Perspective:

The following are 10 points to remember from a review article on the severe hypercholesterolemia phenotype:

1. The severe hypercholesterolemia phenotype includes all patients with low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dl, regardless of cause. Approximately 600,000 people in the United States manifest this phenotype.

2. Autosomal dominant hypercholesterolemia results from mutations in genes controlling LDL levels. This includes familial hypercholesterolemia (FH), a common monogenic disorder caused by abnormalities in the LDL receptor (LDLR) protein. It also includes defects in two other major genes, APOB and PCSK9, which impact plasma LDL clearance. Many individuals with LDL-C levels >190 mg/dl do not have defects in any of the three genes, and a polygenic origin may be suspected.

3. The risk of vascular disease in those with the severe hypercholesterolemia phenotype is determined by exposure to hypercholesterolemia, not by the genotype that produces it. Accordingly, the authors propose that ‘screening should focus on identifying subjects with the phenotype without investing resources in the identification of the genetic causes.’

4. FH is clinically diagnosed by five major criteria including: family history of premature coronary artery disease (CAD), presence of early CAD in the index case, elevated LDL-C, tendon xanthomas, and corneal arcus.

5. Patients with FH can be true FH homozygotes (HoFH), with two identical mutations; compound heterozygotes, with a different mutation in each allele; or FH heterozygotes (HeFH), with only one mutated allele.

6. Individuals with true HoFH typically have LDL-C levels 4-8 times above average (>500 mg/dl), whereas in patients with HeFH, LDL-C levels are 2-3 times above average.

7. Risk assessment algorithms (e.g., Framingham Risk Score) do not apply to FH patients.

8. Statin monotherapy is frequently not adequate to reach LDL-C goal in FH patients. Intensification of therapy may be achieved with ezetimibe, niacin, fibrates, and bile acid sequestrants. Lipoprotein apheresis may be necessary when drug therapy is ineffective or not tolerated; it is typically performed biweekly in those with HoFH or severe HeFH when LDL is >300 mg/dl.

9. Patients with HoFH may be treated with the following orphan drugs as an adjunct to diet and other lipid-lowering drugs: the microsomal triglyceride transfer protein inhibitor lomitapide and the apoB antisense oligonucleotide mipomersan. Aminotransferases should be carefully monitored in patients on these therapies.

10. PCSK9 is an enzyme that binds to the LDLR and targets it for lysosomal degradation. Gain-of-function mutations in PCSK9 may lead to elevated plasma LDL-C levels. Inhibitors of PCSK9 to lower LDL-C have shown promise and may revolutionize the treatment of patients with the severe hypercholesterolemia phenotype. Two phase III outcome trials (ODYSSEY and FOURIER) are in progress.