Figure 42-25. The intragastric pressure at which the lower esophagus endoscopically opened in response to gastric distention by

air during endoscopy. Note that the dome architecture of a hiatus hernia (HH) influences the ease with which the sphincter can be

pulled open by gastric distention. (Reproduced with permission from Ismail T, Bancewicz J, Barlow J. Yield pressure, anatomy of

the cardia and gastro-oesophageal reflux. Br J Surg 1995;82:943–947.)

A transient loss of the high-pressure zone can also occur and usually results from a functional problem

of the gastric reservoir.33 Excessive air swallowing or food can result in gastric dilatation and, if the

active relaxation reflex has been lost, an increased intragastric pressure. When the stomach is distended,

the vectors produced by gastric wall tension pull on the GE junction with a force that varies according

to the geometry of the cardia; that is, the forces are applied more directly when a hiatal hernia exists

than when a proper angle of His is present. The forces pull on the terminal esophagus, causing it to be

“taken up” into the stretched fundus and thereby reducing the length of the high-pressure zone or

“sphincter.” This process continues until a critical length is reached, usually about 1 to 2 cm, when the

pressure drops precipitously and reflux occurs. The mechanism by which gastric distention contributes

to shortening of the length of the high-pressure zone, so that its pressure drops and reflux occurs,

provides a mechanical explanation for “transient relaxations” of the LES without invoking a

neuromuscular reflex. Rather than a “spontaneous” muscular relaxation, there is a mechanical

shortening of the high-pressure zone, secondary to progressive gastric distention, to the point where it

becomes incompetent. These “transient sphincter” shortenings occur in the initial stages of GERD and

are the mechanism for the early complaint of excessive postprandial reflux. After gastric venting, the

length of the high-pressure zone is restored and competence returns until distention again shortens it

and encourages further venting and reflux. This sequence results in the common complaints of repetitive

belching and bloating in patients with GERD. The increased swallowing frequency seen in patients with

GERD contributes to gastric distention and is due to their repetitive ingestion of saliva in an effort to

neutralize the acid refluxed into their esophagus.26 Thus, GERD may begin in the stomach, secondary to

gastric distention resulting from overeating and the increased ingestion of fried foods, which delay

gastric emptying. Both characteristics are common in Western society and may explain the high

prevalence of the disease in the Western world.

A recent series of studies from Glasgow assesses the nature of the acid environment at the GE

junction,28 including possible inciting factors in the development of cardia and distal esophageal

adenocarcinoma. The studies were initiated to investigate a long-recognized observation that esophageal

pH monitoring reveals postprandial esophageal acidification at the same time as the gastric contents are

alkalinized. This paradox is hard to explain given that reflux of gastric content into the esophagus is the

primary mechanism underlying GERD. Hypothesizing that acidic material must be present somewhere in

the upper stomach, the investigators studied luminal pH at 1-cm increments across the upper stomach

and lower esophagus in healthy volunteers before and after meals. Surprisingly, they identified a

“pocket” of acid at the GE junction unaffected by the buffering action of the meal, which extended

across the squamocolumnar junction an average of 1.8 cm into the lumen of the esophagus (Fig. 42-26).

The authors concluded that this was the source of postprandial esophageal acid exposure. They

expanded these initial studies, confirming that the same process occurs in patients with endoscopynegative dyspepsia and normal conventional esophageal pH monitoring 5 cm above the upper border of

the LES.89 Perhaps more important, they also identified that dietary nitrate consumed in the form of

green vegetables results in the generation of concentrations of nitric oxide at the GE junction high

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enough to be potentially mutagenic (Fig. 42-27).90 These observations provide the fundamental basis for

the observations of inflammation and other alterations in the epithelium long known to occur at the

squamocolumnar junction in both overt and unrecognized GERD.

Figure 42-26. Fasting and postprandial gastric and esophageal pH measurements in 1 cm increments during a pull through the

gastroesophageal junction. The postprandial tracing reveals an “acid pocket” from 44 to 41 cm from the nares. The fasting tracing

reveals this to be the same area as the pH “step-up” corresponding to the transition from the stomach to the esophagus.

(Reproduced with permission from Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the

gastroesophageal junction after a meal. Gastroenterology 2001;121:775–783.)

Figure 42-27. Mean (±SEM) nitric oxide concentrations in the upper stomach and lower esophagus after administration of water

with 2 mmol nitrate (upper tracing) and water alone (lower tracing) (**p < 0.01, *p < 0.05 compared with value at

gastroesophageal junction pH step-up). (Reproduced with permission from Iljima K, Henry E, Moriya A, et al. Dietary nitrate

generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 2002;122:1248–

1257.)

The data support the likelihood that GERD begins in the stomach. Fundic distention occurs because of

overeating and delayed gastric emptying secondary to the high-fat Western diet. The distention causes

the sphincter to be “taken up” by the expanding fundus, exposing the squamous epithelium with the

high-pressure zone, which is the distal 3 cm of the esophagus, to gastric juice. Repeated exposure causes

inflammation of the squamous epithelium, columnarization, and carditis. This is the initial step and

explains why in early disease the esophagitis is mild and commonly limited to the very distal esophagus.

The patient compensates by increased swallowing, allowing saliva to bathe the injured mucosa and

alleviate the discomfort induced by exposure to gastric acid. Increased swallowing results in aerophagia,

bloating, and repetitive belching. The distention induced by aerophagia leads to further exposure and

repetitive injury to the terminal squamous epithelium and the development of cardiac-type mucosa. This

is an inflammatory process, commonly referred to as “carditis,” and explains the complaint of epigastric

pain so often registered by patients with early disease. The process can lead to a fibrotic mucosal ring at

the squamocolumnar junction and explains the origin of a Schatzki ring. Extension of the inflammatory

process into the muscularis propria causes a progressive loss in the length and pressure of the distal

esophageal high-pressure zone associated with an increased esophageal exposure to gastric juice and the

symptoms of heartburn and regurgitation. The loss of the barrier occurs in a distal-to-proximal direction

and eventually results in the permanent loss of LES resistance and the explosion of the disease into the

esophagus with all the clinical manifestations of severe esophagitis. This accounts for the observation

that severe esophageal mucosal injury is almost always associated with a permanently defective

sphincter. At any time during this process and under specific luminal conditions or stimuli, such as

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exposure time to a specific pH range, intestinalization of the cardiac-type mucosa can occur and set the

stage for malignant degeneration.

Implications

Implications of recognizing anatomic alterations as component of GE barrier:

1. Transient lower esophageal sphincter relaxation is likely a consequence of sphincter shortening by

gastric distention and is the underlying mechanism for belching and physiologic reflux. It does not

play a major role in patients with symptomatic gastroesophageal reflux, particularly those with

erosive disease, Barrett esophagus, or those referred for surgery.

2. Efforts to augment the gastroesophageal barrier either pharmacologically or endoscopically will

commonly fail when a hiatal hernia is present.

3. Patients with abnormal esophageal acid exposure in the presence of normal LES characteristics and no

hiatal hernia have an uncommon reason for reflux and these patients require additional evaluation

since gastric or esophageal clearance failure may be present and may impair the outcome of a

fundoplication.

4. Both reduction of hiatal hernia and augmentation of the lower esophageal sphincter are necessary to

maximally restore gastroesophageal barrier competence.

5. Although acid control without regard to barrier incompetence will improve heartburn and heal

esophageal erosive disease, it results in increasing numbers of patients with pulmonary manifestations

of GERD.

Complications of Gastroesophageal Reflux Disease

The complications of gastroesophageal reflux result from the damage caused by the reflux of gastric

juice onto the esophageal mucosa or laryngeal or respiratory epithelium (Fig. 42-28). Complications can

be conceptually divided into (a) mucosal complications such as esophagitis and stricture; (b)

extraesophageal or respiratory complications such as chronic cough, asthma, and pulmonary fibrosis;

and (c) metaplastic (Barrett esophagus) and neoplastic (adenocarcinoma). The prevalence and severity

of complications is related to the degree of loss of the gastroesophageal barrier, defects in esophageal

clearance, and the content of refluxed gastric juice (Fig. 42-29).

Figure 42-28. Schematic representation of the types of complications of gastroesophageal reflux disease.

Figure 42-29. Prevalence of esophageal mucosal injury related to the presence of a defective lower esophageal sphincter,

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esophageal body motility, or both.

Mucosal Complications

The potential injurious components that reflux into the esophagus include gastric secretions, such as acid

and pepsin; biliary and pancreatic secretions that regurgitate from the duodenum into the stomach; and

toxic compounds generated in the mouth, esophagus, and stomach by the action of bacteria on dietary

substances.

Our current understanding of the role of the various ingredients of gastric juice in the development of

esophagitis is based on classic animal studies performed by Lillimoe et al.91,92 These studies have shown

that acid alone does minimal damage to the esophageal mucosa, but the combination of acid and pepsin

is highly deleterious. Hydrogen ion injury to the esophageal squamous mucosa occurs only at a pH

below 2. In acid refluxate, the enzyme pepsin appears to be the major injurious agent. Similarly, the

reflux of duodenal juice alone does little damage to the mucosa, while the combination of duodenal

juice and gastric acid is particularly noxious. Reflux of bile and pancreatic enzymes into the stomach can

either protect or augment esophageal mucosal injury. For instance, the reflux of duodenal contents into

the stomach may prevent the development of peptic esophagitis in a patient whose gastric acid secretion

maintains an acid environment, because the bile salts would attenuate the injurious effect of pepsin and

the acid would inactivate the trypsin. Such a patient would have bile-containing acid gastric juice that,

when refluxed, would irritate the esophageal mucosa but cause less esophagitis than if it were acid

gastric juice–containing pepsin. In contrast, the reflux of duodenal contents into the stomach of a patient

with limited gastric acid secretion can result in esophagitis, because the alkaline intragastric

environment would support optimal trypsin activity and the soluble bile salts with a high pKa would

potentiate the enzyme’s effect. Hence, duodenal-gastric reflux and the acid-secretory capacity of the

stomach interrelate by altering the pH and enzymatic activity of the refluxed gastric juice to modulate

the injurious effects of enzymes on the esophageal mucosa.

This disparity in injury caused by acid and bile alone as opposed to the gross esophagitis caused by

pepsin and trypsin provides an explanation for the poor correlation between the symptom of heartburn

and endoscopic esophagitis. The reflux of acid gastric juice contaminated with duodenal contents could

break the esophageal mucosal barrier, irritate nerve endings in the papillae close to the luminal surface,

and cause severe heartburn. Despite the presence of intense heartburn, the bile salts present would

inhibit pepsin, the acid pH would inactivate trypsin, and the patient would have little or no gross

evidence of esophagitis. In contrast, the patient who refluxed alkaline gastric juice may have minimal

heartburn because of the absence of hydrogen ions in the refluxate but have endoscopic esophagitis

because of the bile salt potentiation of trypsin activity on the esophageal mucosa. This is supported by

recent clinical studies that indicate that the presence of alkaline reflux is associated with the

development of mucosal injury.93

Although numerous studies have suggested the reflux of duodenal contents into the esophagus in

patients with GERD, few have measured this directly. The components of duodenal juice thought to be

most damaging are the bile acids, and as such, they have been the most commonly studied. Most studies

have implied the presence of bile acids using pH measurements. Studies using either prolonged

ambulatory aspiration techniques (Fig. 42-30) or spectrophotometric bilirubin measurement have shown

that, as a group, patients with GERD have greater and more concentrated bile acid exposure to the

esophageal mucosa than normal subjects.23,34 This increased exposure occurs most commonly during the

supine period while asleep and during the upright period following meals. Most studies have identified

the glycine conjugates of cholic, deoxycholic, and chenodeoxycholic acids as the predominant bile acids

aspirated from the esophagus of patients with GERD, although appreciable amounts of taurine

conjugates of these bile acids were also found. Other bile salts were identified but in small

concentrations. This is as one would expect because glycine conjugates are three times more prevalent

than taurine conjugates in normal human bile.

The potentially injurious action of toxic compounds either ingested or newly formed on the mucosa of

the gastroesophageal junction and distal esophagus has long been postulated. Until recently, however,

few studies have substantiated this possibility. Expanding upon studies of acid exposure at the

gastroesophageal junction, investigators from Glasgow, Scotland, have recently shown that dietary

nitrate consumed in the form of green vegetables and food contaminated by nitrate-containing

fertilizers results in the generation of nitric oxide at the gastroesophageal junction in concentrations

high enough to be potentially mutagenic.90 Previous studies have shown that nitrate ingested in food is

reabsorbed in the small bowel, with approximately 25% resecreted into the mouth via the salivary

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