Familial Hypercholesterolemia (FH)

For Researchers and Clinicians

Why FH Matters

Familial hypercholesterolemia (FH) is an autosomal dominant condition that affects 1 in 250 people worldwide, characterized by a genetic mutation that affects how cholesterol is regulated in the body. This allows high amounts of low-density lipoprotein (LDL) to accumulate and cause atherosclerosis. As a result, young adults and even children with this genetic condition can face complications such as heart attacks and strokes.

Though individuals with untreated FH can have up to a 20x increase in lifetime risk of heart disease when compared to the general population, estimates show that only 15-20% of these patients have been diagnosed. Further still, current data suggests that over 25% of documented FH patients have already progressed to heart disease by the time this diagnosis is made. With targeted early interventions, however, FH patients can reduce their risk of heart disease down to that of the general population. Caregiver awareness about the dangers of FH and its early presenting signs can therefore be pivotal in reducing lifetime risk for not only the patient, but also their family members.

Diagnostic Criteria

Though FH is a genetic condition, it is possible to diagnose this condition based on clinical criteria alone. Clinicians should consider a FH diagnosis if the patient:

  • Presents with a family history of premature coronary heart disease (CHD) (at age <55 in males, <65 in females)
  • Has high LDL-C without current treatment** (if ≥20 years old, must be ≥190 mg/dL; if <20 years old, must be ≥160 mg/dL) **If currently being treated, LDL-C levels must be >124 mg/dL

In addition, the presence of xanthomas, corneal arcus or xanthelasmas before age 60 are suggestive of FH.

Though clinical diagnoses are more common, genetic testing identifying mutations in the LDLR gene, apoB gene, or PCSK9 gene are available and can confirm the diagnosis. However, treatment decisions are ultimately made based on phenotype, not thegenetic testing result.

Once an individual with FH has been identified, lipid testing with or without genetic testing for all first-degree relatives should be strongly encouraged.

Treatment

Due to the familial nature of this disease, early and aggressive intervention is key. Pharmacological therapy targeting LDL reduction, such as statins, ezetimibe, bile acid sequestrants, and PCSK9 inhibitors should be considered. For those with heterozygous FH, therapy should be initiated between the ages of 8-10, and statin therapy can be initiated at time of diagnosis. In addition, physicians should engage in discussion with patients about how to reduce risk through lifestyle modifications, such as exercise and a heart-healthy diet.

Ultimately, the target levels of LDL-C for adults with FH is a 50% reduction in pre-treatment LDL-C with:

  • LDL-C < 100 mg/dL without coronary heart disease and/or other factors
  • LDL-C < 70 mg/dL with coronary heart disease and/or other factors

Related Care at Emory