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What is Familial Hypercholesterolemia? | Video
Video: A short video presentation of this article
Familial hypercholesterolemia (FH) is a genetic disorder that causes high levels of low-density lipoprotein (LDL) cholesterol, also known as “bad” cholesterol, in the blood. People with FH have a mutation in one of three genes that control cholesterol metabolism, resulting in excessive production or impaired removal of LDL by the liver. The excess cholesterol can build up in the walls of arteries, leading to atherosclerosis and an increased risk of heart disease, heart attack, and stroke. Individuals with Familial Hypercholesterolemia can have high coronary calcium scores at an early age; however, a calcium score of zero in these high-risk individuals does not rule out underlying coronary artery disease and blockages.
What are the three primary genes associated with familial hypercholesterolemia (FH)?
The three genes involved in FH are:
- LDLR gene: This gene provides instructions for making the LDL receptors. These receptors remove LDL cholesterol from the bloodstream by binding to the LDL particles. Over 95% of the individuals with FH have Mutations in the LDL-R gene.
- APOB gene: This gene provides instructions for making a protein called Apo-lipoprotein B. Apo-B is an essential part of LDL-cholesterol which facilitates the binding of the LDL particle to the LDL receptor to be taken up by cells. Mutations in this gene lead to the production of a variant of Apo-B which is not recognizable by LDL receptors. As a result, LDL particles accumulate in the bloodstream, leading to hypercholesterolemia. Less than 5% of the individuals with FH have mutations in the ApoB gene.
- PCSK9 gene: This gene provides instructions for making a protein called proprotein convertase subtilisin kexin type 9, which regulates the amount of LDL receptors in the liver. However, when there is a gain-of-function mutation in the PCSK9 gene, the PCSK9 protein becomes overactive. This leads to an increased rate of LDL receptor degradation, resulting in fewer LDL receptors available on the liver cells to clear LDL from the bloodstream, leading to hypercholesterolemia. Less than 1% of the individuals with FH have mutations in the PCSK9 gene.
In most cases of FH, mutations in the LDL receptor gene cause the disorder. However, mutations in the APo-B and PCSK9 genes can also lead to FH, but less commonly.
How does a mutation in the LDLR gene lead to hypercholesterolemia?
The LDL receptor, located on cell surfaces, including liver cells, binds to LDL particles that transport cholesterol and lipids in the bloodstream. This binding allows cells to use LDL particles for energy or other purposes like hormone production.
In individuals with FH, mutations in the LDL receptor gene can decrease the number or impair the function of the receptors. This reduction in the binding and clearance of LDL particles leads to the accumulation of LDL cholesterol in the bloodstream and an increased risk of atherosclerotic heart disease.
How many types of Familial Hypercholesterolemia are present, and how common is FH?
FH is often underdiagnosed and undertreated, with many people with FH unaware that they have the condition. There are two types of Familial Hypercholesterolemia:
Heterozygous FH (He-FH)
This is the more common type of FH, where a person inherits one mutated copy of the gene responsible for FH from one of their parents. People with heterozygous FH have elevated cholesterol levels from birth and are at an increased risk for developing premature cardiovascular disease. Heterozygous FH has an estimated prevalence of 1 in 200 to 1 in 500 individuals.
Homozygous FH (Ho-FH)
This is a rare and more severe type of FH, where a person inherits two copies of the mutated gene, one from each parent. Homozygous FH causes extremely high cholesterol levels, often starting in infancy, and can lead to premature cardiovascular disease, even in childhood. Homozygous FH has an estimated prevalence of 1Â in 160,000 to 1 in 1 million individuals.
How does familial hypercholesterolemia differ from non-familial form?
If you have high cholesterol and wondering if you might have FH, consider the following factors:
- Family history: FH is a hereditary disorder, implying that a history of elevated cholesterol levels, premature heart disease, or stroke within your family may signal the presence of FH. Monitoring these conditions among your immediate family members, especially your parents and siblings, is essential as they could indicate this genetic disorder.
- Age and cholesterol levels: FH typically manifests as markedly elevated LDL cholesterol levels from an early age. If you persistently exhibit high LDL cholesterol levels despite maintaining a healthy lifestyle, especially at an early age, it could indicate FH.
- Physical Findings:Â Physical Findings: Some individuals may develop cholesterol deposits in specific areas, such as tendons, called xanthomas or around the eyes, called xanthelasmas. The most characteristic physical finding is the deposition of fat in the Achilles Tendon, causing a lump that could be painful. A white or grey ring around the cornea, known as an arcus cornealis, can also indicate FH, particularly in younger individuals. A few examples of these physical findings in FH are shown below.
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- Arcus Cornealis
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- Achilles Tendon Xanthoma
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- Arcus Cornealis
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- Xanthelasma
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- Achilles Tendon Xanthoma
What is the significance of early detection of familial hypercholesterolemia?
Early detection of familial hypercholesterolemia (FH) is of great significance due to the following reasons:
- Lifestyle modifications: Early detection helps individuals with FH to make necessary lifestyle changes, such as considering a healthy diet, engaging in regular exercise, maintaining a healthy weight, and avoiding tobacco use which improves overall cardiovascular health.
- Medical treatment: With an early diagnosis, we recommend medications, such as statins or other lipid-lowering agents, to reduce the risk of cardiovascular events.
- Monitoring and follow-up: Early detection of FH allows regular monitoring and follow-up to track treatment progress, make adjustments as needed, and ensure the condition is well-managed.
- Family screening: Since FH is a genetic disorder, early diagnosis in one family member can prompt screening and evaluation of other at-risk relatives. This can lead to early detection and intervention for affected family members.
EARLY DETECTION of familial hypercholesterolemia reduces the risk of premature vascular and cardiac diseases by enabling effective lifestyle changes and medical therapy.
How is familial hypercholesterolemia diagnosed?
The diagnosis of FH is based on a combination of clinical suspicion (based on the person’s medical and family history), physical exam, lab results and formal diagnostic criteria such as Dutch Lipid Score or genetic testing.
- Clinical Suspicion:Â Clinical suspicion is a crucial initial step in diagnosing FH. This suspicion arises from a thorough evaluation of a patient’s personal medical history, family history, and laboratory test results. FH should be suspected in patients with a history of premature atherosclerotic cardiovascular disease or stroke, specifically in men under the age of 55 and women under 65. A family history revealing high cholesterol levels or early-onset cardiovascular disease can provide invaluable clues for the potential presence of FH. Furthermore, exhibiting consistently elevated cholesterol levels from a young age should trigger a strong suspicion of FH. It’s important to remember that these consistently high levels should be unusually high, often significantly above the normal range, even in the context of a healthy diet and lifestyle.
- Physical Exam:Â Physical signs such as xanthomas, xanthelasma, and arcus cornealis can significantly support the suspicion of FH. These visible manifestations of excessive cholesterol deposition are often associated with the disease. However, it’s essential to bear in mind that these signs might not always be present, especially in younger patients or those with less severe disease. Therefore, the absence of these physical signs does not conclusively rule out a diagnosis of FH.
- Formal Diagnostic Criteria: To formally diagnose FH, we often use a set of criteria like the Dutch Lipid Score, which considers the above factors, along with specific cholesterol levels and Genetic Testing results, if available.
What is the Dutch Lipid Score or DLCN criteria and FH calculator?
The Dutch Lipid Clinic Network (DLCN) criteria, or the Dutch Lipid Score, was first published in 1999. The score was developed by a group of healthcare professionals and researchers in the Netherlands to help identify and diagnose individuals with familial hypercholesterolemia (FH). Since its introduction, the Dutch Lipid Score has become a widely used tool for assessing the likelihood of FH in patients with elevated cholesterol levels.
The Dutch Lipid Score assigns a numerical value to the individual based on several factors, including:
- LDL-Cholesterol level
- Family history of high cholesterol or early-onset cardiovascular disease
- Personal history of early-onset cardiovascular disease
- Physical examination findings, such as xanthomas or corneal arcus
Based on the cumulative score, calculated via a dedicated FH calculator, individuals are classified into the following categories:
-  Score 1-2  →  Unlikely FH
- Score 3-5  →  Possible FH
- Score 6-8  →  Probable FH
- Score >8   →  Definite FH
It is important to remember that the Dutch Lipid Score does not provide a “definitive” diagnosis of FH. However, it is a valuable tool to identify individuals who “may” have FH and require further evaluation, genetic testing, or specialized care.
When should you suspect Familial Hypercholesterolemia?
The following scenarios should raise the suspicion for likely FH:
- Elevated cholesterol levels: People with high LDL-C levels despite lifestyle modifications. Consistent LDL-C levels above 190 mg/dL (4.9 mmol/L) in adults or above 160 mg/dL (4.1 mmol/L) in children warrant further investigation.
- Family history:Â Individuals with a family history of hypercholesterolemia or diagnosed FH, early-onset cardiovascular disease, or premature heart attacks, especially in first-degree relatives.
- Premature cardiovascular disease: People with premature heart attack, stroke, or other cardiovascular events (usually under 55 years for men and under 60 years for women).
- Physical signs: If a person has physical signs suggestive of excessive cholesterol deposition, such as xanthomas (in tendons), xanthelasmas (around the eyes) and arcus cornealis (around cornea).
When is genetic testing recommended to detect Familial Hypercholesterolemia?
Genetic testing to establish the diagnosis of FH, should be considered in the following individuals:
- LDL-C > 252 mg/dl (6.5 mmol/L)
- LDL-C level > 193 mg/dl (5.0 mmol/L) plus clinical features suggestive of FH or established ASCVD (MI, CABG, angioplasty or severe chronic CAD)
- Dutch Lipid Score > 6
- First- or second-degree relative with a confirmed genetic diagnosis of FH in one of the three genes known to cause FH (Cascade testing)
What outcomes can you anticipate from the genetic testing for Familial Hypercholesterolemia?
Genetic testing for familial hypercholesterolemia (FH) involves analysing specific genes associated with the condition, such as LDLR, APOB, or PCSK9. The results of the test can provide different outcomes:
- Positive result: This indicates that a mutation associated with FH is identified in one of the analyzed genes and confirms the diagnosis. It also helps determine if you have a heterozygous or homozygous form of the disease. Heterozygous FH (HeFH) is milder and more common, while homozygous FH (HoFH) is more severe and rare.
- Negative result: This means that no “known” FH-causing mutations were detected. This result could indicate that you do not have FH, or it could mean that the test did not identify a mutation due to limitations in current genetic testing technology. In some cases, individuals may still have FH caused by mutations in other, less common genes or unidentified mutations.
- Variant of uncertain significance (VUS):Â Variant of uncertain significance (VUS): Sometimes, genetic testing identifies a variant in one of the analysed genes, but its clinical relevance is unclear. This means it is not certain whether the identified variant is responsible for FH. In such cases, we may consider other factors, such as cholesterol levels and family history, to determine the likelihood of FH. Family members cannot use these variations for cascade testing.
- Inconclusive result: Occasionally, genetic test results may be inconclusive due to technical issues or insufficient sample quality. In these cases, you might need to repeat the test or consider alternative testing methods.
What is the difference between the diagnostic test and cascade tests in genetic testing for FH?
When discussing FH testing, it is essential to differentiate between diagnostic testing and cascade testing. Both are used to identify individuals with FH, but they serve different purposes and target different populations.
- Diagnostic testing: performed on individuals who are suspected of having FH due to high cholesterol levels, family history, physical signs, or early-onset cardiovascular disease. Diagnostic testing typically involves a combination of assessing clinical criteria, blood tests to measure cholesterol levels, and genetic testing.
- Cascade testing:Â Cascade testing: Cascade testing (or cascade screening) is a process in which relatives of individuals diagnosed with FH are tested for the condition. Since FH is a hereditary disorder, family members of affected individuals have an increased risk of having the disease. Cascade testing typically starts with first-degree relatives (parents, siblings, and children) and may extend to more distant relatives. Genetic testing plays a crucial role in this case as we only search, in the relatives, for the same mutation identified in the index case, meaning the initially diagnosed family member.
Both the diagnostic and cascade testing aim to identify individuals with FH but target different groups. Diagnostic testing is used to confirm or rule out the presence of FH in individuals with clinical suspicion. In contrast, cascade testing identifies undiagnosed relatives of individuals already established to have FH.
What is the inheritance pattern of FH and how early should family members be genetically tested?
Familial hypercholesterolemia (FH) is an inherited disorder characterized by an “Autosomal Dominant” pattern, which outlines how FH is passed down within a family. When a person receives a genetic diagnosis of FH:
- There is a 50% chance (1 in 2) that their first-degree relatives possess the genetic mutation and will exhibit FH symptoms. First-degree relatives consist of parents, siblings, and children.
- There is a 25% chance (1 in 4) that their second-degree relatives carry the genetic mutation and will display FH symptoms. Second-degree relatives include grandparents, grandchildren, aunts, uncles, nieces, and nephews.
As early management and diagnosis of FH is crucial, It is recommended that first- and second-degree relatives undergo genetic testing for FH, typically by the age of 10.
What steps should be taken if the FH genetic test finds an abnormality?
The following steps should be taken if an FH-related genetic abnormality is found in your test:
- Confirming the diagnosis: genetic test results should correlate with other factors – cholesterol levels, family history, and physical signs of FH, such as xanthomas – to confirm the diagnosis.
- Family testing: If the genetic test confirms a diagnosis of FH, it is important to inform family members, as they may choose to undergo genetic testing to determine their risk.
- Lifestyle modifications: Individuals diagnosed with FH should make lifestyle changes, including adopting a healthy diet, increasing physical activity, maintaining a healthy weight, and avoiding tobacco products.
- Medication: Depending on the severity of the condition and cholesterol levels, you may require medications, such as statins, to help lower cholesterol levels. Other cholesterol-lowering medications, such as Bempedoic acid, Ezetimibe, PCSK9 inhibitors and Inclisiran, may also be considered depending on the specific circumstances.
- Regular monitoring: People with FH should have regular check-ups with their healthcare provider to monitor cholesterol levels and assess their risk for cardiovascular disease. This ensures that the condition is managed effectively and treatments adjusted regularly.
- Emotional support: A diagnosis of FH can be challenging for individuals and their families. It may be helpful to seek support from friends, family, or support groups to help cope with the emotional aspects of living with a chronic condition.
Treatment
The aim of therapy in FH patients is to reduce LDL cholesterol by 50-60% from baseline. Registry data show that a large proportion (30%) of FH patients are not receiving statins, and from those treated, only about half of them are on recommended high-dose statin therapy. Even after a confirmed genetic diagnosis, a mere one in five patients achieves the target LDL cholesterol (< 1.8 mmol/L or 70 mg/dl). Evidence shows that early and persistent treatment, starting as young as 8-10, yields the best outcomes. This strategy can slow arterial thickening in kids and reduce their risk of heart disease.
The advised treatment combo of maximum-tolerated statin and ezetimibe can notably lower heart disease morbidity and mortality. However, for those patients with FH who don’t respond to this combination therapy by achieving the target LDL-C levels (<1.8 mmol/L) or cannot tolerate statins, other agents such as PCSK9 Inhibitors, Inclisran and Bempedoic Acid are recommended.
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References and further reading
- Jose M, et al. Genetic basis of hypercholesterolemia in adults. NPJ Genom Med.
- Safarova M.S, Kullo I.J. My approach to the patient with familial hypercholesterolemia. Mayo Clin Proc.Â
- Santos R.D, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol.
- Safarova M.S, Liu H, Kullo I.J. Rapid identification of familial hypercholesterolemia from electronic health records: the SEARCH study.Â
- Banda J.M, et al. Finding missed cases of familial hypercholesterolemia in health systems using machine learning. NPJ Digit Med.
- Santos R.D, et al. Long-term evolocumab in patients with familial hypercholesterolemia. J Am Coll Cardiol.
- Sabatine M.S, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med.
- Santos R.D, et al. Evolocumab in pediatric heterozygous familial hypercholesterolemia. N Engl J Med.
- Huijgen R, et al. Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS One.
- Luirink I.K, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med
- Nordestgaard BG, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease. Eur Heart J
Thank you very much for the very informative material and discussion. I am 45 and had bypass surgery last year. I was diagnosed with FH at 35 but I always had high cholesterol since I was very young. Doctors always were telling my parents “She is young to start medications”! until I had advanced coronary disease. My dad dies from heart attack at 48. My son, who is now 20, has very high cholesterol and was started on statins 5 years ago but still has high LDL. Doctors hesitate to start him on other available medications. I heard there are injections for this. Can I ask your opinion.
Hi Sharma
Thank you for sharing your thoughts. Your case clearly shows the importance of early diagnosis and treatment of Familial Hypercholesterolemia. It’s unfortunate that your hypercholesterolemia wasn’t addressed until later. At times, complacency can hinder healthcare professionals from taking timely action. Nevertheless, I’m glad to hear that you’re doing well and, hopefully, your LDL is now below 1.4 mmol/L (50 mg/dl). As for your son, his treatment thus far and his current LDL level will determine the next steps. In such cases, I prefer to see LDL levels as low as possible while minimizing side effects. If his LDL remains high despite adhering to “maximum-tolerated” medical therapy and lifestyle modifications, other options exist to lower his LDL further. As you mentioned, PCSK-9 inhibitor medications are one such option, currently available as biweekly or monthly injections, with oral forms expected soon. For individuals like your son, I always examine Lp(a) as well, since it is an independent risk factor for early-onset coronary disease. Keep in mind that following a healthy lifestyle and avoiding tobacco are essential initial measures, even before considering medical therapy.