Third, the metabolic syndrome is accompanied by increases in acute phase proteins, such as C-reactive protein. Several reports suggest that these proteins may have proatherogenic properties. And finally, there is a cellular inflammatory response in the arterial way secondary to interaction with the known metabolic risk factors; this inflammatory response may be heightened by increases in circulating inflammatory cytokines.
As indicated above, each of the components of the metabolic syndrome hasbeen implicated in atherogenesis. Because of their colinearity within the syndrome, it has been difficult to dissect the relative contributions of each to atherosclerotic cardiovascular disease events. For this reason, the metabolic syndrome can be considered to be a multiplex cardiovascular risk factor. The metabolic syndrome belongs in the category of causative risk factors similar to individual risk factors of cigarette smoking, hypercholesterolemia, and hypertension.
The introduction of a multiplex risk factor is something new to the cardiovascular field, and not surprisingly, the understanding of the place of the metabolic syndrome in cardiovascular risk has been slow in development.
The question has arisen whether the risk for metabolic syndrome as a whole is greater than the sum of the risk factors of its individual components. This is a complex question, but can be addressed in several ways. First, epidemiological studies suggest that multiple risk factors are synergistic in raising risk and not just additive. This synergism has long been called multiplicative risk . Second, several of the risk components, e.g., elevated apolipoprotein B, a prothrombotic state, and a proinflammatory state, are not usually measured in clinical practice.
Consequently, their contribution to risk is not identified with the typical clinical measures. Third, some of the measured risk factors, such as low high-density lipoprotein cholesterol, may be predictive but not necessarily causative; thus, the individual risk factors that are used for prediction may be only markers for the true causative factors accompanying the syndrome. And fourth, the metabolic syndrome is a progressive disorder, that is, it worsens over time. Consequently, risk measured at any one time underestimates the long-term risk accompanying the syndrome.
Considerable confusion has arisen regarding the relation of the component metabolic risk factors to the risk surrogates (categorical risk markers) for these factors that are the basis for clinical diagnosis. In both updated Adult Treatment Panel III and International Diabetes Federation formulations of the risk the following surrogates are included:
- Serum triglycerides <150 mg/dL (<1.7 mmol/L)
- High-density lipoprotein cholesterol < 40 mg/dL (<1.0 mmol/L) in men, and <50 mg/dL (<1.3 mmol/L) in women
- Blood pressure <130 mmHg systolic, and <85 mmHg diastolic
- Fasting glucose <100 mg/dL (<5.6 mmol/L)
- Increased waist circumference (population-dependent thresholds)
The following waist circumference thresholds are recommended:
- Non-Asian <94 cm in men (<102 cm in U.S. men); <80 cm in women (<88 cm in U.S. women)
- Asian <90 cm in men; <80 cm in women
The higher waist circumference in U.S. men and women relates in large part to practicality because of the high prevalence of obesity. However, recent studies have shown that in the United States, a similar prevalence of metabolic syndrome exists by International Diabetes Federation and updated Adult Treatment Panel III criteria.
International Diabetes Federation requires that elevated waist circumference be present for a diagnosis of the metabolic syndrome. Adult Treatment Panel III does not require this when other risk surrogates are present. According to both criteria, when three or more (3+) risk markers are present, a diagnosis of the metabolic syndrome can be made. It has been shown that most persons with 3+ metabolic markers are affected with all of the metabolic risk factors that constitute the metabolic syndrome.
Although the metabolic syndrome is multifactorial in origin, the pathogenesis can be simplified into two general categories of causation. The first category can be called metabolic susceptibility. For the syndrome to develop there must be an underlying propensity. Reaven and other workers have suggested that this susceptibility be called insulin resistance. Without question, most people who exhibit the metabolic syndrome also manifest insulin resistance. Even so, the metabolic connection between insulin resistance and the multiple components of the syndrome have not been elucidated. One view holds that insulin resistance, or concomitant hyperinsulinemia, is a direct cause of all of the components of the syndrome. Certainly, insulin resistance contributes directly to the dysglycemia of prediabetes and Type 2 diabetes. On the other hand, the mechanistic link between insulin resistance and other components- atherogenic dyslipidemia, vascular dysfunction, and prothrombotic and proinflammatory states- remains to be clarified.
The possibility exists that other causes that are responsible for these abnormalities also produce insulin resistance. If so, insulin resistance may be a marker for the presence of these underlying causes without itself being a direct causative factor.
Thus, more research is needed to understand the mechanistic basis of metabolic susceptibility for the metabolic syndrome.
Several factors appear to contribute to metabolic susceptibility. Among these are physical inactivity, advancing age, adipose-tissue disorders, certain drugs, and ethnic, racial, and family propensity. At a more mechanistic level, susceptibility has been related to deficiencies and maldistribution of adipose tissue, loss of muscle mass, genetic defects in insulin-signaling pathways, and other genetic variations. All of these changes are associated with insulin resistance, but whether the latter is a cause or a marker of the several components of the metabolic syndrome is yet to be determined. Certainly, the possibility must be considered that these susceptibilities act on development of metabolic syndrome components in ways that are independent of insulin resistance.
The second large category of causation for syndrome is an excess in body fat. This typically is a manifestation of energy overload. It results in either overweight or obesity. Epidemiological studies show that increases in obesity in a population are accompanied by increases in the prevalence of the metabolic syndrome. Thus, obesity can be viewed as the driving force behind the metabolic syndrome. This is true even for individuals who are metabolically susceptible.
Still, obesity is particularly likely to precipitate the syndrome in persons who are susceptible based on other factors. The mechanisms whereby obesity worsens the syndrome is a subject of intense research interest. Recent discoveries show that an excess in body fat is accompanied by abnormalities in release of many factors from adipose tissue. Among these are increased outputs of nonesterified fatty acids, resistin, angiotensinogen, and others. All of these have been implicated in systemic metabolic abnormalities related to the metabolic syndrome. In addition, adiponectin, a putative protective adipokine, is reduced with obesity.
Consequently, obesity and its accompanying abnormalities may be a direct cause of several of the metabolic syndrome constituents. The actions of these several adipokines represent an area of great importance in research on the development of the metabolic syndrome.
One of the features of the metabolic syndrome is a tendency to accumulate fat in tissues outside of adipose tissue. This is called ectopic fat. Two prime locations are muscle and liver. In muscle, ectopic fat accumulation is accompanied by insulin resistance. The pathways whereby excess fatty acids in muscle cause insulin resistance are becoming better understood. In liver, ectopic fat accumulation, called fatty liver, is accompanied by insulin resistance and increased outputs of glucose and very low-density lipoprotein triglyceride. The pathways underlying these changes are only partially understood. The reasons for ectopic fat accumulation have not been fully elucidated. One possibility is that patients with the metabolic syndrome may be relatively deficient in adipose-tissue storage capacity. Most of the body fat is normally stored in subcutaneous adipose tissue. If fat storage capacity is limited, caloric overload may result in accumulation of fat elsewhere, hence excess ectopic fat. An example of this phenomenon occurs in patients with lipodystrophy- which is characterized by a loss of body fat, particularly subcutaneous fat. Patients with lipodystrophy typically have large accumulations of ectopic fat and many metabolic complications. One of the features of ectopic fat accumulation is the presence of excess intraperitoneal (visceral) fat.
Thus, visceral obesity can be viewed as a marker of a relative deficiency of subcutaneous fat stores.
The above model of the pathogenesis of the metabolic syndrome provides a rational approach to its management. Highest priority goes to prevention and/or treatment of obesity. Second is modification of metabolic susceptibility. And third is to treat residual risk-factor components of the syndrome. A few comments can be made about each.
Scott M. Grundy, MD, PhD
Professor of Internal Medicine
Distinguished Chair in Human Nutrition
Director, Center for Human Nutrition
University of Texas, Southwestern Medical Center
Dallas, Texas, U.S.A.