Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic ...testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
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To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine.
Familial hypercholesterolemia is both much more common and more ...phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility.
In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.
Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase ...subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands.
The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event.
The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.
Background Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and ...resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. Design The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. Summary The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.
A plethora of mutations in the LDL-receptor gene (LDLR) underlie the clinical phenotype of familial hypercholesterolaemia (FH). For the diagnosis of FH, it is important, however, to discriminate ...between pathogenic and non-pathogenic mutations. The aim of the current study was to assess whether true pathogenic mutations were indeed associated with the occurrence of coronary artery disease (CAD) when compared with non-functional variants. The latter variants should not exhibit such an association with CAD.
We assessed 29 365 individuals tested the 64 most prevalent LDLR variants. First, we determined pathogenicity for each of these sequence variants. Subsequently, a Cox-proportional hazard model was used to compare event-free survival, defined as the period from birth until the first CAD event, between carriers and non-carriers of LDLR mutations. Fifty-four sequence variants in the LDLR gene were labelled as pathogenic and 10 as non-pathogenic. The 9 912 carriers of a pathogenic LDLR mutation had a shorter event-free survival than the 18 393 relatives who did not carry that mutation; hazard ratio 3.64 95% confidence interval (CI): 3.24-4.08; P< 0.001. In contrast, the 355 carriers of a non-pathogenic LDLR variant had similar event-free survival as the 705 non-carrying relatives; hazard ratio 1.00 (95% CI: 0.52-1.94; P= 0.999).
These findings with respect to clinical outcomes substantiate our criteria for functionality of LDLR sequence variants. They also confirm the CAD risk associated with FH and underline that these criteria can be used to decide whether a specific sequence variant should be used in cascade screening.
Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left ...untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL;
=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.
The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ...ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed.
In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in The Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42+/-12 years; mean LDL-C at molecular diagnosis (baseline): 4.1+/-1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2+/-1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of < or = 2.5 mmol/L.
The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through genetic cascade screening. The attained LDL-C levels were lower than those reported in previous surveys on medication use in FH, which could reflect the effect of more stringent lipid target levels. However, only a minority of the medication users reached the LDL-C target.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch ...Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. Objective To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. Methods We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: “clinical diagnosis,” MEDPED, Simon Broome, DLCN, and other. Results Most adults enrolled in CASCADE FH (55.0%) received a “clinical diagnosis.” The most commonly used formal criteria was Simon–Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a “clinical diagnosis,” 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. Conclusions Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.
To evaluate the efficacy of an individualised tailored lifestyle intervention on physical activity, dietary intake, smoking and compliance to statin therapy in people with Familial ...Hypercholesterolemia (FH).
Adults with FH (n = 340) were randomly assigned to a usual care control group or an intervention group. The intervention consisted of web-based tailored lifestyle advice and face-to-face counselling. Physical activity, fat, fruit and vegetable intake, smoking and compliance to statin therapy were self-reported at baseline and after 12 months. Regression analyses were conducted to examine between-group differences. Intervention reach, dose and fidelity were assessed.
In both groups, non-significant improvements in all lifestyle behaviours were found. Post-hoc analyses showed a significant decrease in saturated fat intake among women in the intervention group (β = -1.03; CI -1.98/-0.03). In the intervention group, 95% received a log on account, of which 49% logged on and completed one module. Nearly all participants received face-to-face counselling and on average, 4.2 telephone booster calls. Intervention fidelity was low.
Individually tailored feedback is not superior to no intervention regarding changes in multiple lifestyle behaviours in people with FH. A higher received dose of computer-tailored interventions should be achieved by uplifting the website and reducing the burden of screening questionnaires. Counsellor training should be more extensive.
Dutch Trial Register NTR1899.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To assess the follow-up of children diagnosed as having familial hypercholesterolemia (FH) in the nationwide DNA-based cascade screening program (the Netherlands). Study design ...Questionnaires covering topics such as demographics, family history, physician consultation, and treatment were sent to parents of patients with FH (age 0-18 years), 18 months after diagnosis. Results We retrieved 207 questionnaires of patients aged 10.9 ± 4.2 years (mean ± SD) at diagnosis; 48% were boys, and the mean low-density lipoprotein cholesterol (LDL-C) level at diagnosis was 167 ± 51 mg/dL. Of these patients, 164 (79%) consulted a physician: a general practitioner (35%), lipid-clinic specialist (27%), pediatrician (21%), internist (11%), or another physician (6%). LDL-C level at diagnosis and a positive family history for cardiovascular disease were independent predictors for physician consultation. Of the patients who visited a physician, 62% reported to have received lifestyle advice, and 43 (26%) were prescribed statin treatment. Independent predictors for medication use were age, LDL-C level, and educational level of parents. Conclusion The follow-up of children with FH after diagnosis established through cascade screening is inadequate. Better education of patients, parents, and physicians, with a structured follow-up after screening, should improve control of LDL-C levels and hence cardiovascular risk in children with FH.
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