ReviewIntegrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation
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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