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Can I Have Familial Hypercholesterolemia if Neither of My Parents Have High Cholesterol

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Genetic disorder characterized by high cholesterol levels

Medical condition

Familial hypercholesterolemia
Other names Familial hypercholesterolaemia
Xanthelasma palpebrarum.jpg
Xanthelasma palpebrarum, yellow patches consisting of cholesterol deposits above the eyelids. These are more common in people with FH.
Specialty Endocrinology

Familial hypercholesterolemia (FH) is a genetic disorder characterized by loftier cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early on cardiovascular illness. The most common mutations diminish the number of functional LDL receptors in the liver.[ commendation needed ] Since the underlying torso biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH (such equally dietary modification and statin tablets). Nevertheless, treatment (including higher statin doses) is usually effective.

FH is classified as a type 2 familial dyslipidemia.[1] At that place are five types of familial dyslipidemia (non including subtypes), and each are classified from both the altered lipid profile and past the genetic aberration. For example, high LDL (often due to LDL receptor defect) is type 2. Others include defects in chylomicron metabolism, triglyceride metabolism, and metabolism of other cholesterol-containing particles, such as VLDL and IDL.

Most 1 in 100 to 200 people accept mutations in the LDLR gene that encodes the LDL receptor poly peptide, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare.[2] People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (beingness homozygous) may cause severe cardiovascular disease in babyhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal ascendant design, occurring in ane:250 people in most countries;[iii] homozygous FH is much rarer, occurring in 1 in 300,000 people.[ commendation needed ]

Heterozygous FH is ordinarily treated with statins, bile acid sequestrants, or other lipid-lowering agents that lower cholesterol levels. New cases are by and large offered genetic counseling. Homozygous FH frequently does non respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.[4]

Signs and symptoms [edit]

Physical signs [edit]

High cholesterol levels normally do not cause whatsoever symptoms. Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known equally xanthelasma palpebrarum), the outer margin of the iris (known as arcus senilis corneae), and in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon (known as a tendon xanthoma).[4] [5]

Cardiovascular disease [edit]

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 evolution of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would exist expected in the general population. This may lead to angina pectoris (breast pain or tightness on exertion) or heart attacks. Less unremarkably, arteries of the encephalon are afflicted; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the torso or disability to talk) or occasionally stroke. Peripheral avenue occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this tin can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased claret supply to the feet (such as gangrene).[6] Atherosclerosis hazard is increased further with historic period and in those who smoke, accept diabetes, high blood force per unit area and a family unit history of cardiovascular disease.[4] [7]

Diagnosis [edit]

Criteria for diagnosis of probable heterozygous FH

(98% specificity)[eight]

1st degree relative general population
age cholesterol mg/dL mmol/L mg/dL mmol/L
< 18 full > 220 > 5.seven > 270 > seven.0
LDL-C > 155 > four.0 > 200 > 5.ii
20–29 total > 240 > half-dozen.2 > 290 > 7.5
LDL-C > 170 > four.iv > 220 > 5.vii
xxx–39 total > 270 > 7.0 > 340 > eight.8
LDL-C > 190 > five.0 > 240 > six.2
≥ 40 full > 290 > 7.5 > 360 > ix.3
LDL-C > 205 > 5.iii > 260 > 6.vii
First-caste relatives are parents, offspring, brothers, and sisters

Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments.[ix] Concrete test findings tin can assist a doctor brand the diagnosis of FH. Tendon xanthomas are seen in 20-40% of individuals with FH and are pathognomonic for the condition.[ix] A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, merely are non-specific findings.[9]

Lipid measurements [edit]

Cholesterol levels may be determined equally part of health screening for health insurance or occupational wellness, when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular illness develop, or a family member has been found to accept FH. A pattern compatible with hyperlipoproteinemia type IIa on the Fredrickson classification is typically constitute: raised level of full cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of loftier-density lipoprotein (HDL), and normal level of triglycerides. Total cholesterol levels of 350–550 mg/dL are typical of heterozygous FH while full cholesterol levels of 650–thou mg/dL are typical of homozygous FH.[9] The LDL is typically above the 75th percentile, that is, 75% of the healthy population would accept a lower LDL level.[four] Cholesterol levels can exist drastically higher in people with FH who are too obese.[six]

Mutation analysis [edit]

On the ground of the isolated loftier LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and ApoB mutations tin 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 every bit combined hyperlipidemia due to metabolic syndrome.[ten]

Differential diagnosis [edit]

FH needs to exist 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 weather condition that tin likewise present with premature atherosclerosis and xanthomas. The latter condition tin can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities.[11]

Genetics [edit]

The most common genetic defects in FH are LDLR mutations (prevalence 1 in 250, depending on the population),[three] ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than ane in 2500) and LDLRAP1. The related affliction sitosterolemia, which has many similarities with FH and also features cholesterol aggregating in tissues, is due to ABCG5 and ABCG8 mutations.[4]

LDL receptor [edit]

Schematic representation of the LDL receptor protein.

The LDL receptor gene is located on the curt arm of chromosome 19 (19p13.1-xiii.3).[ix] It comprises 18 exons and spans 45 kb, and the protein gene production contains 839 amino acids in mature form. A single aberrant copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in virtually 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 action of LDL receptor (LDLR). Homozygotes accept LDLR action of less than 2%, while heterozygotes take defective LDL processing with receptor activity being two–25%, depending on the nature of the mutation. Over 1000 different mutations are known.[4]

There are five major classes of FH due to LDLR mutations:[12]

  • Form I: LDLR is not synthesized at all.
  • Class 2: LDLR is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface.
  • Form Iii: LDLR does non properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R.
  • Class 4: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis (pathway step 2).
  • Class V: LDLR is not recycled dorsum to the jail cell surface (pathway step 5).

Apolipoprotein B [edit]

Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is 46.2 kb long. FH is frequently 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 poly peptide that normally binds with the LDL receptor, and binding is reduced as a effect of the mutation. Like LDLR, the number of aberrant copies determines the severity of the hypercholesterolemia.[4] [13]

PCSK9 [edit]

Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring simply one abnormal re-create) FH in a 2003 report.[4] [14] The factor is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid poly peptide that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly past reducing the number of LDL receptors on liver cells.[xv]

LDLRAP1 [edit]

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, only it seems to play a office in the relation between the LDL receptor and clathrin-coated pits. People with autosomal recessive hypercholesterolemia tend to accept more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.[iv]

Pathophysiology [edit]

LDL cholesterol normally circulates in the body for two.5 days, and later the apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion.[9] This process results in the removal of LDL from the circulatory organisation. Synthesis of cholesterol past the liver is suppressed in the HMG-CoA reductase pathway.[17] In FH, LDL receptor function is reduced or absent-minded,[nine] and LDL circulates for an average duration of iv.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins.[6] In mutations of ApoB, reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. Information technology is not known how the mutation causes LDL receptor dysfunction in mutations of PCSK9 and ARH.[4]

Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors all the same expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.[four]

Some studies of FH cohorts suggest that additional hazard factors are generally at play when a person develops atherosclerosis.[xviii] [19] In add-on to the classic risk factors such as smoking, high blood force per unit area, and diabetes, genetic studies have shown that a mutual abnormality in the prothrombin gene (G20210A) increases the adventure of cardiovascular events in people with FH.[20] Several studies establish that a high level of lipoprotein(a) was an additional run a risk factor for ischemic heart disease.[21] [22] The risk was also found to be college in people with a specific genotype of the angiotensin-converting enzyme (ACE).[23]

Screening [edit]

Cholesterol screening and genetic testing among family members of people with known FH is cost-constructive.[24] Other strategies such as universal screening at the age of sixteen were suggested in 2001.[25] [26] The latter arroyo may all the same exist less cost-effective in the short term.[27] Screening at an age lower than 16 was thought probable to lead to an unacceptably loftier rate of imitation positives.[6]

A 2007 meta-analysis constitute that "the proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously."[28] "The use of total cholesterol lonely may best discriminate between people with and without FH between the ages of ane to 9 years."[29] [28]

Screening of toddlers has been suggested, and results of a trial on 10,000 one-year-olds were published in 2016. Piece of work was needed to find whether screening was cost-effective, and acceptable to families.[30] [31] Genetic counseling can help assist in genetic testing following a positive cholesterol screen for FH.[32]

Treatment [edit]

Heterozygous FH [edit]

FH is usually treated with statins.[ix] Statins deed 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 together-on therapy with other drugs is required, such as bile acrid sequestrants (cholestyramine or colestipol), nicotinic acid preparations or fibrates.[33] [four] Command of other risk factors for cardiovascular disease is required, as hazard remains somewhat elevated even when cholesterol levels are controlled. Professional person guidelines recommend that the decision to treat a person with FH with statins should not be based on the usual take chances prediction tools (such as those derived from the Framingham Heart Written report), as they are likely to underestimate the risk of cardiovascular illness; unlike the rest of the population, FH have had high levels of cholesterol since nascency, probably increasing their relative gamble.[34] 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 than controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to better a marker of atherosclerosis called the intima-media thickness. Whether this ways that ezetimibe is of no overall benefit in FH is unknown.[35]

There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH. Rather, testify of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, a 1999 observational study of a large British registry showed that bloodshed in people with FH had started to ameliorate in the early on 1990s when statins were introduced.[36]

A cohort report suggested that treatment of FH with statins leads to a 48% reduction in death from coronary heart disease to a betoken where people are no more likely to die of coronary centre disease than the general population. Withal, if the person already had coronary heart affliction the reduction was 25%. The results emphasize the importance of early identification of FH and handling with statins.[37]

Alirocumab and evolocumab, both monoclonal antibodies against PCSK9, are specifically indicated as offshoot to nutrition and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, who crave additional lowering of LDL cholesterol.[38] On 22 Dec 2021 USFDA approved new drug containing Inclisiran equally new treatment option for familial hypercholesterolemia information technology is to be given in combination with maximally tolerated statin therapy.[39]

Homozygous FH [edit]

Homozygous FH is harder to care for. The LDL (Low Density Lipoprotein) 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.[40] If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a procedure reminiscent of dialysis.[iv] Very astringent cases may be considered for a liver transplant; this provides a liver with normally functional LDL receptors, and leads to rapid comeback of the cholesterol levels, but at the run a risk of complications from any solid organ transplant (such equally rejection, infections, or side-effects of the medication required to suppress rejection).[41] [42] Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to subtract the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allow blood with nutrients from the intestine to featherbed the liver.[43] [44] [45]

Lomitapide, an inhibitor of the microsomal triglyceride transfer protein,[46] was approved past the US FDA in December 2012 as an orphan drug for the treatment of homozygous familial hypercholesterolemia.[47] In January 2013, The United states FDA besides approved mipomersen, which inhibits the action of the gene apolipoprotein B, for the treatment of homozygous familial hypercholesterolemia.[48] [49] [50] Gene therapy is a possible time to come alternative.[51]

Evinacumab, monoclonal antibody inhibiting angiopoietin-similar poly peptide three, was approved in 2021 for adjunct therapy.[52]

Children [edit]

Given that FH is present from birth and atherosclerotic changes may brainstorm early in life,[53] it is sometimes necessary to care for adolescents or even teenagers with agents that were originally developed for adults. Due to rubber concerns, many physicians prefer to apply bile acrid sequestrants and fenofibrate as these are licensed in children.[54] Nevertheless, statins seem rubber and effective,[55] [56] and in older children may exist used as in adults.[6] [54]

An proficient console in 2006 advised on early combination therapy with LDL apheresis, statins, and cholesterol absorption inhibitors in children with homozygous FH at the highest risk.[57]

Epidemiology [edit]

The global prevalence of FH is approximately 10 1000000 people.[9] In about populations studied, heterozygous FH occurs in about one:250 people, but not all develop symptoms.[iii] Homozygous FH occurs in near 1:1,000,000.[four] [6]

LDLR mutations are more common in certain populations, presumably considering of a genetic phenomenon known as the founder effect—they were founded by a minor 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 specially common in these groups. APOB mutations are more mutual in Central Europe.[4]

History [edit]

The Norwegian medico Dr Carl Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938.[58] In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brownish of Dallas, Texas. Initially, they found increased activity of HMG-CoA reductase, just studies showed that this did non explain the very abnormal cholesterol levels in people with FH.[59] The focus shifted to the binding of LDL to its receptor, and effects of impaired binding on metabolism; this proved to be the underlying mechanism for FH.[60] Later, numerous mutations in the poly peptide were directly identified by sequencing.[12] They subsequently won the 1985 Nobel Prize in Medicine for their discovery of the LDL receptor and its impact on lipoprotein metabolism.[61]

See as well [edit]

  • Primary hyperlipoproteinemia
  • Familial hypertriglyceridemia
  • Lipoprotein lipase deficiency
  • Familial apoprotein CII deficiency
  • Akira Endo, discoverer of the first statin

References [edit]

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External links [edit]

  • MedicinePlus: Familial Hypercholesterolemia

martinezpeartrut1958.blogspot.com

Source: https://en.wikipedia.org/wiki/Familial_hypercholesterolemia

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