Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is caused by mutations in the gene for the LDL receptor that prevent its appearance on the cell surface or impair its ability to bind and internalize LDL .More than 200 different mutations in the LDL receptor have been described in patients with FH . FH is an autosomal codominant disorder, meaning that heterozygotes have hypercholesterolemia but homozygotes have even more severe hypercholesterolemia. The presence of one mutant LDL receptor allele results in the production of only approximately one-half the normal number of LDL receptors, whereas the presence of two mutant alleles severely reduces or eliminates functional LDL receptors. The reduction in functional hepatic LDL receptors leads to reduced clearance of plasma LDL by the liver and substantial elevations in LDL cholesterol. Elevated LDL cholesterol levels lead directly to the major complication of this condition, premature ASCVD.
Heterozygous FH occurs in approximately 1 in 500 persons in North America and worldwide, making it one of the most common single gene disorders. It is characterized by elevated LDL cholesterol levels (usually 200 to 400 mg per dL) with normal triglyceride levels and a family history of hypercholesterolemia or premature cardiovascular disease. The finding of tendon xanthomas is virtually diagnostic of FH (although these can also been seen in another disorder, as discussed later). Tendon xanthomas are most easily recognized within the Achilles tendons, where they cause thickening and irregularity. Another common location for tendon xanthomas is the digit extensor tendons of the metacarpophalangeal joints on the dorsa of the hands. Premature arcus corneae is frequently seen in patients with heterozygous FH. There is no definitive diagnostic test for heterozygous FH; the disorder is diagnosed on clinical grounds.
Heterozygous FH is strongly associated with premature ASCVD, especially CHD. Therefore, patients should be aggressively treated to lower the LDL cholesterol level. Most heterozygous FH patients require lipid-lowering drug therapy. Statins are especially effective in treatment of heterozygous FH, inducing up-regulation of the normal LDL receptor allele in the liver. If further lowering of the LDL level is required, the addition of a bile acid sequestrant to the statin is often beneficial. Niacin is also effective in FH and is often used in combination with statins and resins. The combination of all three drug classes (statin, resin, and niacin) is sometimes required to achieve LDL cholesterol level goals. If combination drug therapy is not tolerated or fails to adequately control the cholesterol levels, LDL apheresis should be considered .
Homozygous FH is caused by the inheritance of two mutant LDL receptor alleles, which results in the production of few or no LDL receptors and a severe defect in the catabolism of LDL. Homozygous FH occurs in approximately 1 in 1 million persons worldwide and is a much more severe clinical disorder than heterozygous FH. Patients with homozygous FH are often classified into one of two groups, based on the amount of LDL receptor activity measured in their skin fibroblasts: “Receptor negative” patients have <2% of normal LDL receptor activity, whereas “receptor defective” patients have 2% to 25% of normal LDL receptor activity . This classification is important, because LDL receptor–defective patients have a much better prognosis than LDL receptor–negative patients. LDL receptor–defective patients sometimes have small responses to drug therapy and can survive into the third decade of life and even beyond. In contrast, survival of the untreated LDL receptor–negative patient with homozygous FH into the third decade of life is very unusual. Clinical heterogeneity among homozygous FH patients is due to the significant genetic heterogeneity of the LDL receptor gene mutations .
Patients with homozygous FH usually present in childhood with cutaneous xanthomas on the hands, wrists, elbows, knees, heels, or buttocks. Some patients with homozygous FH do not have cutaneous xanthomas but develop tuberous or tendon xanthomas on the elbows, knees, or Achilles tendons as older children or adolescents. Some degree of arcus corneae is usually present. Total cholesterol levels are usually >500 mg per dL and can be as high as 1,200 mg per dL. The devastating complication of homozygous FH is accelerated atherosclerosis, which can result in clinical sequelae even in childhood. Atherosclerosis often develops first in the aortic root and can cause aortic valvular or supravalvular stenosis. It frequently extends into the coronary ostia, which can develop significant stenoses. Carotid and femoral disease usually occurs somewhat later; the presence of femoral bruits has been reported to be a poor prognostic sign. Children with homozygous FH often develop symptoms of vascular disease before puberty, but symptoms can be atypical or go unreported, and sudden death is common. Untreated LDL receptor–negative patients with homozygous FH rarely survive beyond the second decade. LDL receptor–defective patients have a better prognosis but invariably develop clinical ASCVD by the age of 30 years and often much sooner.
A child who has severe hypercholesterolemia, relatively normal triglyceride levels, and cutaneous or tendon xanthomas should be suspected of having homozygous FH. The biologic parents and other relatives should be tested for hypercholesterolemia. A diagnosis of homozygous FH can be confirmed at specialized centers through assay of the LDL receptor activity on the skin fibroblasts after a skin biopsy is performed. Obstructive liver disease should be excluded by appropriate tests if its presence is suspected. Patients in whom homozygous FH is suspected should be referred to a specialized center. Drug therapy including a statin and a bile acid sequestrant should be tried. Atorvastatin, a new long-acting, potent statin, has been reported to have greater efficacy in homozygous FH than other statins and should be considered. Liver transplantation is effective in decreasing LDL cholesterol levels but is associated with the substantial risks of surgery and long-term immunosuppression. The treatment of choice for homozygous FH is LDL apheresis, which can promote regression of xanthomas and retard progression of atherosclerosis . The age at which LDL apheresis should be initiated is uncertain. Venous access is often problematic in young children, and central venous catheters can promote infections, which are especially risky, given the frequent aortic valvular and supravalvular flow disturbances. It is generally recommended that initiation of LDL apheresis be delayed until the patient is approximately 5 years old, except when evidence of ASCVD is present.
Because of its well-understood pathophysiology, serious consequences, and poor options for treatment, homozygous FH is a model for the development of somatic liver-directed gene therapy. Five patients with homozygous FH were treated in a gene therapy protocol involving ex vivo reconstitution of the LDL receptor gene into autologous hepatocytes with subsequent reimplantation . At 4 months, all patients had evidence of LDL receptor transgene expression by liver biopsy. LDL cholesterol levels were decreased in two patients by 17% and 22%, but in the other three patients, LDL cholesterol levels were essentially unchanged. Metabolic turnover studies in three patients documented an increased rate of LDL catabolism in the patient whose LDL cholesterol level decreased by 22% but no substantial difference in LDL kinetics in two of the patients whose LDL cholesterol levels showed little change . Although this pilot protocol demonstrated the feasibility of somatic gene transfer and expression of the LDL receptor in humans and some impact on LDL cholesterol levels and metabolism, future gene therapy trials await further improvements in technology. In the future, even low-level expression of the LDL receptor in an LDL receptor–negative FH patient could have the potential for substantial clinical benefit to the patient once it is combined with potent cholesterol-lowering drugs.
Familial Defective Apolipoprotein B-100Heterozygous FH occurs in approximately 1 in 500 persons in North America and worldwide, making it one of the most common single gene disorders. It is characterized by elevated LDL cholesterol levels (usually 200 to 400 mg per dL) with normal triglyceride levels and a family history of hypercholesterolemia or premature cardiovascular disease. The finding of tendon xanthomas is virtually diagnostic of FH (although these can also been seen in another disorder, as discussed later). Tendon xanthomas are most easily recognized within the Achilles tendons, where they cause thickening and irregularity. Another common location for tendon xanthomas is the digit extensor tendons of the metacarpophalangeal joints on the dorsa of the hands. Premature arcus corneae is frequently seen in patients with heterozygous FH. There is no definitive diagnostic test for heterozygous FH; the disorder is diagnosed on clinical grounds.
Heterozygous FH is strongly associated with premature ASCVD, especially CHD. Therefore, patients should be aggressively treated to lower the LDL cholesterol level. Most heterozygous FH patients require lipid-lowering drug therapy. Statins are especially effective in treatment of heterozygous FH, inducing up-regulation of the normal LDL receptor allele in the liver. If further lowering of the LDL level is required, the addition of a bile acid sequestrant to the statin is often beneficial. Niacin is also effective in FH and is often used in combination with statins and resins. The combination of all three drug classes (statin, resin, and niacin) is sometimes required to achieve LDL cholesterol level goals. If combination drug therapy is not tolerated or fails to adequately control the cholesterol levels, LDL apheresis should be considered .
Homozygous FH is caused by the inheritance of two mutant LDL receptor alleles, which results in the production of few or no LDL receptors and a severe defect in the catabolism of LDL. Homozygous FH occurs in approximately 1 in 1 million persons worldwide and is a much more severe clinical disorder than heterozygous FH. Patients with homozygous FH are often classified into one of two groups, based on the amount of LDL receptor activity measured in their skin fibroblasts: “Receptor negative” patients have <2% of normal LDL receptor activity, whereas “receptor defective” patients have 2% to 25% of normal LDL receptor activity . This classification is important, because LDL receptor–defective patients have a much better prognosis than LDL receptor–negative patients. LDL receptor–defective patients sometimes have small responses to drug therapy and can survive into the third decade of life and even beyond. In contrast, survival of the untreated LDL receptor–negative patient with homozygous FH into the third decade of life is very unusual. Clinical heterogeneity among homozygous FH patients is due to the significant genetic heterogeneity of the LDL receptor gene mutations .
Patients with homozygous FH usually present in childhood with cutaneous xanthomas on the hands, wrists, elbows, knees, heels, or buttocks. Some patients with homozygous FH do not have cutaneous xanthomas but develop tuberous or tendon xanthomas on the elbows, knees, or Achilles tendons as older children or adolescents. Some degree of arcus corneae is usually present. Total cholesterol levels are usually >500 mg per dL and can be as high as 1,200 mg per dL. The devastating complication of homozygous FH is accelerated atherosclerosis, which can result in clinical sequelae even in childhood. Atherosclerosis often develops first in the aortic root and can cause aortic valvular or supravalvular stenosis. It frequently extends into the coronary ostia, which can develop significant stenoses. Carotid and femoral disease usually occurs somewhat later; the presence of femoral bruits has been reported to be a poor prognostic sign. Children with homozygous FH often develop symptoms of vascular disease before puberty, but symptoms can be atypical or go unreported, and sudden death is common. Untreated LDL receptor–negative patients with homozygous FH rarely survive beyond the second decade. LDL receptor–defective patients have a better prognosis but invariably develop clinical ASCVD by the age of 30 years and often much sooner.
A child who has severe hypercholesterolemia, relatively normal triglyceride levels, and cutaneous or tendon xanthomas should be suspected of having homozygous FH. The biologic parents and other relatives should be tested for hypercholesterolemia. A diagnosis of homozygous FH can be confirmed at specialized centers through assay of the LDL receptor activity on the skin fibroblasts after a skin biopsy is performed. Obstructive liver disease should be excluded by appropriate tests if its presence is suspected. Patients in whom homozygous FH is suspected should be referred to a specialized center. Drug therapy including a statin and a bile acid sequestrant should be tried. Atorvastatin, a new long-acting, potent statin, has been reported to have greater efficacy in homozygous FH than other statins and should be considered. Liver transplantation is effective in decreasing LDL cholesterol levels but is associated with the substantial risks of surgery and long-term immunosuppression. The treatment of choice for homozygous FH is LDL apheresis, which can promote regression of xanthomas and retard progression of atherosclerosis . The age at which LDL apheresis should be initiated is uncertain. Venous access is often problematic in young children, and central venous catheters can promote infections, which are especially risky, given the frequent aortic valvular and supravalvular flow disturbances. It is generally recommended that initiation of LDL apheresis be delayed until the patient is approximately 5 years old, except when evidence of ASCVD is present.
Because of its well-understood pathophysiology, serious consequences, and poor options for treatment, homozygous FH is a model for the development of somatic liver-directed gene therapy. Five patients with homozygous FH were treated in a gene therapy protocol involving ex vivo reconstitution of the LDL receptor gene into autologous hepatocytes with subsequent reimplantation . At 4 months, all patients had evidence of LDL receptor transgene expression by liver biopsy. LDL cholesterol levels were decreased in two patients by 17% and 22%, but in the other three patients, LDL cholesterol levels were essentially unchanged. Metabolic turnover studies in three patients documented an increased rate of LDL catabolism in the patient whose LDL cholesterol level decreased by 22% but no substantial difference in LDL kinetics in two of the patients whose LDL cholesterol levels showed little change . Although this pilot protocol demonstrated the feasibility of somatic gene transfer and expression of the LDL receptor in humans and some impact on LDL cholesterol levels and metabolism, future gene therapy trials await further improvements in technology. In the future, even low-level expression of the LDL receptor in an LDL receptor–negative FH patient could have the potential for substantial clinical benefit to the patient once it is combined with potent cholesterol-lowering drugs.
Familial defective apoB-100 (FDB) resembles heterozygous FH clinically. It is characterized by elevated LDL cholesterol levels with normal triglyceride levels, possible tendon xanthomas, and increased risk of premature ASCVD . In contrast to FH, FDB is caused by mutations in the receptor-binding region of apoB-100, the ligand for the LDL receptor, which impairs its binding and delays the clearance of LDL from the blood. The most common mutation that causes FDB is a substitution of glutamine for arginine at position 3500 in apoB-100 . However, other mutations have been reported that have a similar effect on binding of apoB to the LDL receptor. FDB is a dominantly inherited disorder and occurs in approximately 1 in 700 persons in Europe and North America.
Patients who have FDB clinically resemble those with heterozygous FH, and these disorders cannot be differentiated on purely clinical grounds. The apoB mutation can be detected in specialized laboratories so that a specific diagnosis of FDB can be made. However, there is no compelling reason to make a specific molecular diagnosis, because the clinical management of patients with FDB is similar to that of patients with heterozygous FH. If future therapies are found that are more effective in one condition than in the other, molecular diagnosis could be indicated to guide specific therapy.
Patients who have FDB clinically resemble those with heterozygous FH, and these disorders cannot be differentiated on purely clinical grounds. The apoB mutation can be detected in specialized laboratories so that a specific diagnosis of FDB can be made. However, there is no compelling reason to make a specific molecular diagnosis, because the clinical management of patients with FDB is similar to that of patients with heterozygous FH. If future therapies are found that are more effective in one condition than in the other, molecular diagnosis could be indicated to guide specific therapy.
Polygenic Hypercholesterolemia
Most forms of hypercholesterolemia are not single-gene disorders, but rather are caused by a complex interaction of several genetic and environmental factors. For example, genetic differences in cholesterol absorption, cholesterol synthesis, or rates of bile acid synthesis may result in very different cholesterol levels in people challenged with a diet rich in fat. Polygenic hypercholesterolemia is characterized by a cholesterol level exceeding the 95th percentile for age and gender, with triglyceride levels that are usually relatively normal. In polygenic hypercholesterolemia, LDL cholesterol levels are usually not as elevated as they are in heterozygous FH and FDB, and tendon xanthomas are not observed. In the differentiation of polygenic hypercholesterolemia from the these single-gene disorders, family studies are useful. Only approximately 7% of first-degree relatives of patients with polygenic hypercholesterolemia are hypercholesterolemic, whereas approximately one-half of the relatives of patients with FCHL, heterozygous FH, and FDB have dyslipidemia. Treatment of polygenic hypercholesterolemia follows the same guidelines as the approach to any patient with hypercholesterolemia.
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