Familial hypercholesterolemia: genetic predisposition to atherosclerosis

Familial hypercholesterolemia: genetic predisposition to atherosclerosis

Mary B. Engler

Cardiovascular disease remains the leading cause of death in the United States, with an average one death every 34 seconds. More than 64 million Americans have one or more types of cardiovascular disease that will have an estimated direct and indirect cost of $368.4 billion in 2004 (American Heart Association, 2004). By the year 2020, cardiovascular disease is expected to become the primary cause of death throughout the world (International Atherosclerosis Society [IAS], 2003).

As a result of the atherosclerotic process, cardiovascular disease is due to the interaction between environmental risk factors, such as diet, physical inactivity, smoking, and an individual’s genetic makeup. Hundreds of genes are believed to be involved in the process of atherogenesis and the susceptibility to cardiovascular disease. These include genes that regulate lipid metabolism, inflammatory and immune responses, endothelial function, and coagulation. Other genes involved in obesity, insulin resistance, diabetes, elevated homocysteine levels, and hypertension have been identified, but their mechanisms in the atherosclerotic process are not well understood (Lusis, 2003). The genes involved in lipid metabolism have been extensively studied and identified, specifically the gene coding for the low-density lipoprotein (LDL) receptor.


Many experimental, clinical, and epidemiological studies have demonstrated the strong association between increased levels of LDL-cholesterol (LDL-C) and coronary heart disease (IAS, 2003). Lowering total cholesterol and LDL-C reduces the risk for coronary heart disease, as demonstrated in major clinical trials with statin drugs or the HMG-CoA reductase inhibitors (lovastatin [Mevacor[R]], pravastatin [Pravachol[R]], simvastatin [Zocor[R]]) (Downs et al., 1998; Lipid Study Group, 1998; Sacks et al., 1996; Shepherd et al., 1995; The Scandinavian Simvastatin Survival Study [4S] Group, 1994). Approximately 70% of plasma cholesterol is carried by LDL-C particles (Gotto, 1999). Concentrations of circulating LDL-C are closely linked to atherogenesis and are regulated by a balance between the rates of its synthesis and removal. Hepatic LDL receptors remove most of the LDL-C from the plasma. However, increased LDL-C concentrations in the plasma can lead to LDL-C deposition in extra-hepatic tissues, including the arterial wall. Early events in the process of atherosclerosis are characterized by recruitment of leukocytes and the production of pro-inflammatory cytokines, as well as the accumulation of LDL-C and its subsequent oxidation within the intimal layer of the arterial wall.

Hypercholesterolemia is one of several cardiovascular risk factors that impairs endothelial function. Dysfunctional endothelium promotes lipid and cell permeability, oxidation of lipoproteins, inflammation, proliferation of vascular smooth muscle cells, deposition and lysis of extra-cellular matrix, platelet activation, and thrombus formation. Cytokines are produced and adhesion molecules (selectins, vascular cell adhesion molecules [VCAM], intracellular adhesion molecules [ICAM] are expressed by the dysfunctional endothelium, which promotes leukocyte adhesion and infiltration into the arterial wall (Fuster, Corti, Fayad, & Badimon, 2003).

Once LDL-C has passed through the endothelium into the subendothelial space due to enhanced lipid permeability, oxidation of LDL-C occurs and a number of chemotactic factors are also released. Inflammation is a key process involved in all stages of atherosclerosis. Monocytes adhere and infiltrate into the subendothelial space, becoming macrophages which engulf oxidized LDL-C particles. Foam cells accumulate to form a fatty streak in the arterial wall. With time, the fatty streak progresses to an advanced lesion with a fibrous cap composed of collagen and a lipid core. The lumen of the vessel becomes occluded and the vulnerable plaque may eventually rupture due to weakening of the fibrous cap by matrix metallo-proteinases (proteolytic enzymes), leading to an acute coronary event (Fuster et al., 2003).

Familial hypercholesterolemia, a genetic disorder, is caused by a mutation in the gene for the LDL receptor. This mutation can prevent the synthesis of LDL receptor proteins, or it can cause the formation of a defective LDL receptor that can’t bind or ingest LDL into the liver cells (see Figure 1). This leads to abnormal clearance of LDL by the liver and elevated serum cholesterol levels. Premature atherogenesis and coronary heart disease are eventual outcomes. Familial hypercholesterolemia was the first monogenic disorder shown to cause elevated cholesterol levels (Nabel, 2003). The gene for the LDL receptor is found on chromosome 19, and over 700 mutations have been identified in patients with this disorder (Durrington, 2003).


Five classes of functional LDL receptor defects result from mutations in this gene (Benlian, 2001). Class 1 defects represent an absence of receptor synthesis due to an absence of mRNA or protein. Class 2 defects are characterized by defective receptor maturation or transport within the endoplasmic reticulum and Golgi apparatus. Class 3 defects represent defective binding of receptors to LDL-cholesterol. Class 4 mutations produce endocytosis-defective receptors, which in effect disable entry of LDL into the cytoplasm for further processing. Class 5 defects result in the recycling of defective LDL receptors instead of normal ones after endocytosis. Those affected individuals carrying class 1 mutations with no production of LDL receptors typically have higher plasma LDL levels and earlier, more severe coronary heart disease. The identification of genetic mutations in the LDL receptor has been critical to the understanding of lipid metabolism and to the development of targeted interventions, such as, lipid-lowering therapy with statin drugs (Benlian, 2001).

Familial Hypercholesterolemia: Diagnosis and Prognosis

Familial hypercholesterolemia is a frequent disease worldwide; in fact, it is the most common genetic disorder in the United States and Europe (Durrington & Sniderman, 2002). It is an autosomal dominant disorder which affects both males and females, and can often be traced through many generations of a family. Familial hypercholesterolemia is believed to account for 10% to 20% of all early coronary heart disease, with more than 50% cumulative risk of fatal or nonfatal coronary heart disease in men by age 50 and at least 30% in women by age 60 (Marks, Thorogood, Neil, & Humphries, 2003).

The heterozygous form of familial hypercholesterolemia occurs in a frequency of approximately 1 in 500 (Nabel, 2003). In the heterozygous form, one of the two LDL-receptor genes has a mutation and is nonfunctioning. Serum LDL cholesterol concentrations are typically twice that of normal, and the first cardiovascular event occurs in the 4th or 5th decade (Benlian, 2001). This is due to a decrease in the number of active LDL receptors on the surface of liver cells and the resultant inefficient uptake of LDL by the liver. Premature atherosclerosis and coronary heart disease are common presentations in affected individuals. Serum cholesterol in most heterozygous familial hypercholesterolemic children exceeds 280 mg/dL and ranges between 360 and 560 mg/dL in affected adults (Durrington & Sniderman, 2002).

Endothelial dysfunction, an early manifestation of subclinical atherosclerotic disease, is seen in children and adults with familial hypercholesterolemia (Engler et al., 2003). Characteristic cholesterol deposits called tendon xanthomas are seen deep in the tendons of the dorsum of the hand or knuckles, and the Achilles tendon, often by age 20. Some affected individuals may exhibit cholesterol deposits to the cornea (corneal arcus) and eyelids (xanthelasma). It is estimated that more than half of males and approximately 15% of females with untreated familial hypercholesterolemia (heterozygous form) will not survive past 60 years of age (Durrington 2003).

Homozygous familial hypercholesterolemia, in which both copies of the LDL-receptor gene are defective, is less common with a frequency of about one in a million (Nabel, 2003). There is complete absence of LDL-receptors, and serum LDL-cholesterol is severely elevated starting at birth (levels 3 to 4 times normal) (Durrington & Sniderman, 2002). Xanthomas develop in childhood, often presenting as orange-yellow cutaneous planar xanthomas to the popliteal and antecubital fossa, buttocks, and webs between the fingers.

Serum cholesterol levels exceed 600 mg/dL and are as high as 1,200 mg/dL, with the first cardiovascular event occurring in childhood or adolescence (Durrington & Sniderman, 2002). Specifically, angina on effort may be seen with progression to myocardial infarction as well as aortic stenosis due to atheromatous deposits in the coronary arteries and aortic root, respectively. Without lipid-lowering therapy, the mortality rate in familial hypercholesterolemics with the homozygous form is 100% by age 30 (Benlian 2001). Some have even reported a limited life expectancy to the early 20s (Durrington & Sniderman, 2002).

Obesity, diabetes, and hypertension are not common phenotypes seen in familial hypercholesterolemia. Therefore, early diagnosis of familial hypercholesterolemia may only be made following cholesterol screening in individuals with a positive family history of hypercholesterolemia and/or cardiovascular disease, or with early recognition of other characteristic clinical signs of familial hypercholesterolemia (Durrington & Sniderman, 2002). Nurses can provide the clinical expertise in the early recognition and assessment of familial hypercholesterolemia in a variety of clinical settings.

Interestingly, the same familial hypercholesterolemia syndrome may be caused by a mutation in the genes for apolipoprotein B (apo B), the structural protein component of LDL that directs LDL binding to the LDL receptor (Pullingen et al., 2002). The resulting defect in apolipoprotein B interferes with LDL binding. Decreased uptake of LDL particles leads to the hypercholesterolemia. This genetic disorder is called familial defective apolipoprotein B and occurs in a frequency of approximately 1 in 600 (Durrington, 2003). Serum cholesterol levels are generally not as severe and respond better to drug treatment as compared to familial hypercholesterolemia. Four mutations have thus far been identified in the apoB gene. An estimated 2% to 4% of patients diagnosed with familial hypercholesterolemia can be attributed to familial defective apolipoprotein B (Defesche & Kastelein, 2001; Durrington, 2003).

Recently, rare cases of an autosomal recessive form of homozygous familial hypercholesterolemia (ARH) have been documented due to mutations in a novel gene whose product is involved in the internalization of LDL-receptors (Arca et al., 2002; Norman et al., 1999). Approximately 50 patients, mainly Italian of Sardinian origin, have been described worldwide with the ARH disorder. A mutation in the CYP7A1 gene for cholesterol 7 alpha-hydroxylas, the first enzyme in the bile acid synthesis pathway in the liver, has recently been reported as another genetic cause of hypercholesterolemia.

Current use of genetic diagnosis of monogenic cardiovascular disorders, such as familial hypercholesterolemia, on the basis of a mutation and estimated risk is not widely available (Nabel, 2003). Routine testing and physical exams are currently used to determine a clinical diagnosis followed by genotyping of selected pedigrees in research entities. Some believe predictive genetic testing for cardiovascular disease is not ready for clinical use (Humphries, Ridker, & Talmud, 2004). It is estimated that over the next 2 to 3 years, however, advances in technologies such as DNA chips will increase the speed and sensitivity of mutation detection in familial hypercholesterolemia, as well as decrease the associated costs (Marks et al., 2003).


In homozygous familial hypercholesterolemia, it is very difficult to achieve therapeutic lowering of the high levels of serum cholesterol with even the most potent of statin drugs (atorvastin [Lipitor[R]], simvastatin [Zocor[R]]). These drugs can lower cholesterol in homozygotes by up to 30% (Durrington, 2003). In conjunction with ezetimibe [Zetia[R]], one of a new class of cholesterol-absorption-inhibiting drugs, an additional 20% decrease occurs, but the cholesterol levels seen are not low enough in this patient population (Gagne, Gaudet, & Bruckert, 2002). Plasmapheresis or LDL apheresis is considered the optimal treatment of choice (Durrington, 2003). However, it is a costly procedure done for many hours every 2 weeks, and the risk for infections is increased in treated individuals. Liver transplantation is a major last resort and an expensive option that requires long-term immune suppression. A recent report on 24 patients in Germany documented a 5-year survival of 100% in children and 68% in adults following transplantation (Marks et al., 2003).

Gene therapy currently is not considered a therapeutic intervention for homozygous familial hypercholesterolemia because major advances in the delivery system of the gene or vector technology are needed. Only five cases of genetic therapy have been reported in familial hypercholesterolemia in the mid 1990s that used an ex vivo procedure (Marks et al., 2003). Basically, this entails partial removal of the liver and transfection of hepatocytes ex vivo with a vector carrying the LDL-receptor gene. These cells are re-injected into the patient and then normal LDL-receptors are eventually expressed. Immune suppression is necessary to prevent destruction of the transfected hepatocytes by an immune response to these foreign cells. Safety concerns with the vector are also an issue (Marks et al., 2003).

In most familial hypercholesterolemic adult heterozygotes, the maximum dose of the potent statin drugs is often required to lower the high cholesterol levels. The combination of a bile-acid-sequestrating drug (for example, cholestyramine [Questran[R]], colestipol [Colestid[R]], colesevelam [Melchol[R]]) and ezetimibe can also be prescribed when a potent statin drug is not effective. The statin drugs are generally not indicated in children with heterozygous familial hypercholesterolemia due to long-term safety concerns, although lipid specialists are prescribing statin therapy in males in their late teens or earlier based on adverse family history. For heterozygous familial hyper-cholesterolemic young women, statin therapy may be recommended in their early 20s (Durrington, 2003). Therapeutic lifestyle changes including healthy diets, exercise, weight control, and avoidance of smoking are also concurrently recommended in all familial hypercholesterolemic cases.

As patient advocates, proponents of preventive measures in cardiovascular risk factor reduction, and educators, nurses play a pivotal role in health care. Moreover, nurses in the genomic era are at the forefront of developing and implementing nursing interventions, research, and clinical applications that have genetic relevance. Specific areas of focus may include the influence of a person’s genetic makeup or genotype on health and environmental interventions (such as diet, drugs), the impact of genomic information on health behavior outcomes, or the impact of genetic technology on prevention, risk assessment, diagnosis, therapeutic interventions, or prognosis (Greco, 2003; Nicol, 2003). Understanding the pathophysiology and genetics, diagnosis, prognosis, and current treatment options in familial hypercholesterolemia and applying this knowledge to nursing interventions, clinical practice, and research can have a significant impact on decreasing the morbidity, mortality, and associated costs of cardiovascular disease.


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Mary B. Engler, PhD, MS, RN, is a Professor and the Director of the Cardiovascular and Genomics Graduate Programs, Department of Physiological Nursing, School of Nursing, University of California, San Francisco, CA.

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