Probable Familial Hypercholesterolemia Research Articles

Abstract 435: An Electronic Health Records Query for Severe Hypercholesterolemia Identifies Individuals With Undiagnosed Clinical and Molecular FH at a Tertiary Academic Centre

Background: Familial hypercholesterolemia (FH) is a common heritable disorder of elevated low density lipoprotein cholesterol (LDL-C) with an estimated prevalence of 1/200-300 in the US; however, fewer than 10% of cases have been identified. We wanted to examine whether a simple EHR query for severe hypercholesterolemia could be used to identify clinically and genetically defined cases of FH. Objectives/Purpose: We tested the hypothesis that querying the EHR using an LDL-C criterion would be a novel way to screen for and ultimately identify undiagnosed cases of FH. Methods: An EHR screening query was used to identify active adult patients with LDL-C ≥ 220 mg/dL in the University of Pennsylvania outpatient EHR database. Patients with secondary causes of hypercholesterolemia and those who had previous genetic testing for FH were excluded. The query identified 3,475 individuals, 120 were subsequently consented and enrolled for molecular testing. This was performed with next-generation sequencing using Progenika’s SEQPRO LIPO IS platform, targeting LDLR, APOB, PCSK9 and LDLRAP1 . A literature search was performed to gather information on identified LDLR variants of unknown significance (VUS). In addition, in-silico analysis was employed to evaluate the pathogenicity of the LDLR and LDLRAP1 VUS. Results: Among the 120 subjects, 53 (44.2%) met the Dutch Lipid Clinic Network (DLCN) criteria for probable or definite clinical FH. Molecularly, 19 FH-related pathogenic mutations were found in 18 (15%) individuals. Four had a common APOB ( R3500Q) mutation, 14 had a LDLR mutation. One individual had a double heterozygous mutation in PCSK9 and LDLR. In addition, 17 LDLR VUS were identified in 16 (13.9%) individuals. A literature review and in-silico analysis predicted that 8 VUS found in 10 subjects were “disease causing”. Therefore, a total of 28 (24.3%) subjects from our cohort carried either a FH causal mutation or likely pathogenic variant. Overall, 59 subjects (49.2%) in our cohort were ascertained to have either a clinical or molecular diagnosis of FH. Conclusion: The use of an EHR screening query for severe hypercholesterolemia was a novel, low investment but relatively high yield approach for identifying undiagnosed cases of FH at a tertiary academic centre.

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia.

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

Clinical determinants and treatment gaps in familial hypercholesterolemia: Data from a multi-ethnic regional health service.

Background Familial hypercholesterolemia is characterized by markedly increased low-density lipoprotein cholesterol and risk for premature atherosclerotic cardiovascular disease. Models of care vary and reflect differing health policies and resources. The availability of electronic databases may enable better identification and assessment of familial hypercholesterolemia in the community. Methods A regional healthcare database was utilized to identify patients with a high probability of familial hypercholesterolemia, clinically defined by age-dependent-peak low-density lipoprotein cholesterol cutoffs and exclusion of secondary causes of severe hypercholesterolemia. Clinical characteristics, low-density lipoprotein cholesterol goal attainment, and treatment gaps were investigated. Results Probable familial hypercholesterolemia was diagnosed in 1932 of 685,314 individuals (1:355; median age 47 years). Atherosclerotic cardiovascular disease was present in 16.3% of adults (38% in males aged 50-74 years). Median peak low-density lipoprotein cholesterol was 264 mg/dl (interquartile range 252-288). Statins and/or ezetimibe were prescribed to 83% of patients and high-intensity statins to 53%, whereas prescriptions were filled in 57% and 40% cases respectively over the last six months, p < 0.001. Treatment gaps were wider among ethnic minorities, younger individuals, and those without atherosclerotic cardiovascular disease. Low-density lipoprotein cholesterol < 100 mg/dl was attained in 10.1% overall and 28.7% of those with atherosclerotic cardiovascular disease. Predictors of low-density lipoprotein cholesterol goal attainment included recent issue of high-intensity statins, presence of atherosclerotic cardiovascular disease, diabetes, older age and lack of smoking. Conclusions The population with high probability for familial hypercholesterolemia was characterized by low attainment of low-density lipoprotein cholesterol treatment goals despite high prescription rates of lipid-lowering medications. Low utilization of intensified therapies, non-adherence, and ethnic disparities were contributing factors. These findings emphasize the need to improve awareness and quality of care of familial hypercholesterolemia in the community.

Identifying Undiagnosed or Undertreated Patients with Familial Hypercholesterolemia from the Laboratory Records of a Tertiary Medical Center

Familial hypercholesterolemia (FH) is a life-threatening genetic disease associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease that is undiagnosed and undertreated around the world. This study aimed to examine the demographic characteristics, awareness, and treatment adherence of undiagnosed or undertreated FH patients based on laboratory records. In a 16-month retrospective survey using laboratory records, patients with elevated LDL-C (>250 mg/dL) were identified (n=395). Patients younger than 18 years of age or with secondary causes of dyslipidemia were excluded (n=98). In all, 297 patients were called and asked to participate in a phone interview regarding their demographic characteristics, awareness of dyslipidemia, and treatment adherence. A total of 147 patients (mean age: 51.7±16.6 years; 59.2% female) completed the interview. The mean LDL-C level of the patients was 292.8±49.9 mg/dL. According to the Dutch Lipid Clinic Network criteria, 18.4% of the patients had definite FH, 66.0% had probable FH, and 15.6% had possible FH. Although the majority of the patients (93.9%) were aware of their high LDL-C level, only about half of them (n=75; 51.0%) were in treatment. Of all the patients who were interviewed, 21% (n=31) had never taken medication to lower their LDL-C, and 28% (n=41) had stopped taking a lipid-lowering drug. This pilot study revealed that a significant number of FH patients were not taking statins despite having a very high LDL-C level. Nationwide detection of likely FH patients using hospital records and interviewing them via a phone survey may help to better understand and manage these high-risk patients.

Lipoprotein(a) Adjustment Enhances the Diagnosis of Familial Hypercholesterolaemia

Aim: To investigate the impact of an LDL-cholesterol level adjusted for lipoprotein(a) [Lp(a)] mass in the diagnosis of familial hypercholesterolaemia (FH) by the Dutch Lipid Clinic Network Criteria (DLCNC). Methods: A cross-sectional adult cohort of 768 index patients with and without genetically confirmed FH were studied. The DLCNC score was generated with and without adjusting the pre-treatment LDL-cholesterol level for the cholesterol content of the Lp(a) particle concentration. Patients were reclassified according to the DLCNC categories (Definite/Probable/Possible/Unlikely FH). Receiver operator characteristic (ROC) curves were generated for the adjusted and unadjusted scores in predicting an FH pathogenic mutation. ROC area-under-the-curves (AUC) were compared using an equality test. Results: After adjusting for Lp(a)-cholesterol concentration, 126 patients (16.4%) were reclassified on the DLCNC scale: Definite to Probable FH (n = 29), Probable to Possible FH (n = 59), Possible to Unlikely FH (n = 38). Of these, 113 (89.7%) did not have a pathogenic mutation for FH. The AUC for the ROC for the DLCNC score in predicting FH mutations was significantly improved after adjusting LDL-cholesterol for the cholesterol content of Lp(a) [0.8415 vs. 0.8276, p = 0.003]. Conclusions: Adjusting LDL-cholesterol in the DLCNC for Lp(a)-cholesterol concentration concentrations down-classifies the phenotypic diagnosis of FH and significantly enhances the prediction of a pathogenic mutation in the LDL receptor pathway.

Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia

Background and aimsAutosomal-dominant familial hypercholesterolemia (FH) is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and a dramatically increased risk to develop cardiovascular disease (CVD). Mutations in three major genes have been associated with FH: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). Here we investigated the frequency and the spectrum of FH causing mutations in Germany. MethodsWe screened 206 hypercholesterolemic patients, of whom 192 were apparently unrelated, for mutations in the coding region of the genes LDLR, PCSK9 and the APOB [c.10580G > A (p.Arg3527Gln)]. We also categorized the patients according to the Dutch Lipid Clinic Network Criteria (DLCNC) in order to allow a comparison between the mutations identified and the clinical phenotypes observed. Including data from previous studies on German FH patients enabled us to analyse data from 479 individuals. ResultsNinety-eight FH causing variants were found in 92 patients (nine in related patients and 6 patients with two variants and likely two affected alleles), of which 90 were located in the LDLR gene and eight mutations were identified in the APOB gene (c.10580G > A). No mutation was found in the PCSK9 gene. While 48 of the LDLR mutations were previously described as disease causing, we found 9 new LDLR variants which were rated as “pathogenic” or “likely pathogenic” based on the predicted effect on the corresponding protein. The proportions of different types of LDLR mutations and their localization within the gene was similar in the group of patients screened for mutations here and in the combined analysis of 479 patients (current study/cases from the literature) and also to other studies on the LDLR mutation spectrum, with about half of the variants being of the missense type and clustering of mutations in exons 4, 5 and 9.The mutation detection rate in the 35 definite and 45 probable FH patients (according to DLCNC) was 77.1% and 68.9%, respectively. The data show a similar discriminatory power between the DLCNC score (AUC = 0.789 (95% CI 0.721–0,857)) and baseline LDL-C levels (AUC = 0.799 (95% CI = 0.732–0.866)). ConclusionsThis study further substantiates the mutation spectrum for FH in German patients and confirms the clinical and genetic heterogeneity of the disease.

Prevalence of potential familial hypercholesterolemia (FH) in 54,811 statin-treated patients in clinical practice

Background and aimsFamilial hypercholesterolemia (FH) is a life-threatening disease, characterized by elevated LDL-C levels and a premature, increased risk of coronary heart disease (CHD) that is globally underdiagnosed. The percentage of patients with possible or probable FH in various countries was examined in the Dyslipidemia International Study (DYSIS). MethodsDYSIS is a multinational, cross-sectional observational study of 54,811 adult outpatients treated with statin therapy. The percentages of patients with high levels of LDL-C, and with possible or probable FH, were assessed using the Dutch scoring method for FH across 29 countries, in age subgroups for the analysis population and among diabetes patients. ResultsDespite statin therapy, 16.1% (range 4.4–27.6%) of patients had LDL-C >3.6 mmol/L (140 mg/dL) across countries and the prevalence of possible FH was 15.0% (range 5.5–27.8%) and 1.1% (range 0.0–5.4%) for probable FH. The highest percentages of probable FH occurred in Egypt (5.4%), the Baltic states (4.2%), Russia (3.2%), and Slovenia (3.1%), with the lowest rates in Israel (0.0%), Canada (0.2%), and Sweden (0.3%). Rates of FH were the highest in younger patients (45–54 years) for secondary prevention, regardless of the presence/absence of diabetes. ConclusionsDespite statin therapy, high LDL-C levels and rates of possible and probable FH were observed in some countries. The prevalence of FH was the highest in younger age patients, and >60% of patients with probable FH displayed CHD. Earlier diagnosis and treatment of patients with FH are needed to reduce CHD risk in these patients.

ESTIMATED PREVALENCE OF POSSIBLE AND PROBABLE FAMILIAL HYPERCHOLESTEROLEMIA IN 35,451 STATIN-TREATED PATIENTS IN EUROPE, CANADA, THE MIDDLE EAST, AND SOUTH AFRICA

The EAS consensus paper on familial hypercholesterolemia (FH) indicates a higher prevalence of elevated LDL-C due to genetic reasons than previously estimated. On the basis of the DYSIS registry we aimed to determine the % of patients with possible / probable FH. The cross-sectional, observational

Medication adherence, cascade screening, and lifestyle patterns among women with hypercholesterolemia: Results from the WomenHeart survey

Hypercholesterolemia is a major risk factor for cardiovascular disease. Women with hypercholesterolemia and familial hypercholesterolemia (FH) are a high-risk group often underdiagnosed, undertreated, and unaware of the need for cascade screening. The objectives were to identify the prevalence of hypercholesterolemia and FH in 2 national databases, explore lifestyle/medication adherence, and examine rates of cascade screening (lipid testing in all first-degree relatives) among those with FH. This was a cross-sectional study of women who completed an online survey in 2014. Outcomes were examined for 3 groups: diagnosed, probable, and no FH. For FH, multivariable logistic regression was used to examine the association between family member screening for FH and sociodemographic and/or clinical characteristics. There were 761 respondents with a mean (±standard deviation) age of 59±10.1years; 26% reported FH, 22% probable FH, and 51% no FH. Eighty-three percent of the total sample and 95% with FH take a statin. In those with hypercholesterolemia and FH, 65% and 58% reported high medication adherence, respectively. Women with probable FH consumed significantly fewer fruits/vegetables and were less active. FH cascade screening was: siblings 54%, parents 37%, and children 34%. Marital status, annual household income, and diabetes were significantly associated with cascade screening. In a survey of informed women with hypercholesterolemia and FH, cascade screening is underused. Our findings warrant increased efforts to identify cascade screening barriers. Early detection and treatment of hypercholesterolemia/FH is a priority for women, and their first-degree relatives, as this may dramatically reduce cardiovascular disease impact.

Abstract P030: Long-term Pharmacotherapy for Elevated Low Density Lipoprotein Levels in Children: A Retrospective Analysis

Background: There is limited research detailing LDL trends over the long term in children on various lipid lowering medications. Objectives: This study sought to assess factors associated with stability of LDL levels in children on long-term pharmacotherapy and their ability to reach the current recommended LDL goal of 130 mg/dL or less while on pharmacotherapy. Methods: Medical records of children seen in a university pediatric cholesterol clinic between 1998 and 2012 who were treated with a statin, ezetimibe, or both were reviewed. Aggregate data were obtained to determine the number of children who were able to reach an LDL level of 130 mg/dL or less while on pharmacotherapy. Kaplan-Meier curve and proportional hazard regression analysis were used to examine the propensity for LDL levels to stabilize over time while on pharmacotherapy as well as factors affecting this propensity. Results: 76 patients who contributed 864 total visits met inclusion criteria. 56 of 76 patients developed a stable LDL with median time to stability of 28 months on pharmacotherapy. Younger age of first visit was associated with development of LDL stability (9.8 years for stable LDL vs. 13.3 years for nonstable LDL; p= 0.004). Titration to higher statin doses and/or higher potency statins was also associated with higher propensity for LDL stabilization. There was no significant difference between patients who were taking a statin, ezetimibe, or both in terms of their propensity to stabilize even when stratifying for presence of probable familial hypercholesterolemia (p=0.579). 36 of 76 patients were able to reach an LDL of 130 mg/dL or less, with only 11 of 38 patients with probable familial hypercholesterolemia (&gt;190 mg/dL baseline LDL) reaching this goal. Conclusion: A majority of children in a university pediatric cholesterol clinic were able to reach a stable LDL level on pharmacotherapy after a median 28 month interval. On the other hand, the majority of children had difficulty reaching the current recommended goal LDL of 130 mg/dL or less, even after aggressive titration of medication. This was specifically true for those with probable familial hypercholesterolemia. Further research is needed to assess the utility of goal-directed therapy in children with regards to cardiovascular outcomes.

Abstract P100: Identification of Patients with Familial Hypercholesterolemia (FH) Using the Dutch Lipid Network (DLN) Criteria in Electronic Health Records (EHR)

Introduction: Heterozygous FH is common but under-diagnosed. No uniformly accepted diagnostic criteria for FH exist, and the ability of current algorithms to identify patients using EHR data remains largely untested. Here we present results and challenges in using the DLN criteria to identify FH patients in an EHR. Methods: In the Vanderbilt University Medical Center de-identified EHR, patients &gt; 18 years with 1+ low-density lipoprotein cholesterol (LDL-C) measure from 1996 to 2014 were eligible for study. Using diagnostic and procedure codes, narrative text from clinical care, and laboratory data, patients were assigned points for DLN components (see Table), which were summed to classify definite (DLN≥8) or probable (DLN=6-7) FH. LDL-C values were extracted directly from structured laboratory records. Evidence of physical signs or testing for LDL-C receptor mutations were assessed via keyword searches with simple negation detection rules, the latter including vendor names known to conduct such mutation analyses. Results: Among 218,652 eligible patients, 10,812 (5%) had 1+ LDL-C &gt; 190 mg/dl. We identified 622 probable and 430 definite FH patients (overall prevalence 0.48%). Family history was not ascertainable in a systematic way for most patients and thus not used in scoring. Physical exam signs minimally impacted DLN scores as they were noted infrequently. No definite or probable FH patient records included mention of LDL-C receptor mutation status. Only 5 definite and 3 probable FH patients had narrative keywords noting the presence or suspicion of FH. Conclusions: EHRs may be useful to identify FH patients but existing algorithms lack sensitivity when applied to EHRs as they rely on key elements rarely captured. Further, the sizable population with LDL-C &gt; 190 suggests that FH in this group may not be adequately captured by the DLN criteria. Work is needed to determine how best to utilize EHRs to reliably ascertain FH, via development of new algorithms or by clarifying the positive predictive value of existing algorithms.

Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.

Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not universally available. The aim of the present study was to assess the frequency and predictors of FH causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study. We genotyped for LDLR[W23X;W66G;W556S] and APOB[R3500Q] accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information. The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH vs. unlikely FH. Using the Simon Broome criteria, the odds ratio was 27 (20-36) for possible vs. unlikely FH, and using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, 40 (28-58) for probable vs. unlikely FH. Odds ratios for an FH mutation were 17 (9-31) for LDL-cholesterol of 4-4.9 mmol/L, 69 (37-126) for LDL-cholesterol of 5-5.9 mmol/L, 132 (66-263) for LDL-cholesterol of 6-6.9 mmol/L, 264 (109-637) for LDL-cholesterol of 7-7.9 mmol/L, and 320 (129-798) for LDL-cholesterol above 7.9 mmol/L vs. LDL-cholesterol below 4 mmol/L. The most optimal threshold for LDL-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L. Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L.

0033: Unexpected high prevalence of possible and probable familial hyper-cholesterolemia in clinical practice – the DYSIS study

The recent EAS consensus paper on familial hypercholesterolæmia (FH) indicates a higher prevalence of elevated LDL-C due to genetic reasons than previously estimated. We aimed to determine the percentage of patients with very high LDL-C levels in the DYSIS study. The cross-sectional, observational study DYSIS examined lipid goal attainment among statin-treated patients in Canada, Europe, the Middle East, Egypt and South Africa. In this analysis we evaluated DYSIS patients to determine very high LDL-C with potential genetic background. We examined the number of patients with LDL-C >190mg/dl despite statin therapy, the number of patients with possible FH (Score 3-5 according to the Dutch Advanced Method) and the number of patients with probable FH (Score 6-8). This score includes several parameters: first degree relative known with premature CHD and/or first degree relative with LDL-C >95 th percentile (1 point); first degree relative with tendon xanthomas or children with LDL-C >95 th percentile (2 points); the patient has premature CAD (2 points), the patient has premature cerebral or peripheral vascular disease (1 point); the patient has tendon xanthomas (6 points), the patient has corneal arcus below the age of 45 years (4 points); LDL-C >330mg/dl (8 points), LDL-C between 250 and 329mg/dl (5 points), LDL-C between 190 and 249mg/dl (3 points) and LDL-C between 155 and 189mg/dl (1 point). The prevalence of patients with LDL-C >190mg/dl despite statin therapy was 3% (UK 0.8%, France 3.5%, Spain 4.2%). The prevalence of patients with possible FH (Score 3-5) was 6% (UK 4.4%, France 5.9%, Spain 5.7%). The prevalence of patients with probable FH (Score 6-8) was 0.3% (UK 0%, France 0.1%, Spain 0.2%). In this multinational study of statin-treated patients, 2.9% showed an elevated LDL-C above 190mg/dl. Genetic causes may explain the very high LDL-C levels despite statin therapy in the DYSIS study.

Long-term pharmacotherapy for elevated low density lipoprotein levels in children: A retrospective analysis

There is limited research detailing low-density lipoprotein cholesterol (LDL-C) trends over the long term in children on various lipid-lowering medications. This study sought to assess factors associated with stability of LDL-C levels in children on long-term pharmacotherapy and their ability to reach the LDL-C goal of ≤130 mg/dL while on pharmacotherapy. Medical records of children seen in a university pediatric cholesterol clinic between 1998 and 2012 treated with a statin, ezetimibe, or both were reviewed. Aggregate data were obtained to determine the number of children able to reach an LDL-C level of ≤130 mg/dL while on pharmacotherapy. Kaplan-Meier curve and proportional hazard regression analysis were used to examine the propensity for LDL-C levels to stabilize over time while on pharmacotherapy as well as factors affecting this propensity. Overall, 76 patients who contributed 864 total visits were included. Of the 76 patients, 56 developed a stable LDL-C with median time to stability of 28 months on pharmacotherapy. Younger age at first visit and higher medication potencies/doses were associated with an increased propensity to stabilize. Only 36 patients were able to reach an LDL-C of ≤130 mg/dL, with only 11 of 38 patients with probable familial hypercholesterolemia reaching this goal. Most children reached LDL-C stability on pharmacotherapy after a median 28-month interval. However, most children had difficulty in reaching the LDL-C goal of ≤130 mg/dL even with aggressive medication titration. This was specifically true for those with probable familial hypercholesterolemia.

The use of CT coronary calcium score in asymptomatic patients with familial hypercholesterolaemia

Background: Familial hypercholesterolaemia (FH) is associated with accelerated atherosclerosis. Diagnosis is based on clinical scores and only 45% of those with a clinical diagnosis have a genetic mutation known to be associated with FH. Coronary artery calcium (CAC) scoring can be used as a surrogate marker for coronary artery disease, but data on its use in FH are scarce. Methods: CAC was performed in 52 asymptomatic patients (16 ‘probable FH’ and 36 ‘possible FH’) classified according to modified Simon Broome criteria, who were attending a secondary care lipid clinic. Demographic and disease characteristics, CAC (Agatston) scores and arterial age were audited. Results: Half the patients had an Agatston score of zero. In those with Agatston scores >0 and age >45 years, the mean arterial age was significantly higher than the chronological age (72 versus 59 years; p=0.0001). Only diabetes and hypertension status were significantly different between those with Agatston scores of 0 and >0 (p=0.045 and p=0.0175 respectively). Arterial age provided information useful for individualised clinical management. Conclusions: Atherosclerosis burden varies widely in FH with diabetes mellitus and hypertension appearing to contribute. We have found the information from CT calcium scoring very useful in identifying those patients with significant atherosclerosis who would need more intensive treatment.

Statin desensitization in a patient with probable familial hypercholesterolemia

With cardiovascular disease being the leading cause of morbidity and mortality in the United States, cholesterol-lowering medications have become a prominent focus of medical management and cardiovascular risk reduction, including the use of statins making them the most widely prescribed class of medications in the United States and are the cornerstone of management of hyperlipidemia. This case report describes a 29-year-old female with probable familial hypercholesterolemia (FH) who had allergic reactions to statin therapy on two separate occasions. She required statin therapy based on her elevated carotid intima media thickness test, historic LDL-C ≥ 190 mg/dL, elevated Lp(a), and family history significant for premature coronary heart disease. In this report, we document a case of successful oral desensitization to rosuvastatin and propose a replicable statin desensitization protocol. The patient was admitted for rosuvastatin desensitization following predetermined protocols, utilizing an interdisciplinary team, and monitored for 24 hours following completion of administration prior to discharge. She successfully completed desensitization to rosuvastatin 10mg by mouth daily without anaphylactic reaction. She continued to tolerate rosuvastatin 10mg daily through most recent follow-up, and with this addition, significant improvement in lipid levels was achieved. This case report presented a patient with probable FH who was previously intolerant to other statin therapies that underwent successful desensitization to rosuvastatin with subsequent achievement of therapy goals.

Abstract 19656: What is the Prevalence of Familial Hypercholesterolemia in the US?

Background: The prevalence of Familial Hypercholesterolemia (FH) ranges from 1 in 500, as commonly cited, to 1 in 200 in a population-based Danish study. The prevalence of FH in the US, particularly in those of non-European background, remains unknown. Methods: To estimate the US prevalence of FH in National Health and Nutrition Examination Survey (NHANES) 2001-2012 datasets (n = 59,423), we used the Dutch Lipid Clinic (DLC) criteria (Benn et al 2012), which classifies individuals as definite or probable FH based on personal history of premature coronary artery disease (CAD), family history in a first-degree relative of known premature CAD or vascular disease, LDL level, and genetic criteria. Genetic testing is not available in NHANES and therefore was not included. For persons reporting statin use, we multiplied by 1.43 to estimate untreated LDL levels. Results: The overall US prevalence of probable/definite FH in NHANES was 0.33% (95% CI 0.19-0.48) or 1 in 299 (1 in 210-519). The prevalence of FH was similar in males and females (0.34%; 1 in 293 vs. 0.33%; 1 in 305) and in blacks and whites (0.35%; 1 in 283 vs. 0.37%; 1 in 270), but lower in Mexican Americans (0.16%; 1 in 620) and other races (0.08%, 1 in 1235) and higher in other Hispanics (0.40%; 1 in 252). FH prevalence was lowest in 30-39 year olds (0.15%, Figure ), and highest in 50-59 year olds (0.60%), and higher with obesity (0.49%; 1 in 204) than non-obesity (0.26%; 1 in 387), likely reflecting the impact of increasing age and weight on LDL when using DLC criteria. Summary: Our analysis of NHANES data suggests a US prevalence of FH of 1 in 299, which is higher than the commonly cited estimate of 1 in 500 and is likely an underestimate due to the absence of genetic testing in NHANES. Higher prevalence with obesity and in middle-age highlights the influence of increasing age- and weight-related effects on LDL in FH prevalence estimates. Consideration should be given to incorporating genetic testing into future studies of US FH prevalence.

Can Patients be Accurately Assessed for Familial Hypercholesterolaemia in Primary Care?

Familial Hypercholesterolaemia (FH) is the most prevalent monogenic condition causing premature coronary artery disease, although the majority of individuals remain undiagnosed. We sought to investigate whether individuals with FH could be accurately identified in primary care. The Dutch Lipid Clinic Network Criteria scores (DLCNCS) assessed by general practitioners (GPs) were compared with DLCNCS assessed by specialists using primary care data in 153 individuals. Thirty individuals with DLCNCS ≥4 underwent specialist review and genetic testing. Clinical FH was defined as DLCNCS ≥6, encompassing the probable and definite FH categories. GPs correctly classified 39 (86.7%) individuals with 'clinical FH', and 32 (94%) with 'unlikely FH' relative to specialists. Lin's concordance correlation coefficient was high (0.832 (0.783 - 0.881), p< 0.001) between specialist and GPs, with an overall agreement of 83.6%, κ 0.744 (0.642 - 0.831). After specialist review, 15 individuals (50%) were diagnosed with clinical FH, four (26.7%) had FH mutations. GPs correctly classified 12 (80%) of these individuals with clinical FH. GPs can accurately identify individuals at high and low risk of FH using the DLCNCS, which may augment opportunistic FH detection in the community. Increased education may enhance the diagnostic accuracy of FH in primary care.

Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing.

Maglio C., Mancina R. M., Motta B. M., Stef M., Pirazzi C., Palacios L., Askaryar N., Borén J., Wiklund O., Romeo S. (University of Gothenburg, Gothenburg, Sweden; University Magna Graecia of Catanzaro, Italy; University of Milan, Italy; Progenika Biopharma SA, Derio, Spain). Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing.ObjectivesThe aim of this study was to combine clinical criteria and next-generation sequencing (pyrosequencing) to establish a diagnosis of familial hypercholesterolaemia (FH).Design, setting and subjectsA total of 77 subjects with a Dutch Lipid Clinic Network score of ≥3 (possible, probable or definite FH clinical diagnosis) were recruited from the Lipid Clinic at Sahlgrenska Hospital, Gothenburg, Sweden. Next-generation sequencing was performed in all subjects using SEQPRO LIPO RS, a kit that detects mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLR adapter protein 1 (LDLRAP1) genes; copy-number variations in the LDLR gene were also examined.ResultsA total of 26 mutations were detected in 50 subjects (65% success rate). Amongst these, 23 mutations were in the LDLR gene, two in the APOB gene and one in the PCSK9 gene. Four mutations with unknown pathogenicity were detected in LDLR. Of these, three mutations (Gly505Asp, Ile585Thr and Gln660Arg) have been previously reported in subjects with FH, but their pathogenicity has not been proved. The fourth, a mutation in LDLR affecting a splicing site (exon 6–intron 6) has not previously been reported; it was found to segregate with high cholesterol levels in the family of the proband.ConclusionsUsing a combination of clinical criteria and targeted next-generation sequencing, we have achieved FH diagnosis with a high success rate. Furthermore, we identified a new splicing-site mutation in the LDLR gene.

Detecting familial hypercholesterolaemia in the community: Impact of a telephone call from a chemical pathologist to the requesting general practitioner

ObjectiveTo determine whether a telephone call from a chemical pathologist to the requesting general practitioner (GP) of individuals at high risk of familial hypercholesterolaemia (FH) increases specialist referral and detection of FH. MethodIndividuals with an LDL-cholesterol ≥6.5 mmol/L without secondary causes were identified from a community laboratory; 100 cases and 96 historical controls.All laboratory reports (cases and controls) received interpretative comments highlighting FH. In addition, the cases' GPs received a telephone call from the chemical pathologist to highlight their patient's risk of FH and suggest specialist referral, whereas with the controls' GPs were not telephoned. ResultsAfter 12 months follow-up, 27 (27%) cases were referred to clinic compared with 4 (4%) controls (p < 0.0001). 25 cases were reviewed at clinic, 12 (48%) had definite FH and 18 (72%) had probable or definite FH according to the Dutch Lipid Clinic Network Criteria, 2 cases did not attend their clinic appointments. Genetic testing was performed in 23 individuals: 7 (30%) had pathogenic FH mutations. Genotypic cascade screening of 4 kindreds from the intervention group detected an additional 7 individuals with FH and excluded 5 mutation-negative family members. ConclusionsA telephone call from a chemical pathologist to the requesting GP of patients at high risk of FH was associated with significantly higher rates of FH detection and specialist referral. Over 70% of individuals with an LDL-cholesterol ≥6.5 mmol/L were diagnosed with FH. However, further investigation is required to improve the relatively low referral rate.