The effect of antireflux treatment on the frequency of awakenings from sleep in patients with Gastroesophageal reflux disease.

BACKGROUND: Up to half of gastroesophageal reflux disease (GERD) patients report having heartburn that awakens them from sleep during the night. Recumbent-awake and conscious awakenings from sleep during the night are commonly associated with acid reflux events. The aim of the study was to assess the effect of esomeprazole 40 mg once daily on nighttime acid reflux, frequency of conscious awakenings associated with acid reflux and the recumbent-awake period. METHODS: Patients with heartburn and/or regurgitation at least three times a week were eligible for this study. All patients underwent upper endoscopy and were evaluated by demographic, Epworth Sleepiness scale, Berlin and GERD symptom checklist questionnaires. Subjects then underwent esophageal pH testing concomitantly with an actigraphy. All subjects were given esomeprazole 40 mg once daily for 7 days and completed a daily symptom record diary. On day 7, subjects repeated the pH test with actigraphy. KEY RESULTS: Twenty patients (mean age of 48.95 ± 18.69, age range 20-81 years) were enrolled. Esophageal acid exposure parameters, during recumbent-awake, recumbent-asleep, and conscious awakenings were significantly improved on last day of treatment as compared to baseline (p < 0.05). However, the frequency and duration of conscious awakenings and duration of recumbent-awake period did not improve as compared to baseline (p > 0.05). CONCLUSIONS & INFERENCES: While esomeprazole significantly reduced esophageal acid exposure during conscious awakenings and recumbent-awake and asleep periods, it did not decrease the number and duration of conscious awakening or duration of recumbent-awake period.

Step-by-step management of refractory gastresophageal reflux disease.

Up to a third of the patients who receive proton pump inhibitor (PPI) once daily will demonstrate lack or partial response to treatment. There are various mechanisms that contribute to PPI failure and they include residual acid reflux, weakly acidic and weakly alkaline reflux, esophageal hypersensitivity, and psychological comorbidity, among others. Some of these underlying mechanisms may coincide in the same patient. Evaluation for proper compliance and adequate dosing time of PPIs should be the first management step before ordering invasive diagnostic tests. Doubling the PPI dose or switching to another PPI is the second step of management. Upper endoscopy and pH testing appear to have limited diagnostic value in patients who failed PPI treatment. In contrast, esophageal impedance with pH testing (multichannel intraluminal impedance MII-pH) on therapy appears to provide the most insightful information about the subsequent management of these patients (step 3). In step 4, treatment should be tailored to the specific underlying mechanism of patient's PPI failure. For those who demonstrate weakly acidic or weakly alkaline reflux as the underlying cause of their residual symptoms, transient lower esophageal sphincter relaxation reducers, endoscopic treatment, antireflux surgery and pain modulators should be considered. In those with functional heartburn, pain modulators are the cornerstone of therapy.

Systematic review: the treatment of noncardiac chest pain.

BACKGROUND: Treatment of noncardiac chest pain (NCCP) remains a challenge. This is in part due to the heterogeneous nature of this disorder. Several conditions are associated with NCCP including gastro-oesophageal reflux disease (GERD), oesophageal dysmotility, oesophageal hypersensitivity as well as others. AIM: To determine the currently available therapeutic modalities for NCCP. METHODS: We performed a systematic review of the literature that was published between January, 1980 and March, 2011. We identified 734 studies; 68 of them met entry criteria. RESULTS: Patients with GERD-related NCCP should receive proton pump inhibitors (PPI) twice daily for at least 8 weeks. Smooth muscle relaxants are only recommended for temporary relief of NCCP with motility disorders. Botulinum toxin injection of the distal oesophagus may be effective in the treatment of NCCP and spastic oesophageal motility disorders. Studies assessing the value of tricyclic antidepressants, trazodone and selective serotonin reuptake inhibitors in NCCP are relatively small, but suggest an oesophageal analgesic effect in NCCP patients that is limited by their side effects profile. The usage of theophylline to treat patients with non-GERD-related NCCP should be weighed against its potential toxicity. Use of complementary medicine has been scarcely studied in NCCP. Patients with coexisting psychological morbidity or those not responding to any medical therapy should be considered for psychological intervention. Cognitive behavioural therapy and hypnotherapy may be useful in the treatment of NCCP. CONCLUSIONS: Patients with GERD-related noncardiac chest pain should be treated with at least double dose PPI. The primary treatment for non-GERD-related noncardiac chest pain, regardless if oesophageal dysmotility is present, is pain modulators.

Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease.

BACKGROUND A potential relationship has been suggested between gastro-oesophageal reflux disease (GERD) and interstitial lung diseases (ILDs). AIM To evaluate whether there is a causal relationship between GERD and different ILDs. METHODS We conducted a systematic search of literature published between 1980 and 2010. After a review by two independent authors, each study was assigned an evidence-based rating according to a standard scoring system. RESULTS We identified 319 publications and 22 of them met the entry criteria. Of those, the relationship between GERD and idiopathic pulmonary fibrosis (IPF) was investigated in 14 articles, pulmonary involvement in systemic sclerosis (SSc) in six articles and pulmonary involvement in mixed connective tissue disease (MCTD) in two articles. We found the prevalence of GERD and/or oesophageal dysmotility to be higher in patients with different types of ILD as compared with those without ILD [Evidence B]. Among patients with IPF, 67-76% demonstrated abnormal oesophageal acid exposure off PPI treatment. No relationship was demonstrated between severity of GERD and severity of IPF [Evidence B]. Data are scant on outcomes of antireflux treatment in patients with IPF. There is a correlation between the severity of ILD and the degree of oesophageal motor impairment in patients with SSc and MCTD [Evidence B]. CONCLUSIONS Based on the currently available data, a causal relationship between GERD and idiopathic pulmonary fibrosis cannot be established. There is scant evidence about antireflux therapy in idiopathic pulmonary fibrosis patients. There may be an association between lung and oesophageal involvement in systemic sclerosis and mixed connective tissue disease, but a causal relationship cannot be established.

The lower esophageal sphincter.

The lower esophageal sphincters (LES) together with the crural diaphragm are the major antireflux barriers protecting the esophagus from reflux of gastric content. However, reflux of gastric contents into the esophagus is a normal phenomenon in healthy individuals occurring primarily during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. Transient lower esophageal sphincter relaxation is also the dominant mechanism of pathologic reflux in gastroesophageal reflux disorder (GERD) patients. Frequency of TLESR does not differ significantly between healthy individuals and those with GERD, but TLESRs are more likely to be associated with acid reflux in GERD patients. Understanding the mechanisms responsible for elicitation of a TLESR, using recently introduced novel technology is an area of intense interest. Pharmacologic and non-pharmacologic manipulation of receptors involved in the control of TLESR has recently emerged as a potential target for GERD therapy.

The effect of antireflux treatment on patients with gastroesophageal reflux disease undergoing a mental arithmetic stressor.

BACKGROUND: Acute stress exacerbates heartburn in gastroesophageal reflux disease (GERD) patients by enhancing the perceptual responses to intraesophageal acid. The aim of the study was to determine if antireflux treatment can still alter stimulus response functions to acid in patients undergoing acute stress as compared with placebo. METHODS: Symptomatic GERD patients with erosive esophagitis (EE) or an abnormal pH test were included. Patients underwent stimulus response functions to intraesophageal acid perfusion using the mental arithmetic stressor test. Thereafter, patients were randomized (2 : 1 ratio) to either esomeprazole 40 mg once daily or placebo for 8 weeks. On the last day of treatment, subjects underwent stimulus response functions to intraesophageal acid perfusion using a similar stressor as baseline. KEY RESULTS: A total of 31 patients were randomized into the treatment arm (mean age 48.6 ± 2.8, M/F 21/10) and 16 into the placebo arm (mean age 52.3 ± 4.3, M/F 12/4). In the esomeprazole group, there was a significant increase in lag time to symptom perception (P = 0.02) and decreased in intensity rating (P = 0.01) as well as acid perfusion sensitivity score (P = 0.01). There was no significant difference in any of the stimulus response functions to acid in the placebo group between baseline and treatment. Interpersonal sensitivity was the only independent clinical predictor factor for response to antireflux treatment. CONCLUSIONS & INFERENCES: Long-term antireflux treatment with a proton pump inhibitor is effective in reducing esophageal perception responses to acid during acute stress.

Night-time intra-oesophageal bile and acid: a comparison between gastro-oesophageal reflux disease patients who failed and those who were treated successfully with a proton pump inhibitor.

BACKGROUND: Little is known about the contribution of bile and acid reflux to night-time symptoms generation in patients who failed PPI treatment. AIM: To compare the degree of night-time oesophageal acid and bile [by the surrogate duodenogastroesophageal reflux (DGER)] exposure between gastro-oesophageal reflux disease (GERD) patients who failed and those who fully responded to PPI once a day while on treatment. METHODS: Gastro-oesophageal reflux disease patients were assigned to the PPI failure group if they continued to report symptoms ≥3/week and to the PPI success group if they were asymptomatic for the last 3 months while on PPI once a day. All patients underwent upper endoscopy and subsequently simultaneous 24-h oesophageal Bilitec and pH testing while on PPI treatment. RESULTS: Twenty-three patients were enrolled into the PPI failure group and 24 patients into the PPI success group. The percentage of night-time pH<4 and the number of night-time acid reflux episodes were significantly higher in the PPI failure group as compared with the PPI success group. All night-time DGER parameters were similar between the PPI failure and PPI success groups. CONCLUSIONS: Night-time oesophageal acid exposure is significantly higher in the PPI failure group vs. PPI success group. The degree of night-time bile reflux is similar in the two groups of patients with GERD.

Cost effectiveness of mass screening for coeliac disease is determined by time-delay to diagnosis and quality of life on a gluten-free diet.

BACKGROUND: Coeliac disease is frequently diagnosed after a long delay resulting in increased morbidity and mortality. AIMS: To define the parameters which have the highest impact on the cost-effectiveness of mass screening for coeliac disease. METHODS: A Markov model examined a coeliac disease screening programme of the healthy young-adult general population compared with a no-screening strategy. The main outcome measures were quality adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Effects of variables were examined using sensitivity analyses. RESULTS: The screening strategy resulted in a gain of 0.0027 QALYs. The ICER of screening vs. no-screening strategy was US$48,960/QALYs. The variables with the largest impact on cost effectiveness were: the time delay from symptom onset to diagnosis, the utility of adherence to a gluten-free diet (GFD) and the prevalence of coeliac disease. Screening would be cost-effective if the time delay to diagnosis is longer than 6 years and utility of GFD adherence is greater than 0.978. CONCLUSIONS: Our model suggests that mass screening for coeliac disease of the young-adult general population is associated with improved QALYs and is a cost effectiveness strategy. Shortening of the time-delay to diagnosis by heightened awareness of health-care professionals may be a valid alternative to screening.

Systematic review: the effects of carbonated beverages on gastro-oesophageal reflux disease.

BACKGROUND: Carbonated beverages have unique properties that may potentially exacerbate gastro-oesophageal reflux disease (GERD), such as high acidity and carbonation. Cessation of carbonated beverage consumption is commonly recommended as part of lifestyle modifications for patients with GERD. AIMS: To evaluate the relationship of carbonated beverages with oesophageal pH, oesophageal motility, oesophageal damage, GERD symptoms and GERD complications. METHODS: A systematic review. RESULTS: Carbonated beverage consumption results in a very short decline in intra-oesophageal pH. In addition, carbonated beverages may lead to a transient reduction in lower oesophageal sphincter basal pressure. There is no evidence that carbonated beverages directly cause oesophageal damage. Carbonated beverages have not been consistently shown to cause GERD-related symptoms. Furthermore, there is no evidence that these popular drinks lead to GERD complications or oesophageal cancer. CONCLUSIONS: Based on the currently available literature, it appears that there is no direct evidence that carbonated beverages promote or exacerbate GERD.

Nondigestive symptoms in non-erosive reflux disease: nature, prevalence and relation to acid reflux.

BACKGROUND: Nondigestive symptoms are frequent in the irritable bowel syndrome (IBS). AIM: To characterize nondigestive symptoms in non-erosive gastro-oesophageal reflux disease (NERD) patients, as features of IBS are common in patients with NERD. METHODS: A prospective, case-control study. NERD was defined in patients with reflux symptoms, a normal oesophageal mucosa and oesophageal pH < 4 for > or = 5% of the time during 24-h pH monitoring. Nondigestive symptoms were scored on validated scales of somatic pain, urinary, sleep and neurasthenia. IBS was defined by the Rome I criteria. RESULTS: pH-positive NERD patients (n = 326) scored significantly higher than controls (nonpatient hospital visitors; n = 174) on all scales. The scores of pain, sleep and neurasthenia were highly specific in the discrimination of NERD patients from controls. In patients, nondigestive symptoms were independently associated with age, reflux symptoms severity and IBS status, but not with oesophageal acid exposure. NERD patients who met diagnostic criteria for IBS (49%) scored significantly higher on all the nondigestive symptoms scales than those had not met [IBS(-)]. Yet, IBS(-) patients scored significantly higher than controls on all scales. CONCLUSIONS: Nondigestive symptoms were highly prevalent in NERD patients and were specific in their discrimination from controls. Nondigestive symptoms correlated with reflux symptoms and were predicted by IBS status.

A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT.

SUMMARY: Up to 30% of patients with hepatitis C virus (HCV) infection and normal serum alanine aminotransferase (NALT) have significant liver disease. Currently, many of these patients undergo a liver biopsy to guide therapeutic decisions. The BreathID continuous online (13)C-methacetin breath test (MBT) reflects hepatic microsomal function and correlates with hepatic fibrosis. To assess its role in identifying intrahepatic inflammation and fibrosis in NALT patients, we tested 100 patients with untreated chronic HCV infection, and 100 age- and sex-matched healthy volunteers using (13)C MBT following ingestion of 75 mg methacetin. All HCV patients had undergone a liver biopsy within 12 months of performing the MBT. Patients with a necroinflammatory grade 4, based on Ishak (modified HAI) score, HAIa + HAIb + HAIc + HAId, were defined as having low or high inflammation, respectively. Patients with a histological activity fibrosis stage 2, were defined as having nonsignificant or significant fibrosis, respectively. A proprietary algorithm to differentiate intrahepatic inflammation within chronic HCV patients with NALT achieved an area under the curve (AUC) of 0.90. Setting a threshold on the point of best agreement (at 83%) results in 82% sensitivity and 84% specificity. With application of another proprietary algorithm to differentiate patients with nonsignificant or significant fibrosis, 67% of liver biopsies performed in the patient group could have been avoided. This algorithm achieved an AUC of 0.92, with a sensitivity of 91% and a specificity of 88%. There was no correlation between body mass index (BMI) and MBT scores for patients with the same histological score. The continuous BreathID(13)C MBT is an accurate tool for measuring the degree of inflammation and fibrosis in patients with chronic HCV infection and NALT. As such, it may prove to be a powerful, noninvasive alternative to liver biopsy in the management of this patient population.

Functional heartburn vs. non-erosive reflux disease: similarities and differences.

BACKGROUND: Bowel symptoms have been associated with non-erosive reflux disease (NERD). However, their role in functional heartburn (FH) has not been established. AIMS: To characterize bowel symptoms in FH and NERD patients, and investigate their role as predictors of severity of reflux symptoms. METHODS: A prospective study of patients with normal upper endoscopy undergoing a 24-h oesophageal pH monitoring for the evaluation of reflux symptoms. Patients with oesophageal acid exposure <3.1% and a symptom index <50% were classified as FH (n = 60), while those with oesophageal acid exposure >4% were defined as NERD (n = 160). Symptom severity was scored on validated scales. RESULTS: In FH, a female predominance was noted (P < 0.001). Reflux symptoms were scored higher in NERD patients (P < 0.001) while bowel symptoms were similarly scored in the two groups. In both groups, severity of reflux symptoms was independently associated with a composite score on the bowel scales (P < 0.001) and was not predicted by oesophageal acid exposure. In FH, reflux symptom severity was inversely related to age (P = 0.03), while in NERD, the opposite was true (P = 0.01). CONCLUSIONS: In both FH and NERD, bowel symptoms were the strongest predictors of reflux symptoms severity. A female preponderance, and an opposite relationship between reflux symptom severity and age, indicate that FH and NERD may be distinct entities.

Comparative analysis between dextran sulfate adsorption and direct adsorption of lipoproteins in their capability to reduce erythrocyte adhesiveness/aggregation in the peripheral blood.

The purpose of this study was to compare the degree of erythrocyte adhesiveness/aggregation (EAA) reduction of two low-density lipoprotein (LDL) apheretic procedures, namely direct adsorption of lipoproteins (DALI) and dextran sulfate adsorption (DSA). A significant (P < 0.001) reduction of EAA was noted in six hypercholesterolemic patients who underwent a total of 40 apheretic sessions and no difference was noted in the degree of EAA reduction by the two techniques. Thus. being a real-time and point-of-care test, the erythrocyte adhesiveness/aggregation test can be applied in relevant situations of acute ischemia, where therapeutic LDL apheresis could improve the hemorheology of individuals with increased concentrations of cholesterol and inflammatory sensitive proteins.

Significant dominance of fibrinogen over immunoglobulins, C-reactive protein, cholesterol and triglycerides in maintaining increased red blood cell adhesiveness/aggregation in the peripheral venous blood: a model in hypercholesterolaemic patients.

BACKGROUND: It is not clear what is the relative importance of fibrinogen, immunoglobulins, highly sensitive C-reactive protein (hs-CRP), cholesterol and triglyceride concentrations on the appearance of aggregated red blood cells in the peripheral blood. DESIGN: Six hypercholesterolaemic patients undergoing regular LDL apheresis that were examined repeatedly before and following the procedure. RESULTS: We determined the degree of erythrocyte adhesiveness/aggregation in relation to the concentration of the above-mentioned macromolecules in 80 samples. In a linear logistic regression the respective R2 values for fibrinogen, total cholesterol, triglycerides, hs-CRP, IgG, IgM and IgA were 0.45 (P<0.0001), 0.2 (P<0.0001), 0.02 (P=0.02), 0.001 (P=NS) and 0.002 (P=NS), respectively. We further analyzed the potential of ApoA, ApoB and Lpa to participate in red cell adhesiveness/aggregation and found them to be not significant. CONCLUSIONS: In a milieu of adhesive macromolecules, lipids and inflammation-sensitive proteins including fibrinogen, total cholesterol, triglycerides, hs-CRP and immunoglobins G, M and A, fibrinogen has a dominant role in maintaining the red blood cell adhesiveness/aggregation in the peripheral venous blood. These findings are relevant for the research directed at finding new apheretic modalities to reduce the degree of red blood cell adhesiveness/aggregation in the peripheral blood.

Insulin resistance in obesity: body-weight or energy balance?

Weight reduction is recommended for the treatment of subjects with insulin resistance (IR) syndrome; however, the relative importance of the decrease in body fat or the negative energy balance achieved during a hypo-energetic diet in the improvement of this metabolic syndrome is still debated. Therefore, we undertook to study their relative impact on amelioration of the metabolic abnormalities associated with IR in obese subjects. Twelve obese subjects (six males and six females, mean+/-s.d. body mass index 36.1+/-4.7 kg/m(2)) aged 38-57 years were investigated. During the first phase they were fed a hypo-energetic diet for 6 weeks (week 0-6). During the second phase, lasting 4 weeks (week 6-10) they consumed an iso-energetic diet. During the third phase (week 10-16) the subjects were put again on a hypo-energetic diet. Insulin sensitivity (SI) was assessed by an insulin-enhanced, frequently sampled i.v. glucose tolerance test with minimal model analysis. All subjects reduced weight during both hypo-energetic periods: 5.49+/-0.75 and 2.32+/-0.37%, means+/-s.e.m., P<0.005, week 0-6 and 10-16 respectively. One-third of this loss was achieved within the first week of each period. SI increased by 353+/-121 and 147+/-38% (P<0.005), means+/-s.e.m., at the end of both hypo-energetic periods (week 6 vs 0 and 16 vs 10 respectively). Two-thirds of this improvement were observed within the first week of each period (week 1 vs 0 and 11 vs 10 respectively). During the iso-energetic weight-maintaining period (week 10 vs 6), SI decreased by 43.5+/-7.9% (P<0.002). Serum levels of leptin and triglyceride followed a similar pattern, but to a lesser extent. It may be concluded that negative energy balance is more effective when compared with maintaining a stable lower weight in achieving an improvement in the metabolic parameters of the IR syndrome.