Non-erosive Reflux Disease – What We Know So Far


and their association with symptoms, we applied this technique to a large group of unselected NERD patients off medication and we found, among NERD patients with negative AET, a positive symptom association for acid reflux in 15%, but also a positive association for non-acid reflux in 12% of patients.11


These results were extremely


This study underlined that FH has more in common with FD than with NERD and supported that it must be excluded from the realm of GORD, in agreement with Rome III criteria.


Epidemiology and Natural History


According to various studies, NERD is the most common type of GORD, occurring in from 50% to up to 85% of patients with reflux symptoms.13–18


50% of patients with heartburn in the US,13,14 it seems to be much higher – up to 70%.15–17 al. performed a large epidemiological study19


Several studies have reported a prevalence of about while in European studies More recently, Zagari et in the general population


and demonstrated a 23.7% (out of 1,033 subjects) prevalence rate of patients with reflux symptoms at least twice a week. Of those patients with reflux symptoms, 75.9% were found to have negative endoscopy. Overall, since GORD is a common disease, El-Serag20


Responsive Not responsive


clinically relevant because they allowed us to narrow down the proportion of patients who were otherwise labelled as presenting with FH and permitted us to identify a new subgroup of patients whose symptoms are due to reflux other than acid: a subgroup of patients with non-acid reflux disease (NARD) or weakly acidic reflux disease (WARD) – patients who, at the moment, belong to the ‘hypersensitive oesophagus (HO)’ subgroup (see Figure 2). Our results were also confirmed by another study assessing the overlap between NERD, FH and functional dyspepsia (FD).12


Figure 1: Diagnostic Algorithm for Non-erosive Reflux Disease and Functional Heartburn Based on Rome III Criteria (By Means of pH Testing with Symptom Association Analysis and Proton-pump Inhibitor Trial)


Patients with heartburn and normal endoscopy


– 24-hour pH monitoring + Yes No


Symptom association to acid reflux events


PPI treatment


NERD NERD = non-erosive reflux disease; PPI = proton-pump inhibitor. has estimated


that about 11% of the general population could be affected by NERD and that its prevalence is increasing each year. Whether NERD is one distinct form of GORD or a step towards EO, the debate is open: given the widespread use of proton-pump inhibitors (PPIs), some patients classified as NERD could be patients with healed EO.21


The largest


Therefore, the natural course studies available indicate that lack of progression is more common than progression along the spectrum for patients with NERD and, most importantly, there is no evidence that NERD patients may progress over time to develop Barrett’s oesophagus.25


At the moment, we can only hypothesise that


the vast majority of NERD and EO patients remain within their respective GORD groups throughout their lifetime (see Figure 3).


Pathophysiology


Failure of the normal antireflux barrier with its components (His angle, thorax–abdominal pressure gradient, continence of lower oesophageal sphincter [LOS], normal oesophageal clearance and orthostatic position) is the most involved cause of GORD.26


Indeed, this


phenomenon leads to reflux of gastric or gastro-duodenal contents into the oesophagus and therefore generation of symptoms and/or lesions. Moreover, several peripheral (luminal, mucosal and sensory afferents) as well as central factors (psychological, stress, etc.) seem to be involved in the pathophysiology of NERD.


Overall, no difference in terms of gastric acid output between NERD patients and those with EO has been observed.27


Assessing


the oesophageal AET in NERD patients by using ambulatory 24-hour oesophageal pH monitoring found that, in general, they have slightly higher mean AET than normal subjects and significantly lower AET than


EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW


Normal AET and SAP+ Hypersensitive oesophagus


Abnormal AET Non-erosive reflux disease pH-positive


Normal AET and SAP- Functional heartburn


population-based studies assessing progression of NERD to EO made by Labenz (n=3,894), Sontag (n=2,306) and Bardhan (n=12,374) claim that this progression is limited to a minority of cases or not at all (0–25.5%).22–24


Figure 2: Proposed Classification of Endoscopy-negative Patients by Means of Impedance-pH Testing with Symptom Association Analysis


Symptomatology GORD symptoms (i.e. heartburn and regurgitation)


Functional heartburn


Upper endoscopy


Absence of visible oesophageal injuries


24-hour MII-pH


Normal AET and SAP+ for acid


Hypersensitive acid oesophagus


Normal AET and SAP+ for weakly acid/non-acid


Weakly acidic reflux disease/ non-acid reflux disease


AET = acid exposure time; GORD = gastro-oesophageal reflux disease; MII-pH = multichannel intraluminal impedance with pH-metry; SAP = symptom association probability.


patients with EO. Martinez et al.13 were among the first to assess the


level of oesophageal acid exposure in NERD demonstrating that only 45.1% of NERD patients had an abnormal pH test compared with 75% of patients with EO and 92.9% of patients with Barrett’s oesophagus. By using impedance-pH testing, we observed that 55% of NERD patients


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