Ying Gibbens, MD, PhD1, Ramona Lansing, RN1, Michele Johnson, CCRP1, Christopher Blevins, MD2, Harshith Priyan, MD3, David A. Katzka, MD1, Prasad G. Iyer, MD, MS1; 1Mayo Clinic, Rochester, MN; 2Billings Clinic, Billing, MT; 3SUNY Downstate Medical Center, Brooklyn, NY
Introduction: Central obesity has been identified as a risk factor for esophageal adenocarcinoma (EAC). Accumulating evidence has shown that central obesity may promote EAC through a mechanism that is independent of gastroesophageal reflux (GER). We have previously described structural (dilated intercellular spaces [ICS]) and functional (increased fluorescein flux) esophageal barrier dysfunction in patients with central obesity without reflux. We aimed to explore the cellular mechanisms responsible for the dilation of ICS in a prospective cohort study. Methods: 38 subjects prospectively recruited underwent ambulatory pH testing with Bravo pH probes OFF medications, and endoscopy. Using standard definitions (acid exposure time and waist hip ratios) they were categorized into 4 groups: group 1 (Central obesity-/GER-, 8 subjects), group 2 (Central obesity +/GER-, 12 subjects), group 3 (GER+/Central obesity-, 8 subjects) and group 4 (Central obesity+/GER+, 10 subjects). Transmission electron microscopy (TEM) images were obtained on biopsy samples taken 5cm above the GEJ. ICS diameter and desmosome density were measured. Desmosome density was calculated using a ratio to define the number of desmosomes per ICS membrane length. A total of 10 unique intercellular junctions were used to obtain the mean of the desmosome density for each study subject. Results: The mean ICS of groups 2-4 was substantially greater than that of group 1 (p value 0.001). Intercellular junctions in groups 2-4 had multiple regions that are devoid of desmosomes (Figure 1). Subjects in group 2 (Central Obesity +/GER-) exhibited a 42% reduction in desmosome density as compared to the control group 1 (Figure 2, p< 0.001). Group 3 (GER+/Central obesity-) also has a significant and similar decrease in desmosome density, suggesting that GER is another factor impacting the level of desmosomes. Intriguingly, the mean desmosome density in group 4 (Central Obesity +/GER+) is comparable to both groups 2 and 3, indicating that effects of central obesity and GER may converge on a common pathway that regulates desmosome expression/assembly (Figure 3). Discussion: Central obesity independent of GER is associated with a significant reduction in desmosome density along the esophageal epithelium contributing to barrier dysfunction and potentiating mucosal injury. Molecular mechanisms by which central obesity and GER modulate desmosome assembly and cellular adhesion need to be studied.
Figure 1. Cellular junctions of esophageal squamous epithelium of subjects from the 4 study groups captured by TEM (10K Magnification). Tissue samples were obtained at 5cm above GEJ. Intercellular space diameter is increased in Groups 2, 3 and 4 compared to Group 1. The dark, discrete structures along the intercellular junctions are desmosomes (yellow narrow arrows). Multiple regions in subjects with (either or both) central obesity and GER are devoid of desmosomes (red wide arrows).
Figure 2. Obesity and GER are independently associated with reduced desmosome density. The. Desmosome densities (as expressed as the no. of desmosomes per micrometer of the cellular membrane) in groups 2 (GER-/OBESE+, 0.8+0.11, p<0.001), group 3 (GER+/OBESE-, 0.79+0.19, p<0.001) and group 4 (GER+/OBESE+, 0.76+0.17, p<0.001) are statistically significant as compared to the group 1 control subjects (GER-/OBESE-, 1.37+0.34).
Figure 3. A proposed mechanism for how central obesity and GER may impact ICS by interfering with desmosome expression/assembly in the intercellular junctions.
Disclosures: Ying Gibbens indicated no relevant financial relationships. Ramona Lansing indicated no relevant financial relationships. Michele Johnson indicated no relevant financial relationships. Christopher Blevins indicated no relevant financial relationships. Harshith Priyan indicated no relevant financial relationships. David Katzka: Erbe – Advisory Committee/Board Member. Prasad Iyer: Exact Science – Grant/Research Support. Medtronic – Consultant, Grant/Research Support. Nine Point Medical – Grant/Research Support. Pentax Medical – Grant/Research Support. Symple Surgical – Consultant.