Pediatric Dyslipidemia

Etiology

The etiology of dyslipidemias is divided into primary and secondary causes.  

Primary Dyslipidemias

These are a group of disorders caused by genetic defects in the synthesis, transport, or metabolism of lipoproteins and are typically present in childhood. These defects can be monogenic or polygenic.[6] A list of primary dyslipidemia is summarized:

Familial Hypercholesterolemia (FH): Most common lipid disorder in the pediatric population.[7] It is a group of monogenic conditions that influence LDL receptor function that leads to impaired LDL-C removal and severely elevated LDL-C from birth. It is an autosomal dominant trait with complete penetrance. More than 90% of cases are from defective LDL-Receptor, (LDLR) followed by defective apolipoprotein b (APOB3500), followed by a gain of function mutation of proprotein convertase subtilisin Kexin 9 (PCSK9), which reduces LDL-R.[8] There are two forms of FH- homozygous and heterozygous. Only 20% of patients with FH are diagnosed, and a minority receive appropriate treatment. 

Heterozygous Familial Hypercholesterolemia: The prevalence of heterozygous FH is 1 in 250-500. It is an autosomal dominant genetic disorder that leads to high LDL levels. LDL levels in children are typically up to 2 or 3 times the upper limit and approach and exceed 160 mg/dL. This disorder is caused by LDL receptor mutations, hundreds of which have been described and include defects in synthesis, intracellular transport, ligand binding, and recycling of the receptor.[9] 

Children with heterozygous FH develop coronary atherosclerosis between 30 and 60 years.[10] Cholesterol deposits in the eyelids (xanthelasma) and tendons (xanthomas) are not as common and typically develop during adulthood. 

Homozygous Familial Hypercholesterolemia: Homozygous FH is a rare condition with a prevalence rate of 1 in 1 million. It is caused by biallelic mutations inherited from both parents and is a much more severe presentation than the heterozygous version. LDL levels are often profoundly elevated, usually 4 to 6 times the normal range (above 400mg/dL), and not very responsive to medical therapies. Children will present with xanthomas and xanthelasmas in childhood, by five years of age, and have accelerated coronary atherosclerosis with myocardial infarction in the first decade and death from coronary artery disease in the second decade.[11]

Familial Combined Hyperlipidemia (FCHL): FCHL is the most common genetic dyslipidemia with a prevalence of 1:100. It is present in 40% of myocardial infarction survivors. It is an autosomal dominant condition with variable penetrance. FCHL presents with elevated TG, LDL-C, and apo-B levels and is believed to be from an overproduction of apo-B 100 levels.[12] 

FCHL characteristically has a strong family history of dyslipidemia, and the presentation can be either isolated high LDL and non-HDL-C or isolated hypertriglyceridemia or a combination of hypercholesterolemia and hypertriglyceridemia. Apo-B 100 levels are typically over 120 mg/dl. Phenotypic expression is generally triggered by a secondary factor such as obesity, puberty, medications, or diabetes. One unique feature of FCHL is that there can be variability in lipid profile in the same patient over time, and can be affected by diet, weight, and exercise.

Combined Dyslipidemia (CD): CD is now the most common form of dyslipidemia seen in childhood and is characterized by moderate to a severe elevation of TG and non-HCL cholesterol levels and reduced HDL levels. 30 to 60% of youth with obesity have CD. It is associated with visceral adiposity, insulin resistance, and nonalcoholic fatty liver disease. CD is responsive to weight loss, diet, and lifestyle changes. Pharmacotherapy with statins, omega-3 fish oils, and fibrates can be considered for children who are not responsive to pharmacotherapy.[13] 

Familial Chylomicronemia: Familial Chlymicronemia is autosomal recessive and caused by loss of function mutation in lipoprotein lipase (LPL) or LPL gene regulators. Lack of LPL activity leads to reduced or absent hydrolysis of chylomicrons and increased serum TG levels. It is characterized by markedly elevated TG levels (above 1000 mg/dl) and recurrent pancreatitis along with the characteristic lipemic-looking serum.

Other findings such as hepatosplenomegaly, lipemia retinalis along with tuberoeruptive xanthomas can be seen. Management includes keeping patient NPO, and plasmapheresis may be needed. Once TG levels are under 1000-2000 mg/dl, a stringent fat restriction of less than 15 gm per day is needed. Heterozygous mutations may present with mild to moderate TG elevation.[14]

Familial Hypertriglyceridemia (FHTG): FHTG is autosomal dominant dyslipidemia with a prevalence of 5 to 10% and is expressed predominantly in adulthood. FHTG presents with a moderate elevation of TG in the 200-500 mg/dl range with low to normal LDL and HDL-C levels. It is a disorder caused by the overproduction of VLDL in the liver. Obesity and diabetes can trigger the presentation of FHTG. Fibrates are typically the first line for the reduction of TG levels.[15]

Sitosterolemia: Sitosterolemia, also known as phytosterolemia, is a rare autosomal recessive disease caused by mutations (ABCG5, ABCG8) in the ABC half-transporters that are present in enterocytes and hepatocytes. ABC half-transporters are responsible for limiting the absorption of plant sterols and cholesterol in the enterocytes and promoting biliary excretion of plant sterols and cholesterol.

Defective ABC half- transporters lead to excessive absorption and reduced excretion of plant sterols and cholesterol. This leads to markedly elevated plant sterols and mild-severe elevation of serum cholesterol. It can be differentiated from FH by 30 fold elevation of plant sterols. Children present with xanthomas and premature atherosclerotic disease, including aortic stenosis. Treatment includes avoidance of plant-based unsaturated fats and ezetimibe or bile acid sequestrants.[16]

Low HDL-cholesterol: Low HDL is typically accompanied by a high TG level with or without elevation in small dense LDL cholesterol. This is commonly seen in patients with obesity, and the etiology is thought to be VLDL overproduction. Isolated low HDL is defined as HDL less than 50 mg/dl in men and less than 40 mg/dl in women. There are various genetic disorders that can cause an isolated low HDL level, including familial hypoalphalipoproteinemia, mutations of the ApoA-1 protein, Tangier disease, and lecithin-cholesterol acyltransferase (LCAT) deficiency. In these disorders, the rest of the lipid panel is normal.[17]

Familial Hypobetalipoprotenemia (FHBL): Hypobetalipoprotenemia is caused by mutations in the apo-B gene leading to a truncated version of the apolipoprotein B protein. This leads to very low levels of Apo-B (less than 5%) and LDL-C (20-50 mg/dl). In heterozygous FHBL, the apo B levels are at 25% of normal and hepatic steatosis with mild elevation in transaminases can be seen. In homozygous FHBL, which is extremely rare, the presentation is severe with hypercholesterolemia, fatty liver, steatorrhea, and peripheral neuropathy.[18]

Abetalipoproteinemia (ABL): Abetalipoproteinemia is caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. The MTTP gene protein is responsible for producing VLDL, LDL, and chylomicrons in the liver and small intestine. Therefore mutation in this gene leads to very low concentrations of TG and cholesterol (under 30 mg/dl) and undetectable levels of LDL-C and Apo-B.

Reduced TG export from the liver and lipid accumulation in enterocytes leads to fatty liver, steatorrhea, diarrhea, and malabsorption. Fat-soluble vitamin deficiencies lead to ataxia, bleeding diathesis, and retinitis pigmentosa. HDL-C becomes the primary cholesterol carrier in these patients. Treatment involves giving high doses of vitamin E and restricting long-chain TG to less than 15 gm/day.[18]

Secondary Dyslipidemias

There are multiple secondary causes of dyslipidemia, as listed below, and they must be excluded.[6] The most common cause of secondary dyslipidemia in the United States is obesity. The causes of secondary dyslipidemia are summarized below:

Exogenous

• Overweight
• Obesity
• Alcohol

Drug Therapy

• Corticosteroids
• Isotretinoin
• Beta-blockers
• Some oral contraceptives
• Select chemotherapeutic agents
• Select antiretroviral agents

 Endocrine/Metabolic

• Hypothyroidism/hypopituitarism
• Diabetes mellitus types 1 and 2
• Pregnancy
• Polycystic ovary syndrome
• Lipodystrophy
• Acute intermittent porphyria

Renal

• Chronic renal disease
• Hemolytic uremic syndrome
• Nephrotic syndrome

 Infectious

• Acute viral/bacterial infection
• Human immunodeficiency virus infection (HIV)
• Hepatitis

Hepatic

• Obstructive liver disease/cholestatic conditions
• Biliary cirrhosis
• Alagille syndrome

Inflammatory Disease

• Systemic lupus erythematosus
• Juvenile rheumatoid arthritis

Storage Diseases

• Glycogen storage disease
• Gaucher's disease
• Cystine storage disease
• Juvenile Tay-Sachs disease
• Niemann-Pick disease

Others

• Kawasaki disease
• Anorexia nervosa
• Post solid organ transplantation
• Childhood cancer survivor
• Progeria
• Idiopathic hypercalcemia
• Klinefelter syndrome
• Werner syndrome

Epidemiology

As per NHANES, 20% of 12 to 19-year-olds have lipid disorders. In children with obesity, mixed dyslipidemia occurs in up to 42%.[19][20] The prevalence of individual dyslipidemia  in the pediatric age group is as follows:[21]

• Decreased HDL (less than or equal to 40 gm/dl) - 12.1%
• Elevated TG (greater than or equal to 130 mg/dl) - 10.2%
• Elevated TC (greater than or equal to 200 mg/dl) - 7.1%
• Elevated LDL-C (greater than or equal to 130 MG/DL )- 6.4%
• Elevated non HDL-C (greater than or equal to 145 mg/dl) - 6.4%

Multiple factors can contribute to dyslipidemia, including diet, body mass index (BMI), physical activity, genetic predisposition, medications, and coexisting medical conditions. As per NHANES data, increased BMI was associated with an increase in the prevalence of dyslipidemia. The prevalence of dyslipidemia was 14% in the normal weight category, 22% in the overweight category (BMI above 85%), and 43% in children with obesity (BMI above 95%).[22]

Pathophysiology

Cholesterol and TG are the two most relevant plasma lipids. Because lipids are insoluble in water, they are transported in the blood with the help of lipoproteins. They constitute the hydrophobic core of lipoproteins separated from plasma by phospholipoproteins and apolipoproteins. Lipoproteins are classified into chylomicrons (CM), very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoprotein (HDL). Plasma lipoproteins are subclassified based on their size, density, and composition, as listed in the table.[23]

Plasma cholesterol is primarily derived from the liver, with only 15 to 20% from dietary sources. In the liver, cholesterol is either synthesized de novo with 3-hydroxy-3-methyglutaryl CoA reductase (HMGCR), the rate-limiting enzyme or absorbed from the plasma by lipoprotein uptake.[24] Cholesterol from the diet is absorbed from the intestine by Niemann-Pick C1-like 1 transporter.[25]

Plasma triglycerides are derived from both diet and hepatic biosynthesis. 

CMs are TG-rich particles that contain up to 90% TG content, with the rest containing free cholesterol. They transport TG from the intestine to the liver and periphery. The size of the chylomicron depends on the amount of fat ingested. Apo B 48 is a core protein in CM. CMs are carried by the lymphatic system into the thoracic duct and are cleared from the circulation using lipoprotein lipase. 

VLDL is the principal lipoprotein synthesized by the liver and TG-rich. Apo B 100 is a core structure protein. TG within VLDL is hydrolyzed by lipoprotein lipase. The size of VLDL particles can vary depending on the TG level. 

LDL carries the majority of cholesterol that is present in the circulation. It is derived from VLDL and IDL particles. LDL particles can vary in size and density. Small LDL particles are more atherogenic than large LDL particles. Small LDL particles are increased in obesity, metabolic syndrome type 2 diabetes, and inflammatory states. Small LDL particles have a lower affinity to the LDL receptor, which prolongs their retention in the circulation; they are more prone to oxidation and bind more avidly to the arterial walls. 

HDL is an anti-atherogenic particle that helps in the reverse transport of cholesterol from peripheral tissues to the liver. In addition, to reverse transport, it also has anti-oxidant and anti-thrombotic activity, which may contribute to inhibiting atherosclerosis.  Apo A-I is a core structural protein for HDL. HDL particles are heterogeneous and rich in cholesterol and phospholipids.

History and Physical

The evaluation of dyslipidemia should include a thorough history and physical exam. Most patients with dyslipidemia are asymptomatic. 

Personal History: History should include dietary history (simple sugars, processed foods, fat intake including saturated and unsaturated fats, portion sizes, caloric intake), physical activity, screen time, smoking and alcohol history, liver or kidney disease, history suggestive of hypothyroidism, diabetes, any chronic medical illness and history of any medication use. A history of pancreatitis symptoms such as abdominal pain and vomiting should be elicited. 

Family history: Family history should include- a history of dyslipidemia in childhood, history of statin use, and history of cardiovascular events especially myocardial infarction in women under 65 years and men under 55 years, stroke, interventions for coronary artery disease, angina, and sudden cardiac death. 

Physical Exam: A physical exam should include all vital signs, including height, weight, BMI, heart rate, and blood pressure. The physical exam should also focus on detecting abnormal cholesterol accumulation in the skin and eyelids, which are uncommon in the pediatric age group but can be seen in homozygous FH and sitosterolemia. 

• Tendon xanthomas: Tendon xanthomas are most common in the Achilles tendon and can also be seen on the dorsal side of the hands
• Planar xanthomas: These are painful deposits that occur in the palms of hands and soles of feet
• Xanthelasma: Xanthelesmas are cholesterol deposits that appear as yellow plaques and are usually found on the medial eyelids
• Other signs of high cholesterol such as corneal arcus (white or grey ring around cornea) and signs of arterial disease such as peripheral artery disease or aortic stenosis are rare in pediatrics but should be screened for using peripheral pulse exams in all four extremities,  auscultating for carotid and femoral bruit and cardiac murmurs.

Evaluation

Fasting Lipid Profile

A complete fasting lipid profile should be obtained, which reports total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. An abnormal nonfasting profile should be subsequently confirmed with a fasting profile. Studies show that the differences between total cholesterol and HDL cholesterol between fasting and nonfasting profiles are small and clinically insignificant; triglycerides are influenced by food intake.[26] 

At least two fasting samples obtained two weeks to 3 months apart should be obtained to confirm dyslipidemia and initiate pharmacotherapy. LDL-C is calculated using the Friedewald calculator  (LDL-C = Total cholesterol - (Triglyceride / 5) - HDL-C) but can only be done if the TG levels are lower than 400 mg/dl. If the TG levels are higher than 400 mg/dl, LDL-C must be measured directly (Direct LDL-C).

Non-HDL-C is calculated by subtracting HDL cholesterol from total cholesterol and includes all atherogenic particles, including LDL-C, VLDL-C and IDL-C, and lipoprotein(a). Nonfasting non-HDL-C can also be used as a screening measure in place of a fasting lipid profile. 

Evaluation of Secondary Causes of Dyslipidemia

1. Hypothyroidism: Thyroid-stimulating hormone (TSH), free thyroxine (FT4)
2. Liver dysfunction: Liver function tests (ALT, AST), serum albumin
3. Renal failure: BUN and creatinine
4. Diabetes: Fasting blood glucose levels, hemoglobin a1c
5. Screening for pregnancy (if indicated): urine or serum HCG. 
6. Testing for Lipoprotein(a)

Genetic Testing

Genetic testing is currently underutilized and helps to confirm the diagnosis along with risk stratification, clinical management, and also screening for dyslipidemia in first-degree relatives. For monogenic diseases such as FH, targeted genes like LDLR, APOB, PCSK9, and LDLRAP1 can be checked to screen for pathogenic variants. If targeted gene panels result negative, whole-exome sequencing can be performed. Below is a list of genes associated with dyslipidemia.[27]

Treatment / Management

The treatment of pediatric dyslipidemias in children over ten years is warranted because evidence has shown an increased risk of premature atherosclerotic cardiovascular disease in children with dyslipidemia, especially with elevated LDL-C. This results in a reduced risk of cardiovascular events and mortality in adulthood. The following are treatment guidelines: 

Risk qualification: The American Heart Association (AHA) has developed a risk stratification system for children to identify the intensity of atherosclerotic risk. The three categories are High risk, moderate risk, or at risk, as summarised in the table.[28]

BP: blood pressure; NAFLD: nonalcoholic fatty liver disease; PCOS: polycystic ovary syndrome; CVD: cardiovascular disease; TC: total cholesterol; SLE: systemic lupus erythematosus; JIA: juvenile idiopathic arthritis; HCM: hypertrophic cardiomyopathy; TGA: transposition of the great arteries.* Family history of premature CVD is generally defined as heart attack, treated angina, interventions for coronary artery disease, sudden cardiac death, or ischemic stroke in a first-degree relative (parent or sibling) before age 55 (males) or 65 (females).

1. For a high-risk or moderate-risk condition and greater than or equal to 2 cardiovascular risk factors, lifestyle changes like diet, weight loss, and physical activity should be tried in addition to statin therapy. LDL Goal is under 100 mg/dl.
2. For patients with moderate risk conditions with less than two cardiovascular risk factors and patients who are at-risk, dietary and lifestyle changes should be tried first, and if not successful, statin therapy should be initiated with an LDL goal of less than 130 mg//dl.
3. For patients with no risk factors and over the age of 10 years, statin therapy can be initiated if dietary, and lifestyle changes are not successful, with a goal LDL over less than 190 mg/dl.

Pharmacotherapy should only be started after confirming lipid abnormalities with two fasting samples at least two weeks apart. 

Dietary Management

All patients with dyslipidemia should be counseled about dietary and lifestyle changes. Consultation with a nutritionist is beneficial. The Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) is intended to lower LDL-C levels. It involves restricting saturated fat intake to under 10% of daily calorie intake and reducing cholesterol consumption to under 300 mg/day.[6] Further dietary recommendations as per CHILD-1 with age groups are listed in the following section.[29]

Birth to 6 Months

• All babies should be exclusively breastfed until 6 months of age. Donor breast milk or iron-fortified infant formula may be utilized if maternal breastmilk is unavailable or contraindicated. No supplemental food is recommended.

6 to 12 Months

• Breastfeeding should be continued until at least 12 months of age while gradually adding solids; transition to iron-fortified infant formula until 12 months if maternal breastmilk is unavailable or contraindicated.
• Fat intake should not be restricted unless medically indicated.
• No sweetened beverages should be offered; Limit other beverages to 100% fruit juice (less than 4oz/day); encourage water.

 12 to 24 Months

• Transition to unflavored, reduced-fat cow’s milk. Fat content (2% to fat-free) should be based on the child’s growth, intake of other nutrient-dense foods, total fat intake, and family history of obesity or cardiovascular disease
• Avoid sugar-sweetened beverages; Limit 100% fruit juice to less than 4oz/day; Encourage water
• Offer table foods with:Total fat 30% of daily kcal intakeSaturated fat 8 to 10% daily kcal intakeAvoid trans fatsMono- and polyunsaturated fat up to 20% daily kcal intakeCholesterol under 300mg/day
• Limit sodium intake

2 to 10 Years

• The primary beverage should be unflavored, fat-free milk
• Limit/avoid sugar-sweetened beverages; Limit 100% fruit juice to less than 4oz/day; Encourage waterDietary fat:Total fat 25 to 30% of daily kcal intakeSaturated fat 8 to 10% daily kcal intakeAvoid trans fatsMono- and polyunsaturated fat up to 20% daily kcal intakeCholesterol under 300mg/day
• Encourage high dietary fiber intake
• Encourage at least 1 hour of moderate-to-vigorous physical activity daily for children over 5 years

11 to 21 Years

• Primary beverages should be fat-free unflavored milk and water
• Limit/avoid sugar-sweetened beverages; Limit 100% fruit juice to less than 4oz/day
• Dietary fat:Total fat 25 to 30% of daily kcal intakeSaturated fat 8 to 10% daily kcal intakeAvoid trans fatsMono- and polyunsaturated fat up to 20% daily kcal intakeCholesterol under 300mg/day
• Encourage high dietary fiber intake
• Encourage at least 1 hour of moderate-to-vigorous physical activity daily
• Encourage healthy eating habits such as daily breakfast, limiting fast foods, and eating meals as a family.

If LDL cholesterol is greater than or equal to 130 mg/dL after 3 to 6 months- then the diet plan should be escalated to CHILD-2, which is composed of saturated fat less than 7% of total calories and cholesterol under 200 mg/day. Eliminating simple sugars from processed foods and sweetened beverages is also helpful. 

Dietary Supplements

Plant sterols and stanols are present in various fruits, vegetables, and nuts and added to dressings such as margarine, salad dressings, juice, and yogurts. Plant sterols and stanols work by reducing cholesterol absorption from the intestine. Plant sterols of 2 grams/day have been shown to reduce LDL-C by 5 to 15%; however, no effects were seen on endothelial function.[30][31] (A1)

Plant sterols can prevent the absorption of fat-soluble vitamins, and the levels of these vitamins should be monitored. A study with psyllium fiber (6 grams/day) added to cereal vs. placebo showed a modest reduction of 7% in LDL-C compared to placebo.[32](A1)

Physical Activity

Physical activity and reduced sedentary behavior have been shown to improve lipid profiles and reduce the risk of cardiovascular events. Limiting screen time and age-appropriate physical activity should be encouraged. 

Weight Loss

For overweight children with BMI over 85%, weight reduction is the primary goal, and weight loss can help improve dyslipidemia. 

Avoiding Nicotine Exposure

Children and adolescents should be counseled regarding smoking and secondhand exposure.

Pharmacological Management

Although the first line of treatment for dyslipidemia is dietary and lifestyle intervention, this alone is insufficient for many children to lower their LDL cholesterol, and many children will require pharmacological intervention. Pharmacotherapy options are as follows (summarised in Table below):

HMG Coenzyme A reductase inhibitors (Statins): Statins are the first line of therapy for treating pediatric hypercholesterolemia. They work by blocking the enzyme HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol synthesis. This causes reduced intracellular cholesterol pool and upregulation of LDL receptors leading to reduced serum cholesterol. There are many different types of statins - simvastatin, pravastatin, lovastatin, rosuvastatin, and atorvastatin are FDA-approved in children.

Adverse effects: Adverse effects of statin therapy are rare and include GI complaints, the elevation of transaminases, myopathy (muscle cramping and soreness), and new-onset type 2 diabetes. Statins have a potential teratogenic agent and should not be used during pregnancy. If adolescent females are sexually active, contraceptive techniques such as oral contraceptives should be prescribed. The use of statins should be avoided in breastfeeding mothers. 

Baseline labs prior to statin initiation:

• fasting lipid panel
• creatine kinase
• Liver function tests, especially ALT
• fasting plasma blood glucose, and hemoglobin a1c 
• pregnancy test (if indicated)

Statins are initiated at the lowest starting dose and given once daily, typically at bedtime, because most LDL-C synthesis occurs at nighttime hours. They are used in doses between 5 to 40 mg/day.  After initiation of statins, lipid panel, a1c, CK, fasting plasma glucose, and LFTs should be checked at 4 to 6 weeks and with statin dose titration by 10 to 20 mg until LDL levels are under 130 mg/dl for moderate and at-risk and under 100 mg/dl for high-risk patients.

If there are signs of toxicity, statins should be discontinued, and laboratory function should be rechecked. Once laboratory function is normalized, statins can potentially be restarted at a lower dose.

Once the LDL goals are met, ALT, hemoglobin a1c and CK should be monitored every six months along with a fasting lipid panel.

Laboratory evaluation should then be done every six months.

If LDL goals are not met, the statin dose should be increased until the maximum amount is reached or evidence of toxicity. The clinician can add a second agent if the LDL target is not achieved. Caution must be used if adding fibrates given compounded risk of adverse effects, especially myopathy. 

Bile acid-binding agents: Bile acid binding agents work to lower serum cholesterol by binding with bile acids in the intestine and preventing their reabsorption. Bile-acid binding agents include colestipol, Cholestyramine, and Colesevelam. Reduced hepatic cholesterol, in turn, induces hepatic cholesterol biosynthesis causing increased LDL receptor synthesis and reduced serum cholesterol.[33][34] Bile-acid binding agent use is often limited by poor compliance given side effects. (A1)

Fabric acid derivatives: Fibrates such as gemfibrozil and fenofibrate are primarily utilized in states of hypertriglyceridemia with TG levels of over 1000 mg/dl. They can also be used in cases where TG levels are between 400-1000 mg/dl. Fibrates work by increasing the breakdown of TG and reducing hepatic VLDL production; hence they lower TG and increase HDL-C.

Adult data shows that fibrates lower triglycerides by 40 to 60%. Fibrates are usually well-tolerated, and side effects include elevation of transaminases, dyspepsia, diarrhea, cholelithiasis, risk of myopathy, and rhabdomyolysis. The risk of side effects is increased when combined with statins; hence, therapy is not commonly combined in children. Fibrates are currently not FDA-approved for the pediatric age group. 

Niacin: Niacin or nicotinic acid is rarely used as a primary or adjunct therapy for pediatric dyslipidemia. It is available in regular and slow-release forms, with doses between 100 and 2250 mg/day. In children with heterozygous familial hypercholesterolemia, niacin in doses of 1000 to 2250 mg caused a reduction in LDL cholesterol by 23 to 30%. It is not FDA approved and has multiple side effects affecting up to 76% of children, including nausea, vomiting, abdominal pain, headache, flushing, elevated liver enzymes, and impaired glucose tolerance.[35](B2)

Inhibitors of cholesterol absorption: Ezetimibe is an inhibitor of cholesterol absorption which works by inhibiting the absorption of cholesterol from diet and plant sterols at the level of the brush border of the intestine by inhibiting Niemann-Pick C1 like 1 protein. It is the second most common lipid-lowering agent prescribed after statins.

Reduced cholesterol absorption from the intestine leads to reduced availability of cholesterol at the level of the liver and a compensatory increased biosynthesis of hepatic cholesterol, which in turn causes increased LDL receptor expression and reduced serum cholesterol. Currently, Ezetimibe is not FDA-approved for the pediatric age group.

In children, ezetimibe of 10 mg daily was shown to reduce LDL-C levels by 28% compared to placebo.[36] Ezetimibe is a good adjunct therapy when monotherapy with statins fails to provide goal LDL-C levels. 

Omega 3 fatty acids: High-dose omega 3 fatty acids found in fish oils are used primarily for the management of TG levels, given the risk of pancreatitis. Omega 3 fish oils at a dose of 2-4 grams per day are used in patients with severely high TG levels in the 600 to 1000 mg/dl range. TG lowering effect depends on the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content. In adults, data have shown a reduction in TG levels by 20 to 30%, but data in pediatrics has not demonstrated a statistically significant difference compared to placebo in reduction of TG levels.[37]

Apheresis: Lipoprotein apheresis is the process of physically removing lipoproteins from blood using methods such as extracorporeal precipitation. Apheresis is used for patients with significant LDL-C elevation that is not responsive to standard dietary and pharmacological measures. This process is used in patients with homozygous hypercholesterolemia (LDL over 500 mg/dl), patients with coronary artery disease and LDL over 200 mg/dl, and patients with LDL over 300 mg/dl despite dietary and pharmacological intervention.

With the advent of PCCK9 inhibitors, the use of apheresis has reduced. It is performed once or twice a week. A significant reduction in LDL-C levels of up to 60 to 70% has been reported in the pediatric age group. Although there is data on the reduction of LDL levels, data regarding reduction in cardiovascular events are lacking. The procedure is well tolerated with limited side effects such as hypotension, iron deficiency anemia, nausea, and headaches.[38] Apheresis is FDA-approved. 

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors: PCSK9 is encoded by the PCSK9 gene and is produced in the liver. PCSK9 binds to the LDL receptor (LDL-R) on the surface of hepatocytes, leading to the degradation of the LDL-R and subsequently higher plasma LDL-C levels. 

PCSK9 monoclonal antibody binds to free plasma PCSK9, thereby leading to degradation of PCSK9. This leads to less PCSK9 available to bind to the LDL-R and, therefore, higher hepatic LDL-R expression and lower serum LDL levels. They have been shown to reduce LDL cholesterol by 60-70%. PCSK9 inhibitors were approved in 2015.

Commercially available PCSK9 monoclonal antibodies are Evolocumab and alirocumab. Although highly effective, this treatment modality is expensive and only available as a subcutaneous injection that can be given once or twice a month. 

Lomitapide: Lomitapide is FDA-approved for homozygous FH. It binds to and inhibits microsomal triglyceride transfer protein (MTP), which ultimately causes reduced levels of chylomicrons and VLDL causing a reduction in LDL-C levels. It carries a risk of teratogenicity and liver toxicity, along with severe diarrhea. It is typically started at 5 mg and taken 2 or 3 hours after the evening meal, and the dose can be increased to a maximum of 60 mg daily. 

Table summarising lipid-lowering agents[6]

Differential Diagnosis

Before initiating pharmacotherapy assuming primary dyslipidemia, a thorough workup should be done to rule out any secondary causes of dyslipidemia. The most common secondary cause of dyslipidemia is elevated BMI in the overweight or obese range.

Other secondary causes of dyslipidemia include but are not limited to hypothyroidism, liver disease, renal disease, diabetes, pregnancy, alcohol, and certain medications.

Prognosis

There is clear evidence that supports pediatric dyslipidemia with the onset and severity of atherosclerosis. Lipid profiles during late childhood and adolescence predict lipid profiles in adulthood in the third and fourth decades. Screening for dyslipidemia is beneficial in children with additional risk factors like diabetes, obesity, and a family history of premature atherosclerosis.

Children with FH have a 90% lifetime risk of developing coronary artery disease. In children with FH, changes in endothelial function and carotid intima-media thickness can be detected, which are reliable markers of clinical outcomes in later life. Therefore, early detection and control of dyslipidemia are strongly recommended to reduce the risk of cardiovascular events in adulthood and also reduce morbidity and mortality.[6]

Complications

The most common complication of dyslipidemia is atherosclerosis which can cause vascular disease and lead to morbidity and mortality. Peripheral arterial disease, coronary artery disease (myocardial infarction, sudden cardiac death), cerebrovascular accidents, and hypertension are some of the many complications from untreated dyslipidemia. Severe hypertriglyceridemia can lead to pancreatitis.