What is Familial Hypercholesterolemia, Type 2A?
Familial hypercholesterolemia (FH) is a health condition passed down through families, and it affects the way the body handles fats or lipids. People with this condition have very high levels of a specific type of cholesterol known as ‘low-density lipoprotein cholesterol’ (LDL-C). The high cholesterol levels result from a gene mutation and can lead to early onset of heart disease. People who inherit this condition from both parents typically develop the disease during childhood. Unfortunately, many cases of FH go unnoticed and are not treated effectively. That’s why it’s so crucial to diagnose and manage this condition early to avoid early deaths.
What Causes Familial Hypercholesterolemia, Type 2A?
Genetic disorders that result in high levels of LDL cholesterol, often referred to as the “bad” cholesterol, are usually caused by a gene condition that can be passed down from one or both parents, and is rarely inherited as a recessive trait. Changes in the LDL receptor (LDLR), also known as the “classic FH,” cause 80% to 90% of these cases and are passed down in a dominant manner. In some rare cases, mutations in the APOB and PCSK9 genes can lead to high cholesterol and are also inherited in a dominant manner. It is important to note though, that the physical symptoms themselves can’t reveal which of the three gene mutations is to blame.
The APOB gene is responsible for creating a major protein in LDL, which connects with LDLR. Any mutation here might result in faulty ApoB-100, leading to poor interaction between LDL particles and LDLR, which in turn results in impaired removal of cholesterol.
The PCSK9 gene is responsible for creating a protein that regulates the lifespan of LDL receptors. In case of a mutation, it might result in an excess function, leading to a high cholesterol condition known as FH.
More than 1600 mutations in the LDLR gene that cause high cholesterol condition have been identified. These mutations can be either homozygous, where the same mutation occurs in both sets of a gene, or heterozygous, where each set of a gene has a different mutation. Patients with heterozygous mutations have a similar condition to those with homozygous mutations.
Patients who have less than 2% of LDLR activity are classified as receptor-negative. On the other hand, patients with 2-5% of regular LDLR activity are classified as receptor defective.
Also, about 30 to 50% of patients with symptoms of high cholesterol do not have a detectable gene defect. So, gene testing is not always necessary for diagnosis, which is usually based on physical symptoms. This high cholesterol condition caused by a spontaneous mutation is very rare. Therefore, it’s very important to gather a detailed family history when diagnosing this condition.
Risk Factors and Frequency for Familial Hypercholesterolemia, Type 2A
Familial hypercholesterolemia (HeFH), a gene-related disorder that is passed from parents to their children, is the most common type in humans. It affects about one in 300 people. Another type, Homozygous familial hypercholesterolemia (HoFH), is less common and affects about one in 160,000 to 500,000 people. This condition is 18 times more common in people with a certain heart disease (arteriosclerotic cardiovascular disease) and 21 times more common in people with early onset heart disease. Certain groups of people, like Dutch Afrikaners, French Canadians, Ashkenazi Jews, Christian Lebanese, and some Tunisian groups, have a higher rate of this disorder. People who inherit two copies of the faulty gene, one from each parent (homozygotes), are more seriously affected than those who inherit one faulty gene (heterozygotes).
Signs and Symptoms of Familial Hypercholesterolemia, Type 2A
Getting a comprehensive personal and family medical history along with a physical check-up can help in identifying a potential health condition. Specifically, doctors will look out for any history of heart and blood vessel diseases, such as chest pain, heart attack, artery unblocking procedures, mini-strokes, major strokes, or leg muscle pain due to poor blood circulation. It’s also vital for them to know if other risk factors for these kinds of diseases are present, like high blood pressure, smoking, obesity, diabetes, and chronic kidney disease.
During the physical exam, the doctor will look for certain signs that might indicate the presence of these conditions. These include abnormal fatty growths under the skin (tendon xanthomas), cholesterol deposits around the eyes (xanthelasma), a grey-blue ring around the cornea of the eye (corneal arcus), checking the pulse in major arteries, and signs of narrowed heart valves (aortic stenosis).
- Heart and blood vessel diseases history
- Personal health risk factors: high blood pressure, smoking, obesity, diabetes, and chronic kidney disease
- Physical indicators: tendon xanthomas, xanthelasma, corneal arcus, pulse check, and signs of narrow heart valves
Testing for Familial Hypercholesterolemia, Type 2A
When looking into high cholesterol levels, it’s vital to rule out secondary causes such as an underactive thyroid (hypothyroidism), certain kidney diseases (nephrotic syndrome), and liver disease. These secondary causes can be excluded through medical history and lab tests.
In most cases, Familial Hypercholesterolemia (FH), a genetic disorder characterized by high cholesterol levels, is diagnosed through several methods:
- Your and your family’s medical history; including instances of early coronary artery disease (CAD), which involves narrowing down of heart’s blood vessels or sudden death at a young age.
- Certain physical signs; for example, the formations of fatty lumps under the skin (tendon xanthomas) or cloudiness in the border of the cornea (premature corneal arcus).
- High cholesterol levels (more than 190 mg/dL).
In the past, a Familial Hypercholesterolemia diagnosis was commonly made when a young person suffered a heart attack due to blockage of blood flow to the heart (acute MI). But now, it’s mostly identified through routine lab tests that reveal high LDL-C cholesterol, leading to a suspicion of the disorder.
Triglyceride levels (a type of fat (lipid) in your blood) are generally normal, while good cholesterol or HDL levels may be low. It’s important to remember that any LDL-C cholesterol level above 190 mg/dL should be investigated further for Familial Hypercholesterolemia.
The usual method of diagnosing Familial Hypercholesterolemia is through physical traits. Several tools exist to help diagnose the disorder, including the Dutch Lipid Clinic Network criteria, Simon Broome criteria, Make Early Diagnosis to Prevent Early Deaths (MED-PED) criteria, and the Japanese FH criteria.
Early detection can be done by focusing on individuals with premature heart diseases, regular check-ups in primary care based on the patient’s age, gender and plasma LDL-C levels, or screening everyone based on their age, gender and plasma LDL-C levels before they turn 20.
As a guideline, children suspected to have certain physical findings of Familial Hypercholesterolemia or with family history of a severe form of the disorder should be screened at 2 years old. Those suspected to have a less severe form of the disorder should be screened between the ages of 5 to 10. It’s recommended that two fasting LDL cholesterol values are obtained for children and adolescents. High cholesterol levels (greater than or equal to 155 mg/dL or greater than or equal to 135 mg/dL with family history of high cholesterol or premature heart diseases) indicate a high probability of Familial Hypercholesterolemia.
Testing should not be done during serious illnesses as it can cause lower LDL-C levels leading to inaccurate test results. Pre-treatment values of LDL-C should be obtained if patients are already on cholesterol-lowering medications like statins. If these are not available, an estimate should be made based on the dose of the specific statin.
Heart disease risk assessment tools like Framingham risk score shouldn’t be used, as Familial Hypercholesterolemia poses a lifelong risk for heart diseases.
In patients with Familial Hypercholesterolemia who haven’t yet shown symptoms, heart CT scans and carotid ultrasound for the arteries that supply blood to your brain could be beneficial for assessing risk, though more studies are needed on this.
Criteria for diagnosing the severe form of Familial Hypercholesterolemia:
- Untreated LDL-C levels >500 mg/dL or treated LDL-C ≥300 mg/dL.
- Fatty lumps under the skin or on the tendons before ten years of age.
- High LDL-C levels consistent with less severe form of Familial Hypercholesterolemia in both parents.
However, untreated LDL-C levels less than 500 do not exclude the severe form of Familial Hypercholesterolemia, especially in young children.
Treatment Options for Familial Hypercholesterolemia, Type 2A
Modifying lifestyle choices can greatly help in managing diseases caused by high levels of cholesterol in the body. This means making positive changes such as adopting a healthy diet, exercising regularly, quitting smoking, and managing your weight.
There are medicines that can be used alongside these lifestyle changes to help reach the desired health outcomes. These include high-intensity statin therapy, ezetimibe, bile acid sequestrants, niacin, and fibrates. Statins are usually the first medicines that doctors recommend, but they might not be effective in cases of severe forms of the cholesterol disorder, such as homozygous familial hypercholesterolemia (HoFH), as these rely on an increase in LDL receptor (LDLR) expression for lowering bad cholesterol (LDL-C).
Reducing LDL-C levels is the primary treatment goal for these patients. Doctors often start with high-intensity statin therapy in adults and then add ezetimibe or other therapies depending on individual needs and responses. However, it can sometimes be tricky to reach these targets. In younger patients, if dietary changes are not enough to control cholesterol levels, a low dose of statin therapy, or possibly even additional medicines, might be considered.
In some cases, the LDL-C levels can be decreased by 30%-60% through statin therapy alone, while an additional 20%-30% reduction can be reached by combining different medications. Using statin-based regimens to lower lipids has been shown to significantly improve survival and reduce health issues related to atherosclerosis. Some patients may also benefit from PCSK9 inhibitors, which are FDA-approved for use in adult patients under certain conditions.
Greater attention is needed in treating the disease if additional risk factors for atherosclerosis are present. Even though stronger evidence is needed for combination therapies for preventing atherosclerosis-related health issues, patients are strongly recommended to maintain low LDL-C levels.
The severe form of high cholesterol, HoFH, is more resistant to medicine than other types. A technique called LDL-C apheresis has been developed to manage this condition. This procedure and other medical options can be particularly beneficial when certain medicines have not been enough to control cholesterol levels.
Women of childbearing age are advised to consider contraception before starting statin medication, as this medicine should not be used during pregnancy or breastfeeding. A procedure called LDL apheresis has been used safely during pregnancy and can be particularly beneficial for certain patients.
LDL apheresis might be considered for patients with severe forms of high cholesterol. The procedure is typically recommended to be started before the age of 5 and not later than 8 for young patients. This often takes between 2 to 4 hours and is performed weekly or bi-weekly at specialized centers. The procedure can reduce LDL and Lp (a) levels by 50%-75%, and these levels will gradually return to baseline over 1-2 weeks with regular use. However, the cost of the procedure often limits its use.
Liver transplantation might be considered for younger patients with the severe form of the disorder if their condition is progressing rapidly or if they can’t tolerate LDL apheresis or don’t see adequate cholesterol lowering with the procedure, diet, and medication.
What else can Familial Hypercholesterolemia, Type 2A be?
When diagnosing high cholesterol and early-onset artery disease, doctors consider a number of different conditions that may be causing these issues. These include:
- Familial combined hyperlipidemia (a genetic condition resulting in high blood fat levels)
- Hyperapobetalipoproteinemia (an excess of certain proteins in blood)
- Familial dysbetalipoproteinemia (a disorder causing poor fat breakdown)
- Polygenic hypercholesterolemia (high cholesterol due to multiple genetic factors)
Additionally, tendon xanthomas (fatty deposits under the skin) and early-onset artery disease can also be caused by uncommon hereditary disorders such as sitosterolemia and cerebrotendinous xanthomatosis.
What to expect with Familial Hypercholesterolemia, Type 2A
The outlook for patients with a condition called familial hypercholesterolemia tends to be more challenging compared to those without this condition. Familial hypercholesterolemia is a genetic disorder that results in high levels of low-density lipoprotein cholesterol, often referred to as “bad cholesterol”. When individuals have this condition and also suffer from acute coronary syndrome – a term used to describe conditions that can cause sudden, reduced blood flow to the heart – their risk factors can be quite high.
Patients with both these conditions who are treated with high-dose statins (drugs used to lower cholesterol levels) face up to three times the highest risk of death and heart attack within one year. This is in comparison to people without familial hypercholesterolemia but with similar health conditions and treatments.
Possible Complications When Diagnosed with Familial Hypercholesterolemia, Type 2A
Early heart disease and extensive “hardening of the arteries” are serious health issues that can lead to severe health problems and potentially, death. Other possible complications include yellow patches or plaques on the skin and white or grey rings around the cornea of the eye, which are commonly known as xanthelasmas and corneal arcus.
Common Complications:
- Early heart disease
- Extensive hardening of the arteries
- Severe health problems
- Potential fatality
- Skin complications, such as xanthelasmas
- Eye complications, such as corneal arcus
Preventing Familial Hypercholesterolemia, Type 2A
Children are urged to incorporate more healthy foods into their diet, such as vegetables and fruits, and consume less junk food. It is also recommended that children undergo a lipid profile screening – which is a blood test that measures fats and fatty substances used as a source of energy by your body – between the ages of 9 and 11 as well as between the ages of 17 and 21. However, screening may be required at an earlier age for some children, particularly if they have a parent with familial hypercholesterolemia (a genetic disorder characterized by high cholesterol levels), or if they exhibit signs of this condition, such as xanthomas (yellowish deposits of fat underneath the skin).
Women who are of reproductive age should be informed about the potential risks of using cholesterol-lowering drugs known as statins while pregnant. As a precaution, these women should stop the intake of statins at least three months prior to attempting to get pregnant.
Patients are also urged to keep their lipid (or fat) intake to a minimum in their diet. To aid in this, it’s advised to seek guidance from a dietitian, nutritionist, or lipid specialist. These professionals can provide assistance in creating a healthier and more balanced diet plan.
