METABOLIC SYNDROME
INTRODUCTION
Metabolic syndrome (also known as Syndrome X) is a complex disorder of multiple cardiac and metabolic abnormalities. It is characterized by high fasting serum glucose, an elevated blood pressure, elevated serum triglycerides, low serum high-density lipoprotein (HDL) cholesterol, and a waist circumference significantly above normal. The metabolic syndrome has profound health implications: it increases the risk of developing type 2 diabetes, heart disease, stroke, fatty liver, and some cancers. Metabolic syndrome is common: approximately 1/3 of the population of the United States 20 years of age and older is thought to have metabolic syndrome.
OBJECTIVES
When the student has finished this module, he/she will be able to:
1. Identify the correct definition of the metabolic syndrome.
2. Identify the two pathophysiological disorders involved in the metabolic syndrome.
3. Identify a basic pathophysiological process associated with the metabolic syndrome.
4. Identify three of the diagnostic criteria use to make a diagnosis of metabolic syndrome.
5. Identify the other two diagnostic criteria used to make a diagnosis of metabolic syndrome.
6. Identify a laboratory test that may be useful in confirming a diagnosis of metabolic syndrome.
7. Identify signs and symptoms associated with the metabolic syndrome.
8. Identify three risk factors associated with the development of metabolic syndrome.
9. Identify three risk actors associated with the development of the metabolic syndrome.
10. Identify three diseases that are thought to be caused by the metabolic syndrome.
11. Identify three diseases that are thought to be caused by the metabolic syndrome.
12. Identify the basis of treatment of the metabolic syndrome.
13. Identify the two basic approaches used to treat the metabolic syndrome.
14. Identify two lifestyle changes that can be used to treat the metabolic syndrome.
15. Identify a dietary change that could help treat metabolic syndrome.
EPIDEMIOLOGY
Metabolic syndrome affects all races and ethnic groups, and it is equally common in men and women.1 The incidence of metabolic syndrome increases as people age. Approximately 40% of people 60 years of age or older meet the criteria for the disease.2 The metabolic syndrome also occurs, albeit at a lower rate, in children and adolescents. No one knows how exactly many adults in the US have the metabolic syndrome: estimates for its incidence in the adult population in the US vary from 25% to 33%.3,4 However, there is no doubt that over the past 20 years the incidence of metabolic syndrome has increased, the incidence is expected to continue to increase, and the disease is a very serious public health care issue.
Learning Break: The incidence of metabolic syndrome increases as people age, and it is common in people 60 years of age and older, but it is also seen in children and adolescents. The exact prevalence of metabolic syndrome in children and adolescents appears to vary widely; this is in part because different researchers have used different definitions of the disease when examining for its presence in children and adolescents. It has been reported to be as low as 2% to as high as 60%. There does not seem to be any gender difference in the incidence among children and adolescents.
PATHOPHYSIOLOGY
Metabolic syndrome is a complex disease. It may be present in several forms, and there is disagreement about what clinical signs and laboratory abnormalities should be used to define the disease.5,6 However, it appears that the basic causes of metabolic syndrome are two closely related pathological processes: adipose dysfunction and insulin resistance.7
Adipose Dysfunction
Adipose tissue (commonly called fat) was once though to function simply as insulation and as a storage area for excess calories. It is now known that adipose tissue is very metabolically active and plays an important role as an endocrine organ.8 Fat tissue secretes a wide range of hormones, and cytokines such as interleukin.
When excess calories are consumed in relation to energy expenditure, these calories are stored as fat. People who are obese have excess fat stores. These excess fat stores can, in the metabolic syndrome, become chronically inflamed and this is reflected by elevated levels of C-reactive protein and increased numbers of circulating pro-inflammatory cytokines. It is not clear what triggers this inflammatory process; it is not caused by injury or infection.9 It may be due to hypertrophy and then rupture of the adipose. It may also be due to metabolic stress – caused by the large amounts of adipose that are deposited and must be maintained – that decreases circulation, causes oxidative stress, and causes adipose cell organelle dysfunction.10 Regardless of the mechanism, it is clear that there is a disruption in the homeostasis of the fat tissue in people who are obese, and this leads to a low-level of chronic inflammation.11
Learning Break: C-reactive protein is a protein that is produced in the liver in response to inflammation. It assists in complement binding to damaged cells and helps enhance phagocytosis. C-reactive protein levels are elevated in patients with the metabolic syndrome, and it has been suggested that elevated C-reactive protein levels be added to the diagnostic criteria for metabolic syndrome.
Insulin Resistance
Glucose is the primary source of energy that cells use to form adenosine triphosphate (ATP). The glucose molecule is too large to diffuse through the pores of the cell membrane, and the transport of glucose into the cells is done by insulin. Insulin is a large polypeptide that is secreted by the β cells in the islets of Langerhans in the pancreas. Insulin helps promote the transport of glucose into the liver (where it is stored as glycogen), or into the muscle cells where it is also stored as glycogen or used as an energy source. The process by which insulin promotes glucose entry into the cells is called facilitated diffusion, and it is not completely understood. However, it is thought that when insulin binds to an insulin receptor on a cell membrane, it increases the membrane concentration of a glucose transporter, Glut4. In the normal person, blood glucose is maintained within a narrow range of 80 to 90 mg/dL, and fasting glucose for adults should be < 100 mg/dL.
Insulin resistance is a condition in which the peripheral tissues and the liver have decreased insulin sensitivity; a given amount of insulin produces a less than expected effect on serum glucose. As discussed previously, obesity associated with the metabolic syndrome causes a widespread, low-level inflammation.13 This inflammation is thought to be the major cause of the insulin resistance seen in the metabolic syndrome. The inflammation decreases the number of insulin receptors, inactivates insulin receptors, and directly affects and inhibits the insulin signaling pathways that are initiated when insulin binds to insulin receptors.13,14 (Note: These pathways are complex biochemical processes that increase the membrane concentration of the Glut4 glucose transporter). An excess of circulating fatty acids (very common in obesity) is thought to also play a role in altering insulin signaling pathways.15
DIAGNOSING METABOLIC SYNDROME
The metabolic syndrome was first described many, many decades ago, but it was not until 1998 that the first diagnostic criteria were established. These criteria have been refined since 1998, and there are now generally (but not universally) accepted guidelines that practitioners can use to make the diagnosis of metabolic syndrome.
The National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA) have issued guidelines for the diagnosis of the metabolic syndrome. According to the NHLBI and the AHA, the patient must have at least three of the following in order to diagnosed with the metabolic syndrome:16
· Fasting serum glucose > 100 mg/dL (or receiving drug therapy for hyperglycemia).
· Blood pressure ≥ 135/85 mm Hg (or receiving drug therapy for hypertension).
· Triglycerides ≥ 150 mg/dL (or receiving drug therapy for hypertriglyceridemia).
· High-density lipoprotein cholesterol (HDL-C) < 40 mg/dL, in men; < 50 mg/dL in women (or the patient is receiving drug therapy for elevated HDL-C).
· Waist circumference ≥ 102 cm/40 inches in men; ≥ 88 cm/35 inches in women; if the patient is Asian-American, ≥ 90 cm/35 inches in men; ≥ 80 cm/32 inches in women.
The World Health Organization (WHO) and the International Diabetes Federation (IDF) have also developed diagnostic criteria for the metabolic syndrome. These differ slightly from the NHLBI and AHA criteria – the at-risk level of hypertension is defined as ≥ 140/90 in the WHO criteria – but both the WHO and the IDF criteria look for the same risk factors as the NHLBI and the AHA: waist circumference, blood pressure, HDL-C, fasting serum glucose, and serum triglycerides. There does not appear to be any evidence that one set of criteria is superior to another.
There are no signs and symptoms that are clearly associated with the metabolic syndrome. The problem is made worse by the fact that some physicians are unaware of the metabolic syndrome and as a result it is under-diagnosed.
RISK FACTORS AND CAUSES OF THE METABOLIC SYNDROME
The health, lifestyle, and medical problem factors that increase an individual’s risk of developing the metabolic syndrome include: aging, sedentary lifestyle, obesity (especially central adiposity, i.e., waist circumference), diabetes mellitus, hypertension, coronary heart disease, and liopdystrophic disorders.17 Alcohol abuse may also predispose an individual to development of the metabolic syndrome.
The use of some atypical/second-generation anti-psychotics may also be a risk factor, but this is not definite and the nature and extent of their contribution to the disease is not clear. Major depression has been postulated as increasing the risk for developing the metabolic syndrome, but the evidence for this is considered very weak. Some researchers have suggested that there is an association between Helicobacter pylori infection and the metabolic syndrome, but this has not been proven to date.
Learning Break: Metabolic syndrome can be difficult to understand because many of the risk factors for developing the syndrome are also, themselves, a consequence of the metabolic syndrome. However, not everyone with diabetes or coronary heart disease, or who is obese, etc. will develop the metabolic syndrome. The metabolic syndrome however, increases the risk of developing these diseases.
DISEASES ASSOCIATED WITH THE METABOLIC SYNDROME
The metabolic syndrome can have a devastating impact on health. Aside from increasing the chances of developing atherosclerosis, type 2 diabetes, etc., people with the metabolic syndrome typically have a shorter life span than those without the disease.
The presence of the metabolic syndrome increases the risk for developing the following diseases.
· Athersclerosis/coronary heart disease: The metabolic syndrome can increase an individual’s risk of developing atherosclerosis and coronary heart disease between 1.5 and threefold.18 The risk of developing sub-clinical atherosclerosis is also increased by the presence of the metabolic syndrome, and the greater the number of diagnostic criteria present the greater the risk.19 The risk factors for atherosclerosis and coronary heart disease are often present in patients with the metabolic syndrome, and they are also present in patients without the metabolic syndrome, too. But patients with these risk factors and the metabolic syndrome have a much higher risk of developing cardiovascular disease, suggesting that there are other pathological processes involved in the development of cardiovascular diseases that are specific to the metabolic syndrome.20,21 The risk of suffering a stroke and developing peripheral vascular disease is also increased by the presence of the metabolic syndrome.22,23,24
Learning Break: The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study found that men who were considered unlikely to suffer a serious cardiac event (using a standard risk assessment and a 10-year risk of < 5%) who had the metabolic syndrome had three times the number of fatal cardiovascular events as those men with a similar risk profile who did not have the metabolic syndrome.
Learning Break: Hypertension is a risk factor for developing the metabolic syndrome. However, like these other risk factors, it may also be a consequence of the disease. For example, oxidative stress caused by dysfunctional adipose tissue may decrease nitric oxide (an endogenous vasodilator) and there may also be increased sympathetic tone caused by increased levels of circulating fatty acids.
· Non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is defined as a fatty liver (liver fat > 5%-10% of total liver weight) that is not caused by alcohol consumption. The clinical course of NAFLD is often benign and non-progressive, but it can cause cirrhosis and cancer. NAFLD is often noted in patients with the metabolic syndrome, but the incidence varies widely.25 The exact mechanism by which the metabolic syndrome causes NAFLD is not known, but insulin resistance may be responsible.26 The two diseases coexisting appear to worsen the clinical course of NALFD and increase the risk for developing cardiovascular disease.27
· Colorectal cancer: There is a large amount of epidemiologic research that has linked the metabolic syndrome and colon cancer.28 The risk of developing colorectal cancer can increase up to 75% if the patient has the metabolic syndrome and the greater the body mass index (BMI) and the greater number of risk factors associated with the metabolic syndrome present in any individual, the greater the risk becomes.29 Multiple, complex mechanisms are probably responsible for the increased risk of colorectal cancer in the presence of the metabolic syndrome: insulin resistance, chronic/low-level inflammation, increased cell proliferation, and decreased cell apoptosis are among the possible causes.30
· Other cancers: Obesity is a well-known risk factor for developing certain cancers. As well, elevated glucose levels have been associated with an increased risk of developing cancers, both incident cancers and fatal cancers.31 A large prospective study found that with each additional increase of 1.1mmol/l increment of serum glucose (approximately 18 mg/dL), the risk of developing cancer increased 5% for men and 11% for women.32 There is also some limited information that suggests that the metabolic syndrome acts as a risk factor for the development of breast cancer and prostate cancer.33 In one study that reviewed the health history of over 2000 men, the presence of the metabolic syndrome significantly increased the risk of developing prostate cancer.34
· Non-insulin dependent diabetes mellitus: The metabolic syndrome is a significant risk factor for developing type 2, non-insulin dependent diabetes mellitus (NIDDM).35,36