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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