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ORIGINAL ARTICLE
Year : 2022 | Volume
: 11
| Issue : 3 | Page : 81-85
Familial hypercholesterolemia within cardiology practice – single-center experience during 2-year period
Edin Begic1, Ada Djozic2, Emina Karavelic2, Nadira Zatric3, Adela Sinancevic4, Alen Dzubur4, Azra Durak-Nalbantic4, Alden Begic4, Nedim Begic5, Amina Sahbaz6, Esma Hasanagic6, Ena Gogic4, Nabil Naser7, Fuad Zukic8, Edin Medjedovic9, Amer Iglica4, Mirela Halilcevic4, Zijo Begic5
1 Department of Cardiology, General Hospital “Prim. Dr. Abdulah Nakaš”; Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
2 Department of Cardiology, General Hospital “Prim. Dr. Abdulah Nakaš”, Sarajevo, Bosnia and Herzegovina
3 Health Care Center, Sarajevo, Bosnia and Herzegovina
4 Clinic for Heart, Blood Vessel and Rheumatic Diseases, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina
5 Pediatric Clinic, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina
6 Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
7 Cardiology, Private Polyclinic “Dr. Nabil”, Sarajevo, Bosnia and Herzegovina
8 Clinic for Radiology, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina
9 Clinic for Gynecology and Obstetrics, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Correspondence Address:
Prof. Edin Begic
Department of Cardiology, General Hospital “Prim. Dr. Abdulah Nakaš,” Sarajevo, Bosnia and Herzegovina, Kranjčevićeva 12, 71000 Sarajevo
Bosnia and Herzegovina
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/rcm.rcm_19_22
Background: Familial hypercholesterolemia (FH) is an inherited disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol and is usually diagnosed after the occurrence of major adverse cardiovascular event. Aim: The aim of this study was to evaluate FH existence, increase awareness of this disorder, and highlight the importance of early treatment which leads to a reduction of premature cardiovascular events and death. Methods: The research had a cross-sectional, descriptive, and analytical character, and included 6881 (n = 6881) patients who were hospitalized in the Clinic for Heart, Blood Vessel and Rheumatic Diseases, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina, in the period from January 2019 to January 2021. LDL values were analyzed, and all patients with LDL ≥4 mmol/L were included in the study. The Dutch Lipid Score was calculated for all patients, and the findings of invasive coronary angiography were taken into account in those patients for whom it was performed. Results: From 6881 patients, 74 patients had LDL ≥4 mmol/L. Possible FH (score: 3–5) was found in 25 patients, probable FH (score: 6–8) in 2 patients, while the diagnosis of definite FH was not made in any patient. A ST-elevation myocardial infarction was an indication for hospitalization in 44.60% (n = 33), hypertension in 14.87% (n = 11), and angina pectoris in 14.87% (n = 11) of patients. Patients under the age of 65 had higher Dutch Lipid Score compared to the patients above the age of 65, regardless of male or female. Correlational analysis indicated a significant positive relationship between Dutch Lipid Score and level of cholesterol (r =0.385; P < 0.01) and LDL (r = 0.401; P < 0.001). Statistically significant predictors in the explanation of FH were age (β = −0.45; P < 0.001) and LDL (β = 0.52; P < 0.001). Conclusion: LDL values and age are the main determinants of the FH existence, and the effect on LDL values should be imperative in clinical practice.
Keywords: Cardiovascular diseases, hyperlipoproteinemia Type II, lipoproteins
Familial hypercholesterolemia (FH) is an inherited disorder characterized by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) which results in premature atherosclerosis and early onset of cardiovascular disease.[1] FH is an autosomal dominant disorder which leads to decreased function of LDL receptors (LDLRs) resulting in insufficient clearance of circulating LDL particles. It is most commonly caused by the mutation of the gene that encodes the LDLR.[2] There are more than 900 identified mutations of LDLR.[2] However, there has also been observed a connection between FH and defects in the LDLR binding region of apolipoprotein B (ApoB)[1],[3] and gain-of-function mutations in the proprotein convertase subtilisin/kexin Type 9 (PCSK9) gene.[1],[4] There has been described a rare autosomal recessive form of FH caused by mutation in the LDLR adaptor protein 1 gene that encodes a protein that promotes the internalization of the LDLR/LDL complex.[5] Most commonly, individuals have heterozygous FH (HeFH). It is estimated to affect approximately 1 in 225–500 persons worldwide, while the prevalence of homozygous FH (HoFH) is between 1:300 000 and 1:1 000 000.[4] HoFH patients have higher levels of LDL-C, more accelerated atherosclerosis, and a more severe form of the disease compared to HeFH patients.
FH is usually diagnosed after the occurrence of major adverse cardiovascular events, even though the effects of the elevated LDL-C levels start in the first decade of life, especially in HoFH patients.[1] FH should be considered in all patients with the presence of premature cardiovascular disease. It is diagnosed based on clinical and/or genetic analysis. Diagnostic approach includes lipid levels (total cholesterol higher than 6.7 mmol/L or LDL-C >4.0 mmol/L), physical findings (tendon xanthomas, arcus cornealis, or xanthelasma), and genetic analysis.[1] The most commonly used criteria in diagnosing FH are the Dutch Lipid Clinic Network,[6] the US Make Early Diagnosis to Prevent Early Deaths Program Diagnostic Criteria,[7] and the Simon Broome Register Diagnostic Criteria.[8] Family screening, also known as cascade screening, is recommended when a patient is diagnosed with FH. It is necessary to emphasize that untreated FH patients have a 20-fold increased risk for coronary artery disease (CAD). Untreated women have a 30% risk of a myocardial infarction by the age of 60 while untreated men have a 50% risk by the age of 50.[9] The risk of early onset of symptomatic CAD is higher if one or more other risk factors are present (e.g., diabetes mellitus and cigarette smoking). Therefore, the aim of this study was to evaluate FH in our center, increase awareness of this disorder, and highlight the importance of early treatment which leads to a reduction of premature cardiovascular events and death.
MethodsPatients and study design
The research had a cross-sectional, descriptive, and analytical character, and included 6881 (n = 6881) patients who were hospitalized in the Clinic for Heart, Blood Vessel and Rheumatic Diseases, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina, in the period from January 2019 to January 2021 [Figure 1].
Methods
LDL values were analyzed, and all patients with LDL ≥4 mmol/L were included further in the study. The Dutch Lipid Score[10] was calculated for all patients. Possible FH (score: 3–5) was found in 25 patients, probable FH (score: 6–8) in 2 patients, while the diagnosis of definite FH was not made in any patient. The findings of coronary angiography were taken into account in those patients for whom it was performed. Ethical approval was obtained from the institution (No 03-02-49325 ⁄ 2019).
Statistical analysis
The Software Package SPSS Windows (version 21.0, SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis of the obtained data. Means (percentages) and frequencies were reported for quantitative and qualitative variables, respectively. An independent sample test and hierarchical regression analysis were used for data processing. Spearman's coefficient was used to calculate correlations. All analysis results below P < 0.05 or at a 95% confidence level were considered statistically significant.
ResultsFrom 6881 patients hospitalized at the Clinic for Heart, Blood Vessel and Rheumatic Diseases Clinical Center University of Sarajevo, 74 patients had LDL ≥4 mmol/L, of which 45 men and 29 women, aged between 38 and 87 years (mean = 64.53 and standard deviation = 11.11). A ST-elevation myocardial infarction (STEMI) was an indication for hospitalization in 44.60% (n = 33), hypertension in 14.87% (n = 11), and angina pectoris in 14.87% (n = 11) of patients. In 29.7% (n = 22) of the patients, there were no clear indications for coronary angiography or it was not performed due to patients' refusal, while in 4.1% (n = 3) of patients, coronarography was without significant stenosis. Single-vessel disease was found in 24.32% (n = 18), two-vessel disease in 13.51% (n = 10), and triple-vessel disease in 28.38% (n = 21) of patients. According to the results [Figure 1], there were statistically significant differences in Dutch Lipid Score between males under 65 and over the age of 65, t = 2.09, df = 43, P = 0.042, and between females under the age of 65 and over the age of 65, t = 3.05, df = 27, P = 0.005. According to the results, patients under the age of 65 have higher Dutch Lipid Score compared to the patients above the age of 65, regardless of male or female. Correlational analysis indicated a positive significant relationship between Dutch Lipid Score and level of cholesterol (r = 0.385; P < 0.01) and LDL (r = 0.401; P < 0.001) [Figure 2]. In the first model, we put nonmodifiable risk factors, and they explained 25.5% (ΔR = 23.4) of the variance of the criteria variable. The obtained results of the hierarchical regression analysis showed that the final model explained 50.8% (ΔR = 46.4) of the variance of the Dutch Lipid Score and diagnosis of FH. Statistically significant predictors in the explanation of FH were age (β = −0.45; P < 0.001) and LDL (β = 0.52; P < 0.001) [Table 1] and [Table 2].
Figure 2: Difference between Dutch Lipid Score according to age and gender
Table 1: Correlation between familial hypercholesterolemia and lipid levels
Table 2: Hierarchical regression analysis of familial hypercholesterolemia Discussion The issue of hyperlipidemia or dyslipidemia is emphasized in both primary and secondary prevention of cardiovascular diseases.[11] Prevention of acute cardiovascular events is based on the reduction of total cholesterol, and in particular on the reduction of LDL.[11] The use of statins is the base of the prevention, along with ezetimibe and PCSK9 inhibitors.[11] There is no proven clinical benefit of fibrate use in primary and secondary prevention.[2] The use of statins in the primary prevention of acute coronary syndrome (ACS) is very important, but it should be done in accordance with the patient's profile and his comprehensive personal, family, and socioepidemiological history.[11] Stratification of patients in relation to the risk of cardiovascular incident is essential. In the low-risk population, LDL values should be <3.0 mmol/L, at moderate risk <2.6 mmol/L, and in high and very high risk should be ≥50% LDL values reduced from baseline (at very high risk, patients should achieve LDL values <1.4 mmol/L).[2] LDL treatment should be part of the puzzle of cardiovascular incident prevention, in addition to smoking cessation, cardioprotective diet, optimal physical activity and body mass index, blood pressure and diabetes control, triglycerides, and other parameters (ApoB and nonhigh-density lipoprotein).[2],[11] Secondary prevention must be in accordance with the characteristics of patients, in optimized pharmacological treatment, knowing all of the patient's characteristics, but also the pharmacodynamics and pharmacokinetic properties of the drug.[2] FH, especially HeFH, is gaining in importance, especially through screening programs.[12] The prevalence of the HeFH is considered to be underestimated.[12] Initially, the prevalence of HeFH was observed at 1 in 500 (0.2%), and later through meta-analyzes, it was concluded that the overall random-effects pooled prevalence of FH was 0.40, and the prevalence itself tended to increase with age.[13],[14] In our study with 6881 patients, 74 had LDL ≥4 mmol/L, and 44.60% of them were admitted due to STEMI. Coronary angiography showed that 28.38% (n = 21) of patients had triple-vessel disease. What is interesting is that patients under the age of 65 have a higher Dutch Lipid Score compared to patients above the age of 65, regardless of male or female. Furthermore, through the hierarchical regression, age and LDL values were the predictors that determine the Dutch Lipid Score. Among 74 patients, 25 were identified with possible FH (Dutch Lipid Clinic Score: 3–5), 2 with probable (Dutch Lipid Clinic Score: 6–8), while the diagnosis of definite FH was not made in any patient based on Dutch Lipid Score. This emphasizes the importance of primary and secondary prevention and pharmacological therapy. Many organizations have recommended universal lipid screening in childhood as a strategy to identify FH.[15],[16] About 8% of adults hospitalized for ACS have been shown to have clinical criteria compatible with FH,[15],[16] although this number could not be obtained through this study. Li et al.[17] reported that the prevalence of FH was 5.8% in Chinese patients with CAD and 3.9% in patients with myocardial infarction. Genetic testing is considered the gold standard for the diagnosis of FH. Since it is not available in low-income countries, screening programs based on LDL values and Dutch Lipid Score parameters should be used.[18] Pojskic et al. during the period March 2008–November 2016 in 307 patients with LDL >4.5 mmol/L that were hospitalized in Cantonal Hospital Zenica, Bosnia and Herzegovina, found 16 patients with diagnosis of definite FH according to Dutch Lipid Score.[12] There are no other data on FH in Bosnia and Herzegovina, and also there is no regular screening program. Initiation of the screening program is essential, especially since the use of PCSK9 inhibitors is a modern approach to hypercholesterolemia, and the patient database itself is necessary for health-care planning. Analysis of larger number of patients is necessary for conclusions on the status of the population of Bosnia and Herzegovina, and all centers in Bosnia and Herzegovina should be included in the analysis, which is one limit of this research. Furthermore, the analysis of lipoprotein (a) should be part of the analysis, which would enrich the research, but it is still not a routine in Bosnia and Herzegovina, which would be imperative to change in the near future.
Presumably, primary health care should be a place where that could be provided, because of the largest number of patients in their daily practice.[19] Professional organizations should educate medical practitioners to increase awareness about the signs, diagnosis, and significance of FH as well as about the benefits of early treatment.[20] LDL values and age are the main determinants of the FH existence, and the effect on LDL values should be emphasized through practice. Consideration of hypertriglyceridemia is also of great importance. For patients aged 45 years or older with clinical atherosclerotic cardiovascular disease, or 50 years or older with type 2 diabetes requiring medication and ≥1 additional risk factor, and fasting triglycerides 1.6–5.6 mmol/L on maximally tolerated statin therapy, with or without ezetimibe, treatment with icosapent ethyl is recommended for the reduction of atherosclerotic cardiovascular disease risk.[21] Bosnia and Herzegovina also does not have registers of rare metabolic disorders, so in practice, one can find isolated cases, from which no large conclusion can be drawn.[22],[23],[24] Genetic analysis should be added as standard of care even in pediatric practice, and screening of FH in the pediatric population is one of the directions of development.[22],[23] Primary prevention programs are of tremendous importance and should be performed in daily clinical practice, especially in primary health care.
ConclusionPrimary prevention programs are of tremendous importance and should be performed in daily clinical practice, especially in primary health care.
Acknowledgment
The researchers would like to extend their sincere thanks and gratitude to Dalila Lisica MA for help in statistical processing of data.
Ethical clearance
Ethical approval was obtained from Ethical Committee ((No 03-02-49325 ⁄ 2019).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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