Cholesterol is a waxy, fat-like substance that occurs naturally in all parts of the body. Your body needs some cholesterol to work properly. But if you have too much in your blood, it can stick to the walls of your arteries. This is called plaque. Plaque can narrow your arteries or even block them.
High levels of cholesterol in the blood can increase your risk of heart disease. Your cholesterol levels tend to rise as you get older. There are usually no signs or symptoms that you have high blood cholesterol, but it can be detected with a blood test. You are likely to have high cholesterol if members of your family have it, if you are overweight or if you eat a lot of fatty foods.
You can lower your cholesterol by exercising more and eating more fruits and vegetables. You also may need to take medicine to lower your cholesterol.
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Cholesterol is a chemical compound that is naturally produced by the body and is a combination of lipid (fat) and steroid. Cholesterol is a building block for cell membranes and for hormones like estrogen and testosterone. About 80% of the body's cholesterol is produced by the liver, while the rest comes from our diet. . Dietary cholesterol comes mainly from meat, poultry, fish, and dairy products. Organ meats, such as liver, are especially high in cholesterol content, while foods of plant origin contain no cholesterol. After a meal, dietary cholesterol is absorbed from the intestine and stored in the liver. The liver is able to regulate cholesterol levels in the blood stream and can secrete cholesterol if it is needed by the body.
There is types of the cholesterol LDL and HDL .
LDL cholesterolÂ is called "bad" cholesterol, because elevated levels of LDL cholesterol are associated with an increased risk of coronaryÂ heart disease. LDL lipoprotein deposits cholesterol on the artery walls, causing the formation of a hard, thick substance called cholesterol plaque. Over time, cholesterol plaque causes thickening of the artery walls and narrowing of the arteries, a process calledÂ atherosclerosis.
HDL cholesterolÂ is called the "good cholesterol" because HDL cholesterol particles prevent atherosclerosis by extracting cholesterol from the artery walls and disposing of them through the liver. Thus, high levels of LDL cholesterol and low levels of HDL cholesterol (high LDL/HDL ratios) are risk factors for atherosclerosis, while low levels of LDL cholesterol and high level of HDL cholesterol (low LDL/HDL ratios) are desirable.
Total cholesterolÂ is the sum of LDL (low density) cholesterol, HDL (high density) cholesterol, VLDL (very low density) cholesterol, and IDL (intermediate density) cholesterol.
So when there is a high level of cholesterol in the blood we'll say it's hypercholesterolemia , so the dangerous about it is that it's a cause to many diseases most known cardiovascular disease .
These increased levels of cholesterol are due to :
Elevated cholesterol in the blood is due to abnormalities in the levels ofÂ lipoproteins, the particles that carry cholesterol in the bloodstream. This may be related toÂ diet like accumulating more eating carbohydrates or fats and it's treated by some diet system includes low cholesterol level .
The other reason is a genetic factor abnormalities n here we can say a familial hypercholesterolemia originate .
So Familial hypercholesterolemia is a disorder of high LDL ("bad") cholesterol that is passed down through families, which means it is inherited due to the genetic abnormality . The condition begins at birth and can cause heart attacks at an early age .
It's also known as Type II hyperlipoproteinemia; Hypercholesterolemic xanthomatosis; Low density lipoprotein receptor mutation
As we know for each content of the human body there is a gene which responsible to it's function and our problem here is the high level of LDL so the genes responsible for it have one or two mutations and so the genetic defect occur .
The most common genetic defects in FH areÂ LDLRÂ mutations (prevalenceÂ 1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000),Â PCSK9Â mutations (less than 1 in 2500) andÂ LDLRAP1
The common genes have defects in familial hypercholesterolemia are :
Always on Time
Marked to Standard
1.LDL receptor .
TheÂ LDL receptorÂ geneÂ is located on the short arm ofÂ chromosome 19Â (19p13.1-13.3). It comprises 18Â exonsÂ and spans 45Â kb, and the protein gene product contains 839Â amino acidsÂ 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. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have 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. Over 1000 different mutations are known .
TheÂ geneÂ coding the LDL receptor is split into 18Â exons. Exon 1 contains a signal sequence that localises the receptor to theÂ endoplasmic reticulumÂ for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the EGFP domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain. The LDL receptor can be described as a chimericÂ protein. It is made up of a number of functionally distinctÂ domainsÂ that can function independently of each other.
There are five major classes of FH due toÂ LDLRÂ mutations :
Class 1Â mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).
Class 2Â mutations prevent proper transport to theÂ Golgi bodyÂ needed for modifications to the receptor.
e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
Class 3Â mutations stop the binding of LDL to the receptor.
e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
Class 4Â mutations inhibit the internalisation of the receptor-ligand complex.
e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; Y residue converted to a C, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
Class 5Â mutations give rise to receptors that cannot recycle properly. This leads to a relatively mildÂ phenotypeÂ as receptors are still present on the cell surface (but all must be newly synthesised).
ApoB, in its ApoB100 form, is the mainÂ apoprotein, or protein part of the lipoprotein particle. Its gene is located on theÂ second chromosomeÂ (2p24-p23) and is between 21.08 and 21.12Â MbÂ long. FH is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. LikeÂ LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia
Mutations in theÂ proprotein convertase subtilisin/kexin type 9Â (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-13"Â The gene is located on theÂ first chromosomeÂ (1p34.1-p32) and encodes a 666 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 theÂ ARHÂ gene, also known asÂ LDLRAP1, were first reported in a family in 1973.Â In contrast to the other causes, 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. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease thanÂ LDLR-heterozygotes but less severe thanÂ LDLR-homozygotes
Signs and symptoms :
High cholesterol levels normally do not cause any symptoms. Cholesterol may be deposited in various places in the body that are visible from the outside, such as in yellowish patches around the eyelids (xanthelasma palpebrarum), the outer margin of theÂ irisÂ (arcus senilis corneae) and in the form of lumps in theÂ tendonsÂ of the hands, elbows, knees and feet, particularly theÂ Achilles tendonÂ (tendon xanthoma)
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Accelerated deposition of cholesterol in the walls ofÂ arteriesÂ leads toÂ atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development ofÂ coronary artery diseaseÂ (atherosclerosis of theÂ coronary arteriesÂ that supply theÂ heart) at a much younger age than would be expected in the general population. This may lead toÂ angina pectorisÂ (chest tightness on exertion) orÂ heart attacks. Less commonly, arteries of theÂ brainÂ are affected; this may lead toÂ transient ischemic attacksÂ (brief episodes of weakness on one side of the body or inability to talk) or occasionallyÂ stroke.Â Peripheral artery occlusive diseaseÂ (obstruction of the arteries of the legs) occurs mainly in people with FH whoÂ smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such asgangrene).
If lipids start infiltrating theÂ aortic valveÂ (theÂ heart valveÂ between theÂ left ventricleÂ and theÂ aorta) or theÂ aortic rootÂ (just above the valve), thickening of these structures may result in a narrow passage calledÂ aortic stenosis.Â Supravalvular aortic stenosis (tightening of the aorta above the level of the aortic valve) can occur in up to half of homozygous patients, whereas heterozygotes are less frequently affected.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid10065027-5"HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid16205026-6"HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid2736820-7"Â Aortic stenosis is characterized byÂ shortness of breath,Â chest painÂ and episodes ofÂ dizzinessÂ orÂ collapse.
Atherosclerosis risk is increased further with age and in those who smoke, haveÂ diabetes,Â high blood pressureÂ and aÂ family historyÂ of cardiovascular disease
Symptoms that may occur include:
Fatty skin deposits called xanthomas over the elbows, knees, buttocks, tendons, and around the cornea of the eye
Cholesterol deposits in the eyelids (xanthelasmas)
Chest pain (angina) or other signs of coronary artery disease; may be present at a young age
Diagnosis , exams and tests .
A physical examination may reveal fatty skin growths called xanthomas and cholesterol deposits in the eye (corneal arcus).
The doctor will ask questions about your personal and family medical history. There may be:
A strong family history of familial hypercholesterolemia or early heart attacks
High levels of LDL in either or both parents
Individuals from families with a strong history of early heart attacks should have blood tests done to determine lipid levels.
Blood tests may show:
High levels of total cholesterol
Greater than 300 mg/dL in adults
Greater than 250 mg/dL in children
High LDL levels
Greater than 170-200 mg/dL in children
Greater than 220 mg/dL in adults
Normal level triglycerides
Other tests that may be done include:
Studies of cells called fibroblasts to see how the body absorbs LDL cholesterol
Genetic test for the defect associated with this condition
CholesterolÂ levels may be determined as part of health screening forÂ health insuranceÂ orÂ occupational health, when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular disease develop, or a family member has been found to have FH. A pattern compatible withÂ hyperlipoproteinemia type IIaÂ on theÂ Fredrickson classificationÂ is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level ofÂ high-density lipoproteinÂ (HDL), and normal level oftriglycerides. The LDL is typically above the 95thÂ percentile, that is, 95% of the healthy population would have a lower LDL level, although patients with ApoB mutations have LDLs below this level in 25% of cases.Â Cholesterol levels can be drastically higher in FH patients who are alsoÂ obese
On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations andÂ ApoBÂ mutations can be performed. Mutations are detected in between 50 and 80% of cases; those without a mutation often have higher triglyceride levels and may in fact have other causes for their high cholesterol, such asÂ combined hyperlipidemiaÂ due toÂ metabolic syndrome
FH needs to be distinguished fromÂ familial combined hyperlipidemiaÂ andÂ polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis.SitosterolemiaÂ andÂ cerebrotendineous xanthomatosisÂ are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations,Â cataracts,Â diarrheaÂ and skeletal abnormalities
The goal of treatment is to reduce the risk of atherosclerotic heart disease. Those who inherit only one copy of the defective gene may respond well to diet changes combined with statin drugs.
The first step is to change what you eat. This is tried for several months before drug therapy is added. Diet changes include reducing total fat intake to less than 30% of the total calories you eat.
You can reduce your saturated fat intake by:
Decreasing amounts of beef, chicken, pork, and lamb
Substituting low-fat dairy products for full-fat ones
Eliminating coconut and palm oils
You can reduce your the amount of cholesterol you eat by eliminating egg yolks and organ meats.
Dietary counseling is often recommended to help people make these adjustments to their eating habits. Weight loss and regular exercise may also aid in lowering cholesterol levels.
See also: Heart disease and diet
If lifestyle changes do not change your cholesterol levels, your doctor may recommend medication. There are several types of drugs available to help lower blood cholesterol levels, and they work in different ways. Some are better at lowering LDL cholesterol, some are good at lowering triglycerides, while others help raise HDL cholesterol.
The most commonly used and effective drugs for treating high LDL cholesterol are called statins. The include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor).
Other cholesterol-lowering medicines include:
Bile acid-sequestering resins
Fibrates (such as gemfibrozil)
Those with more severe forms of this disorder may need a treatment called extracorporeal apheresis. This is the most effective treatment. Blood or plasma is removed from the body. Special filters then remove the extra LDL-cholesterol, and the blood plasma is then returned.
FH is usually treated withÂ statins. Statins act by inhibiting the enzymeÂ hydroxymethylglutaryl CoA reductaseÂ (HMG-CoA-reductase) in the liver. 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 asÂ bile acid sequestrantsÂ (cholestyramineÂ orÂ colestipol),Â nicotinic acidÂ preparations or fibrates.Â Control of other risk factors for cardiovascular disease is required, as risk remains somewhat elevated even when cholesterol levels are controlled. Professional guidelines recommend that the decision to treat an FH patient with statins should not be based on the usual risk prediction tools (such as those derived from theÂ Framingham Heart Study), as they are likely to underestimate the risk of cardiovascular disease; unlike the rest of the population, FH have had high levels of cholesterol since birth, probably increasing their relative risk.Â Prior to the introduction of the statins,Â clofibrateÂ (an older fibrate that often causedÂ gallstones),probucolÂ (especially in large xanthomas) andÂ thyroxineÂ were used to reduce LDL cholesterol levels.
More controversial is the addition ofÂ ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called theÂ intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown.
There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH patients. Rather, evidence of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, an observational study of a large British registry showed that mortality in FH patients had started to improve in the early 1990s, when statins were introduced
Homozygous FH is harder to treat. The LDL receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels.Â If medical therapy is not successful at reducing cholesterol levels,Â LDL apheresisÂ may be used; this filters LDL from the bloodstream in a process reminiscent ofdialysis.Â Very severe cases may be considered for aÂ 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 solidÂ organ transplantÂ (such asÂ rejection,Â infections, orÂ side-effectsÂ of the medication required to suppress rejection).HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-31"Â Other surgical techniques includeÂ partial ileal bypass surgery, in which part of theÂ small bowelÂ is bypassed to decrease the absorption of nutrients and hence cholesterol, andÂ portacaval shunt surgery, in which theÂ portal veinÂ is connected to theÂ vena cavaÂ to allowing blood with nutrients from the intestine to bypass the liver.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid9625405-33"HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid172531-34"
InhibitionÂ of theÂ microsomal triglyceride transfer protein, for example with the investigational drugÂ lomitapide, and infusion ofÂ recombinantÂ humanÂ apolipoprotein A1Â are being explored as medical treatment options.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid10441095-36"Â Gene therapyÂ is a possible future alternative.Â MipomersenÂ is in phase 3 trials
Given that FH is present from birth and atherosclerotic changes may begin early in life,Â it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many doctors prefer to useÂ bile acid sequestrantsÂ andÂ fenofibrateÂ as these are licensed in children.Â Nevertheless, statins seem safe and effective,HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid15265847-41"Â and in older children may be used as in adults.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-Greene-39"
A multidisciplinary expert panel in 2006 advised on early combination therapy with LDL apheresis, statins and cholesterol absorption inhibitors in children with homozygous FH at the highest risk .
Possible complications :
Heart attack at an early age
A diet low in cholesterol and saturated fat and rich in unsaturated fat diet may help to control LDL levels.
Counseling is an option for those who have a family history of this condition, particularly if both parents carry the defective gene
In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms.Â Homozygous FH occurs in about 1:1,000,000.HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-Durrington-2"
LDLRÂ mutations are more common in certain populations, presumably because of a genetic phenomenon known as theÂ founder effect-they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. TheÂ Afrikaner,Â French Canadians,Â LebaneseÂ Christians, andÂ FinnsÂ have high rates of specific mutations that make FH particularly common in these groups.Â APOBÂ mutations are more common in Central Europe