COURSE OBJECTIVE: The purpose of this course is to provide the healthcare professional with a review of metabolic syndrome, including measurements, laboratory tests, causes, potential consequences, and preventive measures.
Upon completion of this course, you will be able to:
Define metabolic syndrome.
Identify two key findings on physical examination that indicate possible metabolic syndrome.
Name three laboratory values that indicate possible metabolic syndrome.
Define insulin resistance.
Discuss the two most serious consequences of developing metabolic syndrome.
Describe two major lifestyle changes that can help treat and prevent metabolic syndrome.
Metabolic syndrome is the name for a particular cluster of health problems first identified in 1988 by Gerald Reaven, a Stanford University endocrinologist, in a lecture to the American Diabetes Association (Reaven et al., 2000). At various times, this syndrome has been called dysmetabolic syndrome, insulin resistance syndrome, obesity dyslipidemia syndrome, and syndrome X. (Now simply known as metabolic syndrome, the “X” was dropped because of confusion with a cardiac syndrome having a similar designation.)
At its core, metabolic syndrome is characterized by the presence of obesity and insulin resistance, a reduced responsiveness of the body tissues to insulin. Associated disorders of metabolic syndrome are high blood pressure and two lipid problems: high blood levels of triglycerides and low blood levels of high-density lipoprotein cholesterol (HDL). Having metabolic syndrome quintuples the individual’s chance of developing type 2 diabetes and doubles the chance of developing coronary heart disease.
Metabolic syndrome has become increasingly common in the United States, and it is a major public health problem. An estimated 47 million American adults, or roughly 35% of the adult population, are affected (AHA, 2011a; AHA, 2011b), and these people incur almost 1.6 times the medical costs of those without metabolic syndrome. A recent study found that individuals with metabolic syndrome averaged $5,732 a year in medical expenses, whereas those without the syndrome averaged $3,581 a year in medical expenses. For those with both diabetes and metabolic syndrome risk factors, annual medical costs were nearly double, compared to individuals who did not have diabetes but had risk factors for metabolic syndrome ($8,067 vs. $4,638) (Boudreau et al., 2009).
The treatment of choice for metabolic syndrome is weight reduction and increased physical activity.
WHAT IS METABOLIC SYNDROME?
The Phenomenon of Insulin Resistance
In the early 1920s, the Canadian surgeon Frederick Banting and his assistant Charles Best, a medical student, extracted from the islets of Langerhans in the pancreas a compound that they named insulin. When injected into diabetic dogs, this compound decreased the level of sugar in the dogs’ blood and reduced the amount of sugar in the dogs’ urine. Before the discovery and purification of insulin, childhood diabetes was a fatal disease; after Banting and Best’s work, diabetes became a chronic illness.
As early as the 1930s, clinicians found that people with diabetes could be divided into two classes according to how they reacted to an injection of insulin. “Insulin-sensitive” diabetics (who tended to be young and prone to developing ketosis, a build-up of ketone bodies in body tissues and fluids, leading to nausea, vomiting, and stomach pain) easily disposed of an oral dose of glucose when they also received a subcutaneous insulin injection. In contrast, “insulin-insensitive” diabetics (who were usually middle-aged and who did not have ketotic episodes) did not significantly reduce their blood glucose levels after receiving the same amount of insulin.
Today, insulin-sensitive diabetics are categorized as type 1 diabetics. In type 1 diabetes, the pancreas produces little or no insulin because the beta cells in the islets of Langerhans of the pancreas are not functioning. Type 1 diabetes shows up most commonly in young people, although it can occur in any age group.
On the other hand, insulin-insensitive diabetics are categorized as type 2 diabetics. Type 2 diabetes usually shows up in older adults, but it can occur at any age. A distinguishing feature of type 2 diabetes is that, even when there is a normal amount of circulating insulin, body tissues do not take up glucose as readily as normal. This is called insulin resistance, a condition in which normal concentrations of insulin in the blood produce less than the normal effects in the body.
At first, insulin resistance was thought of in terms of diabetes. Later, however, insulin resistance began to be recognized in patients who did not have diabetes. Many of these insulin-resistant people also had certain other systemic problems—notably obesity, hypertension, lipid disorders, and coronary heart disease. Insulin resistance was also found to be common in women with polycystic ovarian syndrome (PCOS) (a disorder of the ovaries caused by numerous small cysts in both ovaries and characterized by absent menstruation, sterility, obesity, and a distribution of body hair more characteristic of men).
In the 1980s, researchers stepped back from their focus on diabetes and realized that insulin resistance frequently occurred as part of a particular cluster of systemic metabolic disorders. This cluster includes:
High blood levels of triglycerides
Low blood levels of high-density lipoprotein (HDL) cholesterol
High blood pressure
Looking back, researchers discovered that a similar cluster of metabolic problems had already been identified as a special health risk in the 1920s. Putting all the data together in the late 1980s, clinicians proposed that it would be useful to call this cluster of metabolic disorders a syndrome and give it a name.
Is Metabolic Syndrome a Single Disease?
The group of problems collected under the heading metabolic syndrome does not seem to have one unique cause and does not involve a clear-cut target organ or system. For this reason, some scientists have wondered whether it is necessary to separate out this particular cluster of disorders and give it the status of a syndrome. Most clinicians, however, believe that the formal recognition of metabolic syndrome is justified.
Proponents point out that identifying metabolic syndrome is a strong warning of future health problems in an individual. In particular, if metabolic syndrome remains untreated, the patient is likely to develop serious cardiovascular disease and type 2 diabetes. An important feature of the clinical definition of metabolic syndrome is that it uses a small set of direct measurements—waist circumference; blood pressure; and the blood levels of triglycerides, high-density lipoproteins, and glucose—that allows the syndrome to be diagnosed simply and objectively.
The medical problems in a person with metabolic syndrome are complex and interrelated. Nonetheless, the definition of metabolic syndrome offers a clear therapeutic path for lessening a person’s chance of developing coronary heart disease and diabetes. All components of metabolic syndrome can be treated by exercising regularly, improving eating habits, and staying thin. In those cases where therapeutic lifestyle changes are insufficient, the definition of metabolic syndrome gives clinicians a specific set of disorders (obesity, blood pressure, dyslipidemias, and hyperinsulinemia) to treat individually.
Establishing metabolic syndrome as an entity also focuses attention on certain key malfunctioning processes in the bodies of people who are on the road to serious health problems. Identifying the five disorders that compose metabolic syndrome gives scientists important targets for basic research, drug development, and therapeutic innovation.
The creation of a single entity called metabolic syndrome has many practical benefits. At the same time, doctors caution that metabolic syndrome is a creation of convenience. As currently defined, metabolic syndrome is a good but not an ideal predictor of the chance of developing serious health problems. Research continues, and it is likely that the definition of metabolic syndrome will be modified in the future.
A Formal Definition
Metabolic syndrome is not a disease in the usual sense. Instead, it is a condition, a collection of problems impacting the body’s ability to maintain circulation of useful but not excessive levels of energy molecules (i.e., glucose and lipids) in the bloodstream. Initially, when these problems arise, they interact to worsen each other. Eventually, the set of problems becomes severe enough to lead to serious health consequences. At this point, clinicians say that a person has metabolic syndrome.
It is still not clear whether any one of the individual problems of metabolic syndrome is the primary cause. More likely, two or more of the problems develop independently and then set off the condition. In any case, current definitions are not based on cause. Instead, they have been developed by looking for clusters of signs and symptoms in people who later developed coronary heart disease or type 2 diabetes.
From studies of large populations of people, the most common cluster of signs has been found to include obesity, insulin resistance, dyslipidemia (either too much or too little fat in the blood), and hypertension. As of 2007, a universally accepted set of criteria for identifying metabolic syndrome was still being worked out. The two major competing definitions are outlined in the box below (Grundy et al., 2005; Lorenzo et al., 2007; Sandhofer et al., 2007).
DEFINING METABOLIC SYNDROME
2002 National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III)
Metabolic syndrome includes at least three of the following:
Abdominal obesity: Waist circumference >102 cm (>40 in) in men, >88 cm (>35 in) in women
Hypertriglyceridemia: Blood triglycerides >150 mg/dl (or on triglyceride-lowering medication)
Low high-density lipoprotein cholesterol (HDL): Blood HDL-C <40 mg/dl in men, <50 mg/dl in women
High blood pressure: BP >130/85 mm Hg or already diagnosed with hypertension
High fasting glucose: Blood glucose >100 mg/dl or already diagnosed with type 2 diabetes
2005 International Diabetes Federation (IDF)
Metabolic syndrome includes:
Abdominal obesity: Waist circumference >94 cm (>37 in) in men, >80 cm (>31.5 in) in women
And at least two of the following:
Hypertriglyceridemia: Blood triglycerides >150 mg/dl (or on triglyceride-lowering medication)
Low high-density lipoprotein cholesterol (HDL): Blood HDL-C <40 mg/dl in men, <50 mg/dl in women (or on HDL-C-lowering medication)
High blood pressure: BP ≥130/85 mm Hg or already diagnosed with hypertension
High fasting glucose: Blood glucose ≥100 mg/dl or already diagnosed with type 2 diabetes
The essential difference between the two definitions is the importance placed on abdominal fat. The NCEP/ATP III criteria identify some people as having metabolic syndrome even if they do not have excess abdominal girth. In contrast, the IDF criteria consider large abdominal girth (in this case, waist circumference >37 inches for men or >31.5 inches for women) to be a necessary component of the syndrome. Some studies have shown that the use of the IDF criteria misses identifying a small percentage (5–7%) of people (specifically, people without a large waist size) who will go on to develop atherosclerotic cardiovascular disease or diabetes.
Are demographics helpful in recognizing metabolic syndrome? The race or gender of a person who walks into the clinic is no help in determining whether that person has metabolic syndrome. The person’s age is not much help, either. Older people are more likely than young people to have the disorder, but 1 in 20 teenagers have metabolic syndrome. Prevalence does vary in different populations, but the syndrome is too common everywhere to use demographics as a discriminator in clinical practice.
Adolescents (12–19 years)
An estimated 2.9 million adolescents in the United States—or 9.4% of those aged 12 to 19 years— have metabolic syndrome. It is more common in adolescent boys (13.2%) than in adolescent girls (5.3%), and in Mexican-American (11.1%) and white adolescents (10.7%) than in African-American adolescents (5.2%). Among overweight or obese adolescents, the prevalence of metabolic syndrome is much higher: 44% (Cook et al., 2008). The criteria for diagnosis of metabolic syndrome in adolescents and children are adjusted for age.
Overweight teenagers who do not have metabolic syndrome remain at risk for developing it. Obesity—especially excess intra-abdominal fat—in childhood and adolescence foreshadows higher than normal blood levels of insulin, triglycerides, and LDL cholesterol; low blood levels of HDL cholesterol; and high blood pressure in adulthood.
Adults (19 years and older)
An estimated 35.1% of American men and 32.6% of American women have metabolic syndrome. The syndrome is more common in older adults. It is found, for example, in 20.3% of men and 15.6% of women aged 20–39 years. Among adults aged 40–59 years, the prevalence of metabolic syndrome rises to 40.8% in men and to 37.2% in women. The syndrome affects more than half (51.5% of men, 54.4% of women) of Americans aged 60 years and older (AHA, 2010).
Prevalence of metabolic syndrome varies markedly from country to country. This seems to be caused by two factors: (1) variations in lifestyle (especially, diet, smoking, and level of physical exercise) between countries, and (2) variations in ethnicity. In all settings and all populations, the prevalence of metabolic syndrome increases with age.
As in adolescents, the association of metabolic syndrome and race/ethnicity varies by sex. Among men, the estimated prevalence of metabolic syndrome is 37.2%, 25.3%, and 33.2% for white Americans, African Americans, and Mexican Americans, respectively. Among women, the corresponding percentages are 31.5%, 38.8%, and 40.6% (Ervin, 2009).
Immigrant Asian Indians in the United States also have a high prevalence of metabolic syndrome, ranging from 26.9% (using the NCEP/ATP III definition) to 38.2% (IDF definition) (Misra et al., 2009).
DIAGNOSING METABOLIC SYNDROME
Diagnosing metabolic syndrome requires a physical examination and blood tests. Nonetheless, the medical history offers important information that can confirm the diagnosis and help determine the extent of the problem.
A person who has metabolic syndrome may already have been diagnosed with some components of the syndrome, such as obesity, hypertension, or dyslipidemia. A major complication of the syndrome (atherosclerotic artery disease, ischemic heart disease, diabetes) may also be present.
In addition, the person may come with a diagnosis (or the signs and symptoms) of one of a number of other medical problems that occur especially frequently with metabolic syndrome. Diseases that are often found with metabolic syndrome include:
Gout: Almost two thirds of people with gout have metabolic syndrome (Choi et al., 2007).
Polycystic ovarian syndrome (PCOS): More than one third of women with PCOS have metabolic syndrome (Cussons et al., 2008).
Systemic lupus erythematosus (SLE): An estimated 16% to 32% of women with SLE have metabolic syndrome (Bultink et al., 2008; Chung et al., 2007).
Fatty liver disease (Moore, 2010)
Chronic kidney disease
Obstructive sleep apnea or other sleep disturbance disorders
Subclinical hypothyroidism (low normal T4 levels)
Mild cognitive impairment in older adults
Faster than normal prostate growth rate in benign prostatic hyperplasia (BPH)
Any of these problems should alert one to the possibility of metabolic syndrome.
A 65-year-old male being treated for hypertension comes to the office for a bimonthly appointment. After stepping onto a scale, he is found to have gained 7 pounds over the past two months. The nurse therefore measures his waist circumference, which is 108 cm, and draws some of his blood for a lipids assessment. When asked how well he has been adhering to his antihypertensive medication regimen, the patient admits that he has not been taking his medication every day, and he appears to have trouble remembering his doctor’s name as well as his doctor’s instructions.
The nurse suspects mild cognitive impairment along with metabolic syndrome and writes a note to the doctor to have the patient evaluated for cognitive function, including Alzheimer’s disease. Three days later the results of the blood test show blood triglycerides of 158 mg/dl and an HDL cholesterol level of 36 mg/dl.
The patient is diagnosed with metabolic syndrome; he is started on appropriate therapy and instructed on incorporating lifestyle interventions (e.g., diet, exercise). Additionally, the nurse asks the patient’s wife to monitor her husband’s behavior for signs of possible cognitive impairment and to help her husband remember to take his medication.
Two Key Physical Characteristics
When screening for metabolic syndrome, two physical measurements must be included: waist circumference and blood pressure.
Today, the standard physical examination of a patient includes height and weight but it does not usually include a measurement that is essential for diagnosing metabolic syndrome: the patient’s waist circumference. Over the last 8 to 10 years, it has been shown that the specific aspect of obesity that best warns of future cardiovascular problems is the amount of fat concentrated inside the abdomen (Gonzalez et al., 2007; Rasouli et al., 2007; Phillips & Prins, 2008), and waist circumference is a good measure of intra-abdominal fat.
Obesity is a condition identified with having more stored body fat than is considered normal. Clinically, obesity is measured indirectly. The simplest obesity tables compare two external physical measurements—height and weight—and obese is then defined as “more than the normal weight for a given height.”
The most commonly used measure of obesity is the body mass index (BMI). This is measured using the formula:
BMI = weight in kilograms / height in meters2
BMI = weight in pounds x 703 / height in inches2
BMI has been shown to be a good indirect indication of the percentage of body fat, and it is the most commonly used measure of total body fat.
When weight is measured in kilograms and height in meters, the BMI obesity definitions for adults are as follows:
OBESITY DEFINITIONS: BMI (kg/m2) Normal 18.5–24.9
Obese Class 1 30.0–34.9
Class 2 35.0–39.9
Class 3 (extreme obesity) >40.0
Obese people are more likely than people of normal weight to suffer from certain medical problems, including diabetes, hypertension, dyslipidemias, polycystic ovarian syndrome, degenerative joint disease, sleep apnea, cancer (specifically, breast, colon, endometrial, prostatic), gastroesophageal reflux disease, fatty liver disease, and gallstones. For class 3 (extremely) obese people, the list is longer.
All overweight people have an increased risk of developing metabolic syndrome. In overweight and class 1 obese people, the risk of having or developing metabolic syndrome is much greater if their excess fat is located inside the abdomen (i.e., visceral).
When excess fat is concentrated in the abdomen, a person will have a round, apple shape. This is called android obesity, and, of all shapes, it is the most strongly predictive of metabolic syndrome–related conditions such as diabetes, hypertension, dyslipidemias, and atherosclerotic cardiovascular disease. (Another common shape of obesity has excess fat concentrated lower on the body, in the hips and thighs. This gives a person a pear shape and is called gynecoid obesity.)
Measuring Waist Circumference
Many large studies have shown that simply measuring a person’s waist circumference gives a good indication of the amount of excess body fat that is located inside the abdomen. A waist circumference of >94 cm (37 in) in men and >80 cm (31.5 in) in women is considered a warning sign, and a circumference of >102 cm (40 in) in men and >88 cm (35 in) in women puts the person in the high or very high risk category for developing metabolic syndrome and its serious health consequences.
In addition to being an indicator for metabolic syndrome, increased waist circumference is correlated with other health problems. These include decreased pulmonary functioning, lessened quality of life, increased disability in older adults, increased osteoarthritis in the knees, increased likelihood of asthma, increased risk of colon cancer, and increased risk of age-related macular degeneration.
The waist is the narrow band of the abdomen below the lowest margin of the ribs and above the top (iliac crest) of the hipbones. Three slightly different locations have been used when measuring a person’s waist size:
Halfway between the lowest margin of the ribs and the top of the hip bones
At the level of the umbilicus
The smallest (minimal) circumference anywhere in the waist region
The latter—the minimal waist circumference—has been found to be the best when making a diagnosis of metabolic syndrome (Willis et al., 2007).
A 42-year-old woman has come to the office for her first appointment. She appears to be obese, with an android shape, prompting the nurse to measure her waist circumference, which is 92 cm. After weighing the patient and measuring her height, the nurse calculates the patient’s BMI as 35.2 kg/m2. The nurse draws some blood and sends the sample to the lab for a lipids assessment. When asked about her recent medical history, the patient reports having pain in her joints, occasional difficulty in breathing, excessive thirst, and having to get up several times during the night to urinate. The nurse suspects metabolic syndrome with possible coexisting osteoarthritis and asthma and writes a note to the physician to have her evaluated for all three conditions.
HIGH BLOOD PRESSURE
The second component of metabolic syndrome that can be picked up in a physical exam is high blood pressure. To be used as a diagnostic condition for metabolic syndrome, a person’s blood pressure must be >130/85 mm Hg. (If a person is already taking antihypertensive medication, it is assumed that his or her blood pressure would normally be >130/85 mm Hg.)
Hypertension is defined as blood pressure of >140/90 mm Hg. As with most clinical measurements, the blood pressure values found in people grade smoothly between the healthy and the unhealthy ranges. The boundary of 140/90 mm Hg was chosen because it is at this value that, on average, the benefits of treatment outweigh the risks. The risks of living with hypertension include stroke, myocardial infarction, heart failure, peripheral vascular disease, aortic dissection, and chronic renal failure.
Hypertension has been referred to as a silent killer because, unless they are told their blood pressure measurements, people are usually unaware of any problem. Hypertension is a chronic illness that is largely asymptomatic until it leads to heart, brain, or kidney damage.
Prehypertension is the borderline region of blood pressures of 120 to 139 mm Hg systolic and 80 to 89 mm Hg diastolic (NHLBI, 2011a). Prehypertension warns of future health risks; for example, people with prehypertension are twice as likely to progress to hypertension when compared to people with lower blood pressures.
BLOOD PRESSURE RANGES (mm Hg) Systolic Diastolic
Optimal <120 <80
Prehypertension 120–139 80–89
Hypertension >140 >90
Epidemiologic studies have shown that prehypertension (specifically, >130/85 mm Hg, or being on medication to lower blood pressure) is a sufficient criterion for making a diagnosis of metabolic syndrome (NHLBI, 2011b).
Measuring Blood Pressure
The basic rule is: “Measure on more than one occasion.” Blood pressure varies dramatically throughout a 24-hour period, and blood pressure will be raised by stress, recent meals, and recent physical activity. To take variation into account, two or more readings on two or more different days are needed to estimate a person’s usual blood pressure.
Other basic rules for measuring blood pressure include:
Setting. The patient should have had no caffeine or tobacco for at least 30 minutes and must have been sitting or lying quietly for at least 5 minutes. When blood pressure readings are taken, the patient should be sitting or lying with the back supported. The arm from which the reading is taken should be resting and supported, and it should be positioned horizontally at the level of the patient’s heart.
Cuff size. Large or overweight adults need a large-size adult cuff.
Technique. Begin by palpating the radial artery as the cuff is inflated. The radial pulse will disappear at the systolic value. Continue to inflate the cuff 20 mm Hg beyond that point. Put the bell of the stethoscope lightly over the brachial artery next to the lower edge of the cuff. Deflate the cuff slowly, at a rate of 3 to 5 mm Hg/sec, noting the pressure at which the first sound is heard (the systolic value) and at which the last sound disappears (the diastolic value).
Take two or more readings during an exam, separated by at least 5 minutes of rest. Then take the pressure in the other arm.
The 42-year-old female patient from the previous case returns for a follow-up appointment. At her previous appointment, her blood pressure was found to be 187/93 mm Hg. The nurse measures the patient’s blood pressure once again; this time the reading is 189/94 mm Hg. By now the patient’s blood test results have come in, and they show blood triglycerides of 155 mg/dl and an HDL cholesterol level of 43 mg/dl. The nurse concludes that the patient has metabolic syndrome and counsels her on appropriate diet and exercise as well as on adhering to her prescribed medication regimen to control her condition.
It is important to look at two factors that contribute to metabolic syndrome: insulin resistance and dyslipidemias. In evaluating a patient, laboratory information should include both fasting glucose levels and fasting lipid profiles.
ASSESSING INSULIN RESISTANCE
Among the various measurements of the body’s ability to produce and use glucose, the blood level of glucose after an 8-hour fast is probably the simplest. Fasting glucose levels are a well-calibrated standard that is now widely used to screen for insulin resistance, a common cause of diabetes.
Diabetes mellitus is an endocrine disease that disrupts the body’s energy metabolism. In diabetes there is an insufficient amount of insulin available to the cells, and therefore glucose is not used efficiently throughout the body. One cause of the insulin insufficiency can be a reduced production of insulin by the beta cells in the pancreas (i.e., type 1 diabetes); another cause can be a reduced effect of the available insulin, known as insulin resistance (i.e., type 2 diabetes). Both causes can occur in the same person.
Without sufficient effective insulin, body tissues cannot take up all the glucose that is circulating in the bloodstream, and a hallmark of diabetes is hyperglycemia, the presence of more than the normal amount of glucose in the blood. After an 8-hour fast, the body should maintain blood glucose levels at <110 mg/dL, typically in the range of 95–100 mg/dL. Diabetes is diagnosed when any one of the following hyperglycemic conditions is present:
Fasting blood glucose level is found to be ≥126 mg/dL*
Hemoglobin A1C level (an index measuring the amount of glucose sticking to hemoglobin inside red blood cells, and which indicates a person’s average blood glucose level over the past two to three months) is ≥6.5%*
Two-hour plasma glucose level is ≥200 mg/dl in an oral glucose tolerance test (OGTT)*
Random plasma glucose level is ≥200 mg/dl, accompanied by classic symptoms of hyperglycemia or hyperglycemic crisis
* In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing (ADA, 2011)
GLUCOSE METABOLISM Category Fasting Blood Glucose (mg/dL)
High normal 101–109
Hyperglycemia (impaired maintenance of glucose levels) 110–125
Hyperglycemia, a fasting glucose level of >110 mg/dL, can result from a variety of causes. The two most common causes are decreased secretion of insulin and insulin resistance. Less common causes include a generalized increased activity of the sympathetic nervous system (e.g., during stress) or an increased secretion of glucagon (a pancreatic hormone), epinephrine (an adrenal hormone also known as adrenaline), cortisol (a steroid hormone produced by the adrenal cortex), or growth hormone (a pituitary hormone that stimulates growth of the body and that influences metabolism of proteins, carbohydrates, and lipids).
Although insulin resistance and not hyperglycemia is considered a key problem in metabolic syndrome, the biochemical diagnosis of insulin resistance is technically difficult. Large epidemiologic studies have shown that the presence of fasting hyperglycemia can be used as a surrogate for demonstrating the insulin resistance of metabolic syndrome. Both the NCEP/ATP III and the IDF definitions of metabolic syndrome agree that a fasting blood glucose of >110 mg/dL can be used as one criterion for diagnosing the syndrome.
The four main classes of lipids (fats) found in the bloodstream are fatty acids, triglycerides, phospholipids, and cholesterol. By themselves, lipids do not dissolve in blood. In the circulation, lipids are transported in lipoproteins, soluble packets built around special protein carrier molecules.
Dyslipidemias are conditions in which the bloodstream contains unhealthy amounts of lipids. The dyslipidemias of metabolic syndrome are: (1) elevated blood levels of triglycerides, and (2) reduced blood levels of high-density lipoproteins (HDL). Metabolic syndrome is often accompanied by additional dyslipidemias, although these abnormalities are not necessary for the diagnosis of the syndrome.
CLASSIFICATION OF BLOOD LIPID LEVELS Blood Concentrations (mg/dL)*
Triglycerides Normal <150
Borderline high 150–199
HDL cholesterol Low <40
LDL cholesterol Optimal <100
Borderline high 130–159
*Measured after an 8-hour fast
Metabolic syndrome is characterized by fasting blood triglycerides >150 mg/dL and fasting blood HDL cholesterol <40 mg/dL in men and <50 mg/dL in women.
Two Possible Coexistent Diagnoses
Patients with intra-abdominal obesity, high fasting glucose levels, high blood pressure, high blood levels of triglycerides, and low blood levels of HDL cholesterol have metabolic syndrome and should be treated. Yet it is important to remember that a patient may simultaneously have other diseases with similar or overlapping symptoms. Two specific disorders to keep in mind are Cushing syndrome and hypothyroidism.
Cushing syndrome is caused by excess glucocorticoid (any of a group of steroid hormones that are produced by the adrenal cortex and are involved in protein, carbohydrate, and fat metabolism)—either excess intrinsic cortisol (as is produced by the adrenal glands in Cushing disease) or excess extrinsic glucocorticoids (e.g., prednisone), which might have been prescribed to treat another disorder. Typically, a person with Cushing syndrome has weight gain, skin striae (stretch marks), hirsutism, and proximal muscle weakness.
As in metabolic syndrome, Cushing syndrome leads to central (as opposed to peripheral) obesity, although the fat in Cushing syndrome tends to be most noticeable on the back of the neck, upper shoulders, and in the cheeks. Cushing syndrome also includes hypertension, elevated blood glucose levels, and dyslipidemias, including an elevated level of blood triglycerides. Moreover, patients with Cushing syndrome are more susceptible to cardiovascular disease.
Hypothyroidism is caused by a decreased secretion of thyroid hormone from the thyroid gland, slowing metabolic processes throughout the body. People who have hypothyroidism are typically slow talking, slow to respond, tired, and depressed. Their skin is cool and dry, they look apathetic, they have slow reflexes, and they are constipated. Often, they have an enlarged thyroid gland.
As in metabolic syndrome, people with hypothyroidism tend to be overweight and inactive. They also have dyslipidemia and, sometimes, mild hypertension. Moreover, patients with hypothyroidism are more likely than normal to have cardiovascular disease. On the other hand, unlike metabolic syndrome, low blood glucose levels are typical of hypothyroidism.
The patient is a 55-year-old male recently diagnosed with metabolic syndrome. The nurse has not previously met the patient, but when he arrives in the office, the nurse immediately notices that the patient is obese and is carrying excess fat in his cheeks, upper shoulders, and back of the neck. Additionally, the patient appears tired and is slow to respond to the nurse’s questions. The nurse suspects Cushing syndrome and hypothyroidism and writes a note to the physician to have the patient evaluated for both conditions.
CAUSES OF METABOLIC SYNDROME
In some diseases, the initiating events act on a common target. For example, most of the causes of type 1 diabetes act, ultimately, to disable the beta cells in the pancreas. In contrast, metabolic syndrome appears to result from the interaction of a number of disorders that can be initiated separately.
Currently, scientists believe that both obesity and insulin resistance are critical problems underlying metabolic syndrome and that the two problems can develop independently. It is still unclear whether the dyslipidemias and the hypertension of metabolic syndrome can trigger the syndrome or are, instead, consequences of the interaction of obesity and insulin resistance.
Although the specific chain of events leading to the appearance of metabolic syndrome is still not clear, much is known about the development and interactions of its separate components. Here is a summary of the causes of the individual components of metabolic syndrome.
GENETICS AND LIFESTYLE
The tendency to be obese is heritable, and genes are usually part of the cause of a person’s obesity. In rare cases, a single gene can cause obesity; in most cases, obese people have more than one contributory gene.
In addition to an inherited metabolic tendency to be overweight, eating patterns that a person develops are key causes of excess weight gain. Aspects of a person’s eating patterns are learned, but other parts are inborn and probably genetic. Normally, a number of proteins, hormones, and neural signals communicate with the hunger and satiety centers in the brain. These biochemical cues are triggered by fullness of the stomach, the presence of food in the small intestine, and the levels of fat and glucose in the blood. In many obese people, the food signals do not work properly, and these people’s brains do not recognize when they have eaten a sufficient meal. This “satiety blindness” leads to overeating and weight gain.
Regular consumption of sugar-sweetened beverages is another risk factor for diabetes and metabolic syndrome. In a meta-analysis of eleven studies involving more than 310,000 individuals evaluated for diabetes and more than 19,000 for metabolic syndrome, those who drank one to two 12-ounce servings per day of sugar-sweetened beverages increased their risk of developing type 2 diabetes by 26% and of developing metabolic syndrome by 20%, compared to those who drank less than one serving per month (Malik et al., 2010).
The nurse enters the waiting room and calls the patient’s name. The patient, a 47-year-old man who appears overweight, is holding a large beverage cup, from which he is sipping through a straw. He puts down the cup and gets up slowly from his chair. The nurse asks him what he was drinking, and he tells her it was a sugar-sweetened soft drink, which he likes to drink every day. The nurse ushers the patient into an examination room, whereupon she measures the patient’s weight, waist circumference, and blood pressure, all of which are suggestive of metabolic syndrome. The nurse notes these measurements in the patient’s chart and takes a blood sample for assessment of lipids and glucose before sending the patient in to confer with his doctor.
Prenatal: The non-genetic contributions to a person’s obesity can start in the womb. For example, a fetus who is undernourished in the first two trimesters of pregnancy will have a higher than normal chance of becoming an obese adult.
Psychological: Depression, especially when part of bipolar disorder, can lead to excess eating and weight gain. Emotional, physical, and sexual abuse can also lead to obesity.
Pharmacologic: Many medications have weight gain as a side effect, and it is important to monitor persons taking these medications. They include:
Psychiatric drugs (e.g., lithium, “atypical” antipsychotics such as clozapine and olanzapine, and antidepressants such as the tricyclics)
Neurologic drugs (e.g., antiepileptic drugs such as valproate)
Steroids (e.g., hormonal contraceptives and prednisone)
Anti-diabetic drugs (e.g., insulin)
Diseases: Diseases cause less than 1% of the obesity in the United States. The most common of these diseases are endocrine disorders, such as Cushing’s syndrome.
Insulin triggers the mechanisms that cells use to take up glucose from their surroundings. In addition, insulin tells cells to:
Use their internal glucose for generating energy
Store any excess internal glucose in the form of glycogen
Stop releasing internal stores of glucose into the circulation
The body’s cells have specialized roles in metabolism. Most of the body’s glucose uptake, oxidation, and storage are carried out in skeletal muscle cells and in fat cells. On the other hand, most of the release of stored glucose into the circulation comes from liver cells. Insulin is the signal to all these cells.
Insulin molecules remain outside cells, and they work by interacting with specific receptors on (and in) a cell’s membrane. Once activated, the receptor molecules encourage glucose transport into the cell. The insulin receptors also set off a cascade of events inside the cell. This internal cascade regulates the cell’s oxidation of glucose and lipids, storage and release of glucose, and a host of other processes, including the transport and metabolism of amino acids, protein synthesis, cell growth, cell differentiation, and even cell death.
In a person with insulin resistance, a normal amount of circulating insulin produces:
Less than the normal amount of glucose transport into cells
Reduced use (metabolism) of intracellular glucose
Reduced storage of excess internal glucose in the form of glycogen
Increased glucose release into the circulation (mainly, by the liver)
In insulin resistance, the basic problem lies in the responding cells, specifically, in the mechanisms by which these cells recognize insulin and then produce the intracellular effects of the insulin signal.
The insulin receptor molecule in the membrane of the responding cell is a complex structure with a number of subunits. The malfunctioning or mutation of any of the receptor subunits can make them work inefficiently or make them insensitive to insulin, leading to insulin resistance. Insulin resistance can also be caused by the malfunctioning of any of the components of the intracellular cascade that connects the insulin receptors in the cell membrane to the glucose-processing machinery inside the cell.
As with many pathologic processes, insulin resistance develops most readily in people with a genetic predisposition for it. In predisposed people, it is possible that certain genes produce poorly functioning insulin receptor subunits or other molecules in the intracellular chain leading from the receptor to the actual glucose utilization machinery. It is still not clear, however, if any of these potential problems are common causes of the genetic predisposition to develop insulin resistance.
EXCESS VISCERAL FAT
Intra-abdominal fat is strongly associated with insulin resistance—more so than is extra-abdominal (subcutaneous) fat. Intra-abdominal fat is largely visceral fat, and an overabundance of visceral fat cells will cause insulin resistance.
Visceral fat cells are more responsive than other fat cells to signals from the sympathetic nervous system, which causes the breakdown and release of intracellular fat stores. At the same time, visceral fat cells are less responsive than other fat cells to insulin, which signals them to slow or stop the breakdown and release intracellular fat stores. In other words, visceral fat cells are easy to turn on and difficult to turn off.
The effect of too many visceral fat cells is too much free fatty acid in the bloodstream. High levels of free fatty acids stimulate the liver to release excess glucose into the bloodstream. High levels of free fatty acids also reduce the amount of glucose taken up by cells throughout the body, even when there is sufficient insulin available. The result of both of these effects is hyperglycemia. The pancreas responds to hyperglycemia by secreting more insulin, so, at least temporarily, hyperglycemia always leads to hyperinsulinemia.
If it had been subcutaneous fat cells that were releasing the excess fatty acids, the newly released insulin would turn off the spigot by slowing or stopping the fatty acid release. Visceral fat cells, however, are less sensitive to insulin signals, and the feedback circuit is not very effective when visceral fat cells are the culprits. When visceral fat is the source of excess free fatty acids, the natural balancing mechanisms do not work well, and the hyperinsulinemia persists. This persistent hyperinsulinemia is a direct cause of insulin resistance.
This sequence of events leads to insulin resistance:
Persistent elevation of circulating free fatty acids causes hyperglycemia.
Persistent hyperglycemia causes hyperinsulinemia.
Persistent hyperinsulinemia causes insulin resistance.
Insulin resistance can be triggered by anything that causes high blood levels of free fatty acids, glucose, or insulin. Conditions that lead to insulin resistance through this mechanism include high levels of glucocorticoids (e.g., Cushing’s disease or long-term treatment with prednisone), nonalcoholic fatty liver disease, and treatment with protease inhibitors (e.g., for HIV).
In the bloodstream, most lipids are carried in lipoproteins, a group of conjugated proteins in which at least one of the components is a lipid. The surface of a lipoprotein is made up of the more water-soluble lipids, cholesterol and phospholipids. The least soluble lipids, cholesteryl esters and triglycerides, are carried in the centers of the lipoproteins. This spherical package is held together by apolipoproteins, which are specialized fat-carrying proteins.
Lipoproteins come in five sizes. From the largest to the smallest, they are:
VLDL (very low density)
IDL (intermediate density)
LDL (low density)
HDL (high density)
Each size of lipoprotein has its own characteristic balance of lipids. The largest lipoproteins—chylomicrons and VLDL—are especially rich in triglycerides, while 70% of all blood cholesterol is contained in the LDL lipoproteins.
HDL lipoproteins are the second main carriers of cholesterol. HDL particles have a special role: they are cholesterol scavengers. HDL particles remove cholesterol from nonliver cells, such as fibroblasts and macrophages, and transport the cholesterol back to the liver. Because the cholesterol in HDL particles is unavailable for new atherosclerotic plaque formation, HDL lipoproteins can slow or even reverse cholesterol buildup throughout the vascular system.
Dyslipidemia is an unhealthy amount of lipid circulating in the bloodstream. The specific dyslipidemias of metabolic syndrome include an increase in blood triglycerides and a decrease in blood HDL lipoproteins.
A number of different genetic mutations that affect fat cells will cause the dyslipidemias of metabolic syndrome. In addition, certain genetic mutations of apolipoproteins (e.g., familial combined hyperlipidemia) will cause high blood levels of triglycerides and low blood levels of HDL cholesterol.
Beyond direct genetic causes, the dyslipidemias of metabolic syndrome can result from a variety of problems.
The most common causes of dyslipidemias are other metabolic problems. For example, glycogen storage diseases and hypothyroidism each elevate the levels of blood triglycerides. Insulin resistance and excess visceral fat elevate blood triglycerides and lower blood HDL cholesterol, and type 2 diabetes and poorly controlled type 1 diabetes will do the same.
The same habits that tend to make a person obese will also cause lipid problems. Dyslipidemias can result from insufficient physical activity and a high-calorie diet with excess carbohydrates and too many saturated fats.
Patients with chronic renal failure develop high blood triglycerides and decreased levels of blood HDL cholesterol. Later, if they receive kidney transplants, patients are put on immunosuppressive drugs, typically glucocorticoids and cyclosporine; these drugs also raise blood triglycerides and reduce blood HDL cholesterol.
Blood triglycerides are increased by retinoic acid, estrogens, and thiazide diuretics. Corticosteroids, immunosuppressive drugs, and beta-blockers increase triglyceride levels and also lower HDL cholesterol levels.
Blood pressure depends on two factors: cardiac output (how much blood is ejected with each heartbeat) and vascular resistance (how much opposition the bloodstream encounters from arteries and veins).
The first factor, cardiac output, depends on blood volume, which is normally regulated by the kidneys. The second factor, vascular resistance, is normally regulated by a balance of vasoconstrictors (e.g., angiotensin II, sympathetic nervous system activity) and vasodilators (e.g., prostaglandins, nitric oxide). High blood pressure can be caused by an increase in cardiac output, an increase in vasoconstriction, or a combination of the two factors.
Among the individual problems that constitute metabolic syndrome, obesity and insulin resistance directly cause hypertension. In addition to weight gain and excess salt intake, stress, smoking, and physical inactivity can cause or worsen hypertension.
The tendency toward hypertension is inherited. In most cases, this predisposition seems to depend on the interaction of a number of different genes.
The chance of having high blood pressure increases continuously as one gets heavier. At least two features of obesity lead directly to hypertension. First, obese people have a larger volume of blood, and therefore they have a higher than normal cardiac output. Second, obese people have overactive sympathetic nervous systems. This causes water and salt retention, which increases the blood volume. An overactive sympathetic nervous system will also increase the constriction of peripheral arteries, which increases vascular resistance. Obesity can also cause sleep apnea, which causes hypertension.
For genetically predisposed people, excess salt in their diets will cause hypertension.
The kidneys affect blood pressure by regulating both cardiac output and vascular resistance. Kidneys can adjust the blood volume by changing the reabsorption of sodium and water, and they can adjust the level of vasoconstriction through the renin-angiotensin system.
Hyperinsulinemia causes hypertension by way of the kidneys. Hyperinsulinemia increases the kidneys’ reabsorption of sodium and water and, in this way, increases the blood volume and the potential for hypertension.
Other Risk Factors
For most pregnant women, a healthy pregnancy modestly increases the risk of metabolic syndrome even after accounting for excess weight gain and reduced physical activity. In a study of 1,451 women (of whom 706 had no births and 745 had at least one birth in the past 20 years), those who had children and maintained normal blood sugars were more likely to develop metabolic syndrome later in life; these women’s risk increased with their number of children (33% for one birth, 62% for two or more births). However, those same women did not have a higher risk of type 2 diabetes compared to non-child-bearing women. For women who have had gestational diabetes, the risk of developing metabolic syndrome was 2.4 times greater than that in non-child-bearing women; women who had gestational diabetes were also 4 times more likely to develop diabetes later in life (Gunderson et al., 2009).
URINARY SYMPTOMS IN MEN
Men with mild to severe lower urinary tract symptoms (LUTS) are at increased risk for developing metabolic syndrome, compared to those without such symptoms. A study of nearly 1,900 men showed that so-called “voiding” symptoms—incomplete emptying of the bladder, weak urine stream, intermittency (starting and stopping a urine stream), and straining to urinate—were significantly associated with metabolic syndrome. However, there was no such association between metabolic syndrome and “storage” symptoms such as urgency (the urgent need to urinate), frequency of urination, and nocturia (waking during the night to urinate) (Kupelian et al., 2009).
HEALTH CONSEQUENCES OF METABOLIC SYNDROME
People who have metabolic syndrome tend to have many associated health problems, although it is not always known whether the person’s metabolic syndrome is the direct cause. Two serious medical problems that are the direct result of long-term metabolic syndrome are coronary heart disease and type 2 diabetes.
Coronary Heart Disease
The most striking risk posed by metabolic syndrome is coronary heart disease (also known as coronary artery disease or atherosclerotic cardiovascular disease). By themselves, the dyslipidemias of metabolic syndrome (i.e., high triglycerides and low HDL cholesterol levels) encourage plaque to form along the walls of arteries. When combined with the other components of metabolic syndrome, these atherogenic dyslipidemias (i.e., those that tend to cause atherosclerotic plaque) put a person at high risk for developing serious atherosclerotic vascular disease with coronary artery blockage.
Metabolic syndrome also worsens heart failure, and even when no heart disease is apparent, metabolic syndrome makes a person more likely to develop certain arrhythmias (notably, paroxysmal atrial fibrillation or flutter).
Type 2 Diabetes
Metabolic syndrome is a precursor to type 2 diabetes. The mechanism is as follows: The insulin resistance of metabolic syndrome forces the pancreas to secrete higher than normal amounts of insulin. Meanwhile, some hyperglycemia persists even with the excess circulating insulin. The continuous hyperglycemia and hyperinsulinemia are toxic to the beta cells in the pancreas and over time these cells sicken and the amount of insulin that they produce decreases. Eventually, the pancreas cannot cope with hyperglycemia, and the patient develops diabetes.
A person with diabetes is at risk for serious health problems. Diabetes causes end-stage renal disease. Diabetes is also the most common cause of nontraumatic amputations and is a major cause of blindness in adults. Nerve damage (diabetic neuropathy) occurs in 60% to 70% of people with diabetes. In addition, people with diabetes are approximately 2 to 4 times more likely to have heart disease and stroke than those without diabetes. (CDC, 2011a)
Other Disorders Associated with Metabolic Syndrome
People with metabolic syndrome are at risk for a long list of health problems. It is not always clear whether metabolic syndrome is the cause or whether the problems share common causes with the components of metabolic syndrome. In all cases, however, the presence of metabolic syndrome indicates a higher than normal risk that a person will also have:
Renal disease and microalbuminuria
Atherosclerotic plaques in the carotid arteries
Left ventricular hypertrophy
Polycystic ovarian syndrome
Nonalcoholic fatty liver disease
Low testosterone levels in men
The individual components of metabolic syndrome would not always be treated if found in isolation. For example, these values are below the levels that mandate treatment if the person has no other risk factors:
Blood pressure: 130–139/85–89 mm Hg
Fasting blood glucose: 110–125 mg/dL
Blood triglycerides: 150–199 mg/dL
When found together with other risk factors, and especially when they are found to be part of metabolic syndrome, these values signal the need for treatment. Metabolic syndrome lowers the threshold for the treatment of its components.
Treatment of the components of metabolic syndrome begins with lifestyle changes. Because lifestyle changes are easy to prescribe but difficult to carry out, often medications must be added to ensure that the treatment regimens succeed.
Therapeutic Lifestyle Changes
Therapeutic lifestyle changes, such as increased physical exercise, improved diet, and weight reduction, are the cornerstones of the treatment of obesity, hypertension, insulin resistance, and most dyslipidemias. Reducing dietary calories and fats (especially saturated fats) and increasing exercise can significantly reduce the risk of developing diabetes and atherosclerotic cardiovascular disease.
All aspects of metabolic syndrome benefit from increased physical activity. Physical exercise helps in losing weight and in maintaining weight loss, and it has additional independent metabolic effects that directly reduce insulin resistance. Physical activity is usually a safe and beneficial treatment for people with metabolic syndrome and its consequences, atherosclerotic cardiovascular disease and type 2 diabetes. Even patients with end-stage renal disease can benefit from physical training programs.
Both aerobic and resistance exercise are effective therapies. For most people, the recommendation is to do moderately intense activity for 2 hours and 30 minutes a week, or vigorously intense activity for 75 minutes a week, or an equivalent combination of moderately and vigorously intense aerobic physical activity. Aerobic activity should be performed in episodes of at least 10 minutes, preferably spread throughout the week (U.S. DHHS, 2008). Although a program of regular exercise does not typically reduce LDL cholesterol levels to a significant degree, it will reduce insulin resistance and blood levels of triglycerides, and it will increase blood levels of HDL cholesterol.
Exercise alone rarely leads to significant weight loss. A reduced-calorie diet is usually necessary, and dieting is the second critical part of the initial treatment of metabolic syndrome. Overweight people with metabolic syndrome must reduce the number of calories that they eat each day.
Simply reducing the overall calories in the diet will improve the lipid profile. Reducing the amount of fat improves the lipid profile even further. It is especially important to remove foods that are high in saturated fats, such as:
Fatty meats (e.g., bacon, sausage)
Chicken or turkey eaten with the skin
Lard and shortening
Hydrogenated vegetable oils
Coconut oil, palm oil, and cocoa butter
Cream, half-and-half, and ice cream
Cookies, cakes, muffins, and pastries