By Deirdre Kelly, PhD

Familial Hypercholesterolemia (FH) is an inherited autosomal dominant disorder that results in premature cardiovascular disease. In the USA alone, FH affects 620,000 people, where heterozygous FH is the most common type and is thought to have a prevalence of between one in 300-500 people. Homozygous FH is much rarer, with a prevalence of one in one million. Certain populations are at higher risk of this disorder such as French Canadians, Ashkenazi Jews, Lebanese, and Dutch Afrikaners. FH is caused by functional mutations relating to the low-density-lipoprotein (LDL)-receptor pathway, including genetic mutations of the LDL-receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 gene, PCSK9 or rare mutations in the LDLRAP1 gene. This ultimately leads to higher levels of lipoproteins (up to 3 times higher with heterozygous FH, and 6 times higher with homozygous FH) in the bloodstream, particularly LDL cholesterol.

If left untreated, patients with high LDL levels are at risk of cardiovascular events such as coronary heart disease by as much as 20-fold. Men have a lower age on onset (42-46 years) of the disease and tend to have heart attacks in their 40’s and 50’s. Approximately 85% of men with untreated FH have a heart attack by age 60. Women have a higher age of onset and cardiovascular events by 10 years. However, if a patient has homozygous FH, then prognosis is poor, where heart attacks due to aggressive coronary atherosclerosis have been seen in children as young as 2. If left untreated, the majority of homozygous FH patients will suffer heart attacks during their teenage years and may prove fatal by age 30.

The American National Lipid Association Expert Panel recommends that early identification and aggressive treatment of FH is performed. As FH is an autosomal dominant condition, children of FH patients have a 50% chance of inheriting the affected mutation. Therefore screening of all first-degree relatives is recommended to reduce the risk for premature CHD.

First line therapy for FH is through statins as with conventional hypercholesterolemia. However, FH patients may require a more potent treatment type and dosage. Combination and adjunctive therapy may also be required such as LDL-C apheresis. The FDA approved a new treatment option in January 2013 – mipomersen, an oligonucleotide inhibitor of apolipoprotein B-100 synthesis. In patients with homozygous FH, the FDA has approved lomitapide, a microsomal transfer protein. PCSK9 inhibitors are also promising e.g., the monoclonal antibodies AMG 145 and REGN727/SAR236553.

A number of diagnostic companies now screen for FH mutations in APOB and LDLR genes including Athena Diagnostics and Ambry Genetics. Europe is leading the way in FH genetic screening programs with the Netherlands, Italy, Norway, France, and Spain all providing government subsidized testing. LDLR and APOB testing should be considered not only by primary and consultant healthcare providers but also the US, UK and Irish governments in order to diagnose sufferers of this disease.


For further information:

J Manag Care Pharm. 2013 Mar;19(2):139-49. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Robinson JG.

Clin Cardiol. 2013 Nov 5. doi: 10.1002/clc.22223. Familial Hypercholesterolemia: An Under-recognized but Significant Concern in Cardiology Practice. Foody JM.

Nat Clin Pract Cardiovasc Med. 2007 Apr;4(4):214-25.Mechanisms of disease: genetic causes of familial hypercholesterolemia. Soutar AK, Naoumova RP.

Biotechnol Healthc. 2010 Spring; 7(1): 8–9.Familial Hypercholesterolemia Captures Gene Test Controversies, Bob Carlson, MHA


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