Hari Kumar R*, Varghese Thomas**
*DM Trainee,**Head of the Department of Gastroenterology

Address for correspondence:
Dr Hari Kumar R, 
DM Trainee,Dept of Gastroenterology,
Calicut Medical college
Calicut-673008,Kerala,India
E-Mail: harikumnair@yahoo.com 

Introduction:

Gastro esophageal reflux disease (GERD) is a multifactorial disease caused by the combination of excess reflux of gastric juice and impaired clearance of this refluxate from the oesophagus. This disease makes the patient symptomatic during daytime and damages silently during the night, leading on to complications at a later date. It is one of the most common gastrointestinal disorder presenting to the general physician and can lead on to reduction in quality of life greater than that caused by duodenal ulcer, untreated hypertension, mild CCF, angina or menopause[1]. There is no clear consensus among general physicians regarding what constitutes a “typical GERD”. Also, confusion prevails regarding recently characterized entities like Non Erosive Reflux Disease (NERD), Extra esophageal manifestations of GERD etc.

GERD is a chronic disorder caused by retrograde flow of gastro duodenal contents into esophagus and/or adjacent organs resulting in a variable spectrum of symptoms with or without tissue damage. Some amount of reflux occurs in normal individuals many times a day. The term GE reflux disease is used to denote any symptomatic clinical condition with or without histopathological alteration in the lower esophageal mucosa consequent to acid reflux. This needs to be distinguished from reflux esophagitis, which denotes a subset of patients with GERD who have histopathological or endoscopic evidence of esophagitis[2].

Approximately 70% of GERD patients in community-based practice demonstrate lack of any esophageal mucosal injury[3]. This endoscopy negative reflux disease is termed as Non-erosive reflux disease (NERD). Although less characterized, there is an increasing awareness regarding extra esophageal manifestations like laryngitis, pharyngitis, bronchial asthma etc[4].

Thus the term GERD is broader one, which include reflux esophagitis, non-erosive reflux disease and extra esophageal manifestations.

Disease Burden:

GERD is among the most common GI problem seen in primary care settings. In the U.S., 44% of adult population experience hearts burn at least once a month, 14% weekly and 7% daily[5]. The incidence in the West appears to be increasing; also there is evidence that prevalence in the east is on the rise[6,11] . There appear to be racial differences in the clinical presentation and natural history between and west. Asians are less likely to develop symptomatic disease as well as complications compared to whites[7].

Approximate prevalence of esophagitis in the general population is 3-4% with similar sex predilection. But there is a definite male preponderance of esophagitis (2:1) and of Barrett’s esophagus (10:1). Pregnant women have highest incidence of heartburn ranging from 48%-79%. Incidence among elderly patients is significantly high compared to younger[8, 9,10,11].

Disease Causation:

The conventional wisdom on aetiopathogenesis of GERD is that it is an imbalance between injurious and protective factors affecting the oesophageal mucosa. The defense mechanisms constituted by anti reflux barrier (LES and diaphragmatic crus), esophageal acid clearance and tissue resistance, when disturbed results in pathological reflux.

Esophageal Defense: The Three Tier System
I) First Tier: Anti reflux barrier

(1) LES
(2) Right crus of diaphragm
(3) Phrenoesophageal ligament
(4) Intraabdominal location of LES
(5) Acute angle of His at GE junction

II) Second Tier: Esophageal clearance

(1) Gravity
(2) Normal esophageal peristalsis
(3) Neutralization of salivary & esophageal HCO3-

III) Third Tier: Tissue Resistance

(1) Pre epithelial (poorly developed)
Mucus layer
Surface HCO3-
(2) Epithelial (very well developed)
20-30 layer non-keratinised
Stratified squamous epithelium
(3) Post epithelial
- Delivery of O2, HCO3-
- Removal of H+, CO2

The high-pressure zone of 10-30mm at the lower end of esophagus maintained by the LES and the cru of diaphragm acts as a watchdog preventing reflux. During swallow, LES relaxes to let passage of food bolus, but this doesn’t result in reflux since swallow induced relaxation is brief and also accompanied by peristaltic wave.

Transient lower esophageal sphincter relaxation (TLESR) plays a key pathogenic role in mild GERD. TLESR occur in response to gastric distension after a meal in order to belch out excess air (silent belch) [12,13]. Electrical and mechanical inhibition of diaphragmatic crus occurs during TLESR, which promote reflux. TLESR is not accompanied by a peristaltic wave, which would have otherwise swept down the acid refluxate. All these, along with the fact that TLESR occur maximally during night and reduced nocturnal salivary clearance cause maximum damage to occur during night. Hence symptoms during daytime need not tally with the actual damage. To put in nutshell, TLESR play a central role in disease causation but what makes some individuals prone for more frequent TLESR is still an enigma.

The neural pathways that mediate TLESR can be targets of pharmacotherapy. GABA receptor has been shown to play a central role. Baclofen, a GABA receptor agonist, reduces triggering of TLESR in normal subjects and reduces ambulatory esophageal acid exposure time to 40% [14,15].

Nitric oxide (NO) has been shown to be involved in the mucosal defense of the esophagus and acid induced reduction in mucosal NO synthase may predispose the esophageal mucosa to injury [16].

^{Table: 1}

Causes other than TLESR which induce reflux in specific clinical situations are diabetes, scleroderma, Ryles tube insertion, pregnancy etc, where hypotonic LES and increased Intraabdominal pressure play a role.



GERD – A Motor Disease:

The working committee of the world congress of Gastroenterology 2002, opined that GERD should be listed as an esophageal dysmotility disorder because it is primarily caused by motor dysfunction, i.e., malfunctioning of dynamic antireflux barrier, that is composed of the LES and surrounding diaphragmatic crus. But the very fact that GERD is diagnosed by assessing the consequences of barrier failure rather than motility per se, stands against placing this entity amongst dysmotility disorder. Moreover, in addition to dysmotility, hypersensitivity of esophageal mucosa to acid plays some role in symptom generation as signified by the entity called NERD[17]. Hence GERD in a strict sense cannot narrow down to dysmotility alone.

Genetic factors?
Evidence in favor of genetics playing a role is gradually accumulating [18]. There is an increased concordance for reflux disease among monozygotic twin pairs [19].

Immunological factors:

Immunological response of the esophageal mucosa to injury may influence its phenotypic response to reflux. A study evaluated the immunoregulatory environment in three groups of patients-non-erosive reflux disease, erosive reflux disease and Barrett’s esophagus. Compared to non-erosive disease, erosive esophagitis had an acute inflammatory response as evidenced by raised levels of interleukin-1beta, interleukin-8 and interferon –gamma consistent with a T-helper-1 (Th-1) response. In contrast Barrett’s showed a T helper-2 (Th-2) response [20].

Helicobacter Pylori
The pattern of gastritis induced by chronic H.Pylori infection has some influence on disease causation. In populations with antral predominant gastritis with associated acid hyper secretion predisposes to GERD, while those with atrophic gastritis with decreased acid production protects against GERD [21, 22] .In Asian populations, the predominant pattern of gastritis appears to be corpus predominant atrophic gastritis. That explains why studies addressing the effect of eradication show a beneficial response in the west and unfavorable response in east [23].

Clinical Features [24,25]:

Heart Burn (Pyrosis):

Retrosternal burning sensation that begins at xiphisternum and radiates up to the neck; most experience this postcibally or while going to bed. This is believed to be due to acid irritation of sensory nerve endings in the lower esophageal mucosa. Paradoxically, some people with reflux esophagitis are asymptomatic and those with NERD can be extremely symptomatic – the frequency and severity of heartburn is a poor predictor of the degree of esophageal injury.

Regurgitation is effortless return of gastric or esophageal contents into the pharynx without nausea, retching or abdominal wall muscle contraction. Usually, patients regurgitate acidic material mixed with small amounts of undigested food, rarely bile.


Dysphagia of mild degree can occur in GERD due to peptic stricture, but more commonly peristaltic dysfunction. Its important to keep in mind that odynophagia almost never occur in uncomplicated GERD.


Water brash: Sudden appearance of tasteless fluid or frothing due to reflex salivary hyper secretion due to acid stimulation of lower esophageal mucosa. (Esophago- salivary reflex).


Extra Esophageal Manifestations:

GERD has now definitely been associated with pulmonary symptoms and diseases like asthma, bronchitis, micro aspiration, Ear Nose Throat symptoms etc. Majority of patients presenting with extra esophageal symptoms do not have the classic symptoms of heartburn or acid regurgitation (silent reflux). For example, classic reflux symptoms are absent in 40-60% of asthmatics, 57-94% of ENT problems and 43-75% of patients with chronic cough in whom GERD is suspected or confirmed. Also, patients with extra esophageal presentation have low prevalence of endoscopic esophagitis. In view of this and “silent reflux” it is worthwhile considering GERD in the differential diagnosis of the problems listed bellow when alternative diagnosis have been excluded [24].

An association of GERD and sleep disorders has been suggested, but the strength of causality is controversial. A study identified 73% of patients who were referred for overnight sleep studies reported sleep apnea, but the occurrence of reflux symptom was not related to the severity of sleep apnea [26].

Table: 2 Extra esophageal manifestations.

Complications:

Complications usually occur in a long-standing disease, particularly when uncontrolled. Those with erosive disease are more prone for complications than those with NERD. They are:
1) Ulceration (5%)
2) Peptic stricture (4-20%)
3) Barrett’s esophagus (8-20%)
4) Chronic blood loss anemia (<1%)
Barrett’s Esophagus:
Updated American College of Gastroenterology guidelines 2002, defines Barrett’s as a “change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of cardia”[27]
The importance of detecting Barrett’s is due to its propensity to evolve into adenocarcinoma. Presence of gastric-fundic epithelium need not raise an alarm, as these epithelia do not predispose to malignancy. Endoscopy is a must to detect Barrett’s transformation since symptoms poorly predict the same. On Endoscopy, it appears as reddish mucosa in contrast to lighter orange pink squamous mucosa.
There has been a recent focus on “Short segment Barrett’s” – Intestinal metaplasia in the distal esophagus <3cm in length. This entity can be confused with intestinal metaplasia of the cardia; hence biopsy should be taken 2cm above the beginning of gastric folds [28, 29].
Peptic Stricture:
This is due to reflux esophagitis lesion healing with fibrosis – usually circumferential and involves lower esophagus. It can be eccentric and also may involve middle and upper third of esophagus. An astute clinician may pick up formation of stricture in a case of GERD, on follow up, by noting change in pattern of symptomatology. Symptoms change in such a way that reflux symptoms come down (as stricture may act as an antireflux barrier) and predominant complaint becomes one of dysphagia. Barium studies and endoscopy confirms peptic stricture.
Blood Loss Anaemia:
Esophageal erosion can result in chronic blood loss anemia. Very rarely, it may cause acute blood loss.

Natural History:

Most patients who present with reflux esophagitis usually have symptom lasting for 1-3 years before seeking medical care. Many continue to sail on OTC medications before ending up in complications. No clear relationship exists between symptom severity, amount of reflux, and presence of esophagitis or complications. There are very few large scale follow up series, which clearly delineate natural history of the disease; still GERD has traditionally been approached as a “spectrum of diseases”(despite lack of evidence)[30]

Towards evolution of a new conceptual framework – Spectrum Vs Unique groups?
The spectrum of disease concept was primarily born from the observation that patients presented with or without esophageal mucosal injury. On one end of the spectrum is NERD and as patients progress along the spectrum, they go through erosive reflux disease (esophagitis) with advancing grades of erosion with far end of the spectrum occupied by patients with complications such as esophageal ulceration, stricture, Barrett’s and adenocarcinoma [31,32].

In actuality, there is only scant data to support that GERD is a spectrum of diseases. It is clear that patients have different pathophysiological mechanism, resulting in symptoms and that patients with NERD do not behave as milder disease, as far as symptoms are concerned. If NERD is a milder disease, it should respond fast to antireflux treatment that too at lower doses, but in reality they demonstrate an unpredictable symptom response to antireflux treatment. NERD patients have more extra oesophageal manifestations like chronic cough, asthma, hoarseness etc. reducing quality of life considerably. So, NERD does not behave as a milder disease. To complicate the issue, NERD patients on follow up relapse as NERD and not as erosive disease and erosive disease rarely only regress to NERD group[33].

At the other end of the spectrum, it is believed that erosive disease progress to Barrett’s and then to adenocarcinoma. This is based on epidemiological observations and we do recommend screening of GERD patients for Barrett’s transformation to prevent development of adenocarcinoma. It is confusing to state the truth that presently there are no data confirming the effectiveness of surveillance in Barrett’s esophagus.

All these prompt us to shed the spectrum concept and approach the GERD population as 3 unique groups – NERD, Erosive esophagitis and Barrett’s. Evidence suggests that GERD patients belong to only one of these groups for the rest of their lives (or there is very little movement in between these groups). To summarise, contrary to the conventional wisdom, as one goes strictly by evidence, GERD patients can be conveniently accommodated in 3 unique groups rather than progressing along as a spectrum of diseases [32,34].


MANAGEMENT


Diagnosis is achieved by typical history and endoscopic finding – the combination has 97% specificity. It goes without saying that Endoscopy forms the investigative modality of choice. Although the issue of when to do endoscopy in GERD is still unsettled, the usual indications in day-to-day practice are as follows [25].

1) Non responders to empirical therapy
2) Longstanding disease
3) Patients over 40 years
4) Those who present with alarm symptoms
(Dysphagia, odynophagia, anaemia, weight loss)

Los Angeles grading is the most commonly used system to endoscopically grade reflux oesophagitis [25,34].

A) Mucosal breaks less than 5mm, not crossing tops of adjacent mucosal folds.
B) Mucosal breaks more than 5mm not crossing tops of adjacent mucosal folds.
C) Mucosal breaks crossing tops of mucosal folds but encircling less than 75% circumference.
D) Mucosal breaks encircling entire circumference of lower end of esophagus.

Other investigations that may be useful in the workup of GERD are manometry and 24hours pH metry. These are not first line investigations and have only selected, specific indications.

Oesophageal Manometry:

This test measures the function of the esophageal body muscle and its sphincters by obtaining pressure profiles using a system of water perfused catheters or solid-state transducers.

Manometry alone has limited value in the diagnosis of GERD, although it may help, predict, those likely to have more severe form of disease. It is also useful for accurate placement of pH electrode for 24 hour ambulatory pH monitoring. In patients undergoing antireflux surgery, there is increasing concern about performing total fundoplication in patients with significant impairment of oesophageal motor function because of the risk of development of obstructive symptoms. Hence, some centres now advocate a tailored approach for anti-reflux surgery, tailoring the antireflux surgery to the pre-operative motility [35, 36,37].

24-hour pH metry:

This test has high sensitivity and specificity in the diagnosis, quantification and assessing temporal profile of acid exposure. It involves the transnasal placement of a pH probe, 5cm above the manometrically identified lower esophageal sphincter, which monitors intraesophageal pH over a circadian cycle.

pH metry is useful in the following situations:

1) Diagnosis of NERD
2) Those with atypical symptoms like non-cardiac chest pain, respiratory and laryngeal problems.
3) In patients with endoscopic diagnosis of GERD, but responding poorly to optimal medical therapy (to rule out predominant alkaline reflux)
4) As preoperative workup before antireflux surgery.

Thus, pHmetry is not indicated in reflux patients in whom the diagnosis is reasonably certain and the response to therapy is satisfactory [36,37].

Bernstein’s Test: has use only in research settings. It assesses induction of pain on instilling 0.1 normal HCl to lower oesophagus[25].

Treatment:

The armamentarium is constituted by lifestyle modification, drug therapy and surgery.
Pharmacotherapy: is aimed at either neutralizing the acid refluxate (PPI, H2 blocker) or to promote peristalsis (prokinetics) [38,39].

Pharmacotherapeutic agents for treating GERD
1) Antacid
2) Mucosal protectant (sucralfate)
3) H2 receptor blocker (Ranitidine, Famotidine)
4) Proton pump inhibitor (Omeprazole, Esomeprazole, Lanzoprazole,
Rabeprazole)
5) Prokinetics (Cisapride, Mozapride, Itopride, Domperidone)
6) Experimental – Baclofen, Sildenafil, Riluzole [40]

Pharmacotherapy of GERD is based primarily on acid suppression. Despite the fact that very few patients will “over produce” acid, acid is responsible for esophageal mucosal damage. Healing of esophagitis and symptom relief are strongly correlated with percentage time that gastric pH is kept above 4, over a 24-hour period [41]. Although lifestyle modifications are recommended, there is no data supporting their efficacy as sole therapy.
Antacids and antirefluxants such as alginic acid may be useful in treating occasional or mild GERD [42]. Randomized trials have shown antacids and alginic acid as superior to placebo in relieving symptoms induced by a heartburn inducing meal [43,44].

H2Ras had been the mainstay of therapy for GERD previously. American College of Gastroenterology (ACG) compiled the results of 33 randomized trials involving over 3000 patients. Symptom relief was formed in 27% of placebo treated subjects and 60% of those using H2RAs. Esophagitis was healed in 24% on placebo and 50% on H2RAs. Histamine-2 receptor antagonists are limited by the need for frequent dosing, sub optimal meal stimulated acid suppression and tachyphylaxis is with chronic use [44,45,46].

Proton pump inhibitors have become the therapeutic agent of choice for severe GERD [42,47]. Once a day dosing of a PPI (Omeprazole 20mg, Lansoprazole 30mg, Pantoprazole 40mg or Rabeprazole 20mg) will heal 80-90% of reflux oesophagitis within 8 weeks. These agents also reduce symptoms by 80-90%. A seminal randomized controlled trial directly compared PPI, H2RA and prokinetic agents and found Omeprazole superior to ranitidine, as well as ranitidine plus cisapride, for healing and symptom relief [48,49,50].

All PPIs in the class have been considered equally efficacious as far as mucosal healing and symptom relief are considered; however, the recently approved PPI, esomeprazole (the S-isomer of omeprazole) has proven superior to omeprazole.

The use of prokinetic agents is guided towards correcting the underlying pathophysiology of GERD including LES incompetence, delayed esophageal clearance, and slow gastric emptying [49,50]. Data suggest these agents are no more effective than standard dose H2Ras when used alone. Cisapride the most widely used prokinetic agent is less preferred due to reports of fatal cardiac dysrrhythmias associated with its use. Newer agents like mozapride and itopride are devoid of this side effect [51].In a recent trial,effect of motilin receptor agonist ABT-229 was assessed.ABT-229 significantly reduced the mean esophageal acid exposure time but had no effect on esophageal motility or gastric emptying time .

These remains considerable debate as to what medications should be used first. There are two strategies – step up treatment and step-down treatment [52,53,54].

I. Step Up Treatment: This is the predominant strategy in primary care practice. Treatment is commenced with non-pharmacological intervention, i.e., life style modification.

Life Style Modifications

* Elevation of head end of bed (4-6 inches)
* Decreased fat intake
* Cessation of smoking
* Avoid lying down for 3 hours after meal
* Avoid chocolates, alcohol, pepper mint, onion
* Avoid drugs like theophylline, beta-blockers, alpha-blocker, prostaglandins, nitrates, and anticholinergics.
* Stress management

If symptoms persist, treatment is initiated with H2RA/PPI. A prokinetic may be added along with stepping up of PPI dose in case symptoms persist.

II. Step-down Treatment:

Usually done in tertiary care setting. This approach is applicable for more symptomatic cases. Treatment is initiated with PPI + Prokinetic. With symptomatic improvement may be stepped down to maintenance therapy with low dose PPI or H2RA (along with life style modifications).

III. Maintenance Treatment:

GERD is a chronic problem with relapses. Approximately 50% or more will have symptomatic relapse (as well as mucosal damage) within 6 months of stopping antisecretory therapy. Hence long-term treatment is crucial to assure quality of life and long symptomatic periods. It has been proven that patients in combination therapy do well than those on monotherapy 39.

Atypical GERD:

An evolving area of research involves study of non-erosive reflux disease (NERD). The majority of clinical studies in GERD have involved patients with erosive esophagitis. This is because clinical trials had required an unequivocal diagnosis of GERD [54]. Because drug trials only included patients with esophagitis, the results cannot be extrapolated to patients without mucosal damage [55]. The patients with NERD may be a heterogeneous group as already discussed. Data clearly show that PPIs are superior to H2RAs and prokinetics in patients with erosive esophagitis [56]. Data for patients with NERD are just emerging and no single therapy yields 90% or greater symptom relief. Two placebo controlled trials showed approximately 60% symptom relief with PPI versus 20% to 25% with placebo [54-57].

There is limited data to guide medical therapy of extra esophageal symptoms. Most trials are small and uncontrolled. A small well-done RCT for therapy of chronic laryngitis suggested PPI is superior to H2RA, but response rates were significantly lower than for erosive esophagitis [57]. A trial involving 30 patients with asthma revealed patients needed escalating doses of PPI, and some therapeutic responses did not occur until 3 months (improvement in asthma scores) [58]. A critical review of the literature evaluated 12 studies involving 326 patients. Nearly 70% had symptom improvement, 62% reduced asthma medication use, but there was little to no change in objective pulmonary function testing [59]. Despite the lack of data, most reviews suggest high dose PPI therapy for at least 4-6 months to treat patients with suspected extra esophageal symptoms [30,31]. If there is not adequate response, the diagnosis should be re-evaluated.

Surgical Intervention:

The usual indications are:
1) Failure of medical therapy: Persistent symptoms, intractable esophagitis, non compliance
2) Development of complications – stricture, Barrett’s
3) Reflux associated with motility disorders.

The commonly employed surgical procedures are:
Nissen – 360 degrees of 2cm loose wrap of gastric fundus around abdominal esophagus
Toupet – 270 degrees of partial posterior fundoplication
Dor (Watson) – 180-degree anterior fundoplication

Nowadays laparoscopic fundoplication is preferred over open surgery.

There have been very few studies that have attempted to randomize patients to medical therapy versus surgical therapy. An earlier comparison between surgery versus Ranitidine and Metoclopramide suggested a clear superiority over the surgical approach. Another study compared long term omeprazole therapy with surgery in an RCT and surgery to be superior to long term PPI [60,61].But there are conflicting results whereby side effects like dysphagia are more with surgery. Also, the sign of general anaesthesia and inherent morbidity of surgery are to be taken into account.

Although some studies suggested marginal advantage for laparoscopic surgery, this advantage may be weighed against substantial side effects including dysphagia, bloating and diarrhea [62].

All trials showing good results were done in centres with good surgical expertise, with surgical team already crossing the learning cure. It is worthwhile mentioning that prescribing of PPI does not suffer from the same learning curve problem!

ENDOSCOPIC THERAPY FOR GERD – BAKING, SEWING & STUFFING!

Innovative technology has played a significant role in the evolution and advancement of GI endoscopy. The pursuit of an endoscopic method for altering the esophagogastric junction (EGJ) to treat GERD dates back to early 1980s. Although the initial endotherapies for GERD resulted only in temporary success, the last 5 years have seen a resurgence of interest in this area.

Attributes of an ideal endoluminal therapy are:
- Consistent results
- Efficacy comparable to existing therapies
- Less risk than surgery
- Ability to retreat
- Allow antireflux surgery at a later date

To date there have been three main endoluminal approaches to treat GERD.
a) Suturing (Sewing)
b) Radio frequency (RF) energy (Baking)
c) Injections/Implantation Technique (Stuffing)

Table3:     Endotherapies for GERD:

 a) STRETTA procedure:
This involves delivery of temperature controlled radio frequency energy to the lower esophageal sphincter and gastric cardia. The radio frequency energy is delivered using a special device – a balloon basket assembly and a 4 needle electrode positioned around the balloon. The balloon is inflated and needles are deployed into the muscles. Radio frequency current is delivered in a controlled manner with simultaneous cooling of mucosa. The instrument is located to create additional lesion sets at each level, and a total of 12-15 lesion sets are usually performed [63].

STRETTA works by 2 mechanisms:

1) Stiffening of the treated area (creating an anti-reflux barrier)
2) Interruption of afferent vagal pathways from gastric cardia involved in tLESR

b) Endocinch – The suturing device:

This is a novel mechanical treatment, which can be carried out without general anaesthesia in an outpatient setting; the procedure takes only 30 minutes.

A 9mm endoscopic sewing machine is attached through the biopsy port of the endoscope. Procedure involves placing sutures below the cardio esophageal junction. If the mechanical barrier created is found to be insufficient or become less effective over time, it could be more easily and safely repeated than surgery. Disadvantages of this procedure are mainly cost factor and also long-term results are not yet available[64].


c) Endoscopic Implants:

Submucosal injection of PMMA (Polymethyl Methacrylate – Plexiglas) microspores or Ethinyl Vinyl alcohol (EVA) into the muscle of cardia, increase the LES pressure and symptomatic improvement noted in used patients. Trials with hydrogel prosthesis implants in the submucosa of oesophagogastric junction are underway [65,66].

Future of endotherapy:

The predominant mechanism of these three techniques is to alter the anatomic and mechanical properties of the Esophagogastric Junction (EGJ) to decrease the frequency of reflux events and/or the volume of the refluxate. The techniques are believed to cause fibrosis and other tissue changes that result in tightening, lengthening, thickening and narrowing of the EGJ. The use of RF energy also has the theoretical possibility of ablating the neural elements residing in EGJ that may play a role in triggering TLESR.

Although endotherapies show beneficial effects, there is insufficient data to support the use of any of these in routine clinical practice. Also, the durability, long-term safety and cost-effectiveness of these treatments are to be addressed in future randomized controlled trials.



CONCLUSIONS
Considerable advances have occurred in the understanding of GERD. The novel concept of segregating GERD into unique groups rather than a spectrum (continuum) happens to be an epidemiological revolution. More research is needed to elucidate pathophysiology and management of GERD and extra esophageal manifestations. It is alarming to know that disease burden in the east is also in the rise, although eastern population is less symptomatic and has less complications. It is interesting to note that genetic factors and immunological factors are etiologically implicated in addition to infective agents like H.Pylori. Endoscopic therapy for GERD stands an example of utility of technological advancement in medicine, although more studies are needed to assess the cost-effectiveness of gastroenterologists engaging themselves in stitching (Endocinch), Baking (Stretta) and stuffing (implants).

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