Hiperlipidemia familiar combinada: documento de consenso / Familial combined hyperlipidemia: consensus document

La hiperlipidemia familiar combinada (HFC) es un trastorno muy frecuente asociado a enfermedad coronaria prematura. Se transmite de forma autosómica dominante, aunque no existe un gen único asociado al trastorno. El diagnóstico se realiza mediante criterios clínicos, y son importantes la variabilidad del fenotipo lipídico y la historia familiar de hiperlipidemia. Es frecuente la asociación con diabetes mellitus tipo 2, hipertensión arterial y obesidad central. Los pacientes con HFC se consideran de riesgo cardiovascular alto y el objetivo terapéutico es un colesterol-LDL < 100 mg/dl, y < 70 mg/dl en presencia de enfermedad cardiovascular establecida o diabetes mellitus. Los pacientes con HFC requieren tratamiento con estatinas potentes y, a veces, tratamiento combinado. La identificación y el manejo de otros factores de riesgo cardiovascular, como la diabetes y la hipertensión, son fundamentales para reducir la carga de enfermedad cardiovascular. Este documento proporciona recomendaciones para el diagnóstico y el tratamiento integral de los pacientes con HFC especialmente dirigidas a médicos de atención primaria (AU)

Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries. Frequently, the disorder is associated with type 2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL-cholesterol < 100 mg/dL, and < 70 mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners (AU)

Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation.

OBJECTIVE: Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1beta, and that in vitro both PGC-1beta and PGC -1alpha increase PPARalpha-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPARalpha agonist Wy14,643 (Wy). METHODS AND RESULTS: C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1alpha or PGC-1beta. On chow, hepatic PGC-1beta overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPARalpha and hepatic lipase mRNA levels were reduced. PGC-1beta overexpression blunted Wy-mediated changes in expression levels of PPARalpha and downstream genes. Furthermore, PGC-1beta did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1beta and PGC-1alpha overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1beta overexpression decreased hepatic SREBP-1c, yet increased FAS and ACCalpha mRNA and plasma triglyceride levels. CONCLUSIONS: Hepatic PGC-1beta overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1beta overexpression reduced the potentially beneficial effects of PPARalpha activation on gene expression. Thus, inhibition of hepatic PGC-1beta may provide a therapy for treating combined hyperlipidemia.

[Familial combined hyperlipidemia: detection and characterisation of the hyperlipidemic profile among children and adolescents]. / Hiperlipemia familiar combinada: detección y caracterización del fenotipo hiperlipémico en niños y adolescentes.

BACKGROUND: Familial combined hyperlipidemia is the commonest genetic form of hyperlipidemia among survivors of myocardial infarction and, therefore, its early detection is crucial for the prevention of coronary artery disease. The aim of the study was to establish the prevalence of hyperlipidemia in the offspring of affected families and to characterize their lipid, lipoprotein and apolipoprotein profile. PATIENT AND METHODS: Forty five subjects below the age of 19 were studied from which 30 were from affected families and 15 from healthy control families. Cholesterol and triglycerides in plasma, VLDL, IDL, LDL and HDL as well as apolipoproteins AI, B, C-II and C-III were measured. RESULTS: Hyperlipidemia was detected in 13 children (43%) from affected families. They also presented significantly elevated concentrations of cholesterol in plasma (p < 0.0001), LDL (p < 0.0001) and HDL (p < 0.05); triglycerides in plasma (p < 0.007), VLDL (p < 0.05) and LDL (p < 0.008), together with significantly increased concentrations of apolipoproteins AI (p < 0.02), B (p < 0.0004), C-II (p < 0.0005) and C-III (p < 0.03). No changes were observed in the IDL fraction. CONCLUSIONS: There is an elevated prevalence of hyperlipidemia among the offspring of patients with familial combined hyperlipidemia. On the contrary to that observed in adults, no alterations of the IDL fraction are present among affected children.

Detection of the apolipoprotein B-100 arg(3500) > gl mutation in familial defective apoB-100 by temperature-gradient gel electrophoresis.

Familial defective apolipoprotein B-100 (FDB) is caused by a point mutation in exon 26 of the apolipoprotein B gene leading to a decreased binding to the LDL-receptor. Patients with FDB have hypercholesterolemia and atherosclerotic disease. Since other mutations of apoB-100 could also cause binding abnormalities we established a temperature-gradient gel electrophoresis (TGGE) method and started to screen hypercholesterolemic patients for the presence of point mutations in this region. 4 of 43 patients were positive according to TGGE and subsequent sequencing showed the familiar guanine to adenine transition in codon 3500 in all cases.

[Hyperlipoproteinemias in childhood]. / Hyperlipoproteinämien im Kindesalter.

There is general agreement that hyperlipidemic states, in particular hypercholesterolemia, should be diagnosed during childhood, and treatment should start beyond the age of 2 years. The rationale for this procedure is the fact that increased cholesterol levels have been accepted to act as major risk factors for coronary vascular disease in adult populations, and therefore the significance of cholesterol must be inferred from less direct evidence. The diagnosis of hyperlipidemias is based on reference levels for the various age groups which are mainly transferred from studies in the USA. The classification of hyperlipidemias refers to a clinical and genetic concept; thus, familial hypercholesterolemia (incidence 1:500) is the most important disorder for the pediatric age group. Treatment of affected children should include dietary restrictions, in particular for saturated fats, but substitution of animal protein by soy protein has been shown to increase the cholesterol lowering effect. It is concluded that children from families with cardiovascular disease and/or hyperlipidemias should be referred to a special metabolic clinic for appropriate diagnosis and treatment. So far, a general screening for hyperlipidemias is not recommended in the neonatal period or during childhood.

Strategy for diagnosis and treatment of hyperlipidemia.

As hypercholesterolemia is an essential risk factor of atherosclerosis, a strategy for diagnosis and treatment of hyperlipidemia is indispensable. Differences in mortality from coronary heart disease in different cultures seem to be due to environmental, not to genetic factors. Trials in Finland and the United States have shown that cholesterol levels and smoking can be reduced by information and education with an ensuing drop in cardiovascular mortality. This experience warrants national programmes for cholesterol-lowering in high risk countries. Programmes should be directed to doctors and health officials as well as legislators and the public. Within any given population individual differences of lipid levels are due to both nutritional habits and genetic variations concerning e.g. LDL-receptors and lipase activity. At present the only means of identifying subjects at risk is to measure their lipid levels and to scrutinize their family history. Measurements should be repeated to exclude biologic and laboratory variability. Drugs currently available include HMG CoA reductase inhibitors, bile acid binding resins, clofibrate derivatives and nicotinic acid. Formerly defined age groups with regard to therapeutic measures have meanwhile been abandoned.

[Results of prevention trials by intervention with lipids]. / Bilan des essais de prévention par intervention sur les lipides.

When only statistically comparable studies are taken into account, there are three primary prevention and eight secondary prevention studies. In 9 out these 11 studies the calculated decrease in the incidence of coronary disease are in favour of a beneficial effect of the lipid-lowering treatment. Some studies suggest that femoral atherosclerosis is receding and that coronary atherosclerosis is stable or progresses more slowly, but this always provided the plasma lipids are significantly and durably reduced. Subjects at high cardiovascular risk, therefore, must be treated, but one should now proceed even further, since the decrease of total cholesterol in the general population is paralleled by a decrease of coronary disease. This is in keeping with the results of extensive epidemiological surveys (notably the Framingham survey) which show that the lower the total cholesterol level the brighter the cardiovascular prognosis.