الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Despite all the efforts conducted to diagnose FH as it is a treatable risk factor for premature CAD, it is underdiagnosed and undertreated as less than 1% of them have genetic diagnosis.(12,209) Kramer, et al (2019) conducted a systematic review to estimate the prevalence of clinically diagnosed FH among premature IHD patients showing highly heterogeneous results ranging from 0.4-25.4%.(210) In Egypt, CardioRisk project estimated the prevalence of definite, probable and possible FH among 2743 patients who had available LDL-C measures from a total of 3224 cases to be 0.1%, 0.25% and 16.8% respectively.(91) While another study conducted at Cairo University in 2020 on 2000 patients with ACS in which (40.4%) have premature presentation. The study estimated the prevalence of definite/probable FH to be 7.8% and 31.3% had possible FH.(211) In the current study the estimated prevalence of definite and probable FH in premature IHD patients is 2.5% and 3.9% respectively. The prevalence of FH in CardioRisk project is underestimated because they depended exclusively on 2 factors (premature IHD and LDL-C levels) and did not take into consideration the positive family history or the presence of arcus cornealis and tendon xanthoma.
In the current study, the mean age at diagnosis of the studied cases was 37.6 years. In the literature, the prevalence of FH among IHD patients < 60 years was estimated to be 1 in 14 and 1 in 7 in patients below 45 years.(210) In the present study, about 94% of the selected cases have positive family history of either IHD, hypercholesterolemia or both. The risk of the genetic disease increases with the younger age of onset and positive family history.(3) In our study, about 73% of the selected cases are males, and about 40% have hypertension. These results are comparable to the CardioRisk project results in which male patients represent about 65% of patients with premature IHD and 48% are hypertensive.(5) In the present study, 40% of the patients have positive consanguinity with a higher prevalence among definite FH patients (78%). The high prevalence of consanguinity in Arabs increases the incidence of homozygous FH.(141, 212) In the current study, six patients had homozygous mutation, 3 in the LDLR gene (AD) and 3 in the LDLRAP1 gene (AR) representing 12.7% of the sequenced cases which is attributed to the high prevalence of consanguineous marriage among Egyptian (35.3%).(213)
About 23% of our cases were not compliant to treatment and even patients on lipid lowering treatment had a mean LDL-C 164 mg/dl which is much higher than the recommended level by the European Society of Cardiology (ESC) guidelines which is <55 mg/dl for high-risk patients.(214)
Genetic testing does not only provide definitive diagnosis, cascade screening and precise counseling for FH patients and their family members but also it increases the patient’s adherence to treatment and improve the patient’s management.(12) Understanding the underlying molecular causes of FH helps in achieving precision medicine as Lomitapide and Mipomersen are approved only for homozygous familial hypercholesterolemia patients.(215) PCSK9 inhibitor is another drug approved for FH patients. Patients with gain of function mutations in the PCSK9 gene have the best response to this treatment,(216) while patients with homozygous null allele mutation in the LDLR gene have no response due to absent LDLR at the cell surface. PCSK9 inhibitors can decrease the LDL-C up to 35% in patients with at least 1 functioning LDLR allele even if it has residual activity.(12, 217)