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Adv Ther (2012) 29(5):456-463.DOI 10.1007/s12325-012-0021-0
ORIGINAL RESEARCH
The Detection of Heterozygous Familial Hypercholesterolemia in Ireland
Maurice J. O’Kane · Ian B. Menown · Ian Graham · Vincent Maher · Gerald Tomkin · Paul Nicholls ·
Colin Graham
On behalf of the Irish Atherosclerosis Society
To view enhanced content go to www.advancesintherapy.comReceived: March 2, 2012 / Published online: May 17, 2012© Springer Healthcare 2012
ABSTRACT
Heterozygous familial hypercholesterolemia
(HeFH) is an autosomal dominant condition
with a population prevalence of 1 in 500, and
is associated with significant cardiovascular
morbidity and mortality. It may be caused by
mutations in the low-density lipoprotein (LDL)
receptor, apolipoprotein B100 (Apo B100),
or proprotein convertase subtilisin/kexin
type 9 (PCSK9) genes, with over 1,000 causative
mutations described. Statin therapy in HeFH is
considered effective and safe. Audit data suggest
that approximately 80% of the putative HeFH
population remains unidentified and, therefore,
there is a need to develop a strategy for the
identification of affected individuals so that early
lipid-lowering treatment may be offered. There
is good evidence showing the effectiveness and
acceptability of HeFH screening programs in
Europe. The authors describe a protocol for an
all island approach to HeFH detection in the
Republic of Ireland/Northern Ireland. Index
cases will be identified by opportunistic screening
using the Simon Broome, or Make Early Diagnosis
to Prevent Early Death (MedPed) and World
Health Organization (WHO) criteria. Patients
identified as “definite,” “probable,” or “possible”
M. J. O’Kane (*) Clinical Chemistry Laboratory, Altnagelvin Hospital, Londonderry, Northern Ireland e-mail: Maurice.OKane@westerntrust.hscni.net
I. B. Menown Craigavon Cardiac Centre, Southern Health and Social Care Trust, Craigavon, Northern Ireland
I. Graham Charlemont Cardiology, Charlemont Clinic, Charlemont Mall, Dublin 2, Ireland
V. Maher Division of Cardiology, Department of Medicine, The Adelaide and Meath Hospital, Trinity College Dublin, Tallaght, Ireland
Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com
G. Tomkin Diabetes Institute of Ireland, Beacon Hospital Dublin 18 and Trinity College Dublin, Dublin 2, Ireland
P. Nicholls Lipid Clinic, Royal Victoria Hospital, Belfast, Northern Ireland
C. Graham Regional Medical Genetics Laboratory, Belfast City Hospital, Belfast, Northern Ireland
Adv Ther (2012) 29(5):456-463. 457
affected males develop heart disease by age 50
and die by age 60, with similar figures for
woman at ages 60 and 70 years, respectively) [4].
FH may be caused by mutations in the low-density
lipoprotein (LDL) receptor, or apolipoprotein
B100 (Apo B100), and proprotein convertase
subtilisin/kexin type 9 (PCSK9) genes, with
over 1,000 causative mutations described [5].
Adult patients with HeFH typically have
serum cholesterol concentrations in the range
7.5–15.0 mmol/L [5]. Homozygous FH is very
rare (reported prevalence less than one case in a
million) with patients having a much more severe
phenotype, typically with serum cholesterol
concentrations in the range 20–30 mmol/L,
and the development of ischemic heart disease
in teenage years [6]. Due to its much higher
prevalence, this paper will focus on the detection
of HeFH.
At present, the great majority of patients
with HeFH are undiagnosed. Audit data from the
Northern Ireland lipid clinics and the Regional
Medical Genetics Centre suggest that only about
20–25% of the putative HeFH population has
been identified (unpublished data), and this
figure is in line with data reported elsewhere [5].
Although individual patients with undiagnosed
HeFH may be receiving lipid-lowering treatment
for secondary or primary prevention of CVD, the
failure to make a specific diagnosis of HeFH will
result in a missed opportunity to identify and
treat the condition in family members (half of
whom will be affected).
There is robust evidence that statin therapy
lowers LDL cholesterol in HeFH patients and,
although there have been no mortality outcome
studies specifically targeting HeFH patients, there
is no reason to believe that the clinical efficacy
will differ from that in non-HeFH patients [7].
Given the high morbidity and mortality
associated with HeFH and the present low
detection rates, the challenge is to develop
HeFH criteria will be offered genetic testing.
The authors expect causative mutations to be
identified in approximately 80% of patients
with “definite” HeFH but in only approximately
20% of patients with “possible” HeFH. Cascade
screening will be undertaken in first-degree
relatives of the index case using genetic testing
(where a causative mutation has been identified),
or otherwise using LDL cholesterol concentration.
The establishment of a HeFH screening program
on an all-island basis will require: expansion of the
existing molecular genetics diagnostic services,
the establishment of a cohort of nurses/genetic
counselors, a HeFH database to support cascade
testing, the development of a network of lipid
clinics (in a primary or secondary care setting),
and an educational initiative to raise awareness
of HeFH among healthcare professionals and the
general population.
K e y w o r d s : D e t e c t i o n ; F a m i l i a l
hypercholesterolemia; Ireland; Lipid clinics;
Primary healthcare; Screening
INTRODUCTION
Atherosclerotic cardiovascular disease (CVD)
remains the biggest cause of death in the island
of Ireland and is a major cause of disability [1, 2].
The most important causal risk factors are cigarette
smoking, high blood pressure, and hyperlipidemia,
although risk factors often coexist to increase
vascular risk. Furthermore, hyperlipidemia may
have a genetic or nutritional basis.
Heterozygous familial hypercholesterolemia
(HeFH) is a genetically linked condition
(autosomal dominant) with a prevalence of 1 in
500 in the population and results in premature
vascular disease [3]. It is among the commonest
of all inherited single gene disorders and is
associated with significant morbidity and
mortality (approximately 50% of all untreated
458 Adv Ther (2012) 29(5):456-463.
PROPOSAL FOR HeFH DIAGNOSIS IN THE ISLAND OF IRELAND
Diagnosis of Index Cases
Various criteria exist for the clinical diagnosis of
HeFH (Simon Broome criteria [Table 1] [8], Dutch
Lipid Clinic criteria [9], and Make Early Diagnosis
to Prevent Early Death [MedPed]/World
Health Organization [WHO; Table 2] [10,11]),
all of which are based on the serum
cholesterol/LDL concentrations in the index
case, personal and family history of premature
ischemic heart disease, family history of
hypercholesterolemia, and the presence of
cutaneous stigmata of dyslipidemia (tendon
xanthomata, arcus cornealis).
The Simon Broome criteria (Table 1), which
are widely used in Britain and Ireland, classify
patients into “definite” or “possible” HeFH,
a strategy that will identify affected patients
so that they can be offered early treatment.
Although the island of Ireland encompasses
two separate political jurisdictions (Republic of
Ireland and Northern Ireland) and, therefore,
two different healthcare systems, there is
considerable merit in adopting an all island
approach to HeFH detection. First, from a
genetic perspective, the population is relatively
homogeneous with a limited array of causative
mutations accounting for the majority of cases,
which will facilitate genetic testing. Second,
many affected kindred straddle the two
jurisdictions and it is important that a family-
based approach to screening is not limited by
a land border. Third, an all-island approach to
HeFH detection will permit the consolidation
of expertise in clinical and laboratory teams.
In this paper, the authors propose a protocol
for the detection of HeFH in the island of Ireland.
Table 1 Simon Broome criteria for the diagnosis of familial hypercholesterolemia [8]
Definite familial hypercholesterolemia
Total cholesterol > 6.7 mmol/L or LDL cholesterol > 4.0 mmol/L in a child aged < 16 years, or total cholesterol > 7.5 mmol/L or LDL cholesterol > 4.9 mmol/L in an adult (either levels pre-treatment or highest on treatment)
Plus
Tendon xanthomata in patient or in first-degree relative (parent, sibling, child) or in second-degree relative (grandparent, uncle, or aunt)
Or
DNA-based evidence of an LDL receptor mutation, familial defective apo B, or a PCSK9 mutation
Possible familial hypercholesterolemia
Total cholesterol > 6.7 mmol/L or LDL cholesterol > 4.0 mmol/L in a child aged < 16 years, or total cholesterol > 7.5 mmol/L or LDL cholesterol > 4.9 mmol/L in an adult (either levels pre-treatment or highest on treatment), and at least one of the following:
Family history of myocardial infarction: < 50 years of age in second-degree relative, or < 60 years of age in first-degree relative
Or
Family history of raised total cholesterol: > 7.5 mmol/L in first or second-degree relative, or > 6.7 mmol/L in child or sibling aged < 16 years.
Apo B apolipoprotein B, LDL low-density lipoprotein, PCSK9 proprotein convertase subtilisin/kexin type 9
Adv Ther (2012) 29(5):456-463. 459
while the MedPed and WHO criteria (Table 2)
have an additional category of “probable”
HeFH [8, 10, 11]. A diagnosis of “definite”
HeFH requires the presence of tendon
xanthomata in the patient or a first/second-
degree relative, or a DNA-based diagnosis.
Although the finding of tendon xanthomata is
virtually pathognomonic of FH, their presence
is variable (found in 8–70% of patients by age
30 years) and, therefore, their absence does
not exclude the diagnosis [12].
In patients with a diagnosis of “definite”
HeFH using Simon Broome criteria, a causative
mutation can be identified in > 80% [13, 14].
For patients with a diagnosis of “possible”
HeFH, a causative mutation will be identified
in only 20% [7, 8]. Using genetic diagnosis
as the reference standard, a Danish study
suggested that the Simon Broome criteria
have a sensitivity of 34% and specificity
of 89% [15].
Case Finding and Screening for HeFH
There is broad agreement that familial
hypercholesterolemia fulfills the Wilson and
Jungner criteria for a valid screening program [16].
There are a number of possible approaches to
case finding and screening.
• Population screening. The phenotypic and
genotypic variability of FH combined with
a prevalence rate, which is low in absolute
terms, means that population screening is
unlikely to be cost-effective [8]. This is the
Table 2 MedPed and WHO criteria for clinical diagnosis of HeFH [10, 11]
Criteria Score
Family history First-degree relative known with premature coronary artery disease and/or first-degree relative with LDL cholesterol > 95th centile 1
First-degree relative with tendon xanthomata and/or children < 18 years with LDL cholesterol > 95th centile 2
Clinical history Patient has premature coronary artery disease 2
Patient has premature cerebral/peripheral vascular disease 1
Physical examination Tendon xanthomata 6
Arcus cornealis < 45 years of age 4
LDL cholesterol, mmol/L > 8.5 8
6.5–8.4 5
5.0–6.4 3
4.0–4.9 1
Definite FH Score > 8
Probable FH Score 6–8
Possible FH Score 3–5
No diagnosis Score < 3
FH familial hypercholesterolemia, HeFH heterozygous familial hypercholesterolemia, LDL low-density lipoprotein, MedPed Make Early Diagnosis to Prevent Early Death, WHO World Health Organization
460 Adv Ther (2012) 29(5):456-463.
case even in those populations with a higher
prevalence due to a “founder effect” [14].
• Systematic case finding. This refers to a
systematic interrogation of clinical databases
or case-note review to identify patients
who fulfill the diagnostic criteria for HeFH.
However, there is little evidence available on
the effectiveness of this approach [17].
• Opportunistic case finding followed by
cascade screening. Opportunistic case
finding refers to the consideration of HeFH
as a diagnosis in a patient presenting
with suggestive features, e.g., a serum
cholesterol concentration > 7.5 mmol/L in
the setting of a personal or family history
of premature coronary heart disease. The
diagnosis may be made on clinical criteria
using Simon Broome or MedPed/WHO
criteria and confirmed with genetic testing
as appropriate [11]. Cascade screening
refers to screening for HeFH in the first-
degree relatives of an index case and is the
approach advocated both by the recent
European Society for Cardiology/European
Atherosclerosis Society guidelines and
National Institute for Health and Clinical
Excellence (NICE) [4, 11]. Screening is
cascaded as secondary index cases are
identified. In HeFH, cascade screening may
be undertaken using either phenotypic or
DNA testing (where the causative mutation
has been identified in the index case).
Phenotypic cascade screening uses age
and gender - spec i f i c cho le s te ro l /LDL
concentrations to assess the likelihood of
having inherited the condition [18]. Cascade
screening on phenotypic criteria has a
sensitivity of 67–93% and a specificity of
74–94% [18]. In contrast, in those kindred
where the causative mutation has been
identified, DNA screening of first-degree
relatives can be undertaken with a sensitivity
and specificity of 100%. However, it must be
remembered that the causative mutation will
be identified in around only 80% of patients
diagnosed as “definite” HeFH and 20% of
patients diagnosed as “possible” HeFH using
Simon Broome criteria [13].
IS CASCADE SCREENING EFFECTIVE?
Research from the Netherlands using DNA-
based cascade screening demonstrated an
increase in the use of lipid-lowering therapy
in affected individuals from 39–93% at 1 year
[19, 20]. In a UK study based on cholesterol
measurement in first-degree relatives of patients
with “definite” or “possible” HeFH attending a
hospital lipid clinic, cascade screening yielded
a positive diagnostic rate of approximately 30%
of those tested. It increased the prevalence
of the condition to about one-third of the
putative HeFH population in the hospital
catchment area [21]. Another UK study also
using cholesterol measurements in first-degree
relatives of patients with “definite” HeFH
attending a hospital lipid clinic found that
cascade screening coordinated through a clinic
nurse had a diagnostic yield of 60% for new
cases [22]. These findings suggest that cascade
screening by DNA or lipid criteria is feasible
and results in the identification and treatment
of previously undiagnosed HeFH cases.
There have been a number of studies assessing
the cost-effectiveness of cascade screening using
DNA or phenotypic criteria. A recent analysis
by NICE suggested that the most cost-effective
strategy was DNA cascade screening in kindreds
with an identified mutation in the index case
combined with lipid-based cascade screening
in mutation negative “definite” and “possible”
HeFH patients [4].
Adv Ther (2012) 29(5):456-463. 461
Proposal
Due to the high prevalence of HeFH and
the associated morbidity and mortality, it is
proposed that identification and screening for
HeFH should take place in the island of Ireland.
A diagnosis of HeFH should be considered, in
an opportunistic manner, in patients with a
personal or family history of premature CVD
or hypercholesterolemia following exclusion
of secondary causes of dyslipidemia. This
would be the responsibility both of primary
healthcare providers and secondary healthcare
teams managing CVD. Simon Broome [4] or
MedPed/WHO [11] criteria should be used to
identify patients with “definite,” “probable,”
or “possible” HeFH who should be referred
to the lipid clinic service for assessment
and DNA testing where appropriate (Fig. 1).
Where a diagnosis of “definite” HeFH has
been made either on clinical grounds or by
DNA testing, cascade screening would be
undertaken by a FH nurse/genetic counselor
linked to each lipid clinic. Cascade screening
would be undertaken using DNA testing where
a causative mutation has been identified in
the index case, otherwise using lipid criteria.
For children of an affected parent, screening
should be carried out by the age of 10 years [4].
Affected individuals identified by cascade
screening would be referred either to their
primary healthcare provider or to the lipid
clinic for treatment, using a common, agreed
clinical management algorithm.
Infrastructure Requirements
The implementation of a HeFH cascade screening
programs requires an infrastructure comprising
four main elements.
1. Familial hyperlipidemia molecular
diagnostic service. If DNA diagnosis is
to be undertaken, there is a requirement
for a high-quality, accredited molecular
genetics laboratory with a specific interest
in familial hyperlipidemia. At present, the
Regional Molecular Genetics Laboratory,
based at Belfast City Hospital, provides
this service to the lipid clinics in Northern
Ireland. It is likely that a second laboratory
service would be required to support the
identification and cascade screening in the
Republic of Ireland.
2. Familial hyperlipidemia nurses/genetic
counselors. Familial hyperlipidemia nurses/
counselors are an essential element of a
Fig. 1 Flow chart for the screening and detection of individuals with HeFH. HeFH heterozygous familial hypercholesterolemia, MedPed Make Early Diagnosis to Prevent Early Death, WHO World Health Organization
Opportunistic assessment of patients with strong personal/family history of either
premature cardiovascular disease and/or hypercholesterolemia
(primary and secondary healthcare teams)
Identification of patients with “definite,” “probable,” or “possible” HeFH using Simon
Broome or MedPed/WHO criteria
Confirmation of diagnosis (including DNA testing) of HeFH
Management at lipid clinic or primary care
Cascade screening of first-degeree relatives using DNA or lipid criteria (if causative mutation not identified) by familial hypercholesterolemia
nurse/genetic counselor linked to each lipid clinic. Continue cascade screening as
new index cases identified
New HeFH case identified
Refer to lipid clinic for assessment
Refer to primary care or lipid clinic for
managment
462 Adv Ther (2012) 29(5):456-463.
cascade screening program and would be
centered on the network of lipid clinics
(see below). The nurses/counselors are
responsible for liaising with first-degree
relatives of index cases and, following full
discussion, offering genetic testing (where
a causative mutation has been identified)
or cholesterol testing, and then referring
patients either to the primary healthcare
provider or the lipid clinic clinical
management (Fig. 1) [22].
3. Clinical database. An effective cascade
screening program cannot be undertaken
without an FH database to allow full
documentation of family trees, screening
status, and screening results in individual
family members. This will ensure that
cascade screening is carried out in an efficient
and effective manner, and is particularly
important given that many families will
straddle the land border between the
Republic of Ireland and Northern Ireland.
4. Lipid clinics/primary care familial
hyperlipidemia treatment teams. Lipid clinic
services for familial hyperlipidemia may be
delivered in a number of ways. One possible
model is a network of lipid clinics delivered
in a secondary care setting to which patients
with “definite,” “probable,” or “possible”
HeFH are referred from both primary
care and other secondary care sources for
assessment and treatment [11]. Assessment
would include DNA testing in patients
fulfilling the clinical diagnostic criteria for
“definite,” “probable,” or “possible” HeFH.
The lipid clinic would be responsible for
organizing cascade screening by the familial
hyperlipidemia nurses/counselors. Any
subsequent HeFH cases identified through
cascade screening would be referred to either
to the primary healthcare provider or to the
lipid clinic for treatment.
CONCLUSION
For a successful case f inding/cascade
screening approach, it is essential that there
is high awareness of the condition among
healthcare professionals (in both primary and
secondary care) likely to encounter patients
with HeFH.
The implementation of a screening program
such as that described on an all-Ireland basis
poses particular challenges as it crosses two
legal and healthcare jurisdictions. It will require
close integration of clinical, laboratory, and data
management teams.
ACKNOWLEDGMENTS
Maurice O’Kane is the guarantor for this article,
and takes responsibility for the integrity of the
work as a whole.
Conflict of Interest. The authors declare no
conflict of interests.
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