Obesity Part II

PATHOLOGI CONSEQUENCES OF OBESITY

Obesity results in morbidity and mortality largely because of its associati on with other diseases, including diabetes, cardiovascular disease, hypertension, sleep apnea, endometrial cancer, colon cancer, and gall bladder disease. Overall , in the United States, the excess mortality of obesity accounts for 300,000 deaths per year. It was estimated that the total spent for both weight reducti on and treatment of the consequences of obesity was $100 billion in the United States in 2001. This represents 5.5% to 7.0% of all medical expenses.

Diabetes

The increased risk for type 2 diabetes in individuals with obesity is considerable. In persons aged 20 to 44, obesity i s associated with a fourfold increase in the relative risk of diabetes. In a
study of a cohort of more than 50,000 U.S. male health professionals, the risk of diabetes correlated strongly with BMI. In men with a BMI of 35 or higher, the multivariate relative risk of diabetes was 42.1 compared with the risk in men with a BMI of l ess than 23. BMI appears to be the dominant risk factor for type 2 diabetes. Even men with average relative weight had a significant increase in risk when compared with men in lower weight groups. A similar increased risk exists for women. Among 43,581 women enrolled in the Nurses' Health Study, the relati ve risk for type 2 diabetes at the 90th percentile of BMI
was 11.2 . Weight was the single most important predictor of diabetes. After adjustment for BMI, lack of exercise and a poor diet (i .e., foods with a high glycemic index and high in trans fat) were also associated with increased risk of diabetes. Another study examined new diagnoses of diabetes in a population between 18 and 44 years of age and found an inverse correl ati on with age and BMI. Adul ts developing
diabetes before age 44 had an average BMI of 39, whereas adults developing diabetes at 45 or older had an average BMI of 33. Among all adults, the odds ratio for developing diabetes is 6.38 for those with a BMI greater than 40. The results of these and other studies lend support to the concept that the vast majority of cases of type 2 diabetes could be prevented by the adoption of therapies and lifestyle characteristics that
decrease obesity.

Although the precise mechanism by which obesity contributes to insulin resistance and type 2 diabetes has not yet been defined, it is likely related to the producti on of various factors derived from the adipocyte that act on fat, liver, or muscle to impair insulin action. Obesity is itself associated with
hyperinsulinemia, and insulin may induce insulin resistance
through down regulation of the insulin receptor. Potential candidate substances produced by fat that may cause insulin resistance include tumor necrosis factor and other cytokines,
such as interleukin -6, and resistin and adiponectin. Increased
levels of free fatty acids are also capable of inhibiting insulin action. It is intriguing that a recent report found that treatment with high-dose salicylate markedly improved insulin resistance, suggesting that obesity may induce an inflammatory state that contributes to insulin resistance.

Cardiovascular Disease

Obesity is an independent risk factor for cardiovascular disease, including coronary artery disease and congestive heart failure, in both men and women. Waist-to-hip ratio is the best predictor, and it i s noteworthy that increased waist -to-hi p ratio has an effect in women even at the relatively low BMI of 25.
Visceral obesity is associated with increased occurrence of hypertension and an atherogenic lipid profile, both of which contribute to the development of cardiovascular disease. In addition, in the obese state, there is a need for perfusion of a greater mass of tissue, resulting in an increase in cardiac work. Blood volume, stroke volume, and cardiac output are all increased and result in increased ventricular mass, which is
reversible with weight loss.

Pulmonary Disease

Abnormalities in pulmonary function may be seen in obese
patients. These range from quantitative abnormalities in pulmonary function tests that have no
established clinical significance to major dysfunction replete with symptoms and morbid consequences. The increased metabolic rate in obese subjects increases O2 consumption and CO2 production, and these changes result in increased minute ventilation. In subjects with marked obesity, the compliance of
the chest wall is reduced, the work of breathing i s increased, and the respiratory reserve volume and vital capacity are reduced; a resultant mismatch between ventilation and perfusion may result in hypoxemia. Severe obesity may cause hypoventilati on, defined by the development of CO 2 retention. The full designation of the obesity-hypoventilati on, or pickwicki an, syndrome includes somnolence, lethargy, and
respiratory acidosi s and typicallyal so includes sleep apnea. Such patients may have reduced ventilatory drive to hypoxia and hypercapni a, as well as obstructive or mechanical causes of hypoventilati on, and sleep studies may be necessary to distinguish among these.

Gallstones

Obesity is associated with enhanced biliary secretion of cholesterol . This results in supersaturation of bile and a higher incidence of gallstones —particularly cholesterol gallstones. Fasting, as opposed to more limited caloric restriction, increases the saturation of bile by reducing the phospholipid component, and cholecystitis induced by fasting is a well -recognized problem in obese individual's.

Cancer

Excess weight has been associated wi th increased rates of cancer. A recent study examining data for more than a million patients enrolled in the Cancer Prevention Study demonstrates convincingly that obese individuals are at increased risk for a number of cancers. The most dramatic increase in risk is seen for liver cancer. The relative risk of liver cancer was almost 2-fold hi gher in men with a BMI of 30.0 to 34.9 than in
normal -weight individual's, an d it was 4.5-fol d higher in men with a BMI greater than 35. In men with a BMI higher than 35, the risk of stomach cancer was increased 1.94 -fol d, that of kidney cancer was increased 1.7 -fol d, and that of esophageal cancer was increased 1.6-foldover the risk in normal -weight individual's. The effect of obesity on cancers of the gastrointestinal tract was not as great in women, but the increase in relative risk i n women was the same as that in men for kidney cancer. In women with a BMI greater than 35, the relative risk of cancer of the uterus was 2.8, of cancer of the
cervix was 3.8, and of breast cancer was 1.7.