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Key Points


  • Disease summary:

    • Familial hypercholesterolemia (FH) is an autosomal dominant, monogenic disorder of lipoprotein metabolism characterized by strikingly elevated low-density lipoprotein-cholesterol (LDL-C), the presence of xanthomas, and premature atherosclerosis.

    • FH is most often caused by a defect in the gene that encodes for the apolipoprotein B or E (ApoB or E) (LDL) receptor (LDLR). Over 1000 different mutations of this receptor have been identified since it was first discovered by Goldstein and Brown in the late 1970s.

    • Impairment in, or in severe cases, a complete absence of function of, LDLR results in reduced clearance of LDL particles from the circulation into many cell types. Because over 60% of total body LDLR is in the liver, decreased clearance of LDL particles by this organ has a particularly potent effect on plasma LDL-C levels. Hypercholesterolemia is present from birth. LDL particles begin to be retained in arterial sites early on in life and their uptake by macrophages turn them into foam cells, the fundamental building block of an atherosclerotic plaque.

    • The FH homozygote frequency is estimated to be 1:1,000,000 worldwide compared with the heterozygote frequency of 1:500.


  • Differential diagnosis:

    • The differential diagnosis includes sitosterolemia, cerebrotendinous xanthomatosis, familial combined hyperlipidemia, polygenic hypercholesterolemia, familial defective ApoB-100, autosomal recessive hypercholesterolemia (ARH), and cholesterol 7 alpha-hydroxylase deficiency based on either clinical presentation (usually xanthoma) or laboratory testing (elevated LDL-C), or family history of elevated LDL or premature coronary artery disease (CAD).


  • Monogenic forms:

    • Most often caused by a mutation of one or both copies of the gene that encodes for the LDLR, located on chromosome 19p13.


  • Family history:

    • The prevalence of heterozygous FH is drastically higher in first-degree relatives of patients with the disorder estimated at one in two. Having a known case of FH in the family lowers the LDL cutoff needed to confirm the diagnosis (Table 15-1).


  • Environmental factors:

    • For patients with homozygous FH, risk is related to an extremely high level of LDL-C that is relatively insensitive to modifications by lifestyle factors. In contrast, for heterozygous FH, the phenotypic expression of the disease is related not only to the severity of the LDLR defect, but also to traditional dietary, genetic, behavioral, and cultural factors. For example, Hill et al. studied a large cohort of heterozygous FH patients and found that men who smoked or had low HDL levels had the greatest risk for developing CAD. This was in contrast to women in whom CAD was most associated with elevated triglycerides or the presence of hypertension.


  • Genome-wide associations:

    • Not surprisingly, the LDLR comes up in genome-wide association studies (GWAS) as associated with both LDL-C levels and risk of myocardial infarction. There are also a number of other genes that are significant in determining LDL-C levels that are not related to the LDLR, such as ApoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and sortillin. An important lesson from the GWAS ...

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