Familial hypercholesterolemia (FH)

Types of FH

Familial Hypercholesterolemia presents in two primary forms:

• Heterozygous Familial Hypercholesterolemia (HeFH): This variant is the more prevalent form, occurring when the faulty gene is inherited from just one parent. Individuals with HeFH can have LDL cholesterol levels that exceed 190 milligrams per deciliter (mg/dL). Without appropriate treatment, those affected by HeFH may face the onset of heart disease in their 30s.
• Homozygous Familial Hypercholesterolemia (HoFH): Much rarer in incidence, HoFH occurs when the individual inherits the defective gene from both parents. In this condition, LDL cholesterol levels can surpass 400 mg/dL. Early identification and treatment are critical because individuals with HoFH can experience heart disease very early in life, potentially within the first decade, and in some cases, as young as two or three years old.

Prevalence

Familial Hypercholesterolemia (FH) ranks as one of the more widespread hereditary disorders, impacting approximately 1 in every 250 individuals. In the United Kingdom, it is believed that close to 270,000 people may be affected by FH, though many remain undiagnosed. In the United States, the condition affects around 1.3 million people.

When considering ethnicity, certain groups exhibit a heightened incidence of FH; these include individuals of Finnish, Afrikaner, Lebanese, Ashkenazi Jewish, and French Canadian descent, where the prevalence of FH is notably higher.

As for gender, FH is inherited equally among males and females since the gene responsible for the condition is located on chromosome 19, which is one of the autosomes, or non-sex chromosomes.

Regarding age, individuals with FH are born with a faulty LDL receptor, leading to high levels of LDL cholesterol from birth. The risk of developing coronary artery disease (CAD) increases progressively with age, as the body endures prolonged exposure to these elevated cholesterol levels.

Symptoms

In the initial stages of Familial Hypercholesterolemia (FH), individuals often exhibit no clear symptoms. However, as the condition progresses, various signs may manifest, including:

• Xanthomas, which are fatty deposits that can appear on the hands, elbows, knees, ankles, and around the eyes’ cornea.
• Xanthelasmas, or cholesterol accumulations, on the eyelids.
• Early-onset chest pain indicative of angina, or other symptoms signaling coronary artery disease, can emerge at a younger age than usual.
• Intermittent claudication, evidenced by cramping in the calves when walking.
• Non-healing sores on the toes.
• Acute neurological deficits resembling a stroke, such as speech difficulties, facial drooping, limb weakness, and issues with balance, may be sudden and unexpected.

The elevated LDL levels associated with FH are conducive to the formation of atherosclerotic plaques, substantially increasing the risk of coronary heart disease. Without proper intervention, individuals with FH face a risk of developing heart disease that is 20 times higher than the general population.

Cause

Familial hypercholesterolemia is a genetic disorder. It is caused by a defect on chromosome 19.

The underlying defect in Familial Hypercholesterolemia impedes the body’s ability to effectively clear out low-density lipoprotein (LDL), commonly termed ‘bad’ cholesterol, from the bloodstream. Consequently, individuals with this condition experience elevated LDL cholesterol levels. This excess cholesterol fosters the premature development of atherosclerosis, which is the narrowing of the arteries due to plaque accumulation. The presence of high cholesterol levels leads to the progressive deposit of fatty substances, known as atheroma, within the walls of coronary arteries.

Additionally, other risk factors such as hypertension or tobacco use exacerbate the accumulation of atheroma. As atheroma accumulates, it gradually constricts the arteries, thereby restricting the flow of blood to essential organs. This arterial narrowing substantially elevates the risk of severe cardiovascular events, such as heart attacks and strokes, due to diminished blood supply to the heart and brain.

Familial hypercholesterolemia (FH) is a genetic condition that can lead to dangerously high levels of cholesterol. This condition arises from mutations in specific genes responsible for cholesterol regulation and removal—primarily LDLR, APOB, and PCSK9. In the majority of FH cases, about 60-80%, these mutations are present. When a child inherits the defective gene from both parents, the condition becomes more severe, with a markedly higher risk for early heart disease and heart attacks, sometimes manifesting as early as childhood. Genetic testing can identify mutations in these known genes, but it’s important to recognize that other genes linked to FH may exist but have not yet been discovered.

Inheritance

Every individual has two sets of genes, one inherited from each parent. With conditions like Familial Hypercholesterolemia (FH), a mutation in just a single copy of any of the implicated genes can lead to the disease. This means that if one of your parents carries a gene mutation that leads to FH, you have a 50% chance of inheriting that mutation.

The majority of people with FH have only one mutated gene associated with the condition, which is sufficient to cause it. However, in very rare instances, an individual may inherit mutations in both copies of one of these genes, one from each parent, leading to a severe and rare type of FH known as homozygous FH. Those with homozygous FH tend to have extraordinarily high cholesterol levels and are at risk of experiencing heart attacks at a very young age.

FH is usually inherited in an autosomal dominant pattern, which means that the presence of the mutation in just one of the two copies of a gene is enough to cause the disorder. Therefore, if a parent has FH, each child has a significant chance of inheriting the condition even if the other parent has a normal pair of genes.

Diagnosing FH

Both Heterozygous FH (HeFH) and Homozygous FH (HoFH) can be identified using a combination of physical examinations, laboratory test results, and an in-depth personal and family medical history. Molecular diagnostics, genetic diagnosis, or genetic testing can also confirm the presence of FH. Genetic testing is particularly valuable as it not only confirms the diagnosis in an individual but also highlights the risk for relatives who may be unaware that they are carriers or affected by the condition.

Although some individuals with FH exhibit physical signs, many do not, making the condition challenging to detect without specific tests. Children at increased risk for FH, due to their family history, should undergo cholesterol screening starting at age 2. It is recommended that all children have their cholesterol levels checked between the ages of 9 to 11 and then again between 17 to 21.

Diagnosing FH can be complex, but there are specific indicators that may prompt a doctor to suspect this condition, such as:

• A routine lipid panel revealing high cholesterol levels, with LDL levels above 190 mg/dL in adults or 160 mg/dL in children, being a primary indicator.
• Blood tests typically show high levels of total cholesterol and LDL cholesterol, but triglyceride levels often remain normal.

The suspicion of FH is heightened if:

• An individual experiences a heart attack or stroke at an unusually young age.
• There is a family history of early-onset heart disease or strokes.
• Family members have known diagnoses of FH.

In such cases, further investigation through genetic testing and consultation with a lipid specialist or genetic counselor may be warranted to manage the condition effectively.

You may also notice physical changes to your body that suggest you have FH. Your doctor will perform a simple physical exam to check for these symptoms. These can include:Gentic Testing:

Genetic testing is a DNA test that’s done to see if you have a faulty gene which can cause an inherited condition. This test may be:

• a blood sample
• a mouth swab, from the inside of your cheek.

If you’re diagnosed with FH, your first-degree relatives (parents, siblings, children) should also be tested as soon as possible. FH is an inherited condition which means that if a parent has FH, their child has a 50% chance of inheriting it.

If familial hypercholesterolemia (FH) is diagnosed in a family member, it is crucial for other relatives to undergo testing too. Identifying FH early allows for timely intervention with treatments and lifestyle adjustments to manage cholesterol levels and reduce health risks. Cascade screening is an approach used to detect at-risk individuals within a family. It starts with the screening of immediate family members of the person who has been diagnosed with the genetic condition and can extend to more distant relatives, with the aim of finding and managing the same mutation in them. This proactive method is essential in preventing the serious consequences of inherited conditions like FH.

In the case of familial hypercholesterolemia and elevated Lp(a), early intervention can help manage LDL cholesterol levels and reduce the risk of cardiovascular disease.

Radiology: Doppler echocardiographic evaluation of the heart and aorta is recommended annually in patients with homozygous FH. Radiographic imaging of the Achilles tendon helps accurately measure Achilles tendon xanthomas.

Biopsy: If a skin lesion or the diagnosis of heterozygous FH is unclear, a biopsy of the skin lesion can be performed. Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol.

Differential Diagnosis

The differential diagnosis for familial hypercholesterolemia (FH) involves distinguishing it from other disorders that can cause similar elevations in cholesterol levels. It’s important to differentiate FH from these conditions because the treatment and management strategies may differ:

– Sitosterolemia: This rare autosomal recessive disorder is characterized by high absorption of plant sterols from the intestine, which leads to elevated levels of plant sterols in the blood and tissues, mimicking the cholesterol profile seen in FH.

– Cerebrotendinous Xanthomatosis (CTX): Another autosomal recessive disorder, CTX results from a defect in the enzyme responsible for bile acid synthesis. This leads to accumulation of cholestanol and cholesterol in various tissues, including neurological, ocular, vascular, and musculoskeletal systems.

– Polygenic Hypercholesterolemia: This condition involves the presence of high LDL cholesterol levels that result from the interaction of multiple genes with environmental factors, making it harder to pinpoint a single genetic cause as in FH.

– Familial Combined Hyperlipidemia: This condition is characterized by variable presentations, including elevated levels of cholesterol, triglycerides, or both, and is often associated with an increased risk of cardiovascular disease.

– Hyperapobetalipoproteinemia: This is characterized by increased levels of apolipoprotein B, the primary protein component of LDL, which can lead to high LDL cholesterol levels similar to FH.

– Familial Dysbetalipoproteinemia (Type 3 Hyperlipoproteinemia): In this condition, there is an abnormality in the clearance of chylomicrons and very-low-density lipoprotein (VLDL) remnants, leading to increased levels of cholesterol and triglycerides.

Accurate diagnosis often requires a combination of clinical evaluation, lipid profiling, genetic testing, and sometimes tissue biopsy. Distinguishing between these conditions is crucial for the effective treatment and management of hypercholesterolemia and associated risks.

Treatment

Medicine

Familial Hypercholesterolemia (FH) is primarily managed with a class of medications known as statins, which are instrumental in reducing cholesterol levels. However, in certain instances, additional or alternative medications may be prescribed to further lower lipid levels or if statins are not suitable.

These alternative cholesterol-lowering agents include:

– Bile acid sequestrants such as cholestyramine or colesevelam, which inhibit cholesterol absorption in the intestines, reducing the amount that enters the bloodstream.

– Nicotinic acid, which can lower LDL cholesterol and triglycerides and raise HDL cholesterol.

– Ezetimibe, which targets the intestinal absorption of cholesterol, further limiting its entry into circulation.

– Bempedoic acid, a newer option that can reduce LDL cholesterol levels.

– Inclisiran, a cutting-edge treatment which helps to lower cholesterol through RNA interference.

– Fibrates like bezafibrate and fenofibrate, which are particularly effective in reducing triglycerides and can also help with small increases in HDL cholesterol.

– PCSK9 inhibitors, such as alirocumab and evolocumab, administered through injections, which can significantly lower cholesterol by enhancing the liver’s ability to remove LDL from the blood.

For individuals with the severe homozygous form of FH, who have extremely high LDL cholesterol levels, a specialized procedure called LDL apheresis may be required. Similar to dialysis, this treatment is performed regularly to mechanically remove cholesterol from the blood.

Managing FH is not solely dependent on medication. A comprehensive approach includes dietary modifications to reduce cholesterol intake and increase consumption of heart-healthy foods. Additionally, lifestyle changes such as engaging in regular physical activity, maintaining a healthy weight, and avoiding tobacco use all contribute to managing cholesterol levels and reducing cardiovascular risk.

Diet

While individuals with high cholesterol may successfully lower their levels through dietary adjustments, those with Familial Hypercholesterolemia (FH) cannot manage the condition with diet alone due to its genetic nature. Nonetheless, adopting a healthy lifestyle is a critical component of managing FH. This includes:

– Striving to keep a healthy body weight.

– Engaging in regular physical activity.

– Avoiding tobacco use, as smoking can exacerbate heart disease risks.

– Moderating alcohol intake.

A heart-healthy diet is beneficial for people with FH and should focus on low cholesterol and reduced saturated fat intake. Substituting saturated fats with unsaturated fats can be particularly effective. This means choosing:

– Vegetable oils like sunflower, olive, and rapeseed oil over butter.

– Nuts, seeds, avocados, and oily fish which are rich in beneficial unsaturated fats.

– Vegetable oil spreads instead of butter.

– Skimmed or semi-skimmed milk over whole milk.

– Natural yogurt as a substitute for sour cream or heavy cream.

– Lower fat meat options such as lean mince, as well as swapping red or processed meats for fish, poultry without skin, or plant-based proteins like lentils, soya, or mycoprotein products such as Quorn.

– Unsalted nuts in place of crisps for healthier snacking.

– Reduced-fat cheese instead of full-fat versions.

– Preparing heart-healthy recipes at home, reducing the frequency of ordering takeaway meals.

Further dietary advice includes:

– Consuming less red meat and opting for lean proteins.

– Choosing low-fat dairy products instead of full-fat ones.

– Eliminating trans fats, which are often found in processed foods.

– Reducing dietary cholesterol by avoiding egg yolks and organ meats such as liver.

Incorporating high-fibre foods into your diet is also advised as fibre can help lower the absorption of cholesterol into your bloodstream. Eating a variety of fruits and vegetables, aiming for at least five portions a day, will not only provide fiber but also essential nutrients that support overall health.

Pregnancy and familial hypercholesterolaemia (FH)

Individuals with Familial Hypercholesterolemia (FH) typically do not face increased difficulties becoming pregnant due to the condition itself. However, it is essential to consult with a healthcare provider before attempting to conceive. This consultation allows for a review and possible adjustment of medications that might be harmful during pregnancy. Additionally, the doctor can provide information regarding the risks associated with pregnancy and the likelihood of the child inheriting FH, including the appropriate timing and methods for testing the child for this condition. Maintaining a healthy, balanced diet and staying active are beneficial for overall health and particularly important during pregnancy.

Outlook (Prognosis)

The prognosis for individuals with Familial Hypercholesterolemia (FH) is closely linked to how well they adhere to their healthcare provider’s treatment plan and how effectively they respond to treatment. Implementing dietary modifications, engaging in regular physical activity, and taking medications as prescribed can lead to a significant reduction in cholesterol levels. These lifestyle changes can help postpone the occurrence of a heart attack, particularly in those with a less severe form of FH. However, both men and women with FH generally face a higher risk of premature heart attacks. The risk of mortality varies among individuals with FH. Those with a homozygous form of the condition, meaning they have inherited two copies of the defective gene, typically have a worse prognosis. This form of FH often does not respond adequately to treatment and can lead to early heart attacks.

Possible Complications

Complications may include:

Stable coronary artery disease

Fatal and non-fatal myocardial infarctions at an early age

Congestive heart failure

Cerebrovascular accidents

Aortic stenosis

Peripheral arterial disease

Cardiovascular death

Peripheral vascular disease 

Prevention

Adopting a diet that is low in cholesterol and saturated fat while being rich in unsaturated fat can be effective in managing LDL cholesterol levels in individuals with Familial Hypercholesterolemia (FH). Such dietary practices are a cornerstone in the treatment of FH and can help mitigate the risk of developing cardiovascular diseases. Additionally, genetic counseling is highly recommended for individuals with a family history of FH, especially if both parents are carriers of the defective gene. Genetic counseling can provide valuable information about the risks of inheriting or passing on the condition and can guide family planning and early intervention strategies.

Other questions

What Are My Family Members’ Chances of Having the Same Genetic Change?

Familial Hypercholesterolemia (FH) can result from genetic changes in several genes, primarily the LDLR, APOB, or PCSK9 genes, and less commonly STAP1 or APOE genes. Here’s how the genetics work out for the two main types of FH:

Heterozygous FH (one faulty gene):

– Immediate Family Risk: Each child, sibling, and each parent has a 50% chance of having FH.

– Extended Family Risk: Half-siblings, aunts, uncles, grandparents have a 25% chance, while cousins and more distant relatives have a 12.5% or less chance.

Homozygous FH (two faulty genes):

– Parents and Children: Parents are obligate carriers of one faulty gene, and children have a 50% chance of being carriers (heterozygous FH) and a 25% chance of being homozygous for FH.

– Siblings: Each sibling has a 50% chance of having heterozygous FH and a 25% chance of having homozygous FH.

– Extended Family: Half-siblings, aunts, uncles, and grandparents have a 50% chance of being carriers, while cousins and more distant relatives have a 25% or less chance.

FH-like conditions (caused by genetic changes in LDLRAP1, LIPA, ABCG5/ABCG8, or PNPLA5 genes):

– Immediate Family Risk: Siblings have a 25% chance of having the condition.

– Carrier Family Members: Those with one copy of the genetic change won’t show the condition but can pass on the gene, which could lead to the condition if the other parent also carries a change in the same gene.

Understanding these risks can guide family members in deciding about genetic testing and managing their cholesterol levels.

What can I expect if I have familial hypercholesterolemia?

Individuals with Familial Hypercholesterolemia (FH) face a significantly elevated risk of developing atherosclerosis, the buildup of cholesterol-rich plaques in the arteries, which can lead to heart attacks and strokes. Without appropriate medical intervention, those with FH are at a 20-fold increase in the risk of coronary artery disease compared to the general population. This risk is further amplified if additional cardiovascular risk factors are present, such as tobacco use, diabetes, or other cardiovascular risk factors. It’s crucial for people with FH to manage these risks through lifestyle changes, medications, and regular monitoring by healthcare professionals to prevent the onset and progression of cardiovascular disease.