Familial hypercholesterolemia (abbreviated
FH, also spelled
familial hypercholesterolaemia) is a
genetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions...
characterized by
high cholesterol levelsHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease...
, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early
cardiovascular diseaseCardiovascular disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels ....
. Many patients have mutations in the
LDLR gene that encodes the
LDL receptorThe Low-Density Lipoprotein Receptor is a mosaic protein 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. The receptor also recognizes the apoE protein found...
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
, which normally removes LDL from the circulation, or
apolipoprotein BApolipoprotein 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
heterozygousZygosity is the similarity of genes for a trait in an organism. If both genes are the same, the organism is homozygous for the trait. If both genes 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
statinThe statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...
s,
bile acid sequestrantThe 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...
s or other
hypolipidemic agentHypolipidemic 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 counselingGenetic counseling 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 in order to prevent, avoid...
. Homozygous FH often does not respond to medical therapy and may require other treatments, including
LDL apheresisIn 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
dialysisIn medicine, dialysis is primarily used to provide an artificial replacement for lost kidney function due to renal failure...
) and occasionally
liver transplantationLiver 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 the donor organ is placed in the same anatomic location as the original...
.
Signs and symptoms
Physical signs
High cholesterol levels normally do not cause any symptoms. Cholesterol may be deposited in various places in the body that are visible from the outside, such as in yellowish patches around the eyelids (
xanthelasma palpebrarumXanthelasma is a sharply demarcated yellowish collection 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 plural is "xanthelasmata". They are common in people of Asian origin and...
), the outer margin of the
irisThe iris is a membrane in the eye, responsible for controlling the diameter and size of the pupil and 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...
(
arcus senilis corneaeArcus senilis is a white or gray opaque ring in the corneal margin present at birth or appearing later in life and becoming quite frequent after age 50.-Alternative names:...
) and in the form of lumps in the
tendonA 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 fascia as they are all made of collagen except that ligaments join one bone to another bone, and fascia connect muscles to other...
s of the hands, elbows, knees and feet, particularly the
Achilles tendonThe Achilles tendon , also known as the calcaneal tendon or the tendo calcaneus, is a tendon of the posterior leg. It serves to attach the gastrocnemius and soleus muscles to the calcaneus bone.-Anatomy:The Achilles is the tendonous extension of three muscles in the lower leg: gastrocnemius,...
(
tendon xanthomaA xanthoma is a deposition of yellowish cholesterol-rich material in tendons and other body parts in various disease states.- External links :...
).
Cardiovascular disease
Accelerated deposition of cholesterol in the walls of
arteriesArteries are blood vessels that carry blood away from the heart. All arteries, with the exception of the pulmonary and umbilical arteries, carry oxygenated blood.The circulatory system is extremely important for sustaining life...
leads to
atherosclerosisAtherosclerosis is the condition in which an artery wall thickens as the result of a build-up 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
heartThe heart is a muscular organ found in all vertebrates 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 tightness on exertion) or heart attacks. Less commonly, arteries of the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
are affected; this may lead to
transient ischemic attackA transient ischemic attack is caused by the changes in the blood supply to a particular area of the brain, resulting in brief neurologic dysfunction that persists, by definition, for less than 24 hours; if symptoms persist longer, then it is categorized as a...
s (brief episodes of weakness on one side of the body or inability to talk) or occasionally
strokeA stroke 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 thrombosis or embolism or due to a hemorrhage...
.
Peripheral artery occlusive diseasePeripheral vascular disease , also known as peripheral artery disease or peripheral artery occlusive disease , includes all diseases caused by the obstruction of large arteries in the arms and legs. PVD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or...
(obstruction of the arteries of the legs) occurs mainly in people with FH who
smoke Tobacco smoking is the practice where tobacco is burned and the vapors either tasted or inhaled. The practice began as early as 5000–3000 BC. Many civilizations burnt incense during religious rituals, which was later adopted for pleasure or as a social tool. Tobacco was introduced to the old world...
; this can cause pain in the calf muscles during walking that resolves with rest (
intermittent claudicationIntermittent claudication is a clinical diagnosis given for muscle pain , classically calf muscle, which occurs during exercise and is relieved by a short period of rest....
) and problems due to a decreased blood supply to the feet (such as
gangreneGangrene is a complication of necrosis or cell death characterized by the decay of body tissues, which become black and malodorous. It is caused by infection or ischemia, such as from thrombosis. It is usually the result of critically insufficient blood supply and is often associated with...
).
If lipids start infiltrating the
aortic valveThe aortic valve is one of the valves of the heart. It lies between the left ventricle and the aorta.-Function and physiology:During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle rises above the pressure in the aorta, the aortic valve opens,...
(the
heart valveIn anatomy, the heart valves maintain the unidirectional flow of blood in the heart by opening and closing depending on the difference in pressure on each side...
between the
left ventricleThe left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
and the
aortaThe aorta is the largest artery in the body, originating from the left ventricle of the heart and bringing oxygenated blood to all parts of the body in the systemic circulation....
) or the aortic root (just above the valve), thickening of these structures may result in a narrow passage called aortic stenosis. Supravalvular aortic stenosis (tightening of the aorta above the level of the aortic valve) can occur in up to half of homozygous patients, whereas heterozygotes are less frequently affected. Aortic stenosis is characterized by shortness of breath,
chest painIn medicine, chest pain is a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the chest pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Cardiovascular:*...
and episodes of
dizzinessDizziness refers to an impairment in spatial perception and stability. It is considered imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or for a non-specific feeling such as giddiness or foolishness....
or
collapseCollapse is a sudden and often unannounced loss of postural tone , often but not necessarily accompanied by loss of consciousness.If the episode was accompanied by a loss of consciousness, the term syncope is used. The main causes are cardiac , seizures or a psychological cause...
.
Atherosclerosis risk is increased further with age and in those who smoke, have
diabetesDiabetes mellitus —often referred to simply as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy...
,
high blood pressureHypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...
and a
family historyIn medicine, a family history consists of information about disorders that a patient's direct blood relatives have suffered from. 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 a...
of cardiovascular disease.
Lipid measurements
CholesterolCholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...
levels may be determined as part of health screening for
health insuranceHealth insurance is insurance that pays for medical expenses. It is sometimes used more broadly to include insurance covering disability or long-term nursing or custodial care needs. It may be provided through a government-sponsored social insurance program, or from private insurance companies...
or
occupational healthOccupational 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
triglycerideis a glyceride in which the glycerol is esterified with three fatty acids. It is the main constituent of vegetable oil and animal fats.- Chemical structure :...
s. The LDL is typically above the 95th
percentileA percentile is the value of a variable below which a certain percent of observations fall. So the 20th percentile is the value below which 20 percent of the observations may be found...
, that is, 95% of the healthy population would have a lower LDL level, although patients with ApoB mutations have LDLs below this level in 25% of cases. Cholesterol levels can be drastically higher in FH patients who are also
obeseObesity 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 hyperlipidemiaIn 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 syndromeMetabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It affects one in five people, 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 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 xanthomatosisCerebrotendineous xanthomatosis is a form of xanthomatosis.- Causes :It is autosomal recessive, and associated with the CYP27A1 gene on chromosome 2....
are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, cataracts,
diarrheaIn medicine, diarrhea , also spelled diarrhoea , is the condition of having frequent loose or liquid bowel movements. Acute diarrhea is a common cause of death in developing countries and the second most common cause of infant deaths worldwide...
and skeletal abnormalities.
Genetics
The most common genetic defects in FH are
LDLR mutations (
prevalenceIn epidemiology, the prevalence of a disease in a statistical population is defined as the total number of cases of the disease 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. It is used as an estimate of how...
1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000),
PCSK9Proprotein 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
LDLRAP1Low 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
sitosterolemiaSitosterolemia 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
ABCG5ATP-binding cassette sub-family G member 5 is a protein that in humans is encoded by the ABCG5 gene....
and
ABCG8ATP-binding cassette sub-family G member 8 is a protein that in humans is encoded by the ABCG8 gene....
mutations.
LDL receptor
The
LDL receptorThe Low-Density Lipoprotein Receptor is a mosaic protein 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. The receptor also recognizes the apoE protein found...
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
is located on the short arm of
chromosome 19125px|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
exonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule after either portions of a precursor RNA have been removed by cis-splicing or by two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA or...
s and spans 45 kb, and the protein gene product contains 839
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
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 a 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 is an eukaryotic organelle that forms an interconnected network of tubules, vesicles, and cisternae within cells. The lacey membranes of the endoplasmic reticulum were first seen by Keith R. Porter, Albert Claude, and Ernest F...
to the Golgi apparatusThe Golgi apparatus is an organelle found in most eukaryotic cells...
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 which 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 which is composed of three clathrin heavy chains and three light chains...
-coated pits for receptor-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 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 chromosomeChromosome 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 9Proprotein 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 chromosomeChromosome 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
LDLRAP1Low 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
LDL cholesterol normally circulates in the body for 2.5 days, and subsequently binds to the LDL receptor on the
liver cellsHepatocytes make up 70-80% of the cytoplasmic mass of the liver.These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous...
, undergoes
endocytosisEndocytosis is the process by which cells absorb molecules from outside the cell by engulfing it with their cell membrane. 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 membrane or cell membrane...
, and is digested. LDL is removed, and synthesis of
cholesterolCholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...
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 apolipoprotein A was an additional risk factor for ischemic heart disease. The risk was also found to be higher in patients with a specific
genotypeThe genotype is the genetic constitution of a cell, an organism, or an individual usually with reference to a specific character under consideration...
of the
angiotensin-converting enzymeAngiotensin 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 positivesIn statistics, the terms type I error and type II error are used to describe possible errors made in a statistical decision process...
.
Heterozygous FH
FH is usually treated with
statinThe statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...
s. Statins act by inhibiting the enzyme
hydroxymethylglutaryl CoA reductaseHMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins...
(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 sequestrantThe 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...
s (
cholestyramineCholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. The resin is a strong anion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind...
or
colestipolColestipol is a bile acid sequestrant....
), 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 StudyThe Framingham Heart Study is a cardiovascular study based in 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,
clofibrateClofibrate 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
gallstoneIn medicine, gallstones are crystalline bodies formed within the body by accretion or concretion of normal or abnormal bile components.Gallstones can occur anywhere within the biliary tree, including the gallbladder and the common bile duct...
s),
probucolProbucol is an anti-hyperlipidemic drug initially developed in the treatment of coronary artery disease.However, clinical trials were stopped after it was found that it causes long QT syndrome in patients....
(especially in large xanthomas) and
thyroxineThyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones is the major hormone secreted by the follicular cells of the thyroid gland. Thyroxine is synthesized via the iodination and covalent bonding of the phenyl portions of tyrosine residues found in an initial peptide,...
were used to reduce LDL cholesterol levels.
More controversial is the addition of
ezetimibeEzetimibe is an anti-hyperlipidemic medication that is used to lower cholesterol levels. 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 Ezetimibe is an...
, 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 thicknessIntima-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 apheresisIn 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
dialysisIn medicine, dialysis is primarily used to provide an artificial replacement for lost kidney function due to 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 transplantOrgan transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site. Organ donors can be living or deceased...
(such as
rejectionTransplant rejection occurs when a transplanted organ or tissue is not accepted by the body of the transplant recipient. This is explained by the concept that the immune system of the recipient attacks the transplanted organ or tissue...
,
infectionAn infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply, usually at the expense of the host. The infecting organism, or pathogen, interferes with the normal functioning of the...
s, or
side-effectsIn 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, and may result from an unsuitable or incorrect dosage or...
of the medication required to suppress rejection). Other surgical techniques include
partial ileal bypass surgeryPartial 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 surgeryA 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 proteinMicrosomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP gene.-Further reading:...
, for example with the investigational drug
AEGR-733AEGR-773 is an investigational drug for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals....
, and infusion of
recombinantRecombinant may refer to :* A recombinant organism - an organism that contains a different combination of alleles from either of its parents. See Recombination.* Recombinant DNA - a form of artificial DNA...
human
apolipoprotein A1Apolipoprotein A-I, also known as APOA1, is a human protein with a specific role in lipid metabolism.It is the major protein component of high density lipoprotein in plasma. The protein promotes cholesterol efflux from tissues to the liver for excretion...
are being explored as medical treatment options.
Gene therapyGene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although controversial, Gene Therapy can also be used for human genetic enhancement changing one's...
is a possible future alternative.
Pediatric patients
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 is a drug of the fibrate class. Fenofibrate was discovered by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. It is mainly used to reduce cholesterol levels in patients at risk of cardiovascular...
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 effectIn 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 1952, 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
AfrikanerAfrikaners are White Afrikaans speakers who have been established in Southern Africa since the 17th century. They are mainly of northwestern European descent , but their native tongue is Afrikaans, a purported close relative of Dutch...
,
French CanadianFrench Canadian refers to a nation or ethnic group of French descent that originated in Canada during the period of French colonization beginning in the 17th century. They constitute the main French-speaking population of Canada...
s,
LebaneseLebanon , officially the Republic of Lebanon
[Republic of Lebanon is the most common term used by Lebanese government agencies...]
ChristianA Christian is a person who adheres to Christianity, an Abrahamic, monotheistic, religion based on the life and teachings of Jesus of Nazareth, who Christians believe was the Messiah prophesied in the Old Testament/Hebrew Bible, and the Son of God.The term "Christian" is also used adjectivally to...
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 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 MedicineThe Nobel Prize in Physiology or Medicine is awarded once a year by the Swedish Karolinska Institute. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in Physics, Chemistry, Literature, Peace, and Physiology or Medicine...
for their discovery of cholesterol and lipoprotein metabolism.
See also
- Primary hyperlipoproteinemia
- Familial hypertriglyceridemia
Familial hypertriglyceridemia is a condition in which there is an accumulation of dietary lipids that may result in eruptive xanthomas and atherosclerotic heart disease.- See also :* Primary hyperlipoproteinemia* Familial apoprotein CII deficiency...
- Lipoprotein lipase deficiency
Lipoprotein lipase deficiency , is caused by a mutation in the gene which codes lipoprotein lipase.- External links :* *...
- Familial apoprotein CII deficiency
Familial apoprotein CII deficiency is a condition caused by a lack of lipoprotein lipase activator.- See also :* Primary hyperlipoproteinemia* Lipoprotein lipase deficiency* Skin lesion...
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 London
University College London is a British university institution and a constituent college of the University of London, based primarily in Bloomsbury, London...
)
- Familial hypercholesterolaemia - report of a WHO consultation - reproduction of WHO
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health...
report WHO/HGN/FH/CONS/98.7 (1998) on the diagnosis and treatment of FH