Early detection and family screening can prevent serious cardiovascular outcomes in this inherited condition, which affects roughly 1 in 250–300 people worldwide, enabling those affected to lead normal lives.

Familial hypercholesterolaemia (FH) is one of the most common genetic disorders in Singapore with a prevalence of about 1 in 140, exceeding global estimates. This genetic condition impairs the body's ability to clear low-density lipoprotein cholesterol (LDL-C), often referred to as 'bad cholesterol' from the blood stream. As a result, individuals with FH have elevated LDL-C levels from birth, which substantially increase their risk of premature cardiovascular diseases (CVD).

Asst Prof Iswaree Devi Balakrishnan, Consultant, Cardiology, NHCS answers some common questions about this serious but treatable genetic threat - from understanding the risks to knowing when to seek testing.

Q: What makes FH so dangerous compared to regular high cholesterol?

A: People with FH develop high LDL-C from a young age resulting in prolonged exposure to elevated LDL-C levels. This lifelong exposure places them at a much higher risk (up to 20-fold) of developing premature CVD such as heart attacks, angina, stroke and peripheral artery disease compared to the general population.

Men with FH typically experience heart attacks at around 50 years of age (compared to 66 years in those without FH), whilst women are affected at around 60 years (compared to 72 years).

Q: How would I know if I have FH?

A: FH often remains undiagnosed and untreated until a premature cardiac event such as a heart attack. Fortunately, early diagnosis and appropriate treatment can significantly reduce the risk of CVD in individuals with FH.

Key indicators include:

• Significantly elevated cholesterol levels (e.g. LDL > 4.9 mmol/L in adults)
• Yellowish deposits around the eyes (xanthelasmata) or tendons (xanthomas)
• A greyish ring around the cornea (corneal arcus), especially in younger people

However, many people with FH may not have these visible signs. If there is a family history of premature heart attacks or stroke, or if multiple family members require cholesterol-lowering medication at a young age, speak to your doctor about getting tested for FH.

Q: If FH is genetic, will I pass it to my children?

A: There is a 50% chance of passing FH to your children if you have the condition. If a person tests positive for FH, their immediate family members including parents, siblings and children are also at risk and should be offered genetic testing. This process, known as cascade screening, helps identify FH in family members who may not yet have any symptoms, so that preventative treatment can begin before premature CV disease develops.

Q: How is FH genetic testing done?

A: The test involves a simple blood draw or cheek swab. There are three possible outcomes:

Positive: a mutation in an FH-related gene is found
Negative: no mutation detected
Uncertain: a variant is found but uncertain if it causes FH

It's important to know that even a negative result doesn't completely rule out FH, your doctor will still manage your condition based on your symptoms and family history. Genetic counselling is provided before and after the test to help one understand what the results mean and the implications for your family members and treatment decisions.

Q: Can FH be treated effectively?

A: Yes. FH can be treated very effectively when diagnosed early and managed intensively. Whilst diet and exercise remain important, people with FH need medication to lower their genetically driven high LDL-C levels, which lifestyle change alone cannot adequately reduce.

Treatment typically starts with statins, and additional medications like ezetimibe and bempedoic acid may be added to further reduce LDL-C levels. For people who need additional lowering, injectable medications such as PCSK9 inhibitors (e.g., evolocumab, alirocumab) and small interfering RNA molecules (e.g., inclisiran) provide highly effective options. In very severe cases, LDL-apheresis, a procedure that directly removes LDL-C from the blood may be considered.

Several emerging therapies are also in development including RNA-based and gene-directed treatments that aim to provide longer-lasting cholesterol lowering.

The goal of treatment in FH is reduce LDL-C to target levels to lower the risk of atherosclerotic CV disease, typically below 1.8 mmol/L, or even lower if you have additional health conditions like long-standing diabetes, kidney disease or hypertension.

REFERENCES

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