Proanthocyanidins mitigate bile acid-induced changes in GSTT2 levels in a panel of racially diverse patient-derived primary esophageal cell cultures.

Persistent and symptomatic reflux of gastric and duodenal contents, known as gastroesophageal reflux disease (GERD), is the strongest risk factor for esophageal adenocarcinoma (EAC). Despite similar rates of GERD and other risk factors across racial groups, EAC progression disproportionately impacts Caucasians. We recently reported that elevated tissue levels of the detoxification enzyme GSTT2 in the esophagi of Blacks compared to Caucasians may contribute protection. Herein, we extend our research to investigate whether cranberry proanthocyanidins (C-PAC) mitigate bile acid-induced damage and GSTT2 levels utilizing a racially diverse panel of patient-derived primary esophageal cultures. We have shown that C-PACs mitigate reflux-induced DNA damage through GSTT2 upregulation in a rat esophageal reflux model, but whether effects are recapitulated in humans or differentially based on race remains unknown. We isolated normal primary esophageal cells from Black and Caucasian patients and assessed GSTT2 protein levels and cellular viability following exposure to a bile acid cocktail with and without C-PAC treatment. Constitutive GSTT2 levels were significantly elevated in Black (2.9-fold) compared to Caucasian patients, as were GSTT2 levels in Black patients with GERD. C-PAC treatment induced GSTT2 levels 1.6-fold in primary normal esophageal cells. GSTT2 induction by C-PAC was greatest in cells with constitutively low GSTT2 expression. Overall, C-PAC mitigated bile-induced reductions of GSTT2 and subsequent loss of cell viability regardless of basal GSTT2 expression or race. These data support that C-PAC may be a safe efficacious agent to promote epithelial fitness through GSTT2 induction and in turn protect against bile acid-induced esophageal injury.

Weak acids induce PGE2 production in human oesophageal cells: novel mechanisms underlying GERD symptoms.

The role of weak acids with pH values in the range of 4-7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E2 (PGE2) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE2 production with a peak at pH 4-5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE2 from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE2 production in KYSE-270 cells. Weak acid-induced PGE2 production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE2 levels in KYSE-270. These results indicated that weak acids induce PGE2 production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.

Refractory GERD, beyond proton pump inhibitors.

Pharmacologic therapy, surgery, minimally invasive therapies, and alternative therapies are different options available for the management of refractory GERD. The choice may depend on the cause of refractoriness. Increased gastric acid suppression therapy might be useful in the rare patients with persistent elevated esophageal acid exposure on proton pump inhibitors (PPI). Potassium-competitive acid blockers (P-CAB) might induce a more important acid inhibition than PPI. Baclofen might act as a reflux inhibitor and demonstrates a significant efficacy in rumination syndrome. The role of topical antacid-alginate in refractory GERD might be limited. Surgery might be a valid option in case of persistent pathological acid esophageal exposure despite PPI. Further evaluation of minimally invasive procedures is necessary. Finally diet, diaphragmatic breathing and transcutaneous electrical acustimulation might be of interest in patients with esophageal hypersensivity or functional symptoms.

Nonerosive reflux disease: clinical concepts.

Esophageal symptoms can arise from gastroesophageal reflux disease (GERD) as well as other mucosal and motor processes, structural disease, and functional esophageal syndromes. GERD is the most common esophageal disorder, but diagnosis may not be straightforward when symptoms persist despite empiric acid suppressive therapy and when mucosal erosions are not seen on endoscopy (as for nonerosive reflux disease, NERD). Esophageal physiological tests (ambulatory pH or pH-impedance monitoring and manometry) can be of value in defining abnormal reflux burden and reflux-symptom association. NERD diagnosed on the basis of abnormal reflux burden on ambulatory reflux monitoring is associated with similar symptom response from antireflux therapy for erosive esophagitis. Acid suppression is the mainstay of therapy, and antireflux surgery has a definitive role in the management of persisting symptoms attributed to NERD, especially when the esophagogastric junction is compromised. Adjunctive approaches and complementary therapy may be of additional value in management. In this review, we describe the evaluation, diagnosis, differential diagnosis, and management of NERD.

Possible intermediary role of ghrelin in seborrhea.

Seborrhea, or oily skin, is a very common condition, especially among young people, caused by the increased secretion of sebum by sebaceous glands in the skin. Based on today's knowledge, a regulatory role of various hormones especially androgens is considered for sebaceous gland secretion; but despite significant evidences emphasis on the effects of the gastrointestinal disorders on coetaneous manifestations, the role of gastrointestinal problems in sebum secretion has not been emphasized yet. This study aimed to explain hormonal changes occurring in gastroesophageal reflux disease which may cause changes in sebaceous gland secretion so that, by explaining these communication mechanisms, common investigations between gastroenterology and dermatology can be performed to evaluate the accuracy of this hypothesis.

Effect of lycopene against gastroesophageal reflux disease in experimental animals.

BACKGROUND: Lycopene is a robust antioxidant with significant antiulcer activity. Henceforth, the present study was ventured to elucidate the effect of lycopene on experimental esophagitis. METHODS: Groups of rats were subjected to forestomach and pylorus ligation with subsequent treatment with lycopene (50 and 100 mg/kg, po) and pantoprazole (30 mg/kg, po). RESULTS: Treatment with lycopene evidenced sententious physiological protection when scrutinized for pH, acidity (total and free), volume of gastric juices and esophagitis index. Lycopene further embarked diminishing effect on oxidative stress through synchronising lipid and protein peroxidation along with regulating the enzymatic activity of SOD and catalase. Lycopene also modified the levels of immunoregulatory cytokines (IL- 1ß and IL-6) favourably. The dose dependent efficacy of lycopene in the current experimental condition was also attested when exemplified morphologically through scanning electron microscopy. CONCLUSION: From the current line of evidences, it was concluded that lycopene can impart momentous protection against experimental esophagitis by wrapping up the reactive oxygen species and through dual inhibition of the arachidonic acid pathway.

Lack of efficacy of a starch-thickened preterm formula on gastro-oesophageal reflux in preterm infants: a pilot study.

BACKGROUND: Gastro-oesophageal reflux (GOR) is common in preterm infants; conservative interventions (i.e. dietary changes) should represent the first-line approach. AIM: To evaluate by combined pH and impedance monitoring (pH-MII) the effect of a new preterm formula thickened with amylopectin (TPF) on GOR features in symptomatic preterm infants. METHODS: Twenty-eight symptomatic preterm newborns underwent a 24-hour pH-MII; each baby received eight meals (four of TPF and four of a preterm formula [PF]). GOR indexes (number, acidity, duration and height of GORs) after TPF and PF meals were compared by Wilcoxon Signed Ranks Test. Viscosity of PF and TPF was measured. RESULTS: TPF significantly decreased the number of acid GORs detected by pH-monitoring (TPF vs. PF: median 20 vs. 24.5, p = 0.009), while it had no influence on Reflux Index (RIpH), nor on acid and non-acid GOR indexes detected by MII, GOR physical features, and GOR height. TPF's viscosity was extremely higher than PF's, and further increased at pH 3 after the addition of pepsin. CONCLUSIONS: The new formula was found to reduce the number of acid GORs detected by pH-monitoring; it did not reduce neither total oesophageal acid exposure nor non-acid GORs. At present its extended clinical use cannot be recommended.

Functional chest pain responds to biofeedback treatment but functional heartburn does not: what is the difference?

BACKGROUND: Patients with functional esophageal disorders represent a challenging treatment group. The purpose of this study was to evaluate the role of biofeedback in the treatment of patients with functional esophageal disorders. METHODS: In this prospective study, patients with typical/atypical symptoms of gastroesophageal reflux disease underwent upper endoscopy and 24-h pH monitoring. All patients filled out gastroesophageal Reflux Disease Symptom, Hospital Anxiety and Depression, and Symptom Stress Rating questionnaires. Patients with functional heartburn and those with functional chest pain were offered biofeedback treatment. A global assessment questionnaire was filled out at the end of treatment and then 2.8 (range 1-4) years later. RESULTS: From January 2006 to December 2009, 22 patients with functional esophageal diseases were included in the study. Thirteen had functional heartburn and nine had functional chest pain. Six patients from each group received biofeedback treatment. After treatment for 1-4 years, patients with functional chest pain showed significant improvements in symptoms compared with those who were not treated. Patients with functional heartburn showed no improvement. Patients with functional chest pain had a longer time of esophageal acid exposure than those with functional heartburn. CONCLUSION: Patients with functional chest pain have different central and intraesophageal factors associated with symptom generation in comparison with patients with functional heartburn. Biofeedback is a useful tool in the treatment of patients with functional chest pain, but not for those with functional heartburn.

Duodenal lipid-induced symptom generation in gastroesophageal reflux disease: role of apolipoprotein A-IV and cholecystokinin.

BACKGROUND: Duodenal lipid intensifies the perception of esophageal acid perfusion. Recently, we showed that genes implicated in lipid absorption were upregulated in the duodenum of fasting gastro-esophageal reflux disease (GERD) patients. This suggests that chylomicron production and secretion may be enhanced and, consequently, the release of apolipoprotein A-IV (apoA-IV), a chylomicron-derived signaling protein. ApoA-IV may stimulate release of cholecystokinin (CCK), an activator of vagal afferents. This study evaluated putative involvement of abnormal apoA-IV and CCK responses to lipid in GERD. METHODS: Ten GERD patients and 10 healthy volunteers (HV) underwent duodenal perfusion with Intralipid 20%, 2 kcal min(-1) , for 60 min. Symptoms were scored, blood samples collected every 15 min during lipid perfusion and 15 min after discontinuation when duodenal biopsies were taken. Plasma and mucosal concentrations of apoA-IV and CCK and transcript levels of 21 genes implicated in lipid absorption, differentially expressed under fasting conditions, were quantified. KEY RESULTS: Heartburn (P = 0.003), abdominal discomfort (P = 0.037) and nausea (P = 0.008) only increased significantly during lipid infusion in GERD patients. Following lipid infusion mean mucosal apoA-IV concentration was lower in GERD patients compared with HV (P = 0.023), whereas plasma concentration tended to be elevated (P = 0.068). Mean mucosal CCK concentration was also lower in GERD patients (P = 0.009). Two genes, HIBADH and JTB, were upregulated in GERD patients (P = 0.008 and P = 0.038, respectively). CONCLUSIONS & INFERENCES: Our results suggest excessive duodenal lipid-induced release of apoA-IV and CCK in GERD. We postulate that the resulting heightened activation of duodenal vagal afferents may underlie central sensitization, thereby increasing the perception of reflux events.

[Impact of laser therapy on PGE2 level, 24-hour pH-metry changes, and quality of life in patients with gastroesophageal reflux disease].

AIM: To study the impact of low-intensity laser irradiation on 24-hour pH-metry parameters and prostaglandin E2 (PGE2) levels in patients with gastroesophageal reflux disease (GERD). SUBJECTS AND METHODS: One hundred and twelve patients aged 19 to 79 years with GERD were examined. Seventy-eight patients received a 10-day course of continuous intravenous laser therapy using a Matrix VLOK laser therapy apparatus (Matrix, Russia) with a wavelength of 0.405 pm, radiation power at the exit of a main light guide 1-1.5 mW, pulse rate 80 Hz. The indicators under study were determined before and after treatment. RESULTS: After treatment, the intravenous laser therapy group showed a significant increase in PGE2 (1376 +/- 93 pg/ml) to the levels typical of those in healthy individuals and a significant decrease in all esophageal pH-metry parameters; the DeMeester score achieved normal values, and all quality of life (QL) indicators, except for physical function index, significantly improved (10.2 +/- 5.7; p < 0.05). CONCLUSION: The findings are suggestive of elevated PGE2 levels and improved QL during laser therapy.

GABAB receptor agonism as a novel therapeutic modality in the treatment of gastroesophageal reflux disease.

Defined pharmacologically by its insensitivity to the GABA(A) antagonist bicuculline and sensitivity to the GABA analogue baclofen, the G protein-linked gamma-aminobutyric acid type B (GABA(B)) receptor couples to adenylyl cyclase, voltage-gated calcium channels, and inwardly-rectifying potassium channels. On the basis of a wealth of preclinical data in conjunction with early clinical observations that baclofen improves symptoms of gastroesophageal reflux disease (GERD), the GABA(B) receptor has been proposed as a therapeutic target for a number of diseases including GERD. Subsequently, there has been a significant effort to develop a peripherally-restricted GABA(B) agonist that is devoid of the central nervous system side effects that are observed with baclofen. In this article we review the in vitro and in vivo pharmacology of the peripherally-restricted GABA(B) receptor agonists and the preclinical and clinical development of lesogaberan (AZD3355, (R)-(3-amino-2-fluoropropyl) phosphinic acid), a potent and predominately peripherally-restricted GABA(B) receptor agonist with a preclinical therapeutic window superior to baclofen.

Enteryx implantation for GERD: expanded multicenter trial results and interim postapproval follow-up to 24 months.

BACKGROUND: Enteryx implantation in the esophagus is an alternative therapy for patients with proton pump inhibitor (PPI) dependent GERD. Although this treatment resulted in highly significant improvement at 6 and 12 months, longer follow-up is needed to more fully assess the durability of these positive effects. METHODS: An open-label, international clinical trial was conducted in 144 PPI-dependent patients with GERD with follow-up at 6 and 12 months. In addition, the durability and the safety of the treatment were assessed for 24 months in 64 patients enrolled in a postapproval study. The primary study outcome measure was usage of PPI. Secondary outcomes in the multicenter trial were GERD health-related quality of life (GERD-HRQL) symptom score and esophageal acid exposure. RESULTS: At 12 months, PPI use was reduced > or =50% in 84%: 95% confidence interval (CI) [76%, 90%] and was eliminated in 73%: 95% CI[64%, 81%] of evaluable patients (intent-to-treat analysis 78%: 95% CI[70%, 84%] and 68%: 95% CI[60%, 76%], respectively). A GERD-HRQL < or =11 was attained in 78%: 95% CI[69%, 85%] of evaluable patients. Esophageal acid exposure (total time pH <4) was reduced by 31%: 95% CI[17%, 43%]. At 24 months, a > or =50% or greater reduction in PPI use was achieved in 72%: 95% CI[59%, 82%] and PPI use was eliminated in 67%: 95% CI[54%, 78%] of patients. CONCLUSIONS: This investigation provides evidence for sustained effectiveness and safety of implantation of Enteryx in the esophagus in PPI-dependent patients with GERD.

Effects of dietary nitrate on oesophageal motor function and gastro-oesophageal acid exposure in healthy volunteers and reflux patients.

BACKGROUND/AIMS: High concentrations of nitric oxide (NO), derived from dietary nitrite in an acid environment, have been demonstrated in the gastric fundus and in the oesophagus. The aim of this study was to investigate whether luminal NO can influence oesophageal smooth muscle performance, lower oesophageal sphincter (LOS) function or gastric and oesophageal acid exposure. METHODS: Eleven healthy volunteers and 9 patients with chronic gastro-oesophageal reflux disease (GORD) received a diet deprived of nitrate/nitrite but supplemented with placebo or potassium nitrate for 4 days in a randomised order. On day 4 in each trial period, manometry was performed including a sleeve sensor registration of the LOS followed by a simultaneous 24-hour intra-gastric and oesophageal pH registration. RESULTS: Nitrate supplementation increased the proportion of effective peristalsis when analysed for the entire study population. No other significant effects of dietary nitrate were found on oesophageal motor variables, on the sphincter resting tone or on the number or duration of transient sphincter relaxations. No effect was found on either gastric acidity or gastro-oesophageal reflux variables. Major reflux symptoms were not influenced by nitrate administration. CONCLUSION: Dietary nitrate did not significantly affect oesophageal motor or LOS function, gastro-oesophageal acid reflux or reflux symptomatology either in healthy volunteers or in GORD patients.

Fundoplication and gastrostomy versus image-guided gastrojejunal tube for enteral feeding in neurologically impaired children with gastroesophageal reflux.

BACKGROUND: Neurologically impaired children with gastroesophageal reflux (GER) usually are treated with a fundoplication and gastrostomy (FG); however, this approach is associated with a high rate of complications and morbidity. The authors evaluated the image-guided gastrojejunal tube (GJ) as an alternative approach for this group of patients. METHODS: A retrospective review of 111 neurologically impaired patients with gastroesophageal reflux was performed. Patients underwent either FG (n = 63) or GJ (n = 48). All FGs were performed using an open technique by a pediatric surgeon, and all GJ tubes were placed by an interventional radiologist. RESULTS: The 2 groups were similar with respect to diagnosis, age, sex and indication for feeding tube. Patients in the GJ group were followed up for an average of 3.11 years, and those in the FG group for 5.71 years. The groups did not differ statistically with respect to most complications (bleeding, peritonitis, aspiration pneumonia, recurrent gastroesophageal reflux [GER], wound infection, failure to thrive, and death), subsequent GER related admissions, or cost. Children in the GJ group were more likely to continue taking antireflux medication after the procedure (P <.05). Also, there was a trend for GJ patients to have an increased incidence of bowel obstruction or intussusception (20.8% v 7.9%). Of the FG patients 36.5% experienced retching, and 12.7% experienced dysphagia. Eighty-five percent of patients in the GJ group experienced GJ tube-specific complications (breakage, blockage, dislodgment), and GJ tube manipulations were required an average of 1.68 times per year follow-up. Nine patients (14.3%) in the FG group had wrap failure, with 7 (11.1%) of these children requiring repeat fundoplication. In the GJ group, 8.3% of patients went on to require a fundoplication for persistent problems. A total of 14.5% of GJ patients had their tube removed by the end of the follow-up period because they no longer needed the tube for feeding. CONCLUSIONS: Image-guided gastrojejunal tubes are a reasonable alternative to fundoplication and gastrostomy for neurologically impaired children with GER. The majority can be inserted without general anesthesia. This technique failed in only 8.3% patients, and they subsequently required fundoplication. A total of 14.5% of GJ patients showed some spontaneous improvement and had their feeding tube removed. Each approach, however, still is associated with a significant complication rate. A randomized prospective study comparing these 2 approaches is needed.

High-dose proton-pump inhibitors as a diagnostic test of gastro-oesophageal reflux disease in endoscopic-negative patients.

BACKGROUND: To evaluate a high dose of a proton-pump inhibitor as a diagnostic test in endoscopy-negative patients presenting with symptoms indicating gastro-oesophageal reflux disease. METHODS: 64 patients were studied in a prospective, randomized, double-blind study, using a cross-over design. After a run-in period with the diary registration of basic GORD symptoms and recording of the consumption of antacid tablets, the patients were given either 60 mg of lansoprazole once daily or placebo in randomized order. Symptoms were recorded, as well as antacid tablets taken in order to relieve pain. GORD was determined by 24-h oesophageal pH monitoring. The test was considered positive when consumption of antacid tablets was reduced > or = 75% compared to pretreatment. RESULTS: In the GORD group, 29 (85%) tested positive during active treatment compared to 3 (9%) when on placebo. Corresponding figures for the non-GORD patients were 50% and 27%, giving a test sensitivity and specificity of 85% and 73%, respectively. During active treatment, VAS scores for acid regurgitation, heartburn and over all were significantly lowered in GORD patients, compared to heartburn only in the non-GORD group. CONCLUSIONS: 60 mg lansoprazole once daily for 5 days is an easy to use method for diagnosing GORD in endoscopy-negative patients. Using 24-h oesophageal pH monitoring as the reference method, the sensitivity was relatively high, while the specificity was lower. Further studies are needed to determine how a PPI could be used as a diagnostic test in GORD.

Efficacy of a pectin-based anti-reflux agent on acid reflux and recurrence of symptoms and oesophagitis in gastro-oesophageal reflux disease.

OBJECTIVE: Gastro-oesophageal reflux disease may be treated with a drug forming a floating neutral raft in the stomach. The pectin-based raft-forming anti-reflux agent Aflurax (Idoflux) was examined, first regarding reduction of oesophageal acid exposure, and next as to its efficacy as maintenance treatment in patients with healed oesophagitis. DESIGN: Double-blind, placebo-controlled randomized clinical trials. SETTING: Open access endoscopy unit. PARTICIPANTS: Fourteen patients with erosive oesophagitis had measurement of acid exposure. Eighty-eight patients with healed erosive/ulcerative oesophagitis and relief of heartburn after pre-treatment with omeprazole received maintenance treatment. INTERVENTIONS: Crossover 12-h oesophageal pH monitoring during Aflurax/placebo treatment. Maintenance treatment for up to 6 months with two tablets of Aflurax 1200 mg or placebo four times daily. MAIN OUTCOME MEASURES: Percentage time pH less than 4 in 6 plus 6 h (upright + supine). Time to recurrence of moderate or severe heartburn (life table analysis). RESULTS: The median (interquartile range) acid exposure times in the upright position were: 3.1% (1.6-13.0%) on Aflurax versus 6.7% (2.5-14.9%) on placebo (P = 0.10). In the supine position no difference was found (Aflurax 13.7%, placebo 13.2%). The time to recurrence of heartburn with Aflurax treatment was prolonged significantly; after 6 months the life table estimates were 48% of patients in remission on Aflurax versus 8% on placebo (P = 0.01). Following treatment, erosive oesophagitis was found in 17/34 on Aflurax versus 28/38 on placebo (P < 0.05). CONCLUSION: Aflurax significantly delays recurrence of moderate or severe heartburn and erosive oesophagitis, when used as maintenance treatment. The acid exposure was not significantly reduced with pH monitoring.