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Familial hypercholesterolaemia
FH increases an individual's risk of developing early-onset cardiovascular diseases, such as heart attacks and strokes. It affects people across all populations and requires lifelong management to reduce health risks.
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Overview
Familial hypercholesterolaemia (FH) is a common inherited condition that leads to very high levels of cholesterol in the blood from birth. Unlike high cholesterol that develops due to lifestyle factors, FH is caused by changes in specific genes, meaning it can affect even young, otherwise healthy individuals [PMID:33606992]. The primary concern with FH is the accumulation of low-density lipoprotein (LDL) cholesterol, often referred to as 'bad' cholesterol, in the arteries. Over time, this build-up can narrow and harden the arteries, a process called atherosclerosis.
This genetic predisposition significantly increases the risk of developing cardiovascular diseases at a much younger age than typically seen in the general population. Conditions like heart attacks and strokes can occur decades earlier if FH is left undiagnosed and unmanaged. Recognising and treating FH early is crucial for preventing serious health complications and improving long-term outcomes.
FH is thought to affect approximately 1 in 250 people in its most common form (heterozygous FH), making it one of the most prevalent inherited conditions [PMID:33606992]. It is important to identify family members who might also be affected, as early diagnosis allows for timely intervention.
Symptoms & clinical features
Many individuals with FH do not experience noticeable symptoms during childhood or early adulthood, despite having very high cholesterol levels. This lack of obvious signs is why FH is often called a 'silent killer', as the damage to arteries can progress without awareness. The first symptom for some individuals might unfortunately be a serious cardiovascular event, such as a heart attack or stroke, at an unusually young age.
When present, symptoms of FH are related to cholesterol deposits in various body tissues. These can include xanthomas, which are fatty deposits that appear as yellowish bumps on the skin, often around the elbows, knees, or buttocks. Tendon xanthomas, specifically, are firm, painless swellings found in tendons, most commonly the Achilles tendon or tendons on the back of the hand [PMID:24760237]. Another possible sign is a xanthelasma, which refers to cholesterol deposits around the eyelids. A corneal arcus, a white or grey ring around the iris (the coloured part of the eye), can also be an indicator of high cholesterol, especially if it appears in individuals under 50 years of age.
It is important to remember that not everyone with FH will develop these visible signs, and their absence does not rule out the condition. Blood tests to measure cholesterol levels are the primary way to identify FH.
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Affected organs
Familial hypercholesterolaemia primarily affects the cardiovascular system, particularly the arteries, which are the blood vessels that carry oxygenated blood from the heart to the rest of the body. The significantly high levels of LDL cholesterol in the bloodstream lead to the gradual build-up of fatty plaques within the artery walls. This process, known as atherosclerosis, causes the arteries to narrow and become less flexible.
Over time, this narrowing and hardening of arteries can restrict blood flow to vital organs. The heart itself is highly vulnerable, as reduced blood flow through the coronary arteries (which supply the heart muscle) can lead to angina (chest pain), heart attacks, and other forms of coronary artery disease. The brain can also be affected, with a higher risk of strokes due to blockages in arteries supplying the brain. Other organs, such as the kidneys and limbs, can be impacted by impaired blood flow, though these are typically secondary to the primary cardiovascular effects.
Risks & severity
The severity of FH can vary, but generally, individuals with untreated FH face a significantly increased risk of premature cardiovascular disease. Those with heterozygous FH (one altered gene copy) have LDL cholesterol levels typically two to three times higher than the average person. This translates to a substantially elevated lifetime risk of developing coronary artery disease, with heart attacks often occurring in their 40s or 50s, sometimes even earlier [PMID:24760237].
A rarer and more severe form, homozygous FH (two altered gene copies), results in even higher cholesterol levels and can lead to very early-onset, severe cardiovascular disease, sometimes requiring interventions in childhood or adolescence. Without treatment, individuals with homozygous FH may experience heart attacks or require coronary bypass surgery before the age of 20.
The age of onset for cardiovascular events is highly dependent on how early FH is diagnosed and how effectively cholesterol levels are managed. Early and consistent treatment can significantly reduce these risks, delaying or preventing the onset of serious complications and improving life expectancy.
Genetic causes
Familial hypercholesterolaemia is typically caused by genetic changes (also known as variants or mutations) in one of several genes that play a crucial role in regulating cholesterol levels. The most commonly implicated genes are LDLR, APOB, and PCSK9.
The LDLR gene provides instructions for making the low-density lipoprotein receptor protein. This receptor is found on the surface of liver cells and is responsible for binding to and removing LDL cholesterol from the bloodstream. Pathogenic variants in LDLR are the most frequent cause of FH, leading to a reduction in the number or function of these receptors, which means LDL cholesterol cannot be effectively cleared from the blood.
Changes in the APOB gene can also cause FH. APOB (apolipoprotein B) is a key protein component of LDL particles. It acts as the 'key' that allows LDL to bind to the LDLR receptor. Variants in APOB can alter this 'key', preventing LDL from binding effectively to the receptors, even if the receptors themselves are normal. The PCSK9 gene encodes a protein that regulates the number of LDLR receptors available on cell surfaces. Variants in PCSK9 can lead to its overactivity, causing the LDLR receptors to be degraded more quickly. This results in fewer receptors being available to remove LDL cholesterol from the blood, leading to its accumulation [PMID:33606992].
- APOB apolipoprotein BThe APOB gene provides instructions for making apolipoprotein B, a key protein involved in the transport of fats and cholesterol throughout the body, playing a central role in lipid metabolism.
- LDLR low density lipoprotein receptorThe LDLR gene codes for the low-density lipoprotein receptor, a protein vital for regulating cholesterol levels in the bloodstream and preventing its accumulation.
- PCSK9 proprotein convertase subtilisin/kexin type 9The PCSK9 gene provides instructions for a protein that plays a crucial role in regulating cholesterol levels in the bloodstream, primarily by controlling the number of low-density lipoprotein receptors.
Inheritance pattern
Familial hypercholesterolaemia is inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one altered copy of a specific gene (LDLR, APOB, or PCSK9) from either parent to develop the condition. If one parent has FH, there is a 50% chance that each child they have will inherit the altered gene and therefore also have FH.
The condition affects males and females equally. Since it is present from birth, FH can be passed down through generations within a family. If an individual is diagnosed with FH, it is recommended that their close relatives (parents, siblings, and children) also be tested to see if they have inherited the condition. This process, known as 'cascade screening', is vital for early diagnosis and management within affected families [PMID:24760237].
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing familial hypercholesterolaemia typically begins with a blood test to measure cholesterol levels, particularly LDL cholesterol. If these levels are significantly elevated, especially in the absence of other common causes of high cholesterol, FH may be suspected. Clinical criteria, such as the Simon Broome Register criteria or the Dutch Lipid Clinic Network criteria, are often used by healthcare professionals to help diagnose FH based on cholesterol levels, family history of high cholesterol or early heart disease, and the presence of physical signs like xanthomas [PMID:24760237].
Genetic testing is the definitive way to confirm a diagnosis of FH and identify the specific gene variant responsible. This testing involves analysing DNA, usually from a blood sample, to look for pathogenic changes in genes like LDLR, APOB, or PCSK9. In the UK, genetic testing for FH is often part of the NHS Genomic Medicine Service, typically following a referral from a GP or specialist to a clinical genetics service. NHS R-codes, such as R320 for inherited lipid disorders, may be used to guide testing pathways. Identifying the exact genetic cause can help with cascade screening for family members and may inform treatment decisions.
Management & lifestyle
Management of familial hypercholesterolaemia aims to significantly lower LDL cholesterol levels and reduce the risk of cardiovascular disease. This typically involves a lifelong approach that combines lifestyle modifications and medication. For most individuals with FH, medication, primarily statins, is usually necessary from a young age to achieve target cholesterol levels. Statins work by reducing cholesterol production in the liver and increasing the number of LDL receptors, helping to clear more LDL cholesterol from the blood.
Other medications, such as ezetimibe, PCSK9 inhibitors, or bile acid sequestrants, may be used alone or in combination with statins if cholesterol levels remain high or if statins are not tolerated. The choice of medication and dosage is individualised, taking into account the patient's age, cholesterol levels, and overall health. Regular monitoring of cholesterol levels and potential side effects of medication is essential.
Lifestyle advice, including a heart-healthy diet low in saturated and trans fats, regular physical activity, maintaining a healthy weight, and avoiding smoking, complements medical treatment. Management plans are developed and overseen by specialists, often within lipid clinics or cardiology services, with input from clinical geneticists and genetic counsellors, particularly for cascade screening of family members.
UK care pathway
In the UK, individuals suspected of having familial hypercholesterolaemia typically enter a care pathway that often begins with their GP. If high cholesterol levels or a family history of early heart disease are identified, a referral may be made to a specialist, such as a lipid clinic, cardiologist, or a clinical genetics service. These services are part of the NHS Genomic Medicine Service (GMS).
Genetic testing for FH is provided through the GMS, guided by NHS R-codes, which ensure appropriate testing is performed. A clinical genetics team can offer a confirmed genetic diagnosis and provide genetic counselling. Genetic counsellors play a crucial role in explaining the inheritance pattern of FH, the implications for the individual and their family, and coordinating 'cascade screening' where other family members are offered testing. This integrated approach helps ensure comprehensive care and risk management for affected individuals and their relatives.
Frequently asked questions
What is the difference between FH and 'regular' high cholesterol?
FH is caused by a genetic change, meaning you are born with very high cholesterol levels. 'Regular' high cholesterol often develops later in life due to lifestyle choices, diet, or other medical conditions. FH typically results in much higher cholesterol levels than lifestyle-induced high cholesterol.
If I have FH, will my children have it?
Yes, if you have FH, there is a 50% chance that each of your children will inherit the genetic alteration and also have FH. This is because FH is an autosomal dominant condition, meaning only one copy of the altered gene is needed for the condition to manifest.
Can FH be cured?
FH is a lifelong genetic condition and cannot be cured. However, it can be very effectively managed with medication and lifestyle changes. Early diagnosis and consistent treatment can significantly reduce the associated health risks and allow individuals to lead full and healthy lives.
What is cascade screening?
Cascade screening is a process where, once someone is diagnosed with FH, their close family members (parents, siblings, children) are offered testing for the condition. This helps to identify other affected individuals early, allowing for timely treatment and prevention of serious complications.
Do I need to change my diet if I have FH?
While FH is primarily managed with medication, adopting a heart-healthy diet is still an important part of overall management. Reducing saturated and trans fats, increasing fibre intake, and maintaining a healthy lifestyle can complement medical treatment in lowering cardiovascular risk.
References
- Alonso R, Perez de Isla L, Muñiz-Grijalvo O. Familial Hypercholesterolaemia Diagnosis and Management. European cardiology. 2018. PMID: 30310464
- McErlean S, Mbakaya B, Kennedy C. Familial hypercholesterolaemia. BMJ (Clinical research ed.). 2023. PMID: 37429609
- Farias FI, Kim SM, Shapiro MD. Familial hypercholesterolaemia and emerging therapeutics. Heart (British Cardiac Society). 2023. PMID: 37130749
- Familial hypercholesterolaemia. Lancet (London, England). 1977. PMID: 66524
- Rees A. Familial hypercholesterolaemia: underdiagnosed and undertreated. European heart journal. 2008. PMID: 18840878
- Familial hypercholesterolaemia. BMJ (Clinical research ed.). 2023. PMID: 37619994
- Henderson R, O'Kane M, McGilligan V. The genetics and screening of familial hypercholesterolaemia. Journal of biomedical science. 2016. PMID: 27084339
- Sharifi M, Futema M, Nair D. Genetic Architecture of Familial Hypercholesterolaemia. Current cardiology reports. 2017. PMID: 28405938