Pediatric Lipid Disorders in Clinical Practice Treatment & Management

Updated: Jun 27, 2019
  • Author: Henry J Rohrs, III, MD; Chief Editor: Stuart Berger, MD  more...
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Treatment

Approach Considerations

2018 American College of Cardiology (ACC)/American Heart Association (AHA), and multisociety guidelines

The ACC/AHA and multisociety recommendations for primary prevention of atherosclerotic cardiovascular disease (ASCVD) include the following [13] :

  • ​In children and adolescents with lipid disorders related to obesity, it is recommended to intensify lifestyle therapy, including moderate caloric restriction and regular aerobic physical activity.
  • In children and adolescents with lipid abnormalities, lifestyle counseling is beneficial for lowering low-density lipoprotein cholesterol (LDL-C).
  • In children and adolescents 10 years of age or older with an LDL-C level persistently 190 mg/dL or higher (≥4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with familial hypercholesterolemia (FH) and who do not respond adequately with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin therapy.

2017 American Association for Clinical Endocrinology (AACE) and American College of Endocrinology (ACE) guidelines

The AACE/ACE guidelines for management of dyslipidemia and prevention of CVD for children and adolescents recommends pharmacotherapy for those older than 10 years who do not respond sufficiently to lifestyle modification, particularly for those satisfying the following criteria [3]

  • LDL-C ≥190 mg/dL, or
  • LDL-C ≥160 mg/dL and the presence of two or more cardiovascular risk factors, even after vigorous intervention, or
  • Family history of premature ASCVD (age < 55 y), or
  • Having overweight, obesity, or other elements of the insulin resistance syndrome

Consider the following factors when prescribing low-fat diets for children and adolescents [3] :

  • Total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels are positively correlated in individuals aged 20 years and younger, and low-fat diets that decrease TC levels have also been associated with HDL-C reductions.
  • Increased intake of carbohydrates may increase plasma triglyceride (TG) concentrations in children. High carbohydrate intake is not recommended for children with hypertriglyceridemia.
  • Fish oil supplements have a profound effect on serum TG levels in children. These supplements have been used effectively in young individuals with end-stage renal insufficiency
  • Water-soluble fiber can help improve serum cholesterol levels in children. Studies have shown that both children and adults can achieve cholesterol reductions with high-fiber, low-fat diets
  • Diets supplemented with plant stanols and sterols can reduce LDL-C in children. Studies indicate that both children and adults can achieve LDL-C reduction between 5 and 10% by eating foods that are supplemented with plant stanols and sterols (eg, spreads/ margarines, orange juice, yogurt drinks, cereal bars, and dietary supplements). The AACE concurs with the American Academy of Pediatrics (AAP) and AHA recommendations suggesting that dietary supplementation with plant stanols and sterols may be considered for children with severe hypercholesterolemia or those who are otherwise at high risk. The main safety concern is that plant stanols and sterols may reduce absorption of fat-soluble vitamins and beta-carotene; therefore, the AHA suggests monitoring fat-soluble vitamin status in children receiving supplementation.
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Medical Care

Nonpharmacologic management

If a child’s total cholesterol (TC) level is less than 170 mg/dL, no further testing is required for 5 years, when the TC measurement should be repeated. Patients and families should be educated about healthy eating patterns, exercise, and risk-factor reduction. If the TC level is 170-199 mg/dL, TC measurements should be repeated within the next few weeks, and the two results should be averaged.

A fasting lipid profile should be obtained, with calculation of low-density lipoprotein cholesterol (LDL-C), in individuals in whom the TC level is initially at least 200 mg/dL or in whom the average TC level is at least 170 mg/dL. Two lipid profiles should be obtained, and the results should be averaged. If the LDL-C level is below 110 mg/dL and the triglyceride (TG) level is less than 125 mg/dL, no further testing is required for 5 years, when the lipid profile should be repeated. Again, patients and families should be educated about healthy eating patterns, exercise, and risk-factor reduction.

Previously, the recommendation was for the child to first be placed on a step-one diet, which allowed as much as 300 mg of cholesterol and as much as 10% of total fat as saturated fat in the diet. However, guidelines now establish a single dietary recommendation to improve blood lipid levels.

The NHLBI guidelines accepted use of the 2010 Dietary Guidelines for Americans (DGA) and have built on both the DGA and NCEP recommendations to create the CHILD-1 (Cardiovascular Health Integrated Lifestyle Diet–1), a diet consisting of evidence-based recommendations for dietary changes to reduce cardiovascular risk in pediatric patients. [19, 20]

CHILD-1

The CHILD-1 encompasses five different age groups, from birth to age 21 years. [20] Table 4 summarizes these recommendations for each group.

Table 4. Summary of Evidence Based Recommendations for the CHILD-1 (Open Table in a new window)

Age

Dietary Recommendations

Birth to 6 months

  • Infants should be exclusively breastfed until age 6 months

6-12 months

  • Continue breastfeeding until at least 12 months of age (or feed iron-fortified formula if unable to breastfeed), gradually adding solid foods

  • No restriction in fat intake without medical recommendation

  • Water should be encouraged

  • Limit other types of drinks to 100% fruit juice, intake of which should be limited to 4 ounces/day or less

  • No sweetened beverages

12-24 months

  • Switch to reduced fat milk (2% to fat free)

  • Limit or avoid sugar-sweetened drinks

  • Water should be encouraged

  • Transition to table food with total fat content of 30% of daily kcal/estimated energy requirement (EER), saturated fat content of 8-10% of daily kcal/EER, and monounsaturated and polyunsaturated fat content of up to 20% of daily kcal/EER

  • Avoid trans fat as much as possible

  • Total daily cholesterol less than 300 mg

2-10 years

  • Fat-free milk

  • Limit or avoid sugar-sweetened drinks

  • Water should be encouraged

  • Limit total fat to 25-30% of daily kcal/EER, saturated fat to 8-10% of daily kcal/EER, and monounsaturated and polyunsaturated fat to up to 20% of daily kcal/EER

  • Avoid trans fat as much as possible

  • Total daily cholesterol less than 300 mg

  • Encourage high dietary fiber intake from foods

11-21 years

  • Fat-free milk

  • Limit or avoid sugar-sweetened drinks

  • Water should be encouraged

  • Limit total fat to 25-30% of daily kcal/EER, saturated fat to 8-10% of daily kcal/EER, and monounsaturated and polyunsaturated fat to up to 20% of daily kcal/EER

  • Avoid trans fat as much as possible

  • Total daily cholesterol less than 300 mg

  • Encourage high dietary fiber intake from foods

 

CHILD-2

The CHILD-2 is reserved for patients aged 2-21 years with elevated LDL-C, non–HDL-C (non-high-density lipoprotein cholesterol), or triglyceride levels. [19]

Recommendations for patients with elevated LDL-C include the following:

  • Refer to a registered dietician for family medical nutritional therapy

  • 25-30% of calories from fat

  • 7% of calories or less from saturated fat

  • Approximately 10% of calories from monounsaturated fat

  • < 200 mg/day of cholesterol

  • Avoid trans fats as much as possible

Recommendations for patients with elevated TGs or non–HDL-C include the following:

  • Refer to a registered dietician for family medical nutritional therapy

  • 25-30% of calories from fat

  • 7% of calories or less from saturated fat

  • Approximately 10% of calories from monounsaturated fat

  • < 200 mg/day of cholesterol

  • Avoid trans fats as much as possible

  • Decrease sugar intake

  • Increase dietary fish to increase omega-3 fatty acids

Medical management of LDL-C levels of 130 mg/dL or higher

A TG level of 125 mg/dL or less with an average LDL-C level of 130 mg/dL or higher defines a Frederickson type IIA phenotype. National Cholesterol Education Program (NCEP) recommendations for children directly address this phenotype. Dietary measures and exercise should be instituted, and secondary causes should be sought. Ideally, the goal should be to achieve an LDL-C level of less than 110 mg/dL.

The child should engage in regular aerobic exercise. Some patients live in areas that are considered unsafe, and parents limit their children's outdoor activity. Video games, computers, and television viewing have replaced many outdoor activities. Active video games such as Dance Dance Revolution, which uses flashing lights on a dance pad, are now gaining popularity. With advancement in video game consoles, this activity is now available at home or in video arcades. Other ways to increase physical activity include doing chores around the house, such as raking leaves, vacuuming, sweeping, and walking the dog.

Ideal weight should be maintained or achieved. Although weight loss may not be feasible in a growing child, weight maintenance is not an unreasonable goal, so that the child can eventually "grow into" his or her weight. Another approach is to set a goal of lowering the rate of weight gain, in order to bring the child to an appropriate weight at some time in the future (eg, within 1-5 years).

Secondary causes of elevated LDL-C levels should be minimized or eliminated (eg, by treating hypothyroidism or improving glycemic control in diabetes). Laboratory testing should include thyroid studies (free thyroxine [T4], thyroid-stimulating hormone [TSH]), glycated hemoglobin studies (if diabetes is present), liver function tests, and renal function testing (eg, creatinine, BUN [blood urea nitrogen], uric acid and urinalysis).

If TG and LDL-C levels are both elevated (eg, TGs ≥125 mg/dL and LDL-C ≥130 mg/dL), a type IIB phenotype is most commonly present (versus the very rare type III phenotype); the nonpharmacologic treatment of the type IIB phenotype is similar to treatment of the type IIA phenotype.

Type I hyperlipoproteinemia (HLP) treatment

Dietary fat should be restricted to 15% of energy intake. Because medium-chain triglycerides (MCTs) are directly absorbed by the capillaries and because they do not contribute to chylomicron formation, MCT oil can be included in the diet. In infants, Portagen is a formula that is appropriate. Although a strict vegetarian diet may reduce the likelihood of severe hypertriglyceridemia, preventing the potential nutritional deficiencies associated with such a diet is important.

Type IV HLP and type V HLP treatment

With mild elevations in triglycerides (125-299 mg/dL), appropriate interventions include: encouraging a healthy lifestyle; reviewing caloric intake; advising against overeating; encouraging exercise; restricting television, video games, and nonscholastic Internet use to one hour a day or less; avoiding alcohol and estrogen use; and, for all degrees of hypertriglyceridemia associated with obesity, slowing the rate of weight gain or achieving weight loss after growth is complete.

Management of hypoalphalipoproteinemias (low HDL-C levels)

Hypoalphalipoproteinemia is most often observed in association with familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH), or acquired (insulin-resistant) hypertriglyceridemia. Therapies should therefore target the underlying disorder.

The treatment of acquired hypoalphalipoproteinemias by etiology is as follows:

  • Smoking: Instruct the patient to stop smoking.

  • Obesity: Slow the rate of weight gain in growing children with obesity; weight loss is required after growth has ceased.

  • Hypertriglyceridemia: Lower TG levels through diet, exercise, and weight loss.

  • Renal failure: Dialysis or transplantation is indicated.

  • Androgen administration: Cease androgen administration.

  • Sedentary lifestyle: Instruct the patient to exercise vigorously with aerobic activities for 30-60 minutes daily.

Type IIA HLP and type IIB HLP treatment

When beginning medications, the assumption is that nonpharmacologic measures (as described above) did not achieve an LDL-C level of 160 mg/dL or lower after 6-12 months. Pharmacotherapy should be considered in children older than 10 years with type IIA or type IIB HLP if the following are noted.

An LDL-C level of 160-189 mg/dL and a family history of premature cardiovascular disease or two of the following risk factors:

  • Smoking.

  • Hypertension.

  • HDL-C level of less than 35 mg/dL.

  • Severe obesity (>30% more than ideal body weight).

  • Diabetes mellitus.

  • Physical inactivity.

  • Male sex.

  • Renal disease.

Also, an LDL-C level of 190 mg/dL or higher, regardless of other risk factor status.

 

The National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend medical therapy based on family history and risk factors. Positive family history includes myocardial infarction, angina, coronary artery bypass graft/stent/angioplasty, sudden cardiac death in a parent, grandparent, aunt, or uncle that is less than 55 years for males and less than 65 years for females. The risk factors are divided into high and moderate levels. [19]

High-level risk factors include the following [19] :

  • Hypertension that requires drug therapy

  • Cigarette smoking

  • Body mass index (BMI) ≥97th percentile

  • Presence of high-risk condition, such as type 1 diabetes mellitus, type 2 diabetes mellitus, chronic kidney disease, end-stage renal disease, post renal transplant, orthotopic heart transplant, or Kawasaki disease with current aneurysms

Moderate-level risk factors include the following [19] :

  • Hypertension that does not require drug therapy

  • BMI ≥95th percentile, but < 97th percentile

  • HDL-C < 40 mg/dL

  • Presence of a moderate-risk condition, such as Kawasaki disease with regressed coronary aneurysms, chronic inflammatory disease, human immunodeficiency virus (HIV) infection, or nephrotic syndrome

If following the CHILD-2 LDL-lowering recommendations does not reduce the patient's LDL-C to less than 130 mg/dL after 6 months, the following additional recommendations are made [19] :

  • LDL-C ≥190 mg/dL: Initiate statin therapy

  • LDL-C ≥160-189 mg/dL with positive family history or one high-level risk factor or two or more moderate-level risk factors: Initiate statin therapy

  • LDL-C ≥130-159 mg/dL with two high-level risk factors or one high-level risk factor and two or more moderate-level risk factors or clinical cardiovascular disease: Initiate statin therapy

  • LDL-C ≥130-189 mg/dL with negative family history and no other risk factors: Continue the CHILD-2 LDL diet; follow every 6 months with a fasting lipid profile

Guidelines published by the American Heart Association (AHA) in 2006 approach pharmacologic intervention similarly to the NHLBI guidelines by assigning patients to a risk tier based on their disease and also recommending more aggressive targets. [21] The guidelines are as follows:

Tier I (high-risk) factors include the following:

Tier II (moderate-risk) factors include the following:

  • FH

  • Kawasaki disease with regressed coronary aneurysms

  • Type 2 diabetes mellitus

  • Chronic inflammatory disease

Tier III (at-risk) factors:

  • Long-term cancer treatment

  • Congenital heart disease

  • Kawasaki disease without detected aneurysms

If a patient has two additional risk factors (eg, including abnormal fasting lipid profile, smoking, family history of early cardiovascular disease, hypertension, elevated BMI, impaired fasting glucose, sedentary lifestyle), they are moved up one risk category. The LDL-C level goal for tier III is < 160 mg/dL, the tier II goal is < 130 mg/dL, and the tier I goal is < 100 mg/dL. Pharmacologic management is recommended in patients aged 10 years and older to achieve these goals.

Statins (3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors)

Statin use has markedly increased in children because these drugs are well tolerated, safe, and efficacious and are now considered first-line therapy. [21] They are approved for use in children as young as age 10 years, and pravastatin is approved for children as young as age 8 years.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate. This is the rate-limiting step in the synthesis of cholesterol. Inhibition of HMG-CoA reductase blocks hepatocyte synthesis of cholesterol. This stimulates the hepatocyte to produce more LDL-Rs. In turn, LDL-R expression on the surface of hepatocytes is increased, which increases LDL clearance from the circulation.

Currently available statins and their doses are shown in Table 5, below. In children, the lowest available dosage form should be used as the starting dose. Dosage increases should be considered every 6-12 weeks until the LDL-C level is less than 130 mg/dL (ideally less than 110 mg/dL) or until the maximum tolerable dose is reached.

After the LDL-C level declines to less than 130 mg/dL, the dose does not need to be further increased.

Table 5. Dosing of HMG-CoA–Reductase Inhibitors (Open Table in a new window)

Generic Name

Adult Dose

Pediatric Dose

Dose Adjustment for Renal Insufficiency or Coadministration with Food or Drugs That Decrease Clearance*

Lovastatin (Mevacor)

Initial: 20 mg/d orally every bedtime

Followed by: 10-80 mg/d orally every bedtime or divided twice daily

10-17 years: 10-20 mg/d orally every bedtime initially; maintenance dosage ranges from 10-40 mg/d

Not to exceed 20 mg/d

Simvastatin (Zocor)

Initial: 5-10 mg/d orally every bedtime

Followed by 5-80 mg/d orally every bedtime or divided twice daily

10-17 years: 10 mg/d orally every bedtime initially; maintenance dosage ranges from 10-40 mg/d

5 mg/d initially; not to exceed 20 mg/d

Pravastatin (Pravachol)

Initial: 10-20 mg/d orally every bedtime

Followed by 5-40 mg/d orally every bedtime

8-13 years: 20 mg orally every day

14-18 years: 40 mg orally every day

Initiate at 5-10 mg/d; not to exceed 20 mg/d (also decrease with hepatic impairment)

Fluvastatin (Lescol)

Initial: 20-30 mg/d orally every bedtime

Followed by 20-80 mg/d orally every bedtime; for 80 mg/d, divide twice daily

10-16 years: 20 mg orally every day initially; maintenance dosage ranges from 20-80 mg/d

No adjustment

Atorvastatin (Lipitor)

Initial: 10 mg/d PO orally every bedtime

Followed by 10-80 mg/d orally every bedtime

10-17 years: 10 mg orally every day initially; maintenance dosages do not exceed 20 mg/d

No adjustment for renal insufficiency; decrease dose or avoid with drugs that decrease clearance

Pitavastatin (Livalo) [22]

Initial: 2 mg/d PO qd

May increase to 4 mg/d

8-17 years: 2 mg PO qd initially; may increase to 4 mg/d

Lower dose with renal impairment, coadministration with erythromycin or rifampin, contraindicated with cyclosporine or active liver disease

Rosuvastatin (Crestor)

10-20 mg orally every day initially; maintenance dosage range is 5-40 mg/d

Not established

5 mg orally every day initially; not to exceed 10 mg/d

* Renal insufficiency is indicated by a creatinine clearance of less than 30 mL/min; agents known to decrease HMG-CoA–reductase inhibitor clearance include grapefruit juice, gemfibrozil, ritonavir, cyclosporine, danazol, amiodarone, azole antifungals, macrolide antibiotics, and verapamil.

Statins have been associated with hepatocellular toxicity and rhabdomyolysis. Frank rhabdomyolysis is rare. The likelihood of rhabdomyolysis increases when a statin is used with cyclosporine, gemfibrozil, erythromycin, azole antifungal agents, niacin, or antiretroviral therapies. The risk also increases with higher doses.

Previously, close monitoring of liver function was recommended, but as of February 28, 2012 the United States Food and Drug Administration (FDA) revised labels for all statins to remove the need for routine periodic monitoring of liver enzymes. The labels now recommend aspartate aminotransferase (AST)/alanine aminotransferase (ALT) should be obtained before starting statin therapy and as clinically indicated thereafter. This change was recommended after the FDA concluded that serious liver injury with statins is rare and unpredictable in individuals and that routine monitoring of liver enzymes did not appear effective in detecting or preventing serious liver injury.

Studies have reported decreases in LDL-C levels of as much as 40% and increases in HDL-C levels of 23%. Increases in ALT, AST, and creatine kinase (CK) levels outside the reference range are reported in most studies to occur in 1-5% of cases. CK screening for myopathy is not recommended. There appears to be no data on the risk of diabetes development in children treated with statins.

Mendelson et al investigated the effectiveness of statins and the effect of baseline factors on low-density lipoprotein cholesterol (LDL-C) reduction in a study of 97 children over 3.5 years. The primary outcome was first achieving goal LDL-C, defined as < 130 mg/dL, or < 100 mg/dL with high-level risk factors. The cumulative probability of achieving goal LDL-C within 1 year was 60%; a lower probability of achieving LDL-C goals was associated with higher baseline LDL-C and male sex. [23]

Bile acid–binding resins

The 1991 NCEP recommendations for children advised using bile acid–binding resins as the drugs of choice to treat type IIA HLP in children. [16] However, bile acid–binding resins can lead to elevations in TG levels. Therefore, they are indicated in the treatment of type IIA HLP, but are not routinely indicated for type IIB HLP.

Bile acid–binding resins block bile acid reabsorption from the gut, resulting in bile acid excretion in the stool. Compensatory hepatocyte bile acid synthesis increases, which increases hepatocyte LDL-R expression. Increased LDL-R expression on the hepatocyte surface increases LDL clearance, resulting in a decrease in LDL-C concentrations. Bile acid–binding resins available in the United States include cholestyramine and colestipol.

Cholestyramine and colestipol are insoluble and must be mixed with water or juice to avoid the development of intestinal obstruction. The resins are taken with meals (when bile acids are secreted) and are dosed in scoops or packets of 4-5 g each. Therapy begins with 1-2 packets or scoops per day, given in orange juice or water. The dose is divided between breakfast and dinner and is increased every month to achieve an LDL-C level of less than 130 mg/dL or until maximum dosage is reached (see dosing information below).

Lack of palatability is a major factor limiting their use. The poor palatability may be compounded by the gritty texture of some resin preparations, which can be disguised with a high-pulp juice (eg, pineapple juice). Poor compliance has been reported in more than 50% of patients in some studies. To try to improve compliance, cholestyramine has been packaged into bars (Cholybar) and pills. Again, water must be ingested following the bars or pills to decrease the risk of intestinal obstruction. Reductions in TC and LDL-C levels of 10-40% have been described.

Stein et al observed a significant improvement in LDL-cholesterol from baseline when colesevelam was administered to children aged 10-17 years with heterozygous familial hypercholesterolemia. [24] Additionally, significant improvement was observed for total cholesterol and HDL-cholesterol. The study included patients who were statin-naive or on a stable statin regimen.

The dosing information is summarized below

Cholestyramine (Questran, Questran Lyte, LoCHOLEST, LoCHOLEST Light, Prevalite)

  • One scoop or pouch equals 4 g of cholestyramine.

  • Begin with 1 scoop or pouch mixed with water or juice; advance slowly to 8-16 g/d (usually divided twice daily immediately before major meals; dosage frequency ranges from 1-6 doses/d), not to exceed 24 g/d.

  • The maximal doses refer to adult-sized adolescents.

  • Optimal dosage for children has not been established, but standard texts list a usual pediatric dosage of 240 mg/kg/d divided in 2-3 doses, not to exceed 8 g/d.

  • When calculating pediatric doses of anhydrous cholestyramine resin, 80 mg is contained in 110 mg of Prevalite, 44.4 mg is contained in 100 mg of Questran powder, and 62.7 mg is contained in 100 mg of Questran Light.

Colestipol (Colestid, Flavored Colestid)

  • This agent is available as a 1-g tablet or granules for oral suspension (5 g per packet).

  • For adults, the starting tablet dose is 2 g once or twice daily, with increases of 2 g once or twice daily over periods of 1-2 months.

  • The maximum recommended dose is 16 g/d.

  • The granule starting dose for adults is 5 g orally every day to twice daily.

  • The dose may be increased by 5-g increments every 1-2 months.

  • Depending on the size of the child, these doses need to be reduced by one half to three quarters. Certainly, adult-sized children or adolescents could be dosed as adult levels.

  • The granules are convenient to administer but must not be taken dry. To administer, mix with liquids, soups, cereals, or pulpy fruits (eg, crushed pineapple, pears, peaches).

Use of bile acid–binding resins may lead to a decline in serum folate, carotinoid, and 25-hydroxyvitamin D concentrations. Fat malabsorption may occur. Children treated with bile acid–binding resins should receive supplementation with multivitamins including folate. Approximately 10% of children treated with cholestyramine have elevations in AST levels, lactate dehydrogenase (LD) levels, or both, which is surprising because these agents are not systemically absorbed.

Bile acid–binding resins bind drugs in addition to bile acids and vitamins; therefore, other drugs should be taken at least one hour before or 3 hours after consumption of bile acid–binding resins. No adverse effects on growth have been noted using bile-acid binding resins.

Niacin

Niacin was the second-line drug recommended by the 1991 NCEP panel for treatment of elevated LDL-C concentrations. [16] Niacin is also effective in patients with combined hyperlipidemia (eg, FCH or type IIB HLP) and in patients with isolated hypertriglyceridemia due to elevated VLDL levels. Niacin (ie, nicotinic acid) has been shown to be effective in adults for treating HLP types IIA, IIB, IV, and V. Niacin decreases lipoprotein production and increases lipoprotein clearance. Decrements in LDL-C levels up to 17% have been reported.

Niacin has been associated with toxicities, including liver disease, GI tract upset (abdominal pain, nausea), and facial flushing. In adults, glucose intolerance and hyperuricemia have been reported. Flushing may be minimized by taking aspirin, although this is not an option in prepubertal children because of the risk of Reye syndrome.

In the authors' experience, many children (or their parents) have been unable to endure the facial flushing and GI tract upset produced by niacin. These complications severely limit its use. [25] Although they produce less flushing, extended-release preparations are more likely to produce liver toxicity than immediate-release preparations because higher niacin levels are sustained for longer periods of time. In children, the extended-release agents should only be used with great care and should be used only in exceptional circumstances (eg, homozygous FH).

Few guidelines for niacin dosing in children are available. An effective dose must be balanced against the toxicities. Niacin should be started at a dose of 50 mg/d and very gradually increased (eg, every 4 wk or less often) until the LDL-C level is less than 160 mg/dL when treating HLP type IIA or HLP type IIB, until the TG level is less than 300 mg/dL when treating type IV HLP, or until a dose of 1500-3000 mg/m2 is reached without liver toxicity. Splitting the dose (ie, administering the dose divided twice daily or three times daily) should be attempted as soon as a dose of 100 mg/d of niacin is reached. ALT levels should be measured every 3 months.

With a decline in LDL-C to less than 160 mg/dL or TG levels to less than 300 mg/dL, the dose does not need to be further increased. If the LDL-C level declines to less than 130 mg/dL (in HLP type IIA or IIB) or if the TG level decreases to less than 125 mg/dL (in type IV HLP), the niacin dose can be reduced or a trial period without the medication can be attempted.

Fibric acid derivatives

These drugs inhibit lipoprotein production and increase lipoprotein clearance. Similar to niacin, fibric acid derivatives are useful in treating various dyslipidemias, including HLP types IIA, IIB, IV, and V. Although fibric acid derivatives are effective in adults for the treatment of type IIA phenotypes, the authors do not use fibric acid derivatives in type IIA HLPs because of the effectiveness and safety of statins. The authors reserve the use of fibric acid derivatives for persistent hypertriglyceridemia. Safety and efficacy data on fibric acid derivatives in children are limited.

The table below lists doses and FDA-approved indications in adults. In adults, common toxicities include myalgias, myositis, myopathy, rhabdomyolysis, liver toxicity, gallstones, and glucose intolerance. Gemfibrozil is less likely to cause gallstones than clofibrate (discontinued from the US market). ALT levels should be monitored every 3 months in children treated with gemfibrozil. The authors have only limited experience with fenofibrate but have used gemfibrozil safely and effectively in the clinic.

Table 6. FDA-Approved Uses and Doses of Fibric Acid Derivatives (Open Table in a new window)

Drug Name

Approved Indications

Adult Dose

Gemfibrozil (Lopid)

HLP types IIB, IV, and V

600 mg orally twice daily (ie, 1200 mg total daily dose) 30 min before meals (ie, before breakfast and dinner)

Fenofibrate (Tricor)

HLP types IIA, IIB, IV and V

Initial: 67 mg/d orally; not to exceed 67 mg orally twice daily

Cholesterol absorption blocking agents

Ezetimibe (Zetia) acts on the brush border of the small intestine, inhibiting the absorption of cholesterol. Decreases of as much as 20% in plasma cholesterol may occur. The absorption of vitamin A, D, and E is not affected, and ezetimibe also does not affect adrenocortical steroid hormone production.

Ezetimibe has been produced as a combination pill with simvastatin (Vytorin) in adults. FDA-approved Vytorin is available in preparations that contain 10 mg of ezetimibe and 10, 20, 40 or 80 mg of simvastatin (Zocor). Because both drugs have different mechanisms of action, a synergistic effect causes a 30-60% decrease in cholesterol levels. Compliance is increased because both medicines are included in a single tablet. Limited data in children are available; therefore, widespread use is not yet established.

Other medications

Although aspirin is widely used in adults with atherosclerosis for prevention of atherosclerotic complications (eg, plaque rupture with thrombosis), aspirin should not be used in children, because of the risk of Reye syndrome. Beta carotenes, vitamin C, and folate should be supplied in the diet in amounts to meet recommended daily allowances (RDA). However, pharmacologic doses should not be used, because no current safety or efficacy data are available regarding their use in children for the treatment of dyslipidemia or the prevention of cardiovascular disease.

Fish oils (eg, omega-3 fatty acids) may improve lipid levels, as demonstrated in adult studies, but more evidence is needed in the pediatric population before specific recommendations can be made. In a small, randomized, double-blind, placebo-controlled study (n=20), supplementation with docosahexaenoic acid significantly increased large and buoyant, less atherogenic LDL particles and decreased small and dense, more atherogenic LDL particles.

Adding fiber to the diet is benign and can lower TC and LDL-C levels. Homeopathic medications purported to lower lipids should not be used in pediatric patients, because the safety and efficacy of these agents in children are unknown. Lovaza (omega-3-acid ethyl esters) has been used in children, but no toxicity data has been reported. [26]

Homozygous FH treatment

In the rare patient with homozygous FH, the standard pharmacotherapy is triple therapy consisting of a bile acid–binding resin, a statin, and a fibric acid derivative.

In children aged 10 years and older, biweekly apheresis with plasma exchange for removal of LDL particles is helpful in lowering LDL-C levels. Although invasive and expensive, plasma exchange removes LDL particles, HDL particles, fibrinogen, and platelets.

Liver transplantation is curative but has considerable morbidity and mortality. Suitable liver sources include cadaveric donors and living related donors who lack LDL-R mutations. Parents should not be donors because each parent is heterozygous for an LDL-R mutation. Liver transplantation could be considered when the risk of mortality from the disease exceeds the risk of dying from the liver transplant. However, the success of liver transplantation does pose important ethical controversies in transplantation for homozygous FH.

Whether liver transplantation should be performed in children without clinical evidence of coronary heart disease or whether the surgeon should wait for clinical evidence of coronary heart disease to develop (eg, when the child is potentially a poor candidate for liver transplantation because of coronary heart disease) is controversial. The issue of combined heart-liver transplantation for homozygous FH is another controversial consideration.

Gene therapy for homozygous FH is in its infancy but may offer a potential cure in the future.

Type I HLP treatment

Pharmacotherapy to lower lipids is not indicated for type I HLP. However, in the future, high-dose vitamin antioxidant therapy may have a role in preventing pancreatic inflammation and chronic pancreatitis. In adults with type I HLP, high-dose antioxidants, including vitamin E, have been used in patients with recurrent pancreatitis. No data on the potential use of the oral lipase blocker orlistat (which may lower TG absorption and TG levels) are available.

Type III HLP treatment

Drugs used in adults include niacin and gemfibrozil.

Type IV HLP and type V HLP treatment

Children with a strong family history of premature cardiovascular disease are not infrequently referred to the authors for evaluation and treatment; their predominant laboratory findings include low HDL-C levels and hypertriglyceridemia. When the TG level is 300 mg/dL or higher and HDL-C levels are less than 35 mg/dL with a family history of premature cardiovascular disease, pharmacotherapy (eg, niacin or fibric acid derivatives) is considered based on professional opinion. Treatment suggestions for types IV HLP and type V HLP are outlined below.

  • TG level of 300-499 mg/dL: Encourage a healthy lifestyle and consider pharmacotherapy when HDL-C concentration is less than 35 mg/dL and the patient has a family history of premature cardiovascular or FCH.

  • TG level of 500-999 mg/dL: Encourage a healthy lifestyle and consider pharmacotherapy because of an increased risk of pancreatitis.

  • TG level of 1000 mg/dL or more: Encourage a healthy lifestyle and institute pharmacotherapy because of the increased risk of pancreatitis.

Management of hypoalphalipoproteinemias (low HDL-C levels)

In experimental studies, statins have been used to raise HDL-C levels in the absence of other lipid abnormalities; however, in the authors' opinion, isolated depressions in HDL-C concentrations in the pediatric population should not be treated with drugs.

Summary of treatment recommendations

Statins are the initial drugs of choice for the treatment of type IIA HLP in children. Statins are safe and highly effective. As a result of a lack of adverse effects, compliance is usually high with the use for statins. Lovastatin, simvastatin, atorvastatin, and pravastatin appear to be equally efficacious and safe in children.

Bile acid–binding resins are safe because they are not systemically absorbed and typically do not produce renal toxicity or hepatotoxicity. However, these drugs are not typically palatable; therefore, compliance is usually poor and prevents their widespread and long-term use in children with type IIA HLP. Bile acid–binding resins do not reduce LDL-C levels as effectively as statins do.

Niacin is useful in various phenotypes (eg, HLP types IIA, IIB, or IV), although LDL-C levels are not lowered as effectively as through the use of statins. Flushing and GI tract upset usually interfere with long-term compliance with niacin. In addition, niacin is likely to display hepatotoxicity equal to that of statins.

The primary use of gemfibrozil is in the treatment of HLP types IIA, IIB, IV or V. In adults, this drug is usually safe and effective.

When treating children with type IIA HLP, the authors believe that it is prudent to discuss the advantages and disadvantages of each agent with the patient’s parents. See the diagram summary below.

Pediatric lipid disorders in clinical practice. Ph Pediatric lipid disorders in clinical practice. Pharmacologic approach to the treatment of type IIA hyperlipoproteinemia (HLP).

In patients with type IIB HLP, a statin would be the initial drug of choice. Physicians should avoid the use of bile acid–binding resins in patients with type IIB HLP because resin therapy can worsen hypertriglyceridemia. See the image below.

Pediatric lipid disorders in clinical practice. Ph Pediatric lipid disorders in clinical practice. Pharmacologic approach to the treatment of type IIB hyperlipoproteinemia (HLP).

Treatment of isolated or predominant hypertriglyceridemia (type IV phenotype) is controversial. Niacin is the drug of choice. See the diagram below.

Pediatric lipid disorders in clinical practice. Ph Pediatric lipid disorders in clinical practice. Pharmacologic approach to the treatment of type IV hyperlipoproteinemia (HLP).

Gemfibrozil can be administered if niacin is ineffective or produces unacceptable adverse effects. Because an increasing number of children are recognized as being at risk for premature cardiovascular disease, the authors believe that studies of the safety and efficacy of lipid-lowering drugs in children should be greatly expanded.

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