Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a targeted approach to identification of high-risk patients in British Columbia, Canada, as an initial strategy for the prevention of coronary disease. Patients with the diagnosis of familial hypercholesterolemia have been identified through the Lipid Clinic. First degree relatives of these persons and subsequently identified individuals will be screened for the presence of hypercholesterolemia. Using this approach, the likelihood of identifying persons at high risk is high, close to 50%. The program will also allow collection of data on factors affecting the expression of hyperlipidemia and atherosclerosis and their response to therapy. In an effort to establish the infrastructure that would be necessary for identification and management of such patients throughout the province, a Lipid Clinic Outreach Program has been developed. The objective is to provide each community in the province with expertise to manage hyperlipidemia without traveling to a major urban area. With this infrastructure in place, this will serve patients who have premature atherosclerosis due to other causes and will also form the framework for dissemination of heart health policies and programs by different levels of government, voluntary and professional organizations, as well as the private sector. From a targeted family centered pilot program, a broad approach to the prevention of coronary artery disease in this community will be possible.
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PMID:Development of a program for identification of patients with familial hypercholesterolemia in British Columbia: a model for prevention of coronary disease. 821 93

The effect of the sulfur-substituted fatty acid analogue 1,10 bis(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, on puromycin aminonucleoside-induced nephrotic hyperlipidemia was studied in rats. Treatment with 3-thiadicarboxylic acid (250 mg/kg) for 5 days reduced plasma levels of triglycerides from 5.8 to 2.7 mmol/L and cholesterol from 11.0 to 7.7 mmol/L. This was accounted for by decreases in very-low-density lipoprotein triglycerides, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, without any major changes in the composition of plasma lipoproteins. The activities of two enzymes involved in fatty acid synthesis (ATP:citrate lyase and fatty acid synthetase) were inhibited by 3-thiadicarboxylic acid treatment, whereas acetyl-coenzyme A carboxylase activity was unchanged. In contrast, treatment with the sulfur-substituted fatty acid analogue induced the peroxisomal beta-oxidation of fatty acids ninefold and the mitochondrial beta-oxidation by 54% to 73%, depending on the substrate used. This was accompanied by a 26% reduction in hepatic triglyceride secretion rate. The hepatic phosphatidate phosphohydrolase activity was unchanged. 3-Thiadicarboxylic acid treatment suppressed the activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, by 58%, whereas hepatic LDL receptor expression was unaltered. The activities of lipoprotein lipase and hepatic lipase were unchanged by treatment. These results demonstrated that treatment with 3-thiadicarboxylic acid ameliorates hyperlipidemia in experimental nephrosis primarily by decreasing the overproduction of very-low-density lipoprotein present. The data also indicate that hepatic very-low-density lipoprotein synthesis and secretion is strongly influenced by the availability of the fatty acid substrate under the same hyperlipidemic conditions.
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PMID:Effect of 3-thiadicarboxylic acid on lipid metabolism in experimental nephrosis. 821 98

Although there is consensus that lipid variables, especially lipoprotein(a), are heritable and that elevated LDL cholesterol levels should be treated, there are no clear definitions of the common familial lipid disorders associated with premature CHD (lipoprotein(a) excess, FCH, familial dyslipidemia, familial hypoalphalipoproteinemia, familial hypercholesterolemia), nor do we have clear guidelines for the treatment of most of these disorders. Implementation of therapy for elevated LDL cholesterol in familial lipid disorders often has not occurred even in the United States. Before recommendations can be made for subjects with lipoprotein(a) excess and HDL deficiency (who often have combined hyperlipidemia or hypertriglyceridemia), prospective studies documenting benefit of CHD risk reduction must be carried out in subjects with lipoprotein(a) excess and HDL deficiency. One such study is being carried out with gemfibrozil in CHD patients with HDL deficiency. Current data do justify treatment of CHD patients with lipoprotein(a) excess with niacin because niacin has been shown to lower lipoprotein(a) levels as well as lower CHD risk mortality in random CHD patients. With regard to CHD patients with or without HDL cholesterol levels less than 35 mg/dL (0.9 mmol/L), efforts should be made to optimize their lipid profile and reduce their LDL cholesterol levels to less than 100 mg/dL (2.6 mmol/L).
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PMID:Familial lipoprotein disorders and premature coronary artery disease. 828 32

Familial hyperlipidemia has received little attention as a possible cause of stroke in young patients. Some recent studies have demonstrated that lipoprotein (a) is a key factor for atherogenesis in familial hypercholesterolemia. Hypogonadism may also contribute to the elevation of serum lipids, but their influence as a risk factor for stroke is still less understood. A 34-year-old patient with heterozygous familial hypercholesterolemia presented with a left pure motor hemiparesis secondary to a right striatocapsular infarction. Arteriography showed atherosclerotic lesions in both internal carotid arteries. High levels of cholesterol, cLDL, apo B, and lipoprotein (a) were found. Clinical signs of hypogonadism were present and the karyotype led to the diagnosis of Klinefelter's syndrome (47,XXY). The early clinical course was excellent, and the levels of serum lipids were normalized with diet, lipid-lowering drugs and androgens. The importance of hyperlipidemia as a risk factor for stroke in the young, specially when it occurs in the context of familial hypercholesterolemia with elevated lipoprotein (a) levels, as well as the possible contribution of hypogonadism to the development of accelerated atherosclerosis in young patients, are discussed upon.
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PMID:[Striatocapsular infarct in a young patient with heterozygous familial hypercholesterolemia and Klinefelter's syndrome]. 828 24

Erythrocyte aggregation (EA) was determined in a Myrenne aggregometer at stasis (EAMo) and low shear (EAM1) in 102 patients suffering from primary hyperlipoproteinemia (PHLP)-46 with familial hypercholesterolemia (FH); 28 with familial combined hyperlipemia (FCHL); 28 with primary hypertriglyceridemia (PHTG)-and in a control group (CG) of healthy matched subjects. EA was also determined in FH after the autologous plasma had been replaced by a control plasma. The following parameters were also measured: fibrinogen (Fbg), plasmatic lipids, apolipoproteins, glucose, HbA1 c and membrane erythrocyte lipids: cholesterol (C) and phospholipids (PL). An increase in both EAMo and EAM1 was observed in all the studied groups of patients. When erythrocytes of FH were resuspended in control plasma, EA normalized, but only in 75% of them. Fbg was elevated only in FH and FCHL. Membrane C was increased mainly in FH and FCHL. EA correlates with both Fbg and apolipoproteins. In FH, EA also correlates with membrane C/PL. In addition, a high significant correlation exists between EA and HbA1 c in FCHL. The results obtained suggest that not only Fbg and apolipoproteins but also possible changes in erythrocyte membrane could encourage EA in PHLP.
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PMID:Red blood cell aggregation and primary hyperlipoproteinemia. 830 49

A variety of robust and model-dependent genetic linkage methods were applied to log transformed lipid levels from a large pedigree in which the LDL receptor defect has been shown to segregate by molecular biologic techniques. Application of the Haseman-Elston and a variance-components based test for linkage identified LDL and cholesterol as cosegregating with the marker C3, which is genetically linked to the LDL receptor defect. Consideration of lipid fractions as a multivariate response identified (0.723 x cholesterol) - (0.551 x triglycerides) as most strongly supporting evidence for linkage with C3. Subsequent segregation and linkage analyses provided support for an autosomal dominant major gene influencing either LDL or the function of cholesterol and triglycerides. Genetic linkage to LDL was only mildly supported, with a maximum lod score of 0.51 at a recombination fraction of theta = 0.33. Genetic linkage of the linear function to C3 was more strongly supported, with a maximum lod score of 1.69 at theta = 0.09. Bivariate analysis of clinical affection (with either type IIa or type IIb hyperlipidemia) and quantitative measures (LDL or the linear function) generally led to decreased lod scores, indicating, in this pedigree, loss of information when using clinical affection.
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PMID:A comparison of univariate and multivariate tests for genetic linkage. 831 79

Hyperlipidemias may play a role in the progression of various renal diseases, including diabetes mellitus. We therefore examined the characteristics of low-density lipoprotein (LDL) binding and uptake in cultured rat mesangial cells. Mesangial cells bound and took up LDL in a manner consistent with specific receptor mediation. Furthermore, exposure of mesangial cells to LDL enhanced intracellular cholesteryl esterification and decreased de novo cholesterol synthesis. Mesangial cells expressed mRNA for LDL receptor and their expression was downregulated after preloading of cells with LDL. These results are consistent with regulation of cholesterol uptake and metabolism by a specific LDL receptor mechanism. During diabetes the apolipoprotein B of LDL undergoes nonenzymatic glycation, which may alter its affinity for the LDL receptor. Glycation of LDL reduced its affinity for binding to the receptor sites and decreased its uptake by mesangial cells. Thus, during diabetes less LDL may be taken up and more remain extracellularly, where it can be trapped in the matrix. Oxidation of LDL bound to extracellular matrix is believed to be a major factor in the pathobiology of hyperlipidemias. Specific scavenger receptors for oxidized LDL have been described and cloned. We therefore examined whether rat mesangial cells bound and took up oxidized LDL. We demonstrated low-affinity but high-capacity binding sites for oxidized LDL on mesangial cells. In contrast to LDL, which supported mesangial cell proliferation, oxidized LDL was cytotoxic for the cells and resulted in stimulation of mesangial cell prostaglandin E2 production. Trapping of LDL in the extracellular matrix is considered an initial event in LDL-induced vascular pathology. We therefore evaluated binding of LDL and modified LDL to extracellular matrix produced by cultured mesangial cells. Mesangial matrix had a high capacity to bind LDL and modified LDL (glycated or oxidized) in a nonsaturable manner. These results obtained with cultured mesangial cells and their matrix allow the formulation of a working hypothesis. Under normal eulipemic conditions mesangial cells handle LDL in a regulated manner. During hyperlipidemia or expansion of extracellular matrix LDL accumulates in the matrix. There LDL would be subject to oxidative modifications, especially under conditions of mesangial cell stress, such as inflammatory, mechanical, or ischemic injury. Part of the oxidized LDL could be taken up by scavenger receptors on mesangial cells and monocyte-macrophages, resulting in foam cell formation. Excess oxidized LDL, and specifically the lipid peroxides and lysolipids of oxidized LDL, would act as cytotoxic agents on mesangial, epithelial, and endothelial cells, thereby contributing to a vicious cycle of cell damage and sclerosis.
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PMID:Cellular mechanisms of lipid injury in the glomerulus. 832 98

Familial combined hyperlipidemia (FCHL) is a dominantly inherited hyperlipidemia that occurs in at least 1% of the adult population and is responsible for 10% of premature coronary artery disease. In families referred for evaluation because of primary hyperlipidemia in a child, FCHL is expressed three times more commonly than familial hypercholesterolemia and half of the siblings are affected. Several metabolic defects apparently are associated with the FCHL phenotype. Most commonly, excess production of very low density lipoprotein apolipoprotein B can be demonstrated. In other families, reduced lipoprotein lipase activity is associated. One allele at a locus influencing apolipoprotein B levels predicts FCHL in a large proportion of families ascertained through affected children. Whether this allele is responsible for the excess of very low density lipoprotein apolipoprotein B detected in metabolic studies has not been elucidated. Management of FCHL in children begins with dietary modification. A bile acid sequestrant may be considered as well if diet cannot reduce the plasma low-density lipoprotein cholesterol level to less than 4.13 mmol/L (160 mg/dl) after the age of 10 years. Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors are not currently recommended for children younger than 19 years of age, we speculate that they will be increasingly utilized for the management of FCHL in teenage boys who continue to have low density lipoprotein cholesterol levels greater than 4.13 mmol/L (160 mg/dl) after dietary modification.
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PMID:Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. 834 11

Hyperlipidemia is first detected by an increase in the plasma concentrations of cholesterol and/or triglycerides, and implies an abnormality of plasma lipoprotein metabolism. Disorders of lipoprotein metabolism are often classified specifically according to the lipoprotein affected. The WHO classification of lipoprotein phenotypes is a useful means of showing which lipoproteins are present in excess in individual hyperlipidemic patients. Hyperlipoproteinemia can be secondary to other well-known diseases that affect plasma lipoprotein metabolism, for example, diabetes mellitus, hypothyroidism or nephrotic syndrome. When such diseases are excluded, the hyperlipoproteinemia is defined as primary hyperlipoproteinemia. Many primary hyperlipoproteinemias have a genetic basis and the underlying molecular defect has been clarified in some genetic disorders. Hyperlipoproteinemia is considered to be one of the major risk factors for atherosclerosis and the development of atherosclerosis depends on the type of hyperlipoproteinemia. In this sense, familial hypercholesterolemia is a clinically important primary hyperlipoproteinemia because of its high risk of ischemic heart disease and its high prevalence in a normal population (1/500). It is necessary to make an exact diagnosis of specific genetic disorder, if possible, to provide prognostic and therapeutic information.
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PMID:[Primary hyperlipoproteinemia]. 841 90

We studied the effectiveness of and compliance with the use of cholestyramine in children with heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). During a 10-year period, 673 children (aged 10.5 +/- 4.0 years) were referred for evaluation of hyperlipidemia, of whom 87 (36 with FH; 51 with FCHL) were treated with cholestyramine (8 to 24 gm/day). In both groups, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B levels were significantly reduced after cholestyramine use. In those with FH, plasma LDL-cholesterol levels decreased from 258 +/- 35 mg/dl (6.67 +/- 0.90 mmol/L) to 190 +/- 31 mg/dl (4.91 +/- 0.80 mmol/L); in those with FCHL, LDL-cholesterol levels dropped from 207 +/- 40 mg/dl (5.35 +/- 1.03 mmol/L) to 141 +/- 35 mg/dl (3.64 +/- 0.90 mmol/L). High-density lipoprotein-cholesterol levels were not significantly changed after cholestyramine use in either group. In the FCHL group, plasma triglyceride levels increased significantly from 81 +/- 35 mg/dl (0.92 +/- 0.40 mmol/L) to 134 +/- 42 mg/dl (1.52 +/- 0.48 mmol/L). Seven patients were lost to follow-up; 18 discontinued the medication within 1 month. Of the remaining 62 children, 59 had a good response to the drug. Of the 62 patients, 52 discontinued the medication after 21.9 +/- 10 months. Adverse effects included foul taste (73%), nausea with bloating (18%), and constipation. Cholestyramine is effective in reducing LDL-cholesterol levels in children with inherited hyperlipidemia, but the majority of children will not comply with its long-term use.
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PMID:Use of cholestyramine in the treatment of children with familial combined hyperlipidemia. 844 Nov 9


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