High blood cholesterol, especially LDL-C, is associated with increased risk of premature CVD. Measurement of serum total cholesterol is a reflection of the amount of cholesterol contained within circulating very-low-density lipoproteins (VLDLs), LDLs, HDLs, and chylomicrons (although chylomicron levels are essentially nil when cholesterol is measured in the fasting state). Thus, a fasting lipoprotein profile is needed when hypercholesterolemia is identified or suspected. Hypercholesterolemia with either a monogenic or multifactorial basis affects approximately 5% of the population, but increased risk of premature atherosclerosis has been mainly established for the monogenic disorders that result in elevated LDL (
7). LDL is rich in cholesteryl esters (CEs), and each particle contains a single molecule of apolipoprotein-B-100 (Apo-B-100). LDL is derived from VLDL, and it serves as a carrier of cholesterol made in the liver to peripheral tissues. Cellular uptake of LDL-C depends on binding of LDL, through Apo-B, to the LDL receptor. Currently, three monogenic disorders causing autosomal dominant hypercholesterolemia (ADH) have been identified, as well as one autosomal recessive form (
Table 64.1). Mutations in the LDL receptor gene (
LDLR) are the most common among these, whereas mutations in other genes (e.g., in
APOB, resulting in defective Apo-B and in proprotein convertase subtilisin/kexin type 9 [
PCSK9] encoding PCSK9 enzyme account for a minor fraction of patients presenting with ADH.
Familial Hypercholesterolemia
Familial hypercholesterolemia (FH), the most common form of ADH, is caused by mutations in the
LDLR gene located on chromosome 19p13. This transmembrane receptor, present in almost all tissues, controls cholesterol homeostasis by a complex process that includes synthesis of the receptor in the endoplasmic reticulum, migration of the receptor protein to the Golgi apparatus and then to the cell surface, the binding of the LDL receptor to plasma LDL via Apo-B-100, internalization of the receptor-ligand complex, and recycling of the LDL receptor to the cell surface while the LDL is processed in the lysosome (
8). More than 1000 mutations have been described, affecting each of the steps involved in LDL receptor biogenesis. When one allele of the LDL receptor is defective (heterozygous FH), a 30% increase in plasma LDL-C is observed. However, a twofold to fourfold increase or more in LDL-C level is observed in homozygous FH in which both alleles are mutated, thus resulting in a lack of function of the LDL receptor.
Most often, the diagnosis is made on the basis of clinical and family history. Definite diagnosis of heterozygous FH requires confirmation by identifying mutations in the
LDLR gene or studies of LDL receptor function in fibroblasts. If FH is left untreated, myocardial infarction may occur at 30 to 40 years of age, and more than 50% of male patients and about 15% of female patients with heterozygous FH will die before 60 years of age (
9).
Homozygous patients with FH develop cutaneous and tendinous xanthomata in the first decade of life, and death from cardiac ischemia and aortic valve involvement often occurs as early as the second decade of life and usually before 30 years of age (
10). Dietary management is usually insufficient for treating children with heterozygous FH, and the use of statins (inhibitors of hydroxymethyl-glutarylcoenzyme A [HMG-CoA] reductase) is recommended from 8 years of age (
11). Adults with heterozygous FH frequently need a combination of two or more medications in addition to dietary management to control plasma LDL-C levels.
For homozygous FH, it may be necessary to perform LDL apheresis as early as the first year of life. Liver transplantation is another option for homozygous FH, but it carries a small risk of mortality and requires chronic immunosuppression.
Mutations in PCSK9
PCSK9 gene encodes PCSK9, a serine protease that regulates the degradation of the LDL receptor and thus plays a major role in the control of cholesterol influx into cells (
12). Loss of function mutations in
PCSK9 result in increased LDL receptor expression and reduced LDL serum levels as well as reduced risk of CVD (
13). In contrast, patients with a heterozygous gain of function mutation in
PCSK9 present clinically with a condition similar to that of heterozygous FH and should be treated in a similar manner.
Familial Defective Apolipoprotein B
Mutations within the region of the
APOB gene that encodes the LDL receptor binding domain reduce the binding affinity of LDL particles to the LDL receptor. LDL-C levels are about twice normal in familial defective apolipoprotein B (FDB), and this form of ADH is phenotypically similar to FH (
14). A few
APOB mutations causing high levels of LDL-C have been described. Of these, the point mutation resulting in the missense change Arg3500Gln is the most common. This mutation was seen in about 3% of the referrals in a pediatric French cohort for hyperlipidemia (
15). Patients with FDB are treated in a manner similar to those with heterozygous FH, namely, with a statin inhibitor of HMG-CoA reductase and sometimes a second medication.
Autosomal Recessive Hypercholesterolemia
This rare form of hypercholesterolemia has been described mainly in probands from Italy (
16), but it occurs in individuals from other regions as well (
10). The disease is caused by mutations in LDL receptor adapter protein 1 (LDLRAP1), an essential adaptor protein within the liver (the organ that contains ˜60% of the body’s complement of LDL receptors). The
LDLRAP1 gene product is essential for clathrin-mediated endocytosis of LDL (
17). In other tissues such as fibroblasts, this mutation does not disrupt LDL uptake. Clinically, patients with autosomal recessive hypercholesterolemia (ARH) resemble patients with homozygous FH, although aortic valve involvement is less common in ARH, whereas patients with homozygous FH have, on average, higher LDL plasma levels and earlier onset of atherosclerotic disease.
