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Mini-Reviews in Medicinal Chemistry, 2020, 20, 000-000 1
REVIEW ARTICLE
1389-5575/20 $65.00+.00 © 2020 Bentham Science Publishers
Proton Pump Inhibitors and Radiofrequency Ablation for Treatment of
Barrett's Esophagus
Predrag Dugalic1,*, Srdjan Djuranovic2, Aleksandra Pavlovic-Markovic2, Vladimir Dugalic3,
Ratko Tomasevic4, Zoran Gluvic5, Milan Obradovic6, Vladan Bajic6 and Esma R. Isenovic6,*
1Department of Gastroenterology and Hepatology, University Clinical-Hospital Centre Zemun-Belgrade, Belgrade,
Serbia; 2Clinical Centre of Serbia, Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Bel-
grade, Belgrade, Serbia; 3Clinical Centre of Serbia, Clinic for Surgery, Faculty of Medicine, University of Belgrade,
Belgrade, Serbia; 4Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Uni-
versity Clinical-Hospital Centre Zemun-Belgrade, Belgrade, Serbia; 5Department of Endocrinology and Diabetes, Fac-
ulty of Medicine, University of Belgrade, University Clinical-Hospital Centre Zemun-Belgrade, Belgrade, Serbia;
6Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Bel-
grade, Serbia
Abstract: Gastroesophageal reflux disease (GERD) is characterized by acid and bile reflux in the dis-
tal oesophagus, and this may cause the development of reflux esophagitis and Barrett’s oesophagus
(BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then low-
grade (LGD) and high-grade dysplastic (HGD) BE, with the expected increase in malignancy transfer
to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution
white-light endoscopy, followed by uniform endoscopy findings description (Prague classification)
with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE in-
cludes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-
term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result
of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of re-
section and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in
everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated
oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is
reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review
aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular
mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and
prevention of its transfer to EAC.
A R T I C L E H I S T O R Y
Received: April 01, 2019
Revised: June 04, 2019
Accepted: June 25, 2019
DOI:
10.2174/1389557519666191015203636
Keywords: GERD, Barrett’s oesophagus, proton pump inhibitors, radio-frequency ablation, action of PPIs, oesophagus.
1. INTRODUCTION
Barrett’s oesophagus (BE) represents a premalignant
condition, and it is considered to be a precursor for the de-
velopment of oesophagal adenocarcinoma (EAC) [1]. Gas-
troesophageal reflux disease (GERD) is characterized by
acid and bile reflux in the distal oesophagus, which can lead
*Address correspondence to these authors at the Department of Gastroen-
terology and Hepatology, University Clinical-Hospital Centre Zemun-
Belgrade, Belgrade, Serbia; E-mail: predrag.dugalic@gmail.com; and De-
partment of Radiobiology and Molecular Genetics, Institute of Nuclear
Sciences Vinca, University of Belgrade, Belgrade, Serbia; Tel: +38111-
3408147; E-mail: isenovic@yahoo.com
to the development of reflux esophagitis and BE [2, 3]. The
prevalence of BE in Western populations is under 5%, and
the estimate is around 1.5% [2, 4-6], while in patients with
GERD, the prevalence of BE is estimated to be 15% [7]. The
gold standard for BE diagnostics involves high-resolution
white-light endoscopy, followed by uniform endoscopy find-
ings description (Prague classification) with biopsy perfor-
mance according to Seattle protocol [8, 9]. Treatment of BE
could be medical, endoscopic, and surgical [10, 11]. Medical
treatment is necessary to control GERD and its associated
symptoms [10]. Medical treatment is related to proton pump
inhibitors (PPIs) use since H2 blockers do not demonstrate
the decrease in risk progression of BE to oesophagal adeno-
2 Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 Dugalic et al.
carcinoma (EAC) [12-14]. In general, current international
and national endoscopy societies recommend endoscopic
treatment in the cases of confirmed high-grade dysplasia
(HGD) and early EAC. Radiofrequency ablation (RFA) is
among the most frequently used ablation techniques of BE
[10, 15]. RFA aims to destroy damaged squamous epithelium
and to allow the growth of neosquamous epithelium [16]. The
EAC rate may significantly decrease by eradicating BE meta-
plasia and dysplasia [17]). Currently, RFA is established as an
endoscopic technique for BE eradication as well as for the
eradication of residual BE after endoscopic resection of early
EAC [18]. RFA should not be the appropriate first choice for
the treatment of nodular BE. The best approach is to treat
visible or nodular BE by resection technique followed by
RFA [17, 19]. Surgery is reserved for patients with persisted
GERD symptoms despite the long-term use of PPIs. Another
indication for surgical treatment is a progressive disease.
Current laparoscopic techniques (partial or total fundoplica-
tion) are the surgical procedures of choice [11, 20]. This
review aims to explain distinct effects of medical (PPIs) and
tissue-acquiring endoscopy technique (RFA) modalities,
illuminate certain aspects of molecular mechanisms in-
volved, as well as the effects of their concomitant use (mul-
timodal therapy) regarding the treatment of BE and preven-
tion of its transfer to EAC.
2. BARRETT’S OESOPHAGUS (BE)
BE is the pathological condition where the normal strati-
fied squamous epithelium of distal oesophagus replaced with
metaplastic columnar epithelium (with goblet cells). BE rep-
resents a premalignant condition, and it is considered to be a
precursor for the development of EAC. Although Norman
Barrett described this condition in the middle of the last cen-
tury [1], some facts regarding the origin, pathogenesis, diag-
nostics, and prevention of BE are not completely understood
[21].
2.1. Predisposing Factors
Several risk factors for development BE have been
identified, where GERD is considered as a predominant risk
factor [2, 3]. The results from the meta-analysis study showed
that symptoms of GERD are associated with a five-fold in-
creased risk of BE [3], while the results from one cross-
sectional study performed on 683 patients younger than 30
years, with weekly symptoms of GERD, indicate even 15-
fold increased risk of BE [22]. Other strong risk factors for
BE include age, male gender, central obesity, white race,
smoking, and also genetic predisposition [6, 23-26]. The
prevalence of BE increases with age, and it is twice more
frequent in men than in women [24, 27].
Furthermore, cigarette smoking considerable amplifies
risk for development BE [28, 29]. Abdominal obesity has been
recognized as a significant risk factor for BE, especially in
patients with a genetic predisposition to develop obesity [30,
31]. Also, there is a positive correlation with insulin re-
sistance, type 2 diabetes, high serum concentrations of leptin,
metabolic syndrome, and sleep apnea with an increased risk of
BE [32-36]. Individuals with a positive family history of BE,
especially first-degree relatives with BE, have a significantly
increased risk of BE [23]. Interestingly, evidence from the
literature indicates that infection with Helicobacter pylori
decreases the risk of BE [37, 38], most likely through a
mechanism that includes reduction of ghrelin and leptin
signaling [39, 40].
2.2. Epidemiology
The prevalence of BE in the general population is not
easy to clarify because BE is asymptomatic, and its diagnosis
is accurate only when endoscopic examination and histologi-
cal confirmation are performed [41]. One of the rare studies
with randomly recruited adults (Swedish study), performed
on 1000 residents who underwent upper gastrointestinal en-
doscopy. The histological results from the Swedish study
confirmed BE in 1.6% subjects, where 5 subjects have a long
segment, and 11 subjects have a short segment [5]. Similarly,
the Loiano-Monghidoro study noted a 3.6% prevalence of
BE in 1033 subjects from Italy, while histological analysis
confirms Barrett’s metaplasia in 1.3% of all respondents [4].
Also, the Chinese SILC study found (by endoscopy) 1.8%
cases of BE in a population of 1030 subjects [42]. Further-
more, systematic review and meta-analysis of the prevalence
of BE in Asian countries which include 51 studies and
453,147 patients, reported that the endoscopic prevalence of
BE was 7.8%, while histologically confirmed prevalence of
BE was 1.3% [43]. Some differences in the prevalence of BE
between populations may be explained by the difference in
the prevalence of risk factors, primarily GERD, obesity, diet,
and smoking [44].
2.3. Origin and Pathogenesis
Besides numerous investigations, the origin of BE remains
poorly understood. Some hypotheses have been proposed to
the defined origin of BE, such as reprogramming of
oesophagal-squamous stem cells, repopulation from submu-
cosal oesophagal glands, or proximal migration of the gastric
cardiac epithelium with subsequent intestinalization [45-50].
By using p63-deficient mice, with a lack of squamous epi-
thelia (an animal model for GERD), Wang et al. reported
that embryos of these mice rapidly develop intestine-like
columnar metaplasia which replaces squamous mucosa, sim-
ilar to Barrett's metaplasia [46]. The same authors also
reported these precursor cells of metaplasia at the squamoco-
lumnar junction (SCJ) in adult mice and humans [46]. The
progressive inflammation, metaplasia, and dysplasia at the
SCJ were also found in another animal model of BE such as
human IL-1β transgenic mice, overexpressing interleukin-1
(IL-1) [47]. The development of BE lesion and progression
to EAC was accelerated by exposure to bile acids and nitros-
amines [47]. It is proposed that BE and EAC arise from gas-
tric progenitors by a mechanism involving IL-1β and IL-6
signaling cascade and Dll1-dependent Notch signaling [47].
Since the transitional zone between different types of epithe-
lium is a critical point for metaplastic and malignant chang-
es, Jiang et al. described a transitional columnar epithelium
with distinct basal progenitor cells (p63+KRT5+KRT7+) at
the SCJ in a tg mice model [46]. The same authors show that
these transitional basal progenitors cells could differentiate
into intestinal-like epithelium with goblet cells, and thus
represent the cells of origin for multi-layered epithelium and
Treatment of Barrett’s Esophagus Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 3
BE [48]. Also, literature data indicate that refluxed gastric
juice plays a role in the pathogenesis of BE probably due to
cytokine-mediated inflammation and damage the oesophagus
tissue, rather than caustic acid injury [51, 52]. Other studies
also found that the clonality of Barrett’s glands underlies the
development of EAC [53, 54].
3. DIAGNOSTICS OF BE
Although the annual rate of BE transfer to the EAC is
small, the high mortality rate of this malignancy increases
the need for an early and reliable diagnosis. However, identi-
fying subjects with BE is a challenge for the physician with
the current diagnostic approach. Also, the use of biomarkers
to identify subjects with BE and for evaluation of risk-
stratification still needs additional assessment [55, 56].
The gold standard for BE diagnostics is high-resolution
white-light endoscopy, followed by uniform endoscopy find-
ings description (Prague classification) with biopsy perfor-
mance according to Seattle protocol [8, 9]. Based on Prague
classification, BE is arbitrarily defined depending on the
length of the columnar epithelium as a long segment (meta-
plastic segments length is equal or more than 3 cm), and as a
short segment (the length of BE is less than 3 cm) [8].
Changes less than 1 cm in length are not considered as BE,
but according to the American College of Gastroenterology,
these changes are defined as specialized intestinal metaplasia
(IM) of the oesophagogastric junction (irregular z-line) or
ultra-short segment BE [11].
Based the most guidelines, a diagnosis of BE implies the
presence of salmon-pink coloured columnar epithelium ≥1 cm
proximal to the gastroesophageal (GE) junction with biopsies
consistent with IM and the presence of mucin-containing gob-
let cells [11, 57, 58]. To increase the probability of finding IM,
it is recommended to increase the number of random biopsy
samples [59]. Use the Seattle protocol required four-quadrant
biopsy for every 1-2 cm of BE segment length [9]. The histo-
logical examination of biopsy samples are categorised as fol-
lows: negative for dysplasia or benign BE (ND), indefinite for
dysplasia, low-grade dysplasia (LGD), HGD, oesophagal ade-
nocarcinoma (EAC) [60, 61].
4. TREATMENT OF BARRETT’S OESOPHAGUS (BE)
Treatment of BE can be medical, endoscopic, and surgi-
cal [10, 11].
4.1. Medical Treatment
Medical treatment is necessary to control GERD and its
associated symptoms [10], and it is related to PPIs use be-
cause H2 blockers do not demonstrate the decrease in risk
progression of BE to oesophagal adenocarcinoma (EAC)
[10, 12-14]. Besides its acid-suppressive activity (chemopre-
vention), PPIs promote anti-inflammatory effects [11, 62].
The use of PPIs is now considered even in BE patients with
no reflux symptoms [19].
4.1.1. Proton Pump Inhibitors (PPIs)
The aim of PPIs use in the treatment of BE is to disrupt
the chain of GERD pathogenesis progression from NERD to
long-segment BE, and as from LGD to HGD and their pro-
gression to the final stage- EAC [10, 63, 64]. Today, statins
and PPIs are defined as factors that influence the natural histo-
ry of BE [41, 65]. Results from one meta-analysis demonstrate
a 71% risk reduction of neoplastic transfer of HGD [66]. The
benefits of PPIs are reflux symptoms and esophagitis control,
prevention of post-endoscopy treatment strictures, prevention
of dysplasia progression, and favouring of its regression
[67]. Some studies suggest the concomitant use of PPI with
NSAIDs/aspirin/statin treatment, regarding their synergistic
anti-inflammatory effects [68-70]. However, the routine use
of NSAIDs/aspirin cannot be recommended, partly because
of their serious adverse effects profile and questionable pro-
tective effects [11, 65]. Disagreements in different guidelines
regarding PPIs dosage are still subject to debates. Some so-
cieties advise using PPIs just in the cases of symptomatic
BE, but another one suggesting PPIs in doses higher than
usual for the control of reflux symptoms [8, 71, 72]. The use
of PPIs can favour neoplastic transformation of BE induced
by the increase in gastrin levels or by direct effects of bile
salts on oesophagal epithelium [9, 73]. It is recommended to
use PPIs once-daily, while the use of twice-daily PPIs regi-
men is reserved in the cases of poor reflux symptoms control
or due to esophagitis presence [11].
A turning point for the treatment of acid-related disorders
was in 1989 when omeprazole, a PPIs, was introduced to
clinical practice. The new class of drugs shows to be more
efficient, have better safety profiles, and more tolerant than
previously synthesized agents, such as histamine receptor
agonist, anticholinergic drugs, and analogues of the prosta-
glandin family [74]. After omeprazole in 1989, several ben-
zimidazole derivates have been synthesized [75], such are
lansoprazole, pantoprazole [74, 76], rabeprazole [74, 77],
and the stereo-isomeric compounds dexlansoprazole [78] and
esomeprazole [79]. Table 1 summarizes some properties of
different PPIs.
The name proton pump inhibitor comes from their prop-
erties to irreversibly bind to hydrogen/potassium adenosine-
triphosphatase (H+/K+-ATPase) enzyme that is found in gas-
tric parietal cells [80]. For most patients, PPIs represent the
first choice for treatment of GERD [81], dyspepsia [82], pep-
tic ulcer, cough, laryngitis [13], Zollinger-Ellison syndrome
[83], BE [63], NERD [84], and prevention of NSAID associ-
ated ulcers. PPIs are also a part of a treatment for eradication
caused by Helicobacter pylori [85].
4.1.2. The Chemical Action of (PPIs)
PPIs are heterocyclic organic molecules that have a
pyridine and benzimidazole moiety linked by a methylsulfinyl
groups (Fig. 1). PPIs as acid-activated prodrugs inhibit the
H+/K+-ATPase by binding covalently to active H+/K+-
ATPase [80, 86]. Evolutionary, H+/K+-ATPase have occurred
in cells independently more than once. The H+/K+-ATPase are
an integral part of the membrane, with the main role to in-
crease the proton gradient across the same membrane [87-89].
H+/K+-ATPase are divided into major classes regarding their
ability for utilizing different sources of energy, different pol-
ypeptide compositions, thus 3D conformation structure sug-
gesting different evolutionary origins [89, 90].
Please replace
4.1.2. The Chemical Action of (PPIs),
with
4.1.2. The Chemical Action of PPIs
4 Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 Dugalic et al.
Table 1. PPIs chemical, structural, pharmacological, toxicological and metabolic properties.
PPIs Name
Chemical structure
Pharmacology
Toxicity/Side Effects
Metabolism
Refs.
Omeprazol
(approved in 1988)
N
N
S
O
O
N
O
H
• Selective and irreversible
H+/K+-ATPase inhibitor
• Peak plasma concentra-
tions: 1h
• Plasma half-life is 1h
• Clostridium difficile colitis
pneumonia
• Risk of bone fractures
• Potential of masking stom-
ach cancer
• Hypomagnesaemia
• Can interact with
clopidogrel, and oxyco-
done
• Metabolized by
CYP2C19 and
CYP3A4
• Absorption: 6 h
• Bioavailability 60%
[74]
[75]
[76]
[91]
Lansoprazol
(approved in 1988)
H
N
N
S
O
N
O
FF
F
• Selective and irreversible
H+/K+-ATPase inhibitor.
• Peak plasma concentrations
attained about 1.7h
• Plasma half-life is 1h
• Can bind to the pathogenic
form of Tau protein,
• Hypomagnesaemia
• Metabolized by
CYP2C19 and
CYP3A4
• Bioavailability 80%
[74]
[76]
[85]
[91]
Pantoprazol
(approved in 1994)
N
N
OF
F
S
O
H
N
O O
• Selective and irreversible
H+/K+-ATPase inhibitor
• Peak plasma concentrations:
2.5h
• Plasma half-life is 1-2h
• Headache
• Diarrhea
• Vomiting
• Abdominal pain
• Joint pain
• Hypomagnesaemia
• Metabolized by
CYP2C19 and
CYP3A4
• Bioavailability 77%
[74]
[76]
[85]
[91]
Rabeprazol
(approved in 1997)
N
N
S
O
H
N
O
O
• Selective and irreversible
H+/K+-ATPase inhibitor
• Peak plasma concentra-
tions: 1h
• Plasma half-life is 1-2h
• Osteoporosis
• Hypomagnesaemia
• Clostridium difficile infec-
tion
• Pneumonia
• Metabolized by
CYP2C19 and
CYP3A4
• Bioavailability 55%
[77]
[91]
Esomeprazol
(approved in 2001)
N
N
O
S
O
H
N
O
:
• Selective and irreversible
H+/K+-ATPase inhibitor
• Peak plasma concentra-
tions: 1h
• Plasma half-life is 1.2 -1.4
• Angioedema
• Clostridium difficile infec-
tion
• Pneumonia
• Hypomagnesaemia
• Metabolized by
CYP2C19 and
CYP3A4
• Bioavailability 64%
[79]
[84]
[85]
[91]
Dexlansoprazol
(approved in 2009)
an R-isomer of
Lansoprazol
N
N
S
O
H
N
O
FF
F
:
• Selective and irreversible
H+/K+-ATPase inhibitor
• Peak plasma concentra-
tions: 1h
• Plasma half-life is 1h
• Osteoporosis
• Hypomagnesaemia
• Clostridium difficile infec-
tion
• Anaphylaxis
• Pneumonia
• Metabolized by
CYP2C19 and
CYP3A4
• Bioavailability 80%
[78]
[85]
[91]
Revaprazan
(approved in 2005)
F
N
N
NN
H
• H+/K+-ATPase antagonist,
or potassium-competitive
acid blockers
• Peak plasma concentra-
tions: 1.3-2.5h
• Plasma half-life is 9h
• Indigestion
• Diarrhea
• Constipation
• Headache
• Metabolized by
CYP2C19
• Bioavailability 90%
[91]
[93]
[94]
The proton pump of the stomach is the H+/K+-ATPase,
which is located in parietal cells, which are a specialized
type of cells, concentrated in the inner lining of the stomach
(gastric mucosa). The H+/K+-ATPase is the major protein
concentrated within the membranes of parietal cells [90].
The role of this specific pump is the exchange of the potassi-
um anion from the intestinal lumen with hydronium within
the cytoplasm [80, 90]. The H+/K+-ATPase enzyme is re-
sponsible for the pH level in the stomach (acidification),
thereby physiologically responsible for protein digestion by
activating the digestive enzyme, pepsin [91]. As the H+/K+-
ATPase is at the last terminal stage of gastric secretion, it
becomes the best target for PPIs to inhibit acid secretion.
PPIs act by irreversibly blocking the H+/K+-ATPase enzyme
system (Fig. 2). PPIs are more effective than histamine
antagonists and PPIs reduce 99% of acid secretion from the
parietal cells to the gastric lumen. Despite the beneficial
effects of PPIs to decrease acid, several should be evaluated
before using PPIs, since secretion is needed for protein
digestion, vitamin B12, calcium, iron absorption, and other
nutrients.
PPIs are in essence pro-drugs, meaning that for their ac-
tivity, an activation process is needed. Activation of PPIs
Treatment of Barrett’s Esophagus Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 5
occurs in the acidic environment of the stomach, in the parie-
tal cells, crossing the cell membrane (lipophilic) where the
inactive drug is protonated and thus rearranges to its active
form. This active form consequently covalently binds to the
H+/K+-ATPase and irreversibly inhibits its action to produce
H+ [19] (Fig. 2).
Since the irreversible properties to covalently bond to the
H+/K+-ATPase is dampened by the short half-life of current-
ly known PPIs like omeprazole (90 minutes) [91], other ap-
proaches have been proposed. One is the synthesis of APIs
or H+/K+-ATPase antagonist. APAs are competitive inhibi-
tors act by blocking acid secretion through K+ sites [92].
Revaprazan is an APA, with a faster action than PPIs as it
does not require acid activation [93, 94]. Revaprazan is reg-
istered in Korea, for gastritis, but not in Europe and the US.
To best of our knowledge, there are no known trials in
GERD and BE [90] for Revaprazan in the EU and US. Even
though Revaprazan provides better acid control as its action
lasts longer than PPIs. For severe acid-related problems such
as BE, PPIs are the prescribed drugs for treatment and cure
[74, 95].
4.1.3. The Risk and Benefit Ratio of PPIs
After more than 20 years of PPIs usage, some concerns
have been addressed related to the possible side effects [74,
96]. Previously, mutations in the α-subunit of H+/K+-ATPase
in mice had led to hypochlorhydria resulting in problems of
iron absorption [97] and consequently to anaemia. In hu-
mans, results of PPIs trials showed that the H+/K+-ATPase
does not play a fundamental role in iron absorption, so the
use of PPIs have not been correlated to the risk of iron ab-
sorption [97], but still some concerns remain regarded to
vitamin B12 absorption [98]. The most concern has been
raised from research on Benzimidazole derivatives, Astemi-
zole (AST) and Lansoprazole (LNS). The use of these deriv-
atives has shown to propagate interaction with a pathological
feature of Alzheimer’s disease, phosphorylated TAU, and its
aggregates (neurofibrillary tangles) leading to an increased
pace to dementia [99-101].
When concerning Alzheimer’s disease, research suggests
that PPIs are active in a non-selective manner, i.e., they act
on sodium-potassium pumps of the brain [102]. This interac-
tion could be utilized solely or by interaction with other
drugs, such as digoxin, warfarin, etc. The other focal point of
action may be associated with the sodium pump in the brain
or the alpha three subunits in astrocytes, a group of cells
important for memory. The chronic use of PPIs is considered
to cause down-regulation of the α subunit, thus damaging
astrocytes [103]. For the treatment of BE, PPIs are approved
for long term use and symptom control [104]. Some con-
cerns of PPIs adverse effects have been addressed in the ob-
servational studies conducted by Nehra et al., 2018; this
study only revelled mild overall associations [98] of PPIs
and their adverse effects suggest that the overall risk remains
small. Still, some recommendations are in effect, blood
count every year, B12 levels every five years, etc. in patients
on long therapy regimes with PPIs [98].
4.1.4. PPI and BE
A basic concern of the chronic use of PPIs should be
addressed, since it is well known that BE could lead to
adenocarcinoma by a progression of pathological stages,
from oesophagus inflammation to IM, then dysplasia, and
EAC. The long list of adverse effects related to PPIs shows
that the quality of evidence is still low [104]. So, in a clinical
setting, the use of PPIs is recommended for GERD, GERD
with BE, and NSAID bleeding prophylaxis, and for these
patients, PPIs show a high benefit-risk ratio, as for the other
groups or categories the risk-benefit ratio is less clear [104].
PPIs reduce acid reflux, which is one of the drivers of
BE, but PPIs also downregulate cyclooxygenase-2 expres-
sion suggesting that it might protect against neoplastic pro-
gression [15]. Results from observational data confirm that
patients taking PPIs have a reduced rate of neoplastic pro-
gression [104]. New studies where PPIs are giving with aspi-
rin [104], (since aspirin reduces the rate of oesophagal carci-
noma [15]), show that the best results were in groups with
the highest dose of Esomeprazole (2x40mg) and aspirin (325
mg once a day). Interestingly, the group of 704 patients
receiving high dose Esomeprazole had 303 serious adverse
events in comparison to high dose Esomeprazole and aspirin
that showed 274 events from 571 patients, suggesting that
there is little difference between these two groups [104]. The
overall results suggest that the combination of PPIs and aspi-
rin in the patients that well-tolerated this combination im-
proves the overall survival rate (death, cancer, and dysplasia)
in Barrett's syndrome patients for a time of 9 years [104].
Pharmacogenomic differences in users and non-users
(one time users) when considering the reaction to PPIs or
their adverse effects make it very difficult to study PPIs in
retrospect despite a vast number of studies. We stand on the
firm line that the overall quality of evidence to PPIs adverse
potential remains poor or very low [104]. Today clinicians
upheld recommendations [104] to appropriately prescribe
PPIs as then the benefits outweigh the risks, while inappro-
priately prescribed, even modest risks can out potential value
benefits.
Fig. (1). Schematic structure of PPIs (updated from Wikipedia).
PPIs have a common structure. All PPIs share a common back-
bone, a pyridine linked to a benzimidazole, the asterisk indicates
stereo centre (methylsulfinyl group).
XN
H
N
R1
SH
O
N
R4
OR2R3
Benzimidazole
Methylsulfinyl
group
Pyridine
moiety
6 Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 Dugalic et al.
Fig. (2). Mechanism of action of the PPIs. The parietal cell represents the cell in the stomach lining that contains enzymes that make H+ and
also is the foundation for the H+/K+-ATPase. The H+/K+-ATPase is an enzyme system that actively transports hydrogen into the stomach and
K+ into the parietal cells by the mechanism of hydrolysis of ATP. All PPIs, from omeprazole to the most recently synthesized Dexlansopra-
zole (in 2009), are prodrugs and require activation. Once activated, they inhibit the H+/K+-ATPase. Their metabolites are inactive and do not
inhibit the H+/K+-ATPase. The next generation of PPIs has been presented in schematic presentation, i.e. acid pump antagonists are under
development. These agents, in which we used Revaprazan as a model suppress gastric activity by blocking the action of the H+/K+-ATPase by
binding to or near the site of the K+ channel. These compounds potentially achieve faster inhibition and longer duration in comparison to
classical PPIs. We also presented a class of drugs, H2RA or H2 blockers that act on histamine at the histamine H2 receptors in the parietal
cell. These drugs have their place in gastrointestinal management but for BER the preferred treatment is with PPIs. Gastrin is a peptide hor-
mone that stimulates acid secretion in two ways, directly through the parietal cell and indirectly through CCK2 receptors and through releas-
ing histamine acts on cells to produce H+ ions. Cl- - chloride ions, H+ - hydrogen ions, HCl - hydrochloric acid, K+ - potassium ions, H+/K+-
ATPase - hydrogen/potassium adenosine-triphosphatase. (A higher resolution/colour version of this figure is available in the electronic copy
of the article).
4.2. Endoscopic Treatment
In general, current international and national endoscopy
societies recommend endoscopic treatment in the cases of
confirmed HGD and early EAC. There is some doubt regard-
ing the endoscopic treatment of BE with confirmed LGD and
patients with simple BE-confirmed IM. This conundrum is
surpassed elegantly with regular chemoprevention and endo-
scopic surveillance in the cases of BE with no dysplasia and
performance of endoscopic treatment in selected patients
with LGD involving patients and physician “shared decision
making” [11, 105, 106].
Regarding modalities of applied endoscopic treatment,
the combined use of tissue acquiring or resection techniques
(i.e. endoscopic mucosal resection-EMR or endoscopic sub-
mucosal dissection-ESD) and ablative techniques (i.e. radiof-
requency ablation-RFA, argon plasma coagulation-APC,
cryoablation-CRY, photodynamic therapy-PDT, and multi-
polar electrocoagulation-MPEC) are currently recommended
in the patients with HGD, early EAC, and selected ones with
LGD [107]. The reason for endoscopic treatment of selected
patients with LGD and patients with HGD is expected high
progression risk to EAC (<13.4% and 10-18% patients per
year) [10, 106]. The precise pre-treatment endoscopic stag-
ing is the most important criterion that determines the choice
of therapy. The usual endoscopic approach to visible lesions
is EMR/ESD of the lesion of interest in combination with the
ablative endoscopic technique of endoscopists’ choice or
experience after histology examination (“multimodal thera-
py”) [17]. The importance of trained pathologists in BE is
cumbersome to ascertain patient risk for disease progression
because 50-85% of patients initially presented as LGD was
downstaged to non-dysplastic BE after expert pathologist
review [108]. According to that, confirmation of LGD by BE
experienced pathologist is crucial in deciding to ablate LGD
[109, 110].
Treatment of Barrett’s Esophagus Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 7
Tissue-acquiring techniques are reserved for the resection
of visible lesions <2cm (EMR) and >2cm (ESD) in diameter.
The achievement of complete remission of dysplasia and IM
is very high (>80% of patients). Both procedures are general-
ly safe with low-rate of potential complications, such as
bleeding, strictures formation, and perforation [10, 106,
107]. Additionally, the findings of endoscopic resection di-
rectly influence the future management plan of the patient. If
histology of the resected specimen reveals no dysplasia, the
patient is selected just for endoscopic surveillance. If histol-
ogy revels LGD, HGD, or EAC, thorough specimen exami-
nation (invasion depth and margins) determined future resec-
tion, ablative, or surgical management as well as surveillance
[11].
4.3. Radiofrequency Ablation (RFA)
RFA is among the most frequently used ablation tech-
niques of BE [10, 15]. RFA aims to destroy damaged squa-
mous epithelium and to allow the growth of neosquamous
epithelium [16]. The EAC rate may significantly decrease by
eradicating BE metaplasia and dysplasia [17]. Currently,
RFA is established as an endoscopic technique for BE eradi-
cation as well as for the eradication of residual BE after en-
doscopic resection of early EAC [18]. RFA should not be the
appropriate first choice for the treatment of nodular BE. The
best approach is to treat visible or nodular BE by resection
technique followed by RFA [17, 19].
High-frequency energy is delivered to the mucosa in
depth 500-1000 micm to induce electromagnetic field with
oscillation and collision of charged ions with thermal energy
(approximately 300W) released for a short period (<300ms)
[106, 111]. When subsequent coagulation necrosis of epithe-
lial and muscularis mucosa cells is achieved [10, 106], treat-
ed mucosa will be removed under endoscopic visualization
with the possibility to repeat RFA delivery during one en-
doscopy session. Depending on the tissue response or the
length of BE, RFA can be repeated, usually in 2-3 months
periods [112]. Regarding achieve complete eradication of
BE, approximately 2-4 repeated RFA sessions are necessary
[106]. Depending on the mode of energy delivery and the
length and type of BE, RFA can be circumferential and focal
[106]. Circumferential RFA is reserved for the management
of long circumferential segment BE (>3cm), and focal RFA
for the management of short-segment BE (<3cm), BE islands
and tongues. Both modes of RFA administration need specif-
ic devices- HALO 360 for circumferential and HALO 90,
60, Ultra Long for focal RFA [11, 106, 112]. Currently, there
are two protocols for RFA use: standard (2x12-15J/cm2-
cleaning-2x12-15J/cm2) and simplified protocol (3x12J/cm2,
no cleaning) [113-115]. The effects are similar, but the sim-
plified protocol is less time consuming than standard and is
preferred regimen for focal RFA of BE [106, 116]. Almost
complete eradication of dysplasia and IM are encountered in
RFA treated patients with LGD, HGD, and “simple” BE
(90%, 81%, and 77% patients, respectively) [117, 118].
RFA is a safe procedure, with low rates of occurred com-
plications, such as bleeding, postprocedure chest pain, stric-
ture formation, and perforation [119, 120]. After RFA ses-
sion, management with PPIs and analgesics and no antimi-
crobials are recommended, with new endoscopy after 3
months [106]. In every fifth treated patient who achieved
complete eradication of IM, BE recurred after 2.4 years of
follow-up [121]. Some factors can influence incomplete or
poor response to RFA regarding dysplasia eradication, such
as longer length and duration of BE, poor reflux control,
abnormalities of p16 locus and p53 and RFA treatment per-
formed in low-frequency centres [109, 110, 122, 123]. IM
under the new squamous epithelium (“buried metaplasia”)
could be endoscopically invisible and carries a significant
risk of malignancy [124]. Post-RFA EAC is rare but indi-
cates endoscopic surveillance after RFA, even after the
treatment goal is achieved [106]. RFA for BE should be car-
ried out by trained and experienced endoscopists if it is pos-
sible in reference centre [16].
4.4. Surgical Treatment
Surgery is reserved for patients with persisted GERD
symptoms despite the long-term use of PPIs. Another indica-
tion of surgical treatment is a progressive disease. Current
laparoscopic techniques (partial or total fundoplication) are
the surgical procedures of choice [11, 20]. Former recom-
mendations regarding mandatory surgical treatment of EAC
are now changed- early EAC can be treated by endoscopic
eradication treatment, especially in early stages [10].
However, in the cases of multifocal HGD, selected patients
can be considered for surgery because of the higher risk of
occult EAC [125, 126].
CONCLUSION
BE represents a premalignant condition for the
development of EAC, so it is mandatory to break BE's
natural history chain by the use of medical, endoscopic, and
surgical strategies [10, 11]. Medical treatment is related to
PPIs in regard to control GERD symptoms and to decrease
the risk in the progression of BE to EAC via anti-acid and
anti-inflammatory effects, opposite to H2 blockers EAC [10,
63, 64]. Some concerns of PPIs adverse effects have been
addressed, such as an increase in gastrin levels and the risk
of Alzheimer's disease, but observational studies suggested
that the overall risk remains small even in long term use [99-
101]. Endoscopic treatment is recommended in those with
confirmed HGD, early EAC, and in selected LGD patients
[10, 103]. RFA is among the most frequently used ablation
techniques of BE [10, 15]. Currently, RFA has established an
endoscopic technique for BE eradication as well as for the
eradication of residual BE after endoscopic resection of early
EAC [18]. The imperfection of RFA as the procedure is
based on possible BE recurrence, the presence of "buried
metaplasia" as well as post-RFA-EAC. So, after RFA
session, management with PPIs is recommended, with new
endoscopy after 3 months and then at regular intervals,
depending on the purpose of endoscopic surveillance. The
conditions for successful RFA are its performance by trained
and experienced endoscopists in reference center and the
biopsy specimens histology examined by a pathologist
experienced in BE and EAC. Despite the well-recognized
8 Mini-Reviews in Medicinal Chemistry, 2020, Vol. 20, No. 0 Dugalic et al.
treatment use for BE and EAC, the best treatment for BE and
EAC needs to be further explored. Currently, the combined
use of chemoprevention (PPIs) and endoscopy treatment
(both tissue acquiring and ablative techniques) are the
mainstays of BE and EAC treatment, but in treatment
indolent and progressive disease surgical procedures are the
preferable choice.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
This work has been supported by grant No. 173033
(E.R.I.) from the Ministry of Science, Education and Tech-
nological Development, Republic of Serbia.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Author’s contribution: P.D. and E.R.I. designed and
wrote the paper, S.Dj., A.P.M., V.D., R.T., Z.G., M.O., and
V.B. wrote the paper.
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