The failure of Proton Pump Inhibitors in Gastro Esophageal Reflux Disease

Gastro-esophageal reflux is a common phenomenon in which gastric contents flow
back into the esophageal lumen. When reflux causes symptoms and/ or esophageal
damage, it is referred to as gastro esophageal reflux disease (GERD). Proton
pump inhibitors (PPIs) are widely used in the treatment of GERD. PPIs diminish
the secretion of acid by blocking the H+/K+ ATPase pump of the parietal cells
of the stomach. In approximately 30% of patients PPI-therapy fails to
completely resolve symptoms, either partially of completely. Additionally, it
appears that less than 50% of patients with GORD are satisfied with their
medical treatment, and only 58% of those receiving PPIs report a high level of
satisfaction with it. The group of patients with GERD with partial PPI failure
is a clinical problem, as there is only limited additional medicinal therapy,
and antireflux surgery can lead to serious morbidity.
It is unknown what causes the failure of PPIs in this group of patients. After
exclusion of patients with a wrong diagnosis and incompliant patients, several
factors are proposed:
1. Increased sensitivity: Treatment with PPI changes the pH of the refluxate,
but leaves the amount of reflux episodes unaffected. An increased sensitivity
for weakly acid reflux might explain symptoms. Two possible explanations are
proposed: hypersensitivity for distension of the upper esophagus, or
hypersensitivity to chemical stimuli.
2. Increased permeability: The permeability of the esophageal stratified mucosa
is shown to be increased in GERD patients, by means of the dilated
intracellular spaces. An increased esophageal permeability enables refluxate
to reach the nerves in the esophageal mucosa. It is proposed that patients who
remain symptomatic during PPI treatment have dilated intercellular spaces.
3 Chemical composition of refluxate: Refluxate contains several potentially
noxious factors, of which H+ is the only factor affected by PPIs. It is already
shown that a significant portion of symptoms during PPI treatment are actually
caused by reflux of bile acids.
4 Position of the gastric acid pocket In recent work of our group we have shown
the importance of the gastric acid pocket, a pool of acid floating on top of a
meal, for the occurrence of acid reflux. By injection of 99mTc-pertechnetate we
were able to visualize this pool of acid scintigraphically. This pocket is also
present during PPI therapy, and therefore we hypothesize that the position and
other properties of the postprandial acid pocket differ in patients with
refractory symptoms compared to patients with good clinical response.
These 4 factors are proposed as factors that influence proton pump failure;
however they have never been examined in patients with proton pump failure
versus patients with good clinical respons.

In this study we aim to determine the esophageal sensitivity by means of weakly
acidic solution and esophageal distension, and determine the position and
composition of the acid pocket in patients with and without PPI. We hypothesize
that these factors influence the (partial) failure of PPIs in patients with
GERD and might enable us to better target therapy beyond PPI in the future.

The study has a prospective cross sectional design.

stop medication for 1 week

Risks and Burden:
Oesophagogastroduodenoscopy
Upper endoscopy is a routenily performed investigation, which belongs to the
standard procedures in patients with GERD. In this short investigation the
esophagus, stomach and proximal duodenum are watched with an endoscope. During
endoscopy, patients will be placed on a monitor that checks heart rate, blood
pressure and oxygen level.
Esophageal biopsies are taken regularly during upper endoscopy. A possible
severe risk of a biopsy is a perforation (0,03%). In most cases perforation
can be treated expectative or endoscopically. In a minority of cases, surgery
has to be perfomed to close the perforation. Another risks of esophageal
biopsies is bleeding, which can be treated endoscopically.
Scintigraphy
During studay 2 350 MBq 99mTc-pertechnetate is applied intravenously.
99mTc-pertechnetate has no known side effects other then the radiation. The
radiation dose is in the intermediate category. Patients who recently
participated in a trial with radiation are excluded from the trial.
All study days have the burden of introduction of catheters or an endoscope.
furthermore patients have to stop using PPI for one week.

Group relatedness and benefit.
The patients studied all have proven reflux disease. Patients do not benefit
from participation in the study.