Editorials: Controversies in Family Medicine

Hyperlipidemia Treatment in Children: The Younger, the Better



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Am Fam Physician. 2010 Sep 1;82(5):460-467.

This is one in a series of pro/con editorials discussing controversial issues in family medicine.

  Related Editorial

Cardiovascular disease is the leading cause of death in the United States. There is substantial evidence that the atherosclerotic process begins in childhood, with the presence of fatty streaks in the aorta by 10 years of age and in the coronary arteries by 20 years of age.1 Atherosclerotic lesions, which occur in up to 38 percent of persons with multiple risk factors, are more common in young persons with elevations in serum total cholesterol and low-density lipoprotein (LDL) levels; body mass index; and systolic and diastolic blood pressures.24

Furthermore, studies in adolescents have shown that mean carotid intimamedia thickness measured by ultrasonography is strongly associated with cardiovascular risk factors and predictive of coronary artery disease and cerebrovascular accidents. Most of these studies evaluated persons with familial hypercholesterolemia in whom carotid intimamedia thickness was increased and the rate of change was much greater than in the control population.5

The percentage of children with hyperlipidemia appears to be increasing. Data from the National Health and Nutrition Examination Survey between 1988 and 1994 found that 10 percent of adolescents had total cholesterol levels greater than 200 mg per dL (5.18 mmol per L).6 In the more recent Child and Adolescent Trial for Cardiovascular Health, 13.3 percent of children nine to 10 years of age had total cholesterol levels greater than 200 mg per dL.7  Despite no long-term studies evaluating the effectiveness of screening for dyslipidemia in childhood and its effect in delaying or reducing the incidence of cardiovascular-related events, the American Academy of Pediatrics released an updated clinical policy statement in 2008 on lipid screening and cardiovascular health in childhood. The recommendations are summarized in Table 1.8,9

Table 1.

Hyperlipidemia Screening and Treatment in Children: Summary Recommendations

Initial screening should occur in children two to 10 years of age with the following*:

Positive family history of dyslipidemia or premature CVD (55 years or younger for men and 65 years or younger for women)

Unknown family history

Risk factors for CVD:

Overweight (BMI ≥ 85th and < 95th percentile)

Obesity (BMI ≥ 95th percentile)

Hypertension (blood pressure ≥ 95th percentile)

Cigarette smoking

Diabetes mellitus

Medical conditions associated with lipoprotein abnormalities:

Organ transplantation (immunosuppressive therapy)

Systemic lupus erythematosus

Nephrotic syndrome

Protease inhibitor treatment (for human immunodeficiency virus infection)

Recommended treatment strategy

Patients younger than 10 years†

Initiate treatment (initial apheresis at diagnosis, then statin and cholesterol absorption inhibitor) and referral to lipid or cardiology subspecialist if patient has LDL cholesterol > 500 mg per dL (12.95 mmol per L), which occurs with homozygous familial hypercholesterolemia

Recommend referral to lipid or cardiology subspecialist (currently, there is no defined LDL cutoff point at which to initiate treatment) if patient is moderate risk‡ and has LDL cholesterol ≥ 130 mg per dL (3.37 mmol per L) and if patient is at risk§ and has LDL cholesterol ≥ 160 mg per dL (4.14 mmol per L)

Goal for treatment is to lower LDL cholesterol to 130 mg per dL

Patients 10 years and older

Treatment is recommended in the following populations:

Patients with LDL cholesterol ≥ 190 mg per dL (4.92 mmol per L); goal is to lower LDL cholesterol to < 160 mg per dL

Moderate-risk‡ patients with LDL cholesterol ≥ 160 mg per dL and a family history of CVD or two or more risk factors; goal is to lower LDL cholesterol to < 130 mg per dL

High-risk∥ patients with LDL cholesterol ≥ 130 mg per dL; goal is to lower LDL cholesterol to ≤ 110 mg per dL (2.85 mmol per L)

Insufficient data for current guidelines to make firm recommendations for non-LDL lipid abnormalities

Consider statin and fibric or nicotinic acid in patients with high LDL cholesterol and triglyceride levels¶ and in patients with high LDL and low high-density lipoprotein cholesterol levels


note: Screening in children younger than two years is not recommended.

BMI = body mass index; CVD = cardiovascular disease; LDL = low-density lipoprotein.

*—If results of screening are normal, repeat in three to five years.

†—The American Academy of Pediatrics policy statement on cholesterol in childhood suggests that statins can be started at eight years of age.

‡—Persons with heterozygous familial hypercholesterolemia, type 2 diabetes mellitus, chronic inflammatory disease, or Kawasaki disease with regressed coronary aneurysm.

§—Persons with congenital heart disease or Kawasaki disease without coronary involvement, or who have received cancer treatment.

∥—Persons with homozygous familial hypercholesterolemia, type 1 diabetes mellitus, chronic renal disease, Kawasaki disease with coronary artery aneurysm, or heart transplantation.

¶ —Patients with persistent elevation of triglycerides > 350 mg per dL (3.95 mmol per L) or random levels > 700 mg per dL (7.91 mmol per L) may benefit from treatment to avoid risk of pancreatitis.

Information from references 8 and 9.

Table 1.   Hyperlipidemia Screening and Treatment in Children: Summary Recommendations

View Table

Table 1.

Hyperlipidemia Screening and Treatment in Children: Summary Recommendations

Initial screening should occur in children two to 10 years of age with the following*:

Positive family history of dyslipidemia or premature CVD (55 years or younger for men and 65 years or younger for women)

Unknown family history

Risk factors for CVD:

Overweight (BMI ≥ 85th and < 95th percentile)

Obesity (BMI ≥ 95th percentile)

Hypertension (blood pressure ≥ 95th percentile)

Cigarette smoking

Diabetes mellitus

Medical conditions associated with lipoprotein abnormalities:

Organ transplantation (immunosuppressive therapy)

Systemic lupus erythematosus

Nephrotic syndrome

Protease inhibitor treatment (for human immunodeficiency virus infection)

Recommended treatment strategy

Patients younger than 10 years†

Initiate treatment (initial apheresis at diagnosis, then statin and cholesterol absorption inhibitor) and referral to lipid or cardiology subspecialist if patient has LDL cholesterol > 500 mg per dL (12.95 mmol per L), which occurs with homozygous familial hypercholesterolemia

Recommend referral to lipid or cardiology subspecialist (currently, there is no defined LDL cutoff point at which to initiate treatment) if patient is moderate risk‡ and has LDL cholesterol ≥ 130 mg per dL (3.37 mmol per L) and if patient is at risk§ and has LDL cholesterol ≥ 160 mg per dL (4.14 mmol per L)

Goal for treatment is to lower LDL cholesterol to 130 mg per dL

Patients 10 years and older

Treatment is recommended in the following populations:

Patients with LDL cholesterol ≥ 190 mg per dL (4.92 mmol per L); goal is to lower LDL cholesterol to < 160 mg per dL

Moderate-risk‡ patients with LDL cholesterol ≥ 160 mg per dL and a family history of CVD or two or more risk factors; goal is to lower LDL cholesterol to < 130 mg per dL

High-risk∥ patients with LDL cholesterol ≥ 130 mg per dL; goal is to lower LDL cholesterol to ≤ 110 mg per dL (2.85 mmol per L)

Insufficient data for current guidelines to make firm recommendations for non-LDL lipid abnormalities

Consider statin and fibric or nicotinic acid in patients with high LDL cholesterol and triglyceride levels¶ and in patients with high LDL and low high-density lipoprotein cholesterol levels


note: Screening in children younger than two years is not recommended.

BMI = body mass index; CVD = cardiovascular disease; LDL = low-density lipoprotein.

*—If results of screening are normal, repeat in three to five years.

†—The American Academy of Pediatrics policy statement on cholesterol in childhood suggests that statins can be started at eight years of age.

‡—Persons with heterozygous familial hypercholesterolemia, type 2 diabetes mellitus, chronic inflammatory disease, or Kawasaki disease with regressed coronary aneurysm.

§—Persons with congenital heart disease or Kawasaki disease without coronary involvement, or who have received cancer treatment.

∥—Persons with homozygous familial hypercholesterolemia, type 1 diabetes mellitus, chronic renal disease, Kawasaki disease with coronary artery aneurysm, or heart transplantation.

¶ —Patients with persistent elevation of triglycerides > 350 mg per dL (3.95 mmol per L) or random levels > 700 mg per dL (7.91 mmol per L) may benefit from treatment to avoid risk of pancreatitis.

Information from references 8 and 9.

The American Heart Association expert panel has also identified children at higher risk of premature atherosclerosis. These children require closer surveillance and more aggressive treatment. Children at highest risk are predicted to have symptomatic coronary artery disease before 30 years of age and include patients with homozygous familial hypercholesterolemia and type 1 diabetes mellitus.9 Additional cardiovascular risk stratification and risk reduction strategies are outlined at http://circ.ahajournals.org/cgi/content/full/114/24/2710.

Pharmacologic treatment of hyperlipidemia in children has evolved over the past decade (Table 2).8 Statins have led to significant reductions in cardiovascular and all-cause mortality for adults. As a result, there has been increasing experience with and clinical trials of statin use in children with familial hypercholesterolemia. Statins have supplanted the less effective and less tolerated bile acid sequestrants as mainstay therapy. One randomized controlled trial (n = 214; two-year study) and one recent meta-analysis (six studies; n = 798; 12 to 104 weeks of treatment) evaluating the safety and effectiveness of statins in children with familial hypercholesterolemia found no statistically significant increases in adverse events compared with placebo (relative risk = 0.99; 95% confidence interval [CI], 0.79 to 1.25). Analysis of the pooled data showed a significant 30 percent reduction in LDL cholesterol (95% CI, –36 to –24 percent). No differences were observed for muscle or liver toxicity or Tanner staging.10,11

Table 2.

Medications Used to Treat Hyperlipidemia in Children and Adolescents

Drug class Action Primary use Adverse effects Comments

Bile acid sequestrants

Decrease LDL cholesterol

Familial or severe hypercholesterolemia

Gastrointestinal symptoms(e.g., constipation, bloating)

Safe, but used infrequently

Consider use in prepuberty

Cholesterol absorption inhibitors(e.g., ezetimibe [Zetia])

Decrease LDL cholesterol

Familial or severe hypercholesterolemia

Gastrointestinal symptoms, hepatotoxicity, myopathy

Generally used as adjunctive therapy

Studies for use as monotherapy currently underway

Limited data on short-term safety

Fibric acids

Decrease LDL cholesterol

Hypertriglyceridemia (> 600 to 1,000 mg per dL [6.78 to 11.30 mmol per L])

Hepatotoxicity, myopathy

Limited data in children

Well tolerated as monotherapy

Be cautious about combining with statin

Increase HDL cholesterol

Nicotinic acid

Decrease LDL cholesterol and triglycerides

Familial or severe hypercholesterolemia

Flushing, glucose intolerance, headaches, hepatotoxicity, myopathy

Infrequently used because of potential for serious adverse events

Increase HDL cholesterol

Statins

Decrease LDL cholesterol and triglycerides

Familial or severe hypercholesterolemia

Hepatotoxicity, myopathy

Becoming standard of care

Multiple studies demonstrate short-term safety

Be cautious about combining with fibric acid

Use in patients eight years and older

Contraindicated in pregnancy

Appropriate contraceptive measures required

Increase HDL cholesterol


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

Information from reference 8.

Table 2.   Medications Used to Treat Hyperlipidemia in Children and Adolescents

View Table

Table 2.

Medications Used to Treat Hyperlipidemia in Children and Adolescents

Drug class Action Primary use Adverse effects Comments

Bile acid sequestrants

Decrease LDL cholesterol

Familial or severe hypercholesterolemia

Gastrointestinal symptoms(e.g., constipation, bloating)

Safe, but used infrequently

Consider use in prepuberty

Cholesterol absorption inhibitors(e.g., ezetimibe [Zetia])

Decrease LDL cholesterol

Familial or severe hypercholesterolemia

Gastrointestinal symptoms, hepatotoxicity, myopathy

Generally used as adjunctive therapy

Studies for use as monotherapy currently underway

Limited data on short-term safety

Fibric acids

Decrease LDL cholesterol

Hypertriglyceridemia (> 600 to 1,000 mg per dL [6.78 to 11.30 mmol per L])

Hepatotoxicity, myopathy

Limited data in children

Well tolerated as monotherapy

Be cautious about combining with statin

Increase HDL cholesterol

Nicotinic acid

Decrease LDL cholesterol and triglycerides

Familial or severe hypercholesterolemia

Flushing, glucose intolerance, headaches, hepatotoxicity, myopathy

Infrequently used because of potential for serious adverse events

Increase HDL cholesterol

Statins

Decrease LDL cholesterol and triglycerides

Familial or severe hypercholesterolemia

Hepatotoxicity, myopathy

Becoming standard of care

Multiple studies demonstrate short-term safety

Be cautious about combining with fibric acid

Use in patients eight years and older

Contraindicated in pregnancy

Appropriate contraceptive measures required

Increase HDL cholesterol


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

Information from reference 8.

Despite short-term safety of statins, long-term monitoring for muscle and liver toxicity in children and adolescents is essential; however, based on current evidence, concern for adverse events is not a reason to withhold statin therapy in this population. Indeed, there is evidence that early statin therapy may be beneficial, because regression of carotid intimamedia thickness has been demonstrated in children taking statins compared with progression in placebo-controlled groups.12,13 Currently, lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor) are approved by the U.S. Food and Drug Administration for use in children.

The prevalence of lipid abnormalities continues to grow and is associated primarily with the obesity epidemic and metabolic syndrome. Despite the absence of data in children demonstrating morbidity and mortality reduction by aggressive treatment of lipid disorders, the overwhelming data in adults (e.g., decreasing LDL cholesterol, improved morbidity and mortality) and evidence of atherosclerotic lesions developing in childhood support the argument for early treatment.

Address correspondence to Robert Gauer, MD, at robert.gauer@us.army.mil. Reprints are not available from the author.

Author disclosure: Nothing to disclose.

The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army Service at large.

REFERENCES

1. Zappalla FR, Gidding SS. Lipid management in children. Endocrinol Metab Clin North Am. 2009;38(1):171–183.

2. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338(23):1650–1656.

3. Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study [published correction appears in JAMA. 2003;290(22):2943]. JAMA. 2003;290(17):2271–2276.

4. McGill HC Jr, McMahan CA, Zieske AW, et al. Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol. 2000;20(8):1998–2004.

5. De Groot E, Hovingh GK, Zwinderman AH, Wiegman A, Smit AJ, Kastelein JJ. Data density curves of B-mode ultrasound arterial wall thickness measurements in unaffected control and at-risk populations. Int Angiol. 2005;24(4):359–365.

6. Hickman TB, Briefel RR, Carroll MD, et al. Distributions and trends of serum lipid levels among United States children and adolescents ages 4–19 years: data from the Third National Health and Nutrition Examination Survey. Prev Med. 1998;27(6):879–890.

7. Jolliffe CJ, Janssen I. Distribution of lipoproteins by age and gender in adolescents. Circulation. 2006;114(10):1056–1062.

8. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122(1):198–208.

9. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114(24):2710–2738.

10. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292(3):331–337.

11. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27(8):1803–1810.

12. de Jongh S, Lilien MR, op't Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol. 2002;40(12):2117–2121.

13. Rodenburg J, Vissers MN, Wiegman A, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007;116(6):664–668.


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