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Excerpt from Hypercholesterolemia, Familial

Synonyms, Key Words, and Related Terms: familial hypercholesterolemia, FH, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, monozygous hypercholesterolemia, low-density lipoprotein cholesterol, LDL cholesterol, LDLc, hypercholesterolemia, coronary artery disease, CAD, premature CAD, coronary atherosclerosis, xanthelasma, xanthoma, valvular abnormalities, heart valve anomaly, aortic stenosis, heart disease, corneal arcus, planar xanthoma, tendon xanthoma, tuberous xanthoma, ischemic heart disease, peripheral vascular disease, cerebrovascular disease, lipid abnormalities, lipid abnormality, lipid disorder

lipid disease, coronary heart disease, CHD, high cholesterol, bad cholesterol, acute myocardial infarction, acute MI, palpebral xanthomas, Achilles tendonitis, cutaneous xanthomas, Achilles tendon xanthomas

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Background

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). Although moderate hypercholesterolemia is a common finding in industrialized countries, heterozygous FH occurs in approximately 1 per 500 persons worldwide.

Because FH is associated with a high risk for premature coronary artery disease (CAD), health professionals should be alert to the signs found during a physical examination and to the laboratory values suggestive of FH. Early detection and aggressive management to lower the LDLc level helps prevent or slows the progression of coronary atherosclerosis. Moreover, if the first-degree relatives of a patient with FH are screened, other gene carriers can be identified and treated.

Pathophysiology

FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. The LDL receptor also binds another ligand, apoE, and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE.

Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. Since then, more than 700 mutations have been identified that have a meaningful impact on receptor function. LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity.

Five classes of mutations have been defined as follows:

Class 1 includes null alleles that result in complete absence of the LDL receptor.
Class 2 includes defective transport alleles, which disrupt normal folding of the receptor and cause either failure in transport to the cell surface or successful transport of truncated, mutated receptors.
- Class 2a mutations completely block the transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
- Class 2b mutations result in a partial blockade of transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
Class 3 includes defective binding alleles that affect binding of LDL and, in some cases, binding of VLDL as well.
Class 4 includes defective internalization alleles that affect the concentration of normal receptors in clathrin-coated pits for internalization by the hepatocyte.
Class 5 includes defective recycling alleles that prevent dissociation of the receptor and the ligand and thereby interrupt recycling of the receptor.

Frequency

United States

The prevalence of heterozygous FH is approximately 1 case per 500 persons. The prevalence of homozygous FH is 1 case per 1 million persons.

International

The prevalence of heterozygous FH in Europe approximates that of the United States, but certain regions, such as Iceland and Finland, or populations have a higher incidence. The prevalence of heterozygous FH among French Canadians is 1 case per 270 persons and is 1 case per 170 persons in Christian Lebanese. Due to the founder effect and relatively isolated populations, 3 distinct populations within South Africa have an extremely high prevalence of FH: 1 case per 67 in Ashkenazi Jews and 1 case per 100 persons in both Afrikaners and South African Indians.

Mortality/Morbidity

Homozygous FH
- Severe and widespread atherosclerosis affects all major arterial beds, including the carotid, coronary, femoral, and iliac.
- Children are at risk for early coronary events, and sudden death or acute myocardial infarction may occur in patients as young as 1-2 years. Without heroic interventions to lower blood cholesterol levels, survival beyond young adulthood is unlikely.
- Valve abnormalities are common, particularly aortic stenosis.
- Accumulation of cholesterol in nonvascular tissue is of less clinical significance. Corneal arcus and planar, tendon, and tuberous xanthomas are present early in childhood and sometimes at birth. Recognition of the cutaneous manifestations of FH permits early diagnosis and treatment to prevent the otherwise severe and inevitable cardiovascular complications.
Heterozygous FH
- Premature CAD is the most serious and preventable manifestation. Untreated men are likely to develop symptoms by the fourth decade of life. The onset of symptoms in women lags behind men by approximately 10-15 years. No accurate estimates of mortality rates are available.
- Cholesterol deposition in nonvascular tissue is common, although heterozygous children do not usually have physical manifestations; adults do not invariably develop them. Corneal arcus is the most frequent finding, particularly in patients older than 30 years, but this finding is also common in older patients and African Americans without hypercholesterolemia. Similarly, xanthelasmas (palpebral xanthomas) can occur in older individuals with normal cholesterol levels. Neither xanthelasma nor corneal arcus is of clinical significance, except possibly cosmetically.
- Xanthomas, most commonly of the Achilles tendon and extensor tendons of the hands, are rare in children and common in untreated adults. Tendon xanthomas may occur with other conditions such as familial defective apoB-100 and type III hyperlipoproteinemia. These deposits can cause Achilles tendonitis and articular symptoms, particularly of the hands, wrists, knees, and ankles.

Race

Certain populations with Finnish, Lebanese, Ashkenazi Jewish, Afrikaner, or French Canadian origins have a higher prevalence of FH.

Sex

The gene for FH is on chromosome 19; therefore, the inheritance pattern is the same for males and females.

In heterozygous FH, the consequences of severe hypercholesterolemia manifest earlier in men than in women because of the sex protection that benefits women until the postmenopausal years. Although a woman with no other major risk factors for CAD may not develop symptomatic CAD during her lifetime, men are rarely so fortunate.
Homozygous girls and boys have the same risk for a very early cardiovascular event.

Age

The consequences of a defective LDL receptor and subsequent elevations of LDLc are present at birth, but age is relevant because the longer patients live with extremely elevated LDLc levels, the higher their risk of CAD.
Early diagnosis and treatment to lower LDL levels and treat other coronary risk factors slows the progression of coronary atherosclerosis.

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