Chief, Division of Endocrinology, Diabetes and Nutrition; Director, New York Obesity Research Center, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York, NY, USA
Obesity is associated with a number of medical conditions that lead to increased morbidity and increased mortality. Both the National Institutes of Health and the World Health Organization define obesity as a body mass index (BMI) ~30 kglm2 and overweight as a BMI 25-30. The most common conditions associated with obesity are insulin resistance, diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, gallstones and cholecystitis, sleep apnea and other respiratory dysfunction, and the increased incidence of certain cancers. These are discussed below.
Epidemiology In recent years, the relative weight of.individuals and populations has been tracked using the BMI. This is calculated by the formula weight(kg) / height(meters)2. The National Institutes of Health) and the World Health Organization2 have both established similar criteria for overweight and obesity (Table 1). The BMI is a good surrogate for measuring the fatness and thinness of a population, as demonstrated in careful studies of body composition.3 The prevalence of obesity is rapidly increasing around the world. In the USA, this has been tracked by the National Health Examination Surveys for the last 40 years, and in the last reported survey (1988-92),4 there was a disconcerting jump in weight. Figure I shows the findings in both men and women of the surveys taken at roughly 10 year intervals.s This last survey shows an extraordinarily large secular leap of 8% in both
Correspondence to: Dr. X. Pi-Sunyer, SI. Luke's-Roosevelt Hospital Center, 111 Amsterdam Ave., New York, NY 10025, USA. E-mail: fxp1 @columbia.edu
6S Obesity Surgery, 12, 2002
Table 1. Classification of overweight and obesity by BMP
Obesity Class BMI (kg/m2)
Underweight <18.5 Normal 18.5-24.9 Overweight 25.0-29.9 Obesity I 30.0-34.9
II 35.0-39.9 Extreme Obesity III >40.0
genders.4 In continued tracking since that time, the movement into the obese category has been increasing at the rate of 1 % of the population per year. Not only is the population gaining weight, but also it is gaining a great deal of weight. Figure 2 shows the distribution of the population in the USA according to BMI.6 There is a large shoulder to the right with many individuals with BMI >35. Thus, severe obesity is a rapidly increasing prob1em.
Diabetes Mellitus Obesity is the greatest risk factor for development of type 2 diabetes. Cross-sectional studies have
Figure 2. Distribution of the U.S. population according to BMI.6
shown a strong positive correlation between the average weight of a population and the prevalence of type 2 diabetes mellitus. In a male population divided into BMI groups of 25 to 26.9, 29 to 30, and >35, the risk for diabetes (compared to a population with BMI <21) increased 2.2, 6.7, and 42-fold, respectively.? This is also true in female populations (Figure 3).8 Not only is the severity of the obesity a determinant, but so is the . length of time obesity has been present.
The development of diabetes is primarily because of the insulin resistance that accompanies obesity, which becomes more severe as the BMI rises.9 The tissues which manifest the insulin resistance are muscle, adipose, and liver. \0 As extra fat accumulates in the body, there is an impairment in the ability of insulin to act effectively at the cellu-
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15 20 25 30 35 40 45
Body Mass Index
Figure 3. Risk of developing diabetes according to BMI.54
The Medical Risks of Obesity
lar level. This impaired cellular effect is manifested both at the insulin receptor and at the post-receptor level. At the insulin receptor, there is a down-regulation of the receptors, so that the total number of these at the membrane surface are decreased, as is the affinity of the insulin for the receptors. These alterations decrease the binding of circulating insulin to the receptors and impair the signals that activate the many intracellular actions of insulin.ll
The post-receptor abnormalities that occur in obese individuals, however, are more important. These are the signals for initiating glucose transport into the cell and then glucose oxidation and storage as glycogen. There is therefore a decrease in the entrance of glucose and its use by insulinsensitive cells. This is found particularly in muscle. Because of inability to enter glucose utilizing tissues, there is an elevation in circulating blood glucose levels, which stimulates the islet cells of the pancreas to secrete greater amounts of insulin in an effort to maintain glucose homeostasis. 12 This phenomenon is continuous day in and day out for as long as an individual is overweight. Finally, in those individuals who have the appropriate genetic predisposition to the disease, the B-cells of the pancreas become exhausted and begin to fail, so that frank diabetes occurs.
Hypertension Hypertension is commonly associated with obesity, with about one-third of all obese persons being hypertensive (Figure 4).13 For every lO-kg rise in
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Figure 4. NHANES III age-adjusted prevalence of hypertension according to BMI.1
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F. Xavier Pi-Sunyer
body weight above nonnal, there is an average increase of 3.0 mmHg in systolic and 2.3 mmHg in diastolic pressure. 14 In the Framingham Heart Study, for every 19% increase in relative weight, systolic blood pressure increased 6.5 mmHg.15 Other studies have shown similar or even greater effects. Also, the longer the duration of obesity, the greater the risk of developing hypertension. Not only is the fat burden a risk factor for hypertension, but also the distribution of body fat is an important detenninant of blood-pressure risk, with central, upper-body or intra-abdominal body fat being a greater risk than peripheral fat. 16,17
The pathophysiology of hypertension in obesity is not clear, although a number of mechanisms have been invoked. 18-21 Sodium retention may occur because of decreased renal filtration surface; insulin enhances the tubular reabsorption of sodium, insulin levels are high in obesity due to the prevailing insulin resistance, and the kidney continues to be sensitive to insulin; there is an increased catecholamine tone in obesity; plasma renin levels may be inappropriately elevated in obese persons. More research is necessary to clarify the pathogenesis of high blood-pressure associated with obesity.
Stroke Probably because of the link of obesity to hypertension, there is also an increased incidence of stroke.22,23 In the Framingham study, the incidence of stroke rose steeply with increasing weight. For example, in the male group under 50 years, the risk of stroke rose from 22 to 30 to 49 per thousand, as relative weights rose from 110% to 129% to >130%, respectively.24
Dyslipidemia The two primary abnonnalities in circulating lipids that occur with obesity are an elevation of triglycerides and a decrease in high density lipoprotein cholesterol (HDL-C). In addition, while the low density lipoprotein cholesterol (LDL-C) may be only modestly elevated, there is an increase in the presence of small dense LDL particles, which are more atherogenic.25-27 The high level of triglycerides occurs because of both an increased production by the liver and a decreased clearance at the
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periphery. Triglycerides are transported predominantly as very-low-density lipoproteins (VLDLs). VLDL production in the liver is enhanced by the hyperinsulinemia, the high levels of free fatty acids (FFA) arriving at the liver from the fat depots,28 and plenty of glucose precursors available to the liver as glycerol. There is also a decreased activity of lipoprotein lipase (LPL) in skeletal muscle.29
LPL hydrolyzes triglycerides, thereby helping in their clearance from the plasma, either into muscle for use as fuel or into adipose tissue for storage. The impainnent of the clearance of triglycerides leads to higher circulating levels.
Since in obesity the HDL-C levels are low (Figure 5) while LDL-C are usually only mildly elevated or within nonnal range, the ratio of LDLC to HDL-C is always elevated. This combination greatly increases the risk of coronary heart disease.
Cardiovascular Disease Epidemiologists include angina pectoris, non-fatal myocardial infarction, and sudden death in cardiovascular disease (CVD). The incidence of these is higher in obese persons. Controversy abounds as to how important obesity is in CVD morbidity and mortality. There is a solid data base showing that, as mentioned above, obesity elevates the risk of hypertension, dyslipidemia and diabetes, all of which are strong independent risk factors for CVD. When these factors are controlled for in statistical multivariate analysis, obesity mayor may not
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Figure 5. NHANES III age-adjusted prevalence of low HDL-cholesterol* according to BMI.1 'Defined as <35 mg/dl in men and <45 mg/dl in women
emerge as an independent risk factor. In the shorter prospective studies, the association is harder to detect. However, in longitudinal studies carried out for longer than 15 years, obesity consistently shows itself to be an independent risk factor.3o In the Nurses' Health Study, at 16-year follow-up, the risk of CVD increased 2-fold at BMI 25 to 28.9, and 3.6-fold at BMI >29, compared with the group with BMI <2t.B When assessing the risk of obesity on morbidity and mortality, it seems unjustified to control for just those conditions that are made worse by obesity.
Obesity can also have an effect on heart morphology. Heart size increases beginning with left ventricular dilatation and then myocardial hypertrophy.3! Increased intravascular volume causes systolic dysfunction with a decline in ventricular contractility.32 Eventually, heart failure can occur.24 This is particularly true as severe obesity occurs.
Gallbladder Disease Formation of gallstones is increased in obese individuals,33.34 because of alterations that develop as obesity increases. Cholesterol excretion from the liver increases, and the bile becomes supersaturated with the cholesterol. 35 The contractility of the gallbladder decreases, so that the sac is emptied much less efficiently.36 This condition is probably due to a diminished sensitivity to the cholecystokinin released with each meal. The risk for developing predominantly cholesterol-containing stones is thus increased. The presence of the stones enhances the propensity to gallbladder inflammation, so that acute and chronic cholecystitis is much more common in obese persons.33,34 The incidence of this condition is higher in women than men, partly because the prevalence of obesity . is higher in women, but there may be other reasons as yet undiscovered. Cholecystectomy rates are much higher in obese persons and more so in women than men.
Respiratory Disease The increased weight of the chest in obesity leads to poor respiratory motion and also decreased compliance of the respiratory system, so that both vital capacity and total lung capacity are often low. As the overweight becomes more severe, ventilation-
The Medical Risks of Obesity
perfusion abnormalities occur that impair adequate oxygenation of the blood, even though carbon dioxide escape is adequate. With continued and persistent obesity, sleep apnea, either peripheral or central, may occur.37,38 Peripheral apnea is manifested by obstruction of the airway caused by excess fatty tissue and the relaxation of the pharyngeal and glossus muscles. Central apnea is the result of a cessation of the signals that initiate inspiration. The mechanism for this cessation of signals is unclear but apneic episodes may occur many times during the night, causing significant hyperventilation. The severity of all the above abnormalities may lead to progressively more severe hypoxemia and hypercapnia, which in turn may lead to pulmonary hypertension, right heart failure, and cor pulmonale.39
Cancer Ohesity has been shown to be associated with various forms of cancer, but more data are required; Recently, there have been a few studies relating the increase in certain cancers with obesity to the prevailing hyperinsulinemia in these individuals.40-42 The hypothesis with regard to the causation is that insulin can have abnormal and undesirable mitogenic effects on certain tissues. This is an interesting and new avenue of inquiry with regard to the association between obesity and certain kinds of cancers, and needs to be followed-up. Also, it is not clear whether the association may be related to other co-associated causes, such as high fat in the diet, excess daily calories, oxidative stress, or other specific components of the diet. However, the associations, while their possible causality is unclear, have been well described.
In women, higher rates have been described for endometrial, gallbladder, cervical, and ovarian cancers.43 For breast cancer, pre-menopausal women who are obese are less at risk, while postmenopausal women are at greater risk.44,45 It is possible that some of this post-menopausal effect on breast cancer is related to the increasing estrogenicity that occurs with increasing obesity as women age. This increased estrogenicity is the result of estrogen production in adipose tissue from sex-hormone precursors that are soluble in fat and are converted there to active estrogen. This com-
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F. Xavier Pi-Sunyer
bined estrogenicity might affect breast cancer incidence. An increased incidence of colorectal and prostate cancers has been found in obese men.43
The mechanisms for this association are unknown.
Arthritis and Gout Both arthritis and gout are increased in obese persons.46-48 The stress on the weight-bearing joints caused by increasing weight can be very great. Degenerative disease of these joints is quite common in obese persons, particularly as the duration and severity of the obesity increases. This is a cause of a great deal of disability, particularly in severely obese individuals.
An association between gout and excess weight has been found repeatedly in cross-sectional studies. This occurs to a much greater degree in men than women.46 In women, higher amounts of excess fat are needed for the disease to develop.
Effects of Fat Distribution Epidemiologic studies from many countries have established fat distribution as an important determinant of disease risk.49-51 It is thus not only the degree of obesity but also where the fat is deposited that is important for health. Which depot is most important with regard to health risk has been much debated, suggesting that both subcutaneous and intra-abdominal sites are important. The intra-abdominal or visceral depot has been thought to be more important because of an increased lipolytic activity of fat cells in this region, which release large amounts of FFA to the liver and the periphery.28,52 The combination of the hyperlipacidemia and hyperinsulinemia which is present in centrally obese individuals leads to an increased VLDL production with resultant hypertriglyceridemia.29 The lip acidemia also inhibits glucose transport and oxidation in muscle, increasing the insulin resistance and the propensity for diabetes.53 The hyperinsulinemia leads to increased sodium absorption and increases the risk of hypertension.
Conclusion The medical complications of obesity are many and constitute a great problem for the public health of most developed countries in the world. Type 2 diabetes mellitus, hypertension, dyslipidemia, car-
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diovascular disease, and stroke are, aside from cancer, AIDS, and violence, the leading causes of morbidity and mortality in the developed world. If cancer, a condition in which obesity can playa part, is added, obesity is a large contributor to the burden of disease affecting industrialized countries. Whether the impact from these conditions is direct and independent or indirect is essentially irrelevant from a public health perspective. If obesity could be prevented, a very significant and positive impact on chronic disease and mortality would occur.
Professor Pi-Sunyer is on the Medical Advisory Board of Transneuronix Inc.
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