Monogenic hypercholesterolemia: new insights in pathogenesis and treatment (original) (raw)
Historical perspective. Familial hypercholesterolemia (FH), the most common and most severe form of monogenic hypercholesterolemia, was the first genetic disease of lipid metabolism to be clinically and molecularly characterized (2). The disease has an autosomal codominant pattern of inheritance and is caused by mutations in the LDLR gene; individuals with two mutated LDLR alleles (FH homozygotes) are much more severely affected than those with one mutant allele (FH heterozygotes). The plasma levels of LDL-C are uniformly very high in FH homozygotes, irrespective of diet, medications, or lifestyle. For example, FH homozygotes living in China, where the dietary intake of cholesterol and saturated fat is low, have plasma LDL-C levels similar to those of FH homozygotes living in Western countries (3).
FH homozygotes develop cutaneous (planar) xanthomas and coronary atherosclerosis in childhood (2). Atherosclerosis develops initially in the aortic root, causing supravalvular aortic stenosis, and then extends into the coronary ostia. The severity of atherosclerosis is proportional to the extent and duration of elevated plasma LDL-C levels (calculated as the cholesterol-year score) (4). If the LDL-C level is not effectively reduced, FH homozygotes die prematurely of atherosclerotic cardiovascular disease. Optimization of other cardiovascular risk factors has little impact on the clinical course of the disease.
Patients with homozygous FH are classified into one of two major groups based on the amount of LDLR activity measured in their skin fibroblasts: patients with less than 2% of normal LDLR activity (receptor-negative), and patients with 2–25% of normal LDLR activity (receptor-defective) (2). In general, plasma levels of LDL-C are inversely related to the level of residual LDLR activity. Untreated, receptor-negative patients with homozygous FH rarely survive beyond the second decade; receptor-defective patients have a better prognosis but, with few exceptions, develop clinically significant atherosclerotic vascular disease by age 30, and often sooner (2).
The plasma levels of LDL-C in FH heterozygotes are lower (elevated two- to threefold) and much more dependent on other genetic and environmental factors than are those in FH homozygotes. Although the nature of the molecular defect has some impact on the severity of hypercholesterolemia, FH heterozygotes with the same LDLR mutation can have widely different plasma levels of LDL-C (2). The clinical prognosis of FH heterozygotes is related not only to the magnitude of the elevation in plasma LDL-C but also to the presence of other coronary risk factors (5).
New insights into pathogenesis. Despite our detailed knowledge of the molecular biology of the LDLR, fundamental questions regarding how the receptor delivers its cargo in cells without being degraded itself have only recently been elucidated. The crystal structure of the extracellular domain of the protein has provided a compelling model of how the receptor binds LDL with high affinity at the cell membrane and then releases it in the appropriate intracellular compartment (6). The extracellular domain consists of a ligand-binding domain, an EGF precursor homology domain, which contains a six-bladed β-propeller flanked by cysteine-rich EGF repeats (7), and an O-linked sugar-rich domain. When the LDLR is on the cell surface, the extracellular domain is extended, exposing the ligand-binding domain to LDL. After the receptor binds LDL, the receptor-ligand complex is internalized and delivered to endosomes. In the acidic environment of the endosome, the LDLR folds back on itself, bringing the β-propeller region of the EGF precursor domain into close apposition to the ligand-binding domain, thus displacing LDL. The β-propeller appears to function as a pseudosubstrate for the ligand-binding domain, permitting release of the lipoprotein in the endosome and recycling of the LDLR to the cell surface. Naturally occurring LDLR mutations in humans that disrupt recycling of the receptor are located in residues critical to the structure of the EGF precursor domain (6, 7).
LDL turnover studies documented the key role of hepatic LDLRs in LDL catabolism (2). More recent studies indicate that the LDLR may also regulate the rate of entrance of VLDL into the circulation. Mice overexpressing the lipogenic transcription factor SREBP-1a have increased hepatic cholesterol and triglyceride synthesis, and hepatic steatosis, but normal plasma lipid levels. When LDLR expression is abolished in these mice, they become profoundly hyperlipidemic due to an increase in secretion of apoB-containing lipoproteins (8). Evidence from studies in cultured mouse hepatocytes suggests that the LDLR may also restrict hepatic apoB-100 secretion by promoting its intracellular degradation (9). Thus, the LDLR may limit the number of circulating triglyceride-rich particles by reducing their secretion and by promoting their recapture before they enter the circulation from the liver. The importance of the LDLR in limiting VLDL secretion in vivo in humans remains controversial, because isotopic studies cannot readily determine the proportion of newly formed VLDL that enters the systemic circulation.
Diagnosis. In general, the diagnosis of FH is straightforward and is based on a family history of hypercholesterolemia and premature coronary atherosclerosis, the lipid profile, and the presence of xanthomas. Heterozygous FH occurs in approximately 1 in 500 persons worldwide but has a much higher incidence in certain populations, such as the Afrikaners, Christian Lebanese, Finns, and French-Canadians, due to founder effects (2). Over 900 mutations in the LDLR gene cause FH (10). Most mutations are unique, making the molecular diagnosis difficult, except in patients from populations where a limited number of mutations predominate. However, to date, there is no evidence that molecular diagnosis of the disease has important therapeutic implications.
Treatment. Heterozygous FH patients are responsive to statins, which inhibit HMG-CoA reductase and result in upregulation of the normal LDLR allele. Combination therapy is frequently required to achieve desired LDL-C levels (Table 2). Historically, bile acid sequestrants or nicotinic acid have been used for this purpose. Stanol esters, which decrease cholesterol absorption by displacing cholesterol from mixed micelles, are also effective in combination therapy (11). Recently, ezetimibe, a drug that specifically inhibits cholesterol absorption, became available (12). Ezetimibe binds to the microvilli of jejunal enterocytes and interferes with the enterohepatic circulation of cholesterol, much as bile acid sequestrants interrupt the enterohepatic circulation of bile acids. The drug is effective at very low concentrations and so presumably works by inhibiting a putative cholesterol transporter. Ezetimibe is more effective than dietary cholesterol restriction in lowering plasma cholesterol levels because it decreases the uptake of both dietary and biliary cholesterol. The reduced flux of cholesterol from the gut to the liver leads to a compensatory increase in hepatic LDLR, resulting in an approximately 20% reduction in LDL-C. The discovery of ezetimibe has rejuvenated the study of intestinal cholesterol absorption.
Major LDL-C–lowering therapies for severe hypercholesterolemia
HMG-CoA reductase inhibitors and ezetimibe have only modest effects on plasma levels of LDL-C in FH homozygotes, even when administered at high doses (13). While some FH homozygotes with receptor-defective mutations may retain sufficient LDLR activity to respond to these potent lipid-lowering agents, drug therapy alone is never adequate treatment for these patients. The current treatment of choice for homozygous FH (and for heterozygotes whose plasma LDL-C remains elevated with drug therapy) is LDL apheresis. This process, in which the LDL particles are selectively removed from the circulation through extracorporeal binding to either dextran sulphate or heparin, can promote regression of xanthomas and may slow the progression of atherosclerosis (14). However, the procedure is time consuming and expensive and must be performed every 1–2 weeks. Although it retards the development of atherosclerosis, it does not prevent it, because of the recurrent hypercholesterolemia between procedures. Therefore, new therapies are urgently needed to treat the hypercholesterolemia of individuals suffering from homozygous FH. Inhibition of microsomal transfer protein (MTP), which is required for synthesis of apoB-containing lipoproteins, reduces plasma cholesterol levels in LDLR-deficient rabbits (15) and may be effective in homozygous FH, though the development of hepatic steatosis may be dose limiting. Liver-directed gene transfer of the LDLR theoretically is attractive but awaits the development of better and safer vectors.