Abstract
Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.
Highlights
The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/ kexin type 9
Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder characterised by elevated levels of low-density lipoprotein cholesterol (LDL-C) whose accumulation leads to the development of atherosclerotic cardiovascular disease (ASCVD); if not treated properly, it may result in premature death (Watts et al, 2016)
This may be explained by the apolipoprotein E (APOE)-regulated clearance of very lowdensity lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles in FDB patients and the interaction between apolipoprotein B (APOB) and LDLR, important for the conversion of IDL to LDL-C (Gaffney et al, 2002; Vohnout et al, 2003)
Summary
The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/ kexin type 9. The prevalence of heterozygous FH (HeFH) is 1 per 200 to 250, with their LDLC levels ranging between 4 and 13 mmol/L (Cuchel et al, 2014; Benn et al, 2016). In homozygous FH patients, the levels of LDLC are >13 mmol/L and the prevalence of this rare disease is approximately 1 per 160,000 to 300,000 (Cuchel et al, 2014). The patients are assigned to their respective categories based on each individuals family history, clinical history, physical examination, levels of LDL-C and, possibly, genetic testing (Benn et al, 2016). Familial hypercholesterolemia patients are most often treated with statins, a class of drugs highly effective in lowering LDL-C levels, especially when combined with ezetimibe (Gagné et al, 2002). A breakthrough in the treatment of FH came with the discovery of PCSK9 inhibitors shown to decrease LDL-C by ≥50% (Watts et al, 2020)
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