ElliottPhelps 2020523703
Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein levels in the blood. High cholesterol levels normally do not cause any symptoms. However, cholesterol may be deposited in various places around the body that are visible from the outside, such as yellowish patches around the eyelids and the outer margin of the iris. Or in the form of lumps in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon.
LDLR mutations are the most common in the population with a prevalence of about 1 in every 500 people. The LDL receptor gene is located on the short arm of chromosome 19 and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. Homozygotes have a LDLR activity of less than 2%, while heterozygotes have a defective LDL processing with receptor activity being 2-25%, depending on the nature of the mutation. There are five major classes of FH due to LDLR mutations. In the first class LDLR is not synthesized at all. Class II involves LDLR not being properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface. In class III a defect causes LDL to improperly bind LDL on the cell surface. Class IV is when LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis, and the final class occurs when LDLR is not recycled back to the cell surface.
The other mutations include ApoB, which is the main Apo protein or protein part of the lipoprotein particle. The mutation is located on a part of the protein that normally binds with the LDL receptor but binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia. PCSK9 is a gene mutation that is located on the first chromosome and encodes an amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells. Abnormalities in the ARH gene, also known as LDLRAP1, are when two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease than heterozygotes but less severe than homozygotes.
The increase risk of heart disease is caused by deficiency of the LDL receptor on the surface of cells in the liver and other organs. As a result, LDL cholesterol is not moved into the cells and thus remains in the blood, eventually accumulating in deposits on the walls of arteries. Another reason that people with familial hypercholesterolemia contract cardiovascular diseases is that their enzymes are relieved of feedback mechanisms and therefore induces excessive amounts of cholesterol in the cells.
The overall goal of treatment is to lower the risk for atherosclerotic heart disease by lowering the LDL cholesterol levels in the blood stream. The first step in treatment for an individual who has heterozygous familial hypercholesterolemia is changing the diet to reduce the total amount of fat eaten to 30 percent of the total daily calories. This can be done by limiting the amount of beef, pork, and lamb in the diet; cutting out butter, whole milk and fatty cheeses as well as some oils like coconut and palm oils; and eliminating egg yolks, organ meats and saturated fat from animals. Dietary counselling is often recommended to help people to make these changes in their eating habits. Exercise also helps in lowering cholesterol levels, as frequent exercise may lead to weight loss and healthier individuals. The second step of treatment for heterozygous FH is usually with statins. They act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase in the liver and in response; the liver produces more LDL receptors, which remove circulating LDL from the blood. Statins effectively lower cholesterol and LDL levels, although sometimes add-on therapy with other drugs is required, such as bile acid sequestrants, preparations or fibrates.
Homozygous FH is harder to treat. The LDL receptors are minimally functional, if at all and therefore only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels. If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis. Very severe cases may be considered for a liver transplant; this provides a liver with normally functional LDL receptors, and leads to rapid improvement of the cholesterol levels, but at the risk of complications from any solid organ transplant (such as rejection, infections, or side-effects of the medication required to suppress rejection).
One reason that some individuals with FH don't have heart attacks is that their condition is diagnosed early and they undergo successful treatments. A second reason is that some individuals with the disorder will be a lot healthier and fitter than others. This will mean that they have less risk of large amounts of cholesterol accumulating on the walls of their arteries.
References:
Jansen AC, van Aalst-Cohen ES, Tanck MW, et al. (2004). The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia. J. Intern. Med. 256 (6): 482-90
Mabuchi H, Koizumi J, Shimizu M, Takeda R (1989). Development of coronary heart disease in familial hypercholesterolemia. Circulation 79 (2): 225-32
Ozumi K, Tasaki H, Yamashita K, et al. (2005). Valvular and supravalvular aortic stenosis in heterozygous familial hypercholesterolemia, a case report. J. Atheroscler. Thromb. 12 (5): 289-93.
Tybjærg-Hansen A, Humphries SE. (1992). Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis, Volume 96, Issues 2-3, 91-107
www.genome.gov
www.nlm.nih.gov/MEDLINEPLUS/ency/article/000392.htm
We provide a professional essay writing service that thousands of our customers use as an effective way of improving their grades, improving their research and saving them lots of time.
