FH is a common inherited hyperlipidaemia, characterized by elevated cholesterol levels from birth which, if untreated, lead to accelerated atherosclerosis and premature coronary artery disease in adulthood. Clearly, there is an urgent need to identify these individuals in childhood so as to instigate treatment as early as possible and thus avoid heart attack and death in middle age. Yet even with a recent push for greater awareness of FH, this scenario tends to be the exception rather than the rule – we need to do better.
FH fulfils classical criteria justifying screening for a condition. The most appropriate approach, be it universal (including opportunistic) or selective (including cascade screening), continues to be a focus of discussion. In the US for example, universal screening of children aged 9-11 years for hypercholesterolaemia has been proposed, although this approach is not specific for FH.2,3 If instead, screening is more directed, using a higher cholesterol threshold (as suggested in the EAS Consensus Statement1), the return is likely to be much higher with fewer false positives, and thus more cost effective. Opportunistic screening, based on a family history of premature atherosclerotic cardiovascular disease or hypercholesterolaemia, has also been suggested, but with limited success to date. This may be in part due to the limitations of the organization of laboratory reporting; however, if this includes interpretive comments and a phone call to the referring primary carer, the likelihood of a diagnosis of FH could improve.4,5
Cascade screening is a strategy for identifying people at risk for a genetic condition by a process of systematic family tracing. This approach is most commonly used to screen populations for FH, but used alone it fails to identify sufficient index cases.6
Recent studies have suggested a combination of universal and reverse cascade testing approaches, identifying the index case in childhood and proceeding to screen the child’s parents and close relatives.7 This strategy has been used successfully in the Netherlands, with 70% of all individuals with FH identified by 2014;8,9 but has been less successful in other countries; in Australia, for example, only 4% of children aged <16 years have been detected since a centralized cascade-screening program was set up in 2007. While a number of reasons underlie this, practical issues and economics are likely to play a part.
There are also questions about how best to identify individuals with likely FH, i.e. whether a phenotypic or genotypic approach is best. It is increasingly recognized that elevated cholesterol due to FH is not just monogenic but may be also polygenic, which may account for variable clinical presentation.10 Indeed, some patients with a pathogenic FH gene variant do not have hypercholesterolaemia but may still be at increased risk of coronary artery disease.11
Clearly, there are still many questions relating to the optimal processes and pathways for the organization of childhood screening for FH (Table 1).
Table 1. Questions about screening for FH?
Phenotypic versus genotypic screening?
Diagnosis of FH in children usually follows cascade testing. As a first screening test a non-fasting lipid profile is sufficient, but LDL cholesterol levels should be measured at least twice over three months in a fasting state to confirm the diagnosis. Detection of a pathogenic mutation in a child is the gold standard for the diagnosis of FH.
The EAS Consensus Statement advises that any child with an LDL-cholesterol level > 5 mmol/L on two successive occasions has a high probability of FH; an LDL-cholesterol level > 4 mmol/L together with a family history of premature coronary heart disease in a close relative and/or high baseline cholesterol in one parent also indicates a high probability of FH. Additionally, if the parent has a genetic diagnosis of FH, an LDL cholesterol > 3.5mmol/L in the child is suggestive of FH.1,12 However, there is limited information on diagnostic criteria for FH in children in diverse populations, including country-, gender-, and age-specific cholesterol thresholds. South Africa is a prime example; while the founder effects are well recognized, information is urgently needed on differential approaches to FH diagnosis in black African populations.13
The risk of early coronary artery disease in individuals with FH is associated with lifelong exposure to elevated LDL-cholesterol levels. Furthermore, the presence of an FH mutation triples this risk at any LDL-cholesterol level.14 Despite this, a clinical event is not inevitable in all individuals with FH. While a number of putative predictors of risk have been investigated, including the combination of clinical and biochemical markers, genetic risk scoring systems, markers of inflammation and different forms of imaging, none have so far proved to be robust enough to allow for application in routine clinical practice. In the paediatric FH setting, the key unknowns to define are 1) the optimal form of cardiovascular imaging; 2) a life-time risk prediction model in children; and 3) biomarkers of cardiovascular risk.
Treatment of children with FH involves a combination of lifestyle and pharmacotherapeutic approaches. Lifestyle intervention incorporating a healthy diet low in saturated and trans-fat, regular exercise and avoidance of cigarette smoking (including environmental tobacco smoke exposure) are a mandatory first step.1 In most guidelines, statins, which lower LDL cholesterol by up to 50% in children with FH, are also recommended from the age of 8 years. The decision to start statin treatment should involve the child and parents and take into account the family history of cardiovascular disease and the level of LDL cholesterol. Children should be started on the lowest dose using the least potent statin and titrated up every 6-8 weeks, depending on the LDL cholesterol response. Guidelines suggest a target LDL-cholesterol level of 3.5 mmol/L or a 50% reduction in LDL-cholesterol from pre-treatment levels.1,15 Treatment response should be assessed at 6-8 weeks, and once LDL cholesterol targets have been achieved, a lipid profile and liver function tests should be repeated every 6-12 months throughout childhood, to confirm adherence and monitor for side effects. Although there are limited long-term data for statins in children with FH, a recent study provided some reassurance, as only 1.5% of individuals stopped statin treatment, and there were no reports of hepatitis or rhabdomyolysis.16
If there is insufficient reduction in LDL cholesterol levels, additional treatment should be considered. Options include ezetimibe, approved from the age of 10 years, or a bile acid sequestrant (colesevelam is best tolerated, approved from the age of 10 years in the US but not Europe). Monoclonal antibody therapy to PCSK9 is highly efficacious in lowering LDL cholesterol, but to date is only approved for use from the age of 18 years (except in individuals with homozygous FH, for which evolocumab is licensed). Ongoing studies are addressing the lack of information on the use of these agents in children with heterozygous FH. Cost is also a barrier to access in adult patients.
In adolescence there are other issues to consider. In any female of childbearing age, advice about contraceptive choices should be given and discussed; women planning to become pregnant should discontinue a statin 3 month before planned conception. Yet even if women do become pregnant on a statin, they should be reassured that the likelihood of complications is small. If LDL- lowering therapy is needed during pregnancy, a bile acid sequestrant can be prescribed, with lipoprotein apheresis recommended in individuals with coronary artery disease or homozygous FH.
As discussed, there are many outstanding questions relating to the treatment of children with FH, as summarised in Table 2.
Table 2. Outstanding questions about the treatment of children with FH
|General||What is the risk/benefit of lifelong FH care for children?|
|How can individual variation in the natural history of atherosclerosis guide the timing and intensity of treatment?
|Lifestyle intervention||Does primordial prevention targeting other cardiovascular risk factors have a role?|
|What is the effectiveness of different heart-healthy and culturally specific diets in children with FH?|
|Do nutraceuticals have a role, either alone or in combination with a statin?
|Pharmacotherapy||Can we define LDL cholesterol thresholds for starting treatment in children with FH, with or without a mutation?|
|What is the long-term safety of statins and other LDL- lowering treatments in children with FH?|
|Are children with FH intolerant to statins?|
|What is the role of novel agents (such as PCSK9 inhibitors) in treating children with FH?|
|What is the impact of withholding statins and ezetimibe during pregnancy and lactation on cardiovascular outcomes of children born with FH?|
Undoubtedly, the management of children with FH involves a partnership between clinicians, children and parents. As treatment is for life, education about FH, its consequences if untreated, and aspects of treatment is essential. As clinicians and associated healthcare workers, we need optimal approaches for the care of children with FH, the most effective tools to inform our patients, as well as studies to inform about the child or adolescent’s perception of living with FH. All of these areas warrant further investigation.
Finally, given that optimal treatment of children with FH should involve multidisciplinary approaches across primary care, specialist paediatric and adult services, we need information on how best to integrate across these interfaces, as well as ensure the best pathways for transitional care as adolescents approach adulthood.
There are clearly gaps in the care of children and adolescents with FH. We need to urgently address these to ensure that, in the future, adoption of optimal models of care can change the natural history of FH.
This editorial is based on a recent review; read the full review here:
Martin AC, Gidding SS, Wiegman A, Watts GF. Knowns and unknowns in the care of pediatric familial hypercholesterolemia. J Lipid Res 2017;58:1765-1776. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28701353
- Wiegman A, Gidding SS, Watts GF et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36: 2425-2437
- Dixon DB, Kornblum AP, Steffen LM et al. Implementation of lipid screening guidelines in children by primary pediatric providers. J. Pediatr 2014;164: 572-6.
- de Ferranti SD, Rodday AM, Parsons SK et al. Cholesterol screening and treatment practices and preferences: A survey of United States pediatricians. J Pediatr 2017; 185:99-105
- Bell DA, Bender R, Hooper AJ et al. Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia. Clin Chim Acta 2013;422: 21-5.
- Bell DA, Hooper AJ, Edwards G et al. Detecting familial hypercholesterolaemia in the community: impact of a telephone call from a chemical pathologist to the requesting general practitioner. Atherosclerosis 2014;234:469-72.
- Morris JK, Wald DS, Wald NJ. The evaluation of cascade testing for familial hypercholesterolemia. Am J Med Genet 2012;58a: 78-84.
- Futema M, Cooper JA, Charakida M et al. Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC). Atherosclerosis 2017;260: 47-55.
- Umans-Eckenhausen M A, Defesche JC, Sijbrands EJ et al. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 2001;357 165-168.
- Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34: 3478-3490a.
- Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case control study. Lancet 2013;381:1293-1301.
- Wald DS, Bestwick JP, Morris JK et al. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med 2016; 375: 1628-1637.
- Gidding SS, Champagne MA, de Ferranti SD et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation 2015;132: 2167-2192.
- Smyth N, Ramsay M, Raal FJ. Population specific genetic heterogeneity of familial hypercholesterolemia in South Africa. Curr Opin Lipidol 2018 Jan 24. doi: 10.1097/MOL.0000000000000488. [Epub ahead of print]
- Perak AM, Ning H, de FerrantI SD et al. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 2016;134: 9-19.
- Watts GF, Gidding S, Wierzbicki AS et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Eur J Prev Cardiol 2015;22: 849-854.
- Kusters DM, Avis HJ, de Groot E et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA 2016;312: 1055-1057