Familial hypercholesterolemia (FH)

People with familial hypercholesterolemia (FH) have very high LDL cholesterol levels in their blood. This can be due to various genetic changes. In most cases, not enough LDL receptors are made as a result. Our bodies need these receptors to absorb LDL cholesterol into our cells. If we don’t have enough, large amounts of the cholesterol stay in our blood. Then it can build up in the walls of the blood vessels, preventing the blood from flowing properly.

The genetic disorder can be passed on by one or both parents. Because of this, there are two types:

• Heterozygous familial hypercholesterolemia (HeFH) is when the disorder comes from one parent. This happens in 3 out of 1,000 people. Without treatment, it’s common for their LDL cholesterol levels to be higher than 190 milligrams per deciliter (mg/dl) or 4.9 millimoles per liter (mmol/l).
• Homozygous familial hypercholesterolemia (HoFH) is passed on by both parents. This form is very rare. It only occurs in fewer than 1 out of 100,000 people. They often have LDL cholesterol levels of over 500 mg/dl (12.9 mmol/l) if they don’t get treatment.

To give you an idea of what this means: Ideally, your LDL cholesterol should be lower than 130 mg/dl (3.4 mmol/l).

High cholesterol isn’t something you can feel. There aren’t any symptoms until it causes problems like poor blood flow or, in more serious cases, a heart attack.

If you have a lot of excess cholesterol, it can start to collect under your skin. This can cause yellowish nodules or lumps (xanthoma) around your Achilles tendons or above your eyelids. They can also appear around the tendons in your hands, resulting in swelling. You might develop a light-colored ring around the iris of your eyes too.

Visible fatty deposits tend to be more common in the rare, homozygous form of familial hypercholesterolemia. Then they often already occur in childhood. Sometimes they develop in people with the heterozygous form too.

Familial hypercholesterolemia is typically diagnosed by a doctor. The diagnosis is based on the following criteria:

• Cholesterol levels: The higher your LDL cholesterol, the more likely it is that you have FH. Levels of more than 400 mg/dl (10.3 mmol/l) are a sign of severe or homozygous FH.
• Your medical history: If you’re a man younger than 55 or a woman younger than 60 and you develop cardiovascular disease, it could be a sign of FH.
• Your family’s medical history: If you have close relatives who have very high LDL cholesterol or developed cardiovascular disease when they were young, that could also be a sign of FH.
• Physical signs of high cholesterol: Visible fat deposits around your tendons or in your eyes are a strong indication that you have FH.

Familial hypercholesterolemia can also be diagnosed through genetic testing. These tests show whether you have a genetic disorder that’s causing FH. They're usually done if it’s not possible to make a diagnosis based on the other criteria. But gene tests can’t detect all types of genetic disorders.

Typically, your blood will be tested to determine your cholesterol levels. This test is also known as a lipid profile or lipid panel. It measures your LDL, HDL, and overall cholesterol levels as well as your triglycerides.

People with familial hypercholesterolemia develop diseases like heart attacks and narrowing of the heart valves (stenosis) more often and at a younger age than other people do.

Around 50 out of 100 men with heterozygous FH develop cardiovascular disease before their 50th birthday if they don’t have treatment. The estimate for women is a good 30 out of 100 before the age of 60.

People with homozygous FH are affected even earlier: It is common for them to develop cardiovascular disease before they turn 20 if their cholesterol levels aren’t reduced with treatment. Even if they do get treatment, they will develop cardiovascular disease for the first time at the age of 37 on average.

If you have familial hypercholesterolemia, you can lower your risk of cardiovascular disease by adopting a healthy lifestyle. That means things like eating a healthy diet, getting enough exercise, and not smoking. Getting good treatment for risk factors like high blood pressure or high blood sugar can help too. If your LDL cholesterol is only slightly too high and you haven’t got any other risk factors, these lifestyle changes might be enough. That doesn’t happen very often though.

Most people with FH can’t reduce their cholesterol enough without taking medication. That’s because most of the cholesterol is produced in the body and the genetic disorder causes it to build up in the blood. So the cholesterol levels and risk of cardiovascular disease can usually only be reduced by taking medication for the rest of your life. Statins are typically used for this purpose.

If you have familial hypercholesterolemia but your cholesterol isn't very high, you still might benefit from taking statins. There are two reasons for this:

• According to current research, LDL cholesterol is not the only factor that increases the risk of cardiovascular disease in people with FH. It seems that those with the condition develop cardiovascular disease more often than people without it even if their LDL cholesterol levels are the same.
• The medication doesn’t just lower your LDL cholesterol. It also reduces inflammation in the walls of your blood vessels and has an antioxidant effect there.

So statins don’t just decrease the amount of cholesterol deposited in those walls. They also stabilize the deposits that are already there, which means that fewer bits break off and cause problems like heart attacks.

There are various types of cholesterol-lowering medication. The main ones are:

• Statins: These are the best-studied cholesterol-lowering drugs. They block a specific enzyme in the liver cells. The cells then produce less cholesterol and can absorb more from the blood. Commonly prescribed statins include atorvastatin, rosuvastatin and simvastatin. Statins are usually taken once a day in the form of a tablet.
• Bempedoic acid: This medication reduces the amount of cholesterol made in the liver. It can either be taken on its own or in combination with ezetimibe. Bempedoic acid is taken once a day in the form of a tablet.
• Ezetimibe: This medication reduces the amount of cholesterol that the body absorbs from food. It is available under a wide range of brand names from various manufacturers. Ezetimibe is taken once a day as a tablet. You can also get products that combine ezetimibe with a statin.
• PCSK9 inhibitors: These include alirocumab, evolocumab and inclisiran. They increase the number of LCL cholesterol receptors. That enables the liver to absorb more cholesterol. PCSK9 inhibitors are given as an injection every two to four weeks or every three to six months, depending on the type. They’re only allowed to be prescribed by doctors specialized in heart problems (cardiologists), kidney diseases (nephrologists), hormone-related diseases (endocrinologists), diabetes, or blood vessels (angiologists), or by people who work at outpatient centers for lipid metabolism disorders.

The doctor will typically prescribe one statin first, usually at a medium or high dose. If that doesn’t reduce your cholesterol enough, the statin can be combined with ezetimibe and/or bempedoic acid. If that doesn’t help enough either, the doctor might suggest PCSK9 inhibitors. In rare cases, treatment with statins isn’t possible. Then the doctor can prescribe other medications from the start.

People with the rare, homozygous form of familial hypercholesterolemia can be prescribed a combination of medications as soon as they begin treatment.

Research has proven that cholesterol-lowering medications significantly reduce the risk of cardiovascular disease. One study involved about 2,000 people who had heterozygous FH and were around the age of 40. This study looked at how many people developed coronary artery disease (like a heart attack) within 5 years. It found that this happened in

• around 30 out of 100 people who did not take statins, and
• only around 5 out of 100 people who took statins.

This protective effect is backed up by other research.

The vast majority of people tolerate statins very well. One possible side effect is muscle pain: According to research, statins caused muscle pain in about 1 out of 100 people. Those who experience side effects can switch to a different statin.

Statins can sometimes cause muscle damage but this is very rare. When it does happen, your muscles become painful, weak, or swollen. This typically affects your shoulders, legs, or back. Damage to your muscles also increases the level of the enzyme creatine kinase in your blood. The most severe form of muscle damage is called rhabdomyolysis. Here, large amounts of muscle cells break down and get into your bloodstream. This can potentially lead to kidney damage. Another sign of rhabdomyolysis is reddish or dark urine.

If you think you might have muscle damage or rhabdomyolysis, it’s important to stop taking the statins and seek medical advice straight away. But this type of complication is very rare: Research on statins in adults showed that around 1 out of 10,000 people per year developed muscle damage and even fewer developed rhabdomyolysis.

Statins shouldn’t be taken in combination with certain other medications because they interact with them. One example is the antibiotic clarithromycin. To prevent interactions like this, it's important to always tell your doctor about any medications you're taking. If you’ve been prescribed statins, you also need to avoid grapefruits. This fruit can make it difficult for your liver to break the statins down.

There has been less research on these drugs than on statins. Because of this, it’s more difficult to assess the risk of rare side effects. The research that has been done focused on combined use with statins.

It was found that bempedoic acid causes gout in around 1 out of 100 people when taken over several years. About 1 out of 100 people develop gallstones.

The research on ezetimibe showed that it didn’t increase the risk of side effects.

PCSK9 inhibitor injections can result in itching, redness and swelling in the area where the needle is inserted.

There’s no standard recommendation here. Some experts recommend reducing LDL cholesterol (LDL-C) to below a certain amount. The German Cardiac Society (DGK), for instance, recommends reducing it to under 70 mg/dl (1.8 mmol/l). For people who already have cardiovascular disease, it recommends going even further and aiming for a level below 55 mg/dl (1.4 mmol/l). But it can be difficult to reach a specific target, especially if your LDL-C was high to begin with. Because of this, other experts recommend a reduction of at least 50%. To give you an idea of what that means: If you started at 300 mg/dl (7.8 mmol/l), you’d need to decrease it to under 150 mg/dl (3.9 mmol/l).

It is useful to get your cholesterol checked regularly. Then you get a feel for how well you’re doing. For some people, these checks are also a helpful way to stay motivated. But there’s no need to worry if your LDL-C is sometimes slightly higher or you don’t reach your target. This is because

• statins don’t decrease everyone’s LDL-C by the same amount.
• Targets are only meant to be used as a guide.
• Your LDL-C levels can vary by around 10% due to your diet, inaccurate measurements, and other factors.

How much you want to lower your cholesterol will also depend on your own, personal situation. So it’s a good idea to talk to your doctor about your treatment goals. The following aspects may play a role in your decision:

• Your age when you’re diagnosed: If FH is diagnosed later in life, your arteries will have been dealing with the high cholesterol levels for a longer time.
• Cholesterol levels before treatment
• Other risk factors for cardiovascular disease, like high blood pressure, diabetes, and smoking
• Any medical conditions that you have (had) due to high cholesterol, like a heart attack

If you have very high cholesterol or already have heart disease, more intensive treatment might be recommended. If FH was already diagnosed when you were quite young or if you have no other risk factors, a less intensive level of treatment might be enough.

Other options are available, mainly for people who have homozygous familial hypercholesterolemia and very high cholesterol. They include special medication and a complex process known as apheresis. In apheresis, the excess LDL cholesterol is removed from your blood by a machine every one to two weeks – a bit like dialysis.

These treatments are only considered if other approaches don’t lower your LDL cholesterol levels enough. It is best to talk to your doctor about whether they're suitable for you.

The recommendation for people with heterozygous familial hypercholesterolemia is to get their cholesterol checked at least once a year, and more frequently than that at the beginning of their treatment. Then the treatment can be adjusted if needed.

You can also use the check-up appointment to talk to your doctor about other possible risk factors (like smoking) and any problems you’re having with the medication. If anyone in your family is diagnosed with a heart disease between your check-ups, it’s a good idea to tell your doctor about that.

Some doctors also offer blood vessel check-ups – for example, an ultrasound scan of the carotid artery in the neck. But there is no proof that these examinations help to prevent cardiovascular disease. Because of this, public health insurers in Germany only pay for examinations like carotid ultrasound scans if there’s reason to think there might be something wrong with your carotid artery or if you have certain symptoms.

If familial hypercholesterolemia is diagnosed early on, the person can start treatment when they’re still young. That way, their arteries won't have to deal with the high cholesterol levels for as long. With this in mind, some groups of experts have suggested doing blood tests to screen for FH in all toddlers. But most experts don’t think that’s necessary. It would require a great deal of planning and the vast majority of children wouldn’t benefit from having the blood test.

Instead, experts recommend carrying out a type of screening called “cascade testing.” Here, the screening is offered specifically for children whose parents have been diagnosed with familial hypercholesterolemia.

The testing is also recommended for first-degree and second-degree relatives. That mainly includes sisters, brothers, children, grandchildren, parents, aunts, uncles, nieces and nephews. In Germany, there are very precise rules on who can have genetic testing and people’s right to get advice about it beforehand.

Children can start taking statins between 6 and 10 years of age, depending on the drug. Parents should decide with the doctor when the right time is for their child to start treatment, based on their individual situation. That involves thinking about things like:

• How did the condition affect other family members?
• Does the child have any visible cholesterol deposits?
• How high is the child’s LDL cholesterol?

When prescribing the medication for a child, the doctor will usually start with the lowest possible dose and then increase it gradually if needed. Sometimes, the child might take other medication as well as statins.

There has been less research on treatment with statins in children and teenagers than in adults. But the research that has been done so far didn't point to any particular risks or any effects on their development.

Statins can cause the levels of certain substances in the blood to increase. These include alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the liver, as well as a muscle enzyme called creatine kinase. The increase in these levels isn’t usually a problem. But if they’re very high, it could be a sign of liver or muscle damage. So the doctor will typically check the levels of these substances before the child starts treatment, four weeks into treatment, and then every few months after that. They usually check the cholesterol levels at the same time.

The studies on treatment with statins in children were too small to assess the risk of muscle damage or rhabdomyolysis. But there may still be a small risk of these complications occurring.

You can still have children even if you or your partner have familial hypercholesterolemia. If you do have children, it’s important to get them tested for high cholesterol at an early age so they can have treatment if needed.

Familial hypercholesterolemia can play a role in family-planning decisions too. One thing it can affect is the type of contraceptive you choose. Taking a combination birth control pill can very slightly affect your blood fat levels, which can lead to a slightly higher risk of thrombosis. That doesn’t mean you can’t take this kind of pill. But some women or couples decide to use a different form of contraception instead.

Women who are planning to get pregnant are advised to talk to a gynecologist or cardiologist first. That way, they can rule out any risks the condition might pose. The main one is narrowing of the heart valves.

What’s more, women are advised to stop taking cholesterol-lowering medication when trying for a baby, during pregnancy, and while breastfeeding. It is a good idea for them to talk to a doctor then, too. Experts recommend coming off statins three months before a planned pregnancy because it’s not clear whether the medication might harm the unborn child. The research so far hasn’t indicated that it could, but only a small number of women participated in the studies so no reliable conclusions can be drawn.