Metabolic syndrome

Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age. Some studies have shown the prevalence in the USA to be an estimated 25% of the population.

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

Definitions and diagnosis
Presently there are a couple of sets of defining criteria for metabolic syndrome set out by two different sources -- the International Diabetes Federation and the revised National Cholesterol Education Program. These are very similar and they identify individuals with a given set of symptoms as having metabolic syndrome. There are two differences, however: the IDF state that if BMI > 30 kg/m2, central obesity can be assumed, and waist circumference does not need to be measured. However, this potentially excludes any subject without increased waist circumference if BMI < 30. Conversely, the NCEP definition indicates that metabolic syndrome can be diagnosed based on other criteria. Also, 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 more similar than the original NCEP and WHO definitions.

IDF
International Diabetes Federation The IDF consensus worldwide definition of the metabolic syndrome (2006)

Central obesity (defined as waist circumference# with ethnicity specific values)

AND any two of the following:


 * Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality.
 * Reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males, < 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality
 * Raised blood pressure: systolic BP > 130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension.
 * Raised fasting plasma glucose :(FPG)>100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes. If FPG >5.6 mmol/L or 100 mg/dL, OGTT Glucose tolerance test is strongly recommended but is not necessary to define presence of the Syndrome.


 * 1) If BMI is >30 kg/m², central obesity can be assumed and waist circumference does not need to be measured

WHO
The World Health Organization criteria (1999) require presence of one of:


 * Diabetes mellitus,
 * Impaired glucose tolerance,
 * Impaired fasting glucose or
 * Insulin resistance;

AND two of the following:
 * Blood pressure: ≥ 140/90 mmHg
 * Dyslipidemia: 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), or body mass index > 30 kg/m2
 * Microalbuminuria: urinary albumin excretion ratio ≥ 20 µg/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)
 * dyslipidemia: TG ≥ 2.0 mmol/L and/or HDL-C < 1.0 mmol/L or treated for dyslipidemia
 * 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)
 * dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dl)
 * dyslipidemia: 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, in 2004, the 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 — greater than 40 inches (102 cm)
 * Women — greater than 35 inches (88 cm)
 * Elevated triglycerides: Equal to or greater than 150 mg/dL (1.7 mmol/L)
 * Reduced HDL (“good”) cholesterol:
 * Men — Less than 40 mg/dL (1.03 mmol/L)
 * Women — Less than 50 mg/dL (1.29 mmol/L)
 * 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

Other
High-sensitivity C-reactive protein (hs-CRP) has been developed and used as a marker to predict coronary vascular diseases in metabolic syndrome and it was recently used as a predictor for non-alcoholic fatty liver disease in correlation with serum markers that indicated lipid and glucose metabolism.

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, observed that upper body obesity appeared to predispose to diabetes, atherosclerosis, gout and calculi.
 * Avogadro, 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 hepatic steatosis 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 hyperlipoproteinemia.
 * 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, hypercholesterolemia, 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).

Etiology
The exact mechanisms of the complex pathways of metabolic syndrome are not yet completely known. The pathophysiology is extremely complex and has been only partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Stress can also be a contributing factor. The most important factors are:
 * 1) weight
 * 2) genetics
 * 3) endocrine disorders, such as polycystic ovary syndrome in women of reproductive age.
 * 4) aging
 * 5) sedentary 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. 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 a variety of causes including increased uric acid levels caused by dietary fructose.

Pathophysiology
It is common for there to be a 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 signaling 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 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. The increase in adipose tissue also increases the number of immune cells present within, which play a role in inflammation. Chronic inflammation contribute to an increased risk of hypertension, artherosclerosis and diabetes.

Stress
Recent research indicates that prolonged stress can be an underlying cause of metabolic syndrome by upsetting the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis). A dysfunctional HPA-axis causes high cortisol levels to circulate which results in raising glucose and insulin levels which cause insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension with direct effects on the bone, causing “low turnover” osteoporosis. HPA-axis dysfunction may explain the reported risk indication of abdominal obesity to cardiovascular disease, type 2 diabetes and stroke. Psychosocial stress is also linked to heart disease.

Overweight and obesity
Central adiposity is a key feature of the syndrome, reflecting the fact that the syndrome's prevalence is driven by the strong relationship between waist circumference and increasing adiposity. However, despite the importance of obesity, patients that are of normal weight may also be insulin-resistant and have the syndrome.

Sedentary lifestyle
Physical inactivity is a predictor of CVD events and related mortality. Many components of metabolic syndrome are associated with a sedentary lifestyle, including increased adipose tissue (predominantly central); reduced HDL cholesterol; and a trend toward increased triglycerides, blood pressure, and glucose in the genetically susceptible. Compared with individuals who watched television or videos or used their computer for less than one hour daily, those that carried out these behaviors for greater than four hours daily have a twofold increased risk of metabolic syndrome.

Aging
Metabolic syndrome affects 44% of the U.S. population older than age 50. With respect to that demographic, the percentage of women having the syndrome is higher than that of men. The age dependency of the syndrome's prevalence is seen in most populations around the world.

Diabetes mellitus
It is estimated that the large majority (~75%, or just above 40 million ) of patients with type 2 diabetes or impaired glucose tolerance (IGT) have metabolic syndrome -. The presence of metabolic syndrome in these populations is associated with a higher prevalence of CVD than found in patients with type 2 diabetes or IGT without the syndrome. Hypoadiponectinemia has been shown to increase insulin resistance, and is considered to be a risk factor for developing metabolic syndrome.

Coronary heart disease
The approximate prevalence of the metabolic syndrome in patients with coronary heart disease (CHD) is 50%, with a prevalence of 37% in patients with premature coronary artery disease ( age 45), particularly in women. With appropriate cardiac rehabilitation and changes in lifestyle (e.g., nutrition, physical activity, weight reduction, and, in some cases, drugs), the prevalence of the syndrome can be reduced.

Lipodystrophy
Lipodystrophic disorders in general are associated with metabolic syndrome. Both genetic (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired (e.g., HIV-related lipodystrophy in patients treated with highly active antiretroviral therapy) forms of lipodystrophy may give rise to severe insulin resistance and many of metabolic syndrome's components.

Schizophrenia and other psychiatric illnesses
Patients with schizophrenia, schizoaffective disorder or bipolar disorder may have a predisposition to metabolic syndrome that is exacerbated by sedentary lifestyle, poor dietary habits, possible limited access to care, and antipsychotic drug-induced adverse effects. It has been found that 32% and 51% of individuals with schizophrenia meet criteria for metabolic syndrome; the prevalence is higher in women than in men.

Rheumatic diseases
There are new findings regarding the comorbidity associated with rheumatic diseases. Both psoriasis and psoriatic arthritis have been found to be associated with metabolic syndrome.

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, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist
 * Decreased HDL cholesterol
 * Elevated triglycerides

Associated diseases and signs are: hyperuricemia, fatty liver (especially in concurrent obesity) progressing to non-alcoholic fatty liver disease, polycystic ovarian syndrome (in women), and acanthosis nigricans.

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 potentially beneficial measures are effective in only a minority of people, primarily due to a lack of compliance with lifestyle and diet changes. 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 (~568 ml) of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Some subsequent studies support the authors' findings, while others dispute them.

Therapy
The first line treatment is change of lifestyle (e.g., Dietary Guidelines for Americans and physical activity). However, if in three to six months of efforts at remedying risk factors prove insufficient, then 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 U.S. Food and Drug Administration.

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.

Restricting the overall dietary carbohydrate intake is more effective in reducing the most common symptoms of metabolic syndrome than the more commonly prescribed reduction in dietary fat intake.

Controversy
The clinical value of using "metabolic syndrome" as a diagnosis has recently come under fire. It is asserted that different sets of conflicting and incomplete diagnostic criteria are in existence, and that when confounding factors such as obesity are accounted for, 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.