The skinny on obesity and reflux

May 2006

SELECTED SUMMARIES

and released natalizumab in the U.S. market, and in early 2005, its use for the treatment of multiple sclerosis seemed to raise the possibility of its imminent use in patients with Crohn’s disease. The use of therapies targeting SAMs in humans was abruptly halted upon the revelation that 3 patients (2 with multiple sclerosis, one with Crohn’s disease) who received natalizumab subsequently developed progressive multifocal leukoencephalopathy (PML), fatal in 2 instances (N Engl J Med 2005;353:369 –374, N Engl J Med 2005;353:362–368). Subsequent evaluations revealed that activation of the JC-virus in these individuals in the setting of their profound immunosuppression was the likely culprit, as had been previously reported in other disease states (Curr Opin Neurol 2004;17:365– 370). Both of the MS patients had received concomitant interferon while the Crohn’s disease patient had previously received a host of immunosuppressive agents and had a history of unexplained pancytopenia. Does the same fate await those who receive other agents targeting SAMs? Differences in the types of adhesion molecules present on various tissue types suggest that PML might be unique to natalizumab as its target, the ␣4␤1 integrin, is expressed on leukocytes and affects their binding on endothelial and dendritic cells throughout the body including the brain (J Immunol 1994;152:282–293). The target of MLN-02, the ␣4␤7 integrin, is expressed on lymphocyte subsets, monocytes, and NK-cells (Cell 1993;74:185–195). These cells are selectively trafficked to the gut-associated lymphoid tissue, and not the brain (N Engl J Med 2005;353;18:1965–1968). In theory, this agent should be more gut-selective (“Super-selective”) and not carry the same risk for PML, but may increase the risk of developing gastrointestinal infections or neoplasms (Anticancer Res 2005;25: 1079 –1085, Curr Opin Gastroenterol 2005;21:85– 89). It is unknown if other opportunistic infections will arise in patients treated with this agent either while still in clinical trials or during postmarketing experience as was the case with the identification of Mycobacterium tuberculosis reactivation in patients treated with antiTNF therapies (N Engl J Med 2001;345:1098 –1104). Trying to understand the immune system, and the implications of new immune-modifiers, can be intriguing, frustrating, and most of all, humbling. The exciting new class of SAM modifiers may truly represent the next great wave of biological therapies in IBD and other diseases. “Super-selective” targeting may avoid unintended effects upon other organ systems; time will tell whether being more selective is truly safer and more efficacious, or whether it will be easier for the immune system to “find a way around” this blockade. RUSSELL D. COHEN, MD, FACG

THE SKINNY ON OBESITY AND REFLUX Hampel H, Abraham NS, El-Serag HB (Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas). Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med 2005;143:199 –211. The rising trend of obesity has been implicated as a possible cause for the increasing prevalence of gastroesophageal reflux disease (GERD) and GERD-related esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. Epidemiologic evidence supporting this association, however, is derived mostly from observational studies that have never been critically

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reviewed. Consequently, the authors of this study conducted a rigorous meta-analysis to evaluate, quantify, and summarize the association of obesity to GERD and its complications. Studies for inclusion were identified by searching MEDLINE and subsequent bibliography citations within identified articles. Only cross-sectional, case-control, or cohort studies of sufficient size and methodology were included. Both unadjusted and adjusted pooled odds ratios (ORs) were calculated; the latter being derived after statistical manipulation of data to account for studies that failed to report adjusted risk estimates. When available, potential confounders used for adjustments were reported with the results. Both overweight and obesity were examined as predictor variables and outcomes of interest included GERD symptoms, endoscopically identified esophagitis, adenocarcinoma of the esophagus, and adenocarcinoma of the gastric cardia. Barrett’s esophagus (BE) was also to be considered, but no studies reporting an association between BE and obesity met inclusion criteria for the meta-analysis. Among 370 potentially relevant studies of obesity and GERD, only 9 met inclusion criteria. The pooled, weighted adjusted ORs for GERD symptoms were 1.43 (95% CI, 1.16 – 1.77) for overweight individuals (BMI 25 kg/m2 to 30 kg/m2) and 1.94 (95% CI, 1.47–2.57) for obese individuals (BMI ⬎30 kg/m2) compared with a normal weight reference category. Unadjusted ORs were similar, suggesting that confounding variables, such as smoking and gender, played a minor role in relative risk. For erosive esophagitis, 111 studies were screened, and 6 were included. The pooled adjusted OR for esophagitis was 1.76 (95% CI, 1.16 –2.68) for those with BMI ⱖ25 kg/m2 compared with BMI ⬍ 25 kg/m2. Six of 93 studies were pooled for an adjusted OR for esophageal adenocarcinoma, and 6 were pooled for an adjusted OR for adenocarcinoma of the gastric cardia. The OR for each cancer among those with BMI ⱖ25 kg/m2 compared with BMI ⬍25 kg/m2 was 2.02 (95% CI, 1.523–2.67) and 1.68 (95% CI, 1.20 – 2.35), respectively. For those with esophageal adenocarcinoma, a dose response trend was suggested for BMI 25–30 kg/m2 and BMI ⬎30 kg/m2. Tests for heterogeneity among all included studies were statistically significant, suggesting caution in pooling their data for meta-analysis. However, the authors point out that, in general, the association between BMI and GERD was consistent, varying more in magnitude than direction. They conclude that obesity is associated with GERD symptoms and GERD complications, and the associated risks seem to increase with increasing weight. Comment. GERD is a common disorder, affecting up to 60% of individuals at some time during the course of a year and 20%–30% of individuals at least weekly (Gastroenterology 1997;112:1448 – 1456, Gastroenterology 2004;126:1692–1699). GERD accounts for almost ten million physician office visits annually in the United States and has been associated with work loss, impaired quality of life, and esophageal adenocarcinoma (Gastroenterology 2002;122:1500 –1511, Am J Gastroenterol 2000;95:788 –792, Am J Med 1988;104:252– 258, N Engl J Med 1999;340:825– 831). Therefore, the finding of an association between overweight and GERD is particularly important

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in light of recent trends of rising BMI among both adults and children (JAMA 2004;291:2847–2850). This well-performed meta-analysis brings together data that has been percolating for several years and provides a helpful estimate of the magnitude of risk for GERD associated with an elevated BMI. Being overweight seems to increase one’s risk of GERD symptoms by 50%, and doubles one’s risk of esophageal adenocarcinoma. A causative mechanism for the association between BMI and GERD is not evident from the data presented. Adjustment for dietary factors had minimal effect on results, suggesting that either mechanical or hormonal factors are more likely to be responsible. Previous authors have postulated that increasing abdominal girth may result in increased intragastric pressure, an increased frequency of transient lower esophageal sphincter relaxations, the development of a hiatal hernia, or slower esophageal acid clearance (Am J Gastroenterol 2005;100: 1243–1250, Arch Intern Med 1991;151:448 – 454, Am J Surg 1985; 149:177–181, Am J Gastroenterol 1999;94:2840 –2844, J Med 1987;18:35– 46). All of these mechanisms are plausible. However, there is also evidence that hormonal factors related to adiposity are also important in the pathophysiology of GERD. Some authors have hypothesized that, at least among women, higher estrogen concentrations may result in increased numbers of transient lower esophageal sphincter relaxations (JAMA 2003;290:66 –72, Scand J Gastroenterol 2002;37:626 – 630). Because women with higher BMIs have greater levels of circulating free estrogen, both from decreased concentrations of sex hormone binding globulin and increased production of estrone within fatty tissues, a hormonal component can be postulated. The field of literature on this subject raises important questions that have yet to be answered. First, as the authors of this meta-analysis discovered, there is scant data available to link BMI and the risk of Barrett’s esophagus. While such an association may appear intuitive, evidence to prove this might further our understanding of the pathogenesis of BE. This same group of investigators has recently reported results of a small case-control study supporting a link between BMI and BE (Am J Gastroenterol 2005;100:2151–2156). Moreover, they

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related this risk of BE to visceral adiposity (compared to subcutaneous adiposity) as measured directly by CT scanning. However, as the authors point out, their findings, based up 36 cases of BE, need to be verified within a larger population. Another question to be answered is the effect of weight loss on the risk of GERD. One recent, large cross-sectional study demonstrated a decrease in risk among people who had lost ⬎3.5 BMI units over the course of a decade (JAMA 2003;290:66 –72). However, studies in this area have been conflicting, and the clinically relevant question of whether weight loss in the short term can alleviate GERD symptoms has not been answered sufficiently despite this being a common suggestion made to patients. Whether weight loss can decrease one’s risk of esophageal adenocarcinoma also remains to be seen. Finally, the association between BMI and GERD among “normal”weight individuals has not been clarified. Almost every study that has examined BMI and GERD has used the broad category of ⬍24 or 25 kg/m2 as the referent, and therefore none have been able to determine whether BMI affects GERD risk in a dose-dependent fashion across all degrees of BMI. A large telephone survey limited to people with GERD symptoms found a dose-response relationship between quartiles of BMI and a daily occurrence of symptoms; however, that study lacked asymptomatic controls (Arch Intern Med 1999;159:1592– 1598). As our nation continues to experience an epidemic of obesity, it is clear that we must work to understand each and every health risk associated with increased BMI. Links between obesity and cancer, diabetes, and heart disease have been known for decades. Yet this understanding has not been enough to motivate our nation’s population to keep thin. Given the high prevalence of GERD symptoms in general, as well as the discomfort and decrease in quality of life that these symptoms cause, perhaps we now have a new informational tool to motivate our patients to avoid gaining weight. BRIAN C. JACOBSON, MD, MPH PAUL C. SCHROY III, MD, MPH