Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment

Abstract

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.

Keywords: Adolescents; Children; Consensus statement; Diagnosis; Ezetimibe; Familial hypercholesterolaemia; LDL cholesterol; PCSK9 inhibitor; Statin; Treatment.

Figure 1

Prevalence of familial hypercholesterolaemia. (A) Familial hypercholesterolaemia is more common than other genetic diseases. 1 Genetic Alliance UK. Incidence of genetic disorders. http://www.geneticalliance.org.uk/education3.htm (13 February 2015); 2 Streetly et al. FH, familial hypercholesterolaemia; PCKD, polycystic kidney disease. (B) The estimated prevalence of FH globally, based on estimated frequencies of 1 : 500 and 1 : 200 (as suggested by recent research), reproduced with permission from Nordestgaard et al.

Figure 2

Development of early atherosclerotic vascular disease in familial hypercholesterolaemia showing the potential impact of early recognition and treatment on evolution of the condition. CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol.

Figure 3

Carotid intima-media thickness is a marker of early atherogenesis in children with familial hypercholesterolaemia. (A) Increased carotid intima-media thickness is already evident at age 7 years in familial hypercholesterolaemia children. Data from Kusters et al. After 10 years treatment with a statin, while mean carotid intima-media thickness is higher in familial hypercholesterolaemia children than their unaffected siblings (B), there is no significant difference between the two groups in carotid intima-media thickness progression over this period (C). Data from Kusters et al. Data in (B) and (C) are given as mean ± SEM and are adjusted for age, gender, blood pressure, body mass index, smoking, and family relations. cIMT, carotid intima-media thickness; FH, familial hypercholesterolaemia; NS, not significant.

Figure 4

Impact of statin treatment on cholesterol burden in familial hypercholesterolaemia. Early initiation of statin treatment reduces the low-density lipoprotein cholesterol burden* in subjects with familial hypercholesterolaemia. Reproduced with permission from Vuorio et al. (A): Cumulative low-density lipoprotein cholesterol burden by age of 18 years is 15% lower in familial hypercholesterolaemia subjects treated with low dose statin from age 10 years (70 mmol) than in untreated familial hypercholesterolaemia subjects (80 mmol). (B) Cumulative low-density lipoprotein cholesterol burden of a 55-year-old non-familial hypercholesterolaemia subject is 160 mmol. In an untreated familial hypercholesterolaemia subject, this is attained by age 35 years, but is delayed in familial hypercholesterolaemia patients treated from age 18 years (48 years), and further delayed in those treated from age 10 years (53 years). *For calculation of the low-density lipoprotein cholesterol burden, the following assumed mean low-density lipoprotein cholesterol values were used. Non-familial hypercholesterolaemia subjects: 2.0 mmol/L for the age range of 0–15 years; 2.5 mmol/L for 15–24 years; 3.0 mmol/L for 25–34 years; 3.5 mmol/L for 35–44 years; and 3.5 mmol/L for 45–54 years. Familial hypercholesterolaemia subjects: 4.5 mmol/L in untreated familial hypercholesterolaemia patients; 3 mmol/L in familial hypercholesterolaemia patients treated during the age range of 10–18 years, and 2.5 mmol/L in familial hypercholesterolaemia patients with treatment started at the age of 18 years. FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol.

Figure 5

Reduction in low-density lipoprotein cholesterol burden associated with early initiation of statin treatment in children with familial hypercholesterolaemia translates to improvement in coronary outcomes. Kaplan–Meier curves of event-free survival in a cohort of 214 familial hypercholesterolaemia subjects treated from childhood (n = 214) compared with their parents with familial hypercholesterolaemia, treated from adulthood (n = 156). Data from Braamskamp et al. FH, familial hypercholesterolaemia.

Figure 6

Potential strategy for diagnosis of familial hypercholesterolaemia in children and adolescents.CHD, coronary heart disease; FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol. Definitions: Premature coronary heart disease is defined as a coronary event before age 55 years in men and age 60 years in women. Definite familial hypercholesterolaemia is defined as genetic confirmation of at least one familial hypercholesterolaemia-causing genetic mutation. Close relative is defined as 1st or 2nd degree. Highly probable familial hypercholesterolaemia is based on clinical presentation (i.e. phenotypic familial hypercholesterolaemia), either an elevated low-density lipoprotein cholesterol level ≥5 mmol/L in a child after dietary intervention or an low-density lipoprotein cholesterol level ≥4 mmol/L in a child with a family history of premature coronary heart disease in close relatives and/or baseline high cholesterol in one parent. Cascade screening from an index case with a familial hypercholesterolaemia-causing mutation may identify a child with elevated low-density lipoprotein cholesterol levels ≥3.5 mmol/L.