Familial Hypercholesterolemia (FH), is the most common monogenic autosomal dominant disorder where affected individuals present with significantly elevated low-density lipoprotein (LDL) cholesterol in the blood, tendinous xanthomas, corneal arcus, and coronary artery disease (CAD)1. This affects about 1 in every 200-250 people globally, but most people are unaware they have it2, 3.
FH is known to be caused by inherited mutations in genes used to regulate and remove cholesterol in the blood. Among the individuals with a clinical diagnosis of FH, pathogenic variants can be identified in one of the four genes – LDLR, APOB, LDLRAP1, and PCSK9 in about 60-80% of adult and 60-95% of pediatric FH patients1, 2, 4. Other known genes implicated in FH are – ABCG8, ABCG5, APOE, and LIPA5, 6.
There are two types of FH – Heterozygous FH (HeFH) and Homozygous FH (HoFH). HeFH is caused by a single inherited variant from one parent. In rare cases, an individual can have HoFH, which is caused by having two causal variants inherited from each parent. Individuals with HoFH typically have a more severe form of the disease. LDL receptors usually remove LDL-C from the blood to the liver by carrying the lipoproteins that fix LDL-C for transport. Genetic mutations in the LDLR gene can cause a decrease in the number of LDL receptors or interfere with its normal functions. This causes the high LDL cholesterol levels seen in FH patients.
Phenotype & Diagnosis
FH remains underdiagnosed and undertreated globally. Additionally, patients with HoFH are diagnosed much later and are at higher premature Atherosclerotic Cardiovascular Disease (ASCVD) risk.
FH can be diagnosed using targeted molecular testing or next-generation sequencing (NGS) gene panel strategies; however, the latter is still not widely used6, 7. In 20-30% of individuals that meet clinical criteria for FH, standard clinical genetic testing may be negative due to either technical limitations (e.g., clinical sensitivity of current technology) or causal genes that are not yet discovered. FH is diagnosed in children with LDL‐C persistently over 160 mg/dL (4.1 mmol/L) and adults with LDL‐C greater than 190 mg/dL (4.9 mmol/L), especially if there is a family history of early‐onset CAD, and in all patients with early CAD.
The results of population-based studies of genetic screening for FH have demonstrated that there is no fixed LDL-C threshold for making the diagnosis of HoFH8. Although an untreated LDL-C of over 400 mg/dL (10 mmol/L) should lead to a consideration of the diagnosis of HoFH, LDL-C levels of less than 400 mg/dL have also been documented in patients with genetically confirmed HoFH. These high cholesterol levels can lead to a variety of symptoms. Cholesterol build-up can deposit in different parts of the body which can lead to deposits around the elbows and knees, Achilles tendon pain, and or a white or grey ring around the iris of the eye. FH is an inherited disease present from birth, but symptoms may not manifest until adulthood, which makes more early testing necessary.
Universal screening for FH is currently not feasible or cost-effective. The most effective means to identify new cases of FH is by cascade screening family members of a known index case8. Cascade genetic testing is beneficial in developing early intervention strategies for affected family members. Screening of relatives can be done by measuring LDL-C, genetic analysis, or both, and FH has been designated as a tier 1 genomics application for family screening by the US Centers for Disease Control and Prevention Office of Public Health Genomics. Universal pediatric screening coupled with reverse cascade screening has been proposed as another strategy to identify new FH cases as the discrimination power between FH and non-FH cases based on LDL-C levels is better during childhood8.
Treatments & Disease Management
Despite the lack of screening, FH disorders are easily actionable. Patients with FH can have an excellent prognosis once the disorder is diagnosed, and a treatment plan is put in place. Dietary and lifestyle modifications are the starting points for LDL‐C lowering in patients with FH, but multidrug treatment is often required to achieve adequate LDL‐C levels. The risk of developing CAD is increased up to 13-fold in untreated FH subjects, and 22-fold when an FH mutation is present.
Statins are potent competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase and have proven useful in the treatment of FH. It is recommended to treat FH patients with high doses of high‐intensity statins, which are capable of lowering LDL‐C by 50% to 60%8. If high‐dose, high‐intensity statins are not tolerated, the maximally tolerated statin dose is prescribed. PCSK9 inhibitors such as inclisiran (small interfering RNA) and evolocumab, (human monoclonal antibody), can also be used to lower lipid levels. Lipoprotein apheresis is indicated in HoFH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. Lastly, significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH.
Studies show that as few as 10% of individuals living with FH could be aware of their diagnosis7. Consequently, FH is most often diagnosed in adulthood after a cardiac event. The widespread access to genetic testing could be part of the solution, but concerted efforts are still necessary to raise awareness of FH and identify barriers to comprehensive screening, early diagnostics, and treatment.
- National Organization for Rare Disorders (NORD). Familial Hypercholesterolemia. September 2022. Available from: https://rarediseases.org/rare-diseases/familial-hypercholesterolemia/
- Centers for Disease Control and Prevention (CDC). Familial Hypercholesterolemia. September 2022. Available from: https://www.cdc.gov/genomics/disease/fh/FH.htm
- Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-79. doi: 10.1016/j.ccl.2015.01.001
- American Heart Society. Familial Hypercholesterolemia. September 2022. Available from: https://www.heart.org/en/health-topics/cholesterol/causes-of-high-cholesterol/familial-hypercholesterolemia-fh
- OMIM® – Online Mendelian Inheritance in Man®. Familial Hypercholesterolemia 1; FHCL1. Entry #143890. September 2022. Available from: https://www.omim.org/entry/143890#phenotypeMap
- Ison HE, Clarke SL, Knowles JW. Familial Hypercholesterolemia. 2014. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174884/
- McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia. J Am Heart Assoc. 2019;8(24):e013225. doi: 10.1161/JAHA.119.013225
- Lui DTW, Lee ACH, Tan KCB. Management of Familial Hypercholesterolemia: Current Status and Future Perspectives. J Endocr Soc. 2020;5(1):bvaa122. doi: 10.1210/jendso/bvaa122