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Familial Hypercholesterolemia (FH), an autosomal dominantly inherited disorder, results from the mutation of the low-density lipoprotein receptor (LDLR) gene on chromosome 19. FH is associated with markedly elevated plasma low-density lipoprotein (LDL) cholesterol levels beginning at birth. This elevation, which is not secondary to environmental, dietary, or other underlying diseases, is characterized by autosomal dominant inheritance with strikingly elevated LDL, the presence of tendinous xanthomas, and the development of premature atherosclerosis and cardiovascular disease. FH is caused by mutations in the protein encoding for the LDL receptor, which is critical in the control of LDL uptake and cholesterol homeostasis in hepatocytes. Normally, the LDL receptor binds apoB100 and apoE. After LDL binds to the receptor, the receptor is internalized by hepatocytes and dissociates from LDL, returning to the cell surface in a cycle that takes approximately 10 minutes to complete. LDL is then degraded within lysosomes, and free cholesterol is released to the cytosol; intracellular cholesterol inhibits 3-hydroxy-3-methlylglutaryl coenzyme A (HMG-CoA reductase), thereby interfering with cholesterol synthesis. Intracellular cholesterol increases the storage of excess cholesterol by promoting esterification, inhibits LDL receptor synthesis, and prevents further internalization and accumulation of cholesterol. If LDL receptors are absent or abnormal, the previously explained feedback mechanism does not occur, thereby causing uncontrolled synthesis of cholesterol within the liver (Groff, 1999). Individuals with FH have mutations in the LDLR gene, resulting in a dysfunctional receptor, which leads to inadequate uptake of LDL cholesterol. These gene mutations are numerous, including more than 420 different variations that have a meaningful impact on receptor function; the LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity. The five functional classes of mutations include the following: Class 1- no LDL receptors, thought to inhibit transcription completely Class 2- mutation blocks the LDLR proteins from the golgi apparatus to the endoplasmic reticulum Class 3- gene codes for receptor proteins, but is unable to bind LDL cholesterol Class 4- receptor binds the LDL but fails to internalize this bound LDL cholesterol Class 5- bound LDL cholesterol is internalized but fails to be recycled back to the cell surface (Geleherter et al, 1998) Two separate and distinct types of FH exist, and unlike most rare autosomal dominant disorders, FH is expressed in both the homozygous and the heterozygous form (Hollman, 2002). Each person has two genes that are responsible for making the LDL receptor; one received from the father and one from the mother. In a heterozygous FH individual, a single copy of the mutant, or abnormal, LDLR gene has been passed on from one parent who has FH, and a normal gene has been passed on from the other parent. Therefore, half of the LDL receptors are absent or fail to work properly, while the other half are normal. The homozygous variation is characterized by two copies of the mutant gene; therefore, these individuals lack any LDL receptors, resulting in excessively increased levels of cholesterol in the blood. The heterozygous variation occurs in approximately 1 in every 500 people, with patients appearing seemingly asymptomatic until adulthood. Serum total cholesterol levels can be elevated to 300 to 600 mg / dL, with LDL cholesterol levels reaching greater than 200 mg/ dL. Without treatment the mean age of onset of coronary heart disease in men with heterozygous FH is around 40 years of age, whereas it occurs some 10 to 15 years later in women (Seashore, 1996). The likelihood of a man with heterozygous FH suffering a myocardial infarction (MI) is 5% below the age of 30, 50% by age 50, and 85% by age 60. Corresponding values for women are less than 1% before age 30, 15% by age 50, and 50% by age 60 (Mueller, 2001). The homozygous variation, far more severe in nature, occurs in about 1 in every 1,000,000 people. Serum total cholesterol levels can be strikingly elevated to 600 to 1,200 mg/ dL. Due to little or no activity from the LDL receptors, levels of cholesterol increase, xanthomas develop, and coronary heart disease progresses, all of which occur at accelerated rates. Individuals with this variation are typically children and young adults who develop coronary heart disease early in life, with children less than age 5 suffering heart attacks and many failing to survive through their teenage years. These patients may have cutaneous xanthomas at birth or by early childhood; several types of xanthomas are usually obvious in the first decade of life and they include (1) planar xanthomas (on the hands, elbows, buttocks, or knees), which are diagnostic for the homozygous state and are distinct from other cutaneous xanthomas because of their yellow-to-orange coloration; (2) tuberous xanthomas (on hands, elbows, or knees); and (3) tendon xanthomas, occurring especially on extensor tendons of hands or Achilles tendon (Goldstein, 2001). LDL receptors of those with homozygous FH are oftentimes resistant to most cholesterol-lowering medications, and so treatment options are few. Either a liver transplant, although rarely performed, provides normal LDL receptors, portacaval anastomosis****, or plasma apheresis, which selectively removes very low density lipoproteins (VLDLs) and LDLs from the plasma, are the most likely treatments for these individuals. Various prescription drug treatments are used in the treatment of FH patients and include “statins” (HMG-CoA reductase inhibitors), bile acid sequestrants, cholesterol absorption inhibitors, fibrates, and nicotinic acid. Statins, the most potent, most effective, and best tolerated drugs for reducing LDL cholesterol, are available in many slightly different forms, which include Mevacor, Pravachol, Zocor, Lescol, Lipitor and Baycol (which is temporarily off the market), each varying in potency, physicochemical properties, and route of metabolism. Statin drugs inhibit the rate-limiting step of cholesterol synthesis, create a transient decrease in intracellular cholesterol, increase the synthesis of the cell surface LDL receptor, and accelerate removal of LDL cholesterol and triglyceride-rich lipoprotein, the latter of which accounts for the associated modest reduction in triglyceride levels that is observed with the use of these drugs. Statin medications have also been shown to have an effect on clotting factors in the blood, which are thought to lower the risk for a person to suffer from a stroke. Some studies have also reported that statins may have an anti-inflammatory effect that may also help to reduce the risk of a heart attack. The data collected on the efficacy of statin drugs is promising. They have been shown to lower LDL (low-density lipoprotein) levels by 18%-55%.
Approximate Word count = 4218
Approximate Pages = 16.9
(250 words per page double spaced)
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