Lipids in Children and Links to Adult Vascular Disease

Abstract

Atherosclerosis often begins in childhood or adolescence. Post-mortem studies in children have shown the presence of coronary atheroma, and there are hereditary conditions associated with hyperlipidaemia in childhood which lead to premature cardiovascular disease. Detection of hyperlipidaemia early in life can be crucial in the prevention of premature death from atherosclerosis.

The circulating lipoproteins are in a constant state of flux, with passage of apolipoproteins and lipids between the various particles. Genetic variants of apolipoproteins can cause both hypercholesterolaemia and hypertriglyceridaemia. Elevated concentrations of lipoprotein(a) predispose to coronary artery disease. Another important molecule in lipid metabolism, proprotein convertase subtilisin/kexin type 9 (PCSK9), plays a crucial role in the removal of low-density lipoprotein (LDL) receptors.

Reference intervals for the various lipid subfractions are now available for children, and there are guidelines regarding when to take action regarding paediatric hyperlipidaemia. The most important genetic condition in children which may lead to premature death from coronary heart disease is familial hypercholesterolaemia (FH). FH is best diagnosed and treated early in life. Most cases are due to defects in the LDL receptor. Pharmacotherapy for FH usually involves the statin group of drugs, although newer medications are now available, especially for the treatment of homozygous FH. Statin therapy has been demonstrated to be successful in preventing cardiac events in FH. Secondary dyslipidaemia in childhood can be associated with numerous diseases including diabetes, lifestyle disorders such as obesity, and drugs. Treatment of the underlying condition usually resolves the hyperlipidaemia.

Introduction

In recent years, increased attention has been paid to plasma lipid measurements in children for a number of reasons. It is important to detect certain genetic hyperlipidaemias, in particular familial hypercholesterolaemia (FH), early in life before serious atherosclerosis develops.¹ Also, obesity and the metabolic syndrome in children have become more prevalent, and these conditions can lead to dyslipidaemia and premature vascular disease.^2,3 Both Type 1 and Type 2 diabetes mellitus in children and adolescents, especially when under poor control, can cause secondary hyperlipidaemia and predispose to coronary heart disease.⁴

Development of Atherosclerosis in Childhood and Adolescence

It is now realised that atherosclerosis can develop early in life. In post-mortem studies in the Bogalusa Heart Study,⁵ fatty streaks were found in the coronary arteries of 50% of 2–15-year-old children, while actual coronary atheroma was found in 8% of this age group. In the 16–20-year-old age group, coronary atheroma was present in 33%.

In the Cardiovascular Risk in Young Finns study,⁶ risk factors were measured in children aged three to eighteen years, and increases in body mass index, low-density lipoprotein (LDL) cholesterol and blood pressure were found to correlate with increased carotid intima-media thickness in adulthood. Carotid intima-media thickness is used as a surrogate marker for atherosclerosis.

Lipid Metabolism

To understand lipid disorders in children, one needs to know how lipids are metabolised in the body. In the plasma, the various lipid particles are in a constant state of flux - they are remodelled both by enzymatic activity, and movement of lipids and proteins between the different particles. A simplified explanation of these processes follows.⁷

There are two pathways of lipid metabolism, one resulting from lipoproteins coming from ingested fat (exogenous) and one from lipoproteins produced by the liver (endogenous). In the exogenous pathway (Figure 1), ingested triglycerides absorbed into the intestinal mucosa are incorporated into chylomicrons and secreted initially into lymphatic vessels, and then into the circulation. In the mucosal cells, triglyceride, and to a lesser extent cholesteryl ester, join with apolipoprotein B-48 [a truncated version of apolipoprotein B-100 (apo B-100)] by means of the microsomal triglyceride transfer protein (MTTP) to form chylomicrons. When the chylomicrons enter the circulation via the thoracic duct, they acquire apolipoprotein C-II and apolipoprotein E. Once in the vascular space, the triglycerides in chylomicrons are hydrolysed by lipoprotein lipase (LPL) on the surface of endothelial cells, which is activated by apolipoprotein CII. In this manner, fatty acids and apolipoproteins are lost from the particles, with the formation of chylomicron remnants, which can then be taken up by the liver. This process takes place by the binding of apolipoprotein E in the remnant particles to specific hepatic receptors.

Figure 1.

Exogenous pathway of lipid metabolism.

apo B-48 = apolipoprotein B-48, apo C-II = apolipoprotein C-II, TG = triglyceride, apo E = apolipoprotein E, LPL = lipoprotein lipase

In the endogenous pathway (Figure 2), very-low-density lipoprotein (VLDL) particles are formed in liver cells in a similar way to chylomicrons, using triglyceride and MTTP. However, in this case, the apolipoprotein is apo B-100. Apolipoprotein E is also incorporated to form nascent VLDL. In the circulation, nascent VLDL acquires cholesteryl ester from high-density lipoprotein (HDL), plus apolipoproteins, including apolipoprotein CII, an essential cofactor for lipoprotein lipase. LPL breaks down VLDL particles with the loss of fatty acids and the formation of VLDL remnants which can be taken up by the liver. Further breakdown leads to the formation of intermediate-density lipoprotein (IDL). The final product of lipase activity on VLDL and IDL is LDL. LDL is rich in apolipoprotein B-100 and cholesteryl ester. There are specific LDL receptors on cells which can bind and internalise LDL by using apo B-100 as a ligand.⁸ Once inside the cell, LDL particles are broken down and cholesterol is released. Increasing cholesterol concentration within the cell has a negative feedback effect on the synthesis of LDL receptors. This fact is important in understanding the actions of the statin group of drugs.

Figure 2.

Endogenous pathway of lipid metabolism.

HDL = high-density lipoprotein, apo A = apolipoprotein A, apo C-II = apolipoprotein C-II, apo C-III = apolipoprotein C-III, apo E = apolipoprotein E, VLDL = very-low-density lipoprotein, CE = cholesteryl ester, apo B-100 = apolipoprotein B-100, LPL = lipoprotein lipase, PL = phospholipid, IDL = intermediate-density lipoprotein, LDL = low-density lipoprotein

While LDL causes atheroma by depositing cholesterol in foam cells, HDL has the opposite effect, and removes cholesterol from these cells.⁹ Nascent HDL is formed in the liver and intestine and consists mainly of phospholipid and apolipoproteins A-I and A-II. It acquires cholesterol from cells by means of the ATP binding cassette transporter A1 (ABCA1), shown in Figure 3. This cholesterol is esterified by the enzyme lecithin cholesterol acyltransferase (LCAT). Cholesteryl ester can then be transferred to VLDL, IDL and LDL by cholesteryl ester transfer protein (CETP). Normally, about two thirds of plasma cholesterol is esterified and one third is free. In the circulation, HDL also gains other apolipoproteins to form mature HDL particles. Low plasma HDL-cholesterol concentration has been shown to be an independent risk factor for vascular disease.¹⁰

Figure 3.

High-density lipoprotein metabolism.

HDL = high-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, CE = cholesteryl ester, FC = free cholesterol, ABCA1 = adenosine triphosphate binding cassette transporter A1, CETP = cholesteryl ester transport protein, LDL = low-density lipoprotein, IDL = intermediate-density lipoprotein, VLDL = very-low-density lipoprotein

Apolipoproteins

There are many different apolipoproteins in the plasma, performing varied and important roles. The most abundant ones, in molecular terms, are apolipoprotein A-I and A-II, while apolipoprotein A-I and apolipoprotein B are most abundant in terms of mass.¹¹ Table 1 sets out the molecular weights and functions of the major apolipoproteins.^7,11

Table 1.

Molecular weights and functions of the major apolipoproteins.

Apolipoprotein	Molecular Weight (Daltons)	Function
Apo A-I	29,016	Structural protein for HDL. Ligand for ABCA1 transporter. Activator of LCAT.
Apo A-II	17,414	Structural protein for HDL. Activator of hepatic lipase.
Apo A-IV	44,465	Activator of LCAT and LPL.
Apo B-48	240,800	Structural protein for chylomicrons.
Apo B-100	512,723	Structural protein for VLDL and LDL. Ligand for the LDL receptor.
Apo C-I	6630	Activator of LCAT.
Apo C-II	8900	Essential cofactor for LPL.
Apo C-III	8800	Inhibits triglyceride hydrolysis and clearance of chylomicron remnants and VLDL. Multiple pro-atherogenic effects.
Apo E	34,145	Ligand for chylomicron remnant, VLDL remnant, IDL and LDL receptors. 3 Apo E alleles: E2 associated with familial dysbetalipoproteinaemia; E4 associated with hypercholesterolaemia.

Apo = apolipoprotein, HDL = high-density lipoprotein, ABCA1= ATP binding cassette transporter A1, LCAT = lecithin cholesterol acyltransferase, LPL = lipoprotein lipase, VLDL = very-low-density lipoprotein, LDL = low-density lipoprotein, IDL = intermediate-density lipoprotein

Lipoprotein(a)

Another important lipoprotein with links to adult vascular disease is lipoprotein(a) [Lp(a)]. Lp(a) is a modified version of LDL in which apolipoprotein(a), [apo(a)], is bound by disulphide bridges to LDL. Apo(a) is a glycoprotein, consisting of cysteine rich domains, called kringles type 4 and type 5. Kringle type 4 can have a variable number of amino acid repeats, so the molecular weight of Lp(a) is highly variable. This can lead to discordance between Lp(a) mass and particle number.¹¹

The effects of Lp(a) on body processes are varied. The fourth kringle has similarities in amino acid sequence to plasminogen¹² which, by conversion to plasmin, breaks down fibrin clots. By inhibiting the action of plasminogen, Lp(a) may promote thrombosis. Lp(a) is also pro-inflammatory, and it contains oxidised phospholipid, which may contribute to its pro-atherogenic effect.¹³ By binding to macrophages, it also increases formation of foam cells containing cholesterol in atheromatous plaques.¹⁴

The plasma concentration of Lp(a) is mainly under genetic control,¹⁵ although it is also a positive acute phase reactant. The 90^th percentile for its plasma concentration in men, according to the Framingham study, is 39 mg/dL.¹⁶ Mendelian randomisation studies have shown that elevated concentrations of Lp(a) are independent risk factors for coronary heart disease¹⁷ and aortic stenosis.¹⁸

Plasma concentrations of Lp(a) have been found to be relatively constant throughout life.¹⁹ When children are found to have hypercholesterolaemia, measurement of their Lp(a) levels is recommended in case they have this second risk factor for coronary heart disease. Unfortunately, there are no medications currently available which can lower Lp(a) concentrations to a large degree. Research into antisense therapy, as has occurred with apolipoprotein B, holds out some promise.²⁰

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

In addition to apolipoprotein B-100, a circulating protein called proprotein convertase subtilisin/kexin type 9 (PCSK9) has been found to be influential in the control of plasma cholesterol. In studies of autosomal dominant hypercholesterolaemia, a small percentage of individuals was found to have activating mutations in the PCSK9 gene.²¹ PCSK9 binds to LDL receptors on the surface of cells and the complex so formed moves into the cell and the LDL receptor is broken down.²² Normally, LDL receptors, having bound apo B-100 in LDL, are internalised, then the LDL is released and the receptor re-circulates to the cell surface.²³ Therefore, increased activity of PCSK9 will lead to less LDL receptors and hypercholesterolaemia. On the other hand, it has been shown that inactivating mutations in PCSK9 cause hypocholesterolaemia, both in heterozygotes, compound heterozygotes and homozygotes.^24,25,26 This knowledge has led to the development of antibodies against PCSK9 for the treatment of refractory hypercholesterolaemia.²⁷

Reference Intervals for Lipids in Children

There have been numerous studies from various countries regarding reference intervals for lipids in children, e.g. the CALIPER study from Canada²⁸ and the Busselton study in Australia.²⁹ One extensive investigation in the United States of America was performed by the National Cholesterol Education Program and published in 1992.³⁰ Table 2 illustrates what are considered from this study to be unacceptably high concentrations of cholesterol, LDL-cholesterol, non-HDL-cholesterol and triglycerides (plus apolipoprotein B). In addition, Table 2 gives the values for unacceptably low concentrations of HDL-cholesterol and apolipoprotein A-1.³⁰ These findings, while derived quite a long time ago, still provide useful cut points for managing lipid problems in children.

Table 2.

Acceptable and non-acceptable values for lipids in children and adolescents.

Category	Low (mmol/L)	Acceptable (mmol/L)	Borderline High (mmol/L)	High (mmol/L)
Total cholesterol		<4.4 mmol/L	4.4–5.1 mmol/L	≥5.2 mmol/L
LDL-cholesterol		<2.8 mmol/L	2.8–3.3 mmol/L	≥3.4 mmol/L
Non-HDL-cholesterol		<3.1 mmol/L	3.1–3.7 mmol/L	≥3.8 mmol/L
Apo B		<90 mg/dL	90–109 mg/dL	≥110 mg/dL
Triglycerides
0–9 years		<0.8 mmol/L	0.8–1.1 mmol/L	≥1.2 mmol/L
10–19 years		<1.0 mmol/L	1.0–1.5 mmol/L	≥1.6 mmol/L
HDL-cholesterol	<1.0 mmol/L	1.0–1.2 mmol/L	≥1.3 mmol/L
Apo A–I	<115 mg/dL	115–120 mg/dL	≥120 mg/dL

LDL = low-density lipoprotein, HDL = high-density lipoprotein, Apo = apolipoprotein. Low cut points for HDL-cholesterol and apo A–I represent approximately the 10th percentile. The cut points for high and borderline high represent approximately the 95th and 75th percentiles, respectively. Adapted from: Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011;128(Suppl 5):S213–56.

The following general rules have been established about lipid concentrations in children:³¹

• Concentrations of lipids increase during the first two years of life. By age two, values are similar to those seen in adults.

• Age specific values for mean cholesterol concentration peak at nine to eleven years of age.

• Lipid concentrations decrease during pubertal development and then increase thereafter.

• Tracking indicates that children generally maintain their percentile ranking for lipid concentrations.^30,32 Females have higher total cholesterol concentrations.

Primary Lipid Disorders and Links to Adult Vascular Disease

Primary, or inherited, lipid disorders may be characterised by either decreased or elevated concentrations of lipids. Those in the former category include abetalipoproteinaemia, due to a deficiency of microsomal triglyceride transfer protein,³³ and other rare genetic disorders, such as familial hypobetalipoproteinaemia, chylomicron retention disease and familial combined hypolipidaemia.³⁴ In addition, there is Tangier disease, an autosomal recessive condition characterised by very low concentrations of HDL. Tangier disease is caused by mutations in the ABCA1 gene.³⁵ As already mentioned, ABCA1 plays a crucial role in transporting cholesterol out of cells into nascent HDL. Therefore, in Tangier disease, mature HDL does not form, and nascent HDL is rapidly excreted by the kidneys. In this condition, cholesteryl esters accumulate in cells, leading to hyperplastic orange tonsils, splenomegaly, peripheral neuropathy and probable increase in coronary heart disease. There is also a condition called hypoalphalipoproteinaemia in which mutations involving the apolipoprotein A-1 gene (APOA1) lead to decreased levels of apo A-1 and HDL. Again, coronary heart disease is a feature of this condition.¹¹

Primary lipid disorders, characterised by excess concentrations of lipids, may manifest hypercholesterolaemia, hypertriglyceridaemia or a combination of the two. Under the heading of primary hypercholesterolaemia are included familial hypercholesterolaemia, polygenic hypercholesterolaemia and the rare condition, sitosterolaemia. In sitosterolaemia, plant sitosterols, along with cholesterol, are absorbed in excess from the intestine due to mutations in two ATP binding cassette transporter (ABC transporter) genes, ABCG5, and/or ABCG8.³⁶ The condition can be treated by the drug, ezetimibe, which inhibits cholesterol and other sterol absorption. All the primary hypercholesterolaemias, if left untreated, may lead to early atherosclerosis.

Primary lipid disorders characterised by both hypercholesterolaemia and hypertriglyceridaemia include familial combined hyperlipidaemia (FCHL) and familial dysbetalipoproteinaemia. FCHL is said to affect about 1 in 100³⁷ of the population. Its underlying pathophysiology is not well understood but there appears to be overproduction of apo B-100.³⁸ FCHL seems to arise by a combination of genetic susceptibility and environmental factors, and it too can lead to early atherosclerosis.

Familial dysbetalipoproteinaemia, also known as Type III hyperlipoproteinemia under the Fredrickson classification,³⁹ is associated with the apolipoprotein E2 genotype. There are three different alleles for apo-E, viz. E2, E3, and E4. E3 may be considered the ‘normal’ allele. Individuals who are homozygous E2/E2 can develop familial dysbetalipoproteinaemia. However, other genetic or environmental factors seem to be required to manifest the disease.⁴⁰ In this disorder, there are high circulating concentrations of remnant lipoproteins. E2 is less able to bind to lipoprotein receptors than E3 – hence more atherogenic lipoprotein remains within the circulation, resulting in premature vascular disease.

The third category of primary lipid disorders includes those diseases characterised by marked hypertriglyceridaemia. In children, the most important, although rare, condition in this category is familial hyperchylomicronaemia (Type I in the Fredrickson classification), caused by defective action of lipoprotein lipase (LPL). There may be a lack of formation of the enzyme protein due to genetic mutation, or there may be an absence of LPL’s co-factor, apolipoprotein CII.¹¹ Deficiencies of other apolipoproteins, such as apo A5, may also cause hypertriglyceridaemia.⁴¹ In addition, the chylomicronaemia syndrome may be caused by biallelic pathogenic variants in lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1).⁴² Chylomicrons are large particles and not considered to be atherogenic. The main complication from massive hypertriglyceridaemia is pancreatitis. This is particularly likely to occur when triglyceride concentrations are greater than 5.6 mmol/L.⁴³ Hyperviscosity syndrome is another unwanted effect of markedly increased triglycerides,⁴⁴ and factitious hyponatraemia may be seen when indirect reading electrodes are used to measure sodium.

This is a very brief overview of the primary hyperlipidaemias. A more detailed review of familial hypercholesterolaemia follows, as this is an important condition to recognise in children in order to prevent later premature vascular disease in adults.

Familial Hypercholesterolaemia (FH)

Under the heading of Familial Hypercholesterolaemia are the following conditions:

• LDL receptor defects

• Familial defective apo B-100

• PCSK9 gene defects

• ARH (Autosomal recessive hypercholesterolaemia) adaptor protein mutations

All are inherited in an autosomal dominant fashion, except for the ARH adaptor protein mutations which are autosomal recessive.⁴⁵ The heterozygous forms of LDL receptor defects are by far the most common of the disorders, affecting one in 200 to 350 persons in the general population.^46,47 The homozygous forms of LDL receptor defects are found in about one in a million persons. Over 1800 different allelic mutations have been reported but less than 15% of these have functional evidence of pathogenicity.⁴⁸ The defects in the LDL receptor have been divided into five classes.⁴⁹

Class I	Null: the LDL receptor protein cannot be synthesised.
Class II	Transport defective: the receptor protein is made but cannot be transported from the endoplasmic reticulum to the Golgi apparatus.
Class III	Binding defective: the receptor protein is transported to the cell surface but LDL cannot bind to it.
Class IV	Internalisation defective: LDL binds to the receptor but the process of transport into the cell is defective.
Class V	Recycling-deficient alleles: the receptor and ligand do not dissociate, leading to degradation of the receptor.

Familial defective apo B-100 is a rare condition in which genetic mutations lead to faulty forms of apo B-100 which cannot bind to the LDL receptors.⁵⁰ In PCSK9 gene defects, there is gain-of-function of PCSK9 so that LDL receptors are destroyed more rapidly.²¹

In the common form of FH, about half the normal number of LDL receptors are present on the surface of cells. Consequently, less LDL-cholesterol can be internalised into cells and broken down. The cells respond by synthesising more cholesterol which contributes to the high circulating plasma cholesterol concentrations.

In FH, elevated plasma cholesterol is found very early in life. With this burden of increased cholesterol, atheroma develops at a younger age than usual. In one study, carotid intima-media thickness measurements were increased in FH children compared to controls.⁵¹ Also, progression of atheroma is greater in FH, as shown by the study of Wiegman et al.⁵² In this investigation, increase in carotid intima-media thickness progressed at five times the rate of controls.

In children, the diagnosis of FH generally rests upon two main considerations – plasma LDL-cholesterol concentrations and family history. In guidelines published by the European Atherosclerosis Society Consensus Panel,⁵³ an LDL-cholesterol level ≥5 mmol/L on two successive occasions after three month’s diet indicates a high probability of FH. A family history of premature cardiovascular disease in close relatives and/or high cholesterol in one parent, along with an LDL-cholesterol ≥4 mmol/L also indicates a high probability of FH. Diagnosis can sometimes be confirmed by identifying in the child or the parent specific mutations known to cause FH. If the parent has a genetic diagnosis, an LDL-cholesterol ≥3.5 mmol/L suggests FH in the child. Similar cut-off values for diagnosis of FH in children can be found in the Australian guidelines, published in 2015.¹ In adults, diagnosis is often done using a scoring system such as the Dutch Lipid Clinic Score.⁵⁴ Skin xanthomas are used as part of this system but are rarely seen in children, except in homozygous FH.

The superiority of genetic diagnosis of FH over LDL-cholesterol concentrations was demonstrated in a study by Starr et al.⁵⁵ In this study, 825 subjects known to carry a mutation for FH had their LDL-cholesterol concentrations measured, along with 2469 controls. When a cut-off of 3.2 mmol/L for LDL-cholesterol was used to diagnose FH, this resulted in a false positive diagnosis in 8% and a false negative diagnosis in 15%. In a recent, similar study in children whose parents carried a pathogenic FH mutation, an LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and a specificity of 96.6% for the diagnosis of FH.⁵⁶

Once an index case of FH is diagnosed, the clinician must look for other cases within the family. Since FH is inherited in an autosomal dominant fashion, 50% of first-degree family members will be affected, 25% of second-degree and 12.5% of third-degree. These percentages are much higher than the 0.3% affected in the general population. Therefore, a case finding protocol called ‘Cascade Screening’ has been recommended for use in Australasia.⁵⁷ Family members of the index case (including second-degree relatives, if possible) should all be screened for FH by measurement of lipids, including LDL-cholesterol, plus or minus genetic screening.

Treatment of FH involves attention to diet and lifestyle. A low fat, low cholesterol diet should be prescribed in children over the age of two years, and exercise encouraged. At most, diet can only lower cholesterol by about 10%. At a certain age, drug therapy will almost certainly need to be introduced. The actual age of introduction depends on several factors, including the severity of the hypercholesterolaemia and the family history. Drug therapy for both boys and girls is recommended from the age of 8–10 years in the European guidelines,⁵³ while the Australian guidelines are slightly more conservative.¹ Statins are the drugs of first choice. They act by inhibiting the enzyme, HMG CoA reductase,⁵⁸ which is a rate limiting enzyme in cholesterol biosynthesis. Statins are generally well tolerated, although myalgia can occur. Actual myositis, with marked rises in creatine kinase, is a rare complication. If statin therapy alone does not bring about good control of hypercholesterolaemia, the drug ezetimibe, which inhibits absorption of cholesterol from the intestine, can be introduced.

Drug treatment of FH in children and adolescents lowers cholesterol concentrations much more than diet alone. In a study by Wiegman et al., treatment of 214 FH children with pravastatin lowered mean LDL-cholesterol by 24%.⁵⁹ In a more recent study, Braamskamp et al. showed that rosuvastatin can bring about 35–45% decreases in LDL-C in children over a 24 months period.⁶⁰ When ezetimibe is added to statin therapy, even greater decreases in plasma cholesterol concentration can be attained.⁶¹

Children with FH undergoing statin therapy have been shown to be at less risk for coronary heart disease than their parents who did not start treatment until adulthood.⁶² Nordestgaard et al. published an interesting analysis regarding age thresholds for coronary heart disease in FH patients, compared to unaffected individuals.⁶³ Most people, by about the age of 55 years, have reached the threshold for coronary heart disease. In heterozygous FH patients, this threshold is reached by about 35 years of age. However, when treated with statins from an early age, the threshold in heterozygous FH patients can be raised to about 53 years, which is approaching the threshold for the unaffected population.

There is still much to learn regarding the optimal care of children with FH. Current knowledge and practice, along with suggestions for future inquiries, are well covered in a recent review.⁴⁷

Homozygous FH

Homozygous FH refers to those individuals who have two defective copies of the LDL receptor gene. Individuals who have less than 2% LDL receptor activity are said to be receptor negative, while those who have 2–25% receptor activity are classified as receptor defective.⁶⁴ The parents of homozygous FH individuals must have heterozygous FH but may carry different mutations. Unless the parents are closely related, homozygous FH patients are often compound heterozygotes. The prevalence of homozygous FH is approximately 1 in a million.

Homozygous FH patients have very high total cholesterol concentrations (often >20 mmol/L). If no treatment is given, death is likely to occur between 10 and 20 years of age from severe coronary artery disease. Tendon and skin xanthomas which contain cholesterol, as well as arcus cornealis, can develop in the first years of life, unlike heterozygous FH (Figure 4).

Figure 4.

Xanthomas on the ankle (A) and wrist (B) of a three-year-old patient with homozygous familial hypercholesterolaemia. (C) Arcus cornealis in a two-year-old patient with compound heterozygous familial hypercholesterolaemia.

Treatment of homozygous FH is difficult. In addition to a low cholesterol, low fat diet, patients may be given ezetimibe to inhibit cholesterol absorption. Treatment with statins may not be as effective as it is in heterozygous patients. This is because part of the success of statin treatment in heterozygous FH relies on the synthesis of new, functional LDL receptors. This is unlikely to occur in homozygous FH unless there is some residual receptor activity. One effective treatment in homozygous FH is plasmapheresis to remove LDL-cholesterol.⁶⁵ This may be carried out on a fortnightly basis and can remove large amounts of cholesterol from the circulation. Another treatment that may be ‘curative’ is liver transplantation.⁶⁶

In recent years, new drugs have been developed to treat homozygous FH. Sometimes, these drugs, especially the PCSK9 inhibitors, are also employed in difficult to treat cases of heterozygous FH. The PCSK9 inhibitors, such as alirocumab and evolocumab, are antibodies which act by destroying PCSK9’s ability to break down LDL receptors, so they may be ineffective in homozygous FH, unless some synthesis of LDL receptors is taking place. Nevertheless, lowering of LDL-cholesterol by about 30% has been reported in homozygous FH patients treated with evolocumab.⁶⁷

Another approach to treatment in homozygous FH is to inhibit the synthesis of apolipoprotein B-100, which is an essential part of all the atherogenic lipoproteins, such as LDL. Mipomersen, an antisense oligonucleotide, becomes incorporated into the messenger RNA which is normally translated to apo B-100. When mipomersen binds to the mRNA, translation to apo B-100 cannot occur. Again, large decreases in LDL-cholesterol can be obtained by this drug.⁶⁸ However, adverse effects can occur, and currently mipomersen is approved for use in homozygous FH in the USA but not in Europe.

Another new drug, lomitapide, blocks the action of the microsomal triglyceride transfer protein (MTTP) in the liver. Consequently, VLDL is not synthesised, leading to considerable reductions in LDL-cholesterol. A significant side effect is accumulation of fat within the liver.⁶⁹ Finally, an inhibitor of angiopoietin-like 3 (ANGPTL3) has recently been shown to bring about large decreases in LDL-cholesterol in homozygous FH patients, independent of LDL receptor function. ANGPTL3 causes increases in plasma concentrations of triglycerides, LDL-cholesterol and HDL-cholesterol.⁷⁰

Secondary Dyslipidaemia

Dyslipidaemia may also occur secondary to other diseases, lifestyle factors or drugs. The common diseases causing secondary dyslipidaemia in children and adolescents are listed in Table 3, along with the typical lipid abnormalities seen. Treatment of the underlying disease will usually resolve the dyslipidaemia.

Table 3.

Diseases in children commonly causing secondary hyperlipidaemia.

Disease	Typical Lipid Abnormality
Primary hypothyroidism	Hypercholesterolaemia
Nephrotic syndrome	Increased cholesterol and triglycerides; occasionally just hypercholesterolaemia
Chronic kidney disease	Hypertriglyceridaemia; increases in apo C III and apo E
Liver disease	In obstructive liver disease, marked hypercholesterolaemia due to the formation of lipoprotein X; in fatty liver disease, hypertriglyceridaemia due to increased formation of VLDL; low HDL in chronic liver disease
Glycogen storage diseases Types I and III	Hypertriglyceridaemia
Anorexia nervosa	Hypercholesterolaemia
Inherited lipodystrophy	Hypertriglyceridaemia
Diabetes Mellitus (Types I and II)	In poorly controlled diabetes, increased triglycerides due to fatty liver; in diabetic ketoacidosis, marked hypertriglyceridaemia may be present at presentation.

apo = apolipoprotein, VLDL = very-low-density lipoprotein, HDL = high-density lipoprotein

Obesity is now prevalent in children and this can have long term consequences for their cardiovascular health. Obesity may be associated particularly with elevation in plasma triglycerides, plus some mild elevation in cholesterol, and low HDL.³⁰ As mentioned previously, obese children exhibit increases in carotid intima medial thickness compared to controls,⁶ a prelude to atherosclerosis. Associated with obesity is the metabolic syndrome or syndrome X, which is also characterised by hypertension, hyperglycaemia, hypertriglyceridaemia and low HDL.⁷¹ As already stated, low HDL is an independent risk factor for coronary artery disease.¹⁰

Finally, drugs may be responsible for hyperlipidaemia. The following drugs or groups of drugs are known to cause elevations in cholesterol, triglycerides or both.⁷²

• corticosteroids

• isotretinoin

• certain contraceptive drugs

• certain chemotherapeutic agents

• certain anti-retroviral drugs

• beta blockers

One chemotherapeutic agent which occasionally causes marked hypertriglyceridaemia in children with leukaemia is asparaginase, which has been shown to inhibit lipoprotein lipase.^73,74 In addition, in the treatment of leukaemia, there is usually concomitant use of corticosteroids, which can also cause dyslipidaemia.⁷³ Treatment with asparaginase may be continued despite the elevated triglycerides.⁷⁵ Patients are usually placed on a low fat diet. Fibrate drugs or plasmapheresis have also been employed to reduce the elevated triglycerides but there is no strong evidence for any particular therapy.

Summary

Coronary atherosclerosis can develop in children or adolescents and it is therefore important to detect causative factors, such as hyperlipidaemia, early in life. The atherogenic lipoprotein most likely to bring about vascular disease is low-density lipoprotein (LDL) which is formed in the circulation from very-low-density lipoprotein (VLDL). On the other hand, high-density lipoprotein (HDL) mitigates against the formation of atheroma by transporting cholesterol out of tissues.

Familial hypercholesterolaemia (FH) is an autosomal dominant condition which brings about large increases in LDL-cholesterol, which can be detected in childhood. It is relatively common (prevalence 1 in 200–350) and if left untreated, 50% of males with FH and 20% of females will develop fatal coronary heart disease before the age of sixty.¹ Once a case of FH is detected, treatment should be initiated. In children over the age of two years, this starts off with a low cholesterol, low fat diet and exercise. Later, possibly about the age of 9 years, statin therapy is instituted. In this way, the buildup of atheroma in the body is slowed and early death from myocardial infarction prevented.

Once a case of FH is identified, other family members, including children, should be tested to see if they have the condition. At the moment, FH is grossly under-diagnosed, with only a small number of cases being detected in Australia. Hopefully, ‘cascade screening’ of family members will bring about improvements in diagnosis.