Familial hypercholesterolemia in Belgium : genetic, clinical and epidemiologic aspects
In its current form, familial hypercholesterolemia (FH) is due to the presence at the heterozygous state of a mutant allele of the LDL receptor gene or of the APO gene. The patients with heterozygous familial hypercholesterolemia (HeFH) can only remove their LDL particles from the blood at about half the normal rate, leading to an approximate doubling of LDL-cholesterol (LDL-C) level, starting at birth and accumulating in many tissue resulting to tendon xanthomas, corneal arcus and early atherosclerosis (coronary heart diseases (CHD) occur typically at 35-55 years among men and at 55-75 years among women). In the early's 1990's, our interest in the field was stimulated by the fact that despite the impressive progress in the understanding of the pathophysiology and treatment of FH and a preferential r! egimen of reimbursement for statins in Belgium, many affected individuals were not diagnosed and adequately treated. In 1995, we initiated a project aimed to obtain objective information on the situation of subjects carrying familial hypercholesterolemia (FH) in Belgium and to develop better means for identifying these subjects amongst the population. During the period 1995-2006, 1305 suspected FH patients originating from 682 families were examined for a DNA-based diagnosis in our laboratory and amongst these, 544 patients (271 families) were confirmed to have FH. Seventy three mutations in the LDLR as well as the unique mutation in APOB (R3500Q) explained their FH, but amongst them, five mutations explained about 38% of FH in Wallonia and 4 mutations explained 29% of FH in Flanders. Such establishment of the spectrum of FH causing mutations and particularly, of the specific mutational spectrum by region can greatly contribute to facilitate the diagnosis of FH in the near future. In our region, we found that FH frequency is likely to be higher than the theoretical prevalence reported in most European countries (1/500). That means that, in Belgium, each GP should know at least 1 FH patient. There are several reasons that advocated for the need to precisely diagnose FH. One of which was clearly demonstrated by two of our studies: in the category of patients with very elevated cholesterol levels (VHC) and family history of early CVD (FHEC), FH patients have always more severe atherosclerosis than age-, sex-, cholesterol- and family history-matched non-FH-individuals, suggesting that the FH status is by itself a strong and independent risk factor. In this category of VHC and FHEC patients, we even found a “paradox of FH” in the fact that they have greater atherosclerosis despite relatively lower risk as predicted by the Framingham equation. Genetic test may also enhance the awareness of a greater risk than expected on the basis of other risk factors. One of the main interests of genetic tests is of course to facilitate the screening in FH family. We also developed some specific criteria in term of cholesterol levels, family history of early CHD and tendon thickening to facilitate the diagnosis of FH in Belgium. These criteria could be used to select patients susceptible to be confirmed by more expensive genetic tests. As shown by our experience in our lipid clinics, the current available lipid-lowering drugs can correct LDL-C to target in about 49% of the very high risk class of FH patients (including more than 80% FH patients of our co! hort), a real success compared to the early 1990's. In 2001, our work has contributed to the change of the reimbursement rules of statins in patients suspected of FH. Even if these new rules are not yet perfect, its positive point was that many more FH patients can now benefit of the special reimbursement compared to the situation before 2003.
In conclusion, this works have illustrated many aspects regarding the existence, the frequency, the diagnostic problems and the clinical management of FH. Specially, our study suggest that FH remains underdiagnosed in despite of the fact that it is severe, can be diagnosed and effectively treated. For this reason, this work is not to be considered as a final point but rather as a “well fixed starting block” ready to support the beginning of more actions to improve the management of these FH patients at the higher level of public health.
School:Université catholique de Louvain
Source Type:Master's Thesis
Keywords:ldl récepteur cholesterol mutation hypercholestérolémie familiale génétique maladie cardiovasculaire
Date of Publication:06/22/2007