Hypercholesterolemia familial, types

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. 

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

Alpha-1 antitrypsin deficiency Cardiovascular diseases Familial hypercholesterolemia Many types using vaccine, toxin or endogenous regulatory protein expression strategies... 

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.]... 

A review of plasma purification using secondary filtration has been presented by Siami et al. [19] and Table 18.4 lists the diseases treated with this technique. Diseases treated include immune-mediated disorders and familial type IIA hypercholesterolemia. These authors concluded that cryoglobulins filters were safe and effective for removing cryoproteins, did not induce complement activation and constituted one of the most promising techniques of secondary membrane application. 

The genetic research of Goldstein and Brown5 (1983) that led to the discovery of cell surface LDL receptors and their mutations elucidated the biochemical basis of familial hypercholesterolemia (FH) types Ha and lib (Table 11-5) and greatly increased the understanding of the controlling mechanisms of plasma cholesterol levels. 

She was diagnosed as having familial hypercholesterolemia (FH) type IIA, which is caused by genetic defects in the gene that encodes the LDL receptor (see Biochemical Comments). As a result of the receptor defect, LDL cannot readily be taken up by cells, and its concentration in the blood is elevated. 

When similar lipid abnormalities are present in other family members in a pattern of autosomal dominant inheritance and no secondary causes for these lipid alterations (e.g., hypothyroidism) are present, the entity referred to as familial hypercholesterolemia (FH), type llA is the most likely cause of this hereditary dys-lipidemia. 

Abnormalities in the excretion of BA were observed in the early studies on fecal fat and steroid excretion of hyperlipoproteinemic patients. Miettinen and Aro (3) first noted that subjects with familial type II hypercholesterolemia have a subnormal fecal BA excretion, whereas this same tends to be elevated in type IV hypertriglyceridemics. Similar findings were later on reported by Nestel and Hunter (4), who, in particular, could find a highly significant increase of BA elimination in type IV patients. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Includes heterozygous familial and nonfamilial hypercholesterolemia. Includes Fredrickson types lla and Mb. 

Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson type I la and lib) - The dose range for rosuvastatin is 5 to 40 mg once daily. Individualize rosuvastatin therapy according to goal of therapy and response. The usual recommended starting dose of rosuvastatin... 

Primary hypercholesterolemia/mixed dyslipidemia For the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types lla and Mb) in the following Patients treated with lovastatin who require further TG-lowering or FIDL-raising who may benefit from having niacin added to their regimen patients treated with niacin who require further... 

Answer The patient has heterozygous familial hypercholesterolemia (type Ila) that is aggravated by lifestyle factors (obesity, high fat diet, stress, no exercise). Her LDL cholesterol is markedly elevated other lipids are normal she has angina and she has a family history of heart disease. Her hypertension would probably improve with a decrease in body weight. 

For treatment of heterozygous familial hypercholesterolemia, most patients require 2-6 g of niacin daily more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5-3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually. 

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. 

Indication Adjunct to diet for the reduction of elevated total cholesterol. LDL. apo B. and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial). mixed dyslipidemia (Fredrickson types Ila and 1 lb), elevated TG (type IV) and primary dysbetali-poproteinemia (type III) Adjunct to other lipid lowering treatments for homozygous familial hypercholesterolemia ... 

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Patient Population. The proband of the B family, T.B., was referred to the Lipid Research Clinic at The Johns Hopkins Hospital at the age of five years because of hypercholesterolemia of 900 mg/100 ml. She had multiple planar xanthomas that had first appeared at three years of age. The patient was free of symptoms of ischemic heart disease. The index lipoprotein pattern was type lib (57), with marked hypercholesterolemia, hyperbeta-lipoproteinemia, a mild hyperprebetalipoproteinemia and hypertriglyceridemia. None of the relatives of T.B. had xanthomas or corneal arcus one (J.S.) developed signs of premature coronary atherosclerosis at the age of 43 years. Increased total plasma and LDL cholesterol levels were transmitted over three generations on both maternal and paternal sides of the family (Fig. I). The parents of the proband, S.B. and K.B., had endogenous hypertriglyceridemia as well. Two normolipidemic members of this family (S.B., Jr. and E.B.), were also studied. 

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. 

Hereditary dyslipidemias such as familial hypercholesterolemia, type II and type IV hyperlipidemia and Tangiers disease predispose to premature large vessel atherosclerosis and hence stroke (Meschia 2003 Hutter et al. 2004). 

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