Metabolic syndrome is a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose deposition and

function.[1] It is a risk factor for coronary heart disease, as well as diabetes, fatty liver, and several cancers. The clinical manifestations of this syndrome may include hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C), and abdominal obesity. (See Prognosis, Workup, Treatment, and Medication.) Under current guidelines, revised in 2005 by the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA),[2] metabolic syndrome is diagnosed when a patient has at least 3 of the following 5 conditions (see Presentation and Workup): Fasting glucose 100 mg/dL (or receiving drug therapy for hyperglycemia) Blood pressure 130/85 mm Hg (or receiving drug therapy for hypertension) Triglycerides 150 mg/dL (or receiving drug therapy for hypertriglyceridemia) HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C) Waist circumference 102 cm (40 in) in men or 88 cm (35 in) in women; if Asian American, 90 cm (35 in) in men or 80 cm (32 in) in women Abundant data suggest that patients meeting these diagnostic criteria have a greater risk of significant clinical consequences, the 2 most prominent of which are the development of diabetes mellitus [3] and of coronary heart disease. Pooled data from 37 studies involving more than 170,000 patients have shown that metabolic syndrome doubles the risk of coronary artery disease.[4] It also increases risk of stroke, fatty liver disease, and cancer.[5] (See Prognosis.)

Controversy
The clinical value of the recognition of metabolic syndrome as a distinct entity has been challenged. One study questioned the predictive value of the metabolic syndrome diagnosis for the development of diabetes and cardiovascular events in older populations (aged 70-82 y and 60-79 y).[6] Neither population showed a relationship between cardiovascular outcomes and 3 of the metabolic syndrome criteria (for waist circumference, triglycerides, and glucose). Moreover, in this group of older patients, the diagnosis of metabolic syndrome was not more predictive of incident diabetes than was the fasting plasma glucose level alone. Clearly, the individual clinical features that make up the syndrome are predictive of clinical outcomes, but whether grouping these features together under the umbrella of metabolic syndrome adds additional diagnostic, therapeutic, and prognostic value remains the subject of ongoing debate. [7, 8]

Pathophysiology
Target organ damage occurs through multiple mechanisms in metabolic syndrome. The individual diseases leading to metabolic syndrome produce adverse clinical consequences. For example, hypertension in metabolic syndrome causes left ventricular hypertrophy, progressive peripheral arterial disease, and renal dysfunction.[9] However, the cumulative risk for metabolic syndrome appears to cause microvascular dysfunction, which further amplifies insulin resistance and promotes hypertension.[10] Metabolic syndrome promotes coronary heart disease through several mechanisms. It increases the thrombogenicity of circulating blood, in part by raising plasminogen activator type 1 and adipokine levels, and it causes endothelial dysfunction.[11] Metabolic syndrome may also increase cardiovascular risks by increasing arterial stiffness.[12]

Etiology
Risk factors for metabolic syndrome include family history, poor diet, and inadequate exercise. Metabolic syndrome is thought to be caused by adipose tissue dysfunction and insulin resistance. Dysfunctional adipose tissue also plays an important role in the pathogenesis of obesity-related insulin resistance.[13] Both adipose cell enlargement and infiltration of macrophages into adipose tissue result in the release of proinflammatory cytokines and promote insulin resistance.[14] Insulin resistance appears to be the primary mediator of metabolic syndrome.[15]Insulin promotes glucose uptake in muscle, fat, and liver cells and can influence lipolysis and the production of glucose by hepatocytes.

Additional contributors to insulin resistance include abnormalities in insulin secretion and insulin receptor signaling, impaired glucose disposal, and proinflammatory cytokines. These abnormalities, in turn, may result from obesity with related increases in free fatty acid levels and changes in insulin distribution (insulin accumulates in fat). The distribution of adipose tissue appears to affect its role in metabolic syndrome. Fat that is visceral or intra-abdominal correlates with inflammation, whereas subcutaneous fat does not. There are a number of potential explanations for this, including experimental observations that omental fat is more resistant to insulin and may result in a higher concentration of toxic free fatty acids in the portal circulation.[16] Abdominal fat is known to produce potentially harmful levels of cytokines, such as tumor necrosis factor, adiponectin, leptin, resistin, and plasminogen activator inhibitor.[17]

Epidemiology
Occurrence in the United States
Metabolic syndrome is increasing in prevalence, paralleling an increasing epidemic of obesity. In the United States, where almost two thirds of the population is overweight or obese, more than one fourth of the population meets diagnostic criteria for metabolic syndrome.[18] In the United States, data from a 1999-2000 survey showed that the age-adjusted prevalence of metabolic syndrome among adults aged 20 years or older had risen from 27% (data from 1988-1994) to 32%.[19]

International occurrence
Metabolic syndrome is a burgeoning global problem. Approximately one fourth of the adult European population is estimated to have metabolic syndrome, with a similar prevalence in Latin America. [18] It is also considered an emerging epidemic in developing East Asian countries, including China, Japan, and Korea. The prevalence of metabolic syndrome in East Asia may range from 8-13% in men and from 2-18% in women, depending on the population and definitions used. [20, 21, 22] In Japan, the Ministry of Health, Labor, and Welfare has instituted a screening and interventional program.[23] Metabolic syndrome has been recognized as a highly prevalent problem in many other countries worldwide.[24, 25, 26, 27, 28, 29]

Race-related demographics
The fact that the diagnostic criteria for metabolic syndrome vary between ethnic populations is testimony to significant nuances in the manifestation of metabolic syndrome in these groups. The original metabolic syndrome criteria were derived in mostly Caucasian populations, and some have argued for modification of individual criteria for specific ethnic subgroups, as has been done with waist circumference for patients of Asian origin.[30] In the United States, metabolic syndrome has a high prevalence in African Americans, particularly African American women, and this has been attributed to the higher prevalence of obesity, hypertension, and diabetes in this population.[31]However, the highest age-adjusted prevalence of metabolic syndrome in the United States is found in Mexican Americans, approximately 31.9% of whom had the condition (compared with 27% of the general population) in a 1988-1994 survey.[32] A study by Ukegbu et al found that African immigrants have a worse metabolic profile than do African Americans but that they have a similar prevalence of metabolic syndrome. This may mean that metabolic syndrome may underpredict metabolic risk in Africans.[33]

Sex-related demographics
Metabolic syndrome is similarly prevalent in men (24%) and women (23%), after adjusting for age. However, several considerations are unique to women with metabolic syndrome, including pregnancy, use of oral contraceptives, and polycystic ovarian syndrome.[34] Metabolic syndrome and polycystic ovarian syndrome share the common feature of insulin resistance; they therefore share treatment implications as well.[35] Cardiometabolic risk is thought to be elevated in both groups.[36]

In addition, a modest association is apparent between metabolic syndrome and breast cancer, especially in postmenopausal women.[37] Overall, the prevalence of metabolic syndrome in women appears to be increasing, particularly in those of childbearing age. [38] Bhasin et al, as part of the Framingham Heart Study, found that sex hormone-binding globulin is independently associated with the risk of metabolic syndrome, whereas testosterone is not. Age, body mass index (BMI), and insulin sensitivity independently affect sex hormone-binding globulin and testosterone levels.[39]

Age-related demographics
The prevalence of metabolic syndrome increases with age, with about 40% of people older than 60 years meeting the criteria.[19] However, metabolic syndrome can no longer be considered a disease of only adult populations. Alarmingly, metabolic syndrome and diabetes mellitus are increasingly prevalent in the pediatric population, again in parallel with a rise in obesity.[40] In the United States, children are becoming obese at triple the rate compared with the 1960s, making the study and treatment of this problem paramount. The epidemic of metabolic syndrome in children and adolescents is an international phenomenon, leading the International Diabetes Foundation to publish an updated consensus statement to guide diagnosis and further study of the condition. [41, 42]

Prognosis
The complications of metabolic syndrome are broad. Numerous associated cardiovascular complications exist, particularly coronary heart disease, but also atrial fibrillation, [43, 44] heart failure, aortic stenosis,[45] and ischemic stroke.[46] Emerging data suggest an important correlation between metabolic syndrome and risk of stroke.[47] Each of the components of metabolic syndrome has been associated with elevated stroke risk, and evidence demonstrates a relationship between the collective metabolic syndrome and risk of ischemic stroke.[48] The metabolic derangements that characterize metabolic syndrome have been implicated in the development of nonalcoholic fatty liver disease.[49, 50] Indeed, the fatty liver is thought to play an important role in the development of metabolic syndrome. In addition, metabolic syndrome has been implicated in the pathophysiology of several other diseases, including obstructive sleep apnea. Breast cancer has also been linked to metabolic syndrome, possibly through dysregulation of the plasminogen activator inhibitor-1 (PAI-1) cycle.[51] Additional studies have linked metabolic syndrome with cancers of the colon, gallbladder, kidney, and, possibly, prostate gland.[52] Evidence is emerging of an association with psoriasis.[53, 54] Additional research has raised the possibility that metabolic syndrome adversely affects neurocognitive performance.[55] In particular, metabolic syndrome has been blamed for accelerated cognitive aging.[56] Patients with mental illnesses also face increased cardiometabolic risk due at least in part to socioeconomic factors such as greater poverty and poorer access to medical care. [57, 58] In addition, psychological characteristics, including anger, depression, and hostility, may be linked to increased risk of metabolic syndrome.[59] Clearly, further study on these and other complications of metabolic syndrome is warranted.

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