Park's Pediatric Cardiology for Practitioners, 6th Ed.

Dyslipidemia and Other Cardiovascular Risk Factors

Atherosclerotic cardiovascular (CV) disease is a major cause of morbidity and mortality and is responsible for more than 50% of all the deaths in the United States and other Western countries. The best and longest known risk factor for coronary artery disease (CAD) is hypercholesterolemia. Other types of dyslipidemia, obesity, smoking, hypertension, and diabetes mellitus are among the known CV risk factors. Although most of the clinical burden of CV disease occurs in adulthood, these risk factors can develop during childhood and adolescence. In fact, there is now clear evidence that atherosclerosis begins during childhood. To reduce CV death, we need to turn our attention to preventing and correcting these risk factors before adulthood when atherosclerotic processes may have progressed too far to be reversible by therapy.

Unfortunately, the importance of preventing heart disease in the pediatric population is not well perceived by pediatricians and pediatric cardiologists. When pediatricians and pediatric cardiologists are asked about heart disease in children, they think about congenital heart defects (CHD). Although CHD is associated with the highest mortality rate of any congenital defects, only 0.4% of deaths from CV diseases are caused by CHDs in the United States. The great majority of CV death is from CAD (54%), stroke (18%), congestive heart failure (6%), and hypertension (5%) (Lauer et al, 2006). Therefore, preventive cardiology is and should be in the pediatric domain. The primary purpose of this chapter is to raise physicians’ attention to the emerging importance of practicing medicine to prevent future CV disease (and type II diabetes) during childhood.

The strongest CV risk factors include a high concentration of low-density lipoprotein (LDL) cholesterol and triglycerides, a low concentration of high-density lipoprotein (HDL), elevated blood pressure, diabetes mellitus, cigarette smoking, and obesity. The prevalence of obesity has increased rapidly in recent decades, which is now known to be an independent risk factor for CV disease and diabetes. Obesity is often associated with other CV risk factors such as atherogenic dyslipidemia. Therefore, early detection and treatment of dyslipidemias and obesity during childhood and adolescence may help reduce CV mortality and morbidity in adulthood.

This chapter discusses the following topics in the order listed below. Hypertension, another CV risk factor, is discussed in a separate chapter (Chapter 28).

1. Evidence of childhood onset of atherosclerotic heart disease

2. Identification of standard CV risk factors and the diagnosis of metabolic syndrome in children

3. In-depth discussion of dyslipidemia in children, including lipid screening and diagnosis and treatment of dyslipidemia. Dyslipidemia includes hypercholesterolemia, hypertriglyceridemia, and low HDL cholesterol.

4. Diagnosis and principles of management of childhood obesity

5. Strategies for smoke cessation

6. The summary table of the American Heart Association (AHA) Guidelines on practice of pediatric preventive cardiology

Childhood Onset of Coronary Artery Disease

Atherosclerotic lesions start to develop in early childhood and progress to irreversible lesions in adolescence and adulthood. The strongest evidence of childhood onset of CAD comes from the Bogalusa Heart Study (Berenson et al, 1998) and the Pathological Determinants of Atherosclerosis in Youth (PDAY) Research Group (Strong et al, 1995McGill et al, 2002). Autopsy studies of the aorta and coronary arteries in the youth after unexpected deaths in the Bogalusa Heart Study and in the study by the PDAY Research Group have found that atherosclerosis originates in childhood, with a rapid increase in the prevalence of coronary pathology during adolescence and young adulthood.

These studies have found the following:

1. Fatty streak, the earliest lesion of the atherosclerosis, occurred by 5 to 8 years of age, and fibrous plaque, the advanced lesion, appeared in the coronary arteries in subjects in their late teens.

2. Fibrous plaque was found in more than 30% of 16- to 20-year-old patients, and the prevalence of the lesion reached nearly 70% by age 26 to 39 years.

3. The extent of pathological changes in the aorta and coronary arteries increased with age and so did the number of known CV risk factors that the individual had at the time of death.

Therefore, one strategy of reducing CAD in adults is to prevent or correct CV risk factors in children and adolescents.

Cardiovascular Risk Factors and Metabolic Syndrome

Box 33-1 lists major risk factors for CV disease, according to the Third Report of the National Cholesterol Education Program (NCEP) (Circulation, 2002).

Cardiovascular risk factors include a positive family history of coronary heart disease, smoking, high levels of cholesterol, hypertension, being overweight, smoking, and diabetic or prediabetic states. These risk factors are all associated with an increased prevalence and extent of atherosclerosis. Obtaining a history of these CV risk factors should be a routine process in the practice of medicine.

A family history of premature CAD in first-degree relatives (parents and siblings) has been found to be the single best predictor of CV risk for adults. For children, however, family history includes the first- andsecond-degree relatives (including parents, siblings, grandparents, or blood-related aunts and uncles) who have or had CAD before age 55 years for boys and before age 60 years for girls. The reason that the second-degree relatives are included in family history for children is because some children’s parents are too young to have developed clinical CAD when their children are examined.

The relationship between obesity and CAD has been a subject of some dispute for many years. However, more recent studies have shown that obesity is a risk factor for CAD independently of the standard risk factors, probably through the emerging risk factors. The emerging risk factors, which are commonly found in obese persons, include atherogenic dyslipidemia (also known as the lipid triad” consisting of raised level of triglycerides; small, dense LDL particles; and low levels of HDL-C), insulin resistance (hyperinsulinemia), a proinflammatory state (elevation of serum high-sensitivity C-reactive protein [CRP]), and a prothrombotic state (increased amount of plasminogen activator inhibitor-1 [PAI-1]).

BOX 33-1 Major Risk Factors for Coronary Heart Disease

Family history of premature coronary heart disease, cerebrovascular or occlusive peripheral vascular disease (with onset before age 55 years for men and 65 years for women in parents or grandparents)

Cigarette smoking

Hypercholesterolemia

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

Low levels of high-density lipoprotein (<40 mg/100 mL)

Diabetes mellitus (as a coronary heart disease risk equivalent)

Adapted from Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Education, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143-3421, 2002.

The cluster of the above risk factors occurring in one person is known as “the metabolic syndrome.” In the metabolic syndrome, LCL-C levels may not be elevated, but apoprotein B (apo B) and small, dense LDL particles are elevated; the smallest particles in the LDL fraction are known to have the greatest atherogenicity (see a later section for further discussion on small, dense LDL particles). This syndrome occurs more commonly in individuals with abdominal (visceral) obesity. The exact mechanism for the role of visceral adiposity is not completely understood, but it appears to be closely related to insulin resistance. It has been assumed that obese adipose tissue releases an excess of fatty acids and cytokines that induce insulin resistance. With increasing adiposity, the lipid triad becomes more pronounced. Hispanics and South Asians seem to be particularly susceptible to the syndrome. Black men have a lower frequency of the syndrome than do white men, likely because of a lower prevalence of atherogenic dyslipidemia.

Clinically identifiable components of the metabolic syndrome for adults are listed in Box 33-2. The presence of at least three of the risk factors is required to make the diagnosis of the metabolic syndrome in adults. Evidence has supported that waist circumference (WC) (reflecting visceral adiposity) is a better predictor of CV disease than body mass index (BMI). Although LCL-C may not be elevated, small, dense LDL particles present in this syndrome are highly atherogenic. Other components of metabolic syndrome, such as proinflammatory and prothrombotic states, are not routinely measured in clinical practice. CRP of 3 mg/L or above may be significant in adults.

A direct association between obesity and insulin resistance also exists in children. Several definitions for use in the clinical setting for diagnosis of the metabolic syndrome in children exist. One in particular, Cook and coworkers’ (Cook et al, 2003) definition, includes triglycerides of 110 mg/dL or above and fasting glucose of 110 mg/dL or above. On the other hand, the International Diabetes Federation (2007) has proposed different cutoff points for these two, 150 mg/dL or above for triglycerides and 100 mg/dL or above for fasting glucose. The triglyceride level of 150 mg/dL is more appropriate according to more recent NHANES (National Health and Nutrition Examination Survey) data (collected between 1988 and 2002); the 90th percentile of triglyceride is much higher than 110 mg/dL (Jolliffe, 2006). Note that the new values for triglycerides and fasting glucose proposed by International Diabetes Federation are the same as in adults (see Box 33-2). As in adults, the presence of at least three of the risk factors is required to make the diagnosis of the metabolic syndrome in children. It is important to note that LDL-cholesterol (LDL-C) levels may not be elevated, but this is because the LDL is mostly made up by small, dense LDL particles, which are much more atherogenic than large LDL particles. The prevalence of the metabolic syndrome in adolescents has been reported to be about 4%, but it increases to 30% to 50% in overweight adolescents (Singh, 2006).

BOX 33-2 Definitions of the Metabolic Syndrome in Adults and in Children and Adolescents

image

BMI, body mass index; WC, waist circumference.

 The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Education, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143-3421, 2002.

 Zimmet P, Alberti G, Kaufman F, et al: International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. The metabolic syndrome in children and adolescents. Lancet 369(9579):2059-2061, 2007.

As in adults, WC is preferable to BMI for children as well, which represents abdominal (visceral or central) obesity. Ethnicity- and gender-specific WC percentiles are now available for children from the NHANES III (Fernandez et al, 2004) (see Tables C-1 through C-3Appendix C). There are significant differences in WC according to ethnicity and gender. In general, Mexican American boys and girls have higher WCs than other ethnic groups. Note that the 75th percentile of WC of African American and Mexican American girls 16 and 17 years old exceed the WC values of 88 cm (35 inches) identified as the cutoff point for increased risk of obesity-related comorbidities in women.

The mainstay of the treatment of the metabolic syndrome for both adults and children is weight control through dietary intervention and promotion of an active lifestyle to achieve and maintain optimum weight, normal blood pressure, and normal lipid profile for age. The pharmacologic intervention is usually not required in children, but drugs may be used in selected high-risk patients. Each component of the syndrome present should be treated aggressively because the presence of the syndrome indicates a higher risk for CV diseases and diabetes.

Metformin (Glucophage) therapy may be effective in preventing or delaying the development of type 2 diabetes in patients with the metabolic syndrome. In conjunction with low-intensity weight control efforts, 6 months of metformin therapy has shown modest but favorable effects on the features of the syndrome, including reduction of weight, BMI, body fat mass (but not intraabdominal adipose tissue), and total cholesterol levels. It also improved fasting plasma glucose and insulin resistance (Yanovski et al, 2011). The principles of managing obesity are presented in the section of obesity in this chapter. Treatment of dyslipidemias is presented in some detail in the section on dyslipidemia.

There appears to be a difference in susceptibility to different risk factors for different populations when they gain weight (Grundy, 2002). For example:

1. The white population of European origin appears to be more predisposed to atherogenic dyslipidemia than other populations when they gain weight.

2. Blacks of African origin are prone to hypertension when they gain weight; they also appear to be susceptible to type 2 diabetes. On the other hand, they develop less atherogenic dyslipidemia than do whites with same degree of weight gain.

3. Native Americans and Hispanics are especially susceptible to type 2 diabetes but less likely to develop hypertension than are blacks.

4. People of South and Southeast Asia also have a high frequency of insulin resistance and type 2 diabetes. They appear more susceptible to CAD than are East Asians.

Dyslipidemia

The pathogenesis of atherosclerosis and death from the coronary atherosclerosis are importantly related to high levels of total cholesterol and LDL-C levels and low levels of HDL-cholesterol (HDL-C) levels. Multiple trials in adults have demonstrated that cholesterol reduction results in reduced angiographic progression of CAD and even modest regression in some cases. Recently, a link has been established between increased levels of triglycerides and coronary heart disease. It is timely for physicians and other health care providers to review and update their knowledge on dyslipidemia.

Quick Review

Biochemistry of Lipids and Lipoproteins

Lipids represent an essential constituent of our daily diet. Four major lipids of plasma are cholesterol, triglycerides, phospholipids, and free fatty acids. Triglycerides form an important energy source for cellular metabolism. Phospholipids are, because of their amphophilic behavior, excellent emulsifiers of fats and constitute the predominant element of all biological membranes. Cholesterol has an ambivalent nature: on the one hand, it is necessary for the stabilization of biological membrane structure and an essential precursor of hormones and bile acids in hepatic metabolism; on the other hand, a surplus of cholesterol is considered to trigger atherosclerosis.

Plasma lipids that are hydrophobic do not circulate freely but rather circulate in the form of lipid-protein macromolecular complexes known as lipoproteins. The nonpolar lipids (cholesterol esters and triglycerides) are present in the lipoprotein core surrounded by a monolayer composed of specific proteins (apos) and the polar lipids (unesterified or free cholesterol and phospholipids). This monolayer allows the lipoprotein to remain miscible in plasma. Lipoproteins function as transport vehicles for water-insoluble lipid fractions and lead them to their sites of metabolism or deposition. Free fatty acids are bound to albumin.

The plasma lipoproteins have been classified into four major groups based on their density: chylomicrons, very low-density lipoprotein (VLDL), LDL, and HDL. Most cholesterol in plasma is transported by LDL (∼65%) with the remainder on HDL (25%) and VLDL (10%). Triglycerides (TGs) are transported primarily by chylomicron and VLDL.

The lipoproteins can be divided into two by the type of apos in the lipoprotein. Apos serve as enzymatic cofactors and recognition elements in binding to specific receptors.

• The apo B lipoproteins are atherogenic and include chylomicrons, LVDL, LDL, and lipoprotein(a) [Lp(a)].

• The apo A-I–containing lipoproteins are associated with reduced CV disease and include HDL and their subfractions.

Small, dense LDL. Recent studies have shown that it is the size of the LDL particles, not the total concentration of LDL, that is more important in the pathogenesis of CAD. Small, dense LDL particles are expected to be better able to penetrate through the intima of the coronary arteries to deposit in the subendothelial space, where plaque forms. They are also more readily oxidized; only oxidized LDL can enter the macrophages in the lining of the arteries and form cholesterol-rich plaques. The small, dense LDL phenotype usually occurs associated with elevated TG levels (>140 mg/dL) and a decreased HDL level (<40 mg/dL in men; <50 mg/dL in women). These are typical features of obesity, the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus.

Lipid and Lipoprotein Metabolism

A review of simplified lipid and lipoprotein metabolism is presented in Figure 33-1 for readers who wish to quickly refresh the metabolism of lipid and lipoproteins before reading clinical aspects of dyslipidemia. The figure legend provides a shorter summary of the topic.

Exogenous Pathway

After ingestion of fat-containing foods, TGs and cholesterol are absorbed into intestinal cells as fatty acids and free cholesterol. Within the intestinal wall, free fatty acids and cholesterol are reesterified to form TGs and cholesteryl ester, respectively. These lipids are then combined with phospholipids and apos A-I, A-IV, and B-48 to form TG-rich chylomicron particles. Apo B-48 is an obligatory protein.

Chylomicrons rapidly enter plasma via the thoracic duct. In the circulation, chylomicrons acquire additional apos (mainly apo E and several forms of apo C). TG-rich chylomicrons are hydrolyzed by the enzyme lipoprotein lipase (LPL) at the capillary endothelium, leaving a smaller and denser, remnant particle because they have lost much of their TGs. (The free fatty acid products of this hydrolysis are transferred primarily to adipose tissues for storage as TGs or to muscle for β-oxidation.) This particle is called chylomicron remnant and is rich in cholesterol and has gained apo E from HDL (and lost apo A and apo C to HDL).

These remnants are bound and internalized in part via hepatic membrane receptors specific for apo E on the particle. By this mechanism, dietary cholesterol is delivered to the liver, where it plays a role in the regulation of hepatic cholesterol metabolism. In normal persons, chylomicron and chylomicron remnants are very short lived in the circulation, and none of them exists in the plasma after a 12-hour fast. Chylomicron and chylomicron remnants may be atherogenic. Delayed clearance of chylomicron occurs in inherited deficiency of LPL or its activator, apo C-II (type I hypertriglyceridemia).

image

FIGURE 33-1 Endogenous and exogenous pathways of plasma lipid and lipoprotein metabolism. Free fatty acid (FA) and cholesterol (C) are esterified in the intestinal mucosa to form triglyceride (TG) and cholesteryl ester (CE), respectively. They combine with apoprotein (apo) A and apo B-48 to form chylomicron and are secreted into the circulation. The clear portion in the circles represents TG, and the shaded portion represents CE. Chylomicron undergoes lipolysis in the capillary endothelium near adipose tissue and muscle tissue, losing TG via lipoprotein lipase (LPL). The resulting chylomicron remnants are taken up by hepatic apo E receptors for degradation by lysosomes. In the liver, TG and CE are combined with apo B-100, apo C, and apo E and then secreted as very low-density lipoprotein (VLDL). The clear portion of the circle represents TG and the shaded portion CE. VLDL undergoes lipolysis in the capillary endothelium near adipose tissue and muscle tissue, losing TG via LPL, similar to what happens with chylomicron remnants. The resulting VLDL remnants (or intermediate-density lipoprotein [IDL]) are either converted to low-density lipoprotein (LDL) for transport to peripheral cells via LDL receptor-mediated uptake or are taken up by hepatic receptors. The other major class of lipoprotein, high-density lipoprotein (HDL), participates in the conversion of free cholesterol from peripheral tissues to cholesteryl ester by the action of lecithin–cholesterol acyltransferase (LCAT). Cholesteryl esters are then directly taken up by the HDL receptors in the liver or are transferred to VLDL remnants and LDL by cholesteryl ester transfer protein (CETP), to be ultimately taken up by the liver. This process is known as reverse cholesterol transport.(Modified from Goldstein JL, Kita T, Brown MS: Defective lipoprotein receptors and atherosclerosis: Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med 309:288-295, 1983.)

Endogenous Pathway

Triglycerides synthesized in the liver are packaged with cholesteryl esters and apos B-100, C, and E and then secreted as VLDL. The synthesis of VLDL by the liver is increased by excess carbohydrate, alcohol, or caloric intake and is decreased in the fasting state.

In the capillary beds, TG in the core of the VLDL is hydrolyzed by LPL, with a cofactor apo C-II, to produce a smaller denser particle called VLDL remnant or intermediate-density lipoprotein (IDL), which is analogous to chylomicron remnant. (The surface components, except for apos B-100 and E, are transferred to HDL.) Free fatty acids generated by hydrolysis of TG are delivered to adipose tissue and muscle. Compared with VLDL, VLDL remnants have more cholesterol ester and less TG.

Some of these remnant particles (IDLs) are taken up by the hepatic receptors specific for apo E, and some others undergo conversion to LDL by hepatic TG lipase. Elevation of VLDL remnants may predispose the patient to premature CAD and peripheral artery disease (characteristically seen in Frederickson’s type III hyperlipoproteinemia).

Low-density lipoprotein is usually formed by means of enhanced conversion of VLDL remnants (see Fig. 33-1) or by direct hepatic production of apo B–containing lipoproteins. LDLs are almost entirely made up of cholesteryl esters and apo B-100.

The content of cholesterol ester in the LDL particle may vary as much as 40%. LDL particles that contain lower amounts of cholesterol ester are known as small, dense LDL particles. Patients with increased amounts of small, dense LDL particles are at increased risk for CAD. Small, dense LDL is commonly associated with male gender, diabetes, low HDL-C levels, high TG levels, and familial combined hyperlipidemia (FCH).

Low-density lipoproteins are transported to peripheral cells or liver cells. Apo B-100, the only protein found in LDL, is recognized by a high-affinity LDL receptor on the surfaces of hepatic and certain nonhepatic cells, where LDLs are internalized into the cells. By this mechanism, LDL particles can deliver cholesterol to extrahepatic tissues for use in membrane or steroid hormone synthesis. LDL receptor expression by the liver is a major regulator of plasma LDL-C levels. LDL particles have a half-life of 3 to 4 days.

The liver and small intestine secrete HDL as nascent discoid particles composed primarily of phospholipids and apolipoproteins (nascent HDL). (Whereas nascent HDL particles secreted by the intestine are rich in apo A-I and apo A-IV, those secreted by the liver contain predominantly apo A-I and apo A-II.) Nascent lipid-poor apo A-I accepts free (unesterified) cholesterol from tissues, and the free cholesterol transferred to the surface of HDL is esterified by the action of enzyme lecithin–cholesterol acyltransferase (LCAT).

High-density lipoprotein cholesteryl esters may be directly transferred to and selectively taken up by the liver via a hepatic HDL receptor called scavenger receptor class BI (SR-BI). Alternatively, HDL cholesteryl esters may transfer from HDL to VLDL and LDL by the cholesteryl ester transfer protein (CETP), after which it may be taken up by the liver or redistributed to peripheral tissues. Thus, HDLs have two pathways by which they return tissue-derived cholesterol to the liver. The removal of cholesterol from cells by HDL for ultimate disposal in the liver has been termed reverse cholesterol transport. These reactions may explain how HDL and apo A-I can protect against the development of atherosclerosis.

Among the several subtypes of HDL particles, HDL2 and HDL3 are clinically important. HDL2 is closely associated with protection against premature atherosclerosis. Alcohol consumption predominantly increases the HDL3 subfraction. Lower levels of both subfractions are associated with male gender, hypertriglyceridemia, diabetes mellitus, obesity, uremia, smoking, and the use of androgens and progesterones. Estrogen raises HDL levels.

Cholesterol returning to the liver is converted into bile acids by the enzymatic hydroxylation of cholesterol, or cholesterol and phospholipids are excreted directly into the bile. A large portion of secreted bile acid is reabsorbed in the enterohepatic circulation and recycled. Bile acid sequestrants reduce the reabsorption of secreted bile acids, eventually reducing serum cholesterol levels by increasing the conversion of hepatic cholesterol to bile acids, thus reducing the cholesterol content of the hepatocytes. The reduced hepatic cholesterol stimulates the production of surface receptors for LDL-C, clearing more LDL from the serum.

The hepatic and extrahepatic cells can control their own cholesterol content through a feedback control system. In conditions of cellular cholesterol excess, the cell can (1) suppress endogenous cholesterol production by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis; (2) decrease its input of cholesterol by suppressing the production of LDL surface receptors through a feedback mechanism; and (3) promote the removal of cholesterol by increasing its movement to the plasma membrane for efflux. The “statins” work through the first mechanism to reduce endogenous cholesterol production.

Diagnosis of Dyslipidemia

The diagnosis of dyslipidemia is made by measuring blood lipid, lipoproteins, or apolipoprotein factors. If any of the measurements are abnormal, the diagnosis of a specific dyslipidemia is made, such as elevated total cholesterol, LDL-C, apo B, non–HDL-C, and TGs or a lower than normal level of HDL-C.

Measurement of Lipid and Lipoproteins

A lipoprotein analysis is obtained after an overnight fast of 12 hours. The routine lipid profile typically includes total cholesterol, HDL-C, LDL-C, and TGs. An extended profile may also include VLDL cholesterol (VLDL-C), non–HDL-C, and the ratio of total cholesterol to HDL.

The LDL level is usually estimated by the Friedewald formula:

image

This formula is not accurate if the child is not fasting, if the TG level is above 400 mg/100 mL, or if chylomicrons or dysbetalipoproteinemia (type III hyperlipoproteinemia) is present. Methods are currently available to measure LDL-C directly, which allow LDL-C determination on specimens with the TG level above 400 mg/dL. Direct LDL-C measurement does not require a fasting specimen.

The following derivatives of lipid profile may be useful in the assessment of risks for CV disease.

1. Non–HDL-C cholesterol: Serum non–HDL-C (Total cholesterol − HDL-C) is considered a better screening tool than LDL-C for the assessment of CAD risk because it includes all classes of atherogenic (apo B–containing) lipoproteins; it includes VLDL-C, IDLs, LDL-C, and lipoprotein (a) (or Lp[a]). It was found in adults that increased level of non‐HDL-C by 1 mg/dL increases the risk of death from CV disease by 5%.

2. TC to HDL-C ratio: The total cholesterol to HDL-C (TC to HDL-C) ratio is a useful parameter for assessing risk for CV disease. The usual TC to HDL-C ratio in children is approximately 3 (based on TC of 150 mg/dL and an HDL-C of 50 mg/dL). According to the Framingham study, the ratio for average risk was 5.0 for men and 4.2 for women. The higher the ratio, the higher the risk of developing CV disease. The ratio of 3.4 halves the risk of developing CV disease for both men and women.

3. Small, dense LDL particles: In recent years, small, dense LDL particles have been shown to be more important than the total LDL levels in CAD. The size of LDL particles is not routinely measured because the presence of this phenotype is predictable. It occurs in association with elevated TG levels (>140 mg/dL) and a decreased HDL level (<40 mg/dL in men; <50 mg/dL in women). Although not routinely measured, small, dense LDL can be measured directly by various methods in commercial laboratories (including Berkeley HeartLab, Inc. [www.bhlinc.com]; Atherotec, Inc. [www.thevaptest.com]; and LipoScience, Inc. [www.lipoprofile.com]).

Normal Levels of Lipids and Lipoproteins

Table 33-1 shows normal, borderline, and abnormal levels of lipid and lipoprotein levels in children, and Table 33-2 shows those values for young adults. Note that to convert total cholesterol, LDL-C, and HDL-C levels in milligrams per deciliter to millimoles per liter, one divides the mg/dL number by a factor of 38.67. To convert TGs in milligrams per deciliter to millimoles per liter, one divides the mg/dL number by a factor of 88.5.

TABLE 33-1

Concentrations of Plasma Lipid, Lipoprotein, and Apolipoprotein in Children and Adolescents (mg/dL): Acceptable, Borderline, and High

image

HDL, High-density lipoprotein; LDL, Low-density lipoprotein.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report. Pediatrics 128(Suppl):S213-S256, 2011.

TABLE 33-2

Recommended Cut Points for Lipid and Lipoprotein Levels IN Young Adults (mg/dL)

image

HDL, High-density lipoprotein; LDL, Low-density lipoprotein.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report. Pediatrics 128(Suppl):S213-S256, 2011.

BOX 33-3 Causes of Secondary Dyslipidemia

Metabolic

Metabolic syndrome, diabetes, lipodystrophies, glycogen storage disorders

Renal disease

Chronic renal failure, nephrotic syndrome, glomerulonephritis, hemolytic uremic syndrome

Hepatic

Biliary atresia, cirrhosis

Hormonal

Estrogen, progesterone, growth hormone, hypothyroidism, corticosteroids

Lifestyle

Obesity, physical inactivity, diets rich in fat and saturated fat, alcohol intake

Medications

Isotretinoin (Accutane), certain oral contraceptives, anabolic steroids, thiazide diuretics, beta-adrenergic blockers, anticonvulsants, glucocorticoids, estrogen, testosterone, immunosuppressive agents (cyclosporine), antiviral agents (HIV protease inhibitor)

Others

Kawasaki’s disease, anorexia nervosa, post–solid organ transplantation, childhood cancer survivor, progeria, idiopathic hypercalcemia, Klinefelter syndrome, Werner syndrome

Classification of Dyslipidemia

Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins (Fredrickson phenotypes), but a more practical system is to classify them as primary (genetic) or secondary dyslipidemia.

1. Primary dyslipidemia is caused by single or multiple gene mutations that result in either overproduction or defective clearance of TGs and LDL-C or in underproduction or excessive clearance of HDL-C (see later discussion). This entity is much less common than secondary dyslipidemia.

2. Secondary dyslipidemia is caused by associated diseases or conditions and is much more common than primary dyslipidemia (see further discussion later). The majority of the cases found during screening are secondary forms.

Screening of all family members is recommended to determine whether the disorder is a familial one. Family screening is important not only to detect dyslipidemia in other members of the family but also to emphasize the need for all family members to change their eating patterns. Young patients with elevated LDL levels are more likely to have a familial disorder of LDL metabolism. Secondary dyslipidemia can occur in any age group.

Secondary Dyslipidemia

Box 33-3 lists the causes of secondary dyslipidemia. The most common cause of pediatric dyslipidemia is obesity. Medications such as oral contraceptives, isotretinoin (Accutane), anabolic steroids, diuretics, beta-blockers, and estrogens are uncommon causes of dyslipidemia. Medical conditions that include hypothyroidism, renal failure, nephrotic syndrome, and alcohol usage are less common causes of secondary dyslipidemia. Evidence of accelerated atherosclerosis from secondary causes of dyslipidemia is as impressive as that of primary causes.

TABLE 33-3

Lipid Profile in Major Lipid Disorders in Children and Adolescents

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FCH, Familial combined hyperlipidemia; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very low-density lipoprotein.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report. Pediatrics 128(Suppl):S213-S256, 2011.

Most secondary causes of dyslipidemia raise TGs and often lower HDL-C levels, with the exception of estrogen excess with which HDL-C levels increase.

Each child with dyslipidemia should have certain blood tests to help rule out secondary causes of dyslipidemia. The blood tests should include fasting blood glucose and tests of kidney, liver, and thyroid function. When the diagnosis of secondary dyslipidemia is made, one should treat the associated disorder producing the dyslipidemia first, such as diabetes, obesity, or nephritic syndrome, and then treat dyslipidemia using the same guidelines as in primary dyslipidemia.

Selected Primary Dyslipidemias

Primary or inherited dyslipidemia is less commonly found in the screening process. Major primary dyslipidemias found in children include familial hypercholesterolemia (FH), FCH, familial hypertriglyceridemia, and several others. Table 33-3 summarizes changes in the lipid profile seen with primary lipid disorders.

Familial hypercholesterolemia. FH is autosomal dominant condition caused by a lack of or a reduction in LDL receptors. Whereas heterozygotes have about a 50% reduction in LDL receptors, homozygotes have little or no receptor activity. FH results in extreme elevation of LDL-C that may distinguish the condition from other primary and most secondary causes of dyslipidemia. Genetic testing remains the criterion standard for diagnosis of the condition, although it is not widely used.

1. Heterozygous disorder. Familial hypercholesterolemia heterozygous disorder is fairly common, occurring in one of every 500 people. It is inherited in an autosomal dominant mode. An evaluation of family members is important in the diagnosis of this condition. In this condition, 50% of siblings and one parent have elevated total and LCL-C levels, but unaffected first-degree relatives have completely normal levels.

In heterozygotes, total cholesterol and LDL-C levels are two to three times higher than normal, present at birth or early in life. Their total cholesterol levels are most often above 240 mg/100 mL, with an average of 300 mg/dL, and their LDL-C levels are above 160 mg/100 mL, with an average of 240 mg/dL. HDL-C is reduced, and TG levels are usually normal. The presence of xanthomas of the extensor tendon in the parents of such children almost confirms the diagnosis. A heterozygous child or adolescent has normal physical findings. Tendon xanthomas are rarely found before the age of 10 years; they develop in the second decade, primarily in the Achilles tendons and extensor tendons of the hands, in only 10% to 15% of patients. These patients are likely to develop premature CV disease; rarely, angina pectoris develops in the late teenage years.

Treatment of heterozygotes includes a diet low in saturated fat and cholesterol and high in water-soluble fibers. Bile acid sequestrants are safe and moderately effective but difficult to tolerate over the long term because of their gritty texture and gastrointestinal (GI) complaints. Statins are safe, effective, and well tolerated and are considered the drug of choice (see later section). The addition to the statin of a bile acid sequestrant or a cholesterol absorption inhibitor (CAI) is often necessary to achieve LDL-C goals. Niacin is generally not used to treat FH heterozygous children.

2. Homozygous disorder. Homozygosity occurs in children who inherit a mutant allele for FH from both parents; it occurs in about one in a million children. The total cholesterol and LDL-C levels in these children are five to six times greater than normal. Such children have cholesterol levels that average 700 mg/dL but may reach higher than 1000 mg/dL. Clinical signs such as planar xanthomas, which are flat, orange-colored skin lesions, may be present by the age of 5 years in the webbing of the hands and over the elbows and buttocks. Tendon xanthomas, arcus corneae, and clinically significant coronary heart disease are often present by the age of 10 years. The generalized atherosclerosis often affects the aortic valve, with resulting aortic stenosis.

Familial hypercholesterolemia homozygous children respond somewhat to high doses of potent statins and to niacin. CAIs also lowers LDL-C in FH homozygotes, especially in combination with a more potent statin. However, most FH homozygotes invariably require LDL apheresis (with extracorporeal affinity LDL absorption column and plasma reinfusion) every 2 weeks to lower LDL to a range that is less atherogenic. The Liposorber system is an example, which selectively binds apo B–containing lipoproteins (LDL, Lp[a], and VLDL).

Familial combined hyperlipidemia. FCH is an autosomal dominant disorder seen three times more frequently than FH. It occurs in one of every 200 to 300 people. It is characterized by variable lipid phenotypic expression: elevated LDL level alone, elevated LDL with hypertriglyceridemia, or normal LDL with hypertriglyceridemia. Clinically, it may be difficult to separate this entity from FH. The diagnosis of FCH is suspected when a first-degree family member (often a parent or sibling) has a different lipoprotein phenotype than the proband. Levels of total and LDL-C are somewhat lower than in patients with FH, and LDL-C levels fluctuate from time to time, with TG levels fluctuating in the opposite direction. These children usually have plasma total cholesterol levels between 190 and 220 mg/dL. The LDL-C level is usually normal or only mildly elevated. In FCH, most patients lack tendon xanthomas, and extreme hyperlipidemia is absent in childhood. It may occur in children of survivors of myocardial infarction. Their phenotypes often have other characteristics such as hyperinsulinemia, glucose intolerance, hypertension, and visceral obesity. The combined expression of three or more of these traits constitutes the metabolic syndrome (see earlier section).

A cornerstone of management should be aimed at a fat- and cholesterol-restricted diet and a simple carbohydrate-restricted diet (low glycemic index foods) together with attention to other CV lifestyle changes (control of overweight and regular aerobic exercise). Low glycemic index foods are important in reducing carbohydrate-induced hypertriglyceridemia. The statins are the most effective in lowering LDL-C and the total number of atherogenic small, dense LDL particles. Fibric acid and niacin, which are effective in adults, are not ordinarily used in pediatric patients. Drug therapy is reasonable in patients with persistently elevated TGs levels (>350 mg/dL), aimed primarily at preventing an episode of pancreatitis. Metformin has been used to treat obese hyperinsulinemic adolescents with the metabolic syndrome. Metformin may enhance insulin sensitivity and reduce fasting blood glucose, insulin levels, plasma lipids, free fatty acids, and leptin.

Familial hypertriglyceridemia. In children, this autosomal dominant disorder is caused by LPL deficiency, resulting in hepatic overproduction of VLDL-C. TG levels are typically increased. Cholesterol levels are not increased. Eruptive xanthomas and lipemia retinalis (a creamy appearance of the retinal veins and arteries caused by a high concentration of lipids in the blood) can also be found. Metabolic consequences of hypertriglyceridemia include (1) a lowering of HDL-C; (2) production of smaller, denser LDL particles with more atherogenicity; and (3) a hypercoagulable state.

Treatment is based first on a diet very low in fat and simple sugar and lifestyle modification, including increasing exercise, withdrawing hormones (estrogen, progesterone), and limiting alcohol intake. When the level of TGs is between 200 and 500 mg/dL, the goal of the treatment is to reduce CAD. When TG levels reach 500 to 1000 mg/dL, pancreatitis is a major concern. One may consider using drugs such as fibrate or niacin (see later sections for the use of these antilipidemic agents). If pancreatitis develops, which is usually characterized by severe abdominal pain, and elevated plasma levels of amylase and lipase, the patient should be admitted to a hospital for care with intravenous fluid.

Dysbetalipoproteinemia (type III hyperlipoproteinemia). This familial disorder is a rare genetic disorder caused by a defect in apo E, which results in increased accumulation of chylomicron remnants and VLDL remnants. This autosomal recessive disorder is characterized by elevation of both cholesterol and TG equally to greater than 300 mg/dL, but this disorder is not usually seen in childhood. Clinical manifestations may include palmar xanthoma. Patients with this disorder have a moderately increased risk of CV disease. A low-fat diet, a low glycemic index diet, and drug treatment (fibric acid or statin) are very effective.

Familial hypoalphalipoproteinemia (low HDL syndrome). This condition is associated with autosomal dominant inheritance. The underlying mechanism is decreased concentration of apo A-I and apo A-II and absent apo C-III. This condition is associated with isolated low HDL-C levels and mild to moderately increased risk of premature CAD. In Tangiers disease, HDL-C is nearly absent (with markedly enlarged yellow tonsils).

Although specific drug therapy is not routinely recommended in pediatric age groups, a low-carbohydrate and low-fat diet is indicated in children with inherited disorders of HDL metabolism. Exercise and weight loss are also helpful. The most effective way to reduce CV risk in these patients is to maintain low LDL-C levels.

Lipid Screening

Past Recommendations

The NCEP Expert Panel (1991) recommended selective screening of children and adolescents with a family history of premature CV disease or at least one parent with high serum cholesterol levels. This selective screening was somewhat controversial because several studies published in the pediatric literature have indicated that about 50% of children with high LDL levels will be missed by following this recommendation. A major reason for this is that there is no reliable family history available on adopted children and because parents of children (and some grandparents) are still too young to have experienced premature coronary heart disease. Universal screening should theoretically detect all children with high LDL-C levels, but no pediatric organizations have recommended universal screening.

In 2008, the American Academy of Pediatrics made the following updated recommendations (Daniels, 2008), but universal lipid screening was not included. The recommendations for lipid screening include (1) children and adolescents with a positive family history of premature CV disease in parents or grandparents; (2) those with family history of dyslipidemia occurring in parents; (3) those whose family history is not known; and (4) those with other CV risk factors such as overweight, obesity, hypertension, cigarette smoking, or diabetes mellitus.

Current Recommendations

In 2011, however, the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents convened by the National Heart Lung and Blood Institute (NHLBI) has made major changes in the recommendation (Pediatrics, 2011).

1. A universal screening for children between the ages of 9 and 11 years (late childhood)

2. Selective screening for children in other age groups who have certain CV risk factors

3. An additional universal screening between the ages of 17 and 21 years

The reasons for choosing the age 9 to 11 years are that there is the strongest statistical correlation between results in late childhood (around 10 years of age) and in the adult life and that cholesterol levels decrease as much as 10% to 20% during puberty. The Expert Panel believed that, in the absence of clinical or historic markers, the identification of lipid disorders that predispose to accelerated atherosclerosis requires universal lipid assessment. Age-specific descriptions of the recommended screening are shown in Box 33-4.

In this recommendation, either a nonfasting lipid profile (non-FLP) or a fasting lipid panel (FLP) is acceptable. A non-FLP is more convenient because it can be obtained at the time of the office visit without fasting. In this case, non–HDL-C is calculated from the nonfasting blood samples (by subtracting HDL-C from total cholesterol) because non–HDL-C has been shown to be as powerful a predictor of atherosclerosis as any other lipoprotein cholesterol measurement in children and adolescents. If non–HDL-C is abnormal (≥145 mg/dL), then two FLP measurements are obtained.

BOX 33-4 Recommendations for Lipid Assessment According to Age Group

image

BMI, body mass index; FLP, fasting lipid panel; HDL, high-density lipoprotein; LDL, low-density lipoprotein; non-FLP, non-fasting lipid profile; TC, total cholesterol.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 128(suppl):S213-S256, 2011.

For children who belong to other age groups who do not require universal screening (i.e., ages 2–8 and 12–16 years), selective screening is recommended if the following apply (see Box 33-4). For these children who need selective screening, FLP is measured. The average of two measurements is used.

1. Positive family history (Box 33-5)

2. Parent(s) with total cholesterol (TC) of 240 mg/dL or above or known dyslipidemia

3. Child who has moderate- to high-level risk factors, such as diabetes, hypertension, BMI at the 85th percentile or above, or smokes cigarettes (see Box 33-5)

4. Child who has a moderate- or high-risk medical condition (e.g., diabetes, chronic renal disease, posttransplant patients, Kawasaki’s disease, HIV infection, nephritic syndrome, and others) (see Box 33-5)

What to Do with the Results of the Screening

1. When non-FLP is obtained, an abnormal level of non–HDL-C is 145 mg/dL or above. In this case, one needs to obtain two FLPs to get LDL-C and TG levels. The average of the two LDL-C and TG levels determine what steps to take.

2. Abnormal levels of LDL-C and TG levels that need attention are as follows:

• LDL-C: >130 mg/dL

• TGs: >100 mg/dL for children younger than 10 years old; 130 mg/dL for those who are 10 to 19 years old

3. Management plans for children with dyslipidemia are presented in the sections to follow.

a. Initially, dietary management and lifestyle change are recommended for children with high levels of LDL-C and TG. The first step is to employ the Cardiovascular Health Integrated Lifestyle Diet (CHILD)-1 for 3 to 6 months. If CHILD-1 is ineffective, CHILD-2 is used for 3 to 6 months.

b. If unsuccessful in lowering LDL-C levels by dietary management, the use of lipid-lowering drugs (statins) is considered. Indications for the use of “statins” depend not only on the level of lipid abnormalities but also on the presence or absence of a positive family history, coexisting risk factors, or medical conditions.

BOX 33-5 Cardiovascular Risk Factor Categories

Positive Family History

Parent, grandparent, aunt or uncle, or sibling with myocardial infarction; angina; coronary artery bypass graft, stent, or angioplasty; or sudden cardiac death at <55 yr for men or <65 yr for women

Risk Factors

High-Level Risk Factors

• Hypertension that requires drug therapy (BP ≥99th percentile + 5 mm Hg)

• Current cigarette smoker

• BMI ≥97th percentile

• Presence of high-risk conditions, including diabetes mellitus (see below)

Moderate-Level Risk Factors

• Hypertension that does not require drug therapy

• BMI at the ≥95th percentile or <97th percentile

• HDL cholesterol <40 mg/dL

• Presence of moderate-risk conditions (see below)

Special Risk Conditions

High-Risk Conditions

• Type 1 and 2 diabetes mellitus

• Chronic kidney disease, end-stage renal disease, postrenal transplant

• Post–orthotopic heart transplant

• Kawasaki disease with current aneurysm

Moderate-Risk Conditions

• Kawasaki disease with regressed coronary aneurysm

• Chronic inflammatory disease (systemic lupus erythematosus, juvenile rheumatoid arthritis)

• HIV infection

• Nephrotic syndrome

BP, blood pressure; BMI, body mass index; FLP, fasting lipid panel; HDL, high-density lipoprotein; LDL, low-density lipoprotein; non-FLP, non-fasting lipid profile; TC, total cholesterol.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 128(suppl):S213-S256, 2011.

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FIGURE 33-2 Target low-density lipoprotein (LDL) cholesterol. Note that the units of milligrams per deciliter (mg/dL) have been omitted. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHILD, Cardiovascular Health Integrated Lifestyle Diet; CK, creatine kinase; FHx, family history; FLP, fasting lipid panel; RF, risk factor; TG, triglycerides; Tx, therapy. (Modified from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report. Pediatrics 128(Suppl):S213-S256, 2011.)

c. For high levels of TG, dietary therapy is used as the primary tool. Continued use of the CHILD-2-TG diet, weight control efforts, reduction of sugar consumption, and increased consumption of fish (or omega-3 fish oil) are added to the effort.

4. Children with LDL-C of 250 mg/dL or above and those with TGs of 500 mg/dL or above should be referred to lipid specialists.

Management of Hypercholesterolemia

Dietary Management of Hypercholesterolemia

Reduced intake of saturated fat and cholesterol is most basic to the dietary therapy of hypercholesterolemia. The efficacy and safety of dietary therapy have been demonstrated in adults as well as children. Diet therapy is prescribed in two steps that progressively reduce the intake of saturated fats and cholesterol. Physicians should follow the algorithm shown in Figure 33-2 for managing high LCL-C levels.

1. The CHILD-1 diet is the first stage in dietary change for children with dyslipidemia, overweight and obesity, risk-factor clustering, and high-risk medical conditions (Table 33-4). The CHILD-1 diet is also the recommended diet for children with a positive family history of premature CV disease, dyslipidemia, obesity, hypertension, diabetes mellitus, or exposure to smoking in the home. This diet is very similar to what has been recommended for the general population of the United States to consume by the Dietary Guidelines for Americans 2010. The use of dietary adjuncts such as plant sterol or stanol esters has shown short-term benefits.

TABLE 33-4

Nutrient Composition of CHILD Diets

image

CHILD, Cardiovascular Health Integrated Lifestyle Diet; LDL, low-density lipoprotein; TG, triglyceride.

2. If this diet fails to achieve the minimal goal of the dietary therapy for LDL-C (≤130 mg/dL) in 6 months, a more stringent diet with saturated fat at 7% or less of total calories and dietary cholesterol of less than 200 mg/day (CHILD-2-LDL) is used, which has been shown to be safe and effective. A registered dietitian or other qualified nutrition professional should be consulted.

3. If the dietary intervention with CHILD-2-LDL fails, one may proceed with drug therapy.

Indications for Drug Therapy

When dietary management with lifestyle changes of 6 to 12 months’ duration fails to lower LCL-C levels to the target level (≤130 mg/dL), the use of medication should be considered. Decisions regarding the need for medication therapy should be based on the average of results from at least two FLPs obtained at least 2 weeks but no more than 3 months apart, and it should be in consultation with the patient and the family.

1. The following are indications for consideration of drug therapy (Box 33-6 and Fig. 33-2).

a. LCL-C of 190 mg/dL or greater after a 6-month trial of lifestyle management (CHILD-1 followed by CHILD-2-LDL) for children 10 years of age or older

b. LCL-C 160 to 189 mg/dL after a 6-month trial of lifestyle and diet management (CHILD-2-LDL) in a child 10 years of age or older with a positive family history of premature CVD or events in first-degree relatives or at least one high-level risk factor or risk condition or at least two moderate-level risk factors or risk conditions (see Box 33-5)

c. LDL-C 130 to 159 mg/dL in a child 10 years of age or older with a negative family history of premature CVD but with at least two high-level risk factors or risk conditions or at least one high-level risk factor or risk condition together with at least two moderate-level risk factors or risk conditions

BOX 33-6 Indications for Drug Therapy for Hypercholesterolemia in Children and Adolescents

• Failure of diet therapy and lifestyle management for 6 to 12 mo plus

• Age ≥10 yr with one of the following lipid profiles or risk factors:

a. LDL cholesterol ≥190 mg/dL

b. LDL cholesterol 160–189 mg/dL with a positive family history of premature CV disease or events in first-degree relatives, at least one high-level risk factor or risk condition, or at least two moderate-level risk factors or risk conditions

c. LDL cholesterol 130–159 mg/dL with at least two high-level risk factors or risk conditions or at least one high-level risk factor or risk condition together with at least two moderate-level risk factors or risk conditions (Box 33-5).

OR

• Children age 8 or 9 years with LDL cholesterol level persistently ≥190 mg/dL together with multiple first-degree family members with premature CV disease or events or the presence of at least one high-level risk factor or risk condition or the presence of at least two moderate-level risk factors or risk conditions

CV, cardiovascular; LDL, low-density lipoprotein.

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 128(suppl):S213-S256, 2011.

d. For children age 8 or 9 years with LDL-C persistently 190 mg/dL or above with multiple first-degree family members with premature CVD or events or the presence of at least one high-level risk factor or risk conditions or the presence of at least two moderate-level risk factors or risk conditions

e. LDL-C 130 to 189 mg/dL in a child 10 years of age or older with a negative family history of premature CVD in first-degree relatives and no high- or moderate-level risk factor or risk condition should continue with lifestyle changes (CHILD-2-LDL), plus weight management if the BMI is at the 85th percentile or above

2. Children with homozygous FH and extremely elevated LDL-C levels (>500 mg/dL) have undergone effective LDL-lowering therapy with biweekly LDL apheresis under the care of lipid specialists.

Lipid-Lowering Drugs

Five well-known classes of lipid-lowering drugs have been used for adults with dyslipidemia. They are bile acid sequestrants, HMG-CoA reductase inhibitors (“statins”), CAIs, nicotinic acid (niacin, vitamin B3), and fibric acid derivatives. The mechanisms of action, side effects, and ranges of adult dosages of the lipid-lowering agents are presented in Table 33-5.

Experience in children is quite limited, especially with drugs other than the statins, and consensus recommendations are lacking with regard to the use of other lipid-lowering drugs, such as fibrate and niacin.

1. It has been established that the HMG-CoA reductase inhibitors (statins) are the most effective in lowering LDL-C in adults as well as in children and adolescents. A further discussion is presented in the section to follow.

2. The bile acid sequestrants (cholestyramine, colestipol) are other lipid-lowering drugs approved for use in children older than 10 years of age. However, these agents are not used widely because they are associated with a low compliance rate (because of their gritty texture and GI complaints), and they provide only a modest reduction of LDL-C level. No further discussion follows on this topic.

3. Ezetimibe, a CAI, is effective in lowering blood cholesterol levels. Contrary to earlier belief, they are absorbed through the enterohepatic circulation and may have systemic effects, such as rare liver toxicity. Even though ezetimibe decreases cholesterol levels, the results of two major, high-quality clinical trials in adults (in 2008 and 2009) showed a lack of clinically significant improvement in CV events. No further discussion follows on this topic.

TABLE 33-5

Summary of Lipid-lowering Drugs

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CPK, Creatine phosphokinase; FH, familial hypercholesterolemia; GI, gastrointestinal; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.

4. Nicotinic acid and fibrates have been shown to lower LDL-C and TG levels and increase HDL levels in adults. Although they are frequently used in adults with hypercholesterolemia as a second line of drug, they are not frequently used in adolescents because of limited data available.

The “Statins”

At this time, a statin is recommended as first-line treatment in adolescents with hypercholesterolemia (McCrindle et al, 2007). The statins inhibit HMG-CoA reductase, which is the rate-limiting step in the endogenous production of cholesterol in the hepatic cells.

BOX 33-7 Initiation, Titration, and Monitoring of Statin Therapy in Children and Adolescents

• Measure baseline CK, ALT, and AST levels.

• Start with lower dose given once orally (see text for dosage).

• Monitor for potential adverse effects.

• Instruct the patient to report immediately all potential adverse effects, especially myopathy (muscle cramps, weakness, asthenia, and more diffuse symptoms).

• If myopathy is present, its relationship to recent physical activities should be assessed, the medication stopped, and CK assessed.

• The patient should be monitored for resolution of myopathy and any associated increases in CK.

• Consideration can be given to restarting the medication after symptoms and laboratory abnormalities have resolved.

• Advise female patients about concerns with regard to pregnancy and the need for appropriate contraception if warranted.

• After 4 weeks, measure fasting lipoprotein profile, CK, ALT, and AST

• The threshold for worrisome level of CK is 10 times above the upper limit of reported normal; consider the impact of physical activity.

• The threshold for worrisome level of ALT or AST is three times above the upper limit of reported normal.

• Target level for LDL: minimal, <130 mg/dL; ideal, 110 mg/dL

• At 4-week follow-up:

• If target LDL levels are achieved and no laboratory abnormalities are noted:

• Continue therapy and recheck in 8 wk and then 3 mo.

• If laboratory abnormalities are noted or symptoms reported:

• Temporarily withhold the drug and repeat the blood work in ≈2 wk.

• When anomalies return to normal, the drugs may be restarted with close monitoring.

• If target LDL levels not achieved:

• Increase the dose by 10 mg and repeat the blood work in 4 wk.

• Continue stepped titration up to the maximum recommended dose until target LDL levels are achieved or there is evidence of toxicity.

• Repeat laboratory tests every 3 to 6 mo: fasting lipoprotein profile, CK, ALT, and AST.

• Continue counseling on:

• Compliance with medications and reduced fat diets

• Other risk factors, such as weight gain, smoking, and inactivity

• Counsel female adolescents about statin contraindication in pregnancy and the need for appropriate contraception. Seek referral to an adolescent medicine or gynecologic specialist as appropriate.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; LDL, low-density lipoprotein.

Modified from McCrindle BW, Urbina EM, Dennison BA, et al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing: Drug therapy of high-risk lipid abnormalities in children and adolescents. Circulation115:1948-1967, 2007.

Adverse Effects of Statins

Adverse effects of statins are infrequent but may include GI upset; elevation of liver transaminases; and myopathy ranging in severity from asymptomatic increases in creatine kinase (CK), muscle aches or weakness, to fatal rhabdomyolysis. Myopathy and elevated liver enzymes are the main concerns.

• More than a 10-time increase in CK levels and more than three times an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels above the upper limits of normal are worrisome levels. Therefore, periodic measurements of ALT, AST (preferred because it is also found in muscles), and CK should be done for possible adverse effects of the statins at the same time lipid levels are measured. Box 33-7 provides step-by-step instruction on initiation, titration, and monitoring of statin therapy (McCrindle et al, 2007).

• Patients should be instructed to report immediately any potential signs and symptoms of myopathy (e.g., muscle cramps, weakness, or more diffuse symptoms). Asymptomatic transient increases in CK, although unusual, have been reported. Practitioners should be aware that an increase in CK may be related to vigorous exercise, particularly contact sports or weightlifting. Myopathy is defined as a serum CK level 10 times the upper limit of normal with or without muscle weakness or pain. Rhabdomyolysis is defined as unexplained muscle pain or weakness with a serum CK level more than 40 times the upper limit of normal.

The likelihood of myopathy increases with high doses, especially of simvastatin (80 mg in adults), and when used concomitantly with other medications, such as cyclosporine, erythromycin, gemfibrozil, niacin, azole antifungal agents, or antiretroviral agents (Egan, 2011).

• Increases in liver enzymes up to three times the upper limits of normal have been reported in several patients treated with high doses of simvastatin (40 mg/day) and atorvastatin (20 mg/day). Liver transaminases are not likely to increase in patients taking pravastatin and rosuvastatin.

• The statins are also teratogenic, and female patients should be advised about appropriate contraception if warranted.

Dosages of the “Statins”

Numerous studies have demonstrated the safety and efficacy of the statins in male and female adolescents with FH (Holmes et al, 2005). Five statins—atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin—are currently approved by the Food and Drug Administration (FDA) for use in adolescents. A recent double-blind, placebo-controlled trial with 2 years of pravastatin treatment has shown not only significant reduction of LDL-C but also regression of carotid atherosclerosis in children and adolescents with FH (Wiegman et al, 2004).

Based on recently published clinical trials in children and adolescents, the following may be a reasonable pediatric dosage of the statins that are approved for pediatric use (Holmes et al, 2005). The Expert Panel has recommended to start with the lowest available dose given once daily at bedtime. The starting doses listed below are the lowest available doses for each statin, except for simvastatin (with 5 mg as the lowest available dose).

• Atorvastatin (Lipitor): The starting dose of 10 mg is increased to 20 mg at 3 months and further to a dose of 40 mg/day (maximum adult dose, 80 mg/day).

• Fluvastatin (Lescol): The starting dose is 20 mg. The maintenance dose ranges from 20 to 40 mg.

• Lovastatin (Mevacor): The starting dose is 10 mg with a 10-mg increase every 3 months to a maximum of 40 mg/day.

• Pravastatin (Pravachol): The starting dose of 10 mg is increased to 20 or 40 mg/day.

• Simvastatin (Zocor): The starting dose is 10 mg. It is increased in increments of 10 mg every 3 months to a maximum of 40 mg/day. Note that 80 mg of the drug carries a high risk of myopathy or rhabdomyolysis in adults.

The dose of statin is increased by 10 mg every 3 months to the half or even full dose of the upper range dosage with periodic measurements of cholesterols. The maintenance dosage of the drug is decided by periodic determinations of cholesterol levels. The minimal target level for LDL-C is less than 130 mg/dL, and the ideal target level is 110 mg/dL. If the target level is not reached, a second agent such as a bile acid sequestrant or CAI may be added under the direction of a lipid specialist.

Hypertriglyceridemia

High TG levels are a marker for atherogenic remnant lipoproteins, such as VLDL-C. Recent studies have found that hypertriglyceridemia is an independent risk factor for major coronary events after controlling for LDL-C and HDL-C. According to the Helsinki Heart Study (1987), people with hypertriglyceridemia alone (without other risk factors for heart disease) had about a 50% increased risk for CAD compared with people with normal TG levels. When high LDL-C coexisted with elevated TG levels, there was a 300% greater risk for CAD.

Management of Hypertriglyceridemia

There are different cutoff points for the treatment of hypertriglyceridemia in children and adults; 100 mg/dL for children younger than 10 years of age, 130 mg/dL for ages 10 to 19 years, and 150 mg/dL for young adults (see Tables 33-1 and 33-2). An algorithm for managing hypertriglyceridemia is shown in Figure 33-3.

1. Diet therapy is the primary tool in treating high TG level, using a low-fat diet and low glycemic index foods, such as CHILD-2-TG (see Table 33-4). Reduction of simple carbohydrate intake (and increased intake of complex carbohydrate), reduced saturated fat intake, and weight loss are associated with decreased TG levels.

It is important for physicians to know that both a high-fat diet and a high-carbohydrate diet raise TG levels. fact, a high-carbohydrate diet may be a more important source of hypertriglyceridemia than high fat intake. The best established metabolic disturbance attributable to high dietary sugar intake may be a rise in plasma lipids, not in plasma glucose (Hellerstein, 2002). A rise in TG levels after consuming high carbohydrate is known as carbohydrate-induced hypertriglyceridemia. The increase in TG is worse with a high glycemic index diet than with a low glycemic index diet. Therefore, all refined carbohydrate foods such as sugary drinks, cookies, ice cream, and desserts, should be avoided and complex carbohydrates such as whole-grain products should be consumed more often.

2. Lifestyle changes with increased physical activity (at least 30 minutes of moderate-intensity exercise 5 days a week) and weight control help reduce TG levels. Exercise also helps decrease LDL-C and increase HDL-C.

3. Increasing dietary fish (to increase omega-3 fatty acids) may be effective.

a. Children with increased TG levels (100–200 mg/dL) after a trial of lifestyle and diet management with CHILD-2-TG should increase dietary fish consumption.

b. Children with fasting TG levels of 200 to 499 mg/dL or above, non-HDL levels of greater than 145 mg/dL, after a trial of lifestyle and diet management with CHILD-2-TG and increased fish intake may be considered for fish oil supplementation.

image

FIGURE 33-3 Target triglycerides (TGs). Note that the units of milligrams per deciliter (mg/dL) have been omitted. CHILD, Cardiovascular Health Integrated Lifestyle Diet; FLP, fasting lipid panel; LDL, low-density lipoprotein; WT, weight. (Modified from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report. Pediatrics 128(Suppl):S213-S256, 2011.)

Omega-3 fatty acids in fish oils lower plasma TGs levels by inhibiting the synthesis of VLDL-C and TGs in the liver. They also have antithrombotic properties. A review of human studies (Harris, 1997) concluded that approximately 4 g/day of omega-3 fatty acids reduced serum TG concentrations by 25% to 30%, increased LDL-C levels by 5% to 10%, and increased HDL-C levels by 1% to 3%. Total cholesterol was not significantly affected by omega-3 fatty acids. A prescription omega-3 fatty acid product (e.g., Omacor) 4 g/day and 8 g/day may be used. (Most fish oil capsules contain omega-3 fatty content, only one third of that contained in Omacor.)

4. Children with average fasting TG levels of 500 mg/dL or above or any single measurement of 1000 mg/dL or above should be treated in conjunction with a lipid specialist. For these patients, in addition to the dietary management with CHILD-2-TG and fish oil, use of fibrate or niacin should be considered to prevent pancreatitis (see below for other lipid-lowering drugs, fibrates and niacin).

Fibrates have the effect of both lowering TGs and raising HDL-C. Side effects seen in adults include myalgia, myositis, myopathy, rhabdomyolysis, liver toxicity, gallstones, and glucose intolerance. Safety and efficacy data in children are limited. Therefore, CK level and liver enzymes should be monitored every 3 months.

Niacin is the best known drug that raises HDL-C, but it also reduces TG levels. Adverse effects of niacin include liver toxicity, GI tract upset, and facial flushing. Less commonly seen side effects are hyperuricemia and glucose intolerance. Extended-release preparations produce less flushing, but they are more likely to produce liver toxicity. Niacin is rarely used to treat the pediatric population because of reported poor tolerance and the potential for very serious adverse effects. Liver transaminases should be checked every 3 months.

Low High-Density Lipoprotein Level

Low levels of HDL-C represent a major CV risk factor. Despite the presence of desirable total cholesterol levels, patients with low HDL-C may be at very high risk of developing a subsequent CV event. In the Framingham study, approximately 50% of primary myocardial infarctions occurred in subjects with total cholesterol levels of 250 mg/dL, and 20% of them had desirable cholesterol levels (200 mg/dL). In the Helsinki Heart Study, HDL-C elevation independently reduced CV event rate. An increase in HDL-C is associated with a reduction in the CV events. It is estimated that a rise of 1 mg/dL in HDL lowers the risk of fatal MI by about 3%.

HDL-C has a number of antiatherogenic effects. The best known of these relates to the ability of HDL-C to promote the efflux of cholesterol from macrophages in the arterial wall through reverse cholesterol transport. Other antiatherogenic potentials of HDL-C include antioxidant, antithrombotic, and antiinflammatory effects.

Low HDL level is defined as less than 40 mg/dL in adolescent boys and girls. In adults, low level is defined as less than 40 mg/dL in men and less than 50 mg/dL in women.

Treatment of Low Levels of High-Density Lipoprotein Cholesterol

The primary approach in managing low levels of HDL-C is lifestyle change and diet therapy. Drugs used for this condition (niacin, fibrates) have unacceptable side effects. The following has been suggested for adult patients with low levels of HDL-C (Ashen et al, 2005; others).

1. Lifestyle change is the best way to deal with low levels of HDL-C. Regular exercise (for 30 minutes of brisk aerobic exercise every day or every other day) is recommended. Weight control (and quitting smoking) is equally important.

2. Dietary intervention

a. A diet low in saturated fat and rich in the polyunsaturated fatty acids is recommended. This is because the most effective way to reduce CV risk in patients with low HDL levels is to maintain low LDL-C levels, not because it raises HDL levels.

b. Omega-3 fatty acids may help raise HDL levels.

c. Restrict consumption of high glycemic index foods. Consumption of carbohydrates, especially simple carbohydrates, is associated with low HDL levels. Some studies have found that a low-carbohydrate diet can raise HDL levels.

d. Mild to moderate consumption of alcohol (1–2 drinks a day) in adults resulted in a rise of 4 mg/dL (not for those with liver or addiction problems).

3. Current pharmacologic options for adults include nicotinic acid (niacin), fibrates, and statins, but none is without major adverse effects. The use of drug should be considered only when all nonpharmacologic measures do not achieve the goal of raising HDL-C level in pediatric patients.

• Among these medications, niacin (nicotinic acid or vitamin B3) is known to be most effective medication for raising HDL-C (raising HDL level by 20% to 35%). However, niacin is rarely used in the pediatric population because of the potential for very serious adverse effects.

One of the major adverse effects of niacin is severe flushing. Flushing is a major reason people stop taking the medication. The flushing problem has been substantially reduced by the development of a newer extended-release formulation of niacin (Niaspan) but it is more likely to increase liver toxicity. Flushing (which may involve prostaglandin D2) can be blocked by taking 300 mg of aspirin half an hour before taking niacin.

• Fibrate therapy is also effective, producing an average increase of 10% to 25%.

• Statins are the least effective of the three drug classes in raising HDL levels (by 2%–15%).

• When used in combination, low-dose statins and high-dose niacin have been shown to produce benefits of 21% to 26%.

Elevated Triglyceride and Low High-Density Lipoprotein

A subgroup of patients with a combination of elevated TG and low HDL-C need special attention. This combination of dyslipidemia is typically seen in patients with obesity, the metabolic syndrome, and diabetes and in some patients with FCH. Although LDL-C may not be elevated, this phenotype is usually associated with small, dense LDL particle, which are much more atherogenic than large LDL particles.

Treatment of the Subgroup of High Triglycerides and Low High-Density Lipoprotein

For this subgroup of patients, the following are recommended.

1. Lifestyle change, in particular with adequate exercise, is probably the most important approach for this subgroup of patients.

2. Low-carbohydrate and low-fat diets. Low glycemic index diets appear to be more beneficial to these patients than low-fat diets, which are traditionally known to lower LDL levels.

3. Cholesterol-lowering drugs that impact small, dense LDL are nicotinic acid and the fibric acid derivatives in adult patients. No consensus guidelines exist for pediatric patients. Of note is that the statin drugs do not appear to affect particle composition, although they lower LDL concentration.

Other Risk Factors

Other CV risk factors beside dyslipidemia need attention in order to prevent CV disease and diabetes. In this section, a brief discussion is presented on the topics of obesity and smoking. Another risk factor, hypertension, is presented in Chapter 28.

Obesity

Information provided in this section should only be used to assist health care providers in making diagnoses of overweight and obesity, recognizing complications of obesity, providing the basic knowledge needed in patient counseling, and helping them with appropriate time for referral to a weight management specialist. This section is not meant to describe in detail treatment of obesity; successful treatment of obesity requires special skills and facilities with the availability of a multidisciplinary team consisting of registered dietitians, specialized nurses, psychologists, and exercise specialists. Such specialized programs are costly and, unfortunately, are insufficient in number.

Prevalence

Obesity is one of the most pressing public health issues today in the United States. Between 1980 and 2002, obesity prevalence doubled in adults and overweight prevalence tripled in children and adolescents age 6 to 19 years (Hedley et al, 2004). According to the most recent national statistics (from the National Health and Nutrition Examination Survey conducted in 2007 and 2008), 16.9% of children and adolescents (2–19 years old) and 33.8% of adults in the United States are obese. In addition, approximately 30% of children and adolescents are overweight. Therefore, nearly half of all American children and adolescents are either overweight or obese.

Pathogenesis

The pathogenesis of obesity may be, in part, inherited, but genetics alone cannot account for the rapid increases in overweight in the US population. Environmental factors appear importantly related to the recent rise in the prevalence of obesity in this country. Increased consumption of calorie-dense foods and a decrease in physical activity and an increased time spent on TV and video games may be causally related to the increasing prevalence of obesity seen in children and adolescents (Gortmaker et al, 1996).

The concept of energy balance applies to the pathogenesis of obesity (Fig. 33-4). When energy intake exceeds energy expenditure on a chronic basis, obesity results. When energy intake is less than energy expenditure, weight loss may result. All energy intake comes from the ingestion of macronutrients. Whereas the caloric value of fat is 9 kcal/g, that of protein and carbohydrate is 4 kcal/g; this is an important reason for recommending reduced fat intake to control weight. A large portion of energy expenditure is the resting metabolic rate (RMR) accounting for 60% to 75% of energy expenditure. Approximately 10% of energy expenditure is dissipated through the thermic effect of food (TEF), which is mainly the result of the energy cost of nutrient absorption, processing, and storage. Energy expenditure resulting from physical activity is relatively small, accounting for only 10% to 15% of the total energy expenditure. This component is least affected by genetics, and it varies greatly from individual to individual depending on the level of physical activities. The level of energy expenditure from RMR and TEF may be predominantly determined by genetic factors.

By measure, 3500 calories is equivalent to l lb. A relatively small positive energy balance can lead to significant weight gain over time. For example, an excess intake of only 100 calories per day will lead to a 10 lb of weight gain over 1 year.

Health Consequences of Obesity

A number of disease states are associated with obesity in adults, which are not only risk factors for heart disease and diabetes but also responsible for significant health care costs: approximately 5% of total health care costs (more than $100 billion) can be attributed to obesity. Common conditions associated with adult obesity include hyperlipidemia, heart disease, hypertension, type 2 diabetes, stroke, and osteoarthritis. Obesity also increases the prevalence of some cancers, gallbladder disease, sleep disorders, gout, and mood disorders.

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FIGURE 33-4 Energy balance. To maintain a stable weight, energy intake (protein, carbohydrate, and fat) of a person should be equal to energy expenditure, which is composed of resting metabolic rate (RMR), the thermic effect of food (TEF), and expenditure associated with physical activities. When intake is greater than expenditure, weight gain will result; when expenditure of energy is greater than the intake, weight loss may result.

The health consequences of obesity in children are somewhat different from those seen in obese adults (Dietz, 1998).

1. Common medical consequences of obesity.

a. Cardiovascular risk factors (data from Becque, 1998; Srinivasan et al, 1999)

(1) Hypercholesterolemia: 31%

(2) Hypertriglyceridemia: 64%

(3) Low HDL-C: 64%

b. Glucose intolerance, which is linked to the recent increase in the prevalence of type 2 diabetes in children

c. Hypertension is present in 10% to 30% of overweight children.

d. Asthma is more common in obese children and is more difficult to control than in nonobese children.

e. Acanthosis nigricans (∼25%), an indication of hyperinsulinemia

f. Hepatic steatosis (fatty degeneration) with elevated liver enzymes (seen in >10% of overweight children), cholelithiasis (caused by increased cholesterol synthesis), and cholecystitis (occurring more often with weight reduction).

2. Less common medical consequences of obesity

a. Pseudotumor cerebri (with manifestations of headache, visual impairment or blindness, papilledema, occurring before adolescence) requires aggressive treatment. About 50% of children with the condition are obese.

b. Sleep apnea occurs in less than 7% of obese children. This requires an aggressive treatment including tonsillectomy and adenoidectomy or weight reduction.

c. Orthopedic complications: Blount disease (bowing of the tibia and femur with resulting overgrowth of the medial aspect of the proximal tibial metaphysis) or slipped capital femoral epiphysis

d. Polycystic ovary disease: Menstrual abnormalities and hirsutism in association with obesity, acanthosis, hyperinsulinemia, and hyperandrogenemia suggest this condition.

3. Psychosocial consequences

a. Early discrimination (in childhood)

b. Negative self-esteem (in adolescence)

c. Inappropriate expectation to be more mature because of their large size. This may lead to frustration, a sense of failure, and social isolation.

d. Learning difficulties

e. Eating disorders (in white girls)

f. Obese men tend to attain lower socioeconomic status and social achievement. Obese women tend to have lower educational level, family income, and rates of marriage and higher rates of living in poverty.

Evaluation of Obese Children

1. The BMI (weight in kilograms divided by square of the height in meters [kg/m2]) is a simple, valid measure of relative weight and is recommended in clinical diagnosis of overweight states. Although parents tend to better understand the term relative weight (the child’s weight divided by the ideal weight of the child for his or her height), physicians should use BMI percentile in following up overweight children. Age- and gender-specific BMI percentile curves for the US pediatric population have been published by the Centers for Disease Control and Prevention (CDC) (see Appendix CFigs. C-1 and C-2).

2. Classification: In adults, obesity is present when BMI is above 30 and overweight is present when BMI is between 25.0 and 29.9. For children, statistical definition of overweight is used. Children whose BMIs are between the 85th and 95th percentile are “overweight,” and children whose BMIs are at or greater than the 95th percentile are “obese.” A large BMI does not always indicate an increase in body fat; lean, muscular individuals may have large BMIs. Percent body fat may be more accurate in determining obesity than BMI, but the method of determining body fat is cumbersome and is not routinely used in clinical practice.

3. Physicians should consider identifiable underlying causes of obesity, such as genetic or endocrine disorders

a. Genetic causes: Prader-Willi, Bardet-Biedl, and Alström syndromes all have severe early onsets of obesity. Most of the genetic conditions associated with obesity have in common mental retardation and short stature, often with dysmorphic features.

b. Endocrine abnormalities, such as hypothyroidism, Cushing’s syndrome, and generalized hypothalamic dysfunction, should be considered. Children with hypothyroidism and cortisol excess have short stature and delayed puberty rather than tall stature and early puberty seen in most obese children. When questions arise, determination of free thyroxine and thyroid-stimulating hormone and 24-hour urinary free cortisol or diurnal salivary cortisol levels should clarify the questions.

4. Check for the presence of other risk factors for CV disease, diabetes, and metabolic syndrome (see Box 33-2).

a. Blood pressure measurement

b. Lipoprotein analysis, fasting insulin, and blood glucose

c. Glycosylated hemoglobin (HbA1C) may also be useful.

5. Search for possible obesity-related complications by history and physical examination, such as those listed below.

a. Acanthosis nigricans is associated with hyperinsulinemia and a higher risk of developing type 2 diabetes.

b. Thyroid enlargement may be associated with hypothyroidism.

c. History of nighttime snoring, breathing difficulties, or daytime somnolence may indicate obstructive sleep apnea or obesity hypoventilation syndrome.

d. Hip or knee pain may be a manifestation of slipped capital femoral epiphysis.

e. Abdominal pain or tenderness may be associated with gallbladder disease.

f. Headaches and blurred optic disk margins may indicate pseudotumor cerebri.

g. Hepatomegaly may be associated with hepatic steatosis.

h. Oligomenorrhea, amenorrhea, striae, or hirsutism may indicate polycystic ovary disease or Cushing’s syndrome.

i. Signs of depression, bulimia nervosa, binge-eating disorder, or other serious psychological disorders require further evaluation and treatment by a child psychiatrist or psychologist.

Management

All successful pediatric weight management programs include four components: (1) dietary component, (2) exercise, (3) behavior modification, and (4) family component. Among these, dietary intervention and regular exercise combined are the cornerstones of weight management. Only through behavior modification can long-term healthy eating and activity patterns can be established; attempts at using diet and exercise for quick weight loss usually fail. Without involvement of the parents and family, behavior modification of children and adolescents is difficult to achieve. Currently, no pharmacologic agents have been shown to be safe and effective for long-term weight management in children and adolescents. Presently, the FDA has approved only two drugs, sibutramine (Meridia) and orlistat (Xenical), that may be used for treating severely obese children. Consultations with registered dietitians, psychologists, and exercise specialists may be sought or a referral to a multidisciplinary weight management program may become necessary.

Assessment of usual diet and activity patterns of overweight children and adolescents is important. Selected questions (or assessments) and appropriate counseling are listed below.

1. Diet

a. The following questions are helpful in assessing the dietary habits of the child and family.

(1) How often vegetables and fruits are eaten as main meal or snack

(2) How often high calorie drinks (soda pops, fruit punches, fruit juices) are consumed

BOX 33-8 American Heart Association’s Pediatric Dietary Strategies for Individuals Age >2 Years: Recommendations to All Patients and Families

• Balance dietary calories with physical activity to maintain normal growth.

• Engage in 60 minutes of moderate to vigorous play or physical activity daily.

• Eat vegetables and fruits daily; limit juice intake.

• Use vegetable oil and soft margarines low in saturated fat and trans-fatty acids instead of butter or most other animal fats in the diet.

• Eat whole-grain breads and cereals rather than refined grain products.

• Reduce the intake of sugar sweetened beverages and foods.

• Use nonfat (skim) or low-fat milk and dairy products daily.

• Eat more fish, especially oily fish, broiled or baked.

• Reduce salt intake, including salt from processed foods

From Gidding SS, Dennison BA, Birch LL, et al; American Heart Association; American Academy of Pediatrics. Dietary recommendations for children and adolescents: A guide for practitioners. Pediatrics 117:544-559, 2006.

(3) Numbers and types of fast foods eaten per week

(4) How often the child eats fish, chicken, and red meats

(5) Type of milk, bread, and butter consumed

(6) How often fried foods are eaten in a week

b. The counseling should include at least the following:

(1) The diet of choice is a diet low in saturated fat and cholesterol and includes five or more daily servings of vegetables and fruits and 6 to 11 servings of whole-grain and other complex carbohydrate foods.

(2) A new Food Guide System, MyPlate, should be introduced. Half of a plate is filled with fruits and vegetables, a quadrant with grains (e.g., bread, wheat, rice), and the last quadrant with protein (e.g., meat, poultry, fish, soy).

(3) To help people better understand what constitutes healthy habits for controlling obesity, some simple guidelines have been developed, such as the “5-2-1-0” message (which includes physical activity). This message developed by the New Hampshire Health Department has been endorsed by the American Academy of Pediatrics as basic healthy lifestyle counseling tool. The message is simple to understand and remember and can be given in a few minutes. The 5-2-1-0 message stands for:

• 5: Eating at least five servings of fruits and vegetables most days.

• 2: Limiting screen time to 2 hours or less daily.

• 1: Participating in at least 1 or more hours of physical activity every day.

• 0: Encouraging no soda and sugar-sweetened drinks. Instead, drink water and low-fat or fat-free milk.

c. Physicians may consider using the following as handout materials for counseling.

(1) Box 33-8 (dietary strategies) and Box 33-9: Tips for parents)

(2) Table C-4Appendix C: Specific foods to choose and to decrease

(3) Table C-5Appendix C: Serving size of various food groups according to age and gender

d. Physicians may recommend parents to read about the new food guide system (MyPlate) recommended by the US Department of Agriculture (http://teamnutrition.usda.gov/myplate.html).

2. Physical activity

Exercise is another integral part of weight management. Without regular exercise, dietary modification alone is insufficient for successful weight management. Physicians should first assess the level of physical activity of overweight children and use their influential position to counsel children and their family to adopt a healthy lifestyle.

a. The following questions are useful in assessing physical activity in children.

(1) Amount of time regularly spent walking, bicycling, swimming, and in backyard play

(2) Use of stairs, playgrounds, and gymnasiums and interactive physical play with other children

BOX 33-9 Tips for Parents to Implement American Heart Association Pediatric Dietary Guidelines

• Reduce added sugars, including sugar-sweetened drinks and juices.

• Use canola, soybean, corn oil, safflower oil, or other unsaturated oils in place of solid fats during food preparation.

• Use recommended portion sizes on food labels when preparing and serving food.

• Use fresh, frozen, and canned vegetables and fruits and serve them at every meal; be careful with added sauces and sugar.

• Introduce and regularly serve fish as an entrée.

• Remove the skin from poultry before eating.

• Use only lean cuts of meat and reduced-fat meat products.

• Limit high-calorie causes such as Alfredo, cream sauces, cheese sauces, and hollandaise sauce.

• Eat whole-grain breads and cereals rather than refined products; read labels and ensure that “whole grain” is the first ingredient on the food label of these products.

• Eat more legumes (beans) and tofu in place of meat for some entrées.

• Breads, breakfast cereals, prepared foods, including soups, may be high in salt or sugar; read food labels for content and choose high-fiber, low-salt, and low-sugar alternatives.

From Gidding SS, Dennison BA, Birch LL, et al; American Heart Association; American Academy of Pediatrics. Dietary recommendations for children and adolescents: A guide for practitioners. Pediatrics 117:544-559, 2006.

(3) Number of hours per day spent watching television or videotapes and playing video or computer games

(4) Time spent participating in organized sports, lessons, clubs, or league games

(5) Time spent in school physical education that includes a minimum of 30 minutes of exercise

(6) Participation in household chores

(7) Positive role modeling for a physically active lifestyle by parents and other caretakers

b. The physician’s counseling and education should include the following areas.

(1) Physicians should formally address the subject of exercise, emphasizing the health benefits of regular physical activity, which include:

(a) Helping weight control by lowering level of weight gain

(b) Metabolic benefits include:

(1) Improved glucose tolerance and insulin sensitivity (even in the absence of weight loss)

(2) Reduction in VLDL and rise in HDL-C levels

(c) Lowering of blood pressure

(d) Improving psychological well-being

(e) Predisposition to increased physical activity in adulthood

(2) Children should participate in at least 30 minutes of moderate physical activity at least 4 or more days of the week, preferably every day.

(3) Parents should be encouraged to help their children reduce excessive time spent on sedentary behaviors such as watching television and videos, playing on a computer, listening to music, and talking on the phone. TV sets should be removed from children’s bedrooms.

(4) More physical activity should be part of their lifestyle, such as walking or biking to school instead of driving, skating, stairs instead of elevators, and helping with active chores inside and outside of the house.

(5) Teach parents the importance of being role models for active lifestyle and providing children with opportunities for increased physical activity.

3. Behavior modification is essential for permanent changes in dietary and exercise habits.

a. Promotion of long-term permanent changes in behavior patterns, rather than short-term diet or exercise program for rapid weight loss, should be the goal of treatment.

b. Emphasis should be on small and gradual behavior changes.

4. Early intervention and family involvement: Physicians should also talk about the importance of early intervention (beginning before adolescence) and family involvement for successful weight management.

a. The importance of early intervention includes:

(1) Many lifestyle habits (eating and exercise habits) are established early in childhood. Parents have much control of their children’s behaviors in the early school years.

(2) There is a tracking of CV risk factors from childhood to adulthood. About 80% of obese adolescents became obese adults. After it is established, obesity is difficult to cure.

b. Family involvement is very important in pediatric weight management programs.

(1) Willingness on the part of both child and family to participate and involvement of the entire family and other caregivers are important.

(2) Parents need to learn certain skills and commit themselves to the program.

(a) Parent role modeling of healthful dietary and activity habits

(b) Understanding the new food guide system (MyPlate)

(c) Ability to read food labels

(d) Appropriate ways of praising and rewarding good progress

(e) Changes in family environment, such as removing high-calorie foods, reducing the number of meals eaten outside of the home, serving portion-controlled meals to the child, promoting active lifestyles, and discouraging a sedentary lifestyle

(f) Inclusion of activities to help families monitor their eating and physical activity behaviors and establishing formal routine exercise program at a scheduled time each day or evening

Primary emphasis in weight control efforts should be the lifestyle change; the weight loss itself is of secondary importance. An active lifestyle improves risk factors even when weight loss is minimal. When a weight loss goal is set, it should be realistic and should not attempt to fully normalize weight. In children without complications of obesity, maintenance of the current weight or modest weight loss, while children continue to grow in height, reduces their degree of overweight. Children with complications of obesity (e.g., hypertension, hyperlipidemias, insulin resistance, hepatic steatosis) should attempt to lose weight to correct those complications.

Cigarette Smoking

Cigarette smoking has been called the chief single avoidable cause of death in our society and one of the most important public health issues of our time, costing more than $167 billion a year. Cigarette smoking is a powerful independent risk factor for myocardial infarction, sudden death, and peripheral vascular disease. Even passive exposure to smoke causes alterations in the risk factors in children.

Prevalence. The prevalence of cigarette smoking nationwide among high school students (grades 9–12) increased during the 1990s, peaking in 1996 and 1997, and then declining slightly since, but a significant number of children and adolescents continue to be smokers. An estimated 6.4 million children younger than 18 years of age who are living today will die prematurely as adults because they began to smoke cigarettes during adolescence.

Some important statistics on the prevalence of smoking among the youth are presented below, based on the 2006 CDC and other recent reports.

1. Current use of any tobacco product (cigarettes, cigars, pipes, smokeless tobacco) ranges from 13% among middle school students to 28% among high school students. Among college students, 33% are current users of tobacco products, and nearly 50% used tobacco product in the past year (Rigotti et al, 2000). More recent CDC data show some decline in the numbers; 20% of high school students and 12% of middle school students. Tobacco use was significantly higher among white students than black students. Cigarette smoking was the most prevalent, and cigar smoking was the second most prevalent form of tobacco use.

2. Approximately 80% of tobacco users initiate use before age 18 years.

3. There were smokers in the household in 72% of middle school student smokers and in 58% among high school student smokers.

4. Nearly 50% of middle school student smokers and 62% of high school student smokers reported a desire to stop smoking cigarettes, and most of them have made at least one cessation attempt during the past 12 months. On the other hand, among students who have never smoked cigarettes, 21% of middle school students and 23% of high school students were susceptible to initiating cigarette smoking in the next year.

Pathophysiologic effects of smoking. The following are some pathophysiologic effects of smoking on the CV system (Lu et al, 2004), all of which appear likely to be involved in accelerating atherosclerosis in the coronary artery and peripheral arteries or increasing the probability of thrombosis (with the potential for stroke). Physicians could use this information in counseling session with smokers.

1. Smoking causes atherogenic dyslipidemia

a. It increases levels of LDL and VLDL-C and TGs.

b. It lowers HDL-C levels.

These effects are greater in children and adolescents than in adults. Even passive smoking lowers HDL-C.

2. Smoking contributes to a prothrombotic predisposition.

a. It increases levels of fibrinogen, factor VII, and other factors involved in the fibrin clotting cascade and decreases the concentration of plasminogen.

b. It activates platelets, increasing their ability to adhere to the vessel wall.

3. Smoking increases blood viscosity by increasing hemoglobin levels (through carbon monoxide–induced increase in carboxyhemoglobin) and by an elevation of plasma fibrinogen levels.

4. Smoking accelerates the atherosclerotic process by:

a. Increasing monocyte adhesion to endothelial cell (the initial step in atherogenesis)

b. Decreasing nitric oxide synthesis (with resulting endothelial dysfunction)

c. Decreasing synthesis of prostacycline

5. Smoking causes peripheral arterial disease through endothelial dysfunction. Smoking raises blood pressure transiently, raises heart rate, and increases myocardial contractility and myocardial oxygen consumption (by stimulation of the sympathetic nervous system).

Psychosociology of smoking. Physicians should be aware of the psychosociology of initiating smoking to help prevent smoking in children.

1. Most smoking starts during adolescence. The high-risk period is the transition from elementary school to middle school and the first and second years of middle school. This should be the target age group to counsel individually or through school systems.

2. Known predictors of smoking include peer influence (the most important), family members who smoke (siblings and parents), less educated parents, being a more independent and rebellious child, and having less academic success.

3. Cited reasons for starting to smoke include wanting to fit into a group, to lose weight, and to appear more mature.

Management

Physicians and health care professionals should assess the status of smoking, provide smoking prevention messages, help counsel parents and children about smoking cessation, and encourage school and community antismoking efforts.

1. Physician should assess the status of smoking during office visits.

a. Smoking history should be obtained in all children older than 8 years of age during routine health assessments and updated. History regarding any siblings and friends who smoke should also be obtained.

b. For current smokers, onset of smoking; number and type of cigarette smoked per day, week, or month; and whether they want to quit smoking and need help to quit the habit should be determined.

c. Smoking history should also be obtained for parents and be updated.

2. Parents who smoke should be encouraged to quit. Physicians should emphasize the adverse effects of passive smoking on their children and to be role models for their children. Physicians should refer parent smokers to community smoking cessation programs.

3. Physicians’ offices should be nonsmoking environments (without ashtrays); antismoking posters, pamphlets, and videos in the waiting room may be productive.

4. Counseling techniques may vary with the age of the child.

a. For elementary school children, antismoking messages at each well-child assessment may counterbalance any negative pro-smoking influences exerted by friends or family. Emphasize the harmful physical consequences of smoking and the addictive nature of cigarettes. Parental assistance in the child’s cessation of smoking should also be sought.

b. For adolescents, emphasis should be on the current negative physiological and social effects of smoking rather than long-term health consequences. Adolescents understand the health consequences of smoking but see them as remote and irrelevant. More immediate negative effects include bad breath, smelling like smoke, yellow-stained fingers, smell from clothing and hair, increasing heart rate and blood pressure, lack of stamina for sports, shortness of breath, and so on.

5. Some adolescents quit smoking on the advice of their physicians, and cessation message as brief as 3 minutes may be effective. Many adolescents require repeated efforts to quit smoking. Physicians should also encourage activities that tend to preclude cigarette smoking, such as regular physical activity and a variety of school and after-school activities.

Pharmacologic approach. For established adult smokers, if counseling is ineffective, physicians may try nicotine replacement and bupropion to help them quit smoking.

1. Nicotine replacement (by nicotine polacrilex gum or transdermal patch) delivers less nicotine than does cigarette smoking, which delivers a bolus of nicotine. It also eliminates carbon monoxide inhalation.

2. Bupropion, an antidepressant, stimulates dopamine release and curbs the severe withdrawal symptoms of smoking cessation.

Practice of Preventive Cardiology

The primary mission of pediatrics has been the prevention of disease and ensuring normal growth and development. It is natural for pediatricians to pay attention to early detection of children at risk of developing CV disease (and type 2 diabetes) and provide counseling, intervention, and treatment whenever possible.

Atherosclerotic CV disease, the leading cause of both death and disability in this country, has an early onset, and its presence and extent correlate positively and significantly with established CV risk factors, namely, LCL-C, TGs, blood pressure, BMI, and presence of cigarette smoking (see Box 33-1). There is a disturbing increase in the prevalence of obesity during childhood, and it is closely related to the development of other risk factors for CAD and diabetes, which is known as the metabolic syndrome (see Box 33-2).

Acquisition of behaviors associated with risk factors occurs in childhood, such as dietary habits, physical activity behaviors, and the use of tobacco. Intervention to reduce the risk factors in childhood has been successful with low-calorie diets, smoking prevention, increasing physical activities, and family-based weight control programs. Some risk factors are detectable, modifiable, or treatable.

1. Family history of CV disease is very important in assessing a child’s risk of developing CAD later in life. Although it is not modifiable, its presence is a marker for a high risk of heart disease. A history of premature CAD in the first- or second-degree relatives (parents, grandparents, blood-related aunts and uncles, or siblings) before age 55 years for men and before age 60 years for women should prompt physicians to check on other risk factors.

2. Hypercholesterolemia is one of the major risk factors that are identifiable and treatable.

3. Hypertension is also an identifiable and treatable risk factor (see Chapter 28).

4. Other risk factors, such as smoking, consumption of atherogenic diets, and physical inactivity, are all modifiable by behavior changes.

5. Obesity is easily detectable. Although treatment of obesity can be frustrating to both patients and physicians, patient education and behavior modification can be productive.

6. Inclusion of HbA1C should be considered in the screening protocol to detect diabetic and prediabetic states.

The American Heart Association has published a guideline for the prevention of CV disease. Table 33-6 is a handy summary that presents goals and recommendations for reducing risks in children and adolescents for future CV disease.

TABLE 33-6

Summary Guidelines for Preventive Pediatric Cardiology

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BMI, Body mass index; BP, blood pressure; CV, cardiovascular; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LFT, liver function test; LVH, left ventricular hypertrophy; TG, triglyceride; TSH, thyroid-stimulating hormone.

Modified from Kavey RW, Daniels SR, Lauer RM, et al: American Heart Association Guidelines for Primary Prevention of Atherosclerotic Cardiovascular Disease Beginning in Childhood. Circulation 107:1562-1566, 2003.