Association between visceral fat and inflammatory cytokines in reflux esophagitis.

The results of several previous studies have suggested that abdominal obesity is an important risk factor for reflux esophagitis.1,2 Among factors related to obesity, visceral fat is more associated with erosive esophagitis than body mass index (BMI).3 Physiologic abnormalities related to prolonged esophageal acid exposure have been found to occur more frequently in obese individuals than in those with normal weight. Obese subjects revealed abnormal esophageal manometric findings such as nonspecific motility disorder, nutcracker esophagus, and hypotensive lower esophageal sphincter as the most common manometric results.4 Transient relaxations of the lower esophageal sphincter (TRLES) is also reported to be more common in patients with obesity. The main stimulus for TRLES is gastric distension especially in the gastric fundus.5 Pandofino et al6 reported esophageal manometric findings suggesting that the pressure morphology within and across the esophagogastric junction were altered in obesity, which could augment the flow of gastric juices into the esophageal lumen. This anatomical disruption of the esophagogastric junction results in further hiatal hernia formation.

Esophageal mucosal injury is associated with increased exposure to gastric acid. However, maintenance of chronic esophageal mucosal inflammation and esophageal metaplasia such as Barrett’s esophagus (BE) or esophageal carcinoma in obese subjects have been proposed to increase inflammatory cytokines from visceral adipose tissue.7 The relationship between obesity and esophageal neoplasia may be due to alterations in the secretion of adipokines such as adiponection and leptin. Adiponection has an anti-inflammatory effect and stimulates apoptosis, which shows inverse relationship between obesity and adiponection.8 Leptin, a satiety hormone, is secreted by adipocytes and gastric chief cells. Esophageal epithelial cells express leptin receptors. In an esophageal adenocarcinoma cell line, leptin has been shown to stimulate cell proliferation and inhibit apoptosis via cyclooxygenase-2 activation of the epidermal growth factor receptor.9 Several studies have suggested a positive association between plasma leptin and BE.10,11 Kendall et al12 reported that a high serum leptin level is associated with an increased risk of BE among men, but not women.

No previous reports have documented the relationship between circulating cytokines and reflux esophagitis (RE). Recently, Nam13 conducted an interesting case-control study that suggested circulating cytokines were correlated with the risk of erosive esophagitis. They used abdominal visceral fat instead of BMI and plasma leptin level had a positive correlation with RE. The visceral fat/total fat ratio was used as an obesity index because there is no standard cut off value for defining obesity. The results indicated that both visceral fat and the visceral fat/total fat ratio were positively correlated with IL-6, IL-8, and IL-1β, but were negatively associated with adiponectin. Leptin showed no association with visceral fat, but had a strong association with the visceral fat/total fat ratio. Only visceral fat/100 and leptin were positively correlated with RE after adjusted analysis for both inflammatory cytokines and obesity indexes.

Despite the positive correlation of visceral fat and leptin with risk of RE, they did not classified reflux symptom strength or severity of esophagitis. Moreover, cytokine has its effect through ligand mediate reaction. Elevated plasma levels of cytokines do not always reflect cytokine bioactivity in inflamed regions. Checking the receptor expression and cytokine levels in target tissue provides more information about cytokine-ligand mediated responses.14,15

In conclusion, obesity is an important risk factor for developing gastroesophageal reflux disease. Abdominal visceral fat is a more useful obesity index for RE than BMI. To clarify the role of circulating cytokines in obese subjects with RE, further studies with large populations are needed, which will also help elucidate the pathophysiology between obesity and RE.