Obesity and Gastrointestinal Disease: A Worldwide Problem
Peter R. Holt, MD, AGAF
Senior Research Scientist, The Rockefeller University, New York, NY; Professor of Medicine (Emeritus), Columbia University, New York, NY
The AGA International Committee organized a symposium at DDW® 2012 entitled “Obesity and the Impact on GI Disease.” Speakers included Luigi Ricciardiello, MD; Arun Sanyal, MD; and me; the aim of the symposium was to emphasize the importance of obesity and its complications, and how these are not restricted to North America and Western Europe, but are a major worldwide problem.
So why study complications of obesity? Principally, because we do not envisage an effective non-surgical approach to the treatment of obesity in the near future. Thus, it is appropriate to accept the fact that obesity will continue to be a widespread problem in the foreseeable future so that an approach to defining the mechanisms and potential therapy for these complications is an appropriate goal. The major complications of obesity that commonly result in death: type II diabetes, cardiovascular disease, liver disease and cancer can all now be seen as a result of low-grade tissue inflammation. Such inflammation appears to derive in many obese individuals as a result of T-cell and macrophage infiltration in visceral and subcutaneous adipose tissue stores. The association between obesity and cancer of the breast, colon and endometrium, as well as adenocarcinoma of the esophagus, may all be directly related to an inflammatory response in these organs in obese individuals before cancer develops. Such chronic inflammation is a well-accepted epidemiologic, clinical and molecular harbinger of cancer and that such a mechanism has a major factor in cancer causation is very plausible. Recent studies have directly described inflammation of the breast and colon in obese individuals as previously shown in blood vessels as well as in the liver — as non alcoholic steatohepatitis (NASH) — and the pancreas.
The international epidemiologic data on the link between obesity and colorectal cancer (CRC) is particularly strong. Obesity trends in developed and developing nations mimic each other even though those in the latter are somewhat less. BMI is related to CRC incidence and mortality in Europe, North America and Northern Asia, and the relationship to visceral fat stores as measured by MRI or waist circumference is even stronger. In men, for each 10 cm increase in waist circumference, the risk increases by one-third. Obesity progressively increases the risk of death from CRC by 80 percent in men and 45 percent in women overall. Similar data has been published in the Asia-Pacific CRC cohort studies and studies from Israel. The data for the relationship of obesity to the presence of adenomatous polyps is somewhat less convincing but sufficient to recommend closer screening as well as surveillance after adenomatous polyps have been found and removed. The relationship between the presence of the metabolic syndrome and CRC is stronger for adenomatous polyps, suggesting that such individuals require even greater attention.
It is clear that the incidence and death rate from CRC is changing. For example, there has been a dramatic four-fold increase in CRC risk in Eastern Europe over the past 40 years, so that now the incidence in some Eastern European countries is even greater than in the U.S. Furthermore, in certain precincts in Japan, the CRC incidence also exceeds U.S. CRC incidence rates. In China, the incidence in middle-aged men is rising at a remarkable rate. In addition, there has been a noticeable increase in right-sided colon cancers in women above the age of 70 in Japan. Overall, there has also been an emphasis on the frequency of depressed or flat neoplasms in Asia. However, the suggestion that this is a particular phenomenon in Asian countries is probably incorrect, since incidence with enhanced colonoscopic techniques in North America and Europe also shows similar rates of such neoplasms.
It is well accepted that liver disease occurs commonly amongst obese individuals — usually as NAFLD, but not uncommonly as NASH. Epidemiologic studies suggest that NAFLD increases overall mortality by 40 percent and liver-related mortality nine fold. In the liver, inflammation is not marked by accumulation of macrophages, but rather by stellate cell activation. It is well recognized that circulating gut-derived microbiota can exacerbate the fat associated with liver disease as seen in the metabolic syndrome. The rates of NAFLD in obese individuals exceed 30 percent in the U.S. and in Israel. The obesity-associated incidence of NAFLD from other countries is less. In Japan and India, for example, a 15 to 20 percent incidence has been reported, whereas in Italy, less than 10 percent of associated liver disease appears to occur.
The optimal therapeutic measure to alleviate these serious obesity-associated complications is through weight loss, although hypothetically, safe anti-inflammatory agents should work. Recent studies suggest that NASH may improve following treatment with vitamin E or with pioglitazone. Overall, since the incidence of obesity worldwide is increasing exponentially, better understanding of the mechanisms and the treatment of obesity-related GI complications is mandatory.
Dr. Holt had no conflicts to disclose.