|Year : 2021 | Volume
| Issue : 3 | Page : 116-121
Dyslipidemia in children
Arti Uniyal, Manish Narang
Department of Pediatrics, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
|Date of Submission||08-Feb-2021|
|Date of Decision||10-Mar-2021|
|Date of Acceptance||25-Mar-2021|
|Date of Web Publication||23-Jul-2021|
Dr. Manish Narang
Department of Pediatrics, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi - 110 095
Source of Support: None, Conflict of Interest: None
Dyslipidemia is a condition characterized by abnormal levels of one or more plasma lipids or lipoproteins. It is a major cause of cardiovascular diseases (CVDs) around the world. Pediatric dyslipidemias can lead to atherosclerosis and extrapolate to premature CVDs. Atherosclerotic lesions begin during childhood and act as the major risk factor for atherosclerotic CVD (ASCVD). Dyslipidemias can be caused by primary genetic disorders or by secondary causes, the most common of which is obesity. In order to diagnose and manage dyslipidemias early, it is important to know the screening guidelines, lifestyle changes, and treatment for childhood dyslipidemias. The appropriate identification and management of dyslipidemia in childhood can lead to decreased risk factors for future CVDs. One of the best ways to manage childhood dyslipidemias is through appropriate lifestyle changes where parents play a vital role, through healthy home environment. Pharmacological interventions include statins and fibrates that play a major role. This article reviews pediatric dyslipidemia and reemphasizes on the importance of lifestyle changes modeled by parents as well as appropriate selection of treatment by health-care providers. The aim of this review article is to draw attention toward the importance of screening, identification, and timely management of dyslipidemias in children which can prevent future risks and complications that may even be life threatening.
Keywords: Atherosclerosis, cardiovascular diseases, dyslipidemias, life style, lipoproteins, obesity
|How to cite this article:|
Uniyal A, Narang M. Dyslipidemia in children. Indian J Med Spec 2021;12:116-21
| Introduction|| |
Dyslipidemias are abnormal amounts of lipid (hydrophobic fat molecules) and/or lipoprotein (aggregate molecules consisting of lipids and apolipoproteins that bind to lipids) in the blood. Hyperlipidemia is considered one of the major risk factors causing cardiovascular diseases (CVDs) which are a leading cause of death around the world. It also leads to various other comorbidities including coronary, cerebrovascular, and peripheral vascular diseases. Most of the clinical burden of CVD occurs in adulthood. However, research has indicated that the process of atherosclerotic CVD begins early in life and is progressive throughout life span. Identifying children with dyslipidemia and successfully improving their lipid profile may reduce their risk of accelerated atherosclerosis and premature CVDs. Obesity, a rising epidemic, is one of the major risk factors for dyslipidemia in children. The Global Burden of Disease Study puts global prevalence of obesity at 5%., According to the American Heart Association (AHA) and National Cholesterol Education Program (NCEP), the prevalence of high low-density lipoprotein cholesterol (LDL-C) is 6.5%, high triglycerides (TGs) are 4.7%, low high–density lipoprotein cholesterol (HDL-C) is 7.1%. In India, the most common dyslipidemias are borderline high LDL-C, low HDL-C, and high TG. Despite studies on dyslipidemias in adults, studies in the pediatric population have mainly focused on high-risk children with family history. The guidelines on screening of childhood dyslipidemias, appropriate selection of treatment method in children is yet to be determined. Family-based interventions, parental guidance, and appropriate time to refer to a specialist and need to start pharmacological treatment are discussed hereafter.
| Pathophysiology|| |
Hyperlipidemia leads to increased oxidative stress causing significant production of oxygen-free radicals, which may lead to oxidative modifications in low-density lipoproteins, which play a significant role in the initiation and progression of atherosclerosis and associated CVDs. The two major forms of lipids are cholesterol and TGs. Cholesterol is essential to normal cell function and can be synthesized by each cell individually or added to the body through diet. However, increased levels of cholesterol and TGs due to genetic or secondary causes can be detrimental to the human body.
During infancy, both cholesterol and TG values are significantly lower than during adulthood. These levels increase significantly over the 1st year of life and then increase more slowly until ages 9–11 years, when they more closely reflect adult levels. Then, the total and LDL-C levels decrease as much as 10% to 20% or more during puberty before returning to baseline around the second decade of life.
| Definition|| |
Lipid cutoff values defined by the United States National Heart, Lung, and Blood Institute in 2011 categorize hyperlipidemia as acceptable, borderline, and high [Table 1].
| Causes|| |
Hyperlipidemia can be caused by primary or secondary causes.
It is familial type, caused due to genetic defects causing alteration in the steps of lipid metabolism. It may be monogenic (a single gene defect) or polygenic (multiple gene defects).. Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of cholesterol metabolism characterized by very high levels of LDL-C from birth. FH leads to premature atherosclerotic CVD (ASCVD) that affects one in every 200 individuals in the heterozygous form. Familial hypertriglyceridemia affects 1% of the population, with no typical physical findings and TG elevations of 250–1000 mg/dl. Although secondary causes of hypertriglyceridemia are encountered much more frequently in primary care settings, genetic causes should be considered for elevation in TG level (>500 mg/dL). [Table 2] describes the Fredrickson classification of primary hyperlipidemia.
Secondary hyperlipidemias are acquired lipid abnormalities caused by an underlying 'nonlipid disorder' rather than an inborn disorder of lipid metabolism. These abnormalities result from an interaction of environmental and genetic factors (multifactorial).
Secondary causes of dyslipidemia are:,
- Renal: Nephrotic syndrome, chronic kidney disease, and hemolytic uremic syndrome
- Endocrine: Hypothyroidism, hypopituitarism, diabetes mellitus, and lipodystrophy
- Infectious: Acute viral or bacterial infection, human immunodeficiency virus, and hepatitis
- Hepatic: Obstructive liver disease or cholestatic conditions, congenital biliary atresia
- Inflammatory: Systemic lupus erythematosus and juvenile rheumatoid arthritis
- Metabolic: Hyperinsulinemia/disturbed glucose metabolism/insulin resistance, arterial hypertension, dyslipidemia, and abdominal obesity
- Medications: Protease inhibitors, retinoids, corticosteroids, and androgenic steroids, glucocorticoids, antiretroviral agents, oral contraceptive pills, and beta blockers
- Storage disorders: Gaucher disease, glycogen storage disease, juvenile Tay–Sachs disease, and Neiman–Picks disease
- Others: Kawasaki disease, solid organ transplant, childhood cancer, anorexia nervosa, Kleinfelter syndrome, Progeria (Hutchinson–Gilford syndrome), and Werner syndrome.
| Clinical Features|| |
Hyperlipidemia mostly does not have any obvious symptoms and is discovered during routine examinations or upon reaching stage of stroke or heart attack. Familial forms or patients with high cholesterol can develop corneal arcus, tendon xanthomas, and deposits of cholesterol under the skin, especially under eyes (xanthelasma). High TG may present as acne like papules in the body. Secondary hyperlipidemia together with significant hypertriglyceridemia can cause pancreatitis. Low HDL-C and high TGs, characteristics of “dyslipidemia of insulin resistance,” are often associated with obesity and the metabolic syndrome.
| Screening|| |
Screening for lipid disorders is based on the rationale that early identification and control of pediatric dyslipidemia will reduce the risk and slow or prevent severity of CVDs in adulthood.
Target screening or selective screening for dyslipidemia in children, a strategy of primary prevention of development of early clinical manifestations of atherosclerosis, will allow us to slow or prevent the early development of CVD.
The NCEP recommends selective screening in children and adolescents aged 2–18 years for the following:,
- Children with a family history of coronary heart disease in first-degree relatives (i.e., myocardial infarction, angina treated, interventions for coronary artery disease, stroke or sudden heart disease in father or brother before age 55 years, or a female sibling before age 65 years)
- Children between 2 and 8 years of age with body mass index (BMI) >95th percentile
- BMI >85th centile in older children (>8 years)
- Children with two or more cardiovascular risk including hypertension, diabetes mellitus, cigarette smoking, low HDL-C, physical inactivity.
Selective screening includes fasting measurements of total cholesterol (TC), LDL-C, HDL-C, and TGs after a 12 h overnight fast on two occasions at least 2 weeks and not more than 12 weeks apart. The LDL-C is calculated using the Friedewald equation: LDL-C = TC-(HDL-C + TG/5). If TG is >400 mg/dL, this formula cannot be used.
Universal screening of dyslipidemia refers to the detection of dyslipidemia in all or as many children as possible, regardless of family history of early CVD or value of the lipid profile of the parents or close relatives. Selective screening for dyslipidemia loses a significant percentage (30%–60%) of those children with dyslipidemia who do not have a family history including those who may require drug treatment. Selective screening also fails to detect many children with high lipid levels (17%–90%), especially those with young parents who are free of CVD and unaware of their lipid profiles. Cholesterol levels are reasonably consistent over 2 years of age, hence not routinely measured before the age of 2 years. Since TC and LDL-C level reduced by 10%–20% during adolescence, children at risk for familial dyslipidemia should ideally be screened before adolescence (age 2 to 10 years). If results during puberty are normal, blood checking should be repeated on the end of puberty (age 16 years in girls and 18 years in boys). In 2010, the results of the Coronary Artery Risk Detection in Appalachian Communities project indicated that the targeted screening processes most likely resulted in missed opportunities; overlooked many with significant dyslipidemia; and failed to detect genetic dyslipidemias, which require pharmacologic treatment. Universal screening recommended by the NHLBI in 2011, to be performed at age 9–11 years and again at 17–21 years, measures nonfasting non-HDL cholesterol, defined as the difference between total and HDL-cholesterol. It includes all cholesterol that is considered atherogenic. Those with nonfasting non-HDL cholesterol more than 145 mg/dL should do a scheduled fasting lipid profile twice as in selective screening to establish abnormality. The average of the two tests is taken to make decisions on starting therapy for pediatric dyslipidemia.
| Treatment|| |
The cornerstone of lipid-lowering therapy is in a healthy lifestyle. In childhood, the introduction of healthy eating habits and exercise must be emphasized, since early preference patterns have a long-term influence later in life. Parents play an important role in dietary and activity levels with children of all age. Research recommends that parents should be the primary focus of pediatric obesity prevention and treatment programs.
Low saturated fat and cholesterol diet are first approach to lower TC and LDL-C levels, to reduce obesity and insulin resistance. Parents can encourage self-regulation, provide positive nonfood-based rewards, and model appropriate portion sizes.
AHA has updated dietetic guidelines with the following diets for higher risk people as described in [Table 3].
After Step I diet is initiated and the fasting lipid panel is rechecked in 6–8 weeks, if the dyslipidemia is not corrected, the Step II diet is begun. Therapeutic lifestyle changes diet, replacing Step I and Step II diets, has recommended balanced caloric intake, increased consumption of whole grains, low-fat dairy products, fruits, vegetables, and fish, and reduced intake of soft drinks and salt.
Healthy home routines
Preschool children developing the habit of adequate night time sleep, limiting screen time (television watching), and physically active lifestyle have lower risk of obesity and thus dyslipidemias.
Although fewer trials exist for the effects of exercise on lipid levels, in adults, the combination of intensive dietary restrictions and physical exercise has been shown to improve lipid metabolism, insulin resistance, and cardiorespiratory fitness, thereby diminishing cardiovascular risk factors. Therefore, children should be encouraged to undertake 60 min or more of vigorous aerobic activity per day.
Pharmacological treatment is recommended in the following cases
- Children aged 10 years or more who fail the diet treatment and lifestyle changes after 6–12 months and the LDL-C is persistently ≥190 mg/dL despite a dietary intervention
- Postdietary LDL-C is ≥160 mg/dL with an at least one risk factor for CVDs, family history of CVDs, or metabolic syndrome
- In children with diabetes mellitus, when LDL-C is ≥130 mg/dL
- Average TG >500 mg/dL or single TG >1000 mg/dL.
- Statins: Hydroxy 3-methyl glutaryl coenzyme A inhibitors act by competitive inhibition of the rate-limiting enzyme of cholesterol synthesis. They are the most commonly used drugs for dyslipidemia acting as first-line drugs. Statins significantly reduce plasma levels of TC, LDL, and ApoB. Statins that are recommended by the US Food and Drug Administration include atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Commonly used statins in India are simvastatin and atorvastatin both of which are started at a dose of 10 mg/d. Common side effects include gastrointestinal symptoms, headache, myalgia, and dizziness. More serious adverse effects include myopathy, rhabdomyolysis, and increase in serum transaminases. Hence, liver function tests and creatinine kinase assessment are recommended every 3–4 months in children. Because the cholesterol synthesis takes place mostly at night, the statin is usually taken at night to maximize their effect.
- Fibrates: Fibrates act as primary ligands for nuclear transcription factor receptor PPAR-alpha. They increase the expression of lipoprotein lipase and downregulate apo C-III, an inhibitor of lipolysis. This results in a significant reduction in plasma TGs and a modest reduction in LDL cholesterol. HDL cholesterol level increases moderately. Fibrates increase clearance of TG and also increase HDL. Fibrates include clofibrate, gemfibrozil, fenofibrate, and bezafibrate. They are the drugs of choice in patients with hypertriglyceridemia and associated risk of pancreatitis (TG ≥450 mg/dL). Side effects include gastrointestinal symptoms, myopathy, arrhythmia, skin rashes, and gallstones.
- Bile Acid Sequestrants (Cholestyramine and Colestipol): These are negatively charged resins that bind to bile acids in intestines to prevent reuptake, depleting bile salts, and increased conversion of bile salts to cholesterol in liver. This results in greater conversion of cholesterol to bile acids. Furthermore, bile acid sequestrants increase HDL levels. However, gastrointestinal effects such as bloating, indigestion, flatulence, and cramps result in poor compliance. On long-term therapy, bile acid sequestering agents may cause osteoporosis due to calcium loss. Some vitamin and mineral deficiency may occur.
- Cholesterol absorption inhibitors (Ezetimibe): Ezetimibe selectively inhibits absorption of cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver by blocking the Niemann–Pick C1-like 1 protein (NPC1 L1), a human sterol transport protein. This causes an increase in the clearance of cholesterol from the blood. Ezetimibe is approved in children aged >10 years as an adjuvant to statins, which results in higher LDL decrease. Ezetimibe was also approved for pediatric use above the age of 10 years. Common side effects include headache, abdominal pain and diarrhea, and elevations in liver function.
- Nicotinic acid derivative (niacin): Increases cholesterol clearance by blocking Neiman Pick C1-Likeprotein (NPC1 L1), a sterol transport protein. Niacin inhibits hormone-sensitive lipase which decreases TGs lipolysis the main producer of circulating free fatty acids besides reducing TC, LDL-C, and TG; it is the most potent HDL enhancer. However, side effects such as cutaneous flushing, itching, hypoglycemia, and hyperuricemia have limited its use. Niacin treatment elevates HDL cholesterol concentrations by reducing the fractional clearance of apo A-1 and increasing HDL synthesis. Administering statins in combination with niacin increases the incidence of rhabdomyolysis. Niacin also promotes glucose intolerance and hyperuricemia which precipitate a gout attack.
- Omega 3 fatty acids (eicosapentaenoic acid, docosahexanoic acid): Act by reducing TG and increasing HDL in adults. Side effects include transient gastrointestinal symptoms.
- Newer drugs: Currently in various phases of clinical trials, newer antihyperlipidemic drugs are expected to have good control over lipid profile with lesser side effect profile. These include Acyl CoA cholesterol acyl transferase inhibitors: (Avasimibe and Eflucimibe), microsomal TG transfer protein inhibitor, squalene synthase inhibitors, ATP citrate lyase inhibitors, lanosterol synthase inhibitors, and many more.
| Treatment Algorithm for Dyslipidemia in Children|| |
- The decision regarding need for medication therapy should be based on average of results from two fasting lipid profiles obtained at least 2 weeks but not more than 3 months apart
- A case of identified dyslipidemia should be started with dietary and lifestyle modification and given a trial of 3 months to observe if they reach the cutoff for therapeutic goals [Table 1] and [Table 3].
Children younger than 10 years
Medication is not recommended unless they have a severe primary hyperlipidemia or a high-risk condition such as homozygous hypercholesterolemia/LDL cholesterol level of 400 mg/dL; primary hypertriglyceridemia with a TG level of 500 mg/dL; evident CVD in the first two decades of life; postcardiac transplantation.
Children aged 10–21 years
- Detailed family history should be taken and assessment for additional risk done
- Children other than LDL cholesterol level of >250 mg/dL or TG level of >500 mg/dL should be managed initially for 3–6 months with diet and lifestyle modification. Pharmacological therapy should be started in case of failure to achieve lipid targets
- Children with an average LDL cholesterol level of 250 mg/dL should be directly started on statin therapy
- If the LDL cholesterol level remains above 190 mg/dL after 6 months, start statins
- If the LDL cholesterol level remains 130–190 mg/dL with a negative family history of premature CVD in first-degree relatives and no risk factors, continue diet changes with follow-up every 6 months
- If the LDL cholesterol level remains 160–189 mg/dL with a positive family history of premature CVD/events in first-degree relatives or at least one high level risk factor, start statins
- If the LDL cholesterol level remains 130–159 mg/dL with at least two high level risk, start statin therapy
- Statin use should begin with the lowest available dose given once daily. If LDL cholesterol target levels are not achieved with at least 3 months of compliant use, then the dose may be increased by one increment (usually 10 mg)
Children with elevated TG or non-HDL cholesterol after control of LDL cholesterol
- Children with average fasting TG levels of 500 mg/dL or any single measurement of 1000 mg/dL related to a primary hypertriglyceridemia are at risk of pancreatitis and of fibrates with fish oil should be started
- Children with fasting TG levels of 200–499 mg/dL after a trial of lifestyle/diet management should be managed to have non-HDL to get to a goal level of <145 mg/dL
- Children aged 10 years or older with non-HDL cholesterol levels of ≥145 mg/dL after the LDL cholesterol goal has been achieved may be considered for further intensification of statin therapy or additional therapy with fibrates or niacin.
| Complications|| |
- Atherosclerosis: It is the accumulation of lipids, cholesterol, and calcium and development of fibrous plaques in walls of large and medium arteries. Hyperlipidemia is the most important risk factor for atherosclerosis, which is a major cause of CVD
- Coronary artery disease: Elevated lipid profile has been connected to the development of coronary atherosclerosis causing narrowing of arteries supplying myocardium
- Myocardial infarction: Partial or complete block in cardiac arteries leading to damage to cardiac cells
- Ischemic stroke: Blockage of an artery by blood clot or plaque in a small vessel within the brain. Clinical trials reveal that lowering of low-density lipoprotein and TC by 15% significantly reduced the risk of first stroke.
| Conclusion|| |
Dyslipidemia in children is difficult to diagnose and can be easily missed. Primary health-care providers must know the screening, diagnosis, and treatment of dyslipidemia in children. Early recognition and aggressive management of dyslipidemias, especially primary dyslipidemias in children will help prevent complications such as atherosclerosis and CVDs in future. ASCVD events rarely occur during childhood. Lifestyle modifications such as consuming a healthy diet, getting adequate sleep, and decreasing screen time will help prevent obesity as well as have a positive impact on preventing/managing dyslipidemia. Statins and fibrates are the major antihyperlipidemic agents for treatment despite the side effects pertaining to myopathy and raised serum transaminases. Newer potential treatments such as lanosterol synthase inhibitors, squalene epoxidase inhibitors, diacylglycerol transferase inhibitors, and ATP citrate lyase inhibitors are being developed for a safer, effective management of dyslipidemia. In view of the side effects of various drugs, the risk-benefit ratio has to be carefully considered before beginning any pharmacological treatment. Studies on pediatric dyslipidemias are scarce, especially in Asian countries. An updated diagnostic and treatment algorithm is needed along with recent advances for dyslipidemia in children.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]