Universal Child FH Screening Proposed

–Novel strategy would identify both children and adults at high risk for CV events.

Doctors in the U.K. are proposing a novel strategy to identify very young children with familial hypercholesterolemia (FH). The strategy would also identify and help prevent events in the parents who also have FH.

The new approach begins with a heel-stick capillary blood sample used to measure cholesterol levels during the routine immunization visit at 13 months. Children with very high cholesterol levels who are subsequently found to have a known FH mutation or high cholesterol level on a second blood sample are deemed to have FH. The parents of the FH children are then screened for FH mutations or elevated cholesterol levels.

In a paper published in the New England Journal of Medicine, researchers reported that after initiating that screening process in more than 10,000 children, they identified 28 children who had cholesterol levels above the 99.2 percentile, 20 of whom had a FH mutation. Another 17 children did not meet the cholesterol level cutoff but had a FH mutation.

The screening program then identified 28 parents who had the same FH mutation as the child or who had the higher cholesterol level, 25 of whom started statin therapy. (One parent couldn’t be contacted and two parents were pregnant.) The authors reported that “all the parents indicated that they thought the screening was worthwhile and none reported negative effects.”

FH has long been known to be an important source of early cardiovascular disease and death. Efforts to improve identification of people with FH have increased based on the success of statins and, more recently, the advent of the extremely potent PCSK9 inhibitors, though these have not yet been shown to reduce cardiovascular events.

There is no widely-accepted standard for identifying and treating FH. Most strategies have focused on screening adults. One strategy that has been proposed is cascade screening, which involves aggressive testing of relatives of FH patients. But early studies of cascade screening indicate that it can’t identify most people with FH unless it is performed very aggressively.

A larger problem is that it is difficult to diagnose FH without widespread lipid and genetic screening, which raises questions about cost-effectiveness and other ethical issues. Further, many people with high LDL levels don’t have a genetic mutation linked to FH and a significant percentage of people with known FH mutations don’t have elevated LDL levels. On the other hand, people with high LDL levels who have a known FH mutation are at significantly higher risk than people with elevated LDL levels alone, likely because the mutation is an indicator of a lifetime exposure to elevated LDL.

Because of the inherent difficulties and problems involving FH screening the authors said that they regard FH, however it is defined, “not as the disorder but rather as a positive screening test for the development of premature cardiovascular disease,” similar to the way BRCA1 is regarded as a risk factor for breast and ovarian cancer. Regarding FH “as a risk factor for cardiovascular disease rather than as a disorder recognizes that cardiovascular disease is not inevitable in persons who have familial hypercholesterolemia and that lowering of cholesterol levels reduces exposure to the main cause of cardiovascular disease rather than treats an existing disease.”

A novel and important feature of the new U.K. strategy is that it incorporates FH screening as part of the routine and nearly-universal childhood vaccination program. “The genius of screening babies is that in almost all cases one of the parents is right there in the room, usually the mom,” commented Marilyn Mann, an FH patient advocate. “Women tend to manage their families’ health care, so telling them they need to be tested and make sure their husband gets tested could work,” she observed. The next step would be “to get the pediatricians and family physicians to endorse the program.”

James Stein, MD, a preventive cardiologist at the University of Wisconsin in Madison, also expressed initial support for the novel program. One advantage is that a heel stick in a baby is far more tolerable than a venipuncture in an older child (a part of other proposals). The child will likely benefit from early risk factor reduction; if necessary, treatment with statins would not be initiated until much later.

“No one (I hope) is going to give a 1 to 2 year old a statin, so the family then becomes motivated to adopt healthy lifestyle changes and the child can be managed with the decision to treat deferred until more information is known and shared decision-making is facilitated,” said Stein. The FH parent would also benefit from the earlier diagnosis and treatment, said Stein.

Stein said he did not see a need for genetic testing, however. “Just do a second heel stick” on all the kids with elevated cholesterol, he suggested.

But genetic testing is important, argued Sek Kathiresan, MD, of Massachusetts General Hospital in Boston. “For any given level of LDL cholesterol, if the high LDL is due to FH mutation, then risk for cardiovascular disease is much higher. This is because of higher cumulative exposure to LDL.”

But Stein and Kathiresan largely agreed in their admiration for the overall strategy proposed in the paper. “Screening children and parents early in life is feasible and likely to be effective,” said Kathiresan.

The biggest limitation to the strategy is the low rate of identification, Stein said. “They had to screen 360 people to find one child, though that number gets better, of course, if they find a parent. And screening does not identify a disease with short term, serious effects (like screening for PKU [phenylketonuria]), it identifies a risk factor for something that will happen decades later, so the efficacy still remains an issue. Lifestyle interventions are relatively innocuous, but statins have real side effects that have been incompletely studied in kids and teens.”

The first author of the study, David Wald, MD, of the University of London, said that “Childhood vaccination is an ideal opportunity to screen because parents are motivated and uptake is high.” By contrast, cascade screening “has been shown to miss large numbers of affected individuals [and] so is an inadequate method of population screening.”

Saurabh Jha, MBBS, a radiologist at the University of Pennsylvania in Philadelphia who has written extensively about the paradoxes of screening, offered the following observation:

“At first, it seems we’re throwing a wide net to catch rare trout, but this net is no wider than other nets. Applying the more liberal threshold, 40 cases of FH were found in 10,095 kids, which is a number-needed-to screen (NNS) of 250. When you include the parents, who were unbeknownst to have FH or high cholesterol, that’s an NNS of 125 – hardly unrespectable compared with cancer screening. For smokers at high risk for lung cancer, the NNS is 320.”

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  1. Many thanks to Marilyn as always for representing us FH patients so well.
    I am by no means saying children should take statins at age 2, but to withhold too long will swing the bell in the wrong direction. You would not withhold diabetes drugs from children,and even short term effects of high LDL are detrimental,when you look at carotid íntima thickness of siblings with,and without, FH.
    Early diagnosis is key,and to be able to capture a parent,with years of high LDL exposure at the same time,before a heart event is a wonderful,when fathers are having heart attacks at age 33.

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