Perception of gastro-oesophageal acid reflux

Perception of gastro-oesophageal reflux

Peripheral mechanisms

Gastrointestinal pain is mediated by spinal visceral afferent fibres, with a probable importantcontribution from vagal afferent fibres [6]. When activated,mechanoreceptors and chemo-sensitive receptors (resident in mesentery, serosa and submucosa) epolarise Ad- and C-fibres. The ability to transduce noxious mechanical, chemical or thermal stimuli into generator currents able to depolarize such fibres is a property of transducer channels such as transient receptor potential (TRP) channels. TRPV1, TRPV4 and TRPA1 channels have been shown to have a role in GI nociception, as have acid sensing ion channels (ASICs) and P2x purinoceptors.( Knowles CH , et al ,2009)

In the presence of tissue inflammation or injury there is an up-regulation of pain transmission. The ability to enhance pain transmission to the brain in these situations is important as heightened bodily awareness can alter behaviour to aid in the protection of injured sites and the promotion of healing. Research in somatic pain has suggested that both peripheral and central mechanisms can increase nociceptive transmission following inflammation or injury to tissues. Peripheral mechanisms include peripheral sensitisation (PS), which is an inflammatory mediator-induced facilitation of nociceptor activity in peripheral tissues. Peripheral sensitisation causes pain hypersensitivity at the site of injury or inflammation, also known as primary hyperalgesia. Here inflammatory products including bradykinin, histamine, 5HT, prostanoids, proteases and cytokines permit nociceptor firing at reduced thresholds.( Hobson AR, et al , 2008)

Central mechanisms

Spinal mechanisms In normal circumstances, the presence of stimuli will activate the peripheral receptors as mentioned above. Action potentials would then be generated via activation of Na/K channels and impulses will be sent to the spinal cord via peripheral afferent nerves. Repetitive stimulation or high intensity stimuli can cause a constant firing of action potential to the spinal cord. Enhanced nociceptor input in turn activates intracellular signalling cascades within spinal dorsal horn neurones,

leading to central sensitisation and amplified responses to noxious and innocuous inputs due to facilitated excitatory synaptic responses and depressed inhibition This facilitation is triggered by the pre-synaptic release of neurotransmitters and neuromodulators such as glutamate .( Woolf CJ,,2000)

brain derived neurotrophic factor (BDNF) and prostaglandins . These neurotransmitters and neuromodulators activate ligand-gated ion channels (NMDA-receptor-glutamate), metabotrophic receptors (metabotrophic glutamate receptor (mGluR)–glutamate and NK1–substance P) and tyrosine kinase receptors (Tyrosine Kinase (Trk) B–BDNF) and increase intracellular calcium via release from intracellular stores and calcium inflow. Consequently, calcium-dependent enzymes such as protein kinase A [31], protein kinase C  and tyrosine kinases are activated, leading to phosphorylation of the NMDA receptors. (Siddiqui A, et al , 2005)This dramatically changes NMDA-receptor kinetics and reduces its voltage-dependent magnesium block, thus augmenting its subsequent responsiveness to glutamate and increasing synaptic strength, enabling previously subthreshold inputs to activate the cell. This increase in gain alters receptive field properties and pain sensitivity, causing tissue hypersensitivity far beyond the site of injury. In addition to producing central sensitisation, which occurs within seconds of appropriate activation of spinal dorsal horn neurones, nociceptive input also generates an activity-dependent change in transcription in dorsal root ganglion and dorsal horn neurones These changes occur in response to a complex mechanism involving both an increase and a modification of constitutively .( Woolf CJ,et al ,1991)


Cortical mechanisms

A major limitation of most visceral hypersensitivity studies is that they rely on subjective methods of reporting sensation intensity .To overcome this, a commonly used neurophysiological technique, cortical evoked potentials (CEP), has been adopted for use as a more objective correlate of oesophageal sensation. CEP allow recording of cortical neuronal electrical fields generated in response to a peripheral nerve stimulus. Signal averaging of cortical electrical activity of up to 200 oesophageal stimuli is conducted to generate an optimal signal to noise ratio and a temporal pattern of cortical activation is obtained. Because of the excellent temporal resolution of this technique (one ms) it is possible to study the conduction velocity of afferent neuronal transmission from the oesophagus to the cortex. Using this technique before and after oesophageal acid infusion a consistent reduction in CEP latency to oesophageal electrical stimulation has been described which demonstrates that facilitation of afferent pathway conduction accompanied the CS.( Sarkar S et al,2001)

In a recent study in NERD and functional heartburn patients there was a correlation between pain threshold and acid exposure,with increased oesophageal sensitivity being associated with lower DeMeester score . Thus reflux negative (functional heartburn) patients had lower pain thresholds when compared to both reflux positive patients and controls. Cortical evoked potentials were normal in reflux negative patients butsignificantly delayed in the reflux positive group. This suggests that increased oesophageal pain sensitivity in functional heartburn patients is associated with heightened afferent sensitivity as normal latency evoked potential responses could be elicited with reduced afferent input. Similar differentiation in the afferent response using cortical evoked potentials has also been shown in subgroups of patients with Non Cardiac Chest Pain .( Hobson AR, et al ,2006)

Functional Magnetic Resonance imaging has also been used to study the brain processing of acid induced oesophageal hypersensitivity. Lawal A et al studied the brain processing to mechanical stimulation of the proximal oesophagus following infusion of acid or control buffer solution into the distal oesophagus. Following distal oesophageal acid infusion, both subliminal and liminal levels of proximal oesophageal distentions, caused a significant increase in brain activity in both the  ingulate and the insular cortices in comparison to the control buffer solution . This suggests the development of acid-induced sensitisation of the oesophagus to mechanical distention and indicates that this sensitisation is accompanied by increased activity in brain areas processing both sensory (insular cortex) and cognitive (cingulated cortex) aspects of sensation. (Lawal A,et al ,2008)


Pathophysiology of gastroesophageal acid reflux (gerd)


 GER is a multifactorial process where gastric contents are allowed to re-enter the esophagus. Three main etiological processes have been described:  – transient relaxation of the lower esophageal sphincter (TRLES);  – hypotonic or incompetent LES; and – anatomic disruption of the esophagogastric junc-tion (EGJ) [as in hiatal hernia]. The consequence of these processes is reflux of gastric contents into the esophagus; in-sufficient esophageal clearance and buffering of the refluxate; and abnormalities in epithelial restitution and repair. By its very nature, the physical barrier between the esophagus and stomach is imperfect and multiple episodes of reflux occur in healthy subjects every day. However, the protective function of this specialized area of digestive anatomy exists in its ability to limit the frequency of reflux episodes, to modulate the circumstances in which acidic gastric content is allowed to reflux back into the esophagus, and to minimize esophageal acid contact time.( Orlando RC.,2001)

1-Transient Relaxation of the Lower Esophageal Sphincter (LES) The LES is a band of specialized smooth muscle found in the terminal few centimeters of the esophagus. Unlike the esophagus, which contracts briefly during swallowing, the LES maintains a sustained state of contraction, acting as a physical barrier and preventing reflux of gastric contents.( Harnett KM, , et al  2005)

The resting tone of the LES is approximately 10–30 mmHg above gastric and esophageal luminal pressures TRLESs are sponta-neous, vagally induced, abrupt decreases in LES pressure un-related to the act of swallowing. In contrast to swallow-induced relaxations of the LES, which usually last 6–8 seconds, TRLESs are longer in duration, typically lasting more than 10 seconds. Furthermore, they are generally defined as having a nadir pressure £2 mmHg. TRLESs are primarily triggered by gastric distension and are therefore seen more frequently in the postprandial state. Overall, TRLES constitutes the major mechanism under-lying GER.( Mittal RK,, 1995)

In GERD, studies show that not only is there an increase in the frequency of TRLES, but there is also an increase in the amount of reflux during these episodes and an increase in the duration of the reflux episode.This prolonged period of reflux allows for longer contact time of acidic gastric contents with the esophageal epithelium resulting in tissue injury. Emerging evidence shows that as the severity of GERD increases, TRLES progressively gives way to other mechanisms that further potentiate LES dysfunction and disease progression.( Orlando RC,2001)

2 Hypotensive or Incompetent LES The neuromuscular mechanisms that regulate the LES are not well understood. The LES maintains a contracted state at rest, transiently relaxing to allow passage of a bolus from the esoph-agus. It is postulated that the LES tone is spontaneous and myogenically regulated, whilst LES relaxation and esophageal contraction are neurally induced (Biancani P, et al ,2006) Orlando describes a hypotensive LES as having a pressure of <10 mmHg, and an in-competent sphincter as having a pressure of <4 mmHg. Episodes of abrupt increases in intra-abdominal pressure, such as that which occur during physical activity, coughing or bending over, result in free reflux if the LES has abnormally low tone. Dys-function of the LES in this setting is now considered to be a secondary motor abnormality that occurs because of impaired neural signaling.( Rieder F,, et al , 2007)

Two distinct intracellular pathways are involved in LES circular smooth muscle contraction. The first is a protein kinase C-dependent pathway activated by exposure to low levels of agonists, such as arachidonic acid, prostaglandin F2, and thromboxane A2, that is dominant during maintenance of spontaneous tone. The second is a Ca++-calmodulin-myosin light chain kinase-dependent pathway that is activated in response to maximally effective doses of agonists, such as acetylcholine, during the initial phase of esophageal contraction. (Biancani P, et al ,2006)

It is the amount of intracellular Ca++ available for contraction, mediated in part by agonist-induced activity of phospholipase C, that de-termines which pathway will be activated.Damage to the esophageal epithelium initially results in the release of specific inflammatory mediators such as substance-P and platelet-activating factor (PAF).( Cheng L, 2005)These mediators diffuse into the surrounding smooth muscle and induce an overproduction of additional inflammatory mediators and re-active oxygen species, such as interleukin (IL)-6, IL-8, and hydrogen peroxide (H2O2). In animal models, PAF has been shown to reduce LES tone and stimulate further release of H2O2. H2O2 appears to affect esophageal neurons and signal transduction, resulting in impairment of LES-sustained con-traction. Furthermore, H2O2 increases production of PAF and inhibits Ca++ adenosine triphosphatase (ATPase) activity, de-pleting releasable intracellular Ca++ stores and further im-pairing LES contractile ability. ( Cheng L, 2005) This establishes a pro-inflammatory feedback loop resulting in further mucosal injury and reduction in esophageal sphincter tone. This spiral of events may lead to permanent impairment of LES tone and lower esophageal peristalsis.( Rieder F,2010)

3 The Esophagogastric Junction The EGJ represents an anatomical distinction separating the esophagus from the stomach and provides a physical barrier to reflux of gastric contents. Structural components that are in-tegral to this barrier include the LES, the crural diaphragm, the phrenoesophageal ligament, the acute angle of His, the mucosal rosette (the circumferential clustering of mucosal folds at the EGJ) and the intra-abdominal segment of the EGJ (the portion situated below the diaphragmatic plane). (Rieder F,2010) Anatomical dis-ruption of the EGJ has been considered a risk factor for the development of GERD, although the exact relationship of these anatomical factors and how they affect TRLES has not been thoroughly explored. The most common abnormality of the EGJ that has been associated with GERD is a hiatus hernia. Hiatal herniae are re-ported to increase the frequency of reflux events through reduc-tions in LES pressure and increases in strain-associated episodes of reflux. Moreover, they have also been shown to delay esophageal clearance of refluxate.( Kahrilas PJ,2000) It is postulated that a hiatal hernia alters the angle of the cardia and allows the gastric wall tension to pull open the LES even if the LES is itself anatomically normal.Adult studies have further shown that the size of the hiatal hernia has a strong correlation with LES dysfunction and impaired EGJ barrier function and that there is an increase in TRLES frequency induced by gastric distension.  Another possible cause of EGJ disruption is esophageal shortening, which has been shown in animal models to occur as a result of increased contractility of esophageal longitudinal smooth muscle.( Dunne DP,,2000) Mucosal acid-induced injury appears to trigger mast-cell degranulation and histamine release that re-sults in this smooth muscle contraction. These findings raise the possibility that the hiatal hernia may occur secondary to acid-related mucosal injury and progressive esophageal shortening. However, over time, the development of the hernia could clearly contribute to the worsening of GERD. In children, special consideration needs to be given to individuals with other conditions that have the potential to disrupt normal esophageal and EGJ function, such as neuro-logical impairment, obesity, and repaired esophageal atresia or diaphragmatic hernia. (Ruigo´ mez A,,2010)


introduction to gastroesophageal reflux (gerd)


 GER is a normal physiological event that occurs when transient relaxation of the lower esophageal sphincter (LES) allows retro-grade passage of gastric contents into the esophagus and beyond. This may occur with or without regurgitation and/or vomiting. The frequency with which reflux occurs, and the duration of events, varies with age, with infants experiencing many more ep-isodes than older children and adolescents. By 12–14 months of life, reflux episodes have normally significantly declined and it is unusual for children older than 18 months to experience clinically significant issues related to physiological reflux.( Nelson SP, et al ,2009)  In contrast,

GERD is a pathological process whereby reflux results in troublesome symptoms and/or complications. Other terms such as ‘regurgitation’, ‘vomit’, and ‘rumination’ are de-scriptive terms, and whilst they may be symptoms of reflux, they do not necessarily constitute a diagnosis of GER or GERD.( Sherman PM, et al ,2009)  In 2006, the Montreal definition of GERD was established providing an international evidence-based consensus on the definition of GERD in the adult population. In 2009, a similar global consensus on the definition of GERD in the pediatric population was developed, with 59 consensus state-ments and recommendations made. ( Sherman PM, et al ,2009)



Figure 13: gastroesophageal reflux disease

Determining GERD in the neonatal and infant group is challenging because of the potential differential diagnoses and the highly variable presentation. Determining reflux from re-flux disease requires significant clinical acumen. To this extent, it may be considered a separate topic for review. As such, this paper will focus on GERD in children (ages 1–10 years) and adolescents (ages 11–17 years).( Hollingworth S,,2010)

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD):

is inflammation of the esophagus and often the larynx (box) caused by acid refluxing backing up from the stomach in the esophagus  many people their refluxing acid reach all the way up to the voice box and higher– sometimes even into the back of the mouth and nose.

This acid causes irritation of the delicate tissues that cover the inside of the esophagus, larynx, and back of the throat. This results in various symptoms including

  • a painful or burning sensation in the chest (“heartburn”)
  • difficult or painful swallowing
  • hoarseness
  • increased mucus in the throat (phlegm)


Figure 2 : GERD related upper respiratory diseases.

  • a feeling that something is stuck in the throat (foreign body sensation or globus). (pleskow, et al; 2009)

Laryngopharyngeal reflux (LPR) may present with similar symptoms and related medical sequelae in the pediatric population as in adults, but children may also experience other problems such as feeding difficulties and anorexia, nasal obstruction or rhinorrhea, otitis media, recurrent upper respiratory infections, sleeping disorders, and subglottic stenosis. There are a variety of other pathologies affiliated with pediatric LPR, but that is beyond the scope of this text. ( Tasker A, et al; 2009)