1
Yohai Waismann
6th Course, group 31
THE
PREVALENCE
AND
THE
CARDIOVASCULAR
OUTCOMES
OF
HETEROZYGOUS
FAMILIAL
HYPERCHOLESTEROLEMIA
AND
ITS
COST
EFFECTIVENESS OF EARLY DIAGNOSIS
A systematic review
Supervisor
PhD, Indre Ceponiene
2
LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
FACULTYOFMEDICINE
THECLINICOFCARDIOLOGY
THE PREVALENCE AND THE CARDIOVASCULAR OUTCOMES OF HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA AND ITS COST EFFECTIVENESS OF EARLY
DIAGNOSIS
A systematic review
The thesis was done
by student ………... supervisor ………... (name surname, year, group) (degree, name surname)
……….. ………
(signature) (signature)
……… 20…. ……… 20….
(day/month) (day/month)
3
EVALUATION TABLE OF THE MASTER’S THESIS OF THE TYPE OF
SYSTEMIC REVIEW OF SCIENTIFIC LITERATURE
Evaluation:
………
Reviewer:
………
(scientific degree. name and surname)
Reviewing date: ...
No. MT parts MT evaluation aspects
Complian ce with MT requirem ents and evaluatio n Yes Parti ally No 1 Summary (0.5 point)
Is summary informative and in compliance
with the thesis content and requirements? 0.3 0.1 0
2 Are keywords in compliance with the
thesis essence? 0.2 0.1 0
3 Introductio n, aim and tasks (1 point)
Are the novelty, relevance and significance of the work justified in the introduction of the thesis?
0.4 0.2 0
4 Are the problem, hypothesis, aim and tasks
formed clearly and properly? 0.4 0.2 0
5 Are the aim and tasks interrelated? 0.2 0.1 0
6 Selection criteria of the studies, search methods and strategy (3.4 points)
Is the protocol of systemic review present? 0.6 0.3 0
7
Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language, publication condition, etc.)
0.4 0.2 0
8
Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and are the last search day
4
indicated?
9
Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and
selected articles according to the
combinations of keywords)?
0.4 0.1 0
10
Is the selection process of studies (screening, eligibility, included in systemic review or, if applicable, included in the meta-analysis) described?
0.4 0.2 0
11
Is the data extraction method from the
articles (types of investigations,
participants, interventions, analyzed factors, indexes) described?
0.4 0.2 0
12
Are all the variables (for which data were
sought and any assumptions and
simplifications made) listed and defined?
0.4 0.2 0
13
Are the methods, which were used to evaluate the risk of bias of individual studies and how this information is to be used in data synthesis, described?
0.2 0.1 0
1 4
Were the principal summary measures (risk
ratio, difference in means) stated? 0.
4 0.2 0 1 5 Systemizati on and analysis of
Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented? 0. 6 0.3 0 1 6
Are the characteristics of studies presented in the included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented?
0. 6
5
1 7
data
(2.2 points)
Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect estimates and confidence intervals)
0. 4
0.2 0
1 8
Are the extracted and systemized data from studies presented in the tables according to individual tasks? 0. 6 0.3 0 1 9 Discussion (1.4 points)
Are the main findings summarized and is their
relevance indicated? 0.
4
0.2 0
2 0
Are the limitations of the performed systemic
review discussed? 0. 4 0.2 0 2 1 Does author results? presen t th e interpretatio n o f th e 0.4 0.2 0 2 2 Conclusions (0.5 points)
Do the conclusions reflect the topic, aim and
tasks of the Master’s thesis? 0.
2
0.1 0
2 3
Are the conclusions based on the analysed material? 0. 2 0.1 0 2 4
Are the conclusions clear and laconic? 0.
1 0.1 0 2 5 References (1 point)
Is the references list formed according to the
requirements? 0.
4
0.2 0
2 6
Are the links of the references to the text correct? Are the literature sources cited correctly and precisely? 0. 2 0.1 0 2 7
Is the scientific level of references suitable for
Master’s thesis? 0.
2
0.1 0
2 8
Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%?
0. 2
0.1 0
Additional sections, which may increase the collected number of points
2 9
Annexes Do the presented annexes help to
understand the analysed topic? +0.2 +0.
1
6 3 0 Practical recommend ations
Are the practical recommendations
suggested and are they related to the received results? +0.4 +0. 2 0 3 1
Were additional methods of data analysis and their results used and described (sensitivity analyses, meta-regression)?
+1 +0.
5
0
32
Was meta-analysis applied? Are the selected statistical methods indicated? Are the results of each meta-analysis presented?
+2 +1 0
General requirements, non-compliance with which reduce the number of points
33
Gener al requir ements
Is the thesis volume
sufficient (excluding annexes)? 15-20 pages (-2 points) <15 pages (-5 points )
34 Is the thesis volume
increased artificially? -2 points -1 point
35 Does the thesis structure
satisfy the requirements of Master’s thesis?
-1 point -2
points
36 Is the thesis written in
correct language,
scientifically, logically
and laconically?
-0.5 point -1
points
37 Are there any
grammatical, style or
computer literacy-related mistakes?
-2 points -1 points
38 Is text consistent, integral,
and are the volumes of its structural parts balanced?
-0.2 point -0.5 points 39 Amount of plagiarism in the thesis. >20% (not evaluated) 40
Is the content (names of sections and sub- sections
and enumeration of
pages) in compliance with
-0.2 point -0.5
7
the thesis structure and aims?
41
Are the names of the thesis parts in compliance with the text? Are the titles of sections and
sub-sections distinguished
logically and correctly?
-0.2 point -0.5
points
42 Are there explanations of
the key terms and
abbreviations (if needed)?
-0.2 point -0.5
points
43
Is the quality of the thesis typography (quality of
printing, visual aids,
binding) good?
-0.2 point -0.5
points
*In total (maximum 10 points):
*Remark: the amount of collected points may exceed 10 points.
Reviewer’s comments: ________________________________________________________________________ ________________________________________________________________________ ___________________________________________________________________________________ ___________________________________________________________________________________ ___________________________________________________________________________________ ___________________________________________________________________________________ ___________________________________________________________________________________ ___________________________________________________________________________________ Reviewer’s name and surname Reviewer’s signature
8
TABLE OF CONTENTS
ABSTRACT………... page 1
INTRODUCTION……….…. page 2
SELECTION CRITERIA OF THE STUDIES. SEARCH METHODS AND STRATEGY ……….……….. page 3-4
1
ABSTRACT
Purpose:
the goal of this study was to illustrate the importance of early FH diagnosis, thecardiovascular consequences on the individual, and its economic consequences at the state level.
Material and methods:
In this systematic review, a search of the published data was performed inseveral electronic databases including PubMed, Science Direct, UptoDate and ESC-european society of cardiology as at January 2019.
Inclusion criteria were: English language, human subjects, articles published from January 1st, 2013 till
3th ofJanuary 2019, study selection, risk of bias assessment using the Cochrane handbook, and
data-extraction were performed.
Results:
After the removal of duplicates, a total of 2,022 scientific publications and articles were identified, and were related to keywords used during the search. 1,921 studies were excluded for not having access to full study or studies written in other languages. Finally, after full-text articles wereassessed for eligibility, 21 articles were included in the review.
This systematic review indicated a prevalence of FH 1:108 to 1:250 which is twice as prevalent as previously suggested (1:200-1:500). Moreover, 35%.4 of HeFH patients on average experience cardiovascular complication and the early diagnosis of FH is high cost effective.
Conclusion:
The prevalence of FH in general population is higher than previously anticipated. Theincidence of cardiovascular outcomes in FH patient is high, and early diagnosis of HeFH is highly cost effective. This suggests the need for national screening for FH starting in as early as childhood. Moreover, cascade screening in the family members of FH patients should be implemented on routine basis.
Keywords:
Familial Hypercholesterolemia, Silent Myocardial Ischemia, Coronary Heart Disease,2
INTRODUCTION
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disease caused by a genetic defect in the LDL-C receptors in the vast majority of the cases, and the APOB gene or PCSK9 genes in the minority of the cases. [1]
These mutations lead to an accumulation of LDL-C and are shown to inflict the carriers of the defect with more cardiovascular complications and premature death than the general population. [2]
Heterozygous is one form of the FH condition, and it was found to be responsible for 78.5% of the entire population which was found to have FH, only 0.8% of the FH patients were found with Homozygous [3], the rest have double mutation.
The most prevalent complications of HeFH are cardiovascular related and are due to the very early atherosclerotic plaques development due to the high circulating LDL-C in these patients, which leads to early manifestation of coronary artery disease (CAD).[4]
The average untreated LDL-C value in heterozygous FH is 190 mg/dL. [5]
The European Atherosclerosis Society FH Studies indicates that the prevalence of FH is 1:200-1:500 . [6]
Although it is believed by many that the lethality of this genetic condition translates solely to elevated serum LDL-C and its contribution to the early development of CAD it is shown to be more dangerous and bear more complications than individuals who have similarly high levels of LDL-C but without heterozygous Familial hypercholesterolemia. [7]
Although this genetic condition is not extremely rare and has major significance, only 1% of the worldwide carriers of the genetic condition are diagnosed. [8]
In this systematic review, the aim is to illustrate the importance and cost effectiveness of early FH
diagnosis by demonstrating its prevalence in society and its cardiovascular consequences on the
patients.
To find the answer to this question, the prevalence of FH in different populations will be examined.
Later, the cardiovascular outcomes and their severity on FH patients will be reviewed. Finally, we will
check whether or not early FH diagnosis is cost effective.
3
SELECTION CRITERIA OF THE STUDIES.
SEARCH METHODS AND STRATEGY
This systematic review was reported according to the protocol of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement for reporting systematic reviews of the health
sciences.[9]
Search strategy:
The systematic literature review is based on a selection from a main information source. The main information source was literature studies from electronic databases.
The keywords that were used in thesearch are:―Familial Hypercholesterolemia, Silent Myocardial
Ischemia, Coronary Heart Disease, Coronary Artery Disease, Cardiovascular outcomes, Screening, Cost effectiveness‖.
Comprehensive electronic searches up to 3rd of January, 2019 were conducted in the following
databases: PubMed and Sciencedirect.
The literature search included assessment of articles from Medicals journals that were also in the
English language,studies that were performed on humans only and published in the years from January
1st 2013 till 3rd ofJanuary 2019and included the keywords that were selected.
In all database the same method of search strategy performed: ―Familial Hypercholesterolemia AND (cardiovascular outcomes OR Silent Myocardial Ischemia OR screening OR Coronary Artery Disease OR Coronary heart Disease OR Cost effectiveness)‖. The references of these articles were then reviewed to identify additional studies
In total after duplicates removed 2,022 scientific publications and articles were identified and were related to keywords used during the search.
Titles and abstracts derived from this broad search were independently screened to eliminate irrelevant publications, commentaries articles and individual case reports. Review articles and letters to the editor
were also excluded. The final stage of screening involved reading the full texts to confirm the
eligibility of each study, based on inclusion and exclusion criteria.
4
Intervention: no intervention needed.
Comparison: between patients with FH and without, men to women. Outcomes: cardiovascular diseases and/or events.
Study design: randomized and non-randomized controlled trials, observational trials (descriptive and analytical) and clinical trials (prospective and retrospective), excluded articles of animal studies, abstracts, discussions, review articles and letters to the editor.
The inclusion criteria for this systematic review were: 1. All the study subjects are humans.
2. Years of articles publication were chosen from January 1st 2013 till the 3th ofJanuary 2019.
3. English language.
The exclusion criteria were: 1. Non- human studies. 2. In vitro studies.
5
SYSTEMIZATION AND ANALYSIS OF DATA
The articles review, and data extraction were performed according to PRISMA flow diagram (figure 1)
[9]. The initial database search displayed 2,401 results. The preliminary exclusion was done by
relevance; 379 duplicated titles and abstracts were excluded. After review of the remaining 2,022
articles,1,921 were excluded due to lack of information, article with no access, not full text of articles,
due to language (not in English), single case report, literature reviews and discussions articles. 101
full-text articles assessed for eligibility. Finally, 21 articles were included in the review. A flow chart of
6
7
Assessment of methodological quality
The quality of all included studies were assessed during the data extraction process and involved evaluating the methodological elements that might influence the outcome of each study (Table 1).
Table 1: Cochrane Risk of bias summary. [10]
8 2017 Lázaro P. et al 2017 ? ? ? ? ? + + Bahia L.R. et al 2017 ? ? ? ? + + + Ahmad Z. S. et al 2016 ? ? ? ? ? ? + Mundal L. et al 2016 ? ? ? ? + + + Benn M. et al 2016 ? ? + ? + + + Pajak A. et al 2016 ? ? + ? + ? + Degoma E.M. et al 2016 ? ? ? ? + + + De Ferranti S. D. et al 2016 ? ? + ? + ? + Brunham L.R. et al 2017 ? ? ? ? + + + Nordestgaard B.G et al 2013 ? ? + ? ? + +
9
The Cochrane handbook for assessing risk of bias [10] was used to assess bias across the studies and to identify papers with intrinsic methodological and design flaws. Based on the information given in each study the potential risk of bias was categorized into: low risk of bias (+), unclear risk of bias (?), or high risk of bias (-). According to Cochrane evaluation the included researches dividing into 4 groups of bias evaluation.
The studies that were included in the first group got the best results of bias with 4 characteristics of ―low risk of bias‖ (+) and 3 with ―unknown risk of bias‖ (?). There were three studies included in the above mentioned group: Benn M. et al 2016, Tada H. et al 2017 and Ershova AL. et al 2017. Second group included most of the studies reviewed in this systematic review- fifteen studies in number, with the results of 4 out of seven ―unknown risk of bias‖ (?) mark and three ―low risk of bias‖ (+). Third group of studies resulted in 5 ―unknown risk of bias‖ (?) mark included two studies which differ in the 2 rests marks: Lázaro P. et al 2017 had 2 marks of ―low risk of bias‖ (+) while: Zamora A. et al 2017 had one mark of ―low risk of bias‖ (+) and one mark of ―high risk of bias‖ (-). The fourth and last group of studies contain only one study: Ahmad Z. S. et al 2016 which had six out of seven marks of ―unknown risk of bias‖ (?) and one mark of ―low risk of bias‖ (+).
10
RESULTS
Detailed report of characteristics for each study and outcomes are presented in Tables 2, 3 and 4.
Table 2: Prevalence of FH in different populations and samples.
11 Ershova AL. et al 2017 Obs Russia, west Siberian region, (Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study) n= 3,252 30 2012-2013 25-64 1/108
* Obs = Observational study.
In table 2 the population data gathered across nine studies that were utilized in this study are presented. The lowest prevalence found of a FH patients from the general population was that of 1:250 in the study populations of research conducted in the Czech Republic, National database (Vrablik M. et al
2017) , the population of the USA (De Ferranti, S. D. et al 2016) and the population of Poland (Pajak A. et al 2016). It is to be noted that two of the population studies we reviewed above had the highest
sample size out of all the studies we used (10,000,000 and 210,000,000 respectively).
On the other end of the spectrum, the highest prevalence found in general population was that of 1:108 done in Russia west and Siberian region during 2012-2013 (Ershova AL. et al 2017) but unlike the studies in which the prevalence was found to be much lower the sample size of this specific study was rather small at a total of 3252. Two other studies used the population sample of Copenhagen were published 3 years apart and the one which was published at 2013 (Nordestgaard B.G et al 2013) found a prevalence of 1:200 with a sample size of 69,000 and the second article published 3 years later (Benn
M. et al 2016) found a lower prevalence of 1:217 with a sample size of 98,000. Within the primary
care records of catalan at the european mediterranean (Zamora A. et al 2017) a prevalence of 1:192 was recorded during the years of 2006-2014 with a sample size of 2,554,644.
12
Table 3: Cardiovascular outcomes of FH.
Author and year of publication Study design Total individua ls with FH (n) Male sex (%) Present of CVD (%) Mean age (years )
Outcomes from most prevalent to least Patients had CVD event Pérez García L. 2018 Retrospe ctive, observati onal study 133 50.40% 8.30% 45.35
Ischemic heart disease, coronary heart disease -
Sun D. et al 2018 cross-sectional study (observa tional study) 148 52% 59% 49 CAD - Zamora A. et al 2017 Cross sectional , observati onal study 14,699 64.30% men 24.6% women 11.6% 69.3 cardiovascular disease, coronary heart disease, stroke, peripheral artery
disease. - Paquette M. et al 2017 Retrospe ctive study 725 43% men 40% women 25.8% 38.4 CVD,CAD,PVD,Stroke n=231 (32%) Ershova AL. et al 2017 Observat ional study 30 23.30% 40% 57 CAD - Pérez de Isla L. et al 2017 Prospect ive study 2,746 47.60% 13.20% 45.4 ASCVD, myocardial infarctions, coronary artery revascularization procedure, stroke,cardiovascular death non fatal=122 , fatal=12
13 et al 2017 ive study =8 (3.5%) Haymana C. et al 2017 Retrospe ctive study 124 45% 30.80% 48.3 CAD,CHD - Tada H. et al 2017 Retrospe ctive study 502 47% 29% 45
CAD- severe stenotic region(s) in coronary arteries, angina pectoris, myocardial infarction. - Vrablik M. et al 2017 Observat ional study 3,067 36.10% 30.40% 52.6 Hypertension, premature atherosclerosis, xanthelasma palpebrarum and tendon xanthomatosis - Brunham L.R. et al 2017 observati onal study 339 48.70% 12.10% 43.9 percutaneous intervention, Angina, Myocardial infarction, Coronary artery bypass
grafting and stroke n=33.5
De Ferranti, S. D. et al 2016 Observat ional study 834,500 51% 53.45% 54 Atherosclerotic cardiovascular disease - Degoma, E.M. et al 2016 cross-sectional study (observa tional study) 1,295 40.70% 38% 57 CHD,stroke, aortic valve disease - Ahmad Z. S. et al 2016 observati onal,
cross-sectional 1,027 43% 38% 51 premature CAD -
Mundal L. et al 2016
Retrospe ctive
14
CVD= cardiovascular disease, CAD= coronary artery disease, PVD= peripheral vascular disease,
CHD= coronary heart disease, ASCVD= atherosclerotic cardiovascular disease.
Table 3 shows us the percentage of individuals with a cardiovascular disease, and its type, out of a total population sample which consist of FH patients.
The two most recent studies published in 2018 (Pérez García L., Sun D. et al) present us with results of great disparity:
Pérez García L found that out of 133 individuals with FH only 8.5% of them presented with a
cardiovascular disease, and Sun D. et al found that 59% of 148 FH patients had a cardiovascular disease.
The mean age of Pérez García L’s study was 45 while the study of Sun D. et al which presented greater rates of cardiovascular pathology had a mean age of 49. Both studies found CAD as the principal outcome the patients had.
Other studies which were published between 2016 and 2017 also found CAD as the primary cardiovascular outcome in FH but mentioned other pathologies as well:
Zamora A. et al, with a sample size of 14,699 found stroke and peripheral artery disease to be the most
prevalent complication aside of CAD, with 64% being male and the mean age being 69. The same findings were found at Paquette M. et al study with peripheral artery disease and stroke as a complication second only to CAD and with Pérez de Isla L. et al, as well.
Vrablik M. et al with a sample size of 3,067 and 30% cardiovascular complication rate mentioned
xanthelasma palpebrarum and tendon xanthomatosis as a cardiovascular finding in its population sample.
Degoma, E.M. et al with a sample size of 1,295 showed that other than CAD stroke and aortic valve
disease are the most prevalent outcomes.
Two other studies mentioned not only a cardiovascular disease outcome in FH patients but also mentioned fatality among those patients.
Pérez de Isla L. et al mentioned 12 fatal cardiovascular events amongst its 2,746 FH patients and Auckle R. et al show 8 deaths out of 230 FH patients (3.5%).
15
The second highest percentage was 59% of patients with cardiovascular complication out of 148 patients in the study of Sun D. et al and with the study of De Ferranti, S. D. et al, 53.45% were diagnosed with a cardiovascular pathology of 834,500 FH patient.
four additional studies done by Brunham L.R. et al., Tada H. et al , Haymana C. et al and Paquette M.
et al found that 48.7%, 47%, 45% and 43%, of their FH patients studied respectively were diagnosed
with a CAD.
Reviewing the studies above we can see that the average age in which a cardiovascular complication manifests itself in a patient diagnosed with FH is 43.9-69, which is much lower than the average age found in non FH population (Annex 1).
It is of no surprise to see that the principle cardiovascular outcome found in FH individuals reviewed in the studies above is that which related to atherosclerotic diseases whether it is mainly CAD or peripheral artery disease and strokes. On the other hand only one study (Vrablik M. et al 2017) mentioned tendon xanthomatosis and xanthelasma palpebrarum which we expected to see a lot more of due to the pathogenetic correlation FH individuals seem to have with elevated cholesterol levels.
Table 4: cost effectiveness
Author and year of publication Study design Country/ society Cost effectiveness Bahia L.R. et al 2017 Retrospectiv e, cross-sectional study
Brazil Cost effective
Nordestgaard B.G et al 2013 Observationa l study European Society Highly cost effective Lázaro P. et al 2017 prospective cohort study
Spain Cost effective
16
Table number 4 confers about our 3rd aim regarding the cost effectiveness of early FH screening. In the first article by Bahia L.R. et al which was conducted in Brazil it is suggested that diagnosis of FH and early intervention with cholesterol -lowering medications can have a strong impact in reducing the clinical and economic burden of the disease , a conclusion which translates early FH diagnosis to a highly cost effective procedure.
In addition, the 2nd article we reviewed was done by Nordestgaard B.G et al at the European Society deduced that for individuals in whom the causative mutation has been found, performing a cascade testing of their undiagnosed and asymptomatic relatives and family members using one of the various genetic tests for FH is highly cost-effective, as roughly 50% will have inherited the mutation -and
manifest the outcomes discussed in second objective of the thesis- and ―roughly €4700 million could be
saved... equating to an economy of €86 million per year.‖
Furthermore, in the article of Lázaro P. et al which was conducted in Spain, they concluded: ―This study shows that a standardized implementation of a national cascade screening program for FH... and appropriate treatment is a cost-effective strategy for preventing CAD in families with FH.‖
Lastly, an article done in the UK by Kerr M. et al came to the conclusion that ―Cascade testing of relatives of those with suspected FH is highly cost effective‖
Of the four articles found and analyzed two came to a verdict that it is highly cost effective to early diagnose FH and to relieve an economic burden of the countries.
Two others simply states that they too found it cost effective and no other study we found claimed otherwise.
17
DISCUSSION
During our assessment and evaluation of the data in the 21 studies that were gathered in this master thesis and while working on this systematic review, we found regarding the prevalence of FH that unlike the suggested figure in the European Atherosclerosis Society FH Studies of 1:200-500 that the prevalence of FH in last 10 years has been closer to 1:108-1:250 in our selected countries, a figure which reveals FH to be two times more prevalent than previously suspected.
A point to consider is that the real prevalence is still generally unknown and could be even far more prevalent than indicated in the studies discussed here due to to the fact the only 1% of the world wide carriers of the FH gene are diagnosed and even a smaller percentage of the population know of their carrier relative.
One of the variables needed in order to solve the equation of whether its cost effective to early diagnose FH is to first uncover its consequences on society and on the individual patients.
We found that an average of 35.4% of the FH patients suffer from various cardiovascular complication
at the average age of 43.9-69 with the most prevalent outcome being coronary artery disease. Given the underdiagnosed state of FH and the underestimated prevalence it has in society and how preventable the CAD complication is if only treated early we hypothesized that the cost effectiveness of early diagnosis will be very high, due to the diagnostic procedures the cardiovascular outcomes of FH require, the doctors time executing them, drugs given and prescribed and the effect on work productivity within the economy as the average age we found, of FH complication is well before the retiring years by law in most european and western countries.
During our evaluation of the relevant literature regarding the cost effectiveness we found 4 studies (Bahia L.R. et al 2017, Nordestgaard B.G et al 2013, Kerr M. et al and Lázaro P. et al 2017) that dealt
18
Limitation:
There is no doubt that the numbers of studies available in our days are not enough to reliably answer all of our questions. There are not enough studies or data sources describing the prevalence of FH among the general population and we have only found seven of them.
Not only that but due to the underdiagnosed state FH is currently at, the numbers could vary greatly once more cascade screening will be initiated and more efforts will be directed towards early diagnosis of FH among general practitioners.
19
CONCLUSION
The hypothesis of this systematic review stated that the FH prevalence will be much higher than previously estimated and due to the severity and frequency of the cardiovascular outcomes that manifest among FH patients the early diagnosis of FH will be highly cost effective and was proven by the following findings:
1) The prevalence of FH we found was 1:108 to 1:250 which is twice as prevalent as previously anticipated 1:200-1:500
2) We found that an average of 35.4% of FH patients will manifest a cardiovascular complication that will require early treatment.
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PRACTICAL RECOMMENDATIONS
After extensive data gathering from various researches and papers we recommend based on our understanding the following:
1) HeFH screening is recommended for- every child during the ages of 8-12, determined by his
general practitioner.
2) Adult with any signs of Hypercholesterolemia:
a) Cholesterol of >310 mg/dL (>mmol/L).
b) Individual which is diagnosed with premature coronary heart disease that could suggest HeFH.
c) Sudden cardiac death in a family member at a premature age range.
21
REFERENCES
1) Austin, M. A., Hutter, C. M., Zimmern, R. L., & Humphries, S. E. (2004). Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. American
Journal of Epidemiology, 160(5), 407–420.
2) Krogh, H. W., Mundal, L., Holven, K. B., & Retterstøl, K. (2016). Patients with familial
hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death.
European Heart Journal, 37(17), 1398–1405.
3) Pérez García, L. (2018). Familial hypercholesterolemia: Experience in the Lipid Clinic of Alava.
Clinica e Investigacion En Arteriosclerosis, 30(5), 224–229.
4) Benn, M., Watts, G. F., Tybjaerg-Hansen, A., & Nordestgaard, B. G. (2012). Familial
hypercholesterolemia in the Danish general population: Prevalence, coronary artery disease, and cholesterol-lowering medication. Journal of Clinical Endocrinology and Metabolism, 97(11), 3956– 3964.
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hypercholesterolæmia in children and adolescents: Gaining decades of life by optimizing detection and treatment. European Heart Journal, 36(36), 2425–2437.
6) https://www.eas-society.org
7) Khera, A. V., Won, H. H., Peloso, G. M., Lawson, K. S., Bartz, T. M., Deng, X.,
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