Review
Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

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Abstract

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal.

To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.

This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Section snippets

Endorsement

The recommendations contained in this document have been fully endorsed by The National Lipid Association, 6816 Southpoint Parkway (Suite 1000), Jacksonville, FL3316, US.

Abbreviations

ApoB, apolipoprotein B-100; CAC, coronary artery calcification; CHD, coronary heart disease; CK, creatine kinase; CIMT, carotid intima-medial thickness; CT, computerized tomography; CVD, cardiovascular disease; DLCNC, Dutch Lipid Clinic Network Criteria; DLCNS, Dutch Lipid Clinic Network Score; DRG, Diagnosis-related Groups; FDA, Food and Drug Administration; FH, familial hypercholesterolaemia: GP, general practitioner; HDL, high-density lipoprotein; ICD, International Classification of

Detection of index cases: screening for FH

A systematic strategy for detecting index cases (i.e. first individuals diagnosed in families) of FH is essential [6], [7], [8], [9]. The index case is the trigger for cascade screening, whereby new cases can be efficiently discovered [3], [8], [9]. Both screening methods need to be well integrated in models of care [8]. Universal screening prior to age 20 years and ideally before puberty, based on age- and gender-specific plasma LDL-cholesterol levels, should also be considered if feasible [9],

Diagnosis and assessment of adults

There are a number of criteria for diagnosing FH phenotypically in adults, but none are internationally agreed [6], [7], [8], [9], [22]. The Dutch Lipid Clinic Network Criteria (DLCNC) are used to calculate a numerical score predicting the probability of the diagnosis of FH [34]. These criteria are increasingly accepted as simple and comprehensive [8], [13], [34]; the numerical score is not highly dependent on the plasma level of LDL-cholesterol and can be more sensitive in detecting index

Diagnosis and assessment of children and adolescents

FH should be identified in youth, certainly before 18 years of age and younger if indicated and feasible [19], [20], [21], [54], [66], [67]. This is particularly important for those at risk for homozygous FH, where recognition at about 2 years or even earlier is considered optimal [19], [20], [21], [54], [66], [67]. Sitosterolaemia may masquerade as homozygous FH in childhood and the diagnosis should be considered [38]. Boys and girls with potential heterozygous FH should also be screened before

Cascade screening: risk notification of families

The most cost-effective approach for detecting new cases of FH is family cascade screening of close relatives of a diagnosed index case using a phenotypic or genotypic strategy [5], [6], [8], [77], [78]. Diagnostic testing based on a pathogenic mutation is more accurate, however, than using the phenotype alone [79]. If a DNA testing service is not available, cascade screening should be carried out using age-, gender- and country-specific plasma LDL-cholesterol levels alone [71]. Because of

Genetic testing

FH is a dominantly inherited disorder, affected individuals having a 50% chance of passing the causative mutation to each offspring [1], [2], [3]. The majority of cases of FH are due to mutations in the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) and proprotein convertase subtilisin/kexin Type 9 (PCSK9) genes [2]. A pathogenic mutation in one of these genes is identified in about 70% of phenotypically definite FH and 20% of phenotypically probable/possible FH [79], [85], [86], [87]. New

Management of adults

FH is associated with a moderately severe to very severe increase in the lifelong exposure to the atherogenic effects of LDL-cholesterol [54], [67]. It warrants aggressive, life-long management from a young age [19], [20], [21], [97].

Management of children and adolescents

It is generally agreed that targets for LDL-cholesterol treatment in children need not be as low as adults [8], [9], [19], [20], [22], [76]. As in adults, good evidence for an absolute or relative target does not exist in children; international guidelines are consequently not uniform in their recommendations [8], [9], [19], [20], [22], [76]. Early cholesterol-lowering treatment can substantially alter the natural history of FH [54], [67], [111], [112], [113], [114], [115], [149]. Although

Lipoprotein apheresis and other invasive therapies

Lipoprotein apheresis (LA) is an extracorporeal treatment that removes apoB-containing lipoproteins from the circulation [65], [156], [157]. The removal of LDL by LA improves CHD outcomes, progression of atherosclerosis and aortic fibrosis, endothelial function and coagulation in FH [146], [157], [158]. LA is an FDA approved therapy that is indicated for patients with homozygous (or compound heterozygous) FH or severe heterozygous FH with progressive CHD, who are refractory or intolerant to

Emerging therapies

Many patients with FH cannot attain optimal and sustained reductions in plasma levels of LDL-cholesterol [18], [32]. This has prompted the development of highly innovative therapies that can provide substantive reductions in LDL-cholesterol additional to standard therapies [169], [170], with significant implications also for the treatment of homozygous FH [179]. The long-term efficacy, safety and tolerability of these agents remain to be demonstrated, however. Clinical registries of patients

Organization and development of care

In spite of the recent explosion of interest and research in FH, the care of patients and families remains suboptimal [18], [21], [25], [193], [194], [195]. This provides an important mandate to standardize and improve service delivery at all levels. The development and implementation of initiatives and strategies to improve the care of FH requires a close collaboration between health care systems, patient support groups, relevant non-government organizations and health networks [8], [31], [33]

Conclusion: into the future

This international guidance is derived from knowledge of best contemporary practice, and aims to achieve the best outcomes for patients with FH by providing a standard of practice that will hopefully remove variability and inequalities in the care of FH worldwide. The recommendations cannot, however, meet universal needs for the care of FH. They therefore need to be complemented by judicious clinical judgement and adjusted for country-specific and local health care needs and resources. Clinical

Disclosures

Some members of the Group have received lecture honoraria, consultancy fees, and/or research funding from: Abbrie (PPT); Abbott (GFW, KKL, KGP, RDS, AVS, BT); Aegerion (WVB, EB, ML, PM, KGP, RDS, JK); Alnylam Pharma (JK); Atherotech (PPT); Amarin Pharma (GFW, PPT, AVS, JK); Amgen (GFW, PPT, WVB, EB, KGP, FJR, RDS, DRS, AVS, BT, JK); AMT (EB); Astra Zeneca (GFW, PPT, WVB, EB, JD, KKL, FJR, RDS, WGS, DRS, AVS, BT, SY, EJGS; JK); Astellas (SY); AtheroNova Inc. (JK); Bayer Yakuhin (SY); Biolab

Acknowledgements

We thank the following experts for completing a brief questionnaire regarding contentious issues in FH: Pascale Benlian; Deepak Bhatnagar; Dirk Blom; Alberico Catapano; Richard Ceska; Ada Cuevas; John Deanfield; Olivier Descamps; Mats Eriksson; Claude Gagne; Anne Goldberg; Paul Hopkins David Marais; Luis Masana; Andre Miserez; Jonathan Morrell; Dermot Neely; Leiv Ose; Henry Purcell; Alan Rees; Handrean Soran; Mario Stoll; Charles Van Heyningen; and Kurt Widhalm.

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