++
Disorders of lipid and lipoprotein metabolism are characterized
by dyslipidemia, which is defined as either elevated or low levels
of one or more of the major lipoprotein classes: chylomicrons, very-low-density
lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density
lipoproteins (HDL). Dyslipidemia can result from the expression
of a mutation in a single gene that plays a paramount role in lipoprotein
metabolism. More often, dyslipidemia reflects the influence of multiple
genes. Environmental influences such as excessive dietary intake
of fat and calories and limited physical activity, particularly
when associated with overweight or obesity, can also contribute
significantly to dyslipidemia. This chapter presents a theoretical
and practical approach to the diagnosis and treatment of dyslipidemia
in infants, children, and adolescents. The major clinical complication
of dyslipidemia is a predilection to atherosclerosis starting early
in life and leading to cardiovascular disease (CVD) in adulthood.
At the extremes of dyslipidemia, where inherited disorders of lipid
and lipoprotein metabolism are more likely to occur, premature CVD
is more frequent and can be accompanied by deposition of lipid in
various tissues. Children with profound hypertriglyceridemia are
at high risk of pancreatitis.
++
A number of clinical, epidemiological, metabolic, genetic, and
randomized clinical trials strongly support the tenet that the origins
of atherosclerosis and CVD risk factors begin in childhood and adolescence
and that treatment should begin early in life.1
++
Several longitudinal pathological studies from the general population have
found that early atherosclerotic lesions of fatty streaks and fibrous
plaques in children, adolescents, and young adults who died from
accidental causes are significantly related to higher antecedent levels
of total cholesterol (TC) and LDL-C (LDL-C); to lower levels of
HDL-C (HDL-C); and to other CVD risk factors such as obesity, higher
blood pressure, and cigarette smoking.1 These risk
factors’ effects on coronary lesion severity are multiplicative
rather than additive.
++
Four major prospective population studies from Muscatine, Bogalusa,
the Coronary Artery Risk Development in Young Adults (CARDIA) and
the Special Turku Coronary Risk Factor Intervention Project (STRIP) showed
that CVD risk factors in children and adolescents, particularly
LDL-C and obesity, predicted clinical manifestations of atherosclerosis
in young adults, as judged by coronary artery calcium, carotid intima
medial thickness (IMT), or brachial flow-mediated dilatation.1 In
regard to CVD events, medical students at Johns Hopkins who had
a TC level >207 mg/dL had five times the risk of developing
CVD 40 years later than students who had a TC level <172. 1
++
Studies have also been performed in high-risk youth; these individuals
were selected because one parent had CVD or because
they have inherited a known metabolic disorder of lipoprotein metabolism
that produces premature CVD. Half of the young progeny of men who
had CVD before age 50 had one of seven dyslipidemic profiles: elevated
LDL-C alone (type IIa) or combined with high TG (type IIb); elevated
TG alone (type IV); low HDL-C alone (hypoalpha); and type IIa, type
IIb, or type IV also accompanied by low HDL-C.1 Elevated
levels of apoB, in the presence of normal LDL-C (hyperapobetalipoproteinemia
or hyperapoB) were prevalent in young offspring of adults with premature
CVD and hyperapoB.1 The levels of apolipoprotein
B (apoB) and apolipoprotein A-I (apoA-I), the major apolipoproteins
of LDL and HDL, respectively, and the ratio of apoB to apoA-I in
young offspring from Bogalusa were stronger predictors of premature
CAD in their parents than LDL-C and HDL-C levels.1
++
Examples of inherited lipoprotein disorders that often present
in youth at high risk of future CVD include familial hypercholesterolemia
(FH; which is caused by a defect in the LDL receptor, LDLR); familial
combined hyperlipidemia (FCHL); and its metabolic cousin hyperapoB,
the prototypes for hepatic overproduction of VLDL. which is often
accompanied by insulin resistance and the dyslipidemic triad of
hyperTG; increased small, dense LDL particles (LDL-P); and low HDL-C
(see below).
+++
Lipoprotein Classification
and Properties
++
Plasma lipoproteins are spherical particles consisting of a core
of nonpolar lipids—TG and cholesteryl ester—surrounded
by a surface coating consisting of proteins (apolipoproteins) and
more polar lipids, phospholipids, and unesterified (free) cholesterol.
Plasma lipoproteins are classified by their density and electrophoretic
mobility into four major groups: chylomicrons, VLDL, LDL, and HDL
(Table 166-1). After electrophoresis, chylomicrons
remain at the origin, and VLDL, LDL, and HDL migrate in the same
positions as pre-β-, β-, and α-globulins,
respectively. The hydrated density of the lipoproteins is related
to their chemical composition and the relative content of lipid and
apolipoprotein. Chylomicrons are 99% lipid, most of it
being TG (Table 166-1). After plasma has
stood overnight, these large particles (80–500 nm) will
rise to the top, where they appear as a creamy layer. VLDL is about 90% lipid,
the majority of it being TG, with lesser amounts of cholesterol.
When present in plasma in increased amounts, VLDL are large enough
(30–80 nm) to create a cloudy or turbid appearance to plasma.
LDL are the major carriers of cholesterol in plasma, and about 50% of their
weight is cholesteryl ester and cholesterol. HDL comprise about
equal amounts of apolipoprotein and lipid, principally phospholipids and
cholesterol.
++
++
Lipoproteins are associated with several apolipoproteins (Table 166-2). Nomenclature for the apolipoproteins
follows an alphabetical scheme. The characteristics of the 10 major apolipoproteins
and their functions are summarized in Table 166-2. The
nucleotide sequences of cDNA for the apolipoproteins have been determined.
++
+++
Origin and Fate
of Plasma Lipids and Lipoproteins
++
The transport of plasma lipids by lipoproteins may be divided
into exogenous (dietary) and endogenous systems (Fig.
166-1).
++
+++
Exogenous Lipid
Transport
++
Most dietary lipid is in the form of neutral fat or TG (75–150
g/d). The amount of cholesterol in the diet is usually
about 300 mg/day but varies from 100 to 600 mg/day.
In addition to dietary cholesterol, about 1100 mg of biliary cholesterol
is secreted each day from liver into the intestine (Fig.
166-1). In the small intestine, lipids are emulsified by bile
salts and hydrolyzed by pancreatic lipases. The bile acids are then
reabsorbed by the intestinal bile acid transporter (IBAT) for return
to the liver through the enterohepatic pathway (Fig.
166-1). TG is broken down into fatty acids and 2-monoglycerides;
cholesteryl ester is hydrolyzed into fatty acids and unesterified
cholesterol. These components are then absorbed by the intestinal
cells. The absorption of cholesterol occurs in the jejunum, through
the high-affinity uptake of dietary and biliary cholesterol by the
Niemann-Pick C-1L-1 (NP-C-1L-1) protein (Fig.
166-1). Normally, about half the dietary and biliary cholesterol
is absorbed daily. Excessive cholesterol absorption is prevented by the
ABCG5/ABCG8 transporters, which act together to pump excess
cholesterol and plant sterols from the intestine back into the lumen
for excretion into the stool (Fig. 166-1).
++
In intestinal cells, monoglycerides are re-esterified into TG,
and cholesterol is esterified by acyl cholesterol acyltransferase
(ACAT). Both lipids are packaged into chylomicrons, along with apolipoproteins
apoA-I, apoA-II, apoA-IV, and apoB-48. Chylomicrons are secreted
into the thoracic duct; from there, they enter the peripheral circulation,
where they acquire apoC-II and apoE from HDL. Chylomicrons are too
large to cross the endothelial barrier, and apoC-II, a cofactor
for lipoprotein lipase (LPL), facilitates the hydrolysis of TG near
the endothelial lining of blood vessels. The fatty acids that are
released are taken up by muscle cells for energy utilization or
by adipose cells for re-esterification into TG. As a result, a chylomicron
remnant is produced that is enriched in cholesteryl ester and apoE.
This remnant is rapidly taken up by the liver by receptor-mediated
endocytosis of remnants through the interaction of apoE with the
chylomicron remnant receptor (LRP), or the LDLR on the surface of
parenchymal cells (Fig. 166-1).
++
The uptake of dietary and biliary cholesterol is part of a process
that regulates the pool of hepatic cholesterol by downregulating
the LDLR and by inhibiting the rate-limiting enzyme of cholesterol
biosynthesis, hydroxymethylglutaryl (HMG)-CoA reductase (see also below).
+++
Endogenous Lipid
Transport
++
In the fasting state, most TG in plasma is carried by VLDL. TG
is synthesized in the liver, packaged into VLDL with other lipids
and apolipoproteins (Table 166-1)—primarily
apoB-100, apoE, apoC-I, apoC-II, and apoC-III—and secreted
into plasma. VLDL TG is subsequently hydrolyzed by LPL and its cofactor
apoC-II to produce VLDL remnants and then intermediate-density lipoproteins
(IDL; d, 1.006–1.019 g/mL). TG can be transferred
from VLDL and IDL to HDL and LDL in exchange for cholesteryl ester
by the cholesterol ester transfer protein (CETP) (Fig.
166-1). Compared with VLDL, IDL are relatively enriched in
cholesteryl ester and depleted in TG. Some IDL are taken up directly
by the liver, but others are hydrolyzed by hepatic lipase (HL) to
produce LDL, the final end product of VLDL metabolism (Fig.
166-1).
++
The apoB-100 component of the cholesteryl ester-rich LDL are
recognized and bound by the high-affinity LDLR either in the liver
or in extrahepatic cells (Fig. 166-1). The
bound LDL are internalized by absorptive endocytosis. In lysosomes,
apolipoprotein B-100 is broken down into amino acids, cholesteryl
esters are hydrolyzed, and unesterified cholesterol are released.
Cholesterol mediates the proteolytic release of a transcription
factor, the sterol regulatory element binding protein (SREBP), from
the endoplasmic reticulum (ER).2 This effect occurs
through the SREBP cleavage-activating protein (SCAP) that is both
a sensor of sterols and an escort of SREBP. For example, when hepatocytes
are depleted of cholesterol, SCAP transports SREBP from the ER to
the Golgi, where two proteases—site-1 protease and site-2
protease—act in sequence to release the NH2-terminal of
SREBP from the membrane.2 The NH2-terminal of SREBP
containing the bHLH-zip domain of SREBP enters the nucleus and binds
to a sterol response element (SRE) in the promoter area of the LDLR
and HMG-CoA reductase genes, increasing their transcription. As
the cholesterol content of the hepatocyte increases, the SREBP/SCAP
complex is not incorporated into the ER, SREBP cannot reach the
Golgi, the NH2-terminal domain of SREBP cannot be released from the
membrane for transport into the nucleus, and the transcription of
the LDLR and HMG-CoA reductase genes decreases.2
++
This pathway has important clinical implications. For example,
excess dietary and biliary cholesterol leads to the downregulation
of the LDLR and HMG-CoA reductase and an increase in LDL-C. Dietary
saturated fat content has an even more profound effect on LDL-C than
dietary cholesterol. When cholesterol is re-esterified by ACAT,
SCAP senses a decrease in hepatic cholesterol, leading to the upregulation of
the LDLR and HMG-CoA reductase genes by SREBP. However, the preferred
substrate for ACAT is oleic acid. Thus, excess saturated fatty acids
decrease ACAT activity and thereby increase unesterified cholesterol,
which inhibits the proteolysis and release of SREBP and thereby
downregulates the LDLR and HMG-CoA reductase genes, followed by
an increase in LDL-C. Decreasing dietary cholesterol and saturated
fatty acids or decreasing the hepatic cholesterol content with drugs,
such as cholesterol absorption inhibitors and the bile acid sequestrants
(Fig. 166-1), leads to an upregulation of LDLR
and HMG-CoA reductase genes and lower LDL-C. Inhibitors of HMG-CoA
reductase (the statins) also reduce the liver’s cholesterol
content, leading to an upregulation of LDLR but without the concomitant
increase in HMG-CoA reductase activity (Fig. 166-1).
++
When plasma LDL-C exceeds 100 mg/dL, the capacity to
process LDL through the LDLR pathway is exceeded. Increased numbers
of LDL particles cross the endothelial barrier; LDL are trapped
in the vascular wall by proteoglycans and are then modified by either
oxidation or glycation. Such modified LDL binds to the scavenger
receptors CD36 and SRA (Fig. 166-1) and enter
cells such as macrophages by a low-affinity, LDL-receptor-independent
mechanism. This alternate pathway is not subject to feedback inhibition of
LDLR synthesis by LDL-derived cholesterol. Thus, LDL continues to
be taken up in an unregulated fashion, leading to excess deposition
of cholesterol and cholesteryl ester in macrophages (Fig.
166-1). Dyslipidemias that favor an increased uptake of LDL
through the scavenger pathway promote the production of foam cells
and the associated atherosclerosis and xanthomas.
+++
Reverse Cholesterol
Transport
++
HDL are synthesized as nascent particles primarily in the liver
but also in the intestine. After entering plasma, HDL participates
in two important reactions. In the process of lipolysis, apoA-I
is transferred from chylomicrons to HDL, and apoC-II and apoE on
HDL are transferred to the TG-rich lipoproteins. ApoA-I is a cofactor
for the enzyme lecithin cholesterol acyltransferase (LCAT; see Tables 166-1 and 166-2).
Unesterified cholesterol is removed from peripheral cells through
the ATP-binding cassette (ABC) protein ABCA1 and esterified through
the action of LCAT and apoA-I (Fig. 166-1).
These cholesteryl esters are then transferred from HDL to the apoB-containing
lipoproteins by CETP, from which they are taken up by LDLR and LRP
(Fig. 166-1). Cholesteryl ester may also
be delivered directly to the liver through an HDL receptor (SRB1). These
reactions reflect a process called reverse cholesterol transport and
may explain the protective effect that HDL and apoA-I have against
the development of atherosclerosis. Conversely, factors that impede
this process appear to promote atherosclerosis.
++
Two major approaches have been considered to detect dyslipidemia
in youth, namely screening in the general population or in a selected
population. The extensive literature related to these two screening
approaches has been reviewed in detail.3
++
Traditionally, screening for dyslipidemias in high-risk children
was recommended, because they have multiple CVD risk factors or a
family history of premature CVD and/or hypercholesterolemia.
LDL-C has been the main focus of diagnosis and treatment. Less attention
has been paid to HDL-C and TG. Now, with obesity and the metabolic
syndrome evident in our youth,1,4 the focus of
screening will likely include other factors such as obesity, low
HDL-C, non-HDL-C (TC minus HDL-C), elevated TG, elevated apoB (reflecting
increased small dense LDL-P), glucose intolerance and insulin resistance,
and higher blood pressure levels. Both the current and evolving concepts
in screening for dyslipidemia in youth will now be discussed.
++
In 1992, the National Cholesterol Education Program (NCEP) Expert
Panel on Blood Cholesterol Levels in Children and Adolescents5 recommended
that selective, not general, screening be performed. We have expanded some
of these recommendations (in italics) in the following NCEP guidelines
for screening:
++
1. A lipoprotein profile in youth whose parents and/or
grandparents required coronary artery bypass surgery or balloon angioplasty
prior to age 55 years
2. A lipoprotein profile in those with a family history of myocardial
infarction, angina pectoris, peripheral or cerebral vascular disease,
or sudden death prior to age 55
3. A TC in those whose parents have high TC levels (>240 mg/dl).
This recommendation might be usefully expanded to a lipoprotein profile
in offspring of parents who have any dyslipidemia involving elevated
LDL-C, non-HDL-C, apoB, TG, or low HDL-C.
4. A lipoprotein profile if the parental/grandparental
family history is not known, and the patient has two or more other
risk factors for CAD, including obesity (BMI > 30), hypertension,
cigarette smoking, low HDL-C, physical inactivity, and diabetes
mellitus. A new recommendation for a specific category is
proposed here: A lipoprotein profile if either obesity (BMI > 95th
percentile) or overweight (BMI 85 to 94th percentile)
is detected, regardless of the presence of other non-lipid CVD risk
factors.
++
Universal lipid screening of all children is controversial.3,5 Some
of the arguments in favor of universal screening propose that recommendations
based on family history of CVD or hypercholesterolemia will
fail to detect substantial numbers (from 17% to 90%)
of children who have elevated lipid levels.3 Universal
screening might be performed to detect those with undiagnosed heterozygous
FH or more marked FCHL; these patients will require more intensive
treatment, including possible drug therapy. In a recent meta-analysis
of screening for FH in a primary care setting, use of TC detected
88%, 94%, and 96% of cases, with false-positive
rates of 0.1%, 0.5%, and 1%, respectively.6 This
approach might be combined with a case finding strategy in relatives
of patients with FH.6
++
Identifying children and adolescents affected with hypercholesterolemia
through universal screening may bring to attention their adult relatives
who will have greater coronary mortality than relatives of children
with normal cholesterol levels.1 If universal lipid
screening is combined with an assessment of obesity and high blood
pressure, it can also lead to detecting additional relatives from
families at high risk for CVD.1
++
It is clear that CVD risk factors cluster in childhood and persist
into adulthood.1,3,5,7 While it is known that offspring
of parents with CVD generally have higher LDL and TG and lower HDL-C
in childhood and in young adulthood, the majority of children with
dyslipidemia and multiple risk factors will be missed by selective
screening.3
++
Ideally, each child and adolescent should have an assessment
of their plasma lipids and lipoproteins. While there are practical
problems (see below), and no longitudinal studies are available
to show that treatment starting in childhood decreases adult CVD,3 one
might argue that universal screening seems all the more urgent,
given the epidemic of obesity and metabolic syndrome in American
youth.
++
But what are some of the concerns about universal lipid screening
in childhood? Using TC in childhood to predict TC or LDL-C in young
adults that is sufficiently high to warrant treatment is often associated
with less-than-optimal sensitivity, specificity, and predictive
power of a positive test. Several longitudinal studies3 have
found that when the 75th percentile for TC in children is used as
a screening cut point, about half the individuals who will require
treatment as adults are identified by universal lipid screening.
In one report, the sensitivity was much lower when screening occurred
during adolescence, presumably reflecting the temporary shift of LDL-C
to lower values during this period of rapid growth and development.1 Another
unresolved issue is whether the detection of elevated TC or LDL-C
in children and young adults will predict those who are destined
to manifest premature CVD. Few data are available to address this
question.
++
For selective screening, a lipoprotein profile after an overnight
fast is measured for youth who have a positive family history of
premature CVD or dyslipidemia, obesity, multiple CVD risk factors,
and for those suspected of having secondary dyslipidemia. Such a
profile includes TC, TG, LDL-C, HDL-C, and non-HDL-C. Levels of
lipoproteins are typically measured and expressed in terms of their
cholesterol content. LDL-C is calculated from the Friedewald equation:
LDL-C = TC – HDL-C – (TG/5).
Total TG in the fasting state divided by 5 is used to estimate the
levels of VLDL-C. If the TG is >400 mg/dl, this formula
cannot be used and a direct LDL-C may be measured. If the patient
is nonfasting, TC HDL-C and non-HDL-C levels can be measured.
++
ApoB and apoA-I might also be determined, using well-standardized
immunochemical methods.8,9 Such measurements might provide
additional useful information, particularly in youth whose parents
have premature CAD.1 Age-, gender-, and race-specific
cut points for apoB and apoA-I, empirically derived from the National
Health and Nutrition Education Survey (NHANES) sample, are available8 and
provide cut points that might be used to define elevated apoB and
low apoA-I (Table 166-3). ApoB provides an
assessment of the total number of apoB-containing lipoprotein particles.9
++
++
Non-HDL-C is determined by subtracting HDL-C from TC and can
be measured in plasma from nonfasting patients. Non-HDL-C reflects
the amount of cholesterol carried by the “atherogenic” apoB-containing
lipoproteins (VLDL, IDL, LDL, and Lp [a]). In
adults, non-HDL appears to be a better independent predictor of
CVD than LDL-C.9 In children, non-HDL-C is at least
as good a predictor as LDL of future dyslipidemia in adulthood.1 Percentiles
for non-HDL-C in children are available from Bogalusa10 (Table 166-3).
+++
Advanced Lipoprotein
Testing
++
The plasma levels of VLDL, LDL, and HDL subclasses have been
determined in children and adolescents by nuclear magnetic resonance
(NMR) spectroscopy1 or by vertical-spin density-gradient
ultracentrifugation1 in research studies (see also
below); cut points derived from these methods for diagnosing and
treating dyslipidemia in youth are not currently available.
++
For universal screening, the simplest approach
is measuring TC, HDL-C, and non-HDL in nonfasting patients. However, treatment
algorithms in pediatrics are usually focused on fasting LDL-C. HyperTG
is usually assessed as part of the dyslipidemic triad and is often
elevated in obesity and the metabolic syndrome.1,4 Thus,
in an ideal screening program, TC, TG, LDL-C, HDL-C, and non-HDL-C would
be assessed by performing a lipoprotein profile in the fasting state.
+++
When to Sample
for Dyslipidemia
++
Human plasma cholesterol levels are lowest during intrauterine
life.1 At birth, the mean (1 SD) plasma levels
(mg/dL) are TC 74,11 LDL-C 31,12 HDL-C
37,13 and TG 37.1 TC and LDL-C
increase rapidly in the first weeks of life. The lipids and lipoproteins
continue to increase gradually until 2 years of age, during which
time the kind and source of the milk in the infant’s diet
can markedly influence these levels. Therefore, screening for dyslipidemia
is not generally recommended before 2 years of age. After 2 years
of age, the levels of the lipids and lipoproteins become quite constant
up to adolescence.5
++
Ten years of age has been proposed as a good time to obtain a
lipoprotein profile.6 Children this age are able
to fast easier, the values are predictive of future adult lipoprotein
profiles, and adolescence has not yet set in. Since TC and LDL-C
may fall 10% to 20% (or more) during adolescence,1 it
is preferable to screen children at risk for familial dyslipidemias
before adolescence, between ages 2 and 10. Even in FH heterozygotes,
there is a significant fall in the 1:1 ratio of affected to normal
in adolescence.1 If sampling occurs during adolescence and
the results are abnormal, then they are likely to be even higher
after adolescence. If the results during adolescence are normal,
then sampling will need to be repeated toward the end of adolescence
(for girls, age 16 and for boys, age 18).
++
The complete phenotypic expression of some disorders, such as
FCHL, can be delayed until adulthood, so the continued evaluation
of such subjects from high-risk families with FCHL should occur
well into adulthood. However, elevated apoB is the first expression of
FCHL in adolescents and young adults.1 Age-related
factors, such as increased BMI, contribute to the degree of dyslipidemia
in such youth.
+++
Definition of Dyslipidemia
++
Cut points to define elevated TC, LDL-C, apoB, non-HDL-C, and
TG, and low HDL-C and apoA-I in children and adolescents are found
in Table 166-3. Dyslipidemia is present if
one or more of these lipid, lipoprotein, or apolipoprotein factors
are abnormal. In offspring of men who had CVD before 50 years of age,
seven different dyslipidemic profiles were present.1 Such
results emphasize the importance of evaluating a lipoprotein profile
in the fasting state.
+++
Single versus
Multiple Cut Points
++
Using data from three major population-based prospective cohort
studies, TC, LDL-C, HDL-C, and TG variables in adolescence were
classified according to NCEP cut points5 (Table 166-3) and to age and gender (not race
specific) NHANES cut points14 and were compared for
their ability to predict abnormal levels in adulthood.14 NCEP
cut points (compared with NHANES cut points) were more strongly
predictive of high TC, LDL-C, and TG levels in adults but were less
predictive of low HDL-C.14 The continued use of
the current NCEP cut points for TC, LDL-C, and TG levels in adolescents
appears indicated. The cut point for HDL-C might be revised upward,
perhaps to 40 mg/dL, to improve the sensitivity of this measurement
to predict low HDL-C in adults and to make the TG cut point congruent
with that used in adults.
+++
Primary versus Secondary Dyslipoproteinemia
++
Before considering a dyslipoproteinemia to be a primary disorder,
secondary causes must be excluded (Table 166-4).
Each child with dyslipidemia should have routine blood tests to help
rule out secondary causes of the disease. These include fasting
blood sugar and tests of kidney, liver, and thyroid function. In
secondary dyslipidemia, the associated disorder producing the dyslipidemia
should be treated first in an attempt to normalize lipoprotein levels; however,
if the dyslipidemia persists—for example, as it often does
in type 1 diabetes and the nephrotic syndrome—the patient
will require dietary treatment and, if indicated, drug therapy using
the same guidelines as in primary dyslipidemias.
++
++
General guidelines for the dietary and pharmacological treatment
of primary and secondary dyslipidemias in youth are presented here.
Specific guidelines germane to each inherited disorder of dyslipidemia
are provided as necessary in subsequent sections of this chapter.
++
The first form of therapy for children with dyslipidemia is a
diet containing decreased amounts of total fat, saturated fat, cholesterol,
and simple sugars but containing increased complex carbohydrates.
No decrease in total protein is recommended. Calories are sufficient
to maintain normal growth and development. The NCEP pediatric panel
recommended diet treatment after 2 years of age.5 Recent
data from randomized clinical trials in general populations, such
as STRIP, indicate that a diet low in total fat, saturated fat, and
cholesterol may be instituted safely and effectively under medical
supervision at 6 months of age.1
+++
When to Initiate
Treatment with Diet
++
If the first lipoprotein profile indicates that TC, LDL-C, non-HDL-C,
or TG is elevated, or if the HDL-C is low (Table
166-3), then another confirmatory profile is obtained at least 3
weeks later. If dyslipidemia persists, secondary causes (Table 166-4) are ruled out and dietary treatment
begun. A Step-One diet is usually started and the lipoprotein profile
repeated in 6 to 8 weeks. If the dyslipidemia persists, then a Step-Two
diet is initiated. Both diets require dietary counseling and physician monitoring.
The Step-One diet calls for less than 10% of total calories
from saturated fatty acids, no more than 30% of calories
from total fat, and less than 300 mg/day of cholesterol. The
Step-One diet is evaluated for at least 3 months before prescribing
the Step-Two diet. The Step-Two diet entails further reduction of the
saturated fatty acid intake to less than 7% of calories
and reduced cholesterol intake to less than 200 mg/day.5
+++
Safety and Efficacy
of Dietary Therapy in Infants, Children, and Adolescents
++
The efficacy and safety of diets to treat dyslipidemia in youth
have been demonstrated across the age spectrum of pediatric patients1—for example,
from age 7 months to 7 years and from age 7 to age 11 in STRIP1 and
from ages 8 to 10 throughout adolescence in the Dietary Intervention
Study in Children (DISC).1 In some studies, there
were lower intakes of calcium, zinc, vitamin E, and phosphorus on
low-fat diets.1 Therefore, while normal growth
is maintained on low-fat diets, attention needs to be paid to ensure
adequate intake of these key nutritional elements.
++
Owen and colleagues1 analyzed 37 publications
on the effect of breast-feeding versus formula-feeding on TC in
adolescents and adults. While TC was higher in breast-fed versus
formula-fed infants, this did not persist in childhood and adolescence,
where there was no relationship of TC to infant feeding. In adults,
TC of breast-fed infants was actually lower than TC of formula-fed
infants. Human milk remains the gold standard for infant feeding.
++
Using margarines (about three servings daily) high in either
plant stanol esters1 or plant sterol esters1 can
reduce LDL-C an additional 10% to 15% when added
to a low-fat diet. Water-soluble fibers such as psyllium can lower
LDL-C an additional 5% to 10%.1
++
Consuming a soy protein beverage does not appear to lower LDL-C
but does lower VLDL-C and TG and increases HDL-C.1 Compared with
placebo, supplementing a low-fat diet with an omega-3 fatty acid (docosahexaenoic
acid, 1.2 g/day) did not lower LDL-C but changed the distribution
between the LDL subclasses with a significant 91% increase
in the largest LDL subclass and a 48% decrease in the smallest
LDL subclass 3.1 Garlic extract therapy does not
lower LDL-C in hyperlipidemic children.1
++
Overall, a diet low in fat for children with dyslipidemia appears
both safe and efficacious. Medical and nutritional support is necessary
to reinforce good dietary behaviors and to ensure nutritional adequacy.
Human milk remains the gold standard for infant feeding.
+++
Effect of a
Low-Fat Diet in Childhood on Future CVD in Adulthood
++
That a low-saturated-fat, low-cholesterol diet in childhood will
prevent CVD in adulthood can only be inferred from epidemiological studies.5 Obesity
already promotes insulin resistance in childhood. In that regard,
a low-saturated-fat dietary counseling program starting in infancy
in STRIP improved insulin sensitivity in 9-year-old healthy children.1 Further,
in STRIP, a low-saturated-fat diet introduced in infancy and maintained
during the first decade of life was associated with enhanced endothelial
function in boys, but not in girls, and was mediated in part by
the diet-induced reduction in TC.1 In the same
Finnish study, at 10 years of age, 10% of the intervention
girls were overweight compared with 19% of the control
girls, but this significant difference was not seen in the boys.1
+++
Pharmacological Therapy
++
There are six main classes of lipid-altering drugs (Fig.
166-1): (1) inhibitors of HMG-CoA reductase (the statins),
(2) bile acid sequestrants (BAS), (3) cholesterol absorption inhibitors (CAI),
(4) niacin (nicotinic acid), (5) fish oils as omega-3 fatty acids
(ecosapentanoic acid and decahexanoic acid), and (6) fibric acid
derivatives.
+++
Guidelines for
Instituting Drug Therapy
++
The primary use of drugs in pediatrics is to lower significantly
elevated LDL-C levels, primarily but not exclusively in those from
families with premature CVD or significant dyslipidemia. Drug treatment
to lower LDL-C is initiated when the postdietary LDL-C is greater than
190 mg/dl and there is a negative or unobtainable family
history of premature CVD. If the postdietary LDL-C is greater than
160 mg/dl and there is a family history of premature CVD,
two or more risk factors for CVD, or the metabolic syndrome is present,
drug treatment is started after 10 years of age.5
++
The statins and the BAS are the two main classes of pharmaceutical
agents currently used in children over 10 years of age who have sufficiently
elevated LDL-C. Ezetimibe, a CAI that blocks the absorption of cholesterol and
plant sterols through the Niemann-Pick C1 Like 1 (NPC1L1) protein
(Fig. 166-1), is also effective but is not
yet approved by the FDA for use in children, except in those rare children
with homozygous FH or sitosterolemia (see below). The statins, BAS
and CAI, act by reducing hepatic cholesterol, leading to release
of SREBP from the cytoplasm into the nucleus, where SREBP binds
to the SRE element of the LDLR gene promoter, increases the number
of LDLR, and decreases LDL-C.2 Since SREBP also
upregulates the gene for HMG-CoA reductase,2 the
BAS and CAI are both associated with a compensatory increase in
cholesterol biosynthesis, limiting their efficacy (Fig.
166-1). Therefore, both classes of agents might effectively
be used in conjunction with the statins, which reduce hepatic cholesterol
by inhibiting HMG-CoA reductase and decreasing cholesterol biosynthesis.
++
Niacin is not routinely used in pediatrics, although some FH
homozygotes respond well to it (55 to 87 mg/kg per day
in divided doses) due to the significant reduction of VLDL production,
leading to a decreased synthesis of LDL. Since aspirin is not used
in children because of Reye’s syndrome, ibuprofen can be used
if necessary to prevent flushing. The fibrates (48 mg, 96 mg, or
145 mg/d) are also not routinely used in pediatrics, except
in the adolescent with a TG level of 500 mg/dL or higher
who may be at increased risk of pancreatitis (see also below). Fish
oils (1 to 2 gm/d) may also be used to treat marked hyperTG
in children and adolescents by decreasing the biosynthesis of TG
(Fig. 166-1), but the prescription version
of omega-3 fatty acids is not yet approved by the FDA for use in
children.
+++
Bile Acid Sequestrants
++
BAS was the only class of pharmacological agents recommended
by NCEP for lipid-lowering therapy because of their extensive track record
of safety over three decades.5 In fact, the sequestrants
have never been approved by the FDA for use in children. These agents
suffer from significant tolerability issues and provide only a modest
LDL-C reduction of about 15%.1A 16.9% decrease
in LDL-C was reported when cholestryramine (8 gm) was used to treat boys
and girls with FH.1 However, Liacouras and others1 found
that 52 of 63 children discontinued cholestyramine treatment after
an average of 21.9 months because of gritty taste and gastrointestinal
complaints. The second-generation sequestrant colesevelam (625 mg tablets)
has a greater affinity for bile salts and therefore can be used
in a lower total dose (3 to 6 tablets daily). In comparison with
the first-generation BAS, colesevalam is associated with less annoying
side effects such as constipation and gritty taste and does not
interfere with the absorption of other drugs.
++
In randomized clinical trials, cholestyramine did not affect
height velocity.1 Fat-soluble vitamins were maintained,
except in one study, where the BAS group had significantly lower
25-hydroxyvitamin D than the placebo group. Low folate and high
homocysteine levels have been reported.1
+++
HMG-CoA Reductase
Inhibitors (Statins)
++
The statins are widely used to lower TC and LDL-C in adults.
Numerous randomized controlled trials have demonstrated the safety
and efficacy of the statins in male and female adolescents with
FH.15 A meta-analysis of six trials showed high
efficacy for LDL-C and apoB lowering and no increase in side effects,
compared with placebo.15 Atorvastatin, lovastatin,
pravastatin, and simvastatin are approved by the FDA for use in
adolescents with FH. Starting doses are atorvastatin, 10 mg/d;
lovastatin, 40 mg/d; pravastatin, 40 mg/d; and
simvastatin, 20 mg/d. All except atorvastatin are available
generically.
++
Using carotid IMT as a surrogate marker for atherosclerosis,
Wiegman and colleagues15demonstrated
that a 24% reduction in LDL-C in FH heterozygote children
and adolescents (8 to 15 years of age) using pravastatin produced
a significant decrease in carotid intima-media thickness (IMT),
compared to those on placebos. A follow-up study of this Dutch cohort
showed that younger age at statin initiation was an independent
predictor of treatment’s effect on carotid IMT.1 Statin
therapy also restores endothelial function in children with FH. Thus,
early intervention with statins appears likely to reduce future
atherosclerosis and CVD in those with FH.
++
The statins may also be useful in those adolescents with FCHL
and metabolic syndrome, whose LDL-C is greater than 160 mg/dL
after diet and weight control and who have multiple risk factors
or a family history of premature CVD. Even in young women with polycystic ovarian
syndrome (PCOS; see also below), there is increased carotid IMT,1 again
suggesting that greater attention be paid to managing dyslipidemia
and other CVD risk factors early in life.
+++
Side Effects
of the Statins in Children and Adolescents
++
Increases in liver function tests up to 3× upper
limit of normal levels have been reported in several adolescents
treated with higher doses of simvastatin (40 mg/day) and
atorvastatin (20 mg/day).15In a meta-analysis,15 the
prevalence of elevated ALAT in the statin group was 0.66% (3
per 454). Instances of asymptomatic increases (>tenfold) in creatine
kinase (CK), while unusual, have been reported in adolescents receiving
statin therapy.No cases of rhabdomyolysis have
been reported.15 Such adolescents
are monitored for elevations in hepatic transaminases and CK concentrations.
Liver function tests are monitored at each clinic visit two to three
times per year. CK is measured at baseline and is repeated if myalgias
develop.
+++
Special Issues
in Young Females
++
Adult women with FH and CVD may be more responsive to LDL-C-lowering
therapy than similarly affected men, as assessed by regression of
coronary plaques and tendon xanthomas.1 Statin
therapy in adult women with CVD has an overall favorable safety
profile, but fewer studies have been performed in adolescent girls.15 Nevertheless,
there has been no adverse effect on growth and development or on
adrenal and gonadal hormones.15
++
Statins are contraindicated during pregnancy because
of the potential risk to a developing fetus. Statins should be administered
to adolescent girls only when they are highly unlikely to conceive.
Birth control is mandatory for those who are sexually active. Because
of the above concerns and the long-term commitment to therapy and
because CAD often occurs after menopause, some believe that statins
should not be used to treat adolescent females.
++
Although treating adolescent patients with FH appears indicated,
especially in those with a strong family history of premature CAD,
additional studies are needed to document the long-term safety of
statin therapy and to determine its potential effects on the prevention
of adult atherosclerosis and coronary events.
+++
Metabolic Syndrome
beyond Dyslipidemia
++
Statin therapy is recommended in patients whose LDL-C level is
greater than 160 mg/dL. For most patients, however, LDL-C
will be lower than 160 mg/dL, and a low-fat diet, exercise,
and weight reduction is paramount. Metformin has been used in several
studies of obese adolescents who have metabolic syndrome and hyperinsulinemia.1
+++
Treatment of Dyslipidemia Secondary
to Other Diseases
++
Children with type 1 diabetes often have a dyslipidemia, the
severity of which is related to diabetic control. The American Diabetes Association
(ADA) recommends dietary and other hygienic measures as the first
step in treating these children. However, if the LDL-C is greater
than 160 mg/dL after such treatment, the ADA strongly recommends
using statins.16 This recommendation is based on
the high risk of CVD in affected adults and on the abnormal carotid
IMT in children with type 1 diabetes.
++
The dyslipidemia in children with nephrotic syndrome can be marked.
LDL-C is close to that in FH heterozygotes (Table
166-5). TG can approach 300 mg/dL.1 Twenty
percent of patients with nephrotic syndrome are unresponsive to
steroids, most cases of which can be attributed to focal segmental
glomerulosclerosis. Such individuals with an LDL-C greater than
160 mg/dL may be at an increased riskfor
developing atherosclerosis and CVD1 and may warrant
treatment with a statin.
++
+++
Disorders Affecting
LDL Receptor Activity
++
There are five disorders expressed in pediatrics that result
from mutations in the LDLR or from mutations in other genes that
impact LDLR activity (Fig. 166-2). Elevated
LDL-C can vary considerably in these five conditions (see also below),
but each disorder causes early atherosclerosis and premature CVD.17,18 These
five disorders include FH; familial defective apoB-100 (FDB); autosomal
recessive hypercholesterolemia (ARH); sitosterolemia; and mutations
in proprotein convertase subtilisin-like kexin type 9 (PCSK9).17-19 Each
disorder warrants diet and drug therapy in childhood to try decreasing
atherosclerosis and subsequent CVD.
++
+++
Familial Hypercholesterolemia
++
FH is the prototype for the diagnosis and treatment of dyslipidemia
in children. Heterozygous FH, an autosomal dominant disorder, presents at
birth and early in life with a two- to threefold elevation in TC
and LDL-C1 (Table 166-5). Half
the children of an FH parent and a normal parent will have FH; in
such families, the cut point for LDL-C that minimizes misclassification
is 160 mg/dL.1 FH affects about 1 in 500 people
and is due to one of more than 900 different mutations in the LDLR
gene that can affect the normal synthesis, transport, LDL-binding
ability, and clustering (in coated pits) of the LDLR17,18 (Fig. 166-2). FH heterozygous children and
adolescents manifest increased carotid IMT, decreased brachial endothelial
reactivity, but rarely overt CAD.1 Less than 10% of
FH adolescent heterozygotes develop tendon xanthomas. HDL-C is below average
in FH children (Table 166-5). In FH adults,
about half of untreated male heterozygotes and 25 percent of untreated
female heterozygotes will develop CVD by 50 years of age.17,18
++
Treatment of FH heterozygotes includes a diet low in cholesterol
and saturated fat that can usefully be supplemented with plant stanol
esters or plant sterol esters and water-soluble fiber.1 BAS
are safe and moderately effective in FH heterozygotes, but compliance is
an issue. The dose of BAS required to achieve an LDL-C below 160
mg/dL is related to the baseline LDL-C level and not to
body weight; an adult dose is usually required.1 FH heterozygous
children respond well to statins, which are well tolerated.15 However,
adding a BAS or CAI (see also above) to a statin is often necessary
to achieve LDL-C goals. Niacin is generally not used to treat FH
heterozygous children, unless LDL-C is persistently elevated or
unusual hyperTG, low HDL-C, or elevated Lp (a) lipoprotein are present.
++
About one in a million children inherit a mutant allele for FH
from both parents, leading to a four- to eightfold
elevated LDL-C that often leads to precocious atherosclerosis and
death from CVD in the second decade.17,18 Atherosclerosis
also often affects the aortic valve, leading to life-threatening
supravalvular aortic stenosis. Virtually all FH homozygotes have
planar xanthomas by the age of 5 years, notably in the webbing of fingers
and toes and over the buttocks. The seminal studies of such FH homozygous children17,18 led
to the discovery of the LDLR, which is absent or markedly deficient
in such children.
++
FH homozygotes respond somewhat to high doses of potent statins
and to niacin.1 Since FH homozygotes have markedly
diminished, if any, LDLR activity, the statins and niacin both work by
decreasing hepatic VLDL production, leading to decreased LDL production.
A CAI also lowers LDL in FH homozygotes, especially in combination
with a more potent statin.1 In the end, however,
FH homozygotes will invariably require LDL apheresis every 2 weeks
to further lower LDL into a less atherogenic range.1
+++
Familial Defective
Apob-100
++
FDB results from mutations in the gene encoding apoB-100, resulting
in an impaired ability of the apoB-100 ligand on LDL to bind to
the LDLR; decreased clearance of LDL; and elevated LDL-C of mild,
moderate, or marked degree17,18 (Fig.
166-2). Heterozygotes for FDB are relatively common (eg, 1
per 1,000 in Europeans).18 About 1 in 20 patients
with FDB has tendon xanthomas and appears clinically similar to
adult heterozygous FH patients. Some adult patients with FDB develop
premature CAD, but FDB itself is not a common cause of premature CAD.
Treatment of FDB is similar to that for heterozygous FH.18
+++
Autosomal Recessive Hypercholesterolemia
++
Children with ARH are clinically similar to those with homozygous
FH, although LDL-C is not usually as elevated (between 350 and 550 mg/dL).18 Both
parents of an ARH child usually have a normal lipoprotein profile.
The ARH protein normally interacts with the cytoplasmic component
of the LDLR and other cell surface–oriented molecules,
allowing their tyrosine phosphorylation. The deficiency of the ARH protein
prevents the normal internalization of the LDLR, leading to marked
elevations of LDL-C (Fig. 166-2). Those patients
with ARH manifest a dramatic response to statins alone or when combined
with the CAI ezetimibe.18
++
Sitosterolemia (also called phytosterolemia)
is a rare autosomal recessive disorder expressed in childhood and
characterized by markedly elevated (>thirtyfold) plasma levels of
plant sterols.17,18 This is due to hyperabsorption
and inefficient excretion of plant sterols. TC and LDL-C can be
normal, moderately elevated, or markedly elevated, depending on
the dietary content of cholesterol and plant sterol. Sitosterolemics
absorb a higher percentage of dietary cholesterol than normal,and
they secrete less cholesterol into bile, which decreases LDLR activity
and in turn increases LDL-C17,18(Fig.
166-2).
++
The diagnosis of sitosterolemia is considered and plant sterols
measured in any child or adolescent who has xanthomas despite disproportionately
low LDL-C. In addition, previously undiagnosed adults can mimic
FH heterozygotes. Patients with sitosterolemia may develop aortic
stenosis as do those with homozygous FH.18 CVD
can present in the first or second decade of life but is usually
delayed until early to middle adulthood.
++
The molecular defects responsible for sitosterolemia are caused
by mutations in two genes that encode the half-transporters, ABCG5
and ABCG8,18 which are located on chromosome 2p
in a head-to-head orientation. ABCG5 and ABCG8 are expressed exclusively
in human liver and intestine, the sites of the two metabolic abnormalities
in sitosterolemia (Fig. 166-2). The dual
functions of ABCG5 and ABCG8 are to limit the absorption of cholesterol
and plant sterols and to promote their excretion from liver into
bile.19
++
The dietary treatment of sitosterolemia is important, and both
cholesterol and plant sterols must be markedly reduced by avoiding
high-fat animal and plant products. Saturated fats are also restricted.
Statins are less effective in this disorder, since the high sterol
content in the liver reduces cholesterol production.18 Bile
acid sequestrants are quite effective, as is ezetimibe.1,18
+++
Mutations in
Proprotein Convertase Subtilisin-Like Kexin Type 9 (Pcsk9)
++
PCSK9 is a serine protease that facilitates the degradation of
LDLR.19 Gain-of-function mutations that increase
PCSK9 activity decrease LDLR activity, producing a phenotype similar to
FH. Loss-of-function mutations that decrease PCSK9 activity increase
LDLR activity, leading to a lifetime of low LDL-C and a markedly
reduced incidence of CVD.19
++
The mechanism(s) of action of PCSK9 on LDLR is not completely
understood. One possible site of action is in the Golgi, where PCSK9
might target LDLR for degradation in the lysosome.20 Secreted
PCSK9 binds to the LDLR at the cell surface, leading to the internalization
of an LDLR/PCSK9 complex in conjunction with ARH20 (Fig. 166-2). PCSK9 may interfere with the
recycling of LDLR from the endosome back to the cell surface, or it
may direct LDLR to the lysosome to be degraded. It is not presently
clear whether PCSK9 cleaves LDLR directly or whether catalytic activity
is necessary for either of these pathways.20 Patients
with hypercholesterolemia and the gain-of-function PCSK9 mutation
respond well to the treatment similar to that used for FH heterozygotes.
+++
Disorders of Overproduction
of Vldl and LDL
+++
Familial Combined Hyperlipidemia
++
FCHL is an autosomal dominant disorder with variable lipid phenotypic
expression: elevated LDL-C level alone (type IIa); elevated LDL-C with
hyperTG (type IIb); or normal LDL-C with hyperTG (type IV).1 The
expression of FCHL can be delayed until adulthood,1 but
it is not unusual to see FCHL children in families with premature
CAD.20 Total apoB can also be elevated in normolipidemic
adolescents and young adults with FCHL before the combined dyslipidemia expresses
itself.1 The mean TC and LDL-C in children with
FCHL is about 100 mg/dL lower than in those with FH, and
TG is elevated (Table 166-5). The ratio of
LDL-C to apoB is low in FCHL, indicating the presence of small,
dense LDL particles, in contrast to FH, where the LDL-C/apoB
ratio is high, manifesting the underlying large LDL particles (Table 166-5). In a pediatric lipid clinic
population, FCHL was three times as prevalent as FH.20 Tendon
xanthomas are not present in children or adults with FCHL. Adolescents
with FCHL are at risk for developing glucose intolerance, insulin
resistance, visceral obesity, hypertension, and CVD as adults.
+++
Metabolic Basis
of Fchl, Hyperapob, and Other Small Dense LDL Syndromes
++
The abnormal FFA metabolism in FCHL and other small dense LDL
syndromes may reflect the primary defect in these patients (Fig. 166-3).1,9 Impaired
insulin-mediated suppression of hormone-sensitive lipase in adipocytes leads
to an elevation in FFA1,9 (Fig.
166-3). Elevated FFA may drive hepatic overproduction of TG
and apoB, leading to a two- to threefold increased production of
VLDL and the dyslipidemic triad (Fig. 166-3).9 Insulin
resistance also interferes with insulin’s normal upregulation
of lipoprotein lipase, leading to decreased lipolysis of TG in VLDL
and in intestinally derived TG-rich lipoproteins. This paradigm may
also result from a cellular defect that prevents the normal effect
of acylation stimulatory protein (ASP; Fig. 166-3),
namely, stimulation of incorporating FFA into TG in the adipocyte.1 Insulin
resistance may also occur in the liver, leading to an increase rather than
a normal decrease in hepatic gluconeogenesis.1 Finally,
FFA and glucose compete as oxidative fuel sources in muscle, such
that increased concentrations of FFA inhibit glucose uptake and
result in insulin resistance.
++
+++
Genetic and
Molecular Defects
++
This group of disorders is clearly genetically heterogeneous,
and several genes1 (oligogenic effect) may influence
the expression of increased small dense LDL, low HDL-C, FCHL,1,21 and
the other small dense LDL syndromes.1,21 Pajunta
and coworkers recently provided strong evidence that the gene underlying the
linkage of FCHL to chromosome1q21–23
is theupstream transcription factor-1 (USF-1) gene,1 which
regulates many importantgenes in lipid metabolism,
including hepatic lipase (Fig. 166-3), and
is linked to type 2 diabetes mellitus.22
++
Obesity is of critical importance in the development of metabolic
syndrome.19,23 There is no current consensus regarding
the definition of metabolic syndrome in youth, one proposal for children
aged 12–17 years was presented by Cook et al in the third
NHANES survey.24 An adolescent is considered to
have metabolic syndrome if three or more of these factors are present:
(1) TG > or = 110; (2) HDL-C < or = 40 mg/dL;
(3) waist circumference > or = 90th percentile; (4) fasting
glucose > or = 110 mg/dL; (5) blood pressure >
or = 90th percentile for age, sex, and height. One alternative
to waist circumference may be a BMI greater than the 95th percentile
for age and gender.
++
The prevalence of metabolic syndrome in adolescents increases
with the severity of obesity and insulin resistance, as does the
dyslipidemic triad, elevated highly sensitive C-reactive protein
(hsCRP), and decreased adiponectin.4 Higher LDL-C
levels and obesity1 as well as higher blood pressure
levels in such adolescents increase carotid IMT as adults. Of note,
metabolic syndrome in childhood predicts adult metabolic syndrome
and CVD two to three decades later.23 The finding
of acanthosis nigricans is a sign of the underlying insulin resistance.
+++
Treatment of
Disorders of Vldl Overproduction
++
A diet reduced in total and saturated fat and simple sugars,
regular aerobic exercise (1,000 calories per week), and reaching
an ideal body weight are critical factors for reducing VLDL and
for improving insulin resistance. Two classes of drugs, fibric acids
and niacin acid, lower TG and increase HDL-C in adults and may also convert
small dense LDL to larger LDL.1 However, fibrates
and niacin are not ordinarily used in pediatric patients.5 The
statins are the most effective in lowering LDL-C and the total number of
atherogenic, small dense LDL particles1,15 and
are reserved for those adolescents with FCHL or the metabolic syndrome
who have an elevation of LDL-C greater than 160 mg/dL (see
also above). Cholestyramine can be used to treat pediatric patients
with FCHL with sufficiently elevated LDL-C.1
+++
Use of Metformin
in Metabolic Syndrome
++
Metformin has been used to treat obese hyperinsulinemic adolescents
with metabolic syndrome.1 Metformin can enhance
insulin sensitivity and can reduce fasting blood glucose, insulin
levels, plasma lipids, FFA, and leptin.
+++
Polycystic Ovarian
Syndrome
++
PCOS often presents in adolescence with menstrual disorders,
acne, and hirsutism.1 Insulin resistance, considered
an important underlying cause of PCOS, puts more adolescent girls
at risk for PCOS and its complications, including dyslipidemia.
After diet and weight control, the majority of endocrinologists
use an estrogen/progesterone combination for treating PCOS.1 While
only about one in three specialists consider metformin to treat
adolescents with PCOS, almost 70% use metformin in obese
teenagers with PCOS.1 Increased carotid IMT has
been detected in young adults with PCOS,1 and earlier diagnosis
and treatment of this disorder in adolescence may prevent its full-blown
expression and CVD complications in adulthood.
++
Metabolic disorders involving the TG-rich lipoproteins—chylomicrons,
VLDL, and their remnants—are heterogeneous. HyperTGemia
may result from increased synthesis or decreased catabolism of one
or more of these lipoprotein classes or from a combination
of enhanced synthesis and suppressed catabolism. Most hyperTG in
children and adolescents is due to VLDL overproduction, often accompanied
by obesity or overweight and other components of metabolic syndrome
(see above). The focus here is on inherited disorders of marked
hyperTG.
+++
Disorders of
Marked Hypertgemia
++
Most hyperTGemia in children and adolescents is due to VLDL overproduction
that results in one of the small dense syndromes (see above). There
are a few rare disorders that are expressed as marked hyperTG: lipoprotein
lipase (LPL) deficiency; defects in apolipoprotein C-II (apoC-II),
the cofactor for LPL; and hepatic lipase (HL) deficiency.23 Once
hyperTG exceeds 1000 mg/dL, pancreatitis is a major concern,
and eruptive xanthomas, lipemia retinalis, and creamy blood can
also be found. The diagnosis requires a determination of lipolytic
activity in plasma after the intravenous injection of heparin (60 U/kg). LPL deficiency
presents at birth or in the first year of life, while the expression
of the other two disorders are usually delayed until adulthood.
HL deficiency is associated with premature CAD, while LPL and apoC-II
defects are not.
++
Treatment of each of these disorders includes a very low fat
diet (10–15% of calories) that can also be usefully
supplemented with medium-chain triglycerides (MCT).23 Portagen,
a soybean-based formula enriched in MCT, is available for infants
with LPL deficiency. Lipid-lowering drugs are ineffective in the
LPL and apoC-II disorders. HL deficiency responds to treatment with
statins and, to a lesser extent, fibrates.
+++
Dysbetalipoproteinemia
(Type III Hyperlipoproteinemia)
++
This unusual disorder usually presents with about equally elevated
TC and TG levels (>300 mg/dl). The more common recessive
form has a delayed penetrance until adulthood and is due to the
combination of an E2/E2 genotype (promotes slower uptake
of TG-rich lipoproteins by the LDLR) and overproduction of VLDL
(Fig. 166-3). The more rare dominant form
of the disorder is expressed as dyslipidemia, starting in
adolescence. A low-fat diet and treatment with fibrates, niacin,
or statins are very effective. Tendon, tuberous, and planar (especially in
the palms) xanthomas; CVD; and glucose intolerance often occur in
adulthood.
+++
Inherited Disorders of
HDL Metabolism
++
Most of the time, low levels of HDL-C, associated with increased
CVD, are secondary to VLDL overproduction (see above) and are expressed
as a component of the dyslipidemic triad.1,9 There are,
however, primary HDL disorders that present as low HDL-C levels
and CVD and that include familial hypoalphalipoproteinemia (hypoalpha),1,24 apolipoprotein
A-I mutations,1,24 and rarer disorders such as
Tangier disease25 and lecithin cholesterol acyl
transferase (LCAT) deficiency.26 The clinical and
chemical characteristics of these disorders are summarized in Tables 166-6 and 166-7.
An opposite disorder, CETP deficiency, often presents as high HDL-C and
may be associated with reduced risk of CVD.1 A
low-fat diet is also indicated in children with inherited disorders
of low HDL. Drugs, including niacin, are rarely used in such children.
++
++
++
Lp (a) lipoprotein is a very large lipoprotein (Mr 3 × 106)
found in the density range 1.050 to 1.080 g/mL.1,27 Its
lipid composition is similar to LDL, but Lp(a) contains two proteins,
apoB-100, and a large glycoprotein called apo(a).
The latter is attached to apoB-100 through a disulfide bond. Apo(a)
is homologous to plasminogen andhas a variable number of repeats
of the kringle 4 region, which are under genetic control. An inverse
relationship exists between the size of apo(a) and the levels of
Lp(a).27 Lp(a) is measured by immunochemical methods.
Elevated Lp (a) appears to be inherited and is often strongly associated
with premature CVD in some families. Lp (a) levels should be measured
in a child who has had a stroke. Niacin is the only lipid-altering
drug that reduces Lp (a). It is not known if treatment of elevated
Lp (a) will prevent future or recurrent CVD.
++
The clinical and chemical findings associated with four inherited
disorders of deficiencies in apoB-containing lipoproteins—abetalipoproteinemia,
heterozygous hypobetalipoproteinemia, homozygous hypobetalipoproteinemia (either
null alleles in the apoB gene, or compound heterozygotes for truncated
apoB)—are summarized in Tables 166-8 and 166-9.
++
++
++
Abetalipoproteinemia is a rare autosomal recessive disorder whose
clinical expression in childhood includes fat malabsorption, severe
hypolipidemia, retinitis pigmentosa, cerebellar ataxia, and acanthocytosis28 (Table 166-8; see Chapter 408). The diagnosis is based on the demonstration of large
intracellular fat particles in biopsy specimens of the jejunum,
on the failure to form chylomicrons following a meal, and on the
absence of apoB in plasma. The clinical findings result from defects
in absorption and transport of the fat-soluble vitamins A, D, K,
and especially E. Abetalipoproteinemia is not caused by a defect
in the apoB gene.28 The defect in the synthesis
and secretion of apoB is secondary to the absence of the microsomal
TG transfer protein (MTP) from the liver and intestine.
++
Hypobetalipoproteinemia can be secondary to anemia, dysproteinemias,
hyperthyroidism, intestinal lymphangiectasia with malabsorption,
myocardial infarction, severe infections, and trauma. Children or
adults have few clinical symptoms (Table 166-8; see Chapter 408). Like familial hyperalphalipoproteinemia, primary hypobetalipoproteinemia
may confer a decreased risk for CVD and concomitant increase in
life span. The disorder is inherited as an autosomal dominant; 25
mutations in the apoB gene causing a truncated apoB. hypobetalipoproteinemia
have been described. Almost all of the mutations are either nonsense mutations
or frameshift mutations that result from the deletion of 1 to 5
bp that create a premature stop codon. A truncated apoB is usually
found in the plasma.
++
The clinical and chemical presentation of homozygous
hypobetalipoproteinemia in children depends on whether they are
homozygous for null alleles in the apoB gene (ie, make no detectable
apoB) or homozygous (or compound heterozygotes) for other alleles,
and whether their lipoproteins contain small amounts of apoB or
a truncated apoB28(Tables
166-8 and 166-9). Null-allele
homozygotes are similar phenotypically to those with abetalipoproteinemia;
however, their parents are heterozygous for hypobetalipoproteinemia.
+++
Treatment of Hypolipoproteinemias
++
Patients with abetalipoproteinemia and those who are null-allele
homozygotes for hypobetlipoproteinemia (Table
166-8) require similar treatment approaches (see Chapter 408). Steatorrhea can be controlled by reducing the intake
of fat to 5 to 20 g/d. This measure alone can result in
marked clinical improvement and growth acceleration. In addition,
the diet should be supplemented with linoleic acid (eg, 5 g corn
oil or safflower oil/d). MCT as a caloric substitute for
long-chain fatty acids may produce hepatic fibrosis; thus, MCT should
be used with caution, if at all. Fat-soluble vitamins should be
added to the diet. Rickets can be prevented by normal quantities
of vitamin D, but 200 to 400 IU/kg per day of vitamin A may
be required to raise the level of vitamin A in plasma to normal.
Enough vitamin K (5–10 mg/d) should be given to
maintain a normal prothrombin time. Most importantly, massive doses
(150–200 mg/kg per day) of vitamin E must be given.
Neurological and retinal complications may be prevented or ameliorated through
oral supplementation with vitamin E. Adipose tissue rather than
plasma may be used to assess the delivery of vitamin E.
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In Tangier disease, a low-fat diet diminishes the abnormal lipoprotein
species that are believed to be remnants of abnormal chylomicron
metabolism. The large LDL species found in LCAT deficiency is also
thought to be a remnant of abnormal chylomicron metabolism. Its
disappearance on a low-fat diet may have a beneficial effect, because
large LDL may be involved in the pathogenesis of renal disease.
Patients with other syndromes associated with deficiencies of HDL
and premature atherosclerosis are also treated with a diet modified
in total fat, saturated fat, and cholesterol.