VIEWPOINT

Familial hypercholesterolaemia
A guide for general practice

Tom Brett, Diane Arnold-Reed the patient’s family history of premature children within families,1 the treatment
cardiovascular disease (CVD), their options available and future management
personal CVD history, their untreated options. Because FH is hereditary,
This guide provides a practical approach LDL-C levels and physical stigmata such dietary and lifestyle measures alone are
to making a clinical, phenotypic diagnosis as tendon xanthomas or arcus cornealis. not sufficient to manage the condition;
of familial hypercholesterolaemia A DLCNS of 6–8 indicates ‘probable’ however, lifestyle modification may be
(FH) in general practice. Although FH FH, while a total score >8 indicates helpful, especially avoidance of smoking.5
is a common, hereditary, autosomal ‘definite’ FH. DNA testing that reveals It is recommended to advise patients
dominant disorder of lipid metabolism,1 a functional mutation in LDLR, APOB that if FH is left untreated, up to half will
it is often not identified in clinical or PCSK9 yields an FH score of eight. A have a fatal or non-fatal CVD event by
practice.2,3 This guide explains when negative genetic test does not exclude FH the age of 50 years (men) or 60 years
a possible diagnosis of FH should because more than 2000 mutations of (women).4,5 It may be helpful to offer
be considered and suggests clinical LDLR exist.2–4 patients an ‘open door’ policy to consider
signs and symptoms to look for and your advice and return at any time. FH
the treatment pathway for patients. It results in very high levels of LDL-C from
includes suggestions for follow-up of Clinical signs birth. If untreated, this cholesterol burden
close family members and for diagnosis Tendon xanthomas are white or yellow remains throughout life, accelerating
and management of children. lumps of cholesterol deposits found around premature CVD, especially myocardial
knuckles or Achilles tendons (Figures 1A, infarction and angina, by 3–4 decades.1–4
1B). They are rarely seen in general practice Early diagnosis and treatment offer
When to consider familial but are pathognomonic for FH. the best opportunity to enable affected
hypercholesterolaemia Corneal arcus is a circular deposit of patients to live a normal lifespan.2,3
FH should always be considered in lipid material at the edge of the cornea
adults with a total cholesterol level (Figure 1C). In young people aged
of ≥7.5 mmol/L or a low-density <45 years,2 it is suggestive of FH. Treatment
lipoprotein cholesterol (LDL-C) level Xanthelasma is a yellowish deposit of Once a diagnosis of FH is confirmed,
of ≥5.0 mmol/L, especially if there is a lipid material found around the eyelid or lipid-lowering treatment (usually a
personal or family history of premature medial canthus area. It may indicate high statin, eg 20 mg rosuvastatin or 40 mg
coronary heart disease (CHD).4,5 cholesterol levels but not necessarily FH atorvastatin) should be commenced.6 The
(Figure 1D). aim is to lower LDL-C by ≥50%.3,5 Dietary
and lifestyle advice, especially avoidance
How to make a phenotypic of smoking, is recommended. Close family
diagnosis Advising patients of familial relatives are encouraged to have their
In Australia, the Dutch Lipid Clinic hypercholesterolaemia diagnosis lipids checked as part of a cascade testing
Network Score (DLCNS; Table 1) is Patients with a DLCNS ≥6 should be process; half the patient’s first-degree
used to make a probable or definite advised they have a phenotypic diagnosis relatives will also have the condition.2,4,7
clinical diagnosis of FH on the basis of FH. It is recommended that they are If symptoms or signs of CVD exist, they
of phenotypic criteria. The DLCNS is provided with information about how should be noted and patients referred for
based on several key factors including the condition is inherited from parents to specialist investigation. Asymptomatic

650 | AJGP VOL. 48, NO. 9, SEPTEMBER 2019 © The Royal Australian College of General Practitioners 2019
FAMILIAL HYPERCHOLESTEROLAEMIA VIEWPOINT

patients should commence lipid-lowering Follow-up

treatment. Six weeks later, a full blood All patients with FH should be regularly
examination can measure the reduction in followed up with at least an annual review.5
LDL-C, and the patient’s medication may Compliance may be difficult, especially
be titrated accordingly.4,6,8 in younger, asymptomatic patients.8

Table 1. Dutch Lipid Clinic Network Criteria scoring for diagnosis of familial
hypercholesterolaemia

Criteria Score A

Family history

First-degree relative with known premature coronary and/or vascular disease

(men aged <55 years, women aged <60 years)
or 1
First-degree relative with known LDL-C above the 95th percentile for age
and sex

First-degree relative with tendinous xanthomata and/or arcus cornealis

or 2
Children aged <18 years with LDL-C above the 95th percentile for age and sex

Clinical history
B
Patients with premature coronary artery disease (men aged <55 years, 2
women aged <60 years)

Patients with premature cerebral or peripheral vascular disease (men aged 1

<55 years, women aged <60 years)

Physical examination

Tendinous xanthomata 6

Arcus cornealis before 45 years of age 4

Investigation
C
LDL-C

≥8.5 mmol/L 8

6.5–8.4 mmol/L 5

5.0–6.4 mmol/L 3

4.0–4.9 mmol/L 1

DNA analysis

Functional mutation in LDLR, APOB or PCSK9 genes 8

Stratification Total score

Definite FH >8

Probable FH 6–8
D
Possible FH 3–5

Unlikely FH <3 Figure 1. Clinical signs of familial

hypercholesterolaemia. a. Xanthoma knuckles;
Adapted from the National Institute for Health and Clinical Excellence and the National Collaborating b. Xanthoma Achilles tendon; c. Arcus
Centre for Primary Care 5 cornealis; d. Xanthelasma medial canthus
FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol

© The Royal Australian College of General Practitioners 2019 AJGP VOL. 48, NO. 9, SEPTEMBER 2019 | 651
VIEWPOINT FAMILIAL HYPERCHOLESTEROLAEMIA

Follow-up checks allow opportunities to help invaluable for many patients, especially if Diane Arnold-Reed PhD, Research Development
Coordinator, General Practice and Primary Health
identify any signs or symptoms of emerging they find their condition difficult to manage Care Research, School of Medicine, The University
CVD and arrange investigations. Medication or are poorly compliant with advice.8 of Notre Dame Australia, WA
Competing interests: None.
side effects can also be monitored and
Funding: The article is based on information
ongoing treatment encouraged.5 disseminated to participants in a study funded by
Women of childbearing age should Use of cardiovascular disease a National Health and Medical Research Council
(NHMRC) Partnership Grant (GNT1142883). Sanofi-
avoid statins for at least three months risk calculators Aventis Australia Pty Ltd was a co-investigator on the
before conception and during pregnancy.2,4 The use of Absolute Cardiovascular Investigator Sponsored Study Grant (study number
DIREGL07823). Financial support was provided
Alternative approaches will be required, Disease Risk Assessment tools are best by Amgen to allow travel to, and attendance and
and specialist involvement in managing the avoided in patients with suspected FH. accommodation at, the European Atherosclerosis
Society meeting in Brisbane, Australia, in May 2018
patients’ FH should be ensured. These patients are already at increased risk and the Familial Hypercholesterolaemia Summit in
of CHD, and the relative risk from their Melbourne, Australia, in February 2019.
Provenance and peer review: Not commissioned,
lifelong cholesterol burden is so great that
externally peer reviewed.
Diagnosis in children it overrides all other risk factors.5,8
Diagnosis of FH in children ideally occurs Acknowledgements
before the age of 10 years.3–5 However, Photographs were supplied by Professor GF Watts,
diagnosis may need to occur by three years Conclusions School of Medicine, University of Western Australia
and Lipid Disorders Clinic, Department of Cardiology,
of age if both parents have FH and the risk Primary care physicians are uniquely Royal Perth Hospital, Perth Australia.
of homozygous FH exists.3 If there is strong placed to play an active part in detection
suspicion of FH in a family, blood levels for and management of FH, but greater public References
1. Austin MA, Hutter CM, Zimmern RL,
LDL-C should be repeated post-puberty, as and health professional awareness of Humphries SE. Genetic causes of monogenic
levels may vary at this time. Sensitivity in the condition is needed. The cholesterol heterozygous familial hypercholesterolemia:
A HuGE prevalence review. Am J Epidemiol
the approach to the management of FH in burden present from birth can be missed 2004;160(5):407–20. doi: 10.1093/aje/kwh236.
children is vital, and parents and guardians if the familial, hereditary nature of the 2. Nordestgaard BG, Chapman MJ, Humphries SE,
should be kept fully informed and closely disorder is not considered. Left untreated, et al. Familial hypercholesterolaemia is
underdiagnosed and undertreated in the
involved. Avoidance of smoking in children FH accelerates the onset of CAD by general population: Guidance for clinicians to
should be stressed, and good dietary and 3–4 decades. FH may be masked if statin prevent coronary heart disease. Eur Heart J
2013;34(45):3478–90. doi: 10.1093/eurheartj/eht273.
lifestyle approaches encouraged.3 therapy is instituted before considering a 3. Wiegman A, Gidding SS, Watts GF, et al. Familial
potential hereditary cause for raised LDL-C hypercholesterolaemia in children and adolescents:
Gaining decades of life by optimizing detection
levels. Outcomes are good if treatment and treatment. Eur Heart J 2015;36(36):2424–37.
Specialist support starts early and adherence is lifelong. doi: 10.1093/eurheartj/ehv157.
Most patients diagnosed with FH 4. Watts GF, Sullivan DR, Poplawski N, et al. Familial
hypercholesterolaemia: A model of care for
in primary care can be managed by Australasia. Atheroscler Suppl 2011;12(2): 221–63.
their general practitioner, especially if Key points doi: 10.1016/j.atherosclerosissup.2011.06.001.

asymptomatic LDL-C levels are well • FH is a hereditary condition affecting 5. National Institute for Health and Clinical
Excellence. Familial hypercholesterolaemia:
controlled, and the patients’ dietary and one in 250 patients (50% of first-degree Identification and management. Clinical
guideline [CG71]. NICE: London, 2018. Available
lifestyle compliance is good.4,6,9,10 relatives).
at www.nice.org.uk/guidance/CG071 [Accessed
Pregnant women and children need • The cholesterol burden present from 26 June 2019].
specialist support and advice from early birth accelerates the onset of CVD. 6. Watts GF, Gidding S, Wierzbicki AS, et al.
stages.2–4 Similarly, specialist involvement • Diet and lifestyle modifications alone
Integrated guidance on the care of familial
hypercholesterolaemia from the International
and support will be required for all patients are not sufficient for management. FH Foundation. Int J Cardiol 2014;171(3):309–25.
who develop CVD symptoms or who have • Greater awareness of FH by health
7.
doi: 10.1016/j.ijcard.2013.11.025.
Austin MA, Hutter CM, Zimmern RL,
difficulty lowering LDL-C levels, poor professionals and the public is needed. Humphries SE. Familial hypercholesterolemia
compliance with diet and medications or • National Institute for Health and Clinical and coronary heart disease: A HuGE association
review. Am J Epidemiol 2004;160(5):421–29.
ongoing side effects with medications.2–6 Excellence guidelines recognise FH as doi: 10.1093/aje/kwh237.
an exemplar for personalised medicine. 8. Brett T, Qureshi N, Gidding S, Watts GF.
• There are unique opportunities for
Screening for familial hypercholesterolaemia in
primary care: Time for general practice to play
Care plans primary care physicians to have a more its part. Atherosclerosis 2018;277:399–406.
doi: 10.1016/j.atherosclerosis.2018.08.019.
Because FH is a hereditary, lifelong active role in managing FH.
9. Lan NSR, Martin AC, Brett T, Watts GF,
condition likely to result in premature CHD Bell DA. Improving the detection of familial
or death unless properly managed, affected hypercholesterolaemia. Pathology 2019;51(2):213–21.
doi: 10.1016/j.pathol.2018.10.015.
patients should have care plans developed Authors 10. Bell DA, Kirke AB, Barbour R, et al. Can
to maximise best practice approach to Tom Brett FRACGP, MD, MA, Professor and Director, patients be accurately assessed for familial
General Practice and Primary Health Care Research, hypercholesterolaemia in primary care? Heart
treatment.8 Specialist lipidologist support School of Medicine, The University of Notre Dame Lung Circ 2014; 23(12): 1153–57. doi: 10.1016/j.
in addition to allied health support can be Australia, WA. [email protected] hlc.2014.06.015.

652 | AJGP VOL. 48, NO. 9, SEPTEMBER 2019 © The Royal Australian College of General Practitioners 2019