All of the following hormones decrease LES tone EXCEPT:
The LES has intrinsic myogenic tone, which is modulated by neural and hormonal mechanisms. Alpha-adrenergic neurotransmitters or beta blockers stimulate the LES, and alpha blockers and beta stimulants decrease its pressure. It is not clear to what extent cholinergic nerve activity controls LES pressure. The vagus nerve carries both excitatory and inhibitory fibers to the esophagus and sphincter. The hormones gastrin and motilin have been shown to increase LES pressure; and cholecystokinin, estrogen, glucagon, progesterone, somatostatin, and secretin decrease LES pressure. The peptides bombesin, L-enkephalin, and substance P increase LES pressure; and calcitonin gene-related peptide, gastric inhibitory peptide, neuropeptide Y, and vasoactive intestinal polypeptide decrease LES pressure. Some pharmacologic agents such as antacids, cholinergics, agonists, domperidone, metoclopramide, and prostaglandin F2 are known to increase LES pressure; and anticholinergics, barbiturates, calcium channel blockers, caffeine, diazepam, dopamine, meperidine, prostaglandin El and E2, and theophylline decrease LES pressure. Peppermint, chocolate, coffee, ethanol, and fat are all associated with decreased LES pressure and may be responsible for esophageal symptoms after a sumptuous meal.
The most common cause of a deficient LES is:
It is important that a portion of the total length of the LES be exposed to the effects of an intra-abdominal pressure. That is, during periods of elevated intra -abdominal pressure, the resistance of the barrier would be overcome if pressure were not applied equally to both the LES and stomach simultaneously. Thus, in the presence of a hiatal hernia, the sphincter resides entirely within the chest cavity and cannot respond to an increase in intra-abdominal pressure because the pinch valve mechanism is lost and gastroesophageal reflux is more liable to occur. Therefore, a permanently defective sphincter is defined by one or more of the following characteristics: An LES with a mean resting pressure ofless than 6 mm Hg, an overall sphincter length of <2 em, and intra-abdominal sphincter length of <1 em. Compared to normal subjects without GERD these values are below the 2.5 percentile for each parameter. The most common cause of a defective sphincter is an inadequate abdominal length.
Maximal esophageal mucosal damage is caused by exposure to:
The potential injurious components that reflux into the esophagus include gastric secretions such as acid and pepsin, as well as biliary and pancreatic secretions that regurgitate from the duodenum into the stomach. There is a considerable body of experimental evidence to indicate that maximal epithelial injury occurs during exposure to bile salts combined with acid and pepsin. These studies have shown that acid alone does minimal damage to the esophageal mucosa, but the combination of acid and pepsin is highly deleterious. Similarly, the reflux of duodenal juice alone does little damage to the mucosa, although the combination of duodenal juice and gastric acid is particularly noxious.
The incidence of metaplastic Barrett esophagus (BE) progressing to adenocarcinoma is:
If reflux of gastric juice is allowed to persist and sustained or repetitive esophageal injury occurs, two sequelae can result. First, a luminal stricture can develop from submucosal and eventually intramural fibrosis. Second, the tubular esophagus may become replaced with columnar epithelium. The columnar epithelium is resistant to acid and is associated with the alleviation of the complaint of heartburn. This columnar epithelium often becomes intestinalized, identified histologically by the presence of goblet cells. This specialized intestinal metaplasia (IM) is currently required for the diagnosis of Barrett esophagus (BE). Endoscopically, BE can be quiescent or associated with complications of esophagitis, stricture, Barrett ulceration, and dysplasia. The complications associated with BE may be due to the continuous irritation from refluxed duodenogastric juice. This continued injury is pH -dependent and may be modified by medical therapy. The incidence of metaplastic Barrett epithelium becoming dysplastic and progressing to adenocarcinoma is approximately 0.2 to 0.5% per year.
The histologic hallmark of BE is:
The definition of BE has evolved considerably over the past decade. Traditionally, BE was identified by the presence of columnar mucosa extending at least 3 em into the esophagus. It is now recognized that the specialized, intestinal-type epithelium found in the Barrett mucosa is the only tissue predisposed to malignant degeneration. Consequently, the diagnosis of BE is presently made given any length of endoscopically identifiable columnar mucosa that proves, on biopsy, to show IM. Although long segments of columnar mucosa without IM do occur, they are uncommon and might be congenital in origin.
The hallmark ofiM is the presence of intestinal goblet cells. There is a high prevalence of biopsy-demonstrated IM at the cardia, on the gastric side of the squamocolumnar junction, in the absence of endoscopic evidence of a columnar-lined esophagus ( CLE). Evidence is accumulating that these patches of what appears to be Barrett in the cardia have a similar malignant potential as in the longer segments, and are precursors for carcinoma of the cardia.
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