Pathophysiology

Heartburn and Acid Reflux Cure Program

How To Cure GERD Naturally

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The pathophysiology of GER is complex and diverse, as it is influenced by factors that are genetic, environmental (e.g. diet and smoking), anatomic, hormonal and neurogenic (Figure 4.1 and Table 4.1). We have recently reviewed the

Gastric distension (gastric mechanoreceptors near cardia)

Vagally mediated abnormal neural control of LES by CNS

Defective LES motility Increased TLESRs -<Low basal LES tone -<-

Increase in GER

Gastric acid Hiatal hernia, obtuse angle of His Delayed (acid) clearance Delayed volume clearance (motility) Impaired pH neutralization (saliva, esophageal secretion) Poor mucosal resistance Increased abdominal pressure Genetic factors

Posture, handling, physical activity, sleep state, feeding, drugs Environmental factors

Figure 4.1 Illustration of multifactorial influences on gastroesophageal reflux (GER). LES, lower esophageal sphincter; CNS, central nervous system; TLESRs, transient lower esophageal sphincter relaxations.

pathophysiology of GER in infants and children.35 The most relevant factors are gastric (gastric acid and non-acid content, gastric emptying, fundus tone, triggering of transient lower esophageal sphincter (LES) relaxations (TLESRs)), the antireflux barrier (LES basal pressure, TLESRs, hiatal hernia), the composition of the refluxate (air-liquid, acid, non-acid, bile), the esophageal tone and the esophageal clearance (volume and chemical clearance).35,36 GER occurs during episodes of transient relaxation of the LES or inadequate adaptation of the sphincter tone to changes in abdominal pressure.

GERD was classically considered to be an acid peptic disease, although as a group, the majority of patients with reflux disease do not have a significant increase in gastric acid secretion. Three major tiers of defense serve to limit the degree of GER, and to minimize the risk of reflux-induced injury to the esophagus. The first line of defense is the 'anti-reflux barrier', consisting of the LES, and the diaphragmatic pinchcock and angle of His; this barrier serves to limit the frequency and volume of refluxed gastric contents. When this line of defense fails, the second, esophageal clearance, assumes greater importance, to limit the duration of contact between luminal contents and esophageal epithelium. Gravity and esophageal peristalsis serve to remove volume from the esophageal lumen, while salivary and esophageal secretions (the latter from esophageal submucosal glands), serve to neutralize acid. The third line of defense, 'tissue or esophageal mucosal resistance' comes into play when acid contact time is prolonged, such as when esophageal clearance is

Table 4.1 Parameters influencing the incidence of gastroesophageal reflux

Mastication, saliva secretion

Swallowing

Esophageal clearance

Esophageal innervation and receptors

Mucosal resistance

Lower esophageal sphincter pressure

Sphincter relaxation

Abdominal esophagus

Sphincter position

Angle of His

Gastric volume, gastric accommodation

Gastric emptying

Gastric acid output

Gastric acid feed buffering

Feeding regimen: type, frequency, volume

Pepsin/trypsin/bile salts

Helicobacter pylori

Intra-abdominal pressure

Genetic factors

Environmental factors

Posture

Physical activity Sleep state Respiratory disease Medication (e.g. xanthines)

defective or not operative (motility disorders, sleep).35

Epidemiological data suggest that Helicobacter pylori plays a protective role in GERD, presumably by decreasing acid secretion. In adults, Helicobacter pylori and especially the cagA positive strains, which cause more severe gastric inflammation, are less prevalent in patients with esophagitis or Barrett's esophagus than in those with endoscopically negative reflux disease or in control patients.37-41

Recent detailed analysis of postprandial acidity in the gastroesophageal junction area suggests that local acid distribution rather than total gastric secretion might be more relevant to the pathogen-esis of GERD.42 Differences may exist in the degree of mixing of fundal contents leading to different distributions of acid in the stomach. Studies using pH monitoring and esophageal scintigraphy and gastric magnetic resonance imaging suggest that gastric mixing can be incomplete and different layers of viscosity within the stomach might therefore influence the distribution of the gastric contents. A collection of acid in the gastric part of the esophageal junction was shown in adults in a supine position, even in the postprandial period when the stomach content was neutralized by the meal.43,44 This newly described mechanism is attractive as an explanation for postprandial distress in infants lying in the supine position.

TLESRs are the major mechanism of GER episodes, in premature infants and in adults.35,45,46 TLESRs are a neural reflex, triggered mainly by the distension of the proximal stomach and organized in the brain stem, with efferent and afferent pathways traveling in the vagus nerve, activating an intramural inhibitory neuron which releases nitric oxide to relax the LES.47,48 When investigated in the supine position, the incidence of TLESRs in healthy adults and those with GERD did not differ. In healthy adults, only 30% of the TLSERs were accompanied by acid reflux, but in patients with GERD the reflux occurred in 65% of the TLESRs. Thus adults, controls and GERD patients have the same incidence of TLESRs, but in patients with GERD these TLESRs are more than twice as frequently accompanied by acid GER.36,49,50 The initial studies performed in the recumbent position found a higher frequency of TLSERs in patients with GERD than in normals.51 These older studies in the recumbent position may be more relevant for infants.

Delayed gastric emptying may increase postprandial reflux possibly by increasing the rate of TLESRs and the likelihood of reflux during the TLESRs. A disturbed gastric accommodation to a meal and prolonged postprandial fundic relaxation where described in patients with GERD.52 Both phenomena can influence postprandial fundic volume and pressure, which in turn may affect the rate of distension-induced triggerings of TLESRs and the volume of the refluxate. A recent study has shown that esophageal acid exposure in patients with GERD is directly correlated with the emptying time of the proximal stomach.53 These new findings are especially of interest in infants with postprandial distress or regurgitation who are not responding to dietary treatment with thickened casein-predominant formula. This has a delayed gastric emptying time, and thus is related to an increased incidence of TLESRs.

Hiatal hernia increases the number of reflux episodes and delays esophageal clearance by promoting retrograde flow across the esophago-gastric junction when the LES relaxes after a swallow. This mechanism underlies the so-called re-reflux phenomenon (acid reflux when the pH is still below 4).

The refluxate might be highly acid, moderately acid, or non-acid. Reflux may be a mixture of gas and liquid or pure liquid, and may or may not contain bile. More than half of the acid and nonacid reflux episodes are associated with reflux of gas.36 Non-acid reflux also occurs predominantly during TLESRs. With liquid meals, patients with reflux disease had a similar total rate of reflux episodes but a higher proportion of acid reflux events than controls.54 Non-acid reflux may be responsible for the remaining symptoms in patients under anti-secretory treatment.55

Acid reflux in patients with GERD is associated with an inhibition of tone in the esophageal body, whereas normals have an increased contractile activity. In order to have an effective volume clearance, motility of the esophageal body needs to be preserved. Acid is emptied from the esophagus with one or two sequences of primary peristalsis, then the residual acidity is neutralized by swallowed saliva.35 Secondary peristalsis is the response to esophageal distension with air or water, and is more important during sleep, when peristalsis is reduced. Patients may have normal primary peristalsis but abnormal secondary peristalsis. Thus, non-acid reflux, as occurs in the postprandial period, may be inefficiently cleared and cause prolonged esophageal distension. The esophageal mucosal defense can be divided into pre-epithelial (protective factors in swallowed saliva and esophageal secretions containing bicarbonate, mucin, prostaglandin E2, epidermal growth factor, transforming growth factor), epithelial (tight junctions, intercellular glycoprotein material) and post-epithelial factors.35 There is a very important interindividual variation of reflux perception suggesting different esophagus-sensitive thresholds. The esophageal mucosa contains acid, and temperature- and volumesensitive receptors. A widening of the intercellular spaces has been found in patients with esophagitis and in patients with endoscopy-negative disease. When esophagitis heals, esophageal sensitivity to acid decreases. The presence of fat in the duodenum increases the sensitivity to reflux. Hypo-sensitivity, as occurs in patients with Barrett's esophagus, is a secondary phenomenon.56

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