Familial hypercholesterolemia (FH) is an inherited condition causing high levels of low-density lipoprotein cholesterol (LDL-C) starting early in life, with the risk of cardiovascular disease, and even death, compounding over time.

The disorder may occur in one in every 200 to 250 people, according to the scientific literature. However, FH is underdiagnosed and undertreated, said Michael Murray, MD, director of clinical genomics at Geisinger Medical Center in Danville, Pennsylvania. Researchers need to find better ways of identifying patients with FH because once they are diagnosed, “we have medications that change the lifetime risks associated with this condition,” he added.

How to best detect FH is still being investigated. While a simple and affordable universal cholesterol blood test identifies FH in children, older family members—who also may have the condition—typically need a more expensive genetic test.

The ability to identify FH by cholesterol measurement alone is age dependent, said Samuel Gidding, MD, professor of pediatrics at Thomas Jefferson University in Philadelphia and head of the Cardiology Division at Nemours Cardiac Center in Wilmington, Delaware. The reason is that the environmental effects on cholesterol levels from things like fat-laden diets, lack of exercise, and smoking start to mount as people age.

Cascade screening, which involves screening first-degree family members after an index case is identified, is one option being explored. Regardless of how FH is identified, Murray anticipates that most people with the condition could be aggressively managed with statins rather than newer, more expensive classes of drugs such as PCSK9 inhibitors.

Universal Testing in Children

In 2011, a panel sponsored by the National Heart, Lung, and Blood Institute (NHLBI) issued guidelines on universal screening for FH, among other lipid disorders, recommending a cholesterol blood test in children ages 9 to 11. However, this recommendation is not being consistently followed, according to Paul Hopkins, MD, MSPH, FNLA, professor of internal medicine in the cardiovascular genetics research program at the University of Utah School of Medicine in Salt Lake City. Moreover, doctors typically don’t extend the testing services to family members who may also be at risk for FH.

Complicating the matter, in 2016, the influential U.S. Preventive Services Task Force stated there was insufficient data to assess benefits or harms of screening for lipid disorders in children or adolescents age 20 or younger. Long-term studies on the benefits of screening in these populations and the effect on heart disease and stroke outcomes are lacking.

Collecting this type of outcomes data could take decades and most clinicians do not want to wait that long to screen and offer patients treatment, said Murray. “Many studies show elevated LDL-C can lead to heart attack and stroke and that medication and diet lower that risk,” he said.

Studies to assess the long-term effects of statins on children aren’t likely to happen because of expense, according to Hopkins. “Maybe there will be long-term observational follow-up studies, but I’d be surprised if anything more were done,” he said.

Newborn Screening: Too Soon or Perfect Time?

Scientists are also deliberating the timing of blood testing. While the NHLBI recommended screening in children ages 9 to 11, a cholesterol test could be added to universal newborn screening, suggested Daniel Rader, MD, Seymour Gray professor of molecular medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia. “It would be very cheap, and the data suggest that a newborn with FH has cholesterol far above that of a newborn without FH,” he said.

While no immediate medical treatment would be possible in a newborn, parents would be aware that their baby has FH and could consult with a doctor when the child is older to see if medication is warranted, said Rader. Ensuring the child has a healthy diet and lifestyle might also be more of a priority. 

While the discussion continues, the U.S. is moving toward universal cholesterol testing, in children ages 9 to 11, said Gidding, who served on the NHLBI panel. “It’s starting to gain some traction.”

Genetic Screening—Complicated and Costly

Genetic testing for FH is also an option, although universal screening “may be a bit of a way off,” said Rader. Genomic sequencing, which is required to detect FH mutations, is too expensive. “It’s not like cystic fibrosis where there are mutations in one gene to look for and about 70 percent of cases are due to a specific mutation that can simply be genotyped, at least initially,” he said. “FH has several different mutations on at least three genes that need to be screened and no prominent mutation in the most commonly affected gene, so the entire gene (and usually the other two genes) need to sequenced,” he said.

About 80 percent of FH mutations are in the LDL receptor (LDLR) gene, said Gidding. Depending on the population studied, defects are typically found in LDLR, APOB, and PCSK9. Other variants have been identified and researchers are expected to find more. “By and large, genetic testing for FH has higher yields and is more accurate than testing for many other genetic diseases,” he said. 

Murray and his colleagues are evaluating data from patients enrolled in MyCode Community Health Initiative at Geisinger Health System, who undergo exome sequencing (Science 2016;354:1550–7). Researchers expect to have genetic and cholesterol data on 90,000 people by the end of this year, generating further information on FH prevalence and genomic variants.

Catching Cases via Cascade Screening

Using results of universal cholesterol screening in children to initiate cascade screening in family members may be the best way to identify all individuals with FH in a given population, said Gidding.

A recent study found that cascade screening is feasible (N Engl J Med 2016;375:1628–37). In this study, researchers conducted blood tests in children to screen for high cholesterol and FH genetic mutations at the time of immunization. If the children tested positive, their parents were screened for FH mutations. A total of 10,096 children ages 1 to 2 years were screened during routine immunization visits. For every 1,000 children screened, 8 people—4 children and 4 parents—were identified as having FH.

“Universal screening in little kids and cascade screening in relatives of these children who test positive makes sense,” said Hopkins. However, “cascade screening implies that you have a proband. Family screening often only goes so far since some people don’t know who their relatives are or contacting them can be difficult. So, you always have to be finding new probands.”

Not one of the parents who carried a gene mutation and who was found through a positive diagnosis of their child was being treated, added Hopkins, who was not involved in the study. Because FH is found in families, the method of screening described in the paper is not just for the child’s benefit but also will help the whole family, he said.

In this paper, the authors found that the cost associated with a cholesterol screening blood test and a genetic test was $7 and $300, respectively. “I’m not sure if the U.S. is ready for this expense,” said Gidding, referring to the genetic screen.

Despite the cost, genetic screening in adults can be particularly useful because some data demonstrate that about 40% of FH patients have LDL-C ≤190 mg/dL, said Murray. Additionally, some adults who have LDL-C of 150 mg/dL have a genetic change indicative of FH. “If you compared two people with an LDL-C of 150 [mg/dL] and one of these individuals had an FH mutation and the other did not, the person with the mutation would have a higher risk of heart attack and stroke,” said Murray. Moreover, the cholesterol-lowering goals of someone with FH are more stringent than those of an individual without FH. “Each decade we wait to intervene shortens that person’s lifespan,” said Murray. “This is why early identification, early intervention, and aggressive management is the goal. We’ll keep working to get there.”

Heather Lindsey is a freelance medical writer in Maplewood, New Jersey.+Email:[email protected]