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Brittany Edwards

Familial hypercholesterolemia (FH)

Familial hypercholesterolemia (FH) is a genetic autosomal dominant disorder characterised by increased plasma levels of total cholesterol and extremely high low-density lipoprotein cholesterol (LDLc) levels as well as tendinous xanthomata and premature symptoms of coronary heart disease ( Austin et al 2004). Heterozygous FH is far more common than homozygous FH, occurring in 1 in 500 with homozygous FH affecting 1 in 1,000,000 (Citkowitz 2009). FH may result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotien B-100 gene (APOB), or propoprotein convertase subtilising/kexin type 9 gene (PCSK9) (Austin et al 2004).

"FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors" (Citkowitz 2009). The LDL receptor gene is the primary determinant of hepatic LDL uptake, the protein is composed of 860 amino acids and is located on the short arm of chromosome 19. Instances of FH due to LDLR mutations can be categorised into five main classes. Class 1, in which there is a complete absence of the LDLR receptor. Class 2,resulting in failure of receptor transport to the cell surface or successful transport of mutated receptors, due to defective transport alleles which disrupt the normal folding process. Class 2 mutations are further divided into types a and b. Class 2a mutations completely block the transport of the receptor from the endoplasmic reticulum to the Golgi apparatus. And Class 2b mutations result in a partial blocking of transport of the receptor from the endoplasmic reticulum to the Golgi apparatus. (Citkowitz 2009). In Class 3 mutations a defect in apolipoprotein B100 or in LDLR cause the inability of LDLR to properly bind LDL to the cell surface. Class 4 mutations arise as a result of the LDLR bound to the LDL not properly being able to cluster in clathrin-coated pits for receptor-mediated endocytesis. And finally Class 5 in which recycling back to the cell surface of LDLR is interrupted.

FH due to defective APOB-100 is caused by an abnormality at the binding site of APOB-100, which obstructs its role as a ligand for the receptor. The gene for APOB-100, located on the short arm of chromosome 2 is a single polypeptide chain comprised of 4536 amino acids. Although this may result from different mutations on a few different codons, the first described mutation of this type was a substitution of glycine for arginine at the codon for amino acid 3500 (Citkowitz 2009). Like LDLR the severity of the hypercholesterolemia is determined by the number of abnormal copies of the gene.

"PCSK9 binds the low density lipoprotein receptor (LDLR) and addition of PCSK9 to cells promotes degradation of LDLR. PCSK9 mutant proteins associated with hypercholesterolemia (S127R and D374Y) are more potent in decreasing LDL uptake than wild-type PCSK9" (Pandit et al. 2008).

Atherosclerosis, the main cause of heart disease is caused by accelerated depositing of cholesterol in the walls of the arteries. Individuals suffering from FH generally have an increased risk of premature heart disease, namely due to coronary artery disease (wikipedia.org), which involves atherosclerosis of the coronary arteries supplying the heart. Normally LDL cholesterol circulates the body for 2.5 days, before binding to the LDL receptor on the liver cells, undergoing endocytosis and finally being digested. LDL is removed and synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway. In individuals with FH although there are normal levels of other lipoproteins the level of LDL cholesterol in the blood is significantly increased. This is due to the LDL circulating the body for about 4.5 days as the LDL receptor function is absent or reduced. Reduced binding of LDL particles to the receptor is what causes the increased LDL cholesterol level in mutations of APOB (wikipedia.org).

"In many heterozygous forms of FH, the LDL receptor functioning is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all" (Rader et al. 2003). And because "the degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors" some individuals with FH may have heart attacks and others may not.

"Proper diet, exercise, and certain medications can bring lipids down to safer levels and reduce the risk of heart disease and heart attacks." (Familial hypercholesterolemia, 2009). The aim of treatment for FH is to lower the cholesterol levels in the blood stream in order to decrease the risk of heart disease due to atherosclerosis. Individuals suffering from heterozygous FH should lower the total amount of fat in their diet to just 30% of their total daily calories (Learning About Familial Hypercholesterolemia, National Human Genome Research Institute, 2009). Achieving weight loss, through exercise also lowers cholesterol levels.

Because the LDL receptors are only minimally functional, and sometimes do not even function, in those suffering from homozygous FH it is harder to treat. "Only high doses of stains, often in combination with other medications, are modestly effective in improving lipid levels" (Marais et al. 2002). "Statins act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase in the liver. In response the liver produces more LDL receptors, which remove circulating LDL from the blood" (Rader et al. 2003). Sometimes other drugs such as bile acid sequestrants, nicotinic acid preparations or fibrates are required as add on therapies. "Prior to the introduction of the statins, clofibrate, probucol and thyroxine were used to reduce LDL cholesterol levels" (www.wikipedia.org).

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Citkowitz, E, 2009, Hypercholesterolemia, Familial. Available from: Medscape < http://emedicine.medscape.com/article/121298-overview>(22 August 2009)

Familial hypercholesterolemia, 2009. University of Maryland. Available from: http://www.umm.edu/ency/article/000392trt.htm (20 August 2009)

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Structure of familial hypercholesterolemia PCSK9 mutant elucidated, Baylor College of Medicine, 2007. Available from: http://www.lipidsonline.org/news/article.cfm?aid=4769 (19 August 2009)

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Zakharova, FM, Damgaard, D, Mandelshtam, MY, Golubkov, VI, Nissen, PH, Nilsen, GG, Stenderup, A, Lipovetsky, BM, Konstantinov, VO, Denisenko, AD, Vasilyev, VB & Faergeman, O, 2005, "Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia", BMC Medical Genetics, vol. 6. Available from: BioMEd Central < http://www.biomedcentral.com/1471-2350/6/6>(20 August 2009)

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