Dyslipidemias





High levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are all risk factors for coronary atherosclerosis. A link has been established between increased levels of triglycerides (TGs) and coronary heart disease as well. Cholesterol reduction results in reduced angiographic progression of CAD and even modest regression in some cases. Therefore controlling dyslipidemia has become a primary goal of reducing premature CAD. It has been established that the coronary arteriosclerosis begins to develop during childhood. In 2011, the Expert Panel convened by the National Heart Lung and Blood Institute (NHLBI) made recommendations on screening for dyslipidemia in children in an effort to reduce the prevalence of premature CAD.


I. Diagnosis of Dyslipidemia


The diagnosis of dyslipidemia is made by measuring blood lipid, lipoproteins, or apolipoprotein factors.



  • 1.

    The routine lipid profile typically includes: TC, HDL-C, LDL-C, and triglycerides (TG). A lipoprotein analysis is obtained after an overnight fast of 12 hours. The LDL level is usually estimated by the Friedewald formula:


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    LDL = Total cholesterol − HDL − ( Triglyceride / 5 )


    This formula is not accurate if the child is not fasting, if the TG level is >400 mg/dL, or if chylomicrons or dysbetalipoproteinemia (type III hyperlipoproteinemia) is present. Methods are currently available to measure LDL-C directly, which does not require a fasting specimen.


  • 2.

    An extended profile may also include very-low-density lipoprotein cholesterol (VLDL-C), non-HDL cholesterol (non-HDL-C), and the ratio of TC to HDL-C.


  • 3.

    Non-HDL-C: Serum non-HDL-C (TC − HDL-C) is considered a better screening tool than LDL-C for the assessment of CAD risk because it includes all classes of atherogenic (apolipoprotein B–containing) lipoproteins: VLDL-C, intermediate-density lipoproteins (IDLs), LDL-C, and lipoprotein (a) or Lp(a). Non-HDL-C from a nonfasting lipid profile is recommended in routine lipid screening.


  • 4.

    The ratio of the TC to HDL cholesterol (TC-to-HDL-C ratio) is a useful parameter for assessing risk for CVD. 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). The higher the ratio, the higher is the risk of developing CVD.


  • 5.

    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 triglyceride levels (>140 mg/dL) and a decreased HDL-C level (<40 mg/dL in men; <50 mg/dL in women). Although not routinely measured, small, dense LDL can be measured directly by commercial laboratories.



II. Normal Levels of Lipids and Lipoproteins


Table 26.1 shows normal, borderline, and abnormal levels of lipid and lipoprotein levels in children. Table 26.2 shows those values for young adults. In children, TC ≥200 mg/dL; LDL-C ≥130 mg/dL; TGs ≥100 mg/dL for patients younger than 10 years and ≥130 mg/dL for 10- to19-year olds; and HDL-C <40 mg/dL are considered abnormal.



Table 26.1

Concentrations of Plasma Lipid, Lipoprotein, and Apolipoprotein in Children and Adolescents (Mg/Dl): Low, Acceptable, Borderline, and High

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescent, National Heart, Lung, and Blood Institute. (2011). Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: Summary report. Pediatrics, 128 (suppl 5), S213-S256.




















































Category Low Acceptable Borderline High
Total cholesterol <170 170-199 ≥200
LDL cholesterol <110 110-129 ≥130
Non-HDL cholesterol <120 120-144 ≥145
Triglycerides: 0-9 years10-19 years −− <75<90 75-9990-129 ≥100≥130
HDL cholesterol <40 >45 40-45
Apolipoprotein A1 <115 >120 115-120
Apolipoprotein B <90 90-109 ≥110

HDL, high-density lipoprotein ; LDL, low-density lipoprotein .


Table 26.2

Recommended Cut Points for Lipid and Lipoprotein Levels in Young Adults (Mg/Dl)

From Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescent, National Heart, Lung, and Blood Institute. (2011). Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: Summary report. Pediatrics, 128 (suppl 5), S213-S256.














































Category Low Borderline-low Acceptable Borderline-high High
Total cholesterol <190 190-224 ≥225
LDL cholesterol <120 120-159 ≥160
Non-HDL cholesterol <150 150-189 ≥190
Triglycerides <115 115-149 ≥150
HDL cholesterol <40 40-44 >45

HDL, high-density lipoprotein ; LDL, low-density lipoprotein .


III. Classification of Dyslipidemia


Dyslipidemia can be classified as primary (genetic) or secondary dyslipidemia.




  • 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.



  • Secondary dyslipidemia is caused by associated diseases or conditions. The majority of the cases found during screening are secondary forms.



A. Secondary Dyslipidemia




  • 1.

    Box 26.1 lists causes of secondary dyslipidemia.



    • a.

      The most common cause of pediatric dyslipidemia is obesity.


    • b.

      Medications such as oral contraceptives, isotretinoin (Accutane), anabolic steroids, diuretics, β-blockers, antipsychotics, and estrogens are uncommon causes of dyslipidemia.


    • c.

      Medical conditions including hypothyroidism, renal failure, nephrotic syndrome, and alcohol usage are less common causes of secondary dyslipidemia.


    • d.

      Most secondary causes of dyslipidemia raise TG and often lower HDL-C levels, with the exception of (1) increased levels of HDL-C seen with estrogen and (2) increased LDL-C seen with nephrosis, systemic lupus, primary biliary cirrhosis, protease inhibitors (for treatment of human immunodeficiency virus [HIV]), and hypothyroidism.


    • e.

      Each child with dyslipidemia should have laboratory tests to help rule out secondary causes of dyslipidemia. The tests should include (1) fasting blood glucose or glycated hemoglobin (Hgb A1c), (2) renal function, (3) liver function, and (4) thyroid function.


    • f.

      When the diagnosis of secondary dyslipidemia is made, one should treat the associated disorder (such as diabetes, obesity, or nephritic syndrome) that is producing the dyslipidemia first and then treat the dyslipidemia using the same guidelines as in primary dyslipidemia.



    Box 26.1

    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, β-adrenergic blockers, antipsychotics, anticonvulsants, glucocorticoids, estrogen, testosterone, immunosuppressive agents (cyclosporine), antiviral agents (HIV protease inhibitor)
    Others Kawasaki disease, anorexia nervosa, post–solid organ transplantation, childhood cancer survivor, progeria, idiopathic hypercalcemia, Klinefelter syndrome, Werner syndrome

    HIV, human immunodeficiency virus.




B. Selected Primary Dyslipidemias


Primary (genetic) dyslipidemias are far less commonly found in the screening process. Five well-known primary dyslipidemias are presented in summary format in Table 26.3 .



Table 26.3

Selected Primary Dyslipidemias

























Lipid disorders Clinical information
Familial hypercholesterolemia (FH): FH heterozygotes


  • Fairly common (1 in 500 people)



  • One out of 2 siblings and one parent have ↑TC (>240 mg/dL; Avg. 300 mg/dL) and ↑LDL (>160 mg/dL; Avg. 240 mg/dL). Unaffected are perfectly normal.



  • Xanthomas (of Achilles tendon or extensor tendons of hands) in parents (seen in 10% to 15%) almost confirm the diagnosis.



  • TX: (a) Diet low in fat and cholesterol and high in fiber. (b) Statins are the drugs of choice.

FH homozygotes


  • One in 1 million children



  • TC and LDL-C are 5 to 6 times higher than normal.



  • (TC average levels 700 mg/dL and may reach ≥1000 mg/dL).



  • Planar xanthomas may be present by age 5 years (flat, orange-colored lesions in the webbing of the hands and over the elbows and buttocks).



  • Tendon xanthomas, arcus corneae, and significant CAD are often present by age 10 years. Atherosclerosis often results in aortic stenosis.



  • TX: (a) High-dose statins and niacin. (b) Will require LDL apheresis (with extracorporeal affinity LDL absorption column and plasma reinfusion) every 2 weeks.

Familial combined hyperlipidemia (FCH)


  • AD disorder (3 times more frequently than FH)



  • Characterized by variable lipid phenotypic expression: ↑LDL alone, ↑LDL + ↑TG, or normal LDL with ↑TG (difficult to separate it from FH). TC (190-220 mg/dL) and LDL (normal or mildly ↑) are lower than in patients with FH.



  • Diagnosis suspected when a parent or sibling has a different lipoprotein phenotype than the proband.



  • LDL levels fluctuate from time to time, with TG levels fluctuating in the opposite direction.



  • Usually no tendon xanthomas are present.



  • Often other signs of the metabolic syndrome (e.g., visceral obesity, hyperinsulinemia, glucose intolerance, and hypertension) are present.



  • TX: (a) Low-fat and low-cholesterol diet, (b) low glycemic index foods, and (c) weight control + exercise. (d) Statins are the most effective drugs in lowering LDL. (e) Drug therapy if TG (>350 mg/dL) to prevent pancreatitis. (f) Metformin (±)

Familial hypertriglyceridemia


  • AD disorder, caused by lipoprotein lipase (LPL) deficiency, resulting in hepatic overproduction of VLDL-C.



  • TG typically increased (200-1000 mg/dL) but TC is not increased.



  • High TG levels accompany (a) ↓HDL, (b) the production of smaller, denser LDL particles (more atherogenic), and (c) a hypercoagulable state.



  • TX: (a) Diet very low in fat and simple sugar; (b) lifestyle change with exercise; (c) when TG reaches 500-1000 mg/dL, pancreatitis is a major concern (fibrate or niacin may be used).

Dysbetalipoproteinemia (type III hyperlipoproteinemia)


  • Rare AR disorder, due to a defect in apolipoprotein E, resulting in increased accumulation of chylomicron remnants and VLDL remnants.



  • Both TC and TG increased equally to >300 mg/dL (not usually seen in childhood). (TC: 250-500 mg/dL; TG: 50-600 mg/dL)



  • TX: (a) Low-fat and low glycemic index diet; (b) fibric acid or statin is very effective.

Familial hypoalphalipoproteinemia (low-HDL syndrome)


  • AD disorder, caused by decreased concentration of apolipoprotein A1 and apolipoprotein AII and absent apolipoprotein CIII.



  • Low HDL-C increases the risk of premature CAD.



  • Tangier disease: HDL nearly absent (with markedly enlarged yellow tonsils).



  • TX: (a) Low carbohydrate and low fat diet. (b) Exercise and weight loss are also helpful. (c) Goal is to keep LDL low.


AD, autosomal dominant ; AR, autosomal recessive ; Avg., average ; CAD, coronary artery disease ; HDL, high-density lipoprotein ; LDL, low-density lipoprotein ; VLDL, very-low-density lipoprotein ; TC, total cholesterol ; TG, triglycerides ; TX, treatment .


IV. Lipid Screening


In 2011, the Expert Panel convened by the NHLBI made the following recommendations. These recommendations are major changes from the past recommendations of selective screening of children and adolescents with a family history of premature CVD or those with at least one parent with high serum cholesterol levels (by the Expert Panel of 1991).


The new recommendations are as follows.



  • 1.

    Universal screening is recommended for children 9-11 years old and patients 17-21 years old (see Box 26.2 ).



    • a.

      For universal screening, either nonfasting lipid profile (non-FLP) or fasting lipid panel (FLP) is acceptable.


    • b.

      When non-FLP is obtained, non-HDL-C is calculated (by subtracting HDL-C from TC. Non-HDL-C has been shown to be as powerful a predictor of atherosclerosis as any other lipoprotein cholesterol measurement in children and adolescents.



    Box 26.2

    Recommendations for Lipid Assessment According to Age Group

    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 Adolescent, National Heart, Lung, and Blood Institute. (2011). Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: Summary report. Pediatrics, 128 (suppl 5), S213-S256.




























    Age group
    <2 years No lipid screening
    2 to 8 years Selective screening. Measure FLP twice and average the result if any of the following applies:


    • Positive family history (see below)



    • Parent with TC ≥240 mg/dL or known dyslipidemia



    • Child has diabetes, hypertension, BMI ≥95th%, or smokes cigarettes



    • Child has a moderate- or high-risk medical condition (see Box 26.3 )

    Interpret the results according to Table 26.1 .
    9 to 11 years


    • Universal screening (by either non-FLP or FLP)



    • Non-FLP: Calculate non-HDL cholesterol (non-HDL cholesterol=TC−HDL cholesterol).



    • If non-HDL cholesterol≥145 mg/dL or±HDL <40 mg/dL, measure FLP twice and average results.



    • OR



    • FLP:



    • If LDL cholesterol≥130 mg/dL; ±non-HDL cholesterol ≥145 mg/dL; ±HDL cholesterol <40 mg/dL; ±triglycerides ≥100 mg/dL if <10 years; or ≥130 mg/dL if ≥10 years, repeat FLP and average results.



    • Interpret the results according to Table 26.1 .

    12 to 16 years Selective screening
    Measure FLP twice and average results if any of the following applies:


    • Positive family history (see Box 26.3 )



    • Parent with TC ≥240 mg/dL or known dyslipidemia



    • Child has diabetes, hypertension, BMI ≥85th percentile, or smokes cigarettes



    • Child has a moderate- or high-risk medical condition (see following)

    Interpret the results according to Table 26.1 .
    17 to 21 years


    • Universal screening once in this time period (by either non-FLP or FLP)



    • For 17-19 yr:



    • Non-FLP: Calculate non-HDL-cholesterol.



    • If non-HDL cholesterol ≥145 mg/dL or ±HDL <40 mg/dL, measure FLP twice and average results



    • OR



    • FLP:



    • If LDL cholesterol ≥130 mg/dL; or non-HDL-cholesterol ≥145 mg/dL; ±HDL cholesterol <40 mg/dL or ±triglycerides ≥130 mg/dL, repeat FLP and average results.



    • Interpret the results according to Table 26.1 .




    • For 20-21 years:



    • Non-FLP: Calculate non-HDL cholesterol



    • If non-HDL cholesterol ≥190 mg/dL or ±HDL cholesterol <40 mg/dL, measure FLP twice and average results.



    • OR



    • FLP:



    • If LDL cholesterol ≥160 mg/dL; ±non-HDL cholesterol ≥190 mg/dL; ±HDL cholesterol <40 mg/dL or ±triglycerides ≥150 mg/dL, repeat FLP and average results.



    • Interpret the results according to Table 26.1 or Table 26.2 .

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Apr 11, 2021 | Posted by in CARDIOLOGY | Comments Off on Dyslipidemias
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