Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia

Abstract

ImportanceFamilial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH.ObservationsIn 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created.Conclusions and RelevanceBy adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

Genetics, Screening, and Treatment of Familial Hypercholesterolemia: Experience Gained From the Implementation of the Vietnam Familial Hypercholesterolemia Registry

“…Because of these challenges, the EAS Familial Hypercholesterolemia Studies Collaboration (EAS-FHSC), the Familial Hypercholesterolemia Foundation, and the World Heart Federation initiated a global call to action for reducing the burden of disease and death due to FH (Vallejo-Vaz et al, 2015;Wilemon et al, 2020). Special attention was given to data registry as an important tool for providing knowledge and support management for FH.…”

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

“…Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic disorder of lipid metabolism that results in high LDL-C levels with or without concomitant elevation in lipoprotein (a) (Lp(a)) at a very early age [1,2]. Patients with HoFH have extremely high LDL-C levels from birth, and this is associated with early-onset atherosclerotic cardiovascular disease (ASCVD) and aortic/supra-aortic valve disease.…”

“…Patients with HoFH have extremely high LDL-C levels from birth, and this is associated with early-onset atherosclerotic cardiovascular disease (ASCVD) and aortic/supra-aortic valve disease. This, in turn, causes a range of associated life-threatening cardiac conditions [1]. If left untreated, HoFH is associated with ASCVD at a mean age of 12.5 years, with mean survival just 18 years [3].…”

“…The condition arises when an individual inherits two mutations that encode defects in proteins involved in the catabolism of LDL-C. Affected genes can include LDLR, LDLRAP1, APOB, and PCSK9 [1]. The pattern of mutations is extremely varied, whereby patients may have a pair of matching mutations ("true" or "simple" homozygotes), a pair of unmatched mutations in the same allele (compound heterozygotes), or two unmatched mutations in two different alleles (double heterozygotes) [1].…”

“…LDL receptor (LDL-R), LDL receptor adapter protein 1 (LDLRAP1), and apolipoprotein B (ApoB) are responsible for clearing LDL-C from plasma, while proprotein convertase subtilisin/kexin type 9 (PCSK9) is responsible for inhibiting the recycling LDL-R to the cell surface by targeting the LDL-R for lysosomal degradation. Therefore, LDL-C levels will be elevated by loss-of-function mutations in LDLR, LDLRAP1, and APOB and by gain-of-function mutations in PCSK9 [1]. The severity of the mutations results in wide phenotypic variability, whereby affected proteins can be completely or partially disabled [1].…”