Clinical and Molecular Assessment of Men With High Risk for Esophageal Disorders
Condition: Esophageal Diseases
MeSH terms: Esophageal Diseases
Study type: Observational

Summary: 
      In this study,the investigators will evaluate participants that have clinical features
      associated with an increased risk of esophageal disorders.The investigators will also see if
      there is a positive association of esophageal disorders in men,40-60 with or without
      abdominal obesity in the diagnosis of the following diseases; Gastroesophageal reflux
      disease, Barrett Esophagus and Esophageal Adenocarcinoma. The investigators hypothesize that
      most obese patients referred for Esophagogastroduodenoscopy will exhibit esophageal
      disorders. Since currently the rates of obesity and adenocarcinoma of the esophagus have
      increased significantly over the past 15 years, the investigators hope to find biochemical
      markers (i.e. pro-inflammatory mediators) in the esophagus. The investigators hope these
      samples will lead us to a differential expression of molecular markers and inflammatory
      mediators in the varying degrees of esophageal disorder
    

Detailed description: 
      Patients with elevated central adiposity have an increased risk of esophageal disorders; we
      will correlate central adiposity with advanced esophageal pathologies (BE and EAC). This will
      be done by comparing body mass and fat distribution to tissue abnormalities found by
      pathology review of EGD biopsy. It is anticipated that the group of men in this study will
      have an increased likelihood of histopathologic alteration, which we will fit into our scale
      (0-no inflammation, 1-inflammation or BE, 2-BE with dysplasia, and 3-carcinoma) according to
      the referral pattern at UAB's outpatient gastroenterology clinic.

      At the molecular level, there is also a relationship between pro-inflammatory cytokines and
      obesity, which may contribute to esophageal disorder [28]. Metabolically active fat cells
      secrete cytokines exclusive to adipose tissue (adipokines, leptin/adiponectin) as well as the
      more classic signaling molecules, tumor necrosis factor alpha (TNF-α); interleukins (IL)-1,
      IL-6, IL-8, and IL-10; monocyte chemoattractant protein 1 (MCP-1); and macrophage
      inflammatory protein 1 (MIP 1) [29-33]. Obesity-triggered pro-inflammatory molecules may
      promote tissue injury, leading to metaplasia and dysplasia in BE and, subsequently, to
      carcinoma.

      Thus, by measuring these pro-inflammatory markers in our prospective patient population, it
      will be determined if patients with elevated levels exhibit pathologic disorders in the
      esophagus and if the differential expression of these molecular markers correlates with
      degree of esophageal disorder. We will analyze samples collected from men for adipocytokines
      and for inflammatory mediators that are released with tissue injury. Additionally, we will
      examine molecular markers that correlate with more advanced esophageal disorders (BE with
      high grade dysplasia and EAC).

      Persistent stimulation is needed to cause stepwise progression from the early stages of
      esophageal injury, to BE, to carcinoma. Since the molecular events that lead to this
      transformation are not known, our goal is to profile biopsy tissues collected from the
      prospective cohort of 60 men, analyzed by IHC for p53, Ki67, cyclin D1, IL-6, IL-8, Cox-2,
      DKK-1, CD44, leptin, and adiponectin. These molecules are known to be involved in
      transformation of normal esophageal epithelium to EACs via progression from metaplasia and BE
      to low-grade dysplasia and high-grade dysplasia. [34]. The clinical outcome measurements will
      be correlated with the levels of these molecules, determined by IHC, with metaplasia, degree
      of dysplasia in BE, and stage of EAC. For BE tissues, there is a correlation between the
      extent of p53 staining and aggressive clinical features. Our preliminary findings on six BEs,
      selected from the patient population at UAB, indicate that a high proportion of p53 staining
      directly correlates with high-grade lesions
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The goal of the study is to further clarify the relationship among esophageal disorders,
        obesity and inflammatory mediators that may identify a high risk patient profile that would
        warrant more frequent screening. We will accrue 60 men between the ages of 25 and 75 who
        are referred for upper endoscopy for the first time or subject who have had a normal upper
        endoscopy in the last 10 years. It is anticipated that some of the participants will not
        have symptoms of reflux or dyspepsia. Due to the pattern of referral, however, most will
        exhibit risk factors of esophageal disorders.
      
Biospecimen description: 
      The H&E sections of all biopsy specimens will be reviewed by a GI diagnostic pathologist,
      Leona Council, MD, for histopathologic parameters including histologic grade and type. The
      histology will be characterized according to the scale depicted in figure 1, where 0
      represents the earliest possible injury and 3 represents malignancy. All specimens will be
      processed in the typical manner, but reviewed by Dr. Council in the pathology department.