Gastro-esophageal reflux disease (GERD)

P Gorecki, M.D.
Department of Surgery, Nassau University Medical Center, N.Y., U.S.A.
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Definition, epidemiology and pathogenesis of GERD

Gastroesophageal reflux disease (GERD) is a clinical manifestation of the excessive reflux of
acidic gastric contents into the esophagus causing various degree of symptomatic irritation or
injury to the esophageal mucosa. Typical symptoms of GERD include heartburn,
regurgitation and dysphagia. Atypical or supraesophageal symptoms include pulmonary
symptoms (asthma, chronic cough), variety of laryngo-pharyngeal symptoms (chronic sore
throat, pharyngitis, laryngitis, globus sensation) and non-cardiac chest pain.
GERD is a very common disorder. Population based survey revealed that 44% of the
population reported monthly heartburn (1) and 19.8% suffered from heartburn or acid
regurgitation at least once a week (2).
The antireflux barrier consists of a lower esophageal sphincter (LES) and a crural portion of
the diaphragm. Clearance of the refluxed content depends on the esophageal peristalsis, saliva
(pH >6) and gravity (3). Therefore, factors contributing to the pathogenesis of GERD
include: defective LES, hiatal hernia, impaired esophageal peristalsis, delayed gastric
emptying, gastric acid production as well as bile reflux.
Significance of different pathomechanisms of GERD has been analyzed in multiple studies.In
the analysis of 375 patients with foregut symptoms, among patients with abnormal
esophageal acid exposure 71% were found to have defective LES and 75.6% were found to
have hiatal hernia, compared to 37% defective LES and 39% hiatal hernia rate in those with
normal acid exposure (4). Hence, the presence of defective LES and hiatal hernia were
identified as significant independent predictors of abnormal esophageal acid exposure (p <
0.0001, odds ratio 3.3 and 3.8 respectively; 95% CI). Total length of the LES, intraabdominal
length and the LES resting pressure are the major components of the competency of the
cardia (5, 6).
Esophageal peristalsis was found to be a very effective mechanism of acid clearance. In a
study reported by Kahrilas et al (7), a single normal peristaltic wave resulted in 100%
clearance of a barium bolus from the esophagus. Helm et al. (8) described virtually complete
acid clearance (0.1 N hydrochloric acid) by one or two peristaltic sequences, and
neutralization of the residual acid by swallowed saliva. Another study by Kahrilas, revealed
progressive peristaltic dysfunction correlating with increasing severity of esophagitis, so that
25% of patients with mild and 48% of patients with severe esophagitis had either failed or
hypotensive peristalsis (9). It is unknown, however, if these motility disturbances are a
primary smooth muscle defect or they represent injury of the esophagus from chronic severe
acid reflux.

Delayed gastric emptying has been proposed as one of the factors contributing to GERD and
is found in 1015% of patients with reflux (3). A study from Holloway et al demonstrated
that gastric distention appeared to be a trigger for transient LES relaxation (10). There are
conflicting data about the role of delayed gastric emptying in the pathophysiology of GERD.
Schwizer et al. (11) studied gastric emptying in 76 GERD patients and 38 asymptomatic
controls. The authors did not find any difference in gastric emptying rates between the two
groups. Fundoplication has been shown to enhance gastric emptying, but patients with
marked delayed emptying might be better served by continuing medical therapy or possibly
pyloromyotomy with fundoplication. In a study reported by Madden, delayed gastric
emptying was suggested to be of value in predicting patients likely to have poor outcome
after fundoplication (12).Another factor contributing to pathophysiology of GERD is gastric
acid hypersecretion. In a study of 75 patients with abnormal esophageal acid exposure 28%
were found to be hypersecretors. Its role in the pathogenesis of GERD may be more
prominent in patients with normal LES (13). Collen et al studied basal acid output in patients
suffering from GERD (14). The mean basal acid output (BAO) in 228 patients recorded by
the authors was 6.5 meq/hour compared to 3.0 meq/hour in normal subjects (p < 0.0001).
Furthermore, as the severity of the disease increased from pyrosis alone to erosive esophagitis
and Barrett's esophagus, the proportion of hypersecretors increased significantly (19%,
28%, 35% respectively, p < 0.01). The greatest prevalence of mucosal damage is found in
patients with increased esophageal exposure time to pH of 0 to 2, which corresponds to a
known pKa of pepsin (15).
Defective LES, hiatal hernia and impaired esophageal peristalsis are the major factors in the
pathophysiology of GERD. Delayed gastric emptying and gastric acid hypersecretion are
probably of secondary importance.
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Diagnostic tests
Gastroesophageal reflux disease (GERD) is a multifactorial disorder and has a wide spectrum
of clinical presentations. Its diagnosis is often challenging. Atypical, pulmonary and laryngopharyngeal symptoms of GERD often occur without presence of typical symptoms such as
heartburn and regurgitation (16). Moreover, complications of GERD such as Barrett's
esophagus, stricture or adenocarcinoma can develop silently (17). Because of this clinical
diversity, utilization of the diagnostic tests is very helpful.
Esophago-gastro-duodenoscopy (EGD) allows a direct visualization and biopsy of the
esophageal mucosa. It enables diagnosis of Barrett's esophagus and documents the presence
of and severity of esophagitis. It evaluates gastric and duodenal pathology and rules out
dysplastic changes and malignancy. It can also provide helpful information regarding the
presence of hiatal hernia or stricture. EGD is a very useful test in all patients with foregut
symptoms, but particularly in those with severe, long-standing symptoms and in patients who
are considered for antireflux surgery. Severity of symptoms, however, does not correlate with
the presence and the severity of esophagitis (18).

24 h pH study

24-hour pH monitoring is the most sensitive test for detection of excessive esophageal acid
exposure. Qualitative and quantitative evaluation of esophageal acid reflux can be obtained
and calculated with a pH catheter placed 5 cm above the LES. Composite score (DeMeester
score) and percent of the total time for pH less than 4 provide the most efficient interpretation
of the pH test with sensitivity of 96%, specificity of 100% and accuracy of 98% (19, 20).
Patients who do not have esophagitis on endoscopy and those patients with pulmonary,
laryngo-pharyngeal symptoms or atypical chest pain should be studied with this modality to
detect correlation of symptoms with increased esophageal exposure to acid. The pattern of
esophageal acid exposure has been shown to influence severity of the disease, which
increases progressively from postprandial to upright, supine and bipositional reflux (21).

Manometry
Manometry identifies LES dysfunction and permits the evaluation of the esophageal
peristalsis, therefore allowing the diagnosis of esophageal motility disorders such as
achalasia, scleroderma, diffused esophageal spasm, nutcracker esophagus and nonspecific
esophageal dysmotility. LES competence depends on its resting pressure, total sphincter
length and intraabdominal length. In a classic study by Zaninotto et al (22), analysis of 50
healthy volunteers and 622 patients with foregut symptoms revealed, that statistically
significant discrimination occurred below the 2.5 percentile for LES pressure, the fifth
percentile for abdominal length and 2.5 percentile for overall length. This corresponded to a
sphincter pressure of 6mm Hg or less, an abdominal length of less than 1 cm and overall
length of less than 2 cm. Overall 60% of 324 patients with increased esophageal acid
exposure had mechanically defective LES. It has been shown that the defective LES is a
major mechanism in pathophysiology of GERD (4). However, the most prevalent mechanism
of acid reflux, both in health and the disease is an intermittent LES relaxation (23), therefore
manometric competence of the sphincter cannot be a sole determinant of a functionally
normal LES (24). Patients with poor body motility may be better served with partial
fundoplication.

Contrast study
Barium esophagram should be performed in all patients with dysphagia, suspected of having
large hiatal hernia, esophageal stricture or shortened esophagus. If a large hiatal hernia fails
to reduce in the upright position esophageal shortening can be suspected. In this situation
esophageal lengthening procedure should be considered (25, 26).

Gastric emptying study

Nuclear study evaluating gastric emptying should be considered in patients with associated
symptoms of nausea vomiting, postprandial bloating, retained food found on endoscopy or
with long standing diabetes. In patients with significantly prolonged gastric emptying,
caution should by given in recommending surgical therapy.

Trial of acid suppressive therapy

Trial of proton pump inhibitors (PPI's) can be given before considering more invasive tests.
Typical primary GERD symptoms and good response to acid suppressive therapy is a good

indicator of acid reflux being responsible for patient's symptomatology. It is also a good
predictor of successful antireflux surgery, if this form of therapy is considered.
Patients considered for surgical treatment of GERD should have detailed preoperative
evaluation. Endoscopy and manometry should be utilized routinely. 24-hour pH study is a
gold standard for evaluation of acid reflux and is particularly indicated for evaluation of
patients with no esophagitis or atypical symptoms. Barium study and gastric emptying study
should be considered in selected patients.

Complications of GERD
Complications of GERD result from prolonged exposure of the esophageal mucosa to acid.
Significance of reflux of duodenal juices in patients with severe GERD is becoming
increasingly appreciated (27). Erosive esophagitis, Barrett's esophagus, esophageal stricture,
and adenocarcinoma are markers of severe GERD. Aspiration pneumonia can be another
potentially life threatening sign of severe reflux.

Erosive esophagitis
About 30% to 40% of patients undergoing endoscopy for troublesome GERD symptoms will
have evidence of mucosal brakes on endoscopy (28). However, erosive or ulcerative
esophagitis is a marker for severe GERD. In a study reported by Hetzel et al. (29), erosive or
ulcerated esophagitis recurred in 82% of patients after discontinuation of omeprazole. The
grade of esophagitis did not show to influence relapse rate. There is no good correlation
between the severity of GERD symptoms and the presence of esophagitis. The severity of
heartburn and regurgitation does not differ between patients with normal mucosa and various
degrees of esophagitis (30). Likewise, the successful outcome from antireflux surgery does
not depend on the presence and severity of esophagitis (31).

Barrett's esophagus
Barrett's esophagus describes a presence of any length of an endoscopically visible columnarlined epithelium with intestinal metaplasia and characteristic goblet cells (32). It develops
approximately in 10% of individuals with GERD (33). Patients with Barrett's esophagus often
describe longer duration of symptoms compared to patients without Barrett's. They also have
a higher prevalence of defective LES (more than 90%) and have more frequently impaired
esophageal body motility (34-37). In addition to acid reflux, patients with Barrett's have had a
significantly higher prevalence of abnormal esophageal exposure to duodenal juice,
compared with patients with esophagitis alone (38, 39). Intestinal metaplasia within a cardiac
type columnar epithelium is thought to develop over the period of at least 5 years and is
indicative of the severe and chronic disease (32). Fundoplication has been shown to provide
effective and durable symptom relief in patients with Barrett's esophagus (40). Surgery also,
rather than medical therapy, appears to be more effective in controlling the progression of the
disease to dysplasia and carcinoma (32, 41). This can be explained in part by the fact that
medical therapy does not stop bile contents from regurgitating to the esophagus, as well as by
incomplete acid suppression and nocturnal acid breakthrough, which has been demonstrated
in three-fourths of individuals treated with proton pump inhibitors (42). Even a short segment
of Barrett's esophagus has a malignant potential and surveillance endoscopy in recommended
(43).

Stricture
Peptic stricture is a late complication of severe GERD. It is estimated to occur in 7% to 23 %
of patients with esophagitis (44) and can develop while on medical therapy. Coexistence of
Barrett's mucosa or esophageal shortening is not uncommon. Most patients require repeated
dilatation (4.5 dilatation per year) in spite of optimal medical therapy (45). Surgical
management of peptic stricture may be challenging due to concomitant esophageal shortening
and periesophagitis increasing the likelihood of fundoplication disruption, herniation or
slippage (46). In a studies reported by Klingler et al (47), surgical therapy for strictures was
effective in relieving dysphagia and the need for dilatation after surgery decreased
approximately 8-fold, compared to the need for dilatation during medical management before
fundoplication. Moreover, dysphagia score improved significantly after surgery (p < 0.001)
and 92% of patients were satisfied with their decision to have operation. Spivac et al (48)
reported equally good results. In their study, the mean dysphagia score improved from severe
dysphagia before surgery to none after surgery (p < 0.001), at a mean follow-up of 1.5 years.
Therefore preoperative dilatation followed by fundoplication should be recommended for his
group of patients.

Adenocarcinoma
There has been a 10-fold increase in the incident of adenocarcinoma of the esophagus over
the last 30 years (49) There is a clear link between reflux symptoms and adenocarcinoma, and
GERD seems to be the major risk factor for its development (50). Among patients with
chronic and severe symptoms the odds ratio for adenocarcinoma was 43.5. The multivariate
analysis has also revealed (50), that use of medications for treatment of GERD increased the
risk of carcinoma compared to patients who did not used such medications (odds ratio 3.0,
95% CI). Conversely, some evidence exists, that surgery may offer better protection from the
progression of Barrett's metaplasia to dysplasia and carcinoma, therefore recommendation of
surgery for this group of patients seems very rational (51).
Erosive esophagitis, stricture and Barrett's esophagus, are the result of severe and longstanding GERD. Surgical treatment should be recommended for this group of patients.
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Therapy
In the only prospective randomized study comparing medical and surgical therapy for the
treatment of severe GERD, surgical therapy was shown to be significantly more effective
(52). Modern medical therapy however, seems to be highly effective in relieving symptoms,
but the need for continuous treatment, relapses, and progression of the disease while on
therapy can occur (53). It has been demonstrated that up to 82% of patients who healed
esophagitis with omeprazole will relapse within 6 months after stopping therapy (54).
McDougal et al. (55) conducted a ten-year follow-up of 101 patients diagnosed with
esophagitis on the initial endoscopy. After at least 10 years, nearly three quarters of patients
previously diagnosed as having esophagitis still had significant morbidity related to GERD
and their quality of life scores were significantly lower than normal population. With the
advances of minimally invasive surgery, operative treatment of GERD remains an attractive
and definite therapy for patients suffering from chronic GERD. Patients who are

nonresponsive to medical therapy or requiring increasing dose of proton pump inhibitors,

those with defective low esophageal sphincter, erosive esophagitis, GERD complicated by
stricture or Barrett's metaplasia, or with associated large hiatal hernia, younger patients
dependent on medical therapy, should all be offered surgical treatment (56). In a multivariate
analysis of 199 patients undergoing laparoscopic Nissen fundoplication (57), three factors
were found to be significant predictors of a successful outcome; an abnormal 24-hour pH
score, a typical primary symptom and a clinical response to acid suppression therapy. On the
other hand, the status of the low esophageal sphincter in patients with increased esophageal
acid exposure and typical GERD symptoms did not affect the successful outcome (58). This
finding is not surprising, since the predominant reflux mechanism, both in healthy controls
and in patients suffering from reflux esophagitis, was shown to be a transient low esophageal
sphincter relaxation (94% and 65% respectively). Free spontaneous reflux accounted for in
1% of reflux episodes in controls and was responsible for 18% of reflux episodes in patients
with esophagitis (59).
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Nissen Fundoplication
Since Nissen original description of fundoplication, surgery became viable option for patients
suffering from severe GERD. Initial reports of feasibility and safety of laparoscopic
fundoplication renewed interest in surgical treatment of severe reflux and increased patient
population interested in operative treatment of their disease.
Up till now, there are two prospective randomized studies comparing laparoscopic technique
with open fundoplication. In the study from Finland (60), 110 patients were randomized. In
the analysis of the results, patients from the laparoscopic group had a shorter hospital stay
(3.2 days vs. 6.4 days), less perioperative complications and better satisfaction from the
procedure (100% in the laparoscopic vs. 86% in the open group). Functional outcome in the
laparoscopic group appeared to be at least as good as in the open fundoplication with normal
postoperative pH tracing in 97% of patients from the laparoscopic group and 68% of patients
in the open group. In the recent randomized trial reported by Bias et al. (62), the authors
noted increased incidence of postoperative dysphagia in the laparoscopic group, which
prompted them to terminate the study. This study however was criticized for their design and
less than optimal experience of the participating surgeons (63).
In the review of the published literature including 2068 patients (64), laparoscopic Nissen
fundoplication proved to be an effective and safe procedure, with late postoperative
dysphagia present in 5.5% of patients and the need for postoperative dilatation in 3.5%. The
reported incidence of reoperation was 0.9% for persistent dysphagia and 0.7% for recurrent
symptoms.
Prospective data analysis of the outcome of laparoscopic fundoplication from multiple
centers confirmed safety, efficacy and high patients satisfaction approaching 99% (65, 66, 67,
68, 69, 70) among patients operated using minimally invasive techniques.
Laparoscopic fundoplication is safe and effective procedure if performed by a well trained
laparoscopic surgeon on a well diagnosed patient. There is a significant learning curve
associated with successful outcome. The best outcome from surgical treatment is expected in

patients with abnormal 24-hour pH score, a typical primary symptom and good preoperative
response to acid suppression therapy. Presence of esophagitis and defective LES do not seem
to be predictors of successful outcome.
Data suggests, that the optimal technique of fundoplication, be it laparoscopic or open, is a
short, less than 2 cm, floppy fundoplication made over size 60 esophageal dilator with
complete or near complete mobilization of the short gastric vessels and approximation of the
hiatal crura 70, 71, 72). The floppy fundoplication was shown in human cadavers to be a
completely competent antireflux valve mechanism suffering degradation before allowing
reflux (73). Longer wrap and lack of division of short gastric vessels can result in increased
rate of postoperative dysphagia (74) as a result of distortion of the wrap or lack of the
receptive LES relaxation (70). Different conclusions came from a study reported by Watson at
al. (75). In this prospective randomized trial, the authors reported no difference in the rate of
postoperative dysphagia when short gastric vessels were not divided. Laparoscopic technique,
however, should follow the principles of an open operation. The difference of the access
should not result in different functional outcome (62, 66). There is a significant learning
curve associated with the laparoscopic fundoplication (76, 77), that may affect the outcome of
studies comparing the laparoscopic and open fundoplication, if not performed by experienced
laparoscopic surgeons (62).
The outcome of laparoscopic fundoplication is as good as open surgery and with all benefits
of minimally invasive approach; shorter recovery, improved postoperative pain, decreased
complications and improved patient satisfaction. Laparoscopic Nissen fundoplication is a
gold standard for surgical treatment of GERD patient.
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Partial fundoplications
Techniques of partial fundoplication originated in the mid 60's as an alternative to Nissen
fundoplication (78). Partial wrap has a potential advantage over the total fundoplication (360
degree) of being more physiologic, allowing better receptive LES relaxation, therefore
causing less postoperative dysphagia and gas bloat (79). It appears however, that partial
fundoplications may not be as effective in controlling reflux as total fundoplication (80, 81)
particularly in patients with severe reflux disease (82). This problem becomes more
prominent when longer follow-up is available (83). Jobe et al. (84) studied 100 consecutive
patients who underwent Toupet fundoplication. Overall 51% of patients had an abnormal 24hour pH testing during 22 months follow-up including 39% of those patients who were
asymptomatic. On the other hand, partial fundoplication (Toupet being most common)
performed on selected patients with impaired esophageal body peristalsis has been shown to
provide an effective antireflux barrier, resulted in diminished postoperative dysphagia (49%
preoperatively to 10% postoperatively p < 0.01) and improved esophageal body peristalsis
(85, 86). Therefore, tailored approach to fundoplication based on careful preoperative
evaluation, particularly manometry findings, should be recommended (78,86,87). This
conclusion was not supported by Rydberg et al. (88). In a prospective randomized study
including 106 open fundoplications (Nissen-Rosseti 53 patients, Toupet 53), he found no
benefit from the tailored approach. In a review of the two, small randomized studies (98, 90),
comparing open Nissen to posterior partial fundoplication, the authors found no advantage
for either operation, thus adding more controversy to the necessity of the tailored approach.
Another randomized trial compared laparoscopic Nissen fundoplication to a stapled Toupet

fundoplication revealed no advantage of one wrap over the other (91). The retrospective
analysis reported by Kamolz et al. (92), revealed equally good improvement of the quality of
life among patients with Toupet and Nissen fundoplication.
Partial fundoplications have been shown to provide less protection against reflux compared to
Nissen fundoplication. Patients with normal esophageal body motility and those with severe
disease should be offered total fundoplication. Partial fundoplication should be reserved for
patients with poor esophageal body motility, particularly those with severe preoperative
dysphagia, or as an antireflux procedure following myotomy.
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Summary
GERD is a common disease. Symptoms of GERD are chronic and can significantly impair
quality of life. Medical treatment with proton pump inhibitors is an effective treatment, but
need for expensive lifelong therapy is usually required. Surgery is a good alternative to
prolonged medical therapy. Patients with severe and complicated GERD should be advised to
undergo surgery, which seems to give better results compared to medical therapy. Operation
corrects underlying causes of GERD; it repairs hiatal hernia, augments low esophageal
sphincter and improves gastric emptying and esophageal body motility. It creates barrier
preventing not only from acid reflux, but also from reflux of bile contents and regurgitation
of food. Therefore, surgery seems to be more effective in controlling both symptoms and
progression of the disease to its more serious form of Barrett's metaplasia and possibly
adenocarcinoma. Laparoscopic fundoplication is a gold standard for surgical treatment of
severe GERD and results in approximately 95% patients' satisfaction.

Figure 1
Proposed algorithm for surgical management of GERD patient.
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