Gastroenterology

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 771-778
Gastroenterology

Special reports and reviews
The pathogenesis of heartburn in nonerosive reflux disease: A unifying hypothesis

https://doi.org/10.1053/j.gastro.2004.08.014Get rights and content

Heartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative ā€œheartburnā€ have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive ā€œheartburn,ā€ ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated ā€œheartburnā€ as an acid-mediated event requiring ā€œrelief by antacidsā€ as a necessary component of the history.

Section snippets

Nonerosive reflux disease

Our approach to examining the pathogenesis of heartburn in NERD first required that NERD be defined and that this definition be uniformly applied to clinical investigations to determine the applicability of their conclusions to the condition. The definition of NERD, as used herein, has 2 major requirements: (1) a history of ā€œheartburnā€ in the absence of esophageal mucosal lesions on endoscopy and (2) supportive evidence that the symptom is acid-mediated, established by either prolonged ACT on

Esophageal visceral hypersensitivity

EVH is 1 of the 3 mechanisms proposed to explain the pathogenesis of heartburn in NERD. The term, itself, implies the presence of an esophageal neuronal defect at the periperal or central level that creates heightened perception of an esophageal stimulus.10, 11 EVH is recognized clinically by the presence of either allodynia or hyperalgesia. Allodynia is the perception of a stimulus at a level not perceived by a healthy subject and hyperalgesia is greater discomfort from a given stimulus than

Sustained esophageal contractions

SEC are another mechanism proposed to explain the pathogenesis of heartburn in NERD. SEC, which represent prolonged contractions of the esophageal longitudinal smooth muscle, can be detected in vivo in humans as an increase in wall thickness by high frequency endoscopic ultrasonography.17 The concept that SEC are the cause of heartburn in NERD evolved from observations in a dozen patients with GERD. GERD was diagnosed by a history of retrosternal burning in the absence of other identifiable

Abnormal tissue resistance

ATR is the third mechanism proposed to explain the pathogenesis of heartburn in NERD. In this context ā€œabnormal tissue resistanceā€ refers specifically to ā€œabnormal esophageal epithelial barrier function.ā€ In the esophagus, the main structural components of the barrier are the apical membranes and junctional complexes of the cells comprising the stratum corneum.22 These protect by preventing the diffusion of ingested and refluxed luminal contents from penetrating into the esophageal mucosa. In

Heartburn revisited

ATR as the proposed basis for reflux-associated heartburn in NERD effectively realigns it with the commonly accepted principles that form the basis for heartburn in erosive esophagitis. Consequently, heartburn in GERD can be viewed as the result of an acidic refluxate contacting a damaged esophageal epitheliumā€”with heartburn in NERD being due more specifically to damage and ATR at the microscopic level and heartburn in erosive esophagitis being due to damage and ATR that has progressed to the

References (46)

  • N.A. Tobey et al.

    The role of pepsin in acid injury to esophageal epithelium

    Am J Gastroenterology

    (2001)
  • N.A. Tobey et al.

    Dilated intercellular spacesA morphological feature of acid reflux-damaged human esophageal epithelium

    Gastroenterology

    (1996)
  • R.C. Orlando et al.

    Esophageal potential difference measurements in esophageal disease

    Gastroenterology

    (1982)
  • C. Calabrese et al.

    Omeprazole and ultrastructural modifications occurring in reflux esophagitis

    Gastroenterology

    (2002)
  • K.H. Steen et al.

    Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in humans

    Neurosci Lett

    (1993)
  • N.A. Tobey et al.

    Serosal bicarbonate protects against acid injury to rabbit esophagus

    Gastroenterology

    (1989)
  • W.H. Hu et al.

    Intraesophageal acid perfusion sensitizes the esophagus to mechanical distensionA barostat study

    Am J Gastroenterol

    (2000)
  • M.K. Kern et al.

    Identification and characterization of cerebral cortical response to esophageal mucosal acid exposure and distention

    Gastroenterology

    (1998)
  • D.A. Lloyd et al.

    Food-induced heartburnEffect of osmolality

    Gastroenterology

    (1981)
  • J.B. So et al.

    Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication

    Surgery

    (1998)
  • R.C. Orlando

    Reflux esophagitis

  • R.C. Heading

    Epidemiology of oesophageal reflux disease

    Scand J Gastroenterol

    (1989)
  • A.A.M. Masclee et al.

    Ambulatory 24-hour pH-metry in the diagnosis of gastroesophageal reflux disease

    Scand J Gastroenterol

    (1990)
  • Cited by (239)

    • Mechanism and Pathophysiology of Gastroesophageal Reflux Disease

      2020, Gastrointestinal Endoscopy Clinics of North America
    • Reflux esophagitis, functional and non-functional

      2019, Best Practice and Research: Clinical Gastroenterology
    View all citing articles on Scopus
    View full text