Eosinophilic Esophagitis Histologic Scoring System: Correlation with Histologic, Endoscopic, and Symptomatic Disease and Clinical Use.

BACKGROUND: The eosinophilic esophagitis histologic scoring system (EoEHSS) was developed to enhance the diagnostic standard of peak eosinophil count (PEC) in evaluating disease activity in EoE. AIMS: (1) Correlate the EoEHSS and PEC to measures of symptomatic and endoscopic disease activity, (2) Correlate EoEHSS grade and stage subcomponents to clinical, radiology, and endoscopic markers of fibrotic disease, (3) Evaluate EoEHSS remission in asymptomatic patients with PEC < 15 eosinophils per high powered field (eos/hpf). METHODS: Secondary analysis of prospective cohort data of 22 patients with EoE that underwent dietary therapy and endoscopy at 3 time points. Active disease was defined by EoEHSS grade or stage > 0.125, symptomatic disease by EoE symptom activity index > 20, endoscopic disease by endoscopic reference score > 2, and histologic disease by PEC ≥ 15 eos/hpf. EoEHSS remission was defined by esophageal inflammation (EI) grade of 0-1, EI stage of 0, total grade ≤ 3, and total stage ≤ 3. RESULTS: EoEHSS grade and stage did not correlate with symptomatic disease but did with endoscopic and histologic disease. PEC showed similar correlation pattern. Abnormal grade and stage had strong sensitivity (87-100%) but poor specificity (11-36%) to detect symptomatic, endoscopic, and histologic disease activity. Lamina propria fibrosis was evaluated in 36% of biopsies and did not correlate with minimum esophageal diameter. Out of 14 patients who were in complete symptomatic, endoscopic, and histologic remission, 8 met criteria for EoEHSS remission. CONCLUSION: The positive and negative correlations of EoEHSS to specific measures of symptomatic, histologic, and endoscopic activity suggest that it provides complementary information in EoE.

Optimized Surveillance Intervals Following Endoscopic Eradication of Dysplastic Barrett's Esophagus: An International Cohort Study.

BACKGROUND & AIMS: Recommended surveillance intervals after complete eradication of intestinal metaplasia (CE-IM) after endoscopic eradication therapy (EET) are largely not evidence-based. Using recurrence rates in a multicenter international Barrett's esophagus (BE) CE-IM cohort, we aimed to generate optimal intervals for surveillance. METHODS: Patients with dysplastic BE undergoing EET and achieving CE-IM from prospectively maintained databases at 5 tertiary-care centers in the United States and the United Kingdom were included. The cumulative incidence of recurrence was estimated, accounting for the unknown date of actual recurrence that lies between the dates of current and previous endoscopy. This cumulative incidence of recurrence subsequently was used to estimate the proportion of patients with undetected recurrence for various surveillance intervals over 5 years. Intervals were selected that minimized recurrences remaining undetected for more than 6 months. Actual patterns of post-CE-IM follow-up evaluation are described. RESULTS: A total of 498 patients (with baseline low-grade dysplasia, 115 patients; high-grade dysplasia [HGD], 288 patients; and intramucosal adenocarcinoma [IMCa], 95 patients) were included. Any recurrence occurred in 27.1% and dysplastic recurrence occurred in 8.4% over a median of 2.6 years of follow-up evaluation. For pre-ablation HGD/IMCa, intervals of 6, 12, 18, and 24 months, and then annually, resulted in no patients with dysplastic recurrence undetected for more than 6 months, comparable with current guideline recommendations despite a 33% reduction in the number of surveillance endoscopies. For pre-ablation low-grade dysplasia, intervals of 1, 2, and 4 years balanced endoscopic burden and undetected recurrence risk. CONCLUSIONS: Lengthening post-CE-IM surveillance intervals would reduce the endoscopic burden after CE-IM with comparable rates of recurrent HGD/IMCa. Future guidelines should consider reduced surveillance frequency.

Histologic response to steroids in eosinophilic esophagitis is dependent on delivery compound.

Topical steroids are commonly used in treatment of eosinophilic esophagitis (EoE), but currently there is lack of data to clarify most effective regimen. We aimed to study the achievement of histologic remission using the same dose of budesonide in two different delivery formulations. Patients with established EoE treated with pharmacy compounded budesonide capsule or budesonide Rincinol gel (both 3 mg twice daily) were studied retrospectively. Those with pre-treatment and post-treatment histologic assessment were included with main endpoint being histologic remission. 103 patients (62 gel, 41 capsule) were included, with higher rate of histologic remission with gel (84 vs. 59%, P=0.004). A subset of patients in both groups had lack of steroid response (<50% drop in eosinophils) (15% for gel, 32% for capsule). Formulation/delivery vehicle of steroid treatments to esophageal mucosa in EoE appears important for treatment efficacy, with budesonide gel having higher likelihood of histologic remission compared to budesonide capsules in our population. A truly steroid refractory group appears likely in our population. Larger, prospective studies may help clarify best regimen of topical steroids in EoE and may work to identify patients likely to benefit from alternative therapies.

Prevalence of Barrett's Esophagus in Female Patients With Scleroderma.

INTRODUCTION: Systemic sclerosis or scleroderma (SSc) is a chronic autoimmune disease that renders the esophagus prone to significant gastroesophageal reflux due to impaired esophageal clearance and reduced lower esophageal sphincter pressure. The reported prevalence of Barrett's esophagus (BE) in women with SSc varies from 2% to 37% and is derived from older studies with small sample sizes. We aimed to assess the prevalence of BE in a large cohort of women with SSc. METHODS: Women with SSc referred from the Mayo Clinic Arizona Rheumatology Clinic who completed esophagogastroduodenoscopy between 2002 and 2020 were included. Demographic and high-resolution manometry data were evaluated. The diagnosis of scleroderma was confirmed by an expert rheumatologist. The BE diagnosis was confirmed by an expert gastrointestinal pathologist. RESULTS: There were 235 women with SSc who underwent EGD. High-resolution manometry (HRM) was completed in 172 patients. Women with SSc with BE were significantly more likely to have scleroderma esophagus (absent contractility with hypotensive lower esophageal sphincter) on HRM than women with SSc without BE (P = 0.018). There were 30 patients with SSc (12.8%) with histologically proven BE. Dysplasia was found in 13 (43.3%): 4 with indefinite, 7 with low grade, and 2 with adenocarcinoma. The incidence of any dysplasia was 5.3% per year (0.9% per year for adenocarcinoma). DISCUSSION: This the largest study on prevalence of BE in women with SSc, yielding a prevalence of 12.8%. Women with SSc with BE were significantly more likely to have absent contractility with hypotensive lower esophageal sphincter findings on HRM. The high prevalence and incidence of dysplasia found suggest that women with SSc should be included in the screening recommendations for BE.

Opioids Interfere With Deglutitive Inhibition Assessed by Response to Multiple Rapid Swallows During High-Resolution Esophageal Manometry.

INTRODUCTION: Normal response to multiple rapid swallows (MRS) during high-resolution esophageal manometry is deglutitive inhibition; opioids may interfere with this. The aim of this study was to evaluate the response to MRS in patients on opioids, not on opioids, and healthy controls. METHODS: Response to MRS was evaluated for complete vs impaired inhibition in 72 chronic opioid users, 100 patients not on opioids, and 24 healthy controls. RESULTS: Impaired deglutitive inhibition was significantly more frequent in chronic opioid users compared with patients not on opioids and healthy controls (54% vs 14% vs 0%; P < 0.0001). DISCUSSION: Impaired deglutitive inhibition during MRS is frequent in opioid users, supporting that opioids interfere with esophageal inhibitory signals.

Opioid-induced esophageal dysfunction.

PURPOSE OF REVIEW: Chronic opioid use is common and can cause opioid-induced esophageal dysfunction (OIED). We will discuss the pathophysiology, diagnosis, and management of OIED. RECENT FINDINGS: OIED is diagnosed based on symptoms, opioid use, and manometric evidence of distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, or jackhammer esophagus. Chronic opioid use appears to interfere with inhibitory signals involved in control of esophageal motility, allowing for unchecked excitatory stimuli, and leading to spastic contractility and impaired esophagogastric junction relaxation. Patients may present with dysphagia and chest pain. OIED is significantly more prevalent in patients taking the stronger opioids oxycodone and hydrocodone compared with the weaker opioid tramadol. Based on 24-h morphine equivalent doses, patients with OIED take higher opioid doses than those without OIED. Impaired inhibitory signaling was recently demonstrated in a study showing reduced deglutitive inhibition during multiple rapid swallows in patients taking opioids. SUMMARY: OIED is frequent in chronic opioid users undergoing manometry for esophageal symptoms, especially at higher doses or with stronger opioids. OIED appears to be due to impaired inhibitory signals in the esophagus. Opioid cessation or dose reduction is recommended, but studies examining management of OIED are lacking.

Effect of bowel preparation volume in inpatient colonoscopy. Results of a prospective, randomized, comparative pilot study.

BACKGROUND: Inpatient status has been shown to be a predictor of poor bowel preparation for colonoscopy; however, the optimal bowel preparation regimen for hospitalized patients is unknown. Our aim was to compare the efficacy of bowel preparation volume size in hospitalized patients undergoing inpatient colonoscopy. METHODS: This prospective, single blinded (endoscopist), randomized controlled trial was conducted as a pilot study at a tertiary referral medical center. Hospitalized patients undergoing inpatient colonoscopy were assigned randomly to receive a high, medium, or low-volume preparation. Data collection included colon preparation quality, based on the Boston Bowel Preparation Scale, and a questionnaire given to all subjects evaluating the ability to completely finish bowel preparation and adverse effects (unpleasant taste, nausea, and vomiting). RESULTS: Twenty-five colonoscopies were performed in 25 subjects. Patients who received low-volume preparation averaged a higher mean total BBPS (7.4, SD 1.62), in comparison to patients who received high-volume (7.0, SD 1.41) and medium-volume prep (6.9, SD 1.55), P = 0.77. When evaluating taste a higher score meant worse taste. The low-volume group scored unpleasant taste as 0.6 (0.74), while the high-volume group gave unpleasant taste a score of 2.2 (0.97) and the medium-volume group gave a score of 2.1 (1.36), P < 0.01. CONCLUSION: In this pilot study we found that low-volume colon preparation may be preferred in the inpatient setting due its better rate of tolerability and comparable bowel cleanliness when compared to larger volume preparation, although we cannot overreach any definitive conclusion. Further more robust studies are required to confirm these findings. TRIAL REGISTRATION: The Affect of Low-Volume Bowel Preparation for Hospitalized Patients Colonoscopies. TRIAL REGISTRATION: NCT01978509 (terminated). Retrospectively registered on November 07, 2013.

Timeline and location of recurrence following successful ablation in Barrett's oesophagus: an international multicentre study.

OBJECTIVE: Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett's oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. DESIGN: Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. RESULTS: 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4-4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI -7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). CONCLUSIONS: BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

Opioid-Induced Esophageal Dysfunction: Differential Effects of Type and Dose.

OBJECTIVE: Data regarding opioid effects on esophageal function are limited. We previously demonstrated an association between chronic opioid use and esophageal motor dysfunction characterized by esophagogastric junction outflow obstruction, distal esophageal spasm, achalasia type III, and possibly Jackhammer esophagus. Our aim was to characterize the influence of different opioids and doses on esophageal dysfunction. METHODS: Retrospective review of 225 patients prescribed oxycodone, hydrocodone, or tramadol for >3 months, who completed high-resolution manometry from 2012 to 2017. Demographic and manometric data were extracted from a prospectively maintained motility database. Frequency of opioid-induced esophageal dysfunction (OIED, defined as distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, or Jackhammer esophagus on high-resolution manometry, was compared among different opioids. The total 24-hour opioid doses for oxycodone, hydrocodone, and tramadol were converted to a morphine equivalent for dose effect analysis. RESULTS: OIED was present in 24% (55 of 225) of opioid users. OIED was significantly more prevalent with oxycodone or hydrocodone use compared with tramadol (31% vs 28% vs 12%, P = 0.0162), and for oxycodone alone vs oxycodone with acetaminophen (43% vs 21%, P = 0.0482). There was no difference in OIED for patients taking hydrocodone alone vs hydrocodone with acetaminophen. Patients with OIED were taking a higher median 24-hour opioid dose than those without OIED (45 vs 30 mg, P = 0.058). DISCUSSION: OIED is more prevalent in patients taking oxycodone or hydrocodone compared with tramadol. There is greater likelihood of OIED developing with higher doses. Reducing the opioid dose or changing to tramadol may reduce OIED in opioid users.

Eosinophilic Esophagitis: Clinical Pearls for Primary Care Providers and Gastroenterologists.

Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated esophageal disorder. Given its increasing incidence, it is now a leading cause of dysphagia and food impaction in the United States. Eosinophilic esophagitis is most common in adult White men and has a high concurrence rate with other atopic conditions like allergic rhinitis, bronchial asthma, and eczema. The initial presentation includes symptoms of esophageal dysfunction, classically solid-food dysphagia. Without treatment, inflammation can progress to fibrosis with the formation of strictures, leading to complications such as food impaction. It is a clinicopathologic disease requiring compatible clinical symptoms and histologic evidence of eosinophil-predominant inflammation of the esophageal epithelium with more than 15 eosinophils per high-power field. The mainstay of management includes the 3 d's (diet, drugs, dilation): dietary modifications to eliminate trigger food groups; medications including proton pump inhibitors, swallowed topical glucocorticoids, and dupilumab; and esophageal dilation to manage strictures. Various elimination diets have been found to be effective, including 1-food, 2-food, 4-food, and 6-food elimination diets. Dupilumab, a humanized monoclonal antibody that regulates interleukin 4 and 13 signaling pathways, has shown promising results in clinical trials and was approved by the Food and Drug Administration in 2022 for use in EoE. Symptom alleviation, although important, is not the sole end point of treatment in EoE as persistent inflammation, even in the absence of symptoms, can lead to esophageal fibrosis and stricture formation over time. The chronic nature and high recurrence rates of EoE warrant maintenance therapy in patients with EoE after initial remission is achieved.

Impact of opioids on esophageal motility.

Opioids are well known to cause adverse effects on the gastrointestinal tract including nausea, vomiting, and constipation. Data regarding how opioids affect the esophagus are more limited. Opioid-induced esophageal dysfunction (OIED) is a clinical syndrome defined by chronic opioid use (≥3 months), esophageal symptoms (mainly dysphagia), and esophageal motility abnormalities diagnosed by manometry including achalasia type III, hypercontractile esophagus, distal esophageal spasm, and esophagogastric junction outflow obstruction. Up until now, the effect of opioids on esophageal motility assessed by the functional lumen imaging probe (FLIP) had not been described. In this issue of NGM, Patel et al. report that FLIP assessment in patients with esophageal symptoms showed that chronic opioid users have a significant increase in repetitive retrograde contractions, but no significant reduction in distensibility at the esophagogastric junction compared to non-users. Additionally, perceptive symptoms were higher, and quality of life metrics were lower in the chronic opioid users. This review article will discuss our current understanding of OIED and provide context for this latest study in chronic opioid users. Further investigation with larger prospective studies is needed to understand the pathophysiology, diagnosis, and management of OIED.

Development of a model to identify patients who do not need oesophageal biopsies when eosinophilic oesophagitis is suspected.

BACKGROUND: Predictive models for eosinophilic oesophagitis (EoE) may not fully rule in the diagnosis. AIM: To develop a reverse model that predicts against EoE to eliminate the need for oesophageal biopsies. METHODS: In this two-centre study, a predictive model was developed (Mayo Clinic) and validated (University of North Carolina [UNC]). Cross-sectional data from consecutive adult patients without prior EoE who underwent upper enoscopy with oesophageal biopsies were used. EoE cases had ≥15 eosinophils/high-power field while controls had no eosinophils. Data were collected on patient clinical and endoscopic features. Multiple variable logistic regression was used to identify predictors of non-EoE status while maintaining specificity ≥95%. A secondary model was developed to predict against the need for endoscopy in patients suspected of having EoE without alarm symptoms. RESULTS: The Mayo and UNC cohorts consisted of 345 (EoE = 94, non-EoE = 251) and 297 patients (EoE = 84, non-EoE = 213), respectively. A primary model based on clinical and endoscopic features predicted against EoE with c-statistic 0.92 (95% CI: 0.88-0.96), specificity 95%, and sensitivity 65%. This model was validated (UNC) with c-statistic 0.87 (95% CI: 0.82-0.92). A simplified scoring system was created and a threshold of ≥12 points excluded EoE with 95% specificity and 50% sensitivity. A secondary model based on clinical characteristics alone predicted against EoE with c-statistic 0.86 (95% CI: 0.82-0.90), specificity 95% and sensitivity 39% and validated (UNC) with c-statistic 0.78 (95% CI: 0.71-0.85). CONCLUSION: A simplified scoring system accurately identified a group of patients with a low likelihood of EoE where unnecessary oesophageal biopsies can be avoided, potentially resulting in resource and cost savings.

Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish.

Niemann-Pick disease, type C (NP-C), often associated with Niemann-Pick disease, type C1 (NPC1) mutations, is a cholesterol-storage disorder characterized by cellular lipid accumulation, neurodegeneration, and reduced steroid production. To study NPC1 function in vivo, we cloned zebrafish npc1 and analyzed its gene expression and activity by reducing Npc1 protein with morpholino (MO)-oligonucleotides. Filipin staining in npc1-morphant cells was punctate, suggesting abnormal accumulation of cholesterol. Developmentally, reducing Npc1 did not disrupt early cell fate or survival; however, early morphogenetic movements were delayed, and the actin cytoskeleton network was abnormal. MO-induced defects were rescued with ectopic expression of mouse NPC1, demonstrating functional gene conservation, and by treatments with steroids pregnenolone or dexamethasone, suggesting that reduced steroidogenesis contributed to abnormal cell movements. Cell death was found in anterior tissues of npc1 morphants at later stages, consistent with findings in mammals. Collectively, these studies show that npc1 is required early for proper cell movement and cholesterol localization and later for cell survival.

Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation.

Tbx5 is involved in congenital heart disease, however, the mechanisms leading to organ malformation are greatly unknown. We hypothesized a model by which the Tbx5 binding protein Pdlim7 controls nuclear/cytoplasmic shuttling and function of the transcription factor. Using the zebrafish, we present in vivo significance for an essential role of Tbx5/Pdlim7 protein interaction in the regulation of cardiac formation. Knock-down of Pdlim7 results in a non-looped heart, strikingly reminiscent of the tbx5 heartstrings mutant phenotype. However, while misregulation of Pdlim7 and Tbx5 produce similar aberrant cardiac morphology, molecular and histological analysis uncovered that the Pdlim7 and Tbx5 cardiac phenotypes are due to opposite effects on valve development. Loss of Pdlim7 function causes no valve tissue to develop while lack of Tbx5 results in increased valve tissue. These opposing defects are evident before valve formation and are the result of distinct gene misregulation during specification of the atrio-ventricular (AV) boundary. We show that Pdlim7/Tbx5 interactions affect the expression of Tbx5 target genes nppa and tbx2b at the AV boundary, and their domains of misexpression directly correlate with the identified valve defects. These studies demonstrate that controlling the correct balance of Tbx5 activity is crucial for the specification of the AV boundary and valve formation.