Kieran Rayney
Familial hypercholesterolemia is a congenital condition
Familial hypercholesterolemia is a congenital condition that affects the removal of cholesterol from the blood and frequently results in cholesterol deposition in the coronary arteries of affected individuals. (Hobbs et al. 1992) The cholesterol responsible for these adverse effects are low density lipoproteins (LDL's). It is understood that receptors for plasma LDL's are responsible for the removal of LDLs from plasma and the prevention of hypercholesterolemia. It was found that in a subject with heterozygous FH, only a 50% deficiency of LDLR's not only impaired this removal, but produced hypercholesterolemia. (Bilheimer et al. 1983)
There are several genetic defects causing FH, the most prevalent of which are defects in the LDL receptors for plasma LDL. Mutations that prevent proper function of LDL receptors result in FH, an autosomal dominant genetic disorder that affects approximately 1 in 500. (Hobbs et al. 1992) As a dominant genetic trait, LDLR abnormalities are present in heterozygotes with only one defective genetic copy as well as homozygotes. An individual with Heterozygous FH has one normal and one mutant gene that 'specifies' the cell surface receptor for plasma low density lipoprotein. (Bilheimer et al. 1983) Mutations of LDLR's fall under five classes, however certain mutations fall under multiple classifications. (Hobbs et al. 1992) Class 1 mutations result in 'null alleles' which do not produce LDLR proteins. This is usually a nonsense mutation and means about 2% of LDLs are absorbed. Class 2 is the most common mutation that results in improper transport of the receptor from the Golgi body to the endoplasmic reticulum due to blockage. Class 3 involves mutations causing binding defective alleles, meaning LDL's are prevented from binding to the receptor. Class 4, involving mutations producing 'Internalization-defective alleles,' mean the LDL's are not 'clustered' and internalized within the cell by 'receptor mediated' endocytosis. Class 5 simply deals with the inability for the cell to recycle the receptors that have internalized the lipoprotein.
LDLR is a cell surface receptor that recognizes and binds with specific apoprotein B100. The LDL is then internalized within the cell after having been clustered in 'clathrin coated pits.' The LDLR's are then recycled in a 'recycling vesicle,' while the cholesterol ester is degraded in separate lysomes. Cholesterol is then able to form membranes, steroid hormones, bile acids and lipoproteins. The mutations discussed above mean that any part of the process is either prevented or ineffective. This results in the circulation of LDL's in the blood and infiltrating the walls of blood vessels. Inflammation and obstruction follows, and if this occurs in coronary arteries, heart disease and heart attacks can follow.
Certain research has suggested reducing cholesterol levels in childhood could 'prevent coronary artery disease later in life'. (Gylling et al. 1995) Results from a six week study of sistostanol found a 15% decrease in low density lipoproteins. The use of plant sterols such as sistostanol and sistosterol to reduce levels of, 'serum lipids,' was also used in earlier studies on FH individuals with similar results. Sistostanol was found to be most effective and reduced LDL levels by 33%. Such sterols are non-absorbable, so can be incorporated into an affected individual's diet with minimal side effects. (Becker et al. 1993) Another popular treatment to lower blood LDL levels is a class of drug call statins. These drugs act by blocking cholesterol synthesis in the liver which reduces liver cholesterol levels. High cholesterol levels in the liver block the passage of receptor protein to the endoplasmic reticulum, and with lowered cholesterol, production of LDLR increases, and blood LDL falls. Statins are very popular with over 20 million users taking every day. (Brown et al. 2009) This incredible usage is justified when studies have found LDL lowering statins reduced heart attacks by 30-40% in individuals who already had some damage to their arteries. (Brown et al. 2009) This drug usage could be very effective preventative action for those at an earlier age as well as a treatment for those with existing arterial damage. Homozygote's have very limited response to medication and require drastic treatments including LDL aphaeresis, where blood is circulated through external apparatus coated with antibodies to apoliprotein B in order to remove LDLs.
Research shows a strong relationship between LDLR function and atherosclerosis due to high cholesterol levels and found a reduction of LDL cholesterol levels 'can induce regression of atherosclerotic lesions' in the arteries of FH patients. (Kane et al. 1990) The key reason why some individuals with FH is that while the genes predisposes individual to high cholesterol, doesn't necessarily result in heart attacks. The levels of LDL are very high in homozygous FH individuals, irrespective of diet, medications, or lifestyle. (Rader et al. 2003) While there is very little chance for preemptive action against heart attacks in individuals with homozygous FH, it is possible to minimize risk in heterozygous cases. Excess cholesterol can also deposit in the skin and tendons and not always to the extent in coronary arteries that a myocardial infarction should occur. (Hobbs et al. 1992) Lifestyle choices that are used by unaffected individuals to prevent heart attacks are also relevant. Dietary options such as moderate consumption of alcohol that increase the ratio of high-density lipoproteins to LDLS have a preventative effect. Exercise has also been shown to reduce the risk of heart attacks. Even though individuals with FH are predisposed to heart attacks, they are not necessarily the outcome.
Reference List
Gylling, H, Siimes, MA, Miettinen, TA. 1995, 'Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia.' Journal of Lipid Research, Vol 36, pp 1807-1812, Available from: Journal of Lipid Research
Seed, M, Hoppichler, F, Reaveley, D, McCarthy, S, Thompson, GR, Boerwinkle, E, Utermann, G.1990, 'Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia.' The New England Journal of Medicine, Vol. 322. No. 21, pp 1494-1499
Bilheimer, DW, Grundy, SM, Brown, MS, Goldstein, JL. 1983, 'Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.' PNAS, vol. 80 no. 13, pp 4124-4128.
Hobbs, HH, Brown, MS, Goldstein, JL. 1992, 'Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.' Human Mutation, vol. 1, no. 6, pp 445-466, Available from Wiley InterScience.
Becker, M, Staab, D, von Bergmann, K. 1993, 'Treatment of severe familial hypercholesterolemia in childhood with Sitosterol and Sitostanol.' The Journal of Pediatrics, vol. 122, no. 2, pp 292-296, Available from: Science Direct
Kane, JP, Malloy, MJ, Ports, TA, Phillips, NR, Diehl, JC, Havel, RJ. 1990, 'Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia With Combined Drug Regimens.' Journal of the American Medical Association, vol. 264, no. 23, pp 3007-3012
Rader, DJ, Cohen, J, Hobbs, HH. 2003, 'Monogenic hypercholesterolemia: new insights in pathogenesis and treatment.' Journal of Clinical Investigation, vol. 111, no. 12, pp 1795-1803
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