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.

Enterohepatic Helicobacter other than Helicobacter pylori.

The Helicobacter genus includes Gram negative bacteria which were originally considered to belong to the Campylobacter genus. They have been classified in a separate genus since 1989 because they have different biochemical characteristics, with more than 24 species having been identified and more still being studied.H. pylori is the best known. It has an important etiopathogenic role in peptic ulcer disease and gastric cancer. Enterohepatic Helicobacters (EHH) other than H. pylori colonize the bowel, biliary tree and liver of animals and human beings with pathogenic potential. The difficulties existing to correctly isolate these microorganisms limit the description of their true prevalence and of the diseases they cause. Many studies have tried to discover the different clinical implications of EHH. Diseases like chronic liver disease, autoimmune hepatitis, hepatocarcinoma, autoimmune hepatobiliary disease, biliary lithiasis, cholangiocarcinoma and gallbladder cancer, Meckel´s diverticulum, acute appendicitis and inflammatory bowel disease have been related with different EHH species with different results, although their prevalence is greater than in healthy subjects. However, these data are currently not sufficient to draw definitive conclusions. Finally, the best known role of EHH in bowel disease is production of acute and chronic diarrhea pictures initially referred to as Campylobacter. H. pullorum has been identified in patients with acute gastroenteritis. The correct identification of EHH as producers of infectious gastroenteritis is found in its antibiotic susceptibility. It is generally macrolide-susceptible and quinolone-resistant.

Multimodal Management of Fecal Incontinence Focused on Sphincteroplasty: Long-Term Outcomes from a Single Center Case Series.

The management of patients with fecal incontinence and an external anal sphincter (EAS) defect remains controversial. A retrospective series of overlapping anal sphincteroplasties performed between 1985−2013 from a single center, supplemented by selective puborectalis plication and internal anal sphincter repair is presented. Patients were clinically followed along with anorectal manometry, continence scoring (Cleveland Clinic Incontinence Score­CCS) and patient satisfaction scales. Patients with a suboptimal outcome were managed with combinations of biofeedback therapy (BFT), peripheral tibial nerve stimulation (PTNS), sacral nerve stimulation (SNS) or repeat sphincteroplasty. There were 120 anterior sphincter repairs with 90 (75%) levatorplasties and 84 (70%) IAS repairs. Over a median follow-up of 120 months (IQR 60−173.7 months) there were significant improvements in the recorded CCIS values (90.8% with a preoperative CCIS > 15 vs. 2.5% postoperatively; p < 0.001). There were 42 patients who required ancillary treatment with four repeat sphincteroplasties, 35 patients undergoing biofeedback therapy, 10 patients treated with PTNS and three managed with SNS implants with an ultimate good functional outcome in 92.9% of cases. No difference was noted in ultimate functional outcome between those treated with sphincteroplasty alone compared with those who needed ancillary treatments (97.1% vs. 85.7%, respectively). Overall, 93.3% considered the outcome as either good or excellent. Long-term functional outcomes of an overlapping sphincteroplasty are good. If the initial outcome is suboptimal, response to ancillary treatments remains good and patients are not compromised by a first-up uncomplicated sphincter repair.

Breaks in peristaltic integrity predict abnormal esophageal bolus clearance better than contraction vigor or residual pressure at the esophagogastric junction.

BACKGROUND: High-resolution impedance manometry (HRIM) evaluates esophageal peristalsis and bolus transit. We used esophageal impedance integral (EII), the ratio between bolus presence before and after an expected peristaltic wave, to evaluate predictors of bolus transit. METHODS: From HRIM studies performed on 61 healthy volunteers (median age 27 years, 48%F), standard metrics were extracted from each of 10 supine water swallows: distal contractile integral (DCI, mmHg cm s), integrated relaxation pressure (IRP, mmHg), and breaks in peristaltic integrity (cm, using 20 mmHg isobaric contour). Pressure and impedance coordinates for each swallow were exported into a dedicated, python-based program for EII calculation (EII ratio ≥ 0.3 = abnormal bolus clearance). Univariate and multivariate analyses were performed to assess predictors of abnormal bolus clearance. KEY RESULTS: Of 591 swallows, 80.9% were intact, 10.5% were weak, and 8.6% failed. Visual analysis overestimated abnormal bolus clearance compared to EII ratio (p ≤ 0.01). Bolus clearance was complete (median EII ratio 0.0, IQR 0-0.12) in 82.0% of intact swallows in contrast to 53.3% of weak swallows (EII ratio 0.29, IQR 0.0-0.57), and 19.6% of failed swallows (EII ratio 0.5, IQR 0.34-0.73, p < 0.001). EII correlated best with break length (ρ = 0.52, p < 0.001), compared to IRP (ρ: -0.17) or DCI (ρ: -0.42). On ROC analysis, breaks predicted abnormal bolus transit better than DCI or IRP (AUC 0.79 vs. 0.25 vs. 0.44, p ≤ 0.03 for each). On logistic regression, breaks remained independently predictive of abnormal bolus transit (p < 0.001). CONCLUSIONS & INFERENCES: Breaks in peristaltic integrity predict abnormal bolus clearance better than DCI or IRP in healthy asymptomatic subjects.

The Spanish version of the esophageal hypervigilance and anxiety score shows strong psychometric properties: Results of a large prospective multicenter study in Spain and Latin America.

BACKGROUND: Anxiety is a significant modulator of sensitivity along the GI tract. The recently described Esophageal Hypervigilance and Anxiety Score (EHAS) evaluates esophageal-specific anxiety. The aims of this study were as follows: 1. translate and validate an international Spanish version of EHAS. 2. Evaluate its psychometric properties in a large Hispano-American sample of symptomatic individuals. METHODS: A Spanish EHAS version was developed by a Delphi process and reverse translation. Patients referred for high-resolution manometry (HRM) were recruited prospectively from seven Spanish and Latin American centers. Several scores were used: EHAS, Hospital Anxiety and Depression Scale (HADS), Eckardt score (ES), Gastroesophageal Reflux Questionnaire (GERDQ), and the Brief Esophageal Dysphagia Questionnaire (BEDQ). Standardized psychometric analyses were performed. KEY RESULTS: A total of 443 patients were recruited. Spanish EHAS showed excellent reliability (Cronbach´s alpha = 0.94). Factor analysis confirmed the presence of two factors, corresponding to the visceral anxiety and hypervigilance subscales. Sufficient convergent validity was shown by moderate significant correlations between EHAS and other symptomatic scores. Patients with high EHAS scores had significantly more dysphagia. There was no difference in EHAS scores when compared normal vs abnormal or major manometric diagnosis. CONCLUSIONS AND INFERENCES: A widely usable Spanish EHAS version has been validated. We confirm its excellent psychometric properties in our patients, confirming the appropriateness of its use in different populations. Our findings support the appropriateness of evaluating esophageal anxiety across the whole manometric diagnosis spectrum.

Validation and psychometric evaluation of the Spanish version of Brief Esophageal Dysphagia Questionnaire (BEDQ): Results of a multicentric study.

BACKGROUND: The recently developed Brief Esophageal Dysphagia Questionnaire (BEDQ) evaluates esophageal obstructive symptoms. Its initial evaluation showed strong psychometric properties. The aims of this study were to (a) translate and validate an international Spanish version of BEDQ and (b) evaluate its psychometric properties in a large Hispano-American sample of symptomatic individuals. METHODS: A Spanish BEDQ version was performed by Hispano-American experts using a Delphi process and reverse translation. Patients were prospectively recruited from seven centers in Spain and Latin America among individuals referred for high-resolution manometry (HRM). Patients completed several scores: Hospital Anxiety & Depression Scale (HADS), Eckardt score (ES), Gastroesophageal Reflux Questionnaire (GERDQ), and the BEDQ. Standardized psychometric analyses were performed. KEY RESULTS: A total of 426 patients were recruited. Spanish BEDQ showed excellent reliability (Cronbach's alpha = 0.91). Factor analysis confirmed its unidimensional character. Moderate significant correlations between BEDQ and other symptomatic scores were found, suggesting sufficient convergent validity. Patients with abnormal or obstructive HRM findings scored significantly higher when compared to normal or non-obstructive findings, respectively. Using a cutoff of 10, BEDQ showed a sensitivity of 65.38% and a specificity of 66.21% and an area under the curve of 0.71 for obstructive or major manometric diagnosis. CONCLUSIONS AND INFERENCES: A widely usable Spanish BEDQ version has been validated. We confirm its excellent psychometric properties in our patients, confirming the appropriateness of its use in different populations.

[Quality of life and its association with the severity of fecal incontinence]. / Calidad de vida en pacientes con incontinencia fecal y su relación con la gravedad de la misma.

BACKGROUND: Wexner's score is widely used to assess the severity of fecal incontinence (FI). The 36-item short form health survey (SF-36) and the Fecal Incontinence Quality of Life Scale (FIQLS), a disease-specific scale, are instruments measuring quality of life that have been validated into Spanish. AIM: To evaluate quality of life in patients with FI by using the FIQL and SF-36 scales to correlate the results with the Wexner's score. METHODS: Wexner's score, SF-36 and FIQLS were completed by 73 patients. The cut-off point for severity, as previously published, was 9 (Wexner's score <9=mild FI; Wexner's score ≥9=severe FI). RESULTS: the scores for all SF-36 sub-scales were lower in patients with FI than in the healthy Spanish population (p<0.001). The mental component of the SF-36 correlated with the subscales of «behavior¼ and «embarrassment¼ of the FIQLS (p<0.05). Wexner's score correlated with all the domains of the FIQLS (p<0.01). The results for all the domains of the FIQLS were lower for the Wexner ≥ 9 group than for the Wexner <9 group (p<0.001). There was no significant correlation between Wexner's score and the SF-36. Age, urge and daily FI, comorbidity and anorectal surgery worsened different aspects of quality of life measured by the FIQLS. CONCLUSIONS: quality of life measured by the SF-36 and FIQLS was substantially impaired in patients with FI. The severity of FI correlated with FIQLS. Other factors such as age, type and frequency of FI should be considered when evaluating quality of life.

Ineffective esophageal motility and bolus clearance. A study with combined high-resolution manometry and impedance in asymptomatic controls and patients.

BACKGROUND: The definition and relevance of ineffective esophageal motility (IEM) remains debated. Our aim was to determine motility patterns and symptoms associated with IEM defined as impaired bolus clearance. METHODS: To define altered bolus clearance, normal range of swallows with complete bolus transit (CBT) on high-resolution impedance manometry (HRIM) was determined in 44 asymptomatic controls. The results were then applied to a cohort of 81 patients with esophageal symptoms to determine the motility patterns which best predicted altered bolus clearance. Subsequently, in a cohort of 281 consecutive patients the identified motility patterns were compared with patients' customary symptoms. KEY RESULTS: In asymptomatic controls, the normal range of swallows with CBT was 50%-100%. In patients, altered bolus transit (<50% CBT) was only associated with 30% or more failed contractions (P < .001). Neither weak peristalsis nor absence of contraction reserve (CR) was associated with altered bolus clearance. The patterns which best predicted altered bolus clearance were failed contractions ≥30% (specificity 88.2% and sensitivity of 84.6%), and ≥70% ineffective (failed + weak) contractions (sensitivity 84.6% and specificity 80.9%). No motility pattern was correlated to symptom scores. CONCLUSIONS AND INFERENCES: Based on bolus clearance assessed by HRIM, ≥30% failed contractions and ≥70% ineffective contractions have the best sensitivity and specificity to predict altered bolus clearance. Weak contractions and absence of CR are not relevant with respect to bolus clearance.

Fair reliability of eckardt scores in achalasia and non-achalasia patients: Psychometric properties of the eckardt spanish version in a multicentric study.

BACKGROUND: Eckardt symptom score (ESS) is the most used tool for the evaluation of esophageal symptoms. Recent data suggest that it might have suboptimal reliability and validity. The aims of this study were as follows: (a) Develop and validate an international Spanish ESS version. (b) Perform psychometric ESS evaluation in patients with achalasia and non-achalasia patients. METHODS: Eckardt symptom score translation was performed by Delphi process. ESS psychometric evaluation was done in two different samples of patients referred for manometry. First sample: 430 dysphagia non-achalasia patients. Second sample: 161 achalasia patients. Internal consistency was evaluated using Cronbach's α and Guttman coefficient (<0.5 = unacceptable. 0.5-0.7 = fair. >0.7 = acceptable). KEY RESULTS: Our data show that in patients without and with achalasia, ESS behaves similarly. Both show a fair reliability with Cronbach's α of 0.57 and 0.65, respectively. Based on our results, we recommend interpretation of the Spanish ESS be done with caution. The psychometric quality of the ESS could not be improved by removal of any items based on the single-factor structure of the scale and no items meeting criteria for elimination. CONCLUSIONS AND INFERENCES: Eckardt symptom score Spanish translation was developed. ESS showed a fair reliability for the evaluation of patients with any causes of dysphagia. Our results highlight the need for development and psychometric validation of new dysphagia scoring tools.

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia.

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.

High Resolution Esophageal Manometry in Patients with Chagas Disease: A Cross-Sectional Evaluation.

INTRODUCTION: Gastrointestinal involvement affects 30-40% of the patients with chronic Chagas disease. Esophageal symptoms appear once the structural damage is established. Little is known about the usefulness of high resolution manometry to early identification of esophageal involvement. METHOD: We performed a cross-sectional study at the Vall d'Hebron University Hospital (Barcelona, Spain) between May 2011 and April 2012. Consecutive patients diagnosed with Chagas disease in the chronic phase were offered to participate. All patients underwent a structured questionnaire about digestive symptoms, a barium esophagogram (Rezende classification) and an esophageal high resolution manometry (HRM). A control group of patients with heartburn who underwent an esophageal HRM in our hospital was selected. RESULTS: 62 out of 73 patients that were included in the study fulfilled the study protocol. The median age of the Chagas disease group (CG) was 37 (IQR 32-45) years, and 42 (67.7%) patients were female. Twenty-seven (43.5%) patients had esophageal symptoms, heartburn being the most frequent. Esophagogram was abnormal in 5 (8.77%). The esophageal HRM in the CG showed a pathological motility pattern in 14 patients (22.6%). All of them had minor disorders of the peristalsis (13 with ineffective esophageal motility and 1 with fragmented peristalsis). Hypotonic lower esophageal sphincter was found more frequently in the CG than in the control group (21% vs 3.3%; p<0.01). Upper esophageal sphincter was hypertonic in 22 (35.5%) and hypotonic in 1 patient. When comparing specific manometric parameters or patterns in the CG according to the presence of symptoms or esophagogram no statistically significant association were seen, except for distal latency. CONCLUSION: The esophageal involvement measured by HRM in patients with chronic Chagas disease in our cohort is 22.6%. All the patients with esophageal alterations had minor disorders of the peristalsis. Symptoms and esophagogram results did not correlate with the HRM results.

Myenteric antiplexus antibodies and class II HLA in achalasia.

Achalasia, a motor disorder of the esophagus, is accompanied by autoimmune phenomena that could be playing a role in the pathogenesis of the disease. Our objective was to establish the genotypic frequency of the HLA-DR and DQ alleles in patients with achalasia and to establish their relationship with the presence of myenteric antiplexus antibodies in our geographic area. A total of 92 patients diagnosed with achalasia and two control groups with 275 healthy subjects were studied for HLA typing and 40 for autoantibodies determination. The myenteric antiplexus antibodies were positive in 50 patients (54.3%) and in 3 healthy subjects (7.5%) (P < 0.001). The patients showed a significantly higher frequency of DQA1*0103 and DQB1*0603 than was found in the controls. The heterodimer DQA1*0103-DQB1*0603 was increased in the patients [odds ratio (OR) = 2.57]. In regard to the association between the HLA DQA1 and DQB1 alleles and the antiplexus antibodies, these antibodies were found in greater prevalence in those patients with the DQA1*0103 and DQB1*0603 alleles, and the differences were statistically significant (OR = 3.17 and OR = 5.82, respectively). All of the women and 66.7% of the men with achalasia and the DQB1*0603 allele or the DQA1*0103-DQB1*0603 heterodimer were positive for antibodies.