A Silent Risk: The Critical Role of Awareness and Early Detection in Familial Hypercholesterolemia

September is celebrated as National Cholesterol Education Month, with September 24th marking Familial Hypercholesterolemia Awareness Day. Familial hypercholesterolemia (FH) is an inherited genetic condition that can be life-threatening if untreated. This genetic mutation leads to extremely heightened levels of low-density lipoprotein (LDL) that can be observed from birth. The drastic build-up of cholesterol contributes to a variety of early-onset cardiovascular issues, such as heart disease, aortic stenosis, and heart attacks.¹

Recognizing Familial Hypercholesterolemia Awareness Day is crucial for helping raise public awareness about the prevalence and risks of FH—which often remains undiagnosed, untreated, and can have serious implications for cardiovascular health. A greater understanding and awareness of FH could help health care providers and patients better identify and manage FH while mitigating the devastating consequences of unchecked cholesterol buildup.

Homozygous familial hypercholesterolemia affects an estimated 1 in 300,000 individuals | image credit: syahrir - stock.adobe.com

There are 2 subtypes of FH: heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH). HoFH constitutes a much more severe and rare diagnosis—LDL levels can rise above 4-10 times the levels of healthy individuals, which significantly increases their risk of premature heart issues. Approximately 1 out of 300,000 people are affected by HoFH, Sam Gidding, MD, World Heart Federation, and lead author, told The American Journal of Managed Care® (AJMC®); however, he explained how this condition often remains asymptomatic.

If symptoms appear, clinicians may find skin rashes resulting from fat or cholesterol build-up (xanthomas), but this hardly sets off alarms for HoFH. This was the case for Allison Jamison, board member of Family Heart Foundation, who told AJMC, “Starting from about age 3, I had these spots on the backs of my knees, on my Achilles tendons, and the bends of my elbows that my parents had taken me to a pediatrician to ask about. They were told, ‘Well, it was probably molluscum,’ which I think is a common misdiagnosis of what turned out, in fact, to be xanthomas.”

While these symptoms manifested at a very young age, Jamison added that "it took a couple of years before somebody said, ‘I think that might somehow be related to cholesterol in her blood.’” Despite this early awareness of cholesterol issues and her father’s experience with FH, it was not until the age of 35, when Jamison suffered from a sudden heart attack and cardiac arrest, that she received an official diagnosis of HoFH. Her stifled, delayed journey toward a HoFH diagnosis sheds light on an overwhelming issue in this condition: HoFH remains severely undiagnosed.

“We know that if you start treatment at birth, you're going to have the best outcomes, but because the diagnosis is typically delayed anywhere from 3-35 years of age, we don't know the true benefit of early intervention,” Gidding noted. Initiating treatment as soon as possible can have lasting benefits for those with HoFH, extend their life expectancy by 20 years, and even help some live a heart-attack-free life altogether, he added. Current treatments for HoFH include lipid- and cholesterol-lowering therapeutics such as lipoprotein apheresis, statins, zetia (Ezetimibe), and more, with a vast multitude of literature supporting the benefits of earlier diagnosis in patient outcomes. Yet, newer medications in this area have not been sufficiently tested in younger patients with HoFH, who could stand to benefit from them the most.²

Not only do these data gaps leave unanswered questions about treatment benefits in HoFH, but lacking awareness and insufficient screening guidelines further complicate clinical approaches. As Gidding, Jamison, and colleagues’ recent report argues, screening-measure reform offers a great opportunity to mitigate the burden of HoFH, bolster awareness, and counteract its history of delayed diagnoses.

“You won’t know you have a problem until you have an event unless you know what [your] LDL number is,” Jamison explained to AJMC. Jamison and her 2 siblings all had high cholesterol in their childhood, inherited from their father, but Jamison’s LDL levels stuck out as the highest of the 3. Her responses to treatment were different, as was her experience managing her cholesterol. By age 13, she had been diagnosed with aortic stenosis and had her first open-heart surgery at age 28 when she needed her aortic valve replaced. After her heart attack and cardiac arrest that came at age 35, she was still living with undiagnosed HoFH until genetic testing was offered during her participation in a clinical trial. “I was able to start treatments in childhood, but probably not as aggressive as we could have if we had known the actual diagnosis,” she told AJMC, describing the moment of her diagnosis as both relieving and empowering.

“This is what I have. So, we don't need to start with a 6-month trial on what happens if you change your diet, which had been suggested at various points in my life. Anytime I changed doctors, it was sort of 'Go back to the beginning. ‘Let's start with diet and exercise changes,’ and ‘Let's try this,’ and ‘Let's try that.’” Having this diagnosis is imperative to “get quicker to where you need to be with physicians,” she added. “I am dealing with a compromised heart muscle that is going to impact everything I do after this. And so, there's a layer of complexity to even dental procedures now that you have this additional history. It complicates, I would say, every facet of health care.”

Genetic testing and lipids screenings are valuable tools for detecting HoFH; however, the report by Gidding et al. outlines the flaws in US guidelines, which recommend pediatric lipid screening to begin around the ages of 9 and 11 years. “It's only being done right now in about 10 to 15% of children,” Gidding told AJMC, “In other places around the world, lipid screening tends to occur at much younger ages.” As their report outlines, countries like Slovakia and Slovenia initiate universal FH screening at age 5, China recommends screening as a part of children’s school entry physical exams, and Germany and the Czech Republic have begun steps to implement newborn screening programs.

“There are models for this screening,” Gidding continued, but there are a variety of complex factors that play into the development and approval of these programs in the US. At present, no validated HoFH newborn screening test exists, Gidding et al. wrote.

Of the primary barriers identified by the report, questions related to cost, direct-to-consumer testing, resource availability, advocacy, and ethics need to be addressed. For starters, a comprehensive economic analysis could more adequately estimate the costs related to newborn panels that screen for HoFH, as well as costs arising from diagnostic processes and treatment. Direct-to-consumer testing refers to a person’s ability to utilize commercial services—such as a blood spot for lipid testing—that would allow them to receive test results outside of a clinical setting. While this may provide some benefits and ease for patients seeking this testing, Gidding et al. note that concrete data is lacking on how primary care physicians would consider results from these sources because they may not be obtained from certified laboratories.

Furthermore, the authors argue that better referral networks should exist to connect patients with HoFH with pediatric lipid specialists to expedite their care, as well as implement hybrid care models to improve patient access. Finally, the role of advocacy organizations cannot be ignored, as they provide essential efforts to improve care access, influence health care policy, address disparities, and connect patients with HoFH to the care, specialists, or clinical trials they need. Unfortunately, some of these organizations act on limited budgets and rely on fundraising to continually offer these services, Gidding et al. add.

“Too many patients suffer premature morbidity and mortality due to delayed recognition. This is now particularly concerning given the plethora of new therapies available and the opportunities for personalized approaches to care based on understanding of genetics,” they write. “To truly identify all individuals with HoFH at an early age and to maximize the benefit of early treatment, newborn screening for the condition is the optimal course of action.”

As they continue to advocate for universal screening, they argue the importance of educating families, physicians, and the public on the value of screening for HoFH, the need to guarantee health care for affected patients—as HoFH can lead to significant lifetime costs—the creation of a diagnostic code specific to HoFH, among other measures.

As their report provides these recommendations for regulatory agencies, clinical communities, and others, Jamison emphasizes the value of undergoing a cholesterol screening regardless of suspicion, awareness, or family history of FH, reiterating the benefits of early intervention.

“What I would say to clinicians is: I think one of the reasons that it took so long for me to get a diagnosis is that I didn't fit the textbook case. When I come in at 28 years old, if they've heard of HoFH, they may not have expected me to have survived that long. So that diagnosis is off the table,” she told AJMC. “And there really is a spectrum of presentation of symptoms . . . So for clinicians, [I would say] to keep this in mind, to keep this as an option and not to dismiss it just because it doesn't seem to fit exactly the profile that you think it's going to.”

When asked about the most valuable efforts in research, advocacy, or awareness that are happening within her organization, Jamison highlighted the multi-pronged approach of the Family Heart Foundation and the community in which they can connect patients who have been diagnosed with FH. Not only does hearing similar stories or relating to the experiences of others affected by FH provide immense support, Jamison added, speaking to her own experience, but the Family Heart Foundation does great work for spreading awareness of FH throughout its immediate communities and various states.

“There is a lot of research that Family Heart puts out; we have access to millions of medical records that we can mine to really show clinicians, providers, payers, and patients that there is this gap," she explained. "There is this community of people out there who are living with FH and HoFH who are not diagnosed. So, to really be able to put a spotlight on this gap between what we know is out there and what has been diagnosed, I think, is huge. And to have the ability to bring together experts from all over the world, to really put together publications and to do research that is focused on this, we are able to highlight it in multiple different venues.”

The collaborative ventures embarked on by this organization and others like it unite the perspectives of patients, providers, insurance, and policymakers, Jamison continues. “As we work across all populations that are involved in the care of individuals who are living with FH and HoFH, it will take community effort across many disciplines to get awareness out.” And this sort of work, she concludes, provides the best opportunity not only for increasing awareness but also for addressing the glaring needs of a patient population that has gone underrecognized for too long.

To learn more about this condition, accessible resources, and the ongoing advocacy, research, and awareness efforts happening in this area, please visit the Family Heart Foundation and FH Europe webpages.

References

1. Familial Hypercholesterolemia. Familyheart.org. Accessed September 20, 2024. https://familyheart.org/familial-hypercholesterolemia

2. Gidding SS, Jamison A, Ballantyne CM, et al. It is time to screen for homozygous familial hypercholesterolemia in the United States. Glob Heart. 2024;19(1):43. doi:10.5334/gh.1316