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.

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.

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.

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.

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.

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.

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.

Two Cases of Intravascular Lymphoma Diagnosed by Gastrointestinal Endoscopic Biopsy.

Two cases of intravascular lymphoma (IVL) were diagnosed by endoscopic biopsy. Both patients were admitted to our hospital with a fever of an unknown origin. An elevated serum level of soluble interleukin-2 receptor antibody suggested IVL. An upper gastrointestinal endoscopy was performed. A biopsy of both the reddened and normal gastroduodenal mucosa (Case 1) and a biopsy of a gastric antral ulcer, multiple polyploid lesions resembling submucosal tumors in the duodenum, and the patient's normal mucosa (Case 2) revealed vascular infiltration by CD20-positive atypical lymphocytes, confirming the diagnosis of IVL. The performance of a gastrointestinal biopsy for suspected IVL is important, even if there are no visible endoscopic abnormalities.

A prospective randomized controlled trial of AJG522 versus standard PEG+E as bowel preparation for colonoscopy.

Polyethylene glycol- (PEG-) based bowel preparations for colonoscopies are often poorly tolerated due to the large volumes of fluid intake required. We compared low-volume "modified" PEG + ascorbic acid (AJG522) with standard PEG with electrolytes (PEG+E) in addition to a stimulant laxative and an agent to improve bowel function for the bowel cleansing before colonoscopy to evaluate its efficacy, safety, and acceptability. Outpatients scheduled to undergo colonoscopy were randomized to receive either AJG522 or PEG+E. Bowel cleansing conditions were assessed via macroscopic fecal findings by blinded and independent investigators. A survey of the patients' feedback regarding the preparation was conducted by questionnaire. Successful cleansing was achieved in all cases, except for 4 cases in the PEG+E group, at 3 hours after taking the preparation. The fecal properties were significantly clearer in the AJG522 group than in the PEG+E group at 2 hours after taking each preparation (P=0.013). Although the total liquid volume of the bowel preparation was not reduced, the AJG522 preparation could significantly reduce the required volume of the preparation (P<0.0001). Moreover, the patients in the AJG522 group had better acceptability (P=0.010). There were no significant differences in the safety profiles between groups (UMIN000013892).

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.

More severe upper gastrointestinal symptoms associated with non-erosive reflux disease than with erosive gastroesophageal reflux disease during maintenance proton pump inhibitor therapy.

BACKGROUND: During maintenance proton pump inhibitor (PPI) therapy, patients with gastroesophageal reflux disease (GERD) sometimes complain of upper gastrointestinal symptoms. AIM: To evaluate upper gastrointestinal symptoms in patients on maintenance PPI therapy for erosive GERD or non-erosive reflux disease (NERD) without endoscopic mucosal breaks by using a new questionnaire. METHODS: At Gunma University Hospital over a 12-month period during 2011-2012, we enrolled 30 consecutive patients with erosive GERD and 46 patients with NERD. All patients had been on maintenance PPI therapy for more than 1 year. We used the modified frequency scale for the symptoms of GERD (mFSSG) questionnaire to assess upper gastrointestinal symptoms. We also asked patients about their satisfaction with maintenance therapy and whether they wished to change their current PPI. RESULTS: The NERD patients had significantly higher symptom scores than the erosive GERD patients. There was no difference in the treatment satisfaction rate between patients with erosive GERD and NERD, but more patients with NERD wanted to change their PPI therapy. There was no difference in the mFSSG score between NERD patients who wished to change their current PPI therapy and those who were satisfied with it. CONCLUSIONS: During maintenance PPI therapy, upper gastrointestinal symptoms were more severe in NERD patients than in patients with erosive GERD. NERD patients often wished to change their PPI therapy, but this was not dependent on the severity of their upper GI symptoms.

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).

A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study.

BACKGROUND: The aim of this study was to investigate the efficacy of rikkunshito (RKT), a traditional Japanese medicine, combined with proton pump inhibitor (PPI) in patients with PPI-refractory non-erosive reflux disease (NERD). METHODS: Patients with PPI-refractory NERD (n = 242) were randomly assigned to the RKT group [rabeprazole (10 mg/day) + RKT (7.5 g/t.i.d.) for 8 weeks] or the placebo group (rabeprazole + placebo). After the 4- and 8-week treatments, we assessed symptoms and quality of life (QOL) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG), Gastrointestinal Symptom Rating Scale (GSRS), and Short-Form Health Survey-8 (SF-8). RESULTS: There were no significant differences in FSSG and GSRS score improvement between these groups after the 4- and 8-week treatments. The mental component summary (MCS) scores of the SF-8 improved more in the RKT group (from 45.8 ± 8.1 to 48.5 ± 7.4) than in the placebo group (from 47.7 ± 7.1 to 48.4 ± 7.5) after the 4-week treatment (P < 0.05). The 8-week treatment with RKT was more effective for improvement of the degree of MCS score in patients with a low body mass index (<22) (P < 0.05) and significantly improved the acid-related dysmotility symptoms of FSSG in female and elderly patients (≥ 65 years). CONCLUSION: There were no significant differences in improvement of GERD symptoms in patients with PPI-refractory NERD between these groups. However, RKT may be useful for improving mental QOL in non-obese patients and acid-related dyspeptic symptoms, especially in women and the elderly.

Gastrointestinal motility and functional gastrointestinal diseases.

Digestive tract motility patterns are closely related to the pathophysiology of functional gastrointestinal diseases (FGID), and these patterns differ markedly between the interdigestive period and the postprandial period. The characteristic motility pattern in the interdigestive period is so-called interdigestive migrating contraction (IMC). IMCs have a housekeeping role in the intestinal tract, and could also be related to FGID. IMCs arising from the stomach are called gastrointestinal IMCs (GI-IMC), while IMCs arising from the duodenum without associated gastric contractions are called intestinal IMCs (I-IMC). It is thought that I-IMCs are abnormal in FGID. Transport of food residue to the duodenum via gastric emptying is one of the most important postprandial functions of the stomach. In patients with functional dyspepsia (FD), abnormal gastric emptying is a possible mechanism of gastric dysfunction. Accordingly, delayed gastric emptying has attracted attention, with prokinetic agents and herbal medicines often being administered in Japan to accelerate gastric emptying in patients who have anorexia associated with dyspepsia. Recently, we found that addition of monosodium L-glutamate (MSG) to a high-calorie liquid diet rich in casein promoted gastric emptying in healthy men. Therefore, another potential method of improving delayed gastric emptying could be activation of chemosensors that stimulate the autonomic nervous system of the gastrointestinal tract, suggesting a role for MSG in the management of delayed gastric emptying in patients with FD.