The role of neurohumoral factors in the development of gastroesophageal reflux disease

The dissertation is devoted to the study of the role of neurohumoral factors in the pathogenesis of gastroesophageal reflux disease (GERD). The work examines the prevalence of the disease, its typical and atypical clinical manifestations, and the socio-economic significance of long-term therapy. Particular attention is paid to the neuromuscular control of the lower esophageal sphincter, the role of neurotransmitters (including serotonin), the state of the autonomic nervous system, and the influence of Helicobacter pylori on the course of GERD. The study includes the clinical characteristics of patients, an assessment of psychological status, an analysis of serotonin mechanisms and autonomic regulation, as well as an examination of the relationship between Helicobacter pylori infection and the features of the course of the disease.

The relevance of the problem of gastroesophageal reflux disease (GERD) lies in the high prevalence of the disease, the presence of both typical symptoms that significantly worsen the quality of life of patients and atypical clinical manifestations that complicate the diagnosis of GERD and lead to overdiagnosis of other diseases. In addition, complications may arise, primarily such as Barrett's esophagus and esophageal adenocarcinoma [Ivashkin V.T., Trukhmanov A.S., 2002]. Most patients with GERD require long-term or even lifelong continuous therapy, which leads to large economic costs for the treatment of GERD and determines the high socio-economic significance of the pathology [Isakov V.A., 2005].

The prevalence of gastroesophageal reflux disease in the world is variable and differs significantly between the developed countries of the West and the countries of Southeast Asia. According to epidemiological studies in the United States, 7% of the population experience heartburn (the key symptom of GERD) daily, 14% experience it weekly, 15% monthly, and 36% more than once a month [Nebel O.T. et al., 1976]. The prevalence of heartburn and erosive esophagitis is maximal in the United States and Western European countries (about 20% of the population) [Nebel O.T. et al., 1976; Locke G.R. et al., 1999; Louis E. et al., 2002; Schwenkglenks S.M. et al., 2004] and minimal in China (2.5%) [Wong W.M. et al., 2003]. Russia occupies an intermediate position in the frequency of these symptoms [Kurilovich S.A., 1999; Timoshenko V.O., 2003; Dzyuba L.P., 2002]. Heartburn occurs equally often in men and women, as well as in different age groups [Kurilovich S.A., Reshetnikov O.V., 2000]. The frequency of Barrett's esophagus is 7.4 per 1000 population [GOSPE, 1991], 12.6% among GERD patients [Starostin B.D., 2001; Winters S.J., 1987], and 23.8% among all reflux esophagitides [Budzinskii A.V., 2002]. Esophageal adenocarcinoma develops in 0.5% of patients with Barrett's esophagus per year with low-grade epithelial dysplasia, and in 6% per year with high-grade dysplasia [Marks R.D., Shuklam R.U., 1997]. The coefficient characterizing the level of "quality of life" of GERD patients not receiving treatment turned out to be lower than that of healthy individuals, patients with heart failure, angina, and untreated peptic ulcer [Kurilovich S.A., 1999; Mack M.E., 2003]. Currently, various factors that could influence the degree of prevalence of reflux disease in Western and Eastern countries are being discussed. Among the main ones, researchers highlight the role of Helicobacter pylori, racial and ethnic affiliations, risk factors, and differences in quality of life standards [Isakov V.A., 2004; McNally P.R., 2005; Nilsson F. et al., Ganskaya Z. et al., Raghunath A. et al., 2003].

GERD is currently regarded as a disease with primary impairment of esophageal and gastric motility, in which the fundamental defect is the disturbed neuromuscular control of the lower esophageal sphincter [Vasiliev Yu.V., 2002].

Gastroesophageal reflux is believed to result from relative or absolute insufficiency of the cardial closing mechanism [Sheptulin A.A., Trukhmanov A.S., 1998; Osadchuk M.A., 2004].

Relative insufficiency of the cardial sphincter is observed in 9-13% of GERD patients and develops as a result of increased intragastric pressure and intensive contraction of the gastric antrum with normal function of the lower esophageal sphincter [Osadchuk M.A., 2004].

Absolute insufficiency occurs much more frequently [Pimanov S.I., 2000; Trukhmanov A.S., 2001]. DeMeester T.R. and co-authors [1992] performed a thorough manometric study of the lower esophageal sphincter in 50 healthy people, as a result of which it was established that the average manometric pressure over a 3.6 cm segment in healthy people is 13 mm Hg, of which 2 cm is located in the abdominal cavity. From the same study, the lower limits of the norm were derived: pressure in the lower esophageal sphincter of 6 mm Hg, the total length of the segment over which it is applied equal to 2 cm, and the length of this segment in the abdominal cavity equal to 1 cm. When studying the tone of the cardial sphincter in GERD patients, it was reduced in 20-80% of patients [Ivashkin V.T., 2004; Pandofino G.L. et al., 2002]. Moreover, in patients with complications of reflux disease, this reduction was more pronounced. However, normal pressure of the lower esophageal sphincter does not prevent the development of GERD. It is known that sphincter pressure <10 mm Hg is detected only in a certain part of patients with GERD [McNally P.R., 2005]. In many patients with mild and moderate symptoms, normal values are revealed during manometric examination [Bilhartz L.I., 1998]. Acid reflux with low lower esophageal sphincter pressure is characterized by esophagitis with the formation of erosions, ulcers, and strictures of the esophagus. With normal lower esophageal sphincter pressure, even at the same frequency of refluxes, the degree of esophageal damage is significantly less [Maev I.V., 2000; Henderson D.M., 2005]. It has been established that the reduction in the tone of the cardial sphincter caused by weakening of esophageal peristalsis correlates with the severity of the disease [Ivashkin V.T., 2000; Smout A.L., Akkermans L.M., 1992; Verlinden M.H., 1993].

The reduction in tone may be due to a disturbance of its nervous regulation or to organic changes in smooth muscle fibers [Ivashkin V.T., Trukhmanov A.S., 2000]. The tone of the lower esophageal sphincter is predominantly myogenic, since it is not disturbed by tetrodotoxin. Since it decreases under the action of atropine, one can also speak of the presence of neuronal regulation. In addition, during fasting and during food intake, hormones and other substances influence the myogenic properties of the smooth muscles of the lower esophageal sphincter [Ivashkin V.T., Sheptulin A.A., 2002]. Relaxation of the gastroesophageal junction is stimulated by the vagus nerve through preganglionic cholinergic fibers and postganglionic non-cholinergic and non-adrenergic fibers. The mechanisms promoting relaxation of the lower esophageal sphincter are probably identical to those that inhibit the entire smooth musculature of the esophagus; therefore, in studying the pathogenesis of reflux disease, much attention is paid to the role of deficiency or excess of neurotransmitters modulating the development of this pathology [Holloway R.N., 2002; Sifrim D., 2004]. The non-cholinergic and non-adrenergic neurotransmitter responsible for maintaining the tone of the lower esophageal sphincter is still unknown [Henderson D.M., 2005]. A number of biologically active substances and gastrointestinal peptides influence the cardial sphincter; among them, serotonin stands out, which contributes to an increase in its tone [Maev I.V., Pimanov S.I., 2000].

Esophageal motility is determined by the balance between the activities of inhibitory NO-ergic innervation and stimulatory cholinergic innervation. With normal functioning of the inhibitory mechanism of nervous control, signs of impairment of the stimulatory mechanism are revealed in patients with reflux disease [Rappoport S.I., Ivashkin V.T., 2000; Janssens J., Sifrim D., 1997]. One of the proofs of this is the favorable clinical effect of prokinetics, in particular, those activating serotonin 5-HT4 receptors [Lundell L. et al., 2002; Judith J., Stephenson S.M., Barghout V., 2005].

An additional pathogenetic mechanism in the development of reflux disease is the presence of a hiatal hernia, leading to dissociation of the external (crura of the diaphragm) and internal (lower esophageal sphincter) components of the antireflux barrier of the esophagogastric junction [Lazebnik L.B., 2004; Titgat G.N., 2004].

According to W. Wienbeck and J. Bamert [1989], a hiatal hernia is detected in 50% of those examined over the age of 50, and in 63-84% of them endoscopic signs of reflux esophagitis are determined.

Reflux in hernia is associated with a number of factors. The main ones are: dystopia of the stomach into the thoracic cavity, which leads to the disappearance of the angle of His and disruption of the valve mechanism of the cardia (Gubarev valve), disruption of the closing action of the diaphragmatic crura in relation to the cardia, and localization of the lower esophageal sphincter in the abdominal cavity. This implies the impact on the sphincter of positive intra-abdominal pressure, which significantly potentiates the closing mechanism of the cardia [Kalinin A.V., 1996; Osadchuk M.A., 2004; Titgat G.N., 1997].

But between GERD and hiatal hernia there is only an indirect connection. This is confirmed by the fact that only 20-33% of patients with diaphragmatic hernias have GERD, and only 25-50% of GERD patients have concomitant hiatal hernias [Osadchuk M.A., 2004].

Transient relaxation of the lower esophageal sphincter is the main mechanism of gastroesophageal reflux, both in healthy people and in patients with reflux disease (75% of patients) [Sifrim D., 1999]. Moreover, in GERD patients, spontaneous transient episodes of relaxation are much more often accompanied by reflux than in healthy people [Mittal R.K., McCallum, 1988]. Dent J. and co-authors [1992] established that gastroesophageal reflux is also present at normal basal tone of the lower esophageal sphincter in healthy people during its transient relaxation, not associated with swallowing. In patients with esophagitis, the frequency of transient relaxations combined with acid reflux is significantly higher than in healthy people. Transient relaxations of the cardial sphincter are the main mechanisms of air release during belching. Therefore, this phenomenon is regarded as physiological. Gastric distension is combined with pronounced relaxation of the lower esophageal sphincter [Maev I.V., 2003; Henderson D.M., 2005]. Mechanoreceptors of the upper part of the stomach activate the brainstem nuclei, which, in turn, leads to transient relaxation of the cardial sphincter. The importance of this reflex arc is explained by the potential possibility of pharmacological blockade of transient relaxation of the lower esophageal sphincter [Holloway R.N., 2005]. The search for a substance that could implement this possibility is still ongoing. GERD patients have more episodes of reflux during transient relaxations of the lower esophageal sphincter than healthy people, which favors the reflux of liquid contents along with air into the esophagus [Mittal R.K., 2001].

Another equally important pathogenetic mechanism of GERD is the decrease in esophageal clearance. It is observed in 50% of patients with reflux disease and is caused by weakening of esophageal peristalsis (volume clearance). A direct correlation has been noted between a decrease in esophageal clearance and the severity of the disease [Smout A.L., Akkermans L.M., 1992; Verlinden M.H., 1993; Sifrim D., 2004]. It has been reliably established that in GERD patients the peristaltic clearance of reflux material is impaired. Accordingly, the duration of exposure of refluxed acid to the esophageal mucosa in GERD patients is longer than in healthy people. It remains unknown whether the impairment of peristaltic clearance is the cause or the consequence of esophagitis [Bilhartz L.I., 1998]. A decrease in chemical esophageal clearance, due to reduced saliva production, which has an alkaline reaction and neutralizes the acid refluxate, also leads to the development of GERD; this mechanism is considered one of the leading ones in elderly patients [Lazebnik L.B., 2004].

Other mechanisms of GERD pathogenesis include: damaging properties of the refluxate (hydrochloric acid, pepsin, bile acids), the inability of the esophageal mucosa to resist the damaging action, impaired gastric emptying, and increased intra-abdominal pressure [Pimanov S.I., 2005].

It is known that the damaging effect of the refluxate increases if intestinal components are involved. Their participation is one of the pathogenetic factors in the development of Barrett's esophagus, due to the activation of cyclooxygenase-2 [Grinevich V.B., Lundell L., 2004]. Acid and bile refluxes in GERD are combined in 10-12% of cases, which increases the aggressive potential of the refluxate [Grinevich V.B., 2004]. At a refluxate pH of less than 4.0, pepsin begins to exert a damaging (proteolytic) effect on the mucosa. Hydrochloric acid itself causes a chemical burn of the esophageal mucosa, due to the fact that hydrogen ions penetrate into the intercellular spaces of the esophageal mucosal epithelium [Ivashkin V.T., Trukhmanov A.S., 2002; Szarszewski A., Korzon M., Kaminska B., Lass P., 1999]. In alkyl reflux, bile acids and lysolecithin "wash off" the protective mucus from the mucosal surface, exposing it and making it vulnerable to pepsin. Bile also inhibits mucus formation, disrupts the synthesis of prostaglandins in the mucosa, and exerts a direct cytotoxic effect on the mucosa [Osadchuk M.A., 2004; Pimanov S.I., 2005].

The factors determining the protective properties of the esophageal mucosa include pre-epithelial, epithelial, and post-epithelial levels. The main "breakdowns" in GERD are detected in the mechanism of pre-epithelial protection. In patients with reflux esophagitis, there is a significant slowdown in the secretion of mucin, non-mucin protein, and epidermal growth factor in response to intraesophageal mechanical and chemical exposure, with a normal level of prostaglandin E2. At the same time, the protective esophago-salivary reflex is disrupted [Ivashkin V.T., Trukhmanov A.S., 2000].

Gastric emptying is not itself an antireflux barrier; it helps remove esophageal-damaging agents from the stomach and theoretically can influence the manifestations of GERD [Grigoriev P.Ya., Yakovenko E.P., 1996]. It has not been possible to prove that gastric emptying is slowed in GERD patients compared with healthy people [Bilhartz L.I., 1998].

At this stage, the possible role of Helicobacter pylori in the pathogenesis of reflux disease is not entirely clear.

In recent years, according to the US Department of Veterans Affairs, an increase in the incidence of GERD has been noted, while at the same time there is a decrease in Helicobacter pylori infection and a sharp decrease in the incidence of Hp-associated peptic ulcer and distal gastric cancer. After reports were published that GERD occurs relatively often after eradication of Helicobacter pylori in patients with duodenal ulcer, it was suggested that Helicobacter pylori somehow prevents the development of GERD [Aruin L.I., Isakov V.A., 2000]. Researchers are currently actively studying the role of Helicobacter pylori in the pathogenesis, occurrence, prevention, and development of GERD, as well as the effect of Hp and eradication on the effectiveness of antisecretory drugs used to treat GERD. Numerous data indicate that Helicobacter pylori plays a protective role in the occurrence and development of the disease. In particular, Helicobacter pylori is detected less frequently in GERD patients than in the population [Connor H.J., 1999]. Helicobacter pylori infection is usually associated with less severe forms of reflux disease [Wu J.C., 2000]. The most virulent strain of the bacterium (cag A+) is more often associated with milder forms of the disease, and the presence of Helicobacter pylori improves the control of acid production and symptoms of esophagitis during treatment with proton pump inhibitors and prevents the rebound of acid hypersecretion. Eradication of the bacterium leads to the resumption of symptoms [Wu J.C., 2000; McColl K.E.L., 2004]. It is likely that the ability of Helicobacter pylori to produce proteins that inhibit hydrochloric acid, as well as interleukin-1β and urease, contributes to the neutralization of the aggressive acid factor and thereby protects the esophageal mucosa from damage [Cave D.R., Vargas M., 1989; McGowan C.C., Cover T.L., Blaser M.J., 1996]. In favor of this hypothesis are also data on the decrease in hydrochloric acid secretion due to atrophy of the gastric mucosa under the influence of Helicobacter pylori infection [El-Serag H.B., Sonnenberg A., Jamal M.M. et al., 1999] and the production of cyclooxygenase COX-2 in Helicobacter pylori-associated gastritis [Quina M.H., 1998].

But there are also opposite data. It is well known that patients with duodenal ulcer, which is usually associated with Hp, often suffer from reflux esophagitis [Boyd E., 1996]. The effect of Helicobacter pylori on the pathogenesis of GERD can be realized through the production of toxins and other bacterial products, mediated production of cytokines and inflammatory mediators (prostaglandins, nitric oxide) [Mane G., 1997]. These substances reduce the tone of the lower esophageal sphincter, affect gastric emptying and afferent nerves, and thereby increase the sensitivity of the esophageal mucosa to the damaging effect of the refluxate, exerting an inductive role in the occurrence and development of GERD [Aruin L.I., Isakov V.A., 2000]. On the other hand, in studies conducted on the general population, in patients with non-ulcer dyspepsia and non-erosive reflux disease, data have been obtained that eradication of Helicobacter pylori does not affect the course of these diseases and the overall morbidity [Talley N.J., Janssens J., Lauritsen K., Malfertheiner P., Gerards C., 1998].

In general, the relationship between Helicobacter pylori infection and GERD is complex and insufficiently studied; data on the influence of neurohumoral factors on this relationship were not found in the literature available to us.

Recently, reports about the introduction of such an additional risk factor for GERD as psychogenic have been appearing more often. Studies have been conducted concerning the determination of the overall level of stress load, the frequency of depressive and anxiety traits in GERD patients, and the dependence of remission duration on its severity [Osipova V.V., 2004]. In a study of patients with reflux disease, a high frequency of concomitant anxiety-depressive disorders (64.6%) and a positive effect of serotonin reuptake inhibitors on the course and frequency of disease recurrence were noted [Antonenko O.M., 2002; Pogromov A.V., 2003]. The level of stress load in the study of V.V. Osipova [2004] is proposed to be used as one of the important prognostic factors of disease recurrence.

The mechanism of the influence of stressors on the course of GERD is the activation of the autonomic nervous system. A.M. Vein [2001, 2003] proposed an explanation of mental and somatic interrelations in the form of a three-part formula: mental disorders - limbic-reticular complex - changes in the functioning of the autonomic and endocrine systems - somatic disorders.

In the available literature, we found a single study of the autonomic nervous system in young patients with varying severity of reflux disease [Chernenko Yu.V., 2003]. In a study of the autonomic nervous system in young people, autonomic dystonia of varying severity was present in all GERD patients and was independent of the severity of the disease. Mainly, parasympathetic tone predominated in patients (73.3%).

Given the possibility of the influence of gastroesophageal regurgitation on the state of the nervous system through the nervous and anatomical connections of the esophagus, one can think that, on the one hand, the development of refluxes in individuals with GERD is due to autonomic dysfunction, and on the other hand, the refluxes themselves significantly enhance this dysfunction, creating a vicious circle [Osadchuk M.A., 2004].

Thus, among the leading pathogenetic mechanisms of GERD, the following are distinguished: a decrease in the function of the antireflux barrier, a decrease in esophageal clearance, the state of the protective levels of the esophagus, gastric motility, and the level of intra-abdominal pressure. The role of Helicobacter pylori infection continues to be debated. At this stage, there is also little data regarding the neurotransmitters regulating the activity of the antireflux barrier.