Familial hypercholesterolemia is an autosomal codominant disorder involving dysregulation in cholesterol uptake by the low-density lipoprotein cholesterol (LDL-C) receptor (located primarily in hepatic cells), leading to very elevated total and LDL cholesterol, accelerated atherosclerosis, and coronary heart disease. Over 1200 different mutations of LDL have been described, which can be divided into 6 different groups, each affecting a particular aspect of LDL function. These classes include the synthesis of precursor LDL receptors; processing of LDL receptor in the golgi body or endoplasmic reticulum; abnormal LDL binding; defective clathrin mediated endocytosis of LDL receptor; increased activity of LDL degradation (ie, increased proprotein convertase subtilisin / kexin type 9 [PCSK9] activity); and inability of LDL receptor to attach to the cell's basolateral membrane. Another way to approach the LDL-C metabolism concerns that occur in those with familial hypercholesterolemia is to determine whether there is a defect in the LDL receptor or the complete absence of the LDL receptor, which presents with a more severe phenotype.

The prevalence of heterozygous familial hypercholesterolemia is 1 in 200 to 1 in 500 worldwide. In America, prevalence differs among races. For instance, the frequency of heterozygous familial hypercholesterolemia is around 1 in 250 among White and Black individuals, whereas for Mexican American individuals and individuals of other races, it is around 1 in 414 and 1 in 343, respectively. Homozygous familial hypercholesterolemia is far rarer, occurring around 1 in 1 000 000. Among certain founder populations, this frequency can be much higher. For instance, in French Canadian individuals in Quebec, the estimated rate is around 1 in 275 000; in Afrikaner individuals in Gauteng, South Africa, this estimated rate is around 1 in 30 000; for Christian Lebanese people, this estimated rate is around 1 in 100 000; and, for Tunisian people, this estimated rate is around 1 in 125 000. In addition to ethnic differences affecting the prevalence rate of familial hypercholesterolemia, gender and racial differences contribute to health disparities among those with the genetic disease. For instance, being a female and/or of Asian or African descent is independently associated with a decreased likelihood of achieving LDL-cholesterol treatment goals as opposed to White patients.

Patients with heterozygous familial hypercholesterolemia tend to present with an LDL-C level that is 2-3 times higher than normal levels, whereas homozygous individuals can present with LDL concentrations up to 10 times higher. Subsequently, there can be premature coronary atherosclerosis and cardiac-related death. In fact, patients with homozygous familial hypercholesterolemia may suffer from a myocardial infarction (MI) in childhood, whereas those who are heterozygous may suffer from an MI in their thirties. Furthermore, there may be subclinical atherosclerosis and increased risk of peripheral arterial disease.

In addition, tendinous xanthomata, which are composed of foam cells from intracellular accumulation of lipids and connective tissue, are present in approximately 30%-50% of those with familial hypercholesterolemia. Locations include the Achilles tendon and tendons on and around the elbows, knees, and hands. There may be tuberoeruptive and tuberous xanthomas, planar xanthomas, including xanthelasma, and lipid deposition in the cornea (corneal arcus).

Two commonly used diagnostic tools for familial hypercholesterolemia that do not require genetic testing and are globally respected are the Simon Broome Register Group criteria (United Kingdom) and the Dutch Lipid Clinic Network criteria.

Related topic: familial defective apolipoprotein B-100