Familial Hypercholesterolemia — Hiding in Plain Sight

Laurence Sperling, MD; Katherine Wilemon


October 21, 2021

This transcript has been edited for clarity.

Laurence Sperling, MD: Welcome to the Medscape InDiscussion podcast series on dyslipidemia. This is the first of six episodes. To launch this series today, we will focus on an extremely important topic: living with hypercholesterolemia and listening for clues of genetic risk. This topic is central to this series.

First, a case presentation. A 38-year-old woman who appears to be in good health comes in for a routine checkup, and during this checkup you note that she has a total cholesterol of 288 mg/dL and an LDL cholesterol of 226 mg/dL. She was first aware of having an elevated cholesterol around the age of 20, and she's made significant dietary changes over the past 18 years, as counseled. She's quite healthy. She has no history of thyroid, liver, or kidney disease. She's never taken any medication for her elevated cholesterol. Our patient has two daughters.

How would you approach this patient? Are there any important clues in this case? We'll come back to this case during our discussion because it's central to today's topic.

It is an honor to have Katherine Wilemon, the CEO and founder of the Familial Hypercholesterolemia (FH) Foundation as my first guest on this podcast. Katherine started the FH Foundation 10 years ago. This foundation has developed the only national FH registry — the CASCADE FH Registry — in the United States, with 40 participating sites across the country. Emory University School of Medicine, where I serve as a faculty member, is one of these sites.

Besides being the founder and CEO of the FH Foundation, Katherine has contributed on many levels. In addition to helping to launch this important national initiative, she has published more than 25 peer-reviewed articles and appeared on the cover of The New York Times and The Wall Street Journal, and on multiple radio and television shows, with the mission of raising awareness and increasing the rate of diagnosis and early treatment for a condition that is hiding in plain sight.

It's an honor to introduce Katherine Wilemon. Katherine, welcome to our podcast.

Katherine Wilemon: Thank you so much, Larry. It's an honor to be here.

Sperling: Today we're going to talk about several relevant clinical clues our listeners should raise their antennas for, because we want them to identify these patients who are often hiding in plain sight. Before we dive into the topic of hypercholesterolemia and the FH Foundation and its amazing work over the past decade, tell us a fun fact about you that our listeners may not know.

Wilemon: I'm an avid bird watcher. I grew up on Amelia Island along the Atlantic coast of Florida. I've lived on different continents and spent the past 20 years in Los Angeles, and I've found that no matter where we are in nature, we're still interacting with birds as well as other creatures. I find such solace in seeing them. So that's my fun fact.

Sperling: Someday we will have to go bird watching together because I'm familiar with Amelia Island. One of my all-time favorite birds to see there is the roseate spoonbill, a cool combination of flamingo and something like a duck-billed platypus. We'll have to go out and spot some of those together.

Wilemon: Sounds like a date.

Sperling: The FH Foundation was launched about a decade ago. What was your inspiration?

Wilemon: I had a heart attack at the age of 39, and even after finding 100% occlusion of my left anterior descending artery and having a long history of elevated LDL cholesterol (over 300 mg/dL) for many decades, I still was not given a specific reason for my cholesterol being so high or for me developing aggressive cardiovascular disease. So I started to do my own research and ended up giving a few talks and then being invited to speak at a scientific meeting in Europe about my own case. That was after I had learned that I had FH. It took me about 5 years of my own research to discover that.

I found that we, as a scientific community, have understood the pathophysiology of FH and how it drives premature cardiovascular disease; we've had treatments for 30 years; and we've understood the natural history; but there were very little data about FH in the United States. It was basically an invisible condition here because, at the time, there was no ICD-9 code for it. We didn't know anything except what was being done at specific academic centers, and that information was siloed.

I started the FH Foundation to be a partnership between physicians, public health servants, and laypeople and their family members who were impacted by FH. I also wanted to work with health systems. I was just amazed by the tools we had at our disposal but dismayed that they were not being consistently applied. Nine out of 10 people with this very common genetic condition were being missed and, as a result, missing the opportunity to have a full life.

Sperling: The FH Foundation has come a long way over the past decade, but there's a lot of work to be done. What have been the seminal steps and milestones thus far for the FH Foundation?

Wilemon: One thing that was key was to apply for an ICD-10 code specifically for FH. The awareness that, at the time, there was no ICD-9 code came about when we were planning for an FH Global Summit. You were on the planning committee and on the phone that day. This scientific meeting has been crucial to bringing the community together. We hold the FH Global Summit once a year. We bring in experts from around the world — not just cardiologists and lipid specialists, but also implementation scientists and public health specialists. We're trying to cross-pollinate to get to how we solve this kind of problem.

Getting the ICD-10 code enabled us to begin to measure how we're doing, along with establishing a national registry. We have 40 centers of excellence participating in this registry. We're learning a lot about how the lucky 10% who were diagnosed in the United States are being treated and where the gaps in care persist. We are building a community of individuals. We hear time and time again that people who are finally diagnosed with FH never had any idea. Even when they had tragic stories of early heart disease and stroke in their families, they had no idea what it was called and they had never met anyone outside of their family with FH. So it's quite meaningful to build a community that is educated and empowered to advocate for itself and, again, to bring the scientists and medical practitioners together with the community. A lot of bidirectional learning occurs when we do that.

To address this problem of FH being invisible and not diagnosed, the FH Foundation initiated an innovative program 7 years ago to apply machine learning to large datasets in order to be able to flag individuals with probable FH. Now we have validated this and published it. It is amazing. Now we can apply this machine learning algorithm in partnership with the health system, for example, and of the individuals who are screened by this algorithm, 8 out of 10 turn out to have FH. It's a very efficient means of accelerating diagnosis.

I would also mention that the World Health Organization designated FH a public health concern in 1998. In 2018, the FH foundation brought together those original authors from all over the globe who had advocated for that, as well as many advocacy organizations and scientific leaders, to renew our call to action to address FH as a public health concern.

Those are some highlights of progress we're making. But as you said, there is still so much work to be done.

Sperling: Katherine, as you know, FH is one of the most common genetic conditions, although it is underdiagnosed, underrecognized, and undertreated. Tell our listeners about the prevalence of FH and how they can recognize it starting tomorrow when they see patients in the office or in the hospital.

Wilemon: FH is pretty straightforward to identify. Even though it's a genetic condition, it can be diagnosed clinically as well as through genetic testing. The majority of individuals in the United States who are diagnosed are diagnosed clinically. Our listeners need to know that anyone with an LDL cholesterol of 190 mg/dL or above should have FH ruled out or ruled in. Many of those people will have FH. They will have a family history of either high cholesterol or, tragically, they will tell you about the many generations of aunts and uncles and grandparents and parents who passed away far too early or had an early stroke or a heart attack that impacted the trajectory of their lives. So we're looking at LDL cholesterol levels of 190 mg/dL and above plus a family history of premature cardiovascular disease. That, in and of itself, is enough to say that this person probably has FH and that time is of the essence.

Sperling: And there can be some physical exam clues as well, such as the presence of a corneal arcus, xanthelasmas, and tendinous xanthomas. Once you get in the habit of looking for those — they are often hiding in plain sight — our astute listeners will find these patients. Once they find them, what kind of conversation should they have with their patients? How should that clinician have a conversation about that diagnosis?

Wilemon: We have heard time and time again that when they finally get a diagnosis, patients often had already been alerted to the fact that their high cholesterol may have been genetic. But they were never given a specific diagnosis. Words do matter and they point to a road map not only for the physician and medical team, but also for the patient. One of the most important components is to give a specific diagnosis: "You have familial hypercholesterolemia. It is a genetic condition and it requires medical management. Lifestyle and diet will never be enough. This is a metabolic disorder that prevents you from clearing the high levels of cholesterol from the blood. That exposure leads to premature cardiovascular disease." It is an autosomal dominant disorder. All it takes is for one parent to have the condition, for each child, like a flip of a coin, to have a 50% chance of having inherited the condition.

The Centers for Disease Control and Prevention (CDC) has designated only three conditions to be Tier 1 applications for family screening and those are BRCA breast cancer, Lynch syndrome, and FH. The CDC has done this because these conditions affect such a large swath of the population and are so easily inherited.

The great news is that we have treatments today that can help people to normalize their risks if they are found and treated early enough. The American Heart Association, the National Heart, Lung and Blood Institute, and the American Academy of Pediatrics all agree and recommend that there should be universal screening for children between the ages of 9 and 11 years. Screening for LDL cholesterol is actually in place specifically to identify children with FH but we know that screening is not occurring. We know screening is not happening systematically in that age group, and when screening is done, the diagnosis isn't being made even if high LDL levels are found. In two children from the same family, by the age of 11 we can consistently see indications of plaque buildup in the carotid artery of the child with FH compared with the nonaffected sibling. So it really is a case where finding and treating this condition in childhood is what's recommended. Family screening is essential whenever you find a patient.

Sperling: I teach a class at Emory for our first-year medical students that is called "Clinical Correlations in Lipids and Atherosclerosis." There are 133 students in the first-year class and about the same number in the second-year class. The global prevalence of heterozygous FH is about 1 in 250. I point out to the students that it's likely at least one student in the first- and second-year class has FH. For our clinicians, if they've seen 250 patients in their careers, they likely have seen someone with FH, and if they're working in the hospital, taking care of individuals with heart attacks and cardiovascular events, that prevalence is likely much greater.

Tell us about the FH registry. How does the care and burden of disease vary among different racial and ethnic populations across the United States?

Wilemon: We're following about 4500 individuals with FH. We just mentioned that screening guidelines recommend that kids be screened and that treatment with statins be initiated around the age of 10 years. Sadly, what we see from the registry is that the average age of diagnosis is 47 years. Interestingly enough, the average age of statin initiation is 39 years, so people are finding out that they have high LDL levels and they're being treated, but FH is not being differentiated until almost 10 years later for those lucky enough to find out that they have FH.

We see a very high burden of cardiovascular disease in this population, on average about 20 years earlier than we would see in the unaffected population. Unfortunately, we also see the registry as a kind of microcosm of some of the disparities we see in the treatment of cardiovascular disease in the United States more broadly. Women are less likely to be put on a statin and they're less likely to reach their treatment goals. Black people are diagnosed later, and Black and Asian people are less likely to reach a safe LDL treatment goal. We see disparities in care that show up in terms of poor outcomes for some of these groups.

Sperling: I want to come back to our case just for a minute. This young woman is 38 years old with an LDL of 226 mg/dL; she's been aware of her high cholesterol for quite some time and has tried to make dietary changes to address it. And by the way, she does have a family history of high cholesterol that she's aware of. Multiple family members have had early cardiovascular events. I mentioned that she has two daughters. Touch on Cascade screening. How can clinicians extend themselves to an entire family and make a difference for many lives, not just that one patient?

Wilemon: The conversation begins with clear communication that offspring and siblings all have a 50% chance of also having the condition. I would encourage physicians who don't have time to do everything to also connect patients with an organization like the FH Foundation so that we can help educate that person. Just telling a patient that their children or siblings may have FH, that there's a 50% chance, is a great beginning because they have no idea. You can suggest that family members undergo lipid screenings.

Sperling: Let's talk a minute about the truly amazing treatment options patients have today that they didn't have 10 years ago. First and foremost, for 35 years we've had statins, which are certainly the foundation of therapy for an individual diagnosed with FH. But we have new agents today and will continue to see new biologic agents developed that can greatly impact those who are living with FH. Could you offer some advice to clinicians about how they can help their patients navigate aggressive and appropriate therapy? What about genetic testing?

Wilemon: We are fortunate to have multiple safe and effective therapies at this point. Therapy has changed dramatically in the past 5-10 years, as you said. The safe zone for patients who don't have established cardiovascular disease is an LDL level of 100 mg/dL. If they do have established ASCVD, the safe level is 70 mg/dL or below. In the registry, we don't see any patients with FH reach those goals without combination therapy. It is so important that individuals with FH are considered high risk from the get-go and are put on high-dose statins and other therapies such as Zetia (ezetimibe). Some clinicians still use bile acid sequestrants but not as much. Nexletol (bempedoic acid), Nexlizet (bempedoic acid and ezetimibe), and PCSK9 inhibitors have changed the landscape for individuals with FH so that they have hope of getting into the safe zone with their LDL cholesterol.

On genetic testing, the most important thing to remember is that it's not a barrier to care. People have different views about how important it is, and physicians and patients both have different levels of comfort with it. FH can be diagnosed clinically. There is some cost to genetic testing and, as with all genetic conditions, the science behind testing continues to evolve. In about 30% of individuals who experts agree have FH, we cannot locate the actual mutation. So it's very specific but it's not 100% sensitive. But for many patients, it has value. They like seeing the genetic test and understanding that yes, this is a genetic condition. I believe that having genetic testing should be a shared decision by the physician and patient.

Sperling: In our case presentation, the conversation to have with this young woman would be that she likely has a genetic cholesterol disorder called familial hypercholesterolemia. Diet alone will not be sufficient to lower cholesterol levels. But the good news is that we have medications to treat it, and if you take these medications and reduce your cholesterol significantly, we can reverse the trajectory of accelerated risk for heart disease. Then we should address her two daughters and other family members, making sure that we extend our screening to the rest of her family because early identification and treatment can save lives.

Katherine, it has been fantastic to have you here today. What are the points you want to make as we close? What should our listeners take to heart?

Wilemon: The most common question we hear from the medical community is, if I'm treating someone's cholesterol, does it matter if I diagnose them with FH? And the resounding answer is yes. It matters for three reasons:

  • One, because FH is different. It requires early diagnosis and early treatment to prevent early cardiovascular disease.

  • Two, you never find only an individual with FH; you always find a family if you're looking.

  • Three, FH is a prototype for precision medicine. We can identify those born at the highest risk for the number-one killer around the world before they develop disease. And with early diagnosis and management, we can completely change the trajectory of that individual's life and, really, the story of an entire family.

Sperling: Katherine Wilemon, it has been wonderful to have you as my guest on our very first Medscape InDiscussion podcast on dyslipidemia.

Our next episode will focus on patient-partnered care, optimizing the care team, and the promise of telehealth, with Dr Martha Gulati, president-elect of the American Society for Preventive Cardiology, and Dr Joseph Saseen, the current president of the National Lipid Association. This is Dr Laurence Sperling for Medscape InDiscussion.


The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association

Familial Hypercholesterolemia Foundation

Cascade Registry

Finding missed cases of familial hypercholesterolemia in health systems using machine learning

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association

Genetic Testing for Managing Dyslipidemia

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