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Key Points

  • Disease summary:

    • Hyperlipidemia describes the phenotype of elevated blood lipids, predisposing a patient to atherosclerotic vascular disease. The overall heritability of blood lipids is often due to the interaction of a variety of alleles.

    • Classic Mendelian monogenic lipoprotein disorders, while rare, have provided profound insight into lipoprotein metabolism and atherosclerotic vascular disease.

    • Originally characterized by Fredrickson and Levy by the type of lipoprotein that accumulated in the circulation, the modern approach to classic Mendelian monogenic disorders emphasizes the molecular basis of the disease and the defect in cholesterol metabolism.

    • Within the population, blood lipid variation is typically the consequence of variation at multiple loci, in addition to significant effect from the environment.

  • Hereditary basis:

    • Monogenic forms of lipoprotein disorders will be emphasized here, however for the majority of patients with lipid disorders, no one causative allele or mutation can be identified%.

      • Genome-wide-association studies (GWAS) have identified a large number of novel loci associated with plasma lipid traits. This application of genomic medicine has uncovered numerous potential targets for therapy, as well as provided insight into the complex interplay of multiple alleles which gives rise to hyperlipidemia in most patients encountered in clinic.

      • In the population, the degree of variation in the major plasma lipid traits attributable to genetic variance is estimated to be approximately 50%. The Framingham Heart Study showed that heritability for single time point measurements of low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (TGs) is 0.59, 0.52, and 0.48, respectively.

  • Differential diagnosis:

    • The vast majority of cases of hyperlipidemia are discovered on routine screening and are infrequently due to a monogenic lipoprotein disorder. However, the presence of markedly elevated lipids or lipoproteins, xanthomas, accelerated atherosclerosis, or other clinical manifestations of hyperlipoproteinemia are suggestive of a monogenic disorder. It is important to screen for secondary causes such as nephrotic syndrome, obstructive liver disease, and hypothyroidism before making a diagnosis of a monogenic disorder and before initiating therapy.

Genetic Differential Diagnosis

Diagnostic Criteria and Clinical Characteristics of Disorders of Elevated LDL-C and Normal TGs

  • Elevated LDL-C (generally >200 mg/dL)

  • TGs normal (generally <200 mg/dL)

Often accompanied by one or more of the following:

  • Tendinous xanthomas

  • Premature corneal arcus

  • Accelerated symptomatic cardiovascular disease (CVD)

  • Family history of substantially elevated cholesterol and/or premature CVD

Table 13-1Mendelian Disorders Causing Elevated LDL-C Levels and Normal TGs

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