Endoscopy negative reflux disease

(Non-erosive reflux, oesophageal hypersensitivity and functional heartburn)

50-70% of patients with symptoms of reflux will have a normal endoscopy. Furthermore, they may have relatively minor abnormalities on a pH study yet their symptoms are severe and their quality of life is just as badly affected as those patients with erosive disease. So why do patients with non-erosive reflux disease (NERD) have symptoms and what can be done to help?

This section examines the oesophageal environment in NERD, the cellular changes at the microscopic level and the implications for neural pain transmission and looks at therapeutic options.

The population:   NERD patients are twice as likely to be colonised with Helicobacter pylori, three times as likely to have Irritable Bowel Syndrome and ten times more likely to have a psychological disorder as patients with erosive reflux disease (ERD). On the other hand they are only half as likely to have a hiatus hernia and pH studies show the NERD oesophagus is on average exposed to acid for about 30% less time per day and indeed up to half may have normal acid exposure times. When exposed to acid the episodes in NERD tend to last less then half the time than in ERD and the oesophageal bolus transit time is shorter than in ERD. Furthermore, ERD patients are more likely to have more marked manometric abnormalities in the distal oesophagus with lower amplitude contractions and a lower oesophageal sphincter pressure.

This is however a heterogenous group of patients and the distinction is not as simple as ERD v NERD. Conventionally, 'NERD' patients with normal amounts of oesophageal acid exposure and good correlation of symptoms with reflux events are considered to have oesophageal hypersensitivity (OH), while patients with no symptom-reflux correlation are considered to have functional heartburn (FH) - see the flow chart on the left.

Patients with NERD and abnormal oesophageal acid exposure have motor dysfunction and acid reflux abnormalities that are broadly similar to patients with ERD and Barrett's, whereas OH and FH patients with normal oesophageal acid exposure have minimal abnormalities and do not differ much from healthy controls. Whilst the number of acid reflux episodes and the number of Transient Lower Oesophageal Relaxations in NERD is similar to normal controls, the rate at which acid is cleared from the more proximal oesophagus is slower thereby increasing contact time of the refluate with the oesophageal mucosa. This defective triggering of secondary peristalsic waves has been reproduced in several studies.

It is possible yet uncommon for NERD to progress to severe ERD. Patients with NERD suffer a similar reduction in quality of life as do patients with ERD - see the bar chart on the right. Although patients with NERD have very low rates of night-time reflux compared with ERD, about 2/3 in each group experience sleep disturbance.

There is evidence to suggest that while patients with functional heartburn have clinical traits of a functional bowel disorder, hypersensitivity to acid is not a general phenomenon when compared to NERD patients. However, all these patients experience a significant reduction in quality of life compared with the general population in many areas of daily living and therefore both ERD and NERD should be seen, at least in one sense, as a multi-system disorder. Up to half of NERD patients satisfy the clinical criteria for the diagnosis of IBS and anxiety and depression are the most common psychiatric diagnoses that are diagnosed in this group of patients.

Dilated inter-cellular spaces (DIS): 

Damage to the oesophageal mucosal layer precedes symptoms of heartburn but this damage is not always macroscopic. Endoscopic biopsies of normal appearing oesophagus in symptomatic patients reveal a variety of abnormalities, including mucosal infiltration with inflammatory cells, elongation of the rete pegs, squamous cell oedema, basal cell hyperplasia, and a recently recognized lesion of squamous epithelium known as "dilated intercellular spaces" (see scanning electron microscopy photograph on the left: normal above, DIS below. This gap is measured in the image on the right: 0.74mm is the cut-off measurement).

It is becoming clear that psychological stress can impair oesophageal mucosal function by mechanisms that mainly involve neuropeptides and mast cells causing increased permeability stratified epithelia. There are many theories as to how this develops. Recent work has shown that there is higher expression of IL-8 mRNA (encoding a pro-inflammatory cytokine) in oesophageal mucosa from NERD patients than in normal subjects, the implication being that its activation through receptors would trigger the start of an inflammatory cascade leading to increased permeability. Nuclear factor kappa-B (NF kappa-B) upregulates IL-8 expression and this too has been shown to be activated, predominantly in nuclei expressing IL-8, in NERD by a Japanese group. Proton pump inhibitor treatment reverses this. Nitric oxide (NO) may also contribute to mucosal injury and a group from Yokahama has shown expression of inducible NO synthetase (iNOS) mRNA in the oesophageal mucosa increasing parallel to the severity of the oesophagitis, thus further adding to the theory that mucosal inflammatory injury is integral to the development of reflux symptoms.

Neural pain transmission:  Click