to those of gastroesophageal reflux disease and esophagitis. In this study, we investigated the potential relationship between E-cadherin expression and inflammation, metaplasia, and carcinogenesis in esophagitis, BE, and esophageal adenocarcinoma. METHODS: Endoscopically obtained mucosal biopsy specimens of esophagitis (n = 6), BE with or without dysplasia (n = 16), and esophageal adenocarcinoma (n = 6) were analyzed for the expression of E-cadherin by both Western analysis and immunoperoxidase staining. RESULTS: Densitometric analysis of Western blots revealed the expression of E-cadherin to be significantly lower in patients with BE compared with normal esophageal epithelium, regardless of the presence or absence of dysplasia (p < 0.03). No significant differences were noticed between the normal esophagus and the esophagitis groups. In the adenocarcinoma group, one patient showed complete loss of E-cadherin expression, and the other five patients showed significantly reduced expression that was even lower than that in BE (p < 0.01). Immunoperoxidase staining matched the Western analysis results. CONCLUSIONS: We conclude that loss of or reduced E-cadherin expression may play a role in the progression of BE to adenocarcinoma.
Adenocarcinoma↗
Endoscopic appearances of colonic lymphoid nodules: new faces of an old histopathological entity.
OBJECTIVES: Colonic lymphoid nodules, also known as focal colonic lymphoid hyperplasia, have been previously described either as an indication of disease or as a normal variant in adults, with current opinion favoring the latter. The finding of isolated or confluent colonic lymphoid nodules on colonoscopy may nevertheless cause confusion with other endoscopic diagnoses. METHODS: In this study, we describe new endoscopic features of colonic lymphoid nodules, and we correlate them with other clinical and histopathological characteristics. Our experience is based on thorough evaluation of 13 cases of colonic lymphoid nodules that were consecutively observed during colonoscopy over the past 2 yr. RESULTS: Colonic lymphoid nodules may appear as red macules, as circumferential target lesions (halo sign), or as raised papules; they occur in both men and women, predominantly affect the rectum, and appear to be of no clinical significance. Histologically, colonic lymphoid nodules may involve the mucosa or the submucosa, in the form of either lymphoid aggregates or lymphatic nodules. CONCLUSIONS: With the widespread use of video colonoscopy, the macular or papular endoscopic characteristics of colonic lymphoid nodules should be increasingly recognized, confirmed histologically, and distinguished from other pathological lesions. Improved endoscopic recognition will allow the potential association of colonic lymphoid nodules with other colonic pathology to be eventually elucidated.
Adult↗
Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Misoprostol Study Group.
OBJECTIVES: To determine the efficacy of misoprostol for the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced duodenal and gastric ulcers in arthritis patients receiving NSAID therapy. DESIGN: A randomized, double-blind, multicenter, placebo-controlled trial. SETTING: Six hundred thirty-eight private, Veterans Affairs, health maintenance, and academic practices. PATIENTS: Six hundred thirty-eight patients with chronic inflammatory or noninflammatory arthritis who were taking an NSAID but who did not have a gastric or duodenal ulcer on screening endoscopy received treatment with ibuprofen, piroxicam, naproxen, sulindac, tolmetin, indomethacin, or diclofenac daily for 3 months. Four hundred fifty-five (71%) patients completed the trial. INTERVENTIONS: Patients meeting the entry criteria were randomized to receive either misoprostol, 200 micrograms, or placebo, four times a day for 12 weeks. MAIN OUTCOME MEASURES: The endoscopy was repeated at 4, 8, and 12 weeks. The development of a duodenal or gastric ulcer (defined as a circumscribed mucosal defect > or = 0.5 cm in diameter and with perceptible depth) was regarded as prophylactic failure. RESULTS: By 12 weeks, a duodenal ulcer developed in 2 of 320 (0.6%; 95% CI, 0.2% to 3.9%) patients randomized to receive misoprostol, compared with 15 of 323 (4.6%; CI, 2.8% to 8%) patients receiving placebo (P = 0.002). A gastric ulcer developed in 6 of 320 (1.9%; (CI, 0.8% to 4.4%) patients, compared with in 25 of 323 (7.7%; CI, 5.1% to 11.4%), respectively. CONCLUSION: Misoprostol significantly lowers the frequency of both duodenal and gastric ulcer development in patients who require long-term therapy with NSAIDS.
Adult↗
Expression of HLA class I antigens in sporadic adenomas and histologically normal mucosa of the colon.
The loss of HLA antigens by neoplastic cells is considered important for tumor growth and metastasis, inasmuch as it may allow tumors to escape immune surveillance. We have observed reduced expression of HLA antigens in sporadic colon cancer and adenomas from familial adenomatous polyposis patients. We now studied the expression of HLA class I antigens in patients with sporadic adenomas, which are precursors of colorectal cancer. Expression of HLA class I antigens was studied by immunohistochemistry in (a) sporadic colon adenomas, (b) histologically normal mucosa distant from the adenomas, (c) histologically normal colonic mucosa from patients with history of sporadic colon adenomas, and (d) colonic mucosa from normal subjects. HLA class I antigen expression was moderately reduced in 56% and severely reduced in 44% of the adenomas; this reduction was significant when compared to controls (P < 0.0001). The reduction of HLA class I expression in adenomas was related to the grade of dysplasia of the adenomas. HLA class I expression of normal appearing mucosa was decreased in 76% of patients with adenoma (P < 0.0001) and in 54% of patients with history of adenoma (P < 0.005) compared to normal controls. These changes were antigen specific, inasmuch as the expression of carcinoembryonic antigen, a surface antigen, was not affected. Our findings suggest that reduced HLA class I expression is an early event in the cell transformation process from normal to neoplastic state, preceding in many cases the onset of histological changes. HLA class I could be potentially used as a premalignant marker in the colon.
Adenoma↗
Glycogenic acanthosis of the esophagus and gastroesophageal reflux.
A nodular appearance of the esophageal mucosa, observed in 3.5% of 2,328 consecutive upper endoscopic examinations, most commonly appeared as multiple, uniformly sized, oval or round elevations usually < 1 cm, involving otherwise normal esophageal mucosa. Endoscopic biopsies in 35 consecutive patients followed prospectively demonstrated the nodules to represent glycogenic acanthosis--a combination of cellular hyperplasia and increased cellular glycogen. When studied by 24-h ambulatory esophageal pH monitoring, 83% of these patients had pathologic gastroesophageal acid reflux; mean percentage of time with pH < 4.0 was 37.3%. Antireflux therapy improved symptoms in all patients but failed to eradicate the lesions of glycogenic acanthosis. Although its etiology and pathogenesis still remain elusive, glycogenic acanthosis may be related to gastroesophageal reflux.
Adult↗
Serum 13C-bicarbonate in the assessment of gastric Helicobacter pylori urease activity.
Noninvasive detection of Helicobacter pylori (HP) requires serum or salivary antibody testing or the CO2 breath test. Since gastric HP produces a potent urease, a meal rich in 13C-labeled urea should lead to a measurable quantity of isotopic CO2 in the serum. This study investigates the feasibility, sensitivity, specificity, and potential of the measurement of serum 13C-bicarbonate (13CHCO3) in determining the presence of gastric HP. Nineteen patients with upper gastrointestinal symptoms assessed by intensity-duration questionnaire underwent endoscopy and biopsies for histology, Giemsa stain, and urease activity testing by CLOtest. Patients also consumed a 13C-urea-rich meal (5 mg/kg body weight, 99% 13C, MSD Isotopes, Montreal Canada). Serum was collected every 30 min for 3 h for quantitative determination of 13C by mass spectrometry. Fractional elevation of 13C after the enriched meal was then correlated with endoscopy, histology, and CLOtest. Fourteen of the 19 patients studied had histologic evidence of gastritis; 11 of 19 had positive CLOtest and had HP by histology and Giemsa stain. All HP-positive patients had significant elevation of 13CHCO3, compared with HP-negative patients. The mean maximum absolute change from baseline was 15.3 delta 13CHCO3 (range, 6.7-29.9) and occurred from 15 to 90 min; 13CHCO3 in HP-negative patients was significantly less (p < 0.05) than HP-positive patients with a mean value of 2.3 delta 13CHCO3 (range, 0-5.3). We conclude that serum 13CHCO3 analysis accurately reflects HP gastritis. This novel method is noninvasive, less labor intensive, less time consuming, and may have a value as a diagnostic screening tool for humans or in the assessment of the results of therapy in patients with HP infection.
Bicarbonates↗
Clinical and pathologic features of the nodular duodenum.
Nodular duodenum, frequently described as nodular duodenitis, is endoscopically characterized by multiple erythematous nodules in the proximal duodenum and may represent a variant of duodenal inflammation. This study examines the incidence, clinical presentation, histologic correlates, natural history, and response to therapy of nodular duodenum in 83 patients who presented with epigastric pain, heartburn, early satiety, bloating, nausea, vomiting, or gastrointestinal bleeding. There was a previous history of peptic ulcer disease in 58% of patients and gastroesophageal reflux in 33%. None of the patients had associated end-stage renal disease. Endoscopically, in addition to nodular duodenum, esophagitis was found in 17% of patients and gastritis in 32%. Histology of duodenal nodules revealed chronic inflammation in 58% of patients, Brunner's gland hyperplasia in 9%, gastric heterotopia in 7%, and normal mucosa in 26% of patients. In a group of 34 patients studied prospectively, high dosage (300 mg orally bid) therapy with the H2-antagonist ranitidine for 8 wk significantly improved symptoms and endoscopic appearance (p < 0.05). In 26 patients who completely or partially failed H2-antagonist therapy, continuation of therapy with omeprazole (40 mg orally qd) for 8 wk significantly improved symptoms and endoscopic findings (p < 0.05) in 10 patients. These therapeutic approaches led to improvement in the endoscopic findings, but to no statistically significant changes in the underlying histologic appearance of the duodenum. We conclude that nodular duodenum is an endoscopically distinct entity that may respond clinically to antisecretory therapy, but remains difficult to eradicate completely.
Adult↗
Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis.
The precise role of lipid peroxidation in the pathogenesis of alcoholic liver disease is still being debated. To explore the issue, this study was undertaken to investigate the status of lipid peroxidation, antioxidants and prooxidants at two discrete stages of experimental alcoholic liver disease. Male Wistar rats were intragastrically fed a high-fat diet plus ethanol for 5 or 16 wk (the duration that resulted in initiation of centrilobular liver necrosis or liver fibrosis, respectively). Lipid peroxidation was assessed in isolated microsomes and mitochondria with three parameters: malondialdehyde equivalents as determined by thiobarbituric acid assay, conjugated diene formation and 4-hydroxynonenal as a 2,4-dinitrophenylhydrazone derivative. To assess antioxidant systems, hepatic concentrations of glutathione, methionine and alpha-tocopherol were determined. The concentration of nonheme iron, a known prooxidant, was also measured. At wk 5, centrilobular liver necrosis was already evident in the ethanol-fed animals, with two- or threefold increases in plasma AST and ALT levels. At this stage, neither malondialdehyde equivalents nor conjugated diene values were elevated, and the 4-hydroxynonemal level was below 0.2 nmol/mg protein. Hepatic concentrations of methionine and alpha-tocopherol in these animals were increased two- and threefold, respectively, whereas the reduced glutathione level remained unchanged. When alcoholic liver disease had progressed to perivenular or bridging fibrosis at wk 16, all three parameters of lipid peroxidation showed consistent increases that were accompanied by significant reductions in the hepatic glutathione and methionine levels. Interestingly, the control animals pair-fed with the high-fat diet also had significantly elevated 4-hydroxynonenal levels at wk 16 compared to the wk 5 level.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldehydes↗
Role of cytochrome P-450 2E1 in ethanol-, carbon tetrachloride- and iron-dependent microsomal lipid peroxidation.
This study investigated the role of cytochrome P-450 2E1 in enhanced microsomal lipid peroxidation in experimental alcoholic liver disease. We also examined the contribution of this isoform to the increased microsomal injury in alcoholic liver disease caused by carbon tetrachloride-induced or iron-induced oxidant stress. Adult male Wistar rats were intragastrically infused with a high-fat diet and ethanol or glucose for 16 wk; this resulted in hepatic lipid peroxidation and fibrogenesis in the ethanol-fed animals. Microsomes were isolated by differential centrifugation in the presence of 100 mumol/L deferoxamine, washed twice in buffer without deferoxamine and incubated in the absence or presence of ethanol (50 mmol/L), carbon tetrachloride (150 mumol/L), ferric citrate (50 mumol/L) or ferric citrate plus ethanol at 37 degrees C for 30 min in an NADPH-generating system. The basal rate of lipid peroxidation in microsomes isolated from ethanol-fed rats was increased by 52% compared with that in microsomes from controls. Carbon tetrachloride-induced and ferric citrate-induced lipid peroxidation were also accentuated in microsomes from ethanol-fed rats, by 76% and 108%, respectively. Ethanol added in vitro significantly reduced basal (-58%) and ferric citrate-induced (-48%) lipid peroxidation in microsomes from ethanol-fed rats, whereas it had an insignificant effect on that in control microsomes. In fact, this protective effect of ethanol on microsomes from ethanol-fed rats resulted in attenuation of the difference in the level of microsomal lipid peroxidation between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗