Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum

doi:10.1016/j.jacl.2013.01.005

Journal of Clinical Lipidology

Volume 7, Issue 3, May–June 2013, Pages 217-221

https://doi.org/10.1016/j.jacl.2013.01.005 Get rights and content

Abstract

Heterozygous familial hypercholesterolemia (HFH) affects on average 1 in 500 individuals in European countries, and it is estimated that HeFH in Poland may affect more than 80,000 people. Cardiovascular mortality in individuals with FH between 20 and 39 years of age is 100 times higher than in the general population. HFH is a relatively common lipid disorder, but usually still remaining undiagnosed and untreated. A very high risk of cardiovascular diseases and a shortened lifespan in patients with this condition require early diagnosis and intensive treatment. The aim of the position paper was to present the importance and scale of this problem in Poland, which has not been raised enough so far, as well as the recommendations of diagnosis, treatment and prevention methods.

Section snippets

Epidemiology and pathogenesis

FH is the most common monogenetic disease.1, 6 Because of the autosomal-dominant inheritance, two forms of the disease are distinguished: heterozygous (ie, HeFH) and homozygous. Homozygous FH occurs in 1 per million live births, whereas HeFH affects on average 1 in 500 individuals in European countries.¹ It is estimated that HeFH in Poland may affect more than 80,000 people.

The phenotype of FH is associated with mutation of one of the three genes: low-density lipoprotein (LDL) receptor gene

FH as a risk factor of CHD

FH is a potent risk factor of CHD.¹⁴ The coexistence of additional risk factors, especially smoking, significantly accelerates the development of premature atherosclerosis.1, 3 It is estimated that in the majority of untreated men and women with HeFH, CHD manifests before the age of 60. Patients with FH are a priori assigned to the high-risk group without the need for the European Society of Cardiology (ESC) HeartScore or Framingham algorithms to estimate the risk of CV in the primary

Diagnostic criteria of HeFH

FH is diagnosed on the basis of the Dutch Lipid Network criteria adopted in Geneva in 1998 by the World Health Organization (WHO).¹ The criteria were also adopted by the ESC and European Atherosclerosis Society (EAS) in “ESC/EAS Guidelines for the Management of Dyslipidaemias” in 2011.³ Clinical criteria of FH include the following: high plasma levels of LDL cholesterol, the presence of arcus cornealis and tendinous xanthomas, premature cardiovascular disease (CVD), and positive family history

Recommendations for identification of HeFH

According to the National Institute for Health and Clinical Excellence guidelines, the coexistence of cholesterol concentrations >300 mg/dL (7.8 mmol/L) with premature CVD in first-degree relatives (siblings, parents, or children) is strongly suggestive of FH.2, 19 In families with FH, the condition should be diagnosed in children and dietetic treatment initiated as soon as possible; treatment with statins should be introduced in children older than 10 years of age.²⁰ If HeFH is diagnosed,

Target LDL cholesterol concentration

After a clinical diagnosis of FH has been established (a score of 5 or more), intensive treatment should be initiated without waiting for the results of molecular testing.2, 3, 4, 5 The target LDL cholesterol concentration in patients with FH in primary prevention of CHD, because of their high risk, should be <2.5 mmol/L (<100 mg/dL). In patients with concomitant CVD, the risk is very high and the goal of treatment is an LDL cholesterol concentration <1.8 mmol/l (<70 mg/dL).2, 5 If this is not

Therapeutic management of HeFH

The most important objective of treatment in patients with FH is to reduce premature CV mortality as well as the incidence of myocardial infarction and the need for revascularization.³ Lifestyle changes are necessary to eliminate additional CV risk factors.³ Recommendations for patients with FH include absolute abstinence from smoking, physical activity (at least 30 minutes of exercise for a minimum of 5 days per week, ie, brisk walking, running, or cycling), arterial blood pressure < 140/90

Conclusions

HeFH is a relatively common lipid disorder that usually remains undiagnosed and untreated. Because these patients are at a very high risk of CVDs and a shortened lifespan, this condition requires early diagnosis and intensive treatment.

Acknowledgment

The position paper has been officially endorsed by Polish Lipid Association (PoLA) and Cardiovascular Pharmacotherapy Working Group of Polish Cardiac Society. The current position paper is also published in parallel in Kardiologia Polska (Polish Journal of Cardiology) in Polish.

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Cited by (28)

The prevalence and management of familial hypercholesterolemia in patients with acute coronary syndrome in the Polish tertiary centre: Results from the TERCET registry with 19,781 individuals
2019, Atherosclerosis
Citation Excerpt :
Extrapolation of the available data allows estimating that the worldwide occurrence of the heterozygous FH varies between 1:200 and 1:250, therefore bringing the total number of patients burdened with the disease to 14–34 million [7]. In Poland, there might be even 120–150,000 patients with FH [9–13]. The higher occurrence of the disease (reaching even 1:67) has been confirmed among the members of the French-speaking Canadian population, Ashkenazi Jews, the Afrikaners from South Africa, the Southern African Hindus, Finns and in the population of the Lebanese Christians, and might be associated with the founder effect [14–17].
The prevalence of familial hypercholesterolemia (FH) is high among patients with stable coronary artery disease (CAD). However, data on FH on admission among patients with acute coronary syndrome (ACS) are still relatively scarce. Therefore, we aimed to assess the prevalence, lipid-lowering therapy and short- and long-term outcomes in patients with FH among ACS patients.
The investigation was performed in a cohort of 19,781 consecutive patients from the TERCET Registry. There were 7319 patients admitted with ACS: 3085 due to STEMI, 2256 due to NSTEMI, and 1978 due to UA. The stable CAD group (n = 12,462) was considered the reference group. Based on the personal and familial history of premature cardiovascular disease and LDL cholesterol concentration, the Dutch Lipid Clinic Network (DLCN) algorithm was used for FH diagnosis.
The overall occurrence of probable/definite FH and possible FH was 1.2% and 13.5% respectively. Among patients with ACS, 1.6% had probable/definite FH and 17.0% possible FH. The highest occurrence of FH was observed in the STEMI subgroup (20.6%). Patients with definite and probable FH had higher 30-day mortality than patients without FH (8.2% and 3.8% vs. 2.0%, respectively; p = 0.0052). No significant differences were observed between the FH groups in the 12-, 36- and 60-month follow-up. Propensity-score matching analysis showed that definite/probable FH patients had significantly higher all-cause mortality at 36- and 60-month follow-up in comparison to non-FH subjects (11.4% vs. 4.8% and 19.2% vs. 7.2%, respectively; p ≤ 0.021 for both).
The prevalence of FH according to the DLCN criteria in the Polish very high-risk population is significantly higher in patients with ACS than in patients with sCAD. FH is a cause of increased all-cause mortality in the long-term follow-up.
The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland
2018, Atherosclerosis
Citation Excerpt :
The diagnostic process includes high LDL (hLDL) detection (in adults one test; in children, another test if the first one is positive). A medical consultation follows hLDL detection; then, secondary causes of hLDL are considered and diagnosis is made according to the Polish Lipid Experts Forum recommendations (using The Dutch Lipid Clinic Network-WHO criteria for adults [25], or The Simon Broome Register Group criteria for children [26]). In UFJ-G, U6, ACS-G-all, and ACS-G-55/65, all patients with likely FH diagnosis (definite/probable FH) perform also genetic tests.
Familial hypercholesterolaemia (FH) elevates the cholesterol level and increases the risk of coronary events and death. Early detection and treatment reduce this risk. We aimed to determine the cost-effectiveness of FH screening in Poland in children, first job takers, and after an acute coronary syndrome (ACS) event, each followed by a cascade screening in the relatives of the positively-diagnosed subjects.
A decision tree was constructed to model the diagnosis process. We considered scenarios with and without genetic testing. A life-time Markov was built to investigate the effectiveness (life years gained, LYG; and quality-adjusted life years, QALY) and cost (public payer perspective) of treatment in FH-affected subjects. The clinical benefits result from early treatment reducing the risk of coronary heart disease (and death, in result). Model parameters were based on published data and experts' opinions. The costs (patients visits, tests, drugs) were estimated from the National Health Fund data and other publicly-available sources.
Screening ACS patients below 55/65 years of age in men/women is the most cost-effective strategy: the cost of one LYG (QALY) amounts to 100 EUR (110 EUR). Removing the age limit or using genetic tests reduced cost-effectiveness; nonetheless, all strategies remained cost effective: the cost of one LYG or QALY was <5040 EUR, much lower than the official threshold of ca. 29,800 EUR/QALY.
Screening for FH is highly cost-effective in Poland. The strategies are complementary, and using a combination thereof is recommended.
Efficacy of clinical diagnostic criteria for familial hypercholesterolemia genetic testing in Poland
2016, Atherosclerosis
Citation Excerpt :
the Dutch Lipid Clinic Network [3–5]. In Poland, the Polish Lipid Experts Forum proposed diagnostic criteria for FH based on the Dutch Lipid Clinic Network score and the Simon Broome Register criteria [6]. This scale includes criteria selected in the Netherlands, modified by the assigned cut points for the concentrations of LDL-cholesterol (LDL-C) taken from the Simone Broome Register criteria.
Familial hypercholesterolemia (FH), which leads to premature cardiovascular events, still remains underrecognized and undertreated in most countries. Untreated FH individuals aged 20–39 years are at 100-fold higher risk of mortality from coronary heart disease compared to those of a general population. Therefore, special efforts should be implemented to diagnose FH patients at early stages of life.
The aim of this study was to evaluate the efficacy of the revised Dutch Lipid Clinic Network (DLCN) criteria proposed by the Polish Lipid Experts Forum to select index FH patients for DNA mutational analysis in Poland.
The study included 193 unrelated adult patients (mean age 48 ± 13 years) with clinical diagnosis of FH based on the revised DLCN score, tested sequentially for mutations in LDLR and APOB genes using bidirectional Sanger sequencing and MLPA techniques. The cut-off points of the clinical FH criteria score were assessed by ROC statistics to identify patients with the highest probability of carrying an FH-causing mutation.
The causal heterozygous LDLR or APOB mutation was identified in 41% (80/193) of probands. Adults aged <40 years were more likely to carry an FH-causing mutation compared to subjects aged ≥40 years (65% vs. 33%; p < 0.001). LDL-C thresholds for the molecular diagnosis of FH were 5.79 mmol/l for individuals aged<40 and 6.7 mmol/l for subjects ≥40 years old. The threshold values of the clinical diagnostic score for efficient selection of patients for genetic testing were 5 and 7 points for individuals aged <40 and ≥40 years, respectively.
The study validated the efficacy of proposed clinical FH criteria for the disease diagnosis in Poland. The clinical criteria score thresholds for positive FH molecular diagnosis differ depending on age (<40 and ≥40 years). We propose that in the healthcare systems with limited genetic testing resources individuals younger than 40 years, who fulfill the clinical criteria for possible, probable or definite FH should qualify for the FH mutation testing. The index patients aged ≥40 years with clinical diagnosis of probable or definite FH should also qualify for the genetic testing.
The genetic spectrum of familial hypercholesterolemia in south-eastern Poland
2016, Metabolism: Clinical and Experimental
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population.
161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation.
We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol.
These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level.
The panorama of familial hypercholesterolemia in Latin America: A systematic review
2016, Journal of Lipid Research
The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.
A simple and effective approach for the treatment of dyslipidemia using anionic nanoliposomes
2014, Colloids and Surfaces B: Biointerfaces
The present study was undertaken to evaluate the anti-dyslipidemic effects of nanoliposomes with different phospholipid compositions. Three sets of liposomal formulations (20 Mm; 100 nM in size) were prepared with low (SPC), medium (POPC) and high (HSPC) phase transition temperature values with and without cholesterol and anionic phosphatidyl glycerol (HSPC/DSPG; POPC/DMPG; SPC/EPG). The liposomal preparations were characterized for their size and zeta potential (dynamic light scattering), J774A.1 macrophages uptake (flow cytometry) and lipid-modifying effects (tyloxapol-induced hyperlipidemic mouse model). Anionic formulations displayed the highest rate of uptake by macrophages. Among them, HSPC/DSPG and SPC/EPG liposomes had the best lipid-modifying activity. These two formulations exerted favorable impact on all lipid profile parameters by reducing LDL-C (by up to 76% [HSPC/DSPG] and 86% [SPC/EPG]), total cholesterol (by up to 52% [HSPC/DSPG] and 68% [SPC/EPG]), triglycerides (by up to 88% [HSPC/DSPG] and 73% [SPC/EPG]), apoB (by up to 44% [HSPC/DSPG] and 35% [SPC/EPG]) and elevating HDL-C (by up to 85% [HSPC/DSPG] and 75% [SPC/EPG]) concentrations. Atherogenic indices were also effectively reduced following HSPC/DSPG (by up to 69%) and SPC/EPG (by up to 79%) injections. Empty, cholesterol-free nanoliposomal formulations containing 75% anionic phospholipid (PG) might serve as effective and rapid acting anti-dyslipidemic agents. Further research is warranted to confirm the observed anti-dyslipidemic effects of anionic nanoliposomes in diet-induced hyperlipidemic models, and also to evaluate the potential protective effects in regressing atheromatous lesions.

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Original ArticleManagement of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum

Abstract

Section snippets

Epidemiology and pathogenesis

FH as a risk factor of CHD

Diagnostic criteria of HeFH

Recommendations for identification of HeFH

Target LDL cholesterol concentration

Therapeutic management of HeFH

Conclusions

Acknowledgment

Atherosclerosis

Atherosclerosis

J Clin Lipidol

J Clin Lipidol

J Clin Lipidol

Lancet

J Am Coll Cardiol

Lancet

Familial hypercholesterolemia. A Report of a WHO consultation

Familial hypercholesterolaemia: summary of NICE guidance

BMJ

ESC/EAS guidelines for management of dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

Eur Heart J

Reductions in all-cause, cancer and coronary mortality in statin-treated patients with heterozygous hypercholesterolemia: a prospective registry study

Eur Heart J

Familial hypercholesterolemia: a missed opportunity in preventive medicine

Nat Clin Practice Cardiovasc Med

How LDL receptors influence cholesterol and atherosclerosis

Sci Am

Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding

Proc Natl Acad Sci U S A

Original Article
Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum