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GERD 7: NERD -- Non-Erosive Reflux DiseaseEpisode keywords: non-erosive reflux disease NERD, functional heartburn definition, reflux hypersensitivity, GERD normal endoscopy, dilated intercellular spaces GERD histology, basal zone hyperplasia esophagus, PPI failure categories, EoE masked by PPI, Rome IV functional heartburnEpisode SummaryUp to 70% of GERD patients have no visible mucosal breaks on endoscopy. NERD is not mild GERD or questionable GERD; it is the majority phenotype, with real pathologic acid exposure and real histologic correlates. This episode covers why a normal endoscopy on PPIs cannot classify a patient as NERD, the four categories of PPI failure and why getting the category right determines treatment success, the histology of NERD including a mechanistic revision to the dilated intercellular spaces model, and the treatment distinctions between NERD, reflux hypersensitivity, and functional heartburn.Key TopicsNERD definition: Troublesome reflux-related symptoms in the absence of endoscopically visible mucosal breaks. Pathologic acid exposure or positive symptom-reflux correlation is present. NERD is not "no GERD" -- it is a distinct phenotype within the GERD spectrum.Clinical diagnosis without endoscopy: The ACG states that a patient with typical heartburn who responds completely to acid suppression has a clinical diagnosis of GERD without requiring endoscopy. Endoscopy in this population is for Barrett's screening, not to confirm GERD.The NERD misclassification trap: To classify a patient as NERD, endoscopy must be performed off PPIs. A normal endoscopy while on active PPI therapy does not establish NERD -- it may simply mean the PPI healed existing erosions. This is also the scenario where EoE can be missed: PPIs suppress EoE features (rings, furrows, eosinophilic infiltration) completely. The guideline recommendation is to stop PPIs 2 to 4 weeks before endoscopy when EoE is a diagnostic consideration.Four categories of PPI failure: Category 1 -- the problem is not esophageal (cardiac chest pain, biliary disease masquerading as heartburn). Category 2 -- esophageal but not GERD (EoE causing chest pain and dysphagia, achalasia producing regurgitation labeled as reflux). Category 3 -- reflux-related, but either acid is genuinely persisting despite PPI (timing, adherence, or PPI-resistant acid production) OR physiologically normal reflux is perceived as painful (reflux hypersensitivity). Category 4 -- functional heartburn (no temporal relationship between symptoms and reflux events, normal acid exposure, negative symptom association). Treatment is completely different for each category.NERD histology: Elongated papillae (finger-like lamina propria projections extending beyond two-thirds of epithelial thickness), basal zone hyperplasia (proliferative layer exceeding 15% of epithelial thickness), and inflammatory cell infiltration consistent with the cytokine-mediated injury model from Episode 1. Dilated intercellular spaces (DIS) are visible on both electron microscopy and standard H&E staining; mean intercellular space diameter is measurably greater in NERD patients versus controls.DIS mechanism revision: The traditional explanation was that acid and pepsin directly damage tight junctions, increasing paracellular permeability. More recent data suggests cytokine-induced damage to mucosal microvasculature causes vascular fluid extravasation into intercellular spaces. The mechanism is inflammatory vascular leakage, not acid dissolving cell adhesion.Reflux hypersensitivity: Normal acid exposure time on ambulatory pH monitoring but positive symptom-reflux association (positive SI or SAP). The reflux is physiologic; the perception is pathologic. Rome IV classifies this as a functional esophageal disorder driven by peripheral or central visceral sensitization. Treatment shifts toward neuromodulators. More acid suppression will not help because acid quantity is not the problem.PPI response in NERD: Approximately 37% symptomatic response at 4 weeks versus 56% in erosive GERD. However, this gap is largely explained by study contamination: NERD trials often failed to exclude functional heartburn patients, who by definition will not respond to acid suppression. Baclofen may help patients where non-acidic reflux plays a prominent role.Board PearlsHigh-yield: NERD affects up to 70% of GERD patients. The majority of heartburn cases have a normal endoscopy. Normal endoscopy does not mean no GERD.Board trap: A young patient with dysphagia has a normal endoscopy while on PPI. What was missed? EoE suppressed by acid suppression therapy. Stop the PPI, repeat the endoscopy with biopsies.High-yield: The four PPI failure categories determine treatment. Functional heartburn requires neuromodulators and CBT, not more acid suppression. Sorting patients correctly is the board-tested skill.