Adolescent Health Care: A Practical Guide

Chapter 12

Cardiac Risk Factors and Hyperlipidemia

Marc S. Jacobson

Michael R. Kohn

Lawrence S. Neinstein

One of the goals of adolescent health care is early intervention to prevent diseases that occur during adulthood. Atherosclerosis results from the interaction of environmental factors with the genetic endowment and begins in childhood. Much has been learned about identifying early risks for cardiovascular disease although questions remain. Interventions to reduce risk factors in children and adolescents have been demonstrated. Whether there is also a reduction in subsequent cardiac disease remains to be determined. However, it is now advisable to screen for risk factors and to provide appropriate interventions for those risk factors that are remediable (Jacobson, 1998).

Cardiac Risk Factors

The National Cholesterol Education Program (NCEP) is directed by the National Heart, Lung and Blood Institute and issues guidelines to help health care professionals determine the best cholesterol management for patients to reduce their risk of myocardial infarctions.

Among the following risk factors, an asterisk [*] indicates those that are identified by NCEP.

Nonintervenable

  1. Age: 45 years and above for men*, 65 years for women*
  2. Sex: Male
  3. Family history: History of cardiovascular disease in first-degree relatives* (≤55 years of age for men, <65 years for women) with atherosclerosis or its sequelae
  4. Parent with elevated cholesterol concentration (>240 mg/dL)

Intervenable

  1. Smoking*
  2. Hypertension: Systolic or diastolic blood pressure (BP) above the 95th percentile*
  3. Diabetes mellitus*
  4. Diet high in saturated fats and cholesterol, with total fat intake accounting for >30% of daily caloric intake
  5. Dyslipidemia: the following are criteria for lipid abnormalities: (modified from recommendations of the NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents [National Cholesterol Education Program, 1992], and the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, the Adult Treatment Panel III [ATP III]) (Stone et al., 2005; National Cholesterol Education Program Expert Panel, http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm).

The following are criteria for lipid abnormalities:

  1. Total cholesterol >170 mg/dL for those younger than 20 years, or >200 mg/dL for those older than 20 years
  2. Low-density lipoprotein cholesterol (LDL-C) >130 mg/dL (for persons older than 20 years see the “Screening in Young Adults” section for new guidelines by the ATP III)
  3. High-density lipoprotein cholesterol (HDL-C) <40 mg/dL*
  4. Triglycerides >150 mg/dL*
  5. Ratio of serum very–low-density lipoprotein (VLDL) cholesterol to triglycerides of >0.3
  6. Obesity, that is, >30% above expected weight, or body mass index (BMI) above the 95th percentile for age*
  7. Insulin resistance with hyperinsulinemia
  8. Homocysteinemia (>10 nmol/L)
  9. Serum lipoprotein a (Lp[a]) concentration
  10. High serum C-reactive protein (CRP) concentrations

In general, individuals are considered at low risk for atherosclerotic disease if they have zero or one cardiovascular risk factor, moderate risk with more than one risk factor other than diabetes mellitus, and high risk with a presence of diabetes or any evidence of atherosclerosis.

Risk Factor Intervention

Important information about the relationship between cardiovascular risk factors and coronary artery disease (CAD) has been revealed by recently published longitudinal studies (Oren et al., 2003; Li et al., 2003; Knoflach et al., 2003). These involve monitoring of arterial disease using high resolution B mode ultrasound to measure carotidintima media thickness (CIMT). In summary, these studies demonstrate that screening in adolescence is a better predictor of adult disease than childhood screening, and that effective management of risk factors diminishes atherosclerosis.

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It remains prudent to recommend a heart-healthy lifestyle to reduce atherosclerosis and arterial disease. This approach includes the following:

  1. Promoting regular physical activity
  2. Counseling on the importance of maintaining an ideal body weight
  3. Advocating smoking prevention or cessation
  4. Monitoring BP and treating when persistently elevated
  5. Recommending a heart-healthy diet that has <30% of the total calories as fat and a diet low in saturated fat for all individuals
  6. Ensuring daily intake of 400 µg of folic acid either through diet or supplementation

Hypertension

The distribution of BP in children and adolescents was described by the Second Task Force on Blood Pressure Control. Hypertension was classified by age as being “significant” or “severe.” For adolescents with “significant” hypertension (i.e., diastolic BP higher than 86 mm Hg at age 13 to 15 years or higher than 92 mm Hg at age 16 to 18 years) and no other risk factors, interventions should include a low-salt diet, weight reduction, and relaxation or other biofeedback techniques. Intervention for hypertension is covered in more detail inChapter 13.

Cigarette Smoking

Cigarette smoke is an atherogenic risk factor due to alterations in lipids and fibrinogen and smoking is associated with more cardiovascular deaths than cancer deaths. Most cigarette smoking begins early in adolescence, suggesting that this is an important period for prevention. Effective education programs must be developed and implemented at the national level, at the local school level, and in the practitioner's office. Every preteen and teen should be questioned regarding his or her smoking habits, and specific interventions should be targeted to prevent or extinguish smoking behavior.

Dyslipidemia

The primary therapy for hyperlipidemia during adolescence is modification of diet, including recommendation for a diet that is low in fat, saturated and trans fats, and cholesterol. Regular physical activity is also indicated. Medications should be reserved for those teenagers with markedly high concentrations of lipids unresponsive to dietary and lifestyle change, and with an extensive family history (see “Therapy for Hyperlipidemia” section).

Obesity

The best therapy for obesity is to prevent it. This requires curbing obesity early and particularly during the adolescent growth spurt. Without intervention, eight of ten obese 12-year-old children will become obese adults (Srinivasan, 1996 and http://www.surgeongeneral.gov/topics/obesity/calltoaction/fact_adolescents.htm). Exercise and other physical activities, combined with dietary modifications, are the best preventive measures, and some studies show positive results in relation to changes in BMI, as well as metabolic changes. In particular, insulin resistance is decreased, as is BP, and there are positive changes in the lipid profile, all of which mitigate against the development of atherosclerosis.

Lipid Physiology

Cholesterol and triglycerides are the major blood lipids. Cholesterol is a key constituent of cell membranes and a precursor of bile acids and steroid hormones. Cholesterol circulates in the bloodstream in spherical particles called lipoproteins containing both lipids and proteins called apolipoproteins. These particles consist of a core of triglycerides, cholesterol, and cholesterol esters, in varying amounts, surrounded by an outer shell of cholesterol and phospholipids. The apolipoproteins are embedded in the outer lipid layers (Fig. 12.1).

 

FIGURE 12.1 Characteristics of lipoproteins. Apoproteins and volume are detailed below each lipoprotein. Ang, angstroms; VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein. (Adapted from Hardoff D, Jacobson MS. Hyperlipidemia. Adolesc Med State Arts Rev 1992;3:475.)

  1. Classification of lipoproteins: Five major classes of lipoproteins act as transport systems for cholesterol and triglycerides. They differ in physical and chemical characteristics and function, as well as in amounts of cholesterol, triglyceride, phospholipid, and protein. The lipoproteins can be separated by ultracentrifugation or electrophoresis, on the basis of differences in densities and surface properties (the characteristics of these particles and their functions are summarized). Ultracentrifugation yields chylomicrons, VLDL,

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low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).

  1. Chylomicrons: Largest and least dense of the lipoproteins; composed mainly of triglycerides with a lipid : protein ratio of 99:1. Chylomicrons carry dietary fat as triglycerides from the intestine to the periphery of the body to be used to meet energy requirements or deposition in fat cells.
  2. VLDL: Secreted by the liver and the second major carrier of triglycerides. It is composed largely of triglycerides and contains <10% of the total serum cholesterol concentration.
  3. LDL: Major carrier of cholesterol, containing 60% to 70% of the total serum cholesterol concentration, and is an important factor in atherogenesis.
  4. HDL: Usually contains 20% to 30% of the total serum cholesterol concentration. It is responsible for the transport of cholesterol back to triglyceride-containing particles for removal in the bile. The calculation of the proportion of LDL is made with the following formula:

HDL is measured directly, and VLDL is estimated by dividing the fasting triglyceride concentration by 5 (true so long as the triglyceride concentration is <400 mg/dL). Therefore,

  1. Apolipoproteins: Numerous apolipoproteins are associated with lipoproteins. Each lipoprotein has a characteristic apolipoprotein profile. Lipoproteins may contain several apolipoproteins. These apolipoproteins serve as cofactors for enzymes involved in lipoprotein metabolism, they help in the binding of lipoproteins to cellular receptors, and they facilitate lipid transfer between lipoproteins. Apolipoprotein B-100 (apoB-100) is an important component of VLDL and is the only apolipoprotein in LDL-Uptake of LDL by cells is dependent on its binding to the LDL receptor, which is regulated by apoB-100. Abnormalities in both quality and quantity of these proteins, even in the absence of an elevated cholesterol concentration, may contribute to atherosclerosis.
  2. Lipoprotein circulation and sources: (Fig. 12.2)
 

FIGURE 12.2 Pathways of lipoprotein metabolism. LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IDL, intermediate density lipoprotein; VLDL, very low-density lipoprotein. (From Weis S, Lacko AG. Role of lipoproteins in hypercholesterolemia. Pract Cardiol1988:12–18.)

  1. Exogenous: Chylomicrons are formed in the gut wall after absorption of dietary fat. They are secreted into the lymph and enter the bloodstream, where the fatty acids are stored in adipose tissue, or are used

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in skeletal muscle and myocardium. Eventually, they release almost all of their diet-derived triglycerides. This reaction is catalyzed by lipoprotein lipase. The chylomicron remnants are rapidly absorbed in the liver by specific receptors for these particles. In liver cells, the remnants are degraded to free cholesterol, which is excreted into bile.

  1. Endogenous: The endogenous transport system includes VLDL, IDL, LDL, and HD Excess calories from carbohydrates and fatty acids are metabolized in the liver into triglycerides. The lipoproteins carrying these triglycerides are primarily VLDL, which moves to adipose tissue, where triglycerides are extracted; the result is the formation of IDL and LDL. The IDL particles are rapidly removed from circulation by LDL receptors in the liver.
  • LDL transports cholesterol to peripheral tissues. In addition to the lipid component, LDL particles contain a single apoB-100 molecule, the protein that binds to LDL receptors. After binding to LDL cell surface receptors, the LDL particles deliver cholesterol for synthesis of cell membranes in all cells; for steroid hormones in the adrenal glands, ovary, and testes, and for bile acids in the liver. The LDL-C found in macrophages and smooth muscle cells of atherosclerotic lesions enters by additional mechanisms. This LDL-C is modified by oxidation intravascularly and is taken up in lesions by oxy-LDL receptors and scavenger receptors. This process may provide alternative pathways for therapeutic intervention.
  • HDL is secreted from the liver or intestine in a lipid-poor form or is made de novo in the plasma. As it matures, HDL accumulates cholesterol from tissues, including blood vessel walls, and therefore has a major role in removing excess cholesterol and delivering it to the liver by means of the triglyceride-rich lipoproteins and cholesterol ester transfer protein.

Lipid Pathophysiology and CAD

  1. Epidemiological evidence:
  2. In populations throughout the world, there is a direct correlation between serum cholesterol levels and CAD rates. Individuals moving to a country with higher mean cholesterol levels gradually acquire the dietary habits, cholesterol levels, and CAD rates of their new country. In societies where the total cholesterol concentration is <150 mg/dL, CAD is rare.
  3. Bogalusa Heart Study (Berenson, 1986; Freedman et al., 1999): Observations from this study clearly show that the major risk factors of adult heart disease begin in childhood. Documented atherosclerotic changes (e.g., fatty streak) were seen to occur by age 5 to 8 years. This group noted the significance of environmental factors for hyperlipidemia, hypertension, and obesity. They also showed that the level of risk factors in childhood is different from that in the adult years and that levels change with growth phase. Most importantly, they documented the correlation of risk factor levels with severity of lesions in autopsy material from adolescents who had died of unrelated causes and who had previously been prospectively assessed (Berenson et al., 1998).
  4. Epidemiology: Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study described the relationship between atherosclerosis and serum lipoprotein cholesterol concentrations and smoking in young men. A preliminary report demonstrated an association between commonly accepted risk factors (elevated LDL-C and low HDL-C concentrations and smoking) and the severity of atherosclerotic plaques in adolescents.
  5. Genetic evidence:
  6. Familial hypercholesterolemia: Individuals who lack LDL cell surface receptor activity may have very high cholesterol levels. Severe atherosclerosis may develop in the first two decades of life. These individuals are referred to as having familial hypercholesterolemia. Those heterozygous for the LDL-receptor defect account for 15% of premature CAD cases. Clinical manifestations such as xanthomas and other signs of cutaneous lipid deposition are generally seen in the fourth decade of life in heterozygotes and during adolescence in homozygotes.
  7. Familial combined hyperlipidemia (FCHL): Autosomal dominant syndrome that affects approximately 1% to 2% of the population. Most, if not all, patients with this condition have elevated levels of LDL apoB. Abnormal metabolism of VLDL and partial lipoprotein lipase deficiency have also been described in association with this syndrome. Individuals with FCHL account for a significant proportion of early CAD cases.
  8. Apolipoprotein E (apoE): Three common alleles of apoE, at a single-gene locus on chromosome 19, code for three isoforms of apoE: designated as apoE-II, apoE-III, and apoE-IV which are distinguished in the laboratory by isoelectric focusing. Both homozygous and heterozygous genotypes have been found. Increased cardiovascular risk is associated with apoE-II and apoE-IV, in comparison with the more common apoE-III. Type III hyperlipidemia is an uncommon disorder in which >95% of individuals are homozygous for the apoE-II allele. EII-EII occurs in <1% of the population. However, most EII-EII homozygotes are normolipidemic, confounding the relationship between genes and cardiovascular disease.
  9. Animal models: Atherosclerosis develops in animals that were fed diets elevating their serum cholesterol concentrations. In other animal experiments, a change of diet and the use of lipid-lowering drugs reduced elevated cholesterol concentrations and caused regression in atherosclerotic plaques.
  10. Interventional trials: More than a dozen randomized clinical trials in adults have examined the effects of lowering cholesterol concentrations on CAD. These trials support the conclusion that lowering total and LDL-C concentrations reduces the incidence of CAD events. The degree of benefit is greatest in individuals who have other associated risk factors, such as cigarette smoking, diabetes, and hypertension. Examples of the most significant studies include the following:
  11. Coronary Primary Prevention Trial: A longitudinal double-blind study of asymptomatic men with hypercholesterolemia. This study demonstrated a decreased CAD risk of 2% for every 1% decrease in the serum cholesterol concentrations in adults with levels initially in the 250 to 300 mg/dL range.

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  1. Helsinki Heart Study: In this study, the use of gemfibrozil lowered LDL-C concentration by 8% and increased HDL-C concentration by 10%. This led to a 34% decrease in the incidence of CAD.
  2. Multiple Risk Factor Intervention Trial: This study demonstrated that there is no threshold level of cholesterol for the development of atherosclerotic lesions. The study reported a relative risk of 0.7 with a cholesterol concentration of 150 mg/dL, 1.0 with 200 mg/dL, 2.0 with 250 mg/dL, and 4.0 with 300 mg/dL.

Studies examining the use of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors commonly known as “statins” include the following:

  • West of Scotland Coronary Prevention Study: In a large cohort of middle-aged men with high cholesterol concentrations, the use of pravastatin significantly reduced the incidence of nonfatal myocardial infarction and cardiac death without increasing the risk of death from other causes (Shepherd et al., 1995).
  • Air Force/Texas Coronary Atherosclerosis Prevention Study: This study evaluated the use of cholesterol-lowering therapy in healthy adults with average total cholesterol but below-average HDL-C concentrations. Treatment with lovastatin resulted in a 37% reduction in risk of a first major cardiac event in both men and women (Downs et al., 1998).
  • Recent Clinical Trials for the NCEP—ATP III Guidelines, Stone et al., 2005: This updates the ATP III guidelines of the NCEP on the basis of five major clinical trials of statin therapy with clinical end points. These trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of LDL-C <100 mg/dL in high-risk individuals, with an option of <70 mg/dL if the risk is very high.
  1. Relationship of particular lipoproteins
  2. LDL-C: Studies show a positive relationship between the level of cholesterol, particularly LDL, and the frequency of CAD. There appear to be several outcomes for LDL. Any LDL that is not cleared by LDL receptors is metabolized by nonreceptor mechanisms, which may play a role in atherosclerosis. LDL molecules deposit their excess cholesterol at various tissue sites, including the intima of blood vessels.
  3. HDL-C: Population studies suggest an inverse relation between HDL-C and CAD. An HDL-C level of <30 mg/dL carries a significantly increased risk of CAD. A level >50 mg/dL yields a low risk, whereas octogenarians average >75 mg/dL. HDL has two components, HDL2and HDL3. The former is considered a better indicator of negative CAD risk than is total HDL. Exercise raises the level of cardioprotective HDL2, whereas ethanol raises the level of HDL3. The Framingham Heart Study showed a 10% increase in CAD for each 4-mg/dL decrease in HDL. In addition, low HDL-C levels have been correlated with an increased number of diseased coronary arteries. There also appears to be a higher rate of restenosis after angioplasty in individuals with low HDL-C levels.
  4. Apolipoproteins: Preliminary evidence suggests that apolipoproteins A-I (apoA-I), A-II (apoA-II), and apoB may be better than LDL, HDL, and total cholesterol in predicting the risk of CAD. Elevated concentrations of apoA-I and apoA-II are associated with a lower risk, and an elevated apoB concentration is associated with a higher risk of CAD. Isoforms of apoE have also been implicated in cardiovascular risk, as noted previously. In addition, the measurement of the apoB-100 to apoA-I ratio may provide another assessment of cardiovascular risk.
  5. Ratios: The correlation between CAD and the LDL:HDL ratio has also been examined in adults. The risk increases sharply with ratios that exceed 3.0. A ratio of >5.0 carries a very high risk of CAD. Individuals with CAD average a ratio of >5:1, whereas newborns have an average ratio of 2:1. Another ratio is that of total cholesterol to HDL-C. A ratio of <4.5 denotes below-average risk, whereas the optimum ratio is 3.5:1. However, the clinical use of ratios is problematic because LDL and HDL represent independent risk factors and respond differently to different interventions. The American Heart Association (AHA) recommends that the absolute numbers for total blood cholesterol and HDL-C be used. The AHA suggests that these are more useful to the physician than the cholesterol ratio, in determining the appropriate treatment for individuals. The ATP III assigns points to various levels of HDL-C as part of the equation that is used to determine LDL-C treatment goals for primary and secondary prevention, rather than focusing on ratios.
  6. Other experimental work: Lp(a) is a very large lipoprotein composed of apoB-100 and cholesterol, similar to LDL. In addition, this lipoprotein has a large glycoprotein, homologous to plasminogen, attached through a disulfide bond. It has no known physiological function. Plasma levels appear to be genetically determined and associated with risk of cardiovascular disease and may also increase the risk of thrombotic complications through its interaction with plasminogen. Nicotinic acid has been shown to lower Lp(a) by up to 30% (Knopp, 1999).

Classification of Hyperlipidemias

Historically, patients with hyperlipidemia have been classified into five major groups according to plasma lipoprotein patterns (lipoprotein phenotyping). More recent classifications of hyperlipidemia are either extensions of the earlier models based on more specific data obtained from newer laboratory techniques (Table 12.1) or are based on recently described genetic and metabolic disorders (Table 12.2). The nomenclature remains cumbersome and there is still much overlap, particularly when attempts are made to reconcile these two systems. Previously well-described syndromes, such as familial hypercholesterolemia, have been shown to have a specific genotype and yet may vary in phenotype (i.e., types IIa and IIb). Moreover, type IIa and IIb patterns of hyperlipidemia are associated with another syndrome, FCHL. Finally, the lipoprotein phenotyping system fails to account for children and adolescents at risk of atherosclerosis as a result of hyperapobetalipoproteinemia or hypoalphalipoproteinemia, which have been described in the metabolic classification. Each of the two classification systems has clinical utility at present. It is hoped that as the field of molecular genetics advances, the two systems will be fused into one system on the basis of pathophysiology and the degree of risk (Breslow, 1991).

Although familial forms of hyperlipidemia (Table 12.3), identifiable in the standard clinical laboratory assessment,

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account for only 2% of cases they are responsible for >20% of premature CAD. Most cases of hyperlipidemia occur as a result of diet and lifestyle factors, in association with genetic polymorphism in apoE, lecithin-cholesterol acyltransferase, lipoprotein lipase, and other lipid enzymes and cofactors. Hyperlipidemia also occurs as a result of medical conditions or the use of medications such as estrogens, isotretinoin, and β3-adrenergic blockers.

TABLE 12.1
Phenotypic Classification

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol; LCAT, lecithin-cholesterol acyltransferase; SLE, systemic lupus erythematosus.
From Arden MR. Primary hyperlipidemias. In: Jacobson MS, ed. Atherosclerosis prevention: identification and treatment of the child with high cholesterol. London: Harwood Academic Publishers, 1991:30, with permission.

1.  Hypercholesterolemia with normal triglycerides

1.  Elevated LDL-C, type lla

—Primary:

Familial hypercholesterolemia

 

Familial combined hypercholesterolemia

 

Mixed genetic-environmental hypercholesterolemia

—Secondary:

Anorexia nervosa

 

Acute intermittent porphyria

 

Biliary obstruction (lipoprotein X)

2.  Elevated HDL-C

 

Familial hyperalphalipoproteinemia

 

Idiopathic

2.  Hypercholesterolemia and hypertriglyceridemia

1.  Elevated LDL-C and VLDL-C, type IIB

—Primary:

Familial hypercholesterolemia

 

Familial combined hypercholesterolemia

 

Familial LCAT deficiency

—Secondary:

Hypothyroidism

 

Nephrotic syndrome

 

Cushing's syndrome/glucocorticoid therapy

2.  Dysbetalipoproteinemia, type III

3.  Hypertriglyceridemia with normal cholesterol level

1.  Elevated VLDL only, type IV

—Primary:

Familial hypertriglyceridemia

 

Familial combined hyperlipidemia

—Secondary:

Diabetes mellitus

 

SLE

 

Alcohol

 

Pancreatitis

 

Pregnancy

 

Idiopathic hypercalcemia

 

Medications: Estrogens

2.  Elevated chylomicrons, type I

—Primary:

Lipoprotein lipase deficiency

 

Familial deficiency of apolipoprotein C-II

—Secondary:

Autoimmune hyperchylomicronemia: SLE

 

Diabetes mellitus

 

Alcohol

3.  Elevated VLDL and chylomicrons, type V

—Primary:

Familial hypertriglyceridemia

 

Familial combined hyperlipidemia

 

Apolipoprotein E (apoE-4 and apoE-2)

—Secondary:

Diabetes mellitus

 

Alcohol

 

Estrogen

4.  Increased risk with normal or elevated cholesterol level

1.  Hyperbetalipoproteinemia

2.  Lp(a) hyperlipoproteinemia

  1. Familial hypercholesterolemia:
  2. Monogenic: This is an autosomal codominant disorder resulting from insufficient activity of the cell surface receptors for LDL. A number of different mutations in the LDL receptor gene occur in families, all of which result in the same phenotypical disease. Homozygous familial hypercholesterolemia is a rare disease, occurring in approximately one in a million individuals. Typically, individuals homozygous for this condition have coronary atherosclerosis in the second or third decade of life. Clinically, this condition may manifest in childhood and adolescence by the deposition of cholesterol esters in tendons (xanthomas), as well as in soft tissues of the eyelids (xanthelasma) and in the cornea (arcus cornea). The mean cholesterol concentration in the heterozygous condition ranges from 250 to 500 mg/dL and in the homozygote from 500 to 1,000 mg/dL. Homozygous individuals may respond poorly to drugs and require referral to specialists for consideration of more radical therapies. The heterozygous form has been estimated to occur in 1 of 200 to 500 individuals. A similar clinical presentation is observed in individuals with a heterozygous abnormality; however, the signs and symptoms tend to be milder and develop later, about the fourth or fifth decade of life.
  3. Polygenic: This is a common cause of type IIa hyperlipidemia, probably associated with a combination of multiple genetic abnormalities and environmental factors. Individuals with this condition lack typical features of familial hypercholesterolemia such as xanthelasma, arcus cornea, and tendinous xanthomas.
  4. Familial defective apoB-100: This is a mutation in the apoB gene, which results in decreased affinity of LDL to the LDL receptor. The phenotypical expression of this condition in children has not been described. Homozygous and heterozygous genotypes are known. This condition may occur in as many as 1 of 500 people,

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but the defect appears to account for only a small percentage (<2%) of premature CAD.

TABLE 12.2
Metabolic Classification of Dyslipoproteinemia in Children and Adolescents

LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; AD, autosomal dominant; HDL, high-density lipoprotein.
From Kwiterovich PO Jr. Diagnosis and management of familial dyslipoproteinemia in children and adolescents. Pediatr Clin North Am 1990;37:1489, with permission.

1.  Disorders of LDL metabolism/disorders with increased LDL

1.  Decreased LDL removal
—Familial hypercholesterolemia
—Defective apoB-100

2.  Increased LDL production
—Familial combined hypercholesterolemia
—Hyperapobetalipoproteinemia

3.  Other
—Polygenic hypercholesterolemia

2.  Disorders of triglyceride-rich lipoproteins

1.  Decreased removal (type I dyslipoproteinemia)
—Lipoprotein lipase deficiency
—ApoC-II deficiency (cofactor for lipoprotein lipase)

2.  Production of abnormal VLDL
—Familial hypertriglyceridemia (AD)

3.  Decreased removal/increased production
—Type V dyslipoproteinemia (AD)
—Dysbetalipoproteinemia

3.  Deficiency in HDL

1.  Increased HDL removal

2.  Decreased HDL production

  1. Lipoprotein lipase deficiency: This is a rare condition associated with very high levels of triglycerides and normal cholesterol levels. Eruptive xanthomas may be present. Although the risk of atherosclerosis is not elevated, the individual is at risk of having pancreatitis, particularly when the triglyceride level exceeds 500 mg/dL.
  2. Familial dysbetalipoproteinemia: A very uncommon condition, occurring in approximately 1 of 1,000–2,000 persons in the United States; it is seen only rarely in adolescence. In this condition, the catabolism of VLDL remnants and chylomicrons is delayed because an abnormal apoE alters the normal binding of VLDL remnants to LDL receptors. This problem should be suspected when triglyceride levels are some what higher than cholesterol levels in the presence of a significant cholesterol elevation. These individuals have an increased risk of premature CAD and peripheral vascular disease. They are often obese and have glucose intolerance, hyperuricemia, and tuberoeruptive and palmar xanthomas. Caloric restriction is usually effective.
  3. Familial hypertriglyceridemia: This is a autosomal dominant trait. Dietary factors, obesity, and a sedentary lifestyle are additional elements involved in the degree of expression.
  4. FCHL: Affected individuals have high levels of LDL-C, triglycerides, or both. This condition is usually not associated with tendinous xanthomas but is associated with premature CAD. Multiple lipoprotein phenotypes can occur in a single affected family. Affected individuals may have increases in VLDL alone, LDL alone, or VLDL plus LDL or chylomicrons. The diagnosis is made by a finding of multiple lipoprotein phenotypes in a single family when first-degree relatives are tested or when a typical pattern of modest elevation in concentrations of cholesterol and triglycerides is seen, together with a low HDL-C level. FCHL occurs in approximately 15% of patients with CAD younger than 60 years. The metabolic defect appears to be an overproduction of lipoproteins by the liver, as well as decreased catabolism in the periphery. Dietary therapy, along with physical exercise, plays an important role in treatment.

Lipid Screening and Management

According to NCEP, the process of screening and management differs for adolescents (age 20 years or younger) and young adults (age 20–35 years). In addition to classification of lipid parameters, screening involves the identification of other cardiovascular risk factors by history and physical examination. Once an adolescent with a positive family history is found to have a high total cholesterol, then the algorithm in Figure 12.3 can be used to classify and manage his or her risk.

History

  1. Family history of premature cardiovascular diseases (younger than 55 years for male and 60 for female relatives) such as myocardial infarcts or other sequelae of atherosclerosis
  2. Family history of dyslipidemia or hypertension
  3. History of smoking
  4. Dietary history: May use 24 hour recall for dietary history.

Physical Examination

  1. Signs of peripheral lipid deposition (xanthoma, xanthelasma, corneal arcus)
  2. Weight, height, BP, and sexual maturity rating
  3. Body composition indexes: Adjunctively, it may be useful to evaluate body composition by measurement of mid upper arm circumference and standard skin folds. The waist–hip ratio is also an important predictor of lipoprotein levels (Mansfield et al., 1999). A waist circumference of >40 in. (102 cm) in men or 35 in. (80 cm) in women is considered abdominal obesity, a part of the metabolic syndrome highlighted by the ATP III.

Screening in Adolescents

Selective screening of children and adolescents is recommended by the NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents, the American Academy of Pediatrics, the Bright Futures guidelines from the National Center for Education in Maternal and Child Health, the Guidelines for Adolescent and Preventive Services

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(GAPS) from the American Medical Association, and the American Academy of Family Physicians.

TABLE 12.3
Characteristics of Inherited Hyperlipoproteinemias

Hyperlipoproteinemia

Phenotype

Cholesterol

Triglyceride

Xanthomas

Frequency (%)

Risk of CAD

CAD, coronary artery disease; NL, normal.
From Arky RA, Perlman AJ. Hyperlipoproteinemia. In: Rubenstein E, Federman DD, eds. Scientific American medicine. New York: Scientific American, 1988, with permission.

Familial lipoprotein lipase deficiency

I

Normal

Eruptive

Very rare

0

Familial hypercholesterolemia

IIa

Tendon

0.1–0.5

4+

 

IIb

   

Tuberous xanthelasma

   

Polygenic hypercholesterolemia

II

Normal

Tuberous

5

2+

Familial dysbetalipoproteinemia

III

Palmar
 Planar tuberous tendon

Rare

4+

Familial combined hyperlipoproteinemia

IIa
IIb
IV
Rarely V

Any type

1–2

3+

Familial hypertriglyceridemia

IV
Rarely V

Normal

Eruptive

1

1+

Reference-range values for adolescents and young adults are given in Table 12.4. The NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents and the American Academy of Pediatrics Committee on Nutrition (1998) classify risk on the basis of total cholesterol levels as follows:

Low risk

<170 mg/dL

Borderline risk

170–199 mg/dL

High risk

200 mg/dL (95th percentile)

Providing dietary treatment for adolescents and young adults with the top 25% of cholesterol values is probably desirable, but this has not been proven to reduce CVD. However, establishing such proof would be extremely difficult, requiring lengthy (30–40 years) longitudinal studies. Recommending drug treatment to the top 10% is even more controversial until more is known about the risk–benefit ratio for drug treatment in a younger population. Several recent studies have proven the short term (1-2 yr) safety and efficacy of statins in adolescents with FH so that the FDA has now approved Atrovastatin, Lovastatin, Pravastatin, and Simvistatin for use in 12-18 yr olds with FH (see Drug Therapy below) (Gotto 2004)

At present, it seems reasonable to recommend that individuals in the borderline-risk group receive hygienic measures, including exercise instruction, nutritional advice such as the NCEP Step 1 prudent diet, and nonsmoking advice. Those in the high-risk group should receive all these measures plus dietary counseling by a dietitian and more frequent follow-up. Although the LDL-C level is more closely correlated with CAD risk, total cholesterol, which can be drawn nonfasting, can be used for follow-up to save on laboratory costs and inconvenience to patients.

  1. Who: If possible, all adolescents should be screened once during this age period. If not possible, then the following adolescents should be screened:
  2. Teens whose parents or relatives have had premature CAD or stroke, or clinical evidence of atherosclerosis before the age of 55 years in male members and before the age of 65 years in female members
  3. Teens whose parents have elevated concentrations of lipoproteins
  4. Teens with hypertension, obesity, diabetes, or other significant cardiac risk factors
  5. Smokers

The optimal screening frequency for high blood cholesterol in this risk group has not been determined and is left to clinical discretion.

  1. How: Serum lipids are best measured after a 12- to 14-hour fast; however, the total cholesterol level can be determined in a nonfasting sample because chylomicrons from dietary fat contribute essentially no cholesterol. If a nonfasting cholesterol level is borderline or above, a fasting sample should be obtained and analyzed for triglyceride, total cholesterol, and HDL-C with a calculation of LDL-C. Risk based on LDL-C is as follows:

Acceptable

<110 mg/dL

Borderline

110–129 mg/dL

High risk

>130 mg/dL

The AHA does not recommend mass screenings of plasma cholesterol concentration for all children and adolescents. The reasoning behind this was that such

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screenings may reach many individuals who are either at low risk or already know their cholesterol level.

 

FIGURE 12.3 Classification, education, and follow-up based on LDL-C (low-density lipoprotein cholesterol) in adolescents (<20 years) with elevated total cholesterol. HDL-C, high-density lipoprotein cholesterol. (From the National Cholesterol Education Programs. Report of the expert panel on blood cholesterol levels in children and adolescents.Pediatrics 1992;89(suppl):498.)

Screening in Young Adults

The ATP III of the NCEP issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, several major clinical trials of statin therapy with clinical end points have been published (Grundy et al., 2004).

  1. ATP III recommendations for young adults between the ages of 20 and 35 years are as follows:
  2. Fasting lipid profile is the preferred method of assessing lipid risk and should be determined in every young adult regardless of family history at least once every 5 years. Next, the number of risk factors is counted (Table 12.5) for those with two or more risk factors; Framingham scoring is then used to assign 10-year risk of a coronary event. Last, the lipid profile is interpreted by the following guidelines:
  • LDL-C

Optimal

<100 mg/dL

Near optimal

100–129 mg/dL

Borderline high

130–159 mg/dL

High

160–189 mg/dL

Very high

190 mg/dL

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  • Total cholesterol

Desirable

<200 mg/dL

Borderline

200–239 mg/dL

High risk

>240 mg/dL

  • HDL-C

Low

<40 mg/dL

High

>60 mg/dL

TABLE 12.4
Lipid Values by Age and Sex

 

Percentile

 

Cholesterol

Triglycerides

LDL-C

HDL-C

Age (yr)

75th

90th

75th

90th

75th

90th

10th

25th

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
From The Lipid Research Clinics Population Studies data book. I. The prevalence study. Publication No. 80–1527. Bethesda, MD: National Institutes of Health, 1980, with permission.

Males

               

 5–9

168

183

 58

 70

103

117

42

49

 10–14

173

188

 74

 94

109

122

40

46

 15–19

168

183

 88

125

109

123

34

39

 20–24

179

197

107

146

118

138

32

38

 25–29

199

223

120

171

138

157

32

37

Females

               

 5–9

177

190

 74

103

115

125

38

47

 10–14

171

191

 85

104

110

126

40

45

 15–19

173

195

 84

108

110

127

38

43

 20–24

176

202

 81

100

113

136

37

43

 25–29

192

213

 86

108

122

141

40

47

  1. In those without CAD, which will be the vast majority of 20- to 35-year-old adults, the following LDL-C goals and treatments apply: LDL-C goal is <160 mg/dL, at which point therapeutic lifestyle changes (TLC) are indicated. At LDL-C >190 mg/dL, lipid-lowering medications should be considered. At 160 to 189 mg/dL, LDL-C lipid-lowering drugs are optional and based on clinical judgment, which takes into account the presence or absence of two broad classes of additional factors: life habits(e.g., obesity, sedentary lifestyle, and atherogenic diet) and emerging risk factors (e.g., Lp[a], homocysteine, prothrombotic and proinflammatory plasma factors, as well as impaired glucose tolerance).
  2. Results from recent trials have resulted in updated ATP III recommendations as follows (Stone, 2005):
  3. TLC remain an essential modality in clinical management.
  4. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of LDL-C <100 mg/dL.
  5. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients.
  6. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following:
  • In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, that is, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL.

TABLE 12.5
Major Risk Factors (Exclusive of Low-Density Lipoprotein Cholesterol) that Modify Low-Density Lipoprotein Goals
a

aDiabetes is regarded as a coronary heart disease (CHD) risk equivalent.

b High-density lipoprotein (HDL) cholesterol ≥60mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.
From JAMA. Executive summary of the third report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (ATP III). JAMA 2001;285(19):2486–2497, with permission.

§  Cigarette smoking

§  Hypertension (blood pressure ≥140/90 mm Hg or on antihypertensive medication)

§  Low HDL cholesterol (<40 mg/dL)b

§  Family history of premature CHD (CHD in first-degree male relative <55 yr; CHD in first-degree female relative <65 yr)

§  Age (men ≥45 yr; women ≥55 yr)

  • Moreover, when a high-risk patient has high triglycerides or low HDL-C, consideration can be

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given to combining a fibrate or nicotinic acid with an LDL-lowering drug.

  • For moderately high-risk persons (2+ risk factors and 10-year risk 10%–20%), the recommended LDL-Cgoalis <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence.
  • The latter option also extends to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL.
  • When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels.
  • Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (e.g., obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) should make TLC to modify these risk factors regardless of LDL-C level.
  • Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

A complete report is available online (http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm), which includes an executive summary, a full report, a quick desk reference, a slide show, an interactive tool for handheld devices, and a 10-year risk calculator from the ATP III on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.

Hypertriglyceridemia

Moderate hypertriglyceridemia alone is not independently correlated with CAD. Severe hypertriglyceridemia (≥1,000 mg/dL) is associated with an increased incidence of acute life-threatening pancreatitis and must be aggressively treated with diet, weight loss, and pharmacotherapy. The Framingham study has found that a triglyceride concentration of >150 mg/dL, in combination with a HDL level of <35 mg/dL, is as good a predictor of CAD as LDL elevation. Therefore, in the presence of an elevated triglyceride and a low HDL concentration, treatment with the TLC diet and exercise intervention is recommended. The ATP III now defines hypertriglyceridemia more strictly than previously:

Normal triglycerides

<150 mg/dL

Borderline-high triglycerides

150–199 mg/dL

High triglycerides

200–499 mg/dL

Very high triglycerides

>500 mg/dL

For adolescents, the 90th percentile (Table 12.4) should be used as the upper limit of normal for age and sex.

Nonlipid (Novel) Risk Factor Assessment

Insulin/Glucose Ratio

Insulin resistance is indicated by an elevated ratio. It is associated with accelerated atherosclerosis through various mechanisms including lipid oxidation, endothelial dysfunction, and thrombogenic abnormalities (Hayden and Reaven, 2000). It is associated with the metabolic syndrome (syndrome X) (Reaven, 2002), which consists of at least three of the following five: central adiposity, hypertension, elevated triglyceride levels, decreased HDL-C levels, impaired glucose tolerance. In adolescents, the metabolic syndrome is best managed with lifestyle changes aimed at overweight and obesity. ATP III recognizes metabolic syndrome as a secondary target of cardiovascular risk reduction after LDL lowering. Routine screening of fasting insulin is not indicated, rather it should be reserved for individuals with risk factors for type 2 diabetes (such as family history, obesity, or acanthosis nigricans).

Homocysteine

Elevated plasma total homocysteine is an independent risk factor for atherosclerotic vascular disease and has been linked to an increased risk of thrombosis. Risk increases continuously across the spectrum of homocysteine concentrations and may become appreciable at levels higher than 10 µmol/L. A compelling case can be made for screening all individuals with atherosclerotic disease or at high risk. Folic acid is the mainstay of treatment, because homocysteine levels can be reduced with folic acid supplementation, but vitamins B12 and B6 may have added benefit in selected patients. The results of ongoing randomized, placebo-controlled trials will help in determining whether lowering the homocysteine concentration reduces the risk of cardiovascular disease (Gerhard and Duell, 1999).

Other potential emerging risk factors explored have included CRP and other inflammatory markers, coagulation factors (such as fibrinogen and factors VIII and VII), deficiency of antioxidant vitamins, and chlamydia infections.

Therapy for Hyperlipidemia

General Principles

  1. Diagnose and treat secondary causes.
  2. Reduce risk factors. Intervene with those risk factors that can be altered, including smoking, hypertension, and diabetes.
  3. Start a heart-healthy diet. The principal treatment of hyperlipidemia in adolescents and adults is a diet with modified amounts of fat, saturated fat, and cholesterol without increased simple carbohydrates. The goals of dietary therapy are to lower total cholesterol and LDL-C concentration to below the 90th percentile—preferably below the 75th percentile. Nutritional management is described in two steps as recommended by the NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents, as shown in Table 12.6. If adherence to the NCEP Step 1 diet fails to achieve the minimal goals of therapy, the Step 2 diet should be prescribed.

The pediatric recommendations differ from those for adults in that careful consideration and monitoring of energy and micronutrient consumption are needed for support of normal growth and development. This is particularly important during the adolescent growth years, when energy, protein, mineral, and vitamin requirements are increased. Nutritional counseling focusing on meeting fat and cholesterol recommendations while ensuring adequate macronutrient and micronutrient intake is needed. The Committee on Nutrition of the American Academy of Pediatrics recently set lower limits on the recommended fat intake of children and adolescents at no more than 30% of the average daily caloric intake and no less than 20% of the average daily caloric intake.

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TABLE 12.6
Recommended Diet Modifications to Lower Blood Cholesterol

 

Step 1 Diet

 

Choose

Decrease

From The Expert Panel. Report of The National Cholesterol Education Program. Arch Intern Med 1988;148:49, with permission.

Fish, chicken, turkey, and lean meats

Fish, poultry without skin, lean cuts of beef, lamb, pork or veal, shellfish

Fatty cuts of beef, lamb, pork; spare ribs, organ meats, regular cold cuts, sausage, hot dogs, bacon, sardines, roe

Skim and low-fat milk, cheese, yogurt, and dairy substitutes

Skim or 1% fat milk (liquid, powdered, evaporated), buttermilk

Whole milk (4% fat): regular, evaporated, condensed; cream, half and half, 2% milk, imitation milk products, most nondairy creamers, whipped toppings

 

Nonfat (0% fat) or low-fat yogurt

Whole-milk yogurt

 

Low-fat cottage cheese (1% or 2% fat)

Whole-milk cottage cheese (4% fat)

 

Low-fat cheese, farmer or pot cheese (all of these should be labeled no more than 2–6g of fat/oz)

All natural cheeses (e.g., blue, roquefort, camembert, cheddar, Swiss), low-fat or “light” cream cheese, low-fat or “light” sour cream, cream cheese, sour cream

 

Sherbet, sorbet

Ice cream

Eggs

Egg whites (two whites equal one whole egg in recipes), cholesterolfree egg substitutes

Egg yolks

Fruits and vegetables

Fresh, frozen, canned, or dried fruits and vegetables

Vegetables prepared in butter, cream, or other sauces

Breads and cereals

Homemade baked goods using unsaturated oils sparingly, angel food cake, low-fat crackers, low-fat cookies

Commercial baked goods: pies, cakes, doughnuts, croissants, pastries, muffins, biscuits, high-fat crackers, high-fat cookies

 

Rice, pasta

Egg noodles

 

Whole-grain breads and cereals (oatmeal, whole wheat, rye, bran, multi-grain, etc.)

Breads in which eggs are a major ingredient

Fats and oils

Baking cocoa

Chocolate

 

Unsaturated vegetable oils: corn, olive, rapeseed (canola oil), safflower, sesame, soybean, sunflower

Butter, coconut oil, palm oil, palm kernel oil, lard, bacon fat

 

Margarine or shortenings made from one of the unsaturated oils listed above, diet margarine

 
 

Mayonnaise, salad dressings made with unsaturated oils listed above, low-fat dressings

Dressings made with egg yolk

 

Seeds and nuts

Coconut

  1. Set dietary goals.
  2. Reduced dietary fats
  3. Reduced saturated fat and improved fatty acid balance
  4. Reduced dietary cholesterol
  5. Increased complex carbohydrates Achieving these dietary goals can be difficult for teens, so help from a physician, a dietitian, and the family is crucial. Helpful suggestions include the following:
  • Snacks: Most candies should be limited. Replace with Graham crackers, Rye Krisp, melba toast, soda crackers, bagels, English muffins, and fruits and vegetables. Popcorn should be air popped.
  • Desserts: Try fruits, low-fat yogurt, fruit ices, and jello.
  • Cooking methods: Choose methods that use little or no fat, such as steaming, baking, or broiling.
  • Eating away from home: Order entrées, potatoes, and vegetables without sauces or butter.
  • Ask for salad dressings to be served on the side. Limit high-fat toppings such as bacon, crumbled eggs, cheese, and sunflower seeds.
  • A regular exercise program is an important adjunct to a change in eating habits.
  • Initiate diets that closely correspond to the adolescent's usual eating habits.

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  • Implement specific goals in a graduated manner, rather than all at once.
  • Encourage family participation in the dietary management and the exercise program.
  • Stress the maintenance of ideal body weight, an exercise program, and the prevention of nicotine and alcohol use.

Dietary Therapy

Step 1 and Step 2 diets are outlined at the AHA Web site (http://www.americanheart.org). (Table 12.7).

  1. Reduce dietary fats: The typical fat intake of children in the United States is 36% of total energy consumption. To meet the goal of 30%, the teen must make several modifications in the intake of “visible” and “invisible” fats. Visible fats include butter, margarine, oils, salad dressing, mayonnaise, cream, and gravies. They are often added to foods or used in preparation (e.g., fried chicken or French fries). Invisible sources of fat include oils and other fats incorporated into baked goods, processed foods (e.g., cold cuts, frozen meats, and franks), whole milk, other dairy products, and snack foods (e.g., chips, doughnuts). Sources of fats should be identified in the adolescent's diet. The amount and frequency of consumption of high-fat food should be reduced and lower-fat alternatives given.
  2. Reduce saturated fats and improve fatty acid balance: Saturated fatty acids with chain lengths of 12 carbons (lauric), 14 carbons (myristic), and 16 carbons (palmitic) have the most hypercholesterolemic effect in humans. Stearic acid, an 18-carbon saturated fatty acid, has been found to be less atherogenic than 12- to 16-carbon fatty acids. These 12- to 16-carbon fatty acids are found in certain vegetable oils (e.g., palm or coconut), animal fats, and whole-milk dairy products. The 18-carbon stearic acid is found in chocolate and beef.

Data from the 1988 Continuing Survey of Food Intakes by Individuals show that 14% of total calories is contributed to the diet from saturated fatty acids, a percentage that is higher than the recommended 10% limit. Therefore, when saturated fats are reduced to <10% of total calories, the balance of monounsaturated and polyunsaturated fatty acids must be considered. Major sources of monounsaturated fatty acids include olive oil, canola oil, peanuts, hazelnuts, avocado, lean beef, and poultry. Substituting these for saturated fatty acids in the context of a low-fat diet can lead to a reduction in LDL-C, no elevation in triglycerides, and preservation of HDL-C.

The major categories of polyunsaturated fatty acids are ω-6 or ω-3 fatty acids, terms referring to the positions of their double bonds. Linoleic acid, the major ω-6 fatty acid in the diet, is found in vegetable oils such as safflower, sunflower seed, soybean, and corn oils. ω-6 Fatty acids, when used in the context of the other dietary recommendations, lower total cholesterol and LDL-C concentrations without decreasing HDL-C concentration. Taken in amounts higher than 10% of total calories, these fatty acids may cause subsequent lowering of HDL-C levels. The long-term safety of a diet high in polyunsaturated fats, in relation to the incidence of cancers, has not been established.

ω-3 Fatty acids are primarily found in cold-water fish as eicosapentaenoic acid and docosahexaenoic acid and in soybean and walnut oils as linolenic acid. ω-3 Fatty acids, given as fish-oil supplements, have been shown to lower elevated triglyceride levels in adult patients with hypertriglyceridemia and to improve the dyslipidemia in pediatric patients with systemic lupus erythematosus. Fish-oil supplementation should be monitored medically for side effects such as decreased clotting time. In general, increasing the number of meals with cold-water fish (e.g., salmon, mackerel, bluefish, trout, and sable fish) to a minimum of twice weekly while decreasing fatty beef and poultry dishes would be beneficial.

  1. Reduce dietary cholesterol: Dietary cholesterol will elevate both plasma concentrations of total cholesterol and LDL-C. The current consumption of cholesterol by children is <300 mg/day, which is almost within reach of the current recommendations. The following suggestions are given to guide the patient with hyperlipidemia and his or her family:

TABLE 12.7
Dietary Therapy for High Blood Cholesterol Levels: Characteristics of Step 1 and Step 2 Diets for Lowering Blood Cholesterol Levels

 

Recommended Intake

Nutrient

Step 1 Diet

Step 2 Diet

Total fat

20% of–30% of total calories

Same

Saturated fatty acids

<10% of total calories

<7% of total calories

Polyunsaturated fatty acids

≤10% of total calories

Same

Monounsaturated fatty acids

Remaining total fat calories

Same

Cholesterol

<300 mg/d

<200 mg/d

Carbohydrates

≈55% of total calories

Same

Protein

≈15%–20% of total calories

Same

Calories

To promote normal growth and development and to reach or maintain desirable body weight

Same

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  2. Reduce visible egg yolks such as fried eggs and egg yolks used in home recipes and replace with egg whites or egg substitutes.
  3. Limit portions of cooked meat, chicken, and fish to 7 to 8 oz daily; if lean cuts of beef and pork and controlled amounts of shellfish (six medium-sized shrimp) are used, they can be incorporated into the diet and can provide a significant source of minerals and vitamins.
  4. Use skim milk or the lowest-fat dairy products available. Cholesterol-restricted diets have been shown to be safe in relation to growth and cognitive development in several European studies (Rask-Nissila et al., 2000) and in the United States (Jacobson et al., 1998).
  5. Increase complex carbohydrates: When fat is removed from an adolescent's diet, an energy deficit may occur. In the overweight or obese teenager, this may aid in cessation of weight gain, but in the normal-weight to underweight individual, it may result in undesirable weight loss. Therefore, it is important to replace the fat energy with complex carbohydrate sources. Complex carbohydrates are found in fruits, vegetables, and whole-grain products, such as unsweetened cereals, pasta, breads, corn, rice, and crackers.

Fatfree baked products offer a wide variety of snacks for adolescents and encourage adherence to the diet regimen. These products are isocaloric with their full-fat counterparts and thereby contain a significant amount of simple sugar; therefore, their intake must be limited for the patient with elevated triglyceride concentrations, impaired glucose tolerance, or obesity.

What are the Differences between the American Heart Association Diet, and the Step 1 and Step 2 Diets?

The Step 1 diet from the AHA is very similar to the diet recommended by the AHA for the general public, with the exception that the Step 1 diet is followed in a medical setting. The Step 2 diet has further reductions in cholesterol and saturated fat for those already on a Step 1 diet or for those with a higher level of cholesterol or more risk factors. Step 1 and Step 2 diets should be combined with regular physical activity in all patients and with weight reduction in the overweight.

What is New in the ATP III Therapeutic Lifestyle Changes Diet?

The Step 2 diet's limit on saturated fat of 7% of energy intake has been adopted for all adults and combined with a more liberal total fat intake of 25% to 35%, with the majority coming from monounsaturated fats. These changes recognize the contribution of excess intake of fatfree commercial baked goods with extra sugar, which have contributed to the epidemic of obesity, metabolic syndrome, and type 2 diabetes.

Vitamin Therapy

The ATP III acknowledges the importance of meeting the daily recommended intake (DRI) of vitamins and minerals but does not recommend megavitamin therapy beyond the DRI because of the negative data from clinical trials of β-carotene and antioxidant vitamins. We recommend all adolescents take an over-the-counter multivitamin with 100% of the DRI for folic acid (400 µg), as well as all the other water-soluble and fat-soluble vitamins and minerals for which there are DRIs.

Stanols and Plant Sterols

As adjunctive LDL-C–lowering therapy, the ATP III recommends the addition of plant-derived cholesterol absorption-inhibiting compounds such as esters of cholestanol or other nonabsorbed sterols available as margarine or salad dressing (at two to three servings/day). Studies, mainly from Europe, have shown an additional 10% to 15% LDL-C reduction with daily use of these compounds in persons consuming a low-saturated fat, low-cholesterol diet.

Drug Therapy

The risk-benefit ratio for any drug therapy is unknown in adolescents. However, pharmacotherapy is considered when

  1. Xanthomas are present on physical examination or all of the criteria 2 to 4 are met
  2. Supervised diet modification fails to lower LDL-C to acceptable levels or by at least 15% below baseline, plus
  3. A parent has died or had severe atherosclerotic sequelae in his or her forties or younger, plus
  4. The adolescent's LDL-C concentration is >190 mg/dL in the absence of other risk factors or >160 mg/dL in the presence of any of the following: smoking, hypertension, diabetes, and clinical signs of atherosclerosis.

In individuals older than 20 years, base the treatment on the ATP III LDL goals outlined previously in the section “Screening in Young Adults.”

Table 12.8 summarizes mechanisms of action and major effects and lists recommended doses and side effects of the drugs used for hyperlipidemic conditions. These drugs are further detailed here.

Available Drugs

  1. Bile acid sequestrants
  2. Cholestyramine (Questran), a hydrophilic, insoluble anion-exchange resin powder
  • Action: Interrupts the enterohepatic circulation of bile acids and binds bile acids in the intestine to form an insoluble complex, which is excreted in feces and thereby increases hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in LDL-receptor activity in the liver. This, in turn, stimulates removal of LDL from plasma and lowers LDL-C concentration. There may be an increase in hepatic VLDL production and thereby an increase in triglyceride concentration. The advantage of this drug in the treatment of adolescents is that there is no systemic absorption or toxic effects. However, the gastrointestinal (GI) side effects are frequent, leading to problems in compliance.
  • Effects: Lowering of both total cholesterol and LDL-C levels by 15% to 30% at 16 to 24 g/day.
  • Side effects
  • –GI effects include nausea, bloating, and constipation.
  • –Drug is difficult to take because it must be suspended in a liquid vehicle. If water is unsatisfactory, an unsweetened juice may improve palatability. Rapid ingestion may cause air swallowing.

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TABLE 12.8
Drug Therapy for Hyperlipidemia

Type of Drug

Mechanism of Action

Major Effects

Example

Starting Dose

Adverse Reactions

LDL, low-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL, very low-density lipoprotein; GI, gastrointestinal.

Statin

Inhibits cholesterol synthesis in hepatic cells, resulting in increased LDL-receptor activity

Lowers LDL cholesterol and triglyceride, raises HDL-C

Atorvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin

5–20 mg depending on which drug is used

Raised hepatic enzymes, muscle soreness possibly progressing to myolysis

Bile acid sequestrants

Binds intestinal bile acids interrupting enterohepatic recirculation, which in turn results in LDL-receptor up regulation

Lowers LDL-C Raises triglycerides

Cholestyramine, colesevelam

One to two packs of powder or four tablets (1 g) daily, with 8 oz water

Limited to GI tract; gas, bloating constipation, cramps, fat-soluble vitamin deficiency

Fibric acid

Probably inhibits hepatic synthesis of VLDL

Mainly lowers triglycerides and raises HDL-C, with less effect on LDL-C

Gemfibrozil, fenofibrate

Varies with preparation

Dyspepsia, constipation, raised liver enzymes, myositis, rhabdomyolisis, anemia

Nicotinic acid

Upregulates hepatic LDL receptors, decreases hepatic LDL and VLDL production

Lowers triglycerides LDL-C and Lp(a), raises HDL-C

Niaspan

500 mg begin slowly to minimize side effects

Flushing, hepatic toxicity, hyperglycemia

Cholesterol absorption inhibitor

Inhibits cholesterol absorption in small intestine, interferes with enterohepatic recirculation

Lowers LDL-C

Ezetimibe

10 mg

Hepatitis, pancreatitis, cholecystitis, diarrhea, abdominal pain, athralgia

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  • –Bleeding tendencies, osteoporosis, or iron deficiency may result from poor absorption of vitamin K, calcium, or iron, but these complications are rare.
  • Dose: Available in powder form (16–24 g). Should be started at one pack (4 g of cholestyramine; 5 g of orange-flavored filler) twice a day and gradually increased over a month to the full dose. The average dose is two or three packs (8–12 g) taken orally, twice daily with meals.
  1. Colesevelam (WelChol)
  • Action, effects, and side effects: Are similar to those of cholestyramine but GI side effects are considerably reduced.
  • Dose: Available in pill form, making it more convenient for many teens, although the large size of the tablet can be a deterrent to compliance in some. The average dose is two tablets taken orally twice daily with 8 oz of fluid. The maximum adult dose is seven tablets a day.
  1. Nicotinic acid (niacin)
  2. Action: Reduces VLDL production by inhibiting lipoprotein synthesis in the liver. Also has effects on lipoprotein lipase in the adipocyte. Niacin is an effective drug but requires considerable patient education because of flushing. A newer proprietary form, Niaspan has shown increased efficacy and reduced flushing in adults. It is also the least costly of the drugs.
  3. Effects: Primarily reduces triglyceride levels but also lowers LDL-C levels and causes a rise in HDL-C. A dose of 1 to 2 g/day can result in a 40% decrease in triglyceride and VLDL levels, a 20% decrease in LDL levels, and a 30% increase in HDL levels. Nicotinic acid is particularly valuable in combination therapy with a bile acid sequestrant because of the complementary modes of action—niacin inhibiting LDL and VLDL production and the bile acid sequestrant increasing LDL excretion. Statin plus niacin is also effective in mixed dyslipidemias.
  4. Side effects: The vitamin preparation is poorly tolerated in the dose needed for lipid lowering.
  • Gastritis, peptic ulcer disease, vomiting, and diarrhea can occur.
  • Liver function abnormalities can occur.
  • Vasodilatation with flushing is also a troublesome side effect.
  1. Dose: The side effects can be reduced by using the sustained release product and starting with a dose of 500 mg with meals or at bed time and gradually increasing for 1 month to 6 weeks. The average daily dose is 1 to 2 g. The possibility of flushing as a side effect should be discussed in advance with the adolescent and parent. Because the flushing is due to prostaglandin effects, it can be ameliorated by taking one aspirin (81 mg) 30 minutes before each dose. Individuals taking niacin should have regular monitoring of aminotransferase, glucose, alkaline phosphatase, and uric acid values.
  2. Inhibitors of HMG-CoA reductase (Table 12.9)
  3. Lovastatin (Mevacor)
  • Action: Competitively inhibits the rate-limiting enzyme in cholesterol biosynthesis. LDL-receptor activity is also increased, leading to an increase in the rate of removal of LDL.
  • Effects: Causes an average reduction in the LDL-C concentration of 25% to 45%.
  • Side effects: Usually well tolerated. The most common side effects include GI upset, muscle aches, and hepatitis. There is an increase in aminotransferase levels in 1.9% of patients. Careful monitoring of liver function is essential. Myalgias occur in approximately 2.4% of individuals. Others include headaches, nausea, fatigue, insomnia, skin rashes, and myositis. Transient mild elevations in creatinine kinase (CK) are commonly seen; in the few patients in whom markedly elevated CK levels and myositis develop, the drug should be discontinued. Results from the lovastatin adolescent trial on 132 male adolescents with familial hypercholesterolemia show efficacy similar to that seen in adults, with normal growth and development (Stein et al., 1998).
  • Dose: Usually, the starting dose is 20 mg once daily with the evening meal, with increases to 40 mg and then 80 mg as a single evening dose or in divided doses. Liver function should be checked at the start of therapy at 4 to 6 weeks, 6 months, and then yearly.
  1. Pravastatin (Pravachol)
  • Action, effects, and side effects: Similar to those of lovastatin.
  • Dose: 10 to 40 mg
  1. Simvastatin (Zocor)
  • Action, effects, and side effects: Similar to those of lovastatin.
  • Dose: 5 to 80 mg
  1. Atorvastatin (Lipitor)
  • Action, effects, and side effects: Similar to those of lovastatin, with the additional effect of lowering triglycerides.
  • Dose: 5 to 80 mg
  1. Simvastatin and atrovastatin have now had several randomized clinical trials in adolescents with familial hypercholesterolemia. They are becoming first-line therapy when TLC fail to lower LDL-C to target ranges in this age-group (Kohn and Jacobson, 2004).
  2. Drugs that interfere with statin metabolism: As indicated in Table 12.9, the cytochrome P-450 CYP3A4 and CYP2C9 pathways are involved in metabolism of some of the statins. This can cause problems, for example, with the following medications:
  • Inhibits CYP3A4 (raises serum drug concentrations): erythromycin, clarithromycin, cyclosporine, ritonavir, fluconazole, verapamil, grapefruit juice
  • Induces CYP3A4 (lowers serum drug concentrations): barbiturates, carbamazepine, nafcillin, phenytoin, primidone, rifampin
  • Inhibits CYP2C9 (may raise serum fluvastatin concentrations): amiodarone, cimetidine, trimethoprim-sulfamethoxazole, fluoxetine, isoniazid, ketoconazole, metronidazole
  • Induces CYP2C9 (may lower serum fluvastatin concentrations): barbiturates, carbamazepine, phenytoin, primidone, rifampin
  1. Fibric acid derivatives
  2. Gemfibrozil (Lopid)
  • Action: Increases lipoprotein lipase activity and decreases hepatic triglyceride production and inhibits peroxisome proliferator-activated receptor gamma(PPARγ ).

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TABLE 12.9
Characteristics of Statin Drugs

Characteristic

Lovastatin

Pravastatin

Simvastatin

Atorvastatin

Fluvastatin

LDL, low-density lipoprotein; HDL, high-density lipoprotein; CNS, central nervous system.
Adapted from Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498, with permission.

Maximum dose (mg/d)

80

40

80

80

80

Maximal LDL cholesterol reduction (%)

40

34

47

60

24

Serum triglyceride reduction produced (%)

16

24

18

29

10

Serum HDL cholesterol reduction produced (%)

8.6

12

12

6

8

Plasma half-life (hr)

2

1–2

1–2

14

1.2

Optimal time of administration

With meals (morning and evening)

Bedtime

Evening

Evening

Bedtime

CNS penetration

Yes

No

Yes

No

No

Hepatic metabolic mechanism

Cytochrome P-450 3A4

Sulfation

Cytochrome P-450 3A4

Cytochrome P-450 3A4

Cytochrome P-450 2C9

  • Effects: Reduces both VLDL and triglyceride levels. In some individuals, cholesterol levels may decrease and HDL levels may rise. The drug is primarily used for lowering high levels of triglycerides.
  • Side effects: Biliary tract disease, and contraindicated in liver or kidney disease. Abdominal discomfort, diarrhea, muscle ache, and increased appetite can occur.
  • Dose: 600 to 1,200 mg/day in two doses.
  1. Fenofibrate (Tricor)
  • Action, effects, and side effects: Similar to those of gemfibrozil.
  • Dose: 48 or 145 mg/day
  1. Ezetimibe (Zetia)
  • Action: Blocks cholesterol absorption at the intestinal brush border. Interferes with the enterohepatic reabsorption of cholesterol.
  • Effects: Lowers LDL-C and is synergistic with statins allowing for a lower statin dose with increased efficacy and fewer side effects.
  • Side effects: Hepatitis, pancreatitis, cholecystitis, diarrhea, abdominal pain, and athralgia are reported but rarely seen in clinical practice. Randomized placebo-controlled clinical trials are currently under way in adolescents, which will give further information about efficacy and safety. As of April 2007, ezetimibe is not approved for use in those younger than 18 years.
  • Dose: 10 mg/day

Generally, in the past the bile acid sequestrants used together with nicotinic acid have been considered firstline agents. Fibrates have been used as a second step. However, they are less effective in lowering LDL-C. Now, inhibitors of HMG-CoA reductase, statins, have become first-line agents. Statins are even more effective when used in conjunction with a bile acid sequestrant, niacin, or ezetimibe.

  1. Antioxidants

Research by Steinberg and Witzum (1990) on the effects of oxidized LDL has suggested a therapeutic role for antioxidants in the treatment of elevated levels of LDL-C. These drugs have not been widely accepted in the treatment of adolescents and should be considered investigational.

  1. Pancreatic lipase inhibitors: orlistat (Xenical)

These medications cause fat malabsorption and have been primarily used as an adjunct for weight management. Use of these medications, independent of weight loss, has also been noted to significantly improve cardiovascular risk factors and glycemic control. The usual dose is 120 mg thrice daily approximately 20 minutes before meals. Research into these drugs as lipid-lowering agents for adolescents may provide another method of therapy.

Adherence to Drug Therapy

  1. Drug therapy should be considered an adjunct and not a replacement for TLC. Many teens, once they are able to make healthier food choices and get regular vigorous physical activity, can get their LDL-C into the target range without medications.
  2. The teen must be well informed about the goals of drug treatment and the side effects.
  3. It is important to start with small doses of drugs, particularly with sequestrants or nicotinic acid.
  4. The frequency of use of the medication and the impact on lifestyle must be discussed.
  5. It is important to maintain regularly scheduled follow-ups with the teen.

Support Materials

The full report and executive summary of the ATP III, Web-based and Palm software for assessing Framingham

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risk score, and print materials for professionals and patients are available at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.

The following publications to assist in hypercholesterolemia therapy are available from the AHA (7320 Greenville Ave, Dallas, TX 75231) (many of the handouts are available at the AHA Web site at: http://www.americanheart.org/).

The AHA Diet (publication no. 51-018-B). Moderate, fat-controlled low-cholesterol meal plan.

Cholesterol and Your Heart (publication no. 50-069-A). Explanation of what cholesterol is and why it is a risk factor.

Recipes for Fat-Controlled, Low-Cholesterol Meals (publication no. 50-020-B). Recipes for healthy meals.

AHA Cookbook (publication No. 53-001-A). A fat and cholesterol calorie chart and 250 recipes.

In addition, the following is available from the NCEP, National Heart, Lung, and Blood Institute (Box C-200, Bethesda, MD 20892): Physician's Kit on High Blood Cholesterol.

Further dietary information for a heart healthy diet is available in Chapter 6.

Web Sites

For Teenagers and Parents

http://www.americanheart.org. Topics include cholesterol, cholesterol in children, fiber and oat bran, home testing devices, cholesterol levels, cholesterol ratio, screening, dietary guidelines, drugs, risk factors, and triglycerides.

http://www.cdc.gov/cvh/library/fact_sheets.htm. A list of fact sheets for parents describing types of heart disease and stroke and how to prevent them.

http://www.nhlbi.nih.gov/about/ncep/index.htm. This site is the home page for the National Cholesterol education program and has useful links and information for the public and for professionals

http://www.brightfutures.org. The Bright Futures Organization site presents guidelines for healthy nutrition and physical activity for children and adolescents.

http://www.adolescenthealth.org/Health_Guide_for_Americas_Teens.pdf. This document from the Society for Adolescent Medicine has tips to help teens live a healthy lifestyle.

For Health Professionals

http://www.americanheart.org. Cholesterol screening position paper from the AHA.

http://www.cdc.gov/growthcharts/. The source for the most up-to-date growth charts including the new BMI percentile charts.

http://eurodiet.med.uoc.gr/. This site is useful for a European perspective on healthy lifestyles. It contains consensus statements by a European working group on food-based nutrient guidelines

http://www.usda.gov/. This site is a good place to find the latest dietary guidelines for Americans. Also useful is www.mypyramid.gov for the new food guide pyramid.

http://www.aap.org/policy/re9805.html. American Academy of Pediatrics policy on cholesterol in children.

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