Perfil clínico de la hipercolesterolemia severa en 156.000 adultos en atención primaria / Clinical profile of severe hypercholesterolemia in 156.000 adults in primary care

Objetivo Estimar la frecuencia y el perfil clínico de la hipercolesterolemia severa (HS) y del fenotipo de hipercolesterolemia familiar (HF) en el ámbito de atención primaria, en un área sanitaria de la comunidad de Madrid (CAM). Material y métodos Estudio transversal, multicéntrico de sujetos con tarjeta sanitaria adscritos a 69 centros de salud (área NorOeste/CAM). Se definió HS como colesterol ≥300mg/dl o colesterol-LDL ≥220mg/dl en alguna analítica realizada (1-1-2018 a 30-12-2021), y fenotipo de HF como cLDL ≥240mg/dl (≥160mg/dl si tratamiento hipolipemiante), con triglicéridos <200mg/dl y TSH <5μIU/ml. Resultados Se analizaron 156.082 adultos ≥18años con perfil lipídico disponible. 6.187 sujetos tenían HS (3,96% de las analíticas estudiadas; IC95%: 3,87-4,06%). El tiempo medio de evolución del diagnóstico de hiperlipemia en la historia clínica informatizada fue 10,8años; el 36,5% tenían hipertensión, el 9,5%, diabetes, y el 62,9%, sobrepeso/obesidad. El 83,7% tomaban hipolipemiantes (65,7% de baja/moderada y 28,6% de alta/muy-alta intensidad). El 6,1% tenían enfermedad cardiovascular (94,2% tratados con hipolipemiantes), con colesterol LDL <55, <70 y <100mg/dl de 1,8%, 5,8% y 20,2%, respectivamente (vs 1%, 2,3% y 11,2% si no había enfermedad cardiovascular). Mil seiscientos sujetos tenían fenotipo de HF (IC95%: 1,03%, 0,98-1,08%). Conclusiones Cuatro de cada 100 pacientes analizados en atención primaria tienen HS. Hay un elevado nivel de tratamiento farmacológico, pero de insuficiente intensidad, y escaso logro de objetivos terapéuticos. Uno de cada 100 tiene fenotipo de HF. La identificación de ambas situaciones por registros informatizados permitiría su detección más precisa y precoz y establecer estrategias preventivas cardiovasculares. (AU)

Objective To examine the frequency of severe hypercholesterolemia (HS) and its clinical profile, and the phenotype of familial hypercholesterolemia (FH), in the primary-care setting in a large health area of the Community of Madrid (CAM). Material and methods Multicenter study of subjects with a health card assigned to 69 health centers (Northwest/CAM area). HS was defined as cholesterol ≥300mg/dL or LDL-cholesterol ≥220mg/dL in any analysis performed (1-1-2018 to 12-30-2021); and FH phenotype as c-LDL ≥240mg/dL (≥160mg/dL if lipid-lowering treatment) with triglycerides <200mg/dL and TSH <5μIU/mL. Results 156,082 adults ≥18years with an available lipid profile were analyzed. 6187 subjects had HS (3.96% of the laboratory tests studied, 95%CI: 3.87-4.06%). The mean evolution time of the diagnosis of hyperlipidemia in the computerized clinical record was 10.8years, 36.5% had hypertension, 9.5% diabetes and 62.9% overweight/obesity. 83.7% were taking lipid-lowering drugs (65.7% low/moderate and 28.6% high/very high intensity). 6.1% had cardiovascular disease (94.2% treated with lipid-lowering agents), with LDL-cholesterol <55, <70 and <100mg/dL of 1.8%, 5.8% and 20.2%, respectively (vs. 1%, 2.3% and 11.2% if no cardiovascular disease). 1600 subjects had FH phenotype (95%CI: 1.03%, 0.98-1.08%). Conclusions Four out of 100 patients analyzed in primary care have HS, with high treatment level, but insufficient intensity, and poor achievement of treatment goals. One in 100 have the FH phenotype. The identification of both dyslipidemias by computerized records would allow their more precise and early detection and establish cardiovascular preventive strategies. (AU)

Widespread xanthomas regression by personalized lipid lowering therapy in heterozygous familial hypercholesterolemia / Regresión generalizada de xantomas mediante terapia hipolipemiante personalizada en hipercolesterolemia familiar heterocigótica

“The lower, the better” is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas. (AU)

«Cuanto más bajo, mejor» es el enfoque recomendado en el tratamiento del colesterol LDL alto. Lamentablemente esto no siempre se logra como en el caso de una mujer de 69 años remitida a nuestro Instituto por su perfil lipídico (colesterol LDL 412 mg/dL), xantelasma bilateral y xantomas cutáneos. Con terapias hipolipemiantes maximizadas y personalizadas (rosuvastatina, ezetimiba, iPCSK9 y aféresis de lipoproteínas), después de solo seis meses, la paciente mostró una regresión impresionante en sus xantomas cutáneos. (AU)

Factors associated with the presence of tendon xanthomas in familial hypercholesterolemia.

INTRODUCTION AND OBJECTIVES: Tendon xanthomas (TX) are lipid deposits highly specific to familial hypercholesterolemia (FH). However, there is significant variability in their presentation among FH patients, primarily due to largely unknown causes. Lipoprotein(a) is a well-established independent risk factor for atherosclerotic cardiovascular disease in the general population as well as in FH. Given the wide variability of lipoprotein(a) among FH individuals and the likelihood that TX may result from a proatherogenic and proinflammatory condition, the objective of this study was to analyze the size of TX in the Achilles tendons of FH participants and the variables associated with their presence, including lipoprotein(a) concentration. METHODS: A cross-sectional study was conducted on 377 participants with a molecular diagnosis of heterozygous FH. Achilles tendon maximum thickness (ATMT) was measured using ultrasonography with standardized equipment and procedures. Demographic variables and lipid profiles were collected. A multivariate linear regression model using a log-Gaussian approach was used to predict TX size. Classical cardiovascular risk factors and lipoprotein(a) were included as explanatory variables. RESULTS: The mean low-density lipoprotein cholesterol level was 277mg/dL without lipid-lowering treatment, and the median ATMT was 5.50mm. We demonstrated that age, sex, low-density lipoprotein cholesterol, and lipoprotein(a) were independently associated with ATMT. However, these 4 variables did not account for most the interindividual variability observed (R2=0.205). CONCLUSIONS: TX, a characteristic hallmark of FH, exhibit heterogeneity in their presentation. Interindividual variability can partially be explained by age, male sex, low-density lipoprotein cholesterol, and lipoprotein(a) but these factors account for only 20% of this heterogeneity.

Widespread xanthomas regression by personalized lipid lowering therapy in heterozygous familial hypercholesterolemia.

"The lower, the better" is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas.

Clinical profile of severe hypercholesterolemia in 156,000 adults in primary care. / Perfil clínico de la hipercolesterolemia severa en 156.000 adultos en atención primaria.

OBJECTIVE: To examine the frequency of severe hypercholesterolemia (HS) and its clinical profile, and the phenotype of familial hypercholesterolemia (FH), in the primary-care setting in a large health area of the Community of Madrid (CAM). MATERIAL AND METHODS: Multicenter study of subjects with a health card assigned to 69 health centers (Northwest/CAM area). HS was defined as cholesterol ≥300mg/dL or LDL-cholesterol ≥220mg/dL in any analysis performed (1-1-2018 to 12-30-2021); and FH phenotype as c-LDL ≥240mg/dL (≥160mg/dL if lipid-lowering treatment) with triglycerides <200mg/dL and TSH <5µIU/mL. RESULTS: 156,082 adults ≥18years with an available lipid profile were analyzed. 6187 subjects had HS (3.96% of the laboratory tests studied, 95%CI: 3.87-4.06%). The mean evolution time of the diagnosis of hyperlipidemia in the computerized clinical record was 10.8years, 36.5% had hypertension, 9.5% diabetes and 62.9% overweight/obesity. 83.7% were taking lipid-lowering drugs (65.7% low/moderate and 28.6% high/very high intensity). 6.1% had cardiovascular disease (94.2% treated with lipid-lowering agents), with LDL-cholesterol <55, <70 and <100mg/dL of 1.8%, 5.8% and 20.2%, respectively (vs. 1%, 2.3% and 11.2% if no cardiovascular disease). 1600 subjects had FH phenotype (95%CI: 1.03%, 0.98-1.08%). CONCLUSIONS: Four out of 100 patients analyzed in primary care have HS, with high treatment level, but insufficient intensity, and poor achievement of treatment goals. One in 100 have the FH phenotype. The identification of both dyslipidemias by computerized records would allow their more precise and early detection and establish cardiovascular preventive strategies.

Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO).

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain. MATERIAL AND METHODS: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed. RESULTS: 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular disease. The mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m2 (51.7% of patients had eGFR <60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-c ≥160mg/dL and 29.3% ≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use remained stable. CONCLUSION: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study.

Criterios predictores en el diagnóstico de la hipercolesterolemia familiar / Predictive criteria in the diagnosis of familial hypercholesterolemia

Introducción: La hipercolesterolemia familiar es una enfermedad con alta prevalencia, no tratada acorta la esperanza de vida, por lo que el diagnóstico a edades tempranas resulta fundamental. Las pruebas genéticas constituyen el gold standard para el diagnóstico de hipercolesterolemia familiar, sin embargo, la no disponibilidad del test genético no debe constituir un impedimento para la adecuada conducta en estos casos. Objetivo: Identificar criterios clínicos predictores en el diagnóstico por pesquisa de la hipercolesterolemia familiar. Métodos: Se realizó un estudio descriptivo prospectivo a partir de una muestra de 393 pacientes (casos índices) de HF en el Hospital Clínico Quirúrgico Hermanos Ameijeiras; durante el período 2008-2018. Resultados: En la pesquisa familiar fueron identificados 177 (15,66 por ciento) nuevos casos de hipercolesterolemia familiar, de ellos se clasifican como casos positivos 35 (19,77 por ciento), casos probables 58 (32,77 por ciento) y casos posibles 84 (47,46 por ciento). Las categorías del estrato Make early diagnosis to prevent early death MEDPED y la edad del caso índice resultaron ser las variables clínicas de interés con mayor probabilidad para identificar nuevos casos de hipercolesterolemia familiar. Conclusiones: los criterios clínicos estandarizados de la escala make early diagnosis to prevent early death P y la edad del caso índice resultaron ser indicadores predictivos de gran valor para identificar y estratificar casos con variantes fenotípicas de hipercolesterolemia familiar(AU)

Introduction: Familial hypercholesterolemia is a disease with high prevalence; it shortens life expectancy if it is not treated, so early diagnosis is essential. Genetic tests are the gold standard for the diagnosis of familial hypercholesterolemia, however, the unavailability of the genetic test should not be an obstacle to proper conduct in these cases. Objective: To identify predictive clinical criteria in the diagnosis by screening of familial hypercholesterolemia. Methods: A prospective descriptive study was carried out from a sample of 393 patients (index cases) of FH at Hermanos Ameijeiras Surgical Clinical Hospital from 2008 to 2018. Results: In the family investigation, 177 (15.66 percent) new cases of familial hypercholesterolemia were identified, 35 of them (19.77 percent) are classified as positive cases, 58 (32.77 percent) as probable cases and 84 as possible cases (47.46 percent)The stratum categories of Make Early Diagnosis to Prevent Early Death (MEDPED) and the age of the index case turned out to be the clinical variables of interest with the greatest probability to identify new cases of familial hypercholesterolemia. Conclusions: The standardized clinical criteria of the make early diagnosis to prevent early death P scale and the age of the index case turned out to be highly valuable predictive indicators to identify and stratify cases with phenotypic variants of familial hypercholesterolemia(AU)

Perfil clínico de los pacientes tratados con evolocumab en unidades hospitalarias de nefrología en España (RETOSS-NEFRO) / Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO)

Antecedentes y objetivo : Describir las características clínicas de los pacientes tratados con evolocumab, las razones del inicio de la terapia y los efectos del tratamiento en la fase inicial de disponibilidad de evolocumab en las unidades de nefrología de España.Material y métodosEstudio retrospectivo, observacional y multicéntrico que incluye los pacientes que iniciaron tratamiento con evolocumab (desde febrero de 2016 a agosto de 2018) en 15 unidades de nefrología en España. Se revisaron las características demográficas y clínicas de los pacientes, el tratamiento hipolipemiante y la evolución de los perfiles lipídicos entre 24 semanas antes y 12±4 semanas después del inicio de evolocumab.ResultadosSe incluyeron 60 pacientes: 53,3% mujeres, edad media (DE) de 56,9 (12,8) años, el 45,0% con hipercolesterolemia familiar (HF) (5,0% homocigota y 40,0% heterocigota) y el 65,0% con enfermedad cardiovascular aterosclerótica (ECVA) previa. El filtrado glomerular estimado (FGe) medio fue de 62,6 (30,0) ml/min/1,73m2 (51,7% pacientes con FGe<60ml/min/1,73m2 [ERC estadio >2]), el 50,0% con proteinuria (>300mg/g) y el 10,0% con síndrome nefrótico. Otros factores de riesgo CV fueron: hipertensión (75,0%), diabetes mellitus (25,0%) y hábito tabáquico (21,7%). El 40,0% eran intolerantes a estatinas. Al inicio de evolocumab, el 41,7% tomaban estatinas de alta intensidad, el 18,3% estatinas de moderada intensidad y el 50,0% ezetimiba. Los niveles medios (DE) de c-LDL al inicio de evolocumab fueron de 179,7 (62,9) mg/dl (53,4% pacientes con c-LDL≥160mg/dl y 29,3%≥190mg/dl). Después de 12 semanas del tratamiento con evolocumab se observó una reducción de los niveles de c-LDL del 60,1%. A la semana 12, el 90,0% de los pacientes alcanzó niveles c-LDL<100mg/dl, 70,0%<70mg/dl y 55,0%<55mg/dl, mientras que el FGe medio y el uso de estatinas se mantuvieron estables. (AU)

Background and objective: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain.Material and methodsRetrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed.ResultsSixty patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular (CV) disease. The mean (SD) eGFR was 62.6 (30.0)ml/min/1.73m2 (51.7% of patients had eGFR<60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high-intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9)mg/dL (53.4% of patients with LDL-c≥160mg/dL and 29.3%≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use were remained stable. (AU)

Hipercolesterolemia familiar descripción de un caso en una familia de Armenia - Quindío (Colombia)

Introducción: La Hipercolesterolemia familiar (HF) es una enfermedad genética de carácter autosómico dominante, poco frecuente, generada por la mutación en el cromosoma 19. Es la primera causa de enfermedad cardiovascular prematura. Las mutaciones patogénicas que generan la HF se relacionan con el receptor de LDL (LDLr), la apolipoproteina B-100 (Apo- B100) y la proteína convertasa subtilisina / kexina tipo 9 (PCSK9), que produce elevación del colesterol y alteración de la vía del LDLr en el 80 % de los casos diagnosticados de HF (5). Presentamos un reporte de caso de cuatro pacientes que pertenecen a la misma familia, quienes presentan mutaciones patogénicas de diferente compromiso a nivel cardiovascular y sistémico que ha afectado de manera negativa su cotidianidad. El objetivo de este trabajo es realizar una correlación del hipercolesterolemia familiar de tipo genético a partir de la literatura, con respecto a la serie de casos presentada, y evaluar el impacto que este genera en los servicios de salud, en la vida del paciente y su familia. Discusión: El reporte de caso que presentamos se fundamenta en la sospecha de HF según los criterios de Holanda. En estos pacientes se reconoce mutación del gen LDLr que se relaciona con HF. Sin embargo, no ha sido ampliamente estudiada. Chmara realizó en Polonia por primera vez un estudio en el que reportó la variante ac 11G>T. En Colombia, el estudio de López encontró tres mutaciones, identificadas como variante a c.11G > A, n c.416A > G y c.1187G > A (8). Conclusión: La HF en nuestro medio es poco frecuente y con gran impacto social, en la mayoría de los casos genera síntomas clínicos y aumento del riesgo cardiovascular desde una edad temprana. Es importante resaltar el diagnóstico oportuno y el conocimiento por parte del personal de salud para generar una calidad de vida adecuada a los pacientes y evitar que aumente el riesgo cardiovascular.

Introduction: Familial hypercholesterolemia (FH) is a rare autosomal dominant genetic disease caused by a chromosome 19 mutation. It is the main cause of premature cardiovascular disease. Pathogenic mutations which cause FH are related to the LDL receptor (LDLr), B-100 apolipoprotein (Apo-B100) and type 9 subtilisin/kexin convertase protein (PCSK9), causing blood cholesterol increase and impairment of the LDLr pathway in up to 80% of patients diagnosed with FH. We present the case of 4 patients belonging to the same family and who present pathogenic mutations leading to diverse kinds of cardiovascular and systemic disease. Discussion: The case report we are presenting is based on the suspicion of FH according to the dutch criteria. These patients had the LDLr gene mutation related to FH. However, this mutation has not been thoroughly studied. The ac 11G>T variant was reported for the first time in Poland by Chmara. In Colombia, Lopez found 3 mutations identified as variant a c.11G > A, variant n c.416A > G and variant c.1187G > A. Conclusion: FH is rare in Colombia. Early diagnosis and healthcare worker awareness must be highlighted to improve the quality of life and decrease the cardiovascular risk of patients.

Rastreamento para Hipercolesterolemia Familiar em Pequenos Municípios: A Experiência do Programa HipercolBrasil em 11 Municípios Brasileiros / Screening for Familial Hypercholesterolemia in Small Towns: Experience from 11 Brazilian Towns in the Hipercolbrasil Program

Resumo Fundamento A hipercolesterolemia familiar (HF) é uma doença genética dominante que se caracteriza por níveis sanguíneos elevados de colesterol de lipoproteína de baixa densidade (LDL-C), e está associada à ocorrência de doença cardiovascular precoce. No Brasil, o HipercolBrasil, que é atualmente o maior programa de rastreamento em cascata para HF, já identificou mais de 2.000 indivíduos com variantes genéticas causadoras de HF. A abordagem padrão baseia-se no rastreamento em cascata de casos índices referidos, indivíduos com hipercolesterolemia e suspeita clínica de HF. Objetivos Realizar rastreamento direcionado de 11 pequenos municípios brasileiros com suspeita de alta prevalência de indivíduos com HF. Métodos A seleção dos municípios ocorreu de 3 maneiras: 1) municípios em que houve suspeita de efeito fundador (4 municípios); 2) municípios em uma região com altas taxas de infarto do miocárdio precoce, conforme descrito pelo banco de dados do Sistema Único de Saúde (2 municípios); e 3) municípios geograficamente próximos a outros municípios com alta prevalência de indivíduos com HF (5 municípios). A significância estatística foi considerada como valor p < 0,05. Resultados Foram incluídos 105 casos índices e 409 familiares de primeiro grau. O rendimento dessa abordagem foi de 4,67 familiares por caso índice, o qual é significativamente melhor (p < 0,0001) do que a taxa geral do HipercolBrasil (1,59). Identificamos 36 CIs com variante patogênica ou provavelmente patogênica para HF e 240 familiares de primeiro grau afetados. Conclusão: Nossos dados sugerem que, uma vez detectadas, regiões geográficas específicas justificam uma abordagem direcionada para a identificação de aglomerações de indivíduos com HF.

Abstract Background Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C), and it is associated with the occurrence of early cardiovascular disease. In Brazil, HipercolBrasil, which is currently the largest FH cascade screening program, has already identified more than 2000 individuals with causal genetic variants for FH. The standard approach is based on cascade screening of referred index cases, individuals with hypercholesterolemia and clinical suspicion of FH. Objectives To perform targeted screening of 11 small Brazilian cities with a suspected high prevalence of people with FH. Methods The selection of cities occurred in 3 ways: 1) cities in which a founder effect was suspected (4 cities); 2) cities in a region with high rates of early myocardial infarction as described by the National Health System database (2 cities); and 3) cities that are geographically close to other cities with a high prevalence of individuals with FH (5 cities). Statistical significance was considered as p value < 0.05. Results One hundred and five index cases and 409 first-degree relatives were enrolled. The yield of such approach of 4.67 relatives per index case was significantly better (p < 0.0001) than the general HipercolBrasil rate (1.59). We identified 36 IC with a pathogenic or likely pathogenic variant for FH and 240 affected first-degree relatives. Conclusion Our data suggest that, once detected, specific geographical regions warrant a target approach for identification of clusters of individuals with FH.

Xantomas tuberosos en un paciente pediátrico: la clave en el diagnóstico precoz de una patología grave y poco frecuente / Tuberous xanthomas in a pediatric patient: a clue to the early diagnosis of a severe and infrequent disease

Los xantomas cutáneos reflejan el depósito de lípidos en la piel y pueden ser la única manifestación temprana de dislipidemias de inicio en la infancia. Las características y distribución de los xantomas orientan a la patología de base; los xantomas tuberosos tienen una fuerte asociación con la hipercolesterolemia homocigota familiar, una patología muy infrecuente. Su detección temprana otorga una ventana terapéutica para prevenir la ateroesclerosis acelerada y la mortalidad. Se presenta el caso de una paciente que comenzó a los dos años con xantomas tuberosos, que fueron la clave diagnóstica para identificar la hipercolesterolemia homocigota familiar subyacente.

Cutaneous xanthomas reflect lipid deposition on the skin and may be the only early manifestation of a childhoodonset dyslipidemia. Characteristics and distribution of the xanthomas signalize the underlying pathology, tuberousxanthomas being strongly associated with homozygous familial hypercholesterolaemia, an extremely rare condition. Its early detection provides a therapeutic window to prevent accelerated atherosclerosis and mortality. We present the case of a patient who started at two years with tuberous xanthomas, which were the diagnostic clue to identify the underlying homozygous familial hypercholesterolaemia.

Situación en 2020 de los requerimientos para la utilización de inhibidores de PCSK9 en España: resultados de una encuesta nacional / Situation in 2020 of the requirements for the use of PCSK9 inhibitors in Spain: Results of a national survey

OBJETIVO: Durante los años 2019 y 2020 se realizaró una serie de reuniones en todo el territorio nacional dirigidas a explicar la metodología y los criterios de elaboración de las recomendaciones sobre la utilización de iPCSK9 publicadas por la Sociedad Española de Arteriosclerosis. Al final de cada una de las reuniones se realizó una encuesta entre los médicos participantes dirigida a describir los requerimientos de prescripción de estos fármacos en las diferentes regiones españolas. METODOLOGÍA: El Proyecto Efecto Mariposa fue desarrollado por un comité científico experto en lipídos. Tras la elaboración de todos los materiales necesarios para llevar a cabo el proyecto, se efectuó una reunión de formadores, impartida por los coordinadores del proyecto, a un total de 17 expertos. Posteriormente, se realizaron 16 talleres regionales con la asistencia de 169 médicos implicados en el manejo de la hipercolesterolemia, los cuales respondieron una encuesta donde se planteaban diferentes cuestiones acerca del uso de los iPCSK9 en su práctica clínica. CONCLUSIÓN: Los resultados demuestran importantes diferencias en el tratamiento con iPCSK9 en el contexto de la práctica clínica habitual en España. El análisis de estos resultados permitirá plantear en el futuro actuaciones orientadas a la equidad del acceso a los iPCSK9 a nivel nacional, con el objetivo principal de maximizar su beneficio potencial de acuerdo con el perfil del paciente.

AIMS: During 2019 and 2020 a series of meetings over the country were carried out, with the aim of explaining the methodology and criteria for the ellaboration of the recommendations on the use of iPCSK9, published by the Spanish Society of Atherosclerosis (SEA in Spanish). At the end of the meetings, a survey was conducted among the participants, in order to describe the prescription requirements of these drugs in the Spanish regions. METHODOLOGY: Butterfly Project was developed by a scientific Committee of experts in lipids. After the ellaboration of the materials for the project, a train the trainers program was carried out, imparted by 17 experts who were the Project coordinators. Later, 16 regional workshops were performed, with the attendance of 169 medical doctors involved in the management of hipercolesterolemia. The attendants responded the survey, where they were asked different questions on the use of iPCSK9 on their clinical practice. RESULTS: A high heterogeneity among centers regarding the requirements and difficulties for iPCSK9 prescription was revealed. Twenty one per cent of responders indicated to have low difficulties to prescribe iPCSK9 in their hospitals, whereas 78% found moderate or high difficulties. The difficulties came from burocracy- administrative aspects (18%), restrictions in the indication (41%) and both (38%). In general, the obstacles did not depend on the hospital level, neither the speciality, or the presence of lipid units, although the existance of lipid units was associated with a higher number of patients treated with iPCSK9. The factors which were associated with higher difficulty in the prescription were: the presence of an approval committee in the hospitals, the frequency in the revision of the treatment by hospital pharmacy, the temporal cadence of the prescription, the profile of patients seen and the criteria followed by the specialists for the prescription.

Situation in 2020 of the requirements for the use of PCSK9 inhibitors in Spain: Results of a national survey. / Situación en 2020 de los requerimientos para la utilización de inhibidores de PCSK9 en España: resultados de una encuesta nacional.

AIMS: During 2019 and 2020 a series of meetings over the country were carried out, with the aim of explaining the methodology and criteria for the ellaboration of the recommendations on the use of iPCSK9, published by the Spanish Society of Atherosclerosis (SEA in Spanish). At the end of the meetings, a survey was conducted among the participants, in order to describe the prescription requirements of these drugs in the Spanish regions. METHODOLOGY: Butterfly Project was developed by a scientific Committee of experts in lipids. After the ellaboration of the materials for the project, a train the trainers program was carried out, imparted by 17 experts who were the Project coordinators. Later, 16 regional workshops were performed, with the attendance of 169 medical doctors involved in the management of hipercolesterolemia. The attendants responded the survey, where they were asked different questions on the use of iPCSK9 on their clinical practice. RESULTS: A high heterogeneity among centers regarding the requirements and difficulties for iPCSK9 prescription was revealed. Twenty one per cent of responders indicated to have low difficulties to prescribe iPCSK9 in their hospitals, whereas 78% found moderate or high difficulties. The difficulties came from burocracy- administrative aspects (18%), restrictions in the indication (41%) and both (38%). In general, the obstacles did not depend on the hospital level, neither the speciality, or the presence of lipid units, although the existance of lipid units was associated with a higher number of patients treated with iPCSK9. The factors which were associated with higher difficulty in the prescription were: the presence of an approval committee in the hospitals, the frequency in the revision of the treatment by hospital pharmacy, the temporal cadence of the prescription, the profile of patients seen and the criteria followed by the specialists for the prescription. CONCLUSION: The results show important diferences in the treatment with iPCSK9 in the context of clinical practice in Spain. The analysis of these results will permit to make proposals regarding future actions addressed to reach the equity in the access to iPCSK9 in Spain, with the main aim of maximizing their potential benefit according to the patients profile.

Detection of Familial Hypercholesterolemia through centralized analytical data. HF HUELVA DETECTA Program.

BACKGROUND: Familial Hypercholesterolemia is the most frequent genetic cause of premature coronary heart disease. The delay in the diagnosis prevents the correct early treatment. There are no effective screening strategies at the national level that ensure a correct diagnosis. OBJECTIVE: To determine the capacity of a centralized laboratory for the diagnosis of Familial Hypercholesterolemia through the creation of a health program for population screening in the province of Huelva. METHOD: Active search of patients with primary hypercholesterolemia through the blood tests carried out in the reference laboratories with results of low-density lipoprotein cholesterol greater than 200 mg/dl and assessment in the Lipid Unit of Huelva to identify index cases, with subsequent family cascade screening. RESULTS: 37,440 laboratory tests with lipid profile were examined. After screening, 846 individuals were seen in the Lipid Unit, of which they were diagnosed according to criteria of the Dutch Lipid Clinic Network as possible 654 and probable/definitive 192 individuals, representing 1.74% and 0.51% of the general population examined respectively. CONCLUSIONS: The point prevalence of Familial Hypercholesterolemia in patients submitted to laboratory lipid profile tests was 1:195, higher compared to the prevalence of Familial Hypercholesterolemia in the general population (based on 1 in 200-300). The opportunistic search strategy of the index case through a laboratory alert and centralized screening is an efficient strategy to implement a national screening for the diagnosis of Familial Hypercholesterolemia.

Implantación de un programa de cribado bioquímico y genético de hipercolesterolemia familiar. Colaboración entre el laboratorio clínico y las unidades de lípidos: diseño del Proyecto ARIAN / Implantation of a biochemical and genetic screening programme for family hypercholesterolaemia. Collaboration between the clinical laboratory and lipid units: Design of the ARIAN Project

Introducción y objetivo: La hipercolesterolemia familiar (HF) es el trastorno genético más frecuente asociado con enfermedad coronaria prematura debido a la presencia de cLDL incrementado desde el nacimiento. Se encuentra infradiagnosticada e infratratada. El objetivo primario del proyecto ARIAN es determinar el número de pacientes diagnosticados de HF tras implantar un nuevo procedimiento de cribado desde el laboratorio. Material y métodos: Este proyecto se ha diseñado como un análisis retrospectivo mediante consulta al sistema informático. Se seleccionaron de las bases de datos de laboratorio aquellas muestras de suero de pacientes ≥ 18 años con cLDL directos o calculados > 250 mg/dl, desde el 1 de enero del 2017 hasta el 31 de diciembre del 2018. Una vez descartadas causas secundarias, se comunicó al médico de Atención Primaria solicitante la sospecha de que su paciente pudiera portar una HF y gestionar una cita prioritaria en la unidad de Lípidos. Todos aquellos pacientes con una puntuación ≥ 6 puntos de los criterios de las Clínicas holandesas se les propuso un estudio genético. Resultados: El protocolo se presentó a 55 laboratorios de forma individualizada. Hasta el día 30 de diciembre del 2020, el número centros que han remitido resultados es de 24. El número de muestras analizadas hasta ese momento fue de 3.266.341, lo que representa un 34% de la población atendida en esas áreas de salud (9.727.434). Conclusiones: La identificación de nuevos sujetos con HF mediante esta nueva estrategia desde el laboratorio y su remisión a las unidades de Lípidos debe incrementar el número de pacientes tratados en las unidades de Lípidos y permitir iniciar cribados en cascada familiar.(AU)

Introduction and objective: Familial hypercholesterolaemia (FH) is the most common genetic disorder associated with premature coronary artery disease due to the presence of LDL-C cholesterol increased from birth. It is underdiagnosed and undertreated. The primary objective of the ARIAN project was to determine the number of patients diagnosed with FH after implementing a new screening procedure from the laboratory. Material and methods: This project was designed as a retrospective analysis by consulting the computer system. We selected from databases serum samples from patients ≥ 18 years with direct or calculated LDL-C>250mg/dL from 1 January 2017 to 31 December 2018. Once secondary causes had been ruled out, the requesting primary care physician was notified that their patient might have FH and to arrange a priority appointment in the lipid unit. All patients with a score of ≥ 6 points according to the Dutch Lipid Clinic Criteria were proposed for a genetic study. Results: By December 30th, 2020, 24 centres out of the initial 55 had submitted results. The number of patients analysed up to that point was 3,266,341, which represents 34% of the population served in those health areas (9,727,434). Conclusions: The identification of new subjects with FH through this new strategy from the laboratory and their referral to lipid units should increase the number of patients treated in lipid units and initiate familial cascade screening.(AU)

Hipercolesterolemia familiar en Gran Canaria: mutación con efecto fundador y alta frecuencia de diabetes / Familial hypercholesterolemia in Gran Canaria: Founder mutation effect and high frequency of diabetes

Introducción: Gran Canaria es una región de aislamiento genético para hipercolesterolemia familiar, debido a una mutación fundadora, p.[Tyr400_Phe402del], en el gen del receptor de LDL (LDLR). Datos iniciales indican que sus portadores podrían tener una alta prevalencia de diabetes. Material y métodos: Se reclutó a los pacientes mayores de 30 años con hipercolesterolemia familiar y mutación confirmada en LDLR en un hospital de tercer nivel de Gran Canaria y se comparó la prevalencia de diabetes y otros datos clínicos entre los portadores de p.[Tyr400_Phe402del] y los de otras mutaciones en LDLR. Resultados: El 76,4% de los 89 participantes era portador de p.[Tyr400_Phe402del]. En ese grupo la prevalencia de diabetes fue significativamente más alta (25 vs. 4%, p=0,045). Dichos casos también tenían mayor prevalencia de enfermedad cardiovascular y niveles más altos de colesterol LDL y triglicéridos. No hubo diferencias en edad, peso, índice de masa corporal, cintura, edad de inicio y tiempo de tratamiento con estatinas. Sin embargo, sí precisaban más a menudo inhibidores de PCSK9 (51,5 vs. 24%, p=0,027). Conclusiones: La mutación p.[Tyr400_Phe402del] se asocia a una elevada prevalencia de diabetes, no explicada por factores de riesgo clásicos, como la edad, la obesidad o el uso prolongado de estatinas.(AU)

Introduction: Gran Canaria is a region of genetic isolation of familial hypercholesterolemia due to a founder mutation, p. [Tyr400_Phe402del], in the LDL receptor (LDLR) gene. Initial data suggest that its carriers could have a high prevalence of diabetes. Material and methods: Patients over 30 years of age with familial hypercholesterolemia and a confirmed mutation in LDLR were recruited from a tertiary hospital in Gran Canaria. The prevalence of diabetes and other clinical data were compared among carriers of p. [Tyr400_Phe402del] and those with other LDLR mutations. Results: 76.4% of the 89 participants were carriers of p.[Tyr400_Phe402del]. The prevalence of diabetes in this group was significantly higher (25 vs. 4%, P=.045). These cases also had a higher prevalence of cardiovascular disease and higher levels of LDL cholesterol and triglycerides. There were no differences in age, weight, body mass index, waist, age of onset, and time of statin treatment. However, they required PCSK9 inhibitors more often (51.5 vs 24%, P=.027). Conclusions: The mutation p.[Tyr400_Phe402del] is associated with a high prevalence of diabetes, not explained by classic risk factors, such as age, obesity, or long-term use of statins.(AU)

Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO). / Perfil clínico de los pacientes tratados con evolocumab en unidades hospitalarias de nefrología en España (RETOSS-NEFRO).

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain. MATERIAL AND METHODS: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed. RESULTS: Sixty patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular (CV) disease. The mean (SD) eGFR was 62.6 (30.0)ml/min/1.73m2 (51.7% of patients had eGFR<60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high-intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9)mg/dL (53.4% of patients with LDL-c≥160mg/dL and 29.3%≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use were remained stable. CONCLUSION: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study.

[Real-life efficacy and safety of PCSK9 inhibitors treatment: Experience in three hospitals in Asturias]. / Efectividad y seguridad del tratamiento con iPCSK9 en vida real: experiencia de tres hospitales asturianos.

BACKGROUND: Inhibitors of proprotein convertase subtilisin/kexin type9 (PCSK9 inhibitors) are a treatment option for those patients with familial hypercholesterolemia or in secondary prevention who do not reach the LDL-C target with other therapeutic measures. The aim of this study is to assess the effectiveness and safety of these drugs. METHODS: Retrospective, multicentric, descriptive study. We collected data from all patients that have started PCSK9 inhibitors treatment in three hospitals in Asturias since the beginning of its use in 2016. We analysed changes in lipid profile with PCSK9 inhibitors and its side effects. RESULTS: We registered 98 patients, 75 of them affected by familial hypercholesterolemia (FH) and 23 unaffected. Two months after the beginning of PCSK9 inhibitors treatment, a 61% reduction rate in LDL-C in patients with FH and 52% in those without this condition was observed. This statistically significant reduction remained stable during follow-up. A significant decrease in total cholesterol was observed, without significant changes in HDL-C and triglycerides. 96% of patients had no complications. CONCLUSIONS: PCSK9 inhibitors are safe drugs that rapidly achieve significant reductions in LDL-C after the beginning of treatment, which are maintained over time. Hence, the use of PCSK9 inhibitors is an alternative for the control of LDL-C in those patients in which the LDL-C target is not reached with other therapeutic measures.

Implantation of a biochemical and genetic screening programme for family hypercholesterolaemia. Collaboration between the clinical laboratory and lipid units: Design of the ARIAN Project. / Implantación de un programa de cribado bioquímico y genético de hipercolesterolemia familiar. Colaboración entre el laboratorio clínico y las unidades de lípidos: diseño del Proyecto ARIAN.

INTRODUCTION AND OBJECTIVE: Familial hypercholesterolaemia (FH) is the most common genetic disorder associated with premature coronary artery disease due to the presence of LDL-C cholesterol increased from birth. It is underdiagnosed and undertreated. The primary objective of the ARIAN project was to determine the number of patients diagnosed with FH after implementing a new screening procedure from the laboratory. MATERIAL AND METHODS: This project was designed as a retrospective analysis by consulting the computer system. We selected from databases serum samples from patients ≥ 18 years with direct or calculated LDL-C>250mg/dL from 1 January 2017 to 31 December 2018. Once secondary causes had been ruled out, the requesting primary care physician was notified that their patient might have FH and to arrange a priority appointment in the lipid unit. All patients with a score of ≥ 6 points according to the Dutch Lipid Clinic Criteria were proposed for a genetic study RESULTS: By December 30th, 2020, 24 centres out of the initial 55 had submitted results. The number of patients analysed up to that point was 3,266,341, which represents 34% of the population served in those health areas (9,727,434). CONCLUSIONS: The identification of new subjects with FH through this new strategy from the laboratory and their referral to lipid units should increase the number of patients treated in lipid units and initiate familial cascade screening.

El rastreo masivo de datos es una segunda oportunidad para mejorar el manejo de los pacientes con fenotipo de hipercolesterolemia familiar / Massive data screening is a second opportunity to improve the management of patients with familial hypercholesterolemia phenotype

Introducción: La Hipercolesterolemia Familiar (HF) es una enfermedad autósómica dominante con una prevalencia estimada entre 1/200-250. Se encuentra infra-tratada e infra-diagnosticada. El rastreo masivo de datos puede incrementar la detección de pacientes con HF. Métodos: Población a estudio: Residentes en la zona sanitaria de cobertura (N: 195.000 habitantes) y con al menos una determinación de colesterol ligado a lipoproteínas de baja densidad (C-LDL) realizada entre el 1 de Enero de 2010 y el 30 de Diciembre de 2019. Se seleccionaron los valores más altos de C-LDL. Criterios de exclusión: síndrome nefrótico, hipotiroidismo, tratamiento hipotiroideo o triglicéridos > 400 mg/dL. Se analizaron 7 algoritmos sugestivos de fenotipo de Hipercolesterolemia Familiar (F-HF).Se seleccionó el algoritmo más eficaz y de fácil traslación a la práctica clínica. Resultados: Partiendo de 6.264.877 asistencias y 288.475 pacientes tras aplicar los criterios de inclusión-exclusión se incluyeron 504.316 analíticas correspondiendo a 106.382 adultos y 10.509 < 18 años. El algoritmo seleccionado presentó una prevalencia de 0.62%.Se detectaron 840 pacientes con fenotipo de Hipercolestereolemia Familiar (F-HF) siendo el 55.8% mujeres y 178 <18 años, El 9.3% tenían antecedentes de enfermedad cardio-vascular (ECV) y 16.4% habían fallecido. El 65% de los pacientes en prevención primaria presentaron valores de C-LDL >130 mg/dL y el 83% en prevención secundaria valores >70mg/dL. Se obtuvo una ratio de 7.64 (1-18) pacientes con HF-P por médico solicitante de analítica.Conclusiones: El rastreo masivo de datos y el perfilado de pacientes son herramientas eficaces y fácilmente aplicables en práctica clínica para la detección de pacientes con HF.(AU)

Introduction: Familial Hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence between 1/200-250. It is under-treated and underdiagnosed. Massive data screening can increase the detection of patients with FH. Methods: Study population: Residents in the health coverage area (N: 195.000 inhabitants) and with at least one determination of cholesterol linked to low-density lipoproteins (LDL-C) carried out between January 1, 2010 and December 30, 2019. The highest LDL-C values were selected. Exclusion criteria: nephrotic syndrome, hypothyroidism, Hypothyroid treatment or triglycerides> 400 mg / dL. Seven algorithms suggestive of Familial Hypercholesterolemia Phenotype (HF-P) were analyzed, selecting the most efficient algorithm that could easily be translated into clinical practice. Results: Based on 6.264.877 assistances and 288.475 patients, after applying the inclusion-exclusion criteria, 504.316 tests were included, corresponding to 106.382 adults and 10.509 <18 years. The selected algorithm presented a prevalence of 0.62%. 840 patients with HF-P were detected, 55.8% being women and 178 <18 years old, 9.3% had a history of cardiovascular disease (CVD) and 16.4% had died. 65% of the patients in primary prevention had LDL-C values> 130 mg / dL and 83% in secondary prevention values> 70mg / dL. A ratio of 7.64 (1-18) patients with HF-P per analytical requesting physician was obtained. Conclusions. Massive data screening and patient profiling are effective tools and easily applicable in clinical practice for the detection of patients with FH.