Critérios diagnósticos e estratificação de risco na hipercolesterolemia familiar / Criteria diagnosis and risk stratification of familial hypercholesterolemia

A hipercolesterolemia familiar (HF) é uma doença genética relativamente comum caracterizada por níveis elevados de LDL-colesterol (LDL-C) e, por conseguinte, associada a risco de desenvolvimento prematuro de doença cardiovascular aterosclerótica. O tratamento hipolipemiante reduz significativamente o risco cardiovascular desses pacientes, tornando fundamental a identificação precoce desses indivíduos, seguida de tratamento adequado assim que possível. Para tanto, existem escores diagnósticos de HF, como o escore holandês Dutch Lipid Clinic Network, que avalia níveis de LDL-C, antecedente familiar e/ou pessoal de evento cardiovascular isquêmico e a presença de sinais físicos, como xantomas. Uma vez feito o diagnóstico de HF, torna-se muito importante a estratificação de risco desses pacientes. A identificação de fatores de risco associados (como tabagismo,diabetes mellitus, hipertensão arterial, aumento de Lp(a), entre outros) aliada ao uso de métodos para detecção de doença aterosclerótica subclínica em indivíduos com HF pode auxiliar na identificação daqueles que têm maior risco cardiovascular e são candidatos a estratégias mais agressivas de redução de LDL-C. Nesse artigo, revisamos os principais critérios diagnósticos de HF e a estratificação de risco desses pacientes

Familial hypercholesterolemia (FH) is a relatively common genetic disease that is characterized by elevated LDL-cholesterol (LDL-C) levels. As a consequence, it is associated with the risk of premature development of atherosclerotic cardiovascular disease.Lipid-lowering therapies significantly reduces the cardiovascular risk in these patients, making early identification of these individuals essential, followed by adequate treatment as soon as possible. There are diagnostic scores of FH for this purpose, such as the Dutch Lipid Clinic Network score, which evaluates LDL-C levels, family history and/or personal history of ischemic cardiovascular event and the presence of physical signs, such as xanthomas. Once FH has been diagnosed, it is very important to stratify the risk in these patients. The identification of associated risk factors (such as smoking, diabetes mellitus, high blood pressure, elevated Lp(a), among others), together with the use of methods to detect subclinical atherosclerotic disease in individuals with FH, can assist in the identification of those with a higher cardiovascular risk, and who are therefore candidates for more aggressive strategies to reduce LDL-C. This article gives a review of the main diagnostic criteria of FH, and the risk stratification in these patients

Inibidor da MTP na hipercolesterolemia familiar homozigótica / Inhibitor of MTP in homozygous familial hypercholesterolemia

A MTP (Microsomal Triglyceride Transfer Protein - Proteína Microsomal de Transferência de Triglicérides) é uma proteína chave envolvida na formação e secreção das lipoproteínas que contêm apo B no fígado e intestino. Mutações no gene que codifica a MTP são a base molecular da a betalipoproteinemiae da hipobetalipoproteinemia, doenças caracterizadas,respectivamente, pela ausência total ou parcial de lipoproteínas que contêm apo B de origem intestinal e hepática. Após a descoberta da causa molecular da a betalipoproteinemia no início dos anos 90, a MTP tornou-se potencial alvo terapêutico tanto para a hipercolesterolemia como para a quilomicronemia. Entre os vários fármacos desenvolvidos com esse propósito,apenas a lomitapida chegou ao mercado, tendo sido aprovada,até o momento, para uso exclusivo na hipercolesterol emiafamiliar homozigótica. A restrição de seu uso a esse grupo de pacientes se deve aos efeitos colaterais que dela decorrem: esteatose hepática, diarreia, elevações das transaminases.Estudos de fase 2 e 3 mostraram sua capacidade de reduzir o LDL-colesterol em uso isolado ou em associação com outras terapias hipolipemiantes. Espera-se que sua utilização emportadores de hipercolesterolemia familiar homozigótica possa produzir, paralelamente à melhora do perfil lipídico, os eventos cardiovasculares graves e precoces a que esta população de pacientes está sujeita. São necessários mais estudos para que eventualmente o emprego da lomitapida possa ser estendido para outros grupos, como os intolerantes às estatinas ou os que não atingem as metas terapêuticas apesar de doses máximas dos medicamentos ora disponíveis.

The microsomal triglyceride transfer protein (MTP) is a keyprotein in the assembly and secretion of apolipoprotein (apo)B-containing lipoproteins in the liver and intestine. Mutationsin the gene encoding for MTP are the molecular basis ofabetalipoproteinemia and hipobetalipoproteinemia, diseasescharacterized, respectively, by the complete and partial absenceof apo B containing lipoproteins from hepatic or intestinalorigin. Following the discovery of the molecular cause ofabetalipoproteinemia in the early 1990s, MTP became a potentialtherapeutic target for the treatment of both hypercholesterolemia aswell as chylomicronemia. Among the various products developedfor this purpose, only lomitapide reached the market, having beenapproved, till the present moment for exclusive use in homozygousfamilial hypercholesterolemic patients. The restriction of its usefor this group of patients is due to the side effects caused by it:hepatic steatosis, diarrhea, transaminasis elevations. Phase 2 and3 studies showed its capability of reducing LDL-cholesterol levelsin isolated use or in combination with other therapies commonlyused to reduce cholesterol levels. It is awaited that its use inhomozygous familial hypercholesterolemic patients can produce,in parallel to the improved lipid profile, reduction of the severe andprecocious cardiovascular events that this population is exposed.More studies are needed to eventually extend the lomitapide usefor other groups of patients, as the statins intolerants or those whodo not reach therapeutic targets despite maximal doses of today’savailable medications.

Association of Peripheral Arterial and Cardiovascular Diseases in Familial Hypercholesterolemia / Associação das Doenças Arterial Periférica e Cardiovascular na Hipercolesterolemia Familiar

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c). Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD). Objective: This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD), such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. Methods: The diagnosis of PAD was established by ankle-brachial index (ABI) values ≤ 0.90. This study assessed 202 patients (35% of men) with heterozygous FH (90.6% with LDL receptor mutations), mean age of 51 ± 14 years and total cholesterol levels of 342 ± 86 mg /dL. Results: The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049). Conclusion: Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients. .

Fundamento: A hipercolesterolemia familiar (HF) é uma doença de herança genética autossômica dominante caracterizada pela elevação dos valores séricos de colesterol total e das lipoproteínas de baixa densidade (LDL-c). Conhecida por estar estreitamente relacionada ao processo aterosclerótico, a HF pode determinar o desenvolvimento de lesões obstrutivas precoces em distintos leitos arteriais. Nesse contexto, a HF também tem sido proposta como fator de risco para a doença arterial periférica (DAP). Objetivo: Avaliamos, por meio de um estudo transversal e observacional, a associação da DAP com outras manifestações de doença cardiovascular (DCV), isto é, doença arterial coronária e cerebrovascular em portadores de HF heterozigótica. Métodos: diagnóstico de DAP foi estabelecido pela medida do índice tornozelo-braquial (ITB) com valores ≤ 0,90. Foram estudados 202 pacientes com HF (90,6% apresentando mutações no receptor da LDL), idade 51 ± 14 anos, colesterol total 342 ± 86 mg/dL e 35% do sexo masculino. Resultados: As prevalências de DAP e de DCV prévia foram 17% e 28,2%, respectivamente. Houve associação independente da DAP com a DCV (OR = 2,50, IC 95% 1,004-6,230, p = 0,049) após análise multivariada. Conclusão: A pesquisa sistemática da DAP por meio do ITB é factível na avaliação de portadores de HF e pode sinalizar aumento no risco de DCV. Contudo, mais estudos são necessários para determinar o papel do uso do ITB como ferramenta para avaliação do risco cardiovascular nessa população. (Arq Bras Cardiol. 2014; 103(2):118-123) .

Medición ecográfica del espesor medio-intimal carotídeo en pacientes pediátricos con obesidad, hipercolesterolemia familiar y diabetes tipo 1 / Ultrasonography measurement of carotid intima-media thickness in pediatric patients with obesity, familial hypercholesterolemia and type 1 diabetes

Propósito. Evaluar con ultrasonografía (US) el Espesor Medio Intimal (EMI) como marcador de riesgo cardiovascular (RCV) temprano en pacientes con diagnóstico clínico y de laboratorio de Hipercolesterolemia Familiar (HCF), Diabetes Tipo 1 (DBT-1) y Obesidad(OB), comparando con grupo control. Materiales y Métodos. Estudio prospectivo, descriptivo y de corte transversal. Evaluamos el EMI de las arterias carótidas comunes (CC) e incluimos en una sola variable dicotómica otras alteraciones estructurales de la pared (placas ateromatosas e irregularidades de la íntima). La US fue realizada en forma cegada al resultado de los exámenes de sangre, según las recomendaciones del consenso de Mannheim 2007, en 121 pacientes (de 6 a 18 años): 24 HCF, 40 DBT-1 y 43 OB; y 14 controles. Se excluyeron pacientes con otras patologías que pudieran alterar la pared arterial. Analizamos las variables con el programa Statistix 8. Resultados. Comparados con los controles, los 3 grupos tuvieron un mayor EMI, siendo las diferencias estadísticamente significativas. Los EMI Medio (mm) fueron en HCF: 0,59 (0,31-2,15), p: 0,006; IC: 0,06-0,36. Obesos: 0,48 (0,3-0,85), p: 0,001; IC: 0,06-0,14. DBT-1: 0,46 (0,25-0,65), p: 0,0004; IC: 0,03-0,13. Grupo control: 0,37 (0,30-0,45). Los pacientes con HCF presentaron la mayor diferencia. No se encontró asociación entre el valor de LDL-C y el EMI. El 62,5% recibían tratamiento farmacológico en el momento de la evaluación. En DBT-1 no se encontró asociación entre el EMI y los niveles de HbA1c y lípidos; y en el grupo OB no se encontró asociación entre el EMI y el Z score IMC. El 31% de HCF, el 8% de DBT-1 y el 6% de OB presentaron placas ateromatosas e irregularidades de la íntima. Conclusión. La US del EMI permitió demostrar que los pacientes...

Migratory polyarthritis in familial hypercholesterolemia (type iIa hyperlipoproteinemia).

Metabolic disorders are often encountered in clinical practice. Some of these diseases are associated with dermatological and musculoskeletal manifestations. Familial hypercholesterolemia is a disorder of lipoprotein metabolism characterized by elevated cholesterol, low-density lipoprotein cholesterol, xanthomas and early onset atherosclerosis. Tendinitis and arthritis have been rarely reported in patients with familial hypercholesterolemia. Here is presented a case of a young girl with migratory polyarthritis, who was diagnosed as probable homozygote familial hypercholesterolemia with hypercholesterolemic arthritis. A proper knowledge of cutaneous manifestations helps to identify patients at risk, establish the underlying diagnosis, and start early and effective therapy.

Homozygous familial hypercholesterolemia with generalized arterial disease

This report describes the clinical features and management of an 11-year-old boy with end-stage homozygous familial hypercholesterolemia [hoFH] and generalized arterial disease. The patient presented with recurrent anginal episodes. On examination, he was found to have multiple planar and tendinous xanthomas, an [LDL] cholesterol level of 24.6 mmol/l and family history of hypercholesterolemia. Resting electrocardiogram showed ST depression in the anterior and inferior leads. Coronary angiogram outlined 70% stenosis of the left main coronary, ostial stenosis of the right coronary artery and extensive atherosclerotic disease of the aorta and all its major branches. The lipid profile was grossly abnormal, but the other biochemical and hematological parameters were normal. The patient was managed with metoprolol 12.5 mg twice daily, nitroglycerin infusion, antithrombotics [aspirin 75 mg once daily and heparin infusion 150 units per hour], cholesterol-lowering drugs [simvastatin 10 mg once a day, cholestyramine 4 g twice a day] and analgesics. This case report emphasizes the need to diagnose early familial hypercholesterolemia in families with heart disease and the need to test the partners of affected persons so that the risk of conceiving children with hoFH can be counseled

Recurrent Acute Pancreatitis in a Patient with Type IIb hyperlipoproteinemia: A Case Report and Review of the Literature in Korea

Hyperlipidemia is a rare cause of pancreatitis. It has been believed that free fatty acids released from hydrolyzed serum chylomicrons or triglycerides and chylomicrons induce hyperlipidemic pancreatitis by damaging acinar cells and capillaries. Type I, IV or V hyperlipidemic (Fredrickson's classification) pancreatitides have distinctive features of increased and heightened serum chylomicron and triglyceride levels. In contrast, type IIb hyperlipidemia usually doesn't have increased chylomicrons. It is a dominant inherited genetic disorder and doesn't manifest the subjective symptom before combining vascular complications such as coronary artery disease. Only a few cases of type IIb hyperlipidemic pancreatitis have been reported. We experienced a male patient with recurrent hyperlipidemic pancreatitis combined with type IIb hyperlipidemia. We present the case report and a review of the literature of hyperlipidemic pancreatitis, especially cases in Korea.

Abordagem terapêutica das dislipidemias em situações especiais: hipercolesterolemia familiar homozigótica refratária / Treatment of severe and refractory homozygous form of familial hypercholesterolemia

A hipercolesterolemia familiar é doença autossomica dominante que, em sua forma heterozigótica, afeta cerca de 1/500 pessoas, e, na forma homozigótica, 1/1.000.000 pessoas. Contudo, em familias portadoras das mutações que diminuem a expressão do receptor da lipoproteina de baixa densidade, cerca de uma em cada duas pessoas é afetada. Ambas as formas associam-se a níveis alevados de colesterol e doença arterial coronária precoce e na forma homozigótica há também doença da aorta e da valva aórtica. Em alguns casos da hipercolesterolemia familiar heterozigótica e na maioria dos casos de homozigotos, além de uso de doses elevadas de estatinas associadas aos bloqueadores de absorção do colesterol, podem ser necessários tratamentos alternativos, como derivação ileal, aférese e transplante hepático, para controle eficaz dos níveis extremamemnte elevados de colesterol.

Familial hypercholesterolemia in a paediatric patient

A case of familial hypercholesterolemia [homozygous] leading to coronary artery disease by the age of 10 years is presented in view of its rarity. Besides different xanthomatous eruptions, the child was also having overt angina and was treated with coronary artery bypass grafting to the diseased vessels

Supravalvular aortic stenosis and coronary ostial stenosis in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia exhibit severe hypercholesterolemia, cutaneous and tendon xanthomata, and premature atherosclerosis from childhood. A rare presentation of this condition with supravalvular aortic stenosis and coronary ostial stenosis is described.

Familial hypercholesterolemia.

Abnormalities in the lipid profile though uncommon in pediatric practice pose an increased risk for developing heart disease. Studies suggest that adult cardiovascular disease has its roots in children and young adults. A significant correlation between atherosclerotic changes in children and young adults and total and LDL cholesterol levels also exists. The association is particularly true for Familial Hypercholesterolemia. We report a young boy aged 14 years who presented with all the features of Familial Hypercholesterolemia.

Evoluçäo clínica de pacientes com hipercolesterolemia familiar e doença coronaria submetidas a derivaçäo ileal parcial (bypass ileal) / Clinical outcome of patients with familial hypercholesterolemia and coronary artery disease undergoing partial ileal bypass surgery

Familial hypercholesterolemia is characterized by high serum levels of total cholesterol and LDL-cholesterol. It may be homozygous or heterozygous. In homozygous patients, LDL-cholesterol levels range from 500 to 1000mg/dL and coronary artery disease is precocious, usually manifesting itself between the 2nd and 3rd decades of life. The diagnosis is often made by the presence of xanthoma tuberosum and tendinous xanthomas that appear between the 1st and 2nd decades of life. The use of high doses of statins or even unusual procedures (apheresis, partial ileal bypass surgery, liver transplantation, gene therapy), or both, is necessary for increasing survival and improving quality of life, because a reduction in cholesterol levels is essential for stabilizing the coronary artery disease and reducing xanthomas. We report our experience with 3 patients with xanthomatous familial hypercholesterolemia and coronary artery disease, who underwent partial ileal bypass surgery. Their follow-up over the years (approximately 8 years) showed a mean 30 percent reduction in total cholesterol, with a significant reduction in the xanthomas and stabilization of the coronary artery disease