Screening Gaps Miss Childhood Heart Problems

Jake Remaly

October 13, 2022

People with a rare genetic condition that causes extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) may miss out on decades of treatment because of a lack of lipid screening in childhood, researchers reported at the 2022 annual meeting of the American Academy of Pediatrics (AAP).

The condition, homozygous familial hypercholesterolemia (FH), raises the risk for atherosclerotic cardiovascular disease (ASCVD) as early as the first decade of life.

Routine screening for FH is uncommon, however, the researchers said. Lack of familiarity with guidelines and limited access to lipid specialists have been cited as possible reasons for inconsistent screening practices.

"These findings and recent improvement in lipid lowering therapies make a compelling case for rigorous compliance with AAP's guidelines on lipid screening for children with a family history of FH or ASCVD at age 2," study coauthor Mary P. McGowan, MD, chief medical officer of the Family Heart Foundation, said in a statement about the new study.

Early Consequences

To characterize patients with homozygous FH, McGowan and her colleagues examined data from 67 participants in the CASCADE-FH registry. The Family Heart Foundation created the registry in 2013, and 40 medical centers in the United States contribute data to the repository. The researchers had access to data about patients with homozygous FH from 20 centers in the registry.

McGowan's group compared 16 patients with homozygous FH who enrolled in the registry when they were children and 51 patients who were adults at the time of their enrollment.

Patients enrolled as children had a median age at diagnosis of 2 years (interquartile range [IQR], 2 - 3.5), whereas patients enrolled as adults had a median age at diagnosis of 12.6 years (IQR, 4.1 - 26.5).

The median untreated level of LDL-C in those enrolled as children was 776 mg/dL (IQR, 704 - 892). Among those enrolled as adults, it was 533 mg/dL (IQR, 467 - 702).

Approximately 19% of those enrolled as children had evidence of aortic valve stenosis, and 43.8% had evidence of ASCVD. The median age at onset of ASCVD was 8.9 years. One child was diagnosed with ASCVD at age 2 years and underwent liver transplant at age 4 years. Another was diagnosed with the condition at age 3 years and underwent liver transplant at age 8 years. Two children underwent coronary artery bypass grafting at ages 6 years and 14 years. Five participants underwent liver transplant before age 18 years.

About 56% of participants who enrolled as children had xanthomas, or fat deposits in tendons, and none had corneal arcus — a gray-white line of fat deposits around the edge of the cornea, both of which can indicate homozygous FH in children.

Treatment reduced LDL-C substantially, but only 25% of children achieved goal levels of cholesterol, the researchers reported. Patients who received more lipid-lowering therapies had a better chance of reaching their target levels, they found.

The data raise "the possibility that only children with the most severe phenotypes are diagnosed before adulthood," the researchers said.

Clinical diagnosis of homozygous FH can be based on LDL-C levels, family history, and the presence of xanthomas, the researchers noted. Many children do not have physical findings, however, and a lipid panel or genetic testing may be necessary.

"There is a clear need to implement universal screening" to identify all children with homozygous FH and heterozygous FH, a less severe and more common form of FH, McGowan said.

Possible Missed Cases

As many as 1 in 250 people may have heterozygous FH, and 1 in 300,000 people may have homozygous FH, according to estimates. Patients with homozygous FH have two FH genes, one from each parent. In patients with homozygous FH, levels of LDL-C levels typically range between 400 and 1000 mg/dL without treatment, which is four to 10 times higher than normal concentrations of the blood fat, according to the Family Heart Foundation.

"This study adds to a growing body of literature — including our own work — demonstrating that recommended 'universal screening' occurs in barely 1 in 5 children. This means some patients are not being recognized as having treatable diseases," said Justin H. Berger, MD, PhD, a pediatric cardiologist at Children's Hospital of Philadelphia.

Even among children who are at the highest risk for early onset adult-type heart disease, only a quarter to two-thirds receive recommended screening, Berger, who was not a member of the study team, said.

While Berger advocates universal lipid screening, improving screening rates in practice probably isn't as simple as telling clinicians to screen more, he said. "Increasing testing will increase healthcare spending and the burden on busy primary care providers without addressing who will subsequently evaluate and manage children with abnormal lipid screening results," Berger said.

Instead, clinicians may want to focus on screening patients who are at risk, which "could have dramatic benefits for their life-long cardiovascular health," he said.

McGowan disclosed ties to Abbott and Regeneron, and her coauthors disclosed ties to Esperion Therapeutics and research funding from Regeneron and REGENXBIO. Berger disclosed no relevant financial relationships.

American Academy of Pediatrics (AAP) 2022 National Conference. Presented October 8, 2022.

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