Heartburn pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Overview

The sensation of heartburn is caused by exposure of the lower esophagus to the acidic contents of the stomach. Normally, the lower esophageal sphincter (LES) separating the stomach from the esophagus is supposed to contract to prevent this situation. If the sphincter relaxes for any reason (as normally occurs during swallowing), stomach contents, mixed with gastric acid, can return into the esophagus. This return is also known as reflux, and may progress to gastroesophageal reflux disease (GERD) if it occurs frequently. If this is the case, the gastric acid and pepsin now located in the esophagus can injure the tight junction proteins in the esophageal epithelium. This results in increased paracellular permeability and dilated intercellular space and edema in the submucosa, which is amplified by an immunological mechanism mediated by inflammatory cytokines.^[1]

Pathophysiology

Heartburn is the burning pain caused by the reflux of gastric acid and pepsin from the stomach into the esophagus.
These substances enter the esophagus due to a dysfunctional lower esophagus sphincter, which in normal conditions should now allow the occurrence of such reflux.
This can happen due to many causes such as hiatal hernia, use of medications which causes relaxation of the lower esophagus sphincter or due to abnormal relaxation or weakening of the lower esophagus sphincter which causes the gastroesophageal reflux disease.
The gastric acid and the pepsin damages the epithelium and causes an inflammatory response mediated by IL-8 and IL-1B. These cytokines stimulate inflammation and sensitizes the peripheral nerves in the mucosa which mediates the pain. It is believed that the release of such cytokines is mediated by an increased production of PGE2 and ATP by the epithelium.^[1]

With the most recent research findings, it is believed that the gastric acid does not directly cause heartburn, but causes it using a myriad of inflammatory mechanisms which are being elucidated and may be targets of new therapeutic drugs in the future.^[1]

Source by:BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44923646

Pathology

The esophagus is lined by nonkeratinizing, stratified squamous epithelium, and the stomach by columnar epithelium – in which every cell has a small surface area in contact with the organ lumen.
The squamocolumnar junction is the point, where the epithelium lining the esophagus meets the epithelium lining the gastric mucosal folds.
The gastroesophageal junction is the anatomic place where the esophagus meets the stomach and it is located at the same place as the squamocolumnar junction. *Patients with gastroesophageal reflux disease have a squamocolumnar junction which is moved proximally due to the changes occurring at the esophageal epithelium, which gradually changes into columnar epithelium, looking similarly as the gastric epithelium, and being located above the anatomical junction.^[1]^[2]

Many changes have been reported in the esophageal epithelium in patients with gastroesophageal reflux disease, as a response to damage. These changes have been summarized in the Esohisto project:

Histologic criteria for the recognition and assessment of microscopic lesions related to gastroesophageal reflux disease (GERD) – the Esohisto project criteria^[3]
Proliferative changes of the squamous epithelium	Criterion	Definition and method of assessment	Severity score
Basal cell layer Hyperplasia	Basal cell layer thickness in μm as a proportion (%) of total epithelial thickness (10×)	0 (<15%) 1 (15–30%) 2 (>30%)
Papillary Elongation	Papillary length in μm as a proportion (%) of total epithelial thickness (10×)	0 (<50%) 1 (50–75%) 2 (>75%)
Dilated intercellular spaces	Identify as irregular round dilations or diffuse widening of intercellular space (40×)	0 (absent) 1 (<1 lymphocyte) 2 (≥1 lymphocyte)
Inflammatory infiltrate	Intraepithelial Eosinophils	Count in the most affected high-power field (4×0)	0 (absent) 1 (1–2 cells) 2 (>2 cells)
Inflammatory infiltrate	Intraepithelial Neutrophils	Count in the most affected high-power field (40×)	0 (absent) 1 (1–2 cells) 2 (>2 cells)
Inflammatory infiltrate	Intraepithelial mononuclear cells	Count in the most affected high-power field (40×)	0 (0–9 cells) 1 (10–30 cells) 2 (>30 cells)

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Miwa H, Kondo T, Oshima T (2016). “Gastroesophageal reflux disease-related and functional heartburn: pathophysiology and treatment”. Curr Opin Gastroenterol. 32 (4): 344–52. doi:10.1097/MOG.0000000000000282. PMID 27206157.
↑ De Giorgi F, Palmiero M, Esposito I, Mosca F, Cuomo R (October 2006). “Pathophysiology of gastro-oesophageal reflux disease”. Acta Otorhinolaryngol Ital. 26 (5): 241–6. PMC 2639970. PMID 17345925.
↑ Yerian L, Fiocca R, Mastracci L, Riddell R, Vieth M, Sharma P; et al. (2011). “Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto Project”. Dig Dis Sci. 56 (9): 2656–65. doi:10.1007/s10620-011-1624-z. PMID 21365241.

[pmid27206157-1] 1.0 ^1.1 ^1.2 ^1.3 Miwa H, Kondo T, Oshima T (2016). “Gastroesophageal reflux disease-related and functional heartburn: pathophysiology and treatment”. Curr Opin Gastroenterol. 32 (4): 344–52. doi:10.1097/MOG.0000000000000282. PMID 27206157.

[pmid17345925-2] De Giorgi F, Palmiero M, Esposito I, Mosca F, Cuomo R (October 2006). “Pathophysiology of gastro-oesophageal reflux disease”. Acta Otorhinolaryngol Ital. 26 (5): 241–6. PMC 2639970. PMID 17345925.

[pmid21365241-3] Yerian L, Fiocca R, Mastracci L, Riddell R, Vieth M, Sharma P; et al. (2011). “Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto Project”. Dig Dis Sci. 56 (9): 2656–65. doi:10.1007/s10620-011-1624-z. PMID 21365241.

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