Spectrum Of Gastro-oesophageal Reflux Disease Research Articles

Psychological symptoms do not discriminate between reflux phenotypes along the organic-functional refractory GERD spectrum

ObjectiveHistorically, psychological processes are associated with disorders at the functional end of the gastro-oesophageal reflux disease (GERD) spectrum. However, recent research suggests that psychological symptoms are relevant across the entire...

Systematic review: relationships between sleep and gastro-oesophageal reflux

Gastro-oesophageal reflux disease (GERD) adversely impacts on sleep, but the mechanism remains unclear. To review the literature concerning gastro-oesophageal reflux during the sleep period, with particular reference to the sleep/awake state at reflux onset. Studies identified by systematic literature searches were assessed. Overall patterns of reflux during the sleep period show consistently that oesophageal acid clearance is slower, and reflux frequency and oesophageal acid exposure are higher in patients with GERD than in healthy individuals. Of the 17 mechanistic studies identified by the searches, 15 reported that a minority of reflux episodes occurred during stable sleep, but the prevailing sleep state at the onset of reflux in these studies remains unclear owing to insufficient temporal resolution of recording or analysis methods. Two studies, in healthy individuals and patients with GERD, analysed sleep and pH with adequate resolution for temporal alignment of sleep state and the onset of reflux: all 232 sleep period reflux episodes evaluated occurred during arousals from sleep lasting less than 15 s or during longer duration awakenings. Six mechanistic studies found that transient lower oesophageal sphincter relaxations were the most common mechanism of sleep period reflux. Contrary to the prevailing view, subjective impairment of sleep in GERD is unlikely to be due to the occurrence of reflux during stable sleep, but could result from slow clearance of acid reflux that occurs during arousals or awakenings from sleep. Definitive studies are needed on the sleep/awake state at reflux onset across the full GERD spectrum.

Systematic review: the burden of disruptive gastro‐oesophageal reflux disease on health‐related quality of life

About one-third of patients with gastro-oesophageal reflux disease (GERD) have frequent and/or severe reflux symptoms ('disruptive GERD'). The relative burden of disruptive GERD on health-related quality of life (HRQL) has not been systematically investigated. To assess the burden of disruptive vs. nondisruptive GERD on HRQL. Systematic searches were conducted in PubMed and Embase. To be included, studies had to have used validated questionnaires to assess HRQL. Nineteen studies were included. Data on the comparative burden of frequent (ranging from daily to ≥weekly) and severe reflux symptoms were provided in eight and 13 studies respectively; six reported on the additional burden of nocturnal symptoms. Compared with individuals with nondisruptive GERD, those with disruptive GERD had 2.4-times and 1.5-times higher mean rates of absenteeism and presenteeism respectively (five studies), 1.5-times lower sleep quality scores (three studies), 1.1-times lower mean summary scores for physical and mental health (five studies) and 1.3-times lower mean scores for psychological and general well-being (four studies). Increasing symptom frequency and severity both increased the burden of disease to a similar extent. The presence of nocturnal symptoms in addition to daytime symptoms led to worsening of physical health, but their effect on mental health and work productivity was less clear. Disruptive GERD is associated with a high burden of disease compared with occasional or mild reflux symptoms. Disease management needs to vary across the GERD spectrum and should be tailored to patients' requirements for optimal therapeutic outcomes.

Patients with physiological acid exposure and positive symptom association scores: a distinct group within the GORD spectrum

Studies comparing pH-metrically well-characterized gastro-oesophageal reflux disease (GORD) patients with physiological reflux to GORD patients with pathological reflux, with regard to clinical and epidemiological data, are lacking. We included 273 GORD patients with pathological 24-h pH-monitoring (pH+), defined as pH<4 > or = 6% of time. A symptom index (SI) > or = 50% was considered positive, as well as a symptom association probability (SAP) > or = 95%. We included 84 GORD patients with physiological acid exposure (pH-) and a positive SI and/or SAP. Manometry and endoscopy reports were reviewed. Subjects completed questionnaires about demographics and medical history, functional dyspepsia and irritable bowel syndrome, the Nepean Dyspepsia Index symptom score and the RAND-36 quality of life scale. pH- patients were younger (45 vs 50 years, P = 0.003), more often female (60%vs 39%, P = 0.001), smoked more (31%vs 19%, P = 0.021) and reported proton pump inhibition failure more often (47%vs 32%, P = 0.027). A hypotensive lower oesophageal sphincter was less common in pH- patients (18%vs 34%, P = 0.008) and distal oesophageal contraction amplitude was higher (11 vs 9.5 kPa, P = 0.045). pH- patients had hiatal hernia and oesophagitis less often (48%vs 73%, P < 0.0005; 36%vs 54%, P = 0.012 respectively). pH- patients less often reported no other symptoms besides GORD (20%vs 34%, P = 0.015). pH- patients scored worse at the Nepean (reflux 19 vs 12 out of 39, P < 0.0005; dyspepsia 54 vs 38 out of 156, P < 0.0005). In the subgroup of patients who have physiological oesophageal acid exposure the enhancement of the perceived symptom burden appears to be the most important mechanism in GORD pathogenesis.

Visceral hypersensitivity in non-erosive reflux disease

Non-erosive reflux disease (NERD) is defined as the presence of classic symptoms of gastro-oesophageal reflux disease (GORD) in the absence of oesophageal mucosal injury (or Barrett’s oesophagus) as determined by...

Symptom Resolution Does Not Predict Healing of Erosive Oesophagitis in Chinese

Background: Previous studies suggested that Chinese have a milder spectrum of gastro-oesophageal reflux disease and a lower dose of proton pump inhibitors (PPI) is sufficient for the control of symptoms as compared with the Western population. Aims: To determine if 8 weeks of esomeprazole 20 mg daily would be adequate for both symptom resolution and oesophagitis healing in Chinese patients and the predictive factors for the response. Methods: 66 patients with oesophagitis were included. Oesophagitis severity was graded by Los Angeles (LA) classification. 61 patients underwent 24-hour ambulatory pH study at baseline. All were given esomeprazole 20 mg daily for 8 weeks. Symptom response and healing of oesophagitis was assessed at the end of the treatment period. Results: 75.8% of the patients had complete reflux symptom resolution but only 48% had complete healing of the oesophagitis at endoscopy after 8 weeks of treatment. LA classification grading at baseline endoscopy (p < 0.0001) and total number acid reflux episodes on 24-hour pH monitoring prior to treatment (p = 0.007) were both good predictors of oesophagitis healing but not for symptom resolution. Conclusions: Our results suggested that 8 weeks of lower dose PPI is not sufficient for oesophagitis healing. Symptom resolution with PPI does not predict oesophagitis healing in Chinese.

Review article: the role of acid suppression in patients with non‐erosive reflux disease or functional heartburn

When patients with the typical reflux symptoms of heartburn, regurgitation, or both, undergo endoscopy, up to 75% will not have endoscopic oesophagitis or evidence of Barrett's oesophagus. These patients have been described as having endoscopic negative or, more commonly, non-erosive reflux disease (NERD). Patients without oesophagitis, but with a positive pH test, can be diagnosed with gastro-oesophageal reflux disease (GERD). Some experts also consider a response to proton pump inhibitor therapy as proof of GERD in a patient with the correct symptoms and a negative endoscopy. Patients with normal acid exposure, but who report symptoms with a majority of their reflux episodes documented during an ambulatory pH study, have also been considered to have NERD, although others have labelled them as having 'functional heartburn'. Finally, there are some patients who have reflux symptoms and respond to reflux therapy, but have no demonstrable reflux by either endoscopy or ambulatory reflux testing. Whether these patients are part of the GERD spectrum or have another diagnosis is not clear. It seems that the most widely used definition of functional disease (the Rome II criteria) would include these patients as having functional heartburn, as it was defined as 'greater than or equal to 12 weeks of either continuous or intermittent symptoms of burning retrosternal discomfort or pain without pathologic GERD, achalasia, or other motility disorders with a recognized pathologic basis'. This article reviews potential differences in pathophysiology between erosive oesophagitis and NERD; explores whether symptoms can help distinguish NERD patients from erosive oesophagitis patients; and explores the evaluation and therapy of these patients.

Balanced perspective essential in erosive oesophagitis treatment

Sirs, The recent article by Labenz et al. on the EXPO study is intriguing,1 but it should be objectively considered within the context of recently published peer review trials, such as Gillessen et al., which is appropriately powered to show equivalence between pantoprazole and esomeprazole for endoscopically confirmed healing,2, 3 and within an integrated therapeutic perspective that values the prompt resolution of a broad spectrum of gastro-oesophageal reflux disease (GERD)-related symptoms. Recognizing GERD as a heterogeneous symptom complex, rather than considering only heartburn, is of increasing relevance in reflux studies.4 This approach shows that pantoprazole is at least as effective as esomeprazole for symptom relief.5 In addition to these issues, the greatest problem with the EXPO study is its flawed statistical analysis. The EXPO study was powered to detect a clinically relevant treatment difference of 5%, assuming 8-week healing rates of 88% and 83% for esomeprazole and pantoprazole. However, data show a treatment difference of only 3.5% (survival method) which, by the authors’ own definition, is not clinically significant. Indeed, re-calculation of the EXPO data show cumulative healing rates after 8 weeks’ treatment of 91.6% for esomeprazole and 88.9% for pantoprazole, a difference of 2.7% [Blackwelder 95% confidence interval (CI) 0.6–4.8]. This suggests that esomeprazole is equivalent to pantoprazole, as even the upper limit of the CI (4.8%) is less than the 5.0% necessary to show clinically relevant superiority. Furthermore, when Labenz et al. display the breakdown of healing rates by baseline Los Angeles (LA) grade of erosive oesophagitis severity, the 95% CIs overlap, indicating a non-significant difference between the two treatment groups e.g., LA grade C healing rates: esomeprazole 40 mg 91.3% (95% CI 88.0–94.6), pantoprazole 40 mg 87.6% (95% CI 83.8–91.5). Nonetheless, Labenz et al. were able to show a significant difference in healing rates between treatment groups in patients with LA grade C using the log-rank test, which does not test the difference between healing rates directly but compares the difference of the entire survival curves from beginning to end of treatment. In addition, in the EXPO study, more patients with mild GERD (LA grade A) were included in the esomeprazole group than the pantoprazole group (33.5% vs. 30.1%). This difference of 3.4% reaches statistical significance (Fischer's exact test, P = 0.046) and is similar in magnitude to the difference in healing rates reported between the two treatment groups. Further, if the data for healing rates for the different LA grades found with esomeprazole are transferred to the distribution of LA grades reported for pantoprazole, an overall healing rate of 92.2% can be calculated for esomeprazole compared with the reported 95.5%, which is significantly different (P < 0.00001) i.e., esomeprazole is superior to esomeprazole. The same can be shown vice versa for pantoprazole, which clearly indicates that significant results smaller than the inhomogeneity at baseline can be produced without any difference in treatment. In conclusion, taken as a whole, data from peer-reviewed trials, including re-analysis of the EXPO study, show that pantoprazole and esomeprazole are equivalent for oesophageal healing and symptom relief.

Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities?

As the incidence of both gastric cancer and peptic ulcer disease have declined, that of gastro-oesophageal reflux disease (GORD) and non-ulcer, or functional dyspepsia (FD) have reached virtually epidemic proportions. As we come to appreciate the expression of these disorders in the community, the real spectrum of each disease has become evident. FD and non-erosive reflux disease (NERD), the most prevalent manifestation of GORD, frequently overlap. Where then does GORD end and FD begin? Is it realistic, or even clinically relevant, to attempt a clear separation between these entities? These are more than issues of mere semantics; therapeutic options may be dictated by the classification of the patient as one or the other. Recent work indicates clearly that NERD is a heterogeneous disorder incorporating some patients who may well harbour subtle manifestations of oesophagitis and others who have entirely normal 24-hour pH studies. These differences may be crucial to the concept of NERD/FD overlap. While evidence in support of this concept is far from complete, it would appear that this overlap is most relevant to those NERD patients who do not exhibit abnormal esophageal acid exposure. These patients truly belong in the spectrum of functional gastrointestinal disorders rather than in GORD; attempts to shoe-horn these individuals into the spectrum of GORD will result in therapeutic disappointment and surgical disaster.

The role of cagA Helicobacter pylori strains in gastro-oesophageal reflux disease.

The role of Helicobacter pylori infection in gastro-oesophageal reflux disease is controversial. The aim of this study was to evaluate the prevalence of colonization by cagA-positive and cagA-negative H. pylori strains in the spectrum of gastro-oesophageal reflux disease. A total of 108 patients (50 male/58 female; mean age, 50.3 years) with dyspepsia and peptic ulcer or erosive gastritis/duodenitis were categorized into patients without reflux and patients with reflux oesophagitis graded from I to IV. All patients underwent upper endoscopy with biopsies of the antrum. H. pylori was detected by histology, urease test and polymerase chain reaction. The cagA status was diagnosed in the gastric biopsy by polymerase chain reaction. The overall prevalence of H. pylori colonization in patients with reflux was 68.6% and was 70.2% in those without oesophageal disease (P = 0.862). Colonization by cagA-positive strains was also not statistically different between the two groups (31.4% versus 40.4%, P = 0.332). However, patients with grades II-IV reflux oesophagitis were less colonized by the bacterium (36.4%) than patients with grade I oesophagitis (77.5%) (P = 0.009). H. pylori cagA-positive strains were also less likely to colonize the stomach of patients with grades II-IV oesophagitis (0%), than grade I reflux oesophagitis (40%) patients and controls (40.4%). Infection of the stomach by H. pylori and especially by H. pylori cagA strains may play a protective role against the development of the most severe forms of gastro-oesophageal reflux disease.

Review article: approaches to endoscopic-negative reflux disease: part of the GERD spectrum or a unique acid-related disorder?

Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)-affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.

New developments in the pathophysiology of gastro-oesophageal reflux disease (GERD): implications for patient management.

The spectrum of gastro-oesophageal reflux disease (GERD) has expanded; indeed the majority of individuals with symptomatic GERD do not have erosive reflux disease (ERD); this group has been referred to as nonerosive or negative-endoscopy reflux disease (NERD). There may be important differences between NERD and ERD in terms of pathophysiology and management. Thus, NERD patients appear relatively resistant to proton pump inhibitors and may not be good surgical candidates. The clinician caring for patients with GERD must therefore be aware of the full spectrum of GERD and of the pathophysiological and therapeutic implications of NERD. Recent twin studies have revealed that genetic factors play a role in GERD and form the basis for future studies on the role of inheritance in the various manifestations of GERD. Several recent investigations have reaffirmed the primacy of acid reflux in the pathogenesis of GERD and have also provided insights into the pathophysiology of postprandial heartburn. Transient lower oesophageal sphincter relaxations and hiatal hernias have emerged as major and interacting factors in the genesis of reflux events and in the potentiation of acid exposure; the former are attracting considerable attention as a potential therapeutic target. Nocturnal acid breakthrough, which has been implicated in the failure of some patients to respond to high doses of proton pump inhibitors, appears, on further examination, to be a gastric rather than an oesophageal phenomenon, and may not be of clinical or therapeutic importance.

Improving opportunities for effective management of gastro-oesophageal reflux disease

The recent introduction of proton pump inhibitors has extraordinarily improved the therapeutic approach to gastro-oesophageal reflux disease. The concept of decreasing gastric acid secretion and increasing the pH in the lower oesophagus has been demonstrated to be therapeutically effective and the higher the level of pH achieved, the better the results. In spite of the evident efficacy of these molecules, there are still many patients who will continue to have symptoms despite medical treatment. Proton pump inhibitors suppress gastric acidity, but this effect shows a remarkable interindividual variation depending on different reasons. Thus, it is still possible to optimise medical therapy for gastro-oesophageal reflux disease. Esomeprazole, the S-isomer of omeprazole, has an advantageous metabolism and this particular feature translates into superior clinical efficacy. Clinical trials for initial and long-term treatment across the gastro-oesophageal reflux disease spectrum, have clearly demonstrated the superiority of esomeprazole over omeprazole, even if tolerability and safety are very similar.

An evidence-based appraisal of reflux disease management — the Genval Workshop Report

This report summarises conclusions from an evidence-based workshop which evaluated major clinical strategies for the management of the full spectrum of gastro-oesophageal reflux disease, with an emphasis on medical management....

Gastro-oesophageal refluxate: does it always have to be acid to be noxious?

See article on page297 No-one doubts that acid and pepsin are the major factors responsible for symptoms and oesophageal mucosal damage which comprise the clinical spectrum of gastro-oesophageal reflux disease....