Insights into the genetics of gastroesophageal reflux disease (GERD) and GERD‐related disorders

Gastroesophageal reflux disease (GERD) is associated with obesity and hiatal hernia, and often precedes the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). Epidemiological studies show that the global prevalence of GERD is increasing. GERD is a multifactorial disease with a complex genetic architecture. Genome‐wide association studies (GWAS) have provided initial insights into the genetic background of GERD. The present review summarizes current knowledge of the genetics of GERD and a possible genetic overlap between GERD and BE and EA. The review discusses genes and cellular pathways that have been implicated through GWAS, and provides an outlook on how future molecular research will enhance understanding of GERD pathophysiology.     

Motor events underlying gastro-oesophageal reflux in ambulant patients with reflux oesophagitis

Abstract Information on the mechanism of gastro-oesophageal reflux in patients with reflux disease is limited largely to studies in resting recumbent subjects. Evidence exists that both posture and physical activity may influence reflux. The aim of this study was to investigate reflux mechanisms in ambulant patients with reflux oesophagitis. Concurrent ambulatory oesophageal manometry and pH monitoring were performed in 11 ambulant patients with erosive oesophagitis. Lower oesophageal sphincter (LOS) pressure was monitored with a perfused sleeve sensor. Recordings were made for 90 min before and 180 min after a meal. At set times patients sat in a chair or walked. LOS pressure was ≤2 mmHg at the time of reflux for 98% of reflux episodes. Transient LOS relaxation was the most common pattern overall and the predominant pattern in seven patients, whilst persistently absent basal LOS pressure was the most common pattern in four patients. The pattern of LOS pressure was not altered by the presence of hiatus hernia or by walking. Straining occurred at the onset of 31% of acid reflux episodes but often followed the development of an oesophageal common cavity. The occurrence of straining was not influenced by walking. In ambulant patients with reflux oesophagitis: (1) LOS pressure is almost always absent at the time of reflux, usually because of transient LOS relaxation, (2) persistently absent basal LOS pressure is an important mechanism of reflux in a few patients, (3) straining may help to induce acid reflux in a variable proportion of occasions and may in some instances be a response to gas reflux, and (4) walking does not influence the occurrence of reflux or its mechanisms.     

神经末梢受体在胃食管反流病中的作用

目的探讨辣椒素受体(TRPV1,也称瞬时感受器电位香草酸受体1)在胃食管反流疾病(GERD)患者组织中的表达及其与患者症状的关系。方法利用电子胃镜采集58例GERD患者[反流性食管炎(RE)患者26例,非糜烂性反流病(NRED)患者32例]及胃镜检查正常对象(对照组)的食管黏膜组织(胃食管连接处上方3cm),采用HE染色评估组织炎症反应程度、免疫组化染色S-P法判定组织TRPV1表达情况、反流性疾病诊断问卷(RDQ)对患者的症状评分并进行组间比较和相关性分析。结果 GERD患者的RDQ症状积分、GS炎症积分与对照组比较差异有统计学意义(P0.05);RE患者、NRED患者的RDQ症状积分分别为16.77±5.39、17.52±5.03,均显著高于对照组(P0.05),RE患者NRED患者对照组的GS炎症积分(P0.05)。GERD患者的TRPV1表达OD值显著高于对照组(P0.05),RE组OD值(0.023 1±0.002 6)显著高于NRED组和对照组(P0.05),NRED组显著高于对照组(P0.05)。GERD患者与RDQ症状积分呈显著的正相关(r=0.517),与GS炎症积分呈显著的正相关(r=0.554);RE患者与RDQ症状积分呈显著的正相关(r=0.632),与GS炎症积分呈显著的正相关(r=0.532);NRED患者与RDQ症状积分呈显著的正相关(r=0.671),与GS炎症积分呈显著的正相关(r=0.512)。结论 GERD患者的TRPV1表达显著高于正常人群,且与患者的临床症状、炎症反应的严重程度有一定的相关关系。     

Association between respiratory events and nocturnal gastroesophageal reflux events in patients with coexisting obstructive sleep apnea and gastroesophageal reflux disease

BackgroundLiterature has addressed the increased prevalence of gastroesophageal reflux disease (GERD) in obstructive sleep apnea (OSA). Significant improvement of GERD has been found after OSA treatment. However, precise mechanisms underlying this correlation remain unclear. We examined the association between nocturnal gastroesophageal reflux (GER) and sleep events in patients with coexisting OSA and GERD.MethodsA case-crossover study among 12 patients with coexisting moderate–severe OSA and GERD was conducted. Participants underwent simultaneous polysomnography and esophageal impedance and pH monitoring. GER subtypes (ie, acid reflux, non-acid reflux) were defined as outcomes. Respective control time points were selected in all eligible control periods. Each sleep event was assessed individually. Estimated odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed. A p-value of < 0.05 was considered significant.ResultsPatients were determined as moderate to severe OSA (respiratory disturbance index of 42.66 [±22.09]). There were a total of 50 GER episodes, 22 acid reflux and 28 non-acid reflux. Arousals and awakenings were significantly associated with subsequent GER events. The OR for GER following an arousal was 2.31 (95% CI 1.39–3.68; p < 0.001) and following an awakening was 3.71 (95% CI 1.81–7.63; p < 0.001). GER events were significantly less likely to occur after other respiratory events (OR 0.38 [95% CI 0.18–0.82]; p = 0.01). No sleep events followed GER events (p > 0.05).ConclusionsBoth awakening and arousal appear to precipitate any subtype of GER events in patients with coexisting GERD and moderate to severe OSA. However, GER events were significantly less likely to occur after other respiratory events and did not appear to cause sleep-related events.     

Heart rate variability in patients with different manifestations of gastroesophageal reflux disease

BACKGROUND: Autonomic nervous dysfunction has frequently been observed in patients with gastroesophageal reflux diseases (GERD) and impacts the pathogenesis of GERD. However, the characteristics that distinguish between GERD patients with different manifestations remain unknown. AIM: To investigate the autonomic nervous function in subgroups of GERD patients. PATIENTS: Of the 164 participants in this study, 57 were healthy controls, 34 had non-erosive reflux disease (NERD), 40 had symptomatic esophagitis (SE), and 33 asymptomatic esophagitis (AE). METHODS: Resting autonomic activity was assessed by measuring the 5-min heart rate variability (HRV) and HRV indices including time-domain parameters (standard deviation of normal-to-normal intervals [SDNN] and root mean square of successive differences [RMSSD]) and frequency-domain parameters (low-frequency power [LF; 0.04-0.15 Hz], high-frequency power [HF; 0.15-0.4 Hz], and LF/HF power ratio). Mental stress was assessed by use of a self-reported questionnaire (Brief Symptom Rating Scale [BSRS]). RESULTS: HF power was (ANOVA, p=0.041) but time-domain parameters, LF power, LF/HF power ratio, and BSRS parameters were not significantly different between the four groups. A higher HF power was found in examinees with NERD than in those with SE and AE (LSD methods: both p=0.02). When split into two groups (erosive vs. non-erosive), nearly all measures of autonomic tonus were significantly lower in the erosive than non-erosive group. Age and the presence of endoscopic esophagitis influenced the RMSSD and HF power results in the regression analysis. Mental stress or gender did not correlate with any HRV index. CONCLUSION: In comparison with NERD subjects, autonomic tonus in patients with endoscopically confirmed esophagitis (even without symptom) is lower. This finding may suggest that the structural state of esophagus but not symptomatology dictates autonomic function status.     

Effect of intragastric FODMAP infusion on upper gastrointestinal motility,gastrointestinal, and psychological symptoms in irritable bowel syndrome vs healthy controls

Background

The low fermentable oligo‐, di‐, mono‐saccharides and polyol (FODMAP) diet is a treatment strategy to reduce symptoms of irritable bowel syndrome (IBS). Acute effects of FODMAPs on upper gastrointestinal motility are incompletely understood. Our objectives were to assess the acute effects of intragastric FODMAP infusions on upper gastrointestinal motility and gastrointestinal and psychological symptoms in healthy controls (HC) and IBS patients.

Methods

A high‐resolution solid‐state manometry probe and an infusion tube were positioned into the stomach. Fructans, fructose, FODMAP mix, or glucose was intragastrically administered to HC, and fructans or glucose was administered to IBS patients until full satiation (score 0‐5), in a randomized crossover fashion. Manometric measurements continued for 3 hours. Gastrointestinal and psychological symptoms were assessed by questionnaires at predefined time points. The study was registered on www.clinicaltrials.gov (NCT02980406).

Key Results

Twenty HC and 20 IBS patients were included. Fructans induced higher postprandial gastric pressures compared with glucose over both groups (P<.001). Bloating, belching, and pain increased more in IBS over both carbohydrates (P<.041). In addition, IBS patients reported more flatulence and cramps compared with HC following fructans (P<.001). Glucose induced more fatigue and dominance compared with fructans (P=.028, P=.001). Irritable bowel syndrome patients reported a higher increase in anger (P=.030) and a stronger decrease in positive affect (P=.021).

Conclusions & Inferences

The upper gastrointestinal motility response varies between carbohydrates. Irritable bowel syndrome patients are more sensitive to fructan infusion, reflected in their higher gastrointestinal symptom scores. Acute carbohydrate infusion can have differential psychological effects in IBS and HC.     

Effects of transcranial direct current stimulation on esophageal motility in patients with gastroesophageal reflux disease

ObjectiveTo evaluate the effects of transcranial direct current stimulation (tDCS) on esophageal peristalsis in patients with gastroesophageal reflux disease (GERD).MethodsPatients with GERD preliminary diagnosis were included in a randomized double-blind sham-controlled study. Esophageal manometry was performed before and during transcranial direct current stimulation (tDCS) of the right precentral cortex. Half of patients were randomly assigned to anodal, half to sham stimulation. Distal waves amplitude and pathological waves percentage were measured, after swallowing water boli, for ten subsequent times. Last, a 24 h pH-bilimetry was done to diagnose non-erosive reflux disease (NERD) or functional heartburn (FH). The values obtained before and during anodal or sham tDCS were compared.ResultsSixty-eight patients were enrolled in the study. Distal waves mean amplitude increased significantly only during anodal tDCS in NERD (p = 0.00002) and FH subgroups (p = 0.008) while percentage of pathological waves strongly decreased only in NERDs (p = 0.002).ConclusionsTranscranial stimulation can influence cortical control of esophageal motility and improve pathological motor pattern in NERD and FH but not in erosive reflux disease (ERD) patients.SignificancePathophysiological processes in GERD are not only due to peripheral damage but to central neural control involvement as well. In ERD patients dysfunctions of the cortico-esophageal circuit seem to be more severe and may affect central nervous system physiology.     

The relationship between extraesophageal reflux (EER) and obstructive sleep apnea (OSA)

Obstructive sleep apnea (OSA) and extraesophageal reflux (EER) are common chronic diseases and share several similar risk factors. The prevalence of gastroesophogeal (GERD) in OSA patients is significantly higher than the general population; however, no temporal or causal relationship has ever been demonstrated between the two. The purpose of this review is to understand the association between obstructive sleep apnea (OSA) and extraesophageal reflux disease (EER) in the adult population. We conclude that CPAP treatment of OSA significantly reduces GERD symptoms and acidic pH exposure in the esophagus and this improvement with CPAP physiologically occurs in the presence or absence of OSA; and treatment of GERD in OSA patients improves the number of arousals during sleep, but only one study showed a significant difference in apnea.     

Gait in SWEDDs patients: Comparison with Parkinson's disease patients and healthy controls

Patients diagnosed with Parkinson's disease on clinical grounds who subsequently turn out to have normal dopamine transporter imaging have been referred to as SWEDDs (scans without evidence of dopaminergic deficits). Despite having clinical features similar to those of Parkinson's disease, these patients seem to have different pathophysiology, prognosis, and treatment requirements. In this study we determined the similarities and differences in the gaits of SWEDDs and Parkinson's disease patients to investigate whether walking patterns can distinguish these entities. We used 3‐D motion capture to analyze the gaits of 11 SWEDDs patients (who had unilateral or asymmetric upper limb tremor with a rest component), 12 tremor‐dominant Parkinson's disease patients, and 13 healthy control participants. In common with Parkinson's disease patients, SWEDDs patients had a slow gait mainly because of a small stride length, as well as a reduced arm swing. However, several abnormal features of posture and gait in Parkinson's disease were normal in SWEDDs. Thus, SWEDDs patients had normal trunk and elbow posture, normal stride length variability, and normal bilateral step‐phase coordination, all of which were abnormal in Parkinson's disease patients. We also searched for signs of ataxic movements during normal and tandem walking, but found no evidence that ataxic gait was a general feature in SWEDDs. These findings could aid the clinician in identification of potential tremulous SWEDDs cases. © 2011 Movement Disorder Society