What is familial Hypercholesterolemia?
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.
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 a protein called low-density lipoprotein receptor (LDLR). LDLR is responsible for removing LDL cholesterol from the blood. Mutations in the LDLR gene are the most common cause of FH.
- APOB gene: This gene provides instructions for making a protein called apolipoprotein B (APOB). ApoB is a part of LDL cholesterol.
- PCSK9 gene: This gene provides instructions for making a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates the amount of LDL receptors in the liver.
In most cases of FH, mutations in the LDLR gene is the cause of the disorder. However, mutations in the APOB 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 function of these receptors, impairing LDL particle clearance from the blood. This reduction in the binding and clearance of LDL particles can lead to the accumulation of LDL cholesterol in the bloodstream and an increased risk of atherosclerosis and heart disease.
How many types of Familial Hypercholesterolemia are present, and how common is FH?
There are two types of Familial Hypercholesterolemia (FH):
- 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 more 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 levels of cholesterol, often starting in infancy, and can lead to premature cardiovascular disease, even in childhood. Homozygous FH has an estimated prevalence of 1 in 160,000 to 1 in 1 million individuals.
How does familial hypercholesterolemia (FH) differ from the more prevalent non-familial hypercholesterolemia?
If you have high cholesterol and wondering if you might have FH, consider the following factors:
- Family history: FH is a genetic disorder, so if you have a family history of high cholesterol, early heart disease, or stroke, it may be an indication of FH. Look for these conditions among your close relatives, particularly parents and siblings.
- Age and cholesterol levels: FH often presents with significantly elevated LDL cholesterol levels from a young age. It could be a sign of FH if you have consistently high LDL cholesterol levels despite a healthy lifestyle.
- Physical Findings: Some individuals may develop cholesterol deposits in specific areas, such as tendons (xanthomas) or around the eyes (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. Few examples of the typical physical findings in FH is shown below.
- Medical evaluation: To confirm a diagnosis of FH, consult a healthcare professional specialising in lipids (lipidologist) or Cardiologist. They will conduct a physical examination, review your medical and family history, and order further blood tests to assess your lipid levels. In some cases, genetic testing may be required to identify mutations associated with FH.
Arcus Cornealis
Achilles Tendon Xanthoma
Xanthelasma
Arcus Cornealis
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, healthcare professionals can recommend appropriate medications, such as statins or other lipid-lowering agents, to help manage cholesterol levels and 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.
In summary, early detection of familial hypercholesterolemia is crucial in reducing the risk of serious health complications, implementing effective lifestyle changes and medical treatments, and identifying at-risk family members for timely intervention.
How is familial hypercholesterolemia diagnosed?
The diagnosis of Familial Hypercholesterolemia (FH) is based on a combination of clinical evaluation, family history, and laboratory testing. The following are some of the diagnostic criteria that may be used:
- Clinical evaluation: A healthcare provider may perform a physical exam and ask about family history, personal medical history, and lifestyle factors such as diet and physical activity.
- Cholesterol testing: Blood tests can measure total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Individuals with FH typically have elevated LDL cholesterol levels from birth.
- Family history: FH is an autosomal dominant genetic disorder, which means that affected individuals have a 50% chance of passing the mutated gene on to each of their offspring. Therefore, a family history of high cholesterol or premature cardiovascular disease can also be an important clue in diagnosing FH.
- Physical signs: In some cases, physical signs such as xanthomas (yellowish deposits of cholesterol under the skin) or corneal arcus (a white or greyish ring around the edge of the cornea) may be present, which can also support a diagnosis of FH.
- Genetic testing: can confirm a diagnosis by identifying mutations in genes that are known to cause FH.
It is important to note that the diagnosis of FH can be complex and may require the expertise of a specialist in this field.
What is the Dutch Lipid Score or Dutch Lipid Clinic Network (DLCN) criteria?
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:
- Total cholesterol or low-density lipoprotein cholesterol (LDL-C) levels
- Family history of high cholesterol or early-onset cardiovascular disease
- Personal history of early-onset cardiovascular disease
- Physical examination findings, such as xanthomas (cholesterol deposits in the skin) or corneal arcus (a whitish or greyish ring around the cornea)
Based on the cumulative score, individuals are classified into the following categories:
- Unlikely FH (<3 points)
- Possible FH (3-5 points)
- Probable FH (6-8 points)
- Definite FH (>8 points)
It is important to note that the Dutch Lipid Score is not definitive but rather a tool to help identify individuals who may have FH and require further evaluation, genetic testing, or specialized care. Early diagnosis and management of FH are crucial in reducing the risk of cardiovascular complications.
Who should be assessed for likely Familial Hypercholesterolemia?
The following individuals should be investigated for likely FH:
- Elevated cholesterol levels: People with consistently high LDL cholesterol levels, despite lifestyle modifications, should be evaluated for FH. LDL-C levels above 190 mg/dL (4.9 mmol/L) in adults or above 160 mg/dL (4.1 mmol/L) in children may warrant further investigation.
- Family history: Individuals with a family history of high cholesterol, early-onset cardiovascular disease, or premature heart attacks should be investigated for FH.
- Premature cardiovascular disease: People with a heart attack, stroke, or other cardiovascular events at a young age (usually under 55 years for men and under 60 years for women) should be investigated for FH.
- Physical signs: If a person has physical signs suggestive of high cholesterol, such as xanthomas (cholesterol deposits in the skin or tendons) or xanthelasmas (cholesterol deposits around the eyes), they should be evaluated for FH.
- Cascade screening: Family members of individuals diagnosed with FH should be investigated. This process, known as cascade screening, helps identify affected relatives who may not be aware of their risk.
Who should have genetic testing for likely Familial Hypercholesterolemia?
- An individual with an LDL-cholesterol level of 252 mg/dl (6.5 mmol/L) or more
- An individual with an LDL-cholesterol level of 193 mg/dl (5.0 mmol/L) plus clinical features suggestive of FH.
- An individual with a combination of clinical features, laboratory results, and family history that categorizes them as having “probable or definite FH” according to the internationally accepted scoring system known as the Dutch Lipid Clinic Network score.
- An individual with a first- or second-degree relative who has a confirmed genetic diagnosis of FH in one of the three genes, known to cause FH.
What outcomes can I anticipate from the genetic testing for Familial Hypercholestrolemia?
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): 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. These benign variations cannot be used by family members 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: 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 for the same mutation identified in the index case (the initially diagnosed family member) in their relatives.
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?
I recommend the following steps 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 (e.g., 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 medications, like ezetimibe or PCSK9 inhibitors, 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.
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.