In familial hypercholesterolemia

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-... 

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. 

Takada, D., Ezura, Y., Ono, S., et al. (2003). Apolipoprotein H variant modifies plasma triglyceride phenotype in familial hypercholesterolemia a molecular study in an eight-generation hyperlipidemic family. J. Atheroscler. Thromb., 10(2), 79-84. 

Differences in the lipid content of cultured fibroblasts in familial hypercholesterolemia+... 

Carmena-Ramon RF, Ordovas JM, Ascaso JF, Real J, Priego MA, Carmena R. Influence of genetic variation at the apo A-I gene locus on lipid levels and response to diet in familial hypercholesterolemia. Atherosclerosis. 1998,139 107-113. 

Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia mutational analysis of a membrane protein. Annu Rev Genet 1990 24 133-170. 

Probucol is a lipid-lowering agent, but the results are not consistent with respect to LDL cholesterol. It lowers HDL cholesterol hence it is not the first drug of choice in therapy. The ability of probucol to correct atherosclerosis has been attributed to its antioxidant properties.77 The usual oral dose is 500 mg twice daily and is administered after food. Many experts use it as adjuvant therapy in familial hypercholesterolemia. The drug is well tolerated but causes GI side effects such as nausea and flatulence, headache, and dizziness. Patients taking probucol must be on a low-fat diet. Probucol should not be used in patients with recent myocardial infarction, and it should not be given to children or pregnant women. 

Bilheimer, D.W., Grundy, S.M., Brown, M.S., and Goldstein, J.L. (1983). Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci USA 80 4124-4128. 

The molecular defect in most cases of familial hypercholesterolemia is an absence or deficiency of functional receptors for LDL. Receptor mutations that disrupt each of the stages in the endocytotic pathway have been identified. Homozygotes have almost no functional receptors for LDL, whereas heterozygotes have about half the normal number. Consequently, the entry of LDL into liver and other cells is impaired, leading to an increased plasma level of LDL. Furthermore, less IDL enters liver cells because IDL entry, too, is mediated by the LDL receptor. Consequently, IDL stays in the blood longer in familial hypercholesterolemia, and more of it is converted into LDL than in normal people. All deleterious consequences of an absence or deficiency of the LDL receptor can be attributed to the ensuing elevated level of LDL cholesterol in the blood. 

What is the most common cause of the elevated levels of serum cholesterol in familial hypercholesterolemia ... 

Hobbs HH, Leitersdorf E, Goldstein JL, Brown MS, Russell DW. Multiple crm-mutations in familial hypercholesterolemia. Evidence for 13 alleles, including four deletions. J Chn Invest 1988 81 ... 

A phospholipid-protein-cell interaction was necessary to induce the reductase. Thus, elevated serum cholesterol levels in familial hypercholesterolemia may be attributed to increased cholesterol loss from cells,11 12 due to a lack of feedback regulation in this condition. 

Since LDL is the principal plasma-cholesterol carrier and its concentration in plasma correlates positively with the incidence of coronary heart disease, LDL is the most intensively studied plasma lipoprotein. Production in humans, via the pathway VLDL IDL LDL, accounts for all of the LDL normally present. However, in familial hypercholesterolemia or on a high-cholesterol diet, VLDL is produced that is higher in cholesterol content, smaller in size, and within the LDL density range (1.019-1.063 g/mL). 

Brox, J.H., Killie, J.E., Osterud B, Holme S, Nordoy, A.. Effects of cod liver oil on platelets and coagulation in familial hypercholesterolemia (type Ila). Acta Med Scand 1983 213 137-144. 

Discuss the biochemical defects of the LDL receptor that result in familial hypercholesterolemia. 

A defect in apoprotein B-lOO that prevents the binding of LDL to the cell-surface receptor would result in the stimulation of the synthesis of endogenous cholesterol and LDL receptors and a decrease in the synthesis of cholesterol esters via the ACAT reaction. Indeed, the cellular and physiological consequences of such a mutation may be similar to those seen in familial hypercholesterolemia. 

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. 

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Table II also shows, in agreement with earlier results (62), that subnormal amounts (24 %) of body cholesterol are catabolized by way of bile acids in familial hypercholesterolemia. Thus the elimination defect concerns primarily bile acids, the excretion of neutral sterols being less affected so that the sterol balance and hence the overall cholesterol synthesis tend to be decreased in familial hypercholesterolemia.

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