Clinical characteristics: Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or nonfatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Diagnosis/testing: Several formal diagnostic criteria exist for FH. The diagnostic criteria most widely used in Western countries include: extreme hypercholesterolemia (untreated adults with LDL-C>190 mg/dL or total cholesterol levels >310 mg/dL; untreated children/adolescents with LDL-C levels >160 mg/dL or total cholesterol levels >230 mg/dL); history of premature CAD or other CVD; xanthomas; corneal arcus; and a family history of features suggestive of FH. The diagnosis of FH can also be established by identification of a heterozygous pathogenic variant in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH. The diagnosis of HoFH can be established in a proband by identification of biallelic pathogenic variants in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH.
Management: Treatment of manifestations: Adults with FH: reduce CAD risk factors including cessation of smoking, regular physical activity, healthy diet, and weight control; treatment of hypertension; low-dose aspirin in high-risk individuals; pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels. Children with FH: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years. Children and adults with HoFH: referral to a lipid specialist or specialized center for management of multiple drug therapy; LDL apheresis is often required; liver transplantation in rare circumstances. Prevention of primary manifestations: Statin-based therapy with addition of other medications as needed, in combination with a heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; not smoking. Surveillance: Children with an established diagnosis of FH or risk factors for FH (e.g., elevated serum cholesterol, a family history of FH, a family history of premature CAD or other CVD) should have lipid levels checked before age ten years. All individuals with FH should have lipid levels monitored as recommended. Individuals with HoFH should be monitored with various imaging modalities (including echocardiograms, CT angiograms, and cardiac catheterization) as recommended. Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, excessive intake of cholesterol, sedentary lifestyle, obesity, hypertension, and diabetes mellitus. Evaluation of relatives at risk: Early diagnosis and treatment of first-degree and second-degree relatives at risk for FH can reduce morbidity and mortality. The genetic status of at-risk family members can be clarified by either: (1) molecular genetic testing if the pathogenic variant has been identified in an affected family member; or (2) measurement of LDL-C concentration. Pregnancy management: Pregnant women should incorporate all the recommended lifestyle changes including low saturated fat intake, no smoking, and high dietary soluble fiber. Statins are contraindicated in pregnancy due to concerns for teratogenicity and should be discontinued prior to conception. Bile acid binding resins (e.g., colesevelam) are generally considered safe (Class B for pregnancy), and LDL apheresis is also occasionally used if there is evidence of established CAD.
Genetic counseling: Heterozygous familial hypercholesterolemia (FH) and homozygous familial hypercholesterolemia (HoFH) are inherited in an autosomal dominant manner. Almost all individuals diagnosed with FH have an affected parent; the proportion of FH caused by a de novo pathogenic variant is unknown but appears to be extremely low. Each child of an individual with FH has a 50% chance of inheriting the pathogenic variant. If both parents have FH, each child has a 50% chance of having FH, a 25% chance of having HoFH, and a 25% chance of not having FH. If the pathogenic variant has been identified in a family member with FH (or if both pathogenic variants have been identified in a family member with HoFH), prenatal testing for pregnancies at increased risk is possible.
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