Familial hypercholesterolemia—Improving treatment and meeting guidelines
Introduction
The cell surface receptor for low-density lipoprotein (LDL) removes cholesterol-carrying LDL from plasma by a process of receptor-mediated endocytosis [1]. These LDL receptors are predominantly found on hepatocytes and steroid hormone-producing cells. Mutations in the LDL receptor gene result in familial hypercholesterolemia (FH), a common autosomal dominant disorder that affects around one in 500 individuals in the heterozygous form [2]. The receptor defect reduces the catabolism of LDL by around 50% and results in an approximately two-fold elevation in plasma LDL-cholesterol (LDL-C). The excess plasma LDL-C deposits in tendons and arterial walls, forming tendon xanthomas and atherosclerotic plaques [2]. The most important clinical feature of untreated FH is the development of premature and extensive atherosclerosis leading to coronary heart disease (CHD). Clinically overt CHD usually occurs at the mean age of 45–48 years in males and 55–58 in females [3]. Homozygous FH is much less common but more severe, occurring with a frequency of approximately one in a million and resulting in plasma LDL-C levels four- to five-fold higher than normal. These individuals express few, if any, functional LDL receptors as a result of mutations in both alleles. In addition to large and extensive tendon xanthomas, FH homozygotes often display cutaneous tuberous xanthomas, and frequently die of myocardial infarction (MI) by the second decade [2].
Prompt diagnosis and aggressive treatment is critical to the long-term survival of FH patients. It is, therefore important for cardiologists to be aware of the metabolic or genetic background of these individuals. This will help to promote better medical and preventative care for this population.
Section snippets
Molecular genetics of familial hypercholesterolemia
The LDL receptor gene is located on the short arm of chromosome 19 [4]. It consists of 18 exons and 17 introns that span 45 kilobases (kb) (Fig. 1) [5]. The gene encodes a single-chain transmembrane polypeptide of 839 amino acids, which consists of five functional domains [1]. The amino-terminus of the protein contains the LDL-binding elements that recognise apolipoprotein B100 (apo B100), the major apolipoprotein in LDL (Fig. 1).
Well over 700 different LDL receptor mutations have been
Diagnosis of familial hypercholesterolemia
The diagnosis of FH is a critical one to make given the high risk of morbidity and mortality from premature CHD (Table 2). A recent report of a World Health Organization consultation on FH estimated that only 20% of male FH heterozygotes reach the age of 70 years [3], whilst homozygous FH individuals typically die from MI before age 30 [22], [23].
Current treatment options for familial hypercholesterolemia
Failure to treat male patients with heterozygous FH can lead to the onset of CHD around the age of 40, while untreated females generally develop CHD 10–15 years later (Table 2) [3]. By the age of 60 years, 75% of untreated heterozygous FH males will have developed CHD. These patients qualify for drug therapy under both the American [30] and European [31] treatment guidelines because their plasma LDL-C concentrations generally exceed 220 mg/dl. In addition, cost-effectiveness analysis justifies
The future of familial hypercholesterolemia treatment
Gene therapy is often heralded as the logical approach to treating heterozygous and homozygous FH, with recent developments in viral vectors making this technology a realistic prospect. To date, LDL receptor gene replacement studies have been restricted to animal models [68], [69], [70] and small pilot-studies in humans [71]. The in vivo replacement of LDL receptor genes using recombinant adenoviruses has effectively lowered LDL-C levels in both rabbits and mice. However, expression of the
Conclusion
FH patients are a unique population at risk of developing premature atherosclerosis and fatal heart disease. It is, therefore important to establish a diagnostic program that will identify patients affected by this condition, enabling effective treatment to be administered. International screening programs such as MEDPED have proved successful in identifying FH individuals, although the expansion of these initiatives would provide further benefit. Preventing the early onset of atherosclerosis
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