Metabolic syndrome

Metabolic syndrome is a combination of medical disorders that affect a large number of people in a clustered fashion. In some studies, the prevalence in the USA is calculated as being up to 25% of the population, the end result of which is to increase one's risk for cardiovascular disease and diabetes.

Nomenclature
Other names for this syndrome are:
 * Syndrome X;
 * Metabolic syndrome X;
 * Insulin resistance syndrome;
 * Reaven's Syndrome, after Dr Gerald M. Reaven (who brought attention to the syndrome in 1988 in the Banting lecture, itself named after diabetes pioneer Sir Frederick Banting);
 * CHAOS (Australia);
 * Wohlstandssyndrom (German).

It is not related to:
 * Fragile X syndrome (a chromosomal abnormality);
 * Cardiac syndrome X &mdash; this term is now mainly used for a type of angina pectoris where there is cardiac ischemia on exercise testing but no causative atherosclerosis on a coronary angiogram.

Signs and symptoms
Symptoms and features are:
 * Fasting hyperglycemia &mdash; Diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance or insulin resistance;
 * High blood pressure;
 * Central obesity also known as visceral adiposity;
 * Decreased HDL cholesterol;
 * Elevated triglycerides
 * Elevated Uric acid levels

Associated diseases are:
 * Fatty liver (especially in concurrent obesity).
 * Polycystic ovarian syndrome;
 * Hemochromatosis (iron overload);
 * Acanthosis nigricans (a skin condition featuring dark patches);
 * Non-alcoholic steatohepatitis (extreme form of fatty liver).

Diagnosis
The above diseases are all diagnosed separately; please see the relevant articles. The Adult Treatment Panel III of the United States National Cholesterol Education Program (2001, 2005) defined the diagnosis as three or more of the following five: This was followed by a definition from the International Diabetes Federation (IDF) in May, 2005 (3) – apparently intended to replace the 1999 WHO definition. 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 requires increased waist circumference, while NCEP does not and the IDF uses geography-specific cutpoints for waist circumference, while NCEP uses only one set of cutpoints for waist circumference regardless of geography. These two definitions are much closer to each other than the original NCEP and WHO definitions.
 * Increased waist circumference (>=102 cm in men and >=88 cm in women), indicating central obesity
 * Elevated triglycerides (>=150 mg/dL or 1.7 mmol/l)
 * Decreased HDL cholesterol (<40 mg/dL or 1.03 mmol/l for men, <50 mg/dL or 1.29 mmol/l for women)
 * Blood pressure above 130/85 or active treatment for hypertension
 * Glucose levels above 100 mg/dL (5.6 mmol/l) or active treatment for hyperglycemia

Pathophysiology
The causes of metabolic syndrome are extremely complex and have only been partially elucidated. Most patients are older, obese and have a degree of insulin resistance. There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or a by-product of a more far-reaching metabolic derangement. Systemic inflammation: a number of inflammatory markers (including C-reactive protein) are often increased, as are fibrinogen, InterLeukin&minus;6 (IL&minus;6), Tumor Necrosis Factor alpha (TNFα) and others. Some have pointed to oxidative stress due to dietary fructose mediated increased uric acid levels.

Commonly, there is development of visceral fat followed by the adipocytes (fat cells) of the visceral fat increasing plasma levels of TNFα. TNFα has been shown to not only cause the production of inflammatory cytokines, but may also 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. Relevance of such studies for humans remains unclear.

1. 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/or 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

2. 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 mg/dL or treated for dyslipidaemia – hypertension: blood pressure ≥ 140/90 mmHg or antihypertensive medication – fasting plasma glucose ≥ 6.1 mmol/L

3. The National Cholesterol Education Program Adult Treatment Panel III (2001) requires at least three of the following: – central obesity: waist circumference ≥ 102 cm (male), ≥ 88 cm (female) – dyslipidaemia: TG ≥ 1.695 mmol/L – dyslipidaemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female) -- blood pressure ≥ 130/85 mmHg – fasting plasma glucose ≥ 6.1 mmol/L

Therapy
The main treatment is lifestyle (i.e., caloric restriction and physical activity). However, drug treatment may occasionally be necessary. Generally, the individual diseases that comprise the metabolic syndrome are treated separately (e.g. diuretics and ACE inhibitors for hypertension). Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated. Use of drugs that decrease insulin resistance e.g., metformin and thiazolidinediones is controversial and generally not an approved use.

History
The term "metabolic syndrome" dates back to at least the late 1950's, but came into common usage in the late 1970's to describe various associations of risk factors with diabetes, that had been noted as early as the 1920's.
 * The Marseilles physician, Dr. Jean Vague, in 1956, 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, Dr. 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, Dr. 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). Its etiology remains unknown.