Familial Hypercholesterolemia

About

➀ Read and Learn

The following course content

This course will provide an overview of familial hypercholesterolemia, which is defined by its clinical presentation, inheritance patterns, and prevalence. Diagnostic and screening guidelines will be reviewed, followed by a thorough review of current pharmaceutical and non-pharmaceutical treatments. Finally, an overview of the prognosis for both heterozygotes and homozygotes will be covered.

Introduction   

Definition of familial hypercholesterolemia

Familial hypercholesterolemia (FH) is humans’ most common metabolic genetic condition. It is preliminarily defined as a combination of abnormally high low-density lipoproteins (LDL), positive family history, and suggestive physical manifestations (1). When possible, genetic testing should confirm this.

Scoring systems help clinicians identify individuals who may have FH. These include the US Make Early Diagnosis to Prevent Early Death (MedPed) criteria, Simon Broome Register criteria, and the Dutch Lipid Clinic Network score (2,3,4). These scoring algorithms are calculated based on age, total cholesterol and LDL values, documented genetic mutations, a family history of premature cardiovascular events in close relatives, and xanthomas. The MEDPED scoring system is pretty lax, while the Simon Broome Register Criteria and the Dutch Lipid Clinic Network scores are more involved (2,3,4,5,6).

Another more accurate definition is hypercholesterolemia attributable to a single, specific, causative gene mutation. One challenge with this definition is that genetic testing is not accessible to everyone (5).

Many individuals are diagnosed with FH based on clinical signs and symptoms, lab values, and family history; however, not all have genetically confirmed FH (5).

Three main mutations have been identified, although several rare and sporadic gene mutations have also been identified. These rare mutations are in the STAP1, APOE, and LDLRAP1 genes.1 To date, there are 2,000 known genetic variants (7).

The first of three significant mutations identified was in the LDLR gene, which codes for the LDL receptor. This is the most common mutation in 85-90% of cases (1,6). The LDL receptors sit on the cell surface and bind LDL particles before carrying them into the cell, unloading them, and then recycling them to the surface. Individuals with mutations in the gene have a lower ability to clear cholesterol hepatically because there is either a decreased number of receptors or an inefficient uptake of LDL by its receptors (8).

The second mutation, making up only 5-15% of cases, is in the apolipoprotein-B (APOB) gene (1,6). This mutation, of which there are at least 100 variations, prevents the efficient attachment of LDL to LDL receptors. This leads to impaired removal of plasma LDL and subsequent hepatic clearance (5,9).

Finally, the third mutation, only present in about 1% of individuals with FH, occurs in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene.6 This gain of function mutation causes an abnormally fast breakdown of the LDL receptors, a decreased number of LDL receptors on the cell surface, and a lower clearance of plasma LDL (5,10).

Overall, regardless of the mutation, the body is unable to efficiently remove LDL, leading to higher-than-normal blood levels and potential cardiac effects such as atherosclerosis and early cardiac events (11).

Inheritance

The inheritance pattern for familial hypercholesterolemia is autosomal dominant because only one abnormal gene copy is needed to cause symptoms, and the mutation is on chromosome 19. Some researchers call it semi-dominant because both copies of the gene (abnormal and normal) affect the patient’s symptoms and disease severity (12).

In most cases, only one abnormal copy of the gene is inherited. This is known as heterozygous. Homozygous cases occur when each parent contributes an abnormal copy of the gene. In these rarer cases, the presentation and onset of symptoms (including an abnormally high LDL, early heart attacks, and atherosclerosis) are more common and begin in childhood (11).

About 60-80% of people with FH have a confirmed mutation in LDLR, APOB, or PCSK9 (13).

Prevalence

Familial hypercholesterolemia is a prevalent genetic disorder and reportedly ranges from 1:220 to 1:500 (1,5,6,14). A study reviewing mainly White people of European descent showed that heterozygous FH was found at a ratio of 1:311, and FH (not specified heterozygous or homozygous) was present in 1:500. Additionally, the prevalence of atherosclerotic cardiac disease was 18 times higher in those with FH. This statistic was specifically for heterozygotes compared to the general population (5).

A different study stated the prevalence for heterozygotes was closer to 1:250, and homozygotes were 1:300,000. Those patients tend to have an LDL >400 mg/dL and atherosclerosis by their teenage years (1,14). There is no significant difference in prevalence by gender since this is not a sex-linked condition (15).

Minority populations have been underrepresented in many studies; however, one study revealed that FH seems to be more prevalent in Black people and people with obesity (15).

A study done in the Czech Republic suggests that 80% of FH patients remain undiagnosed. This could skew the prevalence in areas where genetic testing is inaccessible and a diagnosis is made strictly on the scoring algorithms (1).

Several “founder” populations throughout the world appear to be more predisposed to having FH. These include French Canadians, Finnish, Ashkenazi Jews, South African Afrikaners, and Lebanese Christians. This is likely due to historical immigration patterns and close familial relationships when reproducing (15).

Pathophysiology

In an individual who does not have familial hypercholesterolemia, LDL carries most of the plasma cholesterol to the LDL receptors through 2 connections known as APOB and apolipoprotein E. This combined LDL and receptor complex enters the cell and releases the LDL particle. The LDL receptor is then returned to the cell membrane to repeat the process.

There are several places where this goes wrong in people with FH. There can be a problem with the receptor itself (LDLR mutation), the APOB connection is faulty (APOB mutation), or the liver makes PCSK9, which binds the LDL receptor and keeps it from recycling to the cell surface while also increasing the breakdown of the receptors (PCSK9 mutation). All allow for an increase in plasma LDL because the liver cannot efficiently clear the LDL (15).

Risk stratification is essential in caring for an individual with FH since some cases may be more severe. This can affect treatment and monitoring recommendations. The International Atherosclerosis Society stratifies risk by the following criteria: age >40 without treatment, male sex, smoking, lipoprotein(a) >50 mg/dL, history of early coronary artery disease in a first-degree relative, BMI >30 kg/m2, and history of diabetes or chronic kidney disease (6).

Clinical presentation

Onset

Familial hypercholesterolemia is a genetic disorder that begins during intrauterine development. After birth, homozygous FH becomes apparent in childhood. However, in heterozygotes, diagnosis will likely occur later and may occur without obvious physical symptoms (6,14).

Labs

LDL abnormalities will be noticeable in childhood. In those with homozygous FH, the LDL may be >400 mg/dL by puberty (1,14). Heterozygous cases will have less severely elevated LDL.

Cardiac history

Cardiac history is based on both personal and family history. Specifically, those with FH may have chest pain related to atherosclerosis. In homozygous cases, this may begin in childhood. Early atherosclerosis and heart attacks are more likely in FH. For those with heterozygous FH, there is a 30-50% increased risk of a cardiac event by age 50 (men) or 60 (women) (6). Strokes are also more common and may present with facial drooping, slurred or difficult speech, unilateral limb weakness, or a loss of balance (11).

Other physical manifestations

Physical manifestations may be evident. Cholesterol deposits, called xanthomas, can develop in the skin of the hands, elbows, knees, and ankles. Cholesterol can also deposit around the cornea and is called arcus senilis or corneal arcus. Cholesterol can also build up in the eyelid (xanthelasma) (6,14). Cramping in the calves while walking or non-healing sores on the toes may also occur (11).

Diagnosis

Physical signs and symptoms

Providers can assess for xanthomas, xanthelasma, chest pain, stroke symptoms, and non-healing toe sores during a physical exam. The corneal arcus is a highly specific criterion; however, it can occur in other cardiovascular conditions, like atherosclerosis, not related to FH (11).

If FH cannot be confirmed by more traditional methods in the case of xanthomas or xanthelasmas, they can be biopsied (15).

Clinical criteria

Labs

Many people may initially be identified because of an elevated test in a cholesterol blood panel. In the case of familial hypercholesterolemia, LDL and total cholesterol are the usual abnormalities; triglycerides may also be elevated. The American Heart Association classifies an LDL >190 mg/dL as severe for those with heterozygous FH. In homozygous FH, the parameter is >400 mg/dL (16).

For those who have a family history of FH, one or both parents also have high LDL. Individuals may be able to undergo genetic testing (via next-generation sequencing) to determine which gene, if any, is mutated.12

Another older test, which is not used often, can evaluate the absorption of LDL by fibroblasts. This test shows how well fibroblasts bind and remove LDL from the blood (11).

Another diagnostic lab is called lipoprotein(a). This test can indicate those with a higher risk of atherosclerotic cardiac disease, regardless of FH. Lipoprotein(a) is considered a “genetically determined LDL-like particle” and can help with risk stratification in FH (14).

Family history of cardiovascular disease or hypercholesterolemia

Frequently, FH is diagnosed in multiple family members. Initially, the diagnosis may be based on a family history of early heart attacks and not a genetic result. Typically, in FH, cardiac events also happen earlier in the lifespan than expected (6,11).

Several diagnostic tools are useful for risk assessment purposes. These include (14):

• carotid ultrasound- determines if there is plaque present
• carotid intima-media thickness scan- evaluates the inner and middle layers of the carotid artery (proper in children)
• echocardiogram- evaluates for valvular stenosis
• coronary imaging via a cardiac CT- determines a coronary artery calcium score
• coronary CT angiography- determines if there is plaque present

Genetic testing

Genetic testing is not widely available in all areas and some statistics support that between 70-90% of individuals with FH remain undiagnosed (6,7). However, if available, genetic testing is confirmatory and provides valuable information.

Pediatric recommendations

Several organizations, including the National Heart, Lung, and Blood Institute, American Academy of Pediatrics, American Heart Association, National Lipid Association, and American College of Cardiology, have outlined guidelines for pediatric cholesterol screening. This consists of a non-fasting lipid panel collected between the ages of 9 and 11 (6,17). However, children with a strong family history can be screened as early as 2 years old (6).

“Cascade” screening

Cascade screening is used to identify family members with FH and consists of testing first-degree relatives of people known to have FH (5).

Treatment

Treatment aims to correct LDL levels and reduce the risk of atherosclerosis and cardiac events (11,14). In adults, the goal is an LDL of <70 mg/dL. Typically, multiple medications are required to reach this goal.

In children, regardless of whether they have familial hypercholesterolemia, the goal is an LDL <110 mg/dL.6 Treatment recommendations are based on LDL values and vary, but in cases of heterozygous FH, treatment will usually be delayed until the child is at least eight years old. For those with homozygous FH, lipid apheresis will be required early in life (6).

Lifestyle modifications

Diet

Literature suggests that diet and exercise are insufficient to reduce LDL to acceptable levels in those with familial hypercholesterolemia (1). However, dietary changes are suggested, including fat reduction (especially saturated fat), such as with the Mediterranean or DASH diets (14). Weight loss is recommended in those who are obese or overweight. Some dietary suggestions may include eating less meat, full-fat dairy, and egg yolks. Trans fat should be eliminated as much as possible (11).

Exercise

Routine exercise should be done with dietary changes (11).

Pharmacological treatment

Many medications exist to manage cholesterol levels. In addition to a healthier diet and exercise regimen, pharmacological options are a great tool. These include (14):

• statins
• ezetimibe
• bile acid sequestrants
• PCSK9 inhibitors
• fibrates
• nicotinic acid
• adenosine triphosphate (ATP) citrate lyase inhibitors

In severe or refractory cases, lipid apheresis or a liver transplant may be necessary (11,14).

Statins

The first medication choice for high cholesterol, whether or not due to FH, is a high-intensity statin if tolerated. Otherwise, the statin dose can be reduced, and other medications can be added (11).

Statins (HMG-CoA reductase inhibitors) have been clinically linked to a reduction in the risk of stroke and myocardial infarctions related to high cholesterol. Considered the most effective agents available, they work to directly reduce endogenous cholesterol production by the liver, leading to lower LDL and triglycerides (11).

Statins do have several common side effects and may be dose-limiting in some individuals. These include myalgia and abnormally elevated liver function tests (11).

Statins should not be taken in pregnancy or lactation or for those trying to conceive.11,18 However, in those with FH, delaying statin initiation or interrupting a previous statin routine related to childbearing can increase the risk for atherosclerotic plaque development (14).

In individuals with liver failure, statins are inappropriate (18).

In adults whose LDL remains >70 mg/dL while on the maximum dose of a single-agent statin, other medications (such as ezetimibe) can be added (6).

In children, statins can be given beginning at age eight. However, this depends on the specific medication choice, as not all are approved for children.6

Medications include atorvastatin, lovastatin, rosuvastatin, and others (11).

Ezetimibe

Ezetimibe (Zetia) is frequently used as an adjunctive treatment to statins. This medication prevents cholesterol absorption in the body, leading to excretion in the stool (18).

Ezetimibe is approved for children older than 10 (6).

Bile acid sequestrants

Bile acid sequestrants, or bile acid-binding agents, increase cholesterol excretion in the intestinal tract. These medications include cholestyramine, colestipol, and colesevelam (18).

Colesevelam is also approved for children (6).

PCSK9 inhibitors

PCSK9 inhibitors are a relatively new class of injectables. They inactivate the PCSK9 protein in liver cells, allowing LDL receptors to efficiently bind and deliver LDL to the liver and recycle it to the cell surface to repeat the process. Medications include alirocumab, evolocumab, and inclisiran (18).

Many people with confirmed FH do not achieve ideal LDL levels on the maximum dose of statins and ezetimibe alone. PCSK9 inhibitors can fill the gap (11,18).

PCSK9 inhibitors are not currently approved for children (6).

Oral PCSK9 inhibitors are currently being evaluated for hypercholesterolemia, including FH (6).

Other

Many other medications have been approved for treating high cholesterol and are being investigated. However, they are used less frequently in FH.

Adenosine triphosphate-citrate lyase (ACLY) inhibitors, such as bempedoic acid and bempedoic acid with ezetimibe, block cholesterol synthesis in the liver. This medication class is used for those with FH or heart disease and increased LDL (18). It is combined with diet, exercise, and statins.

Fibrates can lower LDL but are better at lowering triglycerides, so they are typically not used in addition to statins. Fibrates include: gemfibrozil, fenofibrate, or fenofibric acid (18).

Niacin (nicotinic acid) is a B vitamin that decreases the liver’s production of cholesterol. This is an effective treatment for lowering triglycerides but not LDL. It can be hepatotoxic (18).

Omega-3 fatty acid ethyl esters are derived from fish oil. These can be used with dietary changes to lower high triglycerides but are ineffective for lowering LDL. Medications include Lovaza, Vascepa, Epanova, and Omtryg (18).

Marine-derived omega-3 polyunsaturated fatty acids, or Omega-3 fish oils, are used to lower triglycerides but not LDL (18).

Another emerging treatment is cholesteryl ester transfer protein (CETP) inhibitors. These drugs reduce LDL and increase HDL. However, they have mixed results. While some are still in development, some have been abandoned (1,11).

Other more intense therapies, including gene therapy, are in the preclinical stages (14).

Lipid apheresis

Lipid apheresis is necessary in homozygous FH by age five (14). However, for those on maximum therapy and with an LDL still >100 mg/dL, lipid apheresis can be considered (6).

Liver transplant

Liver transplantation is rarely used but is definitive. It is primarily used for those with homozygous FH (14).

Prognosis

Familial hypercholesterolemia is a manageable condition, but the outlook depends on how well total cholesterol and LDL are managed. An early and well-managed diagnosis can delay potential cardiac events and decrease the risk of early events (11).

Heterozygous

In heterozygous patients, medication management, in addition to lifestyle changes, is important to achieving a good outcome. The overall goal is risk reduction related to cardiac events.

Homozygous

Historically, homozygous FH portends a poorer outlook because it does not respond well to treatment (11).

Early detection

Early detection and early treatment help improve outcomes.

Genetic counseling

Genetic counseling can be helpful for both educational and screening purposes.

Patient Advocacy

Advocacy is essential and can improve prognosis. Patient education, support groups, and connections with expert clinicians can help patients better understand and manage their FH (19).

Conclusion

Familial hypercholesterolemia is the most common inherited metabolic condition and occurs in about one of every 250 people. While more common in specific populations, it is a global problem. Early diagnosis and appropriate treatments, including diet, exercise, medications, and other medical interventions, are key to reducing the risk of cardiac events and preventing mortality. Patient and family support is crucial since this condition can significantly impact families.

➁ Complete Survey

Give us your thoughts and feedback

➂ Click Complete

To receive your certificate