What is Familial Hypercholesterolemia?
FH is an autosomal co-dominant disorder in the lipid metabolism, characterized by elevated levels of low-density lipoprotein (LDL) cholesterol. Due to the lifelong exposure, LDL cholesterol can accumulate in the blood vessels where it can lead to atherosclerosis and early-onset cardiovascular disease in these patients. FH is caused by pathogenic variants in genes involved in the uptake of LDL cholesterol from the bloodstream by the liver. These genes are the LDL receptor gene (LDLR), Apolipoprotein B gene (APOB) and Proprotein convertase subtilisin–kexin type 9 gene (PCSK9). The prevalence of heterozygous FH is estimated at 1:300, making it the most common genetic metabolic disorder. FH patients have an 3 to 4 times increased risk of cardiovascular disease compared to unaffected individuals.
Diagnosis of FH
FH can be clinically diagnosed using diagnostic criteria. In the Netherlands, the Dutch Lipid Clinic Network (DLCN) criteria are often used (DLCN calculator). The DLCN criteria include for example a patient’s LDL cholesterol level, family history, and presence of physical features of FH. Current international guidelines recommend genetic testing in all individuals with a suspicion of FH (DLCN score > 5).
Genetic testing for FH can be requested by any physician in the Netherlands. General practitioners can also choose to refer patients with a suspicion for FH to a specialist in internal medicine. Since FH has an autosomal dominant inheritance pattern, it is important that first-degree relatives (parents, siblings, and children) are also tested for FH, as they have a 50% chance of also carrying an FH-causing variant. The LEEFH Foundation coordinates the screening of families with FH and can therefore support physicians in this regard.
- FH is an autosomal co-dominant disorder characterized by lifelong elevated levels of LDL cholesterol and, if left untreated, an increased risk for premature cardiovascular disease.
- FH is the most common genetic disorder in the lipid metabolism, with a prevalence of approximately 1:300.
- FH can be phenotypically diagnosed using the DLCN criteria. Genetic testing is advised when the DLCN score is above 5.
- Treatment for FH starts with a statin whether or not in combination with ezetimibe. Other lipid lowering therapies can be added to the therapy if LDL cholesterol reduction is insufficient with this combination therapy.
How to recognize an FH patient?
FH can manifest differently in patients. Generally, this disorder is characterized by high LDL cholesterol levels, cardiovascular disease at a young age (woman <60 years, men <55 years), and a family history of hypercholesterolemia and cardiovascular disease. In some cases, tendon xanthomas, arcus lipoides corneae, and xanthelasma can be present. Often, however, these physical features are absent, especially in children.
Treatment of FH patients at an early age is essential to reduce, or even eliminate, the increased cardiovascular disease risk that these patients carry. Current guidelines recommend starting drug therapy in children with FH from the age of 8-10 years in case of poor response to lifestyle measures. The first step in treatment is starting a statin whether or not in combination with ezetimibe. In some cases therapy with a statin and ezetimibe is insufficient in reaching LDL cholesterol targets, and addition of other LDL cholesterol lowering drugs is needed. Current guidelines recommend LDL cholesterol targets for primary prevention FH patients of <2.6 mmol/L and secondary prevention FH patients of <1.8 mmol/L.