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
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
| Syndrome | Gene Symbol | Pathogenesis |
|---|---|---|
| Familial hypercholesterolemia | LDLR | Loss of function mutation in the LDL receptor (LDLR), reducing clearance of LDL |
| Familial defective apolipoprotein B-100 | APOB | Mutation in the region of ApoB-100 that binds the LDLR, hindering clearance of LDL |
| Autosomal dominant hypercholesterolemia | PCSK9 | Gain of function mutation in proprotein convertase subtilisin/kexin type 9, which causes degradation of the LDLR, thus reducing LDL clearance |
| Autosomal recessive hypercholesterolemia | LDLRAP1 | Loss of function mutation causing decreased receptor-mediated endocytosis of the LDLR, reducing LDL clearance |
| Sitosterolemia | ABCG5 and ABCG8 | Markedly increased absorption and decreased excretion of plant sterols and cholesterol, down regulating the LDLR and reducing LDL clearance |
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.
| Syndrome | Gene Symbol | Pathogenesis |
|---|---|---|
| ApoA-I deficiency | APOA | ApoA-I gene deletion or mutations preventing synthesis of the ApoA-I protein results in the virtual absence of HDL from the plasma, effectively impairing reverse cholesterol transport and leading to premature atherosclerotic CVD. |
| ApoA-I structural mutations | APOA | Results in the synthesis of structurally abnormal ApoA-I, resulting in rapid catabolism and reduced plasma levels of HDL-C. Generally no increased risk of atherosclerotic CVD. Some structural mutations in ApoA-I form amyloid deposits and cause amyloidosis. |
| Tangier disease | ABCA1 | Lack of ABCA1, a key transporter of cholesterol efflux from cells to free ApoA-I, reduces the assembly of mature HDL by the liver and intestine and results in rapid catabolism of ApoA-I, with extremely low levels of HDL-C. Cells of the reticuloendothelial (RE) system have impaired cholesterol efflux and accumulated cholesterol, resulting in large tonsils and spleen. Relationship to CVD remains uncertain. |
| LCAT deficiency | LCAT | Impaired cholesterol esterification in HDL, resulting in inability to generate mature HDL and rapid catabolism of ApoA-I. All patients develop corneal opacification due to unesterified cholesterol. Some patients develop progressive renal disease. |
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
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
| Syndrome | Gene Symbol | Pathogenesis |
|---|---|---|
| Familial chylomicronemia syndrome (type I hyperlipoproteinemia) | LPL and APOC-II | Deficiency in the lipolytic enzyme LPL or its required cofactor ApoC-II causes impaired lipolysis of chylomicron and VLDL TGs and greatly elevated fasting TGs, sometime resulting in pancreatitis. |
| GPIHBP1 deficiency | GPIHBPI | Loss of endothelial attachment for LPL leads to reduced lipolysis and hyperchylomicronemia. |
