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422
ceptible persons. Compared with individuals who watch television or
The Metabolic Syndrome videos or use the computer <1 h daily, those who do so for >4 h daily
Robert H. Eckel have a twofold increased risk of the metabolic syndrome.
Aging The metabolic syndrome affects nearly 50% of the U.S. popula-
tion older than age 50, and at >60 years of age women are more often
The metabolic syndrome (syndrome X, insulin resistance syndrome)
affected than men. The age dependency of the syndrome’s prevalence
consists of a constellation of metabolic abnormalities that confer
is seen in most populations around the world.
increased risk of cardiovascular disease (CVD) and diabetes mellitus.
Evolution of the criteria for the metabolic syndrome since the original Diabetes Mellitus Diabetes mellitus is included in both the NCEP
definition by the World Health Organization in 1998 reflects growing and the harmonizing definitions of the metabolic syndrome. It is
clinical evidence and analysis by a variety of consensus conferences estimated that the great majority (~75%) of patients with type 2 dia-
and professional organizations. The major features of the metabolic betes or impaired glucose tolerance have the metabolic syndrome. The
syndrome include central obesity, hypertriglyceridemia, low levels presence of the metabolic syndrome in these populations relates to a
2450 TABLE 4221 NCEP:ATPIIIa 2001 AND HARMONIZING DEFINITION CRITERIA FOR THE METABOLIC SYNDROME
NCEP:ATPIII 2001 Harmonizing Definitionb
Three or more of the following: Three of the following:
t $FOUSBMPCFTJUZXBJTUDJSDVNGFSFODFDN .
DN '
t 8BJTUDJSDVNGFSFODF DN
higher prevalence of CVD than in patients who have type 2 diabetes or patients receiving antiretroviral therapy) may give rise to severe insulin
impaired glucose tolerance but do not have this syndrome. resistance and many of the components of the metabolic syndrome.
Cardiovascular Disease Individuals with the metabolic syndrome are
twice as likely to die of cardiovascular disease as those who do not, ETIOLOGY
PART 16
and their risk of an acute myocardial infarction or stroke is three- Insulin Resistance The most accepted and unifying hypothesis to
fold higher. The approximate prevalence of the metabolic syndrome describe the pathophysiology of the metabolic syndrome is insulin
among patients with coronary heart disease (CHD) is 50%, with a resistance, which is caused by an incompletely understood defect in
prevalence of ~35% among patients with premature coronary artery insulin action (Chap. 417). The onset of insulin resistance is heralded
disease (before or at age 45) and a particularly high prevalence among by postprandial hyperinsulinemia, which is followed by fasting hyper-
women. With appropriate cardiac rehabilitation and changes in life- insulinemia and ultimately by hyperglycemia.
style (e.g., nutrition, physical activity, weight reduction, and—in some An early major contributor to the development of insulin resistance
Endocrinology and Metabolism
cases—pharmacologic therapy), the prevalence of the syndrome can is an overabundance of circulating fatty acids (Fig. 422-2). Plasma
be reduced. albumin-bound free fatty acids are derived predominantly from
adipose-tissue triglyceride stores released by intracellular lipolytic
Lipodystrophy Lipodystrophic disorders in general are associated with enzymes. Fatty acids are also derived from the lipolysis of triglyceride-
the metabolic syndrome. Both genetic lipodystrophy (e.g., Berardinelli- rich lipoproteins in tissues by lipoprotein lipase. Insulin mediates
Seip congenital lipodystrophy, Dunnigan familial partial lipodystro- both antilipolysis and the stimulation of lipoprotein lipase in adipose
phy) and acquired lipodystrophy (e.g., HIV-related lipodystrophy in tissue. Of note, the inhibition of lipolysis in adipose tissue is the most
sensitive pathway of insulin action. Thus, when insulin resistance
develops, increased lipolysis produces more fatty acids, which further
Metabolic syndrome components decrease the antilipolytic effect of insulin. Excessive fatty acids enhance
100 substrate availability and create insulin resistance by modifying down-
Men stream signaling. Fatty acids impair insulin-mediated glucose uptake
90
Women and accumulate as triglycerides in both skeletal and cardiac muscle,
80 whereas increased glucose production and triglyceride accumulation
take place in the liver.
70
Leptin resistance has also been raised as a possible pathophysiologic
% of subjects
CLINICAL FEATURES obstructive sleep apnea and weight-matched controls, insulin resis-
Symptoms and Signs The metabolic syndrome typically is not associ- tance is found to be more severe in those with apnea. Continuous posi-
ated with symptoms. On physical examination, waist circumference tive airway pressure treatment improves insulin sensitivity in patients
may be expanded and blood pressure elevated. The presence of either with obstructive sleep apnea.
or both of these signs should prompt the clinician to search for other
biochemical abnormalities that may be associated with the metabolic DIAGNOSIS
syndrome. Less frequently, lipoatrophy or acanthosis nigricans is The diagnosis of the metabolic syndrome relies on fulfillment of the
found on examination. Because these physical findings characteristi- criteria listed in Table 422-1, as assessed using tools at the bedside
cally are associated with severe insulin resistance, other components and in the laboratory. The medical history should include evaluation
of the metabolic syndrome should be expected. of symptoms for obstructive sleep apnea in all patients and polycystic
ovary syndrome in premenopausal women. Family history will help
Associated Diseases t CARDIOVASCULAR DISEASE The relative risk for new- determine risk for CVD and diabetes mellitus. Blood pressure and
onset CVD in patients with the metabolic syndrome who do not have waist circumference measurements provide information necessary for
diabetes averages 1.5–3 fold. However, an 8-year follow-up of middle- the diagnosis.
aged participants in the Framingham Offspring Study documented
that the population-attributable CVD risk in the metabolic syndrome Laboratory Tests Measurement of fasting lipids and glucose is needed
was 34% among men and only 16% among women. In the same study, in determining whether the metabolic syndrome is present. The
both the metabolic syndrome and diabetes predicted ischemic stroke, measurement of additional biomarkers associated with insulin resis-
with greater risk among patients with the metabolic syndrome than tance can be individualized. Such tests might include those for ApoB,
among those with diabetes alone (19% vs. 7%) and a particularly large high-sensitivity C-reactive protein, fibrinogen, uric acid, urinary
difference among women (27% vs. 5%). Patients with the metabolic microalbumin, and liver function. A sleep study should be performed
syndrome are also at increased risk for peripheral vascular disease. if symptoms of obstructive sleep apnea are present. If polycystic ovary
syndrome is suspected on the basis of clinical features and anovulation,
5:1& %*"#&5&4 Overall, the risk for type 2 diabetes among patients testosterone, luteinizing hormone, and follicle-stimulating hormone
with the metabolic syndrome is increased three- to fivefold. In the should be measured.
Framingham Offspring Study’s 8-year follow-up of middle-aged par-
ticipants, the population-attributable risk for developing type 2 diabe-
tes was 62% among men and 47% among women. TREATMENT THE METABOLIC SYNDROME
Other Associated Conditions In addition to the features specifically LIFESTYLE SEE ALSO CHAP. 416
associated with the metabolic syndrome, other metabolic alterations Obesity is the driving force behind the metabolic syndrome. Thus,
accompany insulin resistance. Those alterations include increases weight reduction is the primary approach to the disorder. With
in ApoB and ApoCIII, uric acid, prothrombotic factors (fibrinogen, weight reduction, improvement in insulin sensitivity is often accom-
plasminogen activator inhibitor 1), serum viscosity, asymmetric panied by favorable modifications in many components of the
metabolic syndrome. In general, recommendations for weight loss Metabolic or bariatric surgery is an option for patients with the 2453
include a combination of caloric restriction, increased physical metabolic syndrome who have a body mass index >40 kg/m2, or
activity, and behavior modification. Caloric restriction is the most >35 kg/m2 with comorbidities. An evolving application for metabolic
important component, whereas increases in physical activity are surgery includes patients with a body mass index as low as 30 kg/m2
important for maintenance of weight loss. Some but not all evi- and type 2 diabetes. Gastric bypass or vertical sleeve gastrectomy
dence suggests that the addition of exercise to caloric restriction results in dramatic weight reduction and improvement in the fea-
may promote greater weight loss from the visceral depot. The tures of the metabolic syndrome. A survival benefit with gastric
tendency for weight regain after successful weight reduction under- bypass has also been realized.
scores the need for long-lasting behavioral changes.
Diet Before prescribing a weight-loss diet, it is important to LDL CHOLESTEROL SEE ALSO CHAP. 421
emphasize that it has taken the patient a long time to develop an The rationale for the NCEP:ATPIII’s development of criteria for the
expanded fat mass; thus, the correction need not occur quickly. metabolic syndrome was to go beyond LDL cholesterol in identify-
Given that ~3500 kcal = 1 lb of fat, ~500-kcal restriction daily ing and reducing the risk of CVD. The working assumption by the
equates to weight reduction of 1 lb per week. Diets restricted in panel was that LDL cholesterol goals had already been achieved
carbohydrate typically provide a rapid initial weight loss. However, and that increasing evidence supports a linear reduction in CVD
after 1 year, the amount of weight reduction is minimally reduced or events as a result of progressive lowering of LDL cholesterol with
no different from that with caloric restriction alone. Thus, adherence statins. For patients with the metabolic syndrome and diabetes, a
to the diet is more important than which diet is chosen. Moreover, statin should be prescribed. For those patients with diabetes and
there is concern about low-carbohydrate diets enriched in saturated known CVD, the current evidence supports a maximum of penulti-
fat, particularly for patients at risk for CVD. Therefore, a high-quality mate dose of a potent statin (e.g., atorvastatin or rosuvastatin). For
dietary pattern—i.e., a diet enriched in fruits, vegetables, whole those patients with the metabolic syndrome but without diabetes,
grains, lean poultry, and fish—should be encouraged to maximize a score that predicts a 10-year CVD risk exceeding 7.5% should also
overall health benefit. take a statin. With a 10-year risk of <7.5%, use of statin therapy is not
evidence based.
Physical Activity Before a physical activity recommendation is pro-
Diets restricted in saturated fats (<7% of calories) and trans-
vided to patients with the metabolic syndrome, it is important to
fats (as few as possible) should be applied aggressively. Although
ensure that the increased activity does not incur risk. Some high-risk
less evidence exists, dietary cholesterol should also be restricted.
patients should undergo formal cardiovascular evaluation before
If LDL cholesterol remains elevated, pharmacologic intervention
without the metabolic syndrome. mediated glucose uptake in muscle and adipose tissue. Benefits of
both drugs have been seen in patients with nonalcoholic fatty liver
BLOOD PRESSURE SEE ALSO CHAP. 298 disease and polycystic ovary syndrome, and the drugs have been
The direct relationship between blood pressure and all-cause mor- shown to reduce markers of inflammation.
tality rate has been well established in studies comparing patients
Endocrinology and Metabolism