Pathophysiology 25 (2018) 1–11

Contents lists available at ScienceDirect

Pathophysiology
journal homepage: www.elsevier.com/locate/pathophys

Review

Gastroesophageal reflux disease: A clinical overview for primary care

physicians
Sudha Pandit a , Moheb Boktor a , Jonathan S. Alexander b , Felix Becker c , James Morris a,∗
a
Department of Medicine, Section of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center, School of Medicine, Shreveport,
LA, United States
b
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, School of Medicine, Shreveport, LA,United States
c
Department for General and Visceral Surgery, University Hospital Muenster, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Objective: GERD is among the most common outpatient disease processes encountered by clinicians on a
Received 10 April 2017 daily basis. This review provides insights about how to approach GERD in terms of disease management
Received in revised form 26 August 2017 and treatment.
Accepted 7 September 2017
Methods: Review articles were searched using PUBMED and MEDLINE using criteria that included English
language articles published in the last 5 years concerning studies carried out only in humans. The
key words used in the searches were GERD, PPI, and erosive esophagitis. Recommendations from the
American College of Gastroenterology are also included in this manuscript.
Results: The search resulted in ∼260 articles. The manuscript brings together and presents the results of
recent recommendations from professional societies and recently published review articles on GERD.
Conclusion: GERD is one of the most common diagnoses made by gastroenterologists and primary care
physicians. It is important to recognize the typical and atypical presentations of GERD. This paper helps
primary care physicians understand the disease’s pathophysiology, and when, how, and with what to
treat GERD before referring patients to gastroenterologists or surgeons.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Clinical manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. Pathophysiology and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
5. Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
6. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
7. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
8. Non-pharmacologic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
9. Pharmacologic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
10. Comparing H2RA AND PPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
11. Comparing PPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
12. Refractory GERD and resistance to PPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
13. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
14. Adverse effects associated with PPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Abbreviations: GERD, gastroesophageal reflux disease; NERD, non-erosive disease; ERD, erosive disease; LES, lower esophageal sphincter; PPI, proton pump inhibitor;
H2RA, histamine receptor antagonists; ATPase, adenosine 5 triphosphatase; EE, erosive esophagitis; NNT, number needed to treat; QOL, quality of life; GABA, ␥-aminobutyric
acid; EoE, eosinophilic esophagitis; ENT, ear, nose and throat; LINX, trade mark.
∗ Corresponding author.
E-mail address: Jmorri2@lsuhsc.edu (J. Morris).

https://doi.org/10.1016/j.pathophys.2017.09.001
0928-4680/© 2017 Elsevier B.V. All rights reserved.
2 S. Pandit et al. / Pathophysiology 25 (2018) 1–11

15. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Grant support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1. Definition 3. Clinical manifestation

Gastroesophageal reflux disease (GERD) is one of the most The cardinal symptoms of GERD are troublesome heartburn and
common diagnoses made by both primary care physicians and gas- or regurgitation [11]. Heartburn is caused by the contact of refluxed
troenterologists [1]. material with the sensitized or ulcerated esophageal mucosa and
The Montreal Classification provides the most recent consen- perceived as burning behind the breast bone or retrosternal area
sus definition of GERD. It defines GERD as heartburn symptoms whereas regurgitation is sensing the gastric content into the oral
or complications resulting from the reflux of gastric contents into cavity [87]. Heartburn mostly occurs during the postprandial state
the esophagus, up to the oral cavity, and lungs [4]. GERD is fur- [4]. Persistent heartburn causes esophagitis, which manifests as
ther classified into two subgroups. The first subgroup is GERD with dysphagia and is suggestive of peptic stricture. Dysphagia has
heartburn symptoms but without endoscopic evidence of mucosal been noted as the sole presentation of GERD in one-third of the
erosions (Non-Erosive Reflux Disease or NERD). The second sub- patients [10]. GERD can manifest as either esophageal or extra-
group is GERD with heartburn symptoms accompanied by objective esophageal symptoms [87]. Esophageal or typical symptoms of
evidence of erosions (Erosive Reflux Disease or ERD) [5]. GERD are heartburn, regurgitation, and chest pain or epigastric
Functional heart burn also falls under endoscopic negative dis- pain while extra-esophageal symptoms or atypical presentations
ease, however it is important to note that it is a distinct entity from are cough, laryngitis, asthma and dental erosion syndromes [87].
NERD. NERD is defined as typical reflux symptoms without evi- Furthermore, according to Montreal definition of GERD, without
dence of reflux disease in endoscopy but abnormal acid exposure symptoms of heartburn and or regurgitation, there is no causal rela-
on the impedance-pH monitoring and is responsive to PPI. [84,85]. tionship between GERD and unexplained asthma and laryngitis. In
Functional heart burn on the other hand, as defined by Rome IV clas- addition to this, typical GERD symptoms can develop after exer-
sification, is a retrosternal burning discomfort or pain refractory to cise [86]. Some patients who complain of poor sleep are found to
anti-secretory therapy without presence of GERD, histopathologic have heartburn and regurgitation at night time or during their sleep
abnormality, motility disorder or structural abnormality for at least [87]. It is not clear if symptoms of odynophagia, water brash, hyper
three months with symptoms onset at least six months prior to the salivation and globus sensation are directly related to GERD [12,87].
diagnosis. [86]

2. Epidemiology
4. Pathophysiology and risk factors
In ambulatory care settings, GERD accounts for 17.5% of all
digestive diseases recorded [2]. Sandler et al. reported that the Reflux can be both physiologic and pathologic [1]. Physiologic
annual incidence of GERD as the primary diagnosis by primary care reflux mostly occurs during the postprandial state, is transient, does
providers in the United States was 4.6 million [3]. This number not occur during sleep, and does not result in reflux symptoms
would rise as high as 9.1 million when considering GERD among [1]. The pathologic reflux is related to transient loss of pressure
the top three diagnoses during those encounters. GERD has a signif- in the lower esophageal sphincter (LES) [10,29]. Transient loss of
icant impact on both direct and indirect healthcare costs. The direct pressure in the LES is diagnosed when persistent LES relaxation
cost include office visits, diagnostic tests, treatments and hospital occurs, lasting more than 10 s, with the absence of swallow within
admissions, representing 9.3 billion dollars of the total amount of 4 s before and 2 s after the onset of the event, and presence of active
money spent on health care in the United States [3]. The indirect crural diaphragm inhibition [87,88]. Lower esophageal sphincter
cost include missed work, decreased productivity while at work (LES) tone and activity of crural diaphragm maintains the gastroe-
due to GERD related symptoms, and impaired daily living activities sophageal junction (GEJ) pressure, in turn LES tone is maintained by
[3]. the activity of neurotransmitters released by vagus nerve and by the
Estimates of the prevalence of GERD are primarily based on the stimulation of enteric nervous system [87–89]. LES relaxes as a neu-
presence of heartburn and/or acid regurgitation symptoms [6–8]. rogenic reflex in response to swallowing food leading to increased
However, heartburn or acid regurgitation symptoms are not always intra-gastric pressure and volume [90]. Various risk factors have
present in patients with endoscopic evidence of esophagitis or been attributed to transient hypotension of the LES, such as diet and
Barrett’s esophagus [9]. A recent systematic review of 16 epidemi- lifestyle (smoking, alcohol), abdominal obesity, infiltrative disease
ological studies found the prevalence of GERD to be 18.1% − 27.8% (e.g. scleroderma), myopathy associated with chronic intestinal
in North America, 8.8% − 25.9% in Europe, 2.5% − 7.8% in East Asia, pseudo-obstruction, medications (anticholinergics, smooth mus-
8.7% to 33.1% in the Middle East, 11.6% in Australia and 23% in South cle relaxants such as ␤-adrenergic agents, aminophylline, nitrates,
America [7]. Two different population studies from the UK and the calcium channel blockers, and phosphodiesterase inhibitors), sur-
USA, showed the incidence of GERD to be around 5 per 1000 person gical damage to the LES, and esophagitis [10,15]. Among these risk
years [7]. Another population based survey from the United States factors, obesity accounts for 50–70% of patients with reflux symp-
found that up to 22% of the participating population reported heart- toms, and 15% of the obese patients also have hiatus hernia (HH)
burn symptoms, while 16% reported acid regurgitation. Heartburn [83]. The mechanism related to development of reflux symptoms
and regurgitation was considered clinically significant if symptoms in obese patients is thought to be secondary to chronic increased
occur at least twice weekly, which were present in 6% and 3% intra-abdominal pressure, which in turn results in an ineffective
respectively [8]. LES, delayed gastric emptying, and HH [84].
 S. Pandit et al. / Pathophysiology 25 (2018) 1–11 3

Fig. 1. Los Angeles Classification of GERD. Grade A − one or more mucosal breaks each ≤5 mm in length. Grade B − at least one mucosal break >5 mm long, but not
continuous between the tops of adjacent mucosal folds. Grade C − at least one mucosal break that is continuous between the tops of adjacent mucosal folds, but which is
not circumferential. Grade D − mucosal break that involves at least three-fourths of the luminal circumference.

5. Complications epithelium of distal esophagus is replaced by metaplastic colum-

The various complications of GERD described in the literature
are divided into three broad categories: esophagitis, peptic stric-
ture, and Barrett’s esophagus (the last two are consequences of long
standing esophagitis) [10,13]. Esophagitis is caused by constant irri-
tation of the mucosal surface of the esophagus and subsequent loss
of the defense mechanisms against injuries caused by acid, pepsin,
and bile [10]. Esophagitis can be observed as a direct visualization
in upper endoscopy and/or at the cellular level. Most current guide-
lines recommend that the Los Angeles classification system (Fig. 1)
should be used to describe the endoscopic appearance of the erosive
esophagitis [11] and are demonstrated histologically in Fig. 2.
The histologic changes seen in erosive esophagitis include poly-
morphonuclear or mild eosinophilic infiltrates and granulation
tissues [10,16]. Peptic strictures result from fibrosis, causing lumi-
nal constriction during the process of healing from ulcerative
esophagitis [10,13]. The presence of granular or nodular pattern in
the distal third of the esophagus is consistent with reflux esophagi-
tis with luminal irregularities, which suggests esophagitis [13,17]
(Fig. 3).
One study showed the presence of microscopic esophagitis and
dilation of intercellular spaces as the hallmark histological changes
that is seen in GERD and NERD [14], which is absent in functional
heartburn [91].
One of the major complications of prolonged reflux esophagitis
is Barrett’s Esophagus (BE). It is a condition when normal Squamous
nar mucosa, which predisposes to esophageal adenocarcinoma
(EAC) [92]. The American College of Gastroenterology recommends
screening for BE in patients with certain risk factors. These include
Caucasian male age >50 years with current or past history of smok-
ing, patients with chronic ( > 5 years) weekly or more frequent
symptoms of heartburn and regurgitation, patients with central
obesity, and patients with family history of BE or EAC [93]. Endo-
scopically BE is diagnosed when there is extension of salmon
color mucosa ≥1 cm into the distal esophagus proximal to GEJ,
with histologic presence of intestinal metaplasia with goblet cells,
(the presence of goblet cell is not a requirement in United King-
dom) [93]. The American College of Gastroenterology recommends
that BE with low grade dysplasia can be treated endoscopically or
surveillance EGD can be performed in one year, whereas BE with
high-grade dysplasia should be treated endoscopically [93]. All BE
patients should receive Proton Pump Inhibitor (PPI) orally once
daily for acid suppression [93].
6. Diagnosis
When patients present with the typical symptoms of heartburn
and regurgitation, no diagnostic tests are necessary to make a pre-
sumptive diagnosis of GERD [5,10], and it is recommended that a
trial PPI therapy be initiated with once daily dosing for at least eight
weeks [33]. Resolution of symptoms or response to therapy con-
firms the diagnosis of GERD. However, one meta-analysis revealed
4 S. Pandit et al. / Pathophysiology 25 (2018) 1–11

Fig. 2. Progressive histological changes seen in mild and erosive esophagitis A − Normal esophagus histology; B − Increased basilar layer thickness and papillary elongation
of noncornified stratified squamous cells; C − Increased fibrosis in papillary stricture.

Fig. 3. Complications of Erosive Esophagitis. Endoscopic (A) and Histologic (B) findings in peptic stricture as a complication of prolonged erosive esophagitis from GERD.

several limitations of the PPI trial approach, including low sen-
sitivity (78%) and specificity (54%) [18]. It is a common belief in
the day-to-day practice of medicine that symptoms such as heart-
burn and regurgitation are the most sensitive and reliable tools to
make the presumptive diagnosis of GERD; however, one systematic
review of seven studies found the sensitivity to be only 30–76% and
the specificity to be 62–96% when the symptoms of heartburn and
regurgitation both occurred in the presence of erosive esophagitis
[19].
Regurgitation related to GERD is different from rumination syn-
drome, which is a type of functional GI disorder [94]. According
to Rome IV classification, rumination syndrome is diagnosed when
recently ingested food is regurgitated into mouth and subsequent
spitting or remasticating and swallowing in the absence of retching,
lasting for 3 months with symptom present at least 6 months prior
to the diagnosis [94]. Manometry with impedance can be used as a
diagnostic tool to differentiate regurgitation related to GERD from
rumination syndrome [26].
Various diagnostic tests and radiographic studies are indicated
when patients fail to respond to the initial PPI trial as mentioned
above, or to look for complications of GERD, such as peptic stricture,
Barrett’s metaplasia, or EAC [5,10,15], especially when alarming
symptoms (odynophagia, dysphagia, unintentional weight loss,
anemia) are present. Other important diagnostic alternatives that
are important to rule out are coronary artery disease, peptic ulcer
disease, esophageal motility disorders, esophagitis (eosinophilic,
infectious, and pill), and gall bladder disease [5].
As mentioned previously, chest pain is one of the most common
and, occasionally, the only initial presenting symptom of GERD.
Thus, it is strongly recommended that cardiac causes of chest
pain be excluded before initiating a PPI trial or gastroenterologi-
cal workup [15]. One meta-analysis study found that when cardiac
causes of chest pain were excluded, treatment with PPI (sometimes
 S. Pandit et al. / Pathophysiology 25 (2018) 1–11
at a higher dose) could be cost effective and efficacious as well
[20]. The use of oral barium is not recommended to diagnose GERD
unless patients present with symptoms of dysphagia [21], because
while technically well performed double contrast barium esopha-
grams can diagnose esophagitis, the technique lacks sensitivity
[22]. Upper endoscopy has been recommended if patients present
with alarming symptoms such as those mentioned as above, and
to screen for BE in high risk patients, such as overweight white
males, those with chronic heartburn and regurgitation symptoms
[23], and non-cardiac chest pain with negative cardiac workup and
failed PPI trial therapy. Esophageal biopsy is not recommended to
diagnose GERD on a routine basis, as obtaining biopsies from the
esophagogastric junction has not provided any added benefit [24].
However, esophageal biopsy is recommended to rule out causes
for heartburn symptoms other than GERD [5]. Esophageal manom-
etry is only indicated preoperatively when evaluating a patient
for anti-reflux surgery [5], as certain conditions, e.g. scleroderma-
like esophagus and achalasia, could be contraindicative for surgery.
Ambulatory reflux monitoring or impedance pH is indicated in
patients with persistent symptoms but negative endoscopic find-
ings, and also in those who have twice failed a daily PPI trial [25].
Ambulatory esophageal pH monitoring helps to identify abnormal
acid exposure, the quantity, frequency, and symptoms associated
with reflux episodes [5]. According to a recently published review
article from Porto consensus by Roman and Gyawali et al., patients
who are resistant to the treatment of optimal dose of PPI, does
not have endoscopic features of LA Grade C or D esophagitis or
peptic stricture or BE, or have atypical symptoms or resistant
symptoms after anti-reflux surgery, catheter based or wireless pH
monitoring or 24 h pH-impedance monitoring should be used to
diagnose reflux acid exposure. [26]. The pH-impedance monitoring
can distinguish acidic (pH ≤ 4), weakly acidic (4 ≤ pH ≤ 7), weakly
alkaline (pH ≤ 7), gaseous and re-reflux episodes [95–97]. It is rec-
ommended that patients presenting with typical GERD symptom
should be tested and treated for Helicobacter pylori infection [27].
7. Management
Gastroesophageal reflux disease can be managed by using
non-pharmacologic, pharmacologic, endoscopic, and surgical inter-
ventions.
8. Non-pharmacologic intervention
Changes in dietary habits and life style modifications are ini-
tial steps in the management of GERD symptoms. It is important
to counsel patients to avoid certain foods in their diets that can
aggravate reflux symptoms. Although conventional symptoms of
heartburn are associated with consumption of foods which have
caffeine or theobromine e.g. coffee, chocolate, spicy foods, highly
acidic foods, citrus fruits, and fatty foods. However, so far no clini-
cal trials have been performed which definitively demonstrate that
removing such foods from the diet leads to symptom relief. Patients
consuming alcohol and tobacco usually have prolonged acid expo-
sure time, as both have been shown to decrease lower esophageal
sphincter pressure [28]. Decreased salivation has been found in
smokers [28]. However, since the literature lacks studies provid-
ing strong evidence in support of a decrease in heartburn and/or
reflux symptoms after removing the aforementioned foods from
the diet, counseling patients to eliminate these foods from their
diets is recommended only in those who obtain symptomatic relief
from doing so. In patients who have nocturnal GERD symptoms,
such as cough, hoarseness, and constant throat clearing, elevation
of the head of the bed (using 6–8 inch blocks under the legs of the
bed, and wedged foam under the mattress), lying in the left lateral
5
decubitus position, and avoiding the consumption of meals 2–3 h
before bedtime have been shown to improve esophageal pH values
and GERD symptoms [5,28]. Another anti-reflux measure that has
been shown to improve GERD symptoms is to wear loosely fitted
garments, which will prevent an increase in intra-gastric pressure
and the gastroesophageal pressure gradient [30].
One of the most important lifestyle modifications in reducing
GERD symptoms is to lose weight. One large case study showed
that reduction of the body mass index by 3.5% resulted in a 40%
reduction in the frequency of GERD symptoms when compared
with those of controls [31,98].
9. Pharmacologic intervention
Medical management is initiated in patients who have persis-
tent GERD symptoms despite dietary and lifestyle modifications.
The main medical therapies available include antacids, surface
agents and alginates, histamine receptor antagonists (H2RA), and
PPI.
Antacids are agents that do not prevent GERD symptoms but
instead neutralize already secreted acid content in the stomach
and prevent the esophageal mucosa from coming in contact with
refluxed acid. For this reason, antacids are used only in patients
with mild GERD symptoms (occurring once or less than once a
week), or as breakthrough agents in patients taking H2RA or PPI
[32]. Currently available antacids are combinations of calcium car-
bonate, magnesium trisilicate, and aluminum hydroxide. The onset
of action of antacids is quick, within 5 min, and the effects last
30–60 min [33]. Surface agents, such as aluminum sucrose sulfate,
work by adhering to the mucosal surface, preventing acid expo-
sure and promoting healing of the injured mucosa [33], but are
used less frequently because of their lower efficacy and short half-
lives. Alginates, e.g. sodium alginate, are anionic polysaccharides
found in the cell wall of brown algae, which when combined with
water, form a viscous gum-like substance. This gum-like material
floats in the stomach, absorbing post-prandially secreted acid, thus
preventing acid reflux [34]. A recent systemic review and meta-
analysis found that alginates are superior to placebo and antacids
to improve GERD symptoms. However, when compared to PPI and
H2RA, alginates were less effective [34]. A randomized controlled
trial, done by Coyle and Crawford, suggested that alginate-antacid
combination therapy taken along with PPI helped to control break-
through symptoms of GERD or refractory GERD [99]. Of note, similar
improvement was seen in the placebo group as well [100]. Thus, it is
important to note that Alginate based therapy should be prescribed
on case by case basis.
H2RA work by competitively blocking H2 receptors in gastric
parietal cells and preventing histamine stimulated gastric acid
secretion. H2RA are not used as a maintenance therapy as they lead
to the development of tachyphylaxis within 2–6 weeks of treat-
ment [35]. When compared with antacids and placebos, H2RA are
superior in reducing the frequency and severity of GERD symptoms
[33].
PPI binds to the H+/K+ (hydrogen and potassium) exchanging
ATPase pump (proton pump) in gastric parietal cells, prevent-
ing acid secretion, which is the final combined pathway for acid
secretion. PPIs were historically mostly used in patients whose
symptoms who did not improve on a twice daily dose of H2RA,
but now obtain PPIs over the counter regularly as initial therapy
[33]. Patients who have evidence of erosive esophagitis (EE) and
frequent heartburn symptoms (2 or more episodes per week) ben-
efit more from using PPI than from using H2RA [33]. Therapy with
PPI is started at initial standard dose (Table 1 ) for 8 weeks along
with modifications in diet and lifestyle. To increase the effective-
ness of treatment, it is recommended that PPIs be taken 30 min
6 S. Pandit et al. / Pathophysiology 25 (2018) 1–11

Table 1
Currently available H2RA and PPI with standards and market status.

Standard dose Comments

H2RA
• Cimetidine 400 mg twice daily - All H2RA are available over the counter
• Ranitidine 150 mg twice daily - Dose adjustment is recommended for all H2RA
• Nizatidine 150 mg twice daily - Omeprazole, Pantoprazole, Esomeprazole, and Dexlansoprazole are prescription medications
• Famotidine 20 mg twice daily

PPI
• Omeprazole 40 mg daily
• Pantoprazole 40 mg daily
• Esomeprazole 40 mg daily
• Lansoprazole 30 mg daily
• Dexlansoprazole 30 mg, 60 mg daily
• Rabeprazole 20 mg daily
• Omeprazole-sodium bicarbonate

H2RA − Histamine Receptor Antagonists.

PPI − proton pump inhibitors.

before breakfast, as the number of H+/K+ ATPase pumps in pari-
etal cells has been found to be higher in number after prolonged
fasting [36]. In patients with EE, studies have shown that results
obtained with PPI are superior when compared to those of H2RA
and placebo with respect to the resolution of symptoms and healing
of esophagitis [37].
10. Comparing H2RA AND PPI
There have been multiple studies done to evaluate the efficacy
of treatment with either H2RA or PPI in the past. The superiority
of PPI in healing EE and a decreased rate of relapse following their
use compared to that of H2RA has been well established for a long
period of time.
A. Healing EE
A meta-analysis was done in 1997 comparing the uses of PPI,
H2RA, sucralfate, and placebo in the treatment and healing of ero-
sive esophagitis (EE) [38].
i) PPI was found to be superior in healing all grades of EE, regard-
less of dosage or duration of therapy [38]. The means and standard
deviations obtained from the study were PPI (84% ± 11%), H2RA
(52% ± 17%), sucralfate (39% ± 22%), and placebo (28% ± 16%).
ii) PPI use led to a faster rate of healing of EE: PPI (12% per week),
H2RA (6% per week), and placebo (3% per week)
B. Resolution of and relief from heartburn symptoms
The same meta-analysis trial mentioned above also showed that
treatment with PPI provided quicker and more complete relief
from heartburn symptoms (11.5% per week) compared with H2RA
(6.4% per week) [38]. In addition, the mean proportion of patients
who received symptomatic relief was higher in the PPI group
(77.4% ± 10.4%) vs. the H2RA group (47.6% ± 15.5%).
C. Resolution of heartburn symptoms in patients with and with-
out evidence of esophagitis i.e. (ERD vs. NERD)
PPIs were found to provide a greater degree of symptoms relief
in patients with ERD (70–80%) vs. those with NERD (50- 60%)
[39,40].
11. Comparing PPI
In the United States, there are currently seven different PPIs in
the market, four of which are available over the counter (esomepra-
zole, omeprazole, lansoprazole, and omeprazole-sodium bicarbon-
ate) and five of which are available via prescription (omeprazole,
pantoprazole, esomeprazole, dexlanzoprazole, and rabeprazole).
There are variations among PPIs in terms of bioavailability, pKa,
peak plasma level, and mode of elimination [40]. Lansoprazole,
dexlansoprazole, and pantoprazole have the highest bioavailabil-
ity and thus the highest peak plasma levels. The onset of action of
rabeprazole is the fastest as it has a higher pKa than other PPI [40].
The PPI most specific to gastric mucosa is pantoprazole, as it binds
only to cysteine residues in the ␣-subunit of the proton pump.
Many meta-analysis studies have shown that there is no statisti-
cally significant difference in the efficacy of the available PPIs [42].
A meta-analysis done in 2006 by Gralnek et al. (10 studies, 15316
patients with EE) comparing the efficacy of esomeprazole versus
other PPI (omeprazole, pantoprazole, and lansoprazole) (exclud-
ing omeprazole-sodium bicarbonate and dexlansoprazole), found
that at 8 weeks, there was a 5% relative increase (RR − relative
risk, 1.05; 95% CI 1.02-1.08) in the probability of healing erosive
esophagitis with esomeprazole, yielding an absolute risk reduction
of 4% and a number needed to treat (NNT) of 25. The calculated NNT
by LA grade of EE (grades A-D) were 50, 33, 14, and 8, respectively.
Esomeprazole conferred an 8% (RR 1.08; 95% CI 1.05-1.11) relative
increase in the probability of GERD symptoms relief at 4 weeks.
From this study, it appeared that while esomeprazole initially pro-
vided a statistically significant improvement, at 8 weeks its clinical
significance with respect to healing EE and GERD symptoms relief
was negligible [41].
Very few clinical trials have been done with any of the relatively
new PPIs (omeprazole-sodium bicarbonate, which is an immediate
release PPI and dexlansoprazole, which is available since 2009, and
is a dual delayed release PPI) on their effectiveness and outcomes
in symptoms relief. However, it is recommended that these two
new PPIs (omeprazole-sodium bicarbonate and dexlansoprazole)
should be taken 30–60 min before meals at night because in one
trial, they were shown to decrease nocturnal gastric pH, but not
esophageal pH, when compared to treatment with pantoprazole
[43]. However, it has not been studied whether this decrease in
intra-gastric pH leads to better control of the symptomatology of
GERD. A comparative head-to-head trial of dexlansoprazole versus
lansoprazole showed that dexlansoprazole is superior for healing
EE in one trial but non-inferior in another trial [44,45].
It is common in both inpatient and outpatient clinical practice
to switch one PPI for another and/or to double the dose of the cur-
rent PPI in non-responders and partial responders. However, there
is a lack of sufficient data to fully support any one of these clini-
cal practices. In one randomized control trial of patients on once
daily lansoprazole with persistent GERD symptoms, switching to
esomeprazole once daily, or increasing lansoprazole to twice daily,
both resulted in improved symptoms [46]. In another randomized
clinical trial in patients with an incomplete response to once-daily
lansoprazole, switching to omeprazole or increasing lansoprazole
to twice daily were both equally effective at improving outcomes
and symptomatic improvement in about 20% of patients in either
 S. Pandit et al. / Pathophysiology 25 (2018) 1–11
arm [47]. Data that compare the outcome of switching PPI more
than once in incomplete or non-responders are very limited.
12. Refractory GERD and resistance to PPI
It is very common to see patients with symptoms and presumed
diagnosis of GERD, who fail to respond to the empirical treatment
with PPI. As high as 40% of all patients treated with PPIs fail to
respond [48]. There is no established definition of refractory GERD
that evaluates the symptom burden, degree of response, or dose of
PPI at which failure occurs [49]. Hence, refractory GERD is a sub-
jective phenomenon, as there is inter-patient variation in terms of
severity and frequency of symptoms, dosage of PPI, and response
to therapy, either partial or none. Refractory GERD has a signif-
icant effect in the patients’ quality of life (QOL). One systematic
review of nine studies done in 2011 showed patients with persis-
tent symptoms of GERD treated with PPIs were adversely affected,
both mentally and physically, in terms of QOL [50]. A study com-
paring PPI responders to non-responders found that patients with
atypical symptoms had a higher failure rate than those with typi-
cal symptoms (heartburn and regurgitation), as did those patients
with a prolonged course of disease, poor compliance, and/or obesity
[51].
A stepwise approach should be taken while treating refractory
GERD patients or patients resistant to PPI therapy. The first step
should be to confirm adherence to therapy, ensuring that patients
are taking medication at the directed time (before meals) and that
the appropriate dose of PPI has been provided. As mentioned above,
when a once daily dose is increased to twice daily, symptoms
improve in about 20% of patients, so increasing the dose could be
tried.
In patients who are partial responders to optimal PPI therapy,
H2RA could be added at bedtime, which has been shown in multiple
studies to improve intra-gastric pH. However, one study showed
development of tachyphylaxis with respect to pH control after a
month of H2RA therapy [52]. For this reason, it has been suggested
that use of H2RA at bedtime, with doses taken as needed, is bene-
ficial in patients who mostly have nocturnal symptoms. Prokinetic
agents such as metoclopramide have been shown to increase lower
esophageal sphincter pressure, enhancing esophageal peristalsis
and improving gastric emptying, when added to PPI in patients with
a partial response to PPI; however, data that show any clear addi-
tional clinical benefit are lacking [53]. Another prokinetic agent that
could be used in conjunction with PPI is domperidone (a peripher-
ally acting dopamine agonist). However, this drug can only be used
for investigational purposes as it has not been approved by the Food
and Drug Administration (FDA). The efficacy of metoclopramide
and domperidone are similar with respect to gastric emptying, but
there has been very little or no data available concerning their use
in GERD [54]. In addition, the use of these prokinetic agents has
been limited because of their adverse effects. Metoclopramide is
associated with drowsiness, agitation, irritability, dystonic reac-
tion, and tardive dyskinesia, while domperidone is associated with
a prolonged QT interval, which increased the risk of ventricular
arrhythmia and sudden cardiac death [55,56].
In patients with objective evidence of persistent GERD on PPI
therapy, baclofen, a GABA-b agonist, can be added to the therapy at
a dose of 5–20 mg three times a day. Two short-term randomized
control trials showed that when baclofen was added to the regimen,
patients had symptomatic improvements in terms of reduced tran-
sient LES relaxation, decreased reflux episodes, improved nocturnal
symptoms, and a decreased number of post-prandial acid and non-
acid reflux events [57–60]. Baclofen is not approved by the FDA for
the treatment of GERD and its use is limited because of adverse
effects such as dizziness, somnolence, and constipation.
7
If a patient continues to have symptoms despite optimized med-
ical therapy and confirmed medical compliance, a further workup
is necessary. For those with typical esophageal symptoms (heart-
burn and regurgitation), endoscopy with biopsy is recommended to
exclude non-GERD disease, e.g. eosinophilic esophagitis (EoE). If the
results of the endoscopy are normal, the next step is to monitor the
reflux quantity, and the association between reflux episodes and
the patients’ symptoms. Patients with extraesophageal symptoms,
among whom pulmonary, ENT, and allergy workups have been neg-
ative, benefit from reflux monitoring [5]. There is lack of clear data
regarding whether reflux monitoring should be done while on or
off PPI therapy, or the technique that should be used to monitor
reflux (catheter-based pH, wireless pH, or impedance pH). There-
fore, the reflux monitoring test should be performed based on the
patients’ symptoms (high pre-test probability for GERD versus low
pre-test probability), and available equipment and expertise. Reflux
monitoring while on PPI therapy is usually performed in patients
with high pre-test probability, using impedance-pH monitoring,
which measures the both acid and non-acid reflux [5]. One sys-
tematic review done in 2010, which quantified acid and non-acid
(both weakly acidic and weakly alkaline) reflux in patients with
GERD taking PPI, showed that symptoms that persist despite PPI
therapy are due mainly to weakly acidic reflux in the majority of
patients [61]. In patients with low pre-test probability for GERD,
reflux monitoring is done off PPI (7 days after stopping PPI), which
can be done using catheter or wireless pH, or impedance pH. Nega-
tive test results (normal distal esophageal pH) suggest that GERD is
less likely to be the cause of persistent symptoms, so these patients
should be worked up for non-GERD etiologies [5].
13. Surgery
There are several clinical situations where surgery is consid-
ered an option for the management of GERD. Surgery is usually
reserved for patients who do not respond to optimal medical ther-
apy (persistent typical GERD symptoms and no resolution of EE
despite being on PPI) [48], non-compliant patients, patients not
willing to continue medical management, or those with medication
side effects, such as the presence of large hiatal hernia, a high vol-
ume reflux, benign strictures, Barrett’s columnar lined epithelium
without evidence of severe dysplasia, or carcinoma [5,48].
The most common surgical options available for GERD are
Nissen fundoplication, laparoscopic Nissen fundoplication, Nis-
sen modification, Belsey Mark IV, Hill Gastropexy, gastric bypass,
Angelchik prosthesis, LINX prosthesis, or endoscopic methods
[62]. Preoperative evaluations that patients should undergo before
being considered for surgery are: A) upper endoscopy − to assess
the esophageal and gastric mucosa, and rule out malignancy, B)
esophageal manometry − to rule out motility disorders, such as
achalasia or scleroderma-like esophagus, and C) esophageal length
evaluation − to assess the length of the esophagus and the degree
of hiatal hernia, which helps to tailor the type of surgical technique
[63]. The patients who seemed to benefit most from surgery are
those with typical GERD symptoms of heartburn and/or regurgi-
tation, who responded well to PPI therapy, or who had normal
ambulatory pH values with good symptom correlation in reflux
monitoring studies. Symptoms resolution post-surgery is less likely
in patients with refractory dyspeptic symptoms such as nausea,
vomiting, and epigastric pain. [63,64].
A prospective study which followed patients with fundopli-
cation vs. omeprazole therapy for 12 years showed that 53% of
patients who had surgery were in remission at 12 years, versus 45
percent in medically treated patients (P = 0.02), but that gas-bloat
syndrome was common in fundoplication group [65]. In the recent
years, with rising obesity in the United States, gastric bypass has
8 S. Pandit et al. / Pathophysiology 25 (2018) 1–11
become more common and popular than Nissen fundoplication. In a
systematic review study from 2009 that assessed for the efficacy of
surgery in GERD patients postoperatively through questionnaires,
Roux-en-Y was found to be more effective than gastric banding in
relieving GERD symptoms. However, there were conflicting data
from eight other studies regarding the effects of gastric banding on
GERD symptoms [66].
It is evident that persistent GERD symptoms, whether typical
or atypical, have a significant effect on the quality of life (QOL).
In a Cochrane review of four studies of more than 1200 patients
who were randomized to medical and surgical therapy, it was
found that all four studies showed significant improvements to
QOL (symptoms of heartburn, reflux, and bloating were improved,
but dysphagia persisted) after surgery compared to those observed
following medical therapy [67].
The most common symptoms experienced by patients who
underwent surgery were dysphagia and gas-bloat syndrome in up
to 15–20% of patients [68], in addition to the immediate postoper-
ative risks. It has also been reported that within one to three years,
about 7% of patients had to undergo surgical revision because of
complications from surgery [69]. In one follow up study done 10–12
years post-surgery, it was found that about 60% patients continued
to take medications [70].
In recent years, endoscopic therapies have been implemented
and are being studied extensively. The available endoscopic
therapies are radiofrequency augmentation of the LES, silicone
injection into the LES, and endoscopic suturing of the LES [5].
As these therapies did not demonstrate any long-term bene-
fit in relieving GERD symptoms, did not improve esophageal
pH, and patients who underwent them had to continue taking
anti reflux medications, they have a limited indication. Silicone
injection was removed from the United States marketplace due
to adverse events [71]. A new alternative technique has been
introduced, called trans-oral incisionless fundoplication, a sutur-
ing device that creates a full thickness gastroesophageal valve
from inside the stomach; however; data are limited in terms of
long-term efficacy and symptom resolution [72]. Another new
FDA approved approach is a LINX reflux system, a sphincter
augmentation system constructed of titanium beads, which has
shown efficacy in controlling pH and providing symptom relief
with very few side effects when compared to traditional laparo-
scopic fundoplication in carefully selected surgical candidates
[73]
14. Adverse effects associated with PPI
In the recent years, various potential adverse outcomes associ-
ated with the use of PPI (both short-term and long-term use) have
been studied. Common adverse effects of using PPIs are headache,
diarrhea, and dyspepsia in less than 2% of total users [5]. When the
FDA issued a warning stating that PPI users were at a higher risk for
cardiovascular events in patients concomitantly taking clopidogrel,
multiple studies were performed. Multiple meta-analyses revealed
that the strength of association between poor cardiovascular out-
comes in patients using PPI and clopidogrel together is dependent
on multiple variables such as data quality, clinical outcomes, and
adjustments for confounders [5]. Two randomized controlled tri-
als, done using all available PPI except dexlansoprazole, did not
find any increased risk of cardiovascular events (risk difference
[RD] 0.0, 95% CI − 0.01, 0.01). One meta-analysis was done that
included 26 studies (16 published articles and 10 abstracts) in
which the outcome is divided between primary outcomes (myocar-
dial infarction, stroke, stent occlusion, or death), and secondary
outcomes (re-hospitalization for cardiac symptoms or revascular-
ization procedures) [74]. Meta-analysis done for primary outcomes
showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies, and meta-
analysis done for secondary outcomes showed a RD of 0.02 (95% CI
0.01-0.04) that included 19 published papers and abstracts. Upon
combination of the primary and secondary outcome studies, the
consensus was that the risk of an adverse cardiovascular outcome
was 0% [5]. Nonetheless, a study done by Shah and LePendu et al.,
using a clinical data-mining approach, demonstrated an association
between cardiovascular events and PPI use. That study included
patients below the age of 18, who had a diagnosis of GERD and
heartburn. There was also a subset group who were not taking
clopidogrel. The study also looked at the association of H2RA use
and cardiovascular events. This study included 6 available PPIs
excluding dexlansoprazole (because of inadequacy of exposure).
The primary outcome for the study was myocardial infarction. Data
were collected over 5 and 17 years from two different databases
(using electronic medical records). The study found that there was
a 1.16 fold increased association of MI in GERD patients exposed
to PPI with a 95% CI (1.09-1.24). Survival analysis among these
prospective cohorts was also conducted, which showed a two-
fold increased association with cardiovascular-related mortalities
(HR = 2; 95% CI 1.07-3.78, P = 0.031). This risk was independent
of clopidogrel use. Conversely, H2RAs were not associated with
increased risk for MI. The authors of the study did state that
the increased risk of MI among the PPI users might reflect the
fact that PPI users often have higher initial levels of morbid-
ity which could contribute to this finding; however, the lack of
such an association among H2RAs users may support their finding
[83].
In 2010, the FDA had issued another warning to PPI users that
they were at a higher risk for wrist, hip, and spine fractures [5].
However, subsequent studies have shown that the increased hip
fracture risk among PPI users was only present in patients with
at least one other risk factor for osteoporosis [75]. It has also been
demonstrated that there is a small increase in the risk of hip fracture
(odds ration [OR] 1.2), but the data were limited by the presence of
other heterogeneous factors [76,77].
In the past, it was mentioned that PPI users were at risk of devel-
oping Community Acquired Pneumonia (CAP). Studies have shown
that short-term use of PPI was associated with increased odds of
developing CAP (OR 1.92, 95% CI 1.40-2.63, P = 0.003), whereas
chronic PPI users were not at risk (OR 1.11, 95% CI 0.90-1.38, P
< 0.001) [78,79]. Therefore, limiting the use of PPI should not be
predicated on the potential risk of CAP, as the previous studies
were confounded by heterogeneity in the data when determining
the causal effect, an area which needs further study [5].
PPI use has also been linked with the development of Clostrid-
ium difficile colitis (RR 1.2-5.0, 17/27 studies) and other enteric
infections, such as Salmonella (adjusted RR 4.2-8.3, 2 studies) and
Campylobacter jejuni (RR 3.5-11.7 in four studies) [80]. Theoreti-
cally, but not in practice, PPI use has been associated with the
development of iron deficiency anemia (no data exist showing pos-
itive results) and vitamin B12 deficiency (two review articles exist,
neither of which provide any clinical data that shows B12 deficiency
in chronic PPI users) [81,82].
One systematic review of 36 cases found the association
between hypo-magnesemia and PPI. The average duration of onset
was 5.5 years, and was found with the use all available PPIs [101].
Other adverse effects that has likely association with long term use
of PPI include gastric polyp formation, and gastric carcinoids. Long
term PPI use raises serum gastrin level. Persistent elevation of gas-
trin has been associated with entero-chromaffin cells hyperplasia,
however no dysplasia or neoplasm has been reported. Nonethe-
less, one case series of 11 cases of gastric neuroendocrine tumors
has reported the association of these tumors with long term use of
PPI [101].
 S. Pandit et al. / Pathophysiology 25 (2018) 1–11
In summary, the overall clinical context should be considered
when using PPIs and assessing the potential risk of developing the
aforementioned adverse effects.
15. Summary and conclusion
GERD is one of the most common diseases encountered in both
the outpatient and inpatient settings. A presumptive diagnosis of
GERD can be made based on typical symptoms such as heartburn,
regurgitation, and chest pain. Empiric therapy with a PPI should
be initiated for patients with typical symptoms. GERD can also
present with atypical symptoms, such as nocturnal cough, hoarse-
ness, asthma, and laryngitis. Cardiac causes must be ruled out in
patients presenting with chest pain before starting gastroentero-
logical workup. Various diagnostic tests are not usually required
for the diagnosis of GERD. Upper endoscopy with biopsy should
be performed only if alarming symptoms are present to rule out
EoE or NERD. Routine biopsy of the distal esophagus is not recom-
mended. Testing and treatment for Helicobacter pylori is suggested
in patients diagnosed with GERD. Esophageal manometry should
only be performed as a preoperative evaluation in patients carefully
selected for surgery. Ambulatory esophageal reflux monitoring
with pH probe study should be done in patients resistant to optimal
dosing of PPI. Although avoiding foods such as caffeine, chocolate,
spicy foods, and mint has not been shown to lead to any significant
improvement in GERD symptoms, counseling should be done on a
case-by-case basis, and overweight patients should be encouraged
to lose weight. Smoking and alcohol lowers LES pressure, so when
needed, patients should be counseled to stop smoking, and/or to
stop drinking alcoholic beverages. It is recommended that patients
who present with nocturnal GERD symptoms should be instructed
to elevate the head of the bed. PPI should be started as an initial
therapy for eight weeks for symptoms relief and healing of erosive
esophagitis. All PPIs have similar efficacy. If a patient has persistent
symptoms, the dose of PPI can be increased from once daily to twice
daily. Changing from one PPI to another has not been shown to have
any significant clinical benefit. If symptoms relief is obtained, H2RA
could be used as a maintenance option, and could also be taken at
night if the patient has nocturnal symptoms. PPIs are clinically safe
in pregnant patients. Surgical options are for long-term symptom
control and are not recommended for patients who did not respond
to PPI therapy. Surgical therapy is as effective as medical therapy
in well selected patients. Overweight and obese patients benefit
from bariatric surgery, and gastric bypass is recommended. Current
endoscopic therapies can be offered as an alternative for medical or
surgical therapies. PPIs used in the short-term do increase the risk
of CAP and Clostridium difficile infections, CKD, hypomagnesemia,
hence care should be taken when considering this treatment for
high risk patients. Patients with osteoporosis can continue to take
PPI, as the risk of developing hip and other fractures and/or osteo-
porosis was highest for patients with at least one other risk factor
for osteoporosis. The risk of adverse cardiovascular events does not
increase in patients taking clopidogrel in conjunction with PPI.
Complications commonly associated with GERD are EoE, Bar-
rett’s esophagus, and peptic stricture, which should be evaluated
and monitored via upper endoscopy and biopsy as per recom-
mended guidelines.
Grant support
This work was supported by the German Research Foundation
(DFG, BE 5619/1-1) and Department of Defense (PR100451).
9
Disclosure
The authors have no conflicting financial interests to disclose.
Authors’ contributions
SP − author
JM − designed the outline of the paper
JSA − helped in editing the manuscript
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