Introduction
Atherosclerotic cardiovascular disease (ASCVD) is among prevalent severe diseases in Third World countries, and it is the major cause of death in most countries, especially the United States (US) and Iran.[ 1 , 2 ] Dyslipidemia (DLP) is one of the most important risk factors for ASCVD, associated with forming atherosclerotic plaques. DLP is a condition of the abnormal thickness of lipids or lipoproteins in the blood.[ 3 ] In such conditions, the levels of total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C) increase, and the level of high-density lipoprotein cholesterol (HDL-C) declines.[ 4 - 6 ] Long-term excessive accumulation of lipids leads to inflammation of blood vessels (vasculitis) and fatty streaks, which gradually turn into atherosclerotic plaques. Various studies have shown that a higher density of fats and longer exposure to lipid disorders is significantly related to the severity of atherosclerotic plaques.[ 7 - 9 ] DLP starts at early age and gets worse with growing obesity in youth, and it can make these individuals subject to higher risks of ASCVD.[ 1 , 6 , 9 ] Therefore, vital preventive methods to avoid DLP development can start at birth. Early prevention of DLP among children was shown as a necessity in Vaziri Esfarjani et al .[ 6 ] (2013) study. They reported that even the age of the mother and her nutrition during pregnancy is an influential factor in DLP development in children. Hence, a healthy lifestyle is a need, and any changes in lipid profile must be monitored by the family practice physician or paediatrician.[ 10 ]
Results of various studies show that not only 40–50 percent of DLP children suffer from hyperlipidemia in adulthood, but they also develop subclinical atherosclerotic disorders leading to cardiovascular disease (CVD), even in childhood.[ 5 ] DLP is comorbid with elastic carotid arteries, intimal medial thickness, and dilatation due to brachial artery flow from early childhood to adulthood.[ 11 ] In addition, as an important component of metabolic syndrome in children, DLP has a close relationship with pathogens of fatty liver, nephrolithiasis, pancreatitis, and other diseases.[ 12 ]
Results of Hariyanto and Kurniawan’s study (2020) indicated that DLP increased the risk of severe infections from coronavirus disease 2019 (COVID-19).[ 13 ] Therefore, identifying the related factors, screening, managing, and treating DLP in youth is of great importance. Hence, the present review aims to investigate the epidemiology, pathophysiology, screening, managing, and treating DLP in children and adolescents (youth).
DLP Epidemiology
It is clear from the literature that global DLP prevalence among youth has risen and is strongly related to cardiovascular diseases (CVD). In a study, Deeb et al .[ 14 ] (2018) reported an increase in high levels of cholesterol among American youths. Similarly, Barja Yanez et al .[ 15 ] (2015) reported that about 32% of 11.04 ± 0.97-year-old participants in a study in Chile suffered from DLP. Hovsepian et al .[ 16 ] (2015) also reported that the prevalence range of hypercholesterolemia, hypertriglyceridemia, elevated LDL-C, and lower HDL-C among Iranian youth was 3–48, 3–50, 5–20, and 5–88 percent, respectively. Another study on 2363 Korean youth ranged between 10–18 years old indicated that the prevalence of hypercholesterolemia, elevated LDL-C, elevated TG, lower HDL-C was 6.5, 4.7, 10.1, 7.1 percent, respectively.[ 17 ] In the Netherlands, DLP was observed in 82.6% of boys and 47.6% of girls between 5–9 years of age; 38.5% of boys and 51/1% of girls ranged between 1–14 years; and 24.7% of boys and 35.9% of girls between 15–19 years old.[ 18 ] A similar study in Saudi Arabia on 1390 children between 9–12 years old showed that the prevalence of hypercholesterolemia, elevated LDL-C, and hypertriglyceridemic was 32.7, 33.1, and 34.1 percent, respectively.[ 19 ] Likewise, the results of a cross-sectional study on 348 students between 6 to 17 years old in Thailand indicated that the percent of hypercholesterolemia and hypertriglyceridemic prevalence were 1.2 and 10.6, respectively.[ 20 ] A recent study by Ahmadi et al .[ 2 ] (2021) on DLP prevalence among the youth of Yazd Province, Iran, showed that DLP prevalence among the general population of youth was 64.6 for boys and 57.3 for girls. A recent study by Buterbaugh (2021) also reported that childhood DLP influences about 20% of the 9–6-year-old children all over the world.[ 21 ]
Pathophysiology
Lipids are vital for human health. However, the abnormal thickness of lipids and lipoproteins in blood may be a threat of metabolic disorder that leads to DLP development. Depending on the background causes, childhood DLP is classified into two categories: primary and secondary.[ 7 ] Primary DLP is generally caused by inherited disorders of lipid metabolism. Single or multi-gene mutations (e.g., a genetic mutation in LDL receptors) may result in modifying the production and removal of lipids.[ 1 , 7 ] Primary DLP refers to inherited family hypercholesterolemia (FH) and hypertriglyceridemia. FH is a dominant, autosomal genetic disorder of cholesterol metabolism which is characterized by higher levels of LDL-C at birth. Malfunction of LDL receptor, apolipoprotein B mutations, and increased function of PCSK9 gene are amongst common mutations responsible for FH. Genetic mutations in hypertriglyceridemia cause the elevation of levels of TG (> 500 mg/dl).[ 22 ] Genetic causes are often responsible for the most severe lipid disorders.[ 23 ] In contrast, in most cases, secondary DLP is a result of such conditions as underlying ‘non-lipid disorders that may be chronically comorbid with lipid thickness.’ Uncontrolled diabetes, hypothyroidism, malfunction of liver and kidney, as well as obesity are among common causes of secondary DLP. Drugs like contraceptive pills, protease inhibitors, retinoids, corticosteroids, and androgenic steroids can also cause secondary DLP.[ 1 , 24 ]
DLP Diagnostic Criteria
Levels of lipids and lipoproteins in plasma are influenced by various environmental, metabolic, and genetic factors. The density of lipids and lipoproteins is also influenced by age, sex, and ethnicity.[ 11 ] The expected levels of lipids and lipoproteins in children under 19 are different from that of adults, depending on age.[ 1 ] In 2011, experts of the American National Heart, Lung, and Blood Institute (NHLBI) revised the levels of lipid cutoffs according to normal data in the USA.[ 11 ] In Table 1 , the accepted, borderline, and high levels for both children and adolescents are given. Levels of TC, LDL-C, and HDL-C increasingly grow for the first two years of life and remain steady till puberty. During puberty, TC and LDL-C levels are cut off up to 10–20 percent or more [Figure 1 ]. Hence, ten years of age (about nine) is the best time for global children screening.[ 24 ]
Table 1: Limits of accepted, borderline, and high levels of lipids and lipoproteins in youth
[ 25 ] Figure 1: Changes in lipids and lipoproteins based on age
[ 24 ] DLP Screening
DLP screening is based on the reason that early DLP diagnosis and control in children strongly diminish the risk or severity of related diseases (such as cardiovascular and hypercholesterolemia) in adulthood.[ 26 , 27 ] There are two major approaches for diagnostic screening of DLP: selective and global.[ 28 ]
Selective Screening
Target screening
Target screening of DLP in children is a preventive strategy for prevention of early clinical manifestations of atherosclerosis which allows for slowing down or total prevention of early CVD.[ 26 , 29 ] National cholesterol education program (NCEP) recommends selective screening for 2–18-year-old youth with a family history of coronary artery diseases, especially among 1st -degree relatives (e.g., myocardial infarction, cured angina, cerebral stroke, or sudden heart diseases of father, brothers, etc.), 2–8-year-old children with higher than 95% body mass index (BMI) and older children (> 8) with BMI of >85%.[ 26 ] Besides, cases with risk factors like obesity, high blood pressure, diabetes, smoking, bad eating habits, and sedentary lifestyle must also be screened for DLP. All patients with these concerns who are between 2 and 21 years old must be screened by getting a fasting lipid profile.[ 30 ]
Incorporating only selective screening may lead to ignoring many DLP children for many reasons, like lack of parental awareness of their cholesterol level or family history.[ 31 ] Hence, for the screening program to be effective, its criteria must be sensitive enough to identify most of the sufferers. Unfortunately, this is not true with DLP children. In a study, Ritchie et al . (2010)[ 32 ] screened 20,000 children at 12 years of age, where 71% of the children met the criteria of the American Pediatric Academy (APP). Of these children, 8.3% had abnormally high LDL, and 14% of them needed pharmacotherapy. Of the 29% who did not meet the screening criteria, 95% had abnormal LDL, of whom 18% needed therapy. The DLP needing pharmacotherapy was higher in children without screening criteria than the qualified children.[ 32 ] Additionally, Eissa et al .[ 33 ] (2009) conducted a study on 678 children and reported that AAP screening criteria were effective in identifying only 54–66 percent of children with DLP.
Cascade screening
To date, cascade genetic screening is an economical method for screening children with background early atherosclerosis or elevated cholesterol levels.[ 34 , 35 ] Cascade screening is defined as a systematic process of identifying people with a medical condition. The process starts with clinical genetic identification of one of the suffered family members, and it requires periodic replicated or circular tests of closer relatives. All 1st -degree members are screened for similar mutations. After identifying all influenced relatives, the cascade gives a sequence to all 2nd -degree and then sequential relatives. Most importantly, the more the screened relatives, the more economical the cascade is.[ 36 ]
Global screening
Global screening refers to the examination of all children to diagnose DLP regardless of the family background of CVD or the parents’ or other close relatives’ lipid profile value.[ 37 ] Ignoring the family background of early CVD, the value of lipid profile in parents or other close relatives, as well as the general health of the parents, promotes the importance of global screening for DLP in children.[ 26 ] DLP global screening can help identify children with undiagnosed inherited DLP, and a later assessment of parents’ and close relatives’ lipid profiles can demonstrate the risk of cardiovascular diseases.[ 1 ] In European countries like Slovenia, global screening on infants and 5-year-old children is done.[ 38 ] German Medical Association of Youth recommends screening for elevated cholesterol in all 5-year-old children.[ 32 ] Since selective screening in the US has not been successful in identifying children with elevated LDL-C according to data on primary inherited cardiovascular diseases, global screening is done to some extent with 9–11-year-old children. The age range of 9–11 is the desired age for global screening because the imbalance in hormones at the puberty age may lead to lower levels of LDL-C, which in turn yields false-negative results. Global screening can also be done on 17–21 adolescents.[ 37 ] In global screening, non-fasting TC HDL-C is examined, which is more significant in children than fasting lipid profile.[ 11 ]
Management and Treatment of DLP
Life-style management
A healthy lifestyle is the basis of DLP management. Since the primary preference patterns have long-term effects in the future, introducing healthy eating habits and exercise in childhood must be emphasised. Parents have an important role in the diets and levels of activity of children of all ages. Research suggests that parents’ focus must be mainly on prevention plans and obesity treatment in children.[ 26 , 28 ] Parents must provide a healthy lifestyle consisting of healthy diets, enough sleep, providing healthy foods, drinks, and healthy junks food, sharing meals in families, and promoting breakfast.[ 1 ]
Diet
Adequate diets can improve DLP and abnormal lipid levels in children. Special modifications of diets focus mostly on decreasing total and saturated lipid and cholesterol, less received plain carbohydrates, receiving fibers from fruits and vegetables, and omega 3 fatty acids from fish, especially in children with hypertriglyceridemia.[ 28 , 39 , 40 ] The declining effect of fish oil on TG depends on the content of omega 3 fatty acids, including Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA). It is believed that omega-3 fatty acids can cause the decreased synthesis of TGs in the liver and increased oxidation of fatty acids, which in turn results in less secretion of very-low-density lipoprotein (VLDL).[ 41 ] Research results have shown that omega-3 fatty acids decrease the level of TGs to 30–40 percent. They also lead to decreased LDL levels and increased HDL levels among adolescents. Side effects of consuming omega-3 fatty acids include some transient symptoms of the digestion system.[ 42 ]
Limited consumption of proteins in diets for DLP treatment is not recommended.[ 11 ] For children under two years old, we never recommend limited amounts of fat or cholesterol because growth and development need sources of energy. After two years of age, children begin to develop their food diet. At the age of five, the calories of their diet should not be more than 30% and lower than 20%. Sufficient nutrition can decline many risk factors at the same time, including blood fat, high blood pressure, and obesity.[ 37 ] Some studies have indicated that some of the prescribed diets for improving DLP contain lower levels of zinc, vitamin E, and phosphorus. Therefore, although natural growth is obtained through low-fat foods, much attention has been paid to this key nutrition element. Regarding this, soy-based diets seem useful.[ 43 ] Studies on placing soy protein in diets have indicated an increase in HDL-C levels and a decrease in TG and LDL-C levels.[ 28 ] Safavi et al .[ 44 ] (2013) reported that probiotic supplements used in diets are associated with lower levels of total cholesterol, LDL-C, and TG. It has also been shown that taking antioxidant vitamins in youth with family hyperlipidemia leads to improved endothelial function and lipoprotein subgroups.[ 45 ] Healthy Home Routines are among other influencing factors of lipid disorders. Results from a study indicated that when preschool children were exposed to three family routines, i.e., regular dinner times, enough night sleep, and limited time of monitors (TV), they had lower rates of obesity compared to their counterparts. The promotion of healthy family routines must be encouraged by families to decrease obesity and improve DLP in children.[ 46 ] Consulting programs must also contain encouraging programs for alcoholic adolescents to decline or even stop their alcohol abuse.[ 7 ]
Physical exercise
In addition to nutrition changes, exercise and weight loss are important components of DLP in youth.[ 37 ] Physical activity has a positive effect on cardiopulmonary capacity, the density of serum glucose, insulin allergy, blood pressure, bone density, and lipid profile. As a result, children with DLP should always be encouraged to exercise daily. Regular physical activity helps to decrease levels of TC, TG, and LDL-C, increase HDL-C, prevent disorders in vascular function, decrease intima-media complex thickness, and most importantly, decrease body lipid and mass body index (MBI).[ 37 , 47 , 48 ] Therefore, all children and adolescents must have a daily average of 1-hour aerobic exercise.[ 26 ] Weight management via exercise is another important recommendation for children with modified lipid profiles, and it indicates the primary goal of therapy for fat children with DLP. Therefore, maintaining healthy body mass index (BMI), a decrease of 5–10 percent of body mass through diet modification, and increased physical activity are peccary for decreasing risks of cardiovascular problems and improving lipid disorders. Weight loss leads to increased metabolism and TG removal up to 20%, using various mechanisms (improve insulin sensitivity, increased lipase lipoprotein activity, lower rates of free fatty acids secretion from fat tissue).[ 7 , 48 , 49 ]
Family-based approach
Parents have a key role in promoting healthier eating habits and sufficient exercise levels for their children, and the results of the previous studies have indicated parents as one of the major focuses of prevention and treatment of DLP in childhood.[ 7 ] Results from an accidental controlled meta-analysis trial for pediatric obesity treatment showed that family-based approaches have a significant influence on BMI and weight loss in children.[ 50 ] Changes in lifestyle for management and treatment of DLP must be decided by all family members so that if the whole family does not change their eating habits, DLP will scarcely improve. Parents are responsible for the meals served to their children (even during pregnancy) or other foods and drinks they bring home.[ 51 , 52 ] Results have indicated that the children who have been neglected by their parents are nine times more exposed to the risk of obesity.[ 51 ] Although parents cannot control all aspects of children’s daily life, they can control the purchased food that they give to their children and plan and provide meals. The food that is constantly used in the house is the food children learn to consume. Parents play a big role in providing a healthy (e.g., smoke-free) home environment as well as promoting healthy habits (e.g., a healthy sleep pattern). Getting the family members accustomed to regular meals protects them from obesity and other consequences related to DLP.[ 7 , 53 ] One of the most powerful constant factors of children’s physical activity is the time they spend out of the home, which can be controlled in part by parents. Parents can also increase the active hours in children by controlling their use of TV or computer.[ 53 ]
Pharmacotherapy
Occasionally, modification of lifestyle is not enough to decrease the risks of ASCVD, and pharmacotherapy is required to decline LDL-C. When pharmacotherapy starts, it is necessary to continue the lifestyle as a synergic mechanism to decrease LDL-C or TG.[ 1 , 40 ] DLP pharmacotherapy is recommended for over-10-year-old children who have not been cured. Pharmacotherapy to decrease LDL-C starts for children without other CVD risk factors or CVD family background if, despite food interventions, LDL-C remains ≥190 mg/dl. When LDL-C remains ≥190 mg/dl even after food intervention, and it occurs with at least one CVD risk factor, family background with CVD, or metabolic syndrome, pharmacotherapy starts. In addition, in children with diabetes, when LDL-C ≥130 mg/dl, pharmacotherapy must be considered.[ 11 ] Six main classes of DLP treatment for children are astatine, cholesterol absorption inhibitor, Fibric acid derivatives, bile acid sequestrants (BAS) (including cholestyramine and colestipol), niacin (nicotinic acid), and omega-3 fatty acids.[ 54 ]
Established Pharmacotherapy for Children
Astatine
Astatine (3-Hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoA) inhibitors) competitively inhibit HMG-CoA reductase (competitively inhibits the cholesterol synthesis speed). By inhibiting HMG-CoA reductase, astatine blocks the path of cholesterol synthesis in the liver.[ 2 ] Astatine is the most common medication used to cure DLP in children and adolescents. Astatines significantly reduce plasma levels of TC, LDL, and ApoB. A general review of astatines is given in Table 2 .[ 42 , 54 ]
Table 2: Astatines confirmed by FA
[ 54 ] Kusters et al .[ 55 ] (2014) have shown the long-term security and effectiveness of sstatines to reduce LDL-C up to 25–35 percent in children with FH. Results of various studies indicate no or partial side effects in 4–10-year-old children.[ 42 ]
BAS (cholestyramine and colestipol)
BAS attaches to bile acid and inhibits its reabsorb in the ileum. This process results in increased synthesis of bile acids (changing most of the cholesterol to bile acids), decreased intra-liver cholesterol, and increased LDL cleansing from blood with increased expression of LDL receptors.[ 26 ] Results of a study show that a decrease of 7–12 percent in total cholesterol and LDL cholesterol was observed after employing BAS for children with FH.[ 56 ] In addition, it was indicated that, in the long run, constant use of cholestyramine would lead to a decrease in total cholesterol (13.4%) and LDL cholesterol (20.3%) as well as a decline in coronary vessels disease compared to placebo. Hence, they are useful supplements for astatines in decreasing LDL-C.[ 56 ] Results of studies have also shown that colesevelam, a bass of the second generation, will decrease FH up to 7–13 percent in children with FH. According to the reports, this therapy is associated with good adjustment and fewer side effects, and, to date, this is the only BAS drug that is confirmed by the American Food and Drug Administration (FDA) to be used with children.[ 42 ]
Cholesterol absorption inhibitor
Cholesterol absorption inhibitors (like ezetimibe) selectively inhibit intestinal cholesterol absorption of herbal sterols and cholesterol, which in turn leads to upregulation of liver LDL receptors and enhanced LDL cleansing, just like BAS.[ 26 , 42 ] By blocking Niemann–Pick C1-like 1 protein (NPC1 L1), the transferring protein of human sterol, cholesterol absorption inhibitor inhibits the absorption of bile and nutritional cholesterol in the small intestine. This process enhances the cleansing of blood cholesterol.[ 28 , 56 ] Ezetimibe is confirmed for >10-year-old children. Researchers have demonstrated that a combination of ezetimibe and simvastatin leads to a 38% decrease in total cholesterol and 49% decrease in LDL cholesterol in children with FH with no side effects.[ 42 ]
Non-confirmed Pharmacotherapy for Children with DLP
Fibric acid derivatives
Fibric acid derivatives, including Bezafibrate, Gemfibrozil, Ciprofibrate, and Fenofibrate, act as primary ligands of the nuclear transcription factor of the peroxisome proliferator-activated receptor (PPAR-alpha) receptor.[ 40 , 56 ] They increase the expression of lipase and downregulate apo-C-III, which is a lipolysis inhibitor that consequently destroys VLDL-C and TG in plasma. Also, HDL cholesterol level increases on average.[ 28 ] They also activate the absorption and oxidation of fatty acids in cells that decrease VLDL production along with decreasing TG synthesis. Unfortunately, data on employing fibric acid derivatives for children is scarce. Results of a confirmed randomised accidental trial showed that using bezafibrate for 4-year-old children led to a 22% decrease in total cholesterol, 23% decline in TG, and 15% decline in HDL.[ 42 ]
Niacin
Niacin (vitamin B3) decreases TGs analysis to free fatty acids (FFA) in fat tissue, which in turn declines the flow of FFA to the liver. Indeed, with lower levels of liver production and freed VLDL, levels of LDL-C and TG decrease. Niacin immediately inhibits key enzymes of TG synthesis, that is, Diacylglycerol Acyltransferase-2 (DGAT2). It also prevents the destruction of HDL.[ 41 , 42 , 56 ] To date, niacin is the strongest enhancer of HDL. In a study on niacin-based therapy, 500–2250 mg/dl was given to 4–14 year-old children. Results indicated that in 76% of the children, side effects were observed, and 38% of them stopped taking the drug. Because of undesired risks and low tolerance, niacin is rarely prescribed for children.[ 41 ] Some of the newer medications for controlling lipid disorders that seem to control lipid profile properly with fewer side effects are at the clinical testing stage. Some of these drugs are evolocumab and alirocumab, both inhibitors of PCSK9. Others are evinacumab, lomitapide, bempedoic acid, anacetrapib, mipomersen, and inclisiran.[ 7 , 26 ]
Conclusion
The prevalence of DLP as an important risk factor for ASCVD is increasing. Paediatricians must be aware of the diagnosis, treatment, and management of DLP. A healthy lifestyle involving healthy food and regular physical exercise is the backbone of managing and treating DLP. Lifestyle modification for DLP management and treatment must be based on family-based approaches. For children with DLP who have CVD risk factors, employing a therapy plan based on behavioral changes, diet changes, physical activity, and pharmacotherapy is required. Generally speaking, therapy with a food diet and medications is a secure, effective way for children and adolescents. However, in areas of treatment and management, there is a lack of evidence-based research. With recent advances, the need for an up-to-date diagnostic and treatment algorithm to reflect the required changes made by recent advances in this field is felt.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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