Familial Hypercholesterolemia: An Underdiagnosed Disease Gets a Second Look

Cholesterol build up
Cholesterol build up
Despite the frequency with which it occurs, familial hypercholesterolemia often goes undiagnosed, with only 10% of affected patients aware of this genetic disorder.

Despite the frequency with which it occurs, familial hypercholesterolemia (FH) often goes undiagnosed, with only approximately 10% of affected patients aware of this genetic disorder.1 Early detection is critical because patients with FH are at high risk for premature coronary heart disease, myocardial infarction, and death.2 First-degree relatives of patients with FH have a 50% chance of also being diagnosed.3

Why FH Goes Unchecked

Underdiagnosis of FH is a multifactorial problem.1 Many clinicians may be unaware of the genetic disorder and how to treat patients with intensive therapy. To illustrate this point, Laney K. Jones, PharmD, MPH, assistant professor at the Center for Pharmacy Innovation and Outcomes at the Geisinger Health Clinic in Forty Fort, Pennsylvania and colleagues conducted a chart review of 23 patients diagnosed with FH.1 Of the patients with FH, only 17% achieved optimal lipid control.1

“Clinicians are starting to recognize the need and value of prevention [of FH] within their practices,” noted Jones. “FH just received a diagnosis code in 2015, so that has helped bring it to the attention of clinicians. It may [not have] been a condition that was well understood or there [may not have been] much knowledge about when they attended medical school.”

A Closer Look at Clotting Factors

The danger of FH goes beyond high low-density lipoprotein cholesterol (LDL-C).4 Inherited coagulation factors, such as high levels of plasma fibrinogen and factor VIII, may be just as deleterious to patients’ cardiovascular health.4 In a review of studies examining FH, researchers sought to counter long-held opinions that LDL-C should be the main target to reduce the risk for early death from FH-related cardiovascular disease (CVD) events, citing several examples:

  • LDL-C had no association with patients’ atherosclerosis severity.
  • Patients with FH tended to have similar longevity to those without FH.
  • LDL-C did not affect the prevalence of CVD in people with and without FH.
  • In controlled, randomized trials, people with FH did not derive clear benefit from cholesterol-lowering therapies.

Of the successful LDL-C lowering trials, the researchers reported that apheresis, not statins, was the key to reducing CVD events.4 This may be because apheresis reduces lipid levels as well as removes factors that lead to coagulopathy.4

“Our work should redirect clinicians away from cholesterol to clotting factors as the more proximal risk factor for heart disease,” said David Diamond, PhD, from the Department of Psychology and the Department of Molecular Pharmacology and Physiology at the University of South Florida in Tampa, who was 1 of the review authors. “Certain risk factors, particularly levels of fibrinogen and factor VIII, are more useful than LDL in identifying people with FH at greater risk. Most important is for people with FH to have heightened awareness that they can be extraordinarily sensitive to conventional risk factors, including smoking, high blood sugar, obesity, and stress.”

The theory that atherosclerosis is independent of LDL-C was furthered by research that demonstrated that coronary artery calcium score predicted risk for future coronary events.5,6 With the aid of computed tomography imaging, the researchers found that 49% of a cohort of 206 patients (mean age, 45 ± 14 years; 63.6% women) with coronary artery calcium scores of 0 had no CVD events, whereas patients who had coronary artery calcium scores of 1 to 100 and >100 had CVD event rates of 26% and 44%, respectively.5,6

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Parent-Child Testing During Immunization Visits

Because early detection of FH is so important to forestall major premature cardiovascular events in young adulthood, David Wald, MD, from the Wolfson Institute of Preventive Medicine, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom, and colleagues screened children aged 1 to 2 years and their parents during routine immunization visits.7 Screening at this early age had many benefits: parents are most receptive to preventive measures during immunization visits, and according to prior research, FH is best detected in cholesterol levels from ages 1 to 9 years.7

Using a prespecified cholesterol threshold of 1.53 multiples of the median, which corresponded to the 99th percentile of total cholesterol level, and through detection of FH mutations, the researchers identified 28 children with FH in a group of 10,095 children. This value amounted to a positive rate for HF among 10,095 children of 0.3% (95% CI, 0.2%-0.4%). When applied to the screening of a typical population of 10,000 children, these findings translated to an estimated rate of identification of 8 cases (4 children and 4 parents) per 1000 children screened.7

“There is now a recognition that screening needs to start in childhood, ideally between the ages of 1 and 2 years because this is the most accurate time to screen, maximizing the detection rate and minimizing the false-positive rate,” said Dr Wald.

Patient Decision Making for FH Screening and Treatment

Because a diagnosis of FH for 1 patient can affect the rest of the family, especially young children, Medhat Farwati, MD, postdoctoral research fellow in the atherosclerosis and lipid genomics laboratory at the Mayo Clinic in Rochester, Minnesota, and colleagues sought to determine the best approach to developing patient decision aids (brochures that provide patients with essential information) by asking patients and clinicians what should be included in them.8

In a panel of 12 clinicians and 14 patients, the researchers found that information on treatment options, genetic testing, and insurance coverage/costs presented in lay language was most important to patients. Clinicians sought a tool that would explain genetic testing and cardiovascular risks in HF and provide visual aids for patients to absorb the material.8

“We hope that more clinicians appreciate the potential role of decision aids in creating an environment for shared decision making,” said Dr Farwati, the lead author of the study. “This is particularly important, given that most patients in our study voiced their eagerness to participate in the decision-making process alongside their physicians.”

“A Cochrane review of 200 studies using decision aids found that compared [with] regular care, decision aids result in greater patient involvement, more realistic expectations, and a greater level of knowledge regarding clinical decisions,” noted coauthor Iftikhar J. Kullo, MD, professor of medicine at the Mayo Clinic in Rochester. “In addition, it has been reported that when patients are actively involved in making treatment decisions, adherence to the chosen therapy is increased.”

Summary & Clinical Applicability

Diagnosing familiar hypercholesterolemia and treating it early can forestall premature coronary heart disease. The problem is that few people who have hypercholesterolemia know they have FH, which requires more intensive lipid-lowering therapy.

Limitations & Disclosures


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1. Jones LK, Kulchak Rahm A, Manickam K, et al. Healthcare utilization and patients’ perspectives after receiving a positive genetic test for familial hypercholesterolemia. Circ Genom Precis Med. 2018;11(8):e002146.

2. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: guidelines and new therapies. Atherosclerosis. 2018;277:483-492.

3. Brett T, Qureshi N, Gidding S, Watts GF. Screening for familial hypercholesterolaemia in primary care: time for general practice to play its part. Atherosclerosis. 2018;277:399-406.

4. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses. 2018;121:60-63.

5. Shapiro MD, Blankstein R. Reclassifying risk in familial hypercholesterolemia: the power of a coronary artery calcium score of zero [published online November 15, 2018]. JACC Cardiovasc Imaging. doi:10.1016/j.jcmg.2018.10.010

6. Miname MH, Bittencourt MS, Moraes SR, et al. Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy [published online November 15, 2018]. JACC Cardiovasc Imaging. doi:10.1016/j.jcmg.2018.09.019

7. Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med. 2016;375(17):1628-1637.

8. Farwati M, Kumbamu A, Kochan DC, Kullo IJ. Patient and provider perspectives on a decision aid for familial hypercholesterolemia. J Pers Med. 2018;8(4):35.