What Is Hypercholesterolaemia?

Hypercholesterolemia is when you have high levels of total cholesterol, particularly low-density lipoprotein (LDL) cholesterol, in the bloodstream. 

High cholesterol can occur from several causes, including lifestyle factors, underlying medical conditions, or genetics.

One type of hypercholesterolemia is familial hypercholesterolemia (FH), a genetically inherited condition. 

What is familial hypercholesterolemia?

Definition

Familial hypercholesterolemia (FH) is a genetic condition where people have very high levels of LDL cholesterol in the blood. It currently affects more than one million people in the United States.¹ 

Cholesterol is a waxy, fatty substance that’s transported through the bloodstream. It’s present in animal products such as meat, eggs, and dairy, but the body also produces it. It has important functions in the body but needs to be kept at optimal levels for good health. 

One type of cholesterol, LDL cholesterol, is sometimes known as “bad” cholesterol because high levels clog up your arteries, which puts you at a greater risk for developing secondary heart and blood vessel conditions, such as atherosclerosis, at a young age. 

FH runs in families and is passed down from generation to generation due to a mutation. It’s present in children from birth but may not be discovered until adulthood, depending on the symptoms and complications. 

FH is an autosomal dominant condition, meaning that only one of your parents needs to pass on the mutation for you to inherit FH. 

There are two types of FH, based on whether you inherit a mutation from one or both of your parents. The disease of each type presents similarly, but the severity and outlook are different. 

Homozygous familial hypercholesterolemia

People with homozygous FH inherit a mutation from both parents.

Homozygous FH can be life-threatening if left untreated, with many patients developing overt atherosclerosis before their 20s and generally not living past age 30.

Homozygous FH is the rarer form of the condition, and it currently affects approximately one in 160,000–300,000 people.

Someone with homozygous FH has a 100% chance of passing the condition on to their children because they have both alleles that cause FH. 

Heterozygous familial cholesterolemia

People with heterozygous FH inherit a mutation from only one parent. 

Heterozygous FH is the more common form and affects between 70 and 95%² of all people with FH. It’s also the most common inheritable form of high cholesterol caused by a single gene. 

It’s estimated that about one in 220 people³ has heterozygous FH. It’s less severe than homozygous FH and often goes underdiagnosed because people may not have symptoms of high cholesterol for years until more serious complications arise. 

Someone with heterozygous FH has a 50% chance of passing the mutation on to their children because they still have one normal allele. 

In rarer cases, it might be a de novo mutation, which means it’s spontaneous, and you’re the first in your family to have FH.

Diagnosis

It’s thought that only 10–20%¹ of people living with FH in the United States have actually been diagnosed with the condition. Even if they know that they have high cholesterol levels, they may be unaware of why. 

FH is often diagnosed when complications such as atherosclerosis have already developed. 

Diagnosing FH usually involves a combination of:

• examining physical features and symptoms

• checking family history and performing genetic testing to see if you have a mutation that causes FH

• taking blood tests to check your lipid profile and cholesterol levels

• considering heart disease and testing for heart problems with a stress test

• having a biopsy to confirm that the skin lesions are xanthomas (bumps or rashes on the skin)

Although no universal diagnostic criteria exist, one popular way to diagnose people with heterozygous FH is the Simon Broome Register⁴ criteria. This involves: 

Extreme hypercholesterolemia

• a total cholesterol concentration greater than 7.5mmol/L (135mg/dL) in adults or greater than 6.7mmol/l (120mg/dL) in children under 16 years old

• an LDL cholesterol concentration of greater than 4.9mmol/l (88.2mg/dL) in adults or greater than 4.0mmol/l (72mg/dL) in children 

For reference, average total cholesterol levels in healthy people are below 5.2mmol/L (200mg/dL), and LDL cholesterol levels are below 3.4mmol/L (130mg/dL). 

The presence of tendinous xanthomas 

Xanthomas are bumps or rashes that appear on the skin, tendons, and underlying tissue when macrophage cells in the skin take up cholesterol and form cells. 

Tendinous xanthomas are usually located in the Achilles tendons. 

Mutation

DNA evidence of a mutation in the LDL receptor is a key feature of FH. 

Family history of heart problems 

People with FH may have a family history of heart problems, such as:

• a family history of heart attacks in first-degree relatives (your parents, full siblings, or child) under 60 years old

• a family history of heart attacks in second-degree relatives (such as your aunt/uncle, grandparent, nephew/niece, or half-sibling) under 50 years old

Family history of high cholesterol 

People with FH have a family history of high cholesterol: 

• a family history of a total cholesterol concentration of 7.5mmol/l or greater in your first or second-degree relatives 

A diagnosis of FH can be confirmed if the first points of the criteria are met. If only points 1 and 4, or 1 and 5, are met, you likely have heterozygous FH, but confirming it may not be possible. 

The criteria for diagnosing homozygous FH are similar. However, the main differences include:

• the requirement to have two mutations in the LDL receptor

• cutaneous or tendon xanthomas that occur before the age of 10

• untreated LDL levels over 13mmol/L (500mg/dL), or treated LDL levels 8mmol/L (300mg/dL) or greater 

Symptoms

Many people don’t know they have high cholesterol levels. In particular, heterozygous FH has been described as a silent disease, as it’s less severe and often remains asymptomatic until complications arise. 

Some common symptoms of FH include:

Skin problems

People with high cholesterol often develop a rash or bumps on the skin due to excess cholesterol deposits. 

These may worsen with age as cholesterol levels continue to rise. 

You may notice:

• bumps around the knuckles, elbows, or knees

• yellowish patches or small lumps around the eyes (called xanthelasmas)

• a whitish-gray arc, known as corneal arcus, develops on the outside of the cornea of your eye (more common in people under 45)

Pain 

People with high cholesterol may experience different types of pain, including:

• pain and swelling in your Achilles tendons, which may be a sign of tendon xanthomas

• cramping in your calves when you walk

• sores on the toes that don’t heal properly

• tendinitis or joint pain (arthralgia) 

Additional symptoms due to complications of high cholesterol

The complications that arise due to high cholesterol can bring on a range of new and different symptoms, including:

• sudden onset of stroke-like symptoms (can include a drooping face, weak limbs, loss of balance, and difficulty speaking)

• chest pain (angina), which could be a sign of heart disease

• additional symptoms associated with secondary heart disease, vascular disease, aortic stenosis, or heart attacks 

Risk factors

Direct causes of familial hypercholesterolemia

FH is an inherited condition. The direct cause of it is inheriting a mutation in a gene from one or both of your parents. 

Having a mutated gene means you will develop FH, even if you don’t have any other risk factors for high cholesterol. 

However, some factors could cause the disease to worsen or progress further or more quickly. 

A first- or second-degree relative with FH increases one’s chance of getting FH. If you have FH, your parents and siblings have a 50% chance of having it. 

It’s not caused by lifestyle like some other FH forms are. So you can’t prevent it based on risk factors. 

Who is more likely to develop familial hypercholesterolemia?

FH affects men and women equally.

However, it’s thought to be more common in certain populations and ethnic groups. This could be due to the founder effect, which occurs when a small group of individuals becomes separated from a larger group, giving the smaller population an increased chance of inheriting the FH mutations because less genetic variability exists. 

FH is more common in: 

• South African Ashkenazi Jews

• South African Afrikaners

• Christian Lebanese groups

• Old Order Amish

• French Canadians

• Finnish people 

Other risk factors

Genetic and environmental risk factors can play a role in the progress of the disease. Obesity, eating a high saturated fat diet, smoking, and being sedentary can worsen your cholesterol levels if you have FH. 

Treatment

FH has no cure, but it can be treated. 

The treatment is similar for both heterozygous and homozygous FH. Ultimately, it aims to lower cholesterol levels in the blood. Often, LDL cholesterol needs to be lowered by at least 50%, according to the National Lipid Association guidelines. 

Treatment is important to reduce the risk of developing heart disease, a complication of hypercholesterolemia. 

When LDL cholesterol accumulates in your blood, it can narrow, harden, and block your arteries, which causes a condition called atherosclerosis. This makes it harder for blood to flow around the body, meaning that your heart needs to work harder to pump the blood. 

FH can also lead to peripheral artery disease, aortic aneurysms, and other cardiovascular diseases. 

Untreated FH causes heart attacks in 30% of people by age 60 and 50% by age 50. However, it’s also been shown that your risk of coronary artery disease can be reduced by 80% by treating FH. 

If homozygous FH is untreated, people often die before age 20. Because of this, treatment for homozygous FH is usually more aggressive than that for heterozygous FH. 

Medications

You may need to take more than one type of medication to bring your LDL levels into a healthy range. 

 Most medications for FH work by lowering your LDL cholesterol levels and should be started as early as possible for the best outcome. 

Statins

High-dose statins are usually the primary choice of medication for FH. 

Statins slow down the production of cholesterol in the liver by blocking the enzyme that produces it. They also help the liver to remove LDL from the blood. 

Some examples of statins are atorvastatin (Lipitor), lovastatin (Altoprev), and simvastatin (Zocor). 

Statins are also suitable for children who have FH, and it is often advised that they begin taking statins from 8–10 years old. 

Although statins are effective, they only reduce LDL by 10–25%, which may not be enough for treating FH.  

Ezetimibe 

Ezetimibe (Zetta) lowers cholesterol by inhibiting its absorption from the digestive tract when you eat food containing cholesterol. It’s usually taken in combination with another drug, such as statins. 

Ezetimibe is often taken with statins and can add an additional 10–30% reduction in LDL cholesterol. 

PCSK9 inhibitors

PCSK9 inhibitors can help reduce cholesterol levels. PCSK9 is a protein made in the liver that breaks down LDL receptors, resulting in higher cholesterol levels. PCSK9 inhibitors stop the PCSK9 protein mechanism from working. 

Bempedoic acid

Bempedoic acid inhibits an enzyme that’s responsible for producing cholesterol in the liver. It can reduce LDL cholesterol — either in combination with other treatments or as an alternative to them. 

Bempedoic acid is recommended for people with heterozygous FH and those who may be unable to take statins. 

Lomitapide 

Lomitapide(Juxtapid) prevents the liver from secreting VLDL, the type of cholesterol converted to LDL. 

Lomitapide is usually only used for people with homozygous FH. 

One study found that lomitapide reduced LDL by 50% over 26 weeks. 

Aspirin

A low dose of aspirin can be used in people at risk of developing cardiovascular disease or stroke due to their high cholesterol levels. 

Medical procedures 

Low-density lipoprotein apheresis 

LDL apheresis is a similar process to dialysis. It filters and removes excess cholesterol from your blood by separating the cholesterol from the plasma, removing LDL, and then returning the plasma to your body. 

LDL apheresis is generally used for children with homozygous FH from the age of five. 

A single treatment can decrease LDL by 55–70% in relation to pretreatment levels. But this only lasts a short while, so repeating the treatment once a week is recommended — this can achieve near-normal LDL levels. 

Some adverse side effects are associated with LDL apheresis, such as low blood pressure, abdominal pain, nausea, and iron deficiency anemia. 

Liver transplant

In rare cases, some people with homozygous FH benefit from a liver transplant. 

The liver is important for producing and clearing LDL from the bloodstream. Transplanting in a healthy liver that doesn’t have the mutation associated with FH can treat the condition. 

Transplantation can be complex, with a high risk of rejection and the potential need for immunosuppressors. 

Lifestyle changes

A healthy lifestyle is important for anyone with high cholesterol levels. 

Making healthy changes can reduce LDL cholesterol in some people, but it’s unlikely to be enough for treating FH. This is because it’s genetic and not directly caused by lifestyle. A healthy lifestyle also can’t stop FH from developing if the responsible mutation is present. 

However, lifestyle changes can still play an important part in treatment. 

Diet

A heart-healthy diet is recommended. A dietician can help you make healthy diet changes, such as:

• limiting foods high in saturated and trans fats (including fatty meats such as pork and beef, coconut and palm oil, full-fat dairy foods, processed baked goods, and egg yolks)

• limiting foods high in cholesterol (meat, dairy, eggs)

• eating foods high in soluble fiber, such as oats, apples, beans and legumes, avocados, and citrus fruits (It’s recommended to aim for at least five or 10 grams per day; fiber can help reduce cholesterol because it binds to LDL and removes it in your stool.) 

• eating an abundance of fruits and vegetables

• obtaining your protein from lean poultry, fish, and low-fat dairy

• consuming legumes, nuts, and whole-grain foods

• eating foods that contain plant stanols and sterols (these block the absorption of cholesterol)

Reduce your alcohol use

People with high cholesterol should try to limit their use of alcohol as much as possible. Drinking a maximum of 14 units per week and having some days without alcohol are two recommendations. 

Although alcohol doesn’t contain cholesterol, it’s broken down into triglycerides and cholesterol in the body, increasing the amount that circulates in your blood. 

Excessive alcohol use can also damage your liver, which could impair its ability to remove cholesterol from your blood and break it down. 

Stop smoking 

People with high cholesterol are advised to stop smoking⁵ cigarettes. Smoking damages blood vessels and can further increase your risk of heart disease. 

Exercise 

Staying physically active is a healthy way to treat high cholesterol. It’s recommended to undertake the moderate-intensity exercise for 30 minutes five times a week. Aerobic and toning exercises can both prove effective.

Weight management

You should try to maintain a healthy weight and lose weight if you’re overweight. 

People who are overweight or have obesity are more likely to develop heart disease, heart attacks, or strokes — the risk of which is already increased by having FH. 

Manage other risk factors and complications

It’s important to do your best to manage other risk factors for heart disease, such as high blood pressure and diabetes. 

This can reduce your risk of having complications from high cholesterol. 

Other ways to manage familial hypercholesterolemia 

• Check your cholesterol levels regularly, every two to three months.

• Check your cardiovascular health regularly.

• People with the homozygous version may need imaging tests, such as an annual Doppler echocardiogram of the heart and aorta, a CT angiogram, or cardiac catheterization. 

How does familial hypercholesterolemia raise cholesterol?

In healthy people, LDL is transported to the surface of cells that have LDL receptors. When LDL is taken into these cells, it’s broken down, preventing too much LDL from accumulating in the blood. 

People with FH inherit one or two mutations that cause a problem with how cholesterol is broken down in the body, ultimately causing high cholesterol levels in the blood. 

Mutations can occur in a few different genes, such as: 

Low-density lipoprotein receptor 

This is a mutation in the LDL receptor that is most common in FH and occurs almost 80%⁶ of the time. People with this mutation don’t have enough LDL receptors, so cholesterol can’t be removed from the blood. 

Apolipoprotein B gene 

This is a less common mutation that only occurs 5% of the time. It causes LDL to not bind as effectively to the receptors, so it’s removed more slowly from the body. 

PCSK9 gene

This mutation in the PCSK9 gene is very rare and is only present in 1% of people with FH. It causes the LDL receptors to break down in the liver. 

A small number of people with FH have other rare mutations that occur in different genes. 

When you should see a doctor 

If one of your relatives informs you that they have FH, particularly if they’re your parent, sibling, or child, and you have a family history of heart attacks, you should see a doctor because you may also have the condition. 

Your doctor will ask you for details about your family medical history, advise you to get a blood lipid test, and complete a physical examination (looking for xanthomas, blood pressure, etc.). They may refer you for genetic counseling and genetic testing. 

An early diagnosis of FH gives you the best outcome possible and can also help protect your family members. 

If you have FH, you should see your doctor regularly so they can monitor your cholesterol levels and heart health. 

Medical professionals who are involved in FH care include your family doctor, cardiologists (heart specialists), endocrinologists (hormone specialists), lipid (fat) specialists, dieticians, pharmacists, and nurses. 

You should seek urgent medical attention if you have FH and ever develop chest pain. 

The lowdown

FH is a genetic condition that causes very high cholesterol levels in the blood. 

Although no cure for FH exists, it is treatable. An early diagnosis of FH, before high cholesterol damages your blood vessels, gives you the best possible outcome. A combination of medication, lifestyle changes, and sometimes more invasive medical procedures can enhance the quality of life and significantly improve the prognosis of FH.