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Metabolic syndrome

Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It affects a great number of people, and prevalence increases with age. Some studies estimate the prevalence in the USA to be up to 25% of the population.

Metabolic syndrome is also known as metabolic syndrome X, syndrome X, insulin resistance syndrome, Reaven's syndrome, and CHAOS (Australia). A similar condition in overweight horses is referred to as equine metabolic syndrome; it is unknown if they have the same etiology.

Signs and symptoms

Symptoms and features are:

Fasting hyperglycemia — diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance;
High blood pressure;
Central obesity (also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist;
Decreased HDL cholesterol;
Elevated triglycerides;

Associated diseases and signs are: elevated uric acid levels, fatty liver (especially in concurrent obesity), progressing to non-alcoholic fatty liver disease, polycystic ovarian syndrome, hemochromatosis (iron overload); and acanthosis nigricans (a skin condition featuring dark patches).

Diagnosis

There are currently two major definitions for metabolic syndrome provided by the International Diabetes Federation and the revised National Cholesterol Education Program, respectively. The revised NCEP and IDF definitions of metabolic syndrome are very similar and it can be expected that they will identify many of the same individuals as having metabolic syndrome. The two differences are that IDF excludes any subject without increased waist circumference, while in the NCEP definition metabolic syndrome can be diagnosed based on other criteria and the IDF uses geography-specific cut points for waist circumference, while NCEP uses only one set of cut points for waist circumference regardless of geography. These two definitions are much closer to each other than the original NCEP and WHO definitions.

WHO

The World Health Organization criteria (1999) require presence of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, AND two of the following:

blood pressure: ≥ 140/90 mmHg
dyslipidaemia: triglycerides (TG): ≥ 1.695 mmol/L and high-density lipoprotein cholesterol (HDL-C) ≤ 0.9 mmol/L (male), ≤ 1.0 mmol/L (female)
central obesity: waist:hip ratio > 0.90 (male); > 0.85 (female), and/or body mass index > 30 kg/m²
microalbuminuria: urinary albumin excretion ratio ≥ 20 mg/min or albumin:creatinine ratio ≥ 30 mg/g

EGIR

The European Group for the Study of Insulin Resistance (1999) requires insulin resistance defined as the top 25% of the fasting insulin values among non-diabetic individuals AND two or more of the following:

central obesity: waist circumference ≥ 94 cm (male), ≥ 80 cm (female)
dyslipidaemia: TG ≥ 2.0 mmol/L and/or HDL-C < 1.0 mmol/L or treated for dyslipidaemia
hypertension: blood pressure ≥ 140/90 mmHg or antihypertensive medication
fasting plasma glucose ≥ 6.1 mmol/L

NCEP

The US National Cholesterol Education Program Adult Treatment Panel III (2001) requires at least three of the following:

central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 36 inches(female)
dyslipidaemia: TG ≥ 1.695 mmol/L (150 mg/dl)
dyslipidaemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female)
blood pressure ≥ 130/85 mmHg
fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dl)

American Heart Association/Updated NCEP

There is confusion as to whether AHA/NHLBI intended to create another set of guidelines or simply update the NCEP ATP III definition. According to Scott Grundy, University of Texas Southwestern Medical School, Dallas, Texas, the intent was just to update the NCEP ATP III definition and not create a new definition.:

Elevated waist circumference:

Men — Equal to or greater than 40 inches (102 cm)
Women — Equal to or greater than 35 inches (88 cm)

Elevated triglycerides: Equal to or greater than 150 mg/dL
Reduced HDL (“good”) cholesterol:

Men — Less than 40 mg/dL
Women — Less than 50 mg/dL

Elevated blood pressure: Equal to or greater than 130/85 mm Hg or use of medication for hypertension
Elevated fasting glucose: Equal to or greater than 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia

Etiology

The cause of the metabolic syndrome is unknown. The pathophysiology is extremely complex and has been only partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. The most important factors in order are:

aging,
genetics and
lifestyle, i.e., low physical activity and excess caloric intake.

There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or if they are consequences of a more far-reaching metabolic derangement. However, metabolic syndrome is not observed in the absence of insulin resistance, while obesity is not present in many individuals who present with metabolic syndrome. A number of markers of systemic inflammation, including C-reactive protein, are often increased, as are fibrinogen, interleukin 6 (IL–6), Tumor necrosis factor-alpha (TNFα) and others. Some have pointed to oxidative stress due to a variety of causes including increased uric acid levels caused by dietary fructose.

Pathophysiology

Commonly there is development of visceral fat after which the adipocytes (fat cells) of the visceral fat increase plasma levels of TNFα and alter levels of a number of other substances (e.g., adiponectin, resistin, PAI-1). TNFα has been shown not only to cause the production of inflammatory cytokines, but possibly to trigger cell signalling by interaction with a TNFα receptor that may lead to insulin resistance . An experiment with rats that were fed a diet one-third of which was sucrose has been proposed as a model for the development of the metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance . The progression from visceral fat to increased TNFα to insulin resistance has some parallels to human development of metabolic syndrome.

Prevention

Various strategies have been proposed to prevent the development of metabolic syndrome. These include increased physical activity (such as walking 30 minutes every day), and a healthy, reduced calorie diet. There are many studies that support the value of a healthy lifestyle as above. However, one study stated that these measures are effective in only a minority of people. The International Obesity Taskforce states that interventions on a sociopolitical level are required to reduce development of the metabolic syndrome in populations.

A 2007 study of 2,375 male subjects over 20 years suggested that daily intake of a pint of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Other studies both support and dispute the authors' findings.

The most obvious method of prevention is undoubtedly to reduce the amount of carbohydrates, specifically fast digesting starches and sugars.

Therapy

The first line treatment is change of lifestyle (i.e., caloric restriction and physical activity). However, drug treatment is frequently required. Generally, the individual disorders that comprise the metabolic syndrome are treated separately. Diuretics and ACE inhibitors may be used to treat hypertension. Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated, and to raise HDL levels if they are low. Use of drugs that decrease insulin resistance e.g., metformin and thiazolidinediones, is controversial; this treatment is not approved by the FDA in the US.

A 2003 study indicated that cardiovascular exercise was therapeutic in approximately 31% of cases. The most probable benefit was to triglyceride levels, with 43% showing improvement; but fasting plasma glucose and insulin resistance of 91% of test subjects did not improve. Many other studies have supported the value of increased physical activity and restricted caloric intake (exercise and diet) to treat metabolic syndrome.

History

The term "metabolic syndrome" dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes, that had been noted as early as the 1920s.

The Marseilles physician Dr. Jean Vague, in 1947, made the interesting observation that upper body obesity appeared to predispose to diabetes, atherosclerosis, gout, and calculi.
Avogaro, Crepaldi and co-workers described six moderately obese patients with diabetes, hypercholesterolemia, and marked hypertriglyceridemia all of which improved when the patients were put on a hypocaloric, low carbohydrate diet.
In 1977, Haller used the term "metabolic syndrome" for associations of obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia and steatosis hepatis when describing the additive effects of risk factors on atherosclerosis.
The same year, Singer used the term for associations of obesity, gout, diabetes mellitus, and hypertension with hyperlipoprotenemia.
In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for myocardial infarction concur to form a "constellation of abnormalities" (i.e., glucose intolerance, hyperinsulinemia, hyperlipidemia [hypercholesterolemia and hypertriglyceridemia] and hypertension) that is associated not only with heart disease, but also with aging, obesity and other clinical states. He suggested there must be an underlying linking factor, the identification of which could lead to the prevention of cardiovascular disease; he hypothesized that this factor was sex hormones.
In 1988, in his Banting lecture, Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities Syndrome X. Reaven did not include abdominal obesity, which has also been hypothesized as the underlying factor, as part of the condition.

The terms "metabolic syndrome," "insulin resistance syndrome," and "syndrome X" are now used specifically to define a constellation of abnormalities that is associated with increased risk for the development of type 2 diabetes and atherosclerotic vascular disease (e.g. heart disease and stroke).

Controversy

The clinical value of the metabolic syndrome has recently come under fire. It is asserted that different sets of conflicting and incomplete diagnostic criteria are in existence, and that diagnosis of the metabolic syndrome has a negligible association with the risk of heart disease.

These concerns have led to the American Diabetes Association and the European Association for the Study of Diabetes to issue a joint statement identifying eight major concerns on the clinical utility of the metabolic syndrome.

It is not contested that cardiovascular risk factors tend to cluster together, but what is contested is the assertion that the metabolic syndrome is anything more than the sum of its constituent parts.