Familial hypercholesterolemia (FH) is a genetic condition passed down through families. It’s marked by high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. This significantly increases the risk of heart disease at a young age. Defining FH has traditionally been complex, relying on various factors like cholesterol levels, clinical signs, family history, and genetic testing. These factors can be challenging to gather and interpret. This article introduces a simpler way to define FH, making diagnosis more accessible and efficient.
Previously, diagnosing FH involved intricate algorithms that considered total cholesterol or LDL-C levels alongside clinical observations, family medical history, and genetic analyses. However, obtaining comprehensive family history and conducting DNA analysis can be difficult in many clinical settings. To address these challenges, a new, streamlined definition for FH has been proposed, aiming to simplify the diagnostic process while maintaining accuracy.
This novel Familial Definition categorizes FH into “Definite FH” and “Probable FH” based primarily on LDL-C levels and the presence of specific indicators.
Definite FH is identified in individuals who meet either of the following criteria:
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Significantly Elevated LDL-C: An LDL-C level of 8.50 mmol/L (≥ 328 mg/dL) or higher.
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Elevated LDL-C with Additional Risk Factors: An LDL-C level at or above:
- 5.0 mmol/L (≥ 193 mg/dL) for adults aged 40 years and older.
- 4.0 mmol/L (≥ 155 mg/dL) for individuals younger than 18 years.
- 4.5 mmol/L (≥ 174 mg/dL) for those between 18 and 39 years of age.
And at least one of the following must also be present:
- Tendon Xanthomas: These are cholesterol deposits in tendons, commonly found in the Achilles tendon or tendons of the hands and elbows.
- Causal DNA Mutation: Identification of a known disease-causing mutation in the LDLR, APOB, or PCSK9 genes. This mutation can be in the person being tested (proband) or a first-degree relative (parent, sibling, or child).
Probable FH is diagnosed when an individual presents with:
- Elevated LDL-C: An LDL-C level of 5.0 mmol/L (≥ 193 mg/dL) or higher.
- And one of the following risk factors:
- Premature Atherosclerotic Cardiovascular Disease (ASCVD): Diagnosis of ASCVD at a young age (before 55 years for men and before 60 years for women) in the patient or a first-degree relative.
- Elevated LDL-C in a First-Degree Relative: A first-degree relative with known elevated LDL-C levels, indicating a familial pattern of hypercholesterolemia.
The LDL-C cut-off points used in this new familial definition were carefully determined using data from a large database of over 3.3 million individuals. This extensive dataset ensures that the thresholds are statistically relevant and applicable to a broad population.
To evaluate the effectiveness of this simplified familial definition, it was compared against established diagnostic algorithms such as the Simon Broome Register criteria and the Dutch Lipid Clinic Network criteria. A study involving 5987 individuals from Canada was conducted to assess the agreement between the new definition and these existing, more complex criteria. The results demonstrated a very high level of concordance, with kappa (κ) values of 0.969 and 0.966 when compared to the Simon Broome and Dutch Lipid Clinic Network criteria, respectively. These values indicate excellent agreement, confirming that the new definition performs comparably to the more intricate existing methods.
In conclusion, this newly proposed familial definition of FH offers a diagnostic approach that is as effective as current complex algorithms but is simpler and more practical for clinical use. Its adaptation to a contemporary population, as validated in the Canadian study, enhances its relevance and applicability. This simplified definition promises to facilitate the diagnosis of FH patients, enabling earlier identification and management of this prevalent genetic disorder and ultimately contributing to improved cardiovascular health outcomes within families affected by FH.
