Factors influencing lower esophageal sphincter relaxation after deglutition

AIM:To study the relationship between upper esophageal sphincter (UES) relaxation,peristaltic pressure and lower esophageal sphincter (LES) relaxation following deglutition in non-dysphagic subjects.METHODS:Ten non-dysphagic adult subjects had a high-resolution manometry probe passed transnasally and positioned to cover the UES,the esophageal body and the LES.Ten water swallows in each subject were analyzed for time lag between UES relaxation and LES relaxation,LES pressure at time of UES relaxation,duration of LES relaxation,the distance between the transition level (TL) and the LES,time in seconds that the peristaltic wave was before (negative value) or after the TL when the LES became relaxed,and the maximal peristaltic pressure in the body of the esophagus.RESULTS:Relaxation of the LES occurred on average 3.5 s after the bolus had passed the UES and in most cases when the peristaltic wave front had reached the TL.The LES remained relaxed until the peristaltic wave faded away above the LES.CONCLUSION:LES relaxation seemed to be caused by the peristaltic wave pushing the bolus from behind against the LES gate.

Effects and mechanisms of electroacupuncture at PC6 on frequency of transient lower esophageal sphincter relaxation in cats

AIM: To investigate the effects of electroacupuncture (EA) at neiguan (PC6) on gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs) and discuss the mechanisms of this treatment. METHODS: ProtocolⅠ: Twelve healthy cats underwent gastric distention for 60 min on the first day. Electrical acupoint stimulation was applied at the neiguan or a sham point on the hip in randomized order before gastric distention, on the third day and fifth day. Those cats that underwent EA at neiguan on the fifth day were named "Neiguan Group" and the cats that underwent EA at a sham acupoint on the fifth day were named "Sham Group" (control group). During the experiment the frequency of TLESRs and lower esophageal sphincter (LES) pressure were observed by a perfused sleeve assembly. Plasma levels of gastrin (GAS) and motilin (MTL) were determined by radioimmunoassay. Nitrite/nitrate concentration in plasma and tissues were measured by Griess reagent. The nuclei in the brain stem were observed by immunohistochemistry method of c-Fos and NADPH-d dyeing. Protocol Ⅱ: Thirty six healthy cats were divided into 6 groups randomly. We gave saline (2 mL iv. control group), phaclofen (5 mg/kg iv. GABA-B antagonist), cholecystokinin octapeptide (CCK-8) (1 μg/kg per hour iv.), L-Arginine (200 mg/kg iv.), naloxone (2.5 μmol/kg iv.) and tacrine (5.6 mg/kg ip. cholinesterase inhibitor) respectively before EA at Neiguan and gastric distention. And the frequencies of TLESRs in experimental groups were compared with the control group.RESULTS: ProtocolⅠ: Not only the frequency of gastric distention-induced TLESR in 60 min but also the rate of common cavity during TLESRs were significantlydecreased by EA at neiguan compared to that of sham acupoint stimulation. C-Fos immunoreactivity and NOS reactivity in the solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) were significantly decreased by EA at neiguan compared to that of the sham group. However, the positive nuclei of C-Fos and NOS in reticular formation of the medulla (RFM) were increased by EA at neiguan. Protocol Ⅱ: The inhibited effect of EA at neiguan on TLESR’s frequency was completely restored by pretreatment with CCK (23.5/h vs 4.5/h, P < 0.05), L-arginine (17.5/h vs 4.5/h, P < 0.05) and naloxone(12/h vs 4.5/h, P < 0.05). On the contrary, phaclofen (6/h vs 4.5/h, P > 0.05) and tacrine (9.5/h vs 4.5/h, P > 0.05) did not influence it. CONCLUSION: Electric acupoint stimulation at Neiguan significantly inhibits the frequency of TLESR and the rate of common cavity during TLESR in cats. This effect appears to act on the brain stem, and may be mediated through nitric oxide (NO), CCK-A receptor and mu-opioid receptors. But the GABAB receptor and acetylcholine may not be involved in it.

Neuro-regulation of lower esophageal sphincter function as treatment for gastroesophageal reflux disease

The junction between the esophagus and the stomach is a specialized region, composed of lower esophageal sphincter (LES) and its adjacent anatomical structures, the gastric sling and crural diaphragm. Together these structures work in a coordinated manner to allow ingested food into the stomach while preventing reflux of gastric contents across the esophago-gastric junction (EGJ) into the esophagus. The same zone also permits retrograde passage of air and gastric contents into esophagus during belching and vomiting. The precise coordination required to execute such a complicated task is achieved by a finely-regulated high-pressure zone. This zone keeps the junction between esophagus and stomach continuously closed, but is still able to relax briefly via input from inhibitory neurons that are responsible for its innervation. Alterations of the structure and function of the EGJ and the LES may predispose to gastroesophageal reflux disease (GERD).

Investigation of cholecystokinin receptors in the human lower esophageal sphincter

AIM: To compare the binding of cholecystokinin (CCK)-8 to CCK receptors in sling and clasp fibers of the human lower esophageal sphincter.

In vitro effect of pantoprazole on lower esophageal sphincter tone in rats

AIM:To investigate the in vitro effects of pantoprazole on rat lower esophageal sphincter(LES)tone.METHODS:Rats weighing 250-300 g,provided by the Yeditepe University Experimental Research Center(Yü-DETAM),were used throughout the study.They were anesthetized before decapitation.LES tissues whose mucosal lining were removed were placed in a stan-dard 30-mL organ bath with a modif ied Krebs solution and continuously aerated with 95% oxygen-5% carbon dioxide gas mixture and kept at room temperature.The tissues were allowed to stabilize for 60 min.Sub-sequently,the contractile response to 10-6 mol/L carba-chol was obtained.Different concentrations of freshly prepared pantoprazole were added directly to the tis-sue bath to generate cumulative concentrations of 5×10-6 mol/L,5×10-5 mol/L,and 1.5×10-4 mol/L.Activi-ties were recorded on an online computer via a 4-channeltransducer data acquisition system using the software BSL PRO v 3.7,which also analyzed the data.RESULTS:Pantoprazole at 5×10-6 mol/L caused a small,but statistically insignif icant,relaxation in the car-bachol-contracted LES(2.23% vs 3.95%).The 5×10-5 mol/L concentration,however,caused a signif icant relax-ation of 10.47% compared with the control.1.5×10-4 mol/L concentration of pantoprazol caused a 19.89% relaxation in the carbachol contracted LES(P<0.001).CONCLUSION:This is the fi rst study to demonstrate that pantoprazole has a relaxing effect in isolated LESs.These results might have signif icant clinical implications for the subset of patients using proton pump inhibitors who do not receive full symptomatic alleviation from gastroesophageal reflux disease.

Lower esophageal sphincter relaxation is impaired in older patients with dysphagia

AIM: To characterize the effects of age on the mechanisms underlying the common condition of esophageal dysphagia in older patients, using detailed manometric analysis. METHODS: A retrospective case-control audit was performed on 19 patients aged ≥ 80 years (mean age 85 ± 0.7 year) who underwent a manometric study for dysphagia (2004-2009). Data were compared with 19 younger dysphagic patients (32 ± 1.7 years). Detailed manometric analysis performed prospectively included basal lower esophageal sphincter pressure (BLESP), pre-swallow and nadir LESP, esophageal body pressures and peristaltic duration, during water swallows (5 mL) in right lateral (RL) and upright (UR) postures and with solids. Data are mean ± SE; a P-value < 0.05 was considered significant. RESULTS: Elderly dysphagic patients had higher BLESP than younger patients (23.4 ± 3.8 vs 14.9 ± 1.2 mmHg; P < 0.05). Pre-swallow LESP was elevated in the elderly in both postures (RL: 1 and 4 s P = 0.019 and P = 0.05; UR: P < 0.05 and P = 0.05) and solids (P < 0.01). In older patients, LES nadir pressure was higher with liquids (RL: 2.3 ± 0.6 mmHg vs 0.7 ± 0.6 mmHg, P < 0.05; UR: 3.5 ± 0.9 mmHg vs 1.6 ± 0.5 mmHg, P = 0.01) with shorter relaxation after solids (7.9 ± 1.5 s vs 9.7 ± 0.4 s, P = 0.05). No age-related differences were seen in esophageal body pressures or peristalsis duration. CONCLUSION: Basal LES pressure is elevated and swallow-induced relaxation impaired in elderly dysphagic patients. Its contribution to dysphagia and the effects of healthy ageing require further investigation.

Upper esophageal sphincter abnormalities on high-resolution esophageal manometry and treatment response of type Ⅱ achalasia

BACKGROUND Little is known about the clinical significance of upper esophageal sphincter(UES)motility disorders and their association with the treatment response of typeⅡachalasia.None of the three versions of the Chicago Classification of Esophageal Motility Disorders has defined UES abnormality metrics or their function.UES abnormalities exist in some patients and indicate a clinically significant problem in patients with achalasia.AIM To demonstrate the manometric differentiation on high-resolution esophageal manometry between subjects with abnormal UES and normal UES,and the association between UES type and the treatment response of typeⅡachalasia.METHODS In total,498 consecutive patients referred for high-resolution esophageal manometry were analyzed retrospectively.The patients were divided into two groups,those with normal and abnormal UES function.UES parameters were analyzed after determining lower esophageal sphincter(LES)function.Patients with typeⅡachalasia underwent pneumatic dilation for treatment.Using mixed model analyses,correlations between abnormal UES and treatment response were calculated among subjects with typeⅡachalasia.RESULTS Of the 498 consecutive patients,246(49.40%)were found to have UES abnormalities.Impaired relaxation alone was the most common UES abnormality(52.85%,n=130).The incidence rate of typeⅡachalasia was significantly higher in subjects with abnormal UES than those with normal UES(9.77%vs 2.58%,P=0.01).After pneumatic dilation,LES resting pressure,LES integrated relaxation pressure,and UES residual pressure were significantly decreased(41.91±9.20 vs 26.18±13.08,38.94±10.28 vs 16.71±5.65,and 11.18±7.93 vs 5.35±4.77,respectively,P<0.05).According to the Eckardt score,subjects with typeⅡachalasia and abnormal UES presented a significantly poorer treatment response than those with normal UES(83.33%vs 0.00%,P<0.05).CONCLUSION Impaired relaxation alone is the most common UES abnormality.The incidence of typeⅡachalasia is associated with abnormal UES.TypeⅡachalasia with abnormal UES has a poorer treatment response,which is a potentially prognostic indicator of treatment for this disease.

The molecular pathogenesis of achalasia:a paired lower esophageal sphincter muscle and serum 4D label-free proteomic study

Background:Achalasia is a primary esophageal motility disorder with potential molecular pathogenesis remaining uncertain.This study aimed to identify the differentially expressed proteins and potential pathways among achalasia subtypes and controls to further reveal the molecular pathogenesis of achalasia.Methods:Paired lower esophageal sphincter(LES)muscle and serum samples from 24 achalasia patients were collected.We also collected 10 normal serum samples from healthy controls and 10 normal LES muscle samples from esophageal cancer patients.The 4D label-free proteomic analysis was performed to identify the potential proteins and pathways involved in achalasia.Results:Analysis of Similarities showed distinct proteomic patterns of serum and muscle samples between achalasia patients and controls(both P<0.05).Functional enrichment analysis suggested that these differentially expressed proteins were immunity-,infection-,inflammation-,and neurodegeneration-associated.The mfuzz analysis in LES specimens showed that proteins involved in the extracellular matrix–receptor interaction increased sequentially between the control group,type III,type II,and type I achalasia.Only 26 proteins altered in the same directions in serum and muscle samples.Conclusions:This first 4D label-free proteomic study of achalasia indicated that there were specific protein alterations in both the serum and muscle of achalasia,involving immunity,inflammation,infection,and neurodegeneration pathways.Distinct protein clusters between types I,II,and III revealed the potential molecular pathways associated with different disease stages.Analysis of proteins changed in both muscle and serum samples highlighted the importance of further studies on LES muscle and revealed potential autoantibodies.

Botulinum Toxin A in the Treatment of Oropharyngeal or Esophageal Dysphagia

Objectives: In this retrospective analysis, we explored the effect of botulinum toxin A (BTA) injection to treat oropharyngeal dysphagia or esophageal dysfunction caused by diseases of the upper (UES) and lower (LES) esophageal sphincter. Methods: In total, 48 patients (17 patients with UES disorders, and 31 patients with LES dysfunction;mean age 64 years) were treated between 1996 and 2007 in our hospital. Comorbid diseases as well as maintenance medication were documented to evaluate the overall health status of our patients. The mean duration of symptoms, the number of pre-treatments and the specification of dysphagia were considered. Results: One month after injection, the response rates were 73.3% (UES group) and 76.6% (LES group). Most patients in the UES group received 30-40 units BTA (Botox?) whereas most patients in the LES group were treated with 100 units BTA. In cases of re-injection, 50% of patients in the UES group experienced an escalation of dosage (up to 75 units), whereas the other 50% received the same dosage. The dosages in the LES group were mostly kept constant. Conclusion: Comparing the two groups with esophageal dysfunction of fundamentally different etiologies (UES/LES), a discrepancy in the level of symptom relief, onset and a longer cessation of clinical benefit were observed in the LES group. In this analysis, we were able to show that injection of BTA is an effective and safe treatment for disorders of the UES and LES.

Stretta:A valuable endoscopic treatment modality for gastroesophageal reflux disease

One potential option for the management of refractory gastro-esophageal reflux disease(GERD)is the delivery of radiofrequency energy to the gastro-esophageal junction(Stretta).This endoscopic therapy is safe,effective,durable,and repeatable if necessary and serves an unmet need for many GERD sufferers.Stretta could be effective in decreasing esophageal sensitivity to acid and in decreasing the gastro-esophageal junction compliance,which in turn contributes to symptomatic benefit by decreasing refluxate volume.Therefore,Stretta may serve as an endoscopic pain modulator and should be considered in patients with refractory symptoms despite proton pump inhibitors,as well as in patients with functional heartburn.

Modified Xiaochaihu Decoction for gastroesophageal reflux disease:A randomized double-simulation controlled trial

BACKGROUND Gastroesophageal reflux disease(GERD)has a high prevalence worldwide,and its incidence is increasing annually.Modified Xiaochaihu Decoction(MXD)could relieve the symptoms of GERD,but the effects of MXD on GERD manifestations and relapse prevention need to be further explained.Therefore,we performed a prospective,double-blind,and double-simulation study.AIM To verify the efficacy of MXD for GERD and its effect on esophageal motility.METHODS Using randomization,double-blinding,and a simulation design,288 participants with GERD were randomized to the treatment group and control group and received herbs(MXD)plus omeprazole simulation and omeprazole plus herbs simulation,respectively,for 4 wk.The GERD-Q scale score and esophageal manometry were measured at baseline,after treatment,and at 1 mo and 3 mo follow-up visits when medication was complete to evaluate recurrence indicators.RESULTS The GERD-Q scale score in both groups decreased significantly compared to those before treatment(P<0.01).However,no significant difference was observed between the two groups(P>0.05).Esophageal manometry showed that participants with lower esophageal sphincter pressure reduction and the proportion of ineffective swallowing(more than 50%)improved in both groups from baseline(P<0.01),especially in the treatment group(P<0.05).The percentage of small intermittent contractions,large intermittent contractions,and increased pre-phase contractions in the treatment group significantly improved compared with baseline(P<0.05)but did not improve in the control group(P>0.05).There was no significant difference between the groups after treatment(P>0.05).The percentage of weak esophageal contractility(distal contractile integral<450 mmHg·s·cm),improved in both groups(P<0.01),but no significant difference was observed between the groups after treatment(P>0.05).The relapse rate in the treatment group was lower than that in the control group at the 1 mo(P<0.01)and 3 mo follow-up(P<0.05).CONCLUSION MXD has a similar therapeutic effect to omeprazole in mild-to-moderate GERD.The therapeutic effect may be related to increased pressure in the lower esophageal sphincter and reduced ineffective swallowing.

Effects of anti-hypertensive drugs on esophageal body contraction

AIM:To clarify the effects of anti-hypertensive drugs on esophageal contraction and determine their possi-ble relationship with gastro-esophageal reflux disease.METHODS:Thirteen healthy male volunteers were enrolled. Esophageal body peristaltic contractions and lower esophageal sphincter (LES) pressure were measured using high resolution manometry. All subjects were randomly examined on four separate occasions following administrations of nifedipine,losartan,and atenolol,as well as without any drug administration.RESULTS:Peristaltic contractions by the esophageal body were separated into three segments by two troughs. The peak peristaltic pressures in the mid and lower segments of the esophageal body under atenolol administration were signifi cantly higher than those without medication in a supine position. On the other hand,peristaltic pressures under nifedipine administration were lower than those observed without drug ad-ministration. Losartan did not change esophageal body peristalsis. Atenolol elevated LES pressure and slowed peristaltic wave transition,while the effects of nifedip-ine were the opposite. CONCLUSION:Among the anti-hypertensive drugs tested,atenolol enhanced esophageal motor activity,which was in contrast to nifedipine.

Magnetic challenge against gastroesophageal reflux

Almost 15 years have passed since the first paper on the possibility of using magnets to prevent gastro-esophageal reflux(GER)was published and so it is time to assess the results obtained with the first magnetic device available on the market,the Linx magnetic sphincter augmentation(MSA)and to consider what other options are forthcoming.MSA demonstrated an anti-reflux activity similar to that of Nissen fundoplication,considered the“gold standard”surgical treatment for GER disease,and caused less gas-bloating and a better ability to allow vomiting and belching.However,unlike Nissen fundoplication,this magnetic device is burdened by complications,which are roughly similar to those of the non-magnetic anti-reflux Angelchik prosthesis,that,after considerable use in the eighties,was shelved due to these complications.It is interesting to note that some of these complications show the same pathophysiological mechanism in both devices.The upcoming new magnetic devices should avoid these complications,as their anti-reflux magnetic mechanism is completely different.The experiments in animals regarding these new magnetic appliances were examined,remarking their advantages and drawbacks,but the way to apply them in surgical practice is long and difficult,although worthy,as they represent the future of magnetic surgery.

Gastroesophageal reflux disease in children: What’s new right now?

Gastroesophageal reflux(GER)in children is very common and refers to the involuntary passage of gastric contents into the esophagus.This is often physiological and managed conservatively.In contrast,GER disease(GERD)is a less common pathologic process causing troublesome symptoms,which may need medical management.Apart from abnormal transient relaxations of the lower esophageal sphincter,other factors that play a role in the pathogenesis of GERD include defects in esophageal mucosal defense,impaired esophageal and gastric motility and clearance,as well as anatomical defects of the lower esophageal reflux barrier such as hiatal hernia.The clinical manifestations of GERD in young children are varied and nonspecific prompting the necessity for careful diagnostic evaluation.Management should be targeted to the underlying aetiopathogenesis and to limit complications of GERD.The following review focuses on up-to-date information regarding of the pathogenesis,diagnostic evaluation and management of GERD in children.

Current clinical approach to achalasia

Idiopathic achalasia is a rare primary motility disorder of the esophagus. The classical features are incomplete relaxation of a frequently hypertensive lower esophageal sphincter (LES) and a lack of peristalsis in the tubular esophagus. These motor abnormalities lead to dysphagia, stasis, regurgitation, weight loss, or secondary respiratory complications. Although major strides have been made in understanding the pathogenesis of this rare disorder, including a probable autoimmune mediated destruction of inhibitory neurons in response to an unknown insult in genetically susceptible individuals, a definite trigger has not been identified. The diagnosis of achalasia is suggested by clinical features and conf irmed by further diagnostic tests, such as esophagogastroduodenoscopy (EGD), manometry or barium swallow. These studies are not only used to exclude pseudoachalasia, but also might help to categorize the disease by severity or clinical subtype. Recent advances in diagnostic methods, including high resolution manometry (HRM), might allow prediction of treatment responses. The primary treatments for achieving long-term symptom relief are surgery and endoscopic methods. Although limited high-quality data exist, it appears that laparoscopic Heller myotomy with partial fundoplication is superior to endoscopic methods in achieving long-term relief of symptoms in the majority of patients. However, the current clinical approach to achalasia will depend not only on patients' characteristics and clinical subtypes of the disease, but also on local expertise and patient preferences.

Pathogenesis of achalasia cardia

Achalasia cardia is one of the common causes of motor dysphagia.Though the disease was first described more than 300 years ago,exact pathogenesis of this condition still remains enigmatic.Pathophysiologically,achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus.In the initial stage,degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine,resulting in high amplitude non-peristaltic contractions(vigorous achalasia);progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body(classic achalasia).Since the initial description,several studies have attempted to explore initiating agents that may cause the disease,such as viral infection,other environmental factors,autoimmunity,and genetic factors.Though Chagas disease,which mimics achalasia,is caused by an infective agent,available evidence suggests that infection may not be an independent cause of primary achalasia.A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins,siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down's syndrome and Parkinson's disease.Polymorphisms in genes encoding for nitric oxide synthase,receptors for vasoactive intestinal peptide,interleukin 23 and the ALADIN gene have been reported.However,studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained.Currently,the disease is believed to be multi-factorial,with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.

Changes in the esophagogastric junction outflow obstruction manometric feature based on the Chicago Classification updates

BACKGROUND The critical diagnostic criteria for esophagogastric junction outflow obstruction(EGJOO)were published in the latest Chicago Classification version 4.0(CCv4.0).In addition to the previous criterion[elevated integrated relaxation pressure(IRP)in supine position],manometric diagnosis of EGJOO requires meeting the criteria of elevated median-IRP during upright wet swallows and elevated intrabolus pressure.However,with the diagnostic criteria modification,the change in manometric features of EGJOO remained unclear.AIM To evaluate the esophageal motility characteristics of patients with EGJOO and select valuable parameters for confirming the diagnosis of EGJOO.METHODS We performed a retrospective analysis of 370 patients who underwent highresolution manometry with 5 mL water swallows×10 in supine,×5 in upright position and the rapid drink challenge(RDC)with 200 mL water from November 2016 to November 2021 at Peking University First Hospital.Fifty-one patients with elevated integrated supine IRP and evidence of peristalsis were enrolled,with 24 patients meeting the updated manometric EGJOO diagnosis(CCv4.0)as the EGJOO group and 27 patients not meeting the updated EGJOO criteria as the isolated supine IRP elevated group(either normal median IRP in upright position or less than 20%of supine swallows with elevated IBP).Forty-six patients with normal manometric features were collected as the normal high-resolution manometry(HRM)group.Upper esophageal sphincter(UES),esophageal body,and lower esophageal sphincter(LES)parameters were compared between groups.RESULTS Compared with the normal HRM group,patients with EGJOO(CCv4.0)had significantly lower proximal esophageal contractile integral(PECI)and proximal esophageal length(PEL),with elevated IRP on RDC(P<0.05 for each comparison),while isolated supine IRP elevated patients had no such feature.Patients with EGJOO also had more significant abnormalities in the esophagogastric junction than isolated supine IRP elevated patients,including higher LES resting pressure(LESP),intrabolus pressure,median supine IRP,median upright IRP,and IRP on RDC(P<0.05 for each comparison).Patients with dysphagia had significantly lower PECI and PEL than patients without dysphagia among the fifty-one with elevated supine IRP.Further multivariate analysis revealed that PEL,LESP,and IRP on RDC are factors associated with EGJOO.The receiver-operating characteristic analysis showed UES nadir pressure,PEL,PECI,LESP,and IRP on RDC are parameters supportive for confirming the diagnosis of EGJOO.CONCLUSION Based on CCv4.0,patients with EGJOO have more severe esophagogastric junction dysfunction and are implicated in the proximal esophagus.Additionally,several parameters are supportive for confirming the diagnosis of EGJOO.