Pediatric Lipid Disorders in Clinical Practice

Updated: Jan 29, 2015
  • Author: Henry J Rohrs, III, MD; Chief Editor: Stuart Berger, MD  more...
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Overview

Background

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] The purpose of this article is to discuss the basic biology of lipoproteins, the pathophysiology of dyslipidemias, the interpretation of lipid levels in pediatric patients, dyslipidemia screening, and the management of pediatric lipid abnormalities.

For patient education information, see the Cholesterol Center, as well as Lowering High Cholesterol in Children, Cholesterol Charts, Lifestyle Cholesterol Management, Cholesterol-Lowering Medications, and Statins for Cholesterol.

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Pathophysiology

Physiology of lipids and lipoproteins

The two major forms of circulating lipid in the body, triglyceride (TG) and cholesterol, are insoluble in plasma. However, these lipids can be transported throughout the bloodstream as lipoproteins when packaged with phospholipids and proteins (apoproteins). Lipoproteins have an outer core of cholesterol, phospholipids, and apoproteins and an inner core 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 (eg, apoprotein B-100 binds to the low-density lipoprotein receptor [LDL-R], which is also known as the apoprotein B-100 – apoprotein E receptor).

Lipoproteins have been classified into five major classes, as depicted in the table below.

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

Lipoprotein Major Lipid Composition Role in Normal Fasting Plasma Measured Substance
High-density lipoprotein cholesterol (HDL-C) Cholesterol Antiatherogenic (involved in reverse cholesterol transport from the tissues to the liver) HDL-C
LDL-C Cholesterol Major cholesterol carrier Can be measured directly (direct LDL-C) or can be calculated*
Intermediate-density lipoprotein cholesterol (IDL-C) TG and cholesterol Intermediate between very–low density lipoprotein (VLDL) and low-density lipoprotein (LDL) Not routinely measured; can be assessed by LPE† or measured by ultracentrifugation
VLDL TG Major TG carrier TG‡
Chylomicron TG Absent Not routinely measured; can be assessed by LPE or measured by ultracentrifugation
* Calculated using the Friedewald equation: LDL-C = Total cholesterol (TC) - HDL-C - TG/5



† LPE = Lipoprotein electrophoresis



‡ TG/5 is the estimate of the VLDL-C.



 

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, or buoyant, LDL-C and cholesterol-depleted, or dense, LDL-C. Dense LDL-C is more atherogenic than light LDL-C.

Lipoproteins are derived from the exogenous and the endogenous pathways. In the exogenous pathway, dietary lipids are consumed with meals; these lipids (predominantly TGs) are packaged by the intestinal mucosal cells into chylomicrons. Chylomicrons, which are TG rich, enter the lymphatic system. The thoracic duct empties into the vena cava, and chylomicrons systemically circulate. Apoprotein C-II, apoprotein B-48, and apoprotein E are the clinically important apoproteins of chylomicrons.

Apoprotein B-48 is a chylomicron structural protein. Chylomicrons bind to LPL via apoprotein C-II. 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. 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 the fasting state, chylomicrons and chylomicron remnants are not normally detected in plasma.

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. IDL particles may be 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 space, the protective effect of circulating antioxidants is lost, and LDL is oxidized.

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 of LDL is not regulated, and macrophages and smooth muscle cells can take up so much oxidized LDL and cholesterol that they become foam cells. Because oxidized LDL is toxic to cells, it 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 down-regulate the LDL-R to decrease cholesterol uptake into the cell.

Dyslipidemias

Table 2, below, depicts the Frederickson classification scheme, used to distinguish dyslipidemias.

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

Phenotype Elevated Particles Major Lipid Increased Frequency
I Chylomicron TG Very rare
IIA LDL LDL-C Common
IIB LDL and VLDL LDL-C, TG Common
III IDL and remnants TC, TG Rare
IV VLDL TG Common
V Chylomicron and VLDL TG Uncommon

 

The most common dyslipidemias are types IIA, IIB, and IV. Type I and type III hyperlipoproteinemia (HLP) are extremely rare in pediatric patients, and type V is uncommon.

Type I HLP

Type I HLP is present when the TGs are predominantly elevated. TG levels may exceed 1000-2000 mg/dL, and levels as high as 25,000 mg/dL have been observed. Type I HLP is also termed chylomicron syndrome or hyperchylomicronemia syndrome. In type I HLP, the plasma infranatant on standing is clear, whereas the supernatant is cloudy because of elevated chylomicrons that float to the top of the plasma. Supernatants form only 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. Lipoprotein electrophoresis (LPE) is far less quantitative than ultracentrifugation.

Most cases of type I HLP are caused by congenital deficiency of LPL, congenital deficiency of apoprotein C-II, or an LPL inhibitor (eg, an anti-LPL autoantibody). In healthy children and adults, 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 (eg, TG is not released from the chylomicrons to muscle and adipose tissue) in type I HLP, most chylomicrons are taken up by the liver and spleen, resulting in hepatosplenomegaly, macrophage uptake (foam cell formation), and the development of cutaneous xanthomas.

If prolonged hypertriglyceridemia is untreated, eruptive xanthomas (discrete 1-mm 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 in color 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. Recurrent pancreatitis can be debilitating.

In one study of patients with LPL deficiency, 80% presented before age 10 years, with 30% presenting before age one. In contrast, apoprotein C-II deficiency is usually diagnosed later in life (>13 years). 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 have been cousins. Carriers of LPL mutations are asymptomatic.

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

Type II HLP

In children, type IIA HLP is defined by LDL-C concentrations of 130 mg/dL or higher. The plasma is clear in type IIA HLP because LDL particles are not large enough to scatter light, as opposed to IDL, VLDL, or lipoprotein remnants that are large enough to cause turbidity.

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. Thus, individuals with FH may display a type IIA or B phenotype. FH affects approximately one 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.

If an individual inherits two defective alleles of the LDL-R gene (homozygous FH), LDL production increases by approximately 200-300%. Adults who are heterozygous for FH have two- to three-fold higher total cholesterol (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. Homozygous FH leads to extremely premature and hazardous atherosclerosis. In addition, aortic valvar disease can occur in children with homozygous FH.

Besides valve dysfunction, the ostia of the coronary arteries can become obstructed. Fortunately, homozygous FH is very rare, affecting only one in 1 million persons. Children with homozygous FH have suffered myocardial infarctions as early as age 3 years. Death during adolescence is common. Homozygous FH should thus be strongly suspected in deaths from myocardial infarction in individuals aged 20 years or younger.

In heterozygous FH, affected family members have elevated LDL-C concentrations beginning early in life. Cord blood TC and LDL-C levels are already elevated. Untreated 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 untreated FH is 45 years. Untreated 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.

A defect in apoprotein B-100 is phenotypically similar to FH and occurs with a similar frequency. 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, VLDL, and TG levels are usually normal. In contrast to FH, tendon xanthomas and 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, vs 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 because of reduced LDL clearance. Lipoprotein production is typically increased in patients with nephrosis. This may be a compensation for hypoalbuminemia. With glycation of apoprotein B in patients with diabetes mellitus and increased VLDL synthesis, LDL-C levels commonly rise.

Type III HLP

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. Type III HLP is caused by 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.

Type IV HLP

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.

Hypertriglyceridemia (usually the type IV HLP phenotype) 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, HIV protease inhibitors), may also lead to hypertriglyceridemia.

Similar to insulin, thyroid hormone regulates LPL activity; hypothyroidism can cause elevated TG levels by lowering LPL activity.

The combination of type IV HLP and low HDL-C (eg, hypoalphalipoproteinemia) are typical findings in the metabolic syndrome. The metabolic syndrome is a constellation of findings related to reduced insulin sensitivity most commonly caused by centripetal and abdominal obesity. Besides dyslipidemia, features of the metabolic syndrome include hyperinsulinism, dysglycemia (eg, impaired glucose tolerance, impaired fasting glucose or type 2 diabetes), hypertension, hyperuricemia, hyperandrogenism in women, polycystic ovary syndrome, propensity to thrombosis (because of increased plasminogen activator inhibitor levels), and elevated ferritin concentrations. Adults with the metabolic syndrome are at greatly increased risk for cardiovascular disease.

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.

Type V HLP

Type V HLP results when two 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 supernatant.

Other dyslipidemic syndromes

The differential diagnosis of a depressed HDL-C level 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 for low HDL-C. In 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 lecithin-cholesterol acyl transferase (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.

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