Hypercholesterolemias familial

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

In a large population study Goldstein et al. discussed three frequent lipid disorders, familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia. Ascorbate deficiency unmasks these underlying genetic defects and leads to an increased plasma concentration of lipids (e.g. cholesterol, triglycerides) and Hpoproteins (e.g. LDL, VLDL) as well as to their deposition in the impaired vascular wall. As with Lp(a), this deposition is a defense measure counteracting the increased permeability. It should, however, be noted that the deposition of lipoproteins other than Lp(a) is a less S[>ecific defense mechanism and fre-... 

Synonyms Primary hypercholesterolemia, familial hypercholesterolemic xanthomatosis, hyperbetalipoproteinemia. 

Familial hypercholesterolemia Familial hypercholesterolemia occurs when there is a mutation of a gene on chromosome 19, which produces high cholesterol levels that lead to early coronary heart disease in people 30 to 40 years old. 

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

LDL receptor Loss-of-function (familial, autosomal dominant) Familial hypercholesterolemia (impaired clearance of LDL)... 

The hver and many extrahepatic tissues express the LDL (B-lOO, E) receptor. It is so designated because it is specific for apo B-IOO but not B-48, which lacks the carboxyl terminal domain of B-lOO containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is de-... 

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. 

Familial hypercholesterolemia (MIM 143890) Mutations in the gene encoding the LDL receptor... 

Mutations within the SREBPs and the SREBP processing proteins (SCAP, SIP, S2P) have intensively been searched, especially in patients with familial hypercholesterolemia. So far, however, only four polymorphic sites within SCAP [38, 39], one within the promoter of SREBP-la [40], and five mutations in SREBP-2 [41] have been published. Yet, the impact of these polymorphisms and mutations on the response to statins has not been evaluated. 

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. 

Yamamoto A, Matsuzawa Y, Kishino B, Hayashi R, Hirobe K, Kikkawa T. Effects of probucol on homozygous cases of familial hypercholesterolemia. Atherosclerosis 1983 48 157-166. 

Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, et al. Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ( French Canadian mutation ) of the LDL receptor gene. Arteriosder Thromb 1994 14 1258-1263. 

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]. 

A 40-year-old male with markedly elevated cholesterol, diagnosed as having heterozygous familial hypercholesterolemia, is treated with cholestyramine. What is the mechanism of action of cholestyramine ... 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol (LDL-C) being inversely proportional to the deficit in LDL-Rs. 

Familial hypercholesterolemia is characterized by a selective elevation in plasma LDL and deposition of LDL-derived cholesterol in tendons (xanthomas) and arteries (atheromas). 

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