Specific patient groups consisting of those with nasogastric or gastrostom feeding tubes such as those with stroke neurological impairment or other etiologies, patients with difficulty swallowing (i.e. oral pharyngeal dysfunction), unconscious patients and children who dislike or refuse taking or cannot swallow tablets require special attention with regard to the pharmacological treatment of acid-related disorders.In particular, these groups of patients require special formulations in order to achieve optimal compliance with acid suppression therapy. Formulations such as the syrup histamine (H-2)-receptor antagonist in a syrup formulation, or for proton pump inhibitors, either the multiple unit pellet capsules, fast dissolving tablets or intravenous formulations, can be used to overcome swallowing problems or bitter taste.
Night-time heartburn is common in patients with gastro-oesophageal reflux disease and its consequences in terms of sleep disturbance and subsequent effects on daytime functioning are substantial.Most patients with night-time heartburn indicate that it is more bothersome than daytime heartburn. A significant odds ratio has been described between night-time heartburn and daytime sleepiness and fatigue.Sleep-related gastro-oesophageal reflux has characteristics that distinguish it from waking reflux and that have been shown to enhance the risk of the development of reflux oesophagitis. Swallowing and salivary flow are markedly diminished during sleep and behavioural arousal responses to acid mucosal contact are blunted due to the depressed consciousness of the sleeping state. These sleep-related changes conspire to prolong acid mucosal contact, which in turn increases the likelihood of significant hydrogen ion back-diffusion and the risk of oesophageal damage.An awareness of the presence of night-time heartburn suggests significant sleep-related gastro-oesophageal reflux and this should be assessed in order to optimally treat gastro-oesophageal reflux disease patients.Consideration of PPI treatment should involve an assessment of its effectiveness in maintaining acid suppression throughout the sleeping interval.
The population of Japan is rapidly ageing and this, along with the Westernization of the diet, is expected to increase the prevalence of gastro-oesophageal reflux disease.Issues that call for attention by Asian gastroenterologists in the management of gastro-oesophageal reflux disease in the geriatric population include functional changes associated with ageing, such as a lower sensitivity to acid stimulation or pain leading to more atypical presenting symptoms vs. greater severity of disease, common swallowing problems, polypharmacy, and the slower metabolism of the drugs by the kidney. The optimal management of acid-related disorders in the elderly will need to adequately address all these issues.
A number of extra-oesophageal abnormalities ranging from otolaryngo-logic disorders and dysphonia to non-cardiac chest pain and sleep disturbances have been attributed to gastro-oesophageal reflux disease. A significant degree of uncertainty and confusion continues to exist with regard to the pathogenesis, diagnosis and treatment of these conditions.The following conceptual model could be proposed for the pathogenesis of the extra-oesophageal manifestations of gastro-oesophageal reflux disease and, consequently, the likely response to therapy.This model suggests that these disorders are, in fact, multifactorial and that the contributions of refluxed gastric contents comprise only part of the pathogenesis. In the case of asthma, for example, factors that influence airway resistance and symptom production include basal airway resistance, intra-oesophageal events, such as acid reflux-stimulating vagal afferent fibres and inducing further air-way changes, and extra-oesophageal, allergic and other pulmonary factors that can influence airway resistance. This model allows for different degrees of influence from these three main contributors. In this model, if gastro-oesophageal reflux disease-related events contribute minimally to the changes in airway resistance compared with other factors, treating gastro-oesophageal acid reflux would result in minimal or no change in symptoms and vice versa.At present, as it is difficult to identify prospectively those patients in whom reflux comprises the main pathological factor, and who might therefore respond to acid suppression, a trial of empiric proton-pump inhibitor therapy with reflux precautionary measures seems appropriate and has been suggested by some expert panels.
Gastro-oesophageal reflux disease is very common and presents with a spectrum of symptoms with or without oesophageal damage. Gastroo-esophageal reflux disease has an adverse impact on quality of life, especially in those with nocturnal symptoms.Prolonged exposure of the oesophageal mucosa to acidic gastric contents with pepsin and bile increases the risk of oesophageal mucosal injury. The frequency and severity of symptoms and oesophagitis correlate with the frequency, severity and duration of acid exposure, particularly at night-time.This study reviews the mechanisms and evidence for acid-induced symptoms and oesophageal injury, from superficial mucosal injury to Barrett's oesophagus and the long-term risk of oesophageal adenocarcinoma.Optimizing the choice and dose regimen of proton-pump inhibitor is essential for treating gastro-oesophageal reflux disease, and nocturnal acid control is important in preventing complicated gastro-oesophageal reflux disease.
Major points of controversy identified by the workshop included:(i) symptom assessment of acid-related disorders in children, where vomiting was identified as a potential confounding feature, abdominal pain as a common feature of paediatric gastro-oesophageal reflux disease;(ii) extra-oesophageal manifestations of paediatric gastro-oesophageal reflux disease;(iii) abdominal pain perceived as a common feature of Helicobacter pylori-related disorders;(iv) role of testing for H. pylori in children;(v) test-and-treat strategies for H. pylori infection in children before long-term proton pump inhibitor therapy;(vi) an underutilization of triple therapy and proton pump inhibitors in children in areas with a high prevalence of H. pylori infection;(vii) the role of empiric proton pump inhibitor therapy in children.
The workshops developed eight concensus statements for the diagnosis and management of paediatric acid-related disorders or GERD, and five statements for geriatric acid-related disorders or GERD, suitable for clinical use in Asia.
Summary The special needs of the elderly must be considered in the treatment of acid‐related disorders in older patients. Workshop participants discussed the Genval workshop report algorithm as a step toward building a consensus on the management of elderly patients in Asia. The consensus reached is summarized as follows: (i) old age alone is an indication for endoscopic investigation of reflux symptoms; (ii) elderly patients should undergo endoscopy when they present with acid reflux symptoms; (iii) a biopsy‐based test for Helicobacter pylori should be performed if endoscopy is done, and eradication of H. pylori is warranted as it will reduce the risk of peptic ulcers and may retard the progression of early precancerous gastric lesions; (iv) it is not recommended to routinely take additional biopsies for histology in patients with H. pylori infection in the absence of any macroscopic suspicious lesions; (v) patients with reflux disease LA grade B or below should be started on a standard‐dose proton pump inhibitor for 4–8 weeks, and then followed by step‐down to on‐demand therapy; (vi) patients with LA grade C or above reflux oesophagitis should be initially given standard‐dose proton pump inhibitor therapy for at least 8 weeks and then continue with maintenance proton pump inhibitor therapy.
Summary It is critical for the clinician who cares for children to distinguish between normal physiological gastro‐oesophageal reflux (GER), and signs and symptoms that occur due to the persistent reflux, defined as gastro‐oesophageal reflux disease (GERD). The underlying natural history of physiological GER in the paediatric population up to about 12 years of age, is quite distinct from normal reflux in adults. Conversely, the underlying pathophysiology of GERD in both age groups is for the most part similar. Regurgitation symptoms, which peak by 4‐6 months of age, appear to resolve commonly by 12‐18 months of life. However, there is a growing body of evidence that demonstrates that GERD may not be outgrown in a subset of children. In practice, many clinicians include an empiric therapeutic trial of an H 2 receptor antagonist (H 2 RA) or proton pump inhibitor accompanied by symptom resolution for the diagnosis of GERD. GERD‐associated symptoms in the paediatric population range from regurgitation, often accompanied by arching and irritability, to feeding refusal, and/or poor growth to respiratory symptoms such as nocturnal and/or chronic cough. Upper endoscopy with biopsy may be useful in documenting the presence and severity of macroscopic and microscopic mucosal abnormalities, as well as excluding other disorders such as eosinophilic oesophagitis. Conservative management, particularly useful in mild GERD, consists of positioning during and after feeds, a 2‐ to 4‐week trial of hydrolysate formula, addition of cereal to formula, and smaller, more frequent feeds. Among the current pharmacotherapeutic options available in the United States (US), the prokinetic agent metaclopramide and the acid‐inhibitory agents (H 2 RAs, proton pump inhibitors) are the most widely prescribed. Numerous clinical investigations in both adults and children demonstrated that the proton pump inhibitors are more effective than the H 2 RAs in the relief of GERD symptoms and healing of erosive oesophagitis. The safety profile of the proton pump inhibitors in children is excellent with no significant adverse events observed either in the short‐ or long‐term (>5.5 years continuous use). Finally, surgical procedures for GERD may also be indicated in certain circumstances.
Gastro-oesophageal reflux disease can manifest typically with heartburn and regurgitation and atypically with extra-oesophageal symptoms, such as chest pain, worsening asthma, chronic cough or laryngitis.Although acid-suppressive therapy can help identify individuals in whom gastro-oesophageal reflux disease is the cause of their symptoms, diagnostic testing is often needed to evaluate those with persistent symptoms.Recent advances in oesophageal diagnostic testing include the advent of a wireless pH-monitoring device that eliminates the need for a transnasal catheter as well as an ambulatory impedance monitoring device that allows measurement of weakly acidic or non-acidic refluxate.The advantages and disadvantages as well as clinical utility of these new, as well as traditional, oesophageal-measuring devices are discussed in this review.
Summary Once daily, or even twice daily, dosing with proton‐pump inhibitors does not reliably achieve optimal control of nocturnal intragastric acidity. The phenomenon of nocturnal acid breakthrough, defined as intragastric pH < 4 for more than 1 h in the overnight period, was initially described during twice daily dosing with proton‐pump inhibitors and found to affect around 70% of individuals. Given recent renewed interest in the potential consequences of nocturnal oesophageal acid exposure, it is appropriate to consider alternative pharmacological approaches to optimizing the control of nocturnal intragastric acidity. Nocturnal acid control is considered to be the maintenance of intragastric pH > 4 for the duration of the night‐time period. At pH > 4, gastric refluxate entering the oesophagus is non‐caustic because pepsin is biologically inactive in this pH range. Although conventional delayed‐release proton‐pump inhibitors effectively control daytime, food‐stimulated gastric acid secretion, they allow recovery of acid secretion during the night. Bedtime administration of immediate‐release omeprazole with sodium bicarbonate (Zegerid, Santarus, Inc., San Diego, CA, USA) has been shown to be highly effective in maintaining overnight intragastric pH above 4 for prolonged periods. Pharmacodynamic studies in patients with gastro‐oesophageal reflux disease have compared the effects of bedtime administration of immediate‐release omeprazole, to either predinner or bedtime administration of three different delayed‐release proton‐pump inhibitors. Bedtime administration of immediate‐release omeprazole was more effective at controlling overnight intragastric acidity than predinner administration of pantoprazole or bedtime administration of lansoprazole.
A workshop on acid-related disorders in paediatric and elderly populations was held in Asia in 2006 to raise awareness that: (i) these particular age groups require special consideration in their disease management; (ii) to clarify what issues need to be addressed in these populations and (iii) to reach a consensus on recommendations for the management of gastro-oesophageal reflux disease and other acid-related disorders in children and the elderly.Of note, acid-related disorders, particularly gastro-oesophageal reflux disease in these populations are less well recognized and studied than those in the adult population between the ages of 20 and 60 years.A distinguished faculty of practicing gastroenterologists and key opinion leaders from several Asian countries and the United States were thus enlisted to address these issues in the workshop.
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcriptional factor induced by ischaemic crisis in many tissues. Vascular endothelial growth factor (VEGF) is an important growth factor that plays a major role in angiogenesis. We examined the aetiology and pathophysiology of human ischaemic colitis and ulcerative colitis from the viewpoint of the expression of these two ischaemic factors. Thirty-two patients with ischaemic colitis, 16 with ulcerative colitis and 25 normal controls underwent colonoscopy. Biopsy samples were taken from a colitis lesion and a normal region in the same patient. In the normal controls, four biopsy samples were obtained from each subject. Biopsy samples were subjected to real-time polymerase chain reaction. Hypoxia-inducible factor and VEGF were overexpressed in ischaemic colitis lesions and quickly decreased to normal levels in the healing phase. In contrast, HIF but not VEGF was overexpressed in active ulcerative colitis lesions. In the remission phase of ulcerative colitis, VEGF decreased to low levels, although HIF was continuously overexpressed. Overexpression of HIF and VEGF contribute to the tolerance of ischaemia in patients with active ischaemic colitis. The inconsistency in their expression might be associated with the chronic intestinal damage characteristic of ulcerative colitis.
Effects of long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) on the colon have not been well characterized. To investigate colonoscopic findings and prevalence of adverse events following long-term use of NSAIDs. The study included 425 patients (mean 66.4 years) treated for over one year with NSAIDs, and 2125 age- and sex-matched patients without NSAIDs as controls. Eligible candidates were selected by medical record review for underlying diseases, pre-endoscopic symptoms, category of NSAIDs used, and duration of use. We used endoscopy to study lesion characteristics. The occurrence rate of colonic lesions or bleeding in the NSAIDs user (13/425, 3.1%) was higher than that in controls (28/2125, 1.3%) ( p = 0.017). Colitis was found in 10 of the 13 patients. The sigmoid colon, descending colon or both (70.0%) was commonly involved, and showed segmental ischemic colitis features in 8 of the 13 patients (61.5%). Among these, duration of use ranged from 1-30 years (mean 7.8). Nine of 13 patients (69.2%) took low-dose aspirin. The prevalence of colonic lesions in long-term NSAIDs users is much lower than that of upper gastrointestinal side effects, but higher than that of colonic lesions in non-NSAIDs users. The most common features of NSAIDs-associated colitis were segmental ischeznia.
SummaryBackgroundGhrelin, growth‐hormone‐releasing peptide, has been reported to accelerate food intake and gastrointestinal motility.AimThe present study was designed to investigate the plasma ghrelin levels in patients with functional dyspepsia (FD).Patients and MethodsNinety‐seven patients, who showed no evidence of peptic ulcer disease or gastrointestinal cancer on upper gastrointestinal endoscopy, were recruited. Seventeen patients who had no gastrointestinal symptoms were recruited as controls. Forty‐seven patients were diagnosed to be suffering from FD, based on the Rome II criteria. The FD patients were further subdivided into those with ulcer‐like FD, dysmotility‐like FD and non‐specific‐type FD, based on their Gastrointestinal Symptom Rating Scale (GSRS) scores. Fourteen patients were categorized as having gastro‐oesophageal reflux disease, and 19 patients were excluded as having the irritable bowel syndrome, based on the GSRS. The plasma ghrelin levels were measured by radioimmunoassay.ResultsThe plasma ghrelin levels were significantly higher in FD patients, especially in those with dysmotility‐like FD, as compared with those in controls. The plasma ghrelin levels were also correlated well with the indigestion scores.ConclusionPlasma ghrelin levels are significantly higher in patients with dysmotility‐like FD, suggesting that this parameter could become useful as a novel supportive marker for the diagnosis of FD.
Summary Background There is little evidence of changes in genetic variations in gastric intestinal metaplasia (GIM) after the eradication of Helicobacter pylori ( H. pylori ). Aim To investigate the effects of H. pylori eradication on genetic GIM variability in patients with and without gastric cancer in a one‐year prospective study. Methods We analysed microsatellite instability (MSI) and loss of heterozygosity (LOH) in GIM. Subjects included Gr. A ( n = 39): chronic gastritis, and Gr. B ( n = 53): intestinal‐type early gastric cancer patients who underwent endoscopic mucosal resection ( n = 25) and surgical resection ( n = 28). Results The frequency of incidence of MSI in GIM was 10.3% and 28.3% for Gr. A and Gr. B, respectively. Gr. B showed a significantly (p = 0.03) higher incidence rate than Gr. A for MSI, but not for LOH. The frequency of MSI declined in both groups post‐eradication, and patients that were positive for MSI before treatment were negative after H. pylori eradication. Unfortunately, however, GIM scores did not decline significantly post‐treatment for either group. Conclusions MSI in GIM may be associated with gastric carcinogenesis. H. pylori eradication reduced MSI during the one‐year post‐treatment period, although no histological improvement in GIM was observed. These changes in MSI may explain the decrease in gastric cancer incidence after the eradication of H. pylori .
SummaryProton pump inhibitors have become the preferred therapy for gastro‐oesophageal reflux disease and other acid‐related disorders. Without clear‐cut clinical data to help clinicians differentiate the impact of the five currently available proton pump inhibitors on early symptom relief and health‐related quality of life, we can explore potentially relevant differences in pharmacodynamic profiles of these proton pump inhibitors.In general, rabeprazole 10 and 20 mg achieve greater gastric pH >4 and >3 holding times and area under gastric pH–time curves on day 1 of treatment compared with other proton pump inhibitors.Superiority in day 1 pharmacodynamic measures corroborates fast antisecretory onset, and supports the premise that rabeprazole will be especially suitable for on‐demand use. In particular, comparisons with omeprazole and esomeprazole suggest better day 1 nocturnal acid control with rabeprazole.
Summary Aim To examine whether Helicobacter pylori induces structural chromosomal aberrations, such as loss of heterozygosity (LOH) and microsatellite instability (MSI) in the infected gastric mucosa. Methods Subjects were 13 patients with H. pylori ‐positive and 9 with H. pylori ‐negative gastric cancer and 20 patients with H. pylori ‐positive and 4 patients with H. pylori ‐negative chronic gastritis. Gastric mucosal tissues were endoscopically sampled from each subject. Each sample was checked for structural chromosomal aberrations (LOH and MSI) by PCR and microsatellite analysis, using a total of 31 primers corresponding to the regions containing the major genes of chromosomes 1q, 5q, 7q, 17p, 17q, 18q and 21q. Results All tissue samples obtained from cancer‐affected regions of the stomach had structural chromosomal aberrations (LOH or MSI), irrespective of H. pylori infection. The degree of structural chromosomal aberration was greater in poorly differentiated than well‐differentiated adenocarcinoma. In addition, structural chromosomal aberrations were also found in a few samples obtained from the chronic atrophic gastritis group, irrespective of H. pylori infection. Conclusions It seems unlikely that H. pylori serves as a direct promoter of gastric cancer, and H. pylori ‐positive chronic gastritis may not always be a precancerous state.
SummaryBackgroundGhrelin, a recently discovered peptide hormone, has been shown to be produced mainly by the A‐like cells of the gastric mucosa. Ghrelin not only stimulates growth hormone (GH) release but also promotes gastric motility. While the effect of ghrelin on the gastric acid secretion in rats has been reported, no such reports appeared to date from studies in humans.AimTo investigate the effect of ghrelin administration on the gastric pH in humans, using a novel wireless pH capsule (Bravo, Medtronic, Shoreview, MN, USA).MethodsFour healthy volunteers (male; average age, 35.0 years; Helicobacter pylori‐negative) were enrolled. The pH capsule was attached endoscopically to the gastric mucosa and the data were transmitted to a portable receiver. Thirty minutes after a stabilization period, synthetic ghrelin (5 μg/kg body weight) was injected intravenously into the subjects and the data were monitored for more than 120 min while the subjects lay supine.ResultsThe average minimum gastric pH in four cases (1.2 ± 0.10) was significantly decreased after injection of ghrelin, as compared with the basal pH value (1.8 ± 0.06). The serum gastrin level, however, showed no change after the ghrelin injection.ConclusionThese results suggest that exogenous ghrelin could enhance gastric acid secretion in humans.
