High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

CONTEXT: Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). OBJECTIVE: We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. METHODS: Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). RESULTS: We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). CONCLUSION: Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study.

BACKGROUND AND AIMS: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. METHODS: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. RESULTS: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. CONCLUSIONS: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Genetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD. OBJECTIVES: We determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD. METHODS: We examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD. RESULTS: For risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD. CONCLUSIONS: Lipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

Autosomal recessive hypercholesterolemia in a kindred of Syrian ancestry.

Autosomal recessive hypercholesterolemia is a rare genetic disorder due to homozygosity or compound heterozygosity for mutations in the low-density lipoprotein receptor adapter protein 1 gene (LDLRAP1), resulting in elevated low-density lipoprotein cholesterol (LDL-C) levels, large xanthomas, and increased cardiovascular risk. Here, we describe a Danish family of Syrian ancestry carrying a frameshift mutation in LDLRAP1, previously only described in Sardinia and Sicily in Italy and in Spain. In 2 children homozygous for this mutation, we evaluate the effect of long-term lipid-lowering treatment with atorvastatin as monotherapy or in combination with ezetimibe. At referral to the lipid clinic at Viborg Regional Hospital, 3 of 4 children had LDL-C levels of 468, 538, and 371 mg/dL, respectively, with 1 child already showing cutaneous xanthomas at 10 years of age. For comparison, the fourth child and the parents had LDL-C levels of 85, 116, and 124 mg/dL. Genetic testing revealed that all 3 children with severely elevated LDL-C were homozygous for a rare frameshift mutation in LDLRAP1, p.His144GlnfsTer27 (c.431dupA), whereas the fourth child and both parents were heterozygous for this mutation. Lipid-lowering treatment was started in the 2 oldest children (at 10 and 7 years of age). Atorvastatin (40 mg/d) combined with ezetimibe (10 mg/d) reduced LDL-C by 75% in the first child and resulted in near-complete regression of xanthomas. In the second child, atorvastatin (40 mg/d) as monotherapy reduced LDL-C by 61%. Both regimens were superior to treatment with pravastatin as monotherapy (20 mg/d) and to pravastatin in combination with cholestyramine (2 g twice daily). High-intensity statin therapy alone or in combination with ezetimibe resulted in marked reductions in LDL-C in 2 children homozygous for a rare frameshift mutation in LDLRAP1 and lead to regression of large xanthomas.

Prevalence of clinical familial hypercholesterolaemia among patients with high cholesterol levels.

INTRODUCTION: Familial hypercholesterolaemia (FH) can be diagnosed using clinical criteria or by direct mutation identification. The prevalence of clinical FH in Danish lipid clinics remains unknown. The objective of this study was to explore the prevalence of clinical FH in patients admitted on suspicion of FH with plasma low-density lipoprotein cholesterol (LDL-C) concentration ≥ 5.0 mmol/l. METHODS: We reviewed the medical records of 653 patients consecutively (from 1 January 2013 to 1 May 2017) referred to the lipid clinic at Viborg Regional Hospital, Denmark. Patients with LDL-C concentration > 4.9 mmol/l were selected. Clinical FH was assessed using the Dutch Lipid Clinic Network (DLCN) and Simon Broome criteria. RESULTS: Using DLCN, 315 patients (median 82% (95% confidence interval (CI): 78-86%)) had possible FH, 33 patients (median 9% (95% CI: 6-11%)) had probable FH and 36 patients (median 9% (95% CI: 6-12%)) had definite FH. Thus, a total of 69 patients (median 18% (95% CI: 14-22%)) had probable/definite FH. Using the Simon Broome criteria, 284 (median 74% (95% CI: 70-78%)) patients did not have FH, 67 patients (median 17% (95% CI: 14-21%)) had possible FH and 33 patients (median 9% (95% CI; 6-11%)) had definite FH, resulting in a total of 100 (median 26% (95% CI: 22-30%)) patients having possible/definite FH. The concordance between DLCN and Simon Broome FH was high among patients with definite FH (> 90%), but low among patients with probable or possible FH. CONCLUSIONS: Clinical FH was common among patients with LDL-C concentration ≥ 5.0 mmol/l referred to a Danish lipid clinic. However, the concordance between the DLCN and the Simon Broome criteria was low in a specialised clinical setting. FUNDING: The study was supported by a SANOFI grant. TRIAL REGISTRATION: not relevant.