Familial hypercholesterolemia is a disease that is commonly inherited and characterized by a dysfunction in cholesterol metabolism. The disease results in higher-than-normal levels of low-density lipoprotein (LDL), which many people may know as the “bad cholesterol”. This happens due to an impaired function of LDL receptors due to a genetic defect. There are typically five ways in which the LDL receptor is dysfunctional: the LDL receptor is not synthesized, the LDL receptor is not expressed on the cell surface because of improper transport, the LDL receptor does not bind to LDL, the LDL receptor does not properly cluster in clathrin-coated pits for endocytosis, or the LDL receptor is not recycled back to the cell surface. All of these lead the way to higher-than-normal levels of LDL. With familial hypercholesterolemia, there is a lifetime exposure to LDL that can cause complications from an early age. This disease state is not rare, but it is oftentimes missed, and an early diagnosis and treatment can prevent the complications such as the development of premature atherosclerotic cardiovascular disease.
Manifestations of familial hypercholesterolemia usually begin in adulthood, but the clinical effects can be seen earlier in life which is why diagnosis early on is very important. Being able to identify and treat the disease early is key to preventing complications and death. Many barriers exist in the diagnosis of familial hypercholesterolemia including mistaking other coronary artery disease risk factors for familial hypercholesterolemia factors, which can leave the disease undiagnosed for several generations. Cascade screening is a method in which providers screen for familial hypercholesterolemia in first- and second-degree relatives of patients that are diagnosed, but this method can still miss some individuals. The diagnosis of familial hypercholesterolemia is based on lipid levels, family history, physical findings, and genetic analysis. The physical findings can include tendon xanthomas, tuberous xanthomas, arcus corneae, or xanthelasma. It is important to note that these physical findings may not be present in those who have familial hypercholesterolemia and that they help aid in the differential diagnosis. There are three well-defined tools that are currently used to diagnose familial hypercholesterolemia: The US Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria (MEDPED), The Dutch Lipid Clinic Network Diagnostic Criteria, and The Simon Broome Register Diagnostic Criteria.
The treatment of familial hypercholesterolemia should optimally start early, but as it is underdiagnosed it is often treated later in life. Long-term drug treatment can reduce or even eliminate the lifetime risk of coronary heart disease. In addition to lifestyle modifications, statins are the initial drug choice for all adults with familial hypercholesterolemia and children eight years or older with heterozygous familial hypercholesterolemia. Statins increase the expression of LDL receptors by reducing HMG-CoA reductase. It is important to note that the low potency statins are usually not enough to treat this disease and moderate to high potency statins should be used. Combination therapy will most likely need to be employed in many patients. There are now novel drugs on the market to treat familial hypercholesterolemia including a recently approved monoclonal antibody, evinacumab-dgnb, under the brand name Evkeeza. The indication is for an injectable add-on therapy for patients 12 years of age and older with homozygous familial hypercholesterolemia. The FDA designated Evkeeza as an orphan drug meaning that it is considered a breakthrough therapy design for rare diseases.
2. Center for Drug Evaluation and Research. FDA approves add-on therapy for patients with genetic form of severely. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0. Accessed January 18, 2022.
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