INTRODUCTION:

Gastro-esophageal reflux (fig.-1) is the movement of gastric content into the esophagus. It could be associated with evocative symptoms such as heartburn or regurgitation or with extra esophageal symptoms (cough, sore throat.). This phenomenon is physiologic; however, it becomes pathological when symptoms associated with reflux events impair a patient’s quality of life or when they are responsible for esophageal (esophagitis, Barrett’smucosa.) or extra-esophageal lesions. Nevertheless, even if GERD impairs quality of life, it does not increase the long term mortality. ^1,
2

Epidemiology

Commonly twice weekly reflux over several months is used to define Gastro-Esophageal Reflux Disease (GERD) as it is associated with impairment of quality of life.³ Based on these criteria 10–20% of individuals in Western countries have pathological GERD.^4,
5

This is higher than what is observed in Asia (5–7%). ^6-8 Different factors may explain the variable prevalence among the countries.⁹The understanding of heartburn is not the same in different languages. For example there is no translation for the word heartburn in most Asian languages.¹⁰ Cultural differences in diagnostic practices and in physician recognition modifies GERD reporting among the population. Finally the lifestyle, the environmental factors and the genetic backgrounds may influence GERD variations among the various geographic areas.

Fig No. 1: Figure showing Gastro esophageal reflux

Pathophysiology of GERD:

The Pathophysiology of GERD focuses on an interaction between an incompetent anti-reflux barrier, a default of esophageal clearance and/or the causticity of the gastric reflux.

Esophago-Gastric Junction (EGJ):

The EGJ is synonymous with the anti-reflux barrier and is composed of the lower esophageal sphincter (LES), the crural diaphragm and the flap valve. An alteration of this anti-reflux barrier will promote opening of the EGJ; which is a prerequisite for reflux. Transient LES relaxations (tLESRs) represent the main mechanism of GERD and these long duration LES relaxations are triggered by gastric distension, some food components (fat) or medications. Although the overall number of tLESRs is not increased in GERD, the number of acid reflux associated tLESRs is increased in GERD patients¹¹. A hypotensive LES is also a favourable factor in promoting GERD symptoms and complications, such as esophagitis and stricture. Multiple studies have shown a relationship between severe erosive esophagitis and lower basal LES pressure^{12, 13}

The esophageal acid clearance:

The efficacy of esophageal clearance depends on the vigour of esophageal peristalsis and the acid buffering property of saliva. An alteration of these mechanisms leads to an increased contact time between noxious acid content and esophageal mucosa. Ineffective esophageal motility is frequently encountered in GERD patients¹⁴and it is a risk factor for developing esophagitis¹⁵. In healthy volunteers and GERD patients, severe ineffective esophageal motility (>80% ineffective contractions) is also associated with prolonged clearance and acid exposure, especially in supine position^16,17. Saliva contains bicarbonate that helps buffer the acidity of gastric juice during reflux events and increasing the volume of saliva secretion shortens esophageal acid clearance. Epidermal growth factor is also present in saliva and may promote the healing mechanisms of esophageal mucosa.¹⁸

The Refluxate:

The major injurious factor is gastric refluxate¹⁹. The different components of the gastric refluxate are toxic for the esophageal mucosa. Acid is the main component and induces not only symptoms when it is in contact with esophageal mucosa but also esophageal ulcerations. The incidence of GERD is particularly high (around 80%) in patients with acid hyper secretion (with or without Zollinger-Ellison syndrome)²⁰. The other components of gastric juice, pepsin but also bile acids and pancreatic enzymes are also harmful to esophageal epithelium^21-23. Their toxicity is dependent on the background pH: pepsin is activated in an acidic environment; bile acids can penetrate through the cell membrane in a weakly acidic medium (pH 3–5).²⁴

Hital hernia:

Hital hernias contribute to reflux, although the way in which they contribute is not clear. A majority of patients with GERD have hital hernias, but many do not. Therefore, it is not necessary to have a hital hernia in order to have GERD. Normally, the LES is located at the same level where the esophagus passes from the chest through the diaphragm and into the abdomen. (The diaphragm is a muscular, horizontal partition that separates the chest from the abdomen.) When there is a hital hernia, a small part of the upper stomach that attaches to the esophagus pushes up through the diaphragm. As a result, a small part of the stomach and the LES come to lie in the chest, and the LES is no longer at the level of the diaphragm. It appears that the diaphragm that surrounds the LES is important in preventing reflux. That is, in individuals without hital hernias, the diaphragm surrounding the esophagus is continuously contracted, but then relaxes with swallows, just like the LES. The effects of the LES and diaphragm occur at the same location in patients without hital hernias. Therefore, the barrier to reflux is equal to the sum of the pressures generated by the LES and the diaphragm. When the LES moves into the chest with a hital hernia, the diaphragm and the LES continue to exert their pressures and barrier effect. However, they now do so at different locations. Consequently, the pressures are no longer additive. Instead, a single, high-pressure barrier to reflux is replaced by two barriers of lower pressure, and reflux thus occurs more easily. So, decreasing the pressure barrier is one way that a hital hernia can contribute to reflux.^25-26

Complications of GERD:

Complications that develop include esophageal strictures, esophageal ulcers, Barrett’s esophagus, and esophageal adenocarcinoma. Esophageal strictures and ulcers have a prevalence of approximately 0·1% and 0·05%, respectively, and both are associated with white race, male sex, and increasing age.²⁷

Barrett's esophagus:

Barrett’s esophagus describes a metaplastic change from squamous to columnar mucosa with intestinal metaplasia. Barrett’s esophagus is uncommonly detected in patients younger than 50 years, but is present in 1– 2% of patients referred for endoscopy over this age threshold.²⁸Barrett’s esophagus is associated with severe gastro-esophageal reflux disease and it is thought to occur as a response to the mucosa adapting to long-term reflux of gastric contents, although the direct epidemiological data to support this notion are weak²⁹. Obesity has been associated with an increased risk of Barrett’s esophagus in patients who report weekly reflux symptoms. Barrett’s esophagus is associated with an increased risk of esophageal adenocarcinoma, with between 0·5%97 and 1%98 developing cancer each year.³⁰

Strictures:

Esophageal peptic strictures are estimated to occur in 7 – 23% of patients with untreated reflux esophagitis Ulcers of the esophagus heal with the formation of scars (fibrosis). Over time, the scar tissue shrinks and narrows the lumen (inner cavity) of the esophagus. This scarred narrowing is called a stricture. Swallowed food may get stuck in the esophagus once the narrowing becomes severe enough (usually when it restricts the esophageal lumen to a diameter of one centimeter). This situation may necessitate endoscopic removal of the stuck food. Then, to prevent food from sticking, the narrowing must be stretched (widened). Moreover, to prevent a recurrence of the stricture, reflux also must be prevented.^31-32

Pulmonary disorders associated with GERD:

There have been various pulmonary, ear nose and throat, and oral diseases and symptoms that have been linked to reflux symptoms; these have been termed extra-esophageal manifestations of gastro-esophageal reflux disease. Non-cardiac chest pain is also often classified as an extra-esophageal manifestation of the disease, although semantically this is incorrect because the chest pain is probably due to acid in the esophagus. There is some epidemiological evidence of an association between reflux symptoms and many pulmonary or ear nose and throat disorders, but there does not seem to be an increased risk of these diseases with increasing severity of the disease.³³

Diagnosis:

The lack of a gold standard has hampered the assessment of the accuracy of various approaches to the diagnosis of gastro-esophageal reflux disease. The accuracy and use of the different approaches to diagnose the disease are therefore uncertain. The tools available for diagnosis are endoscopy, symptom assessment, barium esophagram, ambulatory pH monitoring, and the proton-pump inhibitor (PPI) test.

Esophageal Biopsies:

Esophageal biopsies have been proposed as a method of identifying patients with non-erosive reflux disease. The presence of eosinophils and markers of increased epithelial cell turnover, such as basal-cell hyperplasia, have reasonable sensitivity but poor specificity, whereas neutrophils in the esophageal mucosa are specific but not very sensitive. Electron microscopy of esophageal biopsies suggested that dilated intercellular spaces could be an early marker of mucosal damage in gastro esophageal reflux disease, which occurs in patients with endoscopy-negative reflux irrespective of esophageal acid exposure.^34-35

Prolonged esophageal pH monitoring:

Twenty-four hour pH monitoring helps to identify patients with GERD. This test is usually done with a pH probe, which is passed trans nasally to 5 cm above the manometrically determined lower esophageal sphincter. The probe is able to obtain pH measurements every few seconds for 24 h and the data are collected by a battery-powered device carried by the patient. The patient also records when meals are eaten and symptoms are experienced. Acid-reflux episodes are defined as a pH fall below 4, and the total time under this threshold is the most reproducible measure of gastro-esophageal reflux disease, with normal limits usually less than 5%.The sensitivity of 24 h pH monitoring in patients with a normal endoscopy is around 60%, with a specificity of 85–90%.³⁶

Radiologic studies (Barium esophagography):

Barium esophagography is a non-invasive, inexpensive, and readily available test that can simultaneously evaluate swallowing function, esophageal motility, gastro esophageal reflux, and a host of structural abnormalities in the pharynx and oesophagus³⁷including Barrett’s esophagus³⁸However, they have low sensitivity for the diagnosis of GERD.³⁹ Radiologic studies can show the bolus movement of liquid and marshmallow and spontaneous reflux after abdominal compression. Scintigraphy after an intragastric bolus of radio labeled technetium cannot detect reflux as well as pH monitoring ^.40

Gastro esophageal Scintigraphic study:

Measurement of gastric emptying of solids is used to screen for gastric motor disorders and this can be accomplished using several techniques, among which is gamma camera Scintigraphy. Scintigraphic gastric emptying tests are used extensively in research and clinical practice. As a physiologic, quantitative, non-invasive test, gastric emptying Scintigraphy is well suited for evaluating patients before and after medical or surgical treatment. This procedure is now widely considered the gold standard for evaluating gastric emptying^41. Using this technique different types of meals and isotopes can be used, the important principle being that the isotope remains totally bound to the meal during the gastric emptying phase. Most commonly a 99mTc labeled egg is used as an ingredient of the meal. Due to differences in test methods, such as composition of the test meal, positioning of the subject, scanning method and calculations, no standardized normal values are available. Because Scintigraphy involves ionizing radiation, various other methods for measurement of gastric emptying has been developed in the past decades. Among these, tests using a test meal labeled with the non-radioactive isotope ¹³C and measurement of 13CO2 in the expired breath have become the most popular. In several studies results obtained using the ¹³C breath test were found to be comparable to those obtained with the gold standard, gastric Scintigraphy. Esophageal Scintigraphy, first described in 1972, allows one to evaluate the transit of a bolus through the entire esophagus. The images acquired make it possible to quantify rates of emptying in all segments simultaneously.⁴²

Manometric studies:

Esophageal manometry, introduced in the 1950’s, has provided a wealth of information in regards to the motor activity of the esophagus. Esophageal manometry may help in ruling out other causes of chest pain and by showing a weak lower esophageal sphincter or peristaltic dysfunction.⁴³ It is not helpful in the primary evaluation of suspected GERD but should be used whenever the diagnosis is unclear. Manometric study of the esophagus may predict severe GERD if either peristaltic dysfunction or hypotensive lower esophageal sphincter exists. Manometric studies are required to determine what kind of surgical fundoplication should be used.⁴⁴Recently; a telemetric system for manometry of the gastrointestinal tract was developed. It consists of a capsule with an inbuilt radio transmitter and sensors for pH, pressure and temperature and a receiver (Smart Pill Corporation, Buffalo, NY, USA). After ingestion of the capsule the transmitted pH, pressure and temperature signals provide information on gastric emptying (the pH rises abruptly when the capsule passes to the duodenum), on total gut transit time and on gastric, small intestinal and colonic motility.⁴⁵

Magnetic resonance imaging (MRI):

MRI can be used to measure gastric emptying and to evaluate gastric motor function. After ingestion of a gadolinium-labeled meal it allows one to assess gastric anatomy, motility and volume. A significant correlation between gastric volumes measured by MRI and barostat was established. Advantages of this method are that it is non-invasive and it does not expose the subject to radiation. Disadvantages of the method are high costs and the limited availability.⁴⁶

Therapeutic strategies for peptic ulcer and GERD

Antacids:

Long ago, people with an upset stomach commonly ingested powdered shells to alleviate the discomfort. Accordingly, it was empirically discovered that CaCO3, a natural antacid, buffered gastric acid. After demonstration of the presence of hydrochloric acid in the stomach, antacid therapy became the popular treatment for peptic acid-related diseases, such as peptic ulcers.⁴⁷ Antacids are compared quantitatively in terms of their acid neutralizing capacity. This is defined as the quantity of 1 N Hcl (expressed in milli equivalents), that can be brought to pH 3.5 in 15 min. Antacids neutralize Hcl to form water and carbon dioxide. Hydroxides of aluminum and magnesium are the most common constituents of antacid preparations. Sodium bicarbonate, calcium carbonate are also used, as are other carbonates, silicates, and phosphates. Some antacid preparations combine Al (OH) 3 and NaHCO3 to achieve both, the rapid effect of carbonate and sustained effect of Al (OH) 3. Simethicone, a surfactant that may decrease foaming and thus, esophageal reflex, is also included in many antacid preparations. Common side effects include alkalosis, belching, nausea, abdominal distension, flatulence, diarrhea, and constipation.⁴⁸

Anticholinergic drugs:

The secretion of acid, mucus, and pepsinogen in the gastric mucosa is stimulated via muscarinic receptors. Over expression of M3 receptors in DU patients is proved by auto radiographic techniques. Thus, blockade of this receptor subtype can reduce the pain by decreasing the duodenal motility and provide an effective anti-secretory therapy.⁴⁹ Based on its high affinity to block the muscarinic receptors on the intramural ganglia of stomach wall; pirenzepine was developed as an anti-secretory drug, which was followed by telenzepine, a more potent derivative with improved healing rates.⁵⁰

H₂ receptor antagonists:

Since histamine was considered to represent a final common mediator for acid secretion, several groups fervently sought an antagonist capable of inhibiting histamine stimulated acid secretion. After painstaking efforts, Black and colleagues⁵¹ succeeded in developing the first H₂R antagonist, burimamide, followed by metiamide. With minor alterations, Brimblecombe and colleagues ⁵² eventually developed cimetidine, which is widely prescribed throughout the world for treatment of acid-related peptic disease. By modifying the chemical structure of cimetidine, the potent H₂R antagonists ranitidine, famotidine, and nizatidine were all developed, resulting in remarkable treatment for acid-related disease, including reflux esophagitis. These new compounds were later found to inhibit gastric acid secretion stimulated by not only histamine, but also carbachol and gastrin in both humans and animals. H₂ receptor antagonists completely inhibit the interaction of histamine with H₂ receptors, thereby reducing both volume and H+ ion concentration of the gastric juice. They are selective and have little or no effect on H₁ receptors. They also inhibit basal and nocturnal acid secretion. This effect contributes in a major way to their clinical efficacy.⁴⁸Recently, H₂R antagonists have become first-line therapy for acid-related peptic disease, leading to a marked improvement in the quality of life for a large number of patients. Paralleling the development of such pharmacotherapy, there has been a dramatic reduction in the use of surgical intervention for ulcer treatment⁵³. H₂ receptor antagonists are generally extremely safe drugs with incidence of adverse effect of cimetidine less than 3%. Adverse effects include dizziness, nausea, skin-rashes, somnolence, confusion, impotence, gynecomastia, hematological effects, and altered function of immune system. Rarely may they cause bone marrow depression, hepatitis, and anaphylaxis.⁴⁸ Cimetidine selectively showed anti-androgen properties in a small number of patients.⁵⁴

Combination of H₂RA plus Antacid:

A combination of H₂RA plus antacid should provide both antacid speed and H₂RA sustained duration. Famotidine 10mg, plus calcium carbonate and magnesium hydroxide reduced gastric acidity more than use of H₂RA alone and for longer than the antacid alone.⁵⁵ Robinson M et.al used integrated gastroesophageal acidity measurements, demonstrated similar synergy between ranitidine 75mg, and calcium carbonate for decreasing both gastric and esophageal acidity⁵⁶.A commercially available combination of famotidine, 10 mg, plus antacid was recently evaluated. Onset of heartburn relief was faster with the combination than with the H₂RA alone or placebo. The combination was associated with a longer duration of action compared with either agent alone or placebo.⁵⁷

Triple therapy for eradication of H. pylori infections:

Helicobacter pylori are a gram-negative rod-shaped bacillus that colonizes in the mucus on the luminal surface of gastric epithelium. H. pylori infection causes inflammatory gastritis and is a putative contributor to peptic ulcer disease, gastric lymphoma, and adenocarcinoma.⁴⁸ Infection may not always be causative as ulcers may recur in patients who have undergone successful eradication treatment⁵⁸. Double or triple antimicrobial therapies, in combination with anti-secretory drugs, are being used successfully to treat peptic ulcers. Bismuth compounds are also been included in regimen probably due to their cytoprotective action. Triple therapy with metronidazole, a bismuth compound and either tetracycline or amoxycillin for two weeks is recommended to treat H. pylori infections. However, therapeutic limitations of this triple therapy include complex regimen and related nausea, diarrhea, and dizziness.⁴⁸

Proton pump inhibitors (PPIs):

Proton pump is the ultimate mediator of gastric acid secretion by parietal cells. With the identification of H+/K+-ATPase as the primary gastric proton pump, it

was proposed that activation of H+ secretion occurred by incorporation of H+/K+-ATPase-rich tubule vesicles into the apical plasma membrane and that the pumps were re-sequestered back into the cytoplasmic compartment on return to the resting state.⁵⁹Inhibition of the protons pumping H+/K+-ATPase as a means of controlling gastric pH has attracted considerable attention in recent years with the discovery of benzimidazole sulfoxide class of anti-secretory agents. Clinically used PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole .These compounds have proved to be effective in clinic for the treatment of acid-related gastrointestinal disorders. They bind to the gastric proton pump on the parietal cell membrane, inhibiting the release of hydrogen ions from the parietal cells into the lumen of the gastric glands and hence stomach.⁶⁰ Extreme acid suppression sometimes leads to achlorohydria at recommended doses and that may produce enteric infections like typhoid, cholera, and dysentery. Significant drug interactions can lead to decreased absorption of some drugs like griseofulvin, ketoconazole, vit.B12, iron salts, etc. Unpredictable action and variation in individual responsiveness can cause hyper gastrinemia, gastric polyps, and carcinoma.⁶¹ other side effects include abdominal pain, diarrhea, nausea, and headache. Acute interstitial nephritis progressing to acute renal failure has also been reported to be associated with the use of PPIs.

Prokinetic Agents:

Because GERD is partially characterized by a disorder of motility, the promotility agents would be a logical choice for the treatment of this disease. Although they act by varying mechanisms, antagonist that promotes motility by increasing LES tone: peristalsis in the stomach, leading to increased emptying; and peristalsis in the duodenum, leading to a reduced transit time.⁶² However, this prokinetic agent may cause extra pyramidal symptoms, anxiety, depression, insomnia, hallucinations, and tardive dyskinesia.⁶³ Bethanechol is a cholinergic agent that increases LES tone, but it has been associated with such side effects as blurred vision, abdominal cramps, sweating, lacrimation, headache, and gastrointestinal discomfort. Due to their side-effect profiles, metoclopramide and Bethanechol are not recommended for the treatment of GERD. Cisapride improves esophageal peristaltic activity, gastric emptying, and LES tone by increasing the release of acetylcholine from postganglionic neurons originating in the myenteric plexus.⁶⁴Vigneri et al ⁶⁵ reported that when Cisapride was used in combination with ranitidine, it was more effective than ranitidine alone in the maintenance treatment of reflux esophagitis. Cisapride has few side effects except dose-related flatulence, abdominal pain, dizziness, and diarrhea. Excessive plasma concentrations of Cisapride due to overdose can result in arrhythmias. Itopride, by virtue of its dopamine D₂ receptor antagonism, removes inhibitory effects on Ach release. It also inhibits the enzyme AchE which prevents the degradation of Ach. The net effect is an increase in Ach concentration, which in turn, promotes gastric motility, increases the lower esophageal sphincter pressure, accelerates gastric emptying and improves gastro duodenal coordination. Itopride is metabolized by FMO₃ while Cisapride is metabolized by CYP₃A₄. Thus Itopride is less likely to be involved in drug-drug interaction than Cisapride.

Cholecystokinin-2(CCK2) receptor antagonists:

Similar to ACh and histamine, both endogenous and exogenous gastrin stimulate gastric acid secretion via CCK2R on parietal and ECL cells upon histamine release Proglumide was first developed as an CCK2R antagonist, but was subsequently found to represent a nonselective antagonist.⁶⁶Thereafter, various selective antagonists, such as L365260, YM022, YF476, S-0509, Z-360, and PD136450, were developed and subjected to preclinical and clinical trials as anti-secretory and anti-ulcer drugs.⁶⁷Animal studies indicated that such antagonists possess a more selective effect on gastric acid secretion than Proglumide. Despite the clear-cut efficacy of the above CCK2R antagonists in animal studies, however, clinical testing indicated inconsistent anti-secretory and anti-ulcer effects compared with other receptor antagonists and pump inhibitors. Accordingly, no CCK2R antagonists have been approved for the treatment of acid-related disease to date.⁶⁷

Prostaglandin Analogues:

Prostaglandins PGE2 and PGI2 are synthesized by gastric mucosa and stimulate the secretion of mucus and bicarbonate. Because the administration of prostaglandins protects the gastric mucosa of animals against various ulcerogenic insults, a number of slowly metabolized prostaglandin analogs have been developed and tested in human beings. Example includes misoprostol; this is currently approved for prevention of gastric ulcers. Side effects of misoprostol include diarrhoea, abdominal cramps, and abortifacient in pregnant women⁶⁸.

Miscellaneous Agents:

Carbenoxolone, an olendane derivative of glycyrrhizic acid, a compound found naturally in licorice, is also useful in the treatment of peptic ulcer. Mechanism of action is not clear, but appears to alter the composition and quantity of mucus. It is not approved for use in U.S., but is being used in Europe since 1962 for the treatment of peptic ulcer. Being a steroid analog, it exhibits substantial mineralocorticoid activity like hypertension, hypokalemia, fluid retention; etc Sucralfated polysaccharides inhibit pepsin mediated protein hydrolysis. The octasulfate of sucrose was observed to inhibit peptic hydrolysis in vitro. Reaction of sucrose octasulfate with Al (OH) 3 forms a viscous substance, Sucralfated. A variety of mechanisms have been proposed to account for the cytoprotective and healing effects of Sucralfated, including stimulation of prostaglandin synthesis, absorption of pepsin, and stimulation of local production of epidermal growth factor.⁶⁹

Surgical Therapy:

Before the availability of the PPIs and H2-receptor antagonists, fundoplication was performed in patients with moderate to severe GERD. Some authorities still feel that patients aged 40 years may benefit from anti-reflux surgery rather than undergo a lifetime of costly drug therapy. Fundoplication has been found to provide effective remission of symptoms associated with GERD. The procedure can now be performed laparoscopically, which improves patient satisfaction and reduces hospital stay. A positive response to a trial of a PPI indicates good potential for a cure with surgery⁷⁰. Current indications for surgery include drug therapy failure, complications from strictures, non healing ulcers, symptoms of aspiration, and severe bleeding as a result of esophagitis.⁷¹

CONCLUSIONS:

GERD is a very common disease that can be diagnosed quite easily nowadays, either clinically or by simple diagnostic tests. The management of gastro esophageal reflux disease has changed dramatically over the past two decades with recognition of the importance of acid and pepsin in the etiology of GERD and the development of PPIs. It is widely accepted, however, that GERD is fundamentally a disorder of motility and structure in the upper GI tract and that PPIs and acid suppression therapy do not; therefore, address the fundamental cause of GERD. Without an understanding of GERD pathophysiology and symptomatology, it will not be possible to devise new treatments and investigations necessary to target specific GERD-related abnormalities. There is a good chance that the next few years will lead to a greater understanding of GERD in its many forms and a larger therapeutic armamentarium that will permit targeted therapy to deal with an individual patient’s specific problems to prevent major complications.

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Received on 10.01.2013 Modified on 13.01.2013

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