13: Dyslipidemia

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

Clinical Characteristics

These patients may present for the first time with premature symptomatic atherosclerotic cardiovascular disease. Alternatively, they may be discovered to have markedly elevated cholesterol on routine screening, which is now recommended for all adults. They typically report a family history of hypercholesterolemia and/or early cardiovascular disease. The exceptions to this are the recessive disorders sitosterolemia and autosomal recessive hypercholesterolemia (ARH). On physical examination, patients may have tendon xanthomas at the Achilles tendons or dorsum of the hands, feet, or knees. Patients that are homozygous for familial hypercholesterolemia often develop CVD in childhood.

Table 13-2   Mendelian Disorders Causing Low Levels of HDL-C 

Diagnostic Criteria and Clinical Characteristics of Disorders of Decreased HDL

  • Very low density lipoprotein (VLDL), less than 10th percentile and generally less than 20 mg/dL

Sometimes accompanied by one or more of the following:

  • Planar xanthomas

  • Enlarged tonsils, hepatosplenomegaly

  • Corneal arcus

  • Progressive renal disease

  • Premature atherosclerotic CVD

Clinical Characteristics

These disorders have a great degree of clinical variability based on the underlying gene defect. Deficiency of ApoA-I is associated with planar xanthomas and corneal opacities, as well as premature CVD. However, structural mutations in ApoA-I, for example those heterozygous for Arg173Cys (ApoA-I Milano), have no increased risk of CVD despite their low HDL. Some structural mutations in ApoA-I form amyloid deposits and cause amyloidosis. Tangier disease presents with profoundly low HDL (<5 mg/dL), hepatosplenomegaly, and pathognomonic enlarged orange tonsils secondary to deposition of cholesterol in the reticuloendothelial (RE) system. Lecithin-cholesterol acyltransferase (LCAT) deficiency is characterized by low HDL-C (<10 mg/dL), corneal opacification, and hypertriglyceridemia. The homozygous form of LCAT deficiency also suffers from hemolytic anemia and progressive renal failure. Other than ApoA-I deficiency, these other Mendelian forms of extreme low HDL are not generally associated with premature atherosclerotic CVD.Table 13-3

Table 13-3   Mendelian Disorders Causing Elevated TGs