Familial Hypercholesterolemia (FH) is a common, inherited disorder that significantly increases the risk of early cardiovascular disease. This condition causes extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth. Since the body cannot effectively clear LDL-C, it builds up in the arteries, leading to premature heart disease. Identifying FH early is important because timely treatment can reduce the risk of a heart attack or stroke by about 80%. The diagnosis involves clinical evaluation, specific blood tests, and advanced genetic sequencing.
Identifying Who Needs Testing
Testing for FH is typically prompted by a patient’s lipid profile or a history of the disorder within the family. Adults with an untreated LDL cholesterol level of 190 mg/dL or higher should be evaluated for FH. For children and adolescents, a persistently high LDL-C level of 160 mg/dL or greater warrants a closer look, especially if there is a known family history of high cholesterol or early heart disease.
A strong family history of premature heart disease also triggers testing. This includes first-degree relatives, such as a parent or sibling, who experienced a heart attack before age 55 for men or age 60 for women. Physical signs can also prompt an evaluation, particularly the observation of xanthomas, which are yellowish cholesterol deposits that accumulate in the tendons.
The Standard Clinical and Bloodwork Evaluation
The initial testing for FH begins with a simple blood draw for a fasting lipid panel. This test measures the key components of cholesterol, including total cholesterol, HDL cholesterol, triglycerides, and the specific LDL cholesterol level. The resulting LDL-C value is the most telling factor and is compared against established thresholds to determine the severity of the hypercholesterolemia.
For diagnosis, healthcare providers often use formal scoring systems that combine the bloodwork results with clinical observations and family history. Two globally recognized tools are the Dutch Lipid Clinic Network (DLCN) Criteria and the Simon Broome Register Criteria. These systems assign points for factors such as the degree of LDL-C elevation, the presence of physical signs like tendon xanthomas, and a history of early coronary artery disease in the family.
A total score from the DLCN Criteria, for instance, categorizes the likelihood of FH as “possible,” “probable,” or “definite.” These clinical criteria help to distinguish the genetic high cholesterol of FH from elevated levels caused by diet or other health conditions. Exclusion of secondary causes for high cholesterol, such as hypothyroidism or kidney disease, is an important step before a clinical diagnosis of FH is made. A probable or definite classification based on these clinical tools often leads to the recommendation for genetic confirmation.
Genetic Sequencing for Definitive Diagnosis
When the clinical evaluation strongly suggests FH, genetic sequencing is utilized to confirm the diagnosis at the molecular level. This advanced test involves analyzing specific genes known to cause the condition, typically performed using a blood sample or cheek swab. The primary genes examined are \(LDLR\), \(APOB\), and \(PCSK9\), which collectively account for the majority of FH cases.
The \(LDLR\) gene provides instructions for the LDL receptor, a protein that removes cholesterol from the blood, and variants in this gene are the most common cause of FH. Mutations in \(APOB\) affect the protein component of the LDL particle itself, which impairs its ability to bind to the receptor. \(PCSK9\) variants can lead to an over-destruction of the LDL receptors, further limiting the liver’s ability to clear cholesterol.
Identifying a pathogenic variant in one of these genes provides a definitive diagnosis of FH. A positive genetic test result is a strong tool for guiding treatment and for subsequent family screening efforts.
Understanding Results and Cascade Screening
A definitive diagnosis of FH means a patient has a lifelong condition that requires aggressive management. This usually involves starting high-intensity lipid-lowering medications, often statins, to reduce the risk of premature heart disease. The diagnosis has immediate implications for the patient’s biological family members.
Once a person, known as the index case, is diagnosed, cascade screening is initiated. This involves systematically testing first-degree relatives such as parents, siblings, and children. Since FH is typically inherited in an autosomal dominant pattern, each first-degree relative has a 50% chance of also having the condition.
If a specific disease-causing genetic mutation was identified in the index case, genetic testing becomes the most efficient method for cascade screening. Relatives can be tested specifically for that one known mutation, offering a clear answer to their FH status. This systematic family tracing is an effective strategy for identifying undiagnosed cases and ensuring early treatment.