Familijarna hiperholesterolemija i kaskadni skrining za detekciju novih pacijenata

Abstract

Familial Hypercholesterolemia (FH) is a metabolic disorder that is inherited in an autosomal dominant manner and is characterized by elevated cholesterol levels and the development of premature atherosclerotic cardiovascular disease (ASCVD). The prevalence of heterozygous FH is 1 in 250-500 individuals, while the prevalence of homozygous FH is 1 in a million. The molecular basis of this condition involves mutations in the genes encoding the LDL receptor (Low-Density Lipoprotein Receptor, LDLR), Apolipoprotein B (ApoB), or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) enzyme. In patients with FH, laboratory analyses are dominated by elevated levels of low-density lipoprotein cholesterol (LDL-C) above the 95th percentile for age and gender, with most commonly normal values of high-density lipoprotein cholesterol (HDL-C) in very low-density lipoprotein cholesterol (VLDL-C), and triglycerides. The gold standard for diagnosing FH is genetic analysis and mutation detection, but it is often inaccessible due to economic reasons. Today, the diagnosis is made by applying a scoring system within well-validated questionnaires, which assess the probability of FH based on the simultaneous analysis of personal and family history, clinical findings of tendon xanthomas or corneal arcus, as well as biochemical analysis of the lipid profile. Despite clear diagnostic recommendations for FH, there is an extremely low rate of diagnosis of these patients, even in developed healthcare systems, as well as a low rate of treatment. A large number of unrecognized FH patients, along with a significantly increased risk of cardiovascular diseases in untreated young FH patients, have prompted global efforts to diagnose the disease earlier and reduce complications through appropriate treatment. Cascade screening in the detection of new patients involves analyzing the relatives, first-, second-, and third-degree, of patients with known FH (index case, proband). Upon identifying a new case, that individual becomes the new proband, and their relatives are analyzed in subsequent cascades. There are three basic models of cascade screening: clinical, genetic, and hybrid models. Currently, selective clinical cascade screening is most commonly applied. Selective cascade screening detects the disease in individuals at high risk of its manifestation. The expert consensus panel recommends a hybrid model, where genetic testing is performed in all patients with definite or probable FH, and in cascade screening, both cholesterol levels and genetic analysis are continued in their high-risk relatives. Adequate detection of FH patients and timely treatment significantly reduce their cardiovascular morbidity and mortality, justifying the implementation of cascade screening. Conducting screening through routine clinical practice does not yield satisfactory results. Therefore, it is necessary to organize a screening program at the national level, including the establishment of lipidology centers and the provision of genetic screening and genetic counseling services.