ArticlesReview of first 5 years of screening for familial hypercholesterolaemia in the Netherlands
Introduction
Familial hypercholesterolaemia is an inherited disorder of lipoprotein metabolism caused by mutations in the LDL-receptor gene. In heterozygous familial hypercholesterolaemia, only 50% of these receptors are functional, which increases plasma cholesterol concentrations to between 7·5 and 16 mmol/L.1 Characteristically, familial hypercholesterolaemia results in premature cardiovascular disease (CVD) and untimely death.1 In patients with hypercholesterolaemia the agestandardised and sex-standardised mortality ratios are four to five times higher than in the general population.2
Lowering LDL-cholesterol concentrations results in a large decrease in cardiovascular morbidity and mortality, especially in patients at highest risk, 3 and lipid-lowering treatment of patients with familial hypercholesterolaemia could prevent premature death.2 In western countries although hypercholesterolaemia is a common disorder most patients are not diagnosed or do not receive proper treatment.4 With the elucidation of the molecular basis of the disorder, an unequivocal diagnosis has now become available.5 The World Health Organization has recommended that if treatment is started early maximum health benefit can be obtained.
In clinical practice, raised cholesterol concentrations, data from personal and family histories, and physical examination are the main criteria for the diagnosis of familial hypercholesterolaemia. The sensitivity and specificity of raised cholesterol concentrations as well as the use and definition of appropriate cutoff points has been studied extensively. 6, 7, 8, 9, 10, 11, 12 However, most studies have been done in small numbers of adults and children in a lipid clinic setting.
We have established a programme in the Netherlands to assess whether identification of substantial numbers of people with heterozygous familial hypercholesterolaemia by active family screening and DNA analysis is feasible. We also aimed to assess whether identification of these new patients would improve their degree of preventive care, and the specificity and sensitivity of cholesterol measurement. We report the first 5 years of this ongoing screening programme in the Netherlands.
Section snippets
Identification of index cases
We did the clinical diagnoses at the lipid clinic according to a uniform diagnostic protocol, with criteria such as LDL cholesterol concentrations, physical signs, and personal and family history in a scoring system.13 Family history was judged as positive when there had been signs of CVD in men before the age of 55 years and in women before 60 years. We analysed DNA samples of patients with familial hypercholesterolaemia for the presence of an LDL-receptor gene mutation. Once a mutation had
Results
Between January, 1994, and January, 1999, family screening was initiated in 237 families of which 5442 members participated in the screening programme. The participation rate was 90% over the duration of the study. 277 individuals declined genetic testing because of: fear of negative effects on employment or insurance (124 [45%]); negative advice from general practitioner (69 [25%]); general lack of interest (51 [18%]); treatment for hypercholesterolaemia already in place or no offspring (23
Discussion
We have shown that familial hypercholesterolaemia is frequently underdiagnosed and that many patients who had been identified previously on clinical grounds were not being treated appropriately. Our first research goal was to establish whether or not active identification–ie, by our method of directly approaching family members of index cases was effective in identifying large numbers of still symptomless, quite young, and untreated patients with familial hypercholesterolaemia. On average,
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