Opioid Exposure Differentially Impacts Esophageal Body Contraction Over the Lower Esophageal Sphincter.

BACKGROUND & AIMS: Studies with limited sample sizes have investigated association of chronic opioid use with motility disorders of esophagogastric junction and esophageal body peristalsis. Our aims were to use a large cohort of patients to assess (1) the impact of opioid exposure on clinical and manometric characteristics, and (2) the association of opioid exposure with higher long-term symptom burden. METHODS: Patients recruited from a tertiary medical center who underwent high-resolution manometry (HRM) between 2007 and 2018 were included. Demographics, opiate exposure, clinical symptoms, and HRM parameters were compared. Patient-Reported Outcomes Measurement Information System-Gastrointestinal swallowing domain (PROMIS-GI swallowing domain) and Eckardt score were administered via phone interviews in patients with hypercontractile esophagus (HE) or distal esophageal spasm (DES) to determine long-term symptom burden between opioid and nonopioid users. RESULTS: Our cohort included 4075 patients (869 with opiate exposure with median morphine milligram equivalent [interquartile range] of 30 [10-45]). Patients in the opioid group were significantly more likely to have dysphagia (65% vs 51%, P < .01) and diagnosis of DES (11% vs 5%, P < .01) and HE (9% vs 3%, P < .01). Partial opioid agonists were not associated with motility abnormalities. Patients on opioids had significantly higher symptom burden on median (interquartile range) follow-up of 8.9 years (5.8-10.4) post manometric diagnosis with median PROMIS-GI swallowing domain score of 21.5 (17-25) compared with the nonopioid group at 15 (9.8-21, P = .03). CONCLUSIONS: Nearly 2 of 3 patients with opioid exposure undergoing HRM have dysphagia and more than 25% of them with dysphagia as the primary symptom have a diagnosis of either DES or HE. Opioid users with spastic disorders have higher symptom burden long-term compared with nonopioid users.

Mucosal impedance testing: A new diagnostic testing in gastroesophageal reflux disease.

Current diagnostic testing for gastroesophageal reflux disease (GERD) include endoscopy, ambulatory pH and intraluminal impedance monitoring. However, they are suboptimal and do not measure chronicity of reflux. Recently, a mucosal impedance (MI) device has been developed to measure esophageal epithelial conductivity changes, a marker of chronic GERD. The aim of this review is to summarize the use of MI testing (MIT) for the evaluation and management of esophageal disease. MIT is a minimally invasive and simple through-the-scope procedure performed during endoscopy. It allows for a rapid derivation of MI values within seconds without an uncomfortable overnight pH- impedance catheter. The MI values can correlate with histological findings of epithelial barrier dysfunction, normalize with effective treatment, and show promise for differentiating GERD from non-GERD conditions such as eosinophilic esophagitis (EoE). In conclusion, endoscopic MIT measurement can differentiate esophageal disorders instantly during endoscopy. It may not only serve as an important tool in diagnosing of GERD but also help guide therapy in clinically difficult situations as a surrogate to predict the treatment response.

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. RESULTS: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. CONCLUSION: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.

Association Between Response to Acid-Suppression Therapy and Efficacy of Antireflux Surgery in Patients With Extraesophageal Reflux.

BACKGROUND & AIMS: The effectiveness of antireflux surgery (ARS) varies among patients with extraesophageal manifestations of gastroesophageal reflux disease (GERD). By studying a cohort of patients with primary extraesophageal symptoms and abnormal physiologic markers for GERD, we aimed to identify factors associated with positive outcomes from surgery, and compare outcomes to those with typical esophageal manifestations of GERD. METHODS: We performed a retrospective cohort study to compare adult patients with extraesophageal and typical reflux symptoms who underwent de novo ARS from 2004 through 2012 at a tertiary care center. All 115 patients (79 with typical GERD and 36 with extraesophageal manifestations of GERD) had evidence of abnormal distal esophageal acid exposure based on pH testing or endoscopy. The principle outcome was time to primary symptom recurrence after surgery, based on patient reports of partial or total recurrence of symptoms at follow-up visits. Patients were followed up for a median duration of 66 months (interquartile range, 52-77 mo). RESULTS: The median time to recurrence of symptoms in the overall cohort was 68 months (11.5 months in the extraesophageal cohort vs >132 months in the typical cohort). Symptom recurrence after ARS was associated with having primarily extraesophageal symptoms (adjusted hazard ratio, 2.34; 95% confidence interval, 1.31-4.17) and poor preoperative symptom response to acid-suppression therapy (AST) (hazard ratio, 3.85; 95% confidence interval, 2.05-7.22). Patients with primary extraesophageal symptoms who had a full or partial preoperative AST response experienced lower rates of symptom recurrence compared to patients with poor AST response (P < .01). The rate of symptom recurrence was lowest among patients with primary typical reflux symptoms who had a partial or full symptom response to AST (P < .01). The severity of acid reflux on pH testing, symptom indices, severity of esophagitis, and hiatal hernia size were not associated with symptom response. CONCLUSIONS: In a retrospective study, we found the effectiveness of ARS to be less predictable in patients with extraesophageal symptoms of GERD than in patients with typical GERD. Response to AST before surgery was associated with ARS effectiveness in patients with extraesophageal reflux symptoms. Caution should be exercised when advocating ARS for patients with extraesophageal symptoms that do not respond to AST.

Methods to identify saline-contaminated electrolyte profiles.

BACKGROUND: With providers becoming more selective in ordering daily chemistry profiles, it is critical that profiles ordered are accurate. Contaminated electrolyte profiles are an overlooked and potentially dangerous source of inaccurate clinical data. This study aimed to develop a method to accurately identify electrolyte profiles contaminated with normal saline to prevent reporting of erroneous measurements. METHODS: We conducted a retrospective cohort study of 76,497 electrolyte profiles from 5032 patients in a deidentified clinical database of all patients in the electronic medical record at Vanderbilt University Medical Center. Five methods to identify errors in quantification based on either deviations from observed concentration distributions or expected numerical changes from saline contamination were developed and tested. Potentially contaminated measurements were validated based on changes in electrolyte concentrations observed in the subsequent sample. RESULTS: Identification of erroneous electrolyte profiles based on absolute and percent deviations from normal variation rarely resulted in >50% of identified samples validated as contaminated. A targeted methodology based on expected changes in calcium and chloride concentrations due to saline contamination validated approximately 80% of identified samples when higher thresholds for changes in electrolyte concentration were used and 50% of identified samples when lower thresholds were used. CONCLUSIONS: Targeted methodology based on changes in chloride and calcium successfully identified electrolyte profiles suspicious for contamination. Implementation of this methodology could prevent misinterpretation of a patient's clinical course, inappropriate interventions, and unwarranted changes in treatment strategy.

Extra-esophageal manifestations of GERD: who responds to GERD therapy?

Gastroesophageal reflux disease (GERD) is a common disease that is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms. In addition to the esophageal manifestations of heartburn and regurgitation, the role of GERD in causing extra-esophageal symptoms, such as laryngitis, asthma, cough, chest pain, and dental erosions, is increasingly recognized with renewed interest. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPI) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. In those who are unresponsive to such therapy, other diagnostic testing such as impedance/pH monitoring may be reasonable in order to exclude continued acid or weakly acid reflux. Recent data suggest that patients with extra-esophageal symptoms who have concomitant typical symptoms, moderate-sized hiatal hernia and moderate reflux on pH testing may respond better to acid suppressive therapy. This group only accounts for 20-30 % of patients commonly referred for suspected GERD. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal signs and symptoms and continued PPI therapy in this group is not recommended.

Outcomes of hook of hamate fracture excision in high-level amateur athletes.

PURPOSE: To determine the overall long-term postoperative clinical and functional results of high-level amateur athletes after hook of hamate excision, based on complications; return to sport; Disabilities of the Arm, Shoulder, and Hand (DASH) score; and a self-reported questionnaire. METHODS: We evaluated 11 patients representing 12 cases of hook of hamate excision. All patients were high-level amateur athletes (rising collegiate or collegiate level). We performed a retrospective chart review to elicit information pertaining to the patient's injury. We assessed long-term postoperative outcomes with a self-reported questionnaire, the DASH form, and the DASH Sport/Performing Arts Module form. RESULTS: All patients successfully returned to full participation in their respective sports an average of 6 weeks after surgery. The average postoperative DASH score was less than 1, and all patients scored a 0 on the DASH Sports form. There was a significant improvement in preoperative pain after surgical intervention. There was no significant difference between preinjury and postoperative performance scores. Finally, every patient was very satisfied with the surgical outcome. There was only 1 postoperative complication in which a patient developed transient ulnar nerve paresthesias, which completely resolved by 6 weeks after surgery. CONCLUSIONS: Surgical excision of hook of hamate fractures in high-level amateur athletes allows for successful return to sports participation at preinjury performance levels, achievement of normal function as measured by validated objective outcome measures, significant reduction in pain, and high overall patient satisfaction. We consider surgical excision to be a safe and effective technique to restore normal function and hasten return to play for high-level amateur athletes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Treatment of Refractory Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is a common disorder that is treated with lifestyle modification, weight loss, and medications, such as proton pump inhibitors (PPIs). An empiric course of PPI therapy is an effective and cost-effective strategy for the management of GERD. However, in some patients, PPI therapy and lifestyle changes are inadequate to control symptoms. When there is persistence of symptoms despite empiric therapy, patients are labeled as having refractory GERD. This label underestimates the wide differential diagnosis of foregut pathology that can mimic symptoms of GERD. A careful history of symptoms, response to PPI therapy, adherence, compliance, and timing helps elucidate if medication has been helping. When patients are refractory, alternative etiologies of GERD must be considered. Many of these alternatives can be determined on an upper endoscopy or with complementary testing, such as high-resolution esophageal manometry or gastric emptying testing as symptoms dictate. When an alternative cause is not found and index endoscopy is normal, additional testing with either traditional pH or impedance testing can be completed based on prior examination results and response to therapy. Further therapy, including medical, endoscopic, or surgical, can then be targeted at the etiology.

Advances in the Diagnosis and Treatment of GERD: New Tricks for an Old Disease.

PURPOSE OF REVIEW: Gastroesophageal reflux disease (GERD) is a common diagnosis encountered by both primary care providers and specialists, but despite its prevalence, there are limitations in the current diagnostic tests for GERD. Once an accurate diagnosis is made, treatment options can be offered, and this field continues to burgeon with options. In this review, we seek to review the recent advances in GERD diagnostics and subsequent treatment options. RECENT FINDINGS: Novel impedance markers and novel techniques (mucosal impedance testing, salivary pepsin, high-resolution manometry, and narrow-band imaging) have shown promise in diagnosing GERD. Advances in medical therapy, including potassium-competitive acid blockers and bile acid sequestrants, along with advances in invasive therapy (transoral incisionless fundoplication, endoscopic radiofrequency, electrical stimulation of the LES, and magnetic sphincter augmentation) have provided additional options for therapy for GERD beyond PPI and anti-reflux surgery. Novel impedance markers and techniques will provide further clarity on mucosal integrity and the barrier function allowing improved diagnostic accuracy of GERD. Improvements in medical and invasive therapy will expand GERD therapy.

Nutritional Consideration in Celiac Disease and Nonceliac Gluten Sensitivity.

Celiac disease is an autoimmune disorder due to the inflammatory response to gluten in genetically predisposed individuals. It causes an enteropathy associated with several nutritional complications. Strict compliance to a gluten-free diet (GFD) is the current primary therapy. Nonceliac gluten sensitivity (NCGS) is a condition in which gluten ingestion leads to systemic symptoms but is not associated with small bowel atrophy or abnormal celiac serologies. A GFD heals celiac disease enteropathy and improves symptoms in NCGS. However, a long-term GFD can be associated with nutritional deficiencies and requires monitoring and guidance.

Recent advances in diagnostic testing for gastroesophageal reflux disease.

INTRODUCTION: Gastroesophageal reflux disease (GERD) has a large economic burden with important complications that include esophagitis, Barrett's esophagus, and adenocarcinoma. Despite endoscopy, validated patient questionnaires, and traditional ambulatory pH monitoring, the diagnosis of GERD continues to be challenging. Areas covered: This review will explore the difficulties in diagnosing GERD with a focus on new developments, ranging from basic fundamental changes (histology and immunohistochemistry) to direct patient care (narrow-band imaging, impedance, and response to anti-reflux surgery). We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: Important advances in novel parameters in intraluminal impedance monitoring such as baseline impedance monitoring has created some insight into alternative diagnostic strategies in GERD. Recent advances in endoscopic assessment of esophageal epithelial integrity via mucosal impedance measurement is questioning the paradigm of prolonged ambulatory testing for GERD. The future of reflux diagnosis may very well be without the need for currently employed technologies and could be as simple as assessing changes in epithelia integrity as a surrogate marker for GERD. However, future studies must validate such an approach.

Consequences of bariatric surgery on oesophageal function in health and disease.

Obesity is a continuing epidemic with substantial associated morbidity and mortality. Owing to the limitations of lifestyle modifications and pharmacological options, bariatric surgery has come to the forefront as an efficient method of achieving sustained weight loss and decreasing overall mortality in comparison with nonsurgical interventions. The most frequently performed bariatric operations are either purely restrictive, such as laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG), or restrictive-malabsorptive, such as the Roux-en-Y gastric bypass (RYGB). Each operation results in weight loss, but can also have unintended effects on the health of the oesophagus. Specifically, operations might lead to oesophageal dilation or the development of GERD. LAGB is the best-studied procedure with notable evidence for postoperative worsening of GERD and pseudo-achalasia, which increases lower oesophageal pressure and causes aperistalsis. In some studies, LSG initiates not only a worsening of GERD, but also the formation of de novo GERD in patients without preoperative GERD symptoms. RYGB demonstrates the most profound evidence for improvement of GERD symptoms and preservation of oesophageal motility. Future high-quality studies will be required to better understand the interaction between bariatric surgery and oesophageal disease.