Management of familial hypercholesterolemia in children and young adults: Consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization

Abstract

Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations.

• Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.

• The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) level above 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children.

• A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.

• The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL).

Conclusion: The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.

Introduction

In patients with heterozygous familial hypercholesterolemia (HeFH), hypercholesterolemia is already present at birth [1] and results in early atherosclerotic lesions, which can be detected by carotid intima media thickness (IMT) measurement as early as 10 years of age [1]. It is reasonable to question when to identify individuals at risk and when to start treatment of HeFH. These questions are not easily answered because there is little evidence to support any particular course of action (or even lack of action). Recently, however, intervention studies in children have provided scientific arguments in favour of treating FH children [2], [3]. Firstly, high cholesterol in children has a substantial subclinical impact, which is already measurable from the age of 5 years. In children with a mutation, endothelial dysfunction can be observed (measured by the dilatation of the brachial artery associated with an intense post-ischaemic flow of arterial blood) [4], as well as a greater IMT thickening detected by carotid echography [5], [6], [7]. Secondly, high cholesterol levels in childhood increasingly appear to be a good predictor of cardiovascular risk later in life [8], [9]. Thirdly, some interventional studies with statins in children were well tolerated at least in the short-term [10], [11]. The statins were highly efficacious at reducing low-density-lipoprotein cholesterol (LDL-C) by −30 to −40% in studies up to 2 years, and, above all, the development/progression of atherosclerosis measured by endothelial function [12] or IMT [13], [14]. It should be noted that the Food and Drugs Administration (FDA) approved treatment with simvastatin in 1995, atorvastatin 10–20 mg in 2000 and pravastatin in 2002 for children aged 10 years or more.

While the benefits, objectives and treatment of HeFH are well defined in adults [15], a clear consensus does not exist for the management of children with HeFH. There is, nevertheless, an urgent need for a consensus between paediatricians, general practitioners and specialists in internal medicine, as the HeFH patient will be successively confronted with these specialities in the course of his/her life. Consistent recommendations are pivotal to ensure compliance with the long-term treatment of these patients. The rationale to develop HeFH guidelines is obvious. Firstly, HeFH is a clearly defined condition where elevated levels of cholesterol in young people persist into adulthood. This is not always the case with other causes of hypercholesterolemia, especially those associated with polygenic disorders, where the elevated levels of cholesterol depend to a greater extent on gene–environmental interaction, and thus, where cholesterol levels vary with the exposure of the patients to a variable environment (food intake, physical activity, etc.). Secondly, HeFH is a dominantly inherited disease, resulting in the transmission of the disease to 50% of the offspring of the parent with HeFH. Thirdly, HeFH may be clearly defined by genetic testing in both the parent and the child. Finally the hypercholesterolemia associated with HeFH is clearly considered as a high risk condition for cardiovascular disease (CVD), even higher than the risk of non-FH-hypercholesterolemia at similar LDL-C levels [16].

The objective of this consensus is to propose recommendations for the diagnosis and treatment, and to define the objectives to be attained in the management, of children and adolescents presenting with FH, taking into account recently available data.