Fh Familial Hypercholesterolemia Analysis Biology Essay

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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.

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 cholesterol is called "bad" cholesterol, because elevated levels of LDL cholesterol are associated with an increased risk of coronary 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 called atherosclerosis.

HDL cholesterol 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 cholesterol 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 of lipoproteins, the particles that carry cholesterol in the bloodstream. This may be related to 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 are LDLR mutations (prevalence 1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in 2500) and LDLRAP1

The common genes have defects in familial hypercholesterolemia are :





1.LDL receptor .

The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, 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. 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 .

Structure :

The gene coding the LDL receptor is split into 18 exons. Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum 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 chimeric protein. It is made up of a number of functionally distinct domains that can function independently of each other.

There are five major classes of FH due to LDLR mutations :

Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).

Class 2 mutations prevent proper transport to the Golgi body 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 3 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 4 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 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).


ApoB, in its ApoB100 form, is the main apoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is between 21.08 and 21.12 Mb 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. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia


Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report.[1]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-13"[14] The gene is located on the first chromosome (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 the ARH gene, also known as LDLRAP1, were first reported in a family in 1973.[16] 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 than LDLR-heterozygotes but less severe than LDLR-homozygotes

Signs and symptoms :

Physical signs

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 the iris (arcus senilis corneae) and in the form of lumps in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon (tendon xanthoma)

Cardiovascular disease

Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest tightness on exertion) or heart attacks. Less commonly, arteries of the brain are affected; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who 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).[3]

If lipids start infiltrating the aortic valve (the heart valve between the left ventricle and the aorta) or the aortic root (just above the valve), thickening of these structures may result in a narrow passage called aortic stenosis.[4] 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.[5]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid10065027-5"[6]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid16205026-6"[7]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid2736820-7"[8] Aortic stenosis is characterized by shortness of breath, chest pain and episodes of dizziness or collapse.

Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history 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

Lipid measurements

Cholesterol levels may be determined as part of health screening for health insurance or 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 with hyperlipoproteinemia type IIa on the Fredrickson classification is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of high-density lipoprotein (HDL), and normal level oftriglycerides. The LDL is typically above the 95th 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.[1] Cholesterol levels can be drastically higher in FH patients who are also obese

Mutation analysis

On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and ApoB 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 as combined hyperlipidemia due to metabolic syndrome

Differential diagnosis

FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis.Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities

Treatment .

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)

Nicotinic acid

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.

Heterozygous FH

FH is usually treated with statins. Statins act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (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 as bile acid sequestrants (cholestyramine or colestipol), nicotinic acid preparations or fibrates.[1] 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 the 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.[27] Prior to the introduction of the statins, clofibrate (an older fibrate that often caused gallstones),probucol (especially in large xanthomas) and thyroxine were used to reduce LDL cholesterol levels.

More controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown.[28]

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

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.[30] 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 ofdialysis.[1] 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).[31]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-31"[32] Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allowing blood with nutrients from the intestine to bypass the liver.[33]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid9625405-33"[34]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid172531-34"[35]

Inhibition of the microsomal triglyceride transfer protein, for example with the investigational drug lomitapide, and infusion of recombinant human apolipoprotein A1 are being explored as medical treatment options.[36]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid10441095-36"[37] Gene therapy is a possible future alternative.[38] Mipomersen is in phase 3 trials

Pediatric patients

Given that FH is present from birth and atherosclerotic changes may begin early in life,[39] 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 use bile acid sequestrants and fenofibrate as these are licensed in children.[40] Nevertheless, statins seem safe and effective,[41]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-pmid15265847-41"[42] and in older children may be used as in adults.[3]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-Greene-39"[40]

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

Heart disease

Prevention :

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

Epidmiology :

In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms.[1] Homozygous FH occurs in about 1:1,000,000.[1]HYPERLINK "http://en.wikipedia.org/wiki/Familial_hypercholesterolemia#cite_note-Durrington-2"[3]

LDLR mutations are more common in certain populations, presumably because of a genetic phenomenon known as the founder effect-they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The Afrikaner, French Canadians, Lebanese Christians, and Finns have high rates of specific mutations that make FH particularly common in these groups. APOB mutations are more common in Central Europe