Disease Description

The typical manifestations of gastroesophageal reflux disease (GERD) are heartburn and/or regurgitation. GERD can be further classified into erosive GERD and nonerosive GERD based on endoscopic appearance of esophageal mucosa. The term “atypical GERD” is used in situations where the predominant symptoms are extraesophageal such as cough, laryngitis, and asthma. GERD is a common disorder with a prevalence of approximately 20% in the United States. The recognized sequelae of GERD include Barrett esophagus (BE) and esophageal adenocarcinoma. Obesity, defined as a body mass index (BMI) greater than or equal to 30, is common in the Western world and is increasing in other parts of the world, particularly Asia. Epidemiologic data demonstrate that overall obesity (typically measured as BMI kg/m ² ) is a risk factor for both GERD and esophageal adenocarcinoma. There is evidence that central abdominal obesity, as opposed to an elevated BMI, is the most important factor associated with BE ( Table 1 ).

Disease Description

The typical manifestations of gastroesophageal reflux disease (GERD) are heartburn and/or regurgitation. GERD can be further classified into erosive GERD and nonerosive GERD based on endoscopic appearance of esophageal mucosa. The term “atypical GERD” is used in situations where the predominant symptoms are extraesophageal such as cough, laryngitis, and asthma. GERD is a common disorder with a prevalence of approximately 20% in the United States. The recognized sequelae of GERD include Barrett esophagus (BE) and esophageal adenocarcinoma. Obesity, defined as a body mass index (BMI) greater than or equal to 30, is common in the Western world and is increasing in other parts of the world, particularly Asia. Epidemiologic data demonstrate that overall obesity (typically measured as BMI kg/m ² ) is a risk factor for both GERD and esophageal adenocarcinoma. There is evidence that central abdominal obesity, as opposed to an elevated BMI, is the most important factor associated with BE ( Table 1 ).

Complications of GERD

Long-term complications of GERD such as EE, BE, and esophageal adenocarcinoma have been associated with obesity. In a large endoscopic study, El-Serag reported that relative to those with no erosions, those with EE were more likely to be overweight or obese. A similar association was seen in Korea where Lee and colleagues did an endoscopy study in Korea studying 3000 participants. They found that obese individuals compared to normal weight subjects had an OR of 3.3 for EE. A meta-analysis by Hampel and colleagues confirmed the association with increasing levels of obesity and esophageal mucosal injury.

Associations of BE and obesity have been demonstrated by Stein and colleagues who established that for each 5-unit increase in BMI, the risk of BE increased by 35%. Abdominal obesity (“central obesity”) has been shown to be a more specific risk factor for BE. Corley and colleagues, using data from the Kaiser Permanente database, found that a larger abdominal circumference (measured at the iliac crest with the abdomen relaxed), independent of BMI, was associated with BE. Edelstein and colleagues found that for individuals in the highest category of waist-to-hip ratio the adjusted OR for BE was 1.9 and 4.1 for long-segment BE. Rubenstein and colleagues found that abdominal obesity as measured by waist circumference increased the risk of EE and BE, whereas gluteofemoral obesity was protective. Finally, El-Serag used abdominal computed tomographic imaging to demonstrate that greater amounts of visceral adipose tissue but not subcutaneous adipose tissue conferred a significantly increased risk for BE.

Not all studies have demonstrated an association between obesity and BE. An Australian study found that BMI was not an independent risk factor for BE. A study in Canada by Veugelers and colleagues also did not show an association between obesity and BE. They did, however, find an association of BMI with esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma has been rising in the United States. From 1975 to 2001, the incidence of esophageal adenocarcinoma has increased approximately 6-fold. There are several studies that have examined the relationship between obesity and esophageal adenocarcinoma. In 1998, a National Cancer Institute study by Chow and colleagues found an association between increasing strata of BMI and esophageal cancer, specifically among younger nonsmoking individuals. A Swedish study identified obesity with an OR of 16.2 for the development of adenocarcinoma compared with the leanest individuals (BMI<22 kg/m ² ). A recently pooled analysis from 12 world-wide epidemiologic studies showed that patients with a BMI greater than or equal to 40 compared with nonoverweight patients had an OR of 4.76 for esophageal adenocarcinoma. Engel and colleagues found that the population attributable risk (proportion of occurrences in the population that may be preventable if a factor were totally eliminated) for body weight (using BMI<23.1 as the control group) increased steadily from 5.4% (BMI = 23.2–25.1) to 21.3% (BMI = 27.3–40.1).

Pathophysiology

Several physiologic abnormalities that could lead to prolonged esophageal acid exposure have been found to occur more frequently in obese compared with normal weight individuals. Many of these disturbances have been identified in the severely obese (BMI>35) before bariatric surgery and may not apply to those with lesser degrees of obesity. For example, esophageal manometry before bariatric surgery has revealed that many patients have a motility disorder. In a study of 345 patients, 25.6% of patients had abnormal manometry. The most common abnormal findings were nutcracker esophagus and nonspecific motility disorder. Other studies in severely obese subjects revealed similar findings, with nonspecific motility disorder, nutcracker esophagus, and hypotensive lower esophageal sphincter (LES) as the most common manometric abnormalities. Interestingly, most of these patients were asymptomatic.

Studies looking specifically at prebariatric surgical patients with symptoms of GERD excluding asymptomatic patients have also been reported. Hong and colleagues studied 61 patients and 32.8% had abnormal manometry, most commonly nonspecific esophageal motor disorder. Another study using manometry, 24-hour pH measurement, and impedance grouped patients into 3 groups. Group 1 (control group) had 10 normal-weight asymptomatic subjects, group 2 had 22 nonobese GERD patients, and group 3 consisted of 22 obese GERD patients. All group 1 patients had normal esophageal acid exposure, motility, and bolus transit. From group 2 there were 5 patients with abnormal manometry, 2 with ineffective esophageal motility, 2 with nutcracker esophagus, and 1 with hypertensive LES (>50 mm Hg). Group 3 also had 5 patients with abnormal manometry, including 2 with ineffective esophageal motility, 2 with nutcracker esophagus, and 1 with diffuse esophageal spasm. The only difference between the obese and nonobese GERD subjects was that obese patients had fewer episodes of complete bolus transit (as measured by impedance) compared with the nonobese, 66% versus 88% P = .01.

A hypotensive LES, defined as basal pressure less than 10 mm Hg, is clearly a predisposing factor for GERD. Studies examining the relationship between LES pressure and BMI have been performed, although the results are inconsistent. One study examined 64 consecutive patients and divided subjects into 3 groups. Group A had 23 subjects with a BMI less than 25, group B had 25 subjects with a BMI between 25 and 30, and group C had 16 subjects with a BMI >30. The investigators observed a strong inverse relationship between BMI and LES pressure ( P <.001).

Transient relaxations of the lower esophageal sphincter (TRLES) have been observed to be more common in patients with obesity. The main stimulus for TRLES is gastric distension, particularly in the fundus. A study by Wu and colleagues divided subjects into 3 groups, 28 obese, 28 overweight, and 28 normal subjects. These individuals were studied with upper endoscopy, manometry, and pH recordings. The overweight and obese groups were found to have significantly higher rates of TRLES during the 2-hour postprandial period (obese group 17.3, overweight 3.8, normal 2.1 episodes per hour; P <.001). Total distal esophageal acid exposure as well as the proportion of TRLES accompanied by acid reflux was also greater in the obese and overweight groups.

The presence of a hiatal hernia has also been associated with obesity. Suter and colleagues studied morbidly obese patients with history of reflux symptoms with upper endoscopy, 24-hour pH monitoring, and manometry. They observed that of 345 subjects approximately half had a hiatal hernia. Furthermore, patients with a hiatal hernia were more likely to have esophagitis compared with those without a hiatal hernia. Pandolfino and colleagues subsequently reported that obese patients have a pressure gradient along the esophagogastric junction that supported the development of a hiatal hernia.

Abdominal obesity likely increases intra-abdominal pressure due to transmission of gravitational force of the adipose tissue to the abdominal cavity. Lambert and colleagues studied morbidly obese patients with a urinary catheter as a surrogate for intra-abdominal pressure and found that obese patients compared with nonobese patients had higher intra-abdominal pressures. This relationship between obesity and elevated intra-abdominal/intragastric pressures has been confirmed by others with use of intragastric manometry.

Gastric volume and motor abnormalities have been proposed as other mechanisms for GERD in obese individuals. Multiple studies have found that the capacitance of gastric contents in obese subjects is larger compared with lean individuals. Whether the greater volume of contents leads to increased GERD is not known. It has also been theorized that obese individuals may have delayed gastric emptying due to neuronal or humoral mechanisms. Buchholz and colleagues using standardized scintigraphic gastric emptying studies showed no difference in gastric emptying in obese and nonobese patients. Retention percentages at 1 hour and 4 hours were 48% and 47% and 1.7% and 1.1%, respectively.

The link between obesity and esophageal neoplasia may be via altered secretion of adipokines such as adiponectin and leptin. Adiponectin is a protein that has antiinflammatory and immunomodulatory functions and stimulates apoptosis. Secretion of adiponectin decreases with obesity. Rubenstein and colleagues found an inverse association between plasma adiponectin levels and the presence of BE in a case-control study. In a separate study, this group found that levels of the low molecular weight subtype of adiponectin were inversely associated with the risk of BE. In contrast to the inverse relationship seen between obesity and adiponectin, leptin levels correlate directly with obesity. Leptin is secreted by adipocytes and gastric chief cells and has been shown to have mitogenic properties and induce proliferation in several human cell lines including esophageal cancer cells. Kendall and colleagues found that male subjects with BE had higher levels of plasma leptin relative to healthy controls. Those with a leptin level in the highest quartile had an OR of 3.3 for the presence of BE. The link between BE and central obesity (rather than BMI) may be partially explained by the fact that leptin reaches very high values in central obesity ( Figs. 2 and 3 ).

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