Familial hypercholesterolemia (FH) is recognized as a genetic disorder passed down through families. It’s characterized by notably high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. This condition significantly elevates the risk of early onset atherosclerotic cardiovascular disease, a serious condition affecting the arteries. However, establishing a clear and straightforward definition for FH has been challenging. Current definitions often involve intricate algorithms based on total or LDL-C levels, clinical observations, family medical history, and genetic DNA analysis. These factors can be complex and not always readily accessible, making diagnosis difficult. Therefore, a new, simplified definition of FH has been proposed to improve diagnostic clarity and accessibility.
To address the complexities of diagnosing FH, a novel simplified definition has been suggested. This new definition categorizes FH into “Definite FH” and “Probable FH” based on specific LDL-C levels and associated clinical or genetic factors.
Definite FH is identified by one of two primary criteria:
- Significantly Elevated LDL-C: Individuals with LDL-C levels at or above 8.50 mmol/L are classified as having definite FH.
- Elevated LDL-C with Additional Risk Factors: For individuals with LDL-C levels at or above 5.0 mmol/L if 40 years or older; ≥ 4.0 mmol/L if younger than 18 years; and ≥ 4.5 mmol/L if between 18 and 39 years, the diagnosis of definite FH is made when accompanied by at least one of the following indicators:
- Tendon Xanthomas: These are cholesterol deposits in tendons, often found in the Achilles tendon or tendons of the hands and elbows.
- Causal DNA Mutation: The presence of a known disease-causing mutation in the LDLR, APOB, or PCSK9 genes, either in the individual being tested (proband) or a first-degree relative (parent, sibling, or child). These genes are critical in the regulation of LDL cholesterol metabolism.
Probable FH is defined by a less stringent set of criteria:
- Elevated LDL-C and Risk Factors: Probable FH is diagnosed in individuals with LDL-C levels at or above 5.0 mmol/L who also present with either:
- Premature Atherosclerotic Cardiovascular Disease: This refers to the early development of heart disease or stroke due to plaque buildup in the arteries, either in the patient themselves or a first-degree relative.
- Elevated LDL-C in a First-Degree Relative: Having a first-degree relative with similarly elevated LDL-C levels further supports the likelihood of probable FH.
The LDL-C thresholds used in this new definition were established using data from a large database encompassing over 3.3 million individuals, ensuring a statistically robust foundation for these cut-off points.
To evaluate the effectiveness of this new simplified FH definition, it was compared against established diagnostic algorithms such as the Simon Broome Register criteria and the Dutch Lipid Clinic Network criteria. The comparison was conducted using data from 5987 individuals in Canada. The results of this analysis demonstrated a very high level of agreement between the new FH definition and both the Simon Broome Register and Dutch Lipid Clinic Network criteria, with kappa (κ) values of 0.969 and 0.966, respectively. A kappa value close to 1 indicates almost perfect agreement between the diagnostic methods.
In conclusion, this newly proposed Definition Of Familial hypercholesterolemia offers a diagnostic approach that is as effective as existing, more complex criteria. It is specifically adapted and validated for the Canadian population, making it particularly relevant in this context. The simplified nature of this definition is expected to significantly facilitate the diagnosis of FH patients, potentially leading to earlier identification and management of this condition, and ultimately reducing the risk of premature cardiovascular disease.
