High Cholesterol Since Childhood: Understanding Familial Hypercholesterolemia

Most heart attacks and premature cardiovascular events are attributed to traditional risk factors. However, in a subset of patients, the cause is present from birth and remains unnoticed for years: a genetic alteration that keeps LDL cholesterol levels persistently elevated.

Although well-established clinical criteria and molecular tests are available to confirm the diagnosis, familial hypercholesterolemia remains a widely underdiagnosed condition, delaying interventions that could significantly improve prognosis, not only for the patient but for the entire family.

Below, learn how to recognize the signs of this silent condition, when to suspect it, and the available pathways for diagnosis and treatment.

Familial Hypercholesterolemia: What Is It?

Familial hypercholesterolemia (FH) is an inherited genetic disorder that impairs the body’s ability to remove LDL cholesterol (low-density lipoprotein) from the bloodstream. The result is a persistent and marked increase in LDL cholesterol levels from birth (1), significantly increasing the risk of ischemic heart disease (2).

Familial hypercholesterolemia is the most common autosomal dominant genetic disorder, affecting approximately 30 million people worldwide (2). In Brazil, the overall prevalence of FH is estimated at approximately 1 case per 263 individuals (3).

What Causes Familial Hypercholesterolemia?

Low-density lipoproteins (LDL) transport cholesterol from the liver to various tissues throughout the body. Under normal conditions, receptors located primarily in the liver remove LDL from circulation.

In familial hypercholesterolemia, this clearance mechanism becomes inefficient. As a result, LDL remains in circulation longer and progressively accumulates in the arterial walls, promoting the development of atherosclerosis (4).

Most cases are associated with alterations in genes involved in LDL metabolism, mainly: LDLR (LDL receptor; >90% of cases), APOB (~5%), PCSK9 (<1%), and more rarely, LDLRAP1 and other genes related to lipid metabolism (4, 5).

There are two main forms (6):

• Heterozygous Familial Hypercholesterolemia (HeFH): occurs when an individual inherits a single disease-associated genetic variant;
• Homozygous Familial Hypercholesterolemia (HoFH): a rarer and more severe condition in which disease-causing variants are inherited from both parents, resulting in extremely high LDL levels and an even earlier cardiovascular risk.

The heterozygous form (HeFH) has an estimated prevalence of approximately 1 in 200–300 individuals and is considered one of the most common hereditary monogenic disorders, whereas the homozygous form (HoFH) is rare (~1 in 400,000) (1, 5, 7).

What Is the Difference Between Hypercholesterolemia and Familial Hypercholesterolemia?

Although the terms are often used interchangeably, hypercholesterolemia and familial hypercholesterolemia are distinct conditions. The main difference lies in the cause of elevated LDL cholesterol and, consequently, the associated cardiovascular risk.

Hypercholesterolemia is defined by elevated LDL cholesterol levels, generally above 190 mg/dL in adults, and may result from different mechanisms. These include secondary causes such as a diet high in saturated fats, hypothyroidism, nephrotic syndrome, cholestatic liver disease, and the use of certain medications.

These conditions are estimated to account for approximately 20–30% of cases of hypercholesterolemia. In such cases, cardiovascular risk varies according to the degree of LDL elevation and the presence of other risk factors (8, 9).

Familial hypercholesterolemia, on the other hand, is an inherited genetic disorder, generally with codominant autosomal inheritance, caused by pathogenic variants primarily in the LDLR, APOB, and PCSK9 genes. These alterations impair LDL clearance by the liver, resulting in persistently elevated cholesterol levels from birth (10, 11).

In addition to elevated cholesterol levels, a family history of premature atherosclerotic cardiovascular disease is common, including acute myocardial infarction or revascularization procedures in first-degree relatives, men younger than 55 years and women younger than 65 years (10).

Continuous exposure to high LDL cholesterol levels from childhood results in a significantly increased cardiovascular risk for individuals with FH. Therefore, once the diagnosis is established, cascade screening of first- and second-degree relatives is recommended. This strategy is considered one of the most effective approaches for early identification of new cases and initiation of interventions before cardiovascular events occur (8).

Differences Between Common Hypercholesterolemia and Familial Hypercholesterolemia

When Can High Cholesterol Be Genetic?

Some signs increase suspicion of familial hypercholesterolemia, such as:

• LDL persistently above 190 mg/dL in adults;
• Family history of very high cholesterol;
• Heart attack, revascularization, or stroke occurring at an early age in the family;
• Presence of xanthomas or premature corneal arcus;
• Known cases of familial hypercholesterolemia among relatives.

What Are the Symptoms of Familial Hypercholesterolemia?

One of the greatest challenges of familial hypercholesterolemia is that it often remains silent for years. Many individuals experience no symptoms until cardiovascular complications such as angina, myocardial infarction, or stroke occur (12).

Some patients may develop characteristic clinical manifestations resulting from cholesterol accumulation in tissues.

• Xanthomas: Cholesterol deposits in tendons, especially the Achilles tendons, hands, and elbows. They are considered one of the most characteristic signs of the disease.
• Xanthelasmas: Small yellowish plaques located around the eyelids. Although they may occur in individuals without familial hypercholesterolemia, their presence warrants clinical investigation.
• Corneal Arcus: A whitish ring around the cornea that appears in young individuals. When it develops before the age of 45, it may be an important sign of familial hypercholesterolemia.

The absence of characteristic physical signs, such as tendon xanthomas, does not exclude the diagnosis of familial hypercholesterolemia. More than half of patients with genetically confirmed FH do not present these manifestations, which have become less frequent due to the widespread use of cholesterol-lowering medications (9).

Therefore, disease screening should be based primarily on identifying elevated LDL levels together with a family history of hypercholesterolemia or premature cardiovascular disease (13).

Relevant Clinical Manifestations (13, 14)

• Premature coronary artery disease, often the first manifestation of the condition: myocardial infarction or the need for revascularization before age 55 in men or before age 65 in women.
• Approximately 20% of individuals with heterozygous FH already present some form of atherosclerotic disease by around 40–45 years of age.
• In the homozygous form (HoFH), findings are typically earlier and more severe, including cutaneous/tendon xanthomas during childhood and coronary artery disease before the age of 20.

According to the Brazilian Familial Hypercholesterolemia Guideline, when left untreated, the disease may lead to the premature development of cardiovascular disease. In individuals with the heterozygous form, coronary events may occur decades earlier than observed in the general population. In the homozygous form, which is more severe and rare, cardiovascular manifestations may arise during childhood or adolescence (15).

How Is Familial Hypercholesterolemia Diagnosed?

The diagnosis of familial hypercholesterolemia (FH) is based on a combination of clinical, laboratory, and family history information. In practice, it is primarily a clinical (phenotypic) diagnosis, while genetic testing serves as a complementary tool for diagnostic confirmation, clarification of uncertain cases, and family cascade screening (8-9).

Personal and Family History

Assessment includes the presence of elevated cholesterol levels in family members; premature myocardial infarction or stroke in relatives; the presence of xanthomas; and previous use of cholesterol-lowering medications.

Lipid Profile

The lipid profile is fundamental for diagnostic suspicion, with LDL-C being the primary marker. In adults, LDL-C values ≥190 mg/dL, especially when associated with a family history of premature atherosclerotic cardiovascular disease (ASCVD), strongly suggest the heterozygous form. Levels above 400 mg/dL suggest the homozygous form. In children, the diagnosis should be considered when LDL-C is ≥190 mg/dL alone, ≥160 mg/dL in the presence of a family history of hypercholesterolemia or premature ASCVD, or ≥130 mg/dL when one parent has a genetically confirmed diagnosis of FH (10, 13).

Genetic Testing

The identification of variants in genes such as LDLR, APOB, and PCSK9 is the most accurate method for confirming the diagnosis. It also plays an important role in cascade screening of relatives. However, a negative result does not exclude FH when clinical and laboratory criteria are consistent with the disease (10, 16, 17).

Lipoprotein(a)

Measurement of Lipoprotein(a) is recommended at least once during adulthood, as elevated levels are observed in approximately 30% to 50% of individuals with FH and may contribute to an even greater cardiovascular risk (13).

Clinical Scores

Several tools help estimate diagnostic probability, including the Dutch Lipid Clinic Network, Simon Broome, and MEDPED criteria. These methods combine LDL-C levels, family history, the presence of clinical signs, and, when available, genetic testing results (10, 13, 18).

Before confirming a diagnosis of FH, it is important to rule out other conditions that may elevate LDL cholesterol, such as hypothyroidism, nephrotic syndrome, cholestatic liver disease, and dietary patterns high in saturated fat (16).

When Might Genetic Diagnosis Be Indicated?

Molecular diagnosis can play an important role in the investigation of familial hypercholesterolemia, especially when diagnostic uncertainty exists or when assessing risk in other family members. Analysis of disease-associated genes such as LDLR, APOB, and PCSK9 provides information that complements clinical and laboratory findings.

Among the main benefits of molecular diagnosis are: diagnostic certainty, supporting earlier clinical decision-making; family screening, in which confirmation of a genetic alteration helps guide testing of relatives; and clinical stratification, which helps distinguish more severe forms of the disease and supports therapeutic planning and follow-up strategies. 

Who Can Benefit from Genetic Testing?

Testing may be considered for:

• Patients with strong clinical suspicion of FH;
• Children and adolescents with very high LDL levels;
• Relatives of individuals already diagnosed with FH;
• Cases of premature cardiovascular disease without an apparent explanation.

How Is Familial Hypercholesterolemia Treated?

The primary goal of familial hypercholesterolemia treatment is to reduce LDL-C levels and, consequently, decrease the risk of premature cardiovascular disease. To achieve this, management combines lifestyle interventions and pharmacological therapies.

Non-pharmacological recommendations include adopting a balanced diet with reduced intake of saturated fats and elimination of trans fats, regular physical activity, maintenance of a healthy body weight, and smoking cessation. However, because FH is a genetically determined condition, lifestyle changes alone are generally insufficient to achieve cholesterol targets.

For this reason, most patients require pharmacological treatment, which is determined according to factors such as age, lipid profile, the presence of cardiovascular disease, and overall cardiovascular risk. The therapeutic strategy is individualized and generally follows a stepwise approach, with treatment intensification if LDL-C levels remain above recommended targets. In both heterozygous and homozygous forms, high-intensity statins are the foundation of treatment and may be combined with other lipid-lowering therapies when necessary (13).

Which Tests Does SYNLAB Offer for the Investigation of Familial Hypercholesterolemia?

SYNLAB offers a comprehensive portfolio for the investigation of familial hypercholesterolemia, including tests for lipid profile assessment, Lipoprotein(a) measurement, and several genetic testing options.

For genetic diagnosis, options range from targeted analysis of specific genes, such as LDLR, APOB, and PCSK9, to multigene NGS panels that evaluate 8 or 24 genes associated with familial hypercholesterolemia and other inherited dyslipidemias.

This integrated approach supports diagnosis, risk stratification, and the investigation of family members who may be affected by the condition.

Get to Know SYNLAB Group, a Reference in Medical Diagnostic Services!

Performing precise and updated tests is essential for more accurate diagnoses and better treatment guidance. SYNLAB is here to help you.

We provide diagnostic solutions with strict quality control to the companies, patients, and physicians we serve. We have been in Brazil for over 10 years, operate in 36 countries across three continents, and are leaders in service provision in Europe.

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Frequently Asked Questions (FAQ)

What Is Familial Hypercholesterolemia?

It is a genetic disorder that causes elevated LDL (“bad”) cholesterol levels from birth and increases the risk of premature cardiovascular disease.

What Causes Familial Hypercholesterolemia?

The condition is caused by genetic variants that impair the removal of LDL cholesterol from the bloodstream, primarily involving the LDLR, APOB, and PCSK9 genes.

How Do I Know If High Cholesterol Is Genetic?

A family history of high cholesterol, persistently elevated LDL levels, premature heart attacks in relatives, and specific clinical criteria increase suspicion of a genetic cause. 

Which Test Detects Familial Hypercholesterolemia?

Diagnosis involves a lipid profile, clinical evaluation, and family history assessment. Genetic testing can confirm the presence of disease-associated variants.

Can Familial Hypercholesterolemia Be Cured?

Currently, there is no cure for familial hypercholesterolemia because its origin lies in inherited genetic alterations. However, appropriate control of LDL cholesterol levels can substantially reduce cardiovascular risk and improve life expectancy.

How Is Inherited High Cholesterol Treated?

Treatment combines a healthy lifestyle with LDL-lowering medications. Therapy is generally required throughout life and should include regular monitoring of lipid levels, cardiovascular risk assessment, and treatment adjustments whenever necessary.

Is Familial Hypercholesterolemia Serious?

Yes. Without proper diagnosis and treatment, it significantly increases the risk of heart attack and other premature cardiovascular diseases. Early diagnosis is one of the most effective measures to reduce the impact of cardiovascular disease associated with familial hypercholesterolemia.

Should People With a Family History of Premature Heart Attack Undergo Genetic Testing?

Depending on the clinical evaluation, genetic testing may be recommended to confirm the diagnosis and guide family screening.

Should Children of Individuals With Familial Hypercholesterolemia Also Be Evaluated?

Yes. Current guidelines recommend cascade family screening, since each child of an individual with heterozygous familial hypercholesterolemia has approximately a 50% chance of inheriting the condition.

References

Referências bibliográficas
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