Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands

doi:10.1016/S0140-6736(00)03587-X

The Lancet

Volume 357, Issue 9251, 20 January 2001, Pages 165-168

https://doi.org/10.1016/S0140-6736(00)03587-X Get rights and content

Summary

Background

Familial hypercholesterolaemia is a common lipid disorder that predisposes for premature cardiovascular disease (CVD). We set up a screening programme in the Netherlands in 1994 to: establish the feasibility of active family screening supported by DNA diagnostics; assess whether or not active identification of these patients with familial hypercholesterolaemia would lead to more cholesterol-lowering treatment; and compare diagnosis by DNA analysis with that by cholesterol measurement.

Methods

Both DNA analysis and measurement of cholesterol concentrations were used to screen families in which a functional mutation in the LDL-receptor gene had been detected.

Findings

In the first 5 years, 5442 relatives of 237 people with familial hypercholesterolaemia were screened; 2039 individuals were identified as heterozygous by LDL-receptor gene mutation analysis. At the time of examination, 667 of these adults with familial hypercholesterolaemia (39%) received some form of lipid-lowering treatment; 1 year later, this percentage had increased to 93%. In addition, laboratory analysis showed that for carriers as well as noncarriers 18% would have been misdiagnosed by cholesterol measurement alone, with sex-specific and age-specific 90th percentiles of the general Dutch population as diagnostic criteria.

Interpretation

Targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolaemia. Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature CVD. Our findings could have wider relevance for the screening of other prevalent genetic disorders in the population at large.

Introduction

Familial hypercholesterolaemia is an inherited disorder of lipoprotein metabolism caused by mutations in the LDL-receptor gene. In heterozygous familial hypercholesterolaemia, only 50% of these receptors are functional, which increases plasma cholesterol concentrations to between 7·5 and 16 mmol/L.¹ Characteristically, familial hypercholesterolaemia results in premature cardiovascular disease (CVD) and untimely death.¹ In patients with hypercholesterolaemia the agestandardised and sex-standardised mortality ratios are four to five times higher than in the general population.²

Lowering LDL-cholesterol concentrations results in a large decrease in cardiovascular morbidity and mortality, especially in patients at highest risk, ³ and lipid-lowering treatment of patients with familial hypercholesterolaemia could prevent premature death.² In western countries although hypercholesterolaemia is a common disorder most patients are not diagnosed or do not receive proper treatment.⁴ With the elucidation of the molecular basis of the disorder, an unequivocal diagnosis has now become available.⁵ The World Health Organization has recommended that if treatment is started early maximum health benefit can be obtained.

In clinical practice, raised cholesterol concentrations, data from personal and family histories, and physical examination are the main criteria for the diagnosis of familial hypercholesterolaemia. The sensitivity and specificity of raised cholesterol concentrations as well as the use and definition of appropriate cutoff points has been studied extensively. 6, 7, 8, 9, 10, 11, 12 However, most studies have been done in small numbers of adults and children in a lipid clinic setting.

We have established a programme in the Netherlands to assess whether identification of substantial numbers of people with heterozygous familial hypercholesterolaemia by active family screening and DNA analysis is feasible. We also aimed to assess whether identification of these new patients would improve their degree of preventive care, and the specificity and sensitivity of cholesterol measurement. We report the first 5 years of this ongoing screening programme in the Netherlands.

Section snippets

Identification of index cases

We did the clinical diagnoses at the lipid clinic according to a uniform diagnostic protocol, with criteria such as LDL cholesterol concentrations, physical signs, and personal and family history in a scoring system.¹³ Family history was judged as positive when there had been signs of CVD in men before the age of 55 years and in women before 60 years. We analysed DNA samples of patients with familial hypercholesterolaemia for the presence of an LDL-receptor gene mutation. Once a mutation had

Results

Between January, 1994, and January, 1999, family screening was initiated in 237 families of which 5442 members participated in the screening programme. The participation rate was 90% over the duration of the study. 277 individuals declined genetic testing because of: fear of negative effects on employment or insurance (124 [45%]); negative advice from general practitioner (69 [25%]); general lack of interest (51 [18%]); treatment for hypercholesterolaemia already in place or no offspring (23

Discussion

We have shown that familial hypercholesterolaemia is frequently underdiagnosed and that many patients who had been identified previously on clinical grounds were not being treated appropriately. Our first research goal was to establish whether or not active identification–ie, by our method of directly approaching family members of index cases was effective in identifying large numbers of still symptomless, quite young, and untreated patients with familial hypercholesterolaemia. On average,

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Using implementation science to develop a familial hypercholesterolemia screening program in primary care: The CARE-FH study
2024, Journal of Clinical Lipidology
We designed the Collaborative Approach to Reach Everyone with familial hypercholesterolemia (CARE-FH) clinical trial to improve FH screening in primary care and facilitate guideline-based care.
The goal was to incorporate perspectives from end-users (healthcare system leaders, primary care clinicians, cardiologists, genetic counselors, nurses, and clinic staff) and improve translation of screening guidance into practice.
We partnered with end-users to sequentially define the current state of FH screening, assess acceptability, feasibility, and appropriateness of implementing an FH screening program, and select clinically actionable strategies at the patient-, clinician-, and system-level to be deployed as a package in the CARE-FH clinical trial. Methods informed by implementation science and human centered design included: contextual inquiries, surveys, and deliberative engagement sessions.
Screening for FH occurred rarely in primary care, and then only after a cardiovascular event or sometimes due to a family history of high cholesterol or early heart attack. Surveys suggested FH screening in primary care was acceptable, appropriate, and feasible. Reported and observed barriers to screening include insufficient time at patient encounters to screen, cost and convenience of testing for patients, and knowledge regarding causes of dyslipidemia. Facilitators included clear guidance on screening criteria and new therapies to treat FH. These results led to the development of multilevel strategies that were presented to end-users, modified, and then pilot tested in one primary care clinic.
A refined implementation strategy package for FH screening was created with a goal of improving FH awareness, identification, and initiation of guideline-based care.
https://clinicaltrials.gov/study/NCT05284513?id=NCT05284513&rank=1 Unique Identifier: NCT05284513
Facilitating family communication of familial hypercholesterolemia genetic risk: Assessing engagement with innovative chatbot technology from the IMPACT-FH study
2023, PEC Innovation
To assess use of two web-based conversational agents, the Family Sharing Chatbot (FSC) and One Month Chatbot (OMC), by individuals with familial hypercholesterolemia (FH).
FSC and OMC were sent using an opt-out methodology to a cohort of individuals receiving a FH genetic result. Data from 7/1/2021 through 5/12/2022 was obtained from the electronic health record and the chatbots’ HIPAA-secure web portal.
Of 175 subjects, 21 (12%) opted out of the chatbots. Older individuals were more likely to opt out. Most (91/154, 59%) preferred receiving chatbots via the patient EHR portal. Seventy-five individuals (49%) clicked the FSC link, 62 (40%) interacted, and 36 (23%) shared a chatbot about their FH result with at least one relative. Ninety-two of the subjects received OMC, 22 (23%) clicked the link and 20 (21%) interacted. Individuals who shared were majority female and younger on average than the overall cohort. Reminders tended to increase engagement.
Results demonstrate characteristics relevant to chatbot engagement. Individuals may be more inclined to receive chatbots if integrated within the patient EHR portal. Frequent reminders can potentially improve chatbot utilization.
FSC and OMC employ innovative digital health technology that can facilitate family communication about hereditary conditions.
Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population
2023, American Journal of Preventive Cardiology
Familial hypercholesterolemia (FH) is common, but underdiagnosed, and few systematic early screening programs exist.
To assess health outcomes among those with a recorded diagnosis of FH and potential cases of FH with no recorded diagnosis.
Retrospective cohort study using the UK Clinical Practice Research Datalink. Records of adults were classified as diagnosed FH (FH_Coded), or via accepted algorithms using LDL-C and clinical characteristics as potential FH (FH_Potential) or unlikely FH (FH_Unlikely) using the DLCN or EUROASPIRE criteria (but no record of FH). Outcomes assessed were premature cardiovascular (CV) events, premature deaths and life expectancy.
Among 1,729,046 individuals free from CV events, a record of FH_Coded before the age of 40 was 0.3/1000 (IQR 0.3–0.4) and increased with age. Where LDL-C levels were available, 1.8/1000 (IQR 1.6–2.0) could be classified as FH_Potential. LDL-C was higher for both FH_Coded and FH_Potential vs FH_Unlikely (185.6 and 216.6 vs 116 mg/dL, respectively, p<0.001). Compared to FH_Unlikely both FH_Coded and FH_Potential cohorts had a higher risk of premature cardiovascular events (both p<0.001) with highest rates among FH_Coded. Risk of premature deaths did not differ between FH_Coded and FH_Unlikely, but was 1.88 (95% CI 1.27–2.78, p = 0.002) for FH_Potential vs FH_Coded and 2.40 (95% CI 1.57–3.67, p<0.001) for FH_Potential vs FH_Unlikely. At age 18, the FH_Potential cohort had a life expectancy 16 years lower than the FH_Coded cohort (p<0.001).
Potential cases of FH had a doubling in risk of premature death and a large reduction in life expectancy compared to individuals with a recorded diagnosis of FH. These findings strengthen the critical importance of identifying potential cases of FH early and early treatment.
Impact of providing genetics-based future cardiovascular risk on LDL-C in patients with familial hypercholesterolemia
2023, Journal of Clinical Lipidology
Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH.
We aimed to evaluate the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program.
We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24.
Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n = 24) or the wait-list control group (n = 26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p = 0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers.
In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers.
Japan Registry of Clinical Trials (jRCTs04218002).
URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027
Family communication and results disclosure after germline sequencing: A mixed methods study
2023, Patient Education and Counseling
Research on family communication of germline genome sequencing (GS) results (versus of genetic results after targeted genetic testing) is still emerging, yet potentially complex results increase the importance of communicating risk to relatives. Promoting equity by ensuring patients have sufficient health literacy to interpret results is important in this context. This study aimed to identify cancer patients’ perceived importance of result disclosure, predictors of perceptions, and perspectives on family communication.
This explanatory-sequential, cross-sectional mixed-methods study involved participants (n = 246) completing a questionnaire and (n = 20) a semi-structured interview. Ordinal logistic regressions determined associations between potential predictors and perceived importance of result disclosure. Interview transcripts were analysed thematically using a constant-comparative approach.
More participants intended disclosing to nuclear (77.4%) than to extended family (42.7%). More than half (59.3%) felt results were family information; 62.7% believed it was important to disclose results to family members. Nuclear and extended family communication scores and education level were significantly positively associated with perceived importance of disclosure (p < 0.05). Six qualitative themes were identified: i) Responsibility to inform, ii) Choice, iii) Autonomy, iv) Family Communication, v) Significance of results, and vi) Health professional role.
Low health literacy and family conflict can complicate communication of GS results. Patients seek clear, interpretable information in a format they can easily communicate.
Healthcare professionals can facilitate discussion of GS results by offering written information, encouraging disclosure, exploring existing family dynamics and communication patterns, and offering strategies to improve family communication. Centralised genetic communication offices and chatbots can also be helpful
Recent advances in the management and implementation of care for familial hypercholesterolaemia
2023, Pharmacological Research
Familial hypercholesterolaemia (FH) is a common autosomal semi-dominant and highly penetrant disorder of the low-density lipoprotein (LDL) receptor pathway, characterised by lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients with FH are not diagnosed and do not attain recommended LDL-C goals despite maximally tolerated doses of potent statin and ezetimibe. Over the past decade, several cholesterol-lowering therapies such as those targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) or angiopoietin-like 3 (ANGPTL3) with monoclonal antibody or ribonucleic acid (RNA) approaches have been developed that promise to close the treatment gap. The availability of new therapies with complementary modes of action of lipid metabolism has enabled many patients with FH to attain guideline-recommended LDL-C goals. Emerging therapies for FH include liver-directed gene transfer of the LDLR, vaccines targeting key proteins involved in cholesterol metabolism, and CRISPR-based gene editing of PCSK9 and ANGPTL3, but further clinical trials are required. In this review, current and emerging treatment strategies for lowering LDL-C, and ASCVD risk-stratification, as well as implementation strategies for the care of patients with FH are reviewed.

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ArticlesReview of first 5 years of screening for familial hypercholesterolaemia in the Netherlands

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Identification of index cases

Results

Discussion

Familial hyperecholesterolemia

Mortality in treated heterozygous familial hypercholesterolemia: implications for clinical management

Atherosclerosis

Cholesterol reduction yields clinical benefit: impact of statin trials

Circulation

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in the Netherlands

Clin Genet

Diagnosing hypercholesterolemia in childhood by measuring serum cholesterol

BMJ

Paediatric implications of heterozygous familial hypercholesterolemia. Screening and dietary treatment

Arteriosclerosis

DNA screening of hyperlipidemic Afrikaners for familial hypercholesterolemia

Clin Genet

Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics

Am J Cardiol

Familial hypercholesterolemia: a molecular, biochemical and clinical characterization of a French-Canadian pediatric population

Pediatrics

Articles
Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands