[Detection and treatment of familial hypercholesterolaemia; the earlier, the better?] / Opsporing en behandeling van erfelijk hoog cholesterol.

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.

Paediatric screening for hypercholesterolaemia in Europe.

Different screening strategies are currently recommended to identify children with (familial) hypercholesterolaemia in order to initiate early lipid management. However, these strategies are characterised to date by low adherence by the medical community and limited compliance by parents and children. In a literature review, the authors assess which children should undergo screening and which children are in effect identified through the currently recommended strategies. Furthermore, the authors discuss the different screening tools and strategies currently used in Europe and what is known about the negative aspects of screening. The authors conclude that currently recommended selective screening strategies, which are mainly based on family history, lack precision and that a large percentage of affected children who are at increased risk of future coronary artery disease are not being identified. The authors propose universal screening of children between 1 and 9 years of age, a strategy likely to be most effective in terms of sensitivity and specificity for the identification of children with familial hypercholesterolaemia. However, this concept has yet to be proven in clinical practice.

Familial hypercholesterolemia: present and future management.

Patients suffering from familial hypercholesterolemia (FH) are characterized by increased plasma levels of low-density lipoprotein cholesterol (LDL-C) levels and are at increased risk for premature cardiovascular disease (CVD). Current guidelines emphasize the need to aggressively lower LDL-C in FH patients, and statins are the cornerstone in the current regimen. However, additional therapies are eagerly awaited, especially for those patients not tolerating statin therapy or not reaching the goals for therapy. Our understanding of LDL metabolism has improved over the last years and an increasing number of potential novel targets for therapy have been recently identified. Apart from novel targets, we have also been confronted with novel modalities of treatment, such as mRNA antisense therapy. Some of these emerging therapies have proven to be effective in lowering plasma LDL-C levels and are as such expected to have beneficial effects on CVD. Hopefully, they will enrich our armamentarium against the severe dyslipidemia observed in FH patients in the not too distant future.

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes.

BACKGROUND: In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. METHODS: Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified FH patients in each postal code area was calculated and visualised in different maps. RESULTS: A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. CONCLUSIONS: Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherlands.

Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy.

Familial hypercholesterolaemia (FH) is a co-dominant monogenic disorder of lipoprotein metabolism, characterised by severely elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth onwards. Treatment of FH patients with cholesterol-lowering medication is mandatory to prevent premature cardiovascular disease (CVD). As a result of a nationwide screening in the Netherlands, a large group of women with FH in the child-bearing age range has been identified. Physicians are faced with a treatment dilemma if these females present either with a wish for pregnancy or an established pregnancy, since all systemically absorbed lipid-lowering medication is contraindicated during pregnancy. Currently, no evidence-based guidelines exist on the optimal clinical approach in these patients. Animal studies have shown conflicting data on potential teratogenicity of statins. In humans, there is no strong adverse safety signal, but prospective studies are lacking. The consequences of maternal hypercholesterolaemia during pregnancy for both mother and child are not well determined, although it has been suggested that it may increase the risk of CVD in the offspring. This review describes two representative cases from clinical practice, and discusses clinical considerations for treating pregnant FH patients supplemented with what is known from the literature.