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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 actors associated with the development of the metabolic syndrome.
9. Identify three diseases that are thought to be caused by the metabolic syndrome.
10. Identify the basis of treatment of the metabolic syndrome.
11. Identify the two basic approaches used to treat the metabolic syndrome.
12. Identify two lifestyle changes that can be used to treat the metabolic syndrome.
13. 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 vary from 25% to 33% of the US adult population.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. There is some thought that it can be present
in several forms, and there is some disagreement about what clinical signs and laboratory
abnormalities should be used to define the disease.5,6 However, it appears that the basic
cause of metabolic syndrome is two closely related processes: adipose dysfunction and
insulin resistance.7
Adipose Dysfunction
Adipose tissue (commonly called fat) was once though to function simply 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 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 diagnostic criteria were first established. These criteria have been refined
since 1998, and there are now some generally (though 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.
The patient must have at least three of the following in order to meet the criteria for the
presence of metabolic syndrome:16
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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 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 and lifestyle 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.
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.
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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
(using standard risk assessment criteria) to suffer a serious cardiac event (10-year risk
< 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.
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Non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is
define 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 nonprogressive, but it can cause cirrhosis and cancer. NAFLD is often noted in
patients with the metabolic syndrome, although the incidence varies widely.25 The
exact mechanism by which the metabolic syndrome causes NAFLD is not known,
but it is suspected that insulin resistance may be the responsible factor.26 The two
diseases coexisting appear to worsen the clinical course of NALFD, and increase
the risk for developing cardiovascular disease.27
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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
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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 and fatal cancers.31 A large prospective study
found that 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
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Non-insulin dependent diabetes mellitus: The metabolic syndrome is a significant
risk factor for developing non-insulin dependent diabetes mellitus (NIDDM).35,36
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Obstructive sleep apnea: Obstructive sleep apnea (OSA) is common condition
characterized by repetitive upper airway collapse/obstruction during sleep that
causes alternating periods of hypoxia and arousal. Obstructive sleep apnea is very
common among patients with metabolic syndrome: the incidence of OSA in this
population has been reported to be as high as 87.5%.37
Learning Break: Adipose dysfunction and insulin resistance are the two
pathophysiological disorders underlying the metabolic syndrome. Although there has
been research investigating how they contribute to the increased risk of atherosclerosis,
NIDDM, etc., and there are some theories, it is still not know with certainty how this
happens.
Metabolic syndrome has been generally accepted as a separate disease entity. There is
a lot of epidemiological evidence that indicates this clustering of risk factors increases the
risk of developing NIDDM, atherosclerosis, and other diseases beyond what would be
expected simply by the presence of these risk factors by themselves. However, this
viewpoint is not universally accepted. The definition of the metabolic syndrome is still
not universally accepted, and it is also somewhat confusing as the current diagnostic
criteria are a combination of the causes of the metabolic syndrome and its consequences.
Some clinicians feel that the metabolic syndrome cannot be used to predict the
development of these disease states.38,39 It has also been pointed out that there is no
agreed upon cause of the syndrome, and the treatment of the metabolic syndrome would
be no different than the treatment of its component pathologies such as hypertension,
elevated serum triglycerides, etc.40
TREATMENT OF THE METABOLIC SYNDROME
The metabolic syndrome is a serious public health issue. Diabetes and heart disease
cause most of the morbidity and mortality in the United States, and as the percentage of
the population that is obese continues to grow (approximately 1/3 of the population is
considered to be obese and approximately 2/3 are overweight or obese), the problems will
get worse. Factors that have been traditionally used to predict the risk for developing
cardiovascular disease and diabetes may not be adequate for identifying patients who are
at risk for these diseases because they have the metabolic syndrome. This represents a
missed opportunity to prevent serious harm to a large part of the population. Reducing
the incidence of atherosclerosis greatly decreases the risk of heart attack and stroke, and
maintaining good control of serum glucose has been clearly proven to reduce the
incidence of diabetes and reduce the incidence of diabetic complications among those
who already have the disease. The basis of treatment of metabolic syndrome is to
decrease the severity of the diagnostic criteria risk factors.
Learning Break: Using criteria derived from the Framingham Study, a patient who is
considered to be at an intermediate level for experiencing a serious cardiovascular event
(6% to 10% risk of this happening within 10 years) would, if that patient had the
metabolic syndrome, be classified as having a risk level of 10% to 20%. The metabolic
syndrome would double the patient’s risk level beyond what is expected from using
traditional criteria.41
Medications can be used to treat aspects of the metabolic syndrome. Aspirin may need
to be prescribed if the patient’s 10-year risk factor for a cardiovascular event is > 6%.
Hypertension should be managed according to current guidelines. Niacin and other
medications can be use to decrease serum triglycerides. Diabetes is typically treated with
an insulin –sensitizing drug such as metformin. The statin drugs are often prescribed for
dyslipidemia.42
Learning Break: The angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril,
enalapril) and the angiotensin receptor blockers (ARBs, e.g., valsartan, losartan) appear
to be a good choice for treating patients who have the metabolic syndrome and
hypertension. These drugs improve glycemic control; other common anti-hypertensives
do not or actually worsen glycemic control.43
However, because in large part, metabolic syndrome is thought to be caused by
lifestyle factors, treating the metabolic syndrome should also focus very strongly on
therapeutic changes in the patient’s diet, exercise patterns and body weight, etc. These
lifestyle changes are the key to treating the metabolic syndrome. Unfortunately, it is
well known that many people have great difficulty changing these lifestyle habits. Added
to that is the fact that there are essentially no signs and symptoms of the metabolic
syndrome that the patient will notice until the attendant complications are well advanced.
The motivation for change has to come not from any obvious, pressing health problems,
but from the knowledge that there is an ongoing, insidious, and dangerous process that
must be changed. The patient can be helped further by knowing that the metabolic
syndrome is not irreversible. Changing lifestyle habits can be an effective approach for
prevention and reversal of the metabolic syndrome.44 Programs that do this are costly
and resource-intensive, but they can work.
Obesity is the factor that is largely responsible for the development of the metabolic
syndrome. If the patient manages to lose weight, insulin resistance can be modified and
other components of the metabolic syndrome can be improved.45 Caloric restriction is the
most important way to lose weight. Decreasing the daily calorie intake by 500 kcal will
typically – but not always – result in the loss of approximately one pound of body weight
per week. It also appears that what is eaten may be as important as how much is eaten. A
diet that is high is trans-fatty acids and saturated fats increases insulin resistance, while
a diet that is monounsaturated and polyunsaturated fats appear to improve insulin
sensitivity.46 Changing the diet to reflect this can also lower serum triglycerides and raise
HDL-C. Increasing the amounts of fruits and vegetables in the diet may also decrease
systemic inflammation.
Increasing physical activity is an effective way to maintain weight reduction, and there
is a substantial amount of information that physical activity also decreases the risk of
developing the metabolic syndrome by affecting insulin sensitivity.47 Men who are
physically inactive and women who are physically inactive are twice and likely and three
times as likely, respectively, to develop the metabolic syndrome than adults that are
physically active.48 Exercise has been shown to be inversely proportional to the incidence
of the metabolic syndrome: the more an individual exercises, the less chance he/she has
of developing the disease.49 Exercise helps an individual lose weight and maintain a
healthy body weight, it helps increase insulin sensitivity, and it decreases risk factors that
are associated with cardiovascular disease.
Unfortunately, many people find losing weight, keeping the weight off, and exercising
regularly to be very difficult – especially if the individual is overweight/obese and
sedentary. Multiple strategies have been tried to increase participation in and adherence
to healthy diets and exercise programs, but the success rate is typically not high.
SUMMARY
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Metabolic syndrome is a complex disorder of multiple cardiac and metabolic
abnormalities.
Metabolic syndrome is very common: approximately 1/3 of all adults in the
United States have the metabolic syndrome.
Different criteria are used to diagnose the metabolic syndrome, but most
authorities agree that in order to make a diagnosis of metabolic syndrome, an
individual must have at least three of the following: elevated blood pressure,
elevated serum triglycerides, elevated serum glucose, abnormally large waist
circumference, and low HDL-C.
The two pathophysiological processes responsible for the metabolic syndrome are
adipose dysfunction and insulin resistance.
The two processes are closely related. Adipose dysfunction is characterized by a
chronic, low-level of inflammation, and this inflammation may be the cause of the
insulin resistance.
Risk factors that are associated with the development of the metabolic syndrome
include age > 60, hypertension, sedentary lifestyle, obesity (especially central
adiposity, i.e., waist circumference), diabetes mellitus, hypertension, coronary
heart disease, and liopdystrophic disorders.
Metabolic syndrome can be difficult to understand because the risk actors for the
disease are often consequences of the disease.
The presence of the metabolic syndrome greatly increases the risk of developing
atherosclerosis, coronary heart disease, stroke, NIDDM, NAFLD, obstructive
sleep apnea, and several cancers.
It appears that the metabolic syndrome is a separate disease entity. There is a lot
of epidemiological evidence that indicates this clustering of risk factors increases
the risk of developing NIDDM, atherosclerosis, and other diseases beyond what
would be expected simply by the presence of these risk factors by themselves.
Treatment for the metabolic syndrome includes medications for elevated blood
pressure and cholesterol and lipid abnormalities. However, lifestyle changes of
weight loss, regular exercise, and a healthy diet are far more effective.
The metabolic syndrome can be prevented and it can be reversed.
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