Recognition, diagnosis and treatment of homozygous familial hypercholesterolemia

ABSTRACT

Introduction: Familial hypercholesterolemia (FH) is a genetically heterogeneous disorder of low density lipoprotein metabolism characterized by lifelong elevation of serum low density lipoprotein cholesterol and premature valvular and atherosclerotic cardiovascular disease. The two manifestations of this disease, homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH) were, until recently, assumed to be genetically and phenotypically distinct with the former assumed to be more severe. However, with the growing use of genetic testing to diagnose FH, considerable phenotypic overlap between HoFH and HeFH is now recognized

Areas covered: We provide a contemporary overview of the genetics, phenotype, current and emerging treatment options for HoFH. We conclude with a discussion of the role genotype and phenotype should play in the diagnosis and management of HoFH as it is now understood.

Expert opinion: The identification of a HoFH genotype has important diagnostic and potentially, management value and should be sought where possible. However, a negative genetic result should not be used to rule out the diagnosis of HoFH. Generally, phenotype should carry more weight in management decisions.

KEYWORDS:

• Homozygous familial hypercholesterolemia
• genetics
• low density lipoprotein cholesterol
• lipid lowering therapy

Article highlights

• Homozygous Familial hypercholesterolemia (HoFH) is an autosomal codominant disorder caused by pathogenic bi-allelic mutations in LDLR, APOB, PCSK9 and LDLRAP1.

• Historically, HoFH has been characterized by markedly elevated serum LDL-C levels that lead to clinically significant aortic valve disease and atherosclerotic cardiovascular disease in the first two decades of life

• The growing use of genetic testing to diagnose HoFH in recent years has led to the recognition of a much broader HoFH phenotype that overlaps considerably with that of heterozygous familial hypercholesterolemia

• The management of HoFH has also evolved considerably over the last thirty years and this is reflected in the significant improvement in the life-expectancy of these patients. Statins and apheresis are the standard of care in HoFH, however, in the past few years, several highly efficacious lipid-lowering agents with pronounced lipid-lowering effects have been developed and approved for exclusive use in the HoFH population

• There is currently a lot of discussion about how to define HoFH. Genotype and phenotype provide important information for the diagnosis, prognosis and management of HoFH. It is phenotype, however, that should guide management decisions and determine access to therapy

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Declaration of interest

M Cuchel has received NIH-NHLBI grant, she has also received funding for the conduction of clinical trials from Sanofi, Regeneron, Ackea, and Regenxbio as well as speaker fees from Aegerion pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded