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.
Table 1. MEDPED Criteria for the Diagnosis of FH
Figure 1. Tendon Xanthoma - Achilles
Figure 2. Complete Corneal Arcus
