Authors: Ankit Garg, S. Radhakrishnan
Categories: Review Article, Cardiovascular diseases, Dyslipidemia, Hyperlipidemia, Pediatric, Pharmacotherapy
Source: Indian Heart Journal
The leading cause of mortality worldwide is atherosclerotic cardiovascular disease. Atherosclerotic plaques are well known to originate early in the childhood. Identifying hyperlipidemia in early childhood creates an opportunity to prevent major cardiovascular events in adults. Children with identified risk factors are at an increased risk of developing cardiovascular incidents in later life. This article emphasizes the diagnosis and management of pediatric hyperlipidemia with reference to the recent guidelines. In terms of etiology pediatric hyperlipidemia are divided into primary and secondary causes. The mainstay of management includes high-risk target screening, early risk factor identification and lifestyle modifications in vulnerable population. Drug therapy is recommended in primary hyperlipidemia and in children with no response to lifestyle changes.
Keywords: Hyperlipidemia, Pediatric, Dyslipidemia, Cardiovascular diseases, Pharmacotherapy
Cardiovascular disease (CVD) remains the leading cause of mortality amongst adult population worldover.^1^ Hyperlipidemia is one of the important modifiable aetiological factors of CVD. Albeit the atherosclerotic cardiovascular events occur rarely during childhood; robust clinical, imaging and autopsy data have demonstrated the origin of atherosclerosis process during childhood.2, 3, 4 This provides the rationale for identifying this vulnerable population and creating opportunity to prevent premature cardiovascular events in adult life by effective management of risk factors at an early stage.^4^^,^^5^ The earliest pathological abnormality begins with the accumulation of abnormal lipids in the vascular intima, with age this progresses to fibrous plaque lesion as a result of continued lipid accumulation and proliferation of macrophages and smooth muscle cells. This ultimately culminates into thrombosis, vascular rupture, or acute ischaemic syndromes.^4^^,^^5^
The existing paediatric hyperlipidaemia guidelines are based on a comprehensive report by the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel updated guidelines for cardiovascular health and risk reduction in youth, which were revised in 2011.^4^ The cornerstone of this consensus report is high-risk target screening, risk factor identification, a population-based approach towards a healthy lifestyle and revising the lipid cut-off values based on the normative data. This review addresses the diagnosis and management of paediatric hyperlipidemia while highlighting the recent guidelines.
The National Health and Nutrition Examination Survey (NHANES) 2011–2014 on the prevalence of high cholesterol in USA estimated it to be 6.0 % in children aged 6–8 years and 8.9 % in adolescents aged 16–19 years.^6^ The prevalence was greater in children and adolescents with obesity (11.6 %) than in those of normal weight (6.3 %) and in those who were overweight (6.9 %). Large scale studies on prevalence of paediatric hyperlipidaemia in Indian population are lacking, however a few studies in limited cohort show a prevalence to be as high as 19–23 %.^7^^,^^8^
The aetiology of hyperlipidemia is varied and can be categorised broadly into primary (genetic) and secondary causes. Primary causes include genetic defects in lipid synthesis and metabolism, and secondary causes are as a result of non-lipid disorders such as poorly controlled diabetes, nephrotic syndrome, obesity, and hepatitis (Table 1).^4^
Genetic hyperlipidaemias are inherited conditions caused by functional mutations in a variety of genes involved in lipid metabolism. Familial hypercholesterolemia (FH) is an autosomal dominant condition caused by mutations in the low-density lipoprotein receptor gene, resulting in extremely high levels of LDL-C from birth.^9^^,^^10^ The homozygous form of FH is extremely rare, whereas the heterozygous form has a general population prevalence of 300 to 500.^10^ A recent Indian study reported a prevalence of 1 in 1000 (0.1 %) for definite FH.^11^
With atherosclerosis beginning as early as 10 years of age, these patients are at an increased risk of stroke and heart attack, necessitating statin treatment to prevent progression. Another genetic cause, familial combined hyperlipidemia (FCHL), is three times more common than FH.^9^ Although the precise defects in FCHL are still unknown, these patients have high LDL-C and triglyceride (TG) levels with lower high density lipoprotein cholesterol (HDL-C) levels. Paediatric patients rarely exhibit symptoms, but weight gain in adolescents may reveal the diagnosis.^9^ Hypertriglyceridemia can be caused by either genetic or environmental factors. Familial hypertriglyceridemia is an autosomal dominant disorder that results in decreased TG catabolism. Other rare genetic hypertriglyceridemia disorders include changes in the function of lipoprotein lipase, ApoCII, and ApoA5. Lipoprotein lipase deficiency is a rare autosomal recessive disorder characterised by chylomicron accumulation in internal organs, resulting in organ enlargement and inflammatory changes in the pancreas, which can manifest as recurrent abdominal pain and pancreatitis if not properly treated. Secondary causes of hypertriglyceridemia are much more common in primary care settings, and genetic causes should be considered for TG levels >500 mg/dL.^12^
Various metabolic, genetic, and environmental factors influence lipid and lipoprotein levels in the blood. NHLBI guidelines revised the lipid cut off values for children and adolescents in 2011 and classified them as acceptable, borderline, and high (Table 2).^4^^,^^5^
For screening, after an overnight fast lipoprotein profile is measured including total cholesterol (TC), TG, LDL-C, HDL-C, and non-HDL-C. If the child is not fasting, a non-HDL-C (TC-HDL-C) is recommended because it is not affected by food or beverages, which often raises triglyceride or triglyceride-dependent values such as a calculated LDL-C.^5^ Low density lipoprotein cholesterol is usually calculated using the Friedewald formula {LDL = TC – (HDL + TG/5)}, however TG levels above 400 mg/dl preclude this formula.^13^ For both children and adults, non-HDL-C are more predictive of persistent hyperlipidemia and, therefore, atherosclerosis and future cardiovascular events.^4^^,^^5^ At least two values of elevated blood cholesterol measurements (2 weeks–3 months apart) are to be obtained before considering a diagnosis of hyperlipidaemia.^5^^,^^8^ The current NHLBI guidelines recommend targeted or selective screening in children ages 2–10 years who have a positive family or personal history and universal screening for all children aged 9–11 years.^5^^,^^9^^,^^12^
The National Cholesterol Education Program (NCEP) USA recommends selective screening in children and adolescents aged 2–18 years for the following^14^:
However, universal screening is controversial and not cost effective hence not recommended.^9^ Target screening for hyperlipidemia in children allows us to detect adults vulnerable to develop atherosclerosis and thus helps to slow or prevent the early development of coronary vascular disease (primary prevention) (Table 3).^5^^,^^9^^,^^12^^,^^15^ Primordial prevention starts at the community level with a population-based approach which relies on encouraging healthy dietary and lifestyle in children including exercise, healthy weight maintenance, and cessation of smoking.^4^^,^^5^^,^^16^
The underlying cause of elevated cholesterol must be addressed in hyperlipidemia treatment. It is necessary to determine whether the cause is primary or secondary. It is critical to rule out secondary causes of hyperlipidemia because treating secondary causes and/or discontinuing the incriminating drug often results in hyperlipidemia resolution. A focused medical history including family history, dietary habits, physical activity, and use of alcohol and tobacco, should be obtained for all positive children. A detailed anthropometric examination, blood pressure, signs of goitre, features of insulin resistance such as acanthosis nigricans, presence of xanthomas, xanthelasma, palpable arterial walls, and gout should all be performed.^9^^,^^16^
The cornerstone of lipid-lowering therapy is to promote a healthy lifestyle that includes dietary changes, weight loss, quitting smoking, and 30–60 min of moderate to vigorous physical activity per day. Sedentary behaviour is discouraged, with a focus on reducing screen time. All children with LDL-C levels >130 mg/dl should receive intervention and follow-up. The diet should be high in complex carbohydrates and low in total fat, saturated fat, cholesterol, and simple sugars. No reduction in total protein is advised. Dietary modifications are recommended for children over the age of 2 years, beginning with the step I diet (Table 4), and the fasting lipid panel should be rechecked in 6–8 weeks. If LDL-C levels remain above 130 mg/dl after 3 months, a more stringent step II diet is implemented (Table 4).^10^^,^16, 17, 18
Drug therapy is only indicated for children older than 10 years unless there is severe primary hyperlipidaemia or a high-risk condition that is associated with serious medical morbidity (TC ≥ 400 mg/dl; TG ≥ 500 mg/dl; post-cardiac transplantation).^4^ Statins and bile acid sequestrants (BAS) are the only two class of drugs currently used in <10 years of age. Pharmacotherapy is indicated in children 1) LDL-C ≥ 190 mg/dl without risk factors 2) 160–189 mg/dl with risk factors or family history of premature CVD, and 3) 130–159 mg/dl with diabetes after 6 months of dietary and lifestyle modification.^4^^,^^3^^,^^18^^,^^19^ Whereas children without any family history or risk factors having LDL-C levels 130–189 mg/dl need to continue on lifestyle and dietary restrictions and to be re-assessed after 6 months.^4^^,^^5^
Children with TG levels ≥500 mg/dl are at risk for pancreatitis and require medication. Although there are no US Food and Drug Administration (FDA) approved medications in paediatric age group,^4^^,^^5^ the NHLBI statement suggest fibric acid derivatives, and omega-3 fatty acids in consultation with a pediatric endocrinologist^4^ Children with TG ≥ 200–499 mg/dl the target LDL-C levels is < 145 mg/dl (with statin therapy) which, if not maintained entails a paediatric endocrinologist consultation.^4^^,^^5^ If TG levels are between 100 mg/dl and 200 mg/dl then intensive diet therapy, weight loss and increasing fish intake along with follow-up every 6 months is recommended. No medications are approved in children with a low HDL-C, other than minimising the risk factors with lifestyle changes.
3-hydroxy-3-methyl-glutaryl-coenzyme (HMG CoA) reductase inhibitors or the statins are the most commonly used lipid-lowering drugs in children and adults with hyperlipidemia. Statins, by inhibiting HMG-CoA reductase, block cholesterol synthesis in the liver, resulting in lower LDL-C levels with minimal side effects and no effect on growth and maturation.^20^ Except for pitavastatin, all statins have been approved by the FDA for use in children with FH. In India, the most commonly used statins are rosuvastatin and atorvastatin, both of which are started at a dose of 5 mg/day or 10 mg/day.^21^ In children, liver function tests and creatine kinase levels should be checked every 3–4 months.^18^^,^^19^ The goal of medical intervention is to reduce LDL-C to 130 mg/dl, preferably 110 mg/dl.^5^ If this goal is not met, the dose of statins is increased following a liver function test. If lifestyle changes and increased statin doses do not achieve the desired level, another drug is added. In a 20-year follow-up study of statin treatment in children with familial hypercholesterolemia, it was shown that starting statins early reduced the risk of cardiovascular disease in adulthood. LDL-C goal in children is < 135 mg/dl and it is achievable with small and moderate dose of statins, which do not interfere with the growth of the child.^22^
Bile acid sequestrants (BAS) causes increased conversion of cholesterol to bile in the liver which in turn leads to upregulation of LDL-C receptor and increased clearance of LDL from the circulation.^23^ Cholestyramine is available in powder form, and colestipol as granules, although, both being unpalatable and associated with gastrointestinal side effects have a lower compliance.^14^ Bile acid sequestrants are considered safe for children >10 years of age albeit they lead to fat-soluble vitamin and folic acid malabsorption warranting supplementation.
Ezetimibe is a cholesterol-absorption inhibitor, which reduces bile acid reuptake as well as absorption of cholesterol. It is approved for age >10 years with fixed dose 10 mg/day as an adjuvant to statins,^9^ which results in higher LDL decrease.^21^ Ezetimibe is also approved for paediatric use above the age of 10 years. Adverse effects include gastrointestinal symptoms, hepatotoxicity, and myopathy.^9^
Niacin decreases LDL-C and TG levels and increases HDL-C levels and has been used in small series in children. It is the most potent HDL-C enhancer and is used as an adjuvant only.^4^ Adverse effects include flushing, glucose intolerance, headaches, hepatotoxicity, and myopathy.^9^
These are first-line therapeutic agents for severe hypertriglyceridemia to prevent pancreatitis.^9^^,^^15^ There is limited data with children but they are well tolerated. Although infrequent, myopathy and rhabdomyolysis may occur particularly when used with a statin.
The efficacy and safety of evolocumab in paediatric patients (10–17 years) with heterozygous familial hypercholesterolemia was evaluated in a randomised controlled trial (HAUSER-RCT)^24^ and it was found that LDL cholesterol was significantly reduced with evolocumab and the incidence of adverse events was similar in the evolocumab and placebo groups.^25^ Evolocumab has been found to be safe and well tolerated in patients (which included 13 patients between 12 and 18 years of age) with Homozygous familial hypercholesterolemia in India.^26^
Monitoring with liver function test, creatine kinase and lipid profile is to be done on follow-up 1 month after the initiation of treatment and every 3–6 months thereafter.^9^ Adverse events such as growth abnormalities or secondary sexual characteristic and growth parameters are to be tracked on each follow-up.
Paediatric hyperlipidemia is underdiagnosed specially in Indian context. This review is an attempt to rationalise the screening and management of hyperlipidaemia in children and adolescent population with emphasis on the latest NHLBI guidelines. Hyperlipidemia commences in early childhood and can progresses to CVD or its complications in adulthood, which provides a rationale for primary prevention by early diagnosis and management of hyperlipidaemia in children. Adherence to pharmacological therapy and lifestyle modifications lead to an effective treatment. Safety of lipid-lowering drugs has been a cause of concern, and more research is required on long-term side effects and potential benefits.
No funding authority or conflict of interest to disclose.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.