of high-density lipoprotein (HDL) cholesterol, hyperglycemia, and 2449
absorption by almost 60%, resulting in a reduction in delivery of
dietary sterols in the liver and an increase in hepatic LDL receptor
expression. The mean reduction in plasma LDL-C on ezetimibe
(10 mg) is 18%, and the effect is additive when used in combina-
tion with a statin. Effects on TG and HDL-C levels are negligible.
When used in combination with a statin, monitoring of liver
transaminases is recommended. The only roles for ezetimibe in
monotherapy are in patients who do not tolerate statins and in
sitosterolemia.
BILE ACID SEQUESTRANTS RESINS Bile acid sequestrants bind bile acids
in the intestine and promote their excretion rather than reabsorp-
tion in the ileum. To maintain the bile acid pool size, the liver
diverts cholesterol to bile acid synthesis. The decreased hepatic
intracellular cholesterol content results in upregulation of the LDL
receptor and enhanced LDL clearance from the plasma. Bile acid
sequestrants, including cholestyramine, colestipol, and colesevelam
(Table 421-5), primarily reduce plasma LDL-C levels but can cause
an increase in plasma TGs. Therefore, patients with hypertriglyceri-
demia generally should not be treated with bile acid–binding resins.
Cholestyramine and colestipol are insoluble resins that must be
suspended in liquids. Colesevelam is available as tablets but gener-
ally requires up to six to seven tablets per day for effective LDL-C
lowering. Most side effects of resins are limited to the gastrointes-
tinal tract and include bloating and constipation. Because bile acid
sequestrants are not systemically absorbed, they are very safe and
the cholesterol-lowering drug of choice in children and in women
of childbearing age who are lactating, pregnant, or could become
pregnant. They are effective in combination with statins and in
combination with ezetimibe and are particularly useful with one or
both of these drugs for patients with severe hypercholesterolemia or
those with statin intolerance.
SPECIALIZED DRUGS FOR HOMOZYGOUS FH Two “orphan” drugs are
approved specifically for the management of homozygous FH. They
include a small-molecule inhibitor of MTP, called lomitapide, and an
antisense oligonucleotide against apoB, called mipomersen. These
drugs reduce VLDL production and LDL-C levels in homozygous
FH patients. Due to their mechanism of action, each drug causes
an increase in hepatic fat, the long-term consequences of which are
unknown. In addition, lomitapide is associated with gastrointestinal-
related side effects, and mipomersen is associated with skin reac-
tions and flu-like symptoms.
LDL APHERESIS Patients who remain severely hypercholesterolemic
despite optimally tolerated drug therapy are candidates for LDL
apheresis. In this process, the patient’s plasma is passed over a
column that selectively removes the LDL, and the LDL-depleted
plasma is returned to the patient. Patients on maximally tolerated
combination drug therapy who have CHD and a plasma LDL-C
level >200 mg/dL or no CHD and a plasma LDL-C level >300 mg/
dL are candidates for every-other-week LDL apheresis and should
be referred to a specialized lipid center.
422
The Metabolic Syndrome
Robert H. Eckel
The metabolic syndrome (syndrome X, insulin resistance syndrome)
consists of a constellation of metabolic abnormalities that confer
increased risk of cardiovascular disease (CVD) and diabetes mellitus.
Evolution of the criteria for the metabolic syndrome since the original
definition by the World Health Organization in 1998 reflects growing
clinical evidence and analysis by a variety of consensus conferences
and professional organizations. The major features of the metabolic
syndrome include central obesity, hypertriglyceridemia, low levels
hypertension (Table 422-1).
EPIDEMIOLOGY
The most challenging feature of the metabolic syndrome to
define is waist circumference. Intraabdominal circumference
(visceral adipose tissue) is considered most strongly related to
insulin resistance and risk of diabetes and CVD, and for any given
waist circumference the distribution of adipose tissue between SC and
visceral depots varies substantially. Thus, within and between popula-
tions, there is a lesser vs. greater risk at the same waist circumference.
These differences in populations are reflected in the range of waist
circumferences considered to confer risk in different geographic loca-
tions (Table 422-1).
The prevalence of the metabolic syndrome varies around the world,
in part reflecting the age and ethnicity of the populations studied and
the diagnostic criteria applied. In general, the prevalence of the meta-
bolic syndrome increases with age. The highest recorded prevalence
worldwide is among Native Americans, with nearly 60% of women
ages 45–49 and 45% of men ages 45–49 meeting the criteria of the
National Cholesterol Education Program and Adult Treatment Panel
III (NCEP:ATPIII). In the United States, the metabolic syndrome
is less common among African-American men and more common
among Mexican-American women. Based on data from the National
Health and Nutrition Examination Survey (NHANES) 2003–2006, the
age-adjusted prevalence of the metabolic syndrome in U.S. adults with-
out diabetes is 28% for men and 30% for women. In France, studies of
a cohort of 30- to 60-year-olds have shown a <10% prevalence for each
CHAPTER 422 The Metabolic Syndrome
sex, although 17.5% of people 60–64 years of age are affected. Greater
global industrialization is associated with rising rates of obesity, which
are expected to increase the prevalence of the metabolic syndrome
dramatically, especially as the population ages. Moreover, the rising
prevalence and severity of obesity among children is reflected in fea-
tures of the metabolic syndrome in a younger population.
The frequency distribution of the five components of the syndrome
for the U.S. population (NHANES III) is summarized in Fig. 422-1.
Increases in waist circumference predominate among women, whereas
increases in fasting plasma triglyceride levels (i.e., to >150 mg/dL),
reductions in HDL cholesterol levels, and hyperglycemia are more
likely in men.
RISK FACTORS
Overweight/Obesity Although the metabolic syndrome was first
described in the early twentieth century, the worldwide overweight/
obesity epidemic has recently been the force driving its increasing
recognition. Central adiposity is a key feature of the syndrome, and
the syndrome’s prevalence reflects the strong relationship between
waist circumference and increasing adiposity. However, despite the
importance of obesity, patients who are of normal weight may also be
insulin resistant and may have the metabolic syndrome.
Sedentary Lifestyle Physical inactivity is a predictor of CVD events
and the related risk of death. Many components of the metabolic
syndrome are associated with a sedentary lifestyle, including increased
adipose tissue (predominantly central), reduced HDL cholesterol, and
increased triglycerides, blood pressure, and glucose in genetically sus-
ceptible persons. Compared with individuals who watch television or
videos or use the computer <1 h daily, those who do so for >4 h daily
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
affected than men. The age dependency of the syndrome’s prevalence
is seen in most populations around the world.
Diabetes Mellitus Diabetes mellitus is included in both the NCEP
and the harmonizing definitions of the metabolic syndrome. It is
estimated that the great majority (~75%) of patients with type 2 dia-
betes or impaired glucose tolerance have the metabolic syndrome. The
presence of the metabolic syndrome in these populations relates to a
 2450 TABLE 4221 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:
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Men Women Ethnicity

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elevated glucose levels)
a
National Cholesterol Education Program and Adult Treatment Panel III. bIn this analysis, the following thresholds for waist circumference were used: white men, ≥94 cm; African-American
men, ≥94 cm; Mexican-American men, ≥90 cm; white women, ≥80 cm; African-American women, ≥80 cm; Mexican-American women, ≥80 cm. For participants whose designation
was “other race—including multiracial,” thresholds that were once based on Europid cutoffs (≥94 cm for men and ≥80 cm for women) and on South Asian cutoffs (≥90 cm for men and
≥80 cm for women) were used. For participants who were considered “other Hispanic,” the International Diabetes Federation thresholds for ethnic South and Central Americans were
used. cHigh-density lipoprotein.

higher prevalence of CVD than in patients who have type 2 diabetes or
impaired glucose tolerance but do not have this syndrome.
Cardiovascular Disease Individuals with the metabolic syndrome are
twice as likely to die of cardiovascular disease as those who do not,
PART 16
patients receiving antiretroviral therapy) may give rise to severe insulin
resistance and many of the components of the metabolic syndrome.
ETIOLOGY

and their risk of an acute myocardial infarction or stroke is three-
fold higher. The approximate prevalence of the metabolic syndrome
among patients with coronary heart disease (CHD) is 50%, with a
prevalence of ~35% among patients with premature coronary artery
disease (before or at age 45) and a particularly high prevalence among
women. With appropriate cardiac rehabilitation and changes in life-
style (e.g., nutrition, physical activity, weight reduction, and—in some
Endocrinology and Metabolism
Insulin Resistance The most accepted and unifying hypothesis to
describe the pathophysiology of the metabolic syndrome is insulin
resistance, which is caused by an incompletely understood defect in
insulin action (Chap. 417). The onset of insulin resistance is heralded
by postprandial hyperinsulinemia, which is followed by fasting hyper-
insulinemia and ultimately by hyperglycemia.
An early major contributor to the development of insulin resistance

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

60 mechanism to explain the metabolic syndrome. Physiologically, leptin

50 reduces appetite, promotes energy expenditure, and enhances insulin
sensitivity. In addition, leptin may regulate cardiac and vascular func-
40 tion through a nitric oxide–dependent mechanism. However, when
30 obesity develops, hyperleptinemia ensues, with evidence of leptin resis-
tance in the brain and other tissues resulting in inflammation, insulin
20 resistance, hyperlipidemia, and a plethora of cardiovascular disorders,
10 such as hypertension, atherosclerosis, CHD, and heart failure.
The oxidative stress hypothesis provides a unifying theory for aging
0 and the predisposition to the metabolic syndrome. In studies of insulin-
↑Waist ↑TG ↓HDL-C ↑BP ↑Glucose resistant individuals with obesity or type 2 diabetes, the offspring of
FIGURE 4221 Prevalence of the metabolic syndrome compo- patients with type 2 diabetes, and the elderly, a defect in mitochondrial
nents, from NHANES 2003–2006. NHANES, National Health and oxidative phosphorylation that leads to the accumulation of triglycer-
Nutrition Examination Survey; TG, triglyceride; HDL-C, high-density ides and related lipid molecules in muscle has been identified.
lipoprotein cholesterol; BP, blood pressure. The prevalence of elevated Recently, the gut microbiome has emerged as an important con-
glucose includes individuals with known diabetes mellitus. (Created tributor to the development of obesity and related metabolic disorders,
from data in ES Ford et al: J Diabetes 2:1753, 2010.) including the metabolic syndrome. Although the mechanism remains
 Hypertension excellent marker of the insulin-resistant condition. 2451
Not only is hypertriglyceridemia a feature of the
C-III HDL cholesterol metabolic syndrome, but patients with the metabolic
B-100 and SNS syndrome have elevated levels of ApoCIII carried
TG
LDL particle no. FFA Insulin Cytokines on VLDLs and other lipoproteins. This increase
VLDL in ApoCIII is inhibitory to lipoprotein lipase, fur-
Glucose ther contributing to hypertriglyceridemia and also
associated with more atherosclerotic cardiovascular
TNF-α disease.
IL-6 Insulin The other major lipoprotein disturbance in the
CRP metabolic syndrome is a reduction in HDL choles-
– ↓Glycogen
terol. This reduction is a consequence of changes in
– HDL composition and metabolism. In the presence
of hypertriglyceridemia, a decrease in the choles-
FFA CO2
–
terol content of HDL is a consequence of reduced
FFA cholesteryl ester content of the lipoprotein core in
combination with cholesteryl ester transfer protein–
– mediated alterations in triglyceride that make the
Fibrinogen
Adiponectin particle small and dense. This change in lipoprotein
PAI-1
composition also results in increased clearance of
Prothrombotic ↑Triglyceride HDL from the circulation. These changes in HDL
state (Lipid droplet) have a relationship to insulin resistance that is prob-
FIGURE 4222 Pathophysiology of the metabolic syndrome. Free fatty acids (FFAs) ably indirect, occurring in concert with the changes
are released in abundance from an expanded adipose tissue mass. In the liver, FFAs in triglyceride-rich lipoprotein metabolism.
result in increased production of glucose and triglycerides and secretion of very low In addition to HDLs, low-density lipoproteins
density lipoproteins (VLDLs). Associated lipid/lipoprotein abnormalities include reduc- (LDLs) are modified in composition in the metabolic
tions in high-density lipoprotein (HDL) cholesterol and an increased low-density lipo- syndrome. With fasting serum triglycerides at >2.0
protein (LDL) particle number (no.). FFAs also reduce insulin sensitivity in muscle by mM (~180 mg/dL), there is almost always a pre-

CHAPTER 422 The Metabolic Syndrome

inhibiting insulin-mediated glucose uptake. Associated defects include a reduction in dominance of small, dense LDLs, which are thought
glucose partitioning to glycogen and increased lipid accumulation in triglyceride (TG). to be more atherogenic although their association
The increase in circulating glucose, and to some extent FFAs, increases pancreatic insu- with hypertriglyceridemia and low HDLs make their
lin secretion, resulting in hyperinsulinemia. Hyperinsulinemia may result in enhanced independent contribution to CVD events difficult to
sodium reabsorption and increased sympathetic nervous system (SNS) activity and con- assess. Individuals with hypertriglyceridemia often
tribute to hypertension, as might higher levels of circulating FFAs. The proinflammatory have increases in cholesterol content of both VLDL1
state is superimposed and contributory to the insulin resistance produced by excessive and VLDL2 subfractions and in LDL particle num-
FFAs. The enhanced secretion of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) ber. Both of these lipoprotein changes may contrib-
produced by adipocytes and monocyte-derived macrophages results in more insulin ute to atherogenic risk in patients with the metabolic
resistance and lipolysis of adipose tissue triglyceride stores to circulating FFAs. IL-6 and syndrome.
other cytokines also enhance hepatic glucose production, VLDL production by the liver, Glucose Intolerance (See also Chap. 417) Defects
hypertension and insulin resistance in muscle. Cytokines and FFAs also increase hepatic in insulin action in the metabolic syndrome lead
production of fibrinogen and adipocyte production of plasminogen activator inhibi- to impaired suppression of glucose production by
tor 1 (PAI-1), resulting in a prothrombotic state. Higher levels of circulating cytokines the liver and kidney and reduced glucose uptake
stimulate hepatic production of C-reactive protein (CRP). Reduced production of the and metabolism in insulin-sensitive tissues—i.e.,
anti-inflammatory and insulin-sensitizing cytokine adiponectin is also associated with muscle and adipose tissue. The relationship between
the metabolic syndrome. (Modified from RH Eckel et al: Lancet 365:1415, 2005.) impaired fasting glucose or impaired glucose toler-
ance and insulin resistance is well supported by stud-
ies of humans, nonhuman primates, and rodents. To
uncertain, interaction among genetic predisposition, diet, and the compensate for defects in insulin action, insulin secretion and/or clear-
intestinal flora is important. ance must be modified so that euglycemia is sustained. Ultimately, this
Increased Waist Circumference Waist circumference is an important compensatory mechanism fails, usually because of defects in insulin
component of the most recent and frequently applied diagnostic secretion, resulting in progression from impaired fasting glucose and/
criteria for the metabolic syndrome. However, measuring waist cir- or impaired glucose tolerance to diabetes mellitus.
cumference does not reliably distinguish increases in SC adipose tissue Hypertension The relationship between insulin resistance
from those in visceral fat; this distinction requires CT or MRI. With and hypertension is well established. Paradoxically, under
increases in visceral adipose tissue, adipose tissue–derived free fatty normal physiologic conditions, insulin is a vasodilator with
acids are directed to the liver. In contrast, increases in abdominal SC secondary effects on sodium reabsorption in the kidney. However, in
fat release lipolysis products into the systemic circulation and avert the setting of insulin resistance, the vasodilatory effect of insulin is lost
more direct effects on hepatic metabolism. Relative increases in vis- but the renal effect on sodium reabsorption is preserved. Sodium reab-
ceral versus SC adipose tissue with increasing waist circumference sorption is increased in whites with the metabolic syndrome but not in
in Asians and Asian Indians may explain the greater prevalence of Africans or Asians. Insulin also increases the activity of the sympa-
the syndrome in those populations than in African-American men, thetic nervous system, an effect that may be preserved in the setting of
in whom SC fat predominates. It is also possible that visceral fat is a insulin resistance. Insulin resistance is characterized by pathway-
marker for—but not the source of—excess postprandial free fatty acids specific impairment in phosphatidylinositol-3-kinase signaling. In the
in obesity. endothelium, this impairment may cause an imbalance between the
Dyslipidemia (See also Chap. 421) In general, free fatty acid flux to production of nitric oxide and the secretion of endothelin 1, with a
the liver is associated with increased production of ApoB-containing, consequent decrease in blood flow. Although these mechanisms are
triglyceride-rich, very low-density lipoproteins (VLDLs). The effect provocative, evaluation of insulin action by measurement of fasting
of insulin on this process is complex, but hypertriglyceridemia is an insulin levels or by homeostasis model assessment shows that insulin
 2452 resistance contributes only partially to the increased prevalence of
hypertension in the metabolic syndrome.
Another possible mechanism underlying hypertension in the meta-
bolic syndrome is the vasoactive role of perivascular adipose tissue.
Reactive oxygen species released by NADPH oxidase impair endo-
thelial function and result in local vasoconstriction. Other paracrine
effects could be mediated by leptin or other proinflammatory cyto-
kines released from adipose tissue, such as tumor necrosis factor α.
Hyperuricemia is another consequence of insulin resistance and
is commonly observed in the metabolic syndrome. There is growing
evidence not only that uric acid is associated with hypertension but
also that reduction of uric acid normalizes blood pressure in hyperuri-
cemic adolescents with hypertension. The mechanism appears to be
related to an adverse effect of uric acid on nitric acid synthase in the
macula densa of the kidney and stimulation of the renin-angiotensin
aldosterone system.
Proinflammatory Cytokines The increases in proinflammatory cyto-
kines—including interleukins 1, 6, and 18; resistin; tumor necrosis
factor α; and the systemic biomarker C-reactive protein—reflect over-
production by the expanded adipose tissue mass (Fig. 422-2). Adipose
tissue–derived macrophages may be the primary source of proinflam-
matory cytokines locally and in the systemic circulation. It remains
unclear, however, how much of the insulin resistance is caused by the
paracrine effects of these cytokines and how much by the endocrine
effects.
Adiponectin Adiponectin is an anti-inflammatory cytokine produced
exclusively by adipocytes. Adiponectin enhances insulin sensitivity
and inhibits many steps in the inflammatory process. In the liver,
PART 16
adiponectin inhibits the expression of gluconeogenic enzymes and the
rate of glucose production. In muscle, adiponectin increases glucose
transport and enhances fatty acid oxidation, partially through the acti-
vation of AMP kinase. Adiponectin levels are reduced in the metabolic
syndrome. The relative contributions of adiponectin deficiency and
overabundance of the proinflammatory cytokines are unclear.
Endocrinology and Metabolism
CLINICAL FEATURES
Symptoms and Signs The metabolic syndrome typically is not associ-
ated with symptoms. On physical examination, waist circumference
may be expanded and blood pressure elevated. The presence of either
or both of these signs should prompt the clinician to search for other
biochemical abnormalities that may be associated with the metabolic
syndrome. Less frequently, lipoatrophy or acanthosis nigricans is
found on examination. Because these physical findings characteristi-
cally are associated with severe insulin resistance, other components
of the metabolic syndrome should be expected.
Associated Diseases t CARDIOVASCULAR DISEASE The relative risk for new-
onset CVD in patients with the metabolic syndrome who do not have
diabetes averages 1.5–3 fold. However, an 8-year follow-up of middle-
aged participants in the Framingham Offspring Study documented
that the population-attributable CVD risk in the metabolic syndrome
was 34% among men and only 16% among women. In the same study,
both the metabolic syndrome and diabetes predicted ischemic stroke,
with greater risk among patients with the metabolic syndrome than
among those with diabetes alone (19% vs. 7%) and a particularly large
difference among women (27% vs. 5%). Patients with the metabolic
syndrome are also at increased risk for peripheral vascular disease.
5:1&

%*"#&5&4
Overall, the risk for type 2 diabetes among patients
with the metabolic syndrome is increased three- to fivefold. In the
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.
Other Associated Conditions In addition to the features specifically
associated with the metabolic syndrome, other metabolic alterations
accompany insulin resistance. Those alterations include increases
in ApoB and ApoCIII, uric acid, prothrombotic factors (fibrinogen,
plasminogen activator inhibitor 1), serum viscosity, asymmetric
dimethylarginine, homocysteine, white blood cell count, proinflam-
matory cytokines, C-reactive protein, microalbuminuria, nonalcoholic
fatty liver disease and/or nonalcoholic steatohepatitis, polycystic ovary
syndrome, and obstructive sleep apnea.
NONALCOHOLIC FATTY LIVER DISEASE SEE ALSO CHAP. 367e Fatty liver is a
relatively common condition, affecting 25–45% of the U.S. population.
However, in nonalcoholic steatohepatitis, triglyceride accumulation
and inflammation coexist. Nonalcoholic steatohepatitis is now present
in 3–12% of the population of the United States and other Western
countries. Of patients with the metabolic syndrome, ~25–60% have
nonalcoholic fatty liver disease and up to 35% have nonalcoholic
steatohepatitis. As the prevalence of overweight/obesity and the meta-
bolic syndrome increases, nonalcoholic steatohepatitis may become
one of the more common causes of end-stage liver disease and hepa-
tocellular carcinoma.
HYPERURICEMIA ʨ4&&
"-40
$)"1
e Hyperuricemia reflects defects in
insulin action on the renal tubular reabsorption of uric acid and may
contribute to hypertension through its effect on the endothelium. An
increase in asymmetric dimethylarginine, an endogenous inhibitor of
nitric oxide synthase, also relates to endothelial dysfunction. In addi-
tion, microalbuminuria may be caused by altered endothelial patho-
physiology in the insulin-resistant state.
POLYCYSTIC OVARY SYNDROME ʨ4&&
"-40
$)"1
ʩ Polycystic ovary syn-
drome is highly associated with insulin resistance (50–80%) and the
metabolic syndrome, with a prevalence of the syndrome between 40%
and 50%. Women with polycystic ovary syndrome are two to four
times more likely to have the metabolic syndrome than are women
without polycystic ovary syndrome.
OBSTRUCTIVE SLEEP APNEA SEE ALSO CHAP. 38 Obstructive sleep apnea is
commonly associated with obesity, hypertension, increased circulating
cytokines, impaired glucose tolerance, and insulin resistance. With
these associations, it is not surprising that individuals with obstructive
sleep apnea frequently have the metabolic syndrome. Moreover, when
biomarkers of insulin resistance are compared between patients with
obstructive sleep apnea and weight-matched controls, insulin resis-
tance is found to be more severe in those with apnea. Continuous posi-
tive airway pressure treatment improves insulin sensitivity in patients
with obstructive sleep apnea.
DIAGNOSIS
The diagnosis of the metabolic syndrome relies on fulfillment of the
criteria listed in Table 422-1, as assessed using tools at the bedside
and in the laboratory. The medical history should include evaluation
of symptoms for obstructive sleep apnea in all patients and polycystic
ovary syndrome in premenopausal women. Family history will help
determine risk for CVD and diabetes mellitus. Blood pressure and
waist circumference measurements provide information necessary for
the diagnosis.
Laboratory Tests Measurement of fasting lipids and glucose is needed
in determining whether the metabolic syndrome is present. The
measurement of additional biomarkers associated with insulin resis-
tance can be individualized. Such tests might include those for ApoB,
high-sensitivity C-reactive protein, fibrinogen, uric acid, urinary
microalbumin, and liver function. A sleep study should be performed
if symptoms of obstructive sleep apnea are present. If polycystic ovary
syndrome is suspected on the basis of clinical features and anovulation,
testosterone, luteinizing hormone, and follicle-stimulating hormone
should be measured.
TREATMENT THE METABOLIC SYNDROME
LIFESTYLE SEE ALSO CHAP. 416
Obesity is the driving force behind the metabolic syndrome. Thus,
weight reduction is the primary approach to the disorder. With
weight reduction, improvement in insulin sensitivity is often accom-
panied by favorable modifications in many components of the
metabolic syndrome. In general, recommendations for weight loss
include a combination of caloric restriction, increased physical
activity, and behavior modification. Caloric restriction is the most
important component, whereas increases in physical activity are
important for maintenance of weight loss. Some but not all evi-
dence suggests that the addition of exercise to caloric restriction
may promote greater weight loss from the visceral depot. The
tendency for weight regain after successful weight reduction under-
scores the need for long-lasting behavioral changes.
Diet Before prescribing a weight-loss diet, it is important to
emphasize that it has taken the patient a long time to develop an
expanded fat mass; thus, the correction need not occur quickly.
Given that ~3500 kcal = 1 lb of fat, ~500-kcal restriction daily
equates to weight reduction of 1 lb per week. Diets restricted in
carbohydrate typically provide a rapid initial weight loss. However,
after 1 year, the amount of weight reduction is minimally reduced or
no different from that with caloric restriction alone. Thus, adherence
to the diet is more important than which diet is chosen. Moreover,
there is concern about low-carbohydrate diets enriched in saturated
fat, particularly for patients at risk for CVD. Therefore, a high-quality
dietary pattern—i.e., a diet enriched in fruits, vegetables, whole
grains, lean poultry, and fish—should be encouraged to maximize
overall health benefit.
Physical Activity Before a physical activity recommendation is pro-
vided to patients with the metabolic syndrome, it is important to
ensure that the increased activity does not incur risk. Some high-risk
patients should undergo formal cardiovascular evaluation before
initiating an exercise program. For an inactive participant, gradual
increases in physical activity should be encouraged to enhance
adherence and avoid injury. Although increases in physical activity
can lead to modest weight reduction, 60–90 min of daily activity is
required to achieve this goal. Even if an overweight or obese adult is
unable to undertake this level of activity, a significant health benefit
will follow from at least 30 min of moderate-intensity activity daily.
The caloric value of 30 min of a variety of activities can be found
at www.heart.org/HEARTORG/GettingHealthy/WeightManagement/
LosingWeight/Losing-Weight_UCM_307904_Article.jsp. Of note, a
variety of routine activities, such as gardening, walking, and house-
cleaning, require moderate caloric expenditure. Thus, physical activ-
ity need not be defined solely in terms of formal exercise such as
jogging, swimming, or tennis.
Behavior Modification Behavioral treatment typically includes rec-
ommendations for dietary restriction and more physical activity,
resulting in weight loss that benefits metabolic health. The sub-
sequent challenge is the duration of the program because weight
regain so often follows successful weight reduction. Long-term
outcomes may be enhanced by a variety of methods, such as the
Internet, social media, and telephone follow-up to maintain contact
between providers and patients.
Obesity (See also Chap. 416) In some patients with the metabolic syn-
drome, treatment options need to extend beyond lifestyle interven-
tion. Weight-loss drugs come in two major classes: appetite suppres-
sants and absorption inhibitors. Appetite suppressants approved by
the U.S. Food and Drug Administration include phentermine (for
short-term use [3 months] only) as well as the more recent addi-
tions phentermine/topiramate and lorcaserin, which are approved
without restrictions on the duration of therapy. In clinical trials,
the phentermine/topiramate combination has resulted in ~10%
weight loss in 50% of patients. Side effects include palpitations,
headache, paresthesias, constipation, and insomnia. Lorcaserin
results in less weight loss—typically ~5% beyond placebo—but can
cause headache and nasopharyngitis. Orlistat inhibits fat absorption
by ~30% and is moderately effective compared with placebo (~5%
more weight loss). Orlistat has been shown to reduce the incidence
of type 2 diabetes, an effect that was especially evident among
patients with impaired glucose tolerance at baseline. This drug is
often difficult of take because of oily leakage per rectum.
Metabolic or bariatric surgery is an option for patients with the 2453
metabolic syndrome who have a body mass index >40 kg/m2, or
>35 kg/m2 with comorbidities. An evolving application for metabolic
surgery includes patients with a body mass index as low as 30 kg/m2
and type 2 diabetes. Gastric bypass or vertical sleeve gastrectomy
results in dramatic weight reduction and improvement in the fea-
tures of the metabolic syndrome. A survival benefit with gastric
bypass has also been realized.
LDL CHOLESTEROL SEE ALSO CHAP. 421
The rationale for the NCEP:ATPIII’s development of criteria for the
metabolic syndrome was to go beyond LDL cholesterol in identify-
ing and reducing the risk of CVD. The working assumption by the
panel was that LDL cholesterol goals had already been achieved
and that increasing evidence supports a linear reduction in CVD
events as a result of progressive lowering of LDL cholesterol with
statins. For patients with the metabolic syndrome and diabetes, a
statin should be prescribed. For those patients with diabetes and
known CVD, the current evidence supports a maximum of penulti-
mate dose of a potent statin (e.g., atorvastatin or rosuvastatin). For
those patients with the metabolic syndrome but without diabetes,
a score that predicts a 10-year CVD risk exceeding 7.5% should also
take a statin. With a 10-year risk of <7.5%, use of statin therapy is not
evidence based.
Diets restricted in saturated fats (<7% of calories) and trans-
fats (as few as possible) should be applied aggressively. Although
less evidence exists, dietary cholesterol should also be restricted.
If LDL cholesterol remains elevated, pharmacologic intervention
CHAPTER 422 The Metabolic Syndrome
is needed. Treatment with statins, which lower LDL cholesterol
by 15–60%, is evidence based and is the first-choice medication
intervention. Of note, for each doubling of the statin dose, LDL
cholesterol is further lowered by only ~6%. Hepatotoxicity (more
than a threefold increase in hepatic aminotransferases) is rare, and
myopathy is seen in ~10% of patients. The cholesterol absorption
inhibitor ezetimibe is well tolerated and should be the second-
choice medication intervention. Ezetimibe typically reduces LDL
cholesterol by 15–20%. The bile acid sequestrants cholestyramine,
colestipol, and colesevalam may be more effective than ezetimibe
but, because they can increase triglyceride levels, must be used with
caution in patients with the metabolic syndrome. In general, bile
sequestrants should not be administered when fasting triglyceride
levels are >250 mg/dL. Side effects include gastrointestinal symp-
toms (palatability, bloating, belching, constipation, anal irritation).
Nicotinic acid has modest LDL cholesterol–lowering capabilities
(<20%). Fibrates are best employed to lower LDL cholesterol when
both LDL cholesterol and triglycerides are elevated. Fenofibrate may
be more effective than gemfibrozil in this setting.
TRIGLYCERIDES SEE ALSO CHAP. 421
The NCEP:ATPIII has focused on non-HDL cholesterol rather than
on triglycerides. However, a fasting triglyceride value of <150 mg/
dL is recommended. In general, the response of fasting triglycerides
relates to the amount of weight reduction achieved: a weight reduc-
tion of >10% is necessary to lower fasting triglyceride levels.
A fibrate (gemfibrozil or fenofibrate) is the drug of choice to lower
fasting triglyceride levels, which are typically reduced by 30–45%.
Concomitant administration with drugs metabolized by the 3A4
cytochrome P450 system (including some statins) increases the risk
of myopathy. In these cases, fenofibrate may be preferable to gemfi-
brozil. In the Veterans Affairs HDL Intervention Trial, gemfibrozil was
administered to men with known CHD and levels of HDL cholesterol
<40 mg/dL. A coronary disease event and mortality rate benefit was
experienced predominantly among men with hyperinsulinemia
and/or diabetes, many of whom were identified retrospectively as
having the metabolic syndrome. Of note, the degree of triglyceride
lowering in this trial did not predict benefit. Although levels of LDL
cholesterol did not change, a decrease in LDL particle number cor-
related with benefit. Several additional clinical trials have not shown
 2454 clear evidence that fibrates reduce CVD risk; however, post hoc
analyses of several studies demonstrated that patients with baseline
triglyceride levels >200 mg/dL and HDL cholesterol levels <35 mg/
dL did benefit.
Other drugs that lower triglyceride levels include statins, nicotinic
acid, and—in high doses—omega-3 fatty acids. For this purpose, an
intermediate or high dose of the “more potent” statins (atorvastatin,
rosuvastatin) is needed. The effect of nicotinic acid on fasting triglyc-
erides is dose related and ~20–35%, an effect that is less pronounced
than that of fibrates. In patients with the metabolic syndrome and
diabetes, nicotinic acid may increase fasting glucose levels. Omega-3
fatty acid preparations that include high doses of docosahexaenoic
acid plus eicosapentaenoic acid (~1.5–4.5 g/d) or eicosapentaenoic
acid alone lower fasting triglyceride levels by ~30–40%. No drug
interactions with fibrates or statins occur, and the main side effect
of their use is eructation with a fishy taste. This taste can be partially
blocked by ingestion of the nutraceutical after freezing. Clinical trials
of nicotinic acid or high-dose omega-3 fatty acids in patients with the
metabolic syndrome have not been reported.
HDL CHOLESTEROL SEE ALSO CHAP. 421
Very few lipid-modifying compounds increase HDL cholesterol
levels. Statins, fibrates, and bile acid sequestrants have modest
effects (5–10%), whereas ezetimibe and omega-3 fatty acids have
no effect. Nicotinic acid is the only currently available drug with
predictable HDL cholesterol-raising properties. The response is dose
related, and nicotinic acid can increase HDL cholesterol by ~30%
above baseline. After several trials of nicotinic acid versus placebo
in statin-treated patients, there is still no evidence that raising HDL
with nicotinic acid beneficially affects CVD events in patients with or
PART 16
without the metabolic syndrome.
BLOOD PRESSURE SEE ALSO CHAP. 298
The direct relationship between blood pressure and all-cause mor-
tality rate has been well established in studies comparing patients
Endocrinology and Metabolism
SECTION 4 DISORDERS OF BONE AND MINERAL METABOLISM
423 Bone and Mineral Metabolism in
Health and Disease
F. Richard Bringhurst, Marie B. Demay,
Stephen M. Krane, Henry M. Kronenberg
BONE STRUCTURE AND METABOLISM
Bone is a dynamic tissue that is remodeled constantly throughout life.
The arrangement of compact and cancellous bone provides strength
and density suitable for both mobility and protection. In addition,
bone provides a reservoir for calcium, magnesium, phosphorus,
sodium, and other ions necessary for homeostatic functions. Bone
also hosts and regulates hematopoiesis by providing niches for hema-
topoietic cell proliferation and differentiation. The skeleton is highly
vascular and receives about 10% of the cardiac output. Remodeling of
bone is accomplished by two distinct cell types: osteoblasts produce
bone matrix, and osteoclasts resorb the matrix.
The extracellular components of bone consist of a solid mineral
phase in close association with an organic matrix, of which 90–95%
is type I collagen (Chap. 427). The noncollagenous portion of the
organic matrix is heterogeneous and contains serum proteins such as
albumin as well as many locally produced proteins, whose functions
are incompletely understood. Those proteins include cell attachment/
with hypertension (>140/90 mmHg), patients with pre-hypertension
(>120/80 mmHg but <140/90 mmHg), and individuals with normal
blood pressure (<120/80 mmHg). In patients who have the metabolic
syndrome without diabetes, the best choice for the initial antihy-
pertensive medication is an angiotensin-converting enzyme (ACE)
inhibitor or an angiotensin II receptor blocker, as these two classes of
drugs appear to reduce the incidence of new-onset type 2 diabetes.
In all patients with hypertension, a sodium-restricted dietary pattern
enriched in fruits and vegetables, whole grains, and low-fat dairy prod-
ucts should be advocated. Home monitoring of blood pressure may
assist in maintaining good blood-pressure control.
IMPAIRED FASTING GLUCOSE SEE ALSO CHAP. 417
In patients with the metabolic syndrome and type 2 diabetes,
aggressive glycemic control may favorably modify fasting levels
of triglycerides and/or HDL cholesterol. In patients with impaired
fasting glucose who do not have diabetes, a lifestyle interven-
tion that includes weight reduction, dietary fat restriction, and
increased physical activity has been shown to reduce the incidence
of type 2 diabetes. Metformin also reduces the incidence of dia-
betes, although the effect is less pronounced than that of lifestyle
intervention.
INSULIN RESISTANCE SEE ALSO CHAP. 418
Several drug classes (biguanides, thiazolidinediones [TZDs]) increase
insulin sensitivity. Because insulin resistance is the primary patho-
physiologic mechanism for the metabolic syndrome, representative
drugs in these classes reduce its prevalence. Both metformin and
TZDs enhance insulin action in the liver and suppress endogenous
glucose production. TZDs, but not metformin, also improve insulin-
mediated glucose uptake in muscle and adipose tissue. Benefits of
both drugs have been seen in patients with nonalcoholic fatty liver
disease and polycystic ovary syndrome, and the drugs have been
shown to reduce markers of inflammation.
signaling proteins such as thrombospondin, osteopontin, and fibro-
nectin; calcium-binding proteins such as matrix gla protein and osteo-
calcin; and proteoglycans such as biglycan and decorin. Some of the
proteins organize collagen fibrils; others influence mineralization and
binding of the mineral phase to the matrix.
The mineral phase is made up of calcium and phosphate and is best
characterized as a poorly crystalline hydroxyapatite. The mineral phase
of bone is deposited initially in intimate relation to the collagen fibrils
and is found in specific locations in the “holes” between the collagen
fibrils. This architectural arrangement of mineral and matrix results
in a two-phase material well suited to withstand mechanical stresses.
The organization of collagen influences the amount and type of min-
eral phase formed in bone. Although the primary structures of type
I collagen in skin and bone tissues are similar, there are differences
in posttranslational modifications and distribution of intermolecular
cross-links. The holes in the packing structure of the collagen are larger
in mineralized collagen of bone and dentin than in unmineralized
collagens such as those in tendon. Single amino acid substitutions in
the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains
of type I collagen disrupt the organization of bone in osteogenesis
imperfecta. The severe skeletal fragility associated with this group of
disorders highlights the importance of the fibrillar matrix in the struc-
ture of bone (Chap. 427).
Osteoblasts synthesize and secrete the organic matrix and regulate
its mineralization. They are derived from cells of mesenchymal origin
(Fig. 423-1A). Active osteoblasts are found on the surface of newly