What Is Familial Hypercholesterolemia (FH)?

Familial hypercholesterolemia is a genetic disorder where the cholesterol levels in your blood are dangerously high.

Cholesterol is a fatty substance that is made by your body, and it is also ingested from foods containing cholesterol. These foods include meats and dairy products. Cholesterol helps digestion, builds cell membranes, and makes hormones.

People with FH are unable to remove the extra cholesterol that builds up in their blood. This puts them at higher risk for developing coronary artery disease (CAD), and at a much younger age.

The extra cholesterol causes plaque to build up in other places, such as blood vessel walls, tendons, and the surface of the eye. As plaque gets larger inside the arteries, it becomes hard. This blocks the flow of blood into and out of the heart, and eventually can cause a heart attack.

Causes

Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are two types of cholesterol found in your blood. HDL is known as the “good” type because it sends the cholesterol used by your body to your liver, where it is removed. LDL is the “bad” cholesterol because too much of it causes plaque to build up and harden in your arteries.

Mutations in a group of genes that govern the processes that remove LDL from your blood cause FH. One of them, the low-density lipoprotein receptor (LDLR) gene, is responsible for most cases of familial hypercholesterolemia. This gene has instructions on how to make the LDLR protein.

LDLR protein binds to LDL in the blood, takes it into cells where it is used, and then removes it from the body. An LDLR mutation prevents the removal of LDL from the blood which causes high levels of cholesterol in the blood. Diet and exercise are not enough to lower it because the mutation is causing the problem.

A person with FH inherited one copy of the mutated gene from one parent. Sometimes, they can inherit two copies, one from each parent. In this rare case, the condition will be more severe and might show up earlier in life during childhood.

The LDLR gene mutation is inherited in autosomal dominant fashion, meaning it takes only one copy from one genetic parent to produce FH, and it is independent of sex. Other genes linked to FH include APOB, LDLRAP1, and PCSK9. These code for proteins needed for the proper operation of the LDLR protein.

Some people with FH may not have any mutations in the genes known to cause FH. This may be due to gene mutations not yet identified.

Signs and Symptoms

FH is diagnosed through a combination of blood tests, a physical exam, and family history. Not everyone will show symptoms, but the most common include:

A cholesterol level of over 190 mg/dL in adults and over 160 mg/dL in childrenLumpy masses around the joints (knees, knuckles, or elbows)Painful or swollen Achilles tendonYellow patches on areas of the eyelidsA light gray color in the shape of a half-moon on the outside of the cornea (the clear dome at the front of the eye)A family history of early onset of heart disease or heart attacks

A person with any of these symptoms may be a good candidate for genetic testing for FH.

Diagnosis: Familial Hypercholesterolemia Test

Mutations in the LDLR gene are the most common cause of FH, but mutations in APOB, LDLRAP1, and PCSK9 genes are also associated with the condition. If you show some of the symptoms of FH, your healthcare professional may recommend you get checked for these mutations. This process is called genetic counseling.

However, a genetic test is not necessary to diagnose FH. The diagnostic criteria are based on family history, personal medical history, symptoms, and LDL cholesterol levels. But because this condition is genetic, knowing you have the mutation may be helpful, especially if you don’t have access to family history.

Genetic Counseling

A certified genetic counselor (a healthcare professional educated in genetic medicine) will talk with you about genetic testing. This will include information on how a positive test for the mutation will impact you, your first-degree relatives (parents, siblings, children), and the value and limitations of testing.

A cholesterol test and a genetic test for the same variant may be recommended for your relatives.

Genetic Testing

If you make the decision to move forward with genetic testing, you’ll need to provide a genetic sample. Options include:

Blood drawCheek swabSaliva sampleOral rinse sample

FH-Causing Mutation: What It Means

A positive FH test means that a gene mutation was found. There is a 50% chance that the siblings, parents, and children of a person with a mutation have it as well.

Identifying the mutation as early as possible is important. Treatment reduces heart disease risk by 80%.

No FH-Causing Mutation: What It Means

A negative test for the FH mutation does not mean you do not have FH. Around 30% to 40% of people diagnosed with FH may test negative. The reason could be that they have an FH mutation that has not been discovered yet.

You will still need treatment for high cholesterol with a negative test result.

FH Management and Treatment

While following a healthy lifestyle won’t lower LDL cholesterol due to FH enough by itself, making necessary changes is still a very important step to take. These include eating a healthy diet, getting adequate exercise, quitting/not smoking, and limiting alcohol intake.

That said, medication or procedures will be the major part of any FH treatment plan. These may include:

Cholesterol-lowering medications: These include statins such as Lipitor (atorvastatin) and Crestor (rosuvastatin calcium), and bile acid sequestrants such as Welchol (colesevelam). LDL apheresis: This treatment uses a filtering machine to remove cholesterol from the blood. It may be considered in adults with LDL cholesterol greater than 100 mg/dL with the maximum tolerable cholesterol-lowering medications. PCSK9 inhibitor injections: These monoclonal antibodies include Repatha (evolucumab), Praluent (alirocumab), and Leqvio (inclisiran). They block the PCSK9 protein to help the body better remove LDL cholesterol from the blood.

Summary

Familial hypercholesterolemia (FH) is a genetic condition that causes very high levels of cholesterol. It increases your risk for heart disease and is caused by a mutation in the LDLR, APOB, and PCSK9 genes. These help your body control how much cholesterol is removed from your body.

Symptoms include a cholesterol level of over 190 mg/dL in adults (160 mg/dL or more in children), lumps around the joints, swollen Achilles tendons, or a family history of early heart attacks.

If your healthcare professional thinks you have FH, they might refer you for genetic counseling, where you will discuss the option for genetic testing. A positive genetic test for one of the mutations can confirm a diagnosis but is not necessary. People can also have a negative test and still have FH.

A positive test impacts your siblings, parents, and children because they have a 50% chance of also having the mutation.

Treatment might include cholesterol-lowering drugs, inhibitor injections to help the body better remove cholesterol from the body, or LDL apheresis, a treatment that removes cholesterol from the blood with a filtering machine.

A Word From Verywell

Often, the first sign that you may have familial hypercholesterolemia is a high cholesterol number on a routine lipid test. Having cholesterol that high can be very concerning. But the good news is that when diagnosed, FH treatment lowers your risk for heart disease by 80%.

While exercise and diet alone won’t lower high cholesterol due to FH, lifestyle changes are still important. These include eating a healthy diet, getting exercise, not smoking, and limiting alcohol intake.

Early diagnosis of FH is critical. If you have a family history of early heart disease, talk with your healthcare provider about your risk for FH.