Hyperlipoproteinemias familial

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

Apo C-ll activates lipoprotein lipase, which degrades the chylomicron s triacylglycerol to fatty acids and glycerol. The fatty acids that are released are stored (in the adipose) or used for energy (by the muscle). The glycerol is metabolized by the liver. Patients with a deficiency of lipoprotein lipase or apo C-ll show a dramatic accumulation of chylomicrons in the plasma (type 1 hyperlipoproteinemia, familial lipoprotein lipase deficiency, or hypertriacylglycerolemia)... 

Type TV hyperlipoproteinemia is common and occurs in adulthood primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or 8-blockers. Two genetic patterns occur in type IV hyperlipoproteinemia familial hypertriglyceridemia, which does not carry a great risk for premature CAD, and familial combined hyperlipidemia, which is associated with increased risk of cardiovascular disease. 

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. 

Hyperlipoproteinemia, Type III, is a rare hereditary disease (also called familial dysbetalipoproteinemia) manifested by the occurrence of an uncommon P-lipo-protein form. Cholesterol and triglyceride contents in the patients may occasion-ally be 2-5 times superior to the norm. 

Hyperlipoproteinemia, Type IV, is characterized by increased contents of pre-P-lipoproteins and triglycerides (2-5 fold) in the blood plasma. Its incidence rate is higher in aged patients. Hereditary forms of this disease (called also familial hyperprebetalipoproteinemia) have been described. 

BARs are useful in treating primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type Ila hyperlipoproteinemia). 

Familial hyperlipoproteinemia Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism. 

The answer is a. (Hardman, pp 875-898.) In type I hyperlipoproteinemia, drugs that reduce levels of lipoproteins are not useful, but reduction of dietary sources of fat may help. Cholesterol levels are usually normal, but triglycerides are elevated. Maintenance of ideal body weight is recommended in all types of hyperlipidemia. Clofibrate effectively reduces the levels of VLDLs that are characteristic of types 111, IV, and V hyperlipoproteinemia administration of cholestyramine resin and lovastatin in conjunction with a low-cholesterol diet is regarded as effective therapy for type 11a, or primary, hyperbetalipoproteinemia, except in the homozygous familial form. 

Familial combined hyperlipoproteinemia VLDL predominantly increased Niacin, fibrate, reductase inhibitor Two or three of the individual drugs... 

As described, some persons with familial combined hyperlipoproteinemia have only an elevation in LDL. Serum cholesterol is usually less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or ezetimibe to normalize LDL. 

This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. Statins should be given at least 1 hour before or 4 hours... 

This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1-3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia. 

This regimen is more effective than either agent alone in treating hypercholesterolemia. Experience indicates that it is an efficacious and practical combination for treatment of familial combined hyperlipoproteinemia. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

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. 

Fate of the remaining chylomicron components After most of tt triacylglycerol has been removed, the chylomicron remnan (which contain cholesteryl esters, phospholipids, apolipoprotein and some triacylglycerol) bind to receptors on the liver (seej 228) and are then endocytosed. The remnants are the hydrolyzed to their component parts. Cholesterol and the nitrogf nous bases of phopholipids (for example, choline) can be req cled by the body. [Note If removal of chylomicron remnants by th liver is defective, they accumulate in the plasma. This is seen i type III hyperlipoproteinemia (also called familial dysbetalipopro teinemia, see p. 229). 

Familial combined hyperlipoproteinemia VLDL increased Niacin, fibrate ... 

In kindreds with this disorder, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate doubling in VLDL secretion. It seems to be transmitted as a semidominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are usually absent. Drug treatment is warranted because the risk of coronary atherosclerosis is increased and diet alone does not normalize lipid levels. A reductase inhibitor or ezetimibe in combination with niacin is usually required to treat these patients. 

U5. Utermann, G., Jaescbke, M., and Menzel, J., Familial hyperlipoproteinemia type III Deficiency of a specific apolipoprotein (apo E-III) in the very-low-density lipoproteins. FEBS Lett. 56, 352-355 (1975). 

W4. Wamick, G. R., Mayfield, C., Albers, J. J., and Hazzard, W. R., Gel isoelectric focusing method for specific diagnosis of familial hyperlipoproteinemia type 3. Clin Chem. 25, 279-284 (1979). 

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. 

Patients with familial type III hyperlipoproteinemia develop the following... 

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