1,721,216 research outputs found
Studies on factors predicting GORD response to proton-pump inhibitors: NERD subpopulations need to be analysed separately.
No full textWe read with interest the paper by Zerbib et al on the factors predicting the response of patients with gastro-oesophageal reflux disease (GORD) to proton pump inhibitors (PPIs) therapy and believe that the results they obtained must be interpreted with caution. The French authors concluded that multivariate analysis, including both clinical and physiological parameters, did not identify any reflux pattern associated with PPI failure. This is at variance with many previous findings, which have clearly shown that an increased oesophageal acid exposure is a robust predictor of reflux response to PPIs. We believe that the surprising result achieved by Zerbib et al is probably due to the fact that only 35% of the patients enrolled in the study had an abnormal oesophageal acid exposure, while the majority of their patients (56%) showed symptoms pertaining to non-erosive reflux disease (NERD) (although it is not clear how 14 patients not identified as NERD or erosive oesophagitis or functional heartburn (FH) have been classified for the analysis and these patients were considered as a unique population instead of separate subgroups as identifiable by pH-impedance. It is well known that the subgroups with hypersensitive oesophagus (HO) and FH have a normal acid exposure. Even though they have performed a subanalysis in patients with only documented GORD (abnormal oesophageal acid exposure and/or positive symptom association analysis) in order to exclude those with FH, this subgroup still contains a greater part of patients with HO (about 50%), who do not have an excess of acid in their oesophagus, which can be responsible for the unexpected finding that increased oesophageal acid exposure is not able to predict a good response to PPIs. Therefore, subgroups of NERD should be analysed as distinct populations instead of pooling them together in order to avoid relevant confounding factors.
Also, the presence of functional digestive disorders as predictive factors of PPI failure is further confirmation that many NERD patients studied by them pertained to the subgroups with HO and FH, because previous studies have clearly documented that functional dyspepsia prevails in patients with FH and HO2 and also irritable bowel syndrome is much more represented in
patients with NERD than in those with erosive oesophagitis.
Moreover, the authors concluded that a BMI #25 kg/m2 is a determinant factor in predicting lack of response to PPIs in all the groups of GORD patients analysed in their study. On the contrary, previous data have
clearly shown that an increase in BMI is significantly associated with poor response to PPI therapy. Once again, this result reported by Zerbib et al may be due to the enrolment of many patients with HO and FH in their study, who have been shown to be significantly thinner than those with
erosive oesophagitis and NERD with abnormal oesophageal acid exposure. Finally, among the clinical factors having the potential to affect the response to PPI therapy, the authors have not considered the presence of hiatal hernia, which has been shown to play a key role in determining the
right dosage of PPIs to obtain therapeutic success.
Therefore, we believe that the factors influencing the response to PPI therapy can no longer be analysed by pooling together all the subpopulations included in the GORD realm. In particular, as pH-impedance has allowed us to subdivide the heterogeneous population of NERD, which represents about 80% of reflux patients, into more definite subgroups (NERD with acid excess in the oesophagus and HO) that are clearly
separated from FH, we believe that all variables that can potentially guide our clinical management of GORD patients should be evaluated by taking into account the above categorisation and thus the old concept of
analysing them as a unique population should be given up
The Relevance of Weakly Acidic Reflux in Patients With Barrett's Esophagus.
No full textWe read with great interest the paper by Krishnan et al1 on the factors predicting the persistence of intestinal metaplasia in patients with Barrett’s esophagus before undergoing radiofrequency ablation (RFA). The authors found that uncontrolled, weakly acidic reflux is an important determinant of the incidence of persistent intestinal metaplasia in the distal esophagus, despite twice daily proton pump inhibitor (PPI) therapy before RFA.
The advent of 24-hour esophageal pH impedance has allowed us to detect both acid and weakly acidic reflux, although the latter cannot necessarily be identified as a fluid containing bile salts. Moreover, it is well known
that PPIs do not reduce the number of reflux episodes, but are only able to change acid into weakly acidic reflux. So, Krishnan et al documented a factor predicting the failure of RFA, but this is mainly the result of an ongoing,
powerful, antisecretory therapeutic regimen taken by patients examined in their study instead of a welldefined pathophysiologic phenomenon.
Using the same ambulatory pH-impedance technique, we have recently studied a group of patients with Barrett’s esophagus off PPI therapy and showed that they have significantly greater acid and weakly acidic refluxes compared with patients with erosive esophagitis, nonerosive reflux disease, and control subjects. This means that patients with esophageal intestinal metaplasia have an increased reflux not only of acid, but also of weakly acid
content independently of the intake of PPI therapy. This combined physiologic abnormality may be responsible for the formation of the esophageal metaplastic epithelium and perhaps for its persistence in those patients who do not benefit from RFA.
In other words, also studying Barrett’s patients off PPI therapy would have allowed Krishnan et al to find an uncontrolled weakly acidic reflux as the predictor of RFA failure without the interference of high-dosage PPI
treatment, which determines a predominant reflux of this type.
Moreover, the results of this study are further confirmation of the fact that weakly acidic reflux is able to induce not only the same symptoms of acid reflux, but is also associated with the same important esophageal histologic
lesions, such as intestinal metaplasia, which characterizes patients with Barrett’s esophagus. These findings reinforce the pathogenetic role of weakly acidic reflux in the generation of microscopic esophagitis, and metaplastic esophageal epithelium, and highlight the necessity of controlling this type of reflux to prevent the development of these histologic alterations. Thus, this investigation clearly claims for future studies aimed at testing whether stopping weakly acidic reflux by means of novel drugs or antireflux surgery may contribute to healing mucosal damage in Barrett’s esophagus, or at least preventing RFA failure
The importance of subgrouping refractory NERD patients according to esophageal pH-impedance testing.
No full textTo The Editor:
We read with great interest the paper by Frazzoni et al. (1) on the role of robot-assisted laparoscopic fundoplication in the treatment of PPI-refractory GERD patients as diagnosed by on-PPI impedance-pH monitoring. We must congratulate with the authors as they clearly demonstrated the efficacy of anti-reflux surgery in PPI-refractory GERD patients, including a long-term (3years) evaluation to reinforce their findings. They clearly showed that the major therapeutic gain of surgery relies on the reduction of weakly acidic reflux episodes, but we argue that some points of the study need to be discussed more in depth.
The authors included in their analysis patients who underwent preoperative on-PPI impedance-pH testing revealing positive symptom association probability (SAP)/symptom index (SI), and/or abnormal oesophageal acid exposure time (AET), and/or abnormal number of total refluxes. Thanks to the clinical application of 24-hour oesophageal impedance-pH, we have previously proposed a subclassification of patients with typical reflux symptoms and normal upper gastrointestinal endoscopy into three different groups: (a) non-erosive reflux disease (NERD) pH-POS patients with normal endoscopy and abnormal distal AET; (b) hypersensitive oesophagus – patients with normal endoscopy, normal distal AET and positive symptom association for either acid or non-acid reflux; and (c) functional heartburn (FH) – patients with normal endoscopy, normal distal AET and negative symptom association for acid and non-acid reflux (2,3). It is not clear whether the authors have totally excluded from their analysis the subgroup of patients with FH, who represent about 25% of those having typical reflux symptoms without any kind of reflux underlying them. They cannot anymore considered within the realm of GERD according to Rome III criteria (4,5) and frequently do not respond to PPIs. It is also obvious that they cannot benefit from surgical anti-reflux therapy.
Since the introduction of impedance-pH monitoring in clinical practice, different normal values have been proposed in order to diagnose GERD. The most common used [i.e. the United States (US), Belgian-French (BF) and Italian (ITA) normal values] have different upper limits of normality for distal AET (USA=6.3%, BF=6.2% and ITA=4.2%, respectively) and total number of reflux episodes (USA=73/daily, BF=72/daily and ITA=54/daily, respectively), the two main parameters used to distinguish normal from abnormal GER (6-8). Moreover, a recent paper by Zerbib et al (9) modified the French impedance normal values reducing their upper limit of normality for total reflux episodes to 53 that was almost the same value we proposed several years before (8). In their study, Frazzoni et al. applied normal values that are significantly lower than those mentioned before (AET=3.3%; total number of reflux episodes=45). Given these lower limits of normality, one can hypothesize that some patients have been enrolled and treated despite the presence of a mild or border-line disease, with the risk of weaken the very good outcomes obtained among their PPI-refractory GERD patients. Therefore, we believe that indicating the number and intensity of symptoms reported by their patients during the testing day could be useful in order to justify the choice of a surgical approach and to corroborate the strength of their findings in terms of post-surgical outcome.
Whereas the diagnostic utility of impedance-pH monitoring in diagnosing GERD in both patients on- and off-PPI therapy have been extensively demonstrated in several recent studies (10-14), very scant data are available on the real clinical impact of this novel technique in GERD management (15). This is particular true for patients with NERD and normal esophageal acid exposure with positive symptom association to acid and/or non-acid reflux who are characterized by an “hypersensitive esophagus” and represent about half of the NERD patients and 1/3 of the entire GERD population (16). To date, these patients are considered a very difficult task for both gastroenterologists and surgeons in terms of management and treatment, since no effective drugs are available in our pharmacological armamentarium (i.e. PPI and H2 antagonists as well as antacids are not effective in these patients). Thus, we think that the Authors, demonstrating the very good efficacy of anti-reflux surgery in patients with positive symptoms association (64%) and without history of esophagitis (50%), had the remarkable opportunity to emphasize this concept and highlight that an excellent therapeutic chance for this large group of patients actually exists and should be strongly considered, although further studies are necessary to confirm these findings.
Moreover, the Authors compared the results of impedance-pH testing performed before and after robot-assisted laparoscopic fundoplication without discussing the fact that the patients were on PPI drugs during the first examination and their results could have been different if the preoperative impedance-pH was done in patients not taking any antisecretory compounds. In fact, it is well known that PPI therapy does not reduce the number of total reflux episodes, but changes the chemical nature of refluxate which becomes predominantly weakly acidic from acid. We are aware that surgical therapy enables to block both acid and weakly acidic refluxes and this certainly affected the positive results obtained by Frazzoni et al (1) on the prevalent control of weakly acidic reflux episodes. We think that it is not fair to compare functional tests on PPIs before and off PPIs after surgery.
In conclusion, we believe that this is a very interesting study showing the benefit of surgical therapy in controlling mainly weakly acidic refluxes of patients not responding to PPIs; however, a better characterization of the study population and a more in depth discussion of the main findings would have been useful for the reader
Esophageal acid exposure still plays a major role in patients with NERD.
No full textTo The Editor:
We read with great interest the paper by Zhong et al (1) on the significant correlation between esophageal intraluminal baseline impedance and the severity of acid reflux as well as esophageal mucosal histopathological changes, such as dilated intercellular spaces (ICS) and tight junction alterations. This means that low baseline impedance values reflect microscopic mucosal inflammatory abnormalities, which are mainly induced by acid and increase across the spectrum of GERD.
In particular, the Chinese study reports that the mean baseline impedance values in non-erosive reflux disease (NERD) were significantly lower than in controls and, among NERD subgroups, the lowest levels pertained to patients with increased acid reflux events and those with mixed acid/weakly acidic reflux episodes. Analyzing the results more in depth, one can realize that an important information is lacking. In fact, patients with NERD were classified into 4 groups on the basis of normal/abnormal number of reflux episodes (i.e. acid, weakly acidic, mixed acid and weakly acidic, alkaline) without mentioning anything about the level of esophageal acid exposure in them. Previous studies documented that about 40% of NERD patients have abnormal distal esophageal acid exposure time (AET) (2-5). For instance, Martinez et al. reported that 45% of their NERD patients had an increased AET (3), while we observed a rate ranging from 33% to 42% of abnormal AET in large samples of endoscopy-negative patients (2,4,5). Moreover, it has been shown that both patients with abnormal number of weakly acidic or mixed reflux events and those with normal number of acid reflux episodes may have also abnormal AET (6,7). Thus, classifying patients only on the basis of the number of reflux episodes without considering the presence of a normal/abnormal AET may lead to an underestimation or overestimation of the role of acid in these patients. Moreover, this could represent a potential confounding factor for the evaluation of baseline impedance values in both weakly acidic and mixed reflux subgroups, thus questioning the conclusion that also weakly acidic reflux decreases baseline impedance values in NERD patients.
It must be also stressed that the number of patients with abnormal number of weakly acidic reflux events is much higher than expected. In fact, the increase in weakly acidic reflux may be the result of PPI therapy (8) and we wonder whether the withdrawal of these drugs had been done for a period long enough to guarantee that impedance-pH testing was not affected by the above treatment. Anyway, the results obtained in this study cannot be easily extrapolated to those we can find in populations of Western countries.
Finally, it is very surprising that the authors acknowledged the use of light microscopy (LM) instead of transmission electron microscopy (TEM) as an important limitation of their study. In fact, we have shown that LM is able to demonstrate with very good accuracy all the histopathological alterations characterizing microscopic esophagitis, including the ICS (9,10). This method is not only easier and cheaper than TEM, but also more practical as it can be used routinely during the daily clinical practice. An expert pathologist permits to exploit on biopsy samples the entire diagnostic information contained in each element proper of esophageal microscopic inflammation and, if it is true that finding low baseline impedance values is expression of subtle inflammatory mucosal changes, a good correlation between this new functional marker and the damage of esophageal mucosa would be better found by using LM rather than TEM
Dysmotility and reflux disease.
No full textAbstract
PURPOSE OF REVIEW: In the last decade, with the advent of new oesophageal testing -h impedance-pH monitoring, combined impedance-manometry, high-resolution manometry (HRM)], relevant progress in understanding the mechanisms contributing to the development of gastro-oesophageal reflux disease (GORD) has been made, allowing a better management of patients with this disorder. The aim of our review is to report the state-of-the-art about oesophageal motor disorders in patients with reflux disease and to stimulate new research in this field. RECENT FINDINGS: Hypotensive lower oesophageal sphincter (LOS), transient LOS relaxations, impairment of oesophagogastric junction including hiatal hernia, oesophageal bolus transit abnormalities and presence of ineffective oesophageal motility have been strongly implicated in GORD development. In particular, the majority of recent studies carried out with HRM and impedance-pH testing reported that these motor abnormalities are increasingly prevalent with increasing severity of GORD, from nonerosive reflux disease and erosive oesophagitis to Barrett's oesophagus. SUMMARY: Defining and characterizing oesophageal dysmotility in patients with reflux disease is of maximum importance in order to properly diagnose these patients and to treat them with the best management of care. New studies are needed in order to better understand the physiomechanic basis of oesophageal dysmotility in GORD patients
Proton pump inhibitors in GORD An overview of their pharmacology, efficacy and safety
No full textGastric acid secretion is a complex phenomenon under nervous and hormonal influence. The stimulation
of proton pump (H+, K+-ATPase) in the parietal cell represents the final step of acid secretion and this
knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are
targeted at blocking this enzyme. Chemically, all the available PPIs consist of a benzimidazole ring and a
pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors
of gastric acid secretion available. Although there are differences among PPIs concerning their pharmacokinetics,
pharmacodynamics, influence by food and antacids as well as potential for drug interactions,
it is not always evident whether these often subtle differences are clinically relevant. A careful evaluation
of the available studies reveals that rabeprazole and esomeprazole achieve more rapid acid inhibition
than other PPIs. Also, the effect of rabeprazole is less dependent upon genetic make-up than all other
PPIs, giving rise to less inter-subject variability and leading to a more predictable effect. Esomeprazole,
by inhibiting its own catabolism, makes all patients slow metabolizers, but could expose them to potential
drug interactions. PPIs are the mainstay of medical treatment of gastro-oesophageal reflux disease
(GORD), in that they are able to provide 80–85% healing rate of oesophageal lesions, including ulcers,
and to reduce the incidence of complications like strictures as well as dysplasia and adenocarcinoma in
Barrett’s oesophagus (BO). Also relief of symptoms can be achieved in about 80% of cases, even though this
benefit is reduced by a factor of approximately 20% in patients with non-erosive reflux disease (NERD).
Their effect on Barrett’s oesophagus and the extra-oesophageal manifestations of GORD is much less consistent.
In general, the tolerability profile of PPIs is good in both short- and long-term clinical trials. This
safety profile is similar across the various PPIs used in clinical practice and is extended to children and
pregnant women, where they do not present any major teratogenic risk
It is time to plan clinical trials on true NERD patients.
No full textWe read with great interest the article by Weijenborg et al. showing that PPI therapy is equally effective in relieving heartburn in patients with both erosive esophagitis (ERD) and well-defined non-erosive reflux disease (NERD). These results are in contrast with the common belief, mainly sustained by a previous metaanalysis, that the response to PPIs is much lower in NERD than in ERD patients and confirm that the pathophysiological characterization of the various subgroups generally comprised under the umbrella term of NERD is fundamental to identify patients with true NERD, who can be expected to respond satisfactorily to powerful antisecretory therapy. At present, functional testing is the only method allowing us to differentiate well-defined NERD from functional heartburn, which does not pertain anymore to the realm of GERD. These patients complaining of
heartburn do not present any esophageal mucosal lesion at endoscopy and do not have any acid reflux underlying their symptoms. Therefore, the lack of any pathogenetic role of acid makes it difficult that they can benefit from PPIs. However, there is an additional subgroup of NERD patients who are characterized by an esophagus hypersensitive to weakly acidic reflux
which has been shown to induce the same typical symptoms of the acidic one. The identification of these patients has permitted to narrow down further the subgroup with functional heartburn, because their heartburn is strictly correlated with weakly acidic reflux. As the role of acid is greatly reduced also in them, the response to PPI therapy can be predicted to
be unsatisfactory. The meta-analysis by Weijnborg et al. is welcome
because the extraction from the medical literature of the two studies in which acid reflux was correctly documented by esophageal pH-metry allowed to avoid the usual contamination of true NERD population
with the patients with functional heartburn who cannot respond to PPIs and eventually to understand that well-defined NERD patients are equally responsive to PPIs as ERD ones.
It is time to plan clinical trials on NERD patients who are no more enrolled simply on the basis of negative endoscopy, but it is necessary to characterize this complex population from a pathophysiological point of view to assess the efficacy of PPI therapy only in patients whose symptoms are really sustained from acid reflux and to exclude the two subgroups of NERD
with weakly acidic reflux generally unresponsive to PPIs and functional heartburn, who do not have reflux disease
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