NORD gratefully acknowledges Joshua W. Knowles, MD, PhD, Attending Physician, Stanford Center for Inherited Cardiovascular Disease and Chief Medical Officer, The FH Foundation, Karen Greendale, MA, CGC, Consultant, The FH Foundation, and Mitchel Pariani, MS, CGC, Genetic Counselor, Stanford Center for Inherited Cardiovascular Disease, for assistance in the preparation of this report.
SummaryFamilial hypercholesterolemia (FH) is a diagnosis which refers to individuals with very significantly elevated low-density lipoprotein (LDL) cholesterol (LDL-C) or "bad cholesterol". In heterozygous familial hypercholesterolemia (HeFH), an individual inherits a mutation (alteration) for FH from one (affected) parent. In homozygous familial hypercholesterolemia (HoFH), an individual inherits a causal FH mutation from both parents. For the purposes of this report, "FH" will refer to HeFH unless otherwise stated. FH is one of the most common genetic diseases and affects at least 1 in 500 individuals. This may be an underestimate as recent genetic studies indicate that FH may be as common as 1 in 250 in European Caucasian populations. If DNA testing is performed, most (60-80%) will be found to have a mutation in one of three relevant genes. Others may express these clinical findings for other reasons or may carry a mutation in a gene or genes that have yet to be discovered. FH is characterized by very high levels of LDL-C, as well as of total cholesterol. The condition greatly increases the risk of hardening of the arteries (atherosclerosis), which can lead to heart attacks, strokes and other vascular conditions. Individuals with FH have a 20-fold increased risk for coronary heart disease (CHD). Untreated men have a 50% risk of a nonfatal or fatal coronary event by age 50 years; untreated women have a 30% risk by age 60 years. If one or more other risk factors for CHD are present, especially cigarette smoking or diabetes mellitus, the risk of developing symptomatic CHD is even higher. FH is treatable and the associated cardiovascular disease is largely preventable with early and intensive treatment, using statins, additional drugs, and other means. Family members of an affected individual found through "cascade screening" or "family tracing" who have not yet exhibited symptoms and who are appropriately treated are likely to live a normal lifespan. HoFH is very rare (~ 1 in 250,000 to 1 in 1 million). LDL-C levels are usually, though not always, > 400 mg/dl. Severe vascular disease including CHD and aortic stenosis are often seen by the teenage years. Without very aggressive treatment including LDL-C apheresis and HoFH specific medications, mortality is common before age 30.
IntroductionIn 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the mutations in the low-density lipoprotein receptor gene (LDLR) that interfered with its function. Normally functioning receptors lower the blood levels of LDL-C by taking up the lipoproteins that carry LDL-C in the liver. Mutations in this gene cause a decrease either in the number or function of the receptors, resulting in the extreme LDL-C elevations seen in FH. Goldstein and Brown became the first investigators to identify a mutation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Their pioneering work and the subsequent studies of LDL-C metabolism in FH patients greatly contributed to our knowledge about the link between cholesterol and heart disease and led to the development of numerous therapeutic agents that benefit a very large number of individuals with high cholesterol. Since that time, other genes causing FH such as the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been identified (see below). Importantly, there is a great deal of evidence showing that early diagnosis and intensive treatment can prevent illness and death due to FH.
Heterozygous Familial Hypercholesterolemia
People with FH have very high levels of LDL-C from birth. In children, LDL-C levels are usually > 160 mg/dl and in adults they are usually > 190 mg/dL, which can lead, if untreated, to CHD, cerebrovascular disease, peripheral vascular disease and/or other serious conditions.
Most common is CHD due to cholesterol build-up in the arteries supplying the heart, which can result in chest pain or discomfort (angina), heart attack (myocardial infarction) or sudden death. People with FH have an approximately 20-fold increased risk for CHD.
Less common are cerebrovascular disease, peripheral vascular disease and aortic aneurysm. Cerebrovascular disease may occur due to cholesterol build-up in the arteries supplying the brain, which may cause stroke or transient ischemic attack (TIA).
Peripheral vascular disease is due to cholesterol build-up in the arteries supplying the legs which may cause pain when walking that is relieved by rest (claudication) and at its most severe, pain at rest that can result in amputation of the affected limb.
Aortic rupture (aortic dissection) can be a result of atherosclerotic stiffening of the aorta which causes it to become fragile and may lead to rupture, causing catastrophic bleeding and often death.
Conditions Other Than Vascular
Xanthomas: Xanthomas are firm nodules caused by cholesterol buildup as a result of the very high levels of LDL-C. The most common sites are the Achilles tendon and the tendons on top of the hands. Achilles tendon xanthomas may cause tendonitis, an inflammation of the tendon that may tear or rupture. Tendon xanthomas are seen in 30 – 50% of individuals with HeFH and in a higher percentage of those with HoFH.
Xanthelesmas: Xanthesmas are cholesterol deposits on, above or under the eyelids often seen in patients with FH. They may also be seen in individuals with normal cholesterol levels, particularly as they age.
Corneal arcus: A white, grey or blue opaque ring around the edge of the cornea in the eye, often seen in patients with FH. Since corneal arcus is common in African Americans with normal cholesterol levels and becomes increasingly common in the general population with age, it is only diagnostic in younger individuals, particularly in those under age 45.
Homozygous Familial Hypercholesterolemia
Individuals with HoFH exhibit extremely high LDL-C levels, usually above 400 mg/dL. They usually have xanthomas by early childhood. Planar xanthomas affecting the skin on the hands, elbows, buttocks and knees in a young child are diagnostic for this condition. Corneal arcus surrounding the entire inside edge of the cornea is often present. Most individuals with HoFH experience severe CHD by their mid-20’s. Young children may die of a major coronary event if not aggressively treated. Narrowing of the heart valve leading to the aorta (aortic stenosis) often occurs, which may make it necessary to replace the aortic valve. Very aggressive therapy is needed to reduce the likelihood of vascular events. Most affected people will require LDL apheresis and/or medications specifically approved by the FDA for HoFH (lomitapide or mipomersen).
Often the other medications that are the mainstay of treatment for HeFH (such as statins) are relatively ineffective in HoFH. This is because the mechanism of action of statins normally “triggers” the liver to express additional LDL receptors. In the most severe cases of HoFH, the LDL receptors are completely inactive which makes this response futile. Statins can be effective in individuals with HoFH if there is some residual LDL-R activity.
FH is known as a “co-dominant” disorder because there is a “dose effect” so that HoFH is more severe than HeFH.
HeFH occurs when a child inherits a nonfunctional copy of one of their genes from an affected parent. The risk of passing the nonfunctional gene from the affected parent to a child is 50% in each pregnancy regardless of the sex of the child. An abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected child, but new mutations appear to be very rare.
Individuals with HoFH have inherited a mutated gene from each parent; so each parent has HeFH. Parents of a child with HoFH have a 25% risk in each pregnancy to have a child with HoFH, and a 50% chance of having a child with HeFH. The remaining 25% will inherit a normal gene from each parent. The risk is the same for males and females and prenatal testing is possible.
When one parent has HoFH and the other has two normal genes, the risk that their children will have HeFH is 100%.
Specific Mutations Which Cause FH
An LDL receptor mutation is the cause of approximately 90% of cases of HeFH. Since the original mutation discovered by Goldstein and Brown, over 1600 other mutations in the same gene have been identified. An adequate number of functioning LDL receptors are needed to remove cholesterol from the bloodstream.
A mutation in APOB is responsible for approximately 10% of FH cases; this mutation is seen most commonly in those of European Caucasian ancestry. Apolipoprotein B-100 is a protein that binds to LDL receptors, which enables uptake of lipoproteins by the liver and reduces the cholesterol level in the blood. Mutations in APOB lead to faulty uptake and increased cholesterol level.
PCSK9 is responsible for only a small percentage of FH cases. The normal PCSK9 gene codes for an enzyme that breaks down the cholesterol receptors after they have done their job. A mutation in this gene is unlike most mutations, which cause dysfunction of the affected gene. The PCSK9 mutation increases the gene’s function, leading to too few remaining LDL receptors and thus an increase in the LDL cholesterol level.
In the US and most other countries where studies have been done, 1 in 250 to 500 people has FH, making it one of the most common genetic diseases. Studies suggest that only 1 – 10% of affected individuals in the US know that they have the disease, although many may know that their cholesterol levels are high or very high. Small subpopulations around the world have a higher incidence, such as Lebanese Christians (1/85), Afrikaners in South Africa (1/72 – 1/100), French Canadians (1/270), and Ashkenazi Jews originating from Lithuania (1/67).
The frequency of HoFH across populations is estimated to be 1 in 1/160,000 to 1 in 1 million. HoFH is more likely to occur in countries where the prevalence of HeFH is very high, especially those where consanguinity (marriage of relatives) is common.
FH should be considered in an untreated child with LDL-C above 160 mg/dL and in an untreated adult with LDL-C above 190 mg/dL, or in those with a personal and/or family history of early CHD, physical signs such as those described under “Symptoms” or a relative known to have FH.
FH can be diagnosed using DNA testing or by utilizing one of three well-accepted sets of criteria — Simon Broome (UK), Dutch Lipid Clinic Network (Netherlands), or MEDPED (US). DNA testing confirms the diagnosis and is considered the “gold standard”, but is not always necessary or feasible. DNA testing should definitely be considered when it’s not clear whether an individual is affected or not, and is very helpful for testing family members.
Once an individual is diagnosed with FH (either with or without the use of DNA testing) a process called “cascade screening”, “cascade testing” or “family tracing” ( testing of close relatives, in a step-wise fashion) is recommended to identify those with FH before symptoms appear, so that early and intensive treatment can be initiated and disease and death prevented. If a mutation is identified, risk in the patient’s first degree relatives (parent, sibling, child) and when appropriate, more distant relatives, can be assessed via DNA testing by tracing the altered gene through the family. If DNA testing is not performed, another version of cascade screening can be implemented using cholesterol testing. Cascade screening by either means has been shown to be effective in finding patients with FH who were not being appropriately treated. A genetic counselor can help a family through this process.
Cascade screening has been shown in numerous studies to be cost-effective and has been recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK. The Office of Public Health Genomics at the Centers for Disease Control and Prevention considers cascade screening of relatives of those with FH a “Tier 1 application” whic. means that there is good evidence that implementation will prevent disease and save lives.
HoFH is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL-C; LDL-C is usually greater than 400 mg/dL. The parents are “obligate heterozygotes” who are considered to have HeFH until proven otherwise.
Clinical Testing and Workup
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with FH, the following evaluations are recommended in adults and children:
Pre-treatment lipid values
Lipoprotein(a) levels when possible
Exclusion of concurrent illnesses (kidney disease, acute myocardial infarction, infection) that can affect lipid values
Lipid panel including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides
Consultation with a lipid specialist or clinician with expertise in FH
Medical genetics (genetic counseling) consultation
In children. Noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) are recommended in some guidelines to help inform treatment decisions.
Treatment of FH is focused on reducing the LDL-C levels in order to decrease the risk for atherosclerotic heart disease.
Adults with FH
Dietary changes such as restricting saturated fat and eliminating trans-fats have significant cholesterol-lowering impact. Decreasing dietary cholesterol and increasing soluble fiber are also helpful. The diet should primarily be made up of vegetables, whole fruit and grains, nuts and legumes. Seafood, lean poultry and low fat dairy products are the preferred sources of animal protein. Weight loss and aerobic exercise have modest effects on cholesterol level bu. can help to lower blood pressure and blood sugar levels and thus cardiovascular disease risk.
Cholesterol lowering medication
For adults, treatment should begin as soon as possible after diagnosis. Almost all will require cholesterol-lowering drug therapy. A firm diagnosis of FH should prompt more aggressive treatment than would otherwise be undertaken in a patient with “garden variety” high cholesterol. Some guidelines state that the untreated cholesterol level should be reduced by at least 50%; others suggest that less than 100 mg/dL is the goal. Goals may be even more stringent when additional risk factors such as diabetes or atherosclerosis are present. Patients with FH should be referred to a lipidologist if these goals cannot be reached in the primary care setting.
Pharmacotherapy should initially be statin-based, followed by addition of other drugs if the targeted LDL-C level is not achieved with statins and lifestyle changes. Preference should be given to one of the higher potency statins (atorvastatin or rosuvastatin) used at the maximal dose.
Muscle injury (rhabdomyolysis) is the major risk of statins but is very rare, seen in approximately 1/10,000 of those taking these drugs. Damage to the liver does not occur at a higher rate than in people not taking a statin. However, myalgia (muscle pain) is a relatively common side effect occuring in 10-15% of patients. Mild myalgia with or without mild creatine kinase elevations (less than 5 times the upper limit of normal) are not necessarily a reason to discontinue statins or other cholesterol lowering medications.
Other drugs such as ezetimibe (Zetia), bile acid sequestrants (colesevelam, Welcol), and/or nicotinic acid (Niaspan, Slo-Niacin) may be necessary. PCSK9 inhibitors are currently being tested in late stage clinical trials (see below).
In patients who cannot achieve the desired LDL-C level, a procedure called LDL apheresis (similar to dialysis for kidney disease) may be necessary. LDL apheresis is indicated if the LDL-C level (on maximally tolerated medical therapy) is > 300 mg/dl in individuals without known CHD or > 200 mg/dl in those with known CHD.
Children with HeFH
Parents should discuss with the pediatrician when to initiate treatment in a child with FH. Treatment should be considered when LDL-C level is greater than 190 mg/dl, or greater than 160 md/dl with at least two other risk factors present. The National Lipid Association guidelines recommend referral to a lipid specialist, management of diet and physical activity from an early age, and consideration of statin treatment. Atorvastatin and rosuvastatin, two of the stronger statins, are approved for use in children by the Federal Drug Administration, as are all of the weaker statins. The goal is at least a 50% reduction in LDL-C or LDL-C below 130mg/dL.
Children or Adults with HoFH
Early initiation of therapy and monitoring using CT coronary angiography and other imaging are recommended; these patients often require additional treatment strategies, as pharmacological treatment and lifestyle changes may not be sufficient. Statins are usually started as soon as the diagnosis is made (though may not be effective as explained above). Two new drugs (lomitapide and mipomersen) have now been FDA-approved for the treatment of adults with HoFH, and should be considered for these patients, especially if LDL-C level cannot be controlled using other drugs. Additional options include LDL apheresis or liver transplantation. All patients with HoFH should be referred to a lipidologist. The goal is to reduce LDL-C by at least 50%.
– LDL apheresis:
Using a process similar to kidney dialysis, blood is withdrawn from a vein via a catheter and processed to remove LDL particles. Normal blood products are returned via another catheter. LDL-C levels will decrease approximately 50% but will rise between apheresis sessions, so they are necessary approximately weekly or every other week. The procedure is effective and well tolerated though time-consuming and only available in 50-60 sites in the US.
– Liver transplantation:
Liver transplant is extraordinarily rare and may become even less common with the new medications available. As the donor liver will have normal LDL receptors, the LDL cholesterol quickly normalizes after the procedure, but the risks of any organ transplant are significant and include complications from major surgery and the effects of lifelong suppression of the immune system. Donor organs are often not available. Patients with familial defective APOB or PCSK9 mutations have normal LDL receptors, so liver transplantation is not an option for them.
Various imaging modalities such as echocardiograms, CT angiograms and cardiac catheterization may be recommended to monitor individuals with HoFH.
PCSK9 inhibitors – Several companies have PCSK9 inhibitors in late stage clinical trials. These particular drugs are injectable antibodies that that inhibit the action of PCSK9. This class of drugs will lead to an increase in the number of functioning LDL-R receptors, thus lowering LDL cholesterol levels.
Clinical trials to assess safety and impact of new drugs to treat FH can be found at: www.clinicaltrials.gov.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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