Metabolic Syndrome

Latest updates: November 14, 2013

On November 12, 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) published four related guidelines on the prevention of atherosclerotic cardiovascular disease (ASCVD) events, with a focus on cholesterol, obesity, and lifestyle management tools.

The new guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults recommends a fundamental change in patient management from the National Heart, Lung, and Blood Institute's (NHLBI) Adult Treatment Panel III (ATP3) recommendations, the acknowledged leading guideline since 2004. In contrast to the ATP3, the ACC/AHA recommends treating all patients who fall into one of four statin benefit groups with either standardized, fixed-dose, high-intensity (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) or moderate-intensity (atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, or pravastatin 40–80 mg, among other statins) therapies.

Most patients with metabolic syndrome probably fall into the fourth group: individuals aged 40 to 75 years without clinical ASCVD or diabetes with an LDL-C level of 70 to 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. According to the ACC/AHA guideline, these patients should receive either moderate- or high-intensity statin therapy.

The new AHA/ACC guideline on lifestyle management to reduce cardiovascular risk continues to recommend any medically recognized heart-healthy dietary program. For lowering LDL-C, the strongest recommendations continue to advise a reduction in the percentage of calories from saturated and trans fats, aiming for 5% to 6% of calories from saturated fat. For lowering blood pressure, the strongest recommendation continues to be reducing sodium sodium intake and following a DASH-type diet.

The 2013 ACC/AHA guideline on the assessment of cardiovascular risk introduces a new 10-year and lifetime cardiovascular risk assessment tool based on a pooled cohort to predict first ASVCD-related event in non-Hispanic men and women. Routine measurement of carotid intima-media thickness is not recommended as part of primary prevention.

Summary

Description

• Metabolic syndrome is a cluster of risk factors of metabolic origin; it is a construct designed to identify individuals at increased cardiovascular risk
• There are several definitions (including those from the World Health Organization and National Cholesterol Education Program's Adult Treatment Panel III); in each definition, the diagnosis is based on defining values for dyslipidemia, hypertension, impaired glucose tolerance, and obesity, with insulin resistance generally considered to be the common link
• Individually, the metabolic disorders are risk factors for cardiovascular disease, particularly coronary heart disease; some evidence suggests that metabolic syndrome increases cardiovascular risk beyond that expected from the individual risk factors alone, but this assertion has not been confirmed
• The metabolic syndrome label may be most useful as a reminder to physicians (and patients) that the presence of one element should heighten awareness that other elements are also likely to be present
• There has been recent concern that metabolic syndrome is imprecisely defined and less valuable as a cardiovascular risk marker than was originally thought. Consequently, some experts and organizations are recommending an emphasis on individual cardiovascular risk factors, regardless of whether or not criteria for metabolic syndrome are met

Synonyms

• Hypertension-hyperglycemia-hyperuricemia syndrome
• Syndrome X
• Dysmetabolic syndrome X
• Insulin resistance syndrome
• Metabolic dyslipidemia
• The deadly quartet (upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension)
• Civilization syndrome

Immediate action

Hypertensive crisis, acute hyperglycemic emergencies (diabetic ketoacidosis or nonketotic hyperosmolar syndrome), and severe hypertriglyceridemia must be treated immediately.

Urgent action

Severe hypertension and severe hyperglycemia require urgent action.

Key points

• Metabolic syndrome is a construct used for assessing and increasing awareness of cardiovascular risk. It is designed to identify patients with a high level of cardiovascular risk
• Individually, the metabolic disorders that characterize metabolic syndrome are risk factors for cardiovascular disease and stroke. They also increase the risk for type 2 diabetes, although glucose intolerance (or diabetes itself) is a criterion for metabolic syndrome in all definitions
• Lifestyle management is advised for all patients with metabolic syndrome. In people at high risk for cardiovascular disease, pharmacologic therapy is appropriate. All patients should be educated about the importance of long-term compliance with the management regimen

There are two major approaches to management:

• The correction of predisposing or exacerbating factors (e.g. body weight and physical inactivity) and associated conditions (e.g. insulin resistance)
• The treatment of metabolic risk factors, i.e. dyslipidemia, hypertension, and hyperglycemia

Background

Cardinal features

• Metabolic syndrome is not a disease, but a cluster of metabolic disturbances
• Insulin resistance (and perhaps also hyperinsulinemia) is considered to be a key pathogenic factor in the development of other features of metabolic syndrome, such as abnormal glucose tolerance, dyslipidemia, and hypertension. Obesity, and perhaps central obesity, promote insulin resistance, although insulin resistance has a strong genetic component and not all insulin-resistant individuals are overweight
• Individually, the metabolic disorders involved in metabolic syndrome are risk factors for cardiovascular disease; some evidence suggests that metabolic syndrome increases cardiovascular risk beyond that expected from the individual risk factors alone, but this assertion has not been confirmed
• Cardiovascular disease morbidity in overweight and obese patients, and those with type 2 diabetes is often related to metabolic syndrome
• Metabolic syndrome has become increasingly common in the US and is increasing in prevalence throughout much of the world, in parallel with obesity and type 2 diabetes
• In all definitions of metabolic syndrome, the diagnosis is based on defining values for dyslipidemia, hypertension, impaired glucose tolerance, and central obesity. The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria are most commonly used
• A large body of evidence suggests that metabolic syndrome is associated with a proinflammatory and/or prothrombotic state that may include elevated levels of C-reactive protein, endothelial dysfunction, hyperfibrinogenemia, increased platelet aggregation, increased levels of plasminogen activator inhibitor-1, elevated uric acid levels, microalbuminuria, and a shift toward small, dense particles of low-density lipoprotein (LDL) cholesterol. These features may contribute to cardiovascular disease risk associated with metabolic syndrome, but they are not included in current definitions
• Insulin resistance may also be associated with increased risk of other conditions in addition to cardiovascular disease, hypertension, and type 2 diabetes. Such conditions include polycystic ovarian syndrome, nonalcoholic steatohepatitis, obstructive sleep apnea, and certain forms of cancer
• Aims of treatment should include management of conditions such as overweight and physical inactivity, which tend to produce or exacerbate insulin resistance, and the treatment of metabolic risk factors for cardiovascular disease such as dyslipidemia, hypertension, and glucose intolerance

The NCEP Adult Treatment Panel III defined metabolic syndrome as the occurrence of three or more of the following criteria (see diagnostic decision for details of further definitions):

• Abdominal obesity (waist circumference: >40 inches (>102cm) in men, >35 inches (>88cm) in women)
• Elevated levels of triglycerides (fasting blood triglycerides equal to or >150mg/dL (>1.7mmol/L))
• Low levels of high-density lipoprotein (HDL) cholesterol <40mg/dL (<1.0mmol/L) for men, <50mg/dL (<1.3mmol/L) for women
• Elevated blood pressure (equal to or >130/85mmHg or documented use of antihypertensive therapy)
• Evidence of insulin resistance (fasting glucose equal to or >110mg/dL (>6.1mmol/L)). Although, the American Heart Association (AHA) in 2004 suggested glucose equal to or >100mg/dL (>5.5mmol/L) as an alternative cut-off point

Causes

Common causes

• Metabolic syndrome is a grouping of cardiovascular risk factors and, as such, probably has more than one cause
• The pathogenesis of metabolic syndrome and each of its components is complex and not well understood, although insulin resistance (and perhaps also hyperinsulinemia) is considered to be a key pathogenic factor in the development of other features of metabolic syndrome, such as abnormal glucose tolerance, dyslipidemia, and hypertension
• Obesity, and perhaps central obesity, promotes insulin resistance, although insulin resistance has a strong genetic component and not all insulin resistant individuals are overweight
• Many theories have been put forward to try and connect the potential etiologies, although none has been universally accepted

Insulin resistance:

• There is some evidence to support the theory that the unifying pathophysiology underlying metabolic syndrome is insulin resistance. In fact, insulin resistance has been postulated to also be a causal factor for other cardiovascular risk factors (e.g. increased C-reactive protein and plasminogen activator inhibitor-1) and medical conditions (e.g. polycystic ovary syndrome and nonalcoholic steatosis)
• In terms of pathophysiology, insulin resistance tends to involve primarily fat and muscle tissue; the pancreas can often prevent the development of diabetes (at least early on) by producing enough insulin to overcome the insulin resistance
• Unfortunately, the compensatory hyperinsulinemia appears to have adverse effects on some tissues that are still insulin sensitive
• The relationships between differential insulin sensitivity, hyperinsulinemia, and metabolic/clinical effects are complex and in many cases still being elucidated. For example, the hypertriglyceridemia associated with insulin resistance appears to result from at least two defects: increased lipolysis and subsequent delivery of fatty acids to the liver due to insulin resistance in fat cells; and increased production of triglycerides due to persistent insulin sensitivity in the liver
• Multiple metabolic pathways have been proposed to link insulin resistance and compensatory hyperinsulinemia to the other metabolic risk factors, however its association with cardiovascular disease has not been fully determined

Obesity:

• Obesity is known to promote insulin resistance, although not all insulin-resistant individuals are overweight
• Some patients, who are not recognized as obese by established criteria, may still be insulin resistant and have other metabolic risk factors. Many of these patients have a fat distribution characterized by upper-body fat
• Upper-body obesity is more strongly correlated to insulin resistance than lower-body obesity. This may be related to the higher level of lipid accumulation in the muscles and liver of patients with upper-body obesity
• Body fat distribution is thought to be an important factor in metabolic syndrome, and excess abdominal fat in particular, is thought to play an important role in the etiology of metabolic syndrome
• Some studies suggest that excess visceral fat is more strongly associated with insulin resistance, although other studies have found that excess subcutaneous abdominal fat also carries a significant association

Adipose tissue abnormalities:

• Abnormalities in adipose tissue metabolism may link insulin resistance and obesity
• Adipose tissue in obese people is insulin resistant. This causes elevated levels of nonesterified fatty-acid levels, which worsens insulin resistance in muscle and alters hepatic metabolism
• In addition, production of several adipokines (including inflammatory cytokines) by adipose tissue in obese people may be abnormal and may affect insulin resistance and cardiovascular disease risk. Adiponectin, which enhances insulin sensitivity and inhibits inflammation, may also be reduced

Inflammation:

• An association has been observed with metabolic syndrome and chronic low-grade inflammation, which may underlie or exacerbate metabolic syndrome, e.g. increased production of proinflammatory cytokines such as interleukin 6, resistin, tumor necrosis factor-alpha, and C-reactive protein
• This may be related to adipose tissue abnormalities in obese patients, however it has also been noted that low-grade inflammation is present in insulin-resistant people without increased body fat

Contributory or predisposing factors

• Genetic factors: such as family predisposition for obesity, hyperlipidemia, coronary heart disease, diabetes mellitus, and probably insulin resistance and related conditions may predispose to metabolic syndrome
• Lack of exercise: sedentary lifestyle and lack of physical exercise may be contributory factors
• Diet: atherogenic diet, rich in saturated fat (>10%), cholesterol (>300mg/day), and trans-fatty acids may predispose to metabolic syndrome. Also, a diet high in carbohydrates may present an increased risk
• Aging: prevalence increases with age

Epidemiology

Incidence and prevalence

• Generally, prevalence of metabolic syndrome increases with age and increasing body weight
• In the US and Europe, the population is ageing and the prevalence of obesity is increasing, consequently the prevalence of metabolic syndrome is increasing

Prevalence

• The National Health and Nutrition Examination Survey III (NHANES III), using a representative study, estimated that in the US overall prevalence among US adults aged 20 years or older was approx. 22,000 cases per 100,000 of total population (22%), with an age-adjusted prevalence of 23.7%
• Approx. 47 million US residents have metabolic syndrome (based on 2000 census data)
• As obesity and sedentary lifestyle increase steadily, metabolic syndrome is also increasing in prevalence and is estimated to affect approx. one-quarter of all Americans

Demographics

Age

Prevalence of metabolic syndrome increases with age.

Results from the NHANES III, from 1988 to 1994, estimated prevalence in US adults by age:

• Aged 20-29 years: 6.7%
• Aged 60-69 years: 43.5%

Gender

• Overall in the US, the prevalence differs little among men (24.0%) and women (23.4%)
• However, among African Americans, women were found to have a 57% higher prevalence than men, and Mexican-American women were found to have a 26% higher prevalence than Mexican-American men

Race

• Results from NHANES III showed significant racial or ethnic differences in US populations
• Mexican Americans had the highest age-adjusted prevalence of metabolic syndrome (31.9%), followed by white Americans (23.8%), and African Americans (21.6%). People reporting an 'other' race or ethnicity had the lowest prevalence (20.3%)
• Other US studies have shown similar trends
• Comparisons between studies of prevalence published for different populations worldwide is problematic; study design, sample selection, year of study, the definition of metabolic syndrome used, and the age and sex structure of the population itself differ between studies
• The components that comprise metabolic syndrome show variation among different racial and ethnic groups. For example, some ethnic groups (in particular, Asian populations) are predisposed to insulin resistance and metabolic syndrome with a waist circumference that is lower than for people of European origin
• There is considerable support for race-specific criteria for obesity and/or central obesity, as recommended by the International Diabetes Federation (see diagnostic decision)

Genetics

A family history of hyperlipidemia, coronary heart disease, and diabetes mellitus can increase the patient's risk of developing metabolic syndrome.

Geography

• The prevalence of obesity is increasing in industrialized countries, especially in the US and Europe
• Geographic differences in lipid profile might be explained by diet and lifestyle differences

Socioeconomic status

NHANES III data suggest that low household income is associated with higher risk of metabolic syndrome.

Codes

ICD-9 code

277.7 Dysmetabolic syndrome X.