Referral rate, profile and degree of control of patients with familial hypercholesterolemia: data from a single lipid unit from a Mediterranean area

Referrals and patientsAnalysis of the referral rate for the study of lipid disorders to the Endocrinology unit

The sample size for evaluating the percentage of referrals to the Endocrinology Outpatient Consultation for lipid disorders was calculated using the GRANMO sample size calculator from IMIM (Hospital del Mar Medical Research Institute) version 7.12, April 2012.

Following a population proportion estimation model, a minimum sample size of 340 subjects was estimated according to a percentage of referral to specialized consultation for lipid disorders of 14.7% [18], accepting an alpha error of 0.05, a beta error of 0.2, and a unilateral contrast model, assuming a loss percentage of 1% and a minimum difference to be detected of 0.05% units.

Following a retrospective observational study model, the main reason for every referral from primary care to the Endocrinology Unit of our center during the period 01/2013 to 12/2016 was recorded until a representative sample of 340 referrals was obtained.

Analysis of the baseline characteristics of patients referred for the study of familial hypercholesterolemia

Using a similar process and among those patients attended in the endocrinology outpatient clinic from 01/2010 to 12/2018 referred for the study of a possible FH, it was calculated that a sample of 116 individuals would allow us to estimate their main characteristics (with a confidence of 95%, a precision of ± 1% and assuming 10% loss).

An initial cohort of 138 patients was enrolled in this cross-sectional study. The established inclusion criteria were being older than 18 years and having been evaluated previously on suspicion of FH, in its heterozygous form, from 01/2010 to 12/2018 in our unit. The exclusion criteria for the study were not fulfilling the inclusion criteria and missing essential data for DLCN score calculation. Twenty patients were excluded due to a lack of information.

As part of the FH follow-up, a high percentage of these patients were evaluated with carotid ultrasonography (CU) for the detection of plaques and with the measurement of lipoprotein(a) (Lp(a)).

Age at diagnosis and current age, sex, weight, height and body mass index (BMI) were recorded in all patients and included in the study as quantitative variables. Waist circumference was collected in 60% of the sample. Characterization into overweight, obesity and central obesity was established following the cutoff points defined by the IDF (International Diabetes Federation) and SEEDO (Spanish Society for the Study of Obesity) [19, 20] and diabetes or prediabetes condition according to ADA (American Diabetes Association) diagnostic criteria [21]. However, to compare with local studies, prediabetes was also established following the guidelines of the SED (Spanish Diabetes Society) working group [22].

The DLCN score was evaluated for each patient, and as qualitative variables, obesity, smoking, the use of statins (establishing the type and dose) and other lipid-lowering drugs were recorded as well as the performance of the genetic study and the mutation detected. Active smokers and ex-smokers who had been quit for less than 5 years were considered the same category in relation to residual cardiovascular (CV) risk [23].

Diagnostic criteriaFamilial hypercholesterolaemia

For the aforementioned reasons, the probability of diagnosis of FH was made using the DLCN scale, which establishes a numerical value for family, personal, pathological and analytical history of the patients and sums the different results in a final score. The identification of a mutation affecting the LDLc receptor gene, apoB or PSCK9 is associated with 8 points [15, 24].

Each patient was stratified into a diagnosis of certainty (> 8 points), probability (6–8 points) and possibility (3–5 points). A score below 3 points was considered unlikely [15].

Established cardiovascular disease and control target

According to the 2019 ESC/EAS Guidelines for the management of dyslipidemia [25], we assumed established cardiovascular disease (CVD) in all patients with a history of acute coronary syndrome (myocardial infarction or unstable angina) or CAD, such as stable angina or coronary revascularization requirements. Moreover, transient ischemic attack, stroke and peripheral arterial disease were included.

The lipid control target, always based on the 2019 European guidelines [25], for patients at high and very high cardiovascular risk (where patients with FH are included) requires a reduction in LDLc of at least 50% from baseline and LDLc concentrations below 70 and 55 mg/dL, respectively.

Evaluation of subclinical atherosclerosis

Most patients were evaluated with the performance of a CU. Every study was performed by a trained radiologist to identify the presence of atheromatous plaques and establish their size. CU was not always performed by the same specialist due to the inclusion of patients over a period of 8 years.

An atheromatous plaque was considered as the detection of a thickening ≥ 1.5 mm, a focal lesion invading the lumen at least 0.5 mm or a lesion invading the lumen ≥ 50% of the surrounding carotid intima-media thickness. The images were recorded by a 13.5 MHz linear transducer of a B-mode ultrasound machine (General Electric Company, LogiQ P9, manufactured in China, 2007).

Biochemical measurements

Blood tests were obtained at approximately 8:00 a.m. after fasting for at least 8 h. The lipid profile was obtained from every patient, including LDLc by the Friedewald formula and total cholesterol, high-density lipoprotein (HDL), non-HDL cholesterol (total cholesterol - HDL) and triglycerides by routine procedures.

HbA1c

HbA1c was calculated in ethylenediaminetetraacetic acid blood samples by high-performance liquid chromatography using a fully automated analyzer (Adams Menarini HI-AUTO A1c 8160, from Arkray (Kyoto, Japan)), interassay coefficient of variation of 1.8 and 1.5% (HbA1c levels of 4.8 and 9.0%) and reference range of 4–6.1%. This test procedure is certified by the National Glycohemoglobin Standardization Program for traceability to the Diabetes Control and Complications Assay reference method.

Lipoprotein (a)

Lp(a) mass was determined in serum by latex-enhanced turbidimetric immunoassay (The Binding Site Optilite®) at the reference laboratory. A risk value of Lp(a) higher than 50 mg/dL was assumed in accordance with most clinical guidelines and the Caucasian nature of the study population [26].

Statistical methods

Statistical package for the social sciences (IBM, SPSS, Chicago, IL, USA) for personal computers, version 19.0, was used for statistical analysis.

All continuous variables were recorded as the mean and standard deviation, except those with a nonnormal distribution, which were expressed as the mean and interquartile range. Instead, categorical variables were collected as frequencies or percentages.

To establish differences between groups, Student’s t test, the Mann‒Whitney U test (nonparametric) and the squared X2 test were used, assuming a P value of less than 0.05 as statistically significant.

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