Familial hypercholesterolemia
Encyclopedia
Familial hypercholesterolemia (abbreviated FH, also spelled familial hypercholesterolaemia) is a genetic disorder
characterized by high cholesterol levels
, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease
. Many patients have mutations in the LDLR gene that encodes the LDL receptor
protein
, 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. Patients who have one abnormal copy (are heterozygous
) of the LDLR gene may have premature cardiovascular disease 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, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.
Heterozygous FH is normally treated with statin
s, bile acid sequestrant
s or other hypolipidemic agent
s that lower cholesterol levels. New cases are generally offered genetic counseling
. Homozygous FH often does not 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
.
), the outer margin of the iris
(arcus senilis corneae
) and in the form of lumps in the tendon
s of the hands, elbows, knees and feet, particularly the Achilles tendon
(tendon xanthoma
).
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 pain or tightness on exertion) or heart attacks. Less commonly, arteries of the brain
are affected; this may lead to transient ischemic attack
s (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 as gangrene
).
Atherosclerosis risk is increased further with age and in those who smoke, have diabetes
, high blood pressure
and a family history
of cardiovascular disease.
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 of triglyceride
s. The LDL is typically above the 75th percentile
, that is, 75% of the healthy population would have a lower LDL level. Cholesterol levels can be drastically higher in FH patients who are also obese
.
due to metabolic syndrome
.
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.
1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9
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.
gene
is located on the short arm of chromosome 19
(19p13.1-13.3). It comprises 18 exon
s and spans 45 kb, and the protein gene product contains 839 amino acid
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:
, 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.
(PCSK9) gene were linked to autosomal dominant (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.
, 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. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.
LDL cholesterol normally circulates in the body for 2.5 days, and subsequently binds to the LDL receptor on the liver cells
, undergoes endocytosis
, and is digested. LDL is removed, and synthesis of cholesterol
by the liver is suppressed in the HMG-CoA reductase pathway. 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, FH patients may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends of 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 an FH patient 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 gene (G20210A) increases the risk of cardiovascular events in patients 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 patients with a specific genotype
of the angiotensin-converting enzyme
(ACE).
.
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
s (cholestyramine
or colestipol
), nicotinic acid 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 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. Prior to the introduction of the statins, clofibrate
(an older fibrate that often caused gallstone
s), 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.
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.
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
(such as rejection
, infection
s, or side-effects
of the medication required to suppress rejection). 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.
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. Gene therapy
is a possible future alternative. Mipomersen
is in phase 3 trials.
as these are licensed in children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults.
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.
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 Canadian
s, Lebanese
Christian
s, and Finns have high rates of specific mutations that make FH particularly common in these groups. APOB mutations are more common in Central Europe.
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 FH patients. 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
for their discovery of the LDL receptor
and its impact on lipoprotein metabolism.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
characterized by high cholesterol levels
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. Many patients have mutations in the LDLR gene that encodes the LDL receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, which normally removes LDL from the circulation, or apolipoprotein B
Apolipoprotein B
Apolipoprotein B is the primary apolipoprotein of low-density lipoproteins , which is responsible for carrying cholesterol to tissues. While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein component and is absolutely required for its formation...
(ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
) of the LDLR gene may have premature cardiovascular disease 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, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.
Heterozygous FH is normally treated with statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s, bile acid sequestrant
Bile acid sequestrant
The bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic...
s or other hypolipidemic agent
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
s that lower cholesterol levels. New cases are generally offered genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis
LDL apheresis
In medicine, LDL apheresis is a form of apheresis, resembling dialysis, to eliminate the cholesterol-containing particle low-density lipoprotein from the bloodstream.-Uses:...
(removal of LDL in a method similar to dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
) and occasionally liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
.
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 palpebrarumXanthelasma
Xanthelasma is a sharply demarcated yellowish deposit of cholesterol underneath the skin, usually on or around the eyelids. Although not harmful or painful, these minor growths may be disfiguring and can be removed...
), the outer margin of the iris
Iris (anatomy)
The iris is a thin, circular structure in the eye, responsible for controlling the diameter and size of the pupils and thus the amount of light reaching the retina. "Eye color" is the color of the iris, which can be green, blue, or brown. In some cases it can be hazel , grey, violet, or even pink...
(arcus senilis corneae
Arcus senilis
Arcus senilis is a white or gray, opaque ring in the corneal margin , or white ring around the iris. It is present at birth, but then fades; however, it is quite commonly present in the elderly...
) and in the form of lumps in the tendon
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...
s of the hands, elbows, knees and feet, particularly the Achilles tendon
Achilles tendon
The Achilles tendon , also known as the calcaneal tendon or the tendo calcaneus, is a tendon of the posterior leg. It serves to attach the plantaris, gastrocnemius and soleus muscles to the calcaneus bone.- Anatomy :The Achilles is the tendonous extension of 3 muscles in the lower leg:...
(tendon xanthoma
Xanthoma
A xanthoma , from Greek xanthos, ξανθος, "yellow", is a deposition of yellowish cholesterol-rich material in tendons or other body parts in various disease states...
).
Cardiovascular disease
Accelerated deposition of cholesterol in the walls of arteriesArtery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
leads to atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, 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
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest pain or tightness on exertion) or heart attacks. Less commonly, arteries of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
are affected; this may lead to transient ischemic attack
Transient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
s (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. Peripheral artery occlusive disease
Peripheral artery occlusive disease
Peripheral vascular disease , commonly referred to as peripheral arterial disease or peripheral artery occlusive disease , refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain. PVD can result from atherosclerosis, inflammatory processes leading to...
(obstruction of the arteries of the legs) occurs mainly in people with FH who smoke
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication
Intermittent claudication
Intermittent claudication is a clinical diagnosis given for muscle pain , classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by a short period of rest.Claudication derives from the Latin verb claudicare, "to limp".-Signs:One of the hallmarks of arterial...
) and problems due to a decreased blood supply to the feet (such as gangrene
Gangrene
Gangrene is a serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies . This may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The primary cause of gangrene is reduced blood...
).
Atherosclerosis risk is increased further with age and in those who smoke, have diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and a family history
Family history (medicine)
In medicine, a family history consists of information about disorders from which the direct blood relatives of the patient have suffered. Genealogy typically includes very little of the medical history of the family, but the medical history could be considered a specific subset of the total history...
of cardiovascular disease.
Lipid measurements
CholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels may be determined as part of health screening for health insurance
Health insurance
Health insurance is insurance against the risk of incurring medical expenses among individuals. By estimating the overall risk of health care expenses among a targeted group, an insurer can develop a routine finance structure, such as a monthly premium or payroll tax, to ensure that money is...
or occupational health
Occupational safety and health
Occupational safety and health is a cross-disciplinary area concerned with protecting the safety, health and welfare of people engaged in work or employment. The goal of all occupational safety and health programs is to foster a safe work environment...
, 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 of triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s. The LDL is typically above the 75th percentile
Percentile
In statistics, a percentile is the value of a variable below which a certain percent of observations fall. For example, the 20th percentile is the value below which 20 percent of the observations may be found...
, that is, 75% of the healthy population would have a lower LDL level. Cholesterol levels can be drastically higher in FH patients who are also obese
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
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 hyperlipidemiaCombined hyperlipidemia
In medicine, combined hyperlipidemia is a commonly occurring form of hypercholesterolemia characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL...
due to metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
.
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. SitosterolemiaSitosterolemia
Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal...
and cerebrotendineous xanthomatosis
Cerebrotendineous xanthomatosis
Cerebrotendineous xanthomatosis or cerebrotendinous xanthomatosis , also called cerebral cholesterosis, is an autosomal recessive form of xanthomatosis.-Characteristics:...
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
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and skeletal abnormalities.
Genetics
The most common genetic defects in FH are LDLR mutations (prevalencePrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9
PCSK9
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in humans is encoded by the PCSK9 gene with orthologs found across many species.- Function :...
mutations (less than 1 in 2500) and LDLRAP1
LDLRAP1
Low density lipoprotein receptor adapter protein 1 is a protein that in humans is encoded by the LDLRAP1 gene.-Interactions:LDLRAP1 has been shown to interact with AP2B1 and LRP2.-Further reading:...
. The related disease sitosterolemia
Sitosterolemia
Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal...
, which has many similarities with FH and also features cholesterol accumulation in tissues, is due to ABCG5
ABCG5
ATP-binding cassette sub-family G member 5 is a protein that in humans is encoded by the ABCG5 gene.- Function :The protein encoded by this gene is a member of the superfamily of ATP-binding cassette transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes...
and ABCG8
ABCG8
ATP-binding cassette sub-family G member 8 is a protein that in humans is encoded by the ABCG8 gene.- External links :...
mutations.
LDL receptor
The LDL receptorLDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is located on the short arm of chromosome 19
Chromosome 19 (human)
125px|rightChromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active...
(19p13.1-13.3). It comprises 18 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s and spans 45 kb, and the protein gene product contains 839 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
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 reticulumEndoplasmic reticulumThe endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
to the Golgi apparatusGolgi apparatusThe Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
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 clathrinClathrinClathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
-coated pits for receptor-mediated endocytosisReceptor-mediated endocytosisReceptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...
. - Class V: LDLR is not recycled back to the cell surface.
ApoB
ApoB, in its ApoB100 form, is the main apoproteinApoprotein
Apoprotein can refer to:*Apoenzyme, the protein part of an enzyme without its characteristic prosthetic group.*Apolipoprotein, a lipid-binding protein that is a constituent of the plasma lipoprotein....
, or protein part of the lipoprotein particle. Its gene is located on the second chromosome
Chromosome 2 (human)
Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second largest human chromosome, spanning more than 237 million base pairs and representing almost 8% of the total DNA in cells.Identifying genes on each...
(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.
PCSK9
Mutations in the proprotein convertase subtilisin/kexin type 9PCSK9
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in humans is encoded by the PCSK9 gene with orthologs found across many species.- Function :...
(PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
(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 LDLRAP1LDLRAP1
Low density lipoprotein receptor adapter protein 1 is a protein that in humans is encoded by the LDLRAP1 gene.-Interactions:LDLRAP1 has been shown to interact with AP2B1 and LRP2.-Further reading:...
, 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. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.
Pathophysiology
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
, undergoes endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, and is digested. LDL is removed, and synthesis of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
by the liver is suppressed in the HMG-CoA reductase pathway. 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, FH patients may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends of 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 an FH patient 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 gene (G20210A) increases the risk of cardiovascular events in patients with FH. Several studies found that a high level of lipoprotein(a)
Lipoprotein(a)
Lipoprotein is a lipoprotein subclass. Studies have identified Lp as a putative risk factor for atherosclerotic diseases such as coronary heart disease and stroke....
was an additional risk factor for ischemic heart disease. The risk was also found to be higher in patients with a specific genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
of the angiotensin-converting enzyme
Angiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
(ACE).
Screening
Although case finding among family members of patients with known FH is a cost-effective approach, other strategies such as universal screening at the age of 16 have also been suggested. The latter approach may however be less cost-effective in the short term. Screening at an age lower than 16 would lead to an unacceptably high rate of false positivesType I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
.
Heterozygous FH
FH is usually treated with statinStatin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s. Statins act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase
HMG-CoA reductase
HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
(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
Bile acid sequestrant
The bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic...
s (cholestyramine
Cholestyramine
Cholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
or colestipol
Colestipol
Colestipol is a bile acid sequestrant.It works in the gut trapping bile salts, and preventing them from being reabsorbed.This leads todecreased enterohepatic recirculation of bile salts,increased synthesis of new bile salts by the liver,...
), nicotinic acid 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 an FH patient with statins should not be based on the usual risk prediction tools (such as those derived from the Framingham Heart Study
Framingham Heart Study
The Framingham Heart Study is a long-term, ongoing cardiovascular study on residents of the town of Framingham, Massachusetts. The study began in 1948 with 5,209 adult subjects from Framingham, and is now on its third generation of participants...
), 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
Clofibrate
Clofibrate is a fibrate. It is a lipid lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL...
(an older fibrate that often caused gallstone
Gallstone
A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...
s), probucol
Probucol
Probucol is an anti-hyperlipidemic drug initially developed in the treatment of coronary artery disease.However, clinical trials were stopped after it was found that may lower HDL in patients with a previous history of heart disease....
(especially in large xanthomas) and thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
were used to reduce LDL cholesterol levels.
More controversial is the addition of ezetimibe
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...
, 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
Intima-media thickness
Intima-media thickness , also called intimal medial thickness, is a measurement of the thickness of artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound catheters, see IVUS, to both detect the presence and to track the progression of atherosclerotic disease in...
. 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
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. If medical therapy is not successful at reducing cholesterol levels, LDL apheresisLDL apheresis
In medicine, LDL apheresis is a form of apheresis, resembling dialysis, to eliminate the cholesterol-containing particle low-density lipoprotein from the bloodstream.-Uses:...
may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
. 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 transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
(such as rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
, infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s, or side-effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
of the medication required to suppress rejection). Other surgical techniques include partial ileal bypass surgery
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 treat a number of hyperlipidemias including familial...
, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery
Portacaval shunt
A portacaval shunt is a treatment for high blood pressure in the liver. A connection is made between the portal vein, which supplies 75% of the liver's blood, and the inferior vena cava, the vein that drains blood from the lower two-thirds of the body...
, in which the portal vein is connected to the vena cava to allowing blood with nutrients from the intestine to bypass the liver.
Inhibition of the microsomal triglyceride transfer protein
Microsomal triglyceride transfer protein
Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP gene.Apoprotein B48 on chylomicra and Apoprotein B100 on LDL, IDL, and VLDL are important for MTP binding.-Interactive pathway map:...
, for example with the investigational drug lomitapide, and infusion of recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
human apolipoprotein A1
Apolipoprotein A1
Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism.Apolipoprotein A-I is the major protein component of high density lipoprotein in plasma. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly...
are being explored as medical treatment options. Gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
is a possible future alternative. Mipomersen
Mipomersen
Mipomersen is a cholesterol-reducing drug candidate. It is an antisense therapeutic that targets the messenger RNA for apolipoprotein B...
is in phase 3 trials.
In 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 doctors prefer to use bile acid sequestrants and fenofibrateFenofibrate
Fenofibrate is a drug of the fibrate class. Fenofibrate was developed by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. In 2009 Solvay Pharmaceutical was acquired by Abbott Laboratories. It is mainly used to...
as these are licensed in children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults.
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.
Epidemiology
In most populations studied, heterozygous FH occurs in about 1:500 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
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, using existing theoretical work by those such as Sewall...
—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The Afrikaner
Afrikaner
Afrikaners are an ethnic group in Southern Africa descended from almost equal numbers of Dutch, French and German settlers whose native tongue is Afrikaans: a Germanic language which derives primarily from 17th century Dutch, and a variety of other languages.-Related ethno-linguistic groups:The...
, French Canadian
French Canadian
French Canadian or Francophone Canadian, , generally refers to the descendents of French colonists who arrived in New France in the 17th and 18th centuries...
s, Lebanese
Lebanon
Lebanon , officially the Republic of LebanonRepublic of Lebanon is the most common term used by Lebanese government agencies. The term Lebanese Republic, a literal translation of the official Arabic and French names that is not used in today's world. Arabic is the most common language spoken among...
Christian
Christian
A Christian is a person who adheres to Christianity, an Abrahamic, monotheistic religion based on the life and teachings of Jesus of Nazareth as recorded in the Canonical gospels and the letters of the New Testament...
s, and Finns 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 C. 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. GoldsteinJoseph L. Goldstein
Joseph L. Goldstein from Kingstree, South Carolina is a Nobel Prize winning biochemist and geneticist, and a pioneer in the study of cholesterol metabolism.-Biography:...
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 FH patients. 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
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for their discovery of the LDL receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
and its impact on lipoprotein metabolism.
See also
- Primary hyperlipoproteinemia
- Familial hypertriglyceridemiaFamilial hypertriglyceridemiaFamilial hypertriglyceridemia is an autosomal dominant condition occurring in approximately 1% of the population. Triglyceride levels, but not cholesterol, are elevated as a result of excess hepatic production of VLDL or heterozygous LPL deficiency. Unlike familial hypercholesterolemia, there is no...
- Lipoprotein lipase deficiencyLipoprotein lipase deficiencyLipoprotein lipase deficiency is caused by a mutation in the gene which codes lipoprotein lipase....
- Familial apoprotein CII deficiency
External links
- MEDPED (Make Early Diagnosis to Prevent Early Deaths) - US screening program based at the University of Utah, Salt Lake City
- H·E·A·R·T UK - Hypercholesterolemia charity based in the United Kingdom
- Database of all known LDLR mutations (maintained by Leiden University Medical Centre, hosted by University College LondonUniversity College LondonUniversity College London is a public research university located in London, United Kingdom and the oldest and largest constituent college of the federal University of London...
) - Familial hypercholesterolaemia - report of a WHO consultation - reproduction of WHOWorld Health OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
report WHO/HGN/FH/CONS/98.7 (1998) on the diagnosis and treatment of FH