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Role of visceral hypersensitivity in patients with functional dyspesia
April 1998 • G1231
HELICOBACTER PYLORI, SYMPTOM SEVERITY AND PATHOPHYSIOLOGICAL MECHANISMS IN FUNCTIONAL DYSPEPSIA. J. Tack, H. Piessevaux, B. Coulie, P. Caenepeel, and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. The pathophysiology underlying functional dyspepsia is unknown. Delayed gastric emptying, hypersensitivity to gastric distension, impaired gastric accommodation to a meal and Helicobacter Pylori (H.P.) infection have all been implicated. However, each of these disturbances is only found in a subset of patients. It is unknown whether H.P. infection is associated with specific dyspepsia symptoms, or whether it is linked to any of the other putative pathophysiological mechanisms. Aim: To study the symptom pattern, gastric emptying rate, visceral sensitivity to gastric distension and gastric accommodation to a meal in functional dyspepsia patients with or without H.P. infection. Methods: In 106 consecutive patients with functional dyspepsia (36 men, 70 women, mean age 43 ± 2 years), the severity score (0-3, 0=absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. In each patient biopsies were obtained to detect H.P. during upper g.i. endoscopy. 90 patients underwent a 14C octanoic acid breath test to assess solid gastric emptying. A gastric barostat study was performed to assess the sensitivity to gastric distension in 55 patients and to study the meal-induced fundus relaxation in 45 patients. All data are given as mean ± SEM. Data were compared by Student's t test or by Chi square. Results: H.P. was present in 32 patients (30%) and absent in 74 (70%). No significant differences were found between both groups in the severity scores for each symptom, or in the prevalence of weight loss. H.P. negative and H.P. positive patients did not differ in the rate of solid gastric emptying (tl/2 98 ± 7 vs 96 ± 11 min, NS) or in the perception or discomfort thresholds during gastric distension (respectively 9.8 ± 0.5 vs 11.4 ± 1.1 mm Hg, NS and 16.4 ± 0.9 vs 17.1 ± 1.3 mm Hg, NS). The size of the meal-induced gastric fundus relaxation was also similar in both groups (124± 24 vs 117 ±46 ml, NS). The prevalence of delayed gastric emptying, of visceral hypersensitivity or of impaired gastric accommodation to a meal did not differ between both groups. Conclusion: In a large cohort of functional dyspepsia patients, H.P. infection is not associated with a specific symptom profile. Moreover, gastric motor or sensory abnormalities are equally prevalent in both groups. These findings question the pathophysiological role of H.P. in functional dyspepsia. • G1232 ROLE OF VISCERAL HYPERSENSITIVITY IN PATIENTS WITH FUNCTIONAL DYSPEPSIA. J. Tack. H. Piessevaux, B. Coulie, P. Caenepeel, and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. The pathophysiology underlying functional dyspepsia is unknown. Delayed gastric emptying, hypersensitivity to gastric distension, impaired gastric accommodation to a meal and Helicobacter Pylori (H.P.) infection have all been implicated. However, each of these disturbances is only found in a subset of patients. It is unknown whether hypersensitivity to gastric distension is associated with specific dyspepsia symptoms, and whether it is linked to any of the other putative pathophysiological mechanisms. Aim: To study the symptom pattern, gastric emptying rate, gastric accommodation to a meal and H.P. status in functional dyspepsia patients with or without visceral hypersensitivity. Methods: In 61 consecutive patients with functional dyspepsia (42 women, mean age 40.9 + 1.8 years), the severity score (0-3, 0=absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. In each patient a gastric barostat study was performed to assess the sensitivity to gastric distension. Biopsies were obtained to detect H.P. during upper g.i. endoscopy. 53 patients underwent a 14C octanoic acid gastric emtpying test. In 45 patients, the amplitude of the meal-induced fundus relaxation was also studied using the gastric barostat. All data are given as mean ± SEM. Data were compared by Student's t test or by Chi square. Results: Hypersensitivity to gastric distension (discomfort pressure < 95% C.I. in controls) was present in 26 patients (43%). No significant differences were found between patients without and with visceral hypersensitivity in the prevalence of relevant or severe bloating, early satiety, nausea, vomiting, weight loss, belching and heartburn. Patients with visceral hypersensitivity had a significantly higher prevalence of postprandial fullness (70 vs 100%, p=0.005) and epigastric pain (53 vs 82%, p=0.03). Patients without and with visceral hypersensitivity did not differ in the rate of solid gastric emptying (tl/2 112 ± 13 vs 102 ± 11 min, NS) or in the size of the meal-induced gastric fundus relaxation (133 ± 36 vs I10 ± 27 ml, NS). No difference was present in the prevalence of delayed gastric emptying (26 vs 27%), of impaired gastric accommodation to a meal (39 vs 37%) and of H.P. infection (26 vs 29%) between both groups. Conclusion; Dyspeptic patients with hypersensitivity to gastric distension are more likely to suffer from postprandial fullness and epigastric pain. Visceral hypersensitivity is not associated with gastric motor abnormalities or with
Esophageal, Gastric, and Duodenal Disorders A301
H.P. infection. These data support the role of visceral hypersensitivity in symptom production in functional dyspepsia. G1233 SYMPTOM PATTERN AND GASTRIC EMPTYING RATE ASSESSED BY THE OCTANOIC ACID BREATH TEST IN FUNCTIONAL DYSPEPSIA. J. Tack, H. Piessevaux, B. Coulie, B. Geypens, P. Caenepeel, Y. Ghoos and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. In functional dyspepsia, the relationship between putative pathophysiological disturbances and symptom production has remained obscure. Recently, using radioscintigraphy to assess solid gastric emptying rate, it was shown that dyspeptic patients with delayed gastric emptying were more likely to suffer from postprandial fullness and vomiting (Stanghellini et al., 1996). Aim: To study the relationship between symptom pattem and gastric emptying rate using the 13C octanoic acid breath test in functional dyspepsia patients. Methods; In 141 consecutive patients with functional dyspepsia (48 men, 93 women, mean age 43.4 _+1.3 years), the severity score (0-3, 0--absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. All patients underwent a 13C octanoic acid breath test to assess solid gastric emptying rate. The number of patients grading individual symptoms as relevant or severe (score >-2) in the subgroups with normal or impaired gastric emptying were were compared by Chi square testing. All data are given as mean ± SEM. Results: Delayed solid gastric emptying (tl/2 > 119 min) was present in 26 patients (18%) and absent in 115 (82%). No significant differences were found between patients with normal and delayed emptying in the prevalence of relevant or severe epigastric pain (64% vs 65%, NS), bloating (71% vs 65%, NS), early satiety (48% vs 48%, NS), belching (44% vs 35%, NS), heartbum (29 vs 24%, NS) and weight loss (33% vs 39%, NS). Compared to those with normal solid emptying, patients with delayed gastric emptying had a significantly higher prevalence of postprandial fullness (70 vs 94%, p=0.04), nausea (35 vs 65%, p=0.03) and vomiting (15 vs 47%, p=0.004. The age (44 ± 1 vs 40 ± 2 years, NS) and sex distribution (36% vs 27% males) did not differ significantly between both groups. Conclusion: Using the 13C octanoic acid breath test, we demonstrated that dyspeptic patients with delayed gastric emptying are more likely to suffer from postprandial fullness, nausea and vomiting. These data confirm the role of delayed gastric emptying in symptom production. They also support the clinical usefulness of the 13C octanoic acid gastric emptying breath test. G1234
HELICOBACTER PYLORI INDUCES GASTRIC MUCOSAL INJURY INDEPENDENTLY OF VACUOLATING CYTOTOXIN. A. Takagi, S. Watanabe, M. Igarashi, K. Kohda, AMA. Kabir, U. Aiba, T. Shirai, Y. Koga, and T. Miwa, Dept of Internal Medicine 6 and Infectious Diseases, Tokai University, Isehara, Kanagawa, 259-11, Japan Cytotoxic strains of Helicobacter pylori play an important role in the pathogenesis of peptic ulcer and gastric carcinoma. It has been reported that acid-activated vacuolating cytotoxin enhances vacuolar degeneration of cells. We previously reported that viable 11. pylori induced cell death in MKN45 cells (Gastroenterol 112,A305, 1997). To determine the role of vacuolating cytotoxin in gastric mucosal injury, we studied the relationship between vacuolating activity and cell death caused by H. pylori under several conditions. Teprenone, an acyclic polyisoprenoid, has been shown to be effective in protecting the gastric mucosa against several types of insult without affecting gastric acid secretion. Furthermore, we examined the effects of this anti-ulcer drug on H. pylori-induced gastric epithelial injury. Methods: Two cytotoxic and 2 non-cytotoxic strains ofH. pylori (107cfu/ml) were used. H. pylori was treated with amoxicillin. Brucella broth supernatants of H. pylori were activated by addition of HC1 solution. Vacuolating cytotoxin activitity was determined using RK-13 cells. The cell death in MKN 45 cells by H. pylori alone and a combination of interferon- ), and TNF- ct was studied using the MTr assay. Results: MTT assay showed that both cytotoxic and non-cytotoxic strains of H. pylori induced cell death in combination with interferon- T and TNF- ct. The cell death induced by cytotoxic strains of H. pylori but not non-cytotoxic strains was significantly augmented by coculture with 5-50 ta g/ml of amoxicillin (p=0.0016). Treatment with amoxicillin did not increase the vacuolation of RK-13 ceils by H. pylori. Furthermore acid-treated supernatants of H. pylori showed enhanced vacuolating activity but did not induce cell death, suggesting that cell death is due to some factor other than vacuolating cytotoxin. Teprenone (10"TM) suppressed cell death induced by both cytotoxic and non-cytotoxic strains of H. pylori, and prevented the augmentation of H. pylori-induced cytotoxicity on coculture with amoxicillin(p=0.0057). In conclusion, these findings suggested that H. pylori induces cell death in a vacuolating cytotoxinindependent manner, and teprenone may reduce H. pylori-induced gastric mucosal injury. This research was made possible in part by a grant from Tokai University.
HELICOBACTER PYLORI, SYMPTOM SEVERITY AND PATHOPHYSIOLOGICAL MECHANISMS IN FUNCTIONAL DYSPEPSIA. J. Tack, H. Piessevaux, B. Coulie, P. Caenepeel, and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. The pathophysiology underlying functional dyspepsia is unknown. Delayed gastric emptying, hypersensitivity to gastric distension, impaired gastric accommodation to a meal and Helicobacter Pylori (H.P.) infection have all been implicated. However, each of these disturbances is only found in a subset of patients. It is unknown whether H.P. infection is associated with specific dyspepsia symptoms, or whether it is linked to any of the other putative pathophysiological mechanisms. Aim: To study the symptom pattern, gastric emptying rate, visceral sensitivity to gastric distension and gastric accommodation to a meal in functional dyspepsia patients with or without H.P. infection. Methods: In 106 consecutive patients with functional dyspepsia (36 men, 70 women, mean age 43 ± 2 years), the severity score (0-3, 0=absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. In each patient biopsies were obtained to detect H.P. during upper g.i. endoscopy. 90 patients underwent a 14C octanoic acid breath test to assess solid gastric emptying. A gastric barostat study was performed to assess the sensitivity to gastric distension in 55 patients and to study the meal-induced fundus relaxation in 45 patients. All data are given as mean ± SEM. Data were compared by Student's t test or by Chi square. Results: H.P. was present in 32 patients (30%) and absent in 74 (70%). No significant differences were found between both groups in the severity scores for each symptom, or in the prevalence of weight loss. H.P. negative and H.P. positive patients did not differ in the rate of solid gastric emptying (tl/2 98 ± 7 vs 96 ± 11 min, NS) or in the perception or discomfort thresholds during gastric distension (respectively 9.8 ± 0.5 vs 11.4 ± 1.1 mm Hg, NS and 16.4 ± 0.9 vs 17.1 ± 1.3 mm Hg, NS). The size of the meal-induced gastric fundus relaxation was also similar in both groups (124± 24 vs 117 ±46 ml, NS). The prevalence of delayed gastric emptying, of visceral hypersensitivity or of impaired gastric accommodation to a meal did not differ between both groups. Conclusion: In a large cohort of functional dyspepsia patients, H.P. infection is not associated with a specific symptom profile. Moreover, gastric motor or sensory abnormalities are equally prevalent in both groups. These findings question the pathophysiological role of H.P. in functional dyspepsia. • G1232 ROLE OF VISCERAL HYPERSENSITIVITY IN PATIENTS WITH FUNCTIONAL DYSPEPSIA. J. Tack. H. Piessevaux, B. Coulie, P. Caenepeel, and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. The pathophysiology underlying functional dyspepsia is unknown. Delayed gastric emptying, hypersensitivity to gastric distension, impaired gastric accommodation to a meal and Helicobacter Pylori (H.P.) infection have all been implicated. However, each of these disturbances is only found in a subset of patients. It is unknown whether hypersensitivity to gastric distension is associated with specific dyspepsia symptoms, and whether it is linked to any of the other putative pathophysiological mechanisms. Aim: To study the symptom pattern, gastric emptying rate, gastric accommodation to a meal and H.P. status in functional dyspepsia patients with or without visceral hypersensitivity. Methods: In 61 consecutive patients with functional dyspepsia (42 women, mean age 40.9 + 1.8 years), the severity score (0-3, 0=absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. In each patient a gastric barostat study was performed to assess the sensitivity to gastric distension. Biopsies were obtained to detect H.P. during upper g.i. endoscopy. 53 patients underwent a 14C octanoic acid gastric emtpying test. In 45 patients, the amplitude of the meal-induced fundus relaxation was also studied using the gastric barostat. All data are given as mean ± SEM. Data were compared by Student's t test or by Chi square. Results: Hypersensitivity to gastric distension (discomfort pressure < 95% C.I. in controls) was present in 26 patients (43%). No significant differences were found between patients without and with visceral hypersensitivity in the prevalence of relevant or severe bloating, early satiety, nausea, vomiting, weight loss, belching and heartburn. Patients with visceral hypersensitivity had a significantly higher prevalence of postprandial fullness (70 vs 100%, p=0.005) and epigastric pain (53 vs 82%, p=0.03). Patients without and with visceral hypersensitivity did not differ in the rate of solid gastric emptying (tl/2 112 ± 13 vs 102 ± 11 min, NS) or in the size of the meal-induced gastric fundus relaxation (133 ± 36 vs I10 ± 27 ml, NS). No difference was present in the prevalence of delayed gastric emptying (26 vs 27%), of impaired gastric accommodation to a meal (39 vs 37%) and of H.P. infection (26 vs 29%) between both groups. Conclusion; Dyspeptic patients with hypersensitivity to gastric distension are more likely to suffer from postprandial fullness and epigastric pain. Visceral hypersensitivity is not associated with gastric motor abnormalities or with
Esophageal, Gastric, and Duodenal Disorders A301
H.P. infection. These data support the role of visceral hypersensitivity in symptom production in functional dyspepsia. G1233 SYMPTOM PATTERN AND GASTRIC EMPTYING RATE ASSESSED BY THE OCTANOIC ACID BREATH TEST IN FUNCTIONAL DYSPEPSIA. J. Tack, H. Piessevaux, B. Coulie, B. Geypens, P. Caenepeel, Y. Ghoos and J. Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium. In functional dyspepsia, the relationship between putative pathophysiological disturbances and symptom production has remained obscure. Recently, using radioscintigraphy to assess solid gastric emptying rate, it was shown that dyspeptic patients with delayed gastric emptying were more likely to suffer from postprandial fullness and vomiting (Stanghellini et al., 1996). Aim: To study the relationship between symptom pattem and gastric emptying rate using the 13C octanoic acid breath test in functional dyspepsia patients. Methods; In 141 consecutive patients with functional dyspepsia (48 men, 93 women, mean age 43.4 _+1.3 years), the severity score (0-3, 0--absent, l=mild, 2=relevant, 3=severe) for each of eight dyspeptic symptoms (epigastric pain, postprandial fullness, bloating, early satiety, nausea, vomiting, belching, heartburn) was obtained, and the presence or absence of significant weight loss ( > 5% of body weight) was noted. All patients underwent a 13C octanoic acid breath test to assess solid gastric emptying rate. The number of patients grading individual symptoms as relevant or severe (score >-2) in the subgroups with normal or impaired gastric emptying were were compared by Chi square testing. All data are given as mean ± SEM. Results: Delayed solid gastric emptying (tl/2 > 119 min) was present in 26 patients (18%) and absent in 115 (82%). No significant differences were found between patients with normal and delayed emptying in the prevalence of relevant or severe epigastric pain (64% vs 65%, NS), bloating (71% vs 65%, NS), early satiety (48% vs 48%, NS), belching (44% vs 35%, NS), heartbum (29 vs 24%, NS) and weight loss (33% vs 39%, NS). Compared to those with normal solid emptying, patients with delayed gastric emptying had a significantly higher prevalence of postprandial fullness (70 vs 94%, p=0.04), nausea (35 vs 65%, p=0.03) and vomiting (15 vs 47%, p=0.004. The age (44 ± 1 vs 40 ± 2 years, NS) and sex distribution (36% vs 27% males) did not differ significantly between both groups. Conclusion: Using the 13C octanoic acid breath test, we demonstrated that dyspeptic patients with delayed gastric emptying are more likely to suffer from postprandial fullness, nausea and vomiting. These data confirm the role of delayed gastric emptying in symptom production. They also support the clinical usefulness of the 13C octanoic acid gastric emptying breath test. G1234
HELICOBACTER PYLORI INDUCES GASTRIC MUCOSAL INJURY INDEPENDENTLY OF VACUOLATING CYTOTOXIN. A. Takagi, S. Watanabe, M. Igarashi, K. Kohda, AMA. Kabir, U. Aiba, T. Shirai, Y. Koga, and T. Miwa, Dept of Internal Medicine 6 and Infectious Diseases, Tokai University, Isehara, Kanagawa, 259-11, Japan Cytotoxic strains of Helicobacter pylori play an important role in the pathogenesis of peptic ulcer and gastric carcinoma. It has been reported that acid-activated vacuolating cytotoxin enhances vacuolar degeneration of cells. We previously reported that viable 11. pylori induced cell death in MKN45 cells (Gastroenterol 112,A305, 1997). To determine the role of vacuolating cytotoxin in gastric mucosal injury, we studied the relationship between vacuolating activity and cell death caused by H. pylori under several conditions. Teprenone, an acyclic polyisoprenoid, has been shown to be effective in protecting the gastric mucosa against several types of insult without affecting gastric acid secretion. Furthermore, we examined the effects of this anti-ulcer drug on H. pylori-induced gastric epithelial injury. Methods: Two cytotoxic and 2 non-cytotoxic strains ofH. pylori (107cfu/ml) were used. H. pylori was treated with amoxicillin. Brucella broth supernatants of H. pylori were activated by addition of HC1 solution. Vacuolating cytotoxin activitity was determined using RK-13 cells. The cell death in MKN 45 cells by H. pylori alone and a combination of interferon- ), and TNF- ct was studied using the MTr assay. Results: MTT assay showed that both cytotoxic and non-cytotoxic strains of H. pylori induced cell death in combination with interferon- T and TNF- ct. The cell death induced by cytotoxic strains of H. pylori but not non-cytotoxic strains was significantly augmented by coculture with 5-50 ta g/ml of amoxicillin (p=0.0016). Treatment with amoxicillin did not increase the vacuolation of RK-13 ceils by H. pylori. Furthermore acid-treated supernatants of H. pylori showed enhanced vacuolating activity but did not induce cell death, suggesting that cell death is due to some factor other than vacuolating cytotoxin. Teprenone (10"TM) suppressed cell death induced by both cytotoxic and non-cytotoxic strains of H. pylori, and prevented the augmentation of H. pylori-induced cytotoxicity on coculture with amoxicillin(p=0.0057). In conclusion, these findings suggested that H. pylori induces cell death in a vacuolating cytotoxinindependent manner, and teprenone may reduce H. pylori-induced gastric mucosal injury. This research was made possible in part by a grant from Tokai University.