Measurement of acid exposure of proximal esophagus: a better tool for diagnosing non‐erosive reflux disease

Background The sensitivity of 24‐h pH monitoring is poor in non‐erosive reflux disease (NERD). In NERD patients, the proximal extent of acid reflux is one of the main determinants of reflux perception. The present study was aimed to compare the diagnostic accuracy of acid exposure time (AET), at 5 cm above the lower esophageal sphincter, with those at 10 cm and at 3 cm below the upper esophageal sphincter as well as the reproducibility of these parameters. Methods A total of 93 consecutive NERD patients, with typical symptoms responsive to proton pump inhibitor treatment, and 40 controls underwent esophageal manometry and multi‐channel 24‐h pH‐test; 13 patients underwent the same study on two occasions. Symptom association probability (SAP) values were evaluated at each esophageal level. Key Results The ROC curve indicates that the area under the curve was 0.79 at distal (SE = 0.039), 0.87 (SE = 0.032) at proximal (P = 0.029 vs distal), and 0.85 (SE = 0.033) at very proximal esophagus (P = 0.148). AET showed a reproducibility of 61% (Kappa 0.22) at distal esophagus, 77% (Kappa 0.45) at proximal and 53% (Kappa 0.05) at very proximal esophagus. The percentage of patients with a positive SAP was not significantly different when assessed at the distal compared with the proximal esophagus. Conclusions & Inferences In NERD patients, the diagnostic yield of the pH test is significantly improved by the assessment of AET at the proximal esophagus. As this variable seems to be less affected by the day to day variability, it could be considered a reliable and useful diagnostic tool in NERD patients.     

Platelet‐activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non‐erosive reflux disease patients and controls

Background A distinction between symptomatic non‐erosive reflux disease (NERD) and erosive esophagitis (EE) patients is supported by the presence of inflammatory response in the mucosa of EE patients, leading to a damage of mucosal integrity. To explore the underlying mechanism of this difference, we assessed inflammatory mediators in mucosal biopsies from EE and NERD patients and compared them with controls. Methods Nineteen NERD patients, 15 EE patients, and 16 healthy subjects underwent endoscopy after a 3‐week washout from PPI or H₂ antagonists. Biopsies obtained from the distal esophagus were examined by quantitative real‐time polymerase chain reaction (qPCR) and multiplex enzyme‐linked immunosorbent assay for selected chemokines and lyso‐PAF acetyltransferase (LysoPAF‐AT), the enzyme responsible for production of platelet‐activating factor (PAF). Key Results Expression of LysoPAF‐AT and multiple chemokines was significantly increased in mucosal biopsies derived from EE patients, when compared with NERD patients and healthy controls. Upregulated chemokines included interleukin 8, eotaxin‐1, ‐2, and ‐3, macrophage inflammatory protein‐1α (MIP‐1α), and monocyte chemoattractant protein‐1 (MCP‐1). LysoPAF‐AT and the chemokine profile in NERD patients were comparable with healthy controls. Conclusions & Inferences Levels of selected cytokines and Lyso‐PAF AT were significantly higher in the esophageal mucosa of EE patients compared with NERD and control patients. This difference may explain the distinct inflammatory response occurring in EE patients’ mucosa. In contrast, as no significant differences existed between the levels of all mediators in NERD and control subjects, an inflammatory response does not appear to play a major role in the pathogenesis of the abnormalities found in NERD patients.     

Increased TRPV1 gene expression in esophageal mucosa of patients with non‐erosive and erosive reflux disease

Background Transient receptor potential channel vanilloid subfamily member‐1 (TRPV1) may play a role in esophageal perception. TRPV1 mRNA and protein expression were examined in the esophageal mucosa of non‐erosive reflux disease (NERD) and erosive esophagitis (EE) patients and correlated to esophageal acid exposure. Methods Seventeen NERD patients, eight EE patients and 10 healthy subjects underwent endoscopy after a 3‐week washout from proton pump inhibitors or H2 antagonists. Biopsies, obtained from the distal esophagus, were used for conventional histology, for Western blot analysis and/or quantitative real‐time polymerase chain reaction (qPCR). Overall 13 NERD patients, four EE patients and five controls underwent ambulatory pH‐testing. Key Results TRPV1 expression was increased in all NERD and EE patients, as measured by Western blot analysis (0.65 ± 0.07 and 0.8 ± 0.05 VS 0.34 ± 0.04 in controls; P < 0.01) and by qPCR (1.98 ± 0.21 and 2.52 ± 0.46 VS 1.00 ± 0.06; P < 0.01). Neutrophilic infiltration, in the mucosa, was detected only in EE patients. Conclusions & Inferences Non‐erosive reflux disease and EE patients presented increased TRPV1 receptors mRNA and protein, although no correlation with acid exposure was demonstrated. Increased TRPV1 in the esophageal mucosa may contribute to symptoms both in NERD and EE patients and possibly account for peripheral mechanisms responsible for esophageal hypersensitivity in NERD patients.     

The added value of quantitative analysis of on-therapy impedance-pH parameters in distinguishing refractory non-erosive reflux disease from functional heartburn

Background By analysis of symptom‐reflux association, endoscopy‐negative refractory heartburn can be related to acid/non‐acid refluxes with impedance‐pH monitoring. Unfortunately, patients frequently do not report symptoms during the test. We aimed to assess the contribution of quantitative analysis of impedance‐pH parameters added to symptom‐reflux association in evaluating patients with endoscopy‐negative heartburn refractory to high‐dose proton pump inhibitor therapy. Methods The symptom association probability (SAP), the symptom index (SI), the esophageal acid exposure time and the number of distal and proximal refluxes were assessed at on‐therapy impedance‐pH monitoring. Relationships with hiatal hernia and manometric findings were also evaluated. Key Results Eighty patients were prospectively studied. Refractory heartburn was more frequently related to reflux by a positive SAP/SI and/or abnormal impedance‐pH parameters (52/80 cases) (65%) than by a positive SAP/SI only (38/80 cases) (47%) (P = 0.038). In patients with refractory non‐erosive reflux disease (NERD) defined by a positive SAP/SI and/or abnormal impedance‐pH parameters, the prevalence of hiatal hernia was significantly higher (56%vs 21%, P = 0.007) and the mean lower esophageal sphincter tone was significantly lower (18.7 vs 25.8 mmHg, P = 0.005) than in those (35%) with reflux‐unrelated, i.e., functional heartburn (FH). On the contrary, no significant difference was observed subdividing patients according to a positive SAP/SI only. Conclusions & Inferences Quantitative analysis of impedance‐pH parameters added to symptom‐reflux association allows a subdivision of refractory‐heartburn patients into refractory NERD and FH which is substantiated by pathophysiological findings and which restricts the diagnosis of FH to one third of cases.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use

van Reedt Dortland AKB, Giltay EJ, van Veen T, Zitman FG, Penninx BWJH. Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Objective: The metabolic syndrome (MetSyn) predisposes to cardiovascular disease and diabetes mellitus. There might also be an association between the MetSyn and anxiety and depression, but its nature is unclear. We aimed to investigate whether diagnosis, symptom severity and antidepressant use are associated with the MetSyn. Method: We addressed the odds for the MetSyn and its components among 1217 depressed and/or anxious subjects and 629 controls, and their associations with symptom severity and antidepressant use. Results: Symptom severity was positively associated with prevalence of the MetSyn, [adjusted odds ratio (OR) 2.21 for very severe depression: 95% confidence interval (CI): 1.06–4.64, P = 0.04], which could be attributed to abdominal obesity and dyslipidemia. Tricyclic antidepressant (TCA) use also increased odds for the MetSyn (OR 2.30, 95% CI: 1.21–4.36, P = 0.01), independent of depression severity. Conclusion: The most severely depressed people and TCA users more often have the MetSyn, which is driven by abdominal adiposity and dyslipidemia.     

Prolonged,wireless pH‐studies have a high diagnostic yield in patients with reflux symptoms and negative 24‐h catheter‐based pH‐studies

Background Catheter‐based esophageal pH‐monitoring is used to evaluate patients with suspected gastro‐esophageal reflux disease (GERD); however false‐negative results may occur due to poor tolerance of the catheter with reduced oral intake and activity, or high day‐to‐day variation in reflux and symptom events. We assessed diagnostic yield and clinical impact of prolonged, wireless pH‐monitoring in patients with negative results from 24‐h catheter‐based studies and ongoing symptoms. Methods Esophageal acid exposure (percentage time pH <4), Symptom Index, and Symptom Association Probability (SAP) were calculated. Diagnostic yield was assessed using Average (mean) and Worst Day (24‐h period with highest acid exposure or symptom load) analyses. Outcome data were assessed 6–36 months (median 24) after initiation of definitive therapy based on physiologic testing. Key Results Data from prolonged pH‐monitoring up to 96‐h (median 72‐h) were available from 38 patients. Using Average and Worst Day analysis, esophageal acid exposure was pathologic in 37% and 47%, whereas SAP was positive in 34% and 63% of patients, respectively. Overall using Average and Worst Day analyses, 61% and 76% patients were diagnosed with GERD based on either pathologic acid exposure or positive symptom association. Of 12 patients that underwent antireflux surgery, 10(83%) reported a good outcome at a median 24 months follow‐up. Conclusions & Inferences Prolonged, wireless pH‐monitoring increases test sensitivity and diagnostic yield in patients with continuing esophageal symptoms despite negative 24‐h catheter‐based pH‐studies. Without a definitive diagnosis, many would not have received effective treatment.     

Poor effectiveness of proton pump inhibitors in non‐erosive reflux disease: the truth in the end!

Despite acid secretion being normal in the majority of patients with gastro‐esophageal reflux disease (GERD) or Barrett’s esophagus, acid inhibition represents the mainstay of treatment for both these conditions, with the aim of reducing the aggressive nature of the refluxate toward the esophageal mucosa. Proton pump inhibitors (PPIs) represent, therefore, the first choice medical treatment for GERD, in that they are able to provide an 80–85% healing rate for esophageal lesions, a 56–76% symptom relief and also reduce the incidence of complications, such as strictures as well as dysplasia and adenocarcinoma in Barrett’s esophagus. According to a widely quoted systematic review, compared to patients with erosive esophagitis, patients with non‐erosive reflux disease (i.e., NERD) display a reduced symptom relief with PPIs, with about 20% reduction of therapeutic gain. In this issue of NeuroGastroenterology & Motility, Weijenborg et al. address for the first time the PPI efficacy in subpopulations of patients with NERD. The study shows clearly that, when the diagnosis is accurately made by including a functional test, NERD patients respond to PPI therapy in a similar way to those with erosive disease. Although not as frequent as previously suggested, however, PPI‐refractory heartburn does exist. Some 20% (range: 15–27%) of correctly diagnosed and appropriately treated patients do not respond to PPI treatment at standard doses. Although the pathophysiology underlying PPI failure in GERD is complex and likely multifactorial, acid (be it the sole component of refluxate or not) still remains a major causative factor. A better and more predictable form of acid suppression should therefore be pursued.