GERD pathology caused by immune reaction, not acid
GERD (gastroesophageal reflux disease) may be caused by a dysregulated inflammatory reaction to the stimulus of gastric hydrochloric acid in the lower esophagus, not 'burning' by the acid itself, according to preliminary research just published in JAMA (Journal of the American Medical Association). The authors note:
"The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid."
They examined patients whose reflux esophagitis was in remission while on acid-blocking medications (proton pump inhibitors (PPIs) with biopsies from noneroded areas of the distal esophagus along with surface changes after medication was stopped.
GERD pathogenesis inflammatory cytokine-mediated from within
The authors were investigating for the first time in human subjects for all the mechanisms of inflammatory damage.
"Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity)."
The fascinating and clinically important implication of their data is that inflammatory damage in GERD happens primarily from the inside out:
"At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week and 2 weeks); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased, mucosal impedance decreased, and all patients had evidence of esophagitis."
The key point here is that the pathological changes noted above occurred without without the loss of cells on the surface. Like so many other conditions, from osteoarthritis to acne, which were formerly thought to be due primarily to trauma (mechanical or chemical) or infection, esophageal damage in GERD appears due to the character of the inflammatory response to a stimulus (in this case some gastric acid).Medscape Medical News quotes the authors:
""[E]sophageal basal cell and papillary hyperplasia developed in areas without surface erosions. If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily."
Medscape also quotes the author of a linked editorial:
"Peter Kahrilas, MD, from Northwestern Feinberg School of Medicine, Chicago, Illinois, notes that the "provocative findings from this investigation are in the details": the earliest pathology occurred deep in the epithelium, not at the mucosal surface, and repair mechanisms started before the death of surface cells previously thought to provoke these changes...[A]lthough the inciting pathophysiology is unquestionably the reflux of gastric and duodenal secretions into the esophagus, this evidence suggests that the effect of that reflux is the initiation of cytokine-triggered inflammation rather than the long held belief of a direct chemical effect of acid, pepsin, and bile on the esophageal epithelium," he wrote."
The authors conclude:
"In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte–predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury."
Clinical Note
GERD, even gastroduodenal ulcer, often occurs in an environment with deficient gastric acid. While medically blocking acid production or neutralizing it with an alkalizing agent (Maalox®, etc.) typically halts symptoms, doing so disables digestion of proteins and the first line of defense against GI pathogens while impairing assimilation of magnesium and vitamin B12—hence the association with PPI medications and increased cardiovascular risk. Incomplete protein digestion byproducts can also promote sensitization of the immune system to those foods and contribute to autoimmune disorders. Better for clinicians to endeavor to normalize cardio-esophageal sphincter function by ensuring well-regulated vagal stimulation of the gut while supporting digestion and removal of irritants as necessary.