15.

GASTROESOPHAGEAL REFLUX ESOPHAGITIS

Etiology
Gastroesophageal reflux is a disorder of the gastroesophageal sphincter permitting
reflux of gastrointestinal fluids or ingesta into the esophagus. Varying degrees of
esophagitis
result from prolonged contact of gastric acid, pepsin, trypsin, bile salts, and duodenal
bicarbonate with the esophageal mucosa.
Pathophysiology
The frequency of reflux and composition of the refluxed material determines the
severity of the esophagitis. Gastric acid alone produces a mild esophagitis, whereas
combinations of acid and pepsin or trypsin, bicarbonate, and bile salts produce a severe
esophagitis. The risk of reflux esophagitis is also greater with multiple episodes than with a
single long episode of acid exposure. Gastroesophageal reflux has been poorly
documented in
dogs and cats, but it is undoubtedly more common than previously thought. Chronic
vomiting, disorders of gastric emptying, hiatal hernia, upper airway obstruction, and
anesthesia-induced reductions in gastroesophageal sphincter pressure have all been
implicated in the pathogenesis
of gastroesophageal reflux in dogs and cats. Many of the preanesthetic agents currently in
use are associated with reductions in gastroesophageal sphincter pressure as are all of
the inhalant anesthetic agents.
The pathophysiology of mucosal injury in gastroesophageal reflux remains to be
completely elucidated, but prolonged contact of the mucosa with acid clearly contributes to
the reflux injury. The central dogma has been that esophagitis develops from an acid (or
other chemical) injury starting at the luminal surface of the squamous epithelium,
progressing through the epithelium and lamina propria into the submucosa, and resulting
in acid-induced necrosis of surface epithelial cells and stimulation of a proliferative
response in the basal cells. This dogma has been recently challenged by new
experimental findings. It has been proposed that refluxed gastric fluid does not directly
damage the esophageal mucosa, but rather stimulates esophageal epithelial cells to
secrete chemokines that attract and activate immune cells, causing damage to the
esophageal squamous epithelial cells. In this model, acid
is believed to activate acid-sensitive transient receptor potential vanilloid 1 (TRPV1)
receptors, causing the production and release of PAF, SP, and IL-8, which attract and
activate immune cells contributing to inflammation and injury of the esophageal mucosa.
These data further suggest that inhibition of IL-8, SP, and PAF-induced neutrophil
migration and activation may be the basis of future therapy in this disorder.
Clinical Signs
The clinical signs of gastroesophageal reflux are similar to those of esophagitis. In
severe cases, animals may develop regurgitation, salivation, odynophagia, extension of
the head and neck during swallowing, and total avoidance of food. In milder cases,
however, affected animals may have only an occasional episode of regurgitation,
particularly in the early morning hours. The latter cases are physiologic and result from
transient relaxations of the gastroesophageal sphincter during sleep. The physical
examination is usually unremarkable, but fever and excessive salivation may be detected
in animals with severe concurrent esophagitis.
Diagnosis
The diagnosis of gastroesophageal reflux may be little more than clinical suspicion.
Survey radiographs typically do not aid in the diagnosis. Videofluoroscopy may
demonstrate intermittent gastroesophageal reflux, but this finding may also be observed in
animals with normal esophageal function. Endoscopy is the current best method for
documenting mucosal inflammation consistent with reflux esophagitis. Definitive diagnosis
of gastroesophageal reflux requires continuous measurements of gastroesophageal
sphincter pressure and 24-hour
intraluminal pH, procedures for which most dogs and cats are not compliant. Hiatal hernia,
esophagitis, and esophageal stricture are the most important differential diagnoses for
gastroesophageal reflux.
Treatment
Because dietary fat delays gastric emptying and reduces gastroesophageal sphincter
pressure, animals should be fed fat-restricted diets. Pet owners should also avoid late
night feedings because this would tend to reduce gastroesophageal sphincter pressure
during sleep.
In addition to nutritional considerations, rational medical therapy for this disorder includes
diffusion barriers (e.g., sucralfate), gastric acid secretory inhibitors (e.g., cimetidine,
ranitidine, famotidine, or omeprazole), and prokinetic agents (e.g., cisapride or
metoclopramide). Diffusion barriers are perhaps the most important medical therapy in
gastroesophageal reflux. Sucralfate (0.5 to 1.0 g PO, TID), for example, protects against
mucosal damage from gastroesophageal reflux and promotes healing of existing
esophagitis.
Refractory cases of gastroesophageal reflux should be concurrently medicated with acid
secretory inhibitors and/or prokinetic agents. The H2 histamine receptor antagonists, for
example, cimetidine (5 to 10 mg/kg PO or IV, TID-QID), ranitidine (1 to 2 mg/kg PO or IV,
BID-TID), and famotidine (0.1 to 0.5 mg/kg PO or IV, BID), inhibit gastric acid secretion
and reduce the amount ofacid reflux. Omeprazole (0.7 mg/kg PO, SID); esomeprazole,
lansoprazole, and pantoprazole (all 1.0 mg/kg IV, SID); and all H+,K+- ATPase inhibitors
could be used to inhibit gastric acid secretion as an alternative to H2 histamine receptor
antagonism. Metoclopramide (0.2 to 0.4 mg/kg PO, TID-QID) and erythromycin (0.5-1.0
mg/kg PO, BID-TID) may be useful in treating gastroesophageal reflux because they
increase gastroesophageal sphincter pressure. 5-HT4 agonists like cisapride and
tegaserod also increase tone in the gastroesophageal sphincter, and are likely superior to
other prokinetic drug classifications. Both cisapride and tegaserod have been withdrawn
from several international markets because of high-potency binding to ventricular 5-HT4
receptors, inhibition of the delayed rectifying K+ channel, delayed repolarization, and
prolongation of the cardiac Q-T interva. Cisapride has continued availability in many
countries through compounding pharmacies. Recent studies show that GABA type B
receptor agonists (e.g., baclofen), cannabinoid receptor agonists (WIN 55,212-2), and
metabotropic glutamate (mGlu) receptor 5 antagonists (MPEP) abolish transient
gastroesophageal relaxations in the dog, and therefore may have future application in the
treatment of gastroesophageal reflux.
Prognosis
The prognosis for most animals with gastroesophageal reflux is good with medical
management. Anatomic correction of upper airway obstruction in brachycephalic breeds
should ameliorate gastroesophageal reflux in affected patients.