Microscopic Esophageal Mucosal Injury in Nonerosive Reflux Disease

doi:10.1016/j.cgh.2006.08.006

Clinical Gastroenterology and Hepatology

Volume 5, Issue 1, January 2007, Pages 4-16.e1

https://doi.org/10.1016/j.cgh.2006.08.006 Get rights and content

This review evaluates the current knowledge about the recognition of histologic esophageal mucosal changes in patients with nonerosive gastroesophageal reflux disease and analyzes the technical factors relevant to their interpretation. Studies investigating histologic changes in individuals with nonerosive reflux disease were identified by systematic Medline/PubMed searches from January 1966 to October 2005. Dilation of intercellular spaces was the most consistently reported histologic change in the esophageal mucosa of patients with nonerosive reflux disease, being observed in 41%–100% of patients and 0%–30% of controls. The mean intercellular space width was at least 2 times greater in patients than in controls, irrespective of esophageal acid exposure. Basal cell hyperplasia was observed in 9%–90% of patients compared with 10%–55% of controls. Papillary elongation was observed in 0%–85% of patients and 5%–20% of controls. Both of these features were more prevalent in reflux disease patients with abnormal esophageal acid exposure. All histologic changes responded to acid-suppressive therapy. Inflammatory cell infiltration was seldom observed or had a similar prevalence in patients and controls. Disparities in reported frequencies of change among studies were most likely caused by methodologic factors, most importantly the use of different methods for identifying patients and controls, for histologic sampling, and for biopsy scoring. The reviewed studies suggest that at least two thirds of patients with nonerosive reflux disease have histologic evidence of esophageal injury. Additional work is needed to assess the potential of these histologic changes for the diagnosis and assessment of reflux disease.

Section snippets

Methods

This systematic review is based on studies investigating histologic changes in individuals with nonerosive reflux disease identified by systematic Medline/PubMed searches from January 1966 to October 2005. The following search terms were used: (GERD [gastroesophageal reflux disease], GORD [gastro-oesophageal reflux disease], reflux, heartburn, esophagitis or oesophagitis) and (histology, histological, DIS [dilation of intercellular spaces], intercellular space, intercellular spaces, basal cell,

Results

The systematic search yielded 293 publications, 17 of which described histologic mucosal changes in adult patients with nonerosive reflux disease. Three studies were excluded because they did not present data on histologic changes separately. Hence, 14 studies remained (Table 1), including the original study by Ismail-Beigi et al.⁷

There are many important variations in study design and reporting of outcomes for each of the 4 main histologic criteria assessed. The reader should refer to the

Methodologic Issues

The studies reviewed earlier suggest that distal esophageal biopsy specimens may be substantially more useful in the diagnosis of reflux disease without mucosal breaks than is generally currently believed. There are, however, quite substantial disparities in some of the reported data, which are likely to be the result of major methodologic differences, as discussed later.

Conclusions

The studies reviewed in this article indicate that most patients who have troublesome reflux-induced symptoms are likely to have histologic evidence of mucosal damage even in the absence of mucosal breaks. The diagnostic potential of esophageal histology, in particular the presence of intercellular space dilation, is especially high in patients with reflux disease in whom endoscopy shows no mucosal breaks. Further research is needed to enable the evaluation of esophageal histology to be

References (31)

F. Ismail-Beigi et al.
Histological consequences of gastroesophageal reflux in man
Gastroenterology
(1970)
N.A. Tobey et al.
Dilated intercellular spaces: a morphological feature of acid reflux-damaged human esophageal epithelium
Gastroenterology
(1996)
D. Armstrong et al.
Esomeprazole therapy and esophageal histology in endoscopy-negative reflux disease (ENRD)—the CHEER Study
Gastroenterology
(2003)
M. Voutilainen et al.
Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consecutive patients referred for endoscopy due to dyspeptic and reflux symptoms
Digestion
(2000)
J. Isolauri et al.
Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients
Am J Gastroenterol
(1997)
A.P. Corder et al.
Heartburn, oesophagitis and Barrett’s oesophagus in self-medicating patients in general practice
Br J Clin Pract
(1996)
J. Ronkainen et al.
High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report
Scand J Gastroenterol
(2005)
R.M. Zagari et al.
Prevalence of asymptomatic endoscopic lesions of the upper gastrointestinal tractPreliminary results of The Loiano-Monghidoro population study
Gastroenterology
(2002)
P. Bytzer et al.
Interobserver variation in the endoscopic diagnosis of reflux esophagitis
Scand J Gastroenterol
(1993)
C.N. Carney et al.
Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus
Lab Invest
(1981)

N.A. Tobey et al.

Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium

Am J Gastroenterol

(2004)

C. Calabrese et al.

Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux

Aliment Pharmacol Ther

(2003)

R. Caviglia et al.

Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure

Am J Gastroenterol

(2005)

E. Solcia et al.

Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease

Virchows Arch

(2000)

P. Zentilin et al.

Reassessment of the diagnostic value of histology in patients with GORD, using multiple biopsy sites and an appropriate control group

Am J Gastroenterol

(2005)

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Heartburn is a common symptom in clinical practice, but as many as 70% of patients have normal findings from upper endoscopy. Most of these patients have nonerosive reflux disease (NERD) or functional esophageal disorders. NERD is the most common phenotype of gastroesophageal reflux disease, and functional heartburn is the most common cause for refractory heartburn. In patients with NERD, symptoms arise from gastroesophageal reflux and esophageal hypersensitivity, whereas in patients with functional heartburn, symptoms result from esophageal hypersensitivity. A diagnosis of NERD requires endoscopy and reflux testing, whereas a diagnosis of functional heartburn also requires esophageal manometry. NERD is treated most commonly with medical, endoscopic, and surgical antireflux approaches, whereas functional heartburn as well as NERD can be treated with neuromodulators, psychological intervention, and complementary medicine options.
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Gastroesophageal reflux is retrograde movement of gastric contents into the esophagus that occurs primarily after meals and is a normal physiologic process that prevents excessive gastric distension and dyspepsia. Gastroesophageal reflux disease (GERD) is defined as an abnormally elevated frequency of gastric reflux and/or volume of gastric refluxate, and typically presents as troublesome symptoms including heartburn and regurgitation. It is one of the most common diseases worldwide, and its incidence is increasing. Although the presence of hiatal hernia and esophageal dysmotility are important cofactors in reflux disease, transient lower esophageal sphincter relaxations (TLESRs) are the single most important mechanism underlying GERD. There are numerous tests available to aid in the diagnosis of GERD, but multichannel intraluminal impedance-pH (MII-pH) is the current gold standard. In patients with typical symptoms who improve with acid suppression, no further testing is necessary to confirm the diagnosis. Upper endoscopy should be obtained if symptoms do not improve with a trial of acid suppression or if “red flag” symptoms are present. Endoscopic findings of GERD include reflux esophagitis, peptic strictures and Barrett's esophagus, though many patients have normal esophageal mucosa. Management of GERD is usually medical, with proton pump inhibitors (PPIs) the initial therapy of choice for patients who experience symptoms at least twice a week. A Nissen fundoplication is an acceptable surgical alternative in patients with typical symptoms who are intolerant of PPIs. The most recent development in the treatment of GERD involves a surgically placed magnetic lower esophageal sphincter augmentation device.
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Epithelial Thickness is a Marker of Gastroesophageal Reflux Disease
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Citation Excerpt :
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At the assessment site for basal cell layer thickness, total epithelial thickness was the best-performing criterion for diagnosis of investigation-defined GERD; it also identified nonerosive reflux disease, reflux esophagitis, and pathologic esophageal acid exposure at 0.5 cm and 2.0 cm above the Z line. Basal cell layer thickness and presence of dilated intercellular spaces did not identify patients with GERD. Among the criteria tested, the best agreement between assessments carried out at the 2 pathology centers was for total epithelial thickness at 0.5 cm and 2.0 cm above the Z line.
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ReviewMicroscopic Esophageal Mucosal Injury in Nonerosive Reflux Disease

Section snippets

Methods

Results

Methodologic Issues

Conclusions

Gastroenterology

Gastroenterology

Gastroenterology

Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consecutive patients referred for endoscopy due to dyspeptic and reflux symptoms

Digestion

Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients

Am J Gastroenterol

Heartburn, oesophagitis and Barrett’s oesophagus in self-medicating patients in general practice

Br J Clin Pract

High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report

Scand J Gastroenterol

Prevalence of asymptomatic endoscopic lesions of the upper gastrointestinal tractPreliminary results of The Loiano-Monghidoro population study

Gastroenterology

Interobserver variation in the endoscopic diagnosis of reflux esophagitis

Scand J Gastroenterol

Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus

Lab Invest

Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium

Am J Gastroenterol

Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux

Aliment Pharmacol Ther

Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure

Am J Gastroenterol

Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease

Virchows Arch

Reassessment of the diagnostic value of histology in patients with GORD, using multiple biopsy sites and an appropriate control group

Am J Gastroenterol

Review
Microscopic Esophageal Mucosal Injury in Nonerosive Reflux Disease