Hypercholesterolemia diseases caused

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Familial hypercholesterolemia is caused by mutations In the gene encoding the low-density lipoprotein (LDL) receptor. Persons with this disorder have elevated plasma LDL levels and develop cardiovascular disease at abnormally young ages. 

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia) Deficiency in remnant clearance by the liver is due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor. Increase in chylomicron and VLDL remnants of density < 1.019 (P-VLDL). Causes hypercholesterolemia, xanthomas, and atherosclerosis. 

I Coronary heart disease can be caused by mutations in the LDL receptor (familial hypercholesterolemia), inherited cancer syndromes can result from mutations in ... 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

The initial steps in BA synthesis are characterised by the introduction of a hy-droxylic group in the la position, or in position 27, followed by another in the la position into the cholesterol nucleus. Both synthetic pathways (the neutral and the acidic pathways) possess a distinct microsomal 7-oxysterol hydroxylase, which is regulated by different genes. The most recently described disorder of BA synthesis is cholesterol 7a-hydroxylase deficiency, in which their decreased production through the classical pathway is partially balanced by activation of the alternative pathway. Cholesterol levels increase in the liver, with a consequent low-density lipoprotein hypercholesterolemia, and cholesterol gallstones may result, although there is no liver disease. In contrast, a defect in the conversion of 27-hydroxy-cholesterol to la,27-dihydroxy-cholesterol due to deficiency of the oxysterol 7a-hydroxylase specific for the alternate pathway, causes severe neonatal liver disease [8]. 

Familial hypercholesterolemia results from a defective LDL receptor. As a result, the cholesteryl ester in the LDL of the bloodstream cannot be cleared by the normal process, hence, high cholesterol levels occur in the plasma of these patients. Somehow, the high levels of cholesterol lead to the formation of the atherosclerotic lesions, the underlying cause of premature heart disease in these patients. 

High-dose glucocorticoid therapy can cause marked hypertriglyceridemia, with milky plasma (SEDA-15, 421 SEDA-16, 450). It has been suggested that this is caused by abnormal accumulation of dietary fat, reduced postheparin lipolytic activity, and glucose intolerance (126). An association between glucocorticoid exposure and hypercholesterolemia has been found in several studies (127) and can contribute to an increased risk of atherosclerotic vascular disease. 

There is a higher incidence of impaired sexual function in men who take finasteride compared with placebo (58,59). The incidence of erectile dysfunction has been estimated at 5% (60), but it is difficult to estimate, since in many users of the drug other causes are present, including advanced age, heart disease, diabetes, hypertension, smoking, and hypercholesterolemia. Benign prostatic hyperplasia itself can also aggravate or even induce erectile dysfunction. A questionnaire study in New Jersey... 

Fluvastatin (Fig. 21) is a member of the drug class of statins used to treat hypercholesterolemia and to prevent cardiovascular disease. It is able to decrease ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. The an-tioxidative effect of fluvastatin was thought to have caused not only the scav-... 

Type I lipoproteinemia is generally caused by the inability of the organism to clear chylomicrons. The problem may be defective ApoC-II or a defective lipoprotein lipase. Very often, chylomicron clearance may be affected by injection of heparin, which apparently releases hepatic lipase from the liver into the circulation. ApoE disorders may be associated with type III lipoproteinemia, in which clearance of IDL is impeded. Increases in circulatory LDL are usually caused by a decrease in tissue receptors specific for ApoB-100. An extreme case of type Ha hyperlipoproteinemia is familial hypercholesterolemia, in which serum cholesterol levels may be as high as 1000 mg/dL and the subjects may die in adolescence from cardiovascular disease. There is total absence of ApoB-100 receptors. Mild type Ila and lib lipoproteinemias are the most commonly occurring primary lipoproteinemias in the general population. 

Increase in LDL levels no effect on HDL, VLDL or plasma triglyceride levels significant cause of hypercholesterolemia and premature coronary artery disease Decreased levels of plasma cholesteryl esters and lysolecithin abnormal LDLs (Lp-X) and VLDLs symptoms also found associated with cholestasis... 

Hypertension. Nearly half of those with hypertension receive no treatment. Yet it is the chief cause of stroke in people under the age of 65. Direct medical expenses in 2000 exceeded 25 billion. Lost wages and decreased produchvity contributed to another 8 billion. Osteoporosis. Most sufferers receive no or little treatment. Ninety percent of women and 99% of men receive no treatment. Hypercholesterolemia. Over 1.5 millions will die from myocardial inf-archon (Ml) and many survivors will have serious morbidity issues. The prevention of coronary heart disease through lipid-lowering and... 

Xanthelasma is caused by an infiltration of the dermis by xanthoma cells, which are benign histiocytes that imbibe lipids. The condition may occur independently, without associated systemic disease, or may be a manifestation of hypercholesterolemia or other associated disturbance of lipid metabolism. 

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