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Key Questions About Familial Hypercholesterolemia: JACC Review Topic of the Week
Allan D Sniderman1, Tamara Glavinovic2, George Thanassoulis3
1Mike and Valeria Rosenbloom Centre for Cardiovascular Prevention, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Insights
Familial hypercholesterolemia (FH) definitions are challenged by new data. Patients with severe hypercholesterolemia, regardless of FH variants, need prompt therapy and family screening for cardiovascular risk.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Biochemistry
Background:
- Familial hypercholesterolemia (FH) is a monogenic disorder causing severe hypercholesterolemia via low-density lipoprotein (LDL) receptor pathway gene variants.
- FH variants are traditionally linked to significantly elevated cardiovascular risk.
Purpose of the Study:
- To re-evaluate the definition and diagnostic criteria for FH.
- To assess the actual impact of FH-causing variants on cardiovascular risk.
- To determine optimal management strategies for severe hypercholesterolemia.
Main Methods:
- Review of recent large-scale population studies on hypercholesterolemia.
- Analysis of patient data correlating FH variants with LDL cholesterol levels and cardiovascular outcomes.
- Comparative analysis of cardiovascular risk in FH variant-positive versus FH variant-negative individuals with severe hypercholesterolemia.
Main Results:
- FH accounts for a smaller proportion of severe hypercholesterolemia cases than previously thought.
- A significant number of individuals with FH variants do not exhibit marked hypercholesterolemia.
- The cardiovascular risk associated with FH variants may be overestimated.
Conclusions:
- Current definitions of FH may be too narrow and require revision.
- Severe hypercholesterolemia, irrespective of FH genetic status, warrants immediate therapeutic intervention.
- Prioritizing all patients with severe hypercholesterolemia for treatment and cascade family screening is crucial for cardiovascular risk management.
Abstract:
Familial hypercholesterolemia (FH) is characterized as a monogenic, autosomal dominant disorder, producing severe hypercholesterolemia within families due to causal variants within genes regulating the low-density lipoprotein receptor pathway. Demonstration of a causal variant is widely accepted as evidence of substantially higher cardiovascular risk. However, recent large-scale population studies challenge this characterization of FH, which appears to account for only a minor portion of those with severe hypercholesterolemia. Moreover, a substantial portion of FH variant positive patients do not have marked hypercholesterolemia. These discordances raise doubt as to how FH should be defined and how the concentration of low-density lipoprotein in plasma is regulated in individuals with and without FH. Moreover, review of the evidence suggests the impact of an FH causal variant on cardiovascular risk may be less than previously accepted and that all patients with severe hypercholesterolemia should be prioritized for therapy and family screening.
