Pediatric Lipid Disorders in Clinical Practice 

Multiple studies have revealed that the early stages of atherosclerosis begin in childhood.^[1] If premature development of cardiovascular disease can be anticipated during childhood, the disease might be prevented.^[2] In adult patients, the lowering of lipid levels results in primary and secondary prevention of cardiovascular disease. The purpose of this article is to discuss the basic biology of lipoproteins, the pathophysiology of various dyslipidemias, the screening and interpretation of lipid levels in pediatric patients, and the management of pediatric lipid abnormalities.

For excellent patient education resources, see eMedicine's Cholesterol Center and Statins Center. Also, visit eMedicine's patient education articles Cholesterol and Children, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, and Statins and Cholesterol.

Physiology of lipids and lipoproteins

The 2 major forms of circulating lipid in the body, triglyceride (TG) and cholesterol, are insoluble in plasma. However, these lipids can be transported throughout the blood stream as lipoproteins when packaged with phospholipids and apolipoproteins (ie, apoproteins). Lipoproteins have an outer core of cholesterol, phospholipids, and apoproteins and their inner core is composed of TG and cholesterol ester (CE). Apoproteins function as (1) structural proteins, (2) proteins that make the lipoprotein particle soluble, (3) enzyme activators (eg, apoprotein C-II activates lipoprotein lipase [LPL], apoprotein A-I activates lecithin-cholesterol acyltransferase [LCAT]), and (4) ligands for receptors.

Lipoproteins have been classified into 5 major classes, as depicted in the table below. The classes of lipoprotein are not homogeneous in size or composition. For example, low-density lipoprotein cholesterol (LDL-C) can be divided into cholesterol-rich light LDL-C and cholesterol-depleted dense LDL-C. Dense LDL-C is more atherogenic than light LDL-C.

Table 1. Biology of Lipoproteins (Open Table in a new window)

This lipoprotein pathway is termed the exogenous pathway because dietary lipids are consumed with meals. Dietary lipids (predominantly TGs) are packaged by the intestinal mucosal cells into chylomicrons. Apoprotein C-II, apoprotein B-48, and apoprotein E are the clinically important apoproteins of chylomicrons. Chylomicrons, which are TG rich, enter the lymphatic system. The thoracic duct empties into the vena cava, and chylomicrons systemically circulate. Once acted on by LPL, which is attached to the luminal side of the capillary endothelium adjacent to muscle and adipose tissue, chylomicrons release TGs as monoglycerides and free fatty acids.

Chylomicrons bind to LPL via apoprotein C-II. Therefore, defects in apoprotein C-II or LPL can lead to defects in chylomicron clearance. Muscle normally burns the free fatty acids and monoglycerides for energy. Resynthesized TGs can be used for plasma and cell organelle membrane synthesis. Adipose tissue uses free fatty acids and monoglycerides to resynthesize TGs that are stored for future energy needs.

As an alternative, adipocytes can use TGs in membrane synthesis, which is similar to muscle. When the chylomicrons are reduced in TG content, they become remnants that are rapidly cleared by the liver (apoprotein E binds to the LDL receptor [LDL-R]). At this time, apoprotein C-II is passed to high-density lipoprotein (HDL) particles in the circulation. In fasting normal plasma, chylomicrons and chylomicron remnants are not detected.

In the endogenous pathway, the liver produces VLDL. The clinically important apoproteins in VLDL are apoprotein C-II, apoprotein B-100, and apoprotein E. Like chylomicrons, VLDL interacts with LPL via apoprotein C-II to release TG-forming intermediate-density lipoprotein (IDL) particles. With the formation of IDL, apoprotein C-II is transferred to HDL particles. IDL particles are rapidly removed by the liver via apoprotein E interaction with the LDL-R. The LDL-R is also known as the apoprotein E, apoprotein B-100 receptor. Alternatively, IDL particles are further metabolized to LDL by continued removal of TG by hepatic lipase.

In the conversion from IDL to LDL, apoprotein E is shed and is picked up by HDL particles. LDL is removed by binding to the LDL-R. Approximately two thirds of circulating LDL is removed by the liver, and approximately one third is removed by extrahepatic tissues, including steroid-producing cells and cells within the subintimal space in which atheromatous plaques develop. In the subintimal (ie, subendothelial) space, the protective effect of circulating antioxidants (ie, vitamin E) is lost, and LDL is oxidized (eg, modified).

Oxidized LDL is removed by the scavenger receptor, which is different from the LDL-R. Smooth muscle cells and macrophages express scavenger receptors. This uptake is not regulated, and macrophages and smooth muscle cells can take up so much LDL and cholesterol that they become foam cells. Oxidized LDL is also toxic to cells and can lead to early endothelial injury, allowing platelet adhesion and localized release of platelet-derived growth factor (PDGF). In contrast, when other cells have sufficient cholesterol, they downregulate the LDL-R to decrease cholesterol absorption into the cell.

Dyslipidemias

A review of the Frederickson phenotypes is helpful in classifying dyslipidemias.

Table 2. Frederickson Classification of Dyslipidemias (Open Table in a new window)

The most common dyslipidemias are types IIA, IIB, and IV. Type I and type III hyperlipoproteinemia (HLP) are rare in pediatric patients, and type V is uncommon. Whether type III HLP occurs in children at all is controversial.

Type I HLP is present when the TG elevation is predominant, with TG levels reaching or exceeding 1000-2000 mg/dL. Type I HLP is also termed chylomicron syndrome or hyperchylomicronemia syndrome for reasons noted below. In type I HLP, the plasma infranatant on standing is clear, whereas the supernate is cloudy because of elevated chylomicrons. Supernatants only form when chylomicrons are present. The presence of chylomicrons is best confirmed by obtaining plasma lipoprotein ultracentrifugation, performed by a referral laboratory that specializes in lipid analysis.

Most cases of type I HLP are caused by a congenital deficiency of LPL, a congenital deficiency of apoprotein C-II, or an LPL inhibitor. In healthy children, chylomicrons are rapidly cleared from the circulation after a meal. When LPL or apoprotein C-II is deficient, chylomicrons can be detected for more than 12 hours after a meal. The normal half-life of chylomicrons in plasma is approximately 17 minutes. Because TGs are not being cleared at the tissue level (ie, TG is not released from the chylomicrons to muscle and adipose tissue), most chylomicrons are taken up by the liver and spleen, resulting in hepatosplenomegaly, macrophage uptake (foam cell formation), and rash.

If prolonged hypertriglyceridemia is untreated, eruptive xanthomas (discrete 1- to 6-mm papules) may appear on the extensor surfaces of the extremities. Lipemia retinalis may also occur. The retinal vessels appear white-to-yellow because of the striking hyperchylomicronemia.

When TG levels exceed 1000-2000 mg/dL, the risk of pancreatitis is increased. Infants may present with colicky abdominal pain and even failure to thrive. In older children, acute pancreatitis can cause tremendous pain, nausea, vomiting, and even death if undetected and untreated.

In one study of patients with LPL deficiency, 80% presented before age 10 years, with 30% younger than 1 year. In contrast, apoprotein C-II deficiency is usually diagnosed later in life (eg, older than 13 y). Apoprotein C-II deficiency rarely presents in infancy.

At least 40 molecular defects in LPL and 12 different molecular defects in apoprotein C-II have been reported. Both LPL and apoprotein C-II deficiencies are inherited as autosomal recessive traits and affect approximately 1 in 1 million persons in the general population. Because LPL and apoprotein C-II deficiencies are inherited as autosomal recessive traits, the family history is generally unrevealing, although some parents of children with LPL or apoprotein C-II deficiency were cousins.

Note that lipemic serum can interfere with many laboratory determinations, including enzyme activity measurements, antigen-antibody assays, and various spectrophotometric assays.

In children, type IIA HLP is defined as LDL-C concentrations of 130 mg/dL or higher. The plasma is clear. In contrast, in type IIB HLP, TG levels (VLDL levels) are elevated to 125 mg/dL or higher, and LDL-C levels are also elevated. If the TG level is typically 300-400 mg/dL or higher, the plasma appears visibly turbid (lipemic).

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated LDL-C levels with or without a concurrent elevation in TG levels. FH affects approximately 1 in 500 persons in the general population. Besides premature cardiovascular disease, clinical findings in adults include tendon xanthomas (especially involving the Achilles tendons and the extensor tendons of the hands) and arcus senilis (involving the cornea). FH results from an inherited defect in the LDL-R. Because the LDL-R also clears IDL, and because VLDL is the precursor of IDL and LDL, patients with FH may also display elevations in IDL and VLDL. Thus, some individuals with FH display a type IIB phenotype.

In FH, LDL production is increased by approximately 30% in people with one defective allele of the LDL-R gene. If an individual inherits 2 defective alleles of the LDL-R gene (eg, homozygous FH), LDL production increases by approximately 200-300%. Adults who are heterozygous for FH have 2- to 3-fold higher TC levels of 300-600 mg/dL, and LDL-C levels are commonly 250 mg/dL or higher. Patients who are homozygous for FH have TC levels of 600-1500 mg/dL (increased 5- to 6-fold). Homozygous FH is a highly hazardous condition for large blood vessels that causes extremely premature atherosclerosis. However, homozygous FH is very rare, affecting only 1 in 1 million persons.

In FH, affected family members have elevated LDL-C concentration beginning early in life. Cord blood TC and LDL-C levels are already elevated. Males with FH often develop cardiovascular disease in the fourth or fifth decade of life, but the disease can manifest in teenagers. The mean age of death in males with FH is 45 years. Women with FH usually have onset of cardiovascular disease in the fifth or sixth decade of life. Of persons who have survived myocardial infarctions that occurred when they were younger than 60 years, 5% have FH. Children as young as 3 years who have homozygous FH have died from myocardial infarction from premature cardiovascular disease. Homozygous FH should be strongly suspected in deaths from myocardial infarction in individuals aged 20 years or younger.

A defect in apoprotein B-100 is phenotypically similar to FH. This disorder has a frequency similar to FH. Elevated LDL-C levels result when the apoprotein B molecule is defective, even if the LDL-R molecule is normal. In FH, IDL and VLDL concentrations can be elevated because IDL is cleared via the LDL-R; however, in familial defective apoprotein B-100, because the LDL-R molecule is normal, IDL and VLDL (and TG) levels are usually normal. In contrast to FH, tendon xanthomas and arcus cornealis (arcus senilis) may be absent in patients with defective apoprotein B-100 Modest hypercholesterolemia (250-300 mg/dL) is usually present, with a TC level lower than in adults with FH (mean TC concentration in defective apoprotein B-100 is 269 mg/dL versus approximately 360 mg/dL in FH). LDL-C levels are raised by approximately 70 mg/dL. As in FH, patients with familial defective apoprotein B-100 may develop premature cardiovascular disease.

Familial defective apoprotein B-100 and FH can be very difficult to clinically differentiate when patients with FH display a type IIA phenotype; however, in the absence of secondary conditions that raise TG levels, the presence of a type IIB phenotype essentially excludes familial defective apoprotein B-100.

Familial combined hyperlipidemia (FCH) is inherited as an autosomal dominant trait. The etiology of FCH appears to be an overproduction of apoprotein B–containing particles (VLDL, LDL, or both). Affected individuals may exhibit type IIA, type IIB, or type IV phenotypes. In a single family with FCH, some individuals may display isolated elevations in TC/LDL (type IIA HLP) or TG (type IV HLP) levels, whereas other affected members may have a combined hyperlipidemia (increased LDL-C and TG levels [type IIB HLP]). The co-occurrence of FCH plus hypertension has been called familial dyslipidemic hypertension. Similar to FH, premature cardiovascular disease can occur in patients with FCH. Overall, FCH affects approximately 1 in 200-300 persons in the general population and occurs in approximately 15% of individuals younger than 60 years who survive a myocardial infarction.

Other causes of type IIA or IIB phenotypes include hypothyroidism, nephrosis, biliary tract disease, and diabetes mellitus. In hypothyroidism, hepatic LDL-R expression is reduced, leading to elevated LDL-C levels. Lipoprotein production is typically increased in patients with nephrosis. With glycosylation of apoprotein B in patients with diabetes mellitus and increased VLDL synthesis, LDL-C levels commonly rise.

Type III HLP (also known as remnant removal disease, remnant lipoprotein disease, or dysbetalipoproteinemia) is estimated to affect approximately 1 in 5000 persons in the general population but rarely manifests in children. It is due to increases in IDL and remnant lipoproteins and is manifested by approximately equal increases in total cholesterol and TGs.

Palmar xanthomas (xanthoma striata palmaris) may occur in type III HLP and are not observed in other disorders. Genetic and environmental factors both influence the development of type III HLP. The entity should be considered when tuberous xanthomas, palmar xanthomas, or both are noted, and the patient may be obese or have underling diseases such as diabetes mellitus, hypothyroidism, alcoholism, and renal or hepatic disease. Type III HLP can be inherited as a recessive trait or, less commonly, as a dominant trait.

Most adults with type III HLP are homozygous for apoprotein E-2 (one of the 3 isoforms of apoprotein E). Adults with type III HLP are at markedly increased risk for cardiovascular disease and, particularly, peripheral vascular disease.

In type IV HLP a predominant increase in VLDL TGs is observed; however, levels are lower (eg, < 1000 mg/dL) than in HLP types I or V.

Type V HLP results when 2 or more causes of type IV HLP combine to produce chylomicronemia and elevated VLDL levels, which push TG levels to 1000 mg/dL or higher. Plasma samples in patients with type V HLP display a turbid infranatant and a cloudy supernate.

Hypertriglyceridemia is frequently observed in children with obesity, diabetes, or both conditions. In type 1 diabetes mellitus, hypertriglyceridemia results from absolute insulin deficiency, whereas in children with obesity and type 2 diabetes mellitus, insulin resistance is the root cause combined with relative insulin deficiency. Other causes of insulin resistance, including renal disease, liver disease, ethanol abuse, pregnancy, endocrinopathies (eg, Cushing disease, hypothyroidism, acromegaly), and drugs (eg, glucocorticoids, growth hormone, androgens, thiazides, beta-blockers, estrogen), may also lead to hypertriglyceridemia. Similar to insulin, thyroid hormone regulates LPL activity. Hypothyroidism can cause elevated TG levels by lowering LPL activity.

Two inherited causes of a type IV phenotype include familial hypertriglyceridemia and FCH. Familial hypertriglyceridemia is rarely expressed in childhood unless another underlying cause of hypertriglyceridemia is present. About 15% of patients with premature cardiovascular disease have hypertriglyceridemia.

Other dyslipidemic syndromes

The differential diagnosis of a depressed HDL-C includes familial disorders, genetic disorders, smoking, obesity, hypertriglyceridemia, renal failure, and drugs (eg, anabolic steroids, progestins, beta blockers, thiazides), with male sex and a sedentary lifestyle being additional risk factors. In both familial hypoalphalipoproteinemia (ie, low HDL-C) and Tangier disease depressed apoprotein A-I levels are found. Other rare genetic causes of low HDL-C levels include fish-eye disease and LCAT deficiency. In fish-eye disease, patients have TG elevations to 250-300 mg/dL, severely depressed HDL-C levels, and corneal opacities. In LCAT deficiency, cholesterol esters cannot be formed; thus, cholesterol does not move into the core of the HDL particle disc.

Causes of acquired low LDL-C levels include malnutrition from starvation or malabsorption, hyperthyroidism, chronic anemia, severe hepatic dysfunction, and acute severe stress (eg, burns, trauma, myocardial infarction). Genetic forms of hypolipidemia are very rare but are potentially serious. Such conditions include abetalipoproteinemia (autosomal recessive), homozygous hypobetalipoproteinemia, heterozygous hypobetalipoproteinemia (with or without GI tract or neurologic symptoms), abetalipoproteinemia with normotriglyceridemia, and chylomicron retention disease. Low cholesterol levels secondary to deficiency of 7-dehydrocholesterol-δ-7 reductase are seen in Smith-Lemli-Opitz syndrome associated with mental retardation and ambiguous genitalia.

Age

In July 2008, the AAP released updates to their lipid screening and cardiovascular health recommendations.^[3] The more recent guidelines agree with most of the NCEP guidelines but are more specific, recommending precise ages and more aggressive repeat testing in high-risk patients. The guidelines state that pediatric patients with a family history of dyslipidemia or premature cardiovascular disease (defined the same as NCEP), those with an unknown family history, or those with risk factors including lifestyle (smoking, physical inactivity), metabolic disorders (eg, low HDL-C, diabetes mellitus), and hypertension should be screened with a fasting lipid profile. Initial screening should take place between age 2 and 10 years; if levels are within normal limits for age, repeat testing does not need to be obtained for 3-5 years.