Mechanisms for heartburn

Heartburn and Acid Reflux Cure Program

Alternative Treatment for Acid Reflux

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The mechanisms by which patients with GERD develop symptoms remain incompletely understood. It is postulated that sensitization of esophageal chemo-receptors either directly by exposure to acid reflux or indirectly through release of inflammatory mediators

CA = Carbonic anhydrase ICS - Intercellular Space

Lumen

CA = Carbonic anhydrase ICS - Intercellular Space

Lumen

Na^HCty HCO3

Cytosol

Na^HCty HCO3

Cytosol

Fig. 3. Epithelial defenses against acid injury that include,cell membrane, intercellular junctional complexes, intracellular buffering and HCO3 and H+ extrusion process (with permission from [67])

is responsible for symptom generation in GERD [39]. Reducing acid exposure in patients with GERD appears to normalize the sensitivity to acid [40]. However, the emergence of symptoms in patients with a normal esophageal mucosa and thus without obvious inflammation remains perplexing, particularly among patients with functional heartburn where little or no reflux actually occurs.

Both animal models and human studies have demonstrated dilation of intercellular spaces during or following esophageal mucosal acid exposure [41], [42]. These mucosal findings were evident regardless of the presence or absence of esophageal inflammation [42], [43]. It is assumed that these morphological changes result in an increase in paracellular permeability, allowing acid to reach sensory nerve endings located within the intercellular spaces [44]. However, this altered permeability does not explain symptoms in GERD, specifically in NERD and in functional heartburn as most acid reflux events (> 95%) that occur in these patients are never perceived and symptoms occur even in the absence of acid reflux, suggesting the importance of other factors in modulating esophageal acid perception.

Heartburn symptoms may represent activation of a common pathway in response to different intra-esopha-geal stimuli. Hypersensitivity to physiological amounts of acid appears to be the underlying mechanism for heartburn in the hypersensitive esophagus subgroup (functional heartburn). This hypersensitivity to acid may stem from peripheral sensitization of esophageal afferents, leading to heightened responses to luminal stimuli or altered modulation of afferent neural function at the level of the spinal dorsal root or the central nervous system [45]. What leads to the development of such hypersensitivity remains an area of controversy. In healthy subjects, Sarkar et al have recently demonstrated that infusion of 0.1 N hydrochloric acid into the distal esophagus for 30 minutes increased the subsequent sensory responses to electrical stimulation in the non-exposed proximal esophagus [46]. In comparison, patients with non-cardiac chest pain already had lower resting esophageal pain thresholds in the proximal esophagus, which fell further and for a longer duration than in healthy subjects after acidification of the distal esophagus. These patients also demonstrated a decrease in pain thresholds in the anterior chest wall. Therefore, this study showed the development of secondary allody-nia (visceral hypersensitivity to innocuous stimulus in normal tissue that is in proximity to the site of tissue injury) in healthy subjects and non-cardiac chest pain patients. In the latter group this phenomenon is amplified and lasts longer. The resulting visceral and somatic hypersensitivity is likely due to central sensitization. The increased excitability of spinal cord neurons appears to be the result of activation of nociceptive C fibers due to local tissue injury induced by acid infusion into the distal esophagus. If extrapolated clinically, this study suggests that prior injury to the esophageal mucosa may lead to the development of central sensitiza-tion and visceral hyperalgesia in a subset of patients long after the local injury has healed.

To date, only a few studies have attempted to assess the cortical processing of esophageal acid exposure sensation in humans. Kern etal [47] evaluated activation of cerebral cortical responses to esophageal mucosal acid exposure using functional magnetic resonance imaging (fMRI). Ten healthy subjects underwent intra-esophageal perfusion of 0.1 N hydrochloric acid over 10 minutes. None of the study subjects reported GERD symptoms during the acid perfusion. Cerebral cortical activity was concentrated in the posterior cingulate, and the parietal and anteromesial frontal lobes. The superior frontal lobe regions activated in this study corresponded to Brodmann's areas 31, the insula, operculum and the anterior cingulate. Further studies are needed to assess cerebral cortical activation in symptomatic GERD patients undergoing esophageal acid perfusion. In addition, it would be of great interest to determine if there are differences in central processing of an intra-esophageal stimulus between GERD patients and those with NERD or functional heartburn.

Patients with GERD do not perceive most acid reflux events. Many patients and healthy subjects demonstrate multiple acid reflux events on pH testing but often report few, if any, heartburn episodes. It has been estimated that no more than 5% of all acid reflux events (pH < 4) produce symptoms, either in patients with or without esophageal mucosal injury [48]. This intriguing observation raises the obvious question of what in a specific acid reflux event leads to its conscious perception. It is not clear if a specific acid reflux event is the determining factor in triggering symptoms or rather the actual hydrogen ion concentration (H+) of the refluxate, the summation of several short reflux events, or an increased number and/or duration of acid reflux events. However, proximal migration of the acid reflux events has been shown repeatedly to be associated with a higher likelihood of symptom perception.

The most common trigger for GERD symptoms is a meal; in particular if the meal is high in fat. However, the mechanism by which fat exacerbates symptoms in patients with GERD remains controversial. Meyer et al found that fat infusion into the duodenum of subjects with GERD significantly shortened latency to onset of heartburn and intensified the perception of acid induced heartburn [49]. The mechanisms by which luminal fat and potentially other nutrients may modulate the perception of esophageal stimuli remains unclear, but may involve cholecysto-kinin or other gut neurotransmitters, hormones, and enzymes. While many of these peptides may exert a local action leading to symptoms, it is also conceivable that their action may also involve central neural pathways. It is even possible that other substances in the refluxate (pepsin, bile) or volume per se are the direct cause of symptoms.

Several studies have recently speculated that central and peripheral neural mechanisms modulate esopha-

Intra-esophageal stimulus

Pathological Physiological

Fig. 4. Proposed conceptual model for esophageal symptom generation. Central and peripheral mechanisms enhance perception of intra-esophageal events (either physiological or pathological), leading to symptom generation [68]

Intra-esophageal stimulus

Pathological Physiological

Fig. 4. Proposed conceptual model for esophageal symptom generation. Central and peripheral mechanisms enhance perception of intra-esophageal events (either physiological or pathological), leading to symptom generation [68]

geal perception [50], [51] (Fig. 4). Psychological comorbidity (anxiety, stress, depression, etc.) can modulate esophageal perception and cause patients to perceive low intensity esophageal stimuli as being painful [Gut: 27], [52]. These psychological factors seem to be associated with patients paying an excessive attention (hypervigilance) to intra-esophageal events and thus perceiving or interpreting these esophageal events as being painful [53]. Stress has been implicated by 64% of GERD patients as an important cause for symptom exacerbation [54]. However, several studies have failed to demonstrate an increase in acid reflux during stressful stimuli [55]-[57]. Nevertheless, interventions aimed at reducing stress (hypnosis and muscle relaxation) have produced subjective improvement in reflux symptoms ratings [57], [58]. In a study assessing the effect of psychologically induced stress on symptom perception in GERD patients, stress reduced perception thresholds and enhanced the perception of acid during infusion, regardless of the degree of esophageal mucosal injury [59].

A recent study demonstrated that increased basal sympathetic activity and lower vagal activity, as measured by power spectral analysis of heart rate variability, are associated with increased sensitivity to intra-esophageal acid perfusion in patients with non-cardiac chest pain compared with healthy matched controls [60].

These data support the concept of humoral, neural, and psychological factors being associated with an increased susceptibility to symptoms such as heartburn but do not provide at this point a satisfactory mechanistic explanation. However, recent advances in our understanding of the mucosal and esophageal neural response to reflux begin to address this deficiency.

There are mounting data to suggest that the axiom "no acid no heartburn'' is obsolete. Non-acid intra-esophageal stimuli may also lead to the development of heartburn. Esophageal balloon distension induces heartburn symptoms in a large subset of normal subjects and reproduces typical heartburn in half of GERD patients [39]. Furthermore, high frequency intra-luminal ultrasonography has demonstrated a close correlation between heartburn episodes and abnormally long durations of longitudinal muscle contractions in the esophagus [61]. These muscle contractions and consequent heartburn episodes can occur in the absence of acid reflux. Thus, both of these studies suggest that mechanical stimuli and motor events may be perceived as heartburn by some patients, even in the absence of actual acid reflux.

Bile reflux has been suggested as a possible cause for heartburn symptoms in patients with NERD, but no study to date has specifically evaluated the role of bile acid in symptom generation in this group. Assessment of bilirubin pigment spectrophotometrically, a proxy indicator for bile reflux, revealed a close correlation between a combination of both acid and duodenogastroesopha-geal reflux and severity of GERD, as determined by the presence of esophageal mucosal injury and GERD complications [33]. However, symptoms were not specifically examined in this study. The combined reflux was documented in only 50% of NERD patients compared with 79% in erosive esophagitis and 95% in Barrett's esophagus. Others have shown that the mean fasting gastric bile acid concentration in patients with NERD is not significantly elevated compared with healthy controls [51]. Future studies are needed to further determine if bile acid is a contributing factor for symptoms in patients with GERD.

Recent studies using simultaneous intra-esophageal impedance and pH measurement demonstrated non-acidic gastroesophageal reflux (liquid, gas or mixture of gas and liquid) that was similarly frequent in patients with GERD and normal controls [62]. However, more acidic reflux occurred in symptomatic patients with GERD. Vela et al [63] with a similar technique, observed that during treatment of GERD patients with a PPI, postprandial reflux became predominately non-acidic. Although less than acidic reflux, non-acidic reflux was also associated with classic GERD symptoms. It has yet to be determined if the content or volume is responsible for GERD symptoms in the studied subjects. Additionally, as with acid reflux, most of the non-acidic reflux events are not perceived.

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Herbal Remedies For Acid Reflux

Herbal Remedies For Acid Reflux

Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.

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