Screening for dysplasia with Lugol chromoendoscopy in longstanding idiopathic achalasia.

BACKGROUND: Achalasia patients with longstanding disease are considered to be at risk for developing esophageal cancer. Endoscopic screening is not standardized and detection of dysplastic lesions is difficult, for which Lugol chromoendoscopy could be helpful. Aim was to evaluate the efficacy of screening for esophageal dysplasia and carcinoma in patients with longstanding achalasia using Lugol chromoendoscopy. METHODS: In this cohort study achalasia patients underwent three-annual screening by Lugol chromoendoscopy between January 2000 and March 2016. Patients with low-grade dysplasia (LGD) underwent yearly screening, patients with high-grade dysplasia (HGD) or carcinoma were treated. RESULTS: In total, 230 achalasia patients (144 male, median age 52 years (IQR 43-63) at first endoscopy) were included. Three patients (1.3%, 2 male, age 68 years (range 50-87)) developed esophageal squamous cell carcinoma (ESCC), without LGD at the preceding screening. Incidence rate for ESCC was 63 (95% CI 13-183) per 100 000 persons-years. LGD was observed in 4 patients (1.7%, 2 male, age 64 years (range 57-73)), without progression to HGD/ESCC during a follow-up of 9 (IQR 7-14) years. ESCC/LGD was diagnosed 30 (IQR 14-36) years after onset of symptoms and 22 (IQR 4-13) years after diagnosis. Lugol chromoendoscopy tripled the detection rate of suspected lesions (111 lesions white light versus 329 lesions Lugol), but only 8% was histopathological confirmed ESCC or LGD. CONCLUSION: Achalasia patients with longstanding disease (>20 years) have an increased risk to develop esophageal dysplasia and carcinoma. Endoscopic screening using white light and Lugol chromoendoscopy does not accurately identify precursor lesions for ESCC and therefore cannot be systematically recommended.

Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia.

BACKGROUND: Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS: 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS: The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-ß-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS: Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.

Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia.

BACKGROUND: Many experts consider laparoscopic Heller's myotomy (LHM) to be superior to pneumatic dilation for the treatment of achalasia, and LHM is increasingly considered to be the treatment of choice for this disorder. METHODS: We randomly assigned patients with newly diagnosed achalasia to pneumatic dilation or LHM with Dor's fundoplication. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). The primary outcome was therapeutic success (a drop in the Eckardt score to ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for retreatment, pressure at the lower esophageal sphincter, esophageal emptying on a timed barium esophagogram, quality of life, and the rate of complications. RESULTS: A total of 201 patients were randomly assigned to pneumatic dilation (95 patients) or LHM (106). The mean follow-up time was 43 months (95% confidence interval [CI], 40 to 47). In an intention-to-treat analysis, there was no significant difference between the two groups in the primary outcome; the rate of therapeutic success with pneumatic dilation was 90% after 1 year of follow-up and 86% after 2 years, as compared with a rate with LHM of 93% after 1 year and 90% after 2 years (P=0.46). After 2 years of follow-up, there was no significant between-group difference in the pressure at the lower esophageal sphincter (LHM, 10 mm Hg [95% CI, 8.7 to 12]; pneumatic dilation, 12 mm Hg [95% CI, 9.7 to 14]; P=0.27); esophageal emptying, as assessed by the height of barium-contrast column (LHM, 1.9 cm [95% CI, 0 to 6.8]; pneumatic dilation, 3.7 cm [95% CI, 0 to 8.8]; P=0.21); or quality of life. Similar results were obtained in the per-protocol analysis. Perforation of the esophagus occurred in 4% of the patients during pneumatic dilation, whereas mucosal tears occurred in 12% during LHM. Abnormal exposure to esophageal acid was observed in 15% and 23% of the patients in the pneumatic-dilation and LHM groups, respectively (P=0.28). CONCLUSIONS: After 2 years of follow-up, LHM, as compared with pneumatic dilation, was not associated with superior rates of therapeutic success. (European Achalasia Trial Netherlands Trial Register number, NTR37, and Current Controlled Trials number, ISRCTN56304564.).

Proton pump inhibitors reduce the size and acidity of the acid pocket in the stomach.

BACKGROUND & AIMS: The gastric acid pocket is believed to be the reservoir from which acid reflux events originate. Little is known about how changes in position, size, and acidity of the acid pocket contribute to the therapeutic effect of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD). METHODS: Thirty-six patients with GERD (18 not taking PPIs, 18 taking PPIs; 19 men; age, 55 ± 2.1 y) were analyzed by concurrent high-resolution manometry and pH-impedance monitoring after a standardized meal. The acid pocket was visualized using scintigraphy after intravenous administration of (99m)technetium-pertechnetate. The size of the acid pocket was measured and its position was determined, relative to the diaphragm, using radionuclide markers on a high-resolution manometry catheter. At the end of the study, the acid pocket was aspirated, and its pH level was measured. RESULTS: The number of reflux episodes was comparable between patients on and off PPIs, but the number of acid reflux episodes was reduced significantly in patients on PPIs. In patients on PPIs, the acid pocket was smaller and more frequently located below the diaphragm. The mean pH of the acid pocket was significantly lower in patients not taking PPIs (n = 6) than in those who were (n = 16) (0.9; range, 0.7-1.2 vs 4.0; range, 1.6-5.9; P < .001). The pH of acid pockets correlated significantly with the lowest pH values measured for refluxate (r = 0.72; P < .01). CONCLUSIONS: Based on analyses of acid pockets in patients with GERD, the acid pocket appears to be a reservoir from which reflux occurs when patients are receiving PPIs. PPIs might affect the size, acidity, or position of the acid pocket, which contributes to the efficacy in patients with GERD.

Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Approximately 30% of patients with gastroesophageal reflux disease have symptoms resistant to treatment with proton pump inhibitors (PPIs). Several mechanisms such as esophageal hypersensitivity, increased mucosal permeability, and possibly the position of the gastric acid pocket might underlie a partial response to PPIs. To what extent these mechanisms interact and contribute to PPI-resistant symptoms, however, has not been investigated previously. METHODS: In 18 gastroesophageal reflux disease patients (9 PPI responders and 9 PPI partial responders), esophageal sensitivity, mucosal permeability, and postprandial reflux parameters were determined during PPI use. Esophageal sensitivity for distension was measured by gradual balloon inflation at 5 and 15 cm above the lower esophageal sphincter. The mucosal permeability of 4 esophageal biopsy specimens per patient was determined in Ussing chambers by measuring the transepithelial electrical resistance and transmucosal flux of fluorescein. Postprandial reflux parameters were determined using concurrent high-resolution manometry/pH impedance after a standardized meal. In addition, the acid pocket was visualized using scintigraphy. RESULTS: No difference in the rate of postprandial acid reflux, in the pH of the acid pocket (PPI responders 3.7 ± 0.7 vs PPI partial responders 4.2 ± 0.4; P = .54), or in the position of the acid pocket was observed in PPI partial responders compared with PPI responders. In addition, the permeability of the esophageal mucosa was similar in both groups, as shown by a similar transepithelial electrical resistance and flux of fluorescein. PPI partial responders had more reflux episodes with a higher mean proximal extent, compared with PPI responders, and were more sensitive to balloon distension, both in the upper and lower esophagus. CONCLUSIONS: PPI-resistant symptoms most likely are explained by increased proximal reflux in a hypersensitive esophagus and less likely by increased mucosal permeability or the position of the acid pocket.

Outcomes of treatment for achalasia depend on manometric subtype.

BACKGROUND & AIMS: Patients with achalasia are treated with either pneumatic dilation (PD) or laparoscopic Heller myotomy (LHM), which have comparable rates of success. We evaluated whether manometric subtype was associated with response to treatment in a large population of patients treated with either PD or LHM (the European achalasia trial). METHODS: Esophageal pretreatment manometry data were collected from 176 patients who participated in the European achalasia trial. Symptoms (weight loss, dysphagia, retrosternal pain, and regurgitation) were assessed using the Eckardt score; treatment was considered successful if the Eckardt score was 3 or less. Manometric tracings were classified according to the 3 Chicago subtypes. RESULTS: Forty-four patients had achalasia type I (25%), 114 patients had achalasia type II (65%), and 18 patients had achalasia type III (10%). After a minimum follow-up period of 2 years, success rates were significantly higher among patients with type II achalasia (96%) than type I achalasia (81%; P < .01, log-rank test) or type III achalasia (66%; P < .001, log-rank test). The success rate of PD was significantly higher than that of LHM for patients with type II achalasia (100% vs 93%; P < .05), but LHM had a higher success rate than PD for patients with type III achalasia (86% vs 40%; P = .12, difference was not statistically significant because of the small number of patients). For type I achalasia, LHM and PD had similar rates of success (81% vs 85%; P = .84). CONCLUSIONS: A higher percentage of patients with type II achalasia (based on manometric tracings) are treated successfully with PD or LHM than patients with types I and III achalasia. Success rates in type II are high for both treatment groups but significantly higher in the PD group. Patients with type III can probably best be treated by LHM. Trialregister.nl number NTR37; ISRCTN56304564.

Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.

BACKGROUND & AIMS: Many patients with persistent dysphagia and regurgitation after therapy have low or no lower esophageal sphincter (LES) pressure. Distensibility of the esophagogastric junction (EGJ) largely determines esophageal emptying. We investigated whether assessment of the distensibility of the EGJ is a better and more integrated parameter than LES pressure for determining efficacy of treatment for patients with achalasia. METHODS: We measured distensibility of the EGJ using an endoscopic functional luminal imaging probe (EndoFLIP) in 15 healthy volunteers (controls; 8 male; age, 40 ± 4.1 years) and 30 patients with achalasia (16 male; age, 51 ± 3.1 years). Patients were also assessed by esophageal manometry and a timed barium esophagogram. Symptom scores were assessed using the Eckardt score, with a score <4 indicating treatment success. The effect of initial and additional treatment on distensibility and symptoms was evaluated in 7 and 5 patients, respectively. RESULTS: EGJ distensibility was significantly reduced in untreated patients with achalasia compared with controls (0.7 ± 0.9 vs 6.3 ± 0.7 mm(2)/mm Hg; P < .001). In patients with achalasia, EGJ distensibility correlated with esophageal emptying (r = -0.72; P < .01) and symptoms (r = 0.61; P < .01) and was significantly increased with treatment. EGJ distensibility was significantly higher in patients successfully treated (Eckardt score <3) compared with those with an Eckardt score >3 (1.6 ± 0.3 vs 4.4 ± 0.5 mm(2)/mm Hg; P = .001). Even when LES pressure was low, EGJ distensibility could be reduced, which was associated with impaired emptying and recurrent symptoms. CONCLUSIONS: EGJ distensibility is impaired in patients with achalasia and, in contrast to LES pressure, is associated with esophageal emptying and clinical response. Assessment of EGJ distensibility by EndoFLIP is a better parameter than LES pressure for evaluating efficacy of treatment for achalasia.

An alginate-antacid formulation localizes to the acid pocket to reduce acid reflux in patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Alginate rafts (polysaccharide polymers that precipitate into a low-density viscous gel when they contact gastric acid) have been reported to form at the acid pocket, an unbuffered pool of acid that floats on top of ingested food and causes postprandial acid reflux. We studied the location of an alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket positioning in patients with gastroesophageal reflux disease (GERD). METHODS: We randomly assigned patients with symptomatic GERD and large hiatal hernias to groups who were given either (111)In-labeled alginate-antacid (n = 8, Gaviscon Double Action Liquid) or antacid (n = 8, Antagel) after a standard meal. The relative positions of labeled alginate and acid pocket were analyzed for 2 hours by using scintigraphy; reflux episodes were detected by using high-resolution manometry and pH-impedance monitoring. RESULTS: The alginate-antacid label localized to the acid pocket. The number of acid reflux episodes was significantly reduced in patients receiving alginate-antacid (3.5; range, 0-6.5; P = .03) compared with those receiving antacid (15; range, 5-20), whereas time to acid reflux was significantly increased in patients receiving alginate-antacid (63 minutes; range, 23-92) vs those receiving antacid (14 minutes; range, 9-23; P = .01). The acid pocket was located below the diaphragm in 71% of patients given alginate-antacid vs 21% of those given antacid (P = .08). There was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux (r = -0.76, P < .001). CONCLUSIONS: In a study of 16 patients with GERD, we observed that the alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux. These findings indicate the importance of the acid pocket in GERD pathogenesis and establish alginate-antacid as an appropriate therapy for postprandial acid reflux.

Effect of peroral endoscopic myotomy on esophagogastric junction physiology in patients with achalasia.

BACKGROUND: Pneumatic dilation and laparoscopic Heller myotomy improve parameters of esophageal function such as lower esophageal sphincter (LES) pressure, esophageal emptying, and esophagogastric junction (EGJ) distensibility. OBJECTIVE: To evaluate the effect of peroral endoscopic myotomy (POEM) on esophagogastric function. DESIGN: Prospective trial. SETTING: Endoscopy department at a university hospital. PATIENTS: All consecutive patients aged >17 years with achalasia and an Eckardt score of ≥3. INTERVENTION: Before and 3 months after POEM, 10 consecutive patients underwent esophageal manometry, timed barium esophagograms, and EndoFLIP as well as an EGD. MAIN OUTCOME MEASUREMENTS: Eckardt symptom score, LES resting pressure, centimeters of barium stasis, EGJ distensibility, and reflux esophagitis. RESULTS: Compared with scores before POEM, patient symptom scores were significantly reduced (1, interquartile range [IQR 0-1] vs 8 [IQR 4-8]; P = .005). LES pressure decreased significantly (6.0 mm Hg [IQR 2.6-7.4] vs 19.0 mm Hg [IQR 13.0-28.0]; P = .008). Esophageal emptying increased significantly, and a 5-minute barium column measured 2.3 cm (IQR 0-3.2 cm) versus 10.1 cm (IQR 5.7-10.8 cm; P = .005). EGJ distensibility increased significantly (6.7 mm(2)/mm Hg [IQR 3.8-16.6] vs 1.0 mm(2)/mm Hg [IQR 0.4-2.3]; P = .02) at 50 mL. In 6 of 10 patients, reflux esophagitis was seen. Of these patients, 3 reported reflux symptoms. LIMITATIONS: Small number of patients, short-term follow-up. CONCLUSION: POEM improves esophagogastric function and suggests favorable long-term results based on Eckardt score, esophageal manometry, esophageal emptying, and EGJ distensibility. Long-term follow-up of larger series will determine whether the high rate of reflux esophagitis affects the clinical application of POEM.

Treatment of the patient with achalasia.

PURPOSE OF REVIEW: In recent years, several studies on the treatment and follow-up of achalasia have been published. This review aims at highlighting interesting publications from the recent years. RECENT FINDINGS: Treatment of achalasia aims at relieving functional obstruction at the level of the esophagogastric junction. Several treatment options such as pneumodilation and laparoscopic Heller myotomy (LHM) are available for this purpose. A large prospective randomized trial comparing pneumodilation and LHM demonstrated comparable success rates and quality of life for the two treatment options. Long-term data demonstrate comparable treatment success rates, when redilation in case of recurrent symptoms after pneumodilation is accepted. The most important risk factor for treatment failure is the manometric subtype, with a worse outcome for type I and type III compared with type II achalasia. Recently, peroral endoscopic myotomy (POEM) has been described with high success rates. Comparative studies with longer follow-up are awaited. A prospective study assessing the risk of esophageal carcinoma in patients with achalasia showed a 28-fold increased risk to develop carcinoma. SUMMARY: Either LHM or pneumodilation have high comparable short-term clinical success rates. Based on the increased risk to develop esophageal carcinoma, a screening program may be indicated. POEM is a new interesting treatment but longer follow-up data are awaited.

Pathophysiology of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is one of the most common digestive diseases in the Western world, with typical symptoms, such as heartburn, regurgitation, or retrosternal pain, reported by 15% to 20% of the general population. The pathophysiology of GERD is multifactorial. Our understanding of these factors has significantly improved in recent years, with increased understanding of the acid pocket and hiatal hernia and how these factors interact. Although our insight has significantly increased over the past years, more studies are required to better understand symptom generation in GERD, especially in patients with therapy-resistant symptoms.