J R Soc Med 2004;97:226-229
doi:10.1258/jrsm.97.5.226
© 2004 Royal Society of Medicine
Clinical management of children and young adults with heterozygous familial hypercholesterolaemia in the UK
Owen Greene BSc
Paul Durrington FRCP FMedSci
University Department of Medicine, Manchester Royal Infirmary, Oxford
Road, Manchester M13 9WL, UK
E-mail:
pdurrington{at}man.ac.uk
 |
SUMMARY
|
|---|
Life expectancy in familial hypercholesterolaemia (FH) has been
greatly
improved by the advent of statin therapy. In the UK,
however, these agents are
not licensed for use in children.
We approached 169 physicians responsible for
lipid clinics for
information on their practice in young patients, and valid
responses
were received from 54%.
A typical lipid clinic has only 3.5 patients aged under 16 with FH. In boys
aged 10-15 years 65% of physicians were prepared to treat with bile acid
sequestrants but only 23% with statins. There was greater reluctance to treat
in girls of the same age, corresponding figures being 52% and 12%.
Despite the efficacy of statins in reducing low-density-lipoprotein
cholesterol, these agents are little used in children with FH. Their safety
and clinical efficacy should be assessed by a randomized double-blind
trial.
|
INTRODUCTION
|
|---|
Familial hypercholesterolaemia (FH) is an autosomal dominant
disorder
leading to high serum concentrations of low-density-lipoprotein
(LDL)
cholesterol. LDL catabolism is delayed usually as a consequence
of a mutation
of the LDL receptor
gene.
1-3
Heterozygous FH affects
1 in 500 people and in most cases is fully penetrant.
In childhood,
when cholesterol levels are generally low, FH is the most likely
cause
of hypercholesterolaemia. It can be diagnosed from soon after
birth. In
families in which FH is running, a cholesterol exceeding
6.8 mmol/L clearly
indicates an affected child.
Heterozygous FH carries a high premature morbidity and mortality from
coronary heart disease (CHD) in adulthood, particularly in early
middle-age.5 Since
the advent of statin therapy, the life expectancy in treated FH has
dramatically
increased.6 There is
thus a cogent need to identify people with FH at an age when clinical
manifestations of CHD are still preventable. Because the condition can be
reliably detected in early childhood, there may be an argument for beginning
treatment, including cholesterol-lowering medication, at that time. Bile acid
sequestrating agents are generally considered safe in
childhood7 but are
poorly tolerated and therefore generally ineffective. One fibrate,
fenofibrate, has been licensed for use in children but its major action is to
lower triglycerides, with less effect on LDL cholesterol. The statins are
highly effective in lowering LDL cholesterol and are well tolerated, but there
is little reliable evidence about their safety in
childhood.8,9
A randomized trial would be the best approach to determine both the safety of
statins and their capacity to reverse surrogate indices of arterial disease
such as carotid intima-media thickness (IMT) measured by ultrasonography. IMT
has been shown to be abnormal in affected siblings with FH by the age of 18
years.10 In adults
the progression of IMT has been shown to be slowed with effective statin
therapy.11
To assess the feasibility of a trial in children it is essential to know
what is current clinical practice, so as to ensure that there are no ethical
or practical objections to randomizing children to placebo or statin therapy.
The present study was undertaken to determine current practice in the UK. The
investigation also covered young adults, because practice with regard to
lipid-lowering medication in young women is also undergoing great change.
|
METHODS
|
|---|
A questionnaire was sent to 169 physicians who were listed as
having
responsibility for lipid clinics in the UK. The questionnaires
(available on
request from PND) asked about the indications
for lipid-lowering drug therapy
in male and female patients
aged up to 35 years with the clinical diagnosis of
heterozygous
FH. Of the 169 physicians, 3 did not have any patients aged
less
than 35 and 10 had retired or ran joint clinics with one
of the other
physicians contacted. 84 completed questionnaires
were returned, representing
a response rate in terms of eligible
clinics of 54%.
|
RESULTS
|
|---|
Most of the children with familial hypercholesterolaemia attended
clinics
specializing in the treatment of lipid disorders; these
clinics saw few other
children. The median number of children
under the age of 16 years at each
clinic was 3.5 (interquartile
range [IQR] 0-10). In the age range 16-35 years
the median number
was 15 (IQR 5-26) at each clinic.
At few clinics was lipid-lowering medication introduced in children aged
less than 10 years, only 15% reporting this practice in boys and 11% in girls
(Figure 1). However, by the age
of 15 years the majority of clinics were employing lipid-lowering medication
(65% in boys and 52% in girls); before the age of 20 years, but not
thereafter, there was a tendency to delay lipid-lowering medication for longer
in girls than in boys. Even though the age range spanned by the questionnaire
was up to 35 years, some 30-40% of physicians were still unprepared to
prescribe lipid-lowering drugs until the serum cholesterol exceeded 8 mmol/L
(Figure 2). In their choice of
lipid-lowering medication physicians showed a clear preference for bile acid
sequestrants until the age of 16 years
(Figure 3). The reluctance to
use statins in younger patients was statistically significant with 65% (95%
confidence interval 55-75) being prepared to use bile acid sequestrants in
boys aged 10-15 years and only 23% (14-30) being prepared to use statins in
boys of a similar age. Corresponding figures for girls were 52% (41-63) and
12% (5-19) (also significantly different). The reluctance to adopt statin
therapy persisted with statistical significance until an older age in females
so that, whilst 83% (75-91) of clinics would prescribe statins to young men
aged 16-20 years, only 62% (71-72) would do so in young women in this age
group.
View larger version (20K):
[in this window]
[in a new window]
|
Figure 1. Cumulative frequency distribution of the age at which physicians would
introduce lipid-lowering medication in young people with heterozygous familial
hypercholesterolaemia
|
|
View larger version (19K):
[in this window]
[in a new window]
|
Figure 2. Cumulative frequency distribution of the level of serum cholesterol at
which the physicians surveyed would introduce cholesterol-lowering medication
in young people with heterozygous familial hypercholesterolaemia
|
|
View larger version (23K):
[in this window]
[in a new window]
|
Figure 3. Age distribution of patients in whom physicians would choose to use a
bile acid sequestrating agent (BAS) on its own or statin treatment alone or in
combination with a BAS agent.
A few physicians use fenofibrate alone in younger children (not shown).
*Alone or in combination
|
|
|
DISCUSSION
|
|---|
Untreated heterozygous FH carries a high
mortality.
1 The
increase
in death rate relative to the general population is almost
exclusively
due to CHD occurring before the age of 60
years.
5 The
condition
can result in angina or acute myocardial infarction in men from
their
early 20s. In affected women from the same family the clinical
onset of
CHD is typically some 9 years later, but can nonetheless
be remarkably early
in
life.
1,12
Even in the general population
of countries such as the UK and USA, fatty
streaks are common
in childhood and raised atheromatous lesions are evident by
early
adulthood.
13,14
In
heterozygous FH children there is no autopsy series, but tests
of
endothelial
dysfunction
15 and
carotid intima-media thickness
by
ultrasonography
10
indicate that atherosclerosis is considerably
more advanced than in children
who have not inherited FH.
The only lipid-lowering medications licensed for use in children are bile
acid sequestrating agents and fenofibrate. Bile acid sequestrants have the
potential to lower serum cholesterol
substantially16 and
can decrease coronary heart disease
risk,17 but are
rarely tolerated in adequate doses, particularly in children. Fibrate drugs,
although better tolerated, are relatively ineffective at lowering cholesterol
as opposed to triglycerides. Statin drugs, which are much more
effective18 and are
well tolerated, are not currently licensed for use in children. The use of
medication in patients under 16 years revealed by our survey seems to reflect
this restriction, bile-acid sequestrants being the most frequently employed.
Younger children were treated with statins even less frequently than with
fibrates. Thus, with fewer than one-quarter of clinicians employing statins in
patients aged less than 16 years, most children are denied effective
LDL-lowering therapy—presumably because of concerns about safety, even
though statins have proved generally safe in
adults.18
In a survey with a response rate of 54% one must be cautious in drawing
quantitative conclusions. However, even with allowance for response bias
certain findings stand out. Specialist centres are attended by only a small
number of children—an observation that may reflect a reluctance to
confirm the diagnosis or to refer young people until adulthood.
Such reluctance might be justifiable if all that was on offer at a referral
centre was unnecessary monitoring and the ineffective exhibition of
lipid-lowering drug therapy. Whilst most clinicians were prepared to use drug
therapy in children whose cholesterol was in the range 6-8 mmol/L, few of
their patients could be expected to achieve levels of cholesterol less than 6
mmol/L with bile-acid sequestrant or fibrate therapy. An earlier study in the
Oxford region revealed considerable underdiagnosis of FH in children and young
adults.19
For girls effective treatment was even less likely to be given than for
boys. A reason for this reluctance might be that physicians view CHD as a
later complication in women. However, serum lipid levels and the extent to
which preatheromatous and frankly atheromatous lesions develop are similar in
boys and girls before
adolescence.4,13,14,20,21
If drug treatment is delayed in girls beyond the age at which it is started in
boys, the question arises as to when it should be commenced. The issue is
complicated by considerations of pregnancy and contraception. Ideally, women
receiving lipid-lowering drugs should have effective contraception. Although
bile-acid sequestrants are not considered directly teratogenic, there is the
possibility that they might cause neural tube defects via an associated folate
deficiency. Women attempting to conceive could take folate supplements, but
most in our experience choose to discontinue bile-acid sequestrant
therapy—as they should be advised to do with fibrate and statin therapy.
It seems from our survey that many centres begin statin therapy in women
around the age of 20 years, well before most have any intention of starting a
family. Coupled with the advice to discontinue statins and any lipid-lowering
drug medication from the time they plan to conceive until after they have
completed breast feeding, this policy would seem logical. Even if they are not
to contemplate pregnancy until their 40s, women treated in this way will have
had 20 years of effective statin therapy. Our survey was completed before
ezetimibe became available in the UK, but clearly, if clinicians are concerned
about statin toxicity in young people, it will be many years before ezetimibe
has any major impact on prescribing practice in children, except in homozygous
FH.22
The major finding of the present study is that clinicians are not using
statins in childhood, despite their LDL-lowering efficacy. It would thus be
reasonable to conduct a placebo-controlled trial of statin treatment in
children with heterozygous FH. Children on both the active or placebo arm
could receive add-in bile-acid sequestrant therapy according to clinicians'
usual practice. The trial could be undertaken between the ages of 10 and 16 in
both boys and girls. It should be powered to establish safety and LDL
lowering, and could also have a non-invasive vascular end-point such as IMT.
In view of the excess morbidity and mortality of FH in young adults and
middle-aged people such a trial would yield important information.
|
Acknowledgments
|
|---|
We thank HEART UK and Professor S Humphries for making available
a
comprehensive list of lipid clinics in the UK, and Ms C Price
for help in
preparing the typescript.
|
REFERENCES
|
|---|
- Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia.
In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and
Molecular Bases of Inherited Disease. 7th edn. New York:
McGraw-Hill, 1995: 1981-2030
- Marks D, Thorogood M, Neil HAW, Humphries SE. A review on the
diagnosis, natural history, and treatment of familial hypercholesterolemia.
Atherosclerosis2003; 168:1
-14[Medline]
- Durrington PN. Dyslipidaemia. Lancet2003; 362:717
-31[Medline]
- Leonard JV, Whitelow AG, Wolff OH, Lloyd JK, Slack J. Diagnosing
familial hypercholesterolaemia in childhood by measuring serum cholesterol.
BMJ 1977;i:1566
-8
- Simon Broome Register Group (Scientific Steering Committee). Risk
of fatal coronary heart disease in familial hypercholesterolaemia.
BMJ1991; 303:893
-6
- Scientific Steering Committee on behalf of the Simon Broome
Register Group. Mortality in treated heterozygous familial
hypercholesterolemia: implications for clinical management.
Atherosclerosis1999; 142:105
-12[Medline]
- West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children with
familial hypercholesterolaemia treated with cholestyramine.
Lancet1980; ii:873
-5
- de Jongh S, Ose L, Szamosi T, et al. Simvastatin in
Children Study Group. Efficacy and safety of statin therapy in children with
familial hypercholesterolaemia. A randomised, double-blind, placebo-controlled
trial with simvastatin. Circulation2002; 106:2231
-7[Abstract/Free Full Text]
- Lambert M, Lupien PJ, Gagne C, et al. Treatment of
familial hypercholesterolemia in children and adolescents: effect of
lovastatin. Canadian Lovastatin in Children Study Group.
Pediatrics1966; 97:619
-28
- Wiegman A, de Groot E, Hutten BA, et al. Arterial
intima-media thickness in childhood. A study in familial hypercholesterolaemia
heterozygotes and their siblings. Lancet2004; 363:369
-70[Medline]
- Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of
aggressive versus conventional lipid lowering on atherosclerosis progression
hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial.
Lancet2001; 357:577
-81[Medline]
- Slack J. Risk of ischaemic heart disease in familial
hyper-lipoproteinaemic states. Lancet1969; ii:1380
-2
- Pathobiological Determinants of Atherosclerosis in Youth (PDAY)
Research Group. Findings from the PDAY Study. Atheroscler
Thromb 1993;13:1291
-8[Abstract/Free Full Text]
- Berenson GS, Wattigney WA, Tracey Re, et al.
Atherosclerosis of the aorta and coronary arteries and cardiovascular risk
factors in persons aged 6 to 30 years and studied at necropsy (the Bogalusa
Heart Study). Am J Cardiol1992; 70:851
-8[Medline]
- De Jongh S, Lilien MR, Op't Roodt J, Stroes ES, Bakker HD,
Kastelein JP. Early statin therapy restores endothelial function in children
with familial hypercholesterolaemia. J Am Coll Cardiol2002; 40:2117
-21[Abstract/Free Full Text]
- Betteridge DJ, Bhatnagar D, Bing D, et al. Treatment of
familial hypercholesterolaemia. The United Kingdom lipid clinics study of
pravastatin and cholestyramine. BMJ1992; 304:1335
-8
- Lipid Research Clinics Program. The Lipid Research Clinics Coronary
Primary Prevention Trial results. I Reduction in incidence of coronary heart
disease. JAMA1984; 251:351
-64[Abstract/Free Full Text]
- Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis. BMJ2003; 326:1423
-7[Abstract/Free Full Text]
- Neil HAW, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of
diagnosis of familial hypercholesterolaemia in routine practice: prospective
registry study. BMJ2000; 321:148[Free Full Text]
- Thompson GR, Miller JP, Breslow JL. Improved survival of patients
with homozygous familial hypercholesterolaemia treated with plasma exchange.
BMJ1985; 295:1671
-3
- Christensen B, Glueck C, Kwiterovich P, et al. Plasma
cholesterol and triglyceride distributions in 13,665 children and adolescents:
the prevalence study of the Lipid Research Clinics Program. Pediat
Res 1980;14:194
-202[Medline]
- Gag
e C, Bays HE, Weiss SR, et al. Ezetimibe Study
Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for
treatment of patients with primary hypercholesterolemia. Am J
Cardiol 2002;90:1084
-91[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
P. Durrington
NICE guidance for identification and treatment of familial hypercholesterolaemia: Commentary 2
Heart,
April 1, 2009;
95(7):
589 - 591.
[Full Text]
[PDF]
|
|
|
TOP
SUMMARY
INTRODUCTION
