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Understanding Familial Hypercholesterolaemia.

Published on

05/08/2024

Familial Hypercholesterolaemia (FH) is a genetic disorder that leads to high levels of LDL cholesterol in the blood. This condition can significantly increase the risk of heart disease if not managed properly. Understanding FH is crucial because early detection and intervention can greatly reduce health risks1,2.

 

Genetic Basis and Prevalence of FH

FH is primarily caused by mutations in three genes: LDLR, APOB, and PCSK9. These mutations result in impaired clearance of LDL cholesterol from the blood, leading to elevated levels. Other genes more recently implicated include LDLRAP1 and APOE. The prevalence of FH varies, with estimates suggesting it affects about 1 in 250 individuals globally1,3,4.

Key Genes for Familial Hypercholesterolaemia

LDLR (Low-Density Lipoprotein Receptor)

LDLR mutations are the most common cause of FH1,3. Impairment of LDLR causes reduced LDL cholesterol clearance.

LDLRAP1 (LDLR Adaptor Protein-1)

LDLRAP1 is a gene that provides instructions for making a protein essential for the proper functioning of LDLRs, which clear LDL cholesterol from the bloodstream. Mutations in LDLRAP1 can impair this process, leading to elevated LDL cholesterol levels and contributing to FH5.

APOB (Apolipoprotein B)

Mutations here affect LDLR binding and therefore reduces LDL cholesterol clearance from the blood, increasing serum LDL-C1,4

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)

Mutations which result in increased PCSK9 activity cause an increase in LDLR degradation1,3. It’s also important to note than mutations which reduce PCSK9 activity have been shown to reduce LDL cholesterol.

APOE (Apolipoprotein E)

APOE is a gene that encodes a protein involved in the metabolism of cholesterol by binding to LDLRs, helping to clear cholesterol from the bloodstream. Mutations in APOE can disrupt this process by altering the protein structure, leading to impaired LDLR binding and elevated LDL levels, contributing to the development of FH6

Clinical Manifestations and Risks

There are 2 main forms of FH: homozygous (HoFH) and heterozygous (HeFH)2. HoFH is the more severe form and cholesterol levels begin to rise from birth. People with HoFH are at very high risk of heart disease, which can develop as early as childhood.

HeFH is more common than HoFH. People with HeFH develop high cholesterol and are more likely to suffer from premature heart disease or stroke.

Homozygous: An individual has two identical alleles for a gene. In Familial Hypercholesterolemia (FH), a homozygous person has inherited the same FH-causing mutation from both parents, often leading to a more severe form of the disease.

Heterozygous: An individual has two different alleles for a gene. For FH, a heterozygous person has inherited one normal allele and one mutated allele, typically resulting in a less severe form of the condition compared to the homozygous form.

Overall, Familial Hypercholesterolaemia can manifest through various physical signs and symptoms, often appearing early in life. Key indications include:

  • Xanthomas: Cholesterol deposits in tendons and skin1,2.
  • Corneal Arcus: Cholesterol deposits around the cornea1,2.
  • Premature Cardiovascular Disease: High risk of heart attacks and strokes at a young age1,2.

Importance of Early Detection and Screening

Early detection of FH is vital and family history is crucial for assessment and diagnosis of FH. Those with very high total or LDL cholesterol levels that meet the criteria for possible FH should consider genetic testing. The Simon Broome Criteria indicate that adults with total cholesterol >7.5 mmol/L or LDL cholesterol >4.9 mmol/L plus family history of premature heart disease in a first-degree relative (e.g. before age 60 in a parent or sibling) may have FH and genetic testing would be beneficial7. In addition, those with a first degree relative with very high cholesterol or premature heart disease may wish to consider getting tested1–3. Screening can be done through lipid profiles and genetic testing for relevant associated genes.

Treatment and Management Options

Managing FH involves a combination of lifestyle changes and medication. The primary goals are to lower LDL levels and reduce cardiovascular risk.

Lifestyle Modifications

  • Diet: Reduce intake of saturated fats and cholesterol. Increase fibre-rich foods1,2.
  • Exercise: Regular physical activity helps lower LDL levels1,2.
  • Quit Smoking: Smoking cessation is crucial for reducing cardiovascular risk1,2.

Pharmacological Interventions

  • Statins: First-line treatment to lower LDL levels1,2.
  • Ezetimibe: Often added to statins to further reduce LDL levels1,2.
  • PCSK9 Inhibitors: Highly effective but more expensive option1,2.

Preventative Health Testing at Randox Health

At Randox Health, we believe in taking charge of your health through early detection and prevention. Our Familial Hypercholesterolaemia Genetic Test is designed to pinpoint genetic mutations in the LDLR, LDLRAP1, APOB, APOE, and PCSK9 genes, which are crucial for assessing risk of FH. This allows you to address potential risks before they become serious health issues.

Booking an appointment is simple and convenient, with flexible scheduling at our clinics. During your visit, we’ll collect your blood samples, and you’ll receive your results securely within 4-6 weeks. To ensure you understand your results and next steps, we offer remote consultations with experienced genetic counsellors who can provide tailored advice and guidance.

  • Sample Collection: A simple blood test.
  • Genetic Analysis: Detailed analysis of key genes.
  • Results and Consultation: Comprehensive report and consultation with a genetic counsellor

The Importance of Genetic Counselling

Genetic counselling plays a vital role in helping individuals make informed decisions about genetic testing. Our dedicated specialists examine both your medical history and that of your family to identify potential genetic concerns. They provide valuable support in understanding test results, explaining what they mean for your health and how they might affect your family members. They also discuss ways to manage any issues that may arise, such as closer monitoring or preventive measures.

Genetic counselling empowers you with the knowledge you need to understand genetic risks and make informed health choices. If you or a family member have symptoms or a diagnosis related to FH, consider our genetic tests.

If you’re unsure, we offer a pre consultation with a genetic counsellor to ensure you fully understand the implications and results of genetic screening. For £100, book a genetic pre-consultation to discuss the test with an expert, along with recommendations on what to book and get £100 off your chosen test!

Take control of your health today with Randox Health’s comprehensive testing services. You can find more information on our FH testing services here. For information on any of our other tests, feel free to reach out to us using our contact form or at any of our socials.

Conclusion

Familial Hypercholesterolaemia is a serious but manageable condition. With early detection of risk through genetic testing and appropriate management, individuals with FH can significantly reduce their risk of heart disease. Randox Health’s comprehensive testing services provide a crucial tool in managing this genetic disorder effectively.

FAQs about FH and Genetic Testing

What is Familial Hypercholesterolaemia?

FH is a genetic disorder that causes high levels of LDL cholesterol, increasing the risk of heart disease1,2.

How is FH diagnosed?

FH is diagnosed through lipid profile tests and genetic testing, especially if there is a family history of high cholesterol or heart disease1,2.

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What are the treatment options for FH?

Treatment includes lifestyle changes (diet, exercise, quitting smoking) and medications like statins, ezetimibe, and PCSK9 inhibitors1,2

Why is early detection important?

Early detection allows for timely management, reducing the risk of serious cardiovascular events1,2.

How can Randox Health help?

Randox Health provides genetic testing to identify mutations associated with FH, helping to manage and reduce associated risks effectively.

Who should consider getting tested?

Individuals with a family history of high cholesterol or premature heart disease, or those with high cholesterol levels, should consider testing1–3.

References

  1. Khera A V., Hegele RA. What Is Familial Hypercholesterolemia, and Why Does It Matter? Circulation. 2020;141(22):1760-1763. doi:10.1161/CIRCULATIONAHA.120.046961
  2. Vaezi Z, Amini A. Familial Hypercholesterolemia. StatPearls Publishing; 2024.
  3. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia. J Am Coll Cardiol. 2020;75(20):2553-2566. doi:10.1016/j.jacc.2020.03.057
  4. Varghese M. Familial hypercholesterolemia: A review. Ann Pediatr Cardiol. 2014;7(2):107. doi:10.4103/0974-2069.132478
  5. Nikasa P, Rabbani B, Hejazi MS, et al. A case of autosomal recessive hypercholesterolemia with a novel mutation in the LDLRAP1 gene. Clinical Pediatric Endocrinology. 2021;30(4):2021-0039. doi:10.1297/cpe.30.201
  6. Rashidi OM, H.Nazar FA, Alama MN, Awan ZA. Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach. Open Cardiovasc Med J. 2017;11(1):84-93. doi:10.2174/1874192401711010084
  7. Heart UK. What are the diagnostic criteria for FH? https://www.heartuk.org.uk/fh/fh-diagnosis-criteria.