What Is Familial Hypercholesterolaemia?

We inherit several traits from our parents and grandparents, including our physical features, our intelligence, and even what diseases we are more likely to get. Did you know that you can inherit high cholesterol (hypercholesterolaemia) from your parents? And that it is a severe form that can increase your risk of heart attacks if left untreated, especially at a young age?¹

This type of high cholesterol is called familial hypercholesterolaemia. Familial hypercholesterolaemia is a relatively uncommon genetic condition. It is estimated to affect 1 in 250 people and, if left untreated, can cause heart attacks in 30% of women by 60 years and 50% of men by 50 years.¹

Read on to learn more about familial hypercholesterolaemia, to find out if you are at risk of having this condition, and what to do if you think you may have it.

Overview

Cholesterol is a type of fat that is essential to the body. Among its many roles, it is part of the membranes of cells that form the organs and structures in your body. In addition, cholesterol helps make hormones, bile salts, and vitamin D.²

The problem starts when your cholesterol level is too high, a condition medically known as hypercholesterolaemia.¹ You may have heard that there are various forms of cholesterol, the common ones being low-density lipoprotein (LDL), often referred to as ‘bad cholesterol,’ and high-density lipoprotein (HDL), which is called ‘good cholesterol.’ Good cholesterol protects the heart, while bad cholesterol does the opposite.³

For a healthy individual, the total cholesterol (the sum of good and bad cholesterol) in the blood should be below 5 mmol/L.⁴ Additionally, the level of bad cholesterol should be below 3 mmol/L, while good cholesterol should be above 1.0 mmol/L for men and above 1.2 mmol/L for women.⁴

In familial hypercholesterolaemia (FH), bad cholesterol levels are often above 4.9 mmol/L in adults and above 4.1 mmol/L in children.¹ This is due to a mutation affecting genes involved in removing bad cholesterol from the blood, which results in high levels of bad cholesterol.¹ FH can be detected from birth, and children with FH tend to have thicker arteries than children who do not have FH.

Without early intervention, FH increases the risk of heart disease later in life, so NICE guidelines state that children should be diagnosed before the age of 10.⁵ However, there is no long-term data on the safety of current treatments in children. The FH Paediatric Register was created to monitor their effects over time.⁵

In addition to the high levels of bad cholesterol in individuals with FH, those affected usually have a history of heart attacks or heart disease affecting family members, often at a young age.^1,5

Causes of familial hypercholesterolaemia

FH is thought to occur due to mutations in genes that regulate cholesterol production and how your body moves cholesterol out of the blood and into cells.^1,5 These are inherited from your parents and affect the following genes:

• The low-density lipoprotein receptor gene (LDLR; lets bad cholesterol enter cells) 
• The apolipoprotein B-100 gene (APOB; a component of bad cholesterol) 
• The proprotein convertase subtilisin/kexin type 9 gene (PC5K9; degrades LDLR to stop bad cholesterol getting into cells) 
• The apolipoprotein E gene (APOE; binds to LDLR to help bad cholesterol enter cells) 

Individuals with FH usually have a mutation affecting one of the genes mentioned above. However, mutations can affect more than one of these or other genes involved in cholesterol regulation.¹

Most individuals with FH inherit these FH-causing mutations from one parent. Mutations inherited from one parent result in heterozygous familial hypercholesterolaemia.¹ In rare cases, some individuals can inherit these mutations from both parents. This causes a severe form of FH called homozygous familial hypercholesterolaemia.¹

Signs and symptoms of familial hypercholesterolaemia

If you have never been tested for high cholesterol, you may not be aware that you have it because it usually doesn’t produce symptoms. However, certain signs and symptoms alongside high levels of bad cholesterol may indicate that you may have FH. These symptoms result from cholesterol buildups, and include (1)(6):

• Bumps around your knees, ankles, and knuckles 
• Swollen or painful Achilles tendons (at the back of your ankles)
• Yellowish bumps around the eyes
• A whitish-grey ring around the iris (the coloured part) of your eyes 

Management and treatment for familial hypercholesterolemia

FH increases your risk of heart attacks by 22% if left untreated. Therefore, those diagnosed with FH should begin treatment to prevent this.⁷

Individuals with high cholesterol are usually advised to make lifestyle changes to lower their cholesterol levels. This includes eating a low-fat and high-fibre diet, increasing activity levels, quitting smoking, limiting alcohol consumption, and controlling blood pressure and diabetes.⁷

In FH, although the above recommendations may be beneficial, diet and lifestyle changes alone will not lower cholesterol levels sufficiently.⁷ In all cases of FH, cholesterol-lowering medicines are recommended in addition to lifestyle changes. Some individuals may need to take more than one type of cholesterol-lowering medication to reduce their cholesterol levels and risk of heart attacks.⁷

The most common type of cholesterol-lowering medicines are statins. Other types are also available, including cholesterol absorption inhibitors, PC5K9 inhibitors and fibrates.^6,7 Children as young as eight years can start treatment with statins, which significantly decrease the risk of heart disease.^5,7 In the UK, treatment for FH is offered at specialist lipid clinics.⁵

Treatment may be slightly different if you inherited mutations in the cholesterol-regulating genes from both parents. In rare cases, these individuals may even need a liver transplant.⁷

Diagnosis of familial hypercholesterolaemia

In the UK, a diagnosis of FH is made using the Simon Broome FH criteria or the Dutch lipid network score.^5,8

Using the Simon Broome criteria: 

A preliminary diagnosis of FH can be made if an individual has high levels of LDL cholesterol (over 4.9 mmol/L) in addition to a family history of early coronary heart disease and/or high LDL cholesterol levels.⁵

A definitive diagnosis of FH is made if the above are present and there are signs of hypercholesterolaemia (cholesterol deposits in the eyes, knees, ankles, knuckles, and/or Achilles tendons) and a positive genetic test result confirming mutations that cause FH.⁵

Using the Dutch lipid network criteria:

A diagnosis of FH can be made based on grading criteria where scores are assigned to each diagnostic criterion. A total score of 9 or greater is a definitive diagnosis of FH; between 6-8, FH is likely; between 3-5, FH is a possibility; and below 3, FH is unlikely. The Dutch lipid network criteria can be found here.⁸

Genetic testing:

The NHS intends to identify more individuals with FH, especially children, by carrying out cascade testing on first-degree relatives of those with confirmed FH.⁵ This is due to evidence that about 50% of these first-degree relatives (e.g. children and siblings) have also inherited genetic mutations that cause FH.⁵

Genetic testing confirms the diagnosis of FH by identifying mutations in the FH-causing genes. This will allow interventions to be started earlier, improving patient outcomes.⁵

Risk factors

FH is a genetic condition; therefore, you are more likely to have FH if:^1,5

• One or both of your parents has a mutation affecting any genes involved in regulating cholesterol (if either of your parents has the mutation for FH, there is a 50% chance that they can pass it on to you)
• You have a strong family history of heart disease affecting male family members before 50 years and female family members before 60 years

Complications

Individuals with FH are at a higher risk of heart disease, such as:^1,6

• Heart attacks 
• Angina (chest pain due to reduced blood flow to heart muscle) 
• Atherosclerosis (fat & cholesterol buildups in arteries) 
• Hypercholesterolaemia 
• Arrhythmias (irregular heart rhythms) 
• Heart failure

FAQs

Can familial hypercholesterolaemia be prevented?

Unfortunately, FH cannot be prevented because it is a genetic disease. However, if you or your partner have FH, you can seek genetic counselling prior to starting a family to determine the likelihood of your children having FH.

How common is familial hypercholesterolaemia?

FH is estimated to affect 1 in 250 people in the UK, but less than 8% of this estimate have been diagnosed.⁵ The 2019 NHS Long Term Plan has set an ambitious 5-year target of finding 25% of FH cases in the UK. 

When should I see a doctor?

See your GP or healthcare professional if:

• If you have a family history of heart disease 
• If your father, son, brother, or uncle had a heart attack or heart disease before the age of 50 
• If your mum, sister, daughter, or aunt had a heart attack or heart disease before the age of 60 
• If your parents or family have FH
• If you have any of the signs of FH listed above

Summary

FH is a genetic condition characterised by high levels of bad cholesterol (LDL) in your blood. Although it is not possible to avoid getting FH, knowing that it can be easily managed by medicines and lifestyle changes makes receiving a diagnosis less daunting.

The key preventative measure against FH complications is getting tested for mutations in the FH-causing genes, especially if you have a family history of FH or any symptoms mentioned above. In addition, you should consider living a healthy lifestyle to reduce your risk of heart disease and improve your quality of life.

The take-home message is that individuals with FH can live long and healthy lives if they adhere to their treatment regimen and adopt a healthy lifestyle.