What is hyperlipidemia

Hyperlipidemia also called hyperlipidaemia or dyslipidemia is a medical term to describe various genetic and acquired lipid metabolic conditions that cause an elevated level of fats or lipids like cholesterol and triglycerides in your blood ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹. However, a more accurate hyperlipidemia definition means greater than the 90th percentile in comparison to the general population of low-density lipoprotein (LDL), total cholesterol and triglyceride levels or less than the 10th percentile when compared to the general population of a high-density lipoprotein (HDL) level ¹⁰, ¹¹. In other words, hyperlipidemia include elevated low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, and elevated triglyceride (hypertriglyceridemia). Some doctors use hyperlipidemia interchangeably with high cholesterol. Hyperlipidaemia has become an important public health problem ¹². And there are over 3 million adults throughout the USA and Europe who currently have a diagnosis of hyperlipidemia, and that number continues to rise at a drastic pace ¹. Patients with hyperlipidaemia are twice as likely to develop cardiovascular disease ¹³. Meanwhile, hyperlipidemia can lead to chronic inflammation in your body; the release of inflammatory factors can increase your risk of atherosclerosis (hardening of the arteries) by damaging vascular endothelial cells and blood vessel walls ¹⁴. Chronic hyperlipidemia in young people can increase their risk of atherosclerosis, so active prevention and treatment for hyperlipidemia are particularly important ¹⁵.

Blood lipids (fats) typically include total cholesterol levels, lipoproteins, chylomicrons, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), apolipoproteins, and high-density lipoprotein (HDL) ¹⁶. Hyperlipidemia or high levels of fat particles (lipids) in your blood can deposit in your blood vessel walls and restrict blood flow. This increase your risk of having heart attack and stroke. Doctors link hyperlipidemia to atherosclerosis (hardening of the arteries) and other serious cardiovascular conditions like heart attack, stroke, and peripheral artery disease. According to the American Heart Association, more than 43% of American adults have cholesterol levels of 200 milligrams (mg) per deciliter (dL) or higher. A healthy lipid profile is to have non-HDL levels below 130 mg/dL with an HDL (“good” cholesterol) of at least 40 mg/dL for men and 50 mg/dL for women. Check with your doctor on the lipid levels that are best for you. The risk of high cholesterol, or hypercholesterolemia, tends to be greater as you age, and the condition affects more women than men. Obesity of any kind, lack of physical activity, and diabetes are other important risk factors.

Hyperlipidaemia doesn’t cause any symptoms. Hyperlipidemia is diagnosed by routine blood tests, recommended every five years for adults.

Treatment for hyperlipidemia can be divided into lifestyle changes and medication if lifestyle changes haven’t adequately help to lower your cholesterol. Lifestyle changes, such as healthy diet, weight control, exercise and correction of poor lifestyle, are the basis of lipid-lowering therapy and are carried out throughout the treatment process ¹⁷, ¹⁸. In patients with hyperlipidemia but without any known cardiovascular disease (e.g., coronary artery disease, rheumatic heart disease, heart attacks, high blood pressure, stroke, peripheral artery disease), treatment decisions should be based on estimated 10-year risk calculators such as the Atherosclerotic Cardiovascular Disease Risk Calculator (https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate). Treatment is recommended at a 10-year risk of 12%, which matches the populations that experienced benefit in clinical trials. People with diabetes and/or LDL (low-density lipoprotein) cholesterol levels of at least 190 mg/dL (4.92 mmol/L) are also at high risk and should be offered treatment regardless of estimated risk. Shared decision-making is recommended with 10-year risk between 6% and 12%, which represents populations less studied in clinical trials.

Lifestyle changes include:

1. Eating a heart-healthy diet
2. Becoming more physically active
3. Quitting smoking
4. Losing weight
5. Manage stress

In terms of hyperlipidemia medication, lipid-lowering drugs in clinical practice include statins, fibrates, cholesterol absorption inhibitors and niacin ¹⁹. Among them, statins have always been the main drugs in the treatment of hyperlipidemia ²⁰, which are widely used in clinical practice with definite efficacy, but some patients cannot tolerate statins due to side effects (liver and kidney damage, rhabdomyolysis, etc) ²¹, ²².

Cholesterol is a waxy, fat-like substance that’s found in all the cells in your body. Cholesterol is produced by your body and also found in some foods. Your body needs some cholesterol to make hormones, vitamin D and substances that help you digest foods. Cholesterol comes from two sources. Your liver makes all of the cholesterol your body needs to form cell membranes and to make certain hormones. Cholesterol is also found in foods from animal sources, such as egg yolks, meat, and cheese, which is called dietary cholesterol. Although we often blame the cholesterol found in foods that we eat for raising blood cholesterol, the main culprit is actually saturated fat. Foods rich in saturated fat include butter fat in milk products, fat from red meat, and tropical oils such as coconut oil.

Cholesterol can enter your artery wall, damage its integrity and lead to the formation of atherosclerotic plaque (hardened deposits). This process of plaque buildup is called atherosclerosis. It can lead to serious problems like:

• Coronary artery disease: Blocked blood flow to your heart.
• Peripheral artery disease: Blocked blood flow to your legs and arms.
• Carotid artery disease: Blocked blood flow to your brain.

Cholesterol and other fats have a special way of reaching all the cells in your body that need it. They use your blood circulation as their ‘road system’ and are carried on ‘special carriers’ made up of lipids (fats) and proteins called lipoproteins. Two of the most important lipoproteins are low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

• Low-density lipoproteins sometimes called LDL cholesterol (LDL-C) or ‘bad cholesterol’ – carry most of the cholesterol from your liver, through the bloodstream, to where it is needed. About 70 per cent of the cholesterol in your body is carried by LDL. The lower the density of the lipoprotein, the more fats it contains, so having high LDL is harmful to you.
• High-density lipoproteins sometimes called HDL cholesterol (HDL-C) or ‘good cholesterol’ – return the extra cholesterol, that isn’t needed, from your cells and your bloodstream to your liver for recycling. HDL cholesterol is a ‘good’ type of cholesterol because it removes cholesterol from your bloodstream. This helps prevent the cholesterol from being deposited in the arteries and causing atheroma (atherosclerosis).

Your cholesterol levels show how much cholesterol is circulating in your blood. Your blood cholesterol levels tell you how much lipid or fat is in your blood and your cholesterol levels are expressed in milligrams per deciliter (mg/dL). High cholesterol usually has no symptoms. You can find out your blood cholesterol levels with a cholesterol or lipid profile blood test. You will need to stop eating for 10 to 12 hours before a cholesterol or lipid profile blood test, and the only liquid you may drink is water.

Total blood or serum cholesterol is a composite of different measurements. Your “total blood cholesterol” is calculated by adding your HDL (“good” cholesterol) and LDL (“bad” cholesterol) cholesterol levels, plus 20% of your triglyceride level. Here’s the formula for calculating your “total blood cholesterol”:

Total cholesterol = HDL + LDL + 20% triglycerides.

• “Total cholesterol” is the total amount of cholesterol that’s circulating in your blood. Your “Total cholesterol” should be below 200 milligrams per deciliter of blood (less than 200 mg/dL) or 5.18 mmol/L.
• Your HDL “good” cholesterol is the one number you want to be high, ideally above 60 mg/dL (1.55 mmol/L) or higher.
• Your LDL “bad” cholesterol should be below 100 mg/dL (less than 2.59 mmol/L).
• Your triglycerides should be below 150 mg/dL (less than 1.70 mmol/L). Triglycerides are the most common type of fat in your blood. Triglycerides come from food, and your body also makes them. When you eat, your body converts calories it doesn’t need into triglycerides, which are stored in fat cells. High triglyceride levels are associated with several factors, including being overweight, eating too many sweets or drinking too much alcohol, smoking, being sedentary, or having diabetes with elevated blood sugar levels.
• According to the American Heart Association, more than 43% of American adults have cholesterol levels of 200 milligrams (mg) per deciliter (dL) or higher. Talk with your doctor about what your results mean for you and how to manage your cholesterol.

“Normal cholesterol levels” are less important than your overall cardiovascular risk. Like HDL and LDL cholesterol levels, your total blood cholesterol level should be considered in context with your other known risk factors. To determine your cardiovascular risk, your doctor will consider your cholesterol test results in context with your age, sex and family history. Other risk factors, such as smoking, diabetes and high blood pressure, will be considered as well. If your risk remains uncertain, and treatment options are unclear, your doctor may consider other factors and/or request a coronary artery calcium measurement to provide greater insight into your risk and help in decision-making.

In general, you want to have a total cholesterol level below 200 mg/dL or 5.18 mmol/L. Between 200 mg/dL and 239 mg/dL, your cholesterol level is elevated or borderline-high and should be lowered if you can. With a total cholesterol level of 240 mg/dL or above, your cholesterol level is high, and there is a need for action. For example, changing your diet, beginning an exercise program, and taking statins or other cholesterol-lowering medicines are all ways to lower your cholesterol level.

Factors that can increase your risk of bad cholesterol include:

• Poor diet. Eating saturated fat, found in animal products, and trans fats, found in some commercially baked cookies and crackers and microwave popcorn, can raise your cholesterol level. Foods that are high in cholesterol, such as red meat and full-fat dairy products, will also increase your cholesterol.
• Age. Your cholesterol levels tend to rise as you get older. For instance, as you age, your liver becomes less able to remove LDL cholesterol. Even though it is less common, younger people, including children and teens, can also have high cholesterol.
• Sex. Between ages 20 and 39, men have a greater risk for high total cholesterol than women. A woman’s risk goes up after menopause. Menopause lowers levels of female hormones that may protect against high blood cholesterol. After menopause, women’s levels of total and “bad” LDL cholesterol usually go up, while their levels of “good” HDL cholesterol go down.
• Heredity. High blood cholesterol can run in families.
• Weight. Being overweight or having obesity raises your cholesterol level. Having a body mass index (BMI) of 30 or greater puts you at risk of high cholesterol.
• Race. Certain races may have an increased risk of high cholesterol.
  • Overall, non-Hispanic White people are more likely than other groups to have high levels of total cholesterol.
  • Asian Americans, including those of Indian, Filipino, Japanese, and Vietnamese descent, are more likely to have high levels of “bad” LDL cholesterol than other groups.
  • Hispanic Americans are more likely to have lower levels of “good” HDL cholesterol than other groups.
  • African Americans are more likely than other groups to have high levels of “good” HDL cholesterol.
• Lack of exercise. Being physically inactive contributes to overweight and can raise LDL and lower HDL. Exercise helps boost your body’s HDL, or “good,” cholesterol while increasing the size of the particles that make up your LDL, or “bad,” cholesterol, which makes it less harmful.
• Smoking. Cigarette smoking damages the walls of your blood vessels, making them more prone to accumulate fatty deposits. Smoking might also lower your level of HDL, or “good,” cholesterol.
• Diabetes. High blood sugar contributes to higher levels of a dangerous cholesterol called very-low-density lipoprotein (VLDL) and lower HDL cholesterol. High blood sugar also damages the lining of your arteries.

The following foods can lower your bad cholesterol.

• Vegetables such as leafy greens (spinach, collard greens, kale, cabbage), broccoli, and carrots
• Fruits such as apples, bananas, oranges, pears, grapes, and prunes
• Whole grains such as plain oatmeal, brown rice, and whole-grain bread or tortillas
• Fat-free or low-fat dairy foods such as milk, cheese, or yogurt
• Protein-rich foods:
  • Fish high in omega-3 fatty acids (salmon, tuna, and trout)
  • Lean meats such as 95% lean ground beef or pork tenderloin or skinless chicken or turkey
  • Eggs
  • Nuts, seeds, and soy products (tofu)
  • Legumes such as kidney beans, lentils, chickpeas, black-eyed peas, and lima beans
• Oils and foods high in monounsaturated and polyunsaturated fats:
  • Canola, corn, olive, safflower, sesame, sunflower, and soybean oils (not coconut or palm oil)
  • Nuts such as walnuts, almonds, and pine nuts
  • Nut and seed butters
  • Salmon and trout
  • Seeds (sesame, sunflower, pumpkin, or flax)
  • Avocados
  • Tofu

There are usually no signs or symptoms that you have high cholesterol. A blood test is the only way to detect if you have it. The American Heart Association recommends all adults age 20 or older with no other risk factors for heart disease should have their cholesterol (and other traditional risk factors) checked every four to six years. If certain factors put you at high risk, or if you already have heart disease, your doctor may ask you to check it more often. Work with your doctor to determine your risk for cardiovascular disease and stroke and create a plan to reduce your risk.

If you have risk factors or if previous testing showed that you had a high cholesterol level, more frequent testing with a full lipid panel is recommended.

Examples of risk factors other than high LDL include:

• Cigarette smoking
• Being overweight or obese
• Unhealthy diet
• Being physically inactive—not getting enough exercise
• Age (if you are a male 45 years or older or a female 50-55 years or older)
• Hypertension (blood pressure of 140/90 or higher or taking high blood pressure medications)
• Family history of premature heart disease (heart disease in a first-degree male relative under age 55 or a first-degree female relative under age 65)
• Pre-existing heart disease or already having had a heart attack
• Diabetes or prediabetes

For people who are age 20 or older:

• Younger adults should have the test every 5 years
• Men ages 45 to 65 and women ages 55 to 65 should have it every 1 to 2 years.

Children, teens, and young adults (ages 2 to 24 years old) with no risk factors should have a lipid panel once between the ages of 9 and 11 and again between 17 and 21, according to the American Academy of Pediatrics.

For people who are age 19 or younger:

• The first test should be between ages 9 to 11
• Children should have the test again every 5 years
• Some children may have this test starting at age 2 if there is a family history of high blood cholesterol, heart attack, or stroke.

Children, teens, and young adults with an increased risk of developing heart disease as adults should have earlier and more frequent screening with lipid panels. Some of the risk factors are similar to those in adults and include a family history of heart disease or health problems such as diabetes, high blood pressure, or being overweight. High-risk children should be tested between 2 and 8 years old with a fasting lipid panel, according to the American Academy of Pediatrics.

Children younger than 2 years old are too young to be tested.

Figure 1. Cholesterol levels

What is Cholesterol?

Cholesterol is a waxy, fat-like substance that’s found in all the cells in your body. Cholesterol is produced by your liver, adrenal glands, intestines, and in gonads and 20 to 25% of cholesterol comes from your diet (foods you eat) ²³. Cholesterol is an essential component of all cell membranes – it helps to maintain structural integrity and fluidity of cell membranes, allowing your cells to change shapes easily without cell walls ²⁴. More than 90% of cellular cholesterol is located at the plasma membrane ²⁵. Your body needs some cholesterol to make hormones such as testosterone and estrogen, vitamin D and the biosynthesis of bile acids in your liver that help you digest foods ²⁶, ²⁷, ²⁸.

Cholesterol comes from two sources. Your liver makes all of the cholesterol your body needs to form cell membranes and to make certain hormones. Cholesterol is also found in foods from animal sources, such as egg yolks, meat, and cheese, which is called dietary cholesterol. Although we often blame the cholesterol found in foods that we eat for raising blood cholesterol, the main culprit is actually saturated fat. Foods rich in saturated fat include butter fat in milk products, fat from red meat, and tropical oils such as coconut oil.

Cholesterol travels through your blood on proteins called lipoproteins. One type, LDL (low-density lipoprotein), is sometimes called the “bad” cholesterol. A high LDL level leads to a buildup of cholesterol in your arteries. Another type, HDL (high-density lipoprotein), is sometimes called the “good” cholesterol. HDL carries cholesterol from other parts of your body back to your liver. Then your liver removes the cholesterol from your body.

Types of cholesterol:

• HDL stands for high-density lipoprotein or HDL-C (high-density lipoprotein cholesterol). HDL is sometimes called “good cholesterol” because it carries harmful cholesterol from other parts of your body including your arteries back to your liver. Your liver then removes the cholesterol from your body and helps protect you from heart attack and stroke. A healthy HDL-cholesterol level may protect against heart attack and stroke. If you have low HDL levels, you have a greater heart disease risk, even if your total cholesterol is below 200 mg/dL. Your doctor will evaluate your HDL and other cholesterol levels and other factors to assess your risk for heart attack or stroke. People with high blood triglycerides usually also have lower levels of HDL. Genetic factors, Type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do, because the female hormone estrogen raises HDL, but this can change after menopause.
• LDL stands for low-density lipoprotein or LDL-C (low-density lipoprotein cholesterol). LDL is sometimes called “bad cholesterol” because a high LDL level leads to the buildup of plaque in your arteries. LDL is the most important lipid for predicting your heart disease risk. Low-density lipoprotein (LDL or ‘bad’) cholesterol can join with fats and other substances to build up (also known as plaque) in the inner walls of your arteries, which starts a disease process called atherosclerosis. The arteries can become clogged and narrow, and blood flow is reduced. When plaque builds up in your coronary arteries that supply blood to your heart, you are at greater risk of having a heart attack. Since LDL is the bad kind of cholesterol, a low LDL level is considered good for your heart health. A diet high in saturated and trans fat is unhealthy because it tends to raise LDL cholesterol levels. Your LDL levels may be high if you eat a diet with a lot of saturated fat, cholesterol, or both. Sometimes, an under-active thyroid called hypothyroidism may also increase LDL levels.
• VLDL stands for very low-density lipoprotein or VLDL-C (very low-density lipoprotein cholesterol). Some people also call VLDL a “bad cholesterol” because it too contributes to the buildup of plaque in your arteries. But VLDL and LDL are different; VLDL mainly carries triglycerides and LDL mainly carries cholesterol. VLDL particles are released into the blood by the liver and circulate in the bloodstream, ultimately being converted into LDL as they lose triglyceride, having carried it to other parts of the body. According to the National Heart, Lung and Blood Institute’s National Cholesterol Education Program Guidelines ATP III, there is growing evidence that VLDL plays an important role in atherogenesis, in which plaques form on the interior walls of arteries, narrowing these passageways and restricting blood flow, which can lead to heart disease and increase the risk of stroke. Currently, direct measurement of VLDL cholesterol requires specialized testing. However, since VLDL-C contains most of the circulating triglyceride (if a person is fasting) and since the composition of the different particles is relatively constant, it is possible to estimate the amount of VLDL-C based on the triglyceride value. To estimate VLDL-C, divide the triglyceride value by 5 if the value is in mg/dL or divide by 2.2 if the value is in mmol/L. In most cases, this formula provides a good estimate of VLDL-C. However, this formula becomes less accurate with increased triglyceride levels when, for example, a person has not fasted before having blood drawn. The calculation is not valid when the triglyceride level is greater than 400 mg/dl (4.5 mmol/L) because other lipoproteins are usually present. In this situation, VLDL-C may be measured directly using specialized testing.
• Triglycerides. Triglycerides are the most common type of fat in your blood. Triglycerides come from food, and your body also makes them. When you eat, your body converts calories it doesn’t need into triglycerides, which are stored in fat cells. Triglycerides are fats that provide energy for your muscles. If you eat foods with a lot of saturated fat or carbohydrates, you will raise your triglyceride levels. High triglyceride levels are associated with several factors, including being overweight, eating too many sweets or drinking too much alcohol, smoking, being sedentary, or having diabetes with elevated blood sugar levels. Elevated triglycerides levels are thought to lead to a greater risk of heart disease, but scientists do not agree that high triglycerides alone are a risk factor for heart disease. Normal triglyceride levels vary by age and sex. People with high triglycerides often have a high total cholesterol level, including a high LDL (bad) cholesterol level and a low HDL (good) cholesterol level. Many people with metabolic syndrome or diabetes also have high triglyceride levels. Extremely high triglyceride levels (more than 1000 mg/dL) can lead to abdominal pain and a life-threatening disorder of the pancreas called pancreatitis. Factors that can contribute to elevated triglyceride levels:
  • Overweight or obesity
  • Insulin resistance or metabolic syndrome
  • Diabetes mellitus, especially with poor glucose control
  • Alcohol consumption, especially in excess
  • Excess sugar intake, especially from processed foods
  • High saturated fat intake
  • Hypothyroidism
  • Chronic kidney disease
  • Physical inactivity
  • Pregnancy (especially in the third trimester)
  • Inflammatory diseases (such as rheumatoid arthritis, systemic lupus erythematosus
  • Some medications may also increase triglycerides.

Your body naturally produces all the LDL (bad) cholesterol it needs. However, the genes you inherit and your lifestyle habits play a major role in your cholesterol levels. The most common cause of high cholesterol is an unhealthy lifestyle. An unhealthy lifestyle makes your body produce more LDL cholesterol than it needs. This can include:

• Unhealthy eating habits or unhealthy diet, such as eating lots of bad fats. One type, saturated fat, is found in some meats, dairy products, chocolate, baked goods, and deep-fried and processed foods. Eating a lot of foods high in saturated fats raises “bad” LDL cholesterol levels. Another type, trans fat, is in some fried and processed foods. Eating these fats can raise your LDL (bad) cholesterol. No more than 10% of your daily calories should come from saturated fats.
• Lack of physical activity, with lots of sitting and little exercise. This lowers your HDL (good) cholesterol.
• Smoking or exposure to tobacco smoke, which lowers HDL cholesterol, especially in women. It also raises your LDL cholesterol.
• Being overweight or obese.
• Stress may raise levels of certain hormones, such as corticosteroids. These can cause your body to make more cholesterol.
• Drinking too much alcohol (more than two drinks a day for men or one drink a day for women) can raise your total cholesterol level.
• Getting little or low-quality sleep has been linked to lower cardiovascular health.

Genetics may also cause people to have high cholesterol. For example, some people inherit genes from their mother, father or even grandparents that cause them to have too much cholesterol. This is called familial hypercholesterolemia (FH). The severity of familial hypercholesterolemia is related to the duration and degree of LDL cholesterol in the blood. Familial hypercholesterolemia is dangerous because it can cause premature atherosclerotic heart disease. If you have a family history of familial hypercholesterolemia or problems related to high cholesterol, get your cholesterol levels checked.

High cholesterol usually causes no signs or symptoms. Cholesterol travels through your blood silently. And it turns into atherosclerotic plaque (hardened deposits) silently. Plaque buildup is like someone tip-toeing on carpet. You might not see or notice its presence for a long time. You may have no symptoms until you have a heart attack or stroke. At that point, the plaque is like high heels on a hardwood floor. And it’s already caused serious damage to your body.

You can live for many years with high cholesterol and not even know it. That’s why it’s essential to get your cholesterol levels checked on a regular basis. If your cholesterol levels are too high (hyperlipidemia), that’s a red flag for you and your doctor. High cholesterol is a major risk factor for heart disease. But catching it early gives you a chance to make changes and get your cholesterol to a healthy level.

You can find out your cholesterol level with a cholesterol or lipid profile blood test. If you are concerned about your cholesterol level, talk to your doctor. You will need to stop eating for 10 to 12 hours before a cholesterol or lipid profile blood test, and the only liquid you may drink is water.

Lifestyle changes such as regular physical activity, losing excess weight, quitting if you smoke and healthy eating are the first line of defense against high cholesterol. Eating lots of fruit and vegetables, whole grains (especially oats), and beans and lentils can help lower your cholesterol. You can also help by losing weight, avoiding foods that are high in saturated fat, quitting smoking and being active. But, if you’ve made these important lifestyle changes and your cholesterol levels remain high, your doctor might recommend medication.

To reduce your risk with high cholesterol, it’s important to:

• Quit cigarette smoking.
• Do regular aerobic exercise.
• Identify and treat high blood pressure.
• Maintain a healthy weight.
• Diagnose and treat diabetes.
• Have a healthy diet.

High cholesterol is one of the major controllable risk factors for coronary heart disease, heart attack and stroke. If you have other risk factors such as smoking, high blood pressure or diabetes, your risk increases even more. The more risk factors you have and the more severe they are, the higher your overall risk.

Remember, making even modest changes now can help to prevent significant medical issues later. Do all you can to reduce your risk for the serious effects of heart attack and stroke.

What is LDL cholesterol?

LDL (“bad”) cholesterol can contribute to the formation of plaque buildup in the arteries (atherosclerosis). This is linked to higher risk for heart attack and stroke.

You want your LDL below 70 milligrams per deciliter (mg/dl).

If you have high LDL or total cholesterol, you can lower your risk of heart disease by:

• Stop smoking if you smoke
• Maintaining a healthy weight
• Avoid foods high in saturated fat, dietary cholesterol, and extra calories
• Limiting your alcohol and salt intake
• Exercise for at least 30 minutes on most days
• Managing stress.

What is HDL cholesterol?

HDL stands for high density lipoprotein or HDL-C (high-density lipoprotein cholesterol). HDL is sometimes called “good cholesterol” because it carries harmful cholesterol from other parts of your body including your arteries back to your liver. Your liver then removes the cholesterol from your body and helps protect you from heart attack and stroke. A healthy HDL-cholesterol level may protect against heart attack and stroke. If you have low HDL levels, you have a greater heart disease risk, even if your total cholesterol is below 200 mg/dL. Your doctor will evaluate your HDL and other cholesterol levels and other factors to assess your risk for heart attack or stroke. People with high blood triglycerides usually also have lower levels of HDL. Genetic factors, type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do, because the female hormone estrogen raises HDL, but this can change after menopause.

Experts believe HDL cholesterol may act in a variety of helpful ways that tend to reduce the risk for heart disease ²⁹:

• High HDL cholesterol 60 mg/dL or higher is Protective against heart disease.
• HDL cholesterol scavenges and removes LDL or “bad” cholesterol.
• HDL reduces, reuses, and recycles LDL cholesterol by transporting it to the liver where it can be reprocessed.
• HDL cholesterol acts as a maintenance crew for the inner walls (endothelium) of blood vessels. Damage to the inner walls is the first step in the process of atherosclerosis, which causes heart attacks and strokes. HDL scrubs the wall clean and keeps it healthy.

People with high blood triglycerides usually also have lower HDL cholesterol. Genetic factors, type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do.

A healthy HDL cholesterol level may protect against heart attack and stroke. Studies show low levels of HDL cholesterol increase the risk of heart disease. HDL cholesterol does not completely eliminate LDL cholesterol. Only one-fourth to one-third of blood cholesterol is carried by HDL.

HDL levels should be around 50 mg/dL. Some people can raise HDL by::

• Exercising for at least 30 minutes 5 times a week
• Quitting smoking
• Avoiding saturated fats
• Losing weight

Others may need medicine to get HDL to a beneficial level, and should work with your doctor on a treatment plan.

What are Triglycerides?

Triglycerides are another type of fatty substance found in your blood. You get some triglycerides from foods such as dairy products, butter, meat, cooking oils and other fats. Some triglycerides are important for good health. However, high triglyceride levels in your blood or hypertriglyceridemia can raise your risk of heart disease and stroke. How severe hypertriglyceridemia is can vary based on sex, age, hormone use, and dietary factors. If you are very overweight, eat a lot of fatty and sugary foods, or drink too much alcohol, you are more likely to have a high triglyceride level (hypertriglyceridemia). Triglyceride levels increase after a meal and are normally cleared from the bloodstream over the following hours. They are usually at their lowest first thing in the morning before breakfast.

Triglycerides can also be produced in your body, either by your body’s fat stores or in the liver. Triglycerides mainly come from extra calories your body does not need right away. Unused calories (energy you don’t need right away) are stored as triglycerides in fat cells, therefore triglycerides is a major source of energy for your body. When your body needs energy, it releases the triglycerides. In between meals, triglycerides are released from fat tissue to be used as an energy source for your body. Most triglycerides are carried in the blood by lipoproteins called very low-density lipoproteins (VLDL).

Footnotes: (A) Lateral borders of thickened Achilles’ tendons are shown with arrows. (B) Tendinous xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees. (C) Xanthelasmas are cholesterol deposits in the eyelids. (D) Arcus cornealis (corneal arcus) is a greyish-white ring of cholesterol infiltration around the corneal rim (arrow). A corneal arcus at a young age can mean that the child has homozygous familial hypercholesterolemia.

Figure 3. Eruptive xanthomas associated with hypertriglyceridemia and new-onset type 2 diabetes

Footnote: Eruptive xanthomas associated with hypertriglyceridemia and new-onset type 2 diabetes. (Panels A and B) A previously healthy, 38-year-old man with a family history of early cerebrovascular accidents presented with a sudden eruption of pink papules with creamy-colored centers on his arms and upper torso. He was otherwise asymptomatic and had no abdominal pain. The results of laboratory tests performed while the patient was fasting included a total cholesterol level of 1268 mg per deciliter (32.8 mmol per liter), a total triglyceride level of 8869 mg per deciliter (100.1 mmol per liter), a glucose level of 241 mg per deciliter (13.4 mmol per liter), and a glycosylated hemoglobin value of 13.4 percent. Triglyceride-lowering therapy with gemfibrozil was initiated to enhance lipoprotein lipase activity, and insulin therapy was initiated to treat the hyperglycemia. Twenty-four hours later, his total triglyceride level was 6466 mg per deciliter (73.0 mmol per liter). At follow-up visits three and five months later, the patient’s eruptive xanthomas had decreased in size and number. After eight months of treatment with gemfibrozil, glyburide, and glucophage, his total cholesterol level was 218 mg per deciliter (5.6 mmol per liter), his total triglyceride level was 302 mg per deciliter (3.4 mmol per liter), and his glycosylated hemoglobin value was 8.3 percent; the eruptive xanthomas had completely resolved.

Mixed hyperlipidemia complications

Mixed hyperlipidemia can cause a dangerous accumulation of cholesterol and other deposits on the walls of your arteries (atherosclerosis). These deposits (plaques) can reduce blood flow through your arteries, which can cause complications, such as:

• Chest pain. If the arteries that supply your heart with blood (coronary arteries) are affected, you might have chest pain (angina) and other symptoms of coronary artery disease.
• Heart attack. If plaques tear or rupture, a blood clot can form at the plaque-rupture site — blocking the flow of blood or breaking free and plugging an artery downstream. If blood flow to part of your heart stops, you’ll have a heart attack.
• Stroke. Similar to a heart attack, a stroke occurs when a blood clot blocks blood flow to part of your brain.
• Hypertriglyceridemia is responsible for a mild amount of acute pancreatitis. There is a direct correlation with increased risk of pancreatitis as triglyceride levels rise above 500 mg/dL. When values rise above 1000 mg/dL, there is a described 5% risk of pancreatitis that then doubles when values reach more than 2000 mg/dL.

Mixed hyperlipidemia diagnosis

There are usually no signs or symptoms that you have high cholesterol. A blood test is the only way to detect if you have it. Lipid profile or lipid panel is a blood test that will give you results for your HDL (good) cholesterol, LDL (bad) cholesterol, triglycerides and total blood (or serum) cholesterol. When and how often you should get this test depends on your age, risk factors, and family history. The general recommendations are:

The American Heart Association recommends all adults age 20 or older with no other risk factors for heart disease should have their cholesterol (and other traditional risk factors) checked every four to six years. If certain factors put you at high risk, or if you already have heart disease, your doctor may ask you to check it more often. Work with your doctor to determine your risk for cardiovascular disease and stroke and create a plan to reduce your risk.

If you have risk factors or if previous testing showed that you had a high cholesterol level, more frequent testing with a full lipid panel is recommended.

Examples of risk factors other than high LDL include:

• Cigarette smoking
• Being overweight or obese
• Unhealthy diet
• Being physically inactive—not getting enough exercise
• Age (if you are a male 45 years or older or a female 50-55 years or older)
• Hypertension (blood pressure of 140/90 or higher or taking high blood pressure medications)
• Family history of premature heart disease (heart disease in a first-degree male relative under age 55 or a first-degree female relative under age 65)
• Pre-existing heart disease or already having had a heart attack
• Diabetes or prediabetes

For people who are age 20 or older:

• Younger adults should have the test every 5 years
• Men ages 45 to 65 and women ages 55 to 65 should have it every 1 to 2 years.

Children, teens, and young adults (ages 2 to 24 years old) with no risk factors should have a lipid panel once between the ages of 9 and 11 and again between 17 and 21, according to the American Academy of Pediatrics.

For people who are age 19 or younger:

• The first test should be between ages 9 to 11
• Children should have the test again every 5 years
• Some children may have this test starting at age 2 if there is a family history of high blood cholesterol, heart attack, or stroke.

Children, teens, and young adults with an increased risk of developing heart disease as adults should have earlier and more frequent screening with lipid panels. Some of the risk factors are similar to those in adults and include a family history of heart disease or health problems such as diabetes, high blood pressure, or being overweight. High-risk children should be tested between 2 and 8 years old with a fasting lipid panel, according to the American Academy of Pediatrics.

Children younger than 2 years old are too young to be tested.

Table 7. Cholesterol test general recommendations

Footnotes: Having your cholesterol levels checked at regular intervals gives doctors a chance to notice any changes that could become harmful to your health. High or increasing cholesterol levels are a risk factor for heart disease, diabetes, or stroke, among other conditions. Doctors may want to test your cholesterol levels more regularly if you or your family have a history of heart disease, smoking, high blood pressure, type 2 diabetes, obesity, a sedentary lifestyle, or a diet high in saturated fat.

Can I test my cholesterol at home?

At-home cholesterol testing is available to measure total cholesterol. You prick your finger and put blood on a piece of paper that will change color based on your cholesterol level or use your blood and a small device to do the same thing. There are also kits available that have you collect a blood sample at home and then mail it to a reference laboratory, which will then perform a lipid panel and send the results back to you.

There are two types of at-home LDL tests that use a fingerstick blood sample:

• Self-tests: In this kind of test, the analysis of your blood happens at home. This can be done by applying a drop of blood on paper that is then placed into a small device that determines the cholesterol levels. Another type of self-test uses chemically treated paper that indicates the levels of cholesterol in your blood.
• Self-collection: For this kind of test, your blood sample is taken at home but is then sent to a laboratory for analysis.

For help deciding whether an at-home cholesterol test kit is right for you, it may be helpful to talk to your doctor or cardiologist. It is common to have a follow-up cholesterol test performed by a doctor if an at-home cholesterol test kit finds abnormal results.

Your doctor can best help you understand what your specific test results mean for your health. Some doctors may set a specific target level when prescribing medication to lower cholesterol. Factors like diet, age, smoking, physical activity, weight, sex, genetics, medicines, and other medical conditions can all affect your LDL cholesterol level.

How much does at-home cholesterol test cost?

The price may depend on the type of cholesterol test, your insurance coverage, and where the test is performed. You may find it helpful to talk with your doctor about the costs of cholesterol testing.

Blood testing is typically covered by insurance when prescribed by a doctor, but you may be responsible for out-of-pocket costs on copays, deductibles, or technician fees.

Other tests

In some patients, additional tests for secondary causes of mixed hyperlipidemia should be done in most patients with newly diagnosed dyslipidemia and repeated when a component of the lipid profile has inexplicably changed for the worse.

• Lipoprotein-A or Lp(a) levels and C-reactive protein (CRP) levels should be measured in patients with premature atherosclerotic cardiovascular disease, cardiovascular disease (even if they have lower risk lipid levels), or high LDL cholesterol levels refractory to drug therapy. Lipoprotein-A or Lp(a) levels may also be directly measured in patients with borderline-high LDL cholesterol levels to determine whether drug therapy is warranted.
• Measurements of LDL particle number or apoprotein B-100 (apo B) is useful in patients with elevated triglycerides and the metabolic syndrome. Apo B provides similar information to LDL particle number because there is one apo B molecule for each LDL particle. Apo B measurement includes all atherogenic particles, including remnants and Lp(a). Apo B value reflects all non-HDL cholesterol (VLDL, IDL, and LDL) and is more predictive of coronary artery disease risk than LDL cholesterol. Non-HDL cholesterol (Total Cholesterol − HDL cholesterol) is also more predictive of coronary artery disease risk than LDL cholesterol, especially in patients with hypertriglyceridemia.
• Creatinine
• Fasting glucose and/or glycosylated hemoglobin (HbA1C)
• Liver enzymes
• Thyroid-stimulating hormone (TSH)
• Urinary protein

Mixed hyperlipidemia treatment

If you’re diagnosed with mixed hyperlipidemia, your overall health and other risks such as smoking, diabetes or high blood pressure will help guide treatment. The main goal for mixed dyslipidemia treatment is prevention of atherosclerotic cardiovascular disease (ASCVD), including acute coronary syndromes, stroke, transient ischemic attack (TIA), or peripheral arterial disease presumed caused by atherosclerosis.

Initial treatment options for mixed hyperlipidemia include lifestyle changes and statin drug therapy ⁶⁵, ⁶⁶, ⁶⁷. The addition of fibrates to statin therapy is more effective in controlling atherogenic hyperlipidemia in patients with mixed hyperlipidemia than the administration of either drug alone with several short-term studies in various patient populations supporting this hypothesis ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷².

If you have high LDL or total cholesterol, you can lower your risk of heart disease by ⁴⁰, ⁴¹, ⁴²:

• Choosing heart-healthy foods. The DASH eating plans can help you lower your “bad” LDL cholesterol. These plans encourage:
  • Limiting saturated fats found in fatty cuts of meats, dairy products, and desserts
  • Eating whole grains, fruits, and vegetables rather than refined carbohydrates such as sweets and other high-sugar foods
  • Eating a variety of nuts
  • Preparing foods with little or no salt
• Getting regular physical activity. Studies have shown that physical activity can lower LDL “bad” cholesterol and triglycerides and raise your “good” HDL cholesterol. For example, resistance training among postmenopausal women may decrease total cholesterol, LDL cholesterol, and triglycerides. Aim for at least 30 minutes of exercise on most days. It’s recommended that you do at least 150 minutes of moderate intensity exercise per week. Moderate exercise is when you feel warm and comfortably breathless like when walking or pushing a lawn mower. Intense exercise is when you breathe hard and fast like when running, swimming or cycling. The recommended types of exercise for improving heart health are:
  • Aerobic exercise – when you’re moving your body in a way that makes you warm and slightly out of breath like when walking, cycling, doing housework or gardening. Over time, this type of exercise helps your heart and circulatory system to work better by helping to lower your blood pressure and resting heart rate, improving cholesterol levels and helping you maintain a healthy weight
  • Balance and flexibility exercise – exercise like yoga, tai chi and Pilates where we hold our bodies in less stable positions. These exercises make sure our muscles don’t get too tight and keep us flexible, helping avoid pain or injury and reduce the risk of having falls
  • Resistance exercise – resistance training like lifting weights or using resistance bands and cables to strengthen your muscles. The stronger your muscles are, the harder they can work which takes the strain off your heart making it easier to do everyday tasks. Check in with your doctor before you start any resistance training as it may not be suitable for some people with heart conditions.
• Aiming for a healthy weight. Research has shown that adults with overweight and obesity can lower “bad” LDL cholesterol and raise “good” HDL cholesterol by losing only 3% to 5% of their weight.
• Managing stress. Research has shown that chronic stress can sometimes increase LDL cholesterol levels and decrease HDL cholesterol levels.
• Quitting smoking. If you smoke, quit. Smoking can raise your risk of heart disease and heart attack and worsen other heart disease risk factors. Talk with your doctor about programs and products that can help you quit smoking. Also, try to avoid secondhand smoke.
• Getting enough good quality sleep. Getting 7 to 9 hours of sleep a day lowers your risk for high “bad” cholesterol (LDL) and total cholesterol.
• Limiting alcohol. Visit the National Institute on Alcohol Abuse and Alcoholism for resources on support and treatment to stop drinking.

If you’ve made these important lifestyle changes and your cholesterol levels remain high, your doctor might recommend medication.

• Statins. Statins are the most common medicine used to treat high blood cholesterol. Statins reduce the amount of cholesterol made in your liver. Studies have shown that statins lower the risk of heart attack and stroke in people with high LDL cholesterol. Statins usually don’t cause side effects, but they may raise the risk of diabetes. However, this mainly happens in people already at high risk of diabetes, such as those who have prediabetes, overweight or obesity, or metabolic syndrome. Statins may also cause abnormal results on liver enzymes tests, but actual liver damage is extremely rare. Other rare side effects include muscle damage and cognitive impairment.
• Cholesterol absorption inhibitors. Your small intestine absorbs the cholesterol from your diet and releases it into your bloodstream. The drug ezetimibe (Zetia) helps reduce blood cholesterol by limiting the absorption of dietary cholesterol. Ezetimibe can be used with a statin drug.
• Bempedoic acid. This newer drug works in much the same way as statins but is less likely to cause muscle pain. Adding bempedoic acid (Nexletol) to a maximum statin dosage can help lower LDL significantly. A combination pill containing both bempedoic acid and ezetimibe (Nexlizet) also is available.
• Bile-acid-binding resins. Your liver uses cholesterol to make bile acids, a substance needed for digestion. The medications cholestyramine (Prevalite), colesevelam (Welchol) and colestipol (Colestid) lower cholesterol indirectly by binding to bile acids. This prompts your liver to use excess cholesterol to make more bile acids, which reduces the level of cholesterol in your blood.
• PCSK9 inhibitors are injected under the skin every few weeks and are expensive. Your liver makes the protein, PCSK9. PCSK9 destroys parts of cells in the liver that allow LDL cholesterol to be absorbed. By stopping the PCSK9 protein, these inhibitors can reduce LDL cholesterol levels. These drugs can help the liver absorb more LDL cholesterol, which lowers the amount of cholesterol circulating in your blood. Alirocumab (Praluent) and evolocumab (Repatha) might be used for people who have a genetic condition that causes very high levels of LDL or in people with a history of coronary disease who have intolerance to statins or other cholesterol medications. Your cardiologist may prescribe a PCSK9 inhibitor and a statin if you are at high risk of complications like heart attack or stroke, or if you have familial hypercholesterolemia. In 2021, the United States Food and Drug Administration (FDA) approved the PCSK9 inhibitor, inclisiran (Leqvio) joining the already approved alirocumab (Praluent), for patients with familial hypercholesterolemia ⁴⁴. The most common side effects are itching, pain, or swelling at the place where you injected it.

If you also have high triglycerides, your doctor might prescribe:

• Fibrates. The medications fenofibrate (Tricor, Fenoglide, others) and gemfibrozil (Lopid) reduce your liver’s production of very-low-density lipoprotein (VLDL) cholesterol and speed the removal of triglycerides from your blood. VLDL cholesterol contains mostly triglycerides. Using fibrates with a statin can increase the risk of statin side effects.
• Niacin. Niacin limits your liver’s ability to produce LDL and VLDL cholesterol. But niacin doesn’t provide additional benefits over statins. Niacin has also been linked to liver damage and strokes, so most doctors now recommend it only for people who can’t take statins.
• Omega-3 fatty acid supplements. Omega-3 fatty acid supplements can help lower your triglycerides. They are available by prescription or over-the-counter. If you choose to take over-the-counter supplements, get your doctor’s OK. Omega-3 fatty acid supplements could affect other medications you’re taking.
• Apo CIII inhibitor (an antisense inhibitor of apo CIII), volanesorsen, is available in some countries. It lowers triglyceride levels in patients with severely elevated triglyceride levels, including people with lipoprotein lipase deficiency. It is given as a weekly injection.

If your doctor or cardiologist prescribes medicines as part of your treatment plan, be sure to continue your healthy lifestyle changes. The combination of the medicines and heart-healthy lifestyle changes can help lower and control your blood cholesterol levels.

Some people with familial hypercholesterolemia (FH) may receive a treatment called lipoprotein apheresis. This treatment uses a filtering machine to remove LDL cholesterol from the blood. Then the machine returns the rest of the blood back to the person.

What is familial combined hyperlipidemia?

Familial combined hyperlidemia (FCHL) is a common inherited lipid metabolic disorder characterized by: (a) increase in blood cholesterol level (hypercholesterolemia) and/or increased levels of triglycerides (triglyceridemia) in at least two members of the same family, (b) intra-individual and intrafamilial variability of the lipid phenotype, and (c) increased risk of premature coronary artery disease ⁷³, ⁵⁷, ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸²,. The laboratory abnormalities most frequently found in familial combined hyperlidemia (FCHL) are an increase of plasma triglycerides (triglyceridemia) and/or cholesterol levels (hypercholesterolemia), and a high prevalence of small very-low-density lipoproteins (VLDLs) and/or low-density lipoproteins (LDLs), mainly related to an increased plasma level of apolipoprotein B100 (apo B) ⁸³. Some familial combined hyperlidemia patients can present with a decrease in high-density lipoprotein (HDL) cholesterol level, often inversely correlated to the triglycerides (TG) plasma level ⁸⁴. There is a predominance of small and dense LDL so-called atherogenic LDL “B” pattern, poor in cholesterol, and with a high apolipoprotein B (apo B)/cholesterol ratio. The main determinants of LDLs size appear to be the triglyceride (TG) and HDL plasma levels ⁸⁵. The synthesis of LDL-apo B increases due to uncontrolled overproduction of apo B ⁸⁶. No major alterations in the LDL liver catabolic rate have been described.

In familial combined hyperlipidemia patients the activity of the LDL receptor (with a high affinity for apo B100) is normal ⁸⁷. The reduction in lipid levels after diet and lipid-lowering drugs does not normalize the kinetic and structural characteristics of the LDLs, at least in a large percentage of patients ⁸⁸. Some studies suggest that a relative deficit of liver lipoprotein lipase (LPL) can reduce the liver uptake of apo B to simulate the increased synthesis of these apolipoproteins ⁸⁹. Moreover, LDL from familial combined hyperlipidemia patients, irrespective of lipid phenotypes, are more susceptible to oxidation in vitro than LDL from healthy controls ⁷⁹. This increased susceptibility of LDL to oxidation in vitro seems to be a consequence of the abundance of small dense LDL particles and not to defects of antioxidant capacity in familial combined hyperlipidemia ⁹⁰. In familial combined hyperlipidemia patients with very high LDL cholesterol plasma levels of lipoprotein-a [Lp(a)] may be high as well ⁹¹.

Reduced levels of HDL cholesterol are a frequent finding in familial combined hyperlipidemia patients ⁷⁹. HDL cholesterol and HDL2 cholesterol reduction could be due to triglyceride-enrichment of HDL particles and enhanced hepatic lipase, while the role of lipoprotein lipase (LPL) and activities of cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) appears to be less evident ⁹². Recent data suggest that HDL cholesterol values are lower in subjects with predominantly small and dense LDL and are associated with a very high concentration of VLDL-1 (with low apo AI and apo E content) ⁷⁹. LDL pattern is suggested to be the main determinant of the phenotype expressed by familial combined hyperlipidemia patients ⁹³.

An increase in the synthesis of VLDL-apo B is usually present ⁹⁴, but the reason why is yet to be fully understood. Some authors suggest that this increase is related to alterations in the incorporation of fatty acids in the triglyceride (TG) ⁸⁸ and/or alterations of the after meal metabolism of the VLDLs, with greater conversion to small and dense LDLs and/or reduced turnover of the VLDLs themselves ⁹⁵. However, other authors showed that VLDL increase in familial combined hyperlipidemia patients is mainly related to defects in activity of lipoprotein lipase ⁹⁶, lecithin:cholesterol acyltransferase ⁹⁷, and/or hepatic lipase ⁹⁸. On the other hand, Evans et al ⁹⁹ recently used stable isotope techniques combined with tissue-specific measurements in adipose tissue and forearm muscle to investigate fatty acid handling by these tissues in the fasting and postprandial states of familial combined hyperlipidemia patients. They found that the major defect appeared to be overproduction of triacylglycerol (TAG) by the liver due to decreased fatty acid oxidation, with fatty acids directed to triglyceride (TG) synthesis, while evidence of decreased lipoprotein lipase action or impaired fatty acid re-esterification in adipose tissue was observed ⁹⁹.

An impaired after meal plasma component C3 response has been observed in familial combined hyperlipidemia patients, most likely as a result of a delayed response by C3, as the precursor for the biologically active acylation-stimulating protein, acting on free fatty acid (FFA) metabolism ¹⁰⁰. Therefore, an impaired postprandial C3 response may be associated with impaired peripheral postprandial free fatty acid (FFA) uptake and, consequently, lead to increased liver free fatty acid (FFA) flux and VLDL overproduction ⁸⁸.

In familial combined hyperlipidemia patients, the VLDL triglyceride (TG) content is inversely related to the LDL cholesterol plasma level: the redistribution of apoB and plasma cholesterol could be a key process in development of various phenotypes. The plasma apoB and cholesterol in VLDL particles, when in abundance, are associated with significantly lower cholesterol levels in the bigger and more buoyant LDL particles. This effect is reversible by reducing plasma triglyceride (TG) levels (by diet, by drugs, and/or by physical activity), which in turn may result in redistribution of apoB and total cholesterol from the VLDL particles to LDL particles ¹⁰¹.

In a recent study, de Graaf et al ¹⁰² point to high remnant-like particles cholesterol (RLP-C) as a potential biomarker of familial combined hyperlipidemia. They observed that patients with familial combined hyperlipidemia have 2-fold elevated plasma remnant-like particles cholesterol (RLP-C) levels, which add to the atherogenic lipid profile and contribute to the increased risk for cardiovascular disease ¹⁰². Plasma remnant-like particles cholesterol (RLP-C) levels above the 90th percentile predicted prevalent cardiovascular disease, independently of non-lipid cardiovascular risk factors and triglyceride (TG) levels. However, in both familial combined hyperlipidemia patients and controls, plasma remnant-like particles cholesterol (RLP-C) did not provide additional information about prevalent cardiovascular disease over and above non-HDL cholesterol levels ⁷⁹.

The prevalence of familial combined hyperlipidemia is estimated at 1 in 100 in the general population. However, familial combined hyperlipidemia can be higher in patients with premature coronary artery disease, being the most frequent in patients affected by coronary artery disease (10%) and among survivors of heart attacks aged less than 60 (11.3%) ¹⁰³, ⁷⁹. According to a conservative estimate (whole population: 0–99 years), over 3.5 million people are affected by familial combined hyperlipidemia in EU and 2.7 million in the US; familial combined hyperlipidemia is the cause of approximately 30,000–70,000 heart attacks/year in the EU and more or less the same number in US, often prematurely (onset at a younger age <50 years of age) ¹⁰⁴.

Figure 4. Familial combined hyperlipidemia diagnostic algorithm

Abbreviations: TC = total cholesterol; TG = triglycerides; apoB = apolipoprotein B-100; CAD = coronary artery disease, FCHL = familial combined hyperlipidemia

Figure 5. Familial combined hyperlipidemia genetics

Footnotes: Genetics of familial combined hyperlipidemia (FCHL). The interplay of large-effect genetic mutations, cumulative small-effect genetic variants, and environmental triggers contribute to developing the familial combined hyperlipidemia phenotype.

What is the difference between familial combined hyperlipidemia and familial hypercholesterolemia?

Familial combined hyperlidemia (FCHL) is a common inherited metabolic disorder characterized by: (a) increase in blood cholesterol level (hypercholesterolemia) and/or increased levels of triglycerides (triglyceridemia) in at least two members of the same family, (b) intra-individual and intrafamilial variability of the lipid phenotype, and (c) increased risk of premature coronary artery disease ⁵⁷, ⁷⁸, ⁷⁹, ⁸⁰. The laboratory abnormalities most frequently found in familial combined hyperlidemia (FCHL) are an increase of plasma triglycerides (triglyceridemia) and/or cholesterol levels (hypercholesterolemia), and a high prevalence of small very-low-density lipoproteins (VLDLs) and/or low-density lipoproteins (LDLs), mainly related to an increased plasma level of apolipoprotein B100 (apo B) ⁸³. Some familial combined hyperlidemia patients can present with a decrease in high-density lipoprotein (HDL) cholesterol level, often inversely correlated to the triglycerides (TG) plasma level ⁸⁴. There is a predominance of small and dense LDL so-called atherogenic LDL “B” pattern, poor in cholesterol, and with a high apolipoprotein B (apo B)/cholesterol ratio. The main determinants of LDLs size appear to be the triglyceride (TG) and HDL plasma levels ⁸⁵. The synthesis of LDL-apo B increases due to uncontrolled overproduction of apo B ⁸⁶. No major alterations in the LDL liver catabolic rate have been described.

Familial hypercholesterolemia also known as familial hyperlipoproteinemia type 2A or Fredrickson type 2A hyperlipidemia is an autosomal dominant genetic lipid disorder where your liver can’t process cholesterol properly and this leads to a severely elevated low-density lipoprotein (LDL) “bad” cholesterol in your blood that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for premature atherosclerotic cardiovascular disease , the leading cause of preventable death in the United States ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³, ¹¹⁴, ¹¹⁵. The gene that causes familial hypercholesterolemia is inherited due to a defect (mutation) in a gene changes how your body processes cholesterol. Familial hypercholesterolemia is present from birth but symptoms may not appear until adulthood and a significant number of people remain undiagnosed. In familial hypercholesterolemia patients, genetic mutations make the liver incapable of metabolizing or removing excess low-density lipoprotein (LDL) “bad” cholesterol, from your blood. The result is very high low-density lipoprotein (LDL) “bad” cholesterol levels which can lead to atherosclerotic plaques deposition in the coronary arteries and proximal aorta occurring at an early age, leading over time to an increased risk for cardiovascular disease and even narrowing of your heart valves. As a result, people with familial hypercholesterolemia have a higher risk of premature coronary artery disease (coronary heart disease) manifesting as angina, early heart attack (myocardial infarction) and stroke ¹¹⁶. Familial hypercholesterolemia likely accounts for 2% to 3% of heart attacks (myocardial infarctions) in individuals younger than age 60 years. Untreated familial hypercholesterolemia, men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years (see Figure 5 below) ¹¹⁷.

Familial hypercholesterolemia is the most common inherited cardiovascular disease:

• About 1 in 200-250 people worldwide have familial hypercholesterolemia ¹¹⁸
• In the United States alone, an estimated 1.3 million people live with familial hypercholesterolemia. Yet only 10% of them are diagnosed. Nearly 2 million people in the US might have familial hypercholesterolemia and not even know it. Perhaps they won’t know it until they have a heart attack.
• Over 90% of people with familial hypercholesterolemia have not been properly diagnosed ¹¹⁸
• Familial hypercholesterolemia runs in families. If one parent has familial hypercholesterolemia, each child has a 50% chance of having familial hypercholesterolemia ¹¹⁹
• If left untreated, men have a 50% rise of having a heart attack by age 50. Untreated women have a 30% risk by age 60 ¹²⁰
• 1 in 160,000 to 1 in 1 million people have homozygous familial hypercholesterolemia ¹¹⁸. Homozygous familial hypercholesterolemia is more likely to occur in countries where the prevalence of heterozygous familial hypercholesterolemia is very high, especially those where consanguinity (marriage between relatives) is common.
• Familial hypercholesterolemia is even more common in certain populations such as French Canadians, Ashkenazi Jews, Lebanese, and South African Afrikaners. Lebanese Christians (1 in every 85 people), Afrikaners in South Africa (1/72 – 1/100), French Canadians (1 in every 270 people), and Ashkenazi Jews originating from Lithuania (1 in every 67 people) known as a founder affect.

There are two forms of familial hypercholesterolemia:

Heterozygous familial hypercholesterolemia

• If you have inherited this genetic mutation (one of three genes: low density lipoprotein receptor (LDLR) gene, apolipoprotein B-100 (APOB) gene and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene) from one parent, then you will have Heterozygous familial hypercholesterolemia (HeFH). Heterozygous familial hypercholesterolemia occurs in 1 in 250 people worldwide. Most people with familial hypercholesterolemia have one affected gene and one normal gene (heterozygous familial hypercholesterolemia). An estimated 70%-95% of familial hypercholesterolemia results from a heterozygous pathogenic variant in one of three genes (apolipoprotein B [ApoB], low density lipoprotein receptor (LDLR), or PCSK9 gene).
• Until recently, it was believed that 1/500 people (630,000 people in the U.S.) had heterozygous familial hypercholesterolemia while about 1/1,000,000 people (300 people in the U.S.) had homozygous familial hypercholesterolemia. New studies suggest that heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia are more common. It is now believed that 1/250 people (or 1.3 million people in the U.S. alone) have heterozygous familial hypercholesterolemia and 1/160,000 (or 2,000 people in the U.S.) have homozygous familial hypercholesterolemia. Even though homozygous familial hypercholesterolemia is still rare, it is a lot more common than we once thought. If you think that you or someone you know may have familial hypercholesterolemia, talk to your doctor.
• Heterozygous familial hypercholesterolemia: LDL-C > 160 mg/dL (4 mmol/L) for children and >190 mg/dL (5 mmol/L) for adults and with one first degree relative similarly affected or with positive genetic testing for an LDL-C raising gene defect (LDL receptor [LDLR], apolipoprotein-B [apo B] or proprotein convertase subtilisin/kexin type 9 [PCSK9])

Homozygous familial hypercholesterolemia

• If you inherit familial hypercholesterolemia from both parents, it is much more severe in its consequences. This form of familial hypercholesterolemia is called Homozygous familial hypercholesterolemia (HoFH). Homozygous familial hypercholesterolemia is very rare, occurring in about 1 in 160,000 to one million people worldwide. Most individuals with homozygous familial hypercholesterolemia experience severe coronary artery disease by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
• Homozygous familial hypercholesterolemia: LDL-C > 400 mg/dL (10 mmol/L) and one or both parents:
  1. having clinically diagnosed familial hypercholesterolemia,
  2. positive genetic testing for an LDL-C raising (LDL receptor, apo B or PCSK9) gene defect, or
  3. autosomal recessive familial hypercholesterolemia If LDL-C > 560 mg/dL (14 mmol/L) or LDL-C > 400 mg/dL (10 mmol/L) with aortic valve disease or xanthomata at less than 20 years of age, homozygous familial hypercholesterolemia is highly likely.

Both types of familial hypercholesterolemia can be diagnosed with a physical examination and lab results, as well as personal and family history. Familial hypercholesterolemia also can be discovered through molecular diagnosis, genetic diagnosis or genetic testing. It’s helpful when genetic testing reveals familial hypercholesterolemia because it can alert relatives to their risk.

Some people with familial hypercholesterolemia have physical symptoms, but many don’t. One symptom of Familial hypercholesterolemia is cholesterol deposits in the Achilles tendons or the tendons of the hands or elbows. People with homozygous familial hypercholesterolemia also can develop cholesterol deposits in other areas, such as the skin surrounding the eyes or on the outer edge of the cornea.

If one person in a family has familial hypercholesterolemia, then all immediate relatives — parents, brothers, sisters and children — should be checked for it. Similarly, if someone in a family has an early heart attack, it’s a good idea for other family members to get tested.

Children with increased risk for familial hypercholesterolemia should be screened beginning at age 2. All children should have their cholesterol checked between ages 9 and 11 and again between ages 17 and 21.

Family history of early heart disease + High LDL “bad” cholesterol = Familial Hypercholesterolemia

Therefore, if you have familial hypercholesterolemia, your LDL-cholesterol levels will be very high, leading to narrowing or blockage of blood vessels (atherosclerosis). This process starts prior to birth and can ultimately result in heart disease, heart attack, or stroke. Because people with familial hypercholesterolemia have excessive cholesterol levels since before their birth, their risk of heart disease is 20 times greater than that of the general population. If a child has Homozygous familial hypercholesterolemia (inherited the familial hypercholesterolemia gene from both parents), she is exposed to an even higher risk, because her LDL-cholesterol levels are extraordinarily elevated and lead to progressive heart disease very early in life (often in the teens). Other cardiovascular disease risk factors include smoking, over-weight, high blood pressure, and a sedentary life. If you have familial hypercholesterolemia, eliminate smoking, control your weight and blood pressure, and lead a physically active lifestyle. All these are important factors, together with medical therapy and a healthful diet, in lowering your risk of an early heart attack.

All individuals with familial hypercholesterolemia should be considered “high risk” (i.e., increased ~20-fold) for coronary artery disease (coronary heart disease). Recent data suggest that individuals with an LDL “bad” cholesterol >190 mg/dL (>4.9 mmol/L) and a pathogenic variant in one of the genes (APOB, LDLR, PCSK9 & unknown genes) have a 22-fold increased risk for coronary heart disease, while those without a pathogenic variant have a sixfold increased risk for coronary artery disease over the general population ¹²¹.

Familial hypercholesterolemia is a lifelong condition. It’s not a temporary condition, like the common cold; it’s in your genes. When you have familial hypercholesterolemia, the most important step to take is therapies prescribed by your physician. But while this is the most essential measure, it’s not the only one. Familial hypercholesterolemia also means controlling weight, not smoking, eating a balanced diet low in saturated fat, and exercising. What is more, Familial hypercholesterolemia means bringing your family together to understand the impact of this disease. Familial hypercholesterolemia means living healthy, as individuals and as a family.

The good news is familial hypercholesterolemia is treatable! If familial hypercholesterolemia is found early, serious problems of the heart and blood vessels may be prevented or dramatically delayed by taking steps to protect yourself. These include:

• Not smoking.
• Exercising regularly.
• Eating a healthy diet low in saturated and trans fats.
• Taking medications.
• Going on LDL-apheresis.

Familial hypercholesterolemia in almost all cases requires aggressive treatment through a combined approach – medication, low-fat diet, exercise, weight control and not smoking. Familial hypercholesterolemia involves heart-healthy meals, regular exercise to get the blood flowing, controlling your weight and eliminating smoking. Because obesity and smoking are risk factors for heart disease and those with familial hypercholesterolemia are already at a 20 times higher risk, it is important to adapt to a healthy lifestyle.

Nearly 100% of people with familial hypercholesterolemia will require cholesterol-lowering medications. For some people with familial hypercholesterolemia, more aggressive measures are needed, including LDL-apheresis (a very simple procedure in which LDL-C cholesterol is removed from the blood on a weekly or biweekly basis.)

The American Academy of Pediatrics recommends that if a family has a pattern of early heart attacks or heart disease defined as before age 55 for men and 65 for women, children in that family should have cholesterol testing after the age of 2 years and before age 10.

It is important to find familial hypercholesterolemia and take action at any age, because when treated, the risk of heart disease can be reduced to levels similar to those of the general population.

Figure 6. Features of Familial Combined Hyperlipidemia and Familial Hypercholesterolemia

Footnotes: Features of Familial Combined Hyperlipidemia and Familial Hypercholesterolemia in Children.

Abbreviations: LDL = low-density lipoprotein; HDL = high-density lipoprotein; TG = triglycerides.

Figure 7. Familial hypercholesterolemia inheritance pattern

Note: HeFH = Heterozygous familial hypercholesterolemia; HoFH = Homozygous familial hypercholesterolemia

How is Familial Hypercholesterolemia different from Hypercholesterolemia or Hyperlipidemia?

Your clue here is “Familial”. By definition, hypercholesterolemia (or hyperlipidemia) simply means high cholesterol. However, Familial Hypercholesterolemia is a lifelong condition that is inherited. Otherwise put, your genes cause it. Therefore, it is a lot more serious than simply having high cholesterol caused from diet and it requires more aggressive treatment. familial hypercholesterolemia is a life-threatening disorder.

One of the most common scenarios in patients with familial hypercholesterolemia is being told that they have high cholesterol and that they need to change their diet. However, with familial hypercholesterolemia, eliminating fried foods and cheesecake from your diet is not enough. While saturated foods should be completely avoided, your high LDL-cholesterol mainly has to do with your genes/ your family’s medical history. With familial hypercholesterolemia, the cause of your high cholesterol is NOT your diet. Even if you ate nothing but oats and fruits, you would still have high LDL-cholesterol because of your liver’s inability to keep up with recycling and removing it.

Familial combined hyperlipidemia cause

The genetic inheritance of familial combined hyperlipidemia remains poorly understood. Familial combined hyperlipidemia (FCHL) was initially suggested to have a autosomal dominant monogenic mode of inheritance ¹²³, ⁷⁴. Later, some authors hypothesized that familial combined hyperlipidemia has a complex pattern related to multiple genetic variants with variable penetrance, environmental factors, and lifestyles ¹²⁴, ¹²⁵, ⁷³. Certain ethnic groups are particularly susceptible to familial combined hyperlipidemia, as demonstrated by Paramsothy et al. ¹²⁶ in a multiethnic cohort of 5923 participants in the United States, reporting a prevalence of 4.8% within Hispanics ¹²⁷, ¹²⁸.

Familial combined hyperlipidemia coexists with other metabolic diseases such as obesity, insulin resistance, type 2 diabetes, high blood pressure (hypertension), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome ¹²⁹. Familial combined hyperlipidemia cases with metabolic comorbidities have remarkably higher apoB plasma levels compared to cases with a similar severity of insulin resistance. In addition, subjects with FCHL have a greater susceptibility to developing type 2 diabetes and are at a higher cardiovascular risk in comparison to matched controls ¹²⁹, ⁸².

Pajukanta et al ¹³⁰, ¹³¹ identified genetic loci linked to familial combined hyperlipidemia from different ethnic backgrounds on chromosome 1 long arm (1q21-1q23) in Finnish families with the disease. This region has also been linked to familial combined hyperlipidemia in families from other populations ¹³², ⁷⁶, ¹³³, ¹³⁴, ¹³⁵ and to type 2 diabetes ¹³⁶, ¹³⁷. The region in chromosome 1q21-1q23 includes several genes which might contribute to familial combined hyperlipidemia phenotype, including the upstream transcription factor 1 gene (USF1) ⁷⁶. The gene encoding upstream transcription factor 1 (USF1) has appeared to be specifically linked to familial combined hyperlipidemia in 60 extended families with familial combined hyperlipidemia, including 721 genotyped individuals, especially males with high triglyceride (hypertriglyceridemia). The upstream transcription factor 1 (USF1) gene encodes a transcription factor that regulates nearly 40 genes implicated in lipid, lipoprotein and glucose metabolism, as well as immune response, and is located 1.5Mb away from TXNIP, a gene linked to mixed hyperlipidemia in mice ⁷⁶, ⁸². The upstream transcription factor 1 (USF1) gene encodes for a basic helix-loop-helix leucine zipper transcription factor located in chromosome 1q23.3, which binds to a palindromic E-box sequence.

USF1 was first described by Sawadogo et al. ¹³⁸ as a key component in adenovirus replication and its role as a regulator of lipid and glucose metabolism was later reported. USF1 has been shown to regulate expression of L-pyruvate kinase, fatty acid synthase, and glucokinase, as well as apoA-V, apoC-III, apoA-II, apoE, hormone-sensitive lipase, and other enzymes involved in lipid and carbohydrate metabolism ¹³⁹, ¹⁴⁰, ¹⁴¹.

The concept that USF1 affects the complex lipid phenotype of familial combined hyperlipidemia, and not only one lipid trait, is supported by the findings of the same authors on allelic associations of the usf1s1-usf1s2 risk haplotype with triglyceride (TG), apo B, total cholesterol, and LDL peak particle size ¹⁴². Pajukanta et al. ¹³⁰ characterized USF1 as the major genetic trait of familial combined hyperlipidemia which was further demonstrated by Huertas-Vázquez et al. in Mexican population ¹⁴³, ¹⁴⁴.

A gene-hunting technique that traces patterns of disease in high-risk families (linkage studies) and association analysis suggested that the association of the newly discovered apo AV gene with APOAI/CIII/AIV cluster contributes to familial combined hyperlipidemia transmission in a case report of 128 European families ¹⁴⁵.

Other authors proposed that LDL size in familial combined hyperlipidemia patients is a trait influenced by multiple loci located to chromosome 9 short arm [p], chromosome 16 long arm [q], and chromosome 11 long arm [q] ¹⁴⁶.

Familial combined hyperlipidemia signs and symptoms

Common features familial combined hyperlipidemia are:

• Frequent hypertriglyceridemia (high blood triglyceride level) and/or low plasma HDL cholesterol level. HDL is sometimes called the “good” cholesterol because it helps remove cholesterol from your arteries.
• Frequent association with non-lipid cardiovascular risk factors as high blood pressure (hypertension), abdominal obesity, reduced glucose tolerance or diabetes
• Frequent association with metabolic syndrome. Metabolic syndrome is the name for a group of risk factors for heart disease, stroke, type 2 diabetes, and other health problems. You can have just one risk factor, but people often have several of them together. When you have at least three of them, it is called metabolic syndrome. These risk factors include:
  • A large waistline, also called abdominal obesity or “having an apple shape.” Too much fat around the stomach is a greater risk factor for heart disease than too much fat in other parts of the body.
  • Having a high triglyceride level.
  • Having a low HDL cholesterol level.
  • Having high blood pressure. If your blood pressure stays high over time, it can damage your heart and lead to other health problems.
  • Having a high fasting blood sugar. Mildly high blood sugar may be an early sign of diabetes.
  • The more factors you have, the higher your risk for heart disease, diabetes, and stroke is.
• Strongly increased cardiovascular disease risk. Familial combined hyperlipidemia is strongly associated with premature coronary artery disease, with up to 10-14% of patients with premature coronary artery disease having comorbid familial combined hyperlipidemia ¹⁴⁷. A patient diagnosed with familial combined hyperlipidemia has 1.7-10-fold higher risk of coronary artery disease compared to the average population 20 years after the initial diagnosis ¹⁴⁷, ¹⁴⁸. Wierzbicki et al. ¹⁴⁹ demonstrated that 38% of premature heart attack survivors had familial combined hyperlipidemia, and a similar study including 706 participants with familial combined hyperlipidemia reported a coronary artery disease prevalence of 15.3%, describing that disease presentation was independent of age, sex, or presence of type 2 diabetes ¹²⁹. Cardiovascular risk in patients with hypertriglyceridemia is also increased, especially in the setting of older age, tobacco use, and hypertension and decreased HDL cholesterol levels ¹²⁴. Among familial combined hyperlipidemia patients, males are more susceptible to inherit and develop the lipid disorder independent of lipid profile, which might also account for the increased risk ¹⁵⁰. Elevated expression of CD11b, a marker of fasting and postprandial leucocyte activation, has been previously reported for familial combined hyperlipidemia subjects and has been associated to increased cardiovascular risk in subjects with familial combined hyperlipidemia and comorbid type 2 diabetes ¹⁵¹, ¹⁵², ¹⁵³, ¹⁵⁴, ¹⁵⁵.

The National Institutes of Health guidelines define metabolic syndrome as having three or more of the following traits, including traits for which you may be taking medication to control:

• Large waist — A waistline that measures at least 35 inches (89 centimeters) for women and 40 inches (102 centimeters) for men
• High triglyceride level — 150 milligrams per deciliter (mg/dL), or 1.7 millimoles per liter (mmol/L), or higher of this type of fat found in blood
• Reduced high-density lipoprotein (HDL) cholesterol or “good” cholesterol — Less than 40 milligrams per deciliter (mg/dL) (1.04 millimoles per liter (mmol/L)) in men or less than 50 mg/dL (1.3 mmol/L) in women of high-density lipoprotein (HDL) cholesterol
• Increased blood pressure — 130/85 millimeters of mercury (mm Hg) or higher
• Elevated fasting blood sugar — 100 mg/dL (5.6 mmol/L) or higher

Cholesterol can enter your artery wall, damage its integrity and lead to the formation of atherosclerotic plaque (hardened deposits). This process of plaque buildup is called atherosclerosis. It can lead to serious problems like:

• Coronary artery disease: Blocked blood flow to your heart.
• Peripheral artery disease: Blocked blood flow to your legs and arms.
• Carotid artery disease: Blocked blood flow to your brain.

Familial combined hyperlipidemia diagnosis

Due to the lack of agreement among researchers because of a lack in specific laboratory or clinical marker of familial combined hyperlipidemia, a high degree of diagnostic uncertainty exists in the categorization familial combined hyperlipidemia ¹⁴⁹, ⁷⁷. Classically, to establish the diagnosis of familial combined hyperlipidemia comprised either isolated hypercholesterolemia or hypertriglyceridemia or a mixed lipid profile along with the first-degree family history of premature coronary artery disease, excluding other causes of hyperlipidemia ⁸². More recent criteria have also included elevated apoB levels as highly suggestive of familial combined hyperlipidemia (see Table 4) ¹⁵⁶.

Due to the polygenic nature of familial combined hyperlipidemia, genetic testing is not yet a possibility ⁸². But familial combined hyperlipidemia diagnosis can be made based on a fluctuating lipid profile, increased apoB levels, and first-degree family history of mixed lipid disorders and premature cardiovascular disease ¹⁵⁷, ¹⁵⁸, ¹²⁴. Some limitations on these criteria include the low practicality of apoB measurements in everyday clinical settings in addition to interethnic differences in establishing the 90th percentile in both lipid and apoB measurements, which require population-specific percentiles that might not always be available.

The following diagnostic criteria are suggested for familial combined hyperlipidemia:

First level diagnosis

1. In the patient: primary hyperlipoproteinemia (LDL > 160 mg/dL and/or triglyceride > 200 mg/dL), PLUS
2. In the patient and in at least one member of the family: primary variability of the lipid phenotype (hypercholesterolemia, hypertriglyceridemia, both, or even a “normal” phenotype) evaluated on the basis of at least 3 consecutive (bimonthly) controls (the repetition of lipid analysis before to define a diagnosis of dyslipidemia is in agreement with the international guidelines) ¹⁵⁹.

Second level diagnosis (specialized labs only)

1. Evaluation of apo B100 plasma level: preferably by standardized immunoturbidimetric assay ¹⁶⁰
2. Detection of small and dense LDL particles (LDL pattern B): there is not yet a standardized method to dose small dense LDLs; different methods have been tested (from preparative and non-equilibrium density gradient ultracentifugation to nuclear magnetic resonance) but the most frequently used is the gradient gel electrophoresis ¹⁶¹
3. Genetic tests to exclude similar more rare forms of familial dyslipidaemias, when indicated (unclear situations, suggestive clinical and laboratory condition)

Specific cases

If family data are not available, the presence of unexplained (primary) IIb phenotype (eg, not related to significant change in dietary habits or body-weight gain or by an evident double heterozygosis for familial hypercholesterolemia and familial hypertriglyceridemia) may suggest the diagnosis ¹⁰⁴. The presence of early onset atherosclerosis (increased carotid artery intima-media thickness (IMT) included) and/or clinical complications (coronary artery disease, cardiovascular disease or peripheral artery disease) in the patient and/or in relatives (probably carriers of the disease on the basis of genealogical tree) is not strictly diagnostic of familial combined hyperlipidemia, but it could suggest an aggressive dyslipidemia or, in any case, a condition at high risk of cardiovascular disease ⁷⁹. Lipid abnormalities including presence of small and dense LDL in non-controlled diabetes will be regarded with caution and have to be re-evaluated after improvement of diabetes control ⁷⁹.

Table 8. Changes in diagnostic criteria for familial combined hyperlipidemia throughout the years

Familial combined hyperlipidemia treatment

The most important treatment for familial combined hyperlipidemia is a heart-healthy lifestyle, which includes:

• A heart-healthy diet, which limits the amount of saturated and trans fats that you eat. It encourages you to choose a variety of nutritious foods, including fruits, vegetables, whole grains, and lean meats. Healthy-eating plans include the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean diet, emphasize eating vegetables, fruits, high-fiber whole grains and lean protein. Healthy-eating plans tend to recommend limiting sugar-sweetened beverages, alcohol, salt, sugar and fat, especially saturated fat and trans fat.
• Healthy weight. Losing 7% of your body weight can reduce insulin resistance and blood pressure and decrease your risk of diabetes. Mateo-Gallego et al. ¹⁶² showed that a weight loss of 5% of total weight in overweight adults with familial combined hyperlipidemia significantly reduces triglyceride and non-HDL cholesterol levels at 3 and 6 months. This justifies the role of weight loss in overweight patients with familial combined hyperlipidemia to complement lipid-lowering therapy in familial combined hyperlipidemia ¹⁶³. In fact, any amount of weight loss is beneficial. It’s also important to maintain your weight loss. If you’re struggling with losing weight and keeping it off, talk to your doctor about what options might be available to help you, such as medications or weight-loss surgery.
• Managing stress. Physical activity, meditation, yoga and other programs can help you handle stress and improve your emotional and physical health.
• Getting regular physical activity. Health experts recommend getting at least 30 minutes of exercise, such as brisk walking, daily. But you don’t have to do that activity all at once. Look for ways to increase activity any chance you get, such as walking instead of driving and using the stairs instead of an elevator.
• Quitting smoking or not starting if you don’t already smoke. Giving up cigarettes greatly improves your overall health. Talk to your doctor if you need help quitting.

If making lifestyle changes is not enough, you may need to take medicines. Your doctor might suggest medications to help control your blood pressure, cholesterol and blood sugar levels.

With regard to medicines, some small clinical trials have been conducted on patients defined as affected by “combined” or “mixed” hyperlipoproteinemia ¹⁶⁴, ¹⁶⁵, ⁶⁹. Other small trials conducted on subjects selected as being affected by familial combined hyperlipidemia suggest some efficacy of statins ¹⁶⁶, ¹⁶⁷, fibrates ¹⁶⁸, omega 3 polyunsaturated fatty acids ¹⁶⁹, and pioglitazone ¹⁷⁰ on secondary outcomes (eg, endothelial function, LDL composition, oxidation markers, inflammation markers). Atorvastatin and fenofibrate displayed comparable efficiency in decreasing oxysterols, but they decreased lipid-corrected alpha-tocopherol levels in plasma, which are already low in familial combined hyperlipidemia patients ¹⁷¹. However a full-dosage of a powerful statin such as rosuvastatin was not able to improve endothelial function of familial combined hyperlipidemia patients ¹⁷². Moreover, pioglitazone 30 mg/day in patients on conventional lipid-lowering therapy acts favorably on several metabolic parameters, such as TG/HDL (atherogenic index of plasma, plasma glucose, alanine-aminotransferase [ALT], and adiponectin) ¹⁷³. Because of the lack of specific long-term data on drug efficacy on strong outcomes of familial combined hyperlipidemia patients, the main proposed recommendations for familial combined hyperlipidemia therapy are based on the results obtained from long-term clinical trials with hard outcomes on cardiovascular morbidity and mortality. However, the majority of available trial analyses are on the same group of patients with familial combined hyperlipidemia, with mixed/multigenic hyperlipoproteinemia (from random association of different genetic factors in the same subjects), metabolic syndrome, secondary hyperlipoproteinemia, etc, and data obtained might be not strictly representative of the effect of tested drugs/lifestyle changes on familial combined hyperlipidemia patients.

In any case, the effectiveness of statins to reduce cardiovascular risk suggests that statins should be the first-line treatment for familial combined hyperlipidemia also ¹⁷⁴, perhaps with a preference for those with a stronger triglyceride-lowering activity ¹⁷⁵. The triglyceride-lowering effect, which is mainly through an increase in the liver reuptake of VLDL, ILDL, and LDL is, however, less than that of fibrates, which increase lipoprotein lipase activity by a mechanism involving peroxisome proliferators activator receptors alpha and gamma ¹⁷⁶.

The fibrates’ cholesterol-lowering effect is, however, smaller than that of statins. Omega-3 polyunsaturated fatty acids also lower VLDL triglycerides, slightly increasing LDL cholesterol and HDL cholesterol ¹⁷⁷. The association of statins with drugs more active on triglyceride plasma levels (omega-3 polyunsaturated fatty acids, fibrates, nicotinic acid) could be an efficacious way to treat this kind of patients ⁶⁹, ¹⁷⁸. Ezetimibe, a selective inhibitor of the bowel cholesterol adsorption, might be an optimal drug to be associated to statins or fibrates instead of the prescribed resins ¹⁷⁹.

Slow-release nicotinic acid is another very interesting and plausible therapeutic weapon to be associated to the standard statin and/or to fibrate therapy ¹⁸⁰; probably, the dose-dependent effects of nicotinic acid derivatives and the good safety and interaction profiles, will open a new therapeutic approach even for more severe (and drug-resistant) familial combined hyperlipidemia patients.

Familial combined hyperlipidemia prognosis

Familial combined hyperlipidemia patients appear to be associated with an increased risk of coronary artery disease and cardiovascular disease ⁵⁷, ⁷⁸, ¹⁸¹, ¹⁸². Until now, no adequately designed trials on familial combined hyperlipidemia patients have been carried out to estimate their peculiar cardiovascular disease risk ⁷⁹. Some authors suggest that it is at least as elevated as that of heterozygous familial hypercholesterolemia patients ¹⁸³. Familial combined hyperlipidemia is clearly also a risk factor for increased carotid artery intima-media thickness (IMT): the increased carotid artery intima-media thickness (IMT) observed in familial combined hyperlipidemia patients corresponds, on average, to a 7-year increase in carotid artery intima-media thickness (IMT) ¹⁸⁴. The parameter best correlated with IMT is the plasma apo B level and consequently the LDL particle size (but not LDL susceptibility to oxidation) ⁹⁰. A worse prognostic factor appears to be the constant association of hypercholesterolemia to hypertriglyceridemia; young people with this kind of lipid phenotype have a reduced coronary flow reserve compared with age-matched hypercholesterolemic non-hypertriglyceridemic subjects ¹⁸⁵. Hypertriglyceridemia per se appears in fact to be a significant predictor of cardiovascular disease in proportion to the baseline triglyceride levels ¹⁸⁶.

What is familial hypercholesterolemia?

Familial hypercholesterolemia also known as familial hyperlipoproteinemia type 2A or Fredrickson type 2A hyperlipidemia is an autosomal dominant genetic lipid disorder where your liver can’t process cholesterol properly and this leads to a severely elevated low-density lipoprotein (LDL) “bad” cholesterol in your blood that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for premature atherosclerotic cardiovascular disease , the leading cause of preventable death in the United States ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³, ¹¹⁴, ¹¹⁵. The gene that causes familial hypercholesterolemia is inherited due to a defect (mutation) in a gene changes how your body processes cholesterol. Familial hypercholesterolemia is present from birth but symptoms may not appear until adulthood and a significant number of people remain undiagnosed. In familial hypercholesterolemia patients, genetic mutations make the liver incapable of metabolizing or removing excess low-density lipoprotein (LDL) “bad” cholesterol, from your blood. The result is very high low-density lipoprotein (LDL) “bad” cholesterol levels which can lead to atherosclerotic plaques deposition in the coronary arteries and proximal aorta occurring at an early age, leading over time to an increased risk for cardiovascular disease and even narrowing of your heart valves. As a result, people with familial hypercholesterolemia have a higher risk of premature coronary artery disease (coronary heart disease) manifesting as angina, early heart attack (myocardial infarction) and stroke ¹¹⁶. Familial hypercholesterolemia likely accounts for 2% to 3% of heart attacks (myocardial infarctions) in individuals younger than age 60 years. Untreated familial hypercholesterolemia, men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years (see Figure 2 below) ¹¹⁷.

Familial hypercholesterolemia is the most common inherited cardiovascular disease:

• About 1 in 200-250 people worldwide have familial hypercholesterolemia ¹¹⁸
• In the United States alone, an estimated 1.3 million people live with familial hypercholesterolemia. Yet only 10% of them are diagnosed. Nearly 2 million people in the US might have familial hypercholesterolemia and not even know it. Perhaps they won’t know it until they have a heart attack.
• Over 90% of people with familial hypercholesterolemia have not been properly diagnosed ¹¹⁸
• Familial hypercholesterolemia runs in families. If one parent has familial hypercholesterolemia, each child has a 50% chance of having familial hypercholesterolemia ¹¹⁹
• If left untreated, men have a 50% rise of having a heart attack by age 50. Untreated women have a 30% risk by age 60 ¹²⁰
• 1 in 160,000 to 1 in 1 million people have homozygous familial hypercholesterolemia ¹¹⁸. Homozygous familial hypercholesterolemia is more likely to occur in countries where the prevalence of heterozygous familial hypercholesterolemia is very high, especially those where consanguinity (marriage between relatives) is common.
• Familial hypercholesterolemia is even more common in certain populations such as French Canadians, Ashkenazi Jews, Lebanese, and South African Afrikaners. Lebanese Christians (1 in every 85 people), Afrikaners in South Africa (1/72 – 1/100), French Canadians (1 in every 270 people), and Ashkenazi Jews originating from Lithuania (1 in every 67 people) known as a founder affect.

The vast majority of the cholesterol circulating in a person’s body is produced by the liver. Cholesterol is a necessary component in the structure and function of human cells. Individuals with familial hypercholesterolemia are unable to recycle this natural supply of cholesterol that their bodies are constantly producing. Therefore, the cholesterol levels of an individual with familial hypercholesterolemia are exceedingly high. Over time the elevated blood cholesterol can lead to blockages in the arteries of the heart and/or brain. The longer a person experiences high low-density lipoprotein (LDL) “bad” cholesterol, the more likely he or she will be to experience angina and myocardial infarctions (heart attacks) and strokes. As familial hypercholesterolemia is a genetic disorder, even when affected children are still in their mother’s womb they are “bathing” in their own high cholesterol. The process of blood vessels disease therefore can have its origins even prior to your children’s birth. Familial hypercholesterolemia gene mutations are passed from parent to child. To have the condition, children need to inherit an altered copy of the gene from one parent.

There are two forms of familial hypercholesterolemia:

Heterozygous familial hypercholesterolemia

• If you have inherited this genetic mutation (one of three genes: low density lipoprotein receptor (LDLR) gene, apolipoprotein B-100 (APOB) gene and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene) from one parent, then you will have Heterozygous familial hypercholesterolemia (HeFH). Heterozygous familial hypercholesterolemia occurs in 1 in 250 people worldwide. Most people with familial hypercholesterolemia have one affected gene and one normal gene (heterozygous familial hypercholesterolemia). An estimated 70%-95% of familial hypercholesterolemia results from a heterozygous pathogenic variant in one of three genes (apolipoprotein B [ApoB], low density lipoprotein receptor (LDLR), or PCSK9 gene).
• Until recently, it was believed that 1/500 people (630,000 people in the U.S.) had heterozygous familial hypercholesterolemia while about 1/1,000,000 people (300 people in the U.S.) had homozygous familial hypercholesterolemia. New studies suggest that heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia are more common. It is now believed that 1/250 people (or 1.3 million people in the U.S. alone) have heterozygous familial hypercholesterolemia and 1/160,000 (or 2,000 people in the U.S.) have homozygous familial hypercholesterolemia. Even though homozygous familial hypercholesterolemia is still rare, it is a lot more common than we once thought. If you think that you or someone you know may have familial hypercholesterolemia, talk to your doctor.
• Heterozygous familial hypercholesterolemia: LDL-C > 160 mg/dL (4 mmol/L) for children and >190 mg/dL (5 mmol/L) for adults and with one first degree relative similarly affected or with positive genetic testing for an LDL-C raising gene defect (LDL receptor [LDLR], apolipoprotein-B [apo B] or proprotein convertase subtilisin/kexin type 9 [PCSK9])

Homozygous familial hypercholesterolemia

• If you inherit familial hypercholesterolemia from both parents, it is much more severe in its consequences. This form of familial hypercholesterolemia is called Homozygous familial hypercholesterolemia (HoFH). Homozygous familial hypercholesterolemia is very rare, occurring in about 1 in 160,000 to one million people worldwide. Most individuals with homozygous familial hypercholesterolemia experience severe coronary artery disease by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
• Homozygous familial hypercholesterolemia: LDL-C > 400 mg/dL (10 mmol/L) and one or both parents:
  1. having clinically diagnosed familial hypercholesterolemia,
  2. positive genetic testing for an LDL-C raising (LDL receptor, apo B or PCSK9) gene defect, or
  3. autosomal recessive familial hypercholesterolemia If LDL-C > 560 mg/dL (14 mmol/L) or LDL-C > 400 mg/dL (10 mmol/L) with aortic valve disease or xanthomata at less than 20 years of age, homozygous familial hypercholesterolemia is highly likely.

Both types of familial hypercholesterolemia can be diagnosed with a physical examination and lab results, as well as personal and family history. Familial hypercholesterolemia also can be discovered through molecular diagnosis, genetic diagnosis or genetic testing. It’s helpful when genetic testing reveals familial hypercholesterolemia because it can alert relatives to their risk.

Some people with familial hypercholesterolemia have physical symptoms, but many don’t. One symptom of Familial hypercholesterolemia is cholesterol deposits in the Achilles tendons or the tendons of the hands or elbows. People with homozygous familial hypercholesterolemia also can develop cholesterol deposits in other areas, such as the skin surrounding the eyes or on the outer edge of the cornea.

If one person in a family has familial hypercholesterolemia, then all immediate relatives — parents, brothers, sisters and children — should be checked for it. Similarly, if someone in a family has an early heart attack, it’s a good idea for other family members to get tested.

Children with increased risk for familial hypercholesterolemia should be screened beginning at age 2. All children should have their cholesterol checked between ages 9 and 11 and again between ages 17 and 21.

Doctors measure blood cholesterol in milligrams per deciliter (mg/dL).

Adults with familial hypercholesterolemia may have untreated low-density lipoprotein (LDL-C) “bad” cholesterol levels that range from 190mg/dL to 400mg/dL or even higher. Children with familial hypercholesterolemia generally have low-density lipoprotein (LDL-C) “bad” cholesterol levels above 160mg/dL, but in pre-teens, levels can be even lower.

• High-density lipoprotein (HDL-C) “good” cholesterol levels are desirable and somewhat protect against coronary heart disease.
• High LDL-C “bad” cholesterol levels are undesirable and contribute to coronary heart disease risk.

Triglycerides, another blood fat, come from the diet and are also produced in the liver. When extremely elevated, triglycerides can cause pancreatitis and can also increase the risk of developing coronary heart disease. High triglycerides are generally not present in people with familial hypercholesterolemia.

All individuals with familial hypercholesterolemia should be considered “high risk” (i.e., increased ~20-fold) for coronary artery disease (coronary heart disease). Recent data suggest that individuals with an LDL “bad” cholesterol >190 mg/dL (>4.9 mmol/L) and a pathogenic variant in one of the genes (APOB, LDLR, PCSK9 & unknown genes) have a 22-fold increased risk for coronary heart disease, while those without a pathogenic variant have a sixfold increased risk for coronary artery disease over the general population ¹²¹.

Figure 8. Familial hypercholesterolemia inheritance pattern

Note: HeFH = Heterozygous familial hypercholesterolemia; HoFH = Homozygous familial hypercholesterolemia

Figure 9. LDL cholesterol burden in individuals with or without familial hypercholesterolemia as a function of the age of initiation of Statin therapy

Figure 10. Estimated number of individuals diagnosed with familial hypercholesterolemia in different countries

Footnotes: As most countries do not have valid nationwide registries for familial hypercholesterolemia, several values in this figure represent informed estimates from clinicians/scientists with recognized expertise in and knowledge of familial hypercholesterolemia in their respective countries.

Family history of early heart disease + High LDL “bad” cholesterol = Familial Hypercholesterolemia

Therefore, if you have familial hypercholesterolemia, your LDL-cholesterol levels will be very high, leading to narrowing or blockage of blood vessels (atherosclerosis). This process starts prior to birth and can ultimately result in heart disease, heart attack, or stroke. Because people with familial hypercholesterolemia have excessive cholesterol levels since before their birth, their risk of heart disease is 20 times greater than that of the general population. If a child has Homozygous familial hypercholesterolemia (inherited the familial hypercholesterolemia gene from both parents), she is exposed to an even higher risk, because her LDL-cholesterol levels are extraordinarily elevated and lead to progressive heart disease very early in life (often in the teens). Other cardiovascular disease risk factors include smoking, over-weight, high blood pressure, and a sedentary life. If you have familial hypercholesterolemia, eliminate smoking, control your weight and blood pressure, and lead a physically active lifestyle. All these are important factors, together with medical therapy and a healthful diet, in lowering your risk of an early heart attack.

Familial hypercholesterolemia is a lifelong condition. It’s not a temporary condition, like the common cold; it’s in your genes. When you have familial hypercholesterolemia, the most important step to take is therapies prescribed by your physician. But while this is the most essential measure, it’s not the only one. Familial hypercholesterolemia also means controlling weight, not smoking, eating a balanced diet low in saturated fat, and exercising. What is more, Familial hypercholesterolemia means bringing your family together to understand the impact of this disease. Familial hypercholesterolemia means living healthy, as individuals and as a family.

The good news is familial hypercholesterolemia is treatable! If familial hypercholesterolemia is found early, serious problems of the heart and blood vessels may be prevented or dramatically delayed by taking steps to protect yourself. These include:

• Not smoking.
• Exercising regularly.
• Eating a healthy diet low in saturated and trans fats.
• Taking medications.
• Going on LDL-apheresis.

Familial hypercholesterolemia in almost all cases requires aggressive treatment through a combined approach – medication, low-fat diet, exercise, weight control and not smoking. Familial hypercholesterolemia involves heart-healthy meals, regular exercise to get the blood flowing, controlling your weight and eliminating smoking. Because obesity and smoking are risk factors for heart disease and those with familial hypercholesterolemia are already at a 20 times higher risk, it is important to adapt to a healthy lifestyle.

Nearly 100% of people with familial hypercholesterolemia will require cholesterol-lowering medications. For some people with familial hypercholesterolemia, more aggressive measures are needed, including LDL-apheresis (a very simple procedure in which LDL-C cholesterol is removed from the blood on a weekly or biweekly basis.)

The American Academy of Pediatrics recommends that if a family has a pattern of early heart attacks or heart disease defined as before age 55 for men and 65 for women, children in that family should have cholesterol testing after the age of 2 years and before age 10.

It is important to find familial hypercholesterolemia and take action at any age, because when treated, the risk of heart disease can be reduced to levels similar to those of the general population.

Is there a cure for familial hypercholesterolemia?

Familial hypercholesterolemia is not curable. However, it is treatable. Now, more than ever, there are various treatment options for people with Familial hypercholesterolemia. This realistically means that individuals with Familial hypercholesterolemia could lead normal lives, if diagnosed early and treated adequately.

What is the difference between Heterozygous and Homozygous Familial Hypercholesterolemia?

Heterozygous Familial Hypercholesterolemia (HeFH) is the most common form of familial hypercholesterolemia (1 in 250 worldwide have it) caused when a child inherits one copy of a “bad gene” from one parent. Homozygous Familial Hypercholesterolemia (HoFH) is a very rare, but extremely severe form of familial hypercholesterolemia (roughly 1 in 160,000 have it) caused when a child gets a “bad gene” from both parents. Typically, Heterozygous familial hypercholesterolemia remains invisible for longer and Homozygous familial hypercholesterolemia manifests itself earlier, with more visible signs such as xanthomas (bumps or lumps in the skin which are deposits of excess fat) and corneal arcus (a white arc near the colored part of the eye, which is often found by an ophthalmologist).

How is Familial Hypercholesterolemia different from Hypercholesterolemia/Hyperlipidemia?

Your clue here is “Familial”. By definition, hypercholesterolemia (or hyperlipidemia) simply means high cholesterol. However, Familial Hypercholesterolemia is a lifelong condition that is inherited. Otherwise put, your genes cause it. Therefore, it is a lot more serious than simply having high cholesterol caused from diet and it requires more aggressive treatment. familial hypercholesterolemia is a life-threatening disorder.

One of the most common scenarios in patients with familial hypercholesterolemia is being told that they have high cholesterol and that they need to change their diet. However, with familial hypercholesterolemia, eliminating fried foods and cheesecake from your diet is not enough. While saturated foods should be completely avoided, your high LDL-cholesterol mainly has to do with your genes/ your family’s medical history. With familial hypercholesterolemia, the cause of your high cholesterol is NOT your diet. Even if you ate nothing but oats and fruits, you would still have high LDL-cholesterol because of your liver’s inability to keep up with recycling and removing it.

How is familial hypercholesterolemia diagnosed? Is there a specific blood test for it?

Diagnosis can be strongly suspected based on cholesterol levels (also called a lipid test or lipid panel). The diagnosis can be confirmed through additional information about your personal and family medical history, and certain physical exam findings (like xanthomas, bumps or lumps of cholesterol deposits on the skin). Learn more about familial hypercholesterolemia diagnosis in a section below.

I have been diagnosed with Familial hypercholesterolemia but I don’t want to take medication. Can I lower my cholesterol through a low-fat diet?

Familial hypercholesterolemia causes excessively high LDL-cholesterol levels. This is dangerous as it leads to cholesterol getting built up in your blood vessels, leading to atherosclerosis, heart attacks, and even death. While it is important to be mindful of your diet, this is almost never enough to manage your condition.

In all cases, familial hypercholesterolemia requires aggressive treatment. Consult an familial hypercholesterolemia specialist to find the best therapy regime for you.

Familial hypercholesterolemia cause

Familial hypercholesterolemia is an inherited genetic condition affecting cholesterol metabolism. Genes that are related to monogenic familial hypercholesterolemia include low density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), STAP1, APOE, LDLRAP1, LIPA, ABCG5, and ABCG8 ¹⁸⁸.

Familial hypercholesterolemia is commonly caused by a mutation in the gene for the low density lipoprotein receptor (LDLR), which is involved in passing LDL from the blood into cells for use by, or removal from, the body. Mutations in other genes can also cause inherited high cholesterol. Those genes include the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and the gene for Apolipoprotein B-100 (APOB). If you inherit a specific type of mutation in any of these three genes, you can develop familial hypercholesterolemia.

One in about 200 adults have the familial hypercholesterolemia genetic mutation. Including children, familial hypercholesterolemia affects about 1.3 million people in the U.S. But only about 10% are aware they have it.

Familial hypercholesterolemia is an autosomal dominant disorder with essentially complete penetrance. What this means is that if you have inherited the familial hypercholesterolemia gene, you will have high LDL-cholesterol (and will require therapy to lower your LDL-cholesterol). In addition, each of your children will have a 50% chance of having familial hypercholesterolemia. If someone else in your family has familial hypercholesterolemia (like a brother or a sister) and has high LDL cholesterol but you have totally normal LDL-cholesterol, then you will not pass on the familial hypercholesterolemia gene to your children. However, if someone in your family has familial hypercholesterolemia and your cholesterol is “borderline” or mildly elevated (ask your physician what LDL-cholesterol levels would be considered borderline or elevated in your case), there is a chance that you have familial hypercholesterolemia and could pass it along to your children. In this case a consultation with a lipid specialist should be considered. Generally, if an adult’s LDL-cholesterol is less than 160 mg/dL without taking cholesterol-lowering medication, there is a very low chance that they have familial hypercholesterolemia. If an adult has an LDL cholesterol level > 190mg/dL there is a stronger suspicion for Familial hypercholesterolemia.

In familial hypercholesterolemia there is a “dose effect” so that homozygous familial hypercholesterolemia (two defective genes – one from each parent) is more severe than heterozygous familial hypercholesterolemia (one defective and one normal gene).

• Heterozygous familial hypercholesterolemia (HeFH) occurs when a child inherits a nonfunctional copy of one of their familial hypercholesterolemia genes from an affected parent and a functional copy from their unaffected parent. Each egg or sperm they produce has a 50% chance of getting the nonfunctional copy (passing down familial hypercholesterolemia) and a 50% chance of getting the functional copy, Therefore, the risk of passing the familial hypercholesterolemia from the affected parent to a child is 50% in each pregnancy. New, spontaneous variants appear to be very rare.
• Most individuals with homozygous familial hypercholesterolemia (HoFH) have inherited one mutated gene from each parent, such that each parent has heterozygous familial hypercholesterolemia. These parents have a 25% risk in each pregnancy to have a child with homozygous familial hypercholesterolemia, a 50% chance of having a child with heterozygous familial hypercholesterolemia and a 25% chance that the child will inherit a normal gene from each parent. The risk is the same for males and females.

If you have familial hypercholesterolemia, every child you have has a 50% chance of having familial hypercholesterolemia.

• When one parent has heterozygous familial hypercholesterolemia and the other has homozygous familial hypercholesterolemia, there is a 50% chance with each pregnancy to have a child with heterozygous familial hypercholesterolemia and a 50% chance to have a child with homozygous familial hypercholesterolemia.
• When one parent has homozygous familial hypercholesterolemia and the other has two normal genes, all children will have heterozygous familial hypercholesterolemia.
• When both parents have homozygous familial hypercholesterolemia, all children will have homozygous familial hypercholesterolemia.

Figure 11. Familial hypercholesterolemia autosomal dominant inheritance pattern

There are two forms of Familial hypercholesterolemia.

1. Heterozygous (HeFH) – Heterozygous Familial hypercholesterolemia inherited from only 1 parent
2. Homozygous (HoFH) – Homozygous Familial hypercholesterolemia inherited from both parents (patients with Homozygous Familial hypercholesterolemia are at an even higher risk of early heart disease)

If Familial hypercholesterolemia is left untreated, it can lead to heart disease, heart attack, or stroke.

Familial hypercholesterolemia genetics

Familial hypercholesterolemia is inherited in families in an autosomal dominant manner. In autosomal dominant inherited conditions, a parent who carries an altered gene that causes the condition has a 1 in 2 (50 percent) chance to pass on that altered gene to each of his or her children. If you have familial hypercholesterolemia, every child you have has a 50% chance of inheriting familial hypercholesterolemia.

Parents can give a disorder to their children through their DNA, which is made up of genes. Genes have all the characteristics that a person gets from their parents (such as eye color, hair color, height, etc.), and some may be mutated and not work properly. When a person gets a mutated gene, they can have mild or severe problems depending on the type of mutation.

LDL is generated in the circulation by the delipidation and modification of very low density lipoproteins (VLDL) secreted by the liver. There are three different genes that may be mutated in familial hypercholesterolemia. The most common gene codes for a protein called the LDL receptor (LDLR). LDL receptors in the liver remove LDL-C “bad cholesterol” from the blood. A LDL receptor (LDLR) gene variant is the most common cause of heterozygous familial hypercholesterolemia, accounting for ~90% of pathogenic variants. If a person has a mutated gene for the LDL receptor, the level of LDL-C “bad cholesterol” in his or her blood will increase. Genes that make other proteins, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B (ApoB), may also be mutated and decrease the removal of LDL-C “bad cholesterol” from the blood. If a person has a mutated gene for any of these proteins, the level of cholesterol in her or her blood will increase.

Apolipoprotein B100 (apoB100) is the major structural apoprotein of VLDL and LDL. LDL is cleared from the circulation by hepatic LDL-receptor with apoB100 acting as the ligand for the receptor. A pathogenic variant in the APOB gene is responsible for ~10% of familial hypercholesterolemia cases; this variation is seen most commonly in those of European Caucasian ancestry. Apolipoprotein B-100 is a protein that binds to LDL receptors, which enables uptake of lipoproteins by the liver and reduces the cholesterol level in the blood. Pathogenic variants in the APOB gene lead to faulty uptake and increased cholesterol level. The major pathophysiological abnormality in homozygous familial hypercholesterolemia is decreased LDL clearance although hepatic overproduction of apoB100-containing lipoproteins may further exacerbate the hyperlipidaemia.

PCSK9 gene variants are responsible for only a small percentage of familial hypercholesterolemia cases. The normal PCSK9 gene codes for an enzyme that breaks down the cholesterol receptors after they have done their job. A pathogenic variant in this gene is unlike most variants, which cause dysfunction of the affected gene. The PCSK9 variant increases the gene’s function, leading to too few remaining LDL receptors and thus an increase in the LDL cholesterol level.

People can have one or two of these mutated genes. When a person has one of these mutated genes (either for the LDL receptor, PCSK9, or ApoB), he or she has heterozygous familial hypercholesterolemia. So, the difference between heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia is that a person with homozygous familial hypercholesterolemia has two mutated genes. Two mutated genes greatly increase a person’s blood cholesterol level and the risk of a heart attack.

I have been diagnosed with Familial hypercholesterolemia. I want to get my family tested, but they refuse. How do I convince them?

First and foremost it is important to remember that familial hypercholesterolemia runs in families. If you have familial hypercholesterolemia, the question isn’t “Does anyone else in my family have it?”. The question is “Who in my family has it?”. Of course, only you know how to best approach your relatives. But make sure they fully understand that this is a lifelong condition that requires consistent treatment and the sooner they rule it out, the better.

I have heard the term “cascade screening” in relation to familial hypercholesterolemia. What is cascade screening?

Cascade screening is not a certain type of blood test or certain kind of examination. It is simply a method of finding individuals with Familial Hypercholesterolemia. This method consists of screening entire families for familial hypercholesterolemia. Cascade screening involves screening close relatives of a person diagnosed with a specific genetic condition to determine if they also have the same genetic mutation. Because familial hypercholesterolemia is genetic condition, this means that more than one person in a family has it (because they inherited it from someone else). Cascade screening means that when a health professional diagnoses someone with familial hypercholesterolemia, they need to test the rest of their immediate family members for familial hypercholesterolemia too.

Risk factors for familial hypercholesterolemia

The risk of familial hypercholesterolemia is higher if one or both of your parents have the gene alteration that causes it. Most people who have familial hypercholesterolemia receive one affected gene. But in rare cases, a child can get the affected gene from both parents. This can cause a more severe form of the condition.

Familial hypercholesterolemia may be more common in certain populations, including:

• Ashkenazi Jews
• Some Lebanese groups
• French Canadians

Familial hypercholesterolemia prevention

Familial hypercholesterolemia is not preventable per se. You either inherit the gene (or genes) or you don’t. What you could potentially prevent, however, is the heart disease associated with it. Scientists like to say that with familial hypercholesterolemia you inherit the condition, but not the heart attack. If left untreated, familial hypercholesterolemia leads to early and aggressive heart disease, atherosclerosis (narrowing and blocking of the blood vessels), and heart attacks. This is why early diagnosis and treatment are crucial.

Familial hypercholesterolemia symptoms

Depending on the severity or form of familial hypercholesterolemia you have (Heterozygous vs. Homozygous), symptoms can start appearing in childhood or they might not appear until much later in life. Because familial hypercholesterolemia is caused by a defective gene, it is present in the body from birth. However, this is not necessarily obvious. In fact, this is doctors like to call it the “invisible” disease. Many people with familial hypercholesterolemia just think they have high cholesterol that can be lowered with the right food until, one day, they are only 38 years old and they have a heart attack. Symptoms are not necessarily present.

Signs of Familial hypercholesterolemia are different in every patient and they may or may not include the following:

• Family history of early heart disease or heart attacks (before age 55 in men and before age 65 in women)
• High LDL-cholesterol (above 190 mg/dL in adults and above 160 mg/dL in children)
• Chest pain or angina
• Bumps or lumps on the skin over parts of the hands, elbows, knees, ankles and around the cornea of the eye these fatty skin deposits are called xanthomas
• Cholesterol deposits in the eyelids called xanthelasmas
• Cramping of one or both calves when walking
• Sores on the toes that do not heal
• Sudden stroke-like symptoms such as trouble speaking, drooping on one side of the face, weakness of an arm or leg, and loss of balance.

But remember, you don’t have to have visible symptoms to have Familial hypercholesterolemia. Here’s a formula to help you remember the two main signs of Familial hypercholesterolemia:

• Xanthomas are collections of cholesterol under the skin or tendons. They are yellow bumps that can be small and hard to see. These are often found in the folds of skin and buttocks in children. Also, there can be xanthomas on the tendons at the ankles and hands. Children often have xanthomas without any signs of heart problems in early childhood.
• Tendon xanthoma occurs in three fourth of middle-aged patients and is largely discovered in the Achilles tendon. It may also occur in the extensor area of the dorsum of the hand, heel or the knee. Since xanthomas (patches of yellowish cholesterol buildup) may be manifested only to the extent of thickening of a tendon, familial hypercholesterolemia patients may be overlooked by clinicians without due concern. Xanthelasma or early arcus cornealis may also be observed.
• Xanthomas may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet.

From figure 5 below:

A) Lateral borders of thickened Achilles’ tendons are shown with arrows.

B) Tendon xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees.

C) Xanthelasmas are cholesterol deposits in the eyelids.

D) Arcus cornealis (corneal arcus) is a greyish-white ring of cholesterol infiltration around the corneal rim (arrow). A corneal arcus at a young age can mean that the child has homozygous familial hypercholesterolemia.

Figure 9. Familial hypercholesterolemia – Physical signs of heterozygous familial hypercholesterolemia, as a result of cholesterol deposition within macrophages in specific sites. 

Figure 10. Homozygous familial hypercholesterolemia

Footnotes: (a) Eruptive xanthoma, (b) tendon xanthoma, (c) tuberous xanthoma and (d) xanthelasma

Heart and blood vessel disease

A heart murmur may be the result of narrowing of the opening of the aortic valve by cholesterol buildup. A child with aortic valve disease and high LDL-C may have homozygous familial hypercholesterolemia. Cholesterol plaque builds up in the coronary arteries supplying blood to the heart, the carotids taking blood to the brain, the arteries to the kidneys, and other arteries. Blockage of the flow of blood to the heart may cause chest pain, shortness of breath, dizziness, or irregular heartbeats. Special tests of the heart such as a EKG (electrocardiogram), echocardiogram, CT angiogram or cardiac catheterization are recommended to check the aortic valve and coronary arteries at diagnosis and at least every 5 years.

Familial hypercholesterolemia complications

Possible complications of familial hypercholesterolemia:

• Heart attack at an early age
• Heart disease
• Stroke
• Peripheral vascular disease

People who have familial hypercholesterolemia have a higher risk of heart disease and death at a younger age. Heart attacks may occur before age 50 in men and age 60 in women. The rarer and more severe variety of familial hypercholesterolemia (homozygous familial hypercholesterolemia), if undiagnosed or untreated, can cause death before age 20.

Familial hypercholesterolemia diagnosis

A detailed family history is an important key to diagnosing familial hypercholesterolemia. Doctors will be interested to know if your siblings, parents, aunts, uncles or grandparents ever had high cholesterol levels or heart disease — especially during childhood.

During the physical exam, doctors usually check for cholesterol deposits that may occur in the skin around the hands, knees, elbows and eyes. Tendons in the heel and hand may be thickened, and a gray or white ring may develop around the iris of the eye.

Homozygous familial hypercholesterolemia can be diagnosed through genetic testing (DNA testing) or a clinical diagnosis utilizing one of three well-accepted sets of criteria — Simon Broome (UK), Dutch Lipid Clinic Network (Netherlands), or MEDPED (US).

DNA testing confirms the diagnosis and is considered the “gold standard”, but is not always necessary or feasible. DNA testing should definitely be considered when it’s not clear whether an individual is affected or not, and is very helpful for testing family members. Recent studies also suggest that individual risks for coronary artery disease vary among the affected gene and type of DNA variation (substitution vs. partial deletion of a gene, etc.).

Unfortunately, genetic testing is not commonly used in some countries including the U.S. Also, not everyone with homozygous familial hypercholesterolemia has the same signs and symptoms. If you have any of the above signs or symptoms, please talk to your doctor.

Once an individual is diagnosed with familial hypercholesterolemia (either with or without the use of DNA testing) a process called “cascade screening”, “cascade testing” or “family screening” (testing of close relatives, in a step-wise fashion) is recommended to identify those with familial hypercholesterolemia before symptoms appear, so that early and intensive treatment can be initiated and disease and death prevented ¹⁸⁹. Cascade screening involves screening close relatives of a person diagnosed with a specific genetic condition to determine if they also have the same genetic mutation. Because familial hypercholesterolemia is genetic condition, this means that more than one person in a family has it (because they inherited it from someone else). Cascade screening means that when a health professional diagnoses someone with familial hypercholesterolemia, they need to test the rest of their immediate family members for familial hypercholesterolemia too. If a pathogenic variant is identified, risk in the patient’s first degree relatives (parent, sibling, child) and when appropriate, more distant relatives, can be assessed via DNA testing by tracing the altered gene through the family. If DNA testing is not performed, another version of cascade screening can be implemented using cholesterol testing. Cascade screening by either means has been shown to be effective in finding patients with familial hypercholesterolemia who were not being appropriately treated. A genetic counselor can help a family through this process.

Cascade screening has been shown in numerous studies to be cost-effective and has been recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK. The Office of Public Health Genomics at the Centers for Disease Control and Prevention considers cascade screening of relatives of those with FH a “Tier 1 application” which means that there is good evidence that implementation will prevent disease and save lives.

Homozygous familial hypercholesterolemia is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL-C; LDL-C is usually greater than 400 mg/dL. The parents are “obligate heterozygotes” who are considered to have heterozygous familial hypercholesterolemia until proven otherwise.

Clinical Testing and Workup

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia, the following evaluations are recommended in adults and children:

• Pre-treatment lipid values
• Lipoprotein(a) levels when possible as lipoprotein(a) is an additional risk factor for coronary heart disease
• Exclusion of concurrent illnesses (kidney disease, acute myocardial infarction, infection) that can affect lipid values
• Lipid panel including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides
• Consultation with a lipid specialist or clinician with expertise in familial hypercholesterolemia
• Medical genetics or a genetic counseling consultation

In children, noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) are recommended in some guidelines to help inform treatment decisions.

Level of LDL cholesterol

This is extremely important. Adults who have familial hypercholesterolemia usually have low-density lipoprotein (LDL) cholesterol levels over 190 mg/dL (4.9 mmol/L). Children who have the disorder often have LDL cholesterol levels over 160 mg/dL (4.1 mmol/L). The higher the LDL cholesterol levels, the more likely it is that a person has homozygous familial hypercholesterolemia (LDL > 500 mg/dL [>13 mmol/L]).

LDL cholesterol is also known as “bad” cholesterol because it can build up in the walls of the arteries, making them hard and narrow. This can increase the risk of heart attacks.

Family History

This is key. If both parents have very high LDL cholesterol (>190 mg/dL) and/or history of heart disease before age 55-65, this may suggest that they both have familial hypercholesterolemia and can each pass a mutated gene to their children. When each parent has heterozygous familial hypercholesterolaemia, by chance, 1 of 4 children will have a normal cholesterol level, 2 of 4 children will have heterozygous familial hypercholesterolaemia and 1 of 4 children will have homozygous familial hypercholesterolemia. Prenatal DNA testing may be available if the mutations are identified in the parents. Download our family tree to track your family history.

Response to cholesterol-lowering medications

If a person is living a healthy lifestyle and taking cholesterol-lowering medications like statins, and/or cholesterol absorption inhibitors, and/or bile acid sequestrates and still has high cholesterol level (> 300 mg/dL), they may have homozygous familial hypercholesterolemia.

Genetic testing

A genetic test can confirm familial hypercholesterolemia, but it’s not always necessary. However, a genetic test can help determine whether other family members also may be at risk.

If one parent has familial hypercholesterolemia, each child has a 50% chance of inheriting it. Inheriting the altered gene from both parents can result in a rarer and more severe form of the disease.

If you are diagnosed with familial hypercholesterolemia, doctors usually recommend that your first-degree relatives — such as siblings, parents and children — be checked for the disorder. This will allow treatment to begin early, if needed.

Diagnostic Criteria for Familial Hypercholesterolemia

There are currently 3 accepted resources for familial hypercholesterolemia diagnosis:

1. The Simon Broome criteria,
2. The MEDPED Criteria, and
3. The Familial Hypercholesterolemia Dutch Lipid Clinic Criteria.

Table 9. Simon Broome Diagnostic Criteria For Familial Hypercholesterolemia

Table 10. Dutch Lipid Clinic Network Diagnostic Criteria For Familial Hypercholesterolemia

Familial hypercholesterolemia diagnosis:

• Definite familial hypercholesterolemia diagnosis can be made if the subject scores >8 points.
• Probable familial hypercholesterolemia diagnosis can be made if the subject scores 6 to 8 points.
• Possible familial hypercholesterolemia diagnosis can be made if the subject scores 3 to 5 points.
• Unlikely familial hypercholesterolemia diagnosis can be made if the subject scores 0 to 2 points.

Footnotes: *Premature = < 55 years in men; < 60 years in women. Use of the per group only one score with the highest applicable. For example, when coronary heart disease and tendon xanthoma as well as dyslipidaemia are present in a family, the highest score for family history is 2. However, if persons with elevated LDL cholesterol levels as well as premature coronary heart disease are present in a family, but no xanthoma or children with elevated LDL cholesterol levels or a causative mutation are found, then the highest score for family history remains 1.

Abbreviations: LDL-C = low density lipoprotein cholesterol; FH, familial hypercholesterolemia; LDLR = low density lipoprotein receptor; Apo B = apolipoprotein B; PCSK9 = Proprotein convertase subtilisin/kexin type 9

Table 11. MEDPED Diagnostic Criteria For Familial Hypercholesterolemia

Footnote: *The total cholesterol cutpoints for familial hypercholesterolemia is dependent upon the confirmed cases of familial hypercholesterolemia in the family. If familial hypercholesterolemia is not diagnosed in the family, then the cutpoint for diagnosis is as per “general population.”

FH = familial hypercholesterolemia

Familial hypercholesterolemia treatment

Familial hypercholesterolemia treatment focuses on reducing the extremely high levels of LDL (bad) cholesterol. This helps lower the risk of heart attack and death.

The treatments for homozygous familial hypercholesterolemia (HoFH) can be quite complex and anyone with this disease is advised to be under the care of a lipid specialist.

There are several important reasons for referring patients with probable familial hypercholesterolemia to a lipid specialist:

• Confirmation of the diagnosis. The Dutch Lipid Clinic Network Criteria (DLNC) score will be confirmed by more extensive clinical and laboratory assessment, including DNA testing for causative mutations in the LDL receptor and other genes. Some patients with classic phenotypic features of familial hypercholesterolemia may still not have a mutation identified (eg. 10% children with definite phenotypic familial hypercholesterolemia), reflecting limitations of the current DNA test and multiple mutations causing the disease ¹⁹². However, identification of a specific mutation is important in confirming the diagnosis and in cascade screening
• Cascade screening of family members, either through an identified genetic mutation or phenotypic assessment using the DLNC criteria. The process of cascade screening can be complex, and while general practice may have a role, a centralised service coordinated via a lipid specialist is probably best placed to undertake extended cascade screening of second and third degree relatives.
• Cascade screening may be a feasible option for parents and children under the care of the same family doctor
• Cardiovascular disease assessment and disease prevention. A lipid specialist can determine appropriate investigations to detect existing cardiovascular disease, determine the best drug regimen to manage the abnormal lipid profile, and reinforce the importance of a healthy lifestyle
• If there is no lipid specialist available, referral to a cardiologist or endocrinologist with special interest in lipid disorders would be alternative referral pathways.

Familial hypercholesterolemia management can include a combination approach – statins, cholesterol absorption inhibitors, and bile acid sequestrants. Often, Homozygous familial hypercholesterolemia patients will require even more intensive therapy to bring their LDL cholesterol (“bad cholesterol”) levels down.

Lifestyle and dietary changes

Lifestyle changes, such as exercising and eating a healthy low-fat diet, are the first line of defense against high cholesterol. Specific recommendations include:

• Reducing the amount of saturated fat in your diet to less than 6-10 percent of your daily calories. The most harmful types of fat are saturated fat and trans fat, which are found in foods from animal sources, such as meat and dairy products, as well as packed snacks, fast food, and baked goods (biscuits, cakes, etc). As a rule of thumb, avoid too much processed foods. Try to eat fresh by cooking homemade healthy meals from scratch. LESS! whole milk, butter, egg yolks, snacks (chips), deep-fried fast food (fries, deep-fried chicken), processed meat (sausage, pâté), liver, organ meats, frozen foods (waffles, pies, pizzas, breaded fish). BEWARE OF HIDDEN TRANS FATS (“partially hydrogenated…”)
• Consuming 25 to 35 grams of soluble fiber a day.  As a rule of thumb, think plants (not animals): fruits, vegetables, grains, and beans. MORE! barley, oatmeal, sunflower seeds, almonds, soy, tofu, edamame, chickpeas, black beans, kidney beans, lentils, Brussels sprouts, carrots, apples, bananas, pears, oranges, grapefruit, prunes, blackberries.
• Add plant sterols and plant stanols to your diet. They actively reduce LDL-cholesterol and can be found in certain food supplements and substitutes (look for margarine or cheese that states “With added plant sterols/stanols”). An enhanced daily consumption of 2000 to 2500 mg of plant sterols/stanols per day may lower LDL-cholesterol by up to 15%!
• Increasing physical activity.
• Maintaining a healthy body weight.
• Not smoking. And quit smoking if you smoke.

With familial hypercholesterolemia, your doctor likely will also recommend that you take medication to help lower your LDL “bad” cholesterol levels. The specific medication or medications depend on various factors, including your risk factors, your age, your current health and possible side effects.

Table 12. Good and bad fats

Medications

Most people with familial hypercholesteremia will need to take more than one medication to control their LDL cholesterol levels. Common medication choices include:

• Statins. Statins — among the most commonly prescribed medications for lowering cholesterol — block a substance your liver needs to make cholesterol. This causes your liver to remove cholesterol from your blood. Statins may also help your body reabsorb cholesterol from built-up deposits on your artery walls, potentially reversing coronary artery disease. Choices include atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altoprev,), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor). Not everyone can take statins especially women who are trying to conceive, pregnant, or nursing. Talk to you doctor about other therapy options.
• Bile-acid-binding resins. Your liver uses cholesterol to make bile acids, a substance needed for digestion. The medications cholestyramine (Prevalite), colesevelam (Welchol) and colestipol (Colestid) lower cholesterol indirectly by binding to bile acids. This prompts your liver to use excess cholesterol to make more bile acids, which reduces the level of cholesterol in your blood.
• Cholesterol absorption inhibitors. Your small intestine absorbs the cholesterol from your diet and releases it into your bloodstream. The drug ezetimibe (Zetia) helps reduce blood cholesterol by limiting the absorption of dietary cholesterol. Zetia can be used in combination with any of the statin drugs. Ezetimibe has been showing to add an extra 10 to 30 percent reduction in LDL levels for patients on maximally tolerated statins ¹⁹³, ¹⁹⁴. Currently, ezetimibe is the drug of choice as the second line in most guidelines ¹⁹⁵.
• Combination cholesterol absorption inhibitor and statin. The combination drug ezetimibe-simvastatin (Vytorin) decreases both absorption of dietary cholesterol in your small intestine and production of cholesterol in your liver. It’s unknown whether Vytorin is more effective in reducing heart disease risk than taking simvastatin by itself.
• Injectable medications. A new class of drugs can help the liver absorb more LDL cholesterol — which lowers the amount of cholesterol circulating in your blood. The Food and Drug Administration recently approved alirocumab (Praluent) and evolocumab (Repatha) for people who have a genetic condition that causes very high levels of LDL. These drugs may also be used for people who have had heart attacks or strokes and need additional lowering of their LDL levels. These injectable drugs are administered at home one or two times a month.
• PCSK9 Inhibitor – antibodies that bind the PCSK9 enzyme. Normally, LDL is recycled in the liver by binding to receptors that move it through the cell. The PCSK9 enzyme weakens this process by connecting to and disabling the receptors, which frees up more receptors on liver cells to remove LDL cholesterol from the blood. When the PCSK9 inhibitor is introduced, it binds to the PCSK9 enzyme stopping it from attaching to the receptors and getting in the way of the recycling process. PCSK9 inhibitors drugs such as alirocumab (Praluent) and evolocumab (Repatha) help the liver absorb more LDL cholesterol, which lowers the amount of cholesterol circulating in the blood. They’re injected under the skin every few weeks and are very expensive. PCSK9 inhibitors have shown a great reduction in LDL levels and cardiovascular outcomes in different randomized clinical trials ¹⁹⁶, ¹⁹⁷. In those trials, PCKS9 inhibitors lowered LDL levels by 50 to 60 percent. While exhibiting higher efficacy than ezetimibe, the use of PCSK9 inhibitors is limited by their high cost and the reluctance of insurance companies to approve their use ¹⁹⁸. Hence, PCSK9 inhibitors can be used as second or third-line drugs for patients with familial hypercholesterolemia.
• Lomitapide (marketed as Juxtapid in the U.S.) – Lomitapide is an inhibitor of the microsomal triglyceride transport protein (MTP), a key protein in the assembly and secretion of apolipoprotein (apo) B-containing lipoproteins in the liver and intestine ¹⁹⁹. By blocking this protein, lomitapide helps reduce how much fat is absorbed and lowers the level of LDL cholesterol in your blood ²⁰⁰. If you take lomitapide you should consume less than 20 per cent of your calories from fat as this has been shown to help reduce unwanted gastrointestinal (stomach related) side effects. This is lower than normally recommended for a heart healthy diet, but advice and support is available to help you make this change. Lomitapide is approved as an adjunct to a low-fat diet and other lipid lowering treatments. It is an oral capsule.
• Mipomersen (marketed as Kynamro in the U.S.) -Mipomersen is an antisense drug (mRNA inhibition of apolipoprotein B) that leads to the decline of apoB RNA in the liver (apoB is necessary for the formation of LDL particles) ²⁰¹. Mipomersen is administered as a weekly injection. Mipomersen is fourth line therapy usually reserved if the LDL does not reach the target level using statins, ezetimibe, and PCSK9 inhibitors

Medications for high triglycerides

If you also have high triglycerides, your doctor may prescribe:

• Fibrates. The medications fenofibrate (Tricor) and gemfibrozil (Lopid) decrease triglycerides by reducing your liver’s production of very-low-density lipoprotein (VLDL) cholesterol and by speeding up the removal of triglycerides from your blood. VLDL cholesterol contains mostly triglycerides.
• Niacin. Niacin (Niaspan) decreases triglycerides by limiting your liver’s ability to produce LDL and VLDL cholesterol. But niacin doesn’t usually provide any additional benefit than using statins alone. Niacin has also been linked to liver damage and stroke, so most doctors now recommend it only for people who can’t take statins.
• Omega-3 fatty acid supplements. Omega-3 fatty acid supplements can help lower your triglycerides. They are available by prescription or over-the-counter. If you choose to take over-the-counter supplements, get your doctor’s OK first. Omega-3 fatty acid supplements could affect other medications you’re taking. Fish is a great source of healthy omega-3 fats. The American Heart Association recommends eating 3.5 ounces of fish (especially oily, omega-3 rich fish) at least twice a week. Note: Tilefish, shark, swordfish, and king mackerel have high mercury content and should be eaten only occasionally.

Tolerance varies

Tolerance of medications varies from person to person. The reported side effects are muscle pains, stomach pain, constipation, nausea and diarrhea. If you decide to take cholesterol-lowering medication, your doctor may recommend liver function tests to monitor the medication’s effect on your liver.

LDL Apheresis

LDL apheresis (also called lipoprotein apheresis) can be performed on homozygous familial hypercholesterolemia patients as well as more serious heterozygous familial hypercholesterolemia patients. This procedure involves blood cleansing every other week (or sometimes weekly) with a special machine that looks like a dialysis machine. The procedure takes between one and a half to three hours, and typically drops LDL levels by 70%. Unfortunately, LDL rises over time and, for this reason, repeat treatments are necessary. About 60 lipoprotein apheresis centers exist in the US.

Treatment Guidelines for Heterozygous familial hypercholesterolemia

In patients with heterozygous familial hypercholesterolemia, lifestyle modification is unlikely to result in acceptable LDL levels; therefore, cholesterol-lowering medication is necessary. European Atherosclerosis Society consensus statement for screening and treatment of heterozygous familial hypercholesterolemia includes the following recommendations ¹⁸⁷:

• An LDL target of less than 135 mg/dL for children with familial hypercholesterolemia
• An LDL target of less than 100 mg/dL for adults with familial hypercholesterolemia
• An LDL target of less than 70 mg/dL for adults with known coronary artery disease or diabetes
• Lifestyle modifications include a diet that severely limits saturated fats, trans fats, and cholesterol
• Desirable weight should be attained
• Significant weight loss should improve all lipid parameters (LDL, HDL, triglycerides)
• Aerobic and toning exercises improve blood lipid levels if performed for longer than 30 minutes, 4 or more days per week

Treatment Guidelines for Homozygous familial hypercholesterolemia

European Atherosclerosis Society guidelines for the screening and treatment of homozygous familial hypercholesterolemia are summarized as follows ²⁰², ²⁰³:

• Treatment of homozygous familial hypercholesterolemia involves a combination of lifestyle changes, statin therapy (first approach), and lipoprotein apheresis for severe cases
• LDL apheresis should begin as early as age 5 years
• For homozygous familial hypercholesterolemia patients, the LDL cholesterol targets are less than 100 mg/dL for adults, less than 70 mg/dL for adults with clinical cardiovascular disease, and less than 135 mg/dL for children
• Other novel agents for LDL cholesterol lowering (eg, lomitapide with or without apheresis) can be considered as adjunctive treatments for patients who do not achieve the recommended LDL cholesterol targets and remain at high cardiovascular risk.

Familial Hypercholesterolemia and Pregnancy

Women with familial hypercholesterolemia planning to get pregnant should discontinue all lipid-lowering agents, including statins, ezetimibe, and PCSK9 inhibitors ¹⁰⁸. Cardiovascular risk assessment is recommended before conception. Lipoprotein apheresis may be used if necessary ²⁰⁴.

Children or Adults with Homozygous familial hypercholesterolemia

Early initiation of therapy and monitoring using CT coronary angiography and other imaging are recommended; these patients often require additional treatment strategies, as pharmacological treatment and lifestyle changes may not be sufficient. Statins are usually started as soon as the diagnosis is made (though may not be effective as explained above). Two new drugs (lomitapide and mipomersen) have now been FDA-approved for the treatment of adults with homozygous familial hypercholesterolemia and should be considered for these patients, especially if LDL-C level cannot be controlled using other drugs. A PCSK9 inhibitor (evolocumab) was also approved for homozygous familial hypercholesterolemia. Additional options include LDL apheresis or liver transplantation.

LDL Apheresis

Using a process similar to kidney dialysis, blood is withdrawn from a vein via a catheter and processed to remove LDL particles. Normal blood products are returned via another catheter. LDL-C levels will decrease approximately 50% but will rise between apheresis sessions, so they are necessary approximately weekly or every other week. The procedure is effective and well tolerated though time-consuming and only available in 50-60 sites in the US.

Liver transplantation

Liver transplant is extraordinarily rare and may become even less common with the new medications available. As the donor liver will have normal LDL receptors, the LDL cholesterol quickly normalizes after the procedure, but the risks of any organ transplant are significant and include complications from major surgery and the effects of lifelong suppression of the immune system. Donor organs are often not available. Patients with familial pathogenic APOB or PCSK9 gene variants have normal LDL receptors, so liver transplantation is not an option for them.

Various imaging modalities such as echocardiograms, CT angiograms and cardiac catheterization may be recommended to monitor individuals with homozygous familial hypercholesterolemia.

Children and cholesterol treatment

Diet and exercise are the best initial treatment for children age 2 and older who have high cholesterol, or who are obese. Children age 10 and older might be prescribed cholesterol-lowering drugs, such as statins, if they have extremely high cholesterol levels.

Current recommendations from both the National Lipid Association and American Academy of Pediatrics recommend beginning cholesterol lowering medications at around the age of 8 for children with familial hypercholesterolemia. Statins are the drugs of first choice. By the age of 8, a child should be able to swallow pills. At least one drug company has experimented with a chewable flavored statin, but this is not yet on the market.

Six statins are FDA-approved for children 10 years of age and older (age 8 years and older for pravastatin):

• rosuvastatin (Crestor®),
• atorvastatin (Lipitor®),
• simvastatin (Zocor®),
• pravastatin (Pravachol®),
• lovastatin (Mevacor®),
• fluvastatin (Lescol®)

Depending on which statin is used and at what dose, reductions in LDL of 50% or more can be achieved with the two most potent statins rosuvastatin (Crestor®), atorvastatin (Lipitor®)]. And thankfully, Lipitor® has recently become available as a generic.

National Lipid Association and American Academy of Pediatrics guidelines: Children with familial hypercholesterolemia begin medications around 8 years of age

If your child fails to achieve an LDL of < 130 mg/dL or an LDL reduction from baseline of at least a 50%, consideration should be given to adding an additional medication. In this situation your child’s health care provider might suggest a bile acid sequestrant such as [colesevelam (Welchol®), cholestyramine (Questran®), or colestipol (Colestid®). These medications work in the intestines and are not absorbed into the blood stream. Although these medications can lower cholesterol by 10-20% and appear to be very safe, only one, colesevelam (Welchol®), has been approved for use in the pediatric population. Unfortunately, many children complain of gas while on a bile acid sequestrant.

Finally, ezetimibe (Zetia®) is a medication that inhibits the absorption of cholesterol from the intestines. It can lower the LDL by about 20% and has been studied in children and found to be well tolerated. It is now approved by the FDA for use in children over the age of 10. If your child is not able to achieve his/her goal cholesterol with a single cholesterol lowering medication, it is often appropriate to ask for a referral to a cholesterol (lipid) specialist. Many parents see a cholesterol specialist for the initiation of cholesterol-lowering medications but follow-up with their pediatrician, family doctor or nurse practitioner once their child’s levels are under control.

Once my child begins medication, how often should he/she be seen?

Some doctors typically see a child back 6 weeks after they start a medication. Subsequent visits might occur every 3 to 6 months. To assess liver function, blood should be drawn prior to starting therapy. The need for follow-up liver function tests is generally determined by your child’s health care provider. Repeat cholesterol profiles are usually drawn at least twice a year.

What are some of the side effects of cholesterol lowering medications?

I have already noted that the bile acid sequestrants can cause gas. The statins are typically very well tolerated but in some cases they can cause muscle and joint aches and can rarely cause liver function and muscle function abnormalities. Thankfully, in almost all situations, these side effects can be reversed with either stopping the drug or reducing the dose. And although Zetia® tends also to be very well tolerated, it too can occasionally cause abdominal pain and diarrhea. When Zetia is taken in conjunction with a statin, rare cases of muscle and liver function abnormalities have occurred.

After my child’s cholesterol level normalizes, can he/she come off the medication?

Unfortunately, because familial hypercholesterolemia is caused by a defective gene, there is currently no cure. Medications can help normalize the cholesterol in a person with familial hypercholesterolemia but if they are discontinued, the genetic disorder is again revealed. Cholesterol-lowering medications only work while you are taking them.

Cholesterol-lowering medications only work while you are taking them.

My teen has an awful diet. What should I do?

This is a very common situation that are encountered countless times in clinical practice. Teens with familial hypercholesterolemia are like any other teen, but obviously the stakes are higher for children with familial hypercholesterolemia. It is very frustrating to see your son or daughter’s eating habits deteriorate. Best advice is to set a good example; make the foods you serve at home as healthy as possible.

My child hates to take his/her medications. What can I do?

Stick with it. The medications are crucial – there is strong evidence that statins reduce the risk of heart attack, stroke and total mortality. And heart disease is what kills young adults with familial hypercholesterolemia. Your child is not at risk of a heart attack right now (unless your child has homozygous familial hypercholesterolemia), but he/she is at risk in the future. Just when people with familial hypercholesterolemia should be enjoying their own children (and you, your grandchildren), a heart attack can strike – sometimes these heart attacks can be fatal. You have to stress the importance of getting your child into the habit of taking his/her medicines. Make it a family affair – take your medications together.

Surgical care

Surgery are usually reserved if the LDL does not reach the target level using medications and lifestyle changes (e.g., eating healthy, getting regular exercise, not smoking, total avoidance of tobacco products, limiting of alcohol intake, managing stress, having adequate sleep).

• Liver transplantation for homozygous familial hypercholesterolemia because a new liver provides functional LDL receptors and causes dramatic decreases in LDL levels
• Partial ileal bypass surgery ²⁰⁵
• Portacaval anastomosis for homozygous familial hypercholesterolemia

Familial hypercholesterolemia prognosis

Familial hypercholesterolemia prognosis (outcome) depends on how closely you follow your doctor’s treatment advice and how well you respond to the recommended treatment. Making dietary changes, exercising, and taking your medicines correctly can lower cholesterol level. These changes can help delay a heart attack, especially for people with a milder form of familial hypercholesterolemia.

Men and women with familial hypercholesterolemia typically are at increased risk of early heart attacks. Risk of death varies among people with familial hypercholesterolemia. If you inherit two copies of the defective gene (homozygous familial hypercholesterolemia), you have a poorer prognosis. Homozygous familial hypercholesterolemia does not respond well to treatment and may cause an early heart attack. They usually die before the third decade of life from cardiovascular events ¹⁹⁶.

The risk of coronary heart disease before the use of statin in patients with heterozygous familial hypercholesterolemia was very high ²⁰⁶. However, the risk of death in patients with heterozygous familial hypercholesterolemia after acute coronary syndrome within the first year is almost more than two times higher than matched individuals without familial hypercholesterolemia despite high-intensity statins therapy ²⁰⁷. The risk of death or coronary artery disease in relatives of patients with familial hypercholesterolemia was 52% and 32% in males and females, respectively ²⁰⁸.

Familial hypercholesterolemia life expectancy

The risk of complications of hypercholesterolaemia can be significantly reduced by therapies that lower serum cholesterol levels. Studies show statins reduce chances of a future heart attack by 30%.

Lowering cholesterol by 1% reduces the risk of coronary artery disease by 2%.

The treatment of other modifiable risk factors such as smoking, high blood pressure and diabetes will further decreases the risk of complications of hypercholesterolaemia.

Maintaining an appropriate weight, eating a low fat diet and exercising can also have a significant impact on cholesterol levels and improve long-term outcomes.

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