Efficacy of Vonoprazan, a Novel Potassium-Competitive Acid Blocker, in Patients with Proton Pump Inhibitor-Refractory Acid Reflux.

BACKGROUND/AIM: We evaluated the efficacy of vonoprazan (VPZ), a novel potassium-competitive acid blocker, in patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD), exhibiting continued pathological esophageal acid exposure (EAE). METHODS: Despite ≥8 weeks of appropriate PPI therapy, patients with -persistent reflux symptoms and pathological EAE times (EAETs ≥4%) were invited to switch to VPZ treatment. After an 8-week-course of once-daily VPZ (20 mg), multichannel intraluminal impedance-pH (MII-pH) monitoring was repeated to compare gastric acid exposure times (GAETs), EAETs, and other reflux parameters relative to the baseline values. Before each MII-pH study, reflux symptom severities were scored using the Gastrointestinal Symptom Rating Scale; erosive esophagitis and fasting plasma gastrin levels were also assessed. RESULTS: From among the 124 patients undergoing MII-pH monitoring, 13 patients (median age, 69 years; females, 64%) were monitored at baseline (while on PPI therapy) and after VPZ therapy. The median GAET associated with VPZ treatment (23.8%) was less than that for PPI treatment (41.1%; p = 0.01), including both daytime and nighttime measurements. VPZ therapy resulted in better median EAET values (4.5%) than did PPI therapy (10.6%) during the 24-h monitoring period (p = 0.055). EAE normalization was achieved in 46% of VPZ-treated patients and was associated with complete gastric acid suppression (p = 0.005). After switching to VPZ, reflux symptoms (p < 0.01) and erosive esophagitis (p = 0.01) improved. CONCLUSION: In patients with PPI-refractory GERD, VPZ provides more potent gastric acid suppression, more effective EAE control, enhanced symptom improvement, and better esophagitis healing than PPIs.

Increase of transient lower esophageal sphincter relaxation associated with cascade stomach.

We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0-60 min), late period (60-120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying.

Medical interview - physical findings.

GERD is a condition in which gastroesophageal reflux(GER) causes either esophageal mucosal break, or troublesome symptoms, or both. It is classified into "erosive GERD" with esophageal mucosal break and "non-erosive GERD" with symptoms alone. Since the diag- nosis is based on symptoms, the medical interview is the most important part in clinical situation. In addition to asking typical symptoms of GERD, a careful interview about extrae- sophageal symptoms might be helpful. Self-reported questionnaires are helpful diagnostic tool of GERD. Appropriate medical interview should include the patient's symptoms, the possible risk factor, and their life style.

Evaluation of proton pump inhibitor-resistant nonerosive reflux disease by esophageal manometry and 24-hour esophageal impedance and pH monitoring.

BACKGROUND: Patients with proton pump inhibitor (PPI)-resistant nonerosive reflux disease (NERD) include subgroups that have markedly different pathophysiology. This study aimed to clarify the pathophysiology of NERD by esophageal manometry with 24-hour esophageal impedance and pH monitoring. METHODS: Eighteen consecutive outpatients referred to our expert center for functional gastrointestinal motility with suspected PPI-resistant NERD were enrolled. Manometry was performed to detect esophageal motility disorders. Subsequently, 24-hour esophageal impedance and pH monitoring was done while patients were on PPI therapy. RESULTS: Manometry revealed 1 case of achalasia, 1 case of nutcracker esophagus and 3 cases of diffuse esophageal spasm. Three patients had ineffective esophageal motility, with impedance and pH monitoring being performed in 2 of them. Esophageal acid exposure (%time pH <4) was normal in both, but the symptom index (SI) was positive for nonacidic reflux in 1 patient. One of the 10 patients with normal esophageal motility had abnormal esophageal acid exposure. The SI was positive for weakly acidic and nonacidic reflux in 3 of the remaining 9 patients with normal esophageal acid exposure. Five of the other 6 patients seemed to have functional heartburn. CONCLUSION: A substantial percentage (28%) of patients with suspected PPI-resistant NERD had primary esophageal motility disorders. Both nonacidic reflux and weakly acidic reflux are important contributors to the symptoms of patients with PPI-resistant NERD. Esophageal manometry is required to exclude motility disorders, while 24-hour esophageal impedance and pH monitoring is invaluable for assessing symptom-reflux associations and the indications for fundoplication in patients with suspected PPI-resistant NERD.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BACKGROUND: The incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. METHODS: Two hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. RESULTS: There were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. CONCLUSIONS: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals). TRIAL REGISTRATION: (UMIN000005880).

Development and evaluation of a modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease to distinguish functional dyspepsia from non-erosive reflux disease.

BACKGROUND AND AIM: The Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) is the standard questionnaire used in Japan for the diagnosis of gastroesophageal reflux disease (GERD) and assessment of the response to treatment. We modified the FSSG in order to assess dyspepsia symptoms, and evaluated the modified questionnaire. METHODS: We modified the FSSG by adding two questions on interdigestive and postprandial epigastric pain. We then assessed the modified FSSG with 100 new untreated symptomatic patients presenting to hospital and in 200 subjects undergoing health checks. Endoscopic assessment of the esophagogastric junction was performed according to the modified Los Angeles classification with addition of Grade N (normal appearance) and Grade M (minimal change). Endoscopic images were assessed by five experienced endoscopists blinded to the questionnaire results. RESULTS: The 100 new patients included 16 with erosive GERD (>Grade A), 12 with peptic ulcer, and two with gastric cancer. Among the 70 patients with no evidence of organic disease, the modified FSSG diagnosed functional dyspepsia (FD) in 41 and non-erosive gastric disease (NERD) in 29. A significant difference was seen in the dyspepsia score between patients with FD and NERD. Subjects with endoscopic GERD undergoing health checks had significantly higher scores for all symptoms, reflux symptoms, and dyspeptic symptoms on the modified FSSG. CONCLUSION: The modified FSSG can clearly distinguish FD from NERD, and is useful for the assessment of dyspeptic symptoms.

Rapid gastric emptying, rather than delayed gastric emptying, might provoke functional dyspepsia.

It has been suggested that there could be three possible mechanisms of gastric dysfunction in patients with FD: (i) delayed gastric emptying, (ii) impaired gastric accommodation of food intake, and (iii) hypersensitivity to gastric distention. Postprandial fullness seems to be the most severe symptom in patients who report aggravation of their symptoms after meals. Therefore, it has been assumed that delayed gastric emptying and consequent prolonged antral distension could reduce hunger, increase satiety, and even cause gastric discomfort, all of which would pose a significant barrier to adequate nutrition. We previously reported that postprandial water intake inhibits gastric antral motility along with an increase of cholecystokinin (CCK) in normal subjects. We assumed that the rapid increase of CCK after water intake was initiated by a feedback mechanism related to the inflow of fatty chyme into the duodenum that inhibits gastric antral activity. This duodeno-gastric interaction is known as the "duodenal break." We also reported that total gastric emptying was more rapid after the intake of a high-viscosity liquid meal than after a low-viscosity meal, because the low-viscosity liquid meal inhibits gastric emptying after rapid initial inflow into the duodenum. Considering these results, we hypothesized that rapid gastric emptying, rather than delayed gastric emptying, could be a cause of FD. In some patients with postprandial distress syndrome (PDS), we have found a significant correspondence between PDS-related dyspepsia and accelerated gastric emptying in the early postprandial period. It is worth emphasizing that the duodenum and the duodeno-gastric interaction (duodenal break) could have an important role in the pathophysiology of FD. We consider that rapid gastric emptying might be a more important factor than delayed gastric emptying in patients with FD.

Comparison of Nonesophageal Eosinophilic Gastrointestinal Disorders with Eosinophilic Esophagitis: A Nationwide Survey.

BACKGROUND: Eosinophilic esophagitis (EoE) has increased rapidly and has been well characterized. However, no nationwide survey has been conducted regarding non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs), and they remain poorly understood. OBJECTIVE: To compare the clinical features and natural histories of non-EoE EGIDs and EoE by using the same questionnaire, for all ages. METHODS: We conducted a nationwide hospital-based survey of patients who visited hospitals from January 2013 through December 2017. We randomly selected 10,000 hospitals that perform endoscopy. We analyzed the demographics, symptoms, gastrointestinal histology, treatments, and natural histories of EoE and non-EoE EGIDs. RESULTS: A total of 2906 hospitals responded to the questionnaire. We identified 1542 patients and obtained detailed data for 786 patients, consisting of 39% EoE and 61% non-EoE EGIDs. The clinical characteristics were analyzed for patients who met the "definite" criteria that excluded comorbidities. Non-EoE EGIDs showed no gender difference, whereas EoE was male-predominant. Tissue eosinophilia was often seen in the small intestine (62%) and stomach (49%). The frequency of hypoproteinemia was high (27%) in childhood. Children also had more serious symptoms and complications than adults: restriction of daily life activity (P = .009), failure to grow/weight loss (P = .008), and surgery (P = .01). For both diseases, the most common natural history was the continuous type: 66% (95% confidence interval [CI]: 58-74) in EoE and 64% (95% CI: 55-72) in non-EoE EGIDs. CONCLUSIONS: The percentage of persistent patients with non-EoE EGIDs was almost the same as those with EoE. Complications were more frequent in children than in adults.

New frontiers in gut nutrient sensor research: monosodium L-glutamate added to a high-energy, high-protein liquid diet promotes gastric emptying: a possible therapy for patients with functional dyspepsia.

Functional dyspepsia is a clinical syndrome that features abdominal symptoms centered in the upper abdomen without an organic basis. Three possible mechanisms of gastric dysfunction could be related to functional dyspepsia: 1) delayed gastric emptying, 2) impaired gastric accommodation to food intake, and 3) hypersensitivity to gastric distention. Delayed gastric emptying has been suggested to lead to prolonged antral distension that causes dyspeptic symptoms. Delayed gastric emptying is therefore a focal point of debate about anorexia caused by dyspepsia, and prokinetic agents are often administered in Japan for its treatment. Recently, we found that addition of monosodium L-glutamate (MSG) to a high-energy liquid diet rich in casein promoted gastric emptying in healthy men. Therefore, another potential method to improve delayed gastric emptying could be enhancement of chemosensors that activate the autonomic nervous system innervating the gastrointestinal tract. In conclusion, enrichment with glutamate promoted gastric emptying after intake of a high-protein meal, suggesting that free glutamate is important for protein digestion and that MSG may be helpful for management of delayed gastric emptying in patients with functional dyspepsia.

Comparison of endoscopic findings with symptom assessment systems (FSSG and QUEST) for gastroesophageal reflux disease in Japanese centres.

BACKGROUND AND AIM: We compared endoscopic findings of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), a written questionnaire developed in Japan, to that for the questionnaire for the diagnosis of reflux esophagitis (QUEST) for the diagnosis of reflux esophagitis. METHODS: We registered 475 patients with untreated symptoms of upper abdominal pain (male/female: 252/223, average age 52.4 +/- 17.8 years). Subjects were assessed first with the FSSG and QUEST questionnaires, then by endoscopy, before allocation to a gastric ulcer (GU), duodenal ulcer (DU), gastroesophageal reflux disease (GERD) or functional dyspepsia (FD) group. RESULTS: On the basis of the endoscopic findings the diagnoses for the 475 subjects were as follows: FD 52.2%, DU 7.6%, GU 7.8%, and GERD 32.4% (Grade M 10.1%, Grade A + B 20.2%, Grade C + D 2.3%). There was no difference between the FSSG and QUEST in sensitivity, specificity or accuracy for any condition. The FSSG score rose with increasing endoscopic severity of GERD, but there was no correlation between the QUEST score and endoscopic severity. The FSSG total score was inferior to QUEST in terms of distinguishing GERD from other conditions, but when only the questions relating to reflux symptoms were used, the FSSG was able to distinguish GERD from other conditions as well as QUEST. CONCLUSIONS: The FSSG score reflects the severity of the endoscopic findings of GERD.

Relationship between esophageal motility abnormalities and skin or lung involvements in patients with systemic sclerosis.

BACKGROUND: Esophageal motility abnormalities (EMAs) and interstitial lung diseases (ILDs) are often seen in patients with systemic sclerosis (SSc). Gastroesophageal reflux disease (GERD) could be associated with ILDs, but it is not fully understood if ILDs are caused by GERD or SSc itself. METHODS: A total of 109 patients with SSc who underwent high-resolution manometry were enrolled. Esophageal motility was diagnosed with the Chicago classification v3.0. The severity of skin thickness was evaluated by the modified Rodnan total skin thickness score (mRSS). The severity of ILDs was assessed with the chest high-resolution computer tomography (HRCT) scoring system. Relationships between EMAs, GERD, autoantibodies, skin thickness and ILDs were evaluated. RESULTS: 44 patients had normal esophageal motility, eight had esophago-gastric junction outflow obstruction, one had distal esophageal spasm, 27 had ineffective esophageal motility and 29 had absent contractility (AC). Patients with AC had more GERD than those with normal esophageal motility (p < 0.05). The mRSS score in patients with AC was significantly higher than that in those with normal esophageal motility (p < 0.05). The HRCT score in patients with AC tended to be higher than that in those with normal esophageal motility (p = 0.05). A multivariable analysis showed that severe skin thickness was a significant predictor of AC. GERD was not a significant predictor for ILDs. CONCLUSIONS: There were significant correlations between EMAs and severe skin thickness. GERD is not an etiology of ILDs.

Clinical impact of different cut-off values in high-resolution manometry systems on diagnosing esophageal motility disorders.

BACKGROUND: The values of the parameters in the Chicago classification measured by a high-resolution manometry (HRM) system with the Unisensor catheter (Starlet) are significantly different from those measured by the ManoScan. The contraction vigor is categorized by values of the distal contractile integral (DCI) in the Chicago classification v3.0; however, reference values of the DCI in the Starlet and the clinical impact of the different reference values in the Starlet and ManoScan on diagnosing esophageal motility disorders are not known. METHODS: We evaluated data from a previous report in which ManoScan and Starlet were compared in the same subjects. The DCI values in each system were compared and reference DCI values were calculated. Moreover, diagnoses assessed by Starlet using reference values in ManoScan were compared with those using calculated reference values and those assessed by ManoScan. RESULTS: There was a significant positive correlation between the DCI values measured by ManoScan and those measured by Starlet (r = 0.80, p < 0.01). Based on a linear functional relationship considering measurement errors, the reference DCI values for diagnosing failed, weak and hypercontractile contraction vigor were calculated as 590.6, 1011.3 and 10,085.8 mmHg-s-cm, respectively, in the Starlet. Therefore, the proposed reference values in the Starlet were 500, 1000 and 10,000 mmHg-s-cm, respectively. When the reference values in the ManoScan were used in the Starlet data, approximately 30% of subjects were diagnosed inappropriately. This issue was resolved using the proposed reference values in the Starlet. CONCLUSION: Recognizing systemic differences in HRM systems is important.

New endoscopic classification of cascade stomach, a risk factor for reflux esophagitis.

BACKGROUND: We recently demonstrated that cascade stomach detected by barium studies was correlated with upper gastrointestinal symptoms. We developed a new endoscopic classification of cascade stomach and examined its relationship with reflux esophagitis. METHODS: Study 1: the classification (grades 0-3) was based on detecting a ridge that runs from the cardia toward the anterior wall crossing the greater curvature. Inter-observer variation was evaluated by kappa statistics when ten experienced endoscopists used this classification three times each. Study 2: in 710 consecutive subjects (500 men and 210 women) undergoing endoscopic screening, the grade of cascade stomach and incidence of reflux esophagitis were compared. RESULTS: In study 1, the kappa values at the third assessment were 0.85, 0.58, 0.50, and 0.78 for each grade, respectively, while overall agreement was 0.68. In study 2, the incidence of reflux esophagitis in men was 20 % in grade 0, 17 % in grade 1, 25 % in grade 2, and 30 % in grade 3, showing significant differences. Among women, the incidence of reflux esophagitis in each grade was 9, 3, 6, and 35 %, respectively, also showing significant differences. Multivariate analysis showed that independent risk factors for reflux esophagitis were cascade stomach (odds ratio = 2.20), body mass index, and hiatus hernia in men, as well as cascade stomach (odds ratio = 9.01) and smoking tobacco in women. CONCLUSIONS: This endoscopic classification of cascade stomach showed acceptable inter-observer variation. Cascade stomach is a risk factor for reflux esophagitis.

Liquid-containing Refluxes and Acid Refluxes May Be Less Frequent in the Japanese Population Than in Other Populations: Normal Values of 24- hour Esophageal Impedance and pH Monitoring.

BACKGROUND/AIMS: Twenty-four-hour esophageal impedance and pH monitoring allows detection of all types of reflux episodes and is considered the best technique for identifying gastroesophageal refluxes. However, normative data for the Japanese population are lacking. This multicenter study aimed to establish the normal range of 24-hour esophageal impedance and pH data both in the distal and the proximal esophagus in Japanese subjects. METHODS: Forty-two healthy volunteers (25 men and 17 women) with a mean ± standard deviation age of 33.3 ± 12.4 years (range: 22-72 years) underwent a combined 24-hour esophageal impedance and pH monitoring. According to the physical and pH properties, distal or proximal esophageal reflux events were categorized. RESULTS: Median 45 reflux events occurred in 24 hours, and the 95th percentile was 85 events. Unlike previous reports, liquid-containing reflux events are median 25/24 hours with the 95th percentile of 62/24 hours. Acidic reflux events were median 11/24 hours with the 95th percentile of 39/24 hours. Non-acidic gas reflux events were median 15/24 hours with the 95th percentile of 39/24 hours. Proximal reflux events accounted for 80% of the total reflux events and were mainly non-acidic gas refluxes. About 19% of liquid and mixed refluxes reached the proximal esophagus. CONCLUSIONS: Unlike previous studies, liquid-containing and acidic reflux events may be less frequent in the Japanese population. Non-acidic gas reflux events may be frequent and a cause of frequent proximal reflux events. This study provides important normative data for 24-hour impedance and pH monitoring in both the distal and the proximal esophagus in the Japanese population.

[Epidemiology of Barrett's esophagus--comparison of Japan and the West].

We compared the epidemiology of Barrett's esophagus in Japan and the West. Japan GERD Society Study Committee conducted the epidemiological survey in 2,595 patients who underwent endoscopy the first time, confirming that Barrett's mucosa was observed in 536 patients (20.8%) out of 2,577. But Barrett's esophagus (>3 cm of columnar lined epithelium) was detected only 5 (0.2%). The prevalence of typical Barrett's esophagus was markedly low in Japanese compared with Westerners. In Western, the incidence of Barrett's esophagus has increased markedly since the 1970s. It is estimated that Barrett's esophagus is found in approximately 6-12% of patients undergoing endoscopy for symptoms of GERD and in 1% or less of unselected patient populations undergoing endoscopy.