Familial Hypercholesterolemia - GeneReviews™ - NCBI Bookshelf
Disease characteristics. Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that cause atherosclerotic plaque deposition in arteries and a markedly increased risk of coronary artery disease at an early age. Cholesterol deposits are also sometimes found in the tendons (xanthomas) and/or around the eyes (xanthelasmas). In FH, the more common cardiovascular disease is coronary heart disease (CHD), which may manifest as angina and myocardial infarction; stroke occurs more rarely.
Heterozygous FH (HeFH) can often be directly attributed to a heterozygous pathogenic variant in one of three genes (LDLR, APOB, PCSK9) known to account for 60%-80% of FH. FH is relatively common (prevalence 1:200-500). Persons with untreated FH are at an approximately 20-fold increased risk for CHD. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years.
In contrast, homozygous FH (HoFH) results from either biallelic (i.e., 2) mutations in one of these known genes or one mutation in each of two different genes. HoFH is much rarer (prevalence 1:160,000 to 1:1,000,000). Most individuals with HoFH experience severe CHD by their mid-20s. 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 likelihood of FH is increased in individuals with high levels of low density lipoprotein cholesterol (LDL-C) (in untreated adults: >190 mg/dL [>4.9 mmol/L] or total cholesterol levels >310 mg/dL [>8 mmol/L]; in untreated children or adolescents: LDL-C levels >160 mg/dL [4.1 mmol/L] or total cholesterol levels >230 mg/dL [>6 mmol/L]); history of premature coronary heart disease (CHD); xanthomas, xanthelasmas, and/or corneal arcus; and a family historyof FH. The diagnosis of HeFH can be confirmed by the presence of a pathogenic variant in one of the three genes (LDLR, APOB,and PCSK9) in which mutation is known to account for 60%-80% of FH.
Management. Treatment of manifestations: Guidelines for the management of adults and children with HeFH and HoFH have been published by multiple national/international organizations. All individuals with HeFH are at high risk for CVD and should be treated actively with diet/lifestyle changes and pharmacotherapy to lower their lipid levels. Pharmacotherapy should initially be statin-based, followed by addition of other drugs if the targeted LDL-C level is not achieved.
Children and adults with HoFH usually require LDL apheresis. Liver transplantation is also being used in rare circumstances at some centers.
Prevention of primary manifestations: Statin therapy in combination with a heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day), and increased physical activity
Surveillance: Guidelines have been published by multiple national and international organizations.
A child who has a family history of FH, who is heterozygous for the FH pathogenic variant in his or her family, who has a family history of premature CVD, or who has an elevated serum cholesterol concentration should have lipid levels checked before age ten years; some guidelines advise checking cholesterol as early as age two to five years.
During treatment, individuals of any age diagnosed with:
- HeFH should have lipid levels monitored as recommended;
- 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 transunsaturated 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 (colesevelam) are generally considered safe (Class B for pregnancy), and LDL apheresis is also occasionally used if there is evidence of established CHD.
Almost all individuals diagnosed with HeFH have an affected parent; the proportion of HeFH caused by de novo mutation is unknown but appears to be extremely low. Each child of an individual with HeFH has a 50% chance of inheriting the pathogenic variant.
If both parents have HeFH, each child has a 75% chance of having FH (i.e., 50% chance of having HeFH and 25% chance of having HoFH).
If the pathogenic variant has been identified in a family member with HeFH (or if both pathogenic variants have been identified in a family member with HoFH), prenatal testing for pregnancies at increased risk is possible. Requests for prenatal testing for conditions which (like FH) do not affect intellect and have some treatment available are not common.