*Gastroesophageal Reflux Disease and Obesity DOI: http://dx.doi.org/10.5772/intechopen.106528*

significantly higher in subjects with obesity than in subjects with a normal BMI [18]. The physiological explanation for the interplay between obesity, risk for hiatal hernia, and subsequent development of GERD was thoroughly explored in a manometry study conducted by Pandolfino *et al* [19]. Their study discovered an altered pressure morphology within and across the EGJ in obese subjects that would augment the movement of acid and bile salts toward the esophagus. Obesity caused greater axial separation between the LES and the diaphragm, that ultimately lead to the development of hiatal hernia [19]. This proximal displacement of the LES creates a lower basal pressure of LES, diminishes the increment in LES pressure that occurs during straining, and increases transient LES relaxation (TLESR) frequency during gastric distention with gas [20, 21]. Transient LES relaxation seems to be the most important mechanism responsible for reflux [22]. Overweight and obese patients showed a significantly higher TLESR rate during the post-prandial period as compared to subjects with normal BMI [23]. It also appeared that both BMI and waist circumference have a dose-effect relationship with TLESR [23].

Central obesity also play a part in the pathogenesis of GERD [18]. Current data suggest that central obesity causes an increase in intra-gastric pressure, which subsequently increased esophageal exposure to gastric content and impaired esophageal acid clearance [24, 25]. Moreover, the visceral fat is a metabolically active organ that produces interleukin-6 and tumor necrosis factor-α, that may have impact on LES. Recent data also suggest that insulin resistance, a consequence of visceral obesity, may be an important contributing factor [26]. Studies also found that abdominal obesity may change the secretion of adipokines such as adiponectin and leptin that has been regarded as the key factor for the development of esophageal neoplasia in the setting of obesity [12, 17]. Adipokine has anti-inflammatory and immunomodulatory properties and may stimulate apoptosis [27]. Obesity decrease the secretion of adiponectin and this was associated with increased risk of BE [28]. Leptin has been shown to have mitogenic properties, that later study found it may induce proliferation of esophageal cancer [29]. Kendall *et al*. found the risk of BE were higher in subjects with high level of serum leptin (OR 4.6) [30]. All of the proposed mechanisms that promotes the development of GERD in obesity is summarized in **Figure 1**.

The traditional theory of refluxed gastric content has caused direct injury to the esophageal mucosa, as discussed above, is challenged by the findings of recent studies in rats and human that found the exposure of esophageal mucosa to gastric content did not cause a direct acid injury in the esophagus [31, 32]. Instead, it stimulated the esophageal mucosa to secrete cytokines that induce proliferative changes in epithelial cells and attract the T lymphocyte and other pro-inflammatory cells that eventually caused mucosal damage [31, 32]. Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that is involved in the mediation of some inflammatory response [33] and appear to be the key mediator that initiate the cytokinemediated mucosal injury [34]. The exposure gastric juice to esophageal epithelial cells leads to the production of reactive oxygen species, a key substance to stabilize HIF-2α in the setting of GERD [35, 36]. This stabilized HIF-2α will accumulate in the nucleus and stimulate the secretion of inflammatory cytokines that lead to the establishment of GERD [34]. This new paradigm in GERD pathogenesis, however, has not been studied in term of its possible role in GERD with obesity. Nonetheless, this undisclosed association between cytokine-mediated mucosal injury and obesity in the pathogenesis of GERD may serve as an opportunity for researches in the future.
