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Familial hypercholesterolemia in childhood: diagnostics, therapeutical optionsand risk stratification

Rodenburg, J.

Publication date2005

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Citation for published version (APA):Rodenburg, J. (2005). Familial hypercholesterolemia in childhood: diagnostics, therapeuticaloptions and risk stratification.

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C h a p t e r

Familial hypercholesterolemia in children

J. Rodenburg3, M.N. Vissers", A. Wiegmanb, M.D. Tripc, H.D.

Bakker andJJ.P. Kastelein3

"Department of Vascular Medicine, Emma Children's Hospital and cDepartment of Cardiology, Academic Medical Centre, University of Amsterdam, The Netherlands

Curr Opin Lipidol 2004;15:405-11

Chapter 1

Purpose of this review This review provides an update on recent advances in the diagnosis and management

of children with familial hypercholesterolemia.

Recent findings A large cross-sectional cohort study of paediatric familial hypercholesterolemia

demonstrated that affected children had a 5-fold more rapid increase of carotid arterial

wall intima-media thickness during childhood years than their affected siblings. This

faster progression led to a significant deviation in terms of intima-media thickness

from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a

strong and independent predictor of carotid artery intima-media thickness in these

children, which confirms the pivotal role of low-density lipoprotein cholesterol for

the development of atherosclerosis. In this condition lipid lowering by statin therapy

is a c c o m p a n i e d by caro t id i n t i m a - m e d i a th ickness r eg ress ion in familial-

hypercholesterolemic children, which suggests that initiation of low-density lipoprotein

cholesterol-reducing medication in childhood already can inhibit or possibly reduce

the faster progression of atherosclerosis. Furthermore, these trials demonstrated that

statins are safe and do not impair growth or sexual development in these children.

Conversely, products containing plant sterols reduced low-density l ipoprotein

cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by

flow-mediated dilatation.

Summary Children with familial hypercholesterolemia clearly benefit from lipid-lowering

strategies. Statins are safe agents and have been proven to reduce elevated low-density

lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers

for atherosclerosis. Therefore these agents should become the pivotal therapy in children

with familial hypercholesterolemia.

22

Familial hypercholesterolemia

Introduction

Familial hypercholesterolemia is a common and inherited metabolic disorder of

lipoprotein metabolism. Clinically, familial hypercholesterolemia is characterized by

elevated levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C)

from birth onwards, due to mutations in the LDL receptor gene . The elevated levels

of total cholesterol and LDL-C strongly predisposes to the early initiation of

atherogenesis and premature cardiovascular disease (CVD), which can already be

observed in children with familial hypercholesterolemia.

In this review we describe recent advances in the diagnosis and management of children

with familial hypercholesterolemia which have been published since early 2003. In

previous years, most studies focused on treatment of these children. This resulted in

a paradigm shift from screening, diagnosis, and treatment with bile acid-binding resins

to better risk stratification and improved treatment through 3-hydroxy-3-methylglutarvl-

CoA reductase (HMG-CoA reductase) inhibitors (statins) and cholesterol-absorption-

inhibitor (ezetimibe, plant sterols and stanols) therapy.

Risk stratification

Although familial hypercholesterolemia is a monogenic disorder, mortality varies to a

large degree among adult patients with the disorder ' . Additional genetic and

environmental risk factors for CVD might determine the variable expression in patients

with this disorder. Identification of these risk factors could lead to a more efficacious

intervention strategy with lipid-lowering drugs or modification of lifestyle at a young

age. Wiegman et al. assessed the diagnostic value of LDL-C levels and were the first

to determine the best available cut-off value to diagnose familial hypercholesterolemia

in a cohort of more than 1000 children of familial hypercholesterolemia relatives.

LDL-C levels below 3.5mM were only found in 4 .3% of children with a mutation in

the LDL-receptor gene. Therefore, in familial hypercholesterolemia families, the

de te rmina t ion of LDL-C levels can reliably establish a diagnosis of familial

hypercholesterolemia in children. Furthermore, Wiegman et al. observed that variations

23

Chapter 1

in I D L - C but also in high-density lipoprotein cholesterol (HDL-C) and lipoprotein (a) in

these children were associated with higher incidence of premature CVD in relatives.

Familial-hypercholesterolemic children with LDL-C levels > = 6.2 mM had a familial-

hypercholesterolemic parent with premature onset of CVD 1.7 times more often. Children

with HDL-C levels below 1.0 mM had a familial-hypercholesterolemic parent with

premature onset of CVD 1.8 times more often, and children whose lipoprotein (a) was

> = 300 mg/dl had a familial-hypercholesterolemic parent with premature CVD 1.5 times

more often. So, children with premature CVD among first relatives had higher LDL-C,

lower HDL-C and higher lipoprotein (a) levels. This suggests that when a diagnosis of

familial hypercholesterolemia is certain in a family, simple measurement of the most

important lipoproteins, LDL-C, HDL-C and lipoprotein (a), allows not only an accurate

diagnosis of familial hypercholesterolemia in childhood but also can lead to identification

of familial-hypercholesterolemia families with the highest risk of premature CVD .

LDL-C levels vary between children with familial hypercholesterolemia, as a result of

both environmental and genetic factors. In the general population the variability of

LDL-C levels is partly influenced by polymorphisms in the Apo £ gene 3. In particular,

the £ 4 allele is associated with higher, and the e 2 with lower, total cholesterol and

LDL-C levels " . Variation at the apoE gene locus might account for as much as 14%

of the genetically determined variation in total cholesterol D' . However, in children

with familial hypercholesterolemia, the presence of the 8 4 allele did not contribute to

the differences in LDL-C levels 10 but, strikingly, the £ 4 allele did explain 7 3 % of the

variance in HDL-C levels. The presence of an £ 4 allele was also associated with lower

HDL-C levels in an affected sib-pair analysis, which suggested that the £ 4 allele carries

an additional disadvantage for familial-hypercholesterolemic children . This

inconsistency between adult and paediatric studies might be explained by the fact that

in an affected sib-pairs analysis the results are independent of additional familial factors.

Surrogate markers for atherosclerosis

Endothelial dysfunction and increased intima-media thickness (IMT) have both been

validated as predictive for future CVD . In children with familial hypercholesterolemia

24


endothelial function is impaired ' ~, particularly in those children with a positive family

history of premature CVD . Furthermore, children with familial hypercholesterolemia

are also characterized by an increased IMT when compared with healthy controls ' .

In fact, familial-hypercholesterolemic children had a 5-fold more rapid increase of

carotid arterial wall IMT during childhood years than their affected siblings . This

increase led to a significant deviation in terms of IMT values from the age of 12 years

onwards. LDL-C proved a strong and independent predictor of carotid artery IMT,

highlighting the pivotal role of this lipoprotein for the development of atherosclerosis

in this condition already at a young age . Therefore, it might be suggested to measure

carotid artery IMT as a marker of the increased atherosclerotic burden. This might

assist in the decision of when to start lipid-lowering medication in children with familial

hypercholesterolemia .

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins)

By far the preferred drugs in the treatment of hypercholesterolemia in adults are

HMG-CoA reductase inhibitors (statins). The use of these agents has been proven to

be effective and safe in adults, and therefore they could also be beneficial for

hypercholesterolemic children. Yet, most statins have not been registered for children

and the recommended lipid-lowering therapy for familial-h)percholesterolemic children 20

above 10 years consists of diet and bile acid-binding resins . However the lipid-

lowering efficacy of bile acid-binding resins is modest (10-15%) and the long-term 21 -23

compliance is poor, mostly due to side effects " .

24 32

In previous years, several controlled and uncontrolled trials " have demonstrated

the efficacv and short- and longer-term safety of statin therapy in children and

adolescents with heterozygous familial hypercholesterolemia (Table 1). In the past

year, two additional trials have been published with statins in hypercholesterolemic

children. First, it was shown that 40 mg of atorvastatin reduced LDL-C by 40% after 7 7

26 weeks of treatment as compared with placebo . Second, in a 1-year uncontrolled

trial, 5 mg of simvastatin reduced LDL-C by 25%, 10 mg reduced LDL-C by 30% and

25

Chapter 1

20 mg reduced LDL-C by 36% " . This study demonstrated that even low doses of

statins reduce LDL-C levels effectively. Taken together, these data ' show that

statin therapy is both effective and safe in the short term in children with familial

hypercholesterolemia.

Table 1. Trials with Statins in Children with Familial Hypercholesterolemia

No of subjects randomised

Trial Treatment placebo statin mean age follow-up Mean reference (year published) y (range) (week) LDI.-C

reduction

Athyros (2002) (letter)

Couture (1998)

Mc Candle (2003)

Dirisamer (2003)

Ducobu (1999) (letter)

dejongh (2002)

Knipschcer (1996)

atorvastatin 10-20-40 mg

simvastatin 20 mg

atorvastatin 10-20 mg

simvastatin 5-10-20 mg



pravastatin 5-10-20 mg

Lambert (1996) lovastatin 10-20-30-40 mg

Sinzinger (1992)) (letter)

Stein (1999)

Stefanutti (1999)

Wiegman (2004)

lovastatin 20 mg

lovastatin 10-20-40 mg

simvastatin 10 mg

pravastatin 20-40 mg

16

47

69

18

65 (male)

8

108

16 (male)

47

140

20

32 (male)

106

54

69 (male)

9

67 (male)

8

106

13 (10-17)

12,6 (8-17)

14,1 (10-17)

13 (10-17)


Furthermore, statins not only reduce LDL-C levels, but also improve surrogate markers

of atherosclerosis. Reversal of endothelial dysfunction as well as regression of IMT

upon lipid reduction reflects an improvement of the atherosclerotic process ^ . Statin

therapy significantly improved endothelial dysfunction in children with familial -5-7

hypercholesterolemia after 28 weeks of therapy* . In adult familial-hypercholesterolemia

patients, aggressive lipid lowering by statins was even accompanied by carotid IMT

regression " . This suggested that initiation of lipid-lowering medication in childhood

inhibits progression or might even lead to regression of atherosclerosis. Therefore, a

placebo-controlled trial in 214 children (8-17 years) with familial hypercholesterolemia

was performed, to measure the effect of 2-year pravastatin therapy on IMT. As expected,

pravastatin (20-40 mg) reduced LDL-C levels by 24% but, strikingly, 2 years of pravastatin

led to regression of carotid IMT compared with placebo " . This shows that the increased

arterial wall thickness, and similarly endothelial dysfunction as present in children with

familial hypercholesterolemia ' , are reversible.

Pharmacokinetics and pharmacodynamics of statins

The pharmacokinetics of statins have been widely studied in healthy adults and patients

with hypercholesterolemia . In order to formulate a rational dosing regimen for

children, such studies had to be carried out in children as well. In fact, two trials have

now described the single-dose pharmacokinetics of pravastatin in children; one with

a single dose of 10 mg pravastatin in 20 children with familial hypercholesterolemia,

aged 5-16 years, and another with a daily dose of 20 mg pravastatin in 24 children with

familial hypercholesterolemia, aged 8-16 years. In fact, pravastatin 10 mg was absorbed

rapidly and the mean maximum concentration was 15.7 ng/ml . The mean half-life of

pravastatin was 1.6 h and the plasma levels were below the detection limit 10 h after

dosing. Pravastatin (20 mg) showed a mean maximum concentration of 52.1 ng /ml in

8-10-year-old children and 31.7 ng /ml in 11-16-year-olds . The mean half-life was

2.5 h in bo th groups. T h e invest igators of bo th studies concluded that the

pharmacokinetic profile of pravastatin in children was similar to that reported in

adults. However, these data cannot be extrapolated to other statins, since pravastatin

is not metabolized by cytochrome P450, in contrast to most other statins.

2"

Chapter 1

Psychosocial aspects of statin use in children

In the more distant past, numerous studies have shown that the emotional impact of

p remature death of an affected parent is much greater than having familial

hypercholesterolemia per se " . As lipid reduction is a life-long prerequisite for

famiBal-hypercholesterolemic children, the question arises about what the consequences

of statin therapy in these children are with respect to anxiety, quality of life and concerns.

A recent study evaluated the influence of simvastatin on psychosocial functioning in

69 children with familial hypercholes terolemia (mean age, 15.3 years). They

demonstrated that 46% of the children with familial hypercholesterolemia suffer from

the fact that they have the disease, but 62% felt safer by taking the medication and

8 1 % expressed that they would not mind taking the medication for their whole life .

So, statin treatment does not seem to negatively influence the psychosocial functioning

of children with familial hypercholesterolemia.

Inhibitors of cholesterol absorption

In contrast to statins, which inhibit cholesterol synthesis in the liver, drugs are now

available that reduce cholesterol absorption in the intestine. Ezetimibe is a novel

cholesterol-lowering agent that prevents the absorption of cholesterol and plant sterols

at the brush border of the small intestine by inhibiting the passage of sterols of

dietary and biliary origin across the intestinal wall. Two target mechanisms for this

drug have recently been proposed, namely the Niemann-Pick CI-like 1 protein

(NPC1L1) 48 and the annexin-caveolin 1 complex ; both seem to be associated with

the regulation of intestinal sterol metabolism. Other agents that reduce cholesterol

absorption are plant sterols and stanols, which inhibit the solubility of cholesterol in

micelles and thereby decrease its absorption n ' . The reduction in cholesterol

absorption leads to a decrease in the amount of intestinal cholesterol presented to the

liver. As a result, there is a compensatory increase in the production of endogenous

cholesterol and an increase of the LDL-receptor expression. The net effect is a

reduction of LDL-C levels ' ".

28


A daily intake of 10 mg of ezetimibe reduces LDL-C levels by approximately 18% in

adul ts ' . A l t h o u g h eze t imibe has already been reg i s t e red for familial

hypercholesterolemia children older than 10 years, it has not been adequately studied

in this group of patients. Therefore, such studies are needed to assess the efficacy and

safety of ezetimibe in children with familial hypercholesterolemia and confirm the

data obtained in adults.

A new trend is the enrichment of food products with plant sterols and stanols. A daily

consumption of 2 g of plant sterols or stanols reduces cholesterol levels by approximately

10% in adults as well as in children with familial hypercholesterolemia " . I n short-

term studies plant sterols and stanols seemed to be safe in children with familial

hypercholesterolemia ' . In line with these data, de Jongh et al. showed that an

intake of 2.3 g/day of plant sterols decreased LDL-C by 14% as compared with the

placebo in young familial-hypercholesterolemic children (5-12 years). However, in 37

contrast to statin therapy , plant sterol consumption did not improve endothelial

dysfunction in these children. The authors suggested that the absence of vascular

effects during sterol therapy might imply a threshold of LDL-C reduction before

improvement of endothelial function can occur. Also, statins might exert direct

'pleiotropic' effects on the vasculature and the absence of an effect on flow-mediated

dilatation of the brachial artery during sterol use might also be the consequence of a

lack of pleiotropic effects of sterols.

As the chemical structures of plant sterols and stanols are very similar to cholesterol ''",

absorption of these compounds might be atherogenic. However, the absorption of

plant sterols and stanols is at least less than 5% and less t han l%, respectively, whereas

that of cholesterol varies from 35 to 70% ' . Furthermore, plant sterols and stanols

cannot be synthesized in the body, and generally the serum concentrations of plant

sterols and stanols are very low; less than 1% plant sterols are found in the serum

sterol fraction in healthy humans "' . Earlier studies demonstrated that plant sterol

consumption increased plasma plant sterol concentrations in children whereas plant

stanol consumption decreased plasma plant sterol concentration ' . Therefore,

Ketomaki et al. ' investigated the changes in ratios of plant sterols and stanols to

cholesterol in red cells and plasma after consumption of plant sterols and stanols in

29

Chapter 1

hypercholesterolemia children. Plant sterol consumption increased and plant stanol

consumption decreased the ratios of plant sterols to cholesterol in red cells. The

authors ' suggest that even though the safety of plant sterol ester spreads has been

evaluated in long-term and short-term studies, the long-term effects on red cells and

vascular endothelial cells need further investigation.

Diet

Cholesterol-lowering therapy in familial-hypercholesterolemic children starts with

dietary intervention and life-style modification. However, most trials demonstrated

that the lipid-lowering effect of diet is modest and moreover that long-term compliance

is poor . In a recent prospective study, Sanchez-Bayle and Soriano-Guillen

demons t ra ted that a fat-restricted diet with a mean durat ion of 7.4 years in 71

hypercholesterolemia children reduced LDL-C by 24% without affecting growth . In

contrast with this unexpectedly high result, Engler etal. showed that a 6-week National

Cholesterol Education Program (NCEP) Step II diet reduced LDL-C only by 8% in 15

hyperlipidemic children. The discrepancy between those studies in LDL-C-lowering effect

of diet might be due to differences in study design and diet restrictions, which were

more stringent in the first study. Apart from the LDL-C reduction, Engler et al. found

that supplementation of 500 mg/day of vitamin C and 400 i.u./l of vitamin E improved

endothelial function whereas diet alone did not . The authors suggested that antioxidants

are beneficial supplements in addition to diet. However, results of antioxidant vitamins

in long-term efficacv trials in adults are controversial to say the least " , and treatment

of familial-hypercholesterolemic children should, in our opinion, be focused on LDL-C

reduction rather than on antioxidant treatment, in particular as -carotene in adults

has been associated with pulmonary cancer .

30


Conclusion

In the last decade, research in familial hypercholesterolemia in children has focused

on the efficacy and safety of statins as well as on the effects of statins on surrogate

endpoints of CVD. Several studies have demonstrated excellent LDL-C-lowering

efficacy as well as reassuring safety of these drugs in prepubertal and pubertal children

with familial hypercholesterolemia (Table 1). LDL-C reductions were of course

dependent on the dosage and the particular statin but, more importantly, the reductions

were much larger than those obtained with other treatments such as bile acid-binding 21 78 79

resins ' ' . Furthermore, statins not only reduced LDL-C levels, but also improved

surrogate markers of atherosclerosis. Statins had already been shown to improve

endothelial function in familial-hypercholesterolemic children " , and recently Wiegman

et al. ' showed that 2-year pravastatin treatment also reduced the carotid IMT compared

to placebo. All these data together stress the need and opportunity for early treatment

of familial hypercholesterolemia children in order to reverse the progress of

atherosclerosis as early as possible.

It is still unclear at what age statin therapy should be initiated. The age of the youngest

patients in the studies varied from 4 to 10 years (Table 1), which indicates that patients can

be treated safely from an age of 10 years onwards. However, as prepubertal children with

familial hypercholesterolemia are already characterized with endothelial dysfunction at the

age of 5 years ' and IMT already deviates from normal from an age of 12 years 19,

treatment of children younger than 10 years should be debated and investigated.

Cholesterol-absorption inhibitors such as ezetimibe or plant sterols and stanols

coadministrated with a statin offer new options in the treatment of adult patients with

familial hypercholesterolemia . This combination therapy may also be beneficial

for children for a number of reasons. First, low doses of statins coadministrated with

cholesterol absorption inhibitors may result in an increased efficacy and therefore

easier-to-reach target LDL-C levels. Secondly, it may avoid uptitration to high doses

of statins, thereby minimizing the chance of statin-associated side effects. Unfortunately,

to date there are no results on the efficacy and safety of ezetimibe, either combined

with statins or alone, in children with familial hypercholesterolemia, and these studies

31

Chapter 1

are urgently needed. Furthermore, treatment with food products containing plant sterols

or stanols alone reduce LDL concentrations by 10-15% in children with familial

hypercholesterolemia 37>56>57>83) but in contras t to statin therapy, plant sterol

consumption did not improve endothelial dysfunction' . This implies that plant sterol

or stanols alone might not be efficacious enough to reduce the progression of

atherosclerosis in children with familial hypercholesterolemia, but in combination with

statins they might be additive 84. Therefore, future studies in paediatnc familial

hypercholesterolemia should focus on combination therapy of statins with cholesterol

absorption inhibitors, like ezetimibe, plant sterols or stanols.

Furthermore, the advent of more potent statins will allow us to reach more stringent

L D L - C goals in an even-increasing n u m b e r of children with familial hyper-

cholesterolemia 85,86. Such low LDL-C levels obtained from a young age onwards

might raise the hope that when familial-hypercholesterolemic children reach adulthood

their CVD risk is virtually eliminated since they will have normal LDL-C levels, restored

endothelial function and normal carotid IMT values. This should be the ultimate goal

in the management of paediatric familial hypercholesterolemia.

In summary, statins and cholesterol absorption inhibitors seem efficacious and safe in

children with familial hypercholesterolemia; however, more long-term studies are

required with statins as well as with combination therapy to restore function and

morphology of the arterial walls in these children.

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33

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Chapter 1

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86. Jones PH, Davidson MH, Stein EA, et a! Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). AmJ Cardiol 2003; 92:152-160.

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UvA-DARE (Digital Academic Repository) Familial hypercholesterolemia … · Familial hypercholesterolemia endothelial function is impaired ' ~, particularly in those children with