HOME

TheInfoList



OR:

Familial hypercholesterolemia (FH) is a
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
characterized by high cholesterol levels, specifically very high levels of
low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densi ...
(LDL cholesterol), in the blood and early
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
. The most common mutations diminish the number of functional LDL receptors in the liver. Since the underlying body 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 as dietary modification and
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...
tablets). Nevertheless, treatment (including higher statin doses) is usually effective. FH is classified as a type 2 familial
dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...
. There are five types of familial dyslipidemia (not including subtypes), and each are classified from both the altered lipid profile and by the genetic abnormality. 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. About 1 in 100 to 200 people have mutations in the ''LDLR'' gene that encodes the
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor t ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, which normally removes LDL from the circulation, or
apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...
(ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. People who have one abnormal copy (are
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...
) of the ''LDLR'' gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (being ''homozygous'') may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
pattern, occurring in 1:250 people in most countries; homozygous FH is much rarer, occurring in 1 in 300,000 people. Heterozygous FH is normally treated with statins,
bile acid sequestrant The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption fr ...
s, or other lipid-lowering agents that lower cholesterol levels. New cases are generally offered
genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
. Homozygous FH often does not respond to medical therapy and may require other treatments, including
LDL apheresis In medicine, LDL apheresis is a form of apheresis, resembling dialysis, to eliminate the cholesterol-containing particle low-density lipoprotein (LDL) from the bloodstream. Uses It is used in diseases featuring high LDL, such as the rare ''homo ...
(removal of LDL in a method similar to dialysis) and occasionally
liver transplantation Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...
.


Signs and symptoms


Physical signs

High cholesterol levels normally do not cause any symptoms. Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as
xanthelasma palpebrarum Xanthelasma is a sharply demarcated yellowish deposit of cholesterol underneath the skin. It usually occurs on or around the eyelids (''xanthelasma palpebrarum'', abbreviated XP). While they are neither harmful to the skin nor Pain, painful, these ...
), the outer margin of the iris (known as arcus senilis corneae), and in the
tendon A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
s of the hands, elbows, knees and feet, particularly the
Achilles tendon The Achilles tendon or heel cord, also known as the calcaneal tendon, is a tendon at the back of the lower leg, and is the thickest in the human body. It serves to attach the plantaris, gastrocnemius (calf) and soleus muscles to the calcaneus ...
(known as a tendon xanthoma).


Cardiovascular disease

Accelerated deposition of cholesterol in the walls of
arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
leads to
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
, the underlying cause of cardiovascular disease. The most common problem in FH is the development of
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
(atherosclerosis of the
coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ ...
that supply the
heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...
) at a much younger age than would be expected in the general population. This may lead to
angina pectoris Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of obstru ...
(chest pain or tightness on exertion) or
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
s. Less commonly, arteries of the
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
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 A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who
smoke Smoke is a suspension of airborne particulates and gases emitted when a material undergoes combustion or pyrolysis, together with the quantity of air that is entrained or otherwise mixed into the mass. It is commonly an unwanted by-produc ...
; this can cause pain in the calf muscles during walking that resolves with rest (
intermittent claudication Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion (ache, cramp, numbness or sense of fatigue), classically in the calf muscle, which occurs during exercise, such as walking, an ...
) and problems due to a decreased blood supply to the feet (such as
gangrene Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the gan ...
). Atherosclerosis risk is increased further with age and in those who smoke, have
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
,
high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
and a
family history Genealogy () is the study of families, family history, and the tracing of their lineages. Genealogists use oral interviews, historical records, genetic analysis, and other records to obtain information about a family and to demonstrate kin ...
of cardiovascular disease.


Diagnosis

Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments. Physical examination findings can help a physician make the diagnosis of FH. Tendon xanthomas are seen in 20-40% of individuals with FH and are
pathognomonic Pathognomonic (rare synonym ''pathognomic'') is a term, often used in medicine, that means "characteristic for a particular disease". A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doub ...
for the condition. A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, but are non-specific findings.


Lipid measurements

Cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
levels may be determined as part of health screening for
health insurance Health insurance or medical insurance (also known as medical aid in South Africa) is a type of insurance that covers the whole or a part of the risk of a person incurring medical expenses. As with other types of insurance, risk is shared among m ...
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 High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
(HDL), and normal level of
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...
s. Total cholesterol levels of 350–550 mg/dL are typical of heterozygous FH while total cholesterol levels of 650–1000 mg/dL are typical of homozygous FH. The LDL is typically above the 75th
percentile In statistics, a ''k''-th percentile (percentile score or centile) is a score ''below which'' a given percentage ''k'' of scores in its frequency distribution falls (exclusive definition) or a score ''at or below which'' a given percentage fall ...
, that is, 75% of the healthy population would have a lower LDL level. Cholesterol levels can be drastically higher in people with FH who are also
obese Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
.


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 Combined hyperlipidemia (or -aemia) is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electropho ...
due to
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...
.


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 A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble ...
,
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
and skeletal abnormalities.


Genetics

The most common genetic defects in FH are ''LDLR'' mutations (
prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
1 in 250, depending on the population), ApoB mutations (prevalence 1 in 1000), ''
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
'' mutations (less than 1 in 2500) and '' LDLRAP1''. The related disease sitosterolemia, which has many similarities with FH and also features cholesterol accumulation in tissues, is due to '' ABCG5'' and '' ABCG8'' mutations.


LDL receptor

The
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor t ...
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
is located on the short arm of
chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromos ...
(19p13.1-13.3). It comprises 18
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s and spans 45 kb, and the protein gene product contains 839
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s 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 defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known. There are five major classes of FH due to ''LDLR'' mutations: *Class I: LDLR is not synthesized at all. *Class II: LDLR is not properly transported from the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
to the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
for expression on the cell surface. *Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R. *Class IV: LDLR bound to LDL does not properly cluster in
clathrin Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When ...
-coated pits for
receptor-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane ( invagination). Th ...
(pathway step 2). *Class V: LDLR is not recycled back to the cell surface (pathway step 5).


Apolipoprotein B

Apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...
, in its ApoB100 form, is the main
apolipoprotein Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. The lipid components of lipoproteins ...
, 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 often associated with the mutation of R3500Q, which causes replacement of
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
by
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
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.


PCSK9

Mutations in the proprotein convertase subtilisin/kexin type 9 (''PCSK9'') gene were linked to
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
(i.e. requiring only one abnormal copy) FH in a 2003 report. 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.


LDLRAP1

Abnormalities in the ''ARH'' gene, also known as '' LDLRAP1'', were first reported in a family in 1973. 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. People with autosomal recessive hypercholesterolemia tend to have more severe disease than ''LDLR''-heterozygotes but less severe than ''LDLR''-homozygotes.


Pathophysiology

LDL cholesterol normally circulates in the body for 2.5 days, and subsequently the
apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...
portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion. This process results in the removal of LDL from the circulatory system. Synthesis of
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
by the liver is suppressed in the
HMG-CoA reductase pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopente ...
. In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. In mutations of ''ApoB'', reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known how the mutation causes LDL receptor dysfunction in mutations of ''PCSK9'' and ''ARH''. 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 still 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. Some studies of FH cohorts suggest that additional risk factors are generally at play when a person develops atherosclerosis. In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the
prothrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
gene (G20210A) increases the risk of cardiovascular events in people with FH. Several studies found that a high level of lipoprotein(a) was an additional risk factor for ischemic heart disease. The risk was also found to be higher in people with a specific
genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
of the
angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconst ...
(ACE).


Screening

Cholesterol screening and genetic testing among family members of people with known FH is cost-effective. Other strategies such as
universal screening Screening, in medicine, is a strategy used to look for as-yet-unrecognised conditions or risk markers. This testing can be applied to individuals or to a whole population. The people tested may not exhibit any signs or symptoms of a disease, or t ...
at the age of 16 were suggested in 2001. The latter approach may however be less cost-effective in the short term. Screening at an age lower than 16 was thought likely to lead to an unacceptably high rate of false positives. A 2007
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
found 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." "The use of total cholesterol alone may best discriminate between people with and without FH between the ages of 1 to 9 years." Screening of toddlers has been suggested, and results of a trial on 10,000 one-year-olds were published in 2016. Work was needed to find whether screening was cost-effective, and acceptable to families. Genetic counseling can help assist in genetic testing following a positive cholesterol screen for FH.


Treatment


Heterozygous FH

FH is usually treated with
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...
s. 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 sequestrant The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption fr ...
s (
cholestyramine Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, wh ...
or colestipol),
nicotinic acid Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a varie ...
preparations or fibrates. 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 a person with FH with statins should not be based on the usual risk prediction tools (such as those derived from the
Framingham Heart Study The Framingham Heart Study is a long-term, ongoing cardiovascular cohort study of residents of the city of Framingham, Massachusetts. The study began in 1948 with 5,209 adult subjects from Framingham, and is now on its third generation of partic ...
), 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. Prior to the introduction of the statins, clofibrate (an older fibrate that often caused
gallstone A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mi ...
s), probucol (especially in large xanthomas) and
thyroxine File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 25 ...
were used to reduce LDL cholesterol levels. More controversial is the addition of
ezetimibe Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken by mouth. It is also ...
, 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. There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH. 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, a 1999 observational study of a large British registry showed that mortality in people with FH had started to improve in the early 1990s when statins were introduced. A
cohort study A cohort study is a particular form of longitudinal study that samples a cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or graduation), performing ...
suggested that treatment of FH with statins leads to a 48% reduction in death from coronary heart disease to a point where people are no more likely to die of coronary heart disease than the general population. However, if the person already had coronary heart disease the reduction was 25%. The results emphasize the importance of early identification of FH and treatment with statins.
Alirocumab Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to ...
and
evolocumab Evolocumab (trade name Repatha) is a monoclonal antibody medication designed for the treatment of hyperlipidemia. Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a p ...
, both monoclonal antibodies against
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
, are specifically indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, who require additional lowering of LDL cholesterol. More recently
Inclisiran Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interferin ...
has been approved for the treatment of HeFH


Homozygous FH

Homozygous FH is harder to treat. 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. If medical therapy is not successful at reducing cholesterol levels,
LDL apheresis In medicine, LDL apheresis is a form of apheresis, resembling dialysis, to eliminate the cholesterol-containing particle low-density lipoprotein (LDL) from the bloodstream. Uses It is used in diseases featuring high LDL, such as the rare ''homo ...
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 Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpor ...
(such as rejection,
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
s, or side-effects of the medication required to suppress rejection). Other surgical techniques include
partial ileal bypass surgery Partial ileal bypass surgery is a surgical procedure which involves shortening the ileum to shorten the total small intestinal length. First introduced in 1962 by Professor Henry Buchwald of the University of Minnesota, the procedure is used to ...
, 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 The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approx ...
is connected to the
vena cava In anatomy, the venae cavae (; singular: vena cava ; ) are two large veins (great vessels) that return deoxygenated blood from the body into the heart. In humans they are the superior vena cava and the inferior vena cava, and both empty into th ...
to allow blood with nutrients from the intestine to bypass the liver.
Lomitapide Lomitapide , sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in cli ...
, an inhibitor of the
microsomal triglyceride transfer protein Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the ''MTTP'' gene. MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) co ...
, was approved by the US FDA in December 2012 as an orphan drug for the treatment of homozygous familial hypercholesterolemia. In January 2013, The US FDA also approved
mipomersen Mipomersen ( INN; trade name Kynamro) is a drug used to treat homozygous familial hypercholesterolemia and is administered by subcutaneous injection. There is a serious risk of liver damage from this drug and it can only be prescribed in the co ...
, which inhibits the action of the gene
apolipoprotein B Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene. Function Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...
, for the treatment of homozygous familial hypercholesterolemia.
Gene therapy Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...
is a possible future alternative. Evinacumab, a monoclonal antibody inhibiting angiopoietin-like protein 3, was approved in 2021 for
adjunct therapy Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used i ...
.


Children

Given that FH is present from birth and atherosclerotic changes may begin early in life, it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many physicians prefer to use bile acid sequestrants and
fenofibrate Fenofibrate (sold under the brand names ''Tricor'', ''Fenobrat'' etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of c ...
as these are licensed in children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults. An 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.


Epidemiology

The global prevalence of FH is approximately 10 million people. In most populations studied, heterozygous FH occurs in about 1:250 people, but not all develop symptoms. Homozygous FH occurs in about 1:1,000,000. ''LDLR'' mutations are more common in certain populations, presumably because of a genetic phenomenon known as the ''
founder effect In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, us ...
''—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The
Afrikaner Afrikaners () are a South African ethnic group descended from predominantly Dutch settlers first arriving at the Cape of Good Hope in the 17th and 18th centuries.Entry: Cape Colony. ''Encyclopædia Britannica Volume 4 Part 2: Brain to Cast ...
,
French Canadian French Canadians (referred to as Canadiens mainly before the twentieth century; french: Canadiens français, ; feminine form: , ), or Franco-Canadians (french: Franco-Canadiens), refers to either an ethnic group who trace their ancestry to Fre ...
s, Lebanese
Christians Christians () are people who follow or adhere to Christianity, a monotheistic Abrahamic religion based on the life and teachings of Jesus Christ. The words ''Christ'' and ''Christian'' derive from the Koine Greek title ''Christós'' (Χρ� ...
, and
Finns Finns or Finnish people ( fi, suomalaiset, ) are a Baltic Finnic ethnic group native to Finland. Finns are traditionally divided into smaller regional groups that span several countries adjacent to Finland, both those who are native to these ...
have high rates of specific mutations that make FH particularly common in these groups. ''APOB'' mutations are more common in Central Europe.


History

The Norwegian physician Dr Carl Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas. Initially, they found increased activity of HMG-CoA reductase, but studies showed that this did not explain the very abnormal cholesterol levels in people with FH. 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. Subsequently, numerous mutations in the protein were directly identified by sequencing. They later won the 1985
Nobel Prize in Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, according ...
for their discovery of the
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor t ...
and its impact on lipoprotein metabolism.


See also

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


References


External links


MedicinePlus: Familial Hypercholesterolemia
{{DEFAULTSORT:Familial Hypercholesterolemia Lipid metabolism disorders Autosomal dominant disorders