A Mastery Approach to Complex Esophageal Diseases

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Introduction: “A Mastery Approach to Complex
Esophageal Diseases”
Over the last few decades, many concepts about esophageal surgery and the
diseases that we treat have changed dramatically. Advances in technology
and the development of new surgical and diagnostic tools have changed the
approach to esophageal diseases. Standardization of disease classification
with the adoption of the newly revised Chicago Classification in
conjunction with the widespread use of high-resolution manometry has
resulted in newer diagnostic criteria for both hypomotility disorders and
hypercontractility disorders, leading to the expansion of surgical therapy for
achalasia. New endoluminal approaches for esophageal disease, such as
POEM (per-oral endoscopic myotomy), have gained greater visibility over
the last few years, and although more knowledge and awareness of this
procedure exists, its effectiveness compared to standard techniques remains
debatable. Robotic-assisted surgeries have also grown in the field of general
surgery, and procedures like robotic-assisted Heller Myotomy are
increasingly more common. Endoscopic ultrasound and endoluminal,
laparoscopic, and thoracoscopic approaches are being utilized much more
frequently in the diagnostic approach to benign esophageal tumors.
Gastroesophageal reflux disease (GERD) remains an extremely common
gastrointestinal disease, requiring a significant portion of health care
resources for effective treatment and management. Newer treatment
modalities have been introduced for GERD, including a variety of
endoluminal devices and therapies. These have allowed for more
noninvasive approaches, including endoluminal ablation and endoscopic
mucosal resection, resulting in a significant change in the standard
treatment of Barrett esophagus. Recently, more focus has centered on the
role of anti-reflux surgery after bariatric procedures. Sleeve gastrectomy as
the bariatric surgery of choice could be a contributing factor in the rise of de
novo postsurgical GERD. This has resulted in an increased need for
revisional Roux-en-Y gastric bypass procedures and has renewed interest in
the development of new therapies for symptomatic and postsurgical GERD.
It is my distinct pleasure to have a very distinguished group of scientists
contribute to this innovative issue. The management of esophageal diseases
is complex and continually changing, and each expert has focused on
important topics that speak to us all about the ongoing challenges in the
treatment of these diseases.
Dmitry Oleynikov
P. Marco Fisichella
Contents
1 Non-operative Treatment of Gastroesophageal​Reflux Disease
Adarsh M. Thaker and V. Raman Muthusamy

2 Approach to Patients with Esophageal Dysphagia

Steven P. Bowers

3 Reoperative Surgery for Failed Antireflux Procedures

Kenan Ulualp and Jon C. Gould

4 Hiatal Hernia and Reflux Following Bariatric Surgery

Dietric L. Hennings, Patrick J. McLaren, Samer G. Mattar and
Dmitry Oleynikov

5 Approach to Esophageal Motility Disorders

Alison Goldin and Wai-Kit Lo

6 Treatment Modalities for Achalasia

Omar Y. Mousa, Bhaumik Brahmbhatt and Timothy A. Woodward

7 Paraesophageal Hernia
Gurteshwar Rana, Priscila Rodrigues Armijo, Crystal Krause and
Dmitry Oleynikov

8 Short Esophagus
Takahiro Masuda and Sumeet K. Mittal

9 Benign Esophageal Tumors

Emanuele Asti, Stefano Siboni and Luigi Bonavina

10 Minimally Invasive Esophagectomy for Benign Disease

Chase Knickerbocker and Kfir Ben-David

11 Barrett Esophagus
Vic Velanovich
12 Approach to Esophageal Strictures and Diverticula
Ciro Andolfi and P. Marco Fisichella

13 Esophageal Cancer
P. R. Boshier, A. Wirsching and Donald E. Low

Index
© Springer International Publishing AG, part of Springer Nature 2018
Dmitry Oleynikov and P. Marco Fisichella (eds.), A Mastery Approach to Complex Esophageal
Diseases, https://doi.org/10.1007/978-3-319-75795-7_1

1. Non-operative Treatment of
Gastroesophageal Reflux Disease
Adarsh M. Thaker1 and V. Raman Muthusamy1
(1) Vatche and Tamar Manoukian Division of Digestive Diseases, David
Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Adarsh M. Thaker (Corresponding author)

Email: [email protected]

V. Raman Muthusamy
Email: [email protected]

Keywords Acid reflux – Heartburn – Esophagitis – Barrett’s esophagus –

Esophageal stricture – Proton pump inhibitor

Physiology and Pathophysiology of GERD

Gastroesophageal reflux occurs when there is loss of the natural anti-reflux
barrier at the gastroesophageal junction (GEJ). Some degree of reflux is
considered physiologic, but when this process causes troublesome
symptoms and/or complications, the condition is defined as
gastroesophageal reflux disease (GERD) [1].
The fundamental mechanisms producing reflux are transient lower
esophageal sphincter relaxations (TLESRs) and decreased lower esophageal
sphincter (LES) pressure, which have been shown to occur physiologically
in asymptomatic subjects [2]. A third factor is anatomic disruption of the
GEJ, the natural antireflux barrier, which may occur due to the presence of
a hiatal hernia, scleroderma, or after myotomy for the treatment of
achalasia. Esophageal dysmotility , which can be severe in 20–30% of
patients, is associated with more severe reflux, worse mucosal injury, and
severe respiratory symptoms due to decreased clearance of refluxed
contents [3, 4]. Gastroparesis has also been linked to GERD, potentially due
to direct reflux of poorly cleared gastric contents into the esophagus or by
distension of the proximal stomach triggering TLESRs [5].
These disturbances allow abnormal acid exposure on the esophageal
mucosa, particularly in times of increased acid secretion after meals.
Despite some buffering of gastric acid by ingested food, the acid forms a
layer on top of the food in the proximal stomach, forming a so-called “acid
pocket ” which refluxes into the distal esophagus. This reservoir appears to
primarily contribute to GERD in most patients rather than acid
hypersecretion [4].
Multiple factors have been shown to decrease LES tone and/or increase
the number of TLESRs on physiologic testing. Dietary agents include fatty
foods, chocolate, coffee, tobacco, alcohol, and carminatives (such as
peppermint and other agents with essential oils) [6, 7]. Other factors
associated with increased esophageal acid exposure and symptomatic reflux
include sleep, belching, pregnancy, exogenous estrogen, certain medications
(i.e. calcium channel blockers, nitrates, muscle relaxants), and exercise [8–
12]. Obesity in particular appears to exaggerate all of the proposed
pathophysiologic mechanisms [4].

Clinical Presentation of GERD

In order to streamline clinical practice and investigations regarding GERD,
it has been divided into several clinical syndromes by the Montreal
definition and classification by consensus (Fig. 1.1). The two major
subgroups are esophageal and extraesophageal syndromes. The esophageal
syndromes include (1) symptomatic syndromes (subdivided into typical
reflux symptoms and chest pain syndrome), and (2) syndromes with
esophageal injury (esophagitis, stricture, Barrett’s Esophagus [BE], and
esophageal adenocarcinoma). The extraesophageal syndromes are
subdivided by the level of evidence supporting their association with
atypical manifestations.
Fig. 1.1 The Montreal Classification of the constituent syndromes of GERD. GERD is defined as a
condition which develops when the reflux of gastric contents causes troublesome symptoms or
complications [1]
The characteristic symptoms of typical GERD are retrosternal burning,
commonly known as “heartburn,” and regurgitation, defined as the
perception of flow of gastric contents into the mouth or hypopharynx [1].
Other symptoms attributed to GERD include angina-like chest pain,
dysphagia (especially in the presence of severe esophagitis or stricture), and
water brash (the sudden appearance of a salty or sour fluid in the mouth
from the salivary glands in response to intraesophageal acid exposure) [1,
13]. Atypical or extraesophageal manifestations of GERD may include
cough, asthma, chronic laryngitis (also called laryngopharyngeal reflux or
LPR), hoarseness, and sinusitis. However, these are felt to be multifactorial
disease processes in which reflux can be an aggravating factor, rather than
the sole cause [1]. Practical, cost-effective methods to identify the subgroup
of patients for whom GERD truly plays a causal role in these conditions or
to determine which patients may respond to acid-suppressive therapy are
still required [14–17].

Complications of GERD
Erosive esophagitis , defined as esophageal mucosal ulceration or erosion
on endoscopy, is among the most predominant complications of GERD with
a reported prevalence ranging from 6% to 30% [18]. Patients may present
with retrosternal pain, dysphagia, or anemia from chronic blood loss. It
appears to be caused by a combination of reflux of gastric contents, poor
esophageal clearance of the refluxed material, and impairment of resistance
mechanisms which protect against mucosal damage [19]. Esophagitis can
occur transiently and/or in asymptomatic patients, and is rated as severe in
20% of cases [5, 18].
A consequence of esophagitis is the development of peptic strictures
due to the deposition of collagen and scar formation, which can contract
over time and narrow the esophageal lumen. Clinically, peptic strictures can
remain asymptomatic or present as dysphagia or food bolus impaction.
They may require endoscopic dilation followed by long-term maintenance
acid-suppression to prevent recurrence [20, 21].
GERD is also an established risk factor for esophageal adenocarcinoma
and its precursor, BE, characterized by changes in the esophageal squamous
mucosa to a specialized columnar epithelium, intestinal metaplasia [22].
The prevailing belief is that malignancy develops through a series of
consecutive changes promoted by GERD, from erosive esophagitis to non-
dysplastic BE, low-grade dysplasia, high-grade dysplasia, adenocarcinoma
in situ, and invasive esophageal adenocarcinoma [22].

Diagnostic Procedures
Proton-Pump Inhibitor (PPI) Trial
GERD is diagnosed presumptively on the basis of typical symptoms of
heartburn or regurgitation, and initiation of empiric treatment with a proton
pump inhibitor (PPI) in this setting is recommended [23]. A meta-analysis
demonstrated that a response to empiric PPI therapy had a sensitivity of
78% and specificity of 54% [24]. However, the sensitivity of these
symptoms for the presence of erosive esophagitis ranges between 30% and
76% and the specificity ranges from 62% to 96% [23, 25]. Therefore, a PPI
trial is a reasonable initial step for patients presenting with typical
symptoms without alarm features but does not necessarily exclude
complicated disease or alternative diagnoses.
Upper Endoscopy
Universal endoscopy for patients with GERD is not recommended or cost
effective, as the vast majority of patients will have normal endoscopic
findings [13, 23, 26, 27]. Less than 65% of the minority of patients who do
undergo upper endoscopy were shown to have abnormal findings [18, 23].
Relative to the prevalence of GERD in the population, the prevalence of
clinically significant findings which would alter the clinical course or
management of these patients is low.
The indications for upper endoscopy in GERD (Table 1.1) are under
continued debate, with slightly varying recommendations from society
guidelines [23, 26–28]. Endoscopy is generally recommended on initial
presentation for patients presenting with alarm features suggestive of
complicated disease, such as stricture, esophagitis, or malignancy. The
alarm features include dysphagia, odynophagia, bleeding, involuntary
weight loss, epigastric mass, recurrent vomiting, or anemia [23, 26–29].
Table 1.1 Indications for endoscopy in patients with GERD [23, 26]
Non-response twice daily PPI trial for 4–8 weeks
Dysphagia or odynophagia
Involuntary weight loss
Evidence of GI bleeding or anemia
Palpable mass on physical exam or finding of mass, ulcer, or stricture on imaging study
Persistent vomiting (7–10 days)
Screening for Barrett’s esophagus in selected patients, if clinically indicated, including as follow-up
of treated erosive esophagitis
Evaluation before or for recurrent symptoms after antireflux procedures
Placement of wireless pH monitoring

Endoscopy is also indicated for patients with persistent or progressive

GERD symptoms despite appropriate medical therapy (i.e. 4–8 weeks of
twice-daily empiric PPI therapy taken appropriately) [26, 27]. Routine
esophageal biopsies are not recommended specifically to diagnose GERD
but are recommended to evaluate for complications of GERD, such as
suspected BE, dysplasia, or malignancy [23]. Biopsies are also suggested to
evaluate for eosinophilic esophagitis (EoE) in patients presenting with
dysphagia, even with a normal endoscopy, although a subset of such
patients may have an overlap with GERD and respond to PPI treatment,
thereby termed, PPI-responsive EoE (PPI-REE) [23, 28].
Upper endoscopy is indicated as a screening test for BE in men with
chronic GERD (>5 years) and/or at least weekly symptoms with two or
more risk factors for BE or esophageal adenocarcinoma including: Age
>50 years, Caucasian race, central obesity, current or past history of
smoking, and a confirmed family history of BE or esophageal
adenocarcinoma in a first-degree relative [30]. Endoscopy is also indicated
in patients who have erosive esophagitis on a prior endoscopy after a period
of twice daily PPI therapy since BE can be identified in as many as 12% of
these patients after healing [26, 31]. Finally, endoscopy is often performed
for preoperative evaluation in patients being considered for anti-reflux
surgery or for wireless esophageal pH monitoring [26].
There is little data to support endoscopy in the evaluation for GERD
without alarm features, for extra-esophageal manifestations, or for BE
screening in women due to the low prevalence of significant findings [26].

pH and Impedance Testing

In addition to upper endoscopy, patients who fail twice daily PPI dosing
should undergo esophageal pH testing in order to verify the diagnosis and to
assess for possible causes for refractory symptoms. This can be performed
via ambulatory intranasal catheter (with or without impedance testing ) or
wireless pH probe monitoring with a portable data recorder for patients to
record symptom events. This allows for providers to establish symptom-
reflux association through validated parameters such as the Symptom Index
and the Symptom Association Probability [32].
Multichannel intraluminal impedance (MII) , which when combined
with pH testing (MII-pH), enables detection of gastroesophageal reflux of
both acid and nonacid contents [32, 33]. Impedance measures resistance to
electrical current flow between metallic rings mounted on a catheter and
decreases in the presence of refluxed gastric liquid, which has good
electrical conductance. Measurement of impedance at multiple sites (i.e.
using a multichannel catheter) over time allows for the establishment of
bolus flow directionality, including the proximal reflux of gastric contents
into the esophagus [32, 33]. Coupled with pH measurements, impedance
testing helps clarify (1) whether the recorded pH change represents
retrograde bolus (reflux) or anterograde bolus (ingested food), (2) whether
reflux events are associated with symptom events, and (3) whether the
refluxed contents represent acid or non-acid (alkaline) reflux [32].
Whether to perform pH testing on or off PPI therapy is an important
initial decision in planning the study. It depends on the clinical presentation
and the question to be answered. Except in specific circumstances, pH
testing should be performed off therapy (with PPI discontinued for at least
7 days preceding the study) since most validation studies on pH monitoring
were performed under this condition [32]. Impedance-pH testing on
medications also does not reliably confirm the presence of GERD in
patients referred for antireflux surgery, so it is recommended these patients
undergo testing off treatment [34].
Testing off PPI is primarily used to verify the diagnosis of GERD since
it reflects the natural esophageal acid exposure without interference from
treatment. This also results in more symptoms and therefore a higher yield
of symptom-reflux associations [32]. Testing on PPI is indicated for patients
with obvious evidence of acid reflux, such as severe esophagitis, peptic
stricture, BE, or prior positive pH testing , to evaluate for ongoing acid or
non-acid reflux to assess for treatment failure [32]. A third alternative is the
96 h wireless pH study, beginning with 48 h off treatment to verify the
diagnosis of GERD followed by 48 h on treatment to evaluate whether
breakthrough acid exposure despite PPI explains their symptoms [35].

Mucosal Impedance
Mucosal impedance (MI) is a promising new technology to aid in the
diagnosis of GERD and assessment of treatment response. The MI catheter
is applied to the esophageal mucosa during endoscopy for immediate and
rapid measurement. MI is related to the presence of dilated intercellular
spaces (DIS), a histologic feature of GERD which affects para-cellular
permeability. Increased permeability results in decreased MI [33].
Preliminary testing has shown that MI can differentiate GERD (with or
without esophagitis) from EoE and non-GERD related conditions
(including normal esophagus and achalasia). MI has been shown to have a
superior specificity for GERD compared to pH monitoring (95% vs. 64%)
as well as a superior positive predictive value (96% vs. 40%) with a similar
sensitivity and negative predictive value [33, 36].
 MI technology obtains information more rapidly than ambulatory pH
testing and may serve as a better reflection of chronic disease in its
correlation with histologic changes rather than isolated events. Impedance
values recover to normal in patients with GERD after PPI therapy,
suggesting MI can be used to monitor acid suppression and treatment
response. It may also be useful to predict likely responders to anti-reflux
procedures. Finally, it may help clarify whether a patient’s extraesophageal
symptoms are truly reflux related [33]. Larger validation studies and wider
availability of this nascent technology are eagerly awaited.

Radiographs
Imaging with barium esophagram can be helpful in patients with dysphagia
to evaluate for stricture, but due to its poor sensitivity for reflux or
esophagitis, it is not recommended as a diagnostic test in GERD [30].

Management of GERD
Lifestyle Modifications
Lifestyle modifications suggested for GERD include dietary and behavioral
changes. Avoidance of foods and substances that can cause reflux episodes
or (e.g. chocolate, coffee, tobacco, alcohol, peppermint, carbonated
beverages) or those that can produce symptoms (e.g. citrus and tomato
products, spicy foods) is often suggested [37]. Behavioral modifications
include weight loss, smoking cessation, avoiding large meals, avoiding
recumbence right after meals, and head of bed elevation [37]. However, the
data supporting each of these practices is mixed, especially for patients with
frequent or severe symptoms. On systematic review, the strongest evidence
supports weight loss and head of bed elevation, although smoking cessation
is recommended for its global health benefits as well [37]. Universal
application of these lifestyle measures are not practical, particularly without
a sacrifice in quality of life. It is therefore recommended that specific
lifestyle modifications are tailored to individual patients instead of global
implementation (e.g. weight loss for overweight or obese patients; head of
bed elevation for patients with symptoms when recumbent; or identification
and avoidance of specific trigger foods rather than a full elimination diet)
[28, 37].
Antacids, Mucosal Protectants, and Prokinetic Agents
Antacids such as sodium bicarbonate, magnesium hydroxide, aluminum
hydroxide, and calcium carbonate can provide symptom relief by
neutralizing intragastric acid. They have the most rapid onset of action of
GERD treatments. However, due to their short duration of action and the
risks of excess use (e.g. milk-alkali syndrome from calcium carbonate),
direct antacids are generally reserved for on-demand treatment in patients
with mild and infrequent symptoms [28].
Sucralfate (sucrose-aluminum sulfate) is a mucosal protectant believed
to reduce symptoms by decreasing esophageal acid exposure. Sucralfate’s
short duration of action and lower efficacy compared to anti-secretory
agents limits its use. It appears to be useful as a first line agent with or
without antacids for mild intermittent symptoms in women who are
pregnant or lactating [38]. There does not appear to be a role for sucralfate
in the non-pregnant GERD patient [23].
Alginate (sodium alginate) is a seaweed based agent which forms a gel
raft in the proximal stomach on top of an ingested meal, co-localizing with
the acid pocket. This creates a barrier that prevents the acid from reaching
the esophagus and thereby reduces acid-related injury and symptoms [39].
Alginate appears to be less effective than PPIs and H2RAs, but more
effective than antacids [40]. It also appears to be more effective as
combination therapy with H2RAs compared to H2RAs alone which makes
it potentially useful to patients who are intolerant or averse to PPIs but
ineffectively treated with H2RAs alone [39].
Prokinetics such as metoclopramide are associated with increased
adverse events and do not have a role in the management of GERD except
transiently if there is concomitant gastroparesis. Metoclopramide has a
black box warning for tardive dyskinesia and treatment greater than
12 weeks should be avoided. Another agent not commercially available in
the United States is domperidone, which is associated with QT prolongation
and cardiac arrhythmias [23].

Histamine 2 Receptor Antagonists

Histamine 2 receptor antagonists (H2RAs) or “H2-blockers” (i.e.
cimetidine, ranitidine, famotidine) reduce acid secretion from parietal cells
by inhibiting activation by histamine, which is released in a paracrine
fashion by nearby enterochromaffin-like cells [41]. The principle limitation
of H2RAs as maintenance therapy for GERD is the development of
tolerance (tachyphylaxis) as early as 1–2 weeks of therapy in some patients
[42–44]. H2RAs also have limited efficacy in healing erosive esophagitis
compared with PPIs [45]. Therefore, they are generally suggested for short-
duration or as-needed treatment for patients with mild, intermittent
symptoms and no esophageal complications. H2RAs can also be considered
as maintenance therapy for the subset of patients without erosive disease
who experience heartburn relief without tachyphylaxis [23].
H2RAs are commonly added at bedtime to patients with persistent or
nocturnal symptoms despite twice daily PPI dosing. This has been shown
physiologically to further improve nocturnal gastric acid levels or
breakthrough in patients already twice-daily PPI doses [42, 46]. However,
this practice has been called into question because improved nocturnal
gastric acid levels do not necessarily result in decreased esophageal acid
exposure and these studies did not address the development of tolerance to
H2RAs [47]. Acid suppression with the addition of nocturnal H2RAs was
found to decrease significantly after only 1 week of therapy and fell to pre-
H2RA levels after 1 month of therapy due to tolerance [44]. However, for
unexplained reasons, some patients maintained some degree of improved
acid control chronically [44, 47]. Therefore, a small subset of patients may
potentially benefit from nocturnal H2RA in combination with twice daily
PPI but it is not recommended as a standard approach. Furthermore,
patients who do not respond to twice daily PPI should be considered for
additional diagnostic evaluations rather than relying on H2RA addition as
an extended therapeutic trial.

Proton Pump Inhibitors

Proton pump inhibitors (PPIs) inhibit gastric acid secretion by selectively
inactivating the H+/K+ ATPase “proton pump” on parietal cells. PPIs are
prodrugs which require acid activation, absorption into the bloodstream,
and active proton pumps in order to bind to them and exert their effects.
They covalently bind to active proton pumps for a longer duration of effect,
but their bloodstream half-life is relatively short (~90–120 min). PPIs
therefore achieve maximum efficacy when the peak bloodstream
concentration coincides with activation of proton pumps during a meal
(especially a protein meal). For this reason, most PPIs are ideally taken
before meals. On one hand, acid suppression by PPIs is increased in the
setting of a meal when compared to the fasting state [48]. On the other
hand, the absorption and bioavailability of PPIs are diminished when they
are administered at the same time as a meal [49]. PPIs are therefore
recommended to be taken in a relatively narrow window of time, ideally
30–60 min prior to a meal, in order to achieve maximum acid suppression
[23].
A newer PPI dexlansoprazole provides an exception to the need for
meal timing adherence. It has a dual-delayed release formulation using two
sets of enteric coated capsules designed to maintain bloodstream
concentrations for longer periods of time [49]. This medication can
therefore be given irrespective of meals or the timing of meals. Another
agent known as VECAM is a combination of omeprazole and succinic acid,
which was shown to induce gastric acid secretion. The addition of succinic
acid thereby eliminates the need for a subsequent meal after taking the PPI
and appeared to be more effective than omeprazole alone in a preclinical
study [50].
PPIs are highly effective in the management of GERD and its
complications. PPIs are associated with superior healing rates and
decreased relapse rates for erosive esophagitis compared to H2RAs (84%
vs. 52%) [23, 51]. For non-erosive reflux disease, PPIs have demonstrated
superiority over H2RAs for heartburn relief with a relative risk for
heartburn remission of 0.66 (95% confidence interval [CI] 0.60–0.73) on
direct comparison [52].
In a review of clinical studies , the relative potencies of PPIs based on
mean 24 h gastric pH compared to omeprazole were 0.23, 0.90, 1.0, 1.60,
and 1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole, and
rabeprazole, respectively [53]. Despite the differences in potency and
statistical evidence of superiority of some agents over others, symptom
relief among the PPIs appears to be similar and the clinical significance of
other differences is minimal [54]. There is limited but inconsistent evidence
to support the use of one PPI over another for erosive esophagitis, but the
relative potencies can be taken into consideration for PPI selection for
patients with refractory symptoms or inflammation [4, 55, 56].
Initial PPI therapy for most patients with typical reflux should start with
once daily dosing, taken before the first meal of the day. For patients with