Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00155805 |
| Other study ID # |
9200200605 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
September 9, 2005 |
| Last updated |
November 25, 2005 |
| Start date |
February 2004 |
| Est. completion date |
December 2006 |
Study information
| Verified date |
February 2004 |
| Source |
National Taiwan University Hospital |
| Contact |
Bor-Ru Lin, M.D. |
| Phone |
886-2-23123456 |
| Email |
brlin[@]ha.mc.ntu.edu.tw |
| Is FDA regulated |
No |
| Health authority |
Taiwan: Department of Health |
| Study type |
Observational
|
Clinical Trial Summary
By using combination of the expression of COX-2 and NOS and immunologic reaction in the
esophagus with manometry of LES and cruel diaphragm and 24 hr esophageal pH monitoring to
investigate the mechanisms and to make a new and more clinically applicable clarification of
these reflux diseases will be valuable in the clinical management and prevention. We will
perform the following works and complete the objectives: 1) comparing the difference of
immuno-inflammatory reactions among NERD, reflux esophagitis and Barrett’s esophagus; 2) the
different expression of PGs & COX-2 in functional heartburn, hiatus hernia, NERD, reflux
disease and Barrett’s esophagus; determining the subtype of EP receptor (EP1~4); 3)
determining and comparing the expression of NOS in the esophagus; 4) investigating the role
of ROS in the esophagus; 5) in correlating cytokine, COX-2 and NOS with LESP, TLESR,
diaphragm EMG and 24-hour esophageal pH ; 6) the difference of expression of cytokine,
atrophic gastritis and Hp in gastric mucosa, in correlating with intragastric acid status,
among functional heartburn, hiatus hernia, NERD, erosive esophagitis and Barrett’s
esophagus; to determine whether should eradicate Hp in reflux esophageal disease; 7) the
effects of lipid peroxidation related immunologic reaction, with relation to COX-2 and NOS,
in the inflammatory activity and esophageal carcinogenesis of esophagus; 8) the effects of
cytokines, COX-2 and NOS on the apoptosis in these reflux esophageal diseases; 9)
integrating immuno-inflamatory reaction, COX-2, NOS with manometry of LES and diaphragm, and
24-hour pH monitoring and intragastric pH to newly clarify GERD into evidence based
categories.
Description:
It has been commonly accepted that there is considerable geographic variation in the
prevalence of gastroesophageal reflux disease (GERD) and much less prevalent in Asia.
However, a tendency of increasing the prevalence of GERD has been observed in Taiwan with
four folds of growth (attached 1 & 2), Japan and Singapore. GERD is a chronic, relapsing
disease, causing a poor quality of life lower than that of CAD and a greater burden with
exhausting socioeconomic and medical resource much higher than peptic ulcer disease. Thus,
thoroughly elucidating the mechanisms of GERD, in combination of basic science and clinical
characteristics, to well and correctly clarify these diseases will be greatly helpful in
clinical application.
Reflux of duodenal contents is believed to contribute to esophageal injury, Barrett’s
esophagus and esophageal cancer. HCL and bile acid, particularly conjugated form at low pH,
has now been considered playing a more important pathogenetic role in the reflux
esophagitis; on the contrary, low gastric acid status may increase the risk of dysplasia and
carcinogenesis on Barrett’s esophagus due to increased pulse of bile acid. While, only
limited reports focusing immune mechanism in the complex populations of GERD. In few
preliminary literatures showed that cytokine and tumor necrosis factors are associated with
GERD and Barrett’s esophagus; it is worthwhile to further investigate. The effect of benefit
or harm of presence of Hp infection in GERD is debated; most are epidemiologic study,
lacking evidence- based data; whether need to eradicate Hp in the patients with reflux
disease or not is difficult to conclude. The current theory of transient relaxation of LES
(TLESRs) as the major pathophysiologic mechanism of GERD has been challenged after pooling
mass clinical experiences. Particularly after recent development of endoscopic therapy of
GERD, we found that current understanding of integration of anatomy and physiology of
motility of LES and related components in GERD is still insufficient. It will be important
to integrate evidence- based basic and clinical data of esophagus, in order to enter new era
of the treatment of GERD.
Recently, Fass R et al., proposed a new conceptual framework of GERD; they suggest that it
should be divided into three categories, instead of a linear relation in the same spectrum,
including NERD, reflux esophagitis and Barrett’s esophagus. In our clinical observation, we
also have got the same concept; TLESR alone cannot fit all of the clinical characteristics
and fails to explain all mechanisms of GERD. Based on currently advanced concepts from the
top of world and our observations, we propose the following hypotheses: (1). LES and cruel
diaphragm are the equally important barriers of lower esophagus in prevention of reflux.
TLESR alone is insufficient to causing these reflux diseases; on the contrary, hiatus hernia
is believed playing an important role in the beginning and late stage of GERD than
previously known; so called small hiatus hernia (< 2 cm) and dynamic abnormality of crual
diaphragm with ‘physiologic’ hernia with transient sac should not be neglected, particularly
in the patients of ‘minimal esophagitis’ and NERD and maybe also in those of Barrett’s
esophagus. (2). Once dysfunction of LES and cruel diaphragm with loss of both intrinsic and
extrinsic sphincters, there should be an indirect or intermediate defense or mediator before
resulting in NERD, reflux esophagitis or Barrett’s esophagus; immuno-inflammatory reaction
and COX-2 expression are the firstly candidates. (3) The mechanism of NERD is dysfunction of
both sphincters with a physiologic hernial sac, but without immunological abnormality. (4).
NOS is the major modulator of the LES and cruel diaphragm. (5). Benefit or harm of Hp
infected stomach to esophagus probably depends on the resulting intragastric acid status
rather than the simplified concept of the presence of Hp itself. (6). Via different patterns
of expression of NOS, COX-2 and immuno-inflammatory reaction, the refluxed HCL and bile acid
in the lower esophagus can make lower esophagus expressed as three categories: (a). Symptom
–NERD, (b). Inflammatory necrosis- reflux esophagitis, (3). Cell cycle abnormality with
metaplasia- Barrett’s esophagus; no linear relationship between these three.
The above hypotheses are mainly based on the following evidences or speculations:
prostaglandins (PGs) possess dual effects of pain sensation and motility in the
gastrointestinal tract. It is believed that PGE2 release during inflammation initiated by
acid injury is a key component of LES dysfunction and reflux damage. Gastric and duodenal
juice can induce production of ROS, thereby damaging esophageal mucosa, which is strongly
associated with reflux esophagitis. ROS may induce DNA modifications and act as carcinogens.
ROS can induce apoptosis in cultured gastric cells. Apoptosis is believed to occur in these
conditions; and suppression or inhibition of apoptosis contributes to carcinogenesis and its
progression. However, this is still lacking sufficient related data in bile acid related
esophagitis and esophageal carcinogenesis with ROS and apoptosis. Therefore, it will be
valuable to elucidate the role of ROS in the HCL and bile acid related esophagitis and
carcinogenesis with relation to apoptosis. Recently, COX-2 is believed to highly contribute
to esophageal carcinogenesis. And ROS can up-regulate COX-2 in bovine luteal cells.
Therefore, we believe to elucidate the role and mechanism of PGs and COX-2 in the reflux
esophagitis. Additionally, NO produced from nNOS can relax lower esophageal sphincter and
play a role in the NANC modulation in the LES. However, pervious hypothesis “cNOS is
beneficial and iNOS is harmful to gastrointestinal tract” has been highly questioned
recently. While, the interaction of COX-2 and NOS has been known to effect on the modulation
of the function and inflammatory activity in the cardiopulmonary system and kidneys. So, we
can believe that in order to elucidate the mechanisms of esophageal function and
esophagitis, simultaneous investigation of the effects and roles of COX-2 and NOS is
necessary and very import. NO modulating agents and COX-2 inhibitor is believed to of the
most promising in the treatment of reflux esophagitis and its related metaplasic or
neoplastic complications in the future. Unfortunately, there is still lacking sufficient
integrated clinical and molecular biologic data in this task.
It has been preliminarily known that IL-8 and IL-1β (TH-1cytokines) play a role in the early
inflammatory stage in reflux esophagitis; IL-4 and L-10 (TH-2cytokines) may play an
important role in the development of Barrett’s esophagus; and TNF-αand p53 mutant are
closely related with dysplasia and carcinogenesis of Barrett’s esophagus, but its clinical
application remains to be further testified, particularly in correlating with COX-2 and NOS
expressions. It has been known that IL-1β is an extremely potent acid suppressant. Hp-
infected stomach with mucosal inflammation can up-regulate the IL-β expression and result in
gastric atrophy with hypoacidic status and increase in the risk of gastric cancer; we
speculate this low acid status may decrease the acid injury to esophagus with lower risk of
NERD and reflux disease; on the contrary, the risk of Barrett’s esophagus, dysplasia and
carcinogenesis may increase by increasing bile acid pulse. This hypothesis is worthwhile to
be testified to elucidate these dates.
By using combination of the expression of COX-2 and NOS and immunologic reaction in the
esophagus with manometry of LES and cruel diaphragm and 24 hr esophageal pH monitoring to
investigate the mechanisms and to make a new and more clinically applicable clarification of
these reflux diseases will be valuable in the clinical management and prevention. We will
perform the following works and complete the objectives: 1) comparing the difference of
immuno-inflammatory reactions among NERD, reflux esophagitis and Barrett’s esophagus; 2) the
different expression of PGs & COX-2 in functional heartburn, hiatus hernia, NERD, reflux
disease and Barrett’s esophagus; determining the subtype of EP receptor (EP1~4); 3)
determining and comparing the expression of NOS in the esophagus; 4) investigating the role
of ROS in the esophagus; 5) in correlating cytokine, COX-2 and NOS with LESP, TLESR,
diaphragm EMG and 24-hour esophageal pH ; 6) the difference of expression of cytokine,
atrophic gastritis and Hp in gastric mucosa, in correlating with intragastric acid status,
among functional heartburn, hiatus hernia, NERD, erosive esophagitis and Barrett’s
esophagus; to determine whether should eradicate Hp in reflux esophageal disease; 7) the
effects of lipid peroxidation related immunologic reaction, with relation to COX-2 and NOS,
in the inflammatory activity and esophageal carcinogenesis of esophagus; 8) the effects of
cytokines, COX-2 and NOS on the apoptosis in these reflux esophageal diseases; 9)
integrating immuno-inflamatory reaction, COX-2, NOS with manometry of LES and diaphragm, and
24-hour pH monitoring and intragastric pH to newly clarify GERD into evidence based
categories.
I. Patient selection by GERD symptom questionnaire with score of severity and frequency, and
quality of life (QoL).
II. Panendoscopic examination: the patients were clarified into NERD, reflux esophagitis or
Barrett’s esophagus (each n=20), with additional group of hiatus hernia (n=20 for each those
> 2 cm and < 2 cm, respectively; the patients are free of symptom and endoscopically erosive
esophagitis); another group of functional heartburn (%time of pH < 4 less than 4 and
DeMeester score < 14.72; n =50).
III. Endoscopic biopsy: specimens of esophagus, cardia and antrum will be obtained for
histology (H&E stain for inflammatory activity, atrophic gastritis and Hp, and special stain
for Barrett’s esophagus).
IV. Immunological and molecular study of esophageal and cardia specimens: EIA,
immunohistochemistry, Western blotting, RT-PCR of COX-2, NOS and cytokine. EIA for PGs.
V. Immunological and molecular study of antral specimens of stomach: EIA,
immunohistochemistry and Western blotting of IL-1β.
VI. Blood sampling for plasma: EIA for cytokines, PGI, PGII, PGI/II, gastrin and Hp titers.
VII. Esophageal manometry: LESP will be divided into hypertensive, normotensive and
hypotensive; calculate TLESRs at the same time. VIII. Diaphragm EMG: DEMG will be divided
into hypertensive, normotensive and hypotensive. IX. 24-hour esophageal pH monitoring:
recording total numbers of reflux episodes, total duration of pH < 4 and DeMester score;
record intragastric pH.
X. In vitro esophageal tissue culture: endoscopic biopsy specimens of esophagus from the
patients. 1) adding HCL or bile acid into tissue culture to measure the expression of
cytokine, COX-2 and NOS; 2) adding cytokine into tissue culture to measure COX-2 expression;
3) adding PGs, arachidonic acid, L-arginine and ROS, respectively or in combination, into
incubated esophageal specimens to measure cytokine and COX-2 expression ; 4) instill PGs
antagonists, COX inhibitors, NOS inhibitors or ROS scavengers, each alone or in combination,
into incubated esophageal specimens to measure cytokine COX-2 expression.
This is a study of an integrated clinical anatomy-physiology, immunology and molecular
biology in gastroesophageal reflux disease. Starting from clinic to bench and back from
bench to bedside, detailed mechanisms of GERD will be obtained and a new clarification will
be provided to further clinical application in the treatment and prevention of GERD. The
role of Hp will be elucidated and to determine whether should eradicate Hp in the reflux
esophageal diseases.
