In 1988, at the Banting Lecture at the annual meeting of the American Diabetes Association,1 Dr. Gerald Reaven of Stanford University described a constellation of metabolic abnormalities associated with an increased risk for diabetes and atherosclerotic cardiovascular disease (CVD). This cluster of risk factors was designated “syndrome X,” or insulin resistance syndrome. Dr. Reaven stated that persons with syndrome X2 manifest glucose intolerance, dyslipidemia, abnormal uric acid metabolism, renal salt retention, increased sympathetic tone, and hypercoagulability due to increases in plasminogen activator inhibitor 1 (PAI-1).
As the defining features of syndrome X have evolved, researchers coined the term metabolic syndrome (metS) to describe the abnormalities that identify the segment of the population at risk for diabetes and atherosclerotic disease. But, there has been a lack of consensus on a precise definition of metS.
The World Health Organization, National Cholesterol Education Project, American Academy of Clinical Endocrinology, and International Diabetes Federation have published somewhat different diagnostic criteria (Table 29-1). Consequently, the National Heart, Lung, and Blood Institute and the American Heart Association in 2004 convened a conference to develop a meaningful definition of metabolic syndrome.3 Clinical features they agreed on include the following:
| Blood Pressure | Lipids | Central Obesity | Glucose | Other | Diagnostic Requirements | |
|---|---|---|---|---|---|---|
| WHO | On antihypertensive therapy or BP ≥ 140/90 mm Hg | Plasma triglycerides over 150 dL/mL and/or HDL-C < 35 mg/dL (men), < 39 mg/dL for women | BMI > 30 and/or waist-hip ratio > 0.9 (men), > 0.85 (women) | IGT or as in type 2 diabetes | Microalbuminuria (UAE ≥ 20 μg/min or albumin-creatinine ratio ≥ 30 mg/g) | Type 2 diabetes or IGT and 2 additional abnormalities; if GT normal, 3 required |
| NCEP ATP III | BP ≥ 130/85 mm Hg | Plasma triglycerides over 150 dL/mL and/or HDL-C < 40 mg/dL (men), < 50 mg/dL for women | Waist circumference > 102 cm (40 in.) (men), > 88 cm (35 in.) (women) | FBG ≥ 110 mg/dL | 3 or more of criteria listed | |
| AACE | Hypertension | Plasma triglycerides over 150 dL/mL and/or HDL-C <35 mg/dL (men), <45 mg/dL for women | Waist circumference > 102 cm (40 in.) (men), >88 cm (35 in.) (women) | IFG or as in type 2 diabetes | Insulin resistance, acanthosis nigricans, hyperuricemia. Minor criteria: hypercoagulability, coronary heart disease, polycystic ovarian disease, vascular endothelial dysfunction, microalbumenuria | Not specified |
Abdominal obesity is the form of obesity most strongly associated with metS. It presents clinically as increased waist circumference.
Atherogenic dyslipidemia manifests in routine lipoprotein analysis by raised triglycerides and low concentrations of high-density lipoprotein (HDL) cholesterol and many times other lipoprotein abnormalities (e.g., increased remnant lipoproteins, elevated apolipoprotein B, small low-density lipoprotein [LDL] particles, and small HDL particles). All of these abnormalities have been implicated as independent atherogenic factors.
Elevated blood pressure strongly associates with obesity, and 50% of persons with hypertension also evidence insulin resistance.
Insulin resistance is present in the majority of people with metS. It strongly associates with other metabolic risk factors and correlates univariately with CVD risk. When glucose intolerance evolves into clinical diabetes, an elevated glucose level constitutes a major independent risk factor for CVD.
A pro-inflammatory state, recognized clinically by elevations of C-reactive protein (CRP), is commonly present in persons with metS. Multiple mechanisms are involved, but obesity and excess adipose tissue cause the release of inflammatory cytokines such as CRP.
A prothrombotic state, characterized by increased plasma PAI-1 and fibrinogen, also is associated with metS, and the prothrombotic and pro-inflammatory states seem to be metabolically interconnected.
The National Heart, Lung, and Blood Institute/American Heart Association Conference set the criteria in Figure 29-1 for a diagnosis of metS. A person must have 3 or more of the following:
Waist circumference greater than 102 cm in men or greater than 88 cm in women
Serum triglycerides 150 mg/dL or greater
HDL cholesterol less than 40 mg/dL in men or less than 50 mg/dL in women
Systolic/diastolic blood pressure of 130/85 mm Hg or greater or taking hypertension medications
Fasting plasma glucose level of 100 mg/dL or greater or taking diabetes mellitus medications
Malik and colleagues4 quantified the impact of metS on CVD mortality. Relative to an individual with no metS risk factors, having 1 to 2 risk factors increased a patient’s hazard ratio by more than 70%, to 1.73. Having 3 or more of the 5 risk factors associated with metS imposes a CVD mortality hazard ratio of 2.71 (Figure 29-2). The highest risks are associated with type 2 diabetes and CVD and with those with coincident CVD and type 2 diabetes mellitus.
FIGURE 29-2.
Hazard ratios for cardiovascular mortality with metabolic syndrome, diabetes, and cardiovascular disease (based on USA data adjusted for gender, age, smoking, physical activity, and total cholesterol). RF, risk factor; T2DM, type 2 diabetes mellitus. (From Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004;110:1245–1250.)
Our understanding of the physiological disturbances associated with metS continues to evolve. A vast array of complexities and subtleties exist within the pathophysiology of insulin resistance, obesity, atherogenic dyslipidemia and hypertension, and metS, while defining a cluster of findings suffers from being too restrained.
The keystone in metS is central obesity, defined by waist circumference. Waist circumference is measured at the high point of the iliac crest at minimal respiration to the nearest 0.1 cm. There has been some research and discussion if waist or waist-hip ratio is a better measure for assessing risk. It is clear that while waist measurement offers some small challenges, hip measurement is difficult to do owing to poor placement of measuring tape and poor reproducibility. The default has become waist circumference.
In the Nurses’ Health Study, with data generated over 8 years on 43,581 subjects, there was a strong positive association between waist circumference and the incidence of diabetes. Those women with a waist circumference greater than 38 inches had a diabetes relative risk (RR) of 22.4, relative to women in the normal waist circumference range of less than 28 inches. While the study also looked at body mass index (BMI) and waist-hip ratio, both of which were validated and predicted the same trend, waist circumference showed the sharpest gradient and was judged to be the best predictor of risk.5
Waist measurement is simple for patients to understand. Are your pants, belts, or dresses tight? You have gained weight. Are they loose? You have lost weight. Moreover, you have lost weight where it counts, from your abdomen. Some weight loss clinics suggested replacing regular weighing at home on a scale with a tape measure. And, when working with patients from economically disadvantaged communities, a retractable cloth tape measure is considerably cheaper than a scale and can be carried in a suitcase, briefcase, or purse.
Waist circumference cut points for CVD risk vary by race and ethnicity. The International Diabetes Foundation (IDF) suggested ethnic-specific values for waist circumference for different populations, although the normative values are not as well validated as the normative values in American and Europid groups (Table 29-2).
| Country/Ethnic Group | Waist Circumference | |
|---|---|---|
| United States | Male | 102 cm (40 in.) |
| Female | 88 cm (35 in.) | |
| Europids | Male | 94 cm (37 in.) |
| Female | 80 cm (31 in.) | |
| South Asian and Chinese | Male | 90 cm (35 in.) |
| Female | 80 cm (31 in.) | |
| Japanese | Male | 85 cm (33 in.) |
| Female | 90 cm (35 in.) | |
| Ethnic South and Central American | Use South Asian until more data are available | |
| Sub-Saharan Africans | Use European until more data available | |
| Eastern Mediterranean and Middle Eastern (Arab) | Use European until more data available | |
Due to a number of factors, the clinical correlates for the lower waist circumference cut points owe to the higher risk of diabetes and CVD, particularly in South Asians and Chinese populations and expatriate groups residing in Westernized societies. The thresholds for risk are lower for acquired traits, including age, obesity, abdominal obesity, and a high percentage of body fat. The risk for diabetes escalates in males from India at a BMI of 23 and waist circumference of 85 cm in men and 80 cm in women. At any given BMI, South Asians have a higher degree of central adiposity and a higher degree of insulin resistance.6
This body type, with thin arms and legs but a cylindrical trunk with chest, waist, and hip circumference being similar, has been termed TOFI, thin on the outside, fat on the inside. Moreover, South Asians, Asians, and Pacific Islanders evidence earlier onset of diabetes and CVD and have a significantly higher number of risk factors when diagnosed.7 They manifest a higher prevalence of retinopathy; higher rates of hypertension; and higher levels of hemoglobin A1c and total cholesterol, despite being younger at the time of diagnosis than Europids.
In addition to high-sensitivity CRP (hsCRP), other cytokines (also called adipokines) are upregulated in obesity and are adipocyte-derived bioactive substances. Adiponectin, a protective adipokine, is downregulated by intra-abdominal obesity. Adiponectin protects the endothelial vasculature by inhibiting foam cell formation and vascular remodeling, processes that promote the formation of atherosclerotic plaque. Adiponectin also improves insulin sensitivity, keeping blood sugar in check. Conversely, interleukin 6 (IL-6) is upregulated by intra-abdominal obesity. IL-6 is a pro-atherogenic hormone; it worsens insulin resistance and is therefore both pro-atherogenic and diabetogenic. Tumor necrosis factor alpha (TNF-α) is also upregulated in obesity, lowers insulin sensitivity in adipocytes, and increases free fatty acid production and triglycerides. TNF-α induces a procoagulant state, and when coupled with increased secretion of PAI-1, proatherogenic, pro-inflammatory, and procoagulant changes are further enhanced.
While much energy has been devoted to developing a definition for metS, it must be mentioned that many experts in the field do not believe that the term is a valuable and viable clinical construct. Coincident with the publication of the report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to the Definition of metS, another consensus group comprising members of the Professional Practice Committee of the American Diabetes Association and an ad hoc committee of the European Association for the Study of Diabetes issued their own statement, arguing that the current definition of metS was still poorly characterized, did not sufficient identify persons at risk, and might lead patients and clinicians to neglect significant markers of disease that are not part of the cluster of risk factor delineated by metS. The committee stated the following:
While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a “syndrome.” Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the “metabolic syndrome (p. 2289).”8
Nonetheless, the term metabolic syndrome has become embedded within our lexicon, in research protocols, and in clinical practice. Paul Huang has perhaps written the most cogent review of the topic, providing a working definition of metS and an excellent review of its clinical utility:
The metabolic syndrome is a clustering of hyperglycemia/insulin resistance, obesity and dyslipidemia. It is important for several reasons. First, it identifies patients who are at high risk of developing atherosclerotic CVD and type 2 diabetes (T2D). Second, by considering the relationships between the components of metabolic syndrome, we may be able to better understand the pathophysiology that links them with each other and with the increased risk of CVD. Third, it facilitates epidemiological and clinical studies of pharmacological, lifestyle and preventive treatment approaches (p. 231).9
Metabolic syndrome should be regarded as one more algorithm for defining persons at risk. But, it is not sufficient. Consider the following three patient profiles:
Patient 1: Marcia
54-year-old white female
Waist 93 cm (38 inches)
Glucose 120 mg/dL
Triglycerides 260 mg/dL
Low-density lipoprotein 180 mg/dL
Patient 2: Mary
54-year-old white female
Waist 93 cm (38 inches)
Glucose 99 mg/dL
Triglycerides 190 mg/dL
High-density lipoprotein 55 mg/dL
Patient 3: Maria
54-year-old white female
Waist 85 cm (33.5 inches)
Glucose 145 mg/dL
Triglycerides 120 mg/dL
High-density lipoprotein 30 mg/dL
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