Applied Evidence

Familial hypercholesterolemia: Clues to catching it early

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Here’s how to spot the red flags that could signal your patient is at risk and steps you can take to potentially extend his or her life.




› When one member of a family has early heart disease, screen the entire family for familial hypercholesterolemia (FH). A
› Consider all patients with FH as being at high risk for coronary heart disease, regardless of their Framingham Risk Score. C
› Treat FH patients with statins early to avoid cardiovascular events. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Familial hypercholesterolemia (FH) poses a “silent” threat to patients with the condition, putting them at great risk of a coronary event. This genetic disorder, in which one or more mutations cause extremely high low-density lipoprotein (LDL) cholesterol levels, goes undiagnosed in approximately 80% of patients who have it.1 As a result, men with FH have a >50% risk of coronary heart disease (CHD) by age 50 and women with FH have a 30% risk of CHD by age 60.2 Patients with FH face a much higher risk of dying from a coronary event than those in the general population.3 For example, women between the ages of 20 and 39 who have this disorder are 125 times more likely to die of a coronary event than those who don’t.3

Unfortunately, FH can be difficult to diagnose. Some patients have physical findings, but these features can be subtle and easily missed. Typically, however, FH is diagnosed based on a patient’s cholesterol level and family history. By implementing screening and early treatment for FH, you may be able to initiate treatment that can temper the development of atherosclerosis and possibly extend a patient’s life.4

Two forms of the disorder, although one is more common

There are 2 types of FH:

Heterozygous FH (HeFH) occurs in about 1 in 300 to 500 people, which makes it more common than Down syndrome.5 More than a half a million people in the United States have HeFH.6

Homozygous FH (HoFH) is more serious than HeFH, and less common, affecting one in 1 million people. Homozygous carriers suffer from CHD much earlier than those with HeFH; some die within the first few years of life.7

Regardless of whether an affected individual inherited FH from one or both parents, more than one thousand mutations are known to cause inadequate clearance of LDL from the bloodstream.8 One of the most common mutations is a defective LDL receptor gene. Other abnormalities are known to occur with the proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B genes.9

Start with screening

Suspect FH in patients who have a family history of premature heart disease. Also consider the patient’s ethnic background. The prevalence of FH is as high as one in 100 among certain groups, including French Canadians, Christian Lebanese, and 3 populations in South Africa (Ashkenazi Jews, Dutch Afrikaners, and Asian Indians).10

When there is high suspicion of FH based on a patient’s family history or ethnicity, additional screening is warranted for any patient older than age 2.11 If a patient’s family history is incomplete (eg, adoption, single-parent family), a lower threshold for screening is appropriate.

Lipid screening includes measuring serum total, LDL, and high-density lipoprotein cholesterol in either fasting or non-fasting samples. The United States Preventive Services Task Force (USPSTF) offers gender-specific recommendations for lipid disorder screening in the general population. For men, universal screening is recommended starting at age 35, and screening for those at increased risk of CHD should start at age 20.12

For women, the USPSTF recommends lipid screening only for those over age 20 who are at increased risk for CHD; such screening is strongly recommended for high-risk women ages 45 and older. In light of the serious consequences associated with FH, the National Lipid Association recommends lipid screening for all adults starting at age 20 (TABLE 1).13

What about kids? The recommendations for lipid screening in children and adolescents are mixed. Both the USPSTF and the American Academy of Family Physicians indicate that there is insufficient evidence to screen for lipid disorders in asymptomatic children and adolescents.14,15 However, in a set of recommendations based on expert opinion, the National Heart, Lung, and Blood Institute (NHLBI) suggests universal screening for younger patients with a non-fasting lipid profile once between ages 9 to 11 and again between ages 17 to 21.16 The American Academy of Pediatrics has adopted the NHLBI recommendations.17

Physical exam findings that suggest familial hypercholesterolemia

Tendon xanthomas (A), a thickening of the soft tissue as a result of infiltration by lipid-rich cells, most commonly occur at the Achilles and metacarpal tendons, but also can be seen at the patellar and triceps tendons.

Tuberous xanthomas or xanthelasmas (B) are waxy-appearing growths that appear to be pasted on the skin in areas around the face, commonly the eyelids.

Arcus corneae (C) is an opaque ring around the outer edge of the cornea.

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