Issue Highlights
Authors: Jonathan M. Buscaglia
Journal: Clinical Gastroenterology and Hepatology (2015)

Central obesity has been recognized as a risk factor for GERD, Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Although the gastroesophageal junction may be compromised in obese patients—thus weakening the structural barrier to esophageal acid exposure—additional non-mechanical factors are believed to contribute to esophageal neoplasia. Adipose tissue is metabolically active, producing adipokines such as leptin and adiponectin, which affect inflammation and cell proliferation. These adipokines have been shown to interact with one another, and appear to play a complex role in the development of EAC. In addition, adipose tissue has significant influence on insulin levels, as well as the degree of insulin resistance. Elevated insulin levels have been implicated in the development of BE, likely through the insulin/IGF signaling pathway. The precise relationship of each of these hormones with BE, however, is not well-understood. Chandar et al report the results of a systematic review and meta-analysis examining the association between leptin, adiponectin, insulin and insulin resistance, and the risk of BE. In total, over 1400 BE patients were analyzed and compared to 3550 control patients within 9 observational studies. The authors found elevated serum leptin levels were associated with a 2-fold higher risk of BE (BE cases vs. population controls; 5 studies; adjusted OR = 2.23; 95% CI = 1.31, 3.78; I2 = 59%) (Figure 1). Conversely, total serum adiponectin levels were not associated with BE (BE cases vs. population controls; 5 studies; adjusted OR = 0.79; 95% CI = 0.46, 1.34; I2 = 65%); with one study actually demonstrating a decreased risk of BE with elevated low-molecular weight adiponectin. High serum insulin levels were associated with an increased risk of BE (BE cases vs. population controls; 3 studies; adjusted OR = 1.74; 95% CI = 1.14, 2.65; I2 = 0%). However, insulin resistance was not associated with BE (BE cases vs. GERD controls; 2 studies; adjusted OR = 0.98; 95% CI = 0.42, 2.30; I2 = 64%). Overall, the authors concluded that serum levels of leptin and insulin are highly likely associated with Barrett's esophagus, and therefore the molecular mechanisms by which these hormones contribute to the development of this disease need to be further investigated. This article is highlighted by an editorial by Bradley J. Kendall and Aaron P. Thrift (page 2273). See page 2241. Also exploring the relationship between BE and obesity-related adipokines in this issue of Clinical Gastroenterology and Hepatology is a study by Greer et al. Patients were recruited prospectively for this case-control study at the time of their EGD or colonoscopy procedures. EGD was performed for either refractory gastroesophageal reflux disease (GERD), or BE surveillance; and colonoscopy for colorectal cancer (CRC) screening. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE, and compared with two separate control groups: 133 subjects with GERD, and 1157 CRC screening controls. In comparing BE cases with CRC screening controls, the adjusted multivariate analysis revealed the highest tertile of serum adiponectin levels to be associated with a decreased odds of BE (odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.22, 0.80). This effect was more pronounced in males (OR = 0.35, 95% CI = 0.17, 0.74) compared to females (OR = 0.71, 95% CI = 0.17, 3.03). Similarly, in comparing BE cases with GERD controls, subjects in the highest tertile of serum adiponectin showed a non-significant decreased odds of BE (OR = 0.65, 95% CI 0.31, 1.36). Patients in the highest tertile of serum leptin did not have a significantly increased risk of BE in comparison to GERD controls (OR =1.32, 95%CI 0.61, 2.88), or CRC screening controls (OR = 1.57, 95% CI = 0.82, 3.04) (Figure 2). Furthermore, gender-specific analyses did not significantly alter the association of leptin with the odds of BE. Of note, this study was included as one of the 9 studies analyzed in the systematic review and meta-analysis published by Chandar et al in this month's issue. The authors conclude that serum adiponectin is inversely associated with BE, with a more pronounced effect in males. Serum leptin was not associated with BE in comparison to multiple control groups. Given the differing results of this study compared to other studies (especially with regards to leptin), the exact mechanism—if any—by which these adipokines promote metaplasia in the esophagus needs to be further explored. This article is highlighted by an editorial by Bradley J. Kendall and Aaron P. Thrift (page 2273). See page 2265. Finally, the association of adiponectin and Barrett's esophagus was investigated in the context of GERD. Almers et al provide data on the relationship of BE and adiponectin that may contradict previous studies suggesting a possible healing effect to the gastrointestinal mucosa by adiponectin-mediated pathways. The authors conducted a case-control study evaluating the associations between adiponectin (total, high molecular weight, and low/medium molecular weight) and Barrett's esophagus within the Kaiser Permanente Northern California population. Patients with a new diagnosis of BE (284 cases) were matched to patients with GERD without BE (294 controls), and to 285 population controls. Almers et al found increasing adiponectin levels were a risk factor for BE among patients with GERD (total adiponectin fourth vs. first quartile odds ratio [OR] = 1.96; 95% confidence interval (CI) 1.17–3.27; high molecular weight adiponectin OR = 1.65; 95% CI 1.00–2.73; low/medium molecular weight adiponectin OR = 2.18; 95% CI 1.33–3.56), but not compared with population controls. Interestingly, the associations were significantly stronger among patients reporting frequent GERD symptoms, and among smokers (P values interaction < .01) (Figure 3). Again, it is noteworthy that this study was included as 1 of the 9 studies analyzed in the systematic review and meta-analysis published by Chandar et al in this month's issue. The authors conclude that there is a positive association between increasing levels of serum adiponectin and a new diagnosis of BE among patients with GERD—not an inverse relationship as suggested in previous studies. This association was stronger among smokers, and among patients with more frequent GERD symptoms. These results suggest the potential for a direct mechanistic role of adiponectin in the process of mucosal healing that may cause Barrett's esophagus. Although the results contradict the expected direction of obesity's association with BE (and with adiponectin levels), they represent one of the first potential biological risk factors identified for why only some patients with GERD and smoking develop Barrett's esophagus. This article is highlighted by an editorial by Bradley J. Kendall and Aaron P. Thrift (page 2273). See page 2256. Pernicious anemia is the final stage of a chronic atrophic autoimmune gastritis where autoantibodies target and destroy the acid-producing parietal cells in the stomach. It is a slowly progressive disease that is estimated to affect 2-5% of the elderly (60 years and older) in the United Kingdom, United States, and other countries. Although treatment with parenteral vitamin B12 corrects the underlying deficiency and resultant anemia, the chronic gastritis persists. Individuals with pernicious anemia have long been suggested to possess a heightened risk of gastric cancer, especially gastric carcinoid tumors. Furthermore, previous studies have suggested a possible association of pernicious anemia with other forms of non-gastric malignancies. In order to investigate this relationship further, Murphy et al report the results of a large population-based, case-control study using the SEER-Medicare database. The authors compared 1,138,390 cancer cases (66-99 years old) to 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Compared with controls, individuals with pernicious anemia were at increased risk for non-cardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94–2.45), and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90–14.69). In addition, these individuals possessed an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40–2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35–2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76–2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32–2.02), liver cancer (OR, 1.49; 95% CI, 1.28– 1.73), myeloma (OR, 1.55; 95% CI, 1.37–1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46–1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53–3.26). In conclusion, the authors provide strong support for the link between pernicious anemia and several gastric and non-gastric malignancies. The paper is highlighted in an editorial by Ernst J. Kuipers (page 2290). See page 2282. Associations of Serum Adiponectin and Leptin With Barrett's EsophagusClinical Gastroenterology and HepatologyVol. 13Issue 13PreviewCentral adiposity is a risk factor for Barrett's esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE. Full-Text PDF Association of Serum Levels of Adipokines and Insulin With Risk of Barrett's Esophagus: A Systematic Review and Meta-AnalysisClinical Gastroenterology and HepatologyVol. 13Issue 13PreviewMetabolically active visceral fat may be associated with esophageal inflammation, metaplasia, and neoplasia. We performed a meta-analysis to evaluate the association of serum adipokines and insulin with Barrett's esophagus (BE). Full-Text PDF Adiponectin May Modify the Risk of Barrett's Esophagus in Patients With Gastroesophageal Reflux DiseaseClinical Gastroenterology and HepatologyVol. 13Issue 13PreviewAbdominal obesity and increasing body mass index are risk factors for esophageal adenocarcinoma and its main precursor, Barrett's esophagus; however, there are no known biological mechanisms for these associations or regarding why only some patients with gastroesophageal reflux disease develop Barrett's esophagus. We evaluated the association between Barrett's esophagus and multimers of an adipose-associated hormone, adiponectin. Full-Text PDF Cancer Risk After Pernicious Anemia in the US Elderly PopulationClinical Gastroenterology and HepatologyVol. 13Issue 13PreviewPernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer. Full-Text PDF