FH Screening Started at Time of Childhood Immunization Feasible and Effective

Primary care physicians who screen for familial hypercholesterolemia (FH) at the time of childhood immunization can successfully identify not only children with the lipid disorder but also their parents through reverse-cascade testing, a new study shows.

Obtaining point-of-care capillary blood samples from 13-month-old children, the researchers report, would identify four children and four parents with FH for every 1,000 children screened.

To TCTMD, lead investigator David Wald, FRCP (Barts and the London School of Medicine, England), said the current method of testing, cascade screening, has been shown to miss large numbers of affected individuals and is inadequate for population screening. The child-parent screening approach overcomes that limitation. “Because children are already seeing their primary care physicians for vaccinations at precisely the right time in life when a cholesterol test is most discriminatory for detecting the disorder, this is an ideal opportunity to screen,” Wald stated in an email.

Joshua Knowles, MD (Stanford University Medical Center, CA), an expert in FH not involved in the study, called the study a “tour de force of merging clinical phenotyping, molecular medicine, and precision medicine.” The effort, he said, shows what might be possible in the United States.

“We’ve known for a long time that screening for FH in childhood is probably going to be much better than screening for it later,” he told TCTMD. “If you really want to identify a genetic condition like FH, the genetic signals are stronger in the pediatric years so misclassification is less when you use lipid levels in relatively young children. These children haven’t had a lifetime of bad environmental exposure that can make it difficult to tease out who has FH and who doesn’t.”

Knowles said that none of these children would be treated—pharmacologic therapy, apart from very rare exceptions, is not started before 8 or 10 years of age in severe FH—but the family would be given counsel about the importance of “going above and beyond” a healthy diet and daily exercise. The family would also have time to mentally prepare for the initiation of statins, if needed.

In an editorial accompanying the study, Brian McCrindle, MD (Sick Children’s Hospital, Toronto, Canada) and Samuel Gidding, MD (A.I. DuPont Hospital for Children, Wilmington, DE), state that childhood is a critical time when atherosclerosis may develop—the presence of elevated LDL cholesterol levels accelerates the process. “The prevention of atherosclerosis beginning in childhood is likely to result in greater reductions in cardiovascular disease morbidity and mortality than those achieved with current efforts that are directed at preventing events in older adults,” they write.

Get a Vaccination, Test for FH

Published October 26, 2016 in the New England Journal of Medicine, the study included children and parents recruited from 92 general medical practices in the United Kingdom. The point-of-care capillary blood samples were obtained from 10,095 children 1 to 2 years old during routine immunization visits. The researchers used a prespecified cholesterol cutoff to identify children with elevated total cholesterol levels, and if elevated, the blood samples were tested for the presence of one of 48 single-nucleotide polymorphisms (SNPs) linked with FH, including the most common LDL receptor mutations.

With a cutoff for elevated total cholesterol equivalent to the 99.2 percentile, they identified 28 children who had a positive screening result for FH. This included 20 children with an FH mutation and eight children with elevated cholesterol on a repeated heel-stick test. When the elevated cholesterol threshold was lowered to the 95th percentile, 40 children with FH were identified. This included 32 children with an FH mutation and 8 children with elevated total cholesterol levels on two screening tests.

“Identifying an FH mutation, among those with a high cholesterol level at or above the 95th percentile, is useful because it identifies those children at highest risk of an inherited heart disease event [and] avoids labelling children with chance high levels as positive,” said Wald. “[It] reduces the positive rate from about 5% to about 0.4%. This makes the screening more accurate and avoids overtreatment.” 

Overall, an FH mutation was identified in 37 of the 10,095 children, or 1 in 237 children. Following up with the parents of 32 children with an FH mutation (for 5 children, a parent declined or was unavailable for testing), the investigators found that in 27 cases the parent with the higher total cholesterol level had the same FH mutation. In total, 25 of these individuals started statin therapy.   

For the researchers, this child-parent screening method is “feasible and effective” in the UK. Wald said it provides evidence and a model for public health agencies to consider this routine testing to prevent premature cardiovascular events resulting from inherited FH. Getting family physicians involved can help avoid extra clinic visits, result in greater screening uptake, and lower costs, he added.

In their editorial, McCrindle and Gidding agree, calling the screening strategy “efficient” and “effective,” adding that it “affords the greatest opportunity for the prevention of atherosclerosis and achievement of a low lifetime risk of cardiovascular disease.”

Screening in the US Controversial

In August, the United States Preventative Services Task Force (USPSTF) issued a statement that came out against widespread cholesterol testing in asymptomatic children and adolescents. The USPSTF stated the “current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders” in children and adolescents.

In contrast, a 2011 expert panel on cardiovascular health and risk reduction from the National Heart, Lung, and Blood Institute as well as the American Academy of Pediatrics recommended screening for elevated cholesterol levels in children aged 9 to 11 years old followed by another full lipid screening between 17 to 21 years old.

Based on the new research, Wald said he believes the USPSTF recommendations “can be reconsidered.” In their paper, they see FH less as a disorder but more as a positive screening test for premature cardiovascular disease. This shift in thinking recognizes that cardiovascular disease is not inevitable in persons with FH and that lowering cholesterol levels “reduces exposure to the main cause of cardiovascular disease rather than treats an existing disease,” the notes.

To TCTMD, Knowles said data from CASCADE FH, the national patient registry tracking patients with the lipid disorder, shows the average age of diagnosis is in the mid-40s, with 25% to 35% of these individuals having already had a cardiovascular event. “People are being diagnosed very late, after they’ve already suffered consequences,” he said. “That’s one of the major problems. Here we have a definitely preventable disease that is being missed, or not being diagnosed, until bad things happen.”

The hope, Knowles added, is that if children are identified with FH, physicians could perform reverse-cascade screening, targeting the undiagnosed parents with the condition. The mantra in FH is that “you never identify individuals with FH, you identify families,” he added. “You have this molecular diagnosis, and you pull the string. You start to unravel the string for the rest of the family. You start to reel in the people who didn’t know they had a diagnosis.”

For the editorialists, universal screening of FH in adults is likely not feasible or cost-effective, but focusing on children would result in more complete and earlier identification of FH. The effect of reverse-cascade screening starting with the child would potentially identify family members with FH at a younger age when treatment has larger benefits.

One of the advantages of the present study is that the spectrum of FH mutations could be identified with a relatively cost-effective assessment of 48 common SNPs that account for FH in the UK, said Knowles. This is significantly cheaper than sequencing the three genes known to cause FH. In the US, the spectrum of SNP mutations hasn’t been as well characterized when compared with the UK, largely because “we’re a bigger melting pot,” he added. “That’s something that would have to be considered as well.”

That said, Knowles believes the screening protocol adopted by the British researchers should be tested in the US, with the goal hopefully being the adoption of similar child-parent screening employed by primary care physicians.