What is Familial Hypercholesterolemia?
Familial hypercholesterolemia (FH) is a condition that you can inherit from your family, causing high cholesterol levels in your blood. Specifically, it leads to a high-level of what’s known as low-density lipoprotein (LDL), often termed as ‘bad cholesterol’. This inherited condition can be split into two subgroups depending on how it’s passed onto the next generation: (1) autosomal dominant (AD), which means you only need the gene from one parent to inherit it, and (2) a codominant transmission type, which has a 90% or higher chance of showing up if you have the genetic material from your parents.
The most common type of familial hypercholesterolemia is the autosomal dominant version. In medical terms, people with this condition typically fall into categories named type 2a, 2b, and 3 hyperlipidemias; however, type 2a is the most common form of this condition. Having high ‘bad cholesterol’ levels in your body due to familial hypercholesterolemia increases your risk of developing diseases related to buildup of cholesterol in your artery walls (atherosclerotic disease), which could lead to an early death.
It’s vital to detect familial hypercholesterolemia early and to aggressively work on lowering the LDL cholesterol level; doing so can prevent or slow down the buildup of cholesterol in your arteries. It’s also recommended that first-degree relatives (parents, siblings, children) of a patient with this condition get tested as well, to identify and treat anyone else in the family who might carry these genes.
What Causes Familial Hypercholesterolemia?
Familial hypercholesterolemia is a genetic condition that causes extremely high levels of “bad” cholesterol, known as low-density lipoprotein (LDL) cholesterol. There are three main genetic mutations that we know can lead to familial hypercholesterolemia: defects in the LDL receptor (which are the most common), in a protein called apolipoprotein B (ApoB), or in another protein called proprotein convertase subtilisin/Kexin type 9 (PCSK9). All of these mutations cause an issue with the LDL receptors on your body’s cells, making it harder for your body to absorb LDL cholesterol. As a result, LDL cholesterol levels in your blood get very high.
Whether the mutation is inherited from one parent (heterozygous defect) or both parents (homozygous defect) can affect how severe the disease is and when symptoms of heart disease start to occur. In cases where children get the defective gene from both parents, they usually have virtually no LDL receptors to absorb LDL cholesterol, which leads to extremely high LDL cholesterol levels and early onset of heart disease.
There are over 1600 possible mutations of the LDL receptor gene, and these are found in 85-90% of people with familial hypercholesterolemia. APOB mutations account for about 10% of cases, with a specific mutation known as Arg3500Gln being the most common. Less than 5% of people with familial hypercholesterolemia have a mutation in the PCSK9 gene, and only severe mutations in this gene can cause the disease. Additionally, a less common mutation in a gene called signal-transducing adaptor family member 1 (STAP1) has been reported to cause familial hypercholesterolemia.
Risk Factors and Frequency for Familial Hypercholesterolemia
Familial hypercholesterolemia, a condition linked to high cholesterol levels in the blood, affects about 1 in 250 individuals over the age of 20 in the U.S. It is most commonly seen between the ages of 60 and 69, and least common between 20 to 29. The condition happens in both men and women equally, but it’s more often seen in people who are obese or of black descent. Studies from other countries show different prevalence rates – 1 in 217 individuals in Denmark, 1 in 150 in Quebec, and 1 in 70 in South Africa. There’s an estimate that worldwide, about 10 million people have this condition.
- Folks of Finnish, Afrikaner, Lebanese, Ashkenazi Jewish, or French Canadian descent are more likely to have familial hypercholesterolemia.
- This condition is inherited the same way in both males and females, as the related gene is found on chromosome 19.
- Patients are born with a faulty LDL cholesterol receptor, and the longer they live with extremely high LDL cholesterol levels, the higher their risk of coronary artery disease (CAD).
Signs and Symptoms of Familial Hypercholesterolemia
Homozygous Familial Hypercholesterolemia is a condition where individuals might experience problems linked to heart disease, problems with the blood flow in the body, disease that affects the brain’s blood vessels, or narrowing of the heart’s main outflow valve. Patients could also be dealing with inflammation of the tendons or joint pain and might have had unusual skin changes in the past. It is challenging for these patients to live past 30 years if they are not treated with special methods.
In Heterozygous Familial Hypercholesterolemia, patients suffer from extremely high cholesterol levels from a young age. It’s not uncommon for these patients to show signs of heart disease, particularly if they have other factors that increase their risk for heart problems. They may also experience regular inflammation of the Achilles tendon or joint issues.
It is very important to take a detailed family history when diagnosing familial hypercholesterolemia. Warning signs are a family history of early heart disease or high cholesterol in close relatives (women under 60 years old and men under 55 years old). Even younger patients with close relatives who had early heart problems should increase suspicions for the presence of familial hypercholesterolemia.
During a physical examination, doctors will often notice abnormalities related to cholesterol deposits in the eye or the skin. This is really common amongst those with Homozygous Familial Hypercholesterolemia. Tendon xanthomas are a kind of tendon thickening due to the cholesterol depositing within certain cells in the body’s connective tissues. The tendons at the back of the heel and those that straighten the fingers are the most common places for this, but it can also happen at the kneecap or on the muscles at the back of the upper arm. Cases of familial hypercholesterolemia can be identified with tendon xanthomas, but it will be seen in less than half of patients. A condition called Corneal arcus is depositing of cholesterol around the edge of the cornea. Participants aged below 45 usually indicate this case. If the patient is between 20 to 25 years, cholesterol can also be seen deposited in other skin areas in a condition known as xanthelasma.
Testing for Familial Hypercholesterolemia
If you have a family history of high cholesterol or early heart disease, it is important that you get tested for a condition known as familial hypercholesterolemia (FH), which is inherited and starts from a young age. This testing should be done starting at the age of 2 and should include measuring your non-high-density lipoprotein (non-HDL) cholesterol levels. This test can be done without fasting and is especially crucial for children aged 9 to 11 years. Children who have a non-HDL cholesterol level higher than 145 mg/dL should have further tests done that require fasting.
Physicians might suspect you have FH if:
1. You are 20 years or younger and have a low-density lipoprotein (LDL, also known as “bad cholesterol”) level of 160 mg/dL or higher, or non-HDL cholesterol levels of 190 mg/dL or higher.
2. You are older than 20 years and your LDL cholesterol levels are 190 mg/dL and higher, or non-HDL cholesterol is 220 mg/dL and higher.
3. There’s a history of FH in your family or one of your parents has a total cholesterol level of greater than 240 mg/dL.
4. Cholesterol deposits are found in your tendons or you have signs of cholesterol deposits in your corneas if you’re less than 45 years old, or skin colored cholesterol filled bumps (Xanthelasma tuberous) if you are between 20 to 25 years old.
There is a possibility of having two types of FH – heterozygous FH (HeFH) where you inherit the gene from one parent and homozygous FH (HoFH) when you inherit the gene from both parents and the condition is much more severe. The most commonly used criteria for diagnosing FH include LDL levels, presence of xanthomas, family history of FH, and specific genetic mutations. Although genetic tests are not always necessary for diagnosis, they can be helpful when the diagnosis is unclear.
In cases of HeFH, patients are usually categorized into different levels of FH, from unlikely FH to definite FH, depending on various factors including LDL levels and the presence of a genetic mutation.
In cases of HoFH, diagnosis is normally confirmed when untreated LDL-C plasma levels are greater than 500 mg/dL or treated LDL-C plasma levels are greater than 300 mg/dL along with tendon xanthoma (a type of cholesterol deposit) presence or related outer skin manifestations before the age of 10 years.
Cascade Screening is the process where the immediate family members of the patient with FH also undergo cholesterol check. If a specific genetic mutation is found in a patient, family members should also undergo genetic screening.
To continuously monitor the condition, an annual heart and aorta check-up using Doppler-echocardiography is highly recommended for patients with HoFH. In some instances, imaging of the Achilles tendon can help to accurately measure the extent of cholesterol deposits.
A skin biopsy can be performed if the diagnosis is unclear or if any skin lesions are found. These lesions called xanthomas and xanthelasmas are filled with the cholesterol that the body wasn’t able to naturally break down.
Treatment Options for Familial Hypercholesterolemia
All patients with familial hypercholesterolemia, a genetic disorder that results in high cholesterol levels, and their families, should be encouraged to embrace lifestyle changes. These changes should include a healthy diet, quitting smoking and regular physical activity. Nutritionists can provide valuable advice on reducing cholesterol-rich foods and managing weight. Treating familial hypercholesterolemia is not just about reducing cholesterol levels, but also about managing other related risks of heart disease.
People with familial hypercholesterolemia have different levels of increase in their LDL cholesterol (‘bad’ cholesterol) levels. Guidelines usually suggest reducing this level by at least 50%. High-risk patients who have already had heart disease or have diabetes are usually advised to get their LDL cholesterol levels below 70 mg/dL. In contrast, patients without these additional health concerns should aim to keep their LDL cholesterol levels below 100 mg/dL. While undergoing treatment, regular checks of your cholesterol levels are important to adjust your medication as needed.
When it comes to drug treatments, statins are the preferred choice for managing familial hypercholesterolemia. Research shows that these drugs can reduce LDL cholesterol levels by around 50% and also decrease the likelihood of cardiovascular events like heart attacks. However, not all patients with familial hypercholesterolemia achieve these targets. In such cases, additional medication like ezetimibe or PCSK9 inhibitors may be required. Ezetimibe has been shown to achieve an additional 10-30% reduction in LDL levels, while PCSK9 inhibitors can lower this level by 50-60%. Other treatment options like mRNA inhibition of apolipoprotein B, microsomal triglyceride transfer protein inhibition, niacin, lipoprotein apheresis, ileal bypass surgery, and liver transplantation may be considered if these treatments do not achieve the desired results.
Guidelines about managing patients with homozygous familial hypercholesterolemia, a more severe form of the condition, recommend lifestyle changes, statin therapy, and for severe cases, lipoprotein apheresis — a procedure that filters cholesterol out of the blood. LDL cholesterol targets are generally below 100 mg/dL for adults, <70 mg/dL for adults with cardiovascular disease, and <135 mg/dL for children. Other treatments can be considered if cholesterol targets are not met and cardiovascular risk remains high.
For patients with heterozygous familial hypercholesterolemia, a milder form of the condition, lifestyle modifications alone typically do not sufficiently lower cholesterol levels, and medication is usually necessary. Guidelines recommend an LDL cholesterol level of <135 mg/dL for children, <100 mg/dL for adults, and <70 mg/dL for adults with known heart disease or diabetes. Maintaining a diet low in saturated and trans fats, and cholesterol, along with regular exercise, can help control cholesterol levels.
Women with familial hypercholesterolemia who wish to become pregnant should discontinue all cholesterol-lowering medications before they conceive. A risk assessment for heart disease is recommended before pregnancy. Lipoprotein apheresis may be used when necessary.
Surgical procedures like liver transplantation and portacaval anastomosis may be considered for patients with the more severe homozygous form of familial hypercholesterolemia. A liver transplant can dramatically decrease LDL cholesterol levels, as the new liver will have functioning LDL receptors, which help remove ‘bad’ cholesterol from the bloodstream.
What else can Familial Hypercholesterolemia be?
When trying to diagnose familial hypercholesterolemia, which is a genetic disorder that results in high cholesterol levels, doctors consider various conditions that can display similar symptoms. These include:
- Sitosterolemia: This is a genetic disorder that causes too much absorption of plant sterols, substances found in vegetable oils and nuts, from the intestines.
- Cerebrotendinous xanthomatosis: Another genetic condition, this causes a block in a certain enzyme that is responsible for breaking down bile acid, resulting in excessive cholestanol and cholesterol deposition in eyes, nerves, blood vessels, and muscles.
- Polygenic hypercholesterolemia: A condition characterized by high cholesterol levels arising from the interaction of multiple genes and lifestyle factors.
- Familial combined hyperlipidemia: A genetic disorder that causes high levels of all types of fats, including cholesterol, in the blood.
- Hyperapobetalipoproteinemia: A condition leading to a high concentration of a specific protein that carries cholesterol in the blood.
- Familial dysbetalipoproteinemia (type 3 hyperlipoproteinemia): This condition is characterized by an abnormal increase in certain types of lipoproteins (substances having fats and proteins).
What to expect with Familial Hypercholesterolemia
Before the introduction of a medication known as statin, people with a condition called heterozygous familial hypercholesterolemia faced a significant risk of developing coronary heart disease, which involves the build-up of plaque in the heart’s arteries.
Even with the use of this high-intensity medication, the chances of death within the first year following an acute coronary syndrome (a serious cardiovascular condition like a heart attack) are still more than double for patients with this type of familial hypercholesterolemia compared to those without the condition.
Studies have found that the risk of death or developing coronary artery disease, a type of heart disease, is at 52% for male and 32% for female relatives of patients with familial hypercholesterolemia.
Patients with a more severe form of the condition called homozygous FH generally have a poor prognosis, meaning their outlook is not good. They often die before reaching their thirties due to cardiovascular events like heart attacks.
Possible Complications When Diagnosed with Familial Hypercholesterolemia
Familial hypercholesterolemia may result in serious health problems. These encompass:
- A stable condition of the coronary artery (the blood vessel supplying the heart muscles)
- Fatal (leading to death) and non-fatal (not leading to death) heart attacks
- Congestive heart failure or a condition where the heart can’t pump blood as well as it should
- Cerebrovascular accidents, or what we know as strokes
- Narrowing of the aorta (the main blood vessel supplying oxygen-rich blood to our body), also known as aortic stenosis
- Peripheral arterial disease, a common circulatory problem in which narrowed arteries reduce blood flow to your limbs
- Death linked to heart- or blood vessel-related conditions
Preventing Familial Hypercholesterolemia
People with familial hypercholesterolemia, a condition that results in high cholesterol levels, should try to live a healthy lifestyle. This includes avoiding smoking, maintaining a healthy weight, and making smart dietary choices. Reducing the intake of high cholesterol, trans fat, and saturated fat laden foods and beverages is necessary. Including foods that can lower cholesterol levels, like plant stanols and sterols, in the diet is also recommended.
Moreover, those with familial hypercholesterolemia need to understand the linked risk of cardiovascular (heart and blood vessel) disease. They should be aware of how they can control modifiable risk factors to prevent it and know about the suitable treatments once diagnosed with familial hypercholesterolemia. It’s also crucial that the immediate family members of someone with this condition be informed of the importance of getting themselves tested for familial hypercholesterolemia.