Bile reflux in patients with nerd is associated with more severe heartburn and lower values of mean nocturnal baseline impedance and chemical clearance.

BACKGROUND: Mean nocturnal baseline impedance (MNBI) and postreflux swallow-induced peristaltic wave (PSPW) index are novel impedance-based markers of reflux, but the effect of bile reflux on these metrics is unknown. The aim of this study was to evaluate bile reflux, MNBI, and PSPW index in patients with endoscopy-negative GERD partially responsive to PPI therapy. METHODS: All patients underwent off-PPI endoscopy, esophageal manometry, multichannel intraluminal impedance pH (MII-pH), and bile reflux monitoring. Abnormal esophageal acid exposure time (AET) was required for inclusion. Symptom intensity (using 10-cm visual analog scales), and conventional and novel MII-pH metrics were compared between patients with and without abnormal bile reflux. KEY RESULTS: We evaluated 42 NERD patients (29 males, mean age: 53.4 ± 13. years), mean AET 6.1 ± 2%, of which 21 had abnormal bile reflux (Group A, 10.2 ± 4.9%), and 21 had normal bile reflux (Group B, 0.4 ± 0.1%, P < .05 compared with Group A). Heartburn reporting on PPI was higher in Group A (7.2 ± 2.1 vs 5.8 ± 0.9; P = .002), but AET, number of reflux events (acidic and weakly acidic), did not differ between the two groups. However, both PSPW index and MNBI were lower in Group A (P < .001). A strong inverse linear correlation was found between bile reflux and both MNBI (Pearson's test; R = -0.714; P < .001) and PSPW index (R = -0.722; P < .001). CONCLUSIONS AND INFERENCES: Compared to acid reflux alone, the presence of bile in an acidic esophageal environment is associated with more severe heartburn, lesser relief from PPI therapy, higher impairment of esophageal mucosal integrity and less effective chemical clearance.

Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model.

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.

Infant with bilious emesis.

Clinical findings and imaging studies revealed an additional cause for concern.

Evaluation of valve function in antireflux biliary metal stents.

BACKGROUND: To overcome duodenobiliary reflux induced by biliary stents, antireflux valve (ARV) biliary stents have been developed and showed improvement in stent patency. However, negative study results have also been reported because stent patency may be decreased by the malfunction of ARV itself. Given such mixed results, the true efficacy of ARV remains unknown and the mechanism of its dysfunction needs to be clearly elucidated. The aim of this study was to investigate the exact mechanism of ARV dysfunction using in vitro phantom models. METHODS: Two experimental models were designed to evaluate two important environmental factors suspected to cause ARV malfunction, i.e. bile flow and pH. Three types of ARV metal stents from different companies were used for the experiments: a funnel type ARV, a windsock type ARV, and a wine glass-shaped ARV. Ten stents of each type were tested (five stents in the bile flow phantom model, and another five stents in the duodenal pH environmental model). To determine ARV malfunction, ARV-induced flow resistance was measured using a custom-made testing device. All stents from the two models were removed every 2 weeks for 12 weeks after stent insertion and were evaluated on morphological and functional changes of the ARV. RESULTS: Only ARV of wine glass-shaped ARV was morphologically changed due to silicone bond detachment in the bile flow model. All types of ARV were morphologically changed in the pH model. The morphological changes of ARV influenced the flow resistance. The antegrade pressure gradients were increased over time in the pH model (p < 0.05). CONCLUSIONS: Morphological change of the ARVs may induce dysfunction of ARV metal stents, which is mainly due to duodenal pH environment. In the future, development of new ARV that is not affected by duodenal environmental factors can be expected to improve stent patency.

Gallbladder mucosal lesions associated with high biliary amylase irrespective of pancreaticobiliary maljunction.

BACKGROUND: Previous studies have focused on the presence of reflux in selected cohorts with pancreaticobiliary maljunction (PBM), but little is known regarding the wider incidence of occult reflux and associated mucosal changes. We aimed to correlate gallbladder mucosal abnormalities with objective evidence of PBM and occult pancreaticobiliary reflux (PBR) in an Australian population undergoing cholecystectomy. METHODS: Patients undergoing cholecystectomy between September 2010 and September 2012 were eligible for inclusion. Demographic and pre-operative clinical data were collated and entered into a pre-defined database. Operative cholangiograms were routinely performed and the presence of PBM noted. Gallbladder bile samples were analysed for bilirubin (<20 µmol/L), amylase (<100 U/L) and lipase (<70 U/L) levels. Evidence of PBR was correlated with gallbladder mucosal findings. RESULTS: A total of 305 cholecystectomies were performed for biliary colic (73%), choledocholithiasis (9%), cholecystitis (8.4%) and pancreatitis (6.4%). A total of 12.7% had cholangiographic evidence of PBM and 11.9% possessed gallbladder mucosal changes. Overall, 7.7% had increased biliary amylase, which was associated with significantly higher rates of gallbladder intestinal metaplasia (33% versus 8.6%; P = 0.012). Elevated biliary amylase was also higher in patients with prior pancreatitis (P = 0.02) or choledocholithiasis (P < 0.01). The presence of PBM did not predict for the presence of PBR. CONCLUSION: PBR is associated with an increased frequency of gallbladder mucosal metaplasia, irrespective of the presence of PBM. Objectively identified reflux represents an additional indication for cholecystectomy but the long-term consequences for extra-hepatic biliary malignancy remain unknown and warrant further investigation. Methods of objectively identifying PBR pre-operatively require further investigation.

Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis.

BACKGROUND & AIMS: A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Pericanalicular actin is known to accumulate during obstructive cholestasis. Therefore, we hypothesized that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response to obstructive cholestasis. METHODS: In vivo investigations were performed in a bile duct-ligated mouse model. Actomyosin contractility was assessed using sandwich-cultured rat hepatocytes transfected with various fluorescently labeled proteins and pharmacological inhibitors of actomyosin contractility. RESULTS: Actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex; and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8µm). Importantly, we show that these vesicles aid in the regurgitation of bile from the bile canaliculi. CONCLUSION: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis. LAY SUMMARY: Bile canaliculi expand and contract in response to the amount of secreted bile, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs, which carry away excess bile to prevent bile build up in the canaliculi.

Biliary Pancreatitis. Liver Function Tests and Common Biliopancreatic Channel Kinetics--Biliopancreatic Reflux.

OBJECTIVE: To determine the prevalence of biliopancreatic reflux (BPR) in patients with biliary pancreatitis (BP) undergoing elective cholecystectomy with intraoperative cholangiography (IOC) in comparison with a control group of symptomatic cholelithiasis (CG). PATIENTS AND METHODS: Retrospective review of 107 consecutive BP cases. BPR was determined by IOC and liver function tests (LFT) were recorded at admission (A), 48hours, and preoperative examination (P). LFT analysis between A and P were analysed between groups with respect to BPR, time interval to cholecystectomy within the same group and by determination of observed value/maximum normal value ratio (OV/MNV). RESULTS: BPR incidence was 38.3% in BP in comparison with 5% in CG (p=0.0001) it was independent from interval time to cholecystectomy, in contrast with Odditis, suggesting an anatomical condition for CCBP and a functional one for Odditis. LFT analysis showed no differences in relation to BPR incidence. LFT excluding AP and GGT returned to normal values with significant differences in OV/MNV when BPR was present which points to an increased cholestasis in BPR group. US dilatation of CBD was noted in 10.3% and was associated to CCBP. CONCLUSIONS: BPR in BP increases cholestasis and contributes to confusion in the estimation of common bile duct stones increasing ERCP-EE rates. US and biochemical markers of CBDS show a low specificity due to BPR-CCBP which suggests that MRI-cholangiography is a mandatory exploration before ERCP-EE examination.

Pancreatobiliary reflux in individuals with a normal pancreaticobiliary junction: a prospective multicenter study.

BACKGROUND: Pancreatobiliary reflux (PBR) can occur in individuals without pancreaticobiliary maljunction. The aim of this study was to elucidate the incidence of PBR in individuals with a normal pancreaticobiliary junction and its impact on the biliary tree. METHODS: Data were prospectively collected from 15 centers on 420 patients with a morphologically normal pancreaticobiliary junction who had undergone bile sampling and measurement of the biliary amylase level. We investigated the incidence and predictive factors for high biliary amylase levels (HBAL), as well as the relationship of HBAL with biliary malignancy. RESULTS: Twenty-three patients (5.5%) showed HBAL (≥10,000 IU/L). Univariate analysis showed that risk factors for the elevation of biliary amylase levels were the existence of a relatively long common channel (≥5 mm), acute pancreatitis, and papillitis. Multivariate analysis revealed that only the existence of a relatively long common channel was a significant factor for PBR. Biliary amylase levels in patients with a relatively long common channel were significantly higher than in patients without a long common channel (12,333 vs. 2,070 IU/L, P = 0.001). The incidence of HBAL (P < 0.001), as well as the overall biliary amylase levels (P = 0.007) were significantly higher in patients with gallbladder cancer than in those without gallbladder cancer. CONCLUSIONS: The PBR was frequently observed in individuals with a relatively long common channel. Patients showing HBAL with normal pancreaticobiliary junction are at high risk for gallbladder cancer.

How reflux causes symptoms: reflux perception in gastroesophageal reflux disease.

In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.

Biliary reflux detection in anomalous union of the pancreatico-biliary duct patients.

AIM: To demonstrate the imaging findings of biliopancreatic and pancreatico-biliary reflux in patients with anomalous union of the pancreatico-biliary duct (AUPBD) on gadoxetic acid-enhanced functional magnetic resonance cholangiography (fMRC). METHODS: This study included six consecutive patients (two men and four women; mean age 47.5 years) with AUPBD. All subjects underwent endoscopic retrograde cholangiopancreatography (ERCP); one subject also underwent bile sampling of the common bile duct (CBD) to measure the amylase level because his gadoxetic acid-enhanced fMRC images showed evidence of pancreatico-biliary reflux of pancreatic secretions. Of the five patients with choledochal cysts, four underwent pylorus-preserving pancreaticoduodenectomy. RESULTS: The five cases of choledochal cysts were classified as Todani classification I. In three of the six patients with AUPBD, injected contrast media reached the distal CBD and pancreatic duct on delay images, suggesting biliopancreatic reflux. In two of these six patients, a band-like filling defect was noted in the CBD on pre-fatty meal images, which decreased in size on delayed post-fatty meal images, suggesting pancreatico-biliary reflux of pancreatic secretions, and the bile sampled from the CBD in one patient had an amylase level of 113,000 IU/L. In one of the six patients with AUPBD, contrast media did not reach the distal CBD due to multiple CBD stones. CONCLUSION: Gadoxetic acid-enhanced fMRC successfully demonstrated biliopancreatic reflux of bile and pancreatico-biliary reflux of pancreatic secretions in patients with AUPBD with and without choledochal cysts.

The evaluation of oesophageal function in patients with different types of oesophageal metaplasia.

AIM: To evaluate the oesophageal function in patients with different types of oesophageal metaplasia and in cases with dysplasia on the basis of the Montreal definition of gastro-oesophageal reflux disease. PATIENTS AND METHODS: 270 consecutive patients [M/F 151/119, mean age 54.2 years (19-84)] with endoscopic and histological evidence of oesophageal metaplasia were prospectively studied: patients with specialized intestinal metaplasia (SIM, n = 109) and patients without SIM (n = 161). Patients with SIM were subdivided into a dysplasia-positive (n = 34) and a dysplasia-negative (n = 75) group. All patients underwent reflux symptom analysis, oesophageal manometry, and simultaneous 24-hour pH and biliary reflux monitoring. RESULTS: Patients with SIM were significantly older and had a significantly higher body mass index than patients without SIM. A significant male predominance was observed in patients with SIM and dysplasia compared to the dysplasia-negative group. The clinical symptom spectrum and the prevalence of erosive oesophageal lesions were similar in all groups. Patients with SIM had longer metaplastic segments, which was further increased in the dysplasia-positive group. During oesophageal manometry, pH and biliary reflux monitoring, patients with SIM had more severe alterations than patients without SIM, and these were further increased in patients with SIM and dysplasia. CONCLUSIONS: Patients with SIM had more severe oesophageal function abnormalities than those with other types of oesophageal metaplasia (e.g. gastric). The oesophageal function was further impaired if dysplasia was present in the metaplastic mucosa.

What influences the acidity in the gastric conduit in patients who underwent cervical esophagogastrostomy for cancer?

The aim of this study was to determine the factors influencing acidity in the gastric conduit after esophagectomy for cancer. Acidity and bile reflux in the stomach and in the gastric conduit were examined by 24-h pH monitoring and bilimetry in 40 patients who underwent transthoracic subtotal esophagectomy followed by esophageal reconstruction using a gastric conduit, which was pulled up to the neck through a posterior mediastinal route in 17 patients, through a retrosternal route in 10 patients, and through a subcutaneous route in 13 patients. They were examined at 1 week before surgery, at 1 month after surgery, and at 1 year after surgery. Helicobacter pylori infection was examined pathologically and using the (13) C-urea breath test. The factors influencing acidity of the gastric conduit were analyzed using the stepwise regression model. Gastric acidity assessed by percentage (%) time of pH < 4 was reduced after surgery and was significantly less in patients with H. pylori infection compared with those without H. pylori infection throughout the period from 1 week before surgery to 1 year after surgery. Duodenogastric reflux (DGR) assessed by % time absorbance > 0.14 into the lower portion of the gastric conduit was significantly increased after surgery throughout the period from 1 month after surgery to 1 year after surgery. Multivariate analysis showed that the acidity in the gastric conduit was influenced by H. pylori infection and DGR at 1 month after surgery, and by H. pylori infection and the route for esophageal reconstruction at 1 year after surgery. Acidity in the gastric conduit was significantly decreased after surgery. Acidity in the gastric conduit for esophageal substitutes is influenced by H. pylori infection and surgery. DGR influences the gastric acidity in the short-term after surgery, but not in the long-term after surgery.

Pancreaticobiliary reflux in patients with a normal pancreaticobiliary junction: Pathologic implications.

Knowledge on pancreaticobiliary reflux in normal pancreaticobiliary junction and its pathologic implications has experienced tremendous progress during the last few years. This editorial reviews the current knowledge on this condition and its pathological implications on gallbladder diseases. The following aspects were defined appropriate for discussion: (1) Evidence of carcinogenesis associated with pancreaticobiliary reflux; (2) Evidence of pancreaticobiliary reflux in normal pancreaticobiliary junction; and (3) Evidence of sphincter of Oddi (SO) dysfunction as a cause of pancreaticobiliary reflux in normal pancreaticobiliary junction. The articles reviewed were selected and classified according to five levels of evidence: Level I, meta-analysis double-blind randomized clinical trials, Level II, cohort non-blinded studies and non-randomized clinical trials, Level III, good quality case-control studies and non-randomized cohort studies, Level IV, case series and poor quality case-control studies, and Level V, case report articles and experts' opinion. Evidence levels II, III, IV and V were found to support biliary carcinogenesis associated with pancreaticobiliary reflux in normal and abnormal pancreaticobiliary junction. The same levels of evidence were found to support the common occurrence of pancreaticobiliary reflux in normal pancreaticobiliary junction, and SO dysfunction as the most plausible cause of this condition. Although an important body of research has been published regarding pancreaticobiliary reflux in normal pancreaticobiliary junction and its clinical significance, the current evidence does not fully support what has been suggested. Studies with evidence level I have not been undertaken. This is a fascinating subject of study, and if finally supported by evidence level I, the importance of this condition will constitute a major breakthrough in biliary pathology.

Gastric juice acidity in upper gastrointestinal diseases.

AIM: To search the independent factors determining gastric juice acidity and to investigate the acidity of gastric juices in various benign and malignant upper gastrointestinal diseases. METHODS: Fasting gastric juice acidity of 165 healthy subjects and 346 patients with esophageal ulcer (n = 21), gastric ulcer (n = 136), duodenal ulcer (n = 100) or gastric cancer (n = 89) were measured and compared. Additionally, gastric specimens were taken from the antrum and body for rapid urease test and histological examination. RESULTS: Multivariate analysis revealed that bile stain of gastric juice, high acute inflammatory score of the corpus, and atrophy of the corpus were independent risk factors for the development of gastric hypoacidity with odds ratios of 3.1 (95% CI: 1.3-7.3), 3.1 (95% CI: 1.2-7.9) and 3.5 (95% CI: 1.3-9.2). Esophageal ulcer and duodenal ulcer patients had a lower pH level (1.9 and 2.1 vs 2.9, both P < 0.05) of gastric juices than healthy subjects. In contrast, gastric ulcer and gastric cancer patients had a higher pH level (3.4 and 6.6 vs 2.9, both P < 0.001) than healthy controls. Hypoacidity existed in 22%, 5%, 29%, 5% and 88% of healthy subjects, esophageal ulcer, gastric ulcer, duodenal ulcer and gastric cancer patients, respectively. CONCLUSION: Bile reflux, atrophy and dense neutrophil infiltrate of the corpus are three independent factors determining the acidity of gastric juice.

Clinical study on the treatment of gastroesophageal reflux by acupuncture.

OBJECTIVE: To explore the clinical efficacy and safety of acupuncture in treating gastroesophageal reflux (GER). METHODS: Sixty patients with confirmed diagnosis of GER were randomly assigned to two groups. The 30 patients in the treatment group were treated with acupuncture at acupoints Zhongwan (CV 12), bilateral Zusanli (ST36), Sanyinjiao (SP6), and Neiguan (PC6), once a day, for 1 week as a therapeutic course, with interval of 2-3 days between courses; the 30 patients in the control group were administered orally with omeprazole 20 mg twice a day and 20 mg mosapride thrice a day. The treatment in both group lasted 6 weeks. Patients' symptoms and times of reflux attacking were recorded, the 24-h intraesophageal acid/bile reflux were monitored, and the endoscopic feature of esophageal mucous membrane was graded and scored at three time points, i.e., pre-treatment (T0), immediately after ending the treatment course (T1) and 4 weeks after it (T2). Besides, the adverse reactions were also observed. RESULTS: Compared with those detected at T0, 24-h intraesophageal pH and bile reflux, endoscopic grading score and symptom score were all decreased significantly at T1 in both groups similarly (P<0.01), showing insignificant difference between groups (P>0.05). These indices were reversed at T2 to high level in the control group (P<0.05), but the reversion did not occur in the treatment group (P>0.05). No serious adverse reaction was found during the therapeutic period. CONCLUSION: Acupuncture can effectively inhibit the intraesophageal acid and bile reflux in GER patients to alleviate patients' symptoms with good safety and is well accepted by patients.

The role of acid and bile reflux in oesophagitis and Barrett's metaplasia.

The precise mechanisms whereby gastro-oesophageal reflux disease causes reflux oesophagitis and Barrett's oesophagus are not clear, even though these diseases have been known to be linked for many years. Recent studies indicate a role for the reflux-induced inflammatory response of oesophageal squamous epithelial cells and the immune cells in the pathogenesis of reflux oesophagitis. Although reflux oesophagitis commonly heals with oesophageal squamous cell regeneration, in some individuals the oesophagus heals through the process of metaplasia, a condition termed Barrett's oesophagus. Recent studies indicate that individual differences in the reflux-mediated response of oesophageal squamous epithelial cells in the type of immune response and/or in signalling pathways that regulate cell proliferation or cell phenotype may determine whether the oesophagus heals with the regeneration of squamous cells or through Barrett's metaplasia.

Emerging concepts of bile reflux in the constellation of gastroesophageal reflux disease.

RATIONALE: Reflux of gastric and duodenal contents in patients with gastroesophageal reflux disease (GERD) has been postulated as a major cause of complications, such as Barrett's esophagus or malignant degeneration. FINDINGS: We present a summary of experimental, clinical, and immunohistochemical studies that show that acid and bile reflux are increased in patients who suffer from GERD, are the key factor in the pathogenesis of Barrett's esophagus, and are possibly related to the development of esophageal adenocarcinoma.

Laparotomy attenuates lipopolysaccharide-induced gastric bleeding in the rat.

Lipopolysaccharide (LPS) increases systemic inflammation and causes duodenogastric reflux of bile and gastric bleeding. Laparotomy prevents gastric injury from the luminal irritant bile, but its effects on LPS-induced gastric injury are unknown. We hypothesized that laparotomy would diminish inflammation and attenuate gastric bleeding caused by LPS. In the rat, laparotomy, done either before or after administration of LPS, attenuated LPS-induced bile reflux, gastric bleeding, and cyclooxygenase-2, but not inducible nitric oxide synthase, expression when compared to controls given LPS. Laparotomy also blunted LPS-induced changes in serum cytokine production. These data suggest that laparotomy has gastroprotective effects by preventing LPS-induced bile reflux and gastric bleeding and by a mechanism mediated, at least in part by cyclooxygenase-2.

[Functional endoscopy : the physiological and pathophysiological basis of reflux disease, diagnosis and therapy]. / Funktionelle Endoskopie : Physiologische und pathophysiologische Grundlagen der Refluxerkrankung, ihre Diagnostik und Therapie.

ENT specialists and gastroenterologists are increasingly confronted with the question of how to recognize and evaluate extra-esophageal complications of reflux. Both specialities need to collaborate, since they are connected via the esophagus, and both need to know more about the speciality of their neighbor than was hitherto usual. This publication presents the observations and measurements of little-known physiological functions. This is followed by an attempt to define the border between healthy and diseased. Finally, the possible consequences of functional disorders are described. The leap from observation of function to the microcosm of biochemical links is discussed and supported using experimental work. This overview highlights the limitations of our current knowledge. The success of functional endoscopy in terms of therapeutic approaches is immense. The required therapy is finally based on a clear diagnostic concept; probatory therapy is a waste of money.