Key Points
- The familial hypercholesterolemias (FHs) are a group of genetic conditions resulting in severe elevations of blood cholesterol levels.
- FH is among the most commonly occurring genetic metabolic disorders.
- The heterozygous form occurs in approximately 1 in 300 to 500 people in many populations (estimated current US prevalence: 620,000), although this ratio is much higher in certain populations in the United States.
- The homozygous form is quite rare, occurring in approximately 1 out of every one million individuals.
- Total cholesterol concentrations in heterozygous FH patients (genetic defect inherited from one parent) are typically in the range of 300 to 550 mg/dL (but sometimes lower) and in homozygoous FH patients (genetic defects inherited from both parents) they range from 650 to 1000 mg/dL.
- Hypercholesterolemia is present from childhood, leading to early development of coronary heart disease (CHD).
- The risk of premature CHD is elevated about 20-fold in untreated FH patients.
- FH is a treatable condition.
- In addition to diet and lifestyle modifications, safe and effective medical therapies are available, including statins and other lipid-lowering drugs.
- FH is both underdiagnosed and undertreated.
- All primary healthcare providers and relevant specialists should screen all children and adults for hypercholesterolemia and initiate therapy in patients with FH and severe hypercholesterolemia.
Lipid Specialists
- Patients with FH who do not respond adequately to, or are intolerant of, initial statin therapy should be referred to a lipid specialist.
- For children with FH, either consultation with or referral to a lipid specialist is recommended.
Diagnosis and Screening
Screening
- Universal screening for elevated serum cholesterol is recommended. FH should be suspected when untreated fasting low-density lipoprotein cholesterol (LDL-C) or non–high-density lipoprotein cholesterol (non–HDL-C; total cholesterol minus HDL-C) levels are at or above the following:
- Adults (≥20 years): LDL-C ≥190 mg/dL or non–HDL-C ≥220 mg/dL
- Children, adolescents, and young adults (<20 years): LDL-C ≥160 mg/dL or non–HDL-C ≥190 mg/dL
- For all individuals with these levels, a family history of high cholesterol and heart disease in first-degree relatives should be collected. The likelihood of FH is higher in individuals with a positive family history of hypercholesterolemia or of premature CHD (onset in men before age 55 years and women before age 65 years).
- Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.
- Although not present in many individuals with FH, the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:
- Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons)
- Arcus corneae in a patient younger than age 45
- At the LDL-C levels listed below the probability of FH is approximately 80% in the general population. These LDL-C levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
- LDL-C ≥250 mg/dL in a patient age 30 or older
- LDL-C ≥220 mg/dL for patients age 20 to 29
- LDL-C ≥190 mg/dL in patients age 20 or younger
Cascade Screening
- Lipid testing of first-degree relatives, known as cascade screening, should be offered to all individuals with FH.
- As cascade screening proceeds, newly identified FH cases provide additional relatives who should be considered for screening.
- Cascade screening is the most cost-effective means of finding previously undiagnosed FH patients and is also cost-effective in terms of cost per year of life saved.
Genetic Screening
- Genetic screening for FH is generally not needed for diagnosis or clinical management but may be useful when the diagnosis is uncertain.
- Identification of a causal mutation may provide additional motivation for some patients to implement appropriate treatment.
- Importantly, a negative genetic test result does not exclude FH, since approximately 20% of clinically definite FH patients will not be found to have a mutation despite an exhaustive search using current methods.
Diagnosis and Assessment
- Age at onset of CHD, even if approximate, is particularly important to note in the family history.
- Physical signs of FH are insensitive but can be quite specific.
- The presence of tendon xanthomas should be sought for by careful palpation (not just visual inspection) of the Achilles tendon and finger extensor tendons.
- Corneal arcus (partial or complete) is only indicative of FH if present in patients younger than age 45.
- Neither xanthelasma nor tuberous xanthomas are specific for FH but, if they are encountered in a younger patient, FH should be considered.
- Importantly, the absence of any of these physical findings does NOT rule out FH.
- Formal clinical diagnosis of FH can be made by applying any one of several validated sets of criteria:
- U.S. Make Early Diagnosis to Prevent Early Death (MEDPED)
http://www.medped.org/who/page10.html - Dutch Lipid Clinic Network
http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf - Simon-Broome Registry
http://www.ncbi.nlm.nih.gov/books/NBK53810/ Comment: It should be noted that LDL-C cut points usually vary with age.
- U.S. Make Early Diagnosis to Prevent Early Death (MEDPED)
- The clinical diagnosis of FH is most likely when two or more first-degree relatives are found to have elevated LDL-C in the range noted above, when pediatric cases are identified in the family, or when the patient or a close relative has tendon xanthomas.
- Once a family is diagnosed with FH, somewhat lower LDL-C cut points can be applied to identify additional affected family members.
- Patients with FH occasionally have elevated triglycerides, and high triglyceride levels should NOT exclude the diagnosis of FH.